Chapter 12: Chapter Two – Answers - Neurology: Self-Assessment for MRCP(UK) Neurology SCE (2023)

Chapter Two Answers

(Read the objective of each question and re-read textbooks to fill in the gaps in your knowledge. You may also expand your information by checking out the references)

1) c

Objective: Review the anatomy and physiology of the olfactory nerve.

The olfactory (first cranial) nerve fibers arise from the mucosa of the upper part of the nasal cavity and carry special visceral afferent fibers (smell); these fibers form the olfactory nerve. Bundles of these nerve fibers pass through the openings of the cribriform plate of the ethmoid bone to enter the olfactory bulb. The olfactory nerve fibers are unmyelinated but are covered with Schwann cells. General somatic afferent (GSA) sensations from the upper nasal cavity are conveyed via the trigeminal nerve. In contrast to all other sensory pathways, the olfactory afferent pathway has only two neurons and reaches the cerebral cortex without synapsing in one of the thalamic nuclei. A decrease in the ability to smell is a normal consequence of human aging and usually is more pronounced in men than in women. Patients with Alzheimer’s disease almost always have an abnormal sense of smell when tested.

Splittgerber, Ryan. Snell’s Clinical Neuroanatomy. 8th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018.

2) e

Objective: Review the anatomy of the optic nerve.

The optic (second cranial) nerve is part of the cranial nerves, but it is part of the central nervous system, rather than the peripheral nervous system because it is derived from an out-pouching of the diencephalon (optic stalks) during embryonic development. Therefore, the fibers of the optic nerve are covered with myelin produced by rather than Schwann cells of the peripheral nervous system, and are encased within the meninges. The optic nerve is ensheathed in all three meningeal layers (dura, arachnoid, and pia mater) rather than the epineurium, perineurium, and endoneurium found in peripheral nerves. Peripheral neuropathies and radiculopathies (e.g., Guillain-Barré syndrome) do not affect the optic nerve. The and cranial nerves are the only cranial nerves that are located totally in the supratentorial compartment of the skull. The optic nerve leaves the skull through the optic canal. The physiological blind spot results from the absence of photoreceptors in the area of the retina where the optic nerve leaves the eye.

Splittgerber, Ryan. Snell’s Clinical Neuroanatomy. 8th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018.

3) d

Objective: Identify the functions of the dominant versus non-dominant cerebral hemispheres.

The frontal lobe is the largest lobe of the brain and makes up about a third of the surface area of each hemisphere. Personality, behavioral responses, micturition, contralateral motor control, language, and social behavior are functions of the frontal lobe. The mesial frontal lobe harbors the urinary bladder center. Lesions of the frontal lobe can result in a multitude of features; disinhibition, incontinence, apathy, lack of initiative, grasp reflexes (and other primitive reflexes), anti-social behavior, impaired memory, Broca’s (expressive) dysphasia, and seizures (e.g., aversive seizures). Simple (non-formed or elementary) visual hallucinations can take the form of multicolored lights, colors, geometric shapes, or indiscrete objects. Simple visual hallucinations without structure are known as phosphenes and those with a geometric structure are known as photopsia. These hallucinations are caused by irritation to the primary visual cortex (Brodmann’s area 17). Formed (complex) visual hallucinations arise from the temporal lobes and tend to be clear, lifelike images or scenes (e.g., faces of animals or people). Wernicke’s dysphasia results from dominant upper posterior temporal lobe lesions. Non-dominant parietal lobe lesions cause contralateral hemineglect, spatial disorientation, construction apraxia, and homonymous hemianopia. Dyslexia results from lesions affecting the dominant temporal lobe while non-dominant temporal lesions cause poor non-verbal memory and loss of musical skills.

Splittgerber, Ryan. Snell’s Clinical Neuroanatomy. 8th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

4) c

Objective: Review the cerebrospinal fluid (CSF).

On average, about 500 mL of CSF is produced every day by the choroid plexus (80%) and ependymal cells (20%), at a rate of 25 mL/hour. It is absorbed by the arachnoid granulations of the intracranial venous sinuses. The CSF volume in adults is 125-150 mL; about 100 mL is in the cranial subarachnoid space (around the brain); about 25 mL lies in the spinal subarachnoid space. The normal CSF pressure is 10-18 CSF contains a higher concentration of sodium and chloride than blood plasma, but less potassium, calcium, glucose, and protein.

Splittgerber, Ryan. Snell’s Clinical Neuroanatomy. 8th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018.

5) c

Objective: Review the origin and nuclei of the cranial nerves.

The mid-pons houses the chief and motor nuclei of the trigeminal nerve while in the lower pons, the nuclei of the abducens, facial, and vestibulocochlear nerves lie. The oculomotor and trochlear nerves nuclei are in the midbrain (mesencephalon). In the medulla oblongata, we can find the nuclei of the lower 4 cranial nerves (glossopharyngeal, vagus, accessory, and hypoglossal).

Splittgerber, Ryan. Snell’s Clinical Neuroanatomy. 8th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018.

6) c

Objective: Review the blood supply of the brain.

The middle cerebral arteries are not part of the circle of Willis. Some authors include the basilar artery in the components of the circle. However, considerable anatomic variation exists in the circle of Willis. The classic anatomy of the circle is only seen in about 35% of individuals. In one common variation, the proximal part of the posterior cerebral artery is narrow and its ipsilateral posterior communicating artery is large; therefore, the internal carotid artery supplies the posterior cerebrum; this is known as a fetal posterior communicating cerebral artery. In another variation, the anterior communicating artery is a large vessel, such that a single internal carotid supplies both anterior cerebral arteries; this is known as an azygos anterior cerebral artery.

Agarwal N, Carare R. Cerebral Vessels: An Overview of Anatomy, Physiology, and Role in the Drainage of Fluids and Solutes.Front Neurol. 2021;11:611485. Available at:

7) b

Objective: Review the different types of neuroglial cells and their function in health and diseases.

In general, neuroglial cells are smaller than neurons. There are approximately 85 billion glial cells in the human brain, about the same number as neurons. Glial cells make up about half the total volume of the brain and spinal cord. The total number of glial cells in the human brain is distributed into different types with oligodendrocytes being the most abundant (45-75%), followed by astrocytes (19-40%) and microglia (about 10% or less). Astrocytes have numerous projections that link neurons to their blood supply while forming the blood-brain barrier. They regulate the external chemical environment of neurons by removing excess potassium ions, and recycling neurotransmitters released during synaptic transmission. Astrocytes may regulate vasoconstriction and vasodilation by producing substances such as arachidonic acid, whose metabolites are vasoactive. There are 2 types, fibrous and protoplasmic; they have similar functions but display different morphology.

Siracusa et al. Astrocytes: Role and Functions in Brain Pathologies. Front Pharmacol. 2019;10:1114. Available at:

8) e

Objective: Review the anatomy and histology of the spinal dorsal root ganglia.

Spinal root ganglia develop from the neural crest, not from the neural tube; therefore, the spinal ganglia are part of the gray matter of the spinal cord that became translocated to the periphery. These ganglia house the first-order neurons, which are pseudo-unipolar (one body with two branches that act as a single axon, often referred to as a distal process and a proximal process). They are located in the intervertebral foramina. Two distinct types of mechanosensitive ion channels have been found in the posterior root ganglion neurons. The two channels are broadly classified as either high-threshold or low-threshold. As their names suggest, they have different thresholds as well as different sensitivities to pressure. The high-threshold ones have a possible role in nociception.

Haberberger et al. Human Dorsal Root Ganglia. Front Cell Neurosci. 2019;13:271. Available at:

9) b

Objective: Review skin receptors.

Signals from the skin may be conveyed by physical change (mechanoreceptors), temperature (thermoreceptors), or pain (nociceptors). Sensory receptors exist in all layers of the skin. There are six different types of mechanoreceptors detecting innocuous stimuli in the skin: those around hair follicles, Pacinian corpuscles, Meissner corpuscles, Merkel complexes, Ruffini corpuscles, and C-fiber LTM (low threshold mechanoreceptors). Mechanoreceptors respond to physical changes including touch, pressure, vibration, and stretch. Hair follicles can detect light touch; Meissner corpuscles in the dermal papillae detect indentation and slipping of objects; Pacinian corpuscles in the deeper dermis detect vibration; Merkel complexes in the basal epidermis create an understanding of structure and texture; Ruffini corpuscles detect stretch; C-fiber LTMs detect pleasant, light tactile sensations. Encapsulated receptors include the Meissner corpuscle and the Pacinian corpuscle. Meissner corpuscles and Pacinian corpuscles show rapid adaptation while Merkel complex and Ruffini corpuscles display slow adaptation.

Marzvanyan A, Alhawaj AF. Physiology, Sensory Receptors. [Updated 2021 Aug 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:

10) d

Objective: Review the types of acetylcholine receptors.

The nicotinic acetylcholine receptors are a group of receptors linked to ion channels in the cell membranes (ligand-gated;). When activated, these receptors act as ion channels. They are of 2 subtypes: and receptors. receptors are found in the neuromuscular junction while receptors are found in the brain and autonomic nervous system. They are excitatory receptors and mediate fast synaptic transmission of nerve impulses. The muscarinic acetylcholine receptors are G-protein coupled ones that phosphorylate various messenger cascades; they mediate metabolic response (also called metabotropic receptors). They are found in the brain, heart, and smooth muscles. They are of 5 subtypes: to

Ho et al. Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins. Front Neurosci. Available at:

11) e

Objective: Differentiate between type 1 and type 2 muscle fibers.

Type 1 myofibers are slow-twitching fibers (slow-oxidative fibers, fatigue slowly). They have a large blood supply and many capillaries. They are red and have high levels of myoglobin but low levels of myosin ATPase. They have a slow contraction time following electrical stimulation, and they generate less force than type 2 myofibers. If the response of a muscle to the application of gradually increasing loads is measured, the slow myofibers are recruited first. They are used for sustained, low-level activity (e.g., deltoid). To accomplish this, they are equipped with numerous large mitochondria and relatively abundant intracellular lipids for oxidative metabolism. Type 2 myofibers are fast-twitch fibers (fast-glycolytic fibers, rapidly fatigable). They are pale and have a high myosin ATPase level. They have a rapid contraction time following stimulation. If the response of a muscle to the application of gradually increasing loads is measured, the fast fibers are recruited late. They are used for brief-duration intense activity and for carrying heavy loads and are specialized for anaerobic metabolism (e.g., vastus lateralis). These myofibers contain smaller, less numerous mitochondria, less lipid, and have larger glycogen stores than type 1 fibers. Type 2 myofibers are subdivided into 1a and 2b. Skeletal muscle fiber 2 specific atrophy is typically induced under cachexia, sepsis, diabetes, and chronic heart failure; muscle disuse (e.g., spinal cord injury) causes type 1 fiber atrophy with a slow-to-fast fiber type shift.

Wang Y, Pessin J. Mechanisms for fiber-type specificity of skeletal muscle atrophy. Curr Opin Clin Nutr Metab Care. 2013;16(3):243-50. Available at:

12) d

Objective: Review the role of MRI in brain diseases.

MRI provides high-quality soft tissue images with excellent visualization of the posterior fossa and temporal lobes as well as the pituitary fossa and peri-sellar region. The investigation is not invasive and does not incur any ionizing irradiation risk. However, it is expensive. Some patients are claustrophobic and cannot do the examination. Magnetic resonance angiography (MRA) detects blood flow rather than pure vascular anatomy. Magnetic resonance venography (MRV) helps detect intracranial venous sinus thrombosis. Reactions to intravenous gadolinium (contrast) may occur. Brain CT is the first-line investigation in patients who present with acute confusion, head trauma, or suspected stroke. Because of boney artifacts, cranial CT scan is poor at the visualization of lesions of the posterior fossa. It also has a risk of ionizing radiation exposure.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

13) e

Objective: Review the absolute and relative contraindications of MRI.

The following are absolute contraindications:

•Cardiac implantable electronic devices (e.g., pacemakers, implantable cardioverter defibrillators, and cardiac resynchronization therapy devices. However, MRI conditional cardiac implantable electronic devices are available

•Metallic foreign bodies, e.g., intraocular

•Implantable neurostimulation systems (a surgically placed pain-killer device that delivers mild electrical signals to the epidural space through one or more thin leads).

•Cochlear implants: if the patient removes the battery, type cochlear implant can be MRIed using a 1.5-tesla scanner.

•Drug infusion pumps (insulin delivery, analgesic drugs, or chemotherapy pumps). If possible, the patient has to remove the device

•Catheters with metallic components (e.g., Swan-Ganz catheter)

•Metallic fragments (e.g., bullets)

•Magnetic dental implants

•Tissue expander

•Artificial limb

•Hearing aid


There are several relative contraindications: coronary and peripheral artery stents; programmable shunts; airway stents or tracheostomy (if the tracheostomy is plastic, you can do MRI); intrauterine device; ocular prosthesis; stapes implants; surgical clips or wire sutures (e.g., sternal ones of CABG); penile prosthesis; joint prosthesis; inferior vena cava filters; Harrington rods; medication patch (the patches require removal before the procedure); tattoos (if the tattoo has been made in the scanned area within less than six weeks, reschedule the MRI); colonoscopy procedures within eight weeks (check out if any endoscopy clips or pill cam were used or placed). MRI is a helpful imaging technique during pregnancy (any trimester) for evaluating obstetric and nonobstetric diseases. No adverse effects on fetuses exposed to non-gadolinium MRI have been observed.

Ghadimi M, Sapra A. Magnetic Resonance Imaging Contraindications. [Updated 2021 May 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:

14) e

Objective: Review the role of EEG in seizure disorders.

Epilepsies are usually easy to diagnose. However, as with any other medical condition, they are sometimes challenging.EEG, as an investigation, is undervalued and overvalued, underused and misused as well. The clinical uses are wide and are not limited to seizures. In seizure disorders, EEG helps confirm the clinical suspicion of epilepsy, categorize seizure type (focal, generalized), localize the epileptic focus (especially in epilepsy surgeries), give a prognostic outlook (patients with highly abnormal EEG before the withdrawal of treatment have a high risk of recurrent in the future), and guide the effectiveness of medical treatment in absence seizures (unhelpful in other seizures, as the EEG abnormalities may persist/lessen while the patient is clinically seizure-free). EEG is also used in sleep disorders (e.g., obstructive sleep apnea, narcolepsy), brain death, persistent vegetative states (and locked-in syndrome differentiation), metabolic encephalopathy (e.g., liver failure), encephalitis (e.g., Herpes simplex encephalitis), and dementia (Creutzfeldt-Jakob disease). The single most significant source of error is that the EEG is often interpreted out of the clinical context. An EEG in chronic epilepsies or treated patients may be uninformative and misleading.The frequency of seizures is not proportional to the EEG paroxysmal “epileptogenic” discharges. Severely “epileptogenic” EEGs may be recorded from patients with infrequent or controlled clinical seizures and vice versa. The EEG abnormalities do not reflect the severity of the epileptic disorder. More than 10% of normal people may have non-specific EEG abnormalities and approximately 1% may have “epileptiform paroxysmal activity” without seizures.The prevalence of these abnormalities is higher in children, with 2-4% having functional spike discharges.

Panayiotopoulos CP. The Epilepsies: Seizures, Syndromes and Management. Oxfordshire (UK): Bladon Medical Publishing; 2005. Available from:

15) e

Objective: Review the EMG findings in certain diseases.

In myositis, there are features of myopathy plus inflammation and these are prolonged insertional activity, spontaneous activities at rest (fibrillation potentials and positive sharp waves; they are absent in normal muscles), low-voltage (low-amplitude), short-duration, polyphasic motor unit potentials (MUPs), and low amplitude full interference pattern. Patients with motor neuron disease (e.g., amyotrophic lateral sclerosis) demonstrate prolonged insertional activity, spontaneous activities at rest (fibrillation potentials and positive sharp waves), high-voltage (high-amplitude) long-duration polyphasic MUPs (indicating chronic denervation with reinnervation), limited recruitment, and an interference pattern with fast firing rate. In myotonic dystrophy, there are myotonic discharges (spontaneous discharge of muscle fibers that waxes and wanes in both amplitude and frequency with a “dive bomber sound” on EMG; in addition, there are features of myopathy (low-voltage short-duration polyphasic MUPs) and myofibrils irritation (fibrillation potentials, positive sharp waves).

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

16) d

Objective: Review the abnormalities in the CSF parameters in various CNS diseases.

The normal CSF is crystal clear (not bloody) and its pressure is between 10-18 The protein level should not exceed 45 mg/dL. The CSF sugar should be >50-60% of the blood glucose level (therefore, blood sugar should be assessed simultaneously; in hyperglycemia, the CSF sugar may appear elevated). The CSF white cell count is up to 5 cells (all should be mononuclear/lymphocytes; the presence of a single neutrophil is abnormal). It must be sterile; smear-negative and culture-negative. In pyogenic infections (e.g., streptococcus meningitis) the typical CSF is under pressure and is cloudy, with pleocytosis (neutrophilic, usually 1000-5000 cells; not lymphocytic), elevated protein, and low sugar (sometimes down to near zero). A very high CSF neutrophilic white cell count (>10,000) indicates a ruptured brain abscess. In patients with partially treated pyogenic meningitis, there is pleocytosis with a predominance of lymphocytes (which may prompt the physician to think of tuberculous meningitis). A negative CSF Gram stain and/or culture does not rule out pyogenic meningitis.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

17) a

Objective: Review the localization of lesions; brainstem syndromes.

This patient has developed left Weber’s syndrome due to occlusion of the median and/or paramedian perforating branches of the basilar artery, damaging the left midbrain crus cerebri (anterior part of the midbrain). The outcome is ipsilateral cranial nerve palsy and contralateral hemiparesis. If the vascular lesion occurs a little bit posteriorly, it will involve the red nucleus and the superior cerebellar peduncle fibers resulting in Claude’s syndrome cranial nerve palsy and contralateral cerebellar signs).

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

18) c

Objective: Review the brain arterial vascular territories; anterior cerebral artery.

Infarctions in the territory of the anterior cerebral artery (ACA) are relatively uncommon. The ACA’s cortical branches supply the paramedian region of the frontal and parietal lobes, while the deep branches (medial lenticulostriate arteries) supply the caudate head, globus pallidus, and anterior limb of the internal capsule. The resulting clinical picture consists of mainly contralateral pyramidal weakness (greater in the legs than arms; the lower limb’s cortical area is damaged more than the upper limb’s), contralateral cortical sensory deficits, and urinary incontinence.

Knipe, H., Sheikh, Y. Anterior cerebral artery (ACA) infarct. Reference article, (accessed on 23 Feb 2022)

19) b

Objective: Review the different types of dysphasia (aphasia); Wernicke’s dysphasia.

Wernicke’s dysphasia results from an occlusion (usually embolic) of the left middle cerebral artery’s posterior-inferior branch (the dominant left posterior-superior temporal cortex is damaged). Patients with Wernicke’s dysphasia demonstrate intact fluency of spontaneous speech but there is impaired comprehension with poor word retrieval (anomia) as well as production of jargon speech, neologism, and word salad. Individuals with Wernicke’s dysphasia are often not aware of their incorrect productions, which would further explain why they do not correct themselves when they produce jargon, paraphasias, or neologisms. There is circumlocution (talking around the target word) with a press of speech. In addition, there is impairment in reading and writing, reduced retention span, and lack of hemiparesis. Thalamic dysphasia occurs with left-sided thalamic lesions that involve the ventrolateral nucleus of the thalamus. It usually presents like a transcortical sensory or motor aphasia. Infarctions of the tuberothalamic artery (which arises from the posterior communicating artery) are associated with impaired comprehension and either fluent dysphasia with both semantic and phonemic paraphasic errors or nonfluent, anomic dysphasia. Repetition is generally intact for all thalamic dysphasia. Thalamic aphasia is thought to result from the disconnection of cortical language centers from the thalamic nuclei. Stroke in these vascular territories may also cause significant neuropsychological deficits predominantly affecting arousal, memory, and personality changes.

Brookshire, R. H., & McNeil, M. R. (2015). Introduction to neurogenic communication disorders (8th ed.). Mosby.

September 19, 2016 e-Pearl of the Week: Thalamic aphasia. Available at:

20) c

Objective: Differentiate between bulbar palsy and pseudobulbar palsy.

Pseudobulbar palsy results from bilateral lesions of the corticobulbar tracts (i.e., bilateral upper motor neuron lesions). The lower 4 cranial nerves controlling mastication, deglutition, and speech are affected.Patients demonstrate spastic and heavy dysarthric speech (hot potato or Donald Duck speech), small spastic conical tongue, exaggerated gag reflex and jaw jerk, mild dysphagia (coughing more than nasal regurgitation), and emotional lability. Depending on the etiology and site of the lesion, there may be frontal release signs (primitive reflexes, e.g., snout reflex, grasp reflex) and bilateral upper motor neuron facial weakness. The list of causes is long but stroke (e.g., multiple bilateral lacunar ischemic stroke), amyotrophic lateral sclerosis, and high brainstem lesions are the usual etiologies. Bulbar palsy on the other hand results from bilateral brainstem nuclear or infranuclear palsies (i.e., lower motor neuron lesions) of the lower 4 cranial nerves. The tongue is atrophied and displays fasciculations. Dysphagia is usually severe with prominent nasal regurgitation. The resulting dysarthria is nasal and breathy. The gag reflex, jaw jerks, frontal release signs, primitive reflexes, and emotional lability are absent. Bilateral lower motor neuron facial weakness may be present. Bulbar palsy may result from motor neuron disease and myasthenia gravis in addition to a long list of etiologies.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

21) e

Objective: Review the myotomes and their corresponding movements/peripheral nerves.

A myotome is a group of muscles that a single spinal nerve innervates. In vertebrate embryonic development, a myotome is the part of a somite that develops into muscle. Each muscle in the body is supplied by one or more levels or segments of the spinal cord and by their corresponding spinal nerves. Testing of myotomes can be an integral part of the neurological examination as each nerve root coming from the spinal cord supplies a specific group of muscles. Testing of myotomes, in the form of isometric resisted muscle testing, provides the clinician with information about the level in the spine where a lesion may be present. During myotome testing, the clinician looks for muscle weakness in a particular group of Results may indicate a lesion to the spinal cord nerve root, or intervertebral disc herniation pressing on the spinal nerve roots. The S1 myotome encompasses hip extension, ankle plantar flexion, and ankle eversion. The great toe extension is represented by the L5 myotome.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

22) d

Objective: Review migraine headaches and their types.

The patient has the classical features of migraine without aura (so-called common migraine). These are:

•At least five attacks fulfilling criteria B, C, and D

•Attack lasting 4-72 hours (untreated or unsuccessfully treated)

•Having at least two of these characteristics: aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs), moderate or severe pain intensity, pulsating quality, unilateral location

•Having at least one of these conditions during the headache: nausea and/or vomiting, phonophobia, or photophobia

Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including FHM), the neurologic symptoms of the aura are unequivocally localizable to the cerebral cortex or brainstem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesia of the face or an extremity), and dysphasia (difficulty with speech). FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Migraine with brainstem aura (previously called basilar-type migraine) is a rare form of migraine with aura wherein the primary signs and symptoms seem to originate from the brainstem, without evidence of weakness.

Jen JC. Familial Hemiplegic Migraine. 2001 Jul 17 [Updated 2021 Apr 29]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from:

23) b

Objective: Review the indications of prophylactic therapy in migraine.

Considerations for starting prophylactic treatment include the following: having four or more headaches per month, at least eight headache days per month, debilitating attacks despite appropriate acute management, difficulty tolerating (or having a contraindication) to acute abortive therapy, medication-overuse headache, patient preference, or the presence of certain migraine subtypes (i.e., familial hemiplegic migraine; migraine with brainstem aura; migrainous infarction; or frequent, persistent, or uncomfortable aura symptoms). Therapy should be started with medications that have the highest level of evidence-based effectiveness (sodium valproate, topiramate, and beta-blockers are the first-line agents). Successful treatment is defined as a 50% reduction in the number of headache attacks or days, a significant decrease in the duration of attacks, or an improvement in response to acute therapy.

Ha N, Gonzalez A. Migraine Headache Prophylaxis. Am Fam Physician. 2019;99(1):17-24. Available at: Ha N, Gonzalez A. Migraine Headache Prophylaxis. Am Fam Physician. 2019;99(1):17-24.

24) a

Objective: Review the treatment (abortive and prophylactic) of cluster headaches.

This patient has recently developed cluster headaches. The presence of pain-free remission of >3 months means that the diagnosis is an “episodic” cluster headache. Cluster headache is characterized by attacks of excruciating unilateral headache or facial pain lasting 15 minutes to 3 hours and is seen as one of the most intense forms of pain. Cluster headache attacks are accompanied by ipsilateral autonomic symptoms (ptosis, miosis, redness or flushing of the face, nasal congestion, rhinorrhea, and peri-orbital swelling) and/or restlessness or agitation. Cluster headache treatment entails fast-acting abortive treatment, transitional treatment, and preventive treatment. The primary goal of prophylactic and transitional treatment is to achieve attack freedom, although this is not always possible. Subcutaneous sumatriptan and high-flow oxygen are the most proven abortive treatments for cluster headache attacks, but other treatment options such as intranasal triptans may be effective. Verapamil and lithium are the preventive drugs of the first choice and the most widely used in first-line preventive treatment. If verapamil and lithium are ineffective, contraindicated, or discontinued because of side effects, the second choice is topiramate. If all these drugs fail, other options with lower levels of evidence are available (e.g., melatonin, clomiphene, dihydroergotamine, pizotifen). A new addition to the preventive treatment options for episodic cluster headaches is galcanezumab although the long-term effects remain unknown. Galcanezumab (approved in 2018 in the treatment of migraine and cluster headaches) is a humanized monoclonal antibody that binds to the calcitonin gene-related peptide ligand and blocks its binding to the receptor. Since effective preventive treatment can take several weeks to titrate, transitional treatment can be of great importance in the treatment of cluster headaches. At present, greater occipital nerve injection is the most proven transitional treatment. The other options are high-dose prednisone or frovatriptan.

Brandt et al. Pharmacotherapy for Cluster Headache. CNS Drugs. 2020; 34(2): 171-84. Available at:

25) d

Objective: Differentiate between central vestibulopathy and peripheral vestibulopathy.

Acute peripheral vestibulopathy usually results in severe vertigo, usually intermittent (seconds to minutes), and worsened by head movements. There are no brainstem or long tract signs. Hearing impairment and/or tinnitus are occasionally present. The resulting nystagmus is unidirectional horizontal or horizontal-torsional but never vertical. Peripheral vestibulopathy may result from acute otitis media, acute vestibular neuronitis, benign paroxysmal positional vertigo, head trauma, and Meniere’s disease. Central vertigo results from brainstem lesions (e.g., stroke, tumors, meningoencephalitis) and causes sudden or gradual vertigo of variable duration (which may be subacute and progressive or brief and intermittent) and shows little/minimal change upon head movements. Audiological features are usually absent but brainstem/long tract signs are present (e.g., hemiparesis, cerebellar signs). Central nystagmus can be bidirectional, horizontal, torsional, or vertical.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

26) d

Objective: Review the vital signs in acute confusional states; the presence of hypothermia.

Hypnosedative drug intoxication (e.g., diazepam, phenobarbitone) results in hypothermia. The other causes of hypothermia (in patients with acute confusional states) are hypothyroidism, hepatic encephalopathy, beta-blockers poisoning, and hypoglycemia. Acute confusional state with hyperthermia may result from alcohol withdrawal, sedative drug withdrawal, sympathomimetic intoxication (e.g., cocaine, amphetamines, methamphetamines, ephedrine over-the-counter cold preparations), ecstasy, anticholinergic intoxication (hyoscine, atropine, antihistamines, antiparkinsonians, antipsychotics), and ephedra alkaloids (dietary supplements).

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

27) e

Objective: Review the vital signs in acute confusional states; the presence of hypertension.

In patients with acute confusion, the presence of hypertension may indicate sympathomimetic intoxication, alcohol and sedative drug withdrawal, anticholinergic intoxication, and acute stroke (including acute aneurysmal subarachnoid hemorrhage). Acute and massive bleeding peptic ulcers result in hypotension and hypoxic-ischemic encephalopathy.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

28) a

Objective: Review the vital signs in acute confusional states; the presence of hypoventilation.

Hepatic encephalopathy increased the respiratory rate. In patients with chronic and/or severe liver disease, a multitude of mechanisms are responsible for hyperventilation associated with liver disease. There are increased levels of progesterone, ammonia, vasoactive intestinal peptide, and glutamine which stimulate respiration. Patients with severe liver disease or the presence of portal hypertension may develop small pulmonary arteriovenous anastomoses or portal-pulmonary shunts; both can cause hypoxemia. The latter stimulates the peripheral chemoreceptors and ends up with hyperventilation. The degree of the resulting respiratory alkalosis correlates with the severity of liver failure. Pulmonary encephalopathy results from type II respiratory failure (e.g., there are hypoxemia and hypercapnia).

Gill RS. Respiratory alkalosis. Medscape. Updated November 06, 2019. Available at:

29) b

Objective: Review the trinucleotide repeat (TNR) expansion diseases.

The mutation, referred to as “trinucleotide repeat expansion,” occurs when the number of triplets present in a mutated gene is greater than the number found in a normal gene. Additionally, the number of triplets in the disease gene continues to increase as the disease gene is inherited. As the TNR number grows, the growing triplet tract alters gene expression and/or function of the gene product; TNRs residing in a coding sequence of a gene typically produce a faulty protein, while expansion of a TNR in a noncoding gene region suppresses protein expression, alters its splicing, or may influence aspects of antisense regulation. For example, in Huntington’s disease (HD), unaffected individuals may have roughly 6–29 CAG triplets in both alleles; yet, in HD patients, the disease allele may contain 36 to hundreds of CAG triplets. As the TNR repeat number grows, the growing polyglutamine tract produces an HD gene product (called huntingtin) with increasingly aberrant properties that cause the death of brain cells controlling movement. Friedreich’s ataxia is an autosomal recessive disease that results from the trinucleotide repeat GAA expansion (>70 triplets) on chromosome 9. The trinucleotide repeats CTG expansion (>90) on chromosome 19 resulting in myotonic dystrophy. CAG repeat expansion can result in dentatorubral pallidoluysian atrophy (>29; autosomal dominant; chromosome 12), Huntington’s disease (>40; autosomal dominant; chromosome 4), and spinobulbar muscular atrophy (>38; X-linked recessive). Fragile X syndrome results from CGG repeat expansion (>200; X-linked dominant).

Budworth H, McMurray C. A Brief History of Triplet Repeat Diseases. Methods Mol Biol. 2013;1010:3-17. Available at:

30) d

Objective: Differentiate between dementia and pseudodementia.

Pseudodementia is a psychiatric condition masquerading as a neurodegenerative disease. The term refers to a unique group of patients but is not a formal diagnosis per se. Depression, apathy, and dementia are common disorders in the elderly and frequently overlap with each other. Each of these disorders can be mistaken for the other two or confused with other psychiatric disorders altogether. In depressive pseudodementia, the onset is more or less rapid with a rapid progression. Patients display a variety of memory changes (with no nighttime worsening) but there are intact insight and a tendency to emphasize the disability. The patients’ behavior does not correspond to the severity of the disability, and they usually reply with general responses (e.g., “I don’t know”). The risk of suicide is high, the mood is prominently depressed, and many patients have a previous psychiatric history. One of the core features is the presence of prominent vegetative symptoms; weight gain or weight loss, insomnia, fatigue, and inattention. The following are features of dementia (in patients who have had memory impairment): slow insidious onset with slow progression, lack of insight, presence of confabulation, a tendency to diminish the disability, a behavior that corresponds to the severity of illness, lack of answers, worsening of the symptoms at night, an incongruity of affect, few vegetative symptoms, low risk of suicide, and infrequent psychiatric history.

Brodaty H, Connors M. Pseudodementia, and pseudodepression. Alzheimers Dement (Amst). Available at:

31) d

Objective: Recognize status epilepticus (SE) and its causes.

SE is a common, life-threatening neurologic disorder that is essentially an acute, prolonged epileptic crisis. It is defined as more than 30 minutes of continuous seizure activity or two or more sequential seizures without full recovery of consciousness between seizures. SE can represent an exacerbation of a preexisting seizure disorder, or the initial manifestation of a seizure disorder (epilepsy), or it can represent an insult other than a seizure disorder. Among such insults, SE can occur in the context of an acute cerebral injury, or be due to a systemic process or illness, in a patient with or without a remote cerebral injury. In patients with known epilepsy, the most common cause of SE is a change in medication (sudden withdrawal, skipped doses). Most seizures terminate spontaneously; however, SE represents a failure of seizure termination.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

32) c

Objective: Review the management of status epilepticus.

If the seizures continue after 30 mins despite initial treatment:

•Administer intravenous infusion (with cardiac monitoring) of phenytoin (15 mg/kg at a rate of 50 mg/min) or sodium valproate (20-30 mg/kg at a rate of 40 mg/min) or phenobarbital (10 mg/kg at a rate of 100 mg/min)

•Meanwhile, do cardiac monitoring and pulse oximetry. Continuously assess the patient’s neurological condition as well as monitor blood pressure and respiration. In addition, check blood gases.

If the seizures continue after 30-60 minutes, transfer the patient to the intensive care unit and start treatment for refractory status with intubation, assisted ventilation, and general anesthesia using propofol or thiopental. Do bedside EEG monitoring. When the status is controlled, start a long-term antiepileptic therapy, using intravenous phenytoin or intravenous sodium valproate or per nasogastric tube carbamazepine (tablets or syrup). Always investigate the inciting cause.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

33) a

Objective: Review alcohol withdrawal syndromes; rum fit.

Rum fits are usually seen within 48 hours of abstinence; however, in 70% of cases, they occur within 7-24 hours of abstinence. The interval between the first and last seizure is usually 6-12 hours in up to 85% of patients. Up to 40 % of patients will have one seizure only. They abate spontaneously; however, diazepam or chlordiazepoxide is given because up to 30% of patients will develop delirium tremens. Unusual and atypical features of these rum fits are the development of focal seizures, prolonged duration of the fits (>6-12 hours), >6 seizures, development of status epilepticus, or a prolonged post-ictal phase. In these cases, a prompt search for a coexistent pathology is required.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

34) c

Objective: Review alcohol withdrawal syndromes; delirium tremens.

Delirium tremens is the most aggressive type of all ethanol withdrawal syndromes. It has a high mortality rate. It usually develops within 3-5 days of abstinence and may last for up to 72 hours. In addition to fever, agitated confusional state, and hallucination, prominent tachycardia, and profuse sweating may occur. The mortality rate is 15% and is mostly due to concomitant infection, pancreatitis, cardiovascular collapse, or trauma. The total requirement of diazepam to produce a calm patient may exceed 100 mg/hour.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

35) c

Objective: Review ethanol intoxication.

Ethanol (alcohol) intoxication is an acute confusional state which is mainly seen in alcoholics. Ethanol intoxication produces nystagmus, dysarthria, and limb and gait ataxia. The severity and clinical features of ethanol encephalopathy correlate roughly with blood ethanol levels; however, chronic heavy alcoholics may have a very high blood ethanol level although they do not appear to be intoxicated. In ethanol intoxication, the plasma osmolality is characteristically The plasma osmolality roughly increases by 22 mOsm/kg for every 100 mg/dL of ethanol present. Sedative-hypnotic drug poisoning can be confused with alcohol intoxication, but the former can be differentiated by the presence of ethanol odor, increased plasma osmolality (in ethanol poisoning it is raised), and blood and urinary toxicology. Ethanol intoxication predisposes to head injury, lung aspiration, and seizures. Chronic alcoholism increases the risk of bacterial meningitis. The treatment is supportive only. All alcoholics should receive 100 mg of thiamin intravenously to prevent Wernicke’s encephalopathy.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

36) d

Objective: Review the management of sympathomimetic intoxication.

The mechanism of action of sympathomimetics involves a variable combination of inhibiting the reuptake and/or increasing the release of noradrenaline and/or dopamine, thus, producing central stimulant and peripheral sympathomimetic effects. Cocaine can cause myocardial infarction. Stroke may occur and may be due to sudden severe hypertension, drug-induced vasculitis, or rupture of cerebral arteriovenous malformation. Beta-blockers should be avoided, especially in cocaine-induced myocardial infarctions (because of the unopposed alpha-receptors stimulation). Alpha-blockers are useful to control hypertension. Haloperidol is helpful in the treatment by attacking the psychotic manifestations of the overdose. Because amphetamines are longer-acting than cocaine, amphetamine intoxication is more likely to require treatment.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

37) d

Objective: Review multi-infarct dementia.

After Alzheimer’s disease and dementia with Lewy bodies, vascular dementia ranks on the list of common causes of dementia. The numbers of ischemic strokes, their brain location, and the total infarct volume required for a stroke to produce dementia are still Almost all patients are hypertensive; the presence of normal baseline blood pressure should prompt the physician to think of an alternative diagnosis. Pseudobulbar palsy is common, and those patients have dysarthria, dysphagia, and pathological emotionality. Cranial MRI is the imaging modality of choice. All patients should be tested for polycythemia, thrombocytosis, and cardiogenic emboli. The mainstay in the treatment is to prevent recurrent strokes; control hypertension and other risk factors and treat any associated disease.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

38) d

Objective: Review AIDS-dementia complex.

In general, AIDS-dementia complex is the commonest neurological complication of HIV infection; it is more common than opportunistic brain infections. At least 50% of patients experience a variable degree of cognitive impairment during the later or the preterminal course of the disease. It is an AIDS-defining illness that might be the presenting feature. HIV-1 does not appear to replicate within brain neurons or glia in vivo, and the loss of these cell types is not prominent in the brains of patients with complex; this may suggest that neuronal function is impaired by indirect neurotoxic mechanism (by releasing certain cytokines from HIV-infected monocytes, or The onset of AIDS-dementia complex is usually insidious with cognitive and behavioral changes (easy forgetfulness, apathy, social withdrawal) and motor symptoms (unsteady gait, leg weakness, and impairment in handwriting). A rapid downhill course suggests another or coexistent disease. At preterminal stages, most patients are vegetative. Brain MRI shows diffuse cortical atrophy with ventricular dilatation and hyperintense subcortical signals on images. The CSF can show mononuclear pleocytosis (not polymorphonuclear one). Oligoclonal CSF bands are detected; a non-specific finding which is also seen in syphilis, sarcoidosis, and multiple sclerosis. While the CSF opening pressure is always normal, its protein content is raised; the latter is the commonest CSF abnormality, which is seen in 65% of cases. Note that the CSF of these patients could be entirely therefore, a normal CSF examination does not refute AIDS-dementia complex. Most patients usually die within 1-9 months from aspiration or opportunistic infections. The course could be steadily progressive or acutely exacerbated by systemic sepsis (e.g., pulmonary infections).

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

39) a

Objective: Review the presentation & diagnosis of depressive pseudodementia.

Elderly depressive patients complaining about cognitive symptoms are at particular risk of being labeled as demented. It is well documented that depressive disorders frequently cause mild cognitive deficits which manifest in psychometric procedures. A wide spectrum of potentially reversible cognitive deficits related to the depressive syndrome is summarized under the term “depressive pseudodementia” (DPD). Most depressive patients who are referred to “DPD” suffer from cognitive dysfunctions outside the range of dementia. The clinical interface between depression and dementia is complex. There is some evidence that depression may be a risk factor for the expression of Alzheimer’s disease in later life and that depression may occur as a prodrome for Alzheimer’s dementia. Moreover, depression often complicates the course of dementing disorders. However, there is no evidence that depressive disorders cause dementia without coexisting depressive symptoms. It is essential to search for depressive symptoms even after cognitive symptoms have been found. Note the prominent vegetative symptoms this man has.

Fischer et al. [Depressive pseudodementia]. Wien Med Wochenschr. 2002;152(3-4):62-5. Available at:

40) b

Objective: Review the clinical features of dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterized by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson’s disease (PD). Extrapyramidal motor features characteristic of PD are common in DLB patients but are not essential for the clinical diagnosis of DLB. Since many PD patients develop dementia as the disease progresses, there has been controversy about the separation of DLB from PD dementia. The presence of cognitive dysfunction and “formed” visual hallucinations at presentation should cast strong doubt on the diagnosis of idiopathic Parkinson’s disease. Parkinsonism occurs in Shy-Dragger syndrome and dementia with Lewy bodies; the presence of well-formed visual hallucinations favors the latter. Pick’s patients have early personality and behavioral changes rather than memory impairment. Patients with normal-pressure hydrocephalus may be misdiagnosed as having Parkinson’s disease.

Outeiro et al. Dementia with Lewy bodies: an update and outlook. Mol Neurodegener. 2019;14:5. Available at:

41) c

Objective: Characteristics of dementia with Lewy bodies (DLB).

Lewy body-type of dementia comes only second to Alzheimer’s disease as a common cause of dementia. About of elderly demented patients who undergo autopsy display round eosinophilic intra-cytoplasmic neuronal inclusion bodies termed Lewy which are present in the cerebral cortex and brainstem. Lewy bodies contain alpha-synuclein (a protein that is also found in Lewy bodies of Parkinson’s disease) and tau protein (also present in Alzheimer’s disease and frontotemporal dementias). A highly distinguishing feature (from Alzheimer’s disease) is that cognitive decline occurs without a prominent early loss of recent memory. Parkinsonian features are common in DLB, especially rigidity, and bradykinesia; however, tremor is uncommon and is usually mild, bilateral, and Those patients may respond to donepezil, but the response is short-lived and not that prominent. Lewy body dementia patients are very sensitive to the extrapyramidal side effects of antipsychotics, and these medications should be avoided.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

42) e

Objective: Review the diagnosis of Creutzfeldt-Jakob disease (CJD).

CJD is a rare, fatal neurodegenerative disease belonging to a family of human transmissible spongiform encephalopathies or prion diseases. These diseases are caused by aberrant metabolism with the accumulation of prion proteins in the brain. Clinically, patients with CJD display signs of rapidly progressive dementia, neurological symptoms, ataxia, and impaired vision. The World Health Organization (WHO) diagnostic criteria for CJD includes the detection of periodic sharp wave complexes on electroencephalographic (EEG) records, spongiform changes in brain biopsy, and positive detection of CJD biomarkers in the CSF. However, these diagnostic tests have proven to be somewhat inconsistent and not always practical. Thus, much effort has been placed into developing premortem assays for prompt and accurate CJD diagnosis, such as biochemical analyses of the CSF contents from CJD patients. These analyses have led to the identification of several potential CJD biomarkers, including tau protein, neuron-specific enolase, amyloid-beta, and 14-3-3 proteins. Positive CSF protein 14-3-3 in the context of rapidly progressive dementia and myoclonus is highly suggestive (but not diagnostic) of CJD; it can be also positive in Herpes simplex encephalitis and vascular dementias but is absent in Alzheimer’s disease. The presence of fever, high ESR, peripheral blood neutrophilic leukocytosis, or CSF neutrophilic pleocytosis should cast strong doubt on the diagnosis of CJD. The 14-3-3 proteins are a family of homologous proteins that consist of seven isoforms (β, γ, ε, η, ζ, σ, and τ/θ). Structurally, 14-3-3 proteins exist as homo- and heterodimers. To date, 14-3-3 proteins are known to interact with over 200 proteins that contain specific pSer/pThr motifs. Through binding to their target proteins, 14-3-3 proteins participate in the regulation of a wide range of biological processes including signal transduction, cell cycle, transcription, apoptosis, and neuronal development.

Foote M, Zhou Y. 14-3-3 proteins in neurological disorders. Int J Biochem Mol Biol. 2012;3(2):152-64. Available at:

43) e

Objective: Characteristics of Creutzfeldt-Jakob disease (CJD).

Human-to-human transmission (e.g., by corneal transplant) is very rare; human-to-animal transmission has been documented. The abnormal prion protein is present only in the CSF (not in any other body fluid); however, it is present in the liver, spleen, kidney, eye, lung, and lymph nodes. The cellular isoform is present normally in healthy neurons, but its function is still unknown. The presence of autonomic and endocrine dysfunction favors fatal familial insomnia over CJD. Characteristic features of the so-called new-variant CJD are:

•Earlier age of onset (mean age of affection is 30 years; the CJD peak is 60-64 years)

•More prolonged course (the disease’s span is >1 year; CJD’s span is <2 years)

•Invariable cerebellar involvement (in CJD, cerebellar involvement is variable).

•Prominent early psychiatric manifestations (the disease can easily escape detection and is usually managed as major depression, psychosis, etc. before other neurological signs and symptoms appear)

The diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) can be difficult, but the real-time quaking-induced conversion (RT-QuIC) assays have made a considerable impact on its clinical diagnosis. This technique exploits the ability of the misfolded pathological form of prion protein found in cerebrospinal fluid (CSF) to induce the conversion of normal PrP to the misfolded form, which subsequently aggregates. The formation of these aggregates of misfolded PrP is monitored in real-time using fluorescent dyes. The current sensitivity of CSF RT-QuIC is 92% and the specificity is 100%. The interpretation of the RT-QuIC traces is affected by the presence of raised CSF red and white cell counts and elevated total protein concentrations.

Green A. RT-QuIC: a new test for sporadic CJD. Pract Neurol. 2019;19(1):49-55. Available at:

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

44) c

Objective: Review the investigations of Creutzfeldt-Jakob disease (CJD).

In the appropriate clinical setting, certain EEG changes are highly suggestive of CJD (e.g., periodic sharp waves or spikes); these changes are unfortunately transient and are absent in the new-variant form of the disease. MRI of the brain may show hyperintense lesions in the basal ganglia; this is not specific. The CSF protein 14-3-3 is increased in CSF samples. The CSF total protein level may be elevated; a non-specific finding. In sporadic cases, CJD can be diagnosed by immuno-detection of in brain tissues obtained by multiple biopsies. The diagnosis of definite CJD is made by standard neuropathological techniques; and/or immunocytochemically; and/or Western blot confirmed protease-resistant PrP; and/or the presence of scrapie-associated fibrils.

CDC’s Diagnostic Criteria for Creutzfeldt-Jakob Disease (CJD), 2018. Page last reviewed: October 18, 2021. Available at:

45) e

Objective: Characteristics of Pick’s frontotemporal dementias.

Pick’s patients are usually younger than Alzheimer’s ones, and the loss of recent memory is not an early or prominent feature. Instead, Pick’s patients demonstrate prominent behavioral dysfunction and personality changes at presentation. A very characteristic MRI feature is the preferential atrophy of frontal and temporal lobes; global cortical atrophy with compensatory hydrocephalus suggests Alzheimer’s disease. The presence of Pick’s cells and Pick’s inclusion bodies is virtually diagnostic of Pick’s dementia. The presence of prominent neuritic plaques and neurofibrillary tangles is consistent with Alzheimer’s disease. The familial occurrence of frontotemporal dementia has been documented and mapped to chromosome 17.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

46) d

Objective: Characteristics of hysterical amnesia.

Patients with psychogenic amnesia usually demonstrate a prior psychiatric history, additional psychiatric symptoms, or precipitating emotional stress. However, all of these can be difficult to obtain. Memory loss is patchy and inconsistent and may be strictly selective to some but not other events during such a period of amnesia. Loss of the patient’s name or identity is a highly characteristic feature of psychogenic amnesia; an exceedingly rare finding in organic amnesias. Despite such disorientation to person, orientation to place and time may well be preserved. Another characteristic feature is the relative preservation of recent memory while the remote ones may be severely impaired; the reverse of the pattern that is customarily seen in organic amnesias. A rare type of dissociative amnesia is the so-called generalized amnesia, i.e., the patient forgets everything suddenly!

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

47) e

Objective: Characteristics of Korsakoff’s amnesic syndrome.

A prior history of Wernicke’s encephalopathy is present in 75% of Korsakoff’s syndrome; the diagnosis may be challenging in some. Most patients are chronic heavy alcoholics, but it also may be seen in malnutrition and famines. Residual signs of preceding Wernicke’s encephalopathy (e.g., horizontal nystagmus or a mild cerebellar gait) might be seen; these are helpful clues. Long-term memory is frequently but registration is characteristically intact. The patient is classically apathetic and lacks insight into his Many patients try to reassure the examiner that everything is OK and speak a lot to cover the memory gap; confabulation is but not always, present. All patients should receive thiamin to prevent the progression of the deficits, the existing deficits are unlikely to be reversed.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

48) b

Objective: Characteristics of transient global amnesia (TGA).

TGA may also occur in elderly people with risk factors for atherosclerosis, especially a prior ischemic event in the posterior cerebral arterial territory. Only 10% of patients will have recurrent attacks; therefore, a single attack is more common, and patients can be reassured with high certainty that they will not have another one. TGA is a primary disorder of short-term memory that can last for minutes or days, typically for hours. The patient appears agitated and perplexed and may repeatedly inquire about their whereabouts, the time, and the nature of what they are experiencing. A highly characteristic feature during the attack is that patients retain their identity as well as their remote memories and registration ability; therefore, for inexperienced physicians, this may be diagnosed as malingering or conversion disorder, or more commonly, an unnoticed head trauma. The inability of the patient to form new memories accounts for the patient’s repetitive questions (e.g., “Where am I? “What time is it?”).

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

49) d

Objective: Review the use of memantine hydrochloride in the treatment of Alzheimer’s disease.

Memantine is a moderate-affinity, uncompetitive, voltage-dependent, NMDA-receptor antagonist with fast on/off kinetics that inhibits excessive calcium influx induced by chronic overstimulation of the NMDA receptors. Memantine is approved in the US and the EU for the treatment of patients with moderate to severe dementia of Alzheimer’s type. Memantine generally modified the progressive symptomatic decline in global status, cognition, function, and behavior exhibited by patients with moderate to severe Alzheimer’s disease. Memantine is an effective pharmacotherapeutic agent for the treatment of moderate to severe Alzheimer’s disease. Use with caution in the presence of seizures, renal failure, and pregnancy. It is contraindicated in breastfeeding. It increases libido and can cause vomiting, anxiety, hypertonia, and cystitis. Aducanumab is a medication designed to treat mild Alzheimer’s disease (the first novel therapy approved for Alzheimer’s disease since 2003). It is an amyloid beta-directed monoclonal antibody that targets aggregated forms of amyloid-beta (Aβ) found in the brains of people with Alzheimer’s disease to reduce its buildup. The medication was approved by the United States food and Drug Administration in June 2021; a highly controversial decision. The United Arab Emirates approved its use in October 2021.

Abyadeh M et al. Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer's Disease. Aging Dis. 2021;12(8):1964-76. Available at:

50) e

Objective: Review the clinical features and management of advanced Alzheimer’s disease.

Many types of seizures, focal or generalized, can complicate the terminal stages of Alzheimer’s disease; however, myoclonus is rare. Psychiatric manifestations gradually become more prominent and frank psychosis can be difficult to manage; this can harm caregivers. Hemiparesis and extensor planters are rare late features, despite being a cortical degenerative disease. Typically, Alzheimer’s patients die after 5-10 years of their diagnosis (from inanition or infection).

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

51) c

Objective: Review the diagnosis of normal-pressure hydrocephalus.

Normal-pressure hydrocephalus (NPH) is a potentially reversible cause of a subcortical type of dementia; it may respond to shunting. NPH is usually idiopathic; however, it can follow meningitis, head trauma, or subarachnoid hemorrhage. The resulting dementia is often mild (and insidious) and is typically preceded by gait disorder and urinary incontinence. Because of the subcortical affection, focal cortical signs are rare. The earliest manifestation of NPH is the gait disorder; there is unsteady standing and difficulty in initiating walking in the absence of ataxia or weakness. Because urinary incontinence is a relatively late feature, many patients may be unaware of it; fecal incontinence has been reported as rare. Pyramidal signs may occur, but they are uncommon features. The prominent involvement of the frontal lobes is reflected by the appearance of frontal release signs. There is no papilledema. Characteristically, the CSF opening pressure is either normal or low; raised CSF pressure should cast doubt on the diagnosis of NPH. Brain imaging should show no obstructing mass lesion; the hydrocephalus is communicating. Delayed clearance and failure of the radioisotope ascent over the cerebral convexities are seen in cisternography. Shunt infection, subdural hematoma, and shunt malfunction (which necessitates shunt removal) occur in 30% of patients who undergo shunting surgery.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

52) c

Objective: Review the mode of presentation of normal-pressure hydrocephalus (NPH).

This is the classical triad of dementia (mild cognitive impairment; a score of 21 on the mini-mental status examination), gait apraxia, and urinary incontinence (note the frequent use of diapers) that are compatible with NPH. This NPH is secondary to a previous acute aneurysmal subarachnoid hemorrhage.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

53) b

Objective: Review the clinical features of idiopathic Parkinson’s disease.

Note the asymmetric onset of his coarse resting tremor and facial expression; this is idiopathic Parkinson’s disease. Essential tremor has a symmetric onset, and the tremor is fast and fine with a prominent postural component. Patients may show soft voice, decreased facial expression, sleep disturbances, rapid eye movement (REM) behavior disorder (loss of normal atonia during REM sleep), decreased sense of smell, autonomic dysfunction (e.g., constipation, sweating abnormalities, sexual dysfunction, seborrheic dermatitis), lassitude, depression, anhedonia, and slowness in thinking.

Hauser R, Lyons K, McClain T, Pahwa R. Parkinson Disease. Medscape. Updated June 04, 2020. Available at:

54) b

The bilateral onset of tremor, as well as the presence of cerebellar and pyramidal signs, suggests a diagnosis other than idiopathic Parkinson’s disease. Advanced Alzheimer’s patients may have a similar picture, but the prominent autonomic failure would make this a remote possibility. Multi-infarct dementia patients demonstrate focal signs and dementia, but there is no autonomic dysfunction. Progressive supranuclear palsy (PSP) is frequently misdiagnosed as Parkinson’s disease because they both involve slowed movements and gait difficulty. Both Parkinson’s disease and PSP have an onset in late middle age and involve slowing and rigidity of movement. However, several distinguishing features exist. Tremor is very common with Parkinson’s, but rare with PSP. Speech and swallowing difficulties are more common and severe with PSP and the abnormal eye movements of PSP are essentially absent in PD. A poor response to levodopa along with symmetrical onset can also help differentiate PSP from PD. The constellation of Parkinsonism, autonomic failure, and global cognitive dysfunction, as well as the presence of pyramidal and cerebellar signs, would fit the Shy-Dragger syndrome form of multiple system atrophy.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

55) d

Objective: Review the anti-Parkinsonian medications.

Benztropine (like all anticholinergics) is effective at treating Parkinsonian tremors (not rigidity); in patients older than 60-65 years, it can produce a confusional state. Amantadine can be used in the early stages, either alone or in combination with anticholinergics; it has a mild short-lived effect that rapidly wears off. L-dopa is the pro-drug of dopamine; levodopa is the most effective drug for treating Parkinson’s Tolcapone (and entacapone) is a COMT inhibitor; it enhances the effect of L-dopa therapy. Pramipexole (and related dopamine agonist medications such as ropinirole) can induce impulsive-compulsive spectrum disorders, such as compulsive gambling, punding, hypersexuality, and overeating, even in people without any prior history of these behaviors.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

56) c

Objective: Review levodopa-induced dyskinesias (LIDs).

Levodopa is the most effective drug for treating Parkinson’s disease, but its long-term use is complicated by motor fluctuations and dyskinesia. Dyskinesia may be mild at the beginning but may progress to become a disabling symptom and may interfere with the quality of life. Different types of movement disorders are seen in LIDs including chorea, ballism, dystonia, myoclonus, or a combination of any of these movements. These dyskinesias are seen in the neck, facial muscles, jaw, tongue, hip, shoulder, trunk, and limb or may appear as involuntary flexion of toes. Peak-dose dyskinesia is seen at a high plasma drug level and is the commonest type of LIDs (80%). Using a frequent smaller dosage of levodopa and fractionation is helpful to minimize peak-dose dyskinesia. If patients are receiving long-acting formulations (e.g., controlled-release ones), switching to immediate-release formulations may be beneficial. Reducing or discontinuing the dosages of COMT inhibitors will also be helpful for such patients. Off-period dystonia is the commonest type (about 20%) and typically occurs in the early morning (or at night), before the dose of levodopa; it usually involves the leg. In off-period dystonia, adding a long-acting formulation at bedtime may be very helpful. The addition of COMT inhibitors or long-acting dopamine agonists can also be very helpful. For sudden or unpredictable offs, apomorphine can be considered, which is a highly selective dopamine agonist acting at and receptors and provides a rapid onset of action.

Pandey S, Srivanitchapoom P. Levodopa-induced Dyskinesia: Clinical Features, Pathophysiology, and Medical Management. Ann Indian Acad Neurol. 2017;20(3):190-8. Available at:

57) c

Objective: Review internuclear ophthalmoplegia (INO).

The patient has developed right-sided INO; the right eye is unable to This is due to lesions in the brainstem medial longitudinal fasciculus. This lesion disconnects the nuclei of the ipsilateral cranial nerve from those of the contralateral cranial nerve producing dissociated or disconjugate eye movements (a characteristic feature of brainstem lesions). Convergence is intact, which differentiates INO from partial oculomotor nerve palsy. The most common causes of INO are multiple sclerosis and brainstem infarction; the other causes are head trauma, brainstem and fourth ventricular tumors, Arnold-Chiari malformation, infection, hydrocephalus, and lupus erythematosus. Abducens palsy would produce an inability to abduct the eye while in pontine horizontal gaze lesions, both eyes cannot move toward the site of the lesion. She has no limitation in up gaze to suggest a midbrain lesion.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

58) b

Objective: Review trochlear nerve palsy.

Head trauma, usually a minor one, is the commonest cause of isolated cranial nerve palsy. In this patient, the left eye cannot be depressed in the adducted position (optimal position for an intact superior oblique muscle). Roughly, horizontal diplopia occurs in abducens palsy; angular diplopia suggests oculomotor palsy; vertical diplopia is a sign of trochlear palsy.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Review acute ophthalmoplegia; diabetic vascular cranial nerve palsy.

Diabetic cranial nerve palsies are the most common etiologic subset of oculomotor nerve palsy in adults. The etiology of diabetic neuropathy is hyperglycemia-induced damage to nerve cells and neuronal ischemic change.The inflammation and immune reaction may also be the cause of diabetic neuropathy.The classical presentation of oculomotor nerve palsy in diabetes is that of acute onset diplopia with ptosis; the pupil is This is due to the anatomical arrangement of the nerve fibers in the cranial nerve since fibers controlling the pupillary reflex are superficial, and therefore, spared from diabetic ischemia-induced sudden and isolated cranial nerve palsy, one should look at the pupil to differentiate between medical (e.g., diabetic vascular palsy, which is usually painless) and surgical palsy (e.g., expanding Berry’s aneurysm causing nerve compression and pain), because the treatment and prognosis are different. Diabetic vascular cranial nerve palsy is painful in 25% of cases (i.e., it is usually painless) and is in 75% of cases (i.e., in 25% of cases, the pupil is compressive lesions are usually painful and pupillary-involving (dilatation).

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Review the lateral medullary syndrome (Wallenberg syndrome).

This syndrome is usually due to vertebral artery occlusion or occlusion of the posterior inferior cerebellar artery is less common. Patients present with nausea, vomiting, and vertigo from the involvement of the vestibular system. Some findings are unilateral while others are contralateral to the damaged dorsolateral wedge-shaped area of the medulla. The ipsilateral clinical features are ataxia and dysmetria (damage to the inferior cerebellar peduncle); Horner’s syndrome (e.g., ptosis and miosis; descending sympathetic fibers damage); facial pain, loss of temperature sensation, and impaired corneal reflex (descending spinal tract and nucleus of the trigeminal nerve damage); nystagmus; impaired hearing (cochlear nucleus involvement); dysarthria, dysphagia, and loss of taste sensation at the posterior third of the tongue (damage to the nuclei or fibers of the glossopharyngeal and vagus cranial nerves). The contralateral features are pain and temperature loss of sensation (body and extremities; due to damage to the lateral spinothalamic tract). Some patients may exhibit tachycardia and dyspnea (damage to the dorsal nucleus of the vagus nerve) and palatal myoclonus.

Kaye V, Brandstater M. Vertebrobasilar Stroke. Medscape. Updated August 09, 2021. Available at:

61) b

Objective: Review carbamazepine.

Carbamazepine is a potent enzyme inducer, including its “own” metabolism, and is usually given 3 times daily (for immediate-release preparations) and twice daily (for extended-release tablets). It can produce neural tube defects in 0.5% of pregnancies as well as craniofacial dysmorphism. A good amount of this medication is excreted in urine and is not safe for renal failure (unlike valproic acid). It is highly effective in partial seizures and can be used as a second-line agent in generalized tonic-clonic seizures (as monotherapy or add-on therapy). The following are adverse reactions of carbamazepine:

Hemopoietic system: a wide range of adverse effects, such as aplastic anemia, pancytopenia, bone marrow depression, monocytopenia (thrombocytopenia, agranulocytosis, leukopenia, anemia), leukocytosis, eosinophilia, acute intermittent porphyria, variegate porphyria, and porphyria cutanea tarda

Skin: the most fearful adverse effects are toxic epidermal necrolysis and Stevens-Johnson syndrome. In addition, carbamazepine may result in pruritic and erythematous rashes, urticaria, photosensitivity, skin pigmentation abnormalities, exfoliative dermatitis, erythema multiforme, erythema nodosum, purpura, aggravation of disseminated lupus erythematosus, scalp hair loss, sweating, and generalized exanthematous pustulosis

Liver: elevation of liver transaminases, cholestatic jaundice, hepatocellular jaundice, and hepatitis; hepatic failure is extremely rare

Cardiac: carbamazepine may induce many ECG changes. Caution should be exercised in patients with conduction abnormalities.

May exacerbate absence seizures

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

Garg A, Bansal RT. Antiepileptic Drugs. New Delhi: Jaypee Brothers Medical Publishers; 2020.

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Objective: Review the interaction of oral antiepileptics with oral contraceptives.

Most epileptic women taking interacting antiepileptics are unaware of their effect on oral contraceptives. Many antiepileptic medications are known to induce the hepatic cytochrome P450 (CYP450) isoenzyme causing decreased sex hormone levels in women taking oral contraceptives; therefore, raising the potential for decreased effectiveness of oral contraceptives and increased risk of unplanned pregnancy. Antiepileptics are being used more often for problems such as migraine headaches, chronic pain syndromes, and bipolar disorder. Many guidelines recommend using oral contraceptive formulations containing at least 50 mcg of estrogen in women taking antiepileptic drugs. In addition, oral contraceptive effectiveness in women using enzyme-inducing antiepileptic drugs remains superior to barrier methods. The World Health Organization advises against using combined oral contraceptive pills and progestin-only pills in women taking enzyme-inducing antiepileptic drugs unless a better contraceptive method is not available or not acceptable to the patient; however, injectable medroxyprogesterone is still a recommended method. Levetiracetam does not affect the pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE) and levonorgestrel, and on the basis of serum progesterone and LH levels, it does not affect the contraceptive efficacy. The metabolism of EE, the most common estrogen component of combined oral contraceptives (COCs), is susceptible to the induction of CYP450 and increased which leads to reduced serum concentrations. Several progestins that are included in COCs and used in progesterone-only preparations also may be affected by enzyme induction. The induction of CYP3A4 by enzyme-inducing antiepileptics increases the metabolism of EE and progestins. Serum concentrations of these hormones are subject to inter-individual variation and may be reduced by 50% or more, possibly resulting in contraceptive failure. Induction continues for up to 4 weeks after the offending antiepileptic is discontinued, necessitating continued use of alternative or backup contraceptive methods during this time. Another possible mechanism involving an increase in sex hormone-binding globulin (SHBG) occurs with phenobarbital, phenytoin, and carbamazepine. The elevation in SHBG increases this glycoprotein’s capacity to bind progestins and reduce their free plasma concentrations.

Williams D. Antiepileptic Drugs and Contraception. US Pharm. 2014;39(1):39-42. Available at:

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Objective: Review topiramate-induced acute angle-closure glaucoma.

Topiramate is an oral sulphamate medication primarily used for seizures, migraine, and neuropathic pain. It has been associated with secondary angle-closure (usually within 2 weeks of administration), which can mimic acute angle-closure glaucoma. Suspicion for medication-induced angle-closure glaucoma should be higher whenever angle-closure presents It also has been associated with the development of acute myopia (within 1 month of starting this medication). Choroidal effusions and anterior displacement of the lens have also been reported. If glaucoma occurs whilst the patient is on this medication:

•Seek ophthalmologic advice immediately

•Use measures to decrease the raised intraocular pressure

•Stop topiramate rapidly as feasible (and use an alternative)

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Review lamotrigine.

In addition to being used as an antiepileptic medication, lamotrigine is an effective mood-stabilizing agent (helpful in bipolar disorders). Consider withdrawing lamotrigine if any one of the following occurs: fever, flu-like illness, or worsening of seizure control occurs whilst the patient is on this medication. Like all antiepileptics, it can cause blood dyscrasias, including aplastic anemia. Concomitant valproic acid therapy increases the plasma level of lamotrigine by 50% (and thus increases the risk of developing Stevens-Johnson syndrome); to reduce this risk, lamotrigine should be started at a low dose with gradual escalation. Note that many lamotrigine-induced rashes are mild; non-serious rashes can present as morbilliform, erythema multiforme, or urticaria. Simple morbilliform or urticarial rash can represent the initial stage of Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms. Consequently, when a rash occurs, patients must be referred for medical evaluation within 24 hours with possible referral to dermatology.

Mufson J. Lamotrigine: Pharmacology, Clinical Utility, and New Safety Concerns. American Journal of Psychiatry Residents' Journal 2018;13(12):2-4. Available at:

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Objective: Review levodopa contraindications and warnings.

Non-selective monoamine oxidase (MAO) inhibitors are contraindicated for use with These inhibitors must be discontinued at least two weeks before starting may be administered concomitantly with the manufacturer’s recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline hydrochloride). is contraindicated in patients with narrow-angle glaucoma and patients with known hypersensitivity to any component of this medication. Since levodopa may activate a malignant melanoma, it should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma. Should be avoided in patients with severe psychoses. Use with caution in the presence of peptic ulcer disease and ischemic heart disease. Levodopa can cause reddish discoloration of urine. The other side effects are anorexia, vomiting, agitation, postural hypotension (labile hypertension is uncommon), dyskinesia, hypomania and psychosis, depression, drowsiness, pruritis, and rarely elevated liver enzymes.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Review the role of apomorphine in the management of idiopathic Parkinson’s disease.

Apomorphine is a non-ergoline dopamine agonist. It is usually prescribed for refractory motor fluctuations and the so-called “off periods” that are inadequately controlled by levodopa or other dopaminergic agents. However, it can result in dyskinesias during the “on” periods. Apomorphine worsens the degree of any cognitive impairment present. It should be avoided in respiratory depression, CNS depression, and hepatic impairment.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Review the treatment of amyotrophic lateral sclerosis (ALS).

Riluzole was considered the only approved treatment for ALS in the past. It is known to have an antiglutamatergic effect, inhibiting the release of glutamate at the presynaptic terminus. Glutamate is an excitatory neurotransmitter, and several receptors bind to glutamate in order to instigate an action potential. Once the glutamate excitotoxicity begins, there is an increase in glutamate, uncontrolled ion channel activity, and high calcium influx. In the end, these outcomes lead to death in neurons. Therefore, with the inhibition of excess glutamate production, riluzole eventually prolongs the length of survival of patients by several months. Edaravone plays a role as a free radical scavenger of peroxyl radicals and peroxynitrite, which has a cytoprotective and neuroprotective mechanism against oxidative stress conditions. Edaravone protects neurons in the brain and spinal cord by eliminating the reactive oxygen species (ROS) such as hydroxyl radicals, peroxyl radicals, hydrogen peroxide, peroxynitrite, and many others that quicken and exacerbate the progression of neuronal degeneration, thus protecting from neurologic damage that leads to the death of motor neurons.Edaravone was approved in Japan in 2015; then, it was approved by the United States Food and Drug Administration as the treatment for ALS in 2017. This is the first approved ALS medication in more than 20 years. Edaravone serves its neuroprotective benefit as a radical scavenger, antioxidant, and anti-inflammatory against oxidative stress and ROS. In addition, with its anti-apoptotic mechanism involved with reducing Fas-associated death domain, it delays motor neuron degeneration in the brain and the spinal cord, thus prolonging the survival of patients and showing a significant improvement in ALSFRS-R score, which measures the patient’s functionality. The American Academy of Neurology does not currently have a publication discussing the role of edaravone in the treatment of ALS; practice parameter and quality measurement updates published since the most recent guidelines were released included no mention of edaravone.

Cho H, Shukla S. Role of Edaravone as a Treatment Option for Patients with Amyotrophic Lateral Sclerosis. Pharmaceuticals (Basel). 2021;14(1):29. Available at:

Barrington et al. Addressing the role of edaravone in the management of amyotrophic lateral sclerosis and gaps in care and access: expert panel recommendations. Am J Manag Care. 2021;27(12 Suppl):S231-S237. Available at:

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Objective: Characteristics of amyotrophic lateral sclerosis (ALS).

The presence of any one of the following should prompt the physician to think of a diagnosis other than ALS: sensory deficits, ophthalmoplegia, cerebellar signs, dysautonomia, and sphincter disturbances.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Characteristics of glioblastoma multiforme (GBM).

These tumors account for about 20% of all intracranial neoplasms, 55% of all glial tumors, and more than 90% of supratentorial gliomas. GBM is usually seen around the age of 60 years, but no age is exempt. These tumors have a slight male preponderance of 1.6:1 and almost all cases are sporadic (i.e., there is a negative family history). Most of them are in the cerebral hemispheres in their deep white matter and quickly infiltrate the brain extensively; sometimes attaining enormous size before attracting medical attention. Characteristically, they are highly infiltrating. Part of the lateral ventricle is usually distorted and both lateral and ventricles may be displaced contralaterally. Apart from extending to the meningeal surfaces, these highly aggressive tumors may reach into the ventricular surface causing raised CSF protein with mononuclear cell pleocytosis. Extracranial spread (mainly seen in the bones and lymph nodes) is very rare, except when craniotomy has been done (i.e., providing a portal for exit). A highly characteristic aggressive nature of the disease is to involve more than one lobe and spreads to the other side via the corpus callosum. Around 3-6% of GBMs are multicentric (which increases their virulence). The tumor may be mottled grey, red, brown, or orange depending on the degree of hemorrhage and Microscopically, there are prominent hypercellularity, cellular pleomorphism, and nuclear atypia (indicating highly aggressive malignancy). The tumor cells arise from anaplasia of mature astrocytes; meningiomas arise from meningothelial cells of the arachnoid. Cystic areas within the tumor mass are commonly seen, which impart a hypodense signal on brain imaging. The tumor vasculature may undergo sarcomatous changes with prominent reticulin and collagen interstitium, due to the elaboration of a growth factor by the tumor tissue.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

Hauser SL, Josephson S. eds. Harrison's Neurology in Clinical Medicine, 4e. McGraw Hill; 2017.

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Objective: Review the treatment modalities of glioblastoma multiforme (GBM).

Regardless of advanced diagnostic modalities and ideal multidisciplinary treatment that includes maximal surgical resection, followed by radiotherapy plus concomitant and maintenance temozolomide chemotherapy, almost all patients experience tumor progression with nearly universal mortality. The median survival from initial diagnosis is less than 15 months, with a 2-year survival rate of 26-33%. The addition of bevacizumab to standard treatment revealed no increase in overall survival but improved progression-free survival. That finding caused considerable debate regarding whether the combination is cost-effective in first-line treatment. In newly diagnosed GBM, methylation of O6-methylguanine-DNA methyltransferase promoter has been shown to predict response to alkylating agents; its status may play a crucial role in the choice of single modality treatment in the fragile elderly population. Currently, no standard of care is established for recurrent or progressive GBM.

Fernandes C, Costa A, Osório L, et al. Current Standards of Care in Glioblastoma Therapy. In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 11. Available from: doi: 10.15586/codon.glioblastoma.2017.ch11

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Objective: Characteristics of low-grade gliomas.

These brain tumors usually target adult people in their to decades of life, while the decade in children is the usual age of affection. Low-grade gliomas are slowly growing tumors but display infiltrative character and a tendency to form large cavities or pseudocysts. A highly characteristic feature of low-grade gliomas is that the location of the tumor is usually influenced by the age of the patient; for optic and thalamic gliomas are almost only seen in children. Fine granules of calcium can be seen in these tumors, but are also commonly seen in oligodendrogliomas; therefore, the presence of calcification does not exclude the diagnosis. They are surrounded by mild vasogenic edema. These tumors tend to show marked enhancement after gadolinium administration.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

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Objective: Characteristics of gliomatosis cerebri (GC).

There is diffuse infiltration of the brain hemispheres with neoplastic glial cells involving much of one cerebral hemisphere or both, with sparing of neuronal elements and without a discrete tumor mass being identified. The tumor cells compress the ventricular system, and one or more large confluent areas of signal changes may appear on brain imaging. The tumor cells can cross to the other side via the corpus callosum (and also thicken the corpus callosum). Pancephalic headache, vague personality changes, impaired mentation, and seizures comprise much of the clinical picture, and florid papilledema (similar to other high-grade gliomas) is usually detected at the time of presentation. Enhancement in brain imaging is which differentiates GC from cerebral lymphoma (the top-ranked differential diagnosis). Generally, the prognosis of these tumors is gloomy, and surgery is futile. Corticosteroids have if any effect, possibly because of the paucity of cerebral edema, and the benefit of radiation is uncertain.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

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Objective: Review intracranial meningioma.

The commonest sites, in descending order, are the Sylvian fissure, the parasagittal surface of the frontoparietal area, the olfactory groove, the lesser wing of the sphenoid bone, the tuberculum sellae, the superior surface of the cerebellum, cerebellopontine angle, and finally the spinal cord.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

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Objective: Review the radiological appearance of intracranial meningiomas.

Meningiomas are extra-axial tumors and are the commonest type of tumor of the meninges. They are a neoplasm that originates from the meningothelial cells; they are found anywhere that meninges are located. Although they are usually easily diagnosed and are typically indolent with a low rate of recurrence following surgery, there are several subtypes with variable imaging features and, in some instances, more aggressive biological behavior and higher grade. Typical meningiomas appear on cranial MRI as dura-based (dural tail) masses, isointense to the grey matter on both and weighted imaging, enhancing vividly and homogenously on both MRI and CT scans. There is no surrounding edema. However, some of the subtypes can impart a highly variable appearance on brain imaging. For example, >50% of meningiomas demonstrate a variable amount of vasogenic (not cytotoxic) edema in the adjacent brain parenchyma. Although in general, the presence of severe adjacent brain edema is considered more compatible with aggressive meningiomas (including atypical meningiomas), in some histologically benign types (e.g., secretory meningioma), the appearance of the underlying cerebral edema can be disproportionately larger than the small tumor size itself. The underlying mechanism is multifactorial.

Gaillard, F., Luong, D. Meningioma. Reference article, (accessed on 23 Feb 2022)

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Objective: Characteristics of intracranial meningioma.

Meningiomas account for 15-20% of all intracranial neoplasms. The male-to-female ratio is 1:2 (i.e., the tumor is more common in females). The highest incidence is seen in the and decades of life (therefore, they are uncommon in young people). Whether environmental or therapeutic, irradiation increases its incidence, and these radiation-induced tumors tend to occur at a younger age and tend to be more aggressive. Meningiomas are associated with the loss of chromosome 22 or a deletion of part of it; therefore, they can be multiple in neurofibromatosis type II (which has the same mutated chromosome). The tumor arises from meningothelial cells, particularly from those forming the arachnoid villi, but the precise origin of these tumors is still not settled. Meningiomas take the shape of the space in which they grow; therefore, some tumors are flat and plaque-like, while others are rounded and lobulated. Because of their origin, they are extra-axial and compressive; some may be invasive. Intraventricular meningiomas are rare and arise from the covering arachnoidal cells of the choroid plexus. A characteristic feature is that the tumor cells tend to encircle each other forming whirls and psammoma bodies (laminated calcific concretions).

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

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Objective: Characteristics of primary cerebral lymphoma.

The incidence of primary cerebral lymphomas in immune-competent hosts is rising with no explanation. There is a preponderance of men with a peak incidence in the through the decades, or in the and decades in AIDS patients. These tumors are usually of large B-cell type. The B-lymphoblastic cell is the tumor cell, and the fine reticulum and microgliacytes are secondary interstitial reactions derived from fibroblasts and microglia or histiocytes. T-cell lymphomas are rare tumors of the brain but do occur in both immune-competent individuals and immune-compromised AIDS patients. The tumor is multicentric and deep within the white matter of the cerebral hemispheres. The cerebral hemispheres are the usual target (60%) and localization is common. The eye (vitreous, uvea, and retina) is involved in 20% of cases; therefore, a vitreous biopsy can secure the diagnosis, but usually, it is not done in clinical practice. The tumor is pinkish grey, soft, ill-defined infiltrative mass. Its clinical course can exactly resemble that of glioblastoma multiforme but with a vastly different response to treatment. The Epstein-Barr virus genome is found in both immune-compromised and immune-competent patients. Because it is multicentric and deep, surgery is ineffective, except in rare instances. Cranial irradiation and steroids produce a partial response in most patients, or rarely a complete response, but the tumor recurs in more than 90% of cases. Generally, the survival is 10-18 months in immune-competent patients; much less in AIDS (or other immune-suppressed) patients.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

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Objective: Review intracranial metastases.

About 80% of secondary tumors localize themselves in the supratentorial while the remaining 20% occur in the posterior fossa, corresponding roughly to the relative size and weights of these portions of the brain and their blood flow. Cancers of the pelvis and colon are exceptional in this respect, tending to spread to the posterior fossa. Cancers of the and skin (except for malignant melanoma) almost never metastasize to the brain. Secondary tumors in the skull and dura are usually seen with prostatic cancer; this is seen in any tumor, but mainly observed in breast and prostate cancers, and with multiple myeloma. About 45-50% of brain metastases are single; solitary metastasis tends to come from the kidney, breast, thyroid, and lung (adenocarcinoma type). Small-cell lung cancers and melanomas tend to be multiple. Metastases from malignant melanoma and choriocarcinoma tend to be but these can also be seen with cancers of the lung, thyroid, and kidney. The presentation can be stroke-like, but it is usually insidious; abrupt presentation can be due to hemorrhage into the tumor or to tumor embolism causing cerebral infarction. Brain CT scans can pick up secondary tumors larger than 1 cm, and MRI with contrast can detect also meningeal disease. In selected patients, solitary metastasis can be excised if the systemic disease is reasonably controlled. Intrathecal methotrexate has no place in the treatment of secondary parenchymal malignant disease. Those with brain parenchymal metastases usually have a shorter life expectancy than those with bone or soft tissue metastases.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Review meningeal carcinomatosis.

In meningeal carcinomatosis, there is widespread involvement of the ventricles and meninges with malignant cells. Apart from leukemia and lymphoma, meningeal carcinomatosis is seen mainly with cancers of the lung, breast, GIT, and melanoma. Meningeal carcinomatosis generally forms 4% of all neurological metastases. Headache, backache, cranial nerve palsies, polyradiculopathies, seizures, and confusional states are the principal features. Hydrocephalus (of the communicating, non-obstructive type) is seen in 50% of patients. Polyradiculopathy, especially of the cauda equina, is surprisingly common. The diagnosis can be done by CSF cytospin analysis, flow cytometry, centrifugation, or Millipore filtration. Multiple large samples are usually needed. The CSF can show mononuclear pleocytosis, raised protein, and low sugar. Measuring the CSF biochemical markers of cancers (e.g., LDH, carcinoembryonic antigen, and beta-2 microglobulin) offers another means of making the diagnosis and following the response to treatment. These markers are most likely abnormal in hematological malignancies but may also be altered in some cases of intracranial infections and parenchymal metastases.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Review the anatomy of the cerebellopontine angle (CPA).

Because of its surgical importance, the cerebellopontine angle deserves special attention. It is a region limited superiorly by the infratentorial portion of the ambient cistern (superior cerebellar artery and trochlear nerve); medially by the prepontine cistern (basilar artery, abducens nerve, origin of the anterior inferior cerebellar artery (AICA), and transverse pontine vein); inferiorly by the lateral cerebellomedullary cistern (lower 4 cranial nerves, vertebral artery, and first segment of the posterior inferior cerebellar artery); and laterally by the petrous portion of the temporal bone. The cerebellopontine angle is composed of the trigeminal nerve, facial nerve, vestibulocochlear nerve, AICA, auditory artery, branches of the petrosal vein, the vein of the middle cerebellar peduncle, the vein of the lateral recess of the fourth ventricle, and the transverse pontine vein.

Winn H. Youmans and Winn Neurological Surgery, 4-Volume Set, 7th Edition. Elsevier Health, UK, 2016.

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Objective: Characteristics of vestibular schwannoma (acoustic neuroma).

These tumors are usually sporadic and unilateral; bilateral tumors are the hallmark of neurofibromatosis type II. The presence of facial palsy (weakness) indicates a late presentation or a complication of surgery. Together with tuberculous meningitis and Guillain-Barré syndrome, an acoustic neuroma can result in a very high CSF Although it is called “acoustic”, it arises from the vestibular portion of the eighth cranial nerve (therefore, it is a misnomer). It is a tumor of the Schwann cells covering the eighth cranial nerve. The commonest reported symptom is hearing loss. Facial pain is rare while facial numbness is common. Signs of raised intracranial pressure are late and uncommon. Vertigo develops in 30% of cases; it is usually mild and well-compensated. The most sensitive screening investigation is brainstem auditory evoked potentials. The corneal reflex is the clinical screening test. Remember that approximately 5-10% of all intracranial tumors are found in the cerebellopontine angle (CPA).Acoustic neuromas (vestibular Schwannoma), meningioma, and epidermoid tumors are the commonly encountered types. Vestibular Schwannoma comprises about 75-85% of all CPA tumors while meningiomas account for up to 10-15%; epidermoids make up 8% of all CPA tumors. Many other tumor types or masses constitute less than 1% of all space-occupying lesions found at the CPA.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

Lak AM, Khan YS. Cerebellopontine Angle Cancer. [Updated 2021 Nov 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:

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Objective: Characteristics of craniopharyngiomas.

These tumors are mainly seen in children, but they are also seen in adults (up to the age of 60 years). Cystic components are very common and are usually calcified. The cyst is usually suprasellar, 3-4 cm in diameter, pressing down the optic chiasma, and extending up into the third ventricle. The tumor arises from the remnant of Rathke’s pouch. The Rathke’s pouch lies at the junction of the infundibular stem and the pituitary gland. Calcification is seen in 70-80% of cases; a very useful clue on CT brain imaging. The underlying sella is usually flattened and enlarged.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

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This is the full-blown picture of a glomus jugulare tumor. It is a purplish-red, highly vascular tumor arising from minute clusters of nonchromaffin paragangilioma cells (glomus bodies) found mainly in the adventitia of the dome of the jugular bulb (glomus jugulare) immediately below the floor of the middle ear. It is a very slowly progressive tumor, sometimes over 10-20 years.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Review foramen magnum tumors.

Tumors in the region of the foramen magnum are of particular importance and must be differentiated from multiple sclerosis, Arnold-Chiari malformation, syringomyelia, and bony anomalies around the craniocervical junction. Failure to recognize these tumors is a serious matter since the majority are benign and extra-axial, i.e., potentially resectable and curable. If unrecognized, they terminate fatally by causing medullary and spinal cord compression. Together with neurofibromas and dermoid cysts, meningiomas and Schwannomas constitute the majority of foramen magnum tumors. Other tumor types are rare there. The clinical course of the above tumors usually extends over 2 years or longer with deceptive and “unexplained” fluctuations. They comprise about 1% only of all brain tumors, but they are extremely important as they are resectable.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

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Objective: Review the paraneoplastic neurological syndromes and their associated autoantibodies.

Anti-Yo antibodies (causing paraneoplastic cerebellar degeneration) can be seen in lung cancer, but they are mainly found in female gynecological cancers (ovarian cancer ranks first on the list). Anti-Hu antibodies are associated with encephalomyelitis, subacute sensory peripheral polyneuropathy, and neuronopathy. Scotomas, glares, and visual hallucinations can be detected in pan-retinal degeneration due to anti-recoverin antibodies in small-cell lung cancer, gynecological cancers, and melanomas. Anti-voltage-gated (P/Q type) calcium channel antibodies are detected in Lambert-Eaton myasthenic syndrome (70% of cases develop in association with small-cell lung cancer). Anti-amphiphysin antibodies may be seen in breast cancer-induced stiff person syndrome (muscle spasms and rigidity).

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

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Objective: Characteristics of paraneoplastic cerebellar degeneration (PCD).

PCD is a rare and severely debilitating immune-mediated disorder.

It has been associated with fewer than 1% of all cancers, including small-cell carcinoma of the lung, Hodgkin’s lymphoma, breast cancer, and gynecologic malignancies. Anti-Yo antineuronal antibody (also called Purkinje cell cytoplasmic antibody type 1) is highly specific and is the antibody most frequently identified in patients with PCD followed by anti-Hu, anti-Tr, anti-Ri, and anti-mGluR. In approximately 40% of PCD patients, no antibodies are identified. Clinically, it is characterized by acute or subacute onset with progressive pan-cerebellar dysfunction, including asymmetry of truncal limbs, gait ataxia, dysarthria, and nystagmus (mostly vertical). PCD occurs at any stage of the course of Guillain-Barré syndrome is usually seen with Hodgkin’s lymphoma and results in flaccid areflexic weakness (paraparesis); dysphagia and facial weakness may occur but there should be no nystagmus. Vitamin deficiency needs at least 3-5 years to develop and does not result in nystagmus or dysarthria; cancer patients are at risk of vitamin deficiency (i.e., Wernicke’s encephalopathy and Korsakoff’s amnesic syndrome).

Cui et al. Anti-Yo positive and late-onset paraneoplastic cerebellar degeneration associated with ovarian carcinoma. Medicine (Baltimore). 2017;96(32):e7362. Available at:

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Objective: Review the clinical manifestation and workup of neuropsychiatric lupus (NPL).

NPL is the commonest cause of autoimmune encephalopathy, commonly seen between the ages of 10 to 40 years. Neuropathologically, there is fibrinoid necrosis of small arterioles and capillaries causing small micro-infarcts and discrete hemorrhages. Although the underlying mechanisms are still largely unraveled, several pathogenic pathways are identified, such as antibody-mediated neurotoxicity, vasculopathy due to anti-phospholipid antibodies and other mechanisms, and cytokine-induced neurotoxicity. The cognitive dysfunction of neuropsychiatric lupus includes acute confusional state, schizophreniform psychosis, depression, and mania. Seizures may be focal. Diplopia, ptosis, hemiparesis, paraparesis, and chorea are less common findings. Although anti-ribosomal P-protein antibodies are supposed to be associated with lupus psychosis, it is still a controversial issue. The EEG is usually diffusely slowed or there are focal abnormalities. A common dilemma is to differentiate cerebral lupus from steroid-induced psychosis, but in practice, cerebral lupus is by far much more common. In addition, the encephalopathy in SLE may be due to infections, severe anemia, lupus endocarditis, and metabolic and electrolyte disturbances. If the patient is not receiving steroids, prednisolone should be started at doses between 60-80 mg/day. Cerebral lupus per se has not been shown to adversely affect the overall prognosis.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Characteristics of Herpes simplex encephalitis (HSE).

HSE is the commonest sporadic fatal encephalitis; there is no seasonal variation. The mortality rate ranges from 40% to 70% and depends on many factors. People older than 40 years of age are commonly targeted; this age group is older than that of the other causes of viral encephalitides in general. HSV type 2 affects neonates (when passing through an infected birth canal). HSV type II in adults usually produces viral meningitis rather than viral encephalitis. Characteristically, the infectious process involves the medial temporal and inferior frontal lobes (unilateral or bilateral affection). Intranuclear inclusions may be seen in neurons and glia. Patients who recover may show cystic necrosis of the involved areas. The presence of herpes labialis does not reliably implicate HSV as a cause of encephalitis. The disease can be rapidly progressive and result in a coma within a few days. Acute behavioral changes may be wrongly diagnosed as acute psychosis. Seizures may occur. The commonest sequelae in survivors are memory and behavioral disturbances, reflecting the predilection of HSV for the limbic system structures. The CSF white cell count is usually between 50-100 cells/μL. HSV is one of the causes of hemorrhagic CSF. The glucose is usually normal (it is low in a few cases). The virus generally cannot be isolated from the CSF, but the viral DNA can be detected in the CSF by PCR. Focal paroxysmal activity in the form of spike-and-wave activities might be seen on the EEG. Brain MRI is uncommonly normal but usually, it shows abnormalities in one or both temporal lobes and the changes may extend to frontal and parietal lobes. The CSF is normal in 2% of cases.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Characteristics of bacterial (pyogenic) meningitis.

The inflammatory response in pyogenic meningitis is associated with the release of inflammatory cytokines (e.g., IL-1, IL-6, and TNF alpha); therefore, promoting the permeability of the blood-brain barrier, vasogenic cerebral edema, changes in cerebral blood flow, and perhaps direct neuronal toxicity. The inflammatory exudate is more marked in the basal cisterns with N. meningitidis infection. Actual bacterial invasion of the underlying brain is very The burden of the pathological process is within the leptomeninges with secondary changes in the underlying brain. Many complications can alter the clinical course of pyogenic meningitis, e.g., stroke and hydrocephalus. Even in immune-competent hosts, the low levels of antibodies and complements in the subarachnoid space are inadequate to contain the infection.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: CSF findings in bacterial (pyogenic) meningitis.

In pyogenic meningitis in general, the CSF appearance ranges from slightly turbid to grossly purulent. It is under pressure in 90% of cases with a very low sugar value (may reach down to zero) and elevated protein level. The pleocytosis is predominantly the presence of predominant mononuclear pleocytosis in bacterial meningitis is consistent with Listeria pyogenic infections (or reflects partially treated cases). CSF white cell count >50,000 cells/μL usually indicates the presence of a burst brain abscess as a cause. Gram stain of the CSF is positive in 60-80% of pyogenic meningitis; in tuberculous meningitis, acid-fast smears are positive in 20% of cases. A useful tool in the diagnosis is PCR; PCR has been used to diagnose N. H. and L. monocytogenes meningitis. CSF bacterial cultures yield bacterial etiology in 70-85% of cases. This yield drops down to 20% in patients who have been treated with antibiotics. In such cases, the use of CSF bacterial antigen assays is advised; this is a latex agglutination technique that can detect the antigens of H. influenzae type B (Hib), S. N. E. coli K1, and S. agalactiae (group B streptococcus). The objective is to detect certain bacterial antigens (many bacteria would have already been killed by antimicrobial therapy). An alternative is an application of “Binax NOW” for detecting S. pneumoniae in the CSF; this assay demonstrates a 99-100% sensitivity and specificity for excluding the commonest bacterial etiologies of pyogenic meningitis.

Vasudeva SS. Meningitis. Medscape. Updated November 16, 2021. Available at:

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Review the management of bacterial (pyogenic) meningitis.

The initial choice of the antibiotic is empirical and is based on the patient’s age and predisposing factors in addition to endemicity. The use of steroids as a treatment adjunct is still controversial, although it is suggested to be given to children less than 2 months of age and to adults with positive CSF Gram stain and features of raised intracranial pressure. Steroids have been shown to decrease hearing loss and neurological sequelae in children with H. influenzae meningitis. After using the correct antibiotic, the CSF should be sterile within 24 hours and CSF pleocytosis and the proportion of polymorphonuclear cells should decrease within 3 A regimen consisting of 20 mg/kg of rifampicin once daily for 4 days is used for H. influenzae infections; in N. meningitidis meningitis, it is given as 20 mg/kg twice daily and for 2 days. A vaccine is available for certain strains of N. meningitidis and is recommended for military recruits, college students, and travelers to areas of ongoing epidemics.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Characteristics of tuberculous meningitis.

In tuberculous meningitis, tubercles can be seen on the surface of the brain as well as the meninges. Hydrocephalus is common (communicating or non-communicating) and the ventricular surfaces may show ependymal exudate or granular ependymitis. Cerebral vasculitis may complicate the picture and increase the disease morbidity by producing focal signs (e.g., hemiparesis). Cranial nerve palsies are either due to vasculitis or nerve compression due to basal fibrosis, both of which are very common. Surprisingly, a history of contact with tuberculosis patients is usually therefore, the diagnosis needs a high index of suspicion. Fever, confusion, and signs of meningeal irritation are the major presenting features, but all of them might be absent. Oculoparesis and optic disc swelling may occur and can wrongly be attributed to a mass lesion. In some patients, seizures can be a prominent feature. Stroke, brain edema, and spinal subarachnoid block may complicate the disease, thus increasing the already increased morbidity. Tuberculous meningitis is an aggressive CNS infection that needs a high index of suspicion.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

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Objective: Review the CSF findings in tuberculous meningitis.

The CSF is usually under pressure and is clear and colorless; however, it may show a clot upon standing due to its high protein content. Early polymorphonuclear pleocytosis may wrongly suggest a pyogenic cause. Afterward, lymphocytic or mononuclear pleocytosis predominates. The CSF protein may reach very high levels, especially in those with spinal subarachnoid block. Measurement of the chloride level in the CSF was used in the past as an aid in the diagnosis, but nowadays it is too non-specific. Unlike pyogenic meningitis (where the CSF glucose might reach zero mg/dL), the sugar level in tuberculous meningitis rarely falls below 20 mg/dL. In tuberculous meningitis, acid-fast smears are positive in 20% of cases. Culture for Mycobacterium is time-consuming (usually takes several weeks) and, therefore, delays the diagnosis. However, cultures are still necessary to detect drug susceptibility. PCR testing can provide a rapid diagnosis; however, false-negative results may occur if the CSF samples contain very few tuberculous microorganisms. CSF can be sent for Xpert MTB/RIF Ultra in patients suspected of tubercular meningitis. The Xpert MTB/RIF assay is an automated molecular test that has improved the detection of tuberculosis and rifampicin resistance, but its sensitivity is inadequate in patients with paucibacillary disease or HIV. Xpert MTB/RIF Ultra (Xpert Ultra) was developed to overcome this limitation.

Vasudeva SS. Meningitis. Medscape. Updated November 16, 2021. Available at:

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Objective: Review the clinical features of Friedreich’s ataxia (FA).

FA is the most frequent type of inherited ataxia. Most patients carry homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9. Due to epigenetic alterations, frataxin expression is significantly reduced. Frataxin is a mitochondrial protein. Its deficiency leads to mitochondrial iron overload, defective energy supply, and generation of reactive oxygen species. the early onset of slowly progressive ataxia associated with areflexia. Ataxia arises from combined afferent peripheral sensory neuropathy plus spinal degeneration, cerebellar, and sometimes also vestibular dysfunction. In addition to ataxia of stance and gait, patients develop appendicular and truncal ataxia. Dysarthria is another cerebellar feature present in 70% of patients. Extensor plantar responses are found in 70-90%.Proprioceptive deficits with abnormal position and vibration sense are present in virtually all FA subjects. Hearing problems are common and worsen over time. Affective disorders affect almost all patients with severe depression in almost 10% of patients. Dementia is not part of the FA phenotype. Cardiac involvement (hypertrophic cardiomyopathy) mainly affects young patients below the age of 40years. It accounts for about half of the deaths in the advanced stages of the disease. The prevalence of diabetes among FA patients varies between 8-49%. The young age of onset and longer disease duration increases the risk for diabetes.Scoliosis is considered typical for FA (33-100%). Foot cavus, club foot, pes planus) may significantly interfere with mobility in 55-90% of patients.

Burk K. Friedreich Ataxia: current status and future prospects. Cerebellum Ataxias. 2017;4:4. Available at:

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Objective: Review the presentation and clinical features of relapsing-remitting multiple sclerosis (RRMS).

The presence of multiple “white matter” signs along the neuroaxis in a patient who presents with acute transverse myelitis should always prompt the neurologist to think of multiple sclerosis (MS). Dorsal column signs (akinesthesia) in one limb should always prompt a search for MS. Her abnormal left pupillary reflex indicates a past/subclinical optic nerve involvement. Argyll-Robertson pupils are found in taboparesis, and a multitude of personality and behavioral changes develop (resulting from frontal lobe atrophy).

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Review epilepsy “triggers”; differentiate epilepsy triggers from migraine triggers.

Some factors make seizures more likely to occur in epileptic patients. These are designated as “triggers”. These triggers don’t cause epilepsy; they make seizures more likely to develop in patients with an epileptic disorder. On the other hand, not all people with epilepsy are influenced by these triggers. Nevertheless, some factors that can trigger seizures in one patient may not affect some other epileptic patients in the same way. The list of triggers includes sleep deprivation, missed doses of antiepileptic medications in treated patients, alcohol (particularly during withdrawal), illicit drug abuse, physical exhaustion, mental exhaustion, rapid flickering lights (TV and computer screens; in generalized epilepsy syndromes only), infections, and metabolic disturbances. Some triggers are uncommonly encountered, and these are loud noises, music, reading, and hot baths. An attack of a migraine headache can be triggered by a long nighttime sleep. There are a number of migraine triggers, and these are hormonal changes in women (fluctuations in estrogen before or during menses, during pregnancy, and after menopause, seem to trigger headaches in many women), hormonal medications (e.g., oral contraceptives; however, some people find that their migraines develop less often after taking these hormones), certain drinks (e.g., alcohol, especially wine, and caffeinated ones, such as coffee), stress (at work or home can induce migraine headaches), some sensory stimuli (bright or flashing lights can induce migraine headaches, as can loud sounds), strong smells (e.g., perfume and secondhand smoke can trigger migraines in some people), sleep changes (missing sleep or getting too much sleep can trigger migraines in some people), physical factors (undue physical exertion, including sexual activity), weather changes (including barometric pressure changes), medications (oral contraceptives and vasodilators), foods (aged cheeses, salty and processed foods), fasting (sometimes skipping meals), and certain food additives (sweetener aspartame and the preservative monosodium glutamate).

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Identify medications that lower the seizure threshold.

The seizure threshold describes the minimum intensity of a stimulus required to induce a seizure. Factors that may contribute to the risk of seizure with medications include overdose, alcohol abuse, organ dysfunction, drug interactions, older age, and a history of seizures. The list of medications that lower the seizure threshold is long and includes antibiotics (penicillin, isoniazid, metronidazole), antimalarials (chloroquine, mefloquine), cyclosporin, amphetamines (mainly during withdrawal), antiarrhythmics (lidocaine, disopyramide), and psychotropic agents (phenothiazines, tricyclics, and lithium). Herbs/natural remedies (e.g., guarana), non-prescription supplements, and abrupt withdrawal from chronic alcohol use, as well as certain prescription medicines (e.g., antiseizure medications, baclofen, benzodiazepines), are also associated with seizure development. Some medications may indirectly induce seizures (e.g., hypoglycemic agents).

Hitchings, AW. Drugs that lower the seizure threshold. Adverse Drug Reaction Bulletin. 2016;298 (1);1151-4. Available at:

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Objective: Differentiate between complex partial seizures (CPS) and absence seizures.

Absence seizures may be confused with complex partial seizures, especially in cases of prolonged seizures with automatisms; i.e., non-convulsive seizures. Automatisms are semi-coordinated, repetitive motor activities that are associated with impaired awareness and occur in both focal and generalized seizures. Automatism also occurs in all children with absence seizures. Automatisms may be perseverative when there is a continuation of an activity that commenced before the seizure, or de novo when automatisms start during the seizure. The occurrence of automatisms is dependent on the duration of the seizure (especially in absence seizures); the longer the seizure, the more likely automatisms are to be observed. The following are characteristics of CPS: aura followed by an abrupt onset of the seizure, automatisms, duration >30 seconds (usually 1-2 minutes), variable daily frequency, no awareness, gradual termination with a post-ictal phase, inter-ictal EEG (anterior temporal lobe sharp waves, focal spikes, or multifocal spikes in 80% of cases). In absence seizures, the seizures start and terminate abruptly with no awareness, are of <20 seconds in duration (usually 2-20 seconds), display duration-dependent automatisms (therefore, automatisms are uncommon), occur multiple times a day, hyperventilation induces the seizures, and there are characteristic EEG findings (the presence of 3 Hz spike-and-wave complexes is diagnostic).

Segan S. Absence Seizures. Medscape. Updated September 25, 2018. Available at:

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Objective: Characteristics of juvenile myoclonic epilepsy (JME).

JME is an idiopathic generalized epileptic syndrome that is characterized by the presence of myoclonic jerks (myoclonus), generalized tonic-clonic seizures (GTCSs), and sometimes (not always) absence seizures. JME is a relatively common seizure disorder and responds well to the appropriate antiepileptic drug. The other features that are suggestive of the diagnosis of JME are normal intelligence, onset around adolescence, and a family history of the same condition. The GTCSs tend to develop shortly after awakening in the morning or after precipitating factors (e.g., sleep deprivation, alcohol use, or psychological stress). Patients usually require lifelong antiepileptic drug therapy, but the overall outlook is generally positive. Patients may exhibit myoclonic jerks in addition to other seizure types. In approximately 60% of patients, JME begins with myoclonus (myoclonic jerks) and after a few years, GTCSs appear. The next common constellation is the presence of myoclonic jerks plus absence seizures and GTCSs; this is seen in about 30% of patients with JME. The combination of myoclonic jerks and absence seizures with no GTCSs is a rare one; observed in 2% of cases. In the majority of cases of JME, the seizures can be well-controlled with monotherapy (i.e., using one medication); valproate is the treatment of choice for JME and gives in a high response rate. Valproate monotherapy produces an 80% rate of seizure-free outcomes. Monotherapy using lamotrigine, topiramate, levetiracetam, and zonisamide has demonstrated similar efficacy to the one achieved with valproate. Levetiracetam can control myoclonic seizures. Lamotrigine may also be a consideration in the treatment of JME; this medication is ideal for patients who cannot tolerate the adverse side effects of valproate (e.g., weight gain and scalp hair loss) or levetiracetam (drowsiness). In some patients, lamotrigine monotherapy can control seizures completely; however, in some other patients, it may paradoxically aggravate the myoclonic jerks. Researchers have concluded that lamotrigine can be used as the first-line medication for JME in adolescent whereas valproate is the first-line antiepileptic drug in adolescent Topiramate is useful in the treatment of primary generalized seizures; it can efficiently control the seizures of JME.

Selph J, Benbadis SR. Juvenile Myoclonic Epilepsy. Medscape. Updated February 15, 2022. Available at:

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Objective: When to start antiepileptic drugs (AEDs) in patients with a single seizure?

The patient’s view on medication should always be considered. For example, women planning a pregnancy may choose to avoid AEDs in the short term, though they must be warned of the potential risks of having another seizure (or seizures) during pregnancy. Individuals wishing to avoid recurrent seizures, for example for should be offered immediate treatment. A detailed history should be taken to exclude previous myoclonic, absence, or focal seizures as patients with undiagnosed epilepsy may present with a single generalized tonic-clonic seizure for the very first time. Whether to treat a single seizure or not is largely decided by the risk of further Estimates of recurrence risk vary. The highest recurrence rates (up to 90%) are observed in patients with epileptic discharges on the EEG or in the presence of a structural cerebral disorder (e.g., brain tumors or cortical scars). The lowest rates (13-40%) are associated with acute symptomatic seizures (i.e., provoked seizures; e.g., acute pyogenic meningitis) or patients with a normal EEG and no identifiable cause for seizures. Overall, the risk of recurrence is about 30-40%; this is greatest in the first twelve months and falls to <10% after two years.

Scottish Intercollegiate Guidelines Network SIGN 143 Diagnosis and management of epilepsy in adults (May 2015). Updated/revised September 2018. Available at:

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Objective: Review the first-line antiepileptic drugs (AEDs) used in the treatment of various epilepsies.

In focal epilepsies, lamotrigine is as effective and better tolerated than carbamazepine, topiramate, or oxcarbazepine. Zonisamide is not approved as a monotherapy for the treatment of focal seizures in adults with newly diagnosed epilepsy. Lamotrigine may have advantages for adolescents, young women, and older people because it is well-tolerated, has a favorable cognitive and behavioral profile, and does not lead to weight gain. In summary, in patients with focal onset seizures, lamotrigine is the drug of choice; where lamotrigine is poorly tolerated, carbamazepine and levetiracetam may be reasonable alternatives. In genetic generalized epilepsy or unclassified epilepsy, sodium valproate is the most effective antiepileptic drug; where sodium valproate is poorly tolerated or contraindicated, lamotrigine and topiramate are suitable alternatives. In women of childbearing age, levetiracetam or lamotrigine may be a reasonable alternative. The use of valproate must consider MHRA (Medicine and Healthcare products Regulatory Agency, UK) safety advice (issued in April 2018) on the use of valproate in women and girls of childbearing potential and the conditions of the Pregnancy Prevention Program.

Scottish Intercollegiate Guidelines Network SIGN 143 Diagnosis and management of epilepsy in adults (May 2015). Updated/revised September 2018. Available at:

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Objective: Identify drug-resistant epilepsy (DRE) and its potential causes.

DRE is defined by the International League Against Epilepsy as the persistence of seizures despite at least two syndrome-adapted antiseizure drugs (ASD) used at efficacious daily doses; i.e., failure to achieve sustained seizure freedom after trials of two tolerated and appropriate antiepileptic drugs (AEDs) schedules (whether as monotherapies or in combination). According to this definition, the single variable that should be considered is whether or not the patient is In contrast, neither the type of seizures, the seizure frequency, nor the other epilepsy-related complications are included in this definition. Most patients with newly diagnosed epilepsy respond well to AEDs. Failure to do so may be due to an incorrect diagnosis of epilepsy, an inappropriate choice of AED for the epilepsy syndrome, failure to take the prescribed AED, an underlying cerebral neoplasm, metabolic condition, or immune process, and concurrent drug or alcohol misuse. Despite the increasing number of available ASD, about a third of patients with epilepsy still suffer from drug resistance. Several factors are associated with the risk of evolution to DRE in patients with newly diagnosed epilepsy, including epilepsy onset in infancy, intellectual disability, symptomatic epilepsy, and abnormal neurological examination. Pharmacological management often consists of polytherapy. Vagus nerve stimulation, deep brain stimulation, or cortical stimulation can also improve seizure control.

Guery D, Rheims S. Clinical Management of Drug Resistant Epilepsy: A Review on Current Strategies. Neuropsychiatr Dis Treat. 2021;17:2229-42. Available at:

Scottish Intercollegiate Guidelines Network SIGN 143 Diagnosis and management of epilepsy in adults (May 2015). Updated/revised September 2018. Available at:

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Objective: Review the management of provoked seizures.

Provoked seizures are defined as seizures occurring within seven days of an acute condition (e.g., encephalitis, head injury, cerebral infarction, craniotomy, and cerebral hemorrhage). There is evidence that treatment can reduce the risk of such provoked seizures in the context of traumatic brain injury (by phenytoin and carbamazepine), craniotomy (by phenytoin), and cerebral malaria (by phenobarbital). There is no evidence, however, that prophylactic treatment of provoked seizures influences the subsequent development of epilepsy. If AED treatment is commenced following the occurrence of provoked seizures, it should be used only in the short term, unless unprovoked seizures occur later. Attacks occurring immediately after a concussive closed-head injury have been described as “concussive convulsions”; there is no evidence that these will recur, and AED treatment is not indicated. Keep in mind that:

•When seizures are provoked by metabolic disturbances or drugs, attention should be directed to the correction or withdrawal of the provocative factor

•Patients with seizures provoked by alcohol or substance misuse may benefit from referral to addiction services and other support agencies

•Following an acute brain insult or neurosurgery, long-term prophylactic AED treatment is not indicated

•Following an acute brain insult, antiepileptic drugs used to treat the provoked seizures should be withdrawn (unless unprovoked seizures occur later)

•Antiepileptic drug treatment is not indicated for concussive convulsions

Scottish Intercollegiate Guidelines Network SIGN 143 Diagnosis and management of epilepsy in adults (May 2015). Updated/revised September 2018. Available at:

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Objective: Identify idiosyncratic reactions of antiepileptic drugs (ADEs) and differentiate them from chronic systemic adverse effects.

Idiosyncratic drug reactions usually occur in the first weeks of treatment and are potentially serious. Skin rashes are the commonest idiosyncratic reactions, occurring in up to 10% of patients taking carbamazepine, phenytoin, or lamotrigine. Most rashes are mild and resolve promptly on discontinuation of the AED, but severe skin reactions are observed in up to 1 in 1,000 patients. This incidence is increased if the initial dose is increased rapidly. Genetic testing can help predict idiosyncratic drug reactions in some racial populations, for example, carbamazepine reactions in Han Chinese and Caucasians. Patients of Asian descent should have their human leukocyte antigen (HLA) status checked before starting carbamazepine. The life-threatening AED hypersensitivity syndrome of fever, rash, lymphadenopathy, and multiorgan failure occurs in up to 4.5 in 10,000 patients, mostly with carbamazepine, lamotrigine, or phenytoin. It is important to note that cross-sensitivity occurs between these AEDs in up to 70% of patients. Rapid titration or drug interactions may make this more likely. Minor blood dyscrasias are associated with many AEDs; the majority (mild leucopenia with carbamazepine, thrombocytopenia with sodium valproate) require no action. Severe blood dyscrasia occurs in 6 in 10,000 patients. Hyponatremia (serum sodium <135 mEq/L) is seen in about 20% of patients taking carbamazepine or oxcarbazepine; it is usually well-tolerated and of no significance. If mild (>120mEq/L) and asymptomatic this should not deter ongoing treatment with AEDs. Elevation of liver enzymes (γ-glutamyl transferase in 90% of patients, alkaline phosphatase in 30%) is seen in people taking enzyme-inducing AEDs and is usually of no clinical significance. Clinical symptoms are more useful than routine monitoring of liver function in identifying the onset of serious adverse drug-induced reactions. Acute psychotic reactions are seen occasionally with vigabatrin, topiramate, and tiagabine, particularly in those patients with a previous history of psychiatric diseases; withdrawal from the drug usually results in recovery.

Scottish Intercollegiate Guidelines Network SIGN 143 Diagnosis and management of epilepsy in adults (May 2015). Updated/revised September 2018. Available at:

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Objective: Review the long-term adverse effects of antiepileptic drugs (AEDs); nephrolithiasis.

Renal tubular acidosis and urolithiasis occur with acetazolamide, topiramate, and zonisamide (i.e., drugs with carbonic anhydrase inhibition properties). These stones are of calcium phosphate types and are radiopaque. A metabolite of phenytoin can cause clinically relevant urolithiasis leading to significant morbidity and even mortality; clinicians should have an increased level of suspicion for metabolite stone formation in symptomatic patients taking antiepileptic medications. Fanconi’s syndrome has been documented with valproate therapy in severely disabled children with epilepsy.

Scottish Intercollegiate Guidelines Network SIGN 143 Diagnosis and management of epilepsy in adults (May 2015). Updated/revised September 2018. Available at:

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Objective: Review the management of epilepsy in pregnancy and labor.

Epilepsy is a common neurological disorder during pregnancy. About 0.7% of pregnancies occur in women with epilepsy. Pre-pregnancy counseling is important for all women with epilepsy. All antiepileptic drugs (AEDs) should be reviewed before pregnancy because of the teratogenic nature of some AEDs, especially valproate. Epileptic women should be informed that valproate displays a higher teratogenic rate compared to other AEDs. In the majority of epileptic women, seizure frequency during pregnancy is either improved or remains unchanged throughout pregnancy. About 50% of women remain seizure-free throughout pregnancy. Women with epilepsy who are seizure-free for nine months or more before becoming pregnant are likely to remain seizure-free during pregnancy. Seizure control is more likely to be a problem in women with focal onset than with primary generalized seizures. Women taking polytherapy during pregnancy are more likely to have seizures than those taking monotherapy. The frequency of status epilepticus in women with epilepsy during pregnancy is quite small (0.55% to 1.8%). Pregnancy is associated with pharmacokinetic changes including an increase in the volume of drug distribution, an increase in drug metabolism through hepatic microsomal enzyme induction, a reduction in serum albumin concentration, and an increase in renal clearance. There is a tendency for plasma levels of AEDs to fall during pregnancy, especially for lamotrigine and levetiracetam. The value of plasma AED monitoring in pregnancy is Total plasma levels may be misleading, and the relationship between free AED levels and seizure control is complex. Plasma level monitoring may occasionally be of use when there is concern about toxicity or adherence to therapy.

Scottish Intercollegiate Guidelines Network SIGN 143 Diagnosis and management of epilepsy in adults (May 2015). Updated/revised September 2018. Available at:

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Objective: Review the causes and management of neurogenic bladder; supra-pontine lesions.

The pontine micturition center is under higher control via inputs from the pre-frontal cortex, midbrain, and hypothalamus. In the absence of conscious control (e.g., in coma or dementia), distension of the bladder to near capacity evokes reflex detrusor contraction (analogous to the muscle stretch reflex), and reciprocal changes in sympathetic activation and relaxation of the distal sphincter result in coordinated bladder emptying. Damage to the frontal lobes may result in loss of awareness of bladder fullness, loss of social control, inappropriate micturition, difficulty initiating micturition, and consequent urinary incontinence. Coexisting cognitive impairment may cause inappropriate micturition. These features may be encountered in hydrocephalus, frontal lobe tumors, dementia, and bifrontal subdural hematomas. Apart from targeting the the treatment is largely composed of intermittent or indwelling catheterization.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Review the causes and management of neurogenic bladder; hypertonic bladder of upper motor neuron lesions.

Damage to the pons or spinal cord (infra-pontine to supra-sacral levels) results in an “upper motor neuron” pattern of bladder dysfunction due to uncontrolled over-activity of the parasympathetic supply. The bladder is small and highly sensitive to stretching. This results in frequency, urgency, and urge incontinence. Loss of the coordinating control of the pontine micturition center will also result in the phenomenon of detrusor-sphincter dyssynergia, in which detrusor contraction and sphincter relaxation are not coordinated; the spastic bladder will often try to empty itself against a closed sphincter. This manifests as both urgency and an inability to pass urine (which is distressing and painful). The resultant incomplete bladder emptying predisposes to urinary infection, and the prolonged high intravesical pressure may result in obstructive/reflux uropathy and renal failure; post-micturition bladder ultrasound may confirm incomplete bladder emptying. More severe lesions of the spinal cord, as in spinal cord compression or trauma, can result in painless urinary retention as bladder sensation, normally carried in the lateral spinothalamic tracts, will be disrupted. Antimuscarinic agents for the bladder include oxybutynin, tolterodine, trospium chloride, solifenacin, darifenacin, and fesoterodine. All target the muscarinic receptors in the bladder muscularis and block acetylcholine from binding the muscarinic receptor effectively inhibiting involuntary bladder contractions. Long QT syndrome is not a contraindication although solifenacin (like tolterodine and darifenacin) binds to hERG channels of the heart and may prolong the QT interval. This mechanism appears to be seldom clinically relevant. Bethanechol is used for selective stimulation of the bladder to produce contraction and thereby initiate micturition and empty the bladder. It is most useful in patients who have bladder provided that they have functional and coordinated sphincters. It is rarely used, because of the difficulty of timing the effect and because of gastrointestinal stimulation.

Camero A. Medical management of neurogenic bladder with oral therapy. Transl Androl Urol. 2016;5(1):51-62. Available at:

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Review the causes of unilateral ptosis.

Ptosis is the presence of an abnormal low-lying upper eyelid margin with the eye in primary gaze. The normal adult upper lid margin lies about 1.5 mm below the upper corneal limbus and is highest just nasal to the pupil. Ptosis can be classified as congenital or acquired, based on the patient's age. Ptosis can also be classified according to etiology (myogenic, aponeurotic, neurogenic, mechanical, traumatic, and pseudoptotic). Congenital ptosis is the commonest cause of unilateral ptosis; the most common etiology of congenital ptosis is the myogenic one (there is improper development of the levator muscle). Ptosis may result from dysfunction of one or both upper eyelid elevator muscles (levator palpebrae superioris and the Mueller’s muscle). Aponeurotic ptosis is the commonest cause of bilateral acquired ptosis; involutional changes, dehiscence, or disinsertion of the levator aponeurosis are common causes. Myasthenia gravis can result in unilateral or bilateral (usually asymmetric) ptosis. Congenital ptosis can be bilateral.

Cohen AJ, Mercandetti M. Ptosis (Blepharoptosis) in Adults. Medscape. Updated July 10, 2020. Available at:

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Objective: Review the causes of bilateral ptosis; with and without frontalis overaction.

The frontalis muscle acts as an accessory upper eyelid elevator and is innervated by the facial nerve. It elevates the brow as well as the upper eyelid. The muscle is attached to the skin of the eyebrows and joins the galea aponeurotica below the coronal suture. Smoothening out of the forehead (absence of wrinkles) indicates myogenic causes of the ptosis; myotonic dystrophy, oculopharyngeal muscular dystrophy, chronic progressive external ophthalmoplegia, and Kearns-Sayre syndrome. Frontalis contraction (i.e., overaction) reflects an attempt to compensate for the ptosis. Patients with bilateral aponeurotic ptosis tend to compensate with overaction of the frontalis muscle; however, persistent brow elevation may lead to frontalis fatigue and even cephalgia. Note that nuclear (midbrain) oculomotor nerve palsy can result in bilateral partial ptosis.

Bacharach et al. A review of acquired blepharoptosis: prevalence, diagnosis, and current treatment options. Eye (Lond). 2021;35(9):2468-81. Available at:

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Objective: Differentiate genuine ptosis from pseudoptosis.

Pseudoptosis is not true ptosis; it is apparent ptosis resulting from abnormalities in certain structures other than the levator muscle. These causes are dermatochalasis, brow ptosis, hypotropia, microphthalmos, anophthalmos, phthisis bulbi, and contralateral eyelid retraction. Blepharospasm and hemifacial spasms may result in apparent ptosis. It is very important to differentiate genuine ptosis from pseudoptosis before embarking upon any surgical correction for eyelid drooping. Mechanical ptosis develops when the eyelid is too heavy for the muscles to elevate it, (e.g., orbital fat prolapses, lid edema, and eyelid tumors).

Koka K, Patel BC. Ptosis Correction. [Updated 2021 Nov 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:

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Objective: Differentiate papilledema from pseudo-papilledema.

Papilledema is an optic disc swelling that is secondary to elevated intracranial pressure. In contrast to other causes of optic disc swelling, vision usually is well preserved with acute papilledema. Papilledema almost always presents as a bilateral phenomenon and may develop over hours to weeks. Intracranial mass lesions and malignant hypertension should be excluded in all patients with papilledema. It is incorrect to use the term “papilledema” to describe optic disc swelling due to primary infection, infiltration, or inflammation of the optic nerve that does not cause increased intracranial pressure. In bilateral optic neuritis (papillitis type), the optic nerve heads are swollen (but this does not translate to papilledema or pseudo-papilledema). On the other hand, pseudo-papilledema is defined as an anomalous elevation of one or both optic discs without edema of the retinal nerve fiber layer. Patients thought to have papilledema are often subjected to lumbar puncture, MRI, and extensive laboratory studies to find the underlying cause. Optic nerve head drusen is the most common cause of pseudo-papilledema (occurring in 0.34%-2.4% of individuals). Congenital anomalies of the optic disc may also mimic papilledema by causing portions of the disc to elevate. Myelinated nerve fibers refer to the atypical myelination of intraocular nerve fibers, occurring in 0.3-0.6% of the population. The presence of myelin may elevate adjacent portions of the optic disc and obscure the disc margin and underlying retinal vessels, simulating papilledema. Hypoplastic optic discs are common and may be enormously elevated. In tilted optic discs, a typically bilateral condition, the superotemporal optic disc is elevated, mimicking optic disc swelling, while the inferonasal disc is posteriorly displaced. Bergmeister’s papillae is a congenital variant of the optic nerve in which an incompletely regressed hyaloid artery can obscure the optic nerve and give the impression of papilledema. Epipapillary glial tissue may be associated with Bergmeister’s papillae and produce anterior traction that elevates the disc. The morning glory disc anomaly is a congenital, typically unilateral funnel-shaped excavation of the posterior fundus that incorporates the optic disc, causing the disc to be markedly enlarged and appear elevated in some patients. Small optic discs can cause the appearance of pseudo-papilledema. In a crowded disc, a normal number of ganglion cells or optic nerve axons converge at a small optic disc to course through a smaller-than-average scleral canal, which can create indistinct margins. Small and crowded discs are commonly associated with hyperopia due to shortened axial length. Orbital hypotelorism has been associated with pseudo-papilledema and situs inversus of the vessels.

Miller, N. R., In Newman, N. J., Walsh, F. B., & Hoyt, W. F. (2005). Walsh & Hoyt's clinical neuro-ophthalmology.

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Objective: Review the papilledema grading system (Frisen Scale or Grade).

This patient has the typical full-blown picture of grade 5 papilledema. When performing a fundus exam on a patient with papilledema, a multitude of signs can be detected depending on the severity and rapidity of papilledema. When doing indirect ophthalmoscopy, focus on the following:

•The optic nerve head: retinal nerve fiber opacification, the elevation of the margins, hyperemia, and obliteration of the cup

•Features related to vascular congestion: venous dilation, vascular tortuosity, hemorrhages, cotton wool spots, and exudates (which can extend to the macula causing a macular star appearance). If spontaneous venous pulsations (SVPs) are present, this suggests that the intracranial pressure (ICP) is probably not high at this time; however, the ICP may have been high before simply due to diurnal variations in intracranial pressure. The absence of SVP is not always suggestive of high ICP as it can be absent in 10-20% of the normal population

•Mechanical features: retinal folds (e.g., peripapillary circumferential watermarks called Paton’s lines), and choroidal folds due to posterior globe deformation

Chronic papilledema may show all the aforementioned signs in addition to optic disc pallor along with decreasing swelling due to loss of axons, gliosis (greying of the retinal fibers due to scarring), opto-ciliary shunts, and refractile bodies.

Rigi et al. Papilledema: epidemiology, etiology, and clinical management. Eye Brain. 2015;7:47-57. Available at:

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Objective: Review the types of optic atrophy and their causes.

The human optic nerve is formed by about 1.2 million axons that originate at the retinal ganglion cell layer. Upon leaving the eyeball, these axons are covered with myelin sheath formed by oligodendrocytes (the mode of myelination is similar to the brain white matter). Once damaged, these axons cannot regenerate. Therefore, the optic nerves behave more like a white matter tract rather than a true peripheral nerve (the peripheral nerves are covered by myelin provided by Schwann cells). The course of the optic nerve can be divided into 4 parts: the intraocular part (about 1 mm; this is the optic nerve head), the intra-orbital part (this is approximately 25-30 mm in length), the intra-canalicular part (within the optic canal of the skull, about 5-10mm), and finally the intracranial part (before joining the chiasma, which is 10-16 mm) The average optic nerve head is 1 mm deep, 1.5 mm wide, 1.8 mm deep at the retinal level. The optic nerve head is located at a major transition between an area of high pressure to an area of low pressure. Four types of cells are found at the optic nerve head, and these are ganglion cell axons, astrocytes, capillary-associated cells, and fibroblasts. Upon doing a fundoscopy, one can recognize 4 types of ophthalmoscopic optic atrophy (primary, secondary, consecutive, and glaucomatous). Primary optic atrophy occurs without any preceding swelling of the optic nerve head (regardless of the etiology). Any lesion insulting the optic nerve fibers from the retinal ganglionic cells to the lateral geniculate body can end up with primary optic atrophy; the commonest cause in clinical practice is multiple sclerosis (causing optic neuritis). The optic disc is white, and its margin is well-demarcated. Secondary optic atrophy follows optic nerve head swelling (e.g., after papilledema of pseudotumor cerebri); the optic disc appears yellowish, and its margin is blurred. Consecutive optic atrophy is a consequence of extensive damage to the inner retina and/or its blood supply (e.g., retinitis pigmentosa, after pan-retinal photocoagulation, extensive chorioretinitis, and aftermath of central retinal artery occlusion. Glaucomatous optic atrophyis an entirely different and unique category characterized by specific mechanico-vascular changes in the optic disc (e.g., increment in the cup:disc ratio with thinning of the surrounding retinal nerve fiber layer).

Ahmad SS, Kanukollu VM. Optic Atrophy. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:

Amula GM. Optic Atrophy. Medscape. Updated October 19, 2021. Available at:

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Objective: Review the central nervous system nuclei responsible for wakefulness.

There are certain areas in the brain, via their nuclei, that are responsible for maintaining wakefulness. Each region’s nuclei have a specific neurotransmitter that plays a critical role in health and disease states. These areas are locus coeruleus (norepinephrine), raphe nucleus (serotonin), tuberomammillary nucleus (histamine), ventral tegmental area (dopamine), and basal forebrain (acetylcholine). These areas also inhibit rapid eye movement (REM) sleep.

Nallu S. Narcolepsy. Medscape. Updated August 03, 2020. Available at:

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Objective: Differentiate between rapid eye movements (REM) sleep and non-rapid eye movements (NREM) sleep.

REM sleep is a unique phase of sleep in some species (mammals and birds). It is characterized by the random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the sleeper to dream vividly. The vital signs fluctuate. Penile erection (in males) and vaginal secretions (in females) are common. Muscle twitching and decreased tone occur. EEG recording shows features of waking states. REM sleep constitutes about 20-25% of the nighttime sleep duration in normal healthy adults. NREM sleep is characterized by little or no rapid eye movements, muscle relaxation with some tone in postural muscles, stable vital signs, and the rarity of penile erection or dreaming. Sleep spindles are unique to NREM sleep and occur in stage 2. NREM sleep is divided into 3 stages:

•Stage 1 is encountered at the beginning of sleep; there is slow eye movement. This state is sometimes referred to as relaxed wakefulness. People aroused from this stage often believe that they have been fully awake. Hypnic jerks are observed during the transition into stage 1 sleep.

•Stage 2: here, there are no eye movements. Dreaming is very rare. The person is very easily aroused. During stage 2, EEG recordings reveal the characteristic “sleep spindles” and “K-complexes”.

•Stage 3: Stage 3 is deep sleep slow-wave sleep (SWS). Dreaming is more common in this stage than in other stages of NREM sleep though not as common as in REM sleep. The content of SWS dreams tends to be disconnected, less vivid, and less memorable than those that occur during REM sleep. This is also the stage during which parasomnias most commonly occur.

Blumberg et al. What Is REM Sleep? Curr Biol. 2020;30(1):2020R38-R49. Available at:

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Objective: Review REM and NREM parasomnias; REM sleep behavioral disorder.

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by dream-enactment behaviors that emerge during a loss of REM sleep atonia. RBD dream enactment ranges in severity from benign hand gestures to violent thrashing, punching, and kicking. Patients typically present to medical attention with a concern related to injurious or potentially injurious actions to themselves and/or their bed partner. In spontaneously occurring cases, RBD is a prodromal syndrome of alpha-synuclein neurodegeneration. Therefore, the vast majority of RBD patients will eventually demonstrate signs and symptoms of Parkinson’s disease (PD) or a related disorder (e.g., multiple system atrophy or dementia with Lewy bodies), often after a prolonged interval. A careful history should distinguish RBD from related parasomnias, such as sleepwalking. In-laboratory video polysomnography can exclude other sleep disorders, quantify REM atonia and capture dream-enactment behaviors, confirming the diagnosis. The objective of treatment is to reduce behavioral events and prevent sleep-related injury; this can be achieved through changes in the sleeping environment and, if necessary, oral bedtime melatonin and/or clonazepam. RBD is more frequent during the last of the sleep cycle. There is marked vocalization, and patients may get out of bed. Patients are easily awakened (and responsive on awakening) with no post-event confusion or amnesia of the event. A family history of parasomnia is occasionally present.

Howell M, Schenck S. Rapid eye movement sleep behavior disorder. UpToDate. Updated December 07, 2021. Available at:

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Objective: Differentiate REM parasomnias from NREM parasomnias.

Parasomnias are abnormal motor behaviors that occur around sleep. They may be encountered in REM or NREM sleep. In both, there are characteristic features and timing of occurrence. NREM parasomnia tends to arise early in sleep. The differential diagnosis of parasomnias is certain sleep-related motor disturbances (e.g., periodic limb movements, hypnic jerks, or sleep talking) and epileptic seizures occurring during sleep. Taking a thorough history from the bed partner or any eyewitness is essential for the diagnosis. NREM parasomnias arise from incomplete arousal from NREM sleep and manifest as night terrors, sleepwalking, and confusional arousals (so-called sleep drunkenness). Such parasomnias typically develop within an hour (or two) of sleep onset and are common in children; usually, there are no pathological consequences. Rarely, they persist into adulthood and may become increasingly complex, including dressing, moving objects, eating, drinking, or even acts of violence. Patients give minimal or no recollection of the events, even though those patients seem to be apparently awake to the eyewitness. The episodes may be precipitated by alcohol ingestion or unfamiliar sleeping situations. They can be familial. No treatment is usually required; however, clonazepam can be helpful in some situations. Sleep paralysis (together with nightmare disorder and REM sleep behavioral disorder) is a REM sleep disorder.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Review restless leg syndrome.

Restless legs syndrome (RLS) is a relatively common disorder; with a prevalence of 10% of the general population. However, many individuals never contact medical services. RLS is characterized by unpleasant leg (rarely arm) sensations that are eased by movement (motor restlessness). The diagnosis is clinical; there is no diagnostic test. It demonstrates a prominent familial clustering. It can present with daytime somnolence (due to poor sleep). RLS is usually idiopathic but may be associated with iron deficiency, pregnancy, peripheral polyneuropathy, idiopathic Parkinson’s disease, or end-stage renal disease. It should be differentiated from akathisia, the daytime motor restlessness (an adverse effect of conventional antipsychotics). Not all patients need treatment. If required, treatment is with one of the dopaminergic medications (dopamine agonists or levodopa preparations) or benzodiazepines (e.g., clonazepam). Unlike RLS, periodic limb movements in sleep (PLMS) only occur during sleep and cause repetitive flexion movements of the limbs, usually in the early (non-REM) stages of sleep. Although patients are unaware of the symptoms, they may disrupt their sleep quality and often disturb their bed partners. The pathological significance of PLMS is uncertain and it often occurs in normal health. There is an overlap with RLS. Clonazepam or dopaminergic medications (e.g., pramipexol) are successful in treating PLMS.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Review the diagnosis of narcolepsy.

The diagnosis of narcolepsy is often apparent from clinical history; however, it is essential to confirm the diagnosis with overnight polysomnography followed by a multiple sleep latency test the next day. The overnight sleep study helps rule out other potential causes of daytime sleepiness; in people with narcolepsy, it may show fragmented, light sleep and an early transition into REM sleep (<15 minutes after the onset of sleep). During the multiple sleep latency test, the patient is encouraged every 2 hours to fall asleep for 20 minutes; the test usually begins at 8 A.M. and ends at approximately 5 to 6 P.M. Allowed to nap, people with narcolepsy usually fall asleep in less than 8 minutes, whereas healthy people generally fall asleep in 15 minutes or more. In addition, people with narcolepsy usually have REM sleep during at least two of these daytime naps (known as sleep-onset REM sleep periods), whereas people without narcolepsy rarely have any daytime REM sleep. A positive multiple sleep latency test (defined as a short time to fall asleep plus REM sleep in at least two of the naps) provides strong, objective evidence of excessive sleepiness and poorly regulated REM sleep.

Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-62. Available at:

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Objective: Characteristics of hypocretin (orexin).

Hypocretin neurons are thought to be auto-excitatory. They project from the lateral hypothalamus into several brain regions and serve to maintain arousal and wakefulness. A deficiency of hypocretin neurons may decrease the threshold for transitioning between wakefulness and sleep (so-called sleep state instability). This is one of the proposed explanations for the sleepiness and REM intrusion into wakefulness found in narcolepsy. There are 2 isoforms; hypocretin-1 and hypocretin-2. These are excitatory neuropeptides that are implicated in a wide range of neuronal circuits, playing important roles in sleep and wake regulation, autonomic regulation, neuroendocrine and locomotor function, regulation of hormonal secretions, feeding behavior, and energy homeostasis as well as in the pathology of narcolepsy. The peptides are produced by 60,000-70,000 neurons (in humans) located in the lateral hypothalamus. The direct regulatory effect of hypocretin peptides is found, not only in the brain but also in peripheral tissues. Hypocretin receptors have been found in a variety of tissues including kidneys, adipose tissue, gastrointestinal tract, pancreas, adrenal gland, and reproductive organs across different species; the source of peripheral hypocretin is unknown. Hypocretin stimulates glucose uptake in 3T3-L1 adipocytes, and that increased energy uptake is stored as lipids (triacylglycerol). Therefore, it increases lipogenesis. It also inhibits lipolysis and stimulates the secretion of adiponectin. Hypocretin increases the craving for food and correlates with the function of the substances that promote its production. It is also shown to increase meal size by suppressing inhibitory post-ingestive feedback. However, the stimulatory effects of hypocretin on feeding may be due to general arousal without necessarily increasing overall food intake. High levels of hypocretin-1 have been associated with happiness in human subjects, while low levels have been associated with sadness. The sleep disorder narcolepsy type 1 (narcolepsy with cataplexy) is associated with a loss of hypocretin production in the brain: low levels of hypocretin-1 in the CSF is a highly specific and sensitive diagnostic marker for narcolepsy-1.

Ægidius et al. Pre-treatment of blood samples reveal normal blood hypocretin/orexin signal in narcolepsy type 1. Brain Communications. 2021;3(1):fcab050. Available at:

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Objective: Review the management of narcolepsy.

The characteristic tetrad of narcolepsy is composed of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis; the latter 2 are also seen in normal healthy individuals. The pathophysiology of narcolepsy is complex and may result from a combination of genetic predisposition, abnormal neurotransmitter functioning and sensitivity, and abnormal immune modulation. The classical tetrad is rarely encountered in children. The hypocretin (orexin) system plays a critical role in the pathophysiology of this narcolepsy. Those patients display little or no hypocretin in their CSF. A striking association has been found between narcolepsy and the HLA haplotype DQA1*01:02-DQB1*06:02. There is a slight male preponderance; the male-to-female ratio is 1.64:1. Narcolepsy exhibits a bimodal age of onset; the highest peak is seen at the age of 15 years while the lesser pronounced peak develops at the age of 36 years. Several medications have been used in the treatment. Medications that target excessive somnolence in narcolepsy are CNS stimulants (e.g., methylphenidate, modafinil, armodafinil, amphetamines, and solriamfetol. Codeine can be used as an alternative in patients who cannot tolerate these CNS stimulants or when these stimulants are contraindicated. Cataplexy may respond to sodium oxybate (which also treats EDS) and antidepressants (e.g., clomipramine, fluoxetine). Narcolepsy can be treated with histamine agonists/inverse agonists (e.g., pitolisant). Pitolisant is a first-in-class medication indicated for excessive daytime sleepiness in adults with narcolepsy.

Nallu S. Narcolepsy. Medscape. Updated August 03, 2020. Available at:

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Objective: Differentiate genuine relapses from pseudo-relapses in multiple sclerosis.

Relapses in multiple sclerosis are defined as periods of clinical worsening and radiological progression. Magnetic resonance imaging data, however, are not always supportive of “clinical worsening,” and clinical symptoms of worsening may not always be present in cases of acute relapse. Typically, in the relapsing-remitting multiple sclerosis (RRMS) variants, acute relapses, defined as symptoms that occur over a minimum of 24 hours and are separated from a previous attack by at least 30 days, accrue. RRMS is clinically characterized by paroxysmal or indolent changes that can occur over time with variations in severity and complexity and exhibit inter-individual differences. A pseudo-relapse is a temporary worsening of symptoms without actual myelin inflammation or damage, precipitated by certain triggers, e.g., infection, exercise, a warm environment, depression, exhaustion, and stress. When symptoms flare, checking for a fever is important; even a minor infection and a slight increase in temperature can cause symptoms to appear (or to worsen). Urinary tract infection is the most common type of infection to cause a pseudo-relapse. Additionally, people with “heat-sensitive” multiple sclerosis will experience a temporary increase in symptoms when their body temperature rises, often after exercise or a hot bath. Therefore, many heat-sensitive individuals try to avoid hot tubs, saunas, or other situations that can raise the body’s temperature. Once the cause of the pseudo-relapse is resolved, this type of symptom flare-up will usually subside within 24 hours. Paroxysmal symptoms start abruptly, end abruptly, and usually last seconds, and there is no expectation of relapse. An important point to remember is that all causes of pseudo-relapses (except menstruation) may also trigger a

Avasarala A. Redefining Acute Relapses in Multiple Sclerosis: Implications for Phase 3 Clinical Trials and Treatment Algorithms. Innov Clin Neurosci. 2017; 14(3-4):38-40. Available at:

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Objective: Review and identify relapses in multiple sclerosis (MS).

Relapse is a neurologic deficit associated with an acute inflammatory demyelinating event that lasts at least one day, in the absence of fever and infection. Up to 70% of MS relapses are in the form of exacerbation of previous symptoms. All causes of pseudo-relapses (except menstruation) may also trigger a relapse. The average frequency of relapses is approximately one per year. The frequency of relapses is higher in women and at younger ages and decreases with time. The frequency of relapses increases during systemic infections, psychological stress, and in the first 3 months after birth. A typical relapse reaches its peak within a few hours and days and recovers partially or completely after a plateau period of days and weeks. Neurologic deficits need to occur at least 30 days after any previous episode or a stable period to be considered a new relapse. Seventy-five percent of relapses are monosymptomatic. The risk of relapses increases 2 weeks before and until 5 weeks after the onset of any severe infection. The most common relapse symptom expressed by patients is Seventeen percent of untreated relapses recover with significant sequelae. Regression is more difficult in polysymptomatic, spinal, and advanced-age relapses. Regression in the first few weeks of relapse is explained by a reduction of the edema, and by remyelination in the following months. Relapses with multiple symptoms, pyramidal symptoms, brainstem, and spinal cord involvement, recovery with a sequel, and large numbers of relapses in the first years are signs of a poor prognosis. A reduction in the number of relapses and progression between relapses can indicate a transformation into the secondary progressive form of multiple sclerosis. Most MS plaques are Contrast enhancement is valuable, but it is not detectable in the majority of relapses. It usually begins before symptoms and the appearance of lesions and lasts an average of 4 weeks. “Open ring” enhancement is typical for MS.

Sevim S. Relapses in Multiple Sclerosis: Definition, Pathophysiology, Features, Imitators, and Treatment. Turk J Neurol. 2016;22:99-108. Available at:

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Objective: Review the treatment of steroid-unresponsive function-threatening relapses in multiple sclerosis (MS).

Treatment of relapses with intravenous methylprednisolone (IVMP) reduces post-relapse disability and shortens the duration of relapses. Unresponsiveness to IVMP treatment can only be considered at least 10 days after the end of the administration and can be treated by plasmapheresis or immunoadsorption therapy. Plasmapheresis is a good option for selected patients who are refractory to steroid treatment and who are predicted to have a permanent disability. Immunoadsorption a therapy response of 80% in relapsing-remitting multiple sclerosis and clinically isolated syndrome and 100% in neuromyelitis optica. Intravenous immunoglobulin treatment has no role in relapses. Interferon-beta and natalizumab are disease-modifying drugs; they are not used in treating relapses.

Sevim S. Relapses in Multiple Sclerosis: Definition, Pathophysiology, Features, Imitators, and Treatment. Turk J Neurol. 2016;22:99-108. Available at:

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Objective: Review the syndromes, signs, and symptoms that are suggestive of white matter demyelination in multiple sclerosis.

Syndromes, signs, and symptoms suggestive of central nervous system demyelination include partial afferent pupillary defect (Marcus-Gunn pupil) and optic atrophy (previous optic neuritis); Lhermitte’s symptom (Barber chair sign; tingling in spine or limbs on neck flexion); progressive non-compressive paraparesis (myelopathy), partial Brown-Séquard syndrome (partial hemisection of the spinal cord, especially if bilateral); internuclear ophthalmoplegia with ataxia (brainstem medial longitudinal fasciculus); postural (also called rubral or Holmes type) tremor; trigeminal neuralgia under the age of 50 (and when bilateral), and recurrent facial palsy. Focal seizures reflect a cortical pathology.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Review the etiological factors in the development of multiple sclerosis (MS).

The concordance rate for MS among monozygotic twins is about 20-35%; this finding suggests that genetic factors play a modest effect in the pathogenesis of MS. Some predisposing non-Mendelian factors (i.e., epigenetic modification in 1 twin) in addition to environmental factors display a critical effect. HLA-DRB1 is the only chromosomal locus that is consistently associated with a susceptibility to develop MS. On the other hand, HLA-C*05 allele confers protection against MS. Geography also plays a role. The number of MS cases is lower in the equatorial regions than in the northern and southern parts of the world. Such environmental factors usually impart their effect during early childhood, not adulthood. However, some racial groups (e.g., Eskimos), despite living in areas with a higher incidence of MS, do not display a high frequency of the disease. In conclusion, the precise role played by geography versus genetics is not well-understood. A low serum level of vitamin D is one of the environmental factors that may be involved in the development of MS. Vitamin D displays a multitude of effects.

Vitamin D, by decreasing the production of proinflammatory cytokines and increasing the production of anti-inflammatory cytokines, plays a role in regulating immune responses. High serum levels of vitamin D seem to decrease the risk of MS development.

Luzzio C, Dangond F. Multiple Sclerosis. Medscape. Updated January 03, 2022. Available at:

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Objective: Review the role of [paraclinical] investigations in the diagnosis of multiple sclerosis (MS).

MS can be diagnosed based on the presence of certain clinical findings and supporting evidence from paraclinical tests (e.g., magnetic resonance imaging of the brain and spinal cord as well as cerebrospinal fluid examination). MRI alone should not be used to diagnose MS. However, MRI remains the imaging modality of choice for confirming MS and monitoring disease progression in the brain and spinal cord. The MRI findings are not MRI is considered the most sensitive imaging modality for the diagnosis of spinal cord MS, the evaluation of MS extent, and following up the response to medical treatment. At best, MRI can reveal brain abnormalities in up to 95% of MS patients while in the spinal cord, MS lesions can be uncovered in up to 75% of cases (especially in elderly patients). One of the problems encountered by using MRI in MS patients is the discordance between lesion (demyelination) location and clinical presentation (signs and symptoms). In general, the use of visual evoked potentials (VEP) is unnecessary to confirm the clinical diagnosis of acute optic neuritis; however, when mild optic neuritis or subclinical optic nerve damage is suspected, VEP testing can be valuable to demonstrate previous or asymptomatic demyelinating injury. The typical abnormal VEP feature in MS-related optic neuritis is the prolonged latencies and reduced amplitudes of the P100 wave. It should be noted that many pathologies (e.g., optic-nerve compression, infiltration, or non-demyelinating inflammation) can result in similar abnormalities; therefore, such findings are not specific to optic neuritis. CSF analysis is not considered a routine test in the workup of MS anymore (it may be useful when MRI is unavailable or MRI findings are nondiagnostic). The CSF parameters evaluated in MS are the oligoclonal bands (OCBs) and intrathecal IgG production. These OCBs are detected in 90-95% of MS patients while intrathecal IgG production is seen in 70-90% of patients. These findings are not specific to MS, however.

Luzzio C, Dangond F. Multiple Sclerosis. Medscape. Updated January 03, 2022. Available at:

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Objective: Review the mechanism of action of therapies used in the treatment of relapsing-remitting multiple sclerosis.

The treatment of multiple sclerosis (MS) has 2 parts. First, immunomodulatory therapy (IMT) should be used to tackle the underlying immune disorder. Second, certain therapies are used for the relief or modification of MS-related symptoms (e.g., fatigue, impotence, pain). IMT should reduce the frequency and severity of MS relapses and may slow disease progression. Disease-modifying therapies display beneficial effects in the RRMS by reducing the frequency and severity of clinical attacks; additionally, such agents slow the progression of disability and reduce the accumulation of the demyelinating lesions within the CNS (brain and spinal cord). The disease-modifying agents for treating MS are categorized into:

•Interferons beta (e.g., IFN beta-1a, IFN beta-1b, and peginterferon beta-1a)

•Sphingosine-1-phosphate (S1P) receptor modulators (e.g., siponimod, fingolimod, and ozanimod)

•Monoclonal antibodies (e.g., natalizumab, alemtuzumab, ocrelizumab)

•Miscellaneous immunomodulators (e.g., glatiramer acetate, teriflunomide, mitoxantrone, monomethyl fumarate, dimethyl fumarate, and cladribine)

Some agents are administered e.g., fingolimod, cladribine, teriflunomide, and dimethyl fumarate. Other agents can be used intravenously, e.g., natalizumab, and mitoxantrone. Interferon-beta 1a is administered intramuscularly while interferon beta-1a and glatiramer acetate are administered Natalizumab is a humanized monoclonal antibody that binds to the adhesion molecule alpha-4 integrin, thus inhibiting its adherence to its receptors. It is used in MS patients who have not responded to the first-line disease-modifying therapies or in patients who have very active disease.

Luzzio C, Dangond F. Multiple Sclerosis. Medscape. Updated January 03, 2022. Available at:

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Objective: Review the adverse reactions of disease-modifying agents for multiple sclerosis.

Beta interferons impart a multitude of adverse reactions; the local injection site reactions (85%) are the commonest ones. In addition, flu-like symptoms (60%) and headaches (57%) are common. Depression and suicidal ideation are observed in patients receiving interferon beta injections; if patients develop depression or express suicidal ideation, beta-interferon therapy should be discontinued. Leukopenia, hypothyroidism, and hyperthyroidism may occur during beta-interferon therapy. Within one hour of ingesting fingolimod, slowness in the heart rate and even severe bradycardia may occur. The lowest heart rate is typically observed at 6 hours, but it can occur up to 24 hours after taking the first dose in some patients. A 12-lead resting ECG should be done in all patients before taking the very first dose of fingolimod in addition to monitoring the blood pressure and pulse rate hourly; an ECG should be performed at the end of the observation period. Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is a potent disease-modifying therapy used in the treatment of RRMS. A variety of secondary autoimmune disorders may occur after starting alemtuzumab; thyroid disease is the commonest one. Anti-glomerular basement membrane disease has been reported and is renal-limited (no lung involvement). Cases of Merkel cell carcinoma have been documented in patients receiving rituximab.

Luzzio C, Dangond F. Multiple Sclerosis. Medscape. Updated January 03, 2022. Available at:

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Objective: Identify and treat multiple sclerosis-related symptoms.

Impairment in cognitive function is one of the major problems that adversely affect the quality of life of MS patients in addition to influencing their family and social relationships and employment. Cognitive dysfunction treatment in those patients should also encompass supportive therapy provided by speech pathologists and/or occupational therapists. In addition, depression is one of the factors that may impair cognition and should be treated when present. Unfortunately, pharmacotherapy does not help improve cognitive impairment in MS. Selective serotonin reuptake inhibitors are the preferred first-line agents for treating depressive symptoms. Tricyclic antidepressants are a second-line choice. Additionally, the tricyclic anticholinergic side effects can be useful to patients with overactive bladder or chronic pain. Fatigue is one of the commonest and most disabling symptoms of MS, observed in about 90% of patients. Fatigue can worsen before and during clinical exacerbations and with increased temperatures. No single medication for the treatment of MS-related fatigue has been approved; however, the use of amantadine is helpful in this regard (although this is an off-label one). Pain is common in MS; about 30-50% of patients experience disabling and troublesome pain at some time during the course of their MS. Pain in MS can be primary or secondary; some patients may experience both of them at the same time. The pain (usually described as burning, gnawing, or shooting) is related to the demyelinating process. Tricyclics are the first-line medications for this primary pain. Antiepileptics (e.g., carbamazepine, phenytoin, and gabapentin) can be used as second-line medications. The pain of MS is mainly musculoskeletal (due to impaired posture, imbalance, or as a result of muscle spasticity). Nonsteroidal anti-inflammatory drugs (or other analgesics) are helpful to alleviate this secondary type of pain. The use of narcotics is rarely indicated. MS-related tremors are difficult to manage; many medications have been used in this regard, with little success. Antiepileptics, isoniazid, primidone, benzodiazepines, propranolol, and ondansetron have been used to treat MS-related tremor.

Luzzio C, Dangond F. Multiple Sclerosis. Medscape. Updated January 03, 2022. Available at:

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Objective: Review the role of autoantibodies in various neurological disorders; anti-AQP4 antibodies in neuromyelitis optica spectrum disorders (NMOSD).

Neuromyelitis optica (NMO; Devic’s disease) is an inflammatory CNS disorder distinct from multiple sclerosis (MS). Traditionally, NMO was considered a monophasic disorder consisting of simultaneous bilateral optic neuritis and transverse myelitis, but relapsing cases were described. MRI revealed normal brain scans and ≥3 vertebral segment longitudinally extensive transverse myelitis lesions (LETM) in NMO. The finding of Anti-AQP4 IgG revealed a wider array of clinical presentations, including patients with recurrent optic neuritis of transverse myelitis alone, now considered part of the NMO spectrum. Furthermore, symptoms other than optic-spinal involvement and the presence of brain lesions, do not exclude the diagnosis of NMO as traditionally accepted. Anti-ganglioside antibodies (anti-GQ1b) are found in the Miller-Fisher variant of Guillain-Barre syndrome; this presents with the classical triad of ataxia, areflexia, and ophthalmoplegia. Anti-ganglioside antibodies (anti-GM1 antibodies) are found in multifocal motor neuropathy with conduction block (80%), severe cases of Guillain-Barres syndrome, and rheumatoid arthritis with peripheral neuropathy. Ma2 antibody-associated encephalitis is an inflammatory brain disease that is associated with a systemic tumor in more than 90% of patients (most commonly a testicular germ-cell tumor, lung cancer, or breast cancer).

Wingerchuk et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-89. Available at:

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Objective: Review the clinical features and diagnosis of acute disseminated encephalomyelitis (ADEM).

ADEM is an acute monophasic demyelinating condition in which areas of perivenous demyelination are widely disseminated throughout the brain and spinal cord. The illness may arise spontaneously but often occurs a week or so after a viral infection, especially measles or chickenpox, or following vaccination, suggesting that it is immunologically mediated. The prognosis for acute disseminated encephalomyelitis is generally good, although occasionally it may be fatal (probably less than 10%). Treatment with high-dose intravenous methylprednisolone, using the same regimen as for a relapse of MS, is recommended.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Review the causes of muscle twitching; neuromyotonia.

Muscle twitching at rest may be due to fasciculation or myokymia. Neuromyotonia is a rare condition with spontaneous and continuous muscle fiber activity of peripheral nerve origin. Clinically is characterized by muscle twitching at rest (visible myokymia), cramps, and impaired muscle relaxation (i.e., pseudo-myotonia) associated with excessive sweating. Neuromyotonia can be hereditary, paraneoplastic, or acquired (usually immune-mediated and represents 80% of all cases of neuromyotonia). Anti-voltage-gated potassium channel antibodies against the motor nerves result in a continuous hyperexcitability state. Paraneoplastic neuromyotonia may occur in small-cell lung cancer or thymoma.

Scola et al. Neuromyotonia: an Unusual Presentation in Inflammatory Myopathy. Neurology. 2015:84(14S);P2.045. Available at:

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Objective: Review the treatment of chorea; Huntington’s disease (HD).

HD typically presents with a progressive behavioral disturbance, abnormal movements (usually chorea), and cognitive impairment leading to dementia. The onset of the disease before the age of 18 years is rare; however, those patients may present with parkinsonism rather than chorea (the so-called Westphal variant). Family history is always present, although this may be concealed (low penetrance; skipped generation). The diagnosis is confirmed by genetic testing. Brain imaging may show caudate atrophy (not a reliable test). The management of HD is symptomatic (not curative). The chorea may respond to neuroleptics (e.g, risperidone) or tetrabenazine (a dopamine-depleting gent). Depression and anxiety are common and should be treated with proper medications.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Review the causes of postural tremor; essential tremor (ET).

ET displays an autosomal dominant pattern of inheritance, but no specific genes have been identified. It may present at any age with bilateral hand tremors (8-10 Hz). The tremor is rarely seen at rest but is typically observed with movement (postural, not intentional). The head and voice may be involved. The tremor improves in about 50% of patients with small amounts of alcohol. The diagnosis is clinical; there are no specific tests. However, it should be differentiated from other tremor types and syndromes. Beta-blockers (especially propranolol) and primidone are usually helpful in decreasing tremors. Deep thalamic brain stimulation is reserved for treating severe cases.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Review the neurological and extra-neurological manifestations of Wilson’s disease (WD).

WD is an inherited genetic disorder of copper metabolism. The mode of presentation is variable and depends on the damaged organ; hepatic, neurological, and psychiatric. Copper accumulates in different body organs and tissues and results in a multitude of clinical manifestations. Patients with WD may present with ophthalmological symptoms, and renal, cardiac, and/or osteoarticular manifestations. The commonest ocular sign is the Kayser-Fleischer ring (results from copper accumulation in the corneal Descemet's membrane) while sunflower cataract is uncommon. Osteoarticular involvement is quite common and includes osteopenia, osteoporosis, and arthropathy, which may lead to bone fractures and joint problems mainly affecting knees and wrists. Renal involvement appears as renal tubular acidosis (types 1 and type 2); the diagnosis is usually biochemical. WD patients display a higher risk of atrial fibrillation and heart failure because of copper deposition in the heart. Dysautonomia develops but the involvement is usually subclinical in most cases. Endocrine disturbances are also common; recurrent abortions, infertility, growth disruption, and parathyroid failure may occur. Hematologic disturbances are frequent; recurrent acute Coombs-negative hemolytic anemia, leucopenia, anemia, and thrombocytopenia. Characteristic skin features of WD are hyperpigmentation of the legs, xerosis, or azure (blue) lunulae of the nails. WD-related tremors can be resting, postural, and/or cerebellar (intentional). Wing-beating tremor is highly suggestive of WD. There are no upper motor neuron signs (i.e., no corticospinal or corticobulbar involvement).

Dzieżyc-Jaworska et al. Clinical manifestations of Wilson disease in organs other than the liver and brain. Ann Transl Med. 2019;7(Suppl 2):S62. Available at:

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Objective: Review the diagnosis and treatment of botulinum; differentiate botulinum from other diseases.

Botulism is a rare, neurotoxin-mediated, life-threatening disease characterized by flaccid descending paralysis that begins with cranial nerve palsies and might progress to extremity weakness and respiratory failure. Botulinum neurotoxin, which inhibits acetylcholine release at the neuromuscular junction, is produced by the anaerobic, Gram-positive bacterium Clostridium botulinum (rarely by C. baratii and C. Exposure to the neurotoxin occurs through ingestion of toxin (foodborne botulism), bacterial colonization of a wound (wound botulism) or the intestines (infant botulism and adult intestinal colonization botulism), and high-concentration cosmetic or therapeutic injections of toxin (iatrogenic botulism). In addition, concerns have been raised about the possibility of a bioterrorism event involving toxin exposure through intentional contamination of food or drink or aerosolization. Neurologic symptoms are similar regardless of exposure route. Treatment involves supportive care, intubation, mechanical ventilation when necessary, and administration of botulinum antitoxin. Certain neurological diseases (e.g., myasthenia gravis and Guillain-Barré syndrome) have signs and symptoms that overlap with botulism.

Rao et al. Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021. MMWR Recomm Rep. 2021;70(2):1-30. Available at:

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Objective: Review the types and causes of pseudotumor cerebri (idiopathic intracranial hypertension; IIH).

The presence of papilledema; an unremarkable neurological examination except for cranial nerve disorders (especially paresis of the abducens, unilateral or bilateral); a brain MRT without structural lesions, signs of hydrocephalus or meningeal enhancement; physiological CSF composition; and opening pressure of ≥ 25 cm CSF in adults) are required for the diagnosis of IIH. A novelty in the current version of the diagnostic criteria is the possibility to diagnose IIH even in the absence of papilledema if unilateral or bilateral abducens paresis is present. If both (papilledema and abducens paresis) are absent, a definitive diagnosis is not possible; however, a probable diagnosis can still be made if the cranial MRT reveals an empty sella, a flattened posterior aspect of the optic globe, a distended peri-optic subarachnoid space (with or without a tortuous optic nerve), and transverse sinus stenosis/thrombosis. Nevertheless, leaving the diagnostic criteria aside, the clinical presentation is characterized primarily by headache, impaired vision (secondary optic atrophy in long-standing poorly controlled pressure), and a number of other symptoms (cranial nerve palsies, olfactory disturbances, and tinnitus/self-audible bruit). Pseudotumor cerebri can be primary (idiopathic) or secondary to clear-cut etiology (e.g., intracranial cerebral venous sinus thrombosis). Cavernous sinus thrombosis results in ptosis, proptosis, chemosis, and ophthalmoplegia.

Hoffmann J, May A. Update on Pseudotumor Cerebri (Idiopathic Intracranial Hypertension). Neurology International Open 2017;01(03): E224-E231. Available at:

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Objective: Review the management of pseudotumor cerebri syndrome (PTSS).

The goals of treatment in an individual with PTSS are twofold: preservation of vision and reduction of symptoms (headache). Multiple factors should be considered when selecting both the form of treatment and its relative urgency. The presence and degree of symptoms (i.e., headache, vision loss), the severity of vision loss, and any apparent progression are all crucial factors in deciding on the urgency of treatment. The first step in treating any patient is to identify and ameliorate conditions such as anemia, causative medications (tetracyclines, oral contraceptive pills, isotretinoin, danazol, cyclosporine, nitrofurantoin), obesity, obstructive sleep apnea, and venous sinus thrombosis. Factors consistent with poor visual prognoses (e.g., high-grade papilledema, macular edema, venous sinus thrombosis, and systemic hypertension) may support a more aggressive form of treatment. Immediate aggressive management is often advocated in cases of severe or rapidly progressive vision loss, and cases at higher risk of rapid progression (male sex, black race) regardless of disease severity. Therapeutic agents currently used in PTSS aim to reduce ICP through a reduction in CSF secretion. Acetazolamide’s side effects include paresthesia, dysgeusia, vomiting, and diarrhea as well as malaise, fatigue, and depression. Acetazolamide is the only therapy that has been evaluated and is regarded as the first-line therapy for PTSS.

Dave S, Subramanian S. Pseudotumor cerebri: An update on treatment options. Indian J Ophthalmol. 2014;62(10):996-8. Available at:

Hoffman et al. European Headache Federation guideline on idiopathic intracranial hypertension. J Headache Pain. 2018;19(1):93. Available at:

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Objective: Differentiate neurofibromatosis type 1 (NF1) from neurofibromatosis type 2 (NF2).

NF2 is responsible for 10% of neurofibromatosis cases (the remainder, 90%, is type 1). NF2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumor suppressor gene on chromosome 22q. It has a frequency of one in 25 000 live births and nearly 100% penetrance by 60 years of age. Half of the patients inherit a germline mutation from an affected parent and the remainder acquire a de novo mutation for NF2. Patients develop nervous system tumors (a multitude of intracranial/spinal schwannomas, meningiomas, ependymomas, astrocytomas, and neurofibromas; CNS involvement occurs in 100% of patients), peripheral neuropathy, ophthalmological lesions (cataracts, epiretinal membranes, and retinal hamartomas), and cutaneous lesions (skin tumors). Bilateral acoustic neuromas are present in almost all patients; meningiomas develop in 50% while non-vestibular Schwannomas are observed in 50% of cases. Spinal cord ependymomas are often multiple. The cutaneous and ocular lesions are less prominent than those of type 1; there are few mild café au lait spots. Lisch nodules (iris hamartomas; one of the pathognomonic features of NF1) are not present in NF2. Malignant change may occur in NF1 neurofibromas but is rare in NF2 schwannomas.

Asthagiri A. Neurofibromatosis type 2. Lancet. 2009;373(9679):1974-86. Available at:

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Objective: Review neurofibromin 1 mutations-associated disease.

Neurofibromin 1 is a tumor suppressor gene. The gene product (neurofibromin) appears to function as a negative regulator of the ras signal transduction pathway. Neurofibromin 1 has a high mutation rate and mutations in this gene can alter cellular growth control and neural development. Neurofibromin 1 mutations have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia, and Watson’s syndrome (an autosomal dominant condition characterized by iris Lisch nodules, axillary and inguinal freckling, pulmonic stenosis, relative macrocephaly, short stature, and neurofibromas).

Upadhyaya M, Cooper DN, eds. (2012). Neurofibromatosis type 1: molecular and cellular biology. Springer Berlin Heidelberg.

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Objective: Characteristic features of von Hippel-Lindau.

Von Hippel-Lindau syndrome (VHL) is a familial neoplastic condition caused by germline mutations of the tumor suppressor gene VHL located on the short arm of chromosome 3. While the majority of the affected individuals have a positive family history; up to 20% of cases arise from de novo mutations. VHL syndrome is characterized by the presence of benign and malignant tumors affecting the central nervous system, kidneys (benign renal cysts, clear cell cancer), adrenals, pancreas, and reproductive organs. Common manifestations include hemangioblastomas of the brain, spinal cord, and retina; pheochromocytoma and paraganglioma; renal cell carcinoma; pancreatic cysts and neuroendocrine tumors; and endolymphatic sac tumors. CNS hemangioblastoma is the most common presenting symptom/feature of VHL (in up to 80% of cases); on average, the age of presentation is 33 years. These hemangioblastomas are benign but are a major cause of morbidity and mortality due to the mass effect on nearby CNS structures. Hemangioblastomas are mainly found in the cerebellum. Renal manifestations of VHL include benign renal cysts and clear cell carcinoma; multiple bilateral renal cysts are found on screening in 50-70% of VHL patients. Renal cancer may affect up to 30% of VHL patients but they are rarely the first sign of VHL. Renal cysts are asymptomatic, and unlike autosomal dominant polycystic kidney disease, the incidence of chronic renal failure is low. Bilateral RCCs and renal cysts are present in the third or fourth decade of life in these patients. Up to 70% of VHL patients develop renal cancer by 60 years of age; RCC is the leading cause of mortality in this group of patients. Type 1 VHL disease has a very low risk of pheochromocytomas. Type 2 VHL is further categorized into type 2a (low risk of renal cancer), type 2b (high risk of renal cancer), and type 2c which only presents with pheochromocytomas.

Varshney et al. A Review of Von Hippel-Lindau Syndrome. J Kidney Cancer VHL. 2017; 4(3): 20-9. Available at:

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Objective: Review the clinical presentation and imaging findings of subdural hematomas (SDHs).

Chronic subdural hematoma (CSDH) is a common disease in neurosurgical practice, especially in elderly patients; motor vehicle accidents are the commonest cause in young individuals. The current understanding is that CSDH is mostly the result of direct or indirect head trauma; other factors such as alcoholism, liver cirrhosis, chronic renal failure, and hematologic disease are also well-known as causes of CSDH. History of trauma could be absent; patients may not recall trivial head trauma. Anticoagulants and antiplatelet agents have an important role in the pathogenesis of CSDH. In adults, they are unilateral in 85% of patients. Subdural hematomas can be acute (up to 3 days; hyperdense), subacute (3-21 days; isodense with the brain), or chronic (>21 days; hypodense, mimicking subdural hygromas).

Sim YW. Recent Changes in Risk Factors of Chronic Subdural Hematoma. J Korean Neurosurg Soc. 2012;52(3):234-9. Available at:

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Objective: Review the etiological factors of syringomyelia.

Syringomyelia is the development of a fluid-filled cavity or syrinx within the spinal cord. About 50% of all cases are due to CSF flow obstruction (without ventricular communication); the commonest etiology is Arnold-Chiari malformation; basilar impression or invagination, basal arachnoiditis (cranial irradiation, after subarachnoid hemorrhage, post-infectious), large masses (arachnoid cysts, rheumatoid pannus, tumors), and meningeal carcinomatosis are the other causes of this type. About 10% of cases of syringomyelia are due to spinal cord insult (trauma, hemorrhage, irradiation, or infection). Intramedullary tumors (ependymoma, hemangioblastoma) can result in syringomyelia through the secretion of neoplastic cells or bleeding. Dissociated sensory loss means selective loss of pain and temperature sensation with preservation of crude touch and proprioception.

Al-Shatoury HAH, Galhom AA. Syringomyelia. Medscape. Updated November 16, 2021. Available at:

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Objective: Review the causes of spinal cord compression.

Extradural extramedullary (vertebral) etiologies are responsible for 80% of all cases of spinal cord compression. The list includes vertebral fractures, disc prolapse, metastasis (breast, prostate, bronchus), myeloma, and tuberculosis. Extradural intramedullary causes of compression are observed in 15% of cases, and these are tumors (meningioma, neurofibroma, leukemia, lymphoma, metastasis) and epidural abscesses. Intradural intramedullary are uncommon causes (5%); the etiology is a tumor (ependymoma, metastasis). Note that secondary tumors (metastases) can result in all 3 types.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

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Objective: Review the causes and clinical presentation of anterior spinal artery (ASA) occlusion.

The ASA is the main arterial supply to the spinal cord. Additional supply is through paired posterior spinal arteries. The anterior spinal artery is located in the midline. In the cervical and upper thoracic cord, contributions to the ASA are from the vertebral, cervical, and superior intercostal arteries. A small component of supply to the mid-thoracic cord arises from the mid-thoracic intercostal arteries. The predominant contribution to the anterior spinal artery in the lower thoracic and lumbar regions (otherwise known as the artery of Adamkiewicz) most often arises from thoracic intercostal or lumbar arteries, usually on the left. ASA occlusion is an uncommon event that may cause ischemia of the ventral of the spinal cord (i.e., damaging the spinothalamic and corticospinal tracts), with signs and symptoms exhibited below the level of the lesion. These include central motor impairment, dissociated sensory loss, and bladder dysfunction. The most frequent causes of ASA syndrome are aortic dissection or traumatic rupture, complications of aortic surgery, thrombosis or embolism, hematomyelia, vasculitis, vertebrocervical arthrosis, and coagulopathy; however, some cases remain cryptogenic. The midthoracic region (T4 to T8) is the most vulnerable one to ischemic damage, owing to its relative hypovascularity.

Manconi et al. Anterior spinal artery syndrome complicated by the ondine curse. Arch Neurol. 2003;60(12):1787-90. Available at:

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Objective: Review the etiology and clinical presentation of carotid artery dissection.

Cervicocerebral arterial dissections (CAD) are an important cause of strokes in younger patients accounting for nearly 20% of strokes in patients under the age of 45 years. Extracranial internal carotid artery dissections comprise 70-80% and extracranial vertebral dissections account for about 15% of all CAD. The pathophysiology of CAD is incompletely understood, though trauma, respiratory infections, and underlying arteriopathy are considered important. The typical picture of local pain, headache, and ipsilateral Horner’s syndrome followed several hours by cerebral or retinal ischemia is The presentation can vary from mild pain symptoms to life-threatening complications; therefore, it poses a diagnostic challenge. Genetic diseases associated with dissection are Ehlers-Danlos syndrome, Marfan’s syndrome, fibromuscular dysplasia, cystic medial necrosis, alpha-1 antitrypsin deficiency, and hyperhomocysteinemia. Doppler ultrasound, MRI/MRA, and CT angiography are useful non-invasive diagnostic tests. The treatment of extracranial CAD is mainly medical using anticoagulants or antiplatelet agents. The prognosis of extracranial CAD is generally much better than that of intracranial CAD. Recurrences are rare in CAD. The jugular foramen syndrome (Vernet’s syndrome) refers to paralysis of the and cranial nerves traversing the jugular foramen.

Thanvi et al. Carotid and vertebral artery dissection syndromes. Postgrad Med J. 2005;81(956):383-8. Available at:

148) b

Objective: Characteristics of cobalamin.

Cobalamin is a water-soluble vitamin. Although it can be stored in large amounts, vitamin cannot be synthesized by the human body and requires supplementation from dietary sources. Therefore, vitamin deficiency can develop if dietary intake is low and body stores are depleted. Cobalamin is mainly present in food derived from animals (meat, fish, dairy products, eggs, and fortified cereals). The richest sources of vitamin are clams and animal liver. Plant-based food does not contain cobalamin. Therefore, strict vegetarians and vegans are at risk of developing vitamin deficiency. Breastfed infants whose mothers have deficiency can also develop a deficiency unless they receive supplementation. Vitamin plays a vital role in DNA synthesis and odd-chain fatty acid metabolism, which are required to maintain the integrity of neuronal myelin. It acts as a cofactor for homocysteine methyltransferase and methylmalonyl-CoA mutase. The latter enzyme is responsible for converting methylmalonyl-CoA to succinyl-CoA, which is required for myelin synthesis. Interruption of this step leads to the accumulation of methylmalonyl-CoA and propionyl-CoA. This, in turn, disrupts the process of normal myelin synthesis and leads to the accumulation of abnormal fatty acids. The commonest cause of deficiency in adults in developed countries is intrinsic factor deficiency. Intravenous hydroxocobalamin (vitamin is generally the first-line treatment for cyanide poisoning.

Qudsiya Z, De Jesus O. Subacute Combined Degeneration of the Spinal Cord. [Updated 2021 Aug 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:

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Objective: Review the clinical features and diagnosis of subacute combined degeneration of the cord (SCDC).

ACDC is a potentially reversible myelopathy typically associated with vitamin deficiency. There is predominant involvement of spinal cord dorsal and lateral tracts. The diagnosis of vitamin deficiency is made by measuring vitamin levels in the serum. Serum vitamin levels do not always represent the correct cellular status. Hematologic changes are absent in one-quarter of patients with neurologic symptoms, which highlights the importance of imaging analysis of patients with normal vitamin levels but clear neurologic symptoms and high clinical suspicion. When clinical judgment suggests vitamin deficiency but the vitamin level is low-normal or hematologic indexes are normal, other tests can be done. They include measuring the following:

•Serum methylmalonic acid (MMA) levels: An elevated MMA level supports vitamin deficiency; serum elevations are also seen in renal failure. MMA levels can also be used to monitor the response to treatment. MMA levels remain normal in folate deficiency.

•Homocysteine levels: Levels may be elevated with either vitamin or folate deficiency.

•Less commonly, holotranscobalamin II (transcobalamin complex) content: When holotranscobalamin II is very low, vitamin is deficient.

Johnson LE. Vitamin B12 Deficiency. MSD Manual Professional Version, 2022. Available at:,-dependency,-and-toxicity/vitamin-b12-deficiency

150) d

Objective: Review the causes of palpable peripheral nerves.

The best sites to palpate an enlarged thickened peripheral nerve are the median nerve at the wrist, the ulnar nerve at the elbow, and the common peroneal nerve at the fibular neck. Charcot-Marie-Tooth type 1 (and type 4) is a demyelinating illness with recurrent remyelination resulting in the onion-bulb formation and palpable nerves; type 2 is an axonal one and does not enlarge the peripheral nerves. The other causes of palpable nerves are leprosy, sarcoidosis, and chronic inflammatory demyelinating polyradiculopathy.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

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Objective: Review the clinical features and types of Charcot-Marie-Tooth disease (CMT).

CMT is the most common inherited neurological disorder. Most patients with CMT display an autosomal dominant mode of inheritance, although many cases exhibit an X-linked or autosomal recessive inheritance. Apparent sporadic cases occur, as dominantly inherited disorders may begin as a new mutation in a given patient. While the majority of CMT neuropathies are demyelinating, up to one-third appear to be primary axonal disorders. Most patients have a “classical” CMT phenotype characterized by onset in the first two decades of life, distal weakness, sensory loss, foot deformities hammertoes), and absent ankle reflexes. CMT type 1A (CMT1A) is the most common form, accounting for about 50% of all CMT cases and 70-80% of CMT type 1. CMT1A has a de novo mutation rate of 10%, and patients, therefore, may report the absence of relevant family history. remains the most common genetic etiology accounting for the majority of CMT1 cases and close to 40% of all CMT cases. The three next most common genetic forms of CMT are those caused by mutations accounting for the majority of the additional yield of current genetic testing, even though there are more than 50 other known genetic forms of CMT.

Saporta et al. Charcot Marie Tooth (CMT) Subtypes and Genetic Testing Strategies. Ann Neurol. 2011;69(1):22-33. Available at:

Hoyle et al. The genetics of Charcot–Marie–Tooth disease: current trends and future implications for diagnosis and management. Appl Clin Genet. 2015;8:235-43. Available at:

152) b

Objective: Review the types of peripheral neuropathies (PN).

PNs can be acute, subacute, or chronic; axonal, demyelinating, or both (including secondary axonopathy due to severe demyelination); sensory, motor, or sensorimotor; with or without dysautonomia; with or without cranial nerves involvement; and predominantly affecting the upper limbs or the lower limbs. For example, lead poisoning is a form of subacute axonal peripheral neuropathy that predominantly affects the upper limbs (wrist and finger extensors). Additional involvement of the autonomic nervous system (dysautonomia) is seen in alcoholism, amyloidosis, diabetes, and HIV infection. Diphtheritic neuropathy is an acute demyelinating polyneuropathy developing three to five weeks after severe diphtheria infection; it is a biphasic illness with initial bulbar and other cranial nerve involvement followed later by motor weakness in extremities and autonomic dysfunction (Guillain-Barre syndrome is the most important differential diagnosis). Sjögren’s syndrome is one of the causes of pure sensory peripheral polyneuropathy (uncommonly it may cause a sensorimotor type and very rarely an acute demyelinating form). Axonal-type polyneuropathy usually indicates toxic, nutritional, organ failure, and vasculitis etiologies. Drug-induced axonal polyneuropathy can result from vincristine, hydralazine, metronidazole, isoniazid, colchicine, didanosine, dapsone, and amitriptyline. On the other hand, a demyelinating type of polyneuropathy may result from gold, suramin (used in the treatment of African sleeping sickness and river blindness), and amiodarone. Uremia results in predominately sensory polyneuropathy.

Watson J, Duke PJ. Peripheral Neuropathy: A Practical Approach to Diagnosis and Symptom Management. Mayo Clin Proc. 2015;90(7):940-51. Available at:

153) c

Objective: Differential diagnosis of rapidly progressive ascending areflexic weakness; Guillain-Barré syndrome (GBS).

This patient exhibits rapidly progressive quadriparesis with normal sensation and sphincter function; Guillain-Barré syndrome is compatible with the patient’s history and findings. Dysautonomias are seen in up to 65% of cases and may cause sudden cardiorespiratory arrest as well as fluctuating blood pressure and pulse rate. Some degree of asymmetry in neurological signs may be seen in up to 9% of cases at the time of diagnosis; however, marked or persistent asymmetry should cast a doubt on this syndrome and should prompt a search for an alternative diagnosis. The CSF proteins level and the nerve conduction study might be entirely normal in the 1st week of the illness; hence, normal nerve conduction studies early in the course don’t refute the diagnosis; follow-up studies are indicated. Some patients (around 6%) may experience relapses which might be associated with certain HLA haplotypes. Myasthenic crisis is rarely the presentation feature of myasthenia gravis and rarely presents as an ascending weakness without ocular abnormalities. The absence of sensory level and sphincter abnormalities would argue against acute transverse myelitis. Although the patient has back pain, unremarkable sensory symptoms, and flexor plantar responses as well as intact bladder and bowel point against a compressive spinal cord pathology.

Greenberg D.A., & Aminoff M.J., & Simon R.P.(Eds.), (2021). Clinical Neurology, 11e. McGraw Hill.

154) c

Objective: Review the investigations of the Guillain-Barré syndrome (GBS).

GBS is an acute inflammatory demyelinating polyradiculopathy. There is no muscle inflammation or damage. The CSF protein may be normal in the first week, but it will rise in the week (GBS is one of the causes of very high CSF protein). The pleocytosis of GBS is mild and is mononuclear/lymphocytic (no single neutrophil should be present), and usually does not exceed 10 cells/μL (in HIV-associated GBS, it may reach higher levels). Therefore, there is CSF albuminocytological dissociation (ACD). Nerve conduction studies would reveal wide-spread demyelination features (prolonged F-wave, prolonged distal latencies, conduction block, and dispersion of compound muscle action potentials). Campylobacter serology may be positive in cases. The differential diagnosis of ACD (raised total CSF protein with minimal pleocytosis) is long and includes post-intrathecal chemotherapy, following subarachnoid hemorrhage, intra-axial and extra-axial tumors, inflammatory and non-inflammatory polyneuropathy, infectious and non-infections meningitis or encephalitis, inflammatory CNS white matter diseases, hydrocephalus (before or after shunting), and optic neuritis.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

155) a

Objective: Identify the poor prognostic signs of Guillain-Barré syndrome (GBS).

In general, about 80% of patients will be able to walk independently after 6 months; however, some residual signs may be present (such as absent ankle jerks or mild foot drop). Around 60% of the patients attain a full motor recovery. Approximately, 1-10% will be left with severe neurological disability. About 2-12% of the patients die. Some patients, especially those who need assisted ventilation, demonstrate a prolonged recovery over several months. The presence of a preceding Campylobacter diarrhea (usually associated with axonal type), absence of a preceding upper respiratory tract infection, need for assisted ventilation or ICU admission, development of dysautonomia, old age (above 57 years), and mean compound muscle action potential amplitudes of <20% of the lower limit, and axonal degeneration on electrophysiological studies are indicators of poor functional outcome. GBS patients (especially those on assisted ventilation) die of pulmonary thromboembolism, sudden cardiorespiratory arrest (because of dysautonomia), respiratory failure, aspiration pneumonia, and sepsis (e.g., bedsores, severe urinary tract infections).

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

156) e

Objective: Review the clinical features of myasthenia gravis (MG).

MG is an autoimmune antibody-mediated disorder of neuromuscular synaptic transmission. The clinical hallmark of MG consists of fluctuating and painless fatigability and weakness affecting ocular, bulbar, and (proximal) limb skeletal muscle groups. MG may either occur as an autoimmune disease with distinct immunogenetic characteristics or as a paraneoplastic syndrome associated with tumors of the thymus. Impairment of central thymic and peripheral self-tolerance mechanisms in both cases is thought to favor an autoimmune CD4+T cell-mediated B cell activation and synthesis of pathogenic high-affinity autoantibodies of either the IgG1 and 3 or IgG4 subclass. These autoantibodies bind to the nicotinic acetylcholine receptor (AChR) itself, or muscle-specific tyrosine kinase (MuSK), lipoprotein receptor-related protein 4 (LRP4), and agrin involved in the clustering of AChRs within the postsynaptic membrane and structural maintenance of the neuromuscular synapse. This results in a disturbance of neuromuscular transmission and thus the clinical manifestation of the disease. Ptosis in MG could be unilateral or bilateral (but usually asymmetric and partial); there should be no pupillary abnormalities. This young woman has unilateral partial ptosis, bulbar weakness, and “generalized” weakness (that is fatigable and painless); myasthenia gravis fits the diagnosis. The ptosis in myotonia dystrophica is bilateral and the weakness is distal.

Melzer et al. Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society. J Neurol. 2016;263:1473-94. Available at:

157) b

Objective: Review the clinical features of Lambert-Eaton myasthenic syndrome (LEMS); differentiate LEMS from myasthenia gravis.

Lambert-Eaton myasthenic syndrome (LEMS) is an uncommon disorder of neuromuscular transmission with distinctive pathophysiological, clinical, electrophysiological, and laboratory features. There are two forms of LEMS. The paraneoplastic (P-LEMS) form is associated with a malignant tumor that is most frequently a small cell lung carcinoma (SCLC), and the autoimmune (A-LEMS) form is often related to other dysimmune diseases. Approximately 90% of LEMS patients develop antibodies against presynaptic membrane P/Q-type voltage-gated calcium channels (VGCC). These antibodies are directly implicated in the pathophysiology of the disorder, provoke reduced acetylcholine (ACh) at the nerve terminal, and consequently lead to muscle weakness. LEMS is clinically characterized by proximal muscle weakness, autonomic dysfunction, and areflexia. The detection of P/Q-type VGCC antibodies is supportive when there is clinical suspicion but should be carefully interpreted in the absence of characteristic clinical or electrodiagnostic features. Typical electrodiagnostic findings (i.e., reduced compound motor action potentials (CMAPs), significant decrements in the responses to low-frequency stimulation, and incremental responses after brief exercise or high-frequency stimulation) reflect the existence of a presynaptic transmission defect and are key confirmatory criteria.The treatment of LEMS involves the removal or treatment of underlying cancer in patients with P-LEMS and symptomatic treatment in clinically affected patients independent of the LEMS form. In patients with symptoms that interfere with daily activities, 3,4-diaminopyridine (3,4-DAP) is usually recommended as initial therapy.3,4-DAP is a potassium channel blocker that prolongs presynaptic nerve terminal depolarization and consequently increases calcium entry through VGCCs, which ultimately leads to increased acetylcholine release.

Ivanovski T, Miralles F. Lambert-Eaton Myasthenic syndrome: early diagnosis is key. Degener Neurol Neuromuscul Dis. 2019;9:27-37. Available at:

158) c

Objective: Review the role of autoantibodies in the pathophysiology and diagnosis of myasthenia gravis; anti-MuSK antibodies.

Muscle-specific tyrosine kinase (MuSK) is a neuromuscular junction (NMJ) protein that is specifically expressed at the postsynaptic membrane, where it co-localizes with acetylcholine receptors (AChRs), and plays a critical role in the maintenance of the normal functional integrity of the NMJ by mediating the clustering of AChRs. Inhibition of MuSK synthesis results in AChR dispersion and end-plate disruption. MuSK and the NMJ protein and low-density lipoprotein receptor-related protein 4 (LRP4) together function as a receptor for neural agrin. The anti-MuSK antibodies are predominantly of the IgG4 subclass and thus do not activate complement. Anti-MuSK antibodies are detected in up to 50% of patients with generalized MG who lack anti-AChR antibodies. The identification of anti-MuSK antibodies effectively confirms the diagnosis of myasthenia gravis (MG). Anti-MuSK antibody serum levels have been shown to correlate with clinical symptoms and response to immunotherapy. Autoantibodies against AChRs can be detected in approximately 80-85% of patients with generalized MG and 50-75% of patients with ocular MG; therefore, the commonest detected autoantibody is the anti-AChR one. While the evidence for the pathogenicity of anti-AChR antibodies in MG is quite strong, non-AChR autoantibodies that react with striated muscle antigens may also be found in up to 95% of MG patients with thymoma and 50% of late-onset MG patients without thymoma. Striated muscle antibodies recognize muscle intracellular proteins (titin, myosin, actin, and ryanodine receptors) and are therefore not directly accessible to autoantibodies.

Meriggioli M, Sanders B. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol. 2012;8(5):427-38. Available at:

159) d

Objective: Review the role of thymectomy in myasthenia gravis (MG) and its contraindications.

Medical treatment of MG (anti-acetylcholinesterase inhibitors and immune suppressants) is a bridge to thymectomy. All MG patients should be evaluated for thymectomy. About 85% of patients demonstrate a remarkable symptomatic improvement after thymectomy (the effect appears after several months and may take up to 2 years); i.e., fewer medications and lesser doses are required to control symptoms. Approximately 35% of cases show drug-free remission with no medications needed. However, not all patients are candidates for this form of treatment; age >55 (usually there is thymic atrophy) or <15 years (prepubertal), neonatal myasthenia, congenital myasthenic syndromes, burnt-out myasthenia (duration >7 years), MG (doesn’t respond to thymectomy), and pure ocular myasthenia (MG limited to the ocular muscles for >2 years). The presence of thymoma calls for thymectomy regardless of the type (benign or malignant).

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

160) d

Objective: Differentiate between myasthenic crisis and cholinergic crisis in patients with generalized myasthenia gravis (MG).

Myasthenic crisis is a common complication of MG and results from undertreatment with anti-acetylcholinesterase inhibitors, usually in the context of a precipitating factor. The most common precipitant is infection; bacterial pneumonia followed by bacterial or viral upper respiratory infections are the usual precipitants. Other precipitants include aspiration pneumonitis, surgery, pregnancy, perimenstrual state, certain medications, and tapering of immune-modulating medications. Other antecedent factors include exposure to temperature extremes, pain, sleep deprivation, and physical or emotional stress. Approximately one-third to one-half of patients may have no obvious cause for their myasthenic crisis. There is tachycardia, increased blood pressure, urinary incontinence, and poor swallowing and cough reflexes. The pupils are either normal in size or dilated. There is a dramatic yet transient improvement upon receiving intravenous edrophonium. Intravenous immunoglobulin or plasmapheresis can treat myasthenic crises. Acetylcholinesterase inhibitors should be withheld (they are not effective). The cholinergic crisis (rare) results from overmedication of acetylcholinesterase inhibitors). Patients demonstrate prominent weakness in addition to profound parasympathetic system activation (miosis, blurring of vision, lacrimation, increased bronchial secretion, diarrhea, and abdominal cramps). Withholding acetylcholinesterase inhibitors and using intravenous atropine is usually effective (usually in repeated doses).

Wendell L, Levine J. Myasthenic Crisis. Neurohospitalist. 2011;1(1):16-22. Available at:

161) e

Objective: Identify the medications which can exacerbate the myasthenic weakness or result in drug-induced myasthenia.

Several medications precipitate autoimmunity and, therefore, symptomatic myasthenia gravis (MG); many more medications adversely affect the neuromuscular junction transmission and have been implicated in the worsening of MG symptomatology, including precipitation of MG crisis, or unmasking of a previously undiagnosed MG. Some medications act through both mechanisms, and in some, the underlying pathogenesis is not known.Regarding antibiotics, the highest risk is observed with macrolides, aminoglycosides, and fluoroquinolones; avoid them in MG patients if there is another alternative (otherwise, closely monitor while treating). Telithromycin is the first ketolide antibiotic; its pyridine moiety acts as an antagonist on the cholinergic receptors located in the neuromuscular junction). Penicillins, in general, pose little risk; exacerbation of myasthenic weakness is rare. High-dose prednisone was most commonly implicated as aggravating myasthenia gravis, and D-penicillamine was most commonly associated with the drug-induced myasthenic syndrome. The greatest frequency of drug-induced neuromuscular blockade was seen with aminoglycoside-induced postoperative respiratory depression.

Sheikh et al. Drugs That Induce or Cause Deterioration of Myasthenia Gravis: An Update. J Clin Med. 2021;10(7):1537. Available at:

162) e

Objective: Differentiate dystrophic myotonia type 1 (DM1) from dystrophic myotonia type 2 (DM2).

DM1 is the most common muscular dystrophy worldwide. It is characterized by the involvement of many different organs. The typical clinical features are myotonia, distal muscle weakness and wasting, Christmas tree cataracts, cognitive dysfunction, behavioral changes, fatigue, frontal balding, and various endocrine dysfunctions. The disease is caused by a dominantly inherited CTG repeat expansion on a non-coding region of the dystrophia myotonica protein kinase gene on chromosome 19; congenital forms and anticipations are present. Type 1 muscle fibers are predominantly affected. DM2 results from CCTG trinucleotide repeat expansion of the ZNF9 gene on chromosome 3; anticipation is doubtful. It is generally milder than DM1 and preferentially affects muscles closer to or on the torso (proximal), including the neck flexors, hip flexors, and hip extensors. Heart issues, while still potentially fatal, are less common and severe in DM2 than in DM1. The onset of symptoms is in early to late adulthood. Severe congenital onset, which can occur in DM1, has not been observed in DM2. Hyperhidrosis is rare in DM1 while it’s present in DM2. Muscle biopsy shows atrophy and nuclear internalization of type 2 fibers.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

163) b

Objective: Review the clinical manifestations of dystrophic myotonia (DM).

Type 1 DM is much more common than type 2. The clinical features of DM type 1 are diverse and involve many organ systems. Weakness and wasting of the face, neck, and distal muscles, in addition to cardiac dysrhythmia and heart block (cardiac causes are the common cause of death after respiratory failure in those patients), frontal balding, hypogonadism (testicular atrophy in males and habitual abortion and menstrual regulates in females), insulin insensitivity and diabetes mellitus, and hypersomnia are the core features. The gastrointestinal tract can be involved from the pharynx down to the anus. In the upper digestive tract, dysphagia, heartburn, regurgitation, and dyspepsia are the most common complaints, while in the lower tract, abdominal pain, bloating, and changes in bowel habits are often reported. Hypogammaglobulinemia can result in recurrent sinopulmonary infections and bronchiectasis. An increased level of gamma-glutamyl transpeptidase in these patients may be responsible for low levels of lenticular glutathione and thus leading to cataract formation; a distinctive cataract presents in 100% of patients, which can aid in the diagnosis of this complex disease.It seems that Christmas cataracts may be the first manifestation of DM1 in a higher percentage of patients than posterior subcapsular cataracts in DM2 patients.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

164) e

Objective: Differentiate between proximal and distal muscle weakness.

Limb weakness can be proximal, distal, or proximal and distal; pyramidal (weakness of antigravity muscles); display a radicular, myotomal, or peripheral nerve pattern; unilateral or bilateral (symmetrical or asymmetrical); and painful and non-painful (i.e., tender and non-tender). The list of conditions causing proximal weakness is quite long. However, distal weakness is caused by a shorter list of conditions and includes myotonic dystrophy type 1, facioscapulohumeral dystrophy, sporadic inclusion body myositis, telethoninopathy, branching and debranching glycogenoses, caveolinopathy, nemaline myopathy, and myeloma-induced amyloid myopathy. Facioscapulohumeral muscular dystrophy is the second most prevalent dystrophy after Duchenne muscular dystrophy. It has a distinct initial pattern of muscle involvement, often affecting the facial muscles (with bilateral ptosis), shoulder girdles, and upper arms, followed by weakness of the trunk, distal lower extremities (foot drop), and more proximal muscles later in the disease course.Patients can show marked side-to-side asymmetry and debilitating truncal weakness.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

165) d

Objective: Review the characteristic features of mitochondrial myopathies; Kearns-Sayre syndrome (KSS).

Mitochondrial myopathies are progressive muscle conditions caused primarily by the impairment of oxidative phosphorylation in the mitochondria. This causes a deficit in energy production in the form of adenosine triphosphate (ATP), particularly in skeletal muscles. Mitochondrial function is under the control of two genomes; the mitochondrial genome (mtDNA) and the nuclear genome (nDNA); as such, mitochondrial myopathy can be caused by pathogenic genetic variants in either of these genomes. This dual genetic control also means that mitochondrial disease is transmitted with the following inheritance patterns: maternal (mtDNA), X-linked, autosomal recessive, or autosomal dominant. In addition, some relatively common mitochondrial myopathies occur de Proximal myopathy (and weakness) is the commonest form of mitochondrial myopathies; it is usually variable but commonly fatigable. Exercise-induced muscle pain is common; however, rhabdomyolysis is rare. Fatigue is the commonest patient-reported complaint. Staining of skeletal muscle cryosections with the modified Gomori Trichrome highlights the presence of ragged-red fibers. KSS is defined by the following triad: onset before the age of 20 years, chronic progressive ophthalmoplegia, and pigmentary retinopathy (diffuse and involves the macula). Individuals should demonstrate an additional of at least 1 of the following conditions: complete heart block, cerebrospinal fluid protein of >100 mg/dL, cerebellar ataxia, short stature, deafness, dementia, and endocrine abnormalities.

Ahmed et al. Diagnosis and Treatment of Mitochondrial Myopathies. Neurotherapeutics. 2018;15(4):943-53. Available at:

166) c

Objective: Review the neurological diseases caused by various channelopathies; sodium channelopathy.

Membrane excitability, which is critical for the function of skeletal muscle, is regulated by ion channels. It is therefore not surprising that voltage-gated ion channels are involved in the pathogenesis of diseases of these tissues. Over 50 channelopathies in human beings have been described; 12 of which affect skeletal muscle. Of these, five are caused by mutations in its voltage-gated sodium channel potassium-aggravated myotonia gene), paramyotonia congenita gene, autosomal dominant), hyperkalemic periodic paralysis gene, autosomal dominant), hypokalemic periodic paralysis gene, autosomal dominant), and a form of a congenital myasthenic syndrome (CMS). Chloride channelopathies result from mutations in the CLCN1 gene, causing myotonia congentia (Thomsen’s disease and Becker’s disease; not to be confused with Becker’s muscular dystrophy). Mutations in the calcium channel’s CACNA1S gene are responsible for some cases of hypokalemic period paralysis and malignant hyperthermia. Andersen-Tawil syndrome is a potassium channelopathy and results from mutations in the KCNJ2 gene (the clinical picture is similar to hypokalemic periodic paralysis; associated with cardiac and non-myopathic skeletal and facial features). Mutations in the ryanodine receptors gene cause malignant hyperthermia as well as central core and multicore diseases.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

167) c

Objective: Review the treatment of familial hypokalemic periodic paralysis (HPP).

HPP is an autosomal dominant condition that causes episodes of extreme muscle weakness typically beginning in childhood or adolescence. Most often, these episodes involve a temporary inability to move muscles in the arms and legs. Attacks cause severe weakness or paralysis that usually lasts from hours to days. Some people may have episodes almost every day, while others experience them weekly, monthly, or only rarely. Attacks can occur without warning or can be triggered by certain factors (e.g., rest after exercise, a viral illness, or certain medications). Often, a large, carbohydrate-rich meal or vigorous exercise in the evening can trigger an attack upon waking the following morning. The treatment focuses on preventing further attacks and relieving acute symptoms. Avoiding carbohydrate-rich meals as well as strenuous exercise and other identified triggers, and taking acetazolamide (or another carbonic anhydrase inhibitor) may help prevent attacks of weakness. Acute attacks can be helped by drinking potassium salts. Rapidly absorbed boluses of liquid potassium are generally needed to abort an attack, but some patients also find positive maintenance results with time-released potassium tablets. Intravenous potassium is seldom justified unless the patient is unable to swallow. A subset of patients with hypokalemic periodic paralysis has thyrotoxicosis (thyrotoxic period paralysis); treatment of the thyroid disease is essential.

Hypokalemic periodic paralysis. U.S. National Library of Medicine. Accessed February 10, 2022. Available at:

168) b

Objective: Review the sites of predilection in hypertensive intracerebral hemorrhage (ICH).

Long-standing arterial hypertension is responsible for about 50% of all cases of primary ICH. The necrotizing effect of long-standing hypertension on the wall of small penetrating blood vessels (<300 μm in diameter) leads to the formation of Charcot-Bouchard micro-aneurysms; rupture of the latter leads to intra-parenchymal hemorrhage. ICH in the putamen (basal ganglia) is the commonest type/location, followed by (in decreasing order) the thalamus, lobar, cerebellum, and pons.

Amin OSM, Zangana H. Recurrent hypertensive intracerebral hemorrhage: a case series from a single institution in Iraq. Gaziantep J. 2012;18(3):169-72. Available at:

169) d

Objective: Review the classical clinical manifestations of hypertensive intracerebral hemorrhage (ICH).

Approximately 20% of hypertensive hemorrhages develop in the posterior fossa; the rest are supratentorial in location. In the cerebellum, the small penetrating branches of superior cerebellar arteries (and posterior inferior cerebellar arteries to a lesser extent) on either side are the usual target for micro-aneurysmal formation. Therefore, most hemorrhages appear in the region of the dentate nuclei. These cerebellar hemorrhages account for approximately 5-15% of all primary ICHs; the cerebellum is the fourth most common site for spontaneous ICHs, trailing thalamic, lobar, and putaminal hemorrhages. The combination of sudden severe headache, ataxia, and vomiting should prompt the physician to think of cerebellar hemorrhage. Pontine hemorrhage results in sudden quadriparesis, coma/obtundation, and pinpoint pupils.

Amin et al. Recurrent, sequential, bilateral deep cerebellar hemorrhages: a case report. J Med Case Reports. 2011;5:360. Available at:

170) e

Objective: Review Berry (saccular) aneurysms and their locations.

Acute non-traumatic subarachnoid hemorrhage comprises around 1-7% of all strokes. Women are affected more than men after the sixth decade. Individuals between the ages of 40-60 years (with a mean age of 55 years) are the usual targets for aneurysmal rupture; however elderly and children are not exempted. Caucasians appear to have a lower risk of this intracranial catastrophe than African Americans. The rupture of a Berry aneurysm is responsible for about 80% of all cases of acute spontaneous non-traumatic subarachnoid hemorrhage. About 90% are located in the anterior circulation; the rest are in the vertebrobasilar system. Berry aneurysms constitute about 97% of all intracranial aneurysms. About 35% are found at the anterior communicating artery, 35% at the posterior communicating artery, 20% at the middle cerebral artery, and 5% at the basilar artery. They are multiple in 20% of patients. Depending on the location and size, these aneurysms can result in acute subarachnoid hemorrhage, intraparenchymal hemorrhage (via the so-called jet hemorrhage), subdural hemorrhage, and/or intraventricular hemorrhage. The rupture typically occurs at the tip of the outpouching.

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

171) e

Objective: Identify the risk factors that increase the risk of Berry’s aneurysmal rupture.

Up to 6% of the general population harbor one (or more) intracranial aneurysm. However, most aneurysms don’t rupture. Certain risk factors increase the risk of rupture of these aneurysms and hence the development of acute subarachnoid hemorrhage and these are cigarette smoking, systemic hypertension, estrogen deficiency, family history of subarachnoid hemorrhage, and sympathomimetic drugs (phenylephrine and cocaine). The use of aspirin (or other antiplatelets) does not appear to increase this risk. Withdrawal of long-term statin therapy has been found to increase the risk of aneurysmal rupture. Sentinel bleeds precede complete rupture of an aneurysm and subarachnoid hemorrhage in 30-50% of patients. The sentinel bleed does not result in meningeal irritation or raise the intracranial pressure, although the resulting headache may be severe, and it usually precedes the full-blown complete aneurysmal rupture by 6-20 days. About 30% of ruptures occur during sleep. Aneurysms less than 3 mm are tiny aneurysms while those larger than 25 mm are called giant aneurysms. Large aneurysms are more likely to rupture. Around 97% of patients develop a sudden severe headache. The pain is usually pancephalic, but one-third of patients report a strictly lateralized headache on the side of the aneurysm (i.e., migraine-like). After several hours, the effect of the red blood cells in the subarachnoid space causes chemical (aseptic) meningitis and neck stiffness to appear. Likewise, lower back pain often develops. Around 25% of patients who visit the Accident and Emergency with this sudden severe headache (so-called, “the worst headache of my life”) have an acute subarachnoid hemorrhage. Therefore, this “type” of headache does not always mean acute subarachnoid hemorrhage. In addition, in approximately 12% of patients, headache is the only complaint (i.e., without a lapse of consciousness, vomiting, or seizures). Therefore, a diagnosis other than acute subarachnoid hemorrhage often comes to mind.

Amin OSM. Acute subarachnoid hemorrhage diagnosis and Management. BMJ Learning. Available at:

172) c

Objective: Identify the early complications of acute subarachnoid hemorrhage (SAH).

Several complications may develop in patients who have had a subarachnoid hemorrhage. The early complications include re-bleeding from the aneurysm, cerebral vasospasm, acute and subacute hydrocephalus, seizures, cardiac abnormalities (changes on the electrocardiogram, dysrhythmia, and left ventricular dysfunction), and hyponatremia. Late complications include another bleed (around 50% of patients rebleed within six months of the presentation; the risk falls to 3% per year thereafter) and normal pressure hydrocephalus. Cerebral vasospasm peaks three days to two weeks after the initial hemorrhage. This vasospasm results in cerebral ischemia and infarction. The resulting symptoms and signs and their severity depend on the artery (or arteries) affected and the state of collateral blood vessels. The clinical hallmark is a decline in neurological functioning, including new or worsening focal deficits. Serial transcranial Doppler ultrasonography is a useful way to screen for it. In contrast to early rebleeding, complete obliteration of an aneurysm, either by endovascular or surgical means, does not reduce the risk of future vasospasm.

Amin OSM. Acute subarachnoid hemorrhage diagnosis and Management. BMJ Learning. Available at:

173) b

Objective: Review the role of conventional angiography in the management of acute subarachnoid hemorrhage (SAH).

The timing of cerebral angiography, with the intention of endovascular treatment or preparing patients for surgical clipping of the aneurysm, should be done as soon as possible but at the latest within 48-72 hours of the initial event. This would tackle the cause of the hemorrhage and allow for the detection and management of any complications. Aneurysms may be multiple in 20% of patients and may arise from the anterior and posterior circulations (and may be associated with other vascular anomalies); therefore, four-vessel cerebral angiography of both carotids and both vertebral arteries should be done. This would visualize the entire cerebral vasculature and may show up other lesions, such as arteriovenous malformations. If an aneurysm is found and the operator is skilled enough, they may use a coil during the same session of angiography and occlude it. Despite the good sensitivity and specificity of angiography for detecting cerebral aneurysms or other vascular lesions that might result in subarachnoid hemorrhage, no cause is found in 15-20% of patients. A negative angiogram may be obtained: if the aneurysm is very small, (especially when it is hidden inside a cistern flooded with fresh blood); if the aneurysm is clotted; due to bleeding from a venous angioma (this may be responsible for the peri-mesencephalic subarachnoid hemorrhage which has a good prognosis); due to bleeding from a cavernous angioma; and due to bleeding from a source in the spine. Because the most common cause of non-traumatic subarachnoid hemorrhage is a ruptured cerebral aneurysm, if the angiography is negative, you should repeat it after four to 14 days. If the angiogram is still negative and there is a high likelihood of cerebral aneurysm, repeat the angiography after 12 weeks, although the precise timing varies between centers.

Amin OSM. Acute subarachnoid hemorrhage diagnosis and Management. BMJ Learning. Available at:

174) b

Objective: Review the management of familial Berry aneurysms.

Between 0.4% and 6% of the general population harbor an intracranial aneurysm, but most do not rupture. Screening families who have two or more first-degree members with a documented intracranial aneurysm is recommended. Several inherited diseases and syndromes are associated with the formation of intracranial berry aneurysms. These include autosomal dominant polycystic kidney disease, pseudoxanthoma elasticum, and Ehlers-Danlos syndrome type IV. Even in those patients, the possibility of having an intracranial aneurysm is low, and screening all individuals is not required in the absence of a positive family history of rupture. Cranial MRA is the imaging method of choice for screening. Digital subtraction angiography is invasive and is not used in screening. Cranial MRA is a good imaging method for screening, but it misses aneurysms smaller than 5 mm in maximum diameter. Cranial CT angiography is a useful alternative for those who have contraindications for MRI or MRA. Ruptured familial aneurysms tend to be smaller in diameter and occur at a relatively younger age than sporadic ones.

Amin OSM. Acute subarachnoid hemorrhage diagnosis and Management. BMJ Learning. Available at:

175) b

Objective: Review the use of antiplatelets and/or anticoagulation in patients with unruptured intracranial Berry aneurysms.

It should be noted that the risk of rupture of asymptomatic aneurysms increases in patients older than 60 years of age, in females, in hypertensive patients, and in patients who smoke. Aneurysms smaller than 7 mm have a lower risk of rupture than those larger than 13 mm in maximum diameter. Aneurysms of the posterior circulation rupture more often than the anterior circulation ones. Therefore, the decision of using antiplatelets or anticoagulants must be individualized according to the best estimates of benefits versus risks. The mere discovery of an asymptomatic/unruptured intracranial aneurysm does not contraindicate the use of aspirin in patients who need this form of therapy for some reason or another (e.g., ischemic heart disease). Anticoagulants have been found to reduce the rate of thrombus formation inside the aneurysmal sac, thus increasing the rate of rupture. In addition, this form of therapy can convert a small sentinel hemorrhage into a severe life-threatening one and exert a negative impact on the long-term neurological outcome. Contrary to what warfarin exerts on the long-term outcome, aspirin does not appear to increase the adverse long-term outlook in patients who were ingesting aspirin before the aneurysmal rupture.

Amin OSM. Acute subarachnoid hemorrhage diagnosis and Management. BMJ Learning. Available at:

176) e

Objective: Review the inclusion and exclusion criteria for using thrombolytic therapy in acute ischemic stroke.

The inclusion criteria are the diagnosis of ischemic stroke causing measurable neurological deficit; onset of symptoms <3 hours before treatment begins; and age ≥18 years. The exclusion criteria are significant head trauma or prior stroke in the previous 3 months; symptoms suggest subarachnoid hemorrhage; arterial puncture at a non-compressible site in previous 7 days; history of previous intracranial hemorrhage; intracranial neoplasm, arteriovenous malformation, or aneurysm; recent intracranial or intraspinal surgery; elevated blood pressure (systolic >185 mmHg or diastolic >110 mmHg); active internal bleeding; acute bleeding diathesis (including but not limited to platelet count <100,000/microliter, heparin received within 48 hours resulting in abnormally elevated aPTT above the upper limit of normal, current use of anticoagulant with INR >1.7 or PT >15 seconds, current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests); blood glucose concentration <50 mg/dL (2.7 mmol/L); and brain CT demonstrates multilobar infarction (hypodensity of the cerebral hemisphere). Recent experience suggests that under some circumstances, with careful consideration and weighting of risk to benefit, patients may receive fibrinolytic therapy despite the presence of ≥1 relative contraindication (i.e., relative exclusion criteria). Consider the risk to benefit of intravenous rtPA administration carefully if any of these relative contraindications are present: only minor or rapidly improving stroke symptoms (clearing spontaneously); pregnancy; seizure at the onset with postictal residual neurological impairments; major surgery or serious trauma within previous 14 days; recent gastrointestinal or urinary tract hemorrhage (within previous 21 days); and recent acute myocardial infarction (within previous 3 months).

Demaerschalk et al. Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2016;47(2):581-641. Available at:

177) a

Objective: Review lacunar stroke syndromes; pure sensory stroke.

When a small single perforating artery is occluded within the deep cerebral white matter and corona radiate, basal ganglia, thalamus, or pons, the area becomes infarcted and then cavitates resulting in a lacune of 2-20 mm in maximum diameter. The mechanism of “occlusion” of these small arteries can be explained by the development of lipohyalinosis of the penetrating arteries (which is the usual cause), particularly of smaller infarcts (3-7 mm in maximum diameter) and/or microatheroma of the origin of the penetrating arteries stemming off the middle cerebral artery main stem, circle of Willis, or distal basilar or vertebral arteries. Although there are more than 20 lacunar stroke syndromes, the following 5 subtypes have been validated as being highly predictive for the presence of lacunes radiologically: pure motor hemiparesis (the commonest, comprising about 45-57% of all lacunar strokes), pure sensory stroke, ataxic hemiparesis, sensorimotor stroke, and dysarthria-clumsy hand syndrome. Pure sensory stroke is defined as numbness of the face, arm, and leg on one side of the body in the absence of motor deficit, limb ataxia, or cortical signs. It is responsible for 7-18% of lacunar strokes. Damage to the thalamus as well as the corona radiata and the posterior limb of the internal capsule are the usual culprits.

Amin OSM. Lacunar Strokes: A Single Institutional Experience. Cukurova Medical Journal. 2013;38(4):659-66. Available at:

178) c

Objective: Review the differential diagnosis of acute and rapidly progressive impairment of consciousness.

The presentation is very rapid and progressive. Did the patient sustain an intracranial event and then fall onto the floor (e.g., embolic or hemorrhagic stroke and then he collapsed), or the reverse is true (i.e., he fell onto the ground and sustained head trauma)? The picture suggests a rapidly growing intracranial space-occupying mass lesion. His vision is most likely not that good because of glaucoma and he is very likely taking warfarin (or another type of anticoagulation) because of atrial fibrillation. The eye problem increases the risk of falls and anticoagulation increases the risk of hemorrhagic complications. An intracranial bleed might well have happened in this man following his fall. The fall might also have resulted from his cardiac problem (which might have resulted in syncope). Syncope per se does not result in hemiparesis, vomiting, and impaired consciousness unless it has caused head trauma (and its consequences).

Ropper AH, Samuels MA, Klein JP, Prasad S. eds. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill;2019.

179) b

Objective: Characteristics of congophilic angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta-peptide deposits within small- to medium-sized blood vessels of the brain and leptomeninges. CAA is an important cause of lobar intracerebral hemorrhage in older adults. In addition to intracerebral hemorrhage, CAA may present with transient neurological symptoms, inflammatory leukoencephalopathy, as a contributor to cognitive impairment, or with incidental microbleeds or hemosiderosis on magnetic resonance imaging. The incidence of CAA is strongly age-dependent. The prevalence of CAA among older patients with dementia is higher than among those without dementia.

Greenberg S. Cerebral amyloid angiopathy. UpToDate. Updated February 8, 2022. Available at:

180) e

Objective: Review the anatomy of the intracranial venous system.

The cerebral venous system can be divided into 2 parts: a superficial system and a deep one. The former is composed of the sagittal sinuses and cortical veins; these drain the superficial surfaces of both cerebral hemispheres. The deep system is made of the lateral sinus, straight sinus, and sigmoid sinus along with draining deeper cortical veins. Both these systems mostly drain themselves into internal jugular veins. The veins draining the brain do not follow the same course as the arteries that supply it. Generally, venous blood drains to the nearest venous sinus, except in the case of that draining from the deepest structures, which drain to deep veins. These, in turn, drain into the venous sinuses. The superficial cerebral veins can be subdivided into three groups; they are interlinked with the anastomotic veins of Trolard and Labbe. However, the superficial cerebral veins are very variable. They drain to the nearest dural sinus. Thus, the superolateral surface of the hemisphere drains to the superior sagittal sinus while the posteroinferior aspect drains to the transverse sinus. The veins of the posterior fossa are variable in their course, and the angiographic diagnosis of their occlusion is extremely difficult. Blood from the deep white matter of the cerebral hemisphere and the basal ganglia is drained by internal cerebral and basal veins, which join to form the great vein of Galen that ultimately drains into the straight sinus. Except for the wide variations of the basal vein, the deep venous system is rather constant compared to the superficial venous system. Hence their thrombosis is easier to get recognized.

Azeem Uddin et al. Cerebral venous system anatomy. J Pak Med Assoc. 2006;56(11):516-9. Available at:

181) b

Objective: Characteristics of isolated cortical venous thrombosis (ICVT); differentiate between dural sinus thrombosis (DST) and ICVT.

ICVT is a distinct subtype of cerebral venous and sinus thrombosis. Thrombosis of the cerebral cortical veins is mostly seen in conjunction with thrombosis of a major cerebral sinus (cerebral venous and sinus thrombosis [CVST]); ICVT is rare. Papilledema is highly unusual in ICVT. Headache is less common and less prominent in ICVT than in patients with dural sinus thrombosis. The almost invariable presence of headaches in CVST is partly explained by intracranial hypertension. Because in ICVT the venous outflow through the large sinuses is not affected, intracranial hypertension is less likely to occur. The absence of papilledema in these cases and the lower frequency of headaches would support this hypothesis. Venus infarctions tend to be hemorrhagic (in about 50% of cases) and epileptogenic (around 60%). In young women, about 55% of ICVT cases are due to the use of oral contraceptives or tend to develop in pregnancy or postpartum period, reflecting a strong hormonal link.

Coutinho et al. Isolated cortical vein thrombosis: systematic review of case reports and case series. Stroke. 2014;45(6):1836-8. Available at:

182) a

Objective: Neurological manifestations of SARS-CoV-2 and its COVID-19; clinical manifestations.

The commonest symptoms of COVID-19 are malaise and fatigue. The pooled prevalence of various neurological manifestations reported in the COVID-19 patients was found to be a headache (14.6%), fatigue olfactory dysfunction (26.4%), gustatory dysfunction (27.2% ), vomiting (6.7%), nausea (9.8%), dizziness (6.7%), myalgia (21.4%), seizures (4.05%), cerebrovascular diseases (9.9%; acute ischemic stroke, acute hemorrhagic stroke, and cerebral venous sinus thrombosis), sleep disorders (14.9%), altered mental status (17.1%), neuralgia (2.4%), arthralgia (19.9%), encephalopathy (23.5%), encephalitis (0.6%), malaise confusion (14.2%), movement disorders (5.2%), and Guillain-Barre syndrome (6.9%).

Vitalakumar et al. Neurological Manifestations in COVID-19 Patients: A Meta-Analysis. ACS Chem Neurosci. 2021;12(15):2776-97. Available at:

183) d

Objective: Review the pathophysiology of central and peripheral nerve damage in COVID-19.

SARS-CoV-2 (and other coronaviruses) exhibits neurotropic properties and therefore, may result in a multitude of neurological conditions. Genetic material and proteins of several coronaviruses have been detected in the CSF or brain tissues. A neuronal pathway is another possible route. The virus may lead to the disruption of the nasal epithelium and is released mostly on the apical as well as the basolateral side of the epithelial cells and reach the bloodstream or lymph to reach other tissues, including the central nervous system (CNS). The viruses can also migrate by infecting motor or sensory nerves, via neuronal transport. Alveolar gas exchange disorders are caused by viral proliferation in the lung tissue cells. This in turn causes CNS hypoxia, increasing anaerobic metabolism in the brain. Another mechanism would be immune-mediated. This is closely related to the development of systemic inflammatory response syndrome. Coronavirus infections can infect macrophages, microglia, and astrocytes. It can activate glial cells and promote a proinflammatory state. Cytokines can cross the blood-brain barrier and are associated with acute necrotizing encephalopathy. The neurovirulence of coronavirus correlates with its ability to induce proinflammatory cytokine signals from astrocytes and microglia. The brain has been reported to express angiotensin-converting enzyme 2 (ACE2) receptors that have been detected over glial cells and neurons, which makes them a potential target of COVID-19. The spike protein S1 of the SARS-CoV-2 virus enables its attachment to the cell membrane by interacting with the host’s ACE2 receptor. By binding to ACE2 receptors, they may cause abnormally elevated blood pressure thereby increasing cerebral hemorrhage risk. The SARS-CoV-2 spike protein could interact with ACE2 expressed in the capillary endothelium, possibly causing damage to the blood-brain barrier and gaining entry into the CNS by attacking the vascular system.

Collantes et al. Neurological Manifestations in COVID-19 Infection: A Systematic Review and Meta-Analysis. Can J Neurol Sci. 2020:1-11. Available at:

184) d

Objective: Characteristics of the retinal rods and cones.

Retinal rods outnumber cones (the normal human retina contains about 90 million rods and 6 million cones). Rods are distributed throughout the retina (but are absent at the fovea), especially at the periphery, and contain rhodopsin. Rods are more sensitive than cones to light but possess poor acuity; rods respond to dim light and are responsible for night vision (monochromatic; scotopic vision). Several rods connect to a single bipolar cell. Rods’ regenerative ability is high. The retinal cones are mainly concentrated at the fovea where they are responsible for sharp central (photopic) vision; they respond to bright light and color (they are 3 types of cones; red, green, and blue). They display low sensitivity and need a bright light to be stimulated (they contain photopsin) and possess a high visual acuity. One cone is connected to one bipolar cell. Cones’ regenerative power is low. Cones constitute about 5% of all retinal photoreceptor cells (the rest, 95%, are rods) but comprise 100% of the retinal photoreceptors at the foveola. Cones display rapid dark adaptation and rapid contrast sensitivity. In humans, the retinal ganglion cell (non-rod non-cone) photoreceptor contributes to conscious sight as well as to non-image-forming functions (e.g., circadian rhythms, behavior, and pupil reactions. Since these cells respond mostly to blue light, it has been suggested that they have a role in mesopic vision (a combination of photopic and scotopic visions).

Lamb TD. Why rods and cones?. Eye (Lond). 2016;30(2):179-85. Available at:

185) e

Objective: Review the anatomy and physiology of the Edinger-Westphal nucleus.

The Edinger-Westphal nuclear complex (part of the cranial nerve nuclei) is a collection of preganglionic parasympathetic neurons that send fibers to the ciliary ganglion in the orbit to supply (via short ciliary nerves) the sphincter pupillae and ciliary muscles. Therefore, there are responsible for pupillary constriction (light reflex) as well pupillary responses in accommodation and convergence of the eyes. In addition, it has been implicated in the mirroring of pupil size in sad facial expressions. The nuclear complex lies at the rostral midbrain, anterolateral to the cerebral aqueduct, at the level of the superior colliculus. Unlike other preganglionic neurons, it does not contain choline acetyltransferase; instead, it contains various neuropeptides. Nuclear cranial nerve lesions result in bilateral ptosis.

Splittgerber, Ryan. Snell’s Clinical Neuroanatomy. 8th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018.

186) e

Objective: Review the causes and characteristics of non-organic visual losses; differentiate between tunnel vision and tubular vision.

Non-organic loss of the visual field usually occurs in association with an alleged reduction in visual acuity. Several types of factitious fields have been reported, but the concentric loss of peripheral vision with “tunnel-like” constriction of the peripheral vision is the most frequently described. Suspicion is initially aroused at the ease with which the patient maneuvers around objects upon entering the consulting room. In cases of suspected non-organic loss of field, appropriate techniques include tangent screen testing, Goldman perimetry, and plotting of the visual field with both eyes open. Automated visual field analysis is inappropriate for several reasons. Psychogenic or feigned field defects remain unchanged in width when tangent screen testing is performed at varying distances while maintaining equivalence by adjusting target size and are consequently known as “tubular fields”. In the presence of genuine loss of peripheral field, the area of constricted field expands with increasing test distance (so-called tunnel vision). Tunnel vision can result from a multitude of causes, but glaucoma and retinitis pigmentosa are the commonest etiologies. The constricted or visual fields with steep slopes are specific findings in

Beatty S. Non-organic visual loss. Postgraduate Medical Journal Available at:

187) c

Objective: Review the visual field defects in chronic open-angle glaucoma.

Early glaucomatous visual field defects are subtle and easily missed. Even with modern automated and sensitive visual field analyzers, glaucomatous visual field loss is not evident until at least 30% of the retinal ganglion cell axons that make up the optic nerve have been lost. Progression of visual field loss in untreated glaucoma can be quite slow, and signs of deteriorating disease can therefore be missed quite easily. The earliest changes in eyes with open-angle glaucoma that could be discovered with the use of static perimetry are paracentral scotomas in the Bjerrum area separated from the blind spot, coalescing into an arcuate scotoma joining the blind spot. The presence of an isolated inferior visual field defect is highly unusual in open-angle glaucoma.

Bilateral inferior field defects rarely develop in retro-chiasmatic lesions, e.g., occipital trauma or meningioma.

Broadway D. Visual field testing for glaucoma a practical guide. Community Eye Health. 2012;25(79-80):66-70. Available at:

188) c

Objective: Differentiate between arteritic and non-arteritic anterior ischemic optic neuropathy (AION).

AION can be arteritic or non-arteritic. The former is usually part of giant cell (temporal) arteritis (throbbing scalp headache and tenderness, malaise, anorexia, myalgia, etc.) while the latter is associated with vascular risk factors (e.g., hypertension, diabetes, hyperlipidemia). AION results from occlusion of the posterior ciliary arteries (not ophthalmic artery or retinal blood vessels). In non-arteritic AION, the optic disc is characteristically pale and swollen and may be associated with hemorrhages around the disc. Absolute inferior nasal visual field defect is much more common than an absolute inferior altitudinal visual field defect in patients with non-arteritic AION; however, AION is the commonest cause of inferior altitudinal defects. This patient has developed non-arteritic AION. Atypical features of non-arteritic AION are age <40 years old, pain, bilateral simultaneous onset, rapidly sequential vision loss, lack of optic disc edema, optic disc edema persisting >4 weeks, unusual field defects (e.g., homonymous hemianopia), absence of a relative afferent pupillary defect, lack of vasculopathic risk factors, large cup-to-disc ratio in the fellow eye, recurrent attacks, and macular star. The optic disc is normal-looking in acute retrobulbar optic neuritis (e.g., in multiple sclerosis). In papilledema (bilateral optic disc swelling due to raised intracranial pressure), the optic nerve heads are The classical fundoscopic findings in acute central retinal artery occlusion are retinal whitening (due to opacification of the nerve fiber layer as it becomes edematous from ischemia) and cherry red spot (the fovea is cherry red because it has no overlying nerve fiber layer). This finding may take hours to develop.

Berry et al. Nonarteritic anterior ischemic optic neuropathy: cause, effect, and management. Eye Brain. 2017; 9: 23–28. Available at:

189) d

Objective: Review the genetics of retinitis pigmentosa (RP).

RP can be autosomal dominant (20%), autosomal recessive (20%), or X-linked (10%); approximately 50% of the patients don’t exhibit any family history. The core feature of RP is mutation-related rod-cone dystrophy resulting in apoptosis of the retinal photoreceptor system, predominantly affecting the rods. RP commonly develops in isolation without a systemic association (non-syndromic RP). Usher’s syndrome is the commonest cause of syndromic RP (autosomal recessive; RP with hearing loss). In Bardet-Biedl syndrome (a form of autosomal recessive ciliopathy), there are polydactyly, truncal obesity, kidney dysfunction (renal failure is rare), learning difficulties, short stature, and RP. Mutations in more than 80 genes are known to cause nonsyndromic retinitis pigmentosa. More than 20 of these genes are associated with the autosomal dominant form of the disorder. Mutations in the RHO gene are the most common cause of autosomal dominant retinitis pigmentosa, accounting for 20-30% of all cases.

Verbakel et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res. 2018;66:157-86. Available at:

190) c

Objective: Characteristics of age-related macular degeneration (ARMD).

ARMG is the leading cause of visual loss in the elderly and is the global cause of blindness after cataracts, prematurity, and glaucoma. While ARMD does not result in complete blindness, the loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. In general, since the peripheral vision is not affected, ARMD patients typically do not require canes or guide dogs. The etiology is complex and multifactorial; a combination of genetic, environmental, and metabolic factors. Well-known risk factors are old age, cigarette smoking, hypertension, diabetes, hyperlipidemia, alcohol, and family history of ARMD (it is a highly heritable condition; many genes have been implicated such as those of complement factors, apolipoprotein E, fibroblast growth factor 2, DNA excision repair protein, and age-related maculopathy susceptibility protein 2), hypothyroidism, and obesity. Antioxidant vitamins and minerals don’t affect the development or progression of the disease. The dry subtype (no macular neovascularization) accounts for 90% of the cases; there is no cure. The wet subtype (exudative; with macular neovascularization) can be treated with vascular endothelial growth factor (VEGF) inhibitors, e.g., ranibizumab and bevacizumab. Although this is considered a breakthrough in the treatment of the wet type of ARMD, no efficacious treatment is yet available to prevent progressive irreversible photoreceptor degeneration, which leads to central vision loss. Ranibizumab can be used to treat the “wet” subtype of ARMD, diabetic retinopathy and maculopathy, and macular edema due to branch retinal vein occlusion or central retinal vein occlusion. Smoking is an inverse risk factor for Parkinson’s disease, although the mechanism for this apparent neuroprotection is not definitively established. Smoking consistently upregulates nicotinic acetylcholine receptor levels in various brain regions known to be involved in Parkinson’s disease.

Fleckenstein et al. Age-related macular degeneration. Nat Rev Dis Primers. 202;7(1):31. Available at:

191) e

Objective: Review the characteristic features of the different types of diabetic retinopathy (DR).

DR is the leading cause of visual loss in patients aged 20-64 years and can be found in 80% of diabetic individuals after 20 years of having diabetes. Diabetic retinopathy often has no early warning signs. Background retinopathy (microaneurysms, hard exudates, retinal hemorrhages) is asymptomatic and detected by indirect or direct ophthalmoscopy. Patients with diabetic macular edema may be asymptomatic or complain of blurring of vision, diminished visual acuity, and metamorphopsia; this can occur at any stage of DR and is responsible for about 10% of diabetic visual losses. In pre-proliferative DR, there are venous loops and beadings, large blot hemorrhages, cotton wool spots, and intraretinal microvascular abnormalities (IRMA), reflecting more widespread retinal capillary ischemia. The hallmark of proliferative DR is the development of new blood vessels (neovascularization) on the optic disc or elsewhere in the retina; this indicates extensive and severe retinal ischemia and hypoxia. These blood vessels are fragile and rupture easily. Rubeosis iridis (together with vitreous hemorrhages and pre-retinal fibrosis) reflects the development of neovascularization on the surface of the iris, indicating advanced diabetic eye disease. Rubeosis iridis can end up in neovascular glaucoma (painful blind eye). Screening for diabetic retinopathy is part of the standard of care for people with diabetes. After one normal screening in people with diabetes, further screening is recommended every year. Note that about 50% of diabetic patients lose vision because of causes of other diabetic retinopathies and these are cataracts, age-related macular degeneration, retinal vein occlusion (central or branch), retinal arterial occlusion (central or branch), non-arteritic ischemic optic neuropathy, and open-glaucoma glaucoma.

Duh et al. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. 2017;2(14):e93751. Available at:

192) d

Objective: Review the etiologies of ectopia lentis.

Trauma is the commonest cause; may be present at birth or occur at any age. Traumatic ectopia lentis usually results from a direct blow to the globe but it can also develop after blunt trauma to the head or orbit. Despite being the commonest cause, if the trauma is trivial, one should consider other underlying diseases that could predispose the patient to lens dislocation. Marfan’s syndrome (due to mutations in the FBN1 gene on chromosome 15) is the commonest cause of heritable ectopia lentis (occurs in 75% of Marfan’s syndrome cases). The lens dislocation in Marfan’s syndrome is typically bilateral and occurs in a superior/temporal direction; however, other directions are not uncommon. In homocystinuria, lens dislocation occurs in 90% of the patients (due to decreased zonular integrity because of the enzymatic defect and is usually bilateral; in 60% of the patients, it occurs in the inferior/nasal direction). Lens dislocation can be detected in Ehlers-Danlos syndrome, Sturge-Weber syndrome, Pierre-Robin syndrome, and Crouzon syndrome. The following ocular conditions may be associated with ectopia lentis: aniridia, buphthalmos, retinitis pigmentosa, intra-ocular tumors, high myopia, hypermature cataract, and syphilis.

Chandra A, Charteris D. Molecular pathogenesis and management strategies of ectopia lentis. Eye (Lond). 2014;28(2):162-8. Available at:

193) c

Objective: Review the ocular adverse effects of deferoxamine therapy: deferoxamine-induced pigmentary retinopathy.

Deferoxamine is used in the treatment of transfusion-associated hemochromatosis. The incidence of deferoxamine-related ocular toxicity is about 1%. The clinical presentations vary and may include, cataracts, night blindness, centrocecal scotoma, peripheral visual field constriction, pigmentary retinopathy, bull’s eye maculopathy, vitelliform maculopathy, and optic neuropathy; retinal pigmentary changes are the commonest adverse effects. It is still unclear whether these ocular toxicities are dose-dependent or not; probably, those with lower iron loads and deferoxamine dosage higher than 50 mg/kg/day are at increased risk for developing systemic toxicity. Ocular toxicity can be asymptomatic; therefore, a regular ophthalmologic examination is recommended.

Simon et al. Desferrioxamine-related ocular toxicity: A case report. Indian J Ophthalmol 2012;60(4):315-7. Available at:

194) a

Objective: Review the ocular manifestations of endocrine diseases.

Apart from retinopathy, diabetes mellitus can result in cataracts (including snowflake cataracts) and small pupils (because of autonomic neuropathy). Lid retraction may result from thyrotoxicosis (regardless of the etiology). However, Graves’ disease may cause proptosis, exposure keratopathy, optic neuropathy, chemosis, and ocular motility restriction. Hyperparathyroidism (via hypercalcemia) may cause band keratopathy and corneal calcium deposition. Posterior subcapsular cataracts and central serous retinopathy are observed in Cushing’s disease. Through local invasion, thyroid cancers can produce Horner’s syndrome. Pheochromocytoma may cause optic nerve head swelling, macular edema, flame-shaped hemorrhages, cotton wool spots, and hypertensive retinopathy. Band keratopathy is a corneal degeneration that is most often composed of fine dust-like calcium deposits in the sub-epithelium, Bowman’s layer, and the anterior stroma.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

195) c

Objective: Review drug-induced ocular toxicities; amiodarone ocular adverse effects.

Amiodarone is one of the most efficient antiarrhythmic medications. Amiodarone reaches the cornea via tear film, aqueous humor, and limbal its long-term administration, intracytoplasmic lamellar deposits develop in the cornea, lens, retina, and optic nerve. The most reported symptom (in up to 40% of patients) is colored rings around lights. Clinically, the commonest ocular finding is corneal epithelial opacities resembling cat’s whiskers (vortex keratopathy; observed in 70-100% of the cases). However, lens opacities have been observed in 50-60% of the patients. The visual acuity is not impaired by both types, and the presence of these deposits does not call for discontinuing amiodarone treatment. Vortex keratopathy has a whorl-like pattern imparted by the lysosomal deposits in the basal epithelial layer. Retinopathy is rare. Optic neuropathy occurs in 1-2% of patients over a period of 8-10 years. If function-threatening optic neuropathy is observed, discontinuing or reducing the dose of amiodarone should be considered. Note that vortex keratopathy can also be seen in Fabry’s disease.

Mäntyjärvi et al. Ocular side effects of amiodarone. Surv Ophthalmol. 1998;42(4):360-6. Available at:

Chan T. Amiodarone-Induced Vortex Keratopathy. N Engl J Med. 2015;372:1656. Available at:

196) c

Objective: Review the ocular manifestations of rheumatological diseases, systemic vasculitides, and diseases of the musculoskeletal system.

The following can be observed in rheumatoid arthritis: episcleritis (painless red eye), scleritis (painful red eye; may impair vision; usually associated with inflammation of the anterior uveal tract), secondary Sjogren’s syndrome (dry eyes and mouth), and corneal melt (peripheral ulcerative keratitis). Seronegative spondyloarthritides may result in anterior uveitis and conjunctivitis. Adult-type polymyositis does not produce periocular skin changes; dermatomyositis may result in periorbital edema and the typical heliotrope violaceous skin rash. Behçet’s disease may result in optic neuritis, posterior uveitis (occlusive retinal vasculitis), and anterior uveitis. Optic neuropathy can occur in Paget’s disease of the bone. Bisphosphonates (treatment of osteoporosis) can result in anterior uveitis while hydroxychloroquine (e.g., treatment of SLE) may cause bull’s eye retinopathy. Several diseases may result in extraocular movement impairment (via myopathy, myositis, cranial nerve palsies), and visual impairment unrelated to uveitis (occipital cortical infarction, anterior ischemic optic neuropathy, optic neuritis).

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

197) d

Objective: Review the red flags in patients who complain of visual loss; the need for urgent referral to an ophthalmologist.

“Red eye” by itself can result from a multitude of etiologies. A red eye can be painless or painful. The presence of any one of the following in a patient who has developed visual loss should prompt the physician to refer him/her urgently to an ophthalmologist: sudden onset (anterior ischemic optic neuropathy, central retinal artery occlusion), preceded by headache or accompanied by headache (giant cell arteritis), painful globe (keratitis, acute angle-closure glaucoma, anterior uveitis, scleritis), the development of pain on moving the globe (optic neuritis, scleritis), presence of image distortion (pathological myopia, posterior uveitis, macular hole), and a prominent worsening in the morning (reflecting macular edema/neovascularization and disruption of the foveal photoreceptors alignment; e.g., diabetic macular edema, uveitis, retinal vein thrombosis).

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

198) e

Objective: Review the characteristic features of thyroid eye disease (TED) and TED treatment.

TED is an autoimmune disease that results from the activation of orbital fibroblasts by autoantibodies directed against thyroid receptors; these thyroid-stimulating hormone receptors are antigens that are found in the orbital fat and connective tissue and are a target for this autoimmune attack. About 90% of TED patients are hyperthyroid (TED develops in about 50% of Graves’ disease patients); the remaining 10% are either euthyroid or hypothyroid (e.g., Hashimoto thyroiditis). Cigarette smoking is strongly associated with the development and progression of TED. Lid retraction is the commonest presenting sign. The inferior rectus is the first muscle to get involved, followed by the medial, superior, levator, lateral rectus, and oblique muscles. This muscle involvement, together with the axial proptosis, results in a malalignment of the globe and diplopia. Hyperthyroidism is the commonest cause of unilateral or bilateral proptosis. In January 2020, teprotumumab was approved for the treatment of TED; it is a human monoclonal antibody that targets the insulin-like growth factor 1 receptor (IGF-1R).

Winn B, Kersten R. Teprotumumab: Interpreting the Clinical Trials in the Context of Thyroid Eye Disease Pathogenesis and Current Therapies. Ophthalmology. 2021;128(11):1627-51. Available at:

199) c

Objective: Review the “normal” age-related changes in the eyes.

Aging changes affect all the structures of the eye resulting in varied symptoms. It is important to identify certain changes that are considered within the “normal limits” of aging in order to be able to distinguish those conditions from true disease processes affecting the globes. Bilateral drooping of eyelids is multifactorial (involutional changes with mechanical effects, skin atrophy, dermatochalasis, brow ptosis). Senile miosis (small pupils) means that more and brighter light is needed to illuminate and see objects. Presbyopia is a striking feature and results from decreased accommodative power of the lenses; elderly people need glasses for reading. A person with early lens nuclear sclerosis may complain of seeing glares (especially at nighttime driving) because of light scattering. Elderly people need more ambient lighting than younger people. Reduction in contrast sensitivity is gradual because of progressive media opacities. In addition, decreased contrast sensitivity reduces older people’s ability to perceive depth. Reduced depth perception would make seeing and managing steps or street curves difficult. Reduction in the visual field is normal with aging and is important to remember while testing visual fields in glaucoma suspects (decreasing manual dexterity and cognitive function often render automated perimetry findings unreliable and this would result in spurious findings). Some upgaze limitation is found in the elderly; however, downgaze limitation is always abnormal (e.g., suggesting progressive supranuclear palsy).

Slavi et al. Ageing changes in the eye. Postgrad Med J. 2006;82(971):581-7. Available at:

200) d

Objective: Review the effect of pregnancy on the eyes.

The normal physiological changes of pregnancy can affect the eyes in several ways. Some preexistent ocular conditions may worsen or improve during pregnancy; on the other hand, some conditions are pregnancy-specific and appear for the first time during pregnancy. Darkening of the skin around the eyes is a normal process; it regresses after pregnancy and cosmetic treatment is rarely needed. Corneal thickness and curvature may increase during pregnancy (particularly in the second and third trimesters) and usually return to normal after labor. Pregnant women who wear contact lenses may experience intolerance to the use of contact lenses. A myopic shift in the lens occurs and results from an increment in the lens curvature during pregnancy; this would cause a change in refraction. Laser refractive surgery is contraindicated in pregnancy for those reasons. Diabetic retinopathy often worsens during pregnancy; visual improvement and spontaneous recovery usually develop in the postpartum period. Pregnancy-related physiological changes are protective against glaucoma. In addition, the increased levels of the female sex hormones during pregnancy protect the optic nerve. These effects and intraocular pressure return to their baseline within three months after labor. In patients with preexistent intracranial meningioma, accelerated growth of the tumor is observed. Central serous chorioretinopathy and uveal melanoma develop during pregnancy.

Qin et al. Ophthalmic associations in pregnancy. Aust J Gen Pract. 2020;49(10):673-80. Available at:

201) c

Objective: Review the causes of central retinal vein occlusion (CRVO).

CRVO is a common cause of vision loss in the elderly and is the second most common retinal vascular disease after diabetic retinopathy. In CRVO, the occlusion occurs at or proximal to the lamina cribrosa of the optic nerve (where the central retinal vein leaves the eye). About 90% of CRVO occurs in people older than 55 years of age. Hypertension is the commonest associated risk factor, observed in 75% of patients older than 55 years of age; inadequate control of the blood pressure may predispose to recurrence of CRVO in the same or contralateral eye. Acquired or inherited hypercoagulability, myeloproliferative disorders, and systemic inflammatory conditions are uncommon causes of CRVO. This patient has developed an ischemic (non-perfused) form of CRVO; the prognosis is poor, and there is a high risk of developing anterior segment neovascularization/neovascular glaucoma (painful blind eye). The hypoxic retinal tissue in CRVO releases vascular endothelial growth factors and inflammatory mediators; therefore, it ends up with macular edema, vitreous hemorrhage, and neovascular glaucoma. Corticosteroids and anti-vascular endothelial growth factors (ranibizumab, bevacizumab, and aflibercept) treatments play a significantly beneficial role in the treatment of CRVO. Non-ischemic CRVO is the milder form of the disease that may resolve on its own or may progress to the ischemic form.

Yang et al. Outcomes of Eyes Lost to Follow-Up in Patients with Central Retinal Vein Occlusion Who are Receiving Anti-Vascular Endothelial Growth Factor Treatment. Ther Clin Risk Manag. 2021;17:489-96. Available at:

202) c

Objective: Identify the types and clinical implications of hallucinations, delusions, and illusions.

Illusion is a misconception of a real external stimulus, e.g., a small tree is mistaken for a man in the dark. Delusions can be classified into several types according to their For example, “My head is missing” is a form of nihilistic delusions, while patients with hypochondriacal delusions think that they have a grave disease, usually cancer. Persecutory delusions are the commonest type of delusions in paranoid schizophrenia. Some hallucinations are considered physiological; e.g., hypnagogic hallucinations (upon falling asleep) and hypnopompic hallucinations (upon waking) are normal phenomena and not pathological. The nature of hallucinations is very important; e.g., “running commentary voices” talking and discussing matters with the patient is highly characteristic of schizophrenia. Delusions and hallucinations commonly coexist. When their content is consistent with the coexisting emotional symptoms, they are “mood-congruent” and highly suggestive of depressive psychosis. On the other hand, incongruence between delusions, hallucinations, and mood points to schizophrenia. Auditory hallucinations usually suggest schizophrenia while non-auditory (e.g., smell, and taste) usually indicate an organic cause (e.g., substance abuse, temporal lobe epilepsy, or dementia with Lewy body).

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

203) e

Objective: Identify the psychological and somatic (vegetative) symptoms of depressive disorders.

Low mood can be part of an organic mood disorder which may result from the direct effect of a medical disease or medication/treatment of a disease on the brain. Depression can be mental or physical and is a common complaint (where it affects about 5% of the general population). Incongruent affect is a psychotic feature that is highly suggestive of schizophrenia and schizoaffective disorders; it means that patient’s expression is of feelings opposite the ones appropriate for the context. Patients with schizophrenia report more negative affect (NA) in response to positive and neutral stimuli (incongruent NA) than people without schizophrenia. The simple definition of inappropriate affect is simply that which does not match the situation or the internal emotional state of the person. Blunted affect, restricted affect, flat affect, labile affect, and shallow affect are all types of inappropriate affect reflecting different patterns of the lowered level of the intensity of emotional expression. For example, patients with a flat affect display no feeling or emotion regardless of the circumstances; this is a step below blunted affect in that it is completely devoid of emotional expression.

Mote J, Kring A. Toward an Understanding of Incongruent Affect in People With Schizophrenia. J Nerv Ment Dis. 2019;207(5):393-9. Available at:

204) d

Objective: Review drug-induced mania.

Mania may be induced by ingesting certain medications (including illicit drugs), particularly in patients predisposed to mood disorder or preexisting mild bipolar disorder. Medications with a definite propensity to induce manic symptoms are levodopa, corticosteroids, and anabolic-androgenic steroids (e.g., nandrolone). Tricyclic antidepressants can induce or uncover mania in patients with pre-existing bipolar affective disorders. Some medications and drugs may probably induce mania and the list includes thyroxine, isoniazid, sympathomimetics, alprazolam, and amphetamine. Rarely, mania develops as an idiosyncratic reaction. Discontinuation of the offending agent or reducing its daily doses (if possible) would suffice; if severe, the manic symptoms can be treated with antipsychotic medications or lithium. Anabolic-androgenic steroids can result in aggression, cognitive impairment, mania, depression, and even extreme psychosis. These symptoms may develop within days of initiating these anabolic-androgenic steroids. Mania-related disorders may result from encephalitis, tertiary syphilis, HIV, brain tumors, dementia, epilepsy, Wilson’s disease, hypothyroidism, and hyperthyroidism.

Peet M, Peter S. Drug-induced mania. Drug Saf. 1995;12(2):146-53. Available at:

Franey D, Esperidion E. Anabolic Steroid-induced Mania. Cureus. 2018;10(8):e3163. Available at:

205) a

Objective: Review the core features of self-harm and differentiate self-harm from parasuicide.

The definition of self-harm provided by the WHO reads, “an act with non-fatal outcome in which an individual deliberately initiates a non-habitual behavior, that without intervention from others will cause self-harm, or deliberately ingests a substance in excess of the prescribed or generally recognized therapeutic dosage, and which is aimed at realizing changes that the person desires via the actual or expected physical consequences.” Self-harm is not a diagnosis per se; it is a presentation. The majority of self-harms occur in the form of overdose (prescribed or non-prescribed medications and drugs). Uncommon methods of self-harm are asphyxiation (via various ways), drowning, hanging, and jumping from a height (usually not that high) or in front of a moving vehicle (rarely successfully hit by a car, for example), and the use of firearms (the most dangerous one). Some methods bear a high likelihood of being fatal; such scenarios are more likely to be associated with a serious psychiatric illness.

Self-cutting is relatively common and might be repetitive; however, contact with medical services is rare. Self-harm is more commonly observed in females than males and young adults than the elderly; this contrasts with completed suicide where it is more common and more fatal in men and the elderly. The incidence is higher among low socioeconomic people (especially those living in crowded, socially deprived urban areas). Alcohol misuse, child abuse (physical, sexual, and/or verbal), unemployment, and recently broken relationships are strong associations. Parasuicide is any nonfatal, self-injurious behavior with a clear intent to cause bodily harm or death. Therefore, parasuicide includes both lethal suicide attempts and more habitual or low-lethality behaviors such as self-cutting or other self-mutilation. It should be noted that self-harm is not a non-lethal process; 1-2% of cases eventually kill themselves (intentional or accidental).

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

206) a

Objective: Review the risk factors for suicide.

In many countries, suicide imparts a major health problem. A prior history of a suicide attempt (especially when a violent method was applied, e.g., a firearm) is considered one of the most robust predictors of eventually completed suicide and death. Marriage, in general, is protective against suicide; a history of recent divorce, separation, or bereavement is highly operative in this regard. Elderly people, history of chronic and severe illnesses (e.g., cancer), male gender, living alone, unemployment, history of psychiatric disease (e.g., major depression), substance or alcohol abuse, and the presence of a written suicide note are risk factors for attempting suicide (and eventually completed suicide). About 60% of individuals succumbing to suicide died on their index attempts; in addition, more than 80% of the subsequently completed suicides occur within a year of the initial failed attempt. Firearms were implicated in nearly 75% of lethal first attempts by men. On the other hand, women, although less likely than men to use firearms, are equally likely to die when they use guns.

Bostwick et al. Suicide Attempt as a Risk Factor for Completed Suicide: Even More Lethal Than We Knew. Am J Psychiatry. 2016;173(11):1094-100. Available at:

207) d

Objective: Identify psychiatric symptoms in elderly people and their implications.

Many people think that old and frail individuals have mild depression and that this is a common event as part of normal aging. Many unexplained medical symptoms in the elderly might be due to depressive disorder; depression should carefully be sought and treated. Elderly people, poor, living alone, with no social or family support are difficult to manage. Organic psychiatric symptoms, abnormal behavior, and delirium may be due to stroke, dementia, falls and head trauma, medications, alcohol, urinary tract infection, thyroid problems, etc.; careful assessment and investigations are needed before labeling the patient as having a non-organic psychiatric disorder. Although self-harm in elderly people is uncommon, many may kill themselves eventually.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

208) d

Objective: Differentiate between conventional and atypical antipsychotics; mode of action on receptors.

The first-generation “conventional” antipsychotic medications exert their action predominantly via inhibiting at least three-quarters of the dopaminergic receptor-mediated neurotransmission in the brain. In addition, they display noradrenergic, cholinergic, and histaminergic blocking actions. Agents which have a weak anticholinergic blocking effect display a high chance of inducing extrapyramidal side effects (e.g., drug-induced parkinsonism). The second-generation “atypical” antipsychotic medications work by blocking the dopamine receptors as well as the subtype of serotonin receptors. 5-HT stands for 5-hydroxy-tryptamine, i.e., serotonin. The receptor is a subtype of the (serotonin) receptor system and is a G protein-coupled one; the receptor is a cell surface receptor. It is the main excitatory receptor subtype among the G-protein coupled receptors for serotonin, although it may display an inhibitory effect on certain areas of the brain (e.g., visual and orbitofrontal cortices). Activation of the receptors results in hallucination, fear, and out-of-body experience; this is the core mode of action of LSD (lysergic acid diethylamide), psilocin (substituted tryptamine alkaloid and a serotonergic psychedelic substance present in most psychedelic mushrooms) and its phosphorylated counterpart, psilocybin (naturally occurring psychedelic prodrug produced by more than 200 species of fungi), and mescaline (naturally occurring psychedelic proto-alkaloid of the substituted phenethylamine class, found naturally in many cacti (e.g., San Pedro cactus, Bolivian torch cactus, and Peruvian torch cactus). The antiretroviral agent efavirenz’s psychiatric side effects result from its partial agonistic activity on the receptors. Many medications block these receptors. The antidepressant agent trazodone is a potent antagonist while mirtazapine is blocks and receptors.

Yohn et al. The role of 5-HT receptors in depression. Mol Brain. 2017 Jun 24;10(1):28. Available at:

209) e

Objective: Review the role of the dopaminergic system in health and disease.

The dopamine receptors and are G-protein-coupled receptors; dopamine is their primary endogenous ligand. These receptors display a wide-ranged activity and are implicated in several neurological processes, including motivation, pleasure, cognition, memory, learning, and fine motor control, as well as modulation of neuroendocrine signaling. Dopamine receptors are also present outside the central nervous system (e.g., kidney, lung, myocardium, etc.). The receptors have a widespread expression in the central nervous system. The and receptors are the most abundant types (10-100 times the number of types). The variant of the receptors has been consistently shown to be more frequent in attention-deficit hyperactivity disorder (ADHD) patients; on the other hand, ADHD patients without the 4.7 alleles display a more benign form of ADHD. Illicit drugs which augment dopaminergic signaling can produce euphoric effects. For instance, many recreational drugs (cocaine and amphetamines) inhibit the dopamine transporter (DAT; the protein responsible for removing dopamine from the neural synapse). When DAT activity is dopamine floods the synaptic areas and increases dopaminergic signaling. The net effect is the rewarding stimulus of drug intake. Pathological gambling (a form of obsessive-compulsive spectrum disorder and behavioral addiction) is associated with the TaqA1 allele of the receptor gene; the TaqA1 allele is associated with other reward and reinforcement disorders (e.g., substance abuse and other psychiatric disorders).

Barnard et al. Dopamine DRD2/ANKK1 Taq1A and DAT1 VNTR polymorphisms are associated with a cognitive flexibility profile in pathological gamblers. J Psychopharmacol. 2014;28(12):1170-7. Available at:

210) d

Objective: Characteristics of anorexia nervosa.

Anorexia nervosa is usually precipitated by weight loss for some reason or another (pathological or intentional, e.g., dieting, exercises, gastrointestinal disease). It usually targets neurotic females between the age of 15-19 years. Anxiety and depression are common. There is a familial (genetic) and environmental predisposition. Patients exhibit marked emaciation (weight loss <15% of total body weight or body mass index <17.5) due to intentional starvation (food avoidance). Characteristically, their body image is profoundly disturbed; despite the profound weight loss, patients still feel overweight and are terrified of gaining any weight. These misbeliefs and preoccupations are intense and pervasive; patients may even become delusional about their weight. Any system can suffer (due to prolonged starvation); for example, there are profound sinus bradycardia, prolonged QTc interval, dysrhythmia, anemia, leukopenia, amenorrhea (low LH and FSH), short stature, severe constipation, renal stones, azotemia, hypercarotenemia (due to low hypercholesterolemia (due to low hypokalemia, hypoglycemia, hypomagnesemia, features of the sick euthyroid syndrome, and elevated serum transaminases. Anorexia nervosa should be differentiated from other causes of weight loss, e.g., cancer, inflammatory bowel disease, and malabsorption. However, these may co-exist with anorexia nervosa.

Ralston, Stuart H., et al., editors. Davidson's Principles and Practice of Medicine. 23rd ed., Elsevier Health Sciences, 2018.

211) e

Objective: Identify the poor prognostic factors in anorexia nervosa.

With good family, psychiatric, and medical care, about 50% of patients recover while 20% of the cases display some degree of partial improvement. Approximately, 20% exhibit a chronic intractable course. The disease may be fatal; about 5% of patients die. Suicide is responsible for about 40% of deaths; the remaining are due to complications of long-term starvation. Onset during adolescence is a good sign. Poor prognostic indicators are male gender, onset <11 years or in adulthood, presence of vomiting, coexisting depression, binge eating, need for frequent hospitalizations, disturbed family relationships, one-parent families, and families in which one or both parents were married before. A minimum lifetime body mass index is the strongest prognostic indicator (a body mass index of <11.5 is associated with increased mortality). Cognitive-behavioral therapy has limited efficacy while family behavior therapy is effective in adolescents (but not in adults). Psychotropic medications are not effective; however, antidepressants are useful in the treatment of coexisting depression. Profound complications of starvation or risk of suicide need inpatient management; most patients without these can be managed on an outpatient basis.

Jagielska G, Kacperska I. Outcome, comorbidity and prognosis in anorexia nervosa. Psychiatr Pol. 2017;51(2):205-18. Available at:

212) e

Objective: Differentiate between anorexia nervosa and bulimia nervosa.

Bulimia nervosa usually targets females in their late adolescents or early adulthood (the age of onset is typically later than that of anorexia nervosa). It is more common than anorexia nervosa; however, bulimia uncommonly meets medical services. In bulimia, the social concept of femininity is the core factor that drives such behavior (weight loss is not driven by the desire to appear feminine in anorexia nervosa), and there is a prominent impulsive and emotional instability (they recurrently embark on eating binges, often followed by corrective measures such as self-induced vomiting, laxative use, or diuretic use). Anorexia nervosa patients display a high self-control behavior. Many bulimia patients misuse alcohol and/or drugs (unlike anorexia nervosa). Bulimia patients are more likely to have been overweight (premorbid weight); their weight fluctuates after then and patients usually maintain a normal or near-normal weight. The self-induced vomiting or diuretic/laxative abuse may result in electrolyte disturbances and certain physical signs (e.g., pitted teeth enamel, bilateral parotid enlargement, calluses on knuckles). Bulimia is not a fatal illness; however, some bulimia patients may develop anorexia nervosa in the long term. After many years, about 70% of cases recover while 20% demonstrate a subclinical illness; only 10% of bulimia continue to be unwell. Remarkable short-term and long-term improvements can be achieved through cognitive-behavioral therapy. In addition, high doses of fluoxetine (for up to 1 year of continuous use) are effective in the treatment (independent of their anti-depressant action).

Hail L, Le Grange D. Bulimia nervosa in adolescents: prevalence and treatment challenges. Adolesc Health Med Ther. 2018;9:11-6. Available at:

213) d

Objective: Characteristics of antisocial personality disorder (ASPD).

ASPD displays no precise etiology; however, a multitude of genetic and environmental factors are operative in some way or another. It is more common in males 24-44 years old; however, the prevalence drops off after the age of 45 with ASPD are at risk for traumatic injuries, accidents, homicide, suicide attempts, hepatitis C infections, and HIV infections; therefore, they have higher mortality than the general population. The prevalence of ASPD may reach 80% in some prisons. This antisocial behavior is typically observed before the age of 8 years.About 80% of people with ASPD develop their first symptom by age 11 years (usually diagnosed as conduct disorder).Boys develop symptoms earlier than girls, who may not develop symptoms until puberty. Education and intelligence display a negative correlation with the development of ASPD; there is a higher prevalence of ASPD amongst individuals with lower IQs and reading levels. Marriage is considered a moderating variable (more than 50% of married people with ASPD improve over time, but few unmarried people improve). Spouses, partners, and others close to the person with ASPD can play an important role in urging therapy, and improvement often comes when one has a source of personal support and motivation. Thedegree of childhood socialization is another moderating factor.

Black D. The Natural History of Antisocial Personality Disorder. Can J Psychiatry. 2015;60(7):309-14. Available at:

214) e

Objective: Characteristics of cluster B personality disorders; narcissistic personality disorder.

“Cluster B” personality disorders are characterized by impulsive, self-destructive, emotional behavior and sometimes incomprehensible interactions with others. This category encompasses 5 personality disorders, and these are antisocial personality disorder, borderline personality disorder, histrionic personality disorder, and narcissistic personality disorder. Patients with narcissistic personality disorders have a strong sense of self-importance, underlying deep self-esteem issues, exaggeration, manipulation, envy, arrogance, impatience, and depression. Like histrionic personality disorders, they demonstrate an excessive need for attention and approval.

Day et al. Living with pathological narcissism: a qualitative study. Borderline Personal Disord Emot Dysregul. 2020;7:19. Available at:

215) c

Objective: Review the factitious disorders; Munchausen’s syndrome.

A factitious disorder is encountered when an individual, without a malingering motive, behaves as if he/she has an illness by deliberately producing, feigning, or exaggerating symptoms, purely to attain (for themselves or another) a patient’s role. Munchausen’s syndrome is a factitious disorder; patients feign or induce disease, illness, injury, abuse, or psychological trauma to draw attention, sympathy, or reassurance to themselves. The feigned illness is usually uncommonly, patients may feign psychiatric symptoms, e.g., hallucinations. Patients usually display a history of recurrent hospitalization, traveling, and dramatic, extremely improbable tales of their past experiences. There are 3 essential features for the diagnosis: pathological lying, peregrination, and recurrent feigned or simulated illnesses. Patients may present with thyrotoxicosis (surreptitious ingestion of thyroxin), Cushing’s disease (surreptitious ingestion of glucocorticoids), hematuria (blood introduction into the urine, or intentional urethral trauma), proteinuria (egg protein introduced into the urine), and chronic diarrhea (laxative abuse). Factitious disorder imposed on another (i.e., Munchausen’s syndrome by is a rare condition in which a caregiver makes health problems in another person, typically their child; this may include injuring the child or altering test samples. The caregiver then presents the person as being sick or injured; permanent injury or death of the victim may occur. The behavior occurs without a specific benefit to the caregiver.

Yates J, Feldman M. Factitious disorder: a systematic review of 455 cases in the professional literature. Gen Hosp Psychiatry. 2016;41:20-8. Available at:

216) b

Objective: Differentiate between malingering, factitious disorder, somatoform disorder, and conversion disorder.

Malingering is the intentional fabrication, feigning, or exaggeration of physical or psychological symptoms motivated by external incentives (e.g., relief from duty or work). Usually, there is a medicolegal context of presentation, a marked discrepancy between the claimed disability and objective signs; the history is vague and unverifiable. Patients show a lack of cooperation during evaluation and refuse painful investigations and/or treatments. Antisocial personalities are very common. In factitious disorders, patients intentionally feign or introduce physical or psychiatric symptoms to attain the sick role without external incentives (i.e., psychological benefit). The history (as in malingering) is vague and unverifiable, but patients show a willingness to undergo painful tests, treatments, and even dangerous surgeries. They usually fit the criteria of borderline personality disorder.

Rumschik SM, Appel JM. Malingering in the Psychiatric Emergency Department: Prevalence, Predictors, and Outcomes. Psychiatr Serv. 2019;70(2):115-22. Available at:

217) c

Objective: Characteristics of somatoform disorders; review hypochondriasis.

The core feature of somatoform disorders is the presence of somatic symptoms that cannot be explained by a medical disease (so-called medically unexplained symptoms), nor better diagnosed as part of a depressive or anxiety disorder. Hypochondriasis equally affects men and women; the onset is early adulthood. Hypochondriasis patients believe that they have a grave illness (usually cancer) and its consequences, as an exaggeration of normal bodily sensations. They frequently request medical visits; seeking reassurance to ward off health threats. Many patients are anxious, phobic, or obsessive-compulsive; in addition, they are overly controlled and perfectionistic. Usually, there is no hypochondriasis aggregation in families. Cognitive-behavioral therapy is helpful; 50% show remission. Somatization disorder usually targets females; onset in teens. The somatic symptoms are multiple and vague and involve many body organ systems; patients believe that these can culminate into disability or illness. Patients with somatization disorder usually state that their complaints are being neglected or mistreated by physicians. They always seek a diagnosis to legitimize the sick role. Many patients display depressive symptoms and exhibit dramatic attention-seeking histrionic traits. In females, a history of somatization disorder is common while males usually have a family history of antisocial personality disorder.

Pavithra et al. Hypochondriasis: Clinical Profile in a Tertiary Care Psychiatry and Neurosciences Hospital in Southern India A Retrospective Chart Review. Indian J Psychol Med. 2019;41(2):178-81. Available at:

218) d

Objective: Differentiate between postpartum (baby) blues, postpartum depression, and postpartum psychosis.

Postpartum blues affect about 80% of puerperal women. Factors most consistently shown to be predictive of postpartum blues are the personal and family history of depression. This is of particular interest given the bidirectional relationship between postpartum blues and postpartum depression: a history of postpartum depression appears to be a risk factor for developing postpartum blues, and postpartum blues confers a higher risk of developing subsequent postpartum depression. The symptoms of postpartum blues are usually mild and start soon after labor, peak in the or day postpartum, and finally resolve in the following week; if symptoms persist for more than 2 weeks, a diagnosis of postpartum depression should be considered. Characteristically, there is no suicidal ideation. Apart from reassurance and watchful waiting, no treatment is necessary. Postpartum depression develops in 10-15% of postpartum women, 2-12 weeks postpartum. Suicidal ideation may be present and symptoms of low mood, anhedonia, insomnia, a feeling of worthlessness and guilt, and poor bonding with the baby are usually prominent. Patients should be treated with antidepressants and psychotherapy. Puerperal (postpartum) psychosis is rare (1-2/1000 new mothers). There is paranoia, auditory and visual hallucinations, anxiety, agitation, as well as suicidal or homicidal thoughts. Many patients have bizarre delusions or commands to hurt the baby. The duration is variable; a few days to 4-6 weeks postpartum. Antipsychotic medications should be used; some patients need hospitalization.

Hutchens B, Kearney J. Risk Factors for Postpartum Depression: An Umbrella Review. J Midwifery Womens Health. 2020;65(1):96-108. Available at:

219) c

Objective: Review the adverse effects of conventional antipsychotic medications: tardive dyskinesia.

Tardive dyskinesia usually develops in people with psychiatric illnesses treated with conventional antipsychotic medications (with powerful receptor-blocking action) for many years. Other receptor-blocking agents (e.g., metoclopramide and promethazine) can result in tardive dyskinesia. The average rate of people affected is about 30% for individuals taking these medications (e.g., used in the treatment of schizophrenia). Old age and female gender are risk factors for tardive dyskinesia. Although tardive dyskinesia is uncommonly seen during the use of atypical antipsychotics, there has been a growing incidence in the development of tardive dyskinesia with aripiprazole. The concurrent use of an antipsychotic and an antiparkinsonian drug (e.g., benzhexol) is useless to avoid early extrapyramidal side effects and may render the person more sensitive to tardive dyskinesia. In 2017, 2 monoamine-depleting agents have been approved for the treatment of tardive dyskinesia: valbenazine and deutetrabenazine. Both act as vesicular monoamine transporter 2 (VMAT2) inhibitors. Deutetrabenazine is also used in the treatment of chorea (e.g., Huntington’s disease).

Cornett E. Medication-Induced Tardive Dyskinesia: A Review and Update. Ochsner J. 2017 Summer; 17(2): 162-74. Available at:

Limandri B. Tardive Dyskinesia: New Treatments Available. J Psychosoc Nurs Ment Health Serv. 2019;57(5):11-14. Available at:

220) d

Objective: Characteristics of bipolar disorder; differentiate between bipolar I, bipolar II, and cyclothymia.

The core feature separating bipolar disorders from other affective disorders is the development of recurring manic or hypomanic episodes which alternate with depressive episodes. “Bipolar I disorder” is characterized by the presence of overt manic episodes in association with overconfidence, grandiosity, talkativeness, extreme disinhibition, irritability, decreased need for sleep, and highly elevated mood. In up to 75% of manic episodes, psychotic symptoms (e.g., delusions and hallucinations) appear. “Bipolar II disorder” is defined by the presence of recurrent episodes of depression alternating with hypomania (rather than mania). Cyclothymic disorder is characterized by recurring depressive and hypomanic states, lasting for at least 2 years, that do not meet the diagnostic threshold for a major affective episode. The onset of bipolar disorder typically occurs at around the age of 20 years. An earlier onset is often associated with a poorer prognosis, longer treatment delays, more severe depressive episodes, and a higher prevalence of concurrent anxiety and substance use disorders. The first episode of bipolar disorder is usually and for most persons with either bipolar I or bipolar II disorder, depressive episodes last considerably longer than manic or hypomanic episodes throughout the course of the illness. For this reason, bipolar disorder is often misclassified as a major depressive disorder.

Carvalho et al. Bipolar Disorder. N Engl J Med 2020; 383:58-66. Available at:

221) d

Objective: Review the role of lumateperone in the treatment of depressive episodes of bipolar disorder.

In December 2021, lumateperone was approved (the only approved) treatment targeting the depressive episodes associated with bipolar I or II disorder in adults, either as a monotherapy or adjunctive (add-on) therapy with lithium or valproate. It is not approved for major unipolar depressive disorders. Bipolar depression is the most common and most debilitating clinical presentation of bipolar disorder. These depressive episodes tend to last longer, recur more often, and are associated with a worse prognosis than manic/hypomanic episodes. Bipolar depression is a significantly underserved medical need. Lumateperone is an atypical antipsychotic with favorable safety and tolerability; it is also used in the treatment of schizophrenia.

Calabrese et al. Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial. Am J Psychiatry. 2021;178(12):1098-106. Available at:

222) d

Objective: Identify serotonin syndrome; differentiate between serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia, and anticholinergics intoxication.

Serotonin syndrome is a diagnosis of exclusion; no single diagnostic test can confirm this syndrome. Therefore, a diagnosis of serotonin syndrome is entirely clinical and is based on the history and physical examination along with a history of the patient’s use of a serotonergic drug. Important components of the history include prescription drug use, over-the-counter medications, dietary supplement use, illicit substance use, any recent changes in dosing, or the addition of new drugs to a drug regimen. The presentation of serotonin syndrome is extremely variable, ranging from mild symptoms to life-threatening syndrome. Symptoms usually begin within 24 hours of an increased dose of a serotonergic agent, the addition of another serotonergic agent to a drug regimen, or overdosing. The presence of hyperthermia of >41.1 defines severe syndrome. The overall clinical picture results from central and peripheral activation of serotonin receptors. No single receptor is responsible for the development of serotonin syndrome; however, several studies provide evidence that the receptors are the most important receptors involved. The differential diagnoses are neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic toxicity, serotonergic discontinuation syndrome, sympathomimetic drug intoxication, meningitis, encephalitis, heatstroke, and central hyperthermia.

Volpi-Abadie J. Serotonin Syndrome. Ochsner J. 2013;13(4):533-40. Available at:

223) b

Objective: Review the indications of (and contraindications to) electroconvulsive therapy (ECT).

In general, there are no absolute contraindications to ECT. Each case should be considered individually. ECT is safe in pregnancy (fetal monitoring is generally unnecessary unless there is a high-risk pregnancy) and the elderly. ECT can be used as a first-line treatment in febrile catatonia, malignant neuroleptic syndrome, severe depressive episodes, schizoaffective psychosis, schizophrenia, and in case of life-threatening or intolerable side effects of psychopharmacological treatments. On the other hand, ECT can be applied as a last-resort treatment for the following: treatment-resistant obsessive-compulsive disorder, treatment-resistant dyskinesia, treatment-resistant Gilles de la Tourette syndrome, treatment-resistant epilepsy, and treatment-resistant Parkinson’s disease. Intracranial space-occupying lesions, raised intracranial pressure, recent myocardial infarction (<6 months), recent stroke, active internal bleeding, cardiac pacemakers, aneurysms, and vascular malformations are relative contraindications. The commonest post-ECT complaint is headaches.

Baghai T, Möller HJ. Electroconvulsive therapy and its different indications. Dialogues Clin Neurosci. 2008;10(1):105-17. Available at:

224) e

Objective: Differentiate between positive symptoms and negative symptoms of schizophrenia.

Hallucinations (auditory and visual), delusional thinking, disorganized thinking, and agitation are the core positive symptoms of schizophrenia. The primary negative symptoms remain a frustrating and obstinate adversary for a worldwide effort at achieving a breakthrough in the management of schizophrenia. The National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia consensus panel has defined five negative symptoms: blunted affect (diminished facial and emotional expression), alogia (decrease in verbal output or verbal expressiveness), asociality (lack of involvement in social relationships of various kinds), avolition (a subjective reduction in interests, desires, and goals and a behavioral reduction of self-initiated and purposeful acts), and anhedonia (inability to experience pleasure from positive stimuli).

Mitra et al. Negative symptoms in schizophrenia. Ind Psychiatry J. 2016;25(2):135-44. Available at:

Correll C, Schooler N. Negative Symptoms in Schizophrenia: A Review and Clinical Guide for Recognition, Assessment, and Treatment. Neuropsychiatr Dis Treat. 2020;16:519-34. Available at:

225) c

Objective: Review the treatment of posttraumatic stress disorder (PTSD).

For most adults newly treated for PTSD, the first-line treatment is trauma-focused psychotherapy; this includes exposure rather than a selective serotonergic reuptake inhibitor (SSRI). Psychotherapies that are effective for PTSD are exposure therapy (e.g., prolonged exposure), a combination of exposure and cognitive therapy, also referred to as trauma-focused cognitive-behavioral therapy (e.g., cognitive processing therapy), or eye movement desensitization and reprocessing. An SSRI is a reasonable alternative for patients who prefer medication to psychotherapy, or when cognitive behavioral therapy is not available.

Bryant R. stress disorder: a review of evidence and challenges. World Psychiatry. 2019;18(3):259-69. Available at:

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