EPILEPSY IN CHILDHOOD

Epilepsy, according to International League Against Epilepsy (ILAE) is defined as:

• At least two unprovoked (or reflex) seizures, at least 24 hours apart;

• One unprovoked (or reflex) seizure and probability of further seizures similar to general recurrence risk (at least 60% after two unprovoked seizures), over next 10 years;

• Diagnosis of an epilepsy syndrome.

In practice, clinical diagnosis of epilepsy requires occurrence of at least one unprovoked seizure with either a second seizure after at least 24 hours or an EEG abnormality to suggest predisposition for recurrence.

Epilepsy syndrome refers to quot;a constellation of signs and symptoms that often occur together, such as seizure type, age of seizure onset, responsiveness to certain anti-seizure drugs, and characteristic EEG findings, underlying genetics, and natural history.quot;

Epileptic encephalopathy denotes an epileptic condi­tion associated with progressive cerebral dysfunction or delay, behavioral or cognitive issues, e.g. West syndrome, Lennox- Gastaut syndrome, etc.

Etiologically, epilepsy in children has been broadly classified as of—(a) genetic, (b) structural, (c) metabolic, (d) infectious, (e) immunological, and f) unknown origin, according to ILAE 2017 classification.

Genetic epilepsy (previously termed as Idiopathic) refers to an underlying known or presumed genetic defect, which is not causative of a brain structural or metabolic disorder other than the epilepsy. Other etiological types of epilepsy (except unknown) denote presence of an underlying cause (secondary epilepsy). Some important and common types of epileptic presen­tations and related syndromes are as follows:

Generalized tonic-clonic seizures (Grandmal epilepsy) are the commonest seizure type in childhood, which may occur de novo or follow a partial seizure with secondary generalization (Jacksonian march).

Typical absence seizures usually start at 5-8 years of age, more common in girls. Aura and post-ictal phase is absent. Muscle tone and posture is well preserved. Frequency may vary from few to countless attacks per day, sometimes presenting with absence status epilepticus. Absence attacks may be precipitated by hyperventilation for 3-4 minutes.

Etiology is generally idiopathic, but learning and behavioral problems are common. Early-onset seizures (lt;4 yrs) may be associated with a glucose transporter defect. EEG is characteristic with a 3/seconds spike and slow wave pattern. While ~50% cases become seizure-free after

some time, rest may develop into tonic-clonic attacks, specially those with very early or late onset.

Atypical absence seizures have associated myoclonic component and tone changes, e.g. head drop, sometimes precipitated by drowsiness. EEG may show 1-2 Hz spike and slow wave discharges.

Juvenile absence seizures are similar to typical absence seizures but occur at a later age, often associated with juvenile myoclonic epilepsy. EEG may show 4-6 Hz spike and slow wave discharges.

Myoclonic seizures are characterized by rapid, brief, repetitive but not rhythmic, muscular contractions with loss of body tone and fall/ slump forward. Etiological spectrum of myoclonic epilepsy spans from essentially benign seizures, e.g. benign myoclonus of infancy to severe intractable disorders, e.g. Lennox-Gastaut syndrome. Some common myoclonic syndromes are as follows:

Infantile spasms is the commonest myoclonic epilepsy, beginning at the age of 4-8 months.

Clinically, infantile spasm is characterized by clusters of brief symmetric myoclonic contractions of neck, trunk and extremities, with three variants—(a) Flexor spasms, with sudden flexion of neck, arms and legs onto the trunk (salaam spells); (b) Extensor spasms, with sudden extension of trunks and extremities (least common); and (c) Mixed, with flexor and extensor spasms during different clusters.

Etiologically, infantile spasms are either cryptogenic (10-20%) without identifiable cause or symptomatic (80­90%) following birth asphyxia, intrauterine infections, perinatal meningitis, neonatal hypoglycaemia, head trauma and developmental CNS malformations. DPT immunization, once implicated etiologically, probably has no cause effect relationship.

Pathogenesis is unclear, though it has been sugges­ted that perinatal stress during critical period of neurodevelopment leads to overproduction of cortico- trophin release hormone (CRH), which may induce neuronal hyperexcitability. CRH suppression with exogenous ACTH/steroids has been found effective in control of infantile spasm.

Management: ACTH therapy is the drug of choice for infantile spasms given intramuscularly as 6 units/ kg/day for 2 weeks, which must be tapered over next 2-4 weeks, depending on the clinical and EEG response. Alternatively, high dose oral prednisolone (4 mg/kg/ day) may be used with similar schedule.

Vigabatrin is the drug of choice for infantile spasms in children with tuberous sclerosis, while it may be used as second-line drug or adjuvant in other cases. Other alternatives include Benzodiazepines or Valproic acid.

Outcome and therapeutic response is better in cryptogenic cases, while those with underlying neuro­pathology tend to be refractory with ~80% risk of mental retardation.

West syndrome is a triad of infantile spasms, deve­lopmental regression and hypsarrhythmia on EEG. Etiologically, while many cases are cryptogenic (unknown etiology) with normal development before the onset of spasms, others may have significant underlying pathologies, e.g. perinatal encephalopathies, brain malformations, metabolic disorders, etc. In boys, some cases may be associated with ARX gene mutations, along with ambiguous genitalia and cortical migration defects.

Typical myoclonic epilepsy of early childhood begins at ~1-4 year with variable frequency of myoclonic and generalized tonic-clonic seizures. Family history of similar seizures and past history of complex febrile seizures is common. EEG usually reveals fast spike-wave complex at gt;2.5/sec with normal background rhythm. While most cases become seizure-free after few years, learning and behavioral disorders are common.

Juvenile myoclonic epilepsy (Janz syndrome) is the commonest generalized epilepsy in young adults, with usually autosomal dominant inheritance, linked to mutations in many genes (e.g. CACNB4).

Clinically, JME presents in early adolescence with early morning myoclonic seizures, often causing the patient to drop things. Seizures are more common in sleep-deprived individuals and usually abate as the day progresses. Some cases may develop early-morning generalized tonic-clonic seizures, when awakened suddenly. EEG shows 4-6/seconds irregular spike and wave pattern, which enhances on photic stimulation.

CNS examination and MRI is normal and seizures responds well to sodium valproate, though life-long therapy is necessary to prevent recurrence. Lamotrigine is the alternative, specially preferred in adolescent girls. Carbamazepine and Phenytoin may worsen the symptoms.

Lennox-Gastaut syndrome typically starts at 2-10 years of age with a characteristic triad of—(a) intractable seizures of various types, e.g. tonic, myoclonic, atonic and a typical absences, (b) mental retardation, and (c) typical EEG findings with slow spike-wave (lt; 2/sec) discharges. These seizures are often secondary to diffuse infective or hypoxic encephalopathies and refractory to multiple anticonvulsants. Most cases are left with long­term cognitive impairment and intractable seizures despite multiple therapies.

Atonic seizures are rare and characterized by sudden and transient (1-4 seconds) loss of body tone with frequent falls, swaying or head drop; without loss of consciousness.

Focal (partial) seizures may be with/without loss of consciousness and with/without secondary generalization. Focal seizures usually indicate symptomatic epilepsy due to underlying disease, e.g. brain malformations, tumors, hypoxic-ischemic injury or severe metabolic disease and tend to be more severe and refractory to the treatment. Some common epileptic syndromes with predominantly focal seizures are as follows:

Self-limited epilepsy with centrotemporal spikes (previously termed as benign rolandic epilepsy) typically starts at ~10 years of age in previously normal children, with strong family history.

Clinically, child typically wakes up at night usually within 1-2 hours of falling asleep or prior to awakening, with a focal seizure involving facial twitching and oropharyngeal symptoms, e.g. tongue paresthesia, dysarthria and excessive salivation. Consciousness is generally preserved though secondary generalization may occur.

EEG is characteristic with broad-based centrotemporal spikes from a rolandic focus, specially during drowsiness and sleep with normal background activity.

Most cases remit spontaneously by 15-16 years of age and anticonvulsant therapy (preferably with carba­mazepine) is indicated only in cases with recurrent troublesome seizures.

Self-limited epilepsy with autonomic features (previously termed as benign epilepsy with occipital spikes) may begin in early childhood at 3-5 years of age, with complex partial seizures and vomiting, retching, pallor, flushing and abdominal pain. Episodes usually remit in few years.

Childhood onset visual epilepsy (COVE) presents in school age group of 6-14 years, with seizures characte­rized by focal sensory visual phenomena like multi­colored circles with/without deviation of eyes with/ without impaired awareness.

Mesial temporal sclerosis presents as temporal lobe epilepsy, often preceded by febrile seizures.

Reflex seizures: Many patients get seizures only in response to a very specific, identifiable sensory stimulus and these seizures are termed as reflex seizures. Sensory stimuli may be external (flickering light, loud music or sound, hot-water, etc.) or internal (reading, thinking, calculation, etc.).

Clinically, reflex seizures may be generalized, partial, non-convulsive, absence or myoclonic. Photosensitive seizures are commonest types of reflex seizures, often triggered by bright or flashing lights, e.g. TV, video games, discotheques, etc. Photomyoclonic seizures often present with forehead muscle twitching or repetitive eye blinking.

EEG may be normal or abnormal on photic stimulation. Patients tend to outgrow photosensitive seizures by 30­40 years of age. Avoidance of stimuli is usually enough in most cases while some may need anticonvulsant therapy, preferably with valproic acid.

Management of Epileptic Disorders

Management of epileptic disorders may be broadly divided into four components:

A. Control of acute attack or status epilepticus, as discussed in Chapter 18.6.1, Table 18.4.

B. Long-term anticonvulsant therapy, based on the principles discussed earlier (Chapter 18.6.1), though the choice of anti-epileptic drugs (AEDs) vary according to the type of seizures and therapeutic response (Table 18.20).

Apart from established AEDs, others, e.g. steroids and IV immunoglobulins are also used in selected cases. Steroids (ACTH or Prednisone) are used in epileptic encephalopathies, e.g. infantile spasms, West syndrome, Lennox-Gastaut syndrome, etc. IV Immunoglobulins are used in West syndrome, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, etc.

Mechanism of action of steroids and of IVIG is not known, presumed to be anti-inflammatory by reducing seizure-induced cytokine levels, which tend to increase neuronal excitability. Steroids might also stimulate brain neurosteroid receptors to enhance GABA activity and reduce corticotrophin-releasing hormone, which is known to be epileptogenic.

TABLE 18.20: Long-term ACT of choice in seizure disorders

ACTH: Adrenocorticotropic hormone; CBZ: Carbamazepine; CLB: Clobazam; CLZ: Clonazepam; ETHX: Ethosuximide; LEV: Levetiracetam; LTG: Lamotrigine; OXC: Oxcarbazepine; PHB: Phenobarbitone; PHT: Phenytoin; TPM: Topiramate; VAL: Valproic acid; VGB: Vigabatrin; ZNS: Zonisamide

C. Non-pharmacological interventions, e.g. surgery or dietary modifications (e.g. ketogenic diet) are of limited value in epileptic children.

Surgery is rarely indicated in childhood epilepsy except select cases of refractory seizures, which involve-ablation of identified epileptic foci (stereotactic surgery), partial excision of affected lobe or resection of corpus callosum to prevent spread of electrical activity. Surgery should be considered only in cases with—

(a) documented failure of medical therapy with mini­mum three anticonvulsants in maximum permitted doses,

(b) a properly defined epileptogenic zone-area that needs to be resected to achieve seizure freedom and

(c) unlikelihood of unacceptable adverse consequences of surgery.

Ketogenic diet has been used for refractory seizures of various type, e.g. infantile spasms, tuberous sclerosis complex, Dravet syndrome and some mitochondrial disorders. It involves an initial period of fasting followed by a diet with Fat:Non-fat ratio of 3-4:1 and fats consisting of animal fat, vegetable oils, or medium­chain triglycerides. Ketogenic diet is contraindicated in carnitine deficiency and other metabolic epileptic disorders. Diarrhea, vomiting, hypoglycemia and dehydration is common with these diets along with poor palatability.

D. General supportive care in children with seizure disorders includes—(a) psychological support and counseling, (b) accident prevention, (c) educational modifications, and (d) rehabilitation.

18.6.5