CONVLUSIVE DISORDERS

CONVULSIVE DISORDERSA convulsion or seizure is a transient disturbance of brain function, manifested by involuntary, motor, sensory, autonomic or psychic phenomenon alone or in any combination usually having associated alteration or loss of consciousness.

Convulsions are relatively more common in infancy and childhood.

Several times, a child may present with a condition that can mimic or be misinterpreted as a seizure. These conditions include convulsive syncope with or without cardiac dysarhythmia, decerebrate posturing, psychogenic events, dystonia migraine and many other depending upon the age of the patient. A seizure has to be differentiated from these conditions as misdiagnosis can have significant therapeutic implications.

Neonatal seizures often present with twitching of the limbs, fluttering of the eyelids, sucking movements, and conjugate deviation of the eyes. These should be distinguish from jitteriness, tremors, startle response to stimuli, sudden jerks on awakening and tremulousness of the hungry child.CAUSES OF CONVULSIONS IN CHILDHOOD: -

Early Neonatal Period: -

i. Birth asphyxia, difficult obstructed labor.

ii. Intraventricular intracerebral hemorrhage.

iii. Pyridoxine dependency, hypoglycemia, and hypocalcema, hypo or hypernatremia

iv. Inborn errors of metabolism.

v. Maternal withdrawl

vi. Accidental injection or local anesthetic into the fetal scalp during the paracervical block given to the mother.

Neonatal period: -

i. Hypocalcemia, hypomagnesemia, hypoglycemia, dyselectrolytemia.ii. Kernicteerus.

iii. Developmental malformations, microcephaly, proncephaly, arteriovenous fistualae, agensis of corpus callosum.

iv. Meningitis, septicemia.

v. Intrauterine injfections (TORCH)

vi. Tetanus neonatorum

vii. Inborn metabolic errors PKU, MSUD, Gala atosemia, homocysteinemia, urea cycle disorders.

From One Month to three years: -

i. Simple febrile convulsions.

ii. Injections of the central nervous system

a. Acquired Bacterial meningitis tuberculous, meningitis, aseptic meningitis, encephalitis, cerebral malaria, tetanus, mumps encephalopathy, measles encephalopathy and Reyes syndrome

b. Intrauterine injections.

iii. Postinfectious or postvaccinal encephalopathy: - Following acute viral infections, pertusis, vaccination, subacuite selerosing panencephalitis post-measles / chicken pox.

iv. Metabolic cause: - Dehydration, dyselectrolytemia, alkalosis, hypocalcemia, hypomagnesemia and inborn errors of metabolism.v. Space occupying lesions in the brain: Neoplasm, brain abscess, tuber culoma, cysticerosis.

vi. Vascular: - Arteriovenous malformations, intracranial thrombosis or hemorrhage and consumptive coagulopathies.

vii. Miscellaneous causes: - The stroke, acute brain swelling poisoning, lead encephalopathy, hypertensive encephalopathy, breath holding spells, residua of birth trauma and birth asphyxia, gray matter degeneration and storage disorders.

viii. Drugs and poisons: - Toxic doses of phenothiazine salicylate, diphenylhydantion, strychnine, carbon monoxide etc.

ix. Epilepsy.

3 years to 6 years: -

Idiopathic epilepsy, febrile convulsions uncommon, rest as , previously enumerate at B.

Classification of Seizures:-

1. Bebrile Convulsions

i. Typical febrile convulsions

ii. Atypical febrile convulsions

2. Chronic/ Recurrent convulsions

3. Status Epilepticus

4. Neonatal seizures

i. Subtle seizures

ii. Multifocal clonic seizures without Jacksonian pattern.

iii. Focal clonic seizures

iv. Tonic seizures

v. Myoclonic seizures.

International Classification of Epileptic seizures: -1. Partial seizures

i. Simple partial seizures

Motor

Sensory

Autonomic

Psychic

ii. Complex partial seizures

Simple partial followed by impaired consciousness, consciousness impaired at onset.

Partial seizure with secondary generalization2. Generalized seizures

i. Absences

Typical

Atypical

ii. Generalized tonic clonic

Tonic

Clonic

Myclonic

Atonic

Infantile spasms

Types of Convulsions: -

I. FEBRILE CONVULSIONS: -

The term denotes seizures associated with fever but excluding those due to CNS infections.

It is one of the most common disorders of infancy and early childhood.

Special Features: -

Some of the remaining salient features are: -

(A) Typical Features: -

These are generally associated with fever of 38o C or more at the time of attack

Generalized rather than focal convulsions are nearly a rule. The first febrile seizure usually occurs between 6 months and 3 years of age. Family history of seizures is frequently present, also higher incidence occurs in twins and children of consanguinous parents. This has led to the speculation that, as a result of genetic susceptibility, immature neuronal membrane responds to the temperature elevation by breaking down. The attack lasts less than10 to 20 minutes. There is no recurrence before 12 to 18 hours of the attack that accompanies rapid rise in body temperature. There is no residual paralysis of a limb following the attack. CSF after the attack is normal. EEG after the attack is normal(B) Atypical Febrile Convulsions: -

A proportion of children may have focal convulsions of greater than 20 minutes duration even without significant fever and/or with persistently abnormal EEG for two weeks or more after the attack.

All these cases (in fact all case of febrile seizures not satisfying the criteria laid down for typical febrile seizures) are labelled atypical febrile convulsion cases. They are basically predisposed to idiopathic epilepsy.

(II) CHRONIC & RECURRENT CONVULSIONS: -

Under this heading are covered epilepsy, epilepsy stimulating states and epilepsy equivalents such as narcolepsy, hysteria, breath holding spills, syncope and migraine.

Epilepsy is defined as a symptom complex characterized by recurrent, paroxysmal attacks of unconsciousness or impaired consciousness, usually with a succession of tonic or clonic muscular spasms or other abnormal behaviour. It may be idiopathic or organic.

The salient details of types of idiopathic epilepsy are given below:

i. Grandmal Commonest, generalized tonic clonic convulsions are its hallmark.

ii. Petitmal Momentary loss of consciousness.

iii. Jacksonian or focal seizures Starting from one part and spreading to other parts in a fixed pattern.

iv. Psychomotor (temporal lobe) Visceral symptoms like nausea, vomiting or epigastric sensation followed by short periods of increased muscular tonicity and, later, semi - purposive movements during a period of impaired consciousness or amnesia. The syndrome of periodic headache in association with abdominal pain , nausea and vomiting has been termed abdominal epilepsy or abdominal migraine.

v. Myoclonic: - Involuntary violent contractons of limbs or groups of muscles with or without loss of consciousness. In infantile myoclonic epilepsy, also called sallam seizures or West Syndrome, the baby (usually under 6 months) has massive attacks of flexion of the head, once or as may as 100 times a day. In the primary type child is microcephalic and mentally retarded. EEG shows typical hypsarrhythmia.

Treatment is preferably with ACTH though steroids, diazepam, valproate and pyridoxie may also prove effective.

ORGANIC EPILEPSY: -

It is frequently accompanied by cerebral palsy, mental retardation and EEG abnormalities. Its main causes are: -

i. Post traumatic Direct damage to brain tissue as followed head injury.

ii. Post hemorrhagic Injury to brain at birth or afterwards, bleeding diathesis, rupture of miliary aneurysm, pachymeningitis.

iii. Post infections Meningitis, ancephalitis cerebral abscess, sinus thrombophlebitis.

iv. Post toxic Kernicterus chronic poisoning (lead arsenic)

v. Degenerative Intracranial neurofibromatosis., cerebromascular digeneratation , subacute selerosing panecephalitis.

vi. Congenital Arteriovenous aneurysm, strurgeweber type of vascular anomaly, cerebral aplasia, porencephaly, hydrocephalus, tuberous sclerosis.

vii. Parasitosis Cysticercosis, hydatid disease, ascariasis, toxoplasmosis.

(III) STATUS EPILEPTICUS: -

Definition: -

Status epilepticus means any true convulsion lasting more than 30min or a series of convulsions extending over such a period wit or without recovery of consciousness between spells.

Loss of consciousness though a prominent feature of status epilepticus with grandmal epilepsy, may be absent in petitmal, psychomotor or myoclonic status. In the latter category, consciousness is generally only impaired status convulsions refer to status epilepticus with preservation of consciousness.PATHOPHYSIOLOGY: -

The relationship between the neurologic outcome and the duration of status epilepticus is unknown in children and adults. Some evidence shows that the period of status epilipticus that produces neuronal injury in a child is less than that for an adult. In primates pathologic changes can occur in the brain of ventilated animals after 60 min of constant seizure activity when metabolic homeostasis is maintained. Thus, cell death may result from excessively increased metabolic demands by continually discharging neurons. The most vulnerable areas of the brain include the hippocampus amygdlala, cerebellum, middle cortical area, and thalamus. Characteristic acute pathologic changes consist of venous congestion, small petechial hemorrhages and oedema. Ishemic cellular changes are the earliest histologic findings, followed by neuronophagia, microglieal proliferation, cell loss and increased numbers of reactive astrocytes. Prolonged seizures are associated with lactic acidosis an alteration in the blood brain barrier and elevation of ICP and temperature. A series of complex, poorly understood hormonal and biochemical changes ensues. Circulating levels of prolactin, ACTH, cortisol, glucagons, growth hormne, insulin, epinephrine and cyclic nucleotides are elevated during status epilepticus in the animal. Neuronal concentrations of Ca, arachidonic acid and prostaglandins rise and my promote cell death. Initially, the animal may be hyper glycemic, but hypoglycemia ultimately occurs. Inevitably dysfunction of the autonomic nervous system develops and may lead to hypotension and shock. These series of biochemical changes are not unique to status epilepticus because they may also follow severe mechanical and stress injuries.Constant tonic clonic muscle activity during a seizure may produce myoglobnuria and acute tubular necrosis.

Several investigations have shown significant increase in cerebral blood flow and metabolic rate during status epilipticus. In animals approximately 20 min of status epilepticus produces regional oxygen insufficiency, which promotes all damage and necrosis. The studies have led to the concept of a critical period during status epilepticus when irreversible neuronal changes may develop. This transitional period varies between 20 & 60 min in animals during constant seizure activity.

(4) NEONATAL SEIZURES:-

i. SUBTLE SEIZURES: -

They account for over 50% of all cell seizures and are more common in preterm babies. They can be easily overlooked. Jerking of the eyes (with or without conjugate deviation), blinking or fluttering of eyelids, starting look, sucking, chewing, or smacking oro buccal movements apneic attacks or included among subtle seizures. Oral, facial & lingual phenomenon are common due to advanced maturation of the limbic system. There is tachycardia at the onset followed by bradycardia after apnea and hypoxemia.

(II) Multifocal clonic seizures without Jacksonian patterna: -

Tonic convulsive movements migrate haphazardly from one limb to another. The twitchings may be predominantly limited to one side of the body. They may occur due to hypoxic ischemic encephalopathy and birth trauma.

(III) Focal clonic seizures: -

They are well localized and often associated with loss of consciousness . Even focal seizures in a newborn baby are a manifestation of bilateral cerebral disturbance. They are common due to metabolic disorder, birth trauma and cerebral infarction. Right sided clonic seizures are most commonly due to blockage of left middle cerebral artery.(IV) Tonic Seizures: -

There is generalized stiffening similar to decerebrate (tonic extension of all limbs) or decorticate (flexion of upper limbs and extension of lower limbs) posturing and may be associated with stertorous breathing and eye signs or occasional clonic jerks. They may be associated with intraventricular hemorrhage and kernicterus.

(V) Myclonic seizures: -

Sudden jerk movements produced by episodic contractions of a group of muscles are rare in the newborn. These are more common in babies with developmental defects including anencephaly. Typical hypsarrhythmic electroencephalogram and massive myoclonic spasm may develop during infancy.

International Classification of Epileptic Seizures: -

1. PARTIAL SEIZURES: -

Partial seizures account for a large proportion of childhood seizures up to 40% in some series. Partial seizures may be classified as simple and complex, consciousness is maintained with simple seizures and is impaired in patients with complex seizures.

Simple Partial Seizures (SPS): -

Motor activity is the most common symptom of SPS. The movements are characterized by asynchronous clonic or tonic movements, and thy tend to involve the face, neck and extremities. Versive seizures consisting of head turning and conjugate eye movements are particularly common in SPS. Automatisms do not occur with SPS, but some patient complain of aura (e.g. chest discomfort and headache), which may be the only manifestation of a seizure. The average seizures persists for 10-20 sec.Complex Partial Seizures (CPS): -

A CPS may begin with a simple partial seizure with or without an aura, followed by impaired consciousness conversely the onset of the CPS may coincide with an altered state of consciousness. An aura consisting of vague, unpleasant feelings, epigastric discomfort or fear is present in approximately one third of children with SPS and CPS. The presence of an aura always indicates a focal onset of the seizures because partial seizures are difficult to document in infants and children, the frequency of their association with CPS may be underestimated. Impaired consciousness in infants and children is difficult to appreciate. Automalisms are a common feature of CPS in infants and children occurring in approximately 50 75% of cases, the older the child, the greater is the frequency of automatisms. Automatisms develop after the loss of consciousness and may persist into the postical phase but they are not recalled by the chld. The automatic behaviour observed in infants is characterized by alimentary automatisms, including up smacking, chewing, swallowing and excessive salivation. Those movement can represent normal infant behaviour and are difficult to distinguish from the automatisms of CPS.

Automatic behaviour in older children consist of semipurposeful, inco-ordinated and unplanned gestural automatisms, including picking and pulling at clothing or the bed sheets, rubbing or caressing objects, and walking or running in a nondirective, repetitive, and often fearful fashion.

Spreading of the epileptiform discharge during CPS can result in secondary generalization with a tonic clonic convulsion. During the spread of the ictal discharge throughout the hemisphere, contralateral, versive turning of the head, dystonic posturing and tonic or clonic movemtns of the extremities and face including eye blinking may be noted. The average duration of a CPS is 1 - 2 min, which is considerably longer than an SPS or an absence seizure.

Benign Partial Epilepsy with centrotemporal spikes (BPEC) :-

BPEC is a common type of partial epilepsy in childhood and has an excellent prognosis. The CIF, EEG findings (rolantic foci) and lack of a neuropathologic lesion are characteristic and readily separate BPEC from CPS, BPEC occurs between the ages of 2 and 14 and has a peak age of onset of 9-10 yrs. The disorder occur in normal children with an unremarkable past history and normal neurologic exam. There is often a positive family history of epilepsy. The seizures are usually partial and motor sign and somatosensory symptoms are often confined to the face. Oropharyngeal symptoms include tonic contractions and paresthesis of the tongue, Unilateral numbness of the cheek, guttural noises, dysphagia and excessive salivation. U/L tonic- clonic contractures of the lower face frequently accompany the oropharyngeal symptoms, as do clonic movements or paresthesias of the ipsilateral extremities, consciousness may be intact or impaired, and the partial seizure may proceed to secondary generalization.2. GENERALIZED SEIZURES: -

Absence Seisures: -

Simple (typical), absence (petitmal) seizures are characterized by a sudden cessation of motor activity or speech with a blank facial expression and flickering of the eylids. These seizures, which are uncommon before age 5 yrs. are more prevalent in girls, they are never associated with an aura, they rarely persist longer than 30 sec and they are not associated with a postictal state.

Children with absence seizures may experience countless seizures daily, whereas complex partial seizures are usually less frequent. Patient do not lose body tone, but their head fall forward slightly. Immediately after the seizure, patients resume preseizures activity with no indication of postictal impairment.Generalize Tonic clonic seizures: -

These seizures are extremely common and may follow a partial seizure with a focal onset. They may be associated with an aura, suggesting a focal origin of the epileptiform form discharge. It is important to inquire about the presence of an aura, because its presence and site of origin may indicate the area of pathology. Patients suddenly lose consciousness and in some cases emit a shrill, piercing cry. Their eyes roll back their entire body musculature undergoes tonic contractions, and they rapidly become cyanotic in association with apnea. The clonic phase of the seizure is heralded by rhythmic clonic contractions alternating with relaxation of all muscle group. The clonic phase slows toward the end of the seizure, which usually persists for a few minutes, and patients often sigh as the seizures comes to an abrupt stop. During the seizure, children may bite their tongue but rarely vomit. Loss of sphincter control, particularly the bladder is common during a generalized tonic clonic seizures.

Tight clothing and jewelry around the neck should be loosened, the patient should be placed on one side, and the neck and jaw should be gently hyper extended to enhance breathing. The mouth should not be opened forcibly by an object or by a finger because patients teeth may be dislodged and aspirated, or significant injury to the oropharyngeal cavity may result.Myoclonic Epilepsies of Childhood: -

This disorder is characterized by repetitive seizures consisting of brief, often symmetric muscular contraction with loss of body tone and falling or slumping forward, which has a tendency to cause & injuries to the face and the mouth.

Benign Myoclonus of Infancy: -

Benign myoclonus begin during infancy and consist of clusters of myoclonic movements confined to the neck, trunk and extremities. The myoclonic activity may be confused with infantile spasm. Cessation of myoclonus by 2 yrs. of age. An anticonvulsant is not indicated.Typical Myoclonic Epilepsy of Early Childhood: -

Children who develop typical myoclonic epilepsy are near normal before the onset of seizures with and unremarkable pregnancy, labour an delivery and developmental milestones. The mean age of onset is approximately 2 years but the range spread from 6 months to 4 years.

The frequency of myoclonic seizures varies, they may occur several times daily, or children may be seizure free for weeks. A few patients have febrile convulsions or generalized tonic clonic afebrile seizure that precede the onset of myoclonic epilepsy. At least one third of the children have a positive family history of epilepsy, which suggests a genetic etiology in some cases. The long term outcome is relatively favorable. Mental retardation develops in the minority and more than 50% are seizures free several years later. However, learning and language problems and emotional and behavioral disorders occur in a significant number of these chidren and require prolonged follow up by a multidisciplinary team.

Complex Myoclonic Epilepsies: -

These consist of a heterogeneous group of disorders with a uniformly poor prognesis. Focal or generalized tonic clonic seizures beginning during the 1st year of life typically antedate the onset of myoclonic epilepsy. The generalized seizure is often associates with an upper respiratory tract infection and a low grade fever and frequently develops into status epilepticus. A history of hypoxi ischemic encephalopathy in the perinatal period and the finding of generalized upper motor neuron and period and extrapyramidal sign with microcephaly constitute a common pattern among these children. A family history of epilepsy is much less prominent in this group compared with typical myoclonic epilepsy. Some children display a combination of frequent myoclonic and tonic seizures.Treatment with valproic acid or the benzodiazepines may decrease the frequency or intensity of the seizures. The Ketogenic diet should be considered for those patients whose seizures are refractory to anticonvulsants.

Juvenile Myoclonic Epilepsy (Janz Syndrome): -

Juvenile myoclonic epilepsy usually begins between the age of 12 and 16 yrs. and accounts for approximately 5% of the epilepsies. Patients not frequent myoclonic jerks on awakening, making hair combing and tooth brushing difficult. As the myoclonus tends to abate later in the morning most patients do not seek medical advice at this stage and some deny the episodes. A few years later, early morning generalized tonin clonic seizures develop in association with the myoclonus. The neurologic exam is normal and the majority responds dramatically to valproate, which is required lifelong. Discontinuance of the drug causes a high rate of recurrence of seizures.Progressive Myoclonic Epilepsies: -This heterogeneous group of rare genetic disorders uniformly has a grave prognosis. These condition include Lafora disease, myclonic epilepsy with ragged red fibers (MERRF). Lafora disease presents in children between 10-18 yrs. with generalized tonic clonic seizures. Ultimately, myoclonic jerks appear, these become mere apparent and constant wit progression of the disease. Mental deterioration is a characteristic feature and becomes evident within one year of the onset of seizures. Neurologic abnormalities, particularly cerebeller and extrapyramidal signs, are prominent findings. The myoclonic jerks are difficult to control, but a combination of valproic acid and a benzodiazepine (e.g. clonazepam) is effective in controlling the generalized seizures.

INFANTTLE SPASM: -Infantile spasm usually begin between the ages of 4 and 8 month and are characterized by brief symmetric contractions of the neck, trunk and extremities.There are three types of infantile spasm: -i. Flexor spasm

ii. Extensor spasm

iii. Mixed spasm

i. Flexor spasm: -

It occurs in clusters or volleys and consist of sudden flexion of the neck, arms and legs onto the trunk.

ii. Extensor spasm: -

Extensor spasm produce extension of the trunk and extremities and are the least common form of infantile spasm.

iii. Mixed spasm: -

Mixed infantile spasm, consisting of flexion in some volleys and extension in others, is the most common type of infantile spasm.

Clusters or volleys of seizures my persist for minutes with brief intervals between each spasm. A cry may precede or follow an infantile spasm, accounting for the confusion with colic in a few cases. The spasm occur during sleep or arousal but have a tendency to develop while patients are drowsy or immediately on awakening.Infantile spasms are typically classified into two groups: -

i. Cryptogenic

ii. Symptomatic

i. Cryptogenic: -

A child with cryptogenic infantile spasms has an uneventful pregnancy and birth history as well as normal developmental milestones before the onset of seizures. The neurologic examination and the CT and MRI scans of the head are normal, and there are no associated risk factors. Approximately 10-20% of infantile spasms are classified as cryptogenic and the remainder is classified as symptomatic.ii. Symptomatic: -

Symptomatic infantile spasm are related directly to several prenatal, perinatal and postnatal factors. Prenatal and perinatal factors include hypoxic ischemic encephalopathy with periventricular leukomalacia, congenital infections inborn errors of metabolism. Post natal conditions include CNS infections, head trauma (especially subdural hematoma and intraventricular hemorrhage), and hypoxic ischemic encephalopathy.

In the past, immunization particularly with the pertusis antigen had been implicated as a cause of infantile spasms. Infants with cryptogenic infantile spasms hava a good prognosis, whereas those with the symptomatic type have an 80 -90% risk of mental retardation. DIAGNOSIS: -

The investigation of a seizure depends on many factors, including the age of the patient, the type and frequency of the seizure, and the presence or absence neurologic findings and constitutional symptoms.

First line Investigations: -

Check hemotocrit, blood, glucose, calcium, phosphorus, magnesium, sodium. Venous pH and base excess. CSF examination and blood culture should be taken in all cases to exclude pyogenic meningitis. Cranial ultrasound and EEG should be done once metabolic disorders are excluded.Second line investigations: -

When convulsions persist and first line investigations are unable to identify the cause, MRI or CT scan is advised to exclude structural or developmental defects like cerebral dysgenesis, lissencephaly and neuronal migration disorders. Appropriate tests including serology for TORCH infections should be undertaken to exclude intrauterine infections. Screening tests for exclusion of inborn error of metabolism include ABG, blood ammonia, lactate/ pyruvate level, plasma and urinary amino acid profile etc. If facilities exist mothers urine and babys meconium should be screened for maternal drug abuse.

Electroencephalography: -

Prolonged EEG monitoring with simultaneous closed circuit video recording is reserved for complicated cases of protracted and unresponsive seizures. It provides an invaluable method for recording ictal seizure event that are rarely obtained during routine EEG studies. This technique is extremely helpful in the classification of seizure because it can accurately determine the location and frequency of seizures discharges while recording alterations in the level of consciousness and the presence of clinical signs. Patient with pseudo seizures can be readily distinguished from those with true epilepsy, and seizures type can be more precisely identified.

MANAGEMENT OF EPILEPSYS/No.DRUGINDICATIONS(Seizure type)DOSE

1CarbamazepinePartial, tonic clonic, atonic, akinetic.10 30 mg/kg Start with low dose

2PhenobarbitoneTonic clonic, akinetic, Partial fibrile convulsions.3 5 mg/kg/24hr. bid

3Diphenylhydation(Phenytoin) (Dilantin)Tonic clonic, atonic akinetic, akinetie partial3 9 mg/kg/24 hr. bid.

4Ethosuximide (Zarontin)Absence may increase tonic clonic seizuresBegin 20 mg/kg/24hr increase to maximum of 40 mg /kg/24hr.

5ACTH (Semacthen)Myoclonus20 40 units per day 4 6 weeks then 1/3 dose for 3 6 months

6PredinisoloneMyocloness2 mg/kg/day in 2 doses

7NitrazepamMyoclonus & PartialBegin 0.2 mg/kg/24hr increase slowly to 1mg/kg/24hr.

S/No.DRUGINDICATIONS

(Seizure type)DOSE

8DiazepamIn status epilepticus0.2 mg/kg/dose IV in children

9ClonazepamAtonic, akinetic0.03 mg/kg/day 2 divided doses (0.25 1 mg/kg/24hr bid or tid)

10Sodium ValproateBroad Spectrum20 50 mg/kg/day divided doses

11Valproic AcidGeneralized tonic clonic

- Myoclonic

- Partial

Begin 10 mg/kg/24hr increase by 5 10 mg/kg/week. Usual dose 30 60 mg/kg per 24 hr tid or bid

12AcetazolamideResistant cases10 20 mg/kg

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