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One of the landmark trials in epilepsy known as “SANAD II” evaluated the efficacy and cost-effectiveness of which drugs in newly diagnosed generalized and unclassifiable epilepsy:
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Perampanel vs. Valproate
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Levetiracetam vs. Valproate
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Topiramate vs. Lamotrigine vs. Valproate
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Phenytoin vs. Levetiracetam vs. Valproate
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The following definition of “Prolonged super-refractory status epilepticus” (SRSE) is right in the context of NORSE/FIRES as per ILAE consensus:
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SRSE that persists for ≥7 days, no use of anesthetics
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SRSE that persists for ≥7 days, with ongoing need for anesthetics
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SRSE that persists for ≥14 days, no use of anesthetics
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SRSE that persists for ≥14 days, with ongoing need for anesthetics
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ILAE Neuroimaging taskforce recommends the following investigation as the initial step in imaging for localizing focal lesions while evaluating a patient with drug refractory epilepsy for epilepsy surgery.
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HARNESS protocol
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SISCOM
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MEG
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SPECT
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A 12-year-old boy with new-onset myoclonic jerks of 2 months duration along with cognitive decline on fundus examination found to have cherry red spot. The most likely cause is:
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SSPE
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Lafora body disease
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Sialidosis type I
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Late-infantile type NCL
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The genetic condition that can mimic EEG features of SeLECTS (with centrotemporal spikes):
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Down syndrome
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Fragile X syndrome
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Noonan syndrome
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Klinefelter syndrome
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Which of the following is not a mechanism of action for Stiripentol implicated in its anticonvulsant effect?
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Which of the following is not a contraindication to ketogenic diet therapy in epilepsy?
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Carnitine palmitoyl transferase (CPT) I deficiency
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Porphyria
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Carnitine palmitoyl transferase (CPT) II deficiency
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Complex I mitochondrial disorders
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Which mutation is commonly targeted in precision medicine using a sodium channel blocker?
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Loss of function mutation of SCN1A
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Loss of function mutation of SLC2A1
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Loss of function mutation on KCNQ2
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Gain of function mutation of KCNT1
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Which statement amongst the following is untrue regarding vagal nerve stimulation in children?
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VNS is U.S. FDA approved for more than 4 years of age
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Left vagal nerve stimulation has increased chance (at least theoretical) of bradycardia and asystole
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VNS is approved for drug refractory focal-onset seizures
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Pulse generator for VNS is implanted subcutaneously in left upper chest region
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A 16-year-old patient is diagnosed with juvenile myoclonic epilepsy (JME). Which of the following combinations accurately reflects the characteristics of JME?
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Myoclonic jerks occurring predominantly in the evening, generalized tonic-clonic seizures, EEG shows focal spikes
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Myoclonic jerks primarily upon awakening, generalized tonic-clonic seizures, EEG shows generalized 4–6 Hz polyspike-wave discharges
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Absence seizures, frequent myoclonic jerks, EEG shows generalized spike-wave discharges
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Generalized tonic-clonic seizures, atonic seizures, EEG shows slow spike-wave discharges
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Ganaxolone is recently approved by FDA for which neurological condition?
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OIRDA is seen in
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Childhood absence epilepsy
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Juvenile Huntington disease
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Subacute sclerosing panencephalitis
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All of the above
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Cannabidiol is not approved by the FDA for which condition amongst those given below:
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LGS
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Dravet
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Tuberous sclerosis
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LKS
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Progressive myoclonic epilepsy is caused by all except
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True about Doose syndrome
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In the adult brain, intracellular chloride concentration is low and GABA is inhibitory. However, in immature brain, there is an excess of intracellular chloride concentration and hence GABA is excitatory. Which of the following explains this change in GABA function in immature brain?
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Relative overexpression or high activity of NKCC1 channel in the immature brain
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Relative overexpression or high activity of KCC2 channel in the immature brain
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Relative low activity of NKCC1 channel in the immature brain
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None of the above
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Identify the finding (black arrow) seen in the below EEG?
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Answer: b. Levetiracetam vs. Valproate.
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Ref: Marson A, Burnside G, Appleton R, et al. The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet 2021;397(10282):1375–1386.
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Answer: b. SRSE that persists for >7 days, with ongoing need for anesthetics.
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Explanation: As per ILAE, super-refractory SE refers to one persisting for at least 24 hours after the onset of anesthesia (midazolam, propofol, pentobarbital, thiopental, ketamine, etc.). Prolonged super-refractory SE refers to one that persists for >7 days with ongoing need for anesthetics. The term “prolonged” is mentioned as a modifier to refractory and super-refractory SE.
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Ref: Hirsch JL, Gaspard N, van Baalen A, et al. Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia 2018;59(4):739–744.
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Answer: a. HARNESS protocol.
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Explanation: The ILAE Neuroimaging Task Force recommends the use of the Harmonized Neuroimaging of Epilepsy Structural Sequences (HARNESS-MRI) protocol with high-resolution 3D T1 gradient echo sequences, 3D fluid-attenuated inversion recovery (FLAIR) sequences, and 2D submillimetric T2 sequences after clinical localization based on seizure semiology and EEG to identify any focal lesion such as focal cortical dysplasia, mesial temporal sclerosis, etc.
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Ref: Bernasconi et al. Recommendations for the use of structural magnetic resonance imaging in the care of patients with epilepsy: A consensus report from the International League Against Epilepsy Neuroimaging Task Force. Epilepsia. 2019;60(6):1054–1068.
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Answer: c. Sialidosis type I.
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Explanation: Sialidosis is a recessively inherited lysosomal storage disorder due to pathogenic variants in NEU1, which results in sialidase deficiency. There is abnormal accumulation of sialic acid-rich substrates in the central nervous system and other organ systems. Type I sialidosis patients usually present as a PME phenotype characterized by ataxia and progressively worsening multifocal myoclonus with seizures. Typical age of onset is between 10 and 20 years. A macular “cherry-red spot” may be seen due to storage material in perifoveal ganglionic cells, and can result in visual impairment as well.
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Ref: Cameron JM, Ellis CA, Berkovic SF; ILAE Genetics Commission; ILAE Genetic Literacy Task Force. ILAE Genetics Literacy series: Progressive myoclonus epilepsies. Epileptic Disord. 2023;25(5):670–680.
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Answer: b. Fragile X syndrome.
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Explanation: In males presenting with intellectual disability, workup for Fragile X syndrome should be done as EEG changes in Fragile X may mimic those seen in SeLECTS. In Fragile X, the most common clinical semiology is of focal impaired aware seizures, and less likely focal motor without impaired awareness or focal to bilateral tonic–clonic seizures.
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Ref: Specchio N, Wirrell EC, Scheffer IE, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022;63(6):1398–1442.
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Answer:
c. L-type calcium channel blocker.
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Explanation: Stiripentol works through several mechanisms, including potentiation of GABA neurotransmission, inhibition of voltage-gated sodium channels, and inhibition of T-type calcium channels. Additionally, it inhibits certain cytochrome P450 enzymes, which play a role in metabolizing other antiseizure drugs, thereby increasing their anticonvulsant effectiveness when used as an add-on therapy. Stiripentol is FDA-approved for treatment of seizures in Dravet syndrome (age >2 years), in combination with clobazam, but not as a monotherapy. Due to its inhibition of CYP3A4 and CYP2C19, Stiripentol raises the plasma levels of clobazam. A reduction in clobazam dose should be considered if adverse reactions occur.
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Ref: Diacomit (Stiripentol). Biocedex, Beauvais, France. Reference ID: 4309499. 2018. Eschbach K, Knupp KG. Stiripentol for the treatment of seizures in Dravet syndrome. Expert Rev Clin Pharmacol 2019;12(5):379–388.
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Answer: d. Complex I mitochondrial disorders.
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Explanation: The ketogenic diet is contraindicated in individuals with fatty acid oxidation disorders, primary carnitine deficiency, carnitine palmitoyl transferase (CPT) deficiency Types I and II, carnitine translocase deficiency, pyruvate carboxylase deficiency, and porphyria. However, the ketogenic diet has been consistently shown to be particularly beneficial in conditions such as Angelman syndrome, complex I mitochondrial disorders, Dravet syndrome, GLUT-1 deficiency, Doose syndrome, West syndrome, pyruvate dehydrogenase deficiency, tuberous sclerosis, FIRES, and super-refractory status epilepticus.
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Ref: D'Andrea Meira I, Romão TT, Pires do Prado HJ, Krüger LT, Pires MEP, da Conceição PO. Ketogenic diet and epilepsy: what we know so far. Front Neurosci 2019;13:5.
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Answer:
c. Loss of function mutation on KCNQ2.
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Explanation: Loss-of-function mutations in SCN1A, commonly associated with Dravet syndrome and the GEFS+ spectrum, are typically not treated with sodium channel blockers as these can exacerbate seizures. However, sodium channel blockers can be effective in treating the rare gain-of-function variants of SCN1A. Loss-of-function mutations in KCNQ2/3 are often treated with sodium channel blockers as a first-line therapy. Potassium channel openers, such as retigabine (currently unavailable), have also been used to treat loss-of-function mutations in potassium channels. Conversely, in cases with gain-of-function mutations in potassium channels, potassium channel openers should be avoided. Gain-of-function mutations in KCNT1 result in hyperpolarization following repetitive action potential firing, and quinidine has been reported to counteract this effect. Mutations in SLC2A1 cause GLUT1-deficiency syndrome, which is treated with a ketogenic diet rather than sodium channel blockers.
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Ref: Nabbout R, Kuchenbuch M. Impact of predictive, preventive and precision medicine strategies in epilepsy. Nat Rev Neurol 2020;16(12):674–688.
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Answer:
b. Left vagal nerve stimulation has increased chance (at least theoretical) of bradycardia and asystole.
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Explanation: Vagal nerve stimulation (VNS) is FDA-approved as adjunctive therapy in patients aged >4 years with drug-refractory focal-onset seizures. Although it is effective in primary generalized epilepsy, it is not FDA-approved for this indication. Good candidates for VNS include those with symptomatic localization–related epilepsy with multiple and bilateral independent foci or a diffuse epileptogenic abnormality, with refractory idiopathic generalized epilepsy, failed epilepsy surgery, presence of contraindications to epilepsy surgery, or a failed ketogenic diet. The device includes an implantable pulse generator placed subcutaneously in the left upper chest region and a lead wire coiled around the left vagus nerve.
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Ref: Ryvlin P, Rheims S, Hirsch LJ, Sokolov A, Jehi L. Neuromodulation in epilepsy: state-of-the-art approved therapies. Lancet Neurol 2021;20(12):1038–1047.
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Answer:
b. Myoclonic jerks primarily upon awakening, generalized tonic-clonic seizures, EEG shows generalized 4–6 Hz polyspike-wave discharges.
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Explanation: JME is a genetic generalized epilepsy syndrome that typically begins between 12 and 18 years, with the average onset around 14 to 15 years. The hallmark of JME is myoclonic jerks of the arms, shoulders, and occasionally legs. They occur typically early in the morning, and are often aggravated by sleep deprivation or stress. Generalized tonic-clonic seizures (GTCSs) are also common and may occur independently or following a series of myoclonic jerks, often in the morning hours. Around one-third of patients with JME may also experience absence seizures. Common triggers include sleep deprivation, stress, alcohol consumption, and flickering lights or photosensitivity, although not all patients are photosensitive. EEG in JME typically shows generalized 4–6 Hz bilateral, synchronous polyspike-wave discharges, especially during myoclonic jerks and GTCS.
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Ref: Hirsch E et al. ILAE definition of the idiopathic generalized epilepsy syndromes: position statement by the ILAE task force on nosology and definitions. Epilepsia. 2022;63(6):1475–99.
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Answer:
c. CDKL5-deficiency disorder.
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Explanation: Ganaxolone is a synthetic analog of the naturally occurring neurosteroid allopregnanolone. It acts as a positive allosteric modulator of GABAAA receptors, which regulate the inhibitory neurotransmission in the brain. By potentiating the activity of these receptors, ganaxolone enhances the inhibitory effect of GABA, thus stabilizes the neural activity and reduces seizures.
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Ref: Yasmen N, Sluter MN, Yu Y, Jiang J. Ganaxolone for management of seizures associated with CDKL5 deficiency disorder. Trends Pharmacol Sci 2023;44(2):128–129
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Answer:
d. All of the above.
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Explanation: Occipital intermittent rhythmic delta activity (OIRDA) is an interictal electroencephalographic (EEG) finding, described as a sinusoidal, 3-Hz, high-amplitude, symmetrical, occipital-maximum activity which may have a spatial field to the posterior temporal or parietal channels, most commonly associated in children with idiopathic generalized epilepsies, such as childhood absence epilepsy (CAE). Nonepilepsy causes include Juvenile Huntington, SSPE, etc.
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Ref: Brigo F. Intermittent rhythmic delta activity patterns. Epilepsy Behav 2011;20(2):254–256.
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Answer: d. LKS.
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Explanation: The U.S. Food and Drug Administration today approved Epidiolex (cannabidiol) [CBD] oral solution for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox–Gastaut syndrome and Dravet syndrome, in patients 2 years of age and older. This is the first FDA-approved drug that contains a purified drug substance derived from marijuana. It is also the first FDA approval of a drug for the treatment of patients with Dravet syndrome. It is also the second FDA approval of a drug for the treatment of seizures associated with TSC.
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Ref: Thiele EA, Bebin EM, Filloux F, Kwan P, Loftus R, Sahebkar F, Sparagana S, Wheless J. Long-term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open-label extension trial. Epilepsia 2022;63(2):426–439.
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Answer: b. Gaucher disease (Type 2).
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Explanation: Progressive myoclonic epilepsy is a neurodegenerative disorder characterized by myoclonic jerks, dementia, and cognitive decline. Common causes include SSPE, Lafora disease, Unverricht–Lundborg disease, Type 3 Gaucher disease, and MERRF.
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Ref: Franceschetti S, Michelucci R, Canafoglia L, et al; Collaborative LICE Study Group on PMEs. Progressive myoclonic epilepsies: definitive and still undetermined causes. Neurology. 2014;82(5):405–411.
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Answer: d. May evolve into LGS.
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Explanation: Onset of MAE is often between the ages of 2 and 6 years, and children are usually developmentally normal. There appears to be a strong male predominance (70–90%). Common genes associated with Doose are SCN1A and SLC2A1. Although this syndrome does not always have a poor neurodevelopmental outcome, it remains an epileptic encephalopathy and, if not appropriately treated, can progress and lead to permanent neurodevelopmental sequelae or evolution into Lennox–Gastaut syndrome.
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Ref: Swaiman KF, Ashwal S, Ferriero DM, eds. Swaiman's Pediatric Neurology: Principles and Practice. 6th ed. Elsevier; 2018.
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Answer: a.
Relative overexpression or high activity of NKCC1 channel in the immature brain.
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Explanation: The intracellular chloride concentration and its impact on neuronal responses to GABA vary with age. In early postnatal stages, intracellular chloride levels are high due to the activity of the membrane transporter NKCC1, which facilitates chloride influx. At this stage, GABAA receptor activation leads to chloride efflux and neuronal depolarization.
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In contrast, in the mature brain, NKCC1 expression is significantly reduced, while another chloride transporter, KCC2, actively expels chloride, maintaining a lower intracellular chloride concentration. As a result, GABAA receptor activation in the mature brain triggers chloride influx and neuron hyperpolarization. The relative expression of NKCC1 and KCC2 at both ages is represented by the size of the symbols, and intracellular chloride levels by the size of the Cl− lettering.
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Ref: Swaiman KF, Ashwal S, Ferriero DM, Schor NF, Finkel RS, Gropman AL, Pearl PL. Swaiman's Pediatric Neurology: Principles and Practice. Philadelphia, PA: Elsevier Health Sciences; 2017.
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Answer: b. Generalized paroxysmal fast activity.
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Explanation: Paroxysmal fast activity (PFA) refers to a distinct type of beta frequency bursting activity that can be either focal or generalized. It is characterized by a sudden onset and resolution, standing out against the surrounding background activity. The amplitude of PFA exceeds that of the background, typically greater than 100 μV. The frequency at the start of the burst is generally within the 10 to 30 Hz range, most often between 15 and 25 Hz. PFA is most commonly observed during sleep but can also occur during wakefulness.
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Differential Diagnoses:
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Muscle artifact: muscle artifact has a broader range of frequencies and a more disorganized appearance due to the frequency mixing. In contrast, PFA is monomorphic and more consistent in its pattern.
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14 and 6 Hz bursts: these bursts differ from PFA by having a broader distribution and a distinct arciform morphology with a positive deflection.
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Sleep spindles: spindles generally have slightly slower frequencies, typically between 12 and 14 Hz, while PFA frequencies are usually above 15 Hz. This frequency distinction is key for differentiating between the two.
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Ref: Stern JM. Atlas of EEG patterns. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
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Answer: a. 1–d, 2–a, 3–c, 4–b.
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Explanation: An epileptogenic zone is defined as “the area of the cortex that is essential and sufficient for triggering seizures, and its removal (or disconnection) is necessary to achieve complete seizure control.”
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Ictal-onset zone: the area of the cortex that initiates clinical seizures.
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Irritative zone: the area responsible for generating interictal spikes.
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Symptomatogenic zone: the region whose activation produces ictal symptoms, such as nausea or dystonic posturing.
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Epileptogenic lesion: a visible lesion that causes seizures, either because it is inherently epileptogenic (e.g., cortical dysplasia) or due to secondary hyperexcitability of the surrounding cortex.
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Functional deficit zone: an area of the cortex that exhibits abnormal functioning during the interictal period, with its activation or deactivation causing neurological or neuropsychological deficits.
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Ref: Madaan P, Gupta A, Gulati S. Pediatric epilepsy surgery: indications and evaluation. Indian J Pediatr 2021;88(10):1000–1006.
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Answer: b. 1–d, 2–b, 3–a, 4–c.
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Explanation: These are the precision medicines that are used in certain types of epilepsy.
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GRIN2A: This gene encodes a glutamate receptor. The associated phenotype can range from milder conditions like SeLECTS (self-limited epilepsy with centrotemporal spikes) to more severe forms such as Landau–Kleffner syndrome (LKS) and continuous spike-wave during slow-wave sleep (CSWS). Memantine, an NMDA receptor blocker, has been shown to reduce seizure frequency and onset in these cases.
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KCNQ2: This gene encodes a potassium channel, with a spectrum of disorders ranging from benign familial seizures to epileptic encephalopathy. Retigabine, a potassium channel opener, has been trialed in adults, but due to its cardiac side effects, its use is limited. Sodium channel blockers have also been found beneficial in managing KCNQ2-related seizures.
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Rett's syndrome: A genetic disorder primarily affecting girls, caused by mutations in the MeCP2 gene. Trofinetide, a synthetic analog of the amino-terminal tripeptide of IGF-1, has shown promise in reducing neuroinflammation and enhancing synaptic function. IGF-1 is crucial for both normal brain development and response to injury and disease.
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SCN1A: This gene is associated with sodium channelopathies, presenting in a range from simple febrile seizures to Dravet syndrome. Sodium channel blockers can exacerbate symptoms, so drugs like phenytoin and carbamazepine should be avoided.
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Ref: Nabbout R, Kuchenbuch M. Impact of predictive, preventive and precision medicine strategies in epilepsy. Nat Rev Neurol 2020;16(12):674–688.
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Answer: c.
Insular lobe.
Explanation: Seizures originating from the insular lobe are uncommon but exhibit a diverse range of symptoms. These may include viscerosensory, somatosensory, and autonomic signs such as nausea, hypersalivation, piloerection, and heart rate changes. Additional symptoms can involve language disturbances, complex auditory auras, and due to spread to frontal and temporal areas, automotor and hypermotor behaviors, as well as tonic or clonic motor manifestations.
Some research suggests that viscerosensory symptoms—like abdominal auras and sensations of laryngeal constriction, along with autonomic signs such as nausea, hypersalivation, and sweating—are more likely to arise from the anterior insula. In contrast, painful sensations like burning, electric shocks, and tingling tend to be associated with the posterior insula.
Ref: Foldvary-Schaefer N, Unnwongse K. Localizing and lateralizing features of auras and seizures. Epilepsy Behav 2011;20(2):160–166.
