GENERAL CONSIDERATIONS

Approximately 3-10% of all children are known to experience at least one attack of seizure before 5 years of age, though most of them are benign febrile seizures. Prevalence of recurrent seizures in childhood is ~ 0.5­1.0% and 60% of epilepsies begin in childhood.

Pathophysiology: While precise mechanisms in causation and recurrence of seizures are unclear, three important contributors are:

a. A group of hyperexcitable neurons, capable of generating significant burst discharge of electrical activity. Seizures may originate from areas of neuronal death in organic brain lesions that promote development of

hyperexcitable neurons and many epileptic patients are known to benefit from removal of these foci by surgery. Genetic factors account for ~20% of childhood epilepsies, specially myoclonic seizures, e.g. infantile spasms.

b. Lower threshold of excitatory glutamatergic synapses, which promote rapid propagation of seizure activity to different areas of brain. Physiological immaturity of developing brain in young children is an important contributory factor in faster propagation of seizure activity.

Repeated sub-convulsive stimulation of the brain, e.g. Amygdala, is known to precipitate generalized seizures in experimental studies-a phenomena termed Kindling. Recurrent seizure activity from an abnormal temporal lobe may produce seizures from contralateral normal temporal lobe by transmission of stimulus via corpus callosum-a phenomena termed mirror-image seizure.

c. Inadequacy of neuroinhibitory system (Gamma aminobutyric acid or GABA), responsible for regulation of electric activity. GABA-sensitive substantia nigra seems to play an important role in control of seizures, specially in immature developing brain. Although not responsible for onset of seizures, inadequate neuroinhibitory mechanisms are important in development of status epilepticus.

Etiologically, seizures can be broadly classified in three categories (Table 18.14):

a. Febrile seizures due to developmental brain immaturity are commonest but generally benign seizures in pre­school children (Ch 18.6.3).

b. Secondary seizures due to underlying brain pathology or metabolic disorders. This group includes:

- Acute symptomatic seizures occurring within one week of acute neurological injury, e.g. trauma, stroke, hypoxia, infection or inflammatory pathology and within 24 hours of acute metabolic derangements. These cases require detailed etiological evaluation with serum biochemistry, neuroimaging and CSF examination and short-term anticonvulsant therapy for 6-9 months, apart from treatment of primary cause.

- Remote symptomatic seizure due to a distant brain injury, e.g. old stroke or structural cerebral lesion, which need long-term anticonvulsant therapy but limited need for investigations.

c. Epilepsy and epileptic syndromes, with enduring predisposition of the brain to generate seizures, discussed later (Ch 18.6.4).

However, this distinction is not mutually exclusive as many cases of febrile seizures or epilepsy are found to have underlying pathology on detailed evaluation.

Clinically, ILAE (2017) broadly classifies seizures as of three types, i.e. those with—(a) focal onset, (b) generalized onset, or (c) unknown onset (Table 18.15).

TABLE 18.15: ILAE 2017 classification of seizures

TABLE 18.14: Causes of seizures in children

Febrile seizures

Epilepsies and epileptic syndromes

Secondary seizures

• Infections:

Meningitis, encephalitis, cerebral malaria

ICSOL: Brain abscess, tuberculoma, NCC

Intrauterine infections

SSPE, post-viral encephalopathy

• Traumatic - head injury, birth trauma

• Vascular - strokes, cerebral edema

• Hypoxic - ischemic Encephalopathy (HIE)

• Metabolic:

Hypoglycemia

Hypocalcaemia, tetany, hypernatremia,

Kernicterus, Reye syndrome

Pyridoxine deficiency/dependency

Inborn errors of metabolism, e.g.

• Poisoning:

Drugs: Aminophylline, phenothiazines, phenytoin

Poisonings: Lead, strychnine, narcotic withdrawal

• CNS malformations: Microcephaly, hydrocephalus

• Intracranial tumors (mainly supratentorial)

• Neurocutaneous disorders: NF, tuberous sclerosis

• Functional (Hysteria)

NF: Neurofibromatosis; SSPE: Subacute sclerosing panencephalitis; ICSOL: Intracranial space occupying lesions; NCC: Neurocysticercosis

A. Focal Onset (with awareness or impaired awareness*)

Motor Onset

• Tonic, tonic-clonic, clonic

• Myoclonic, epileptic spasms

• Automatisms

• Hyperkinetic

Non-motor onset

• Autonomic

• Behavior arrest, emotional

• Cognitive

• Sensory

Focal-to-bilateral

• Tonic-clonic

B. Generalized onset

Motor

• Tonic-clonic, clonic, tonic,

• Myoclonic, myoclonic-tonic-clonic, myoclonic-atonic

• Atonic

• Epileptic spasms

Non-motor(absence)

• Typical, atypical, myoclonic, eyelid myoclonia

C. Unknown onset

• Motor: Tonic-clonic or epileptic spasms

• Non-motor: Behavior arrest

D. Unclassified

*at any time during seizure

A. Seizures with generalized onset may be motor (tonic- clonic, atonic, myoclonic, epileptic spasms) or non-motor (absence).

• Tonic-clonic seizures, the commonest seizure type, are characterized by four stages, though not necessarily distinguishable in all cases: (a) Pre-ictal aura, i.e. premonition of impending seizure, often manifesting as shrill-piercing cry or hallucinations; (b) Tonic phase, i.e. sudden contraction of entire musculature with uprolling of eyeballs, clinching of teeth, passage of urine/stools, loss of consciousness and often apnea/ cyanosis, lasting for few seconds; (c) Clonic phase, i.e. rhythmic contractions and relaxation of muscles for some time before cessation of attack; and (d) Post-ictal phase with drowsiness or sleep for few minutes to few hours. Many cases present with either tonic or clonic phase only.

• Atonic seizures are rare, characterized by sudden and transient loss of body tone with falls, swaying or head drop but with or without loss of consciousness.

• Myoclonic seizures are characterized by sudden, jerky shock like violent muscular contractions with loss of body tone and fall/slump forward.

• Epileptic spasms are common in infants presenting as startling episodes with sudden flexion or extension movements of head, neck or limbs, usually in clusters.

• Absence seizures are characterized by sudden cessation of awareness, motor activity or speech for few seconds (lt;30 sec) without loss of tone; with or without rhythmic movements, e.g. staring spells or fluttering of eyelids, etc. Many such attacks are common in day and may be precipitated with hyperventilation. EEG typically shows 3/second spike and wave activity.

B. Seizures with focal onset usually have an underlying structural cause and are classified as those with (a) preserved awareness or (b) impaired awareness (previously termed as simple partial and complex partial seizures, respectively). These seizures may be of (a) motor or (b) non-motor onset, e.g. sensory or autonomic seizures. Focal seizures with secondary generalizations (previously termed as Jacksonian march) are termed as focal to bilateral tonic-clonic seizures.

Some focal seizures may present as versive seizures (tics-like movements, e.g. sudden head turning and conjugate eye deviation) or associated with automatism, e.g. lip smacking, chewing, swallowing, pulling on cloths, caressing, nondirective running in fear etc, often misdiagnosed as psychiatric problems.

Status epilepticus (SE), i.e. continuous or sequential seizures lasting for gt;30 minutes without return of consciousness between attacks, may be the first presentation of seizures or develop during subsequent attacks, discussed later in Ch 18.6.2.

Diagnostic evaluation usually need to be delayed till the control of acute attack, though a quick clinical evaluation with preliminary history and examination helps to arrive at tentative diagnosis and collect relevant laboratory investigations. Important diagnostic clues may be obtained on:

a.

• Age of onset (Table 18.16)

• Type, duration and frequency of seizures

• Associated features, e.g. fever, coma, headache, etc.

• Past history of illnesses, head injury, poisoning, etc.

• Family history of epilepsy, neural tube defects, etc.

• Perinatal history of birth asphyxia, kernicterus, etc.

• History of delayed development

• History of anticonvulsant medication and default

b. General examination especially for:

• Head size, e.g. hydrocephalus, microcephaly

*Inborn errors of metabolism, e.g. Phenylketonuria, NCC: Neurocysticercosis; PYOM: Pyogenic meningitis; TBM: Tubercular meningitis; ICSOL: Intracranial space occupying lesions

• Neurocutaneous markers

• Organomegaly, e.g.

c. CNS examination after post-ictal phase for:

• State of sensorium

• Signs of meningeal irritation, raised ICP

• Focal neurological deficit

• Fundus examination

d. Laboratory investigations depend on probable cause, though most cases require following basal investigations at the time of first attack, except very typical cases of simple febrile seizures.

• CSF examination to exclude meningitis.

• Neuroimaging with CT/MRI.

• EEG with activation procedures, e.g. sleep deprivation or photic stimulation. However, normal EEG does not exclude epilepsy, while it may be transiently abnormal even in simple febrile seizures.

• Biochemical investigations for Blood sugar, S. ca⁺⁺, Mg⁺⁺, especially during first attack in infants, in whom metabolic seizures are common.

• Other investigations, e.g. metabolic screening for inborn errors, are indicated in selected cases.

Management of seizure disorders may be divided into—

(a) control of acute attack, (b) long-term anticonvulsant therapy and (e) treatment of underlying pathology.

I. Emergency management: All seizures are potentially life-threatening events and emergency management of acute attack or status epilepticus includes:

A. Basic life support:

• Loosening of tight garments and removal of sharp harmful objects from vicinity to prevent injury

• Recovery positioning with head turned to one side to prevent aspiration

• Restoration of airway (suction) and oxygen adminis­tration for prolonged seizures

• Transportation to equipped intensive care

B. Supportive therapy in intensive care:

• Breathing support with oxygen or bag and mask ventilation, as necessary

• IV access for circulatory support

• Collection of samples for blood sugar, S.Ca⁺⁺ and anticonvulsant drug levels (if on treatment).

• Quick clinical evaluation for probable cause

C. Specific anticonvulsant therapy is the first priority in all seizures, irrespective of etiology, using a step-wise approach as shown in (Table 18.17).

However, in strongly suspected metabolic seizures (apparently normal newborns or infants lt; 3 months) with first attack of short-duration seizure (lt;10 minutes) and no other neurological signs, a sequential therapeutic

TABLE 18.17: Step-wise anticonvulsant therapy for acute seizures/status epilepticus

Step I (Immediate, 0-5 min)

• IV Lorazepam 0.1 mg/kg @ 2 mg/min (max 4 mg) or

• IV Diazepam 0.2 mg/kg slowly (or PR* 0.5 mg/kg) or

• IV Midazolam 0.2 mg/kg slowly (max 5 mg) (or IM/nasal/ buccal*)

(*if IV access is not available)

Step II (5-20 minutes)

• IV Fosphenytoin 20 PE/kg @ 3 mg PE/kg/min or

• IV Phenytoin 20 mg/kg in 1:1 NS @ 1 mg/kg/min

• (can repeat Phenytoin/ Fosphenytoin 10 mg/kg or equivalent once)

Step III (No response to step I-II and PICU not available)

• IV Valproate 20 mg/kg in 1:1 NS, @ 6 mg/kg /min, or

• IV phenobarbital 20 mg/kg in NS @ 1.5 mg/kg/min, or

• IV Levetiracetam 20-30 mg/kg @ 5 mg/kg/min, with

- Monitor Airways, Breathing, Circulation

- Shift to the PICU, as early as possible

Step III (No response to step I-II and PICU facility available)

• IV Midazolam infusion (0.2 mg/kg(L) gt; 0.1 mg/kg/h)

• (titrate up every 15 min by 0.05 mg/kg/hr till max 2 mg/kg/ hr) or

• IV Propofol / Ketamine infusion (To be avoided)

Step V (no response to step IV)

• General anesthesia with ventilatory support

PE: Phenytoin equivalent

Caution: Use half of the loading dose is already on same drug

Avoid Valproate in liver disease, children lt; 2 years

Avoid Levetiracetam in renal failure. Preferred in metabolic disorders

Avoid benzodiazepines in liver disease, neuromuscular disorders

trial of IV dextrose and calcium gluconate administration after sample collection for biochemical studies, may be attempted to exclude metabolic seizures (Ch 12.16).

II. Long-term anticonvulsant therapy (ACT): Each attack of seizure may lead to further worsening of neurological injury and increased chance of recurrence. Long-term ACT aims not only to prevent recurrence of seizures but also to improve quality of life and requires understanding of following facts:

• When to start ACT?

• Which drugs to be used?

• How to monitor and modify ACT?

• How long to continue ACT?

When to start ACT? All cases of recurrent seizures do not require prolonged ACT. Long-term ACT is not indicated in simple febrile seizures, benign myoclonus of infancy and in most cases of Rolandic epilepsy. Non-epileptic seizure-like disorders, e.g. syncope, breath-holding spells and benign paroxysmal vertigo must be excluded before initiating ACT.

While there is no uniform agreement, ACT may also be withheld from a previously healthy child with first afebrile seizure, provided—(i) family history is negative, (ii) clinical examination and EEG is normal and (iii) family is cooperative and compliant for follow-up.

TABLE18.18: Common anticonvulsant drugs used in children

Chloride channel facilitators

Calcium channel blockers

**#8725;***indicates number of divided doses/day, i.e.**(2 divided doses),***(3 dividedd oses)

However, all cases with second attack of any afebrile seizure (barring above mentioned benign conditions) need to be started on long-term ACT.

Which drugs to be used? A plethora of antiepileptic drugs (Table 18.18) are available and the choice depends on the type of seizures as well as other factors, e.g. age, safety profile, drug-interactions and therapeutic response to previously used drugs. Antiepileptic drugs act by interfering with the sodium, potassium or calcium ion channels to reduce excitatory neurotransmitter release or function, or by enhancing GABAergic inhibition. Preferred choice of drug/s in various seizure/epilepsy types is discussed in Ch 18.6.4. Certain general principles need to be remembered while using antiepileptics:

• Single drug therapy is preferable to polytherapy, which should be used only in refractory cases.

• Each drug should be started with lowest recommended dose and increased gradually at weekly intervals till seizures are controlled. Most anticonvulsants take ~1 week to achieve sustained blood levels, necessary for seizure control.

• Compliance should be assured before considering a drug as ineffective. Timing of drug ingestion is also important, as absorption of most anticonvulsants is hampered with presence of food in stomach.

• If the seizures are not controlled even with highest dose of single drug, second drug may be added with lowest possible dose and increased gradually.

• Control of seizure after addition of second drug indicates its efficacy and then the first drug may be gradually tapered-off, under close monitoring.

Monitoring and modification of ACT: All cases on ACT should be monitored periodically for control of seizures, adverse effects of drugs and progression of primary lesion. Occasional break-through seizures are not uncommon even in well-controlled children, especially during fever and do not warrants change of ACT.

However, recurrent seizures despite ACT indicate need to review the-(a) compliance, (b) adequacy and timing of the dose, (c) therapeutic drug monitoring for serum levels.

Therapeutic drug monitoring (TDM) is an excellent tool to differentiate drug failure from poor compliance. Sub-therapeutic drug levels indicate need to ensure compliance rather than change of drug. However, recurrence of seizures despite adequate serum drug levels warrants either substitution with second-line drugs or addition of adjuvant drugs (polytherapy)

How long to continue ACT? Most seizures recur within first month (60%) and chances of recurrence decline with increasing seizure-free interval. Risk of recurrence in absence of active or structural brain lesion is almost nil after 2-3 years.

Hence, ACT should be continued till at least-(a) two years after the last seizure, (b) EEG is abnormal, and (c) primary lesion is structural or active, likely to cause recurrence of seizure. ACT drugs should be withdrawn slowly, one at a time, to prevent sudden recurrence. In severe epileptic syndromes, e.g. mesial temporal sclerosis or Lennox-Gastaut syndrome, longer or even life-long therapy may be required while in acute symptomatic seizures or benign epileptic syndromes the duration of ACT therapy can be as short as 6-9 months.

18.6.2