Kerala & IAP Trivandrum - CiteSeerX

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TRIVANDRUM NEUROPED 2011PG TRAINING PROGRAM AND CME

October 22 nd & 23rd 2011

IAP Neurology Chapter –Kerala & IAP Trivandrum

Logo IAP here Pediatric Neurology logo here

PARTICIPANTS HAND BOOK

Chief Editor :Dr. P.A. Mohammed Kunju

Executive Editors :Dr. D. Kalpana

Dr. S. Mini

Cover page designDr. Madhav A.

Dept. of Pediatric NeurologySAT Hospital, Medical College, Thiruvananthapuram - 695 011

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EDITOR�S MESSAGE

Pediatric Neurology services in SAT Hospital, Government Medical College,

Thiruvananthapuram was started in 1982. We have been travelling with you and updating ourselves

through various CME’s. Neurology case discussions are still a difficult proposition for pediatricians.

To make approach to neurological disorders simple, we are organizing a two day Training cum

CME programme. The intention is to bring back the basics in Neurology with special accent on

Pediatric Neurology. We have put together some of the finest Neurology teachers in the State.

They come from AIIMS, New Delhi, AIMS, Kochi and Government, Medical Colleges,

Thiruvananthapuram & Thrissur.

This handbook, which is complementary to the teaching sessions, is designed to include the

basics of clinical Neurology along with the management protocols. Please go through the text. Do

send us your comments so that we can improve the programme next time.

Hope to meet you again.

Prof. P.A. Mohammed Kunju

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PROGRAM

DAY I: 22/10/2011

Venue : Omana Mathew Hall, SAT Hospital

08.25 a.m : Inauguration Prof. R. Anandam

Class I Class II

08.30 am - 09.30 am : Floppy Infant Cerebral PalsyDr. Mary Iype Dr. D. Kalpana

9.3.00 am - 10.30 am : Acute Flaccid Paralysis Large HeadDr. Lalitha Kailas Dr. Ananda kesavan

10.30 am - 10.45 am : TEA

10.45 am - 11.45 am : Developmental Delay / Regression Neuro Muscular DisordersDr. P. A. Mohammed Kunju Dr. Mini S.

11.45am - 12.30 pm : Neurometabolic disorders -a simplified approachDr. P. A. Mohammed Kunju

12.30 pm - 01.15 pm : LUNCH BREAK

01.15 pm - 02.15 pm : Large Head Acute Flaccid ParalysisDr. Ananda Kesavan Dr. Lalitha Kailas

02.15 pm - 03.15 pm : Cerebral Palsy Floppy InfantDr. D. Kalpana Dr. Mary Iype

03.15pm - 03.30 pm : TEA

03.30pm - 04.30 pm : Neuro Muscular Disorders Developmental Delay /Dr. Mini S. Regression

Dr. P. A. Muhammed Kunju

04.30 pm - 06.00 pm : Radiology & EEG Quiz ( Prize Rs 1000/-)& DiscussionDr. P. A. Muhammed Kunju

07.00 pm : DINNER

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DAY II: 23/10/2011

Venue : Mascot Hotel

What will I do?

Session I

Chair persons : Dr. K. Rajamohanan, Dr. Sobha Kumar S.

09.00 am - 09.30 am : ‘Normal new born’ with frequent seizuresDr. Vinayan K. P.

09.30 am - 10.00 am : Six year old child with speech delay and poor social interactionDr. P. A. Muhammed Kunju

10.00 am - 10.30 am : Five year old with ataxia of 1 month durationDr. Mary Iype

10.30 am - 11.00 am : Three year old child with one day fever and status epilepticusDr. Mini S.

11.00 am - 11.30 am : Two year old child with acute hemiplegia

Dr. D. Kalpana

11.30 am - 12.00 pm : Dietary management of medically refractory epilepsyDr. Sheffali Gulati

12.00 pm - 01.00 pm : INAUGURATION

01.00 pm - 02.00 pm : LUNCH

Session II

Chair persons : Dr. K.E. Elizabeth, Dr. Santhosh Kumar A.

02.00 pm - 02.30 pm : Approach to neuromuscular disordersDr. Sheffali Gulati

02.30 pm - 03.00 pm : Child with recurrent headacheDr. Shahnaz Ahmed

03.00 pm - 03.30 pm : Child with movement disorderDr. P. A. Muhammed Kunju

03.30 pm - 04.00 pm : Treatment of Neurogenetic disordersDr. Sankar V. H.

04.00 pm - 04.30 pm : Discussion and interactive sessionDr. Elizabeth K. E.

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CONTENTS

Page No:

1. The Floppy infant Dr. Mary Iype 9

2. Cerebral Palsy Dr. D. Kalpana 15

3. Acute Flaccid Paralysis Dr. Sindhu T.G 19

4. Clinical approach to large head Dr. T.M. Ananda Kesavan 26

5. Approach to Neuro metabolic Disorders Dr. P.A. Mohammed Kunju 29

6. Pattern of Neuromuscular disorders Dr. S. Mini 45

7. Newborn with seizures- approach Dr. Vinayan K.P 48

8. Clinical features of autism Dr. P.A. Mohammed Kunju 53

9. Approach to a child with ataxia Dr. Mary Iype 57

10. Status Epilepticus Dr. S. Mini 65

11. Acute hemiplegia Dr. D. Kalpana 72

12. Approach to headache in Children Dr. M. Shahanaz Ahamed 76

13. Movement disorders in children Dr. P.A. Mohammed Kunju 89

14. Treatment of neurogenetic disorders Dr. V. H. Sankar 98

15. Dietary management of refractory epilepsy Dr. Sheffali Gulati 104

16. Approach to neuromuscular disorders Dr. Sheffali Gulati 107

17. Paediatric Neurological Examination Dr. N. Anand 113

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CONTRIBUTING AUTHORS

Prof. P. A. Mohammed KunjuProfessor and Head, Dept of Pediatric NeurologyMedical college, Trivandrum.

Dr. Sheffali GulatiAddl Professor and Head, Division of child NeurologyAIIMS, New Delhi.

Prof. Vinayan K.P.Division of Pediatric NeurologyAIMS, Kochi.

Dr. Mary IypeAddl Professor, Dept of Pediatric NeurologyMedical college, Trivandrum

Dr. D KalpanaAddl Professor, Dept of Pediatric NeurologyMedical college, Trivandrum.

Dr. Sankar V.H.Genetic specialist, Asso professorDept of PediatricsMedical college, Trivandrum.

Dr. T.M. Ananda KesavanAsso Professor of PediatricsMedical college, Trichur.

Dr. Mini S.Asst Professor, Dept of Pediatric NeurologyMedical college, Trivandrum.

Dr. M. Shahnaz AhmedPediatric NeurologistAsst Professor, Dept of PediatricsMedical college, Trivandrum.

Dr. Sindhu T. G.Assistant Professor, Department of PediatricsNodal officer AFP surveillance, SAT HospitalMedical College, Thiruvananthapuram.

Dr. N. AnandSenior Resident, Department of PaediatricsMedical College, Thiruvananthapuram.

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THE FLOPPY INFANTMARY IYPE

Introduction

The word floppy in the terminology floppy infant refers to

1. Reduction in the tone of muscles2. Laxity of ligaments and joints3. And occasionally to reduction in power of muscles

To be precise the term should be restricted to hypotonia alone. However the tone, power and joint

laxity are inextricably interwoven and hard to separate clinically. This is because tone is a resistance topassive movement at a joint. If the ligaments are lax the movement around a joint will appear to bewithout resistance and the tone will be apparently less. The weak limb may also appear hypotonic.

The appearance of the child

The floppy infants have a similar appearance with rare spontaneous movement of the limbs.Some have chest wall deformities due to long standing weakness of the chest wall muscles. Flattening ofthe occiput and loss of hair in the occipital region are common. The supine infant assumes a frog legposture, with the legs fully abducted at the hips, the lateral surface of the thighs resting on the bed and thearms lying extended at the sides of the body, flexed at the elbows and he hands beside the head.

When the traction response is elicited, the head falls forward and the shoulder appears roundedand drooping and the limbs look floppy. On ventral suspension, the head hangs down, the limbs hanglimply. On vertical suspension the baby tends to slip through the examiner’s hands gripping the axilla,the head falls to one side and the limbs hang limply. In the normal infant the head will be in the midlineand there will be flexion at the hips and knees.

Table 1

Clinical signs in a floppy infant

1. The frog leg posture

2. Slipping through the fingers on vertical suspension

3. Rag doll appearance on ventral suspension

4. The traction response showing head lag and excessively rounded back

5. Associations: Flat occiput, hair loss from occipital region, arthrogryposis,

congenital dislocation of the hips and inguinal hernia

Due to the poor muscle tone there may be inguinal hernia or visceroptosis. Hip dislocation maybe seen even in the newborn. Due to in utero hypotonia one or more joints may show contractures or thebaby may be born with arthrogryposis multiplex congenita.

Modes of presentation

These infants are commonly brought for developmental delay. Rarely the complaint may be weak

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limbs, wasting of extremities, respiratory distress, a limp newborn, acute onset weakness of limbs, clubfeet or multiple contractures.

Assessment of tone

For a term newborn the resting posture is flexion of the extremities with the extremities closelyadducted to the trunk. After the first few days of life, the extremities are still predominantly in the flexedposition but they are not as tightly adducted as they are in the first 48 hours of life.

Upper Extremity Tone

Assessing motor function of the upper extremities begins with passive range of motion. This isdone by moving each extremity at the shoulder, elbow and wrist and feeling the resistance and the rangeof movement. Too little or too much resistance reflects hypotonia or hypertonia.

Arm Traction

Arm traction is done with the baby in the supine position. The wrist is grasped and the arm ispulled until the shoulder is slightly off the mat. There should be some flexion maintained at the elbow.Full extension at the elbow is seen in hypotonia.

Arm Recoil

Arm recoil tests tone and power of the biceps. The arms are held in flexion against the chest for afew seconds, then are quickly extended and released. The arms should spring back to the flexed position.The hypotonic infant will have slow incomplete recoil. Asymmetry to this response with lack of recoilwould be seen with Erb’s or brachial plexus palsy.

Scarf Sign

The baby’s hand is pulled to the opposite shoulder like a scarf. The hand should not go past theshoulder and the elbow should not cross the midline of the chest. This happens in the hypotonic infant.

Fisting

A newborn baby’s hand is held in a fisted position with the fingers flexed over the thumb. Thehand opens intermittently and will not always be held in a tight fisted position. Rubbing the ulnar aspectof the hand or touching the dorsum of the hand will often cause extension of the fingers. Over the first 1to 2 months of life, the baby’s hand becomes more open. Persistence of a fisted hand is a sign of an uppermotor neuron lesion in an infant.

Leg Traction

The leg held at the ankle is pulled upward until the buttock starts to be lifted off the mat. The kneeshould maintain a flexed angle. Full extension of the knee with little resistance to pulling on the leg is asign of hypotonia.

Leg Recoil

The legs are fully flexed on the abdomen for a few seconds, then are quickly extended and released.The legs should spring back to the flexed position. Legs that remain extended could be due to eitherhypotonia or abnormal extensor tone.

Popliteal Angle

The popliteal angle is an assessment of the tone of the hamstring muscles. It is done one leg at atime. The thigh is flexed on the abdomen with one hand and then the other hand straightens the leg bypushing on the back of the ankle until there is firm resistance to the movement. The angle between the

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thigh and the leg is typically about 90 degrees. Extension of the leg beyond 90 to 120 degrees would beseen in hypotonia.

Heel to Ear

Holding the baby’s foot in one hand, draw the leg towards the ear to see how much resistancethere is to the maneuver. The foot should go to about the level of the chest or shoulder, but not all the wayto the ear. If the foot can be drawn to the ear then there is hypotonia.

Neck Tone

Passively rotate the head towards the shoulder. The chin should be able to rotate to the shoulderbut not beyond the shoulder. If the chin goes beyond the shoulder then there is hypotonia of the neckmuscles.

Approach to the floppy infant

Look for ligamentous or joint problems in a floppy infant before you label him as having lowermotor neuron pathology. Look for tell tale evidence of hypothyroidism, malnutrition or rickets.

The first aim is to distinguish a central versus a peripheral pathology.

Table 2

Clues for central nervous system pathology

1. History of global developmental delay, seizures, movement disorder orspeech delay.

2. Persistent fisting

3. Early use of one hand only

4. Dysmorphic features

5. Involvement of other organs like hepatosplenomegaly

6. Psuedobulbar paralysis, exaggerated deep tendon reflexes or clonus

Table 2 lists the features that enable one to distinguish central nervous system pathology from aperipheral pathology. Significant weakness suggests peripheral nervous system pathology.

Table 3

Clues for peripheral nervous system pathology

1. Paucity of limb movement particularly antigravity movements

2. Absent or depressed tendon reflexes

3. Muscle hypertrophy or atrophy

4. Fasciculations

5. Typical facial features peculiar to some myopathies

6. History of consanguinity or family history that is suggestive

7. Myotonia or myotonia in the mother

8. Selective motor delay without cognitive involvement

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It would be useful to keep in mind that some children may have both a central and a peripheral pathologyas in mitochondrial diseases, congenital muscular dystrophy, familial dysautonomia, infantile neuraxonaldegeneration and some lysosomal storage disorders.

Table 4

Central disorders that could result in a floppy infant

1. Cerebral causes

a. Hypotonic Cerebral palsy

b. Chromosomal disorders including Down’s syndrome and Prader Willi

c. Genetic disorders like familial dysautonomia and Lowe’s syndrome

d. Peroxisomal disorders like Zellweger’s

e. Endocrine like hypothyroidism

f. Metabolic disorders like rickets and renal tubular acidosis

g. Cerebral malformations

h. Inborn errors of metabolism like GM1 gangliosidosis

2. Spinal causes

a. Hypoxic injury to the spinal cord

b. Traction injury to the spinal cord

Once one detects the clues to a central pathology the tell tale evidence for each of the disorderslisted in table 4 are sought and the investigations tailored to the clinical scenario.

Table 5

Causes of a peripheral pathology in a floppy infant

1. Anterior horn cell diseasesa. Spinal muscular atrophy (SMA)b. Congenital poliomyelitis2. Radiculopathiesa. Chronic inflammatory demyelinating polyneuropathyb. AIDP when the onset was in utero3. Neuropathiesa. HMSNb. HSANc. Congenital hypomyelinating neuropathy4. Neuromuscular junction pathologya. Botulismb. Transient neonatal myastheniac. The congenital myasthenic syndromes. Autoimmune myasthenia5. Muscle diseases

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Table 6

The muscle diseasesa. The congenital myastheniasb. Congenital muscular dystrophyc. The myotonic muscle diseasesd. The inflammatory myopathiese. The metabolic myopathiesf. The mitochondrial muscle disorders

Investigations when a peripheral disease is suspected

A creatine kinase (CK) level in serum is the first investigation to be done. Depending on the CKvalue and the clinical profile electrophysiological studies are planned. Nerve conduction studies showabnormal distal latency and conduction velocities in the neuropathies. Sensory conduction studies alonemay help in the diagnosis of the Hereditary Sensory Autonomic Neuropathies. Inflammatory musclediseases and anterior horn cell diseases on EMG study may show spontaneous activity in the form offasciculations and positive sharp waves. The myotonic muscle disorders on EMG studies show spontaneousactivity in the form of myotonia.

Muscle diseases need detailed EMG studies but the electrophysiology contributes little to theetiological diagnosis. Genetic studies are done in those cases where it is possible. When one suspects thatthe child has SMA, genetic studies are the choice today if the patient can afford it. Genetic studies canalso be done in the myasthenic syndromes and congenital myotonic dystrophy. Muscle biopsy andimmunohistochemical staining helps to distinguish the various muscle pathologies. The limitation is nonavailability of the antibodies for immunohistochemistry. Selected cases like some of the congenitalmyopathies and some cases of mitochondrial myopathies may benefit from electron microscopic studiesof the biopsy specimen. It is important to sample a moderately affected muscle so that it is representative;however not atrophic. In the case of myasthenia single fiber EMG is needed for diagnosis.

The inflammatory myopathies warrant an erythrocyte sedimentation rate and relevant vasculiticwork up.

Investigations when a central disorder is suspected

A high index of suspicion is the key factor. The investigations cannot be stereotyped but tailoredaccording to the clinical findings. The patient may need brain imaging, a metabolic work up, chromosomalanalysis, assessment of the renal system, expert ophthalmological advice or specific metabolic studieslike very long chain fatty acid assay.

Therapeutic aspects

All the infants will need rehabilitation. Excellent remedial measures would include thyroidreplacement in the hypothyroid, rehabilitation of the malnourished floppy infant, treatment of rickets,surgery for cataract and glaucoma in Lowe’s disease, treatment of myotonia in myotonia congenital andcongenital myotonic dystrophy and the mitochondrial cocktail in the mitochondrial cytopathies.

Dietary therapy in the peroxisomal disorders and other metabolic disorders and enzyme replacementtherapy in cases like Pompe are also encouraging.

Physiotherapy, occupational therapy, special education in the mentally challenged and surgicalcorrection for deformities are offered in cases that need them.

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Prevention

Prevention of these disease states is of paramount importance as the treatment has limitations.Health education to prevent consanguineous parentage is a key point. The exact etiological diagnosisespecially with a genetic corroboration will help to inform the family regarding the chances of a nextoffspring being affected. In the next pregnancy prenatal diagnosis and the option of medical terminationof pregnancy can be discussed. Early detection of several of these disorders helps in treatment and disabilityreduction.

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CEREBRAL PALSYD KALPANA

Definition: A non progressive, but often changing disorder of movement and posture due to an insultto the developing brain.

“a group of disorders of the development of movement and posture, causing activity limitation,that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain.The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, cognition,communication, perception, and/or behavior, and/or by a seizure disorder.” - American Academy forCerebral Palsy and Developmental Medicine 2005

The incidence of CP is considered to be 2 to 2.5/1000 live births.

Aetiology: prematurity and low birth weight are the two major causes

• Prenatal –TORCH infection,PIH,diabetes mellitus, twin pregnancy,APH

• Perinatal – only 10%

• Postnatal –meningitis,encephalitis,hyperbilirubinemia

Early diagnosis can be facilitated by:• Follow up of at risk neonates

• Delayed milestones

• Decreased spontaneous motility

• Irritability,opisthotonic postures,recurrent aspiration and pneumonia

• Early hand preference

• Constant fisting

• Persistent or asymmetric primitive reflexes

Classification1. Spastic

• hemiparesis (hemiplegia)—(predominantly) unilateral impairment of arm and leg on thesame side

• Diplegia—motor impairment primarily of the legs (usually with some relatively limitedinvolvement of arms)

• Triplegia—three limb involvement

• Quadriplegia (tetraplegia)—all four limbs, in fact the whole body, are functionallycompromised

2. Dystonic/Chreoathetoid

3. Ataxic

4. Mixed

Pathology of cerebral palsy:1. Periventricular leukomalacia – in preterms.It is th watershed zone in prematures. Also

oligodendrocytes are vulnerable to injury between 22-32 weeks. Lower limb fibres are close toventricles. Affects lower limb more than upper limb.-diplegia

2. Intraventricular/periventricular hemorrhage also results in cerebral palsy- hydrocephalus,porencephalic cyst

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3. Cystic encephalomalacia in term babies. – spastic quadriplegia

4. Status marmoratus – involves basal ganglia – acute evere asphyxia in term babies, bilirubinencephalopathy.

5. Infarcts in MCA territory – hemiplegic CP

6. Structural malformations in brain – lissencephaly, polymicrogyria, schizencephaly- needsgenetic evaluation

Severity of cerebral palsy: Gross Motor Function Classification System (for children between 6 and12 years)

• Level I—Walks without restrictions; limitations in more advanced gross motor skills

• Level II—Walks without devices; limitations in walking outdoors and in the community

• Level III—Walks with mobility devices; limitations in walking outdoors and in thecommunity

• Level IV—Self mobility with limitations; children are transported or use power mobilityoutdoors and in the community

• Level V—Self mobility is severely limited even with the use of supporting technology \\\

ALGORITHM FOR EVALUATION OF CEREBRAL PALSY – AAN 2004

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“Familial CP”• structural malformations of brain –X linked lissencephaly, polymicrogyria, schizencephaly,Joubert

syndrome• slowly progressive neurodegenerative diseases – pelizaeus merzbacher syndrome, hereditary spastic

paraplegia(AD)• rett syndrome –X linked dominant-only in females• dopa responsive dystonia may present as spastic paraplegia –look for diurnal variation• arginase deficiency -AR• pseudoTORCH(Aicardi Gautiere)- AR.

Note: Degenerative disease may not always present as loss of acquired milestones. Some may notacquire milestones at all. Some children may attain milestones if the growth potential exceeds therate of degeneration. A child with static encephalopathy can lose milestones temporarily if hedevelops a severe infection, seizures etc(West syndrome

Management:Asses the strengths(abilities) and the associated diasabilities of the child.Assess the IQ or DQ,vision, hearing, associated behavior problems, seizures etc. A multidisciplinary individualizedmanagement for each child is planned with the pediatrician, neurologist, physiotherapist, speechtherapist, psychologist, and occupational therapist playing important roles in management.

Antispasticity agents: Spasticity should be treated if it causes pain, irritability; difficulty in passivemovement during physiotherapy, severe adductor spasm preventing cleaning of genital areaetc.Physiotherapy reduces spasticity to a great extent. Some amount of spasticity often helps inwalking. The dose should be titrated for optimal function.The commonly used drugs include:• Diazepam: 0.25 – 0.5 mg / kg / day. Can produce drowsiness or paradoxical irritability• Baclofen: Tablets: 10 mg, 5 mg( Liofen, Lioresal, Baclof)Dose not established in children

Start with smallest dose(0.125 mg twice daily in infants) and slowly titrate the dose. Maximumdose 40 mg in children s/e – sedation, may precipitate seizures

• Tizanidine : 2mg tab. Better side effect profile. Dose: 0.05 mg/kg/day

• Botulinum toxin (Botox A, Myobloc)injected directly into a spastic muscle will reduce orabolish the release of acetylcholine and thereby reduce spasticity; the effect lasts for severalmonths. Needs repeated injections. It is given in a dose of 1 to 3 units/kg for small muscle likepronator . 3 to 6 units/kg for large muscle. Max dose – 12 to 15 units/kg for one child.(max 400unit) Accepted for focal and segmental spasticity. .Limiting factor is cost. Optimizephysiotherapy after Botox injection for maximum bnenefit.

• Phenol injection into the nerve roots is a cheap alternative. Effects are non reversible• Detect seizures early, obtain an EEG and treat with appropriate antiepileptic drugs. West syndrome

is often missed.• In children with dystonia, trihexiphenidyl (0.1 mg/kg/day in 2 to 3 div doses increase upto 1 mg/

kg/day over 3 months) is found to be useful. Give a trial of L- dopa in all cases of spastic CP withdystonia dose – 10 to 20 mg/kg/day in div doses. (Some cases of spasticity with dystonia maybe Dopa Responsive Dystonia especially if there is a diurnal variation).Stop if there is no responsein 3 months. Tetradenezine may be of benefit in some.

• In children with choreoathetosis, dopamine D2 blockers like haloperidol and risperidone mayhelp

• Treatment for drooling of saliva: Anticholinergic agents are used to get the benefit of decreased

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salivary secretion. Procyclidine (Dine) – 0.25 to 0.5 mg/kg/day in 2 div doses. Re-implantation ofthe salivary duct is done to direct the salivary flow into the pharynx.

• Swallowing disorders due to pseudobulbar palsy - Nasogastric feeding or gastrostomy.• GERD – keep the head and chest elevated to 45 degree after feeds,Thicken the feeds.H2 blockers

and domperidone are useful.In intractable cases fundoplication is advised,• Prevent malnutrition and obesity.• Prompt treatment of respiratory infections, GERD,dental problems are important• Irritability in a spastic child : acute infections, dental problems, esophagitis, fractures, hip

subluxation etc.• Physiotherapy: helps to improve gross motor skills and help to reduce abnormal muscle tone and

prevent contractures.- stretching, strengthening and range of movement exercises. Orthoses andsplints at night help to prevent contractures

• Occupational therapy: addresses the activities of daily living like eating, bathing, toileting, dressingetc. Assist devices: Wheel chairs, Feeding devices, Modified typewriter, Walkers, poles and standingframes.

• Surgical procedures : soft tissue release, tendon lengthening, selective dorsal rhizotomy,management of joint subluxation

• Hearing assessment and speech therapy, correction of squint, cataract, refractory errors• In a child with a learning handicap or mental retardation, remedial teaching, special schooling and

special education help.

Prognosis for walking – more than 95% hemiplegic children walk by 3 years, The ability to independentwalking depends on degree of mental retardation,seizures and the type of cerebral palsy. It is worstfor quadriplegic CP.• persistence of primitive reûexes is incompatible with the development of walking• Sitting unsupported at 2 years indicates that the child will eventually walk outdoors. If sitting

is delayed beyond 3 years, the prospects for functional outdoor walking are remote.• Head control in prone position by 9 months, or crawling by 30 months also are predictors of

independent walking by 5 yearsReferences:1. Cerebral palsies,a physiological approach JP Lin J Neurol Neurosurg Psychiatry 2003;74(Suppl

I):i23–i292. Cerebral palsy: what parents and doctors want to know: Peter Rosenbaum BMJ 2003;326:970–43. Cerebral palsy: not always what it seems R Gupta, R E Appleton Arch Dis Child 2001;85:356–360

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ACUTE FLACCID PARALYSISSINDHU. T. G

AFP is a complex clinical syndrome with a number of etiologies. Acute flaccid paralysis is definedas sudden onset of weakness and floppiness in any part of the body in a child < 15 years of age orparalysis in a person of any age in whom polio is suspected. The weakness progresses to maximumseverity within several days to week. There is absence of spasticity and other signs of UMN lesions likehyperreflexia, clonus or extensor plantar. The paralysis can be either severe or slight.

Importance

1. Accurate diagnosis of the cause of AFP has implications for therapy and prognosis. If untreated,AFP may persist or may lead to death due to respiratory muscle paralysis.

2. AFP encompasses all cases of paralytic poliomyelitis. It is of great public health importancebecause of its use in surveillance for poliomyelitis in the context of the global polio eradicationinitiative.

Etiologies of AFP

(Based on anatomic location)

• Spinal cord – acute transverse myelitis, acute myelopathy due to spinal cord compression (spaceoccupying lesion, epidural abscess), anterior spinal artery syndrome.

• Anterior horn cells – poliomyelitis, VAPP, nonpolioenteroviruses, dump rabies, acute postasthmatic amyotrophy (Hopkins Syndrome).

• Peripheral nerve (nerve root/axon) – Guillian- barre syndrome (AIDP, AMAN, ASMNAN)CMV polyradiculoneuropathy associated with HIV infection, toxic neuropathies ( diphtheria,tick bite paralysis, lead, arsenic, food toxins), traumatic neuritis, critical illness polyneuropathy,acute intermittent porphyria, Varicella.

• Neuromuscular junction – myasthenia gravis, botulism, snake bite, organophosphorous poisoning,hypermagnesemia, neuromuscular abnormalities following prolonged neuromuscular blockades.

• Muscle – polymyositis, trichinosis, hypokalemia (familial/sporadic), myopathy of intensive care.

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Figure 1 Anatomic sites of etiologic factors for acute flaccid paralysis

Clinical approach to a patient with AFP

History

Details of weakness including onset, duration, distribution (distal/proximal, patchy/symmetrical),

progression, and diurnal variation should be recorded. The symptoms of paralysis may include gait

disturbance, weakness or troubled coordination. Presence or absence of fever and its relation with

weakness is very important. Specifically ask for myalgia or sensory symptoms. Any history of recent

exanthems ( Lyme), tonsillitis( Diphtheria), trauma, immunization, intramuscular injections, abdominal

pain(porphirialead poisoning), travel, exposure to chemicals and poisons(arsenic, lead) , tick bite, snake

bite, family history ( periodic paralysis) etc should be obtained.

Examination

Detailed neurological evaluation including muscle strength, DTR, cranial nerve function, sensory

examination, meningeal signs, ataxia, bowel and bladder functions and fasciculation should be carried

out. Look for blue lines in gums (lead poisoning) and Mee�s lines (arsenic poisoning) in nails.

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Investigation

2 stool samples as per AFP surveillance must be collected in all cases. Basic investigations include blood

counts, ESR, peripheral smear, electrolytes (K, Ca, Mg) and CPK. Electrophysiological studies (NCV and

EMG) have got very important role in diagnosis of AFP. Lumbar puncture and MRI spinal cord should be

done in relevant cases. In selected cases porphyrins, acetylcholine esterase activity, serological tests

(HIV, EBV, campylobacter, mycoplasma) and anti GM1 antibody may be done.

Figure 2 Algorithm for evaluation of patients with AFP

Important Differential diagnosis of AFP

The four common causes of AFP are poliomyelitis, GBS, transverse myelitis and traumatic neuritis.Their differentiating features are given in Table no 1

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Table 1 Important Differential diagnosis of AFP

Feature Poliomyelitis GBS Transverse

myelitis

Traumatic

neuritis

Progression to

full paralysis

24-48 hrs Hours to days Hours to 4 days Hours to days

Fever onset High, always

present at

onset of

paralysis

No Present before

paralysis

No

Flaccidity asymmetrical,

proximal

symmetrical, distal

ascending

symmetrical

lower limbs

asymmetrical

Muscle tone Diminished Diminished Diminished in

lower limbs

Diminished

Deep Tendon

reflexes

decreased or

absent

Absent Absent early,

hyperreflexia late

decreased or

absent

sensation Severe myalgia

or backache,

no sensory

changes

Cramps, tingling,

hypo anesthesia of

palms and soles

Anesthesia of

lower limbs with

sensory level

Pain in the

gluteal region

Cranial nerves Only when

bulbar or

bulbospinal

Often present ,

affecting nerves

VII, IX, X, XI, XII

Absent Absent

Respiratory

insufficiency

Only when

bulbar and

bulbospinal

In severe cases Sometimes Absent

CSF

examination

High cells, N or

slightly

increased

protein

<10 leukocytes,

high protein

Cellular or

acellular, N or

slightly increased

protein

Normal

Bladder

dysfunction

Absent Transient Present Never

EMG at 3 week Abnormal Normal Normal May be

abnormal

NCV at 3 week Normal Abnormal

demyelination/axo

nal

Normal Abnormal

Sequelae at 3

months

Severe,

asymmetrical

atrophy,

skeletal

deformities

later

Symmetrical

atrophy of distal

muscles, recovery

in milder cases

Diplegia, atrophy

after years,

recovery in

milder cases

Moderate

atrophy of

affected limb

23

ACUTE FLACCID PARALYSIS SURVEILLANCE

WHO Strategies for Polio Eradication

1. Achieving and maintaining high routine coverage in infants younger than 1year with at least 3 doses oforal polio vaccine (OPV3) and zero dose.

2. Administering supplemental doses of OPV to all children aged <5 years during national immunizationdays (Pulse Polio Immunization) to rapidly interrupt transmission:

3. Surveillance of Acute Flaccid Paralysis cases.

4. Conducting “mop-up” vaccination campaigns.

Under the Global Polio Eradication Initiative, surveillance for polio is conducted throughinvestigation of acute flaccid paralysis cases. AFP surveillance helps to detect reliably, areas wherepoliovirus transmission is occurring. For polio free certification, it is essential to provide evidence to thecertification committee of the absence of wild polio virus transmission through a functioning and sensitivesurveillance system for three years after attaining zero polio case status. One case of AFP (excludingpolio) occurs annually for every 100,000 children less than 15 years of age. This is referred to as the“background” rate of AFP among children. The non-polio causes of AFP including (but not limited to)Guillian-Barré Syndrome (GBS), Transverse Myelitis and Traumatic Neuritis account for this backgroundrate, regardless of whether acute Poliomyelitis exists in the community. All cases of acute flaccid paralysisshould be reported, irrespective of diagnosis, if not reported earlier it can be reported upto 6 months ofonset. The consequences of missing a case of polio are more serious than occasionally including an“ambiguous” case, especially during the final stages of polio eradication.

The AFP Surveillance Network

This includes the Reporting units (RU) (like medical colleges, district hospitals) and Informer units at thelocal level and District Immunization Officier (DIO) /Surveillance Medical Officer (SIO) at the districtlevel. Nodal officer of the RU has to send report to DIO weekly on Mondays. This must be sent even ifthere is no AFP case (Zero reporting). SIO has to visit the RU frequently and should investigate thereported cases. These data are sent to the state level and from there to national level and finally to WHO.

AFP Case Investigation

All AFP cases should be notified to the DIO as immediately as possible. All cases are to beinvestigated by the surveillance officer within 48hrs of notification. The Clinical Investigation Form(CIF) should be filled. The EPID no (unique identification no) should be assigned to the case. Adequatestool samples should be collected. Adequate stool means two specimens collected within 14 days ofparalysis onset and at least 24 hours apart; each specimen must be of adequate volume (8-10 grams -about the size of one adult thumb size) and arrive at a WHO-accredited laboratory in good condition (i.e.,no desiccation, no leakage, with adequate documentation and evidence that the cold chain was maintained).It is collected in clean plastic screw-cap container with inbuilt spatula. In case samples cannot be collectedwithin 14 days, the specimens can still be collected up to 60 days of paralysis onset. Label the specimenwith EPID number and completely fill the Lab request form (LRF). The stool specimens should be sentto the laboratory in cold chain (specially marked vaccine carriers) at 2-8oC. It should reach the laboratorywithin 72 hours after dispatch. Primary isolation results are given within 28 days of arrival of the specimen.

24

Primary isolation of poliovirus is done in all of 8 labs of India poliovirus laboratory network. IntratypicDiffrentiation Test (ITD) to identify wild virus from vaccine virus is done in labs at Mumbai, Chennaiand Lucknow. Genetic Sequencing is done only at Enterovirus Reasearch center, Mumbai. OutbreakResponse Immunization (ORI) should be performed by giving one dose of OPV to all children of 0-59months in the areas (usually around 500 children) where the child resided or visited in the incubationperiod (4-35days prior to the weakness). Active case search should be carried out in these areas. It is doneby house to house search. Hot cases (the cases that are likely to be polio) should be identified andexamined by the SIO. These includes cases of age less than 5 years with history of fever at onset ofparalysis and asymmetrical proximal paralysis/ patchy paralysis or age less than 5 years with rapidlyprogressive paralysis leading to bulbar involvement and death. When adequate stool specimens cannotbe collected from hot cases, collection of specimens from contacts of cases should be done. Sixty dayfollow-up is done between the 60th and 90th day in AFP cases with inadequate stool specimen collection,AFP cases with isolation of wild poliovirus and AFP cases with isolation of vaccine-type (Sabin-type)poliovirus to determine the presence/ absence of residual paralysis.

AFP Case Classification

Within 90 days of paralysis onset, all cases should undergo final classification as confirmed

Polio, non-polio AFP or compatible with poliomyelitis. From 2000 onwards virological classificationis used

25

Surveillance System Performance Indicators

Following are basic indicators of surveillance quality that should be carried out by DIO/ SMO on aregular basis.

1. Non Polio AFP rate per 100,000 <15 years children (target >1/100,000, operational target for India>2/100,000)

2. Reported AFP cases with 2 stool specimens collected within14 days of onset of paralysis target>80%)

3. Notification of AFP cases within 10 days of onset of paralysis (target >80%)

4. Reported AFP cases investigated within 48 hours of notification (target >80%)

5. Timeliness of weekly reporting (target >80%)

6. Completeness of weekly reporting (target >90%)

7. Stool specimens reaching a WHO accredited laboratory within 72 hours of being sent (target >80%)

8. Stool specimens reaching laboratory in good condition (target >80%)

9. Stool specimens with a turnaround time <28 days (target >80%)

10. Stool specimens from which non-polio enteroviruses were isolated (target >10%).

References

1. Child Health Division Department of Family Welfare Ministry of Health & Family Welfare NewDelhi (Prepared with assistance from National Polio Surveillance Project - India). Field Guide –Surveillance of Acute Flaccid Paralysis Third Edition September 2005

2. Arthur Marx, 1 Jonathan D. Glass, 2 and Roland W. Sutter. Differential Diagnosis of Acute FlaccidParalysis and Its Role in Poliomyelitis Surveillance. Epidemiologic Reviews 2000; 22:298-316

3. Ghai Essential Paediatrics seventh edition

26

CLINICAL APPROACH TO A CHILD WITH LARGE HEADT.M. ANANDA KESAVAN

Introduction: Large head is termed as Macrocephaly when the Occipito Frontal Circumference (OFC)is more than 2 SD mean(for the age and sex)

Megalencephaly implies abnormal neural proliferation with brain weight and size >2SD

Hydrocepahlus implies pathologic increase in ventricular volume

Serial measurement of OFC is important to coin it as large head. OFC should be measuredmonthly in first year; 3 monthly in 2nd year and 6monthly between 3 to 5years of age

In premature infants catch up growth of OFC will reach by at 18mo

Measurement of OFC is one of the most difficult parameter to measure, particularly in a irritablechild with neurological problem. Maximum OFC should be measure with non stretchable tap by keepingit over the occipital protuberance.

Before making sure that head is enlarged, make sure that there is no cephalohematoma or edemaof the scalp and the measurement is accurate.

Aetiology: Large head may be due to a primary neurological or non neurological condtions (Table I)

Table I: Aetiology of large head

Congenital: Degenerative Infectious: Metabolic: Space Occu -pation Misc

Benign/Familial White Matter Hydrocephalus GM1 Tumors, subdural Tuberous

Achondroplasia degeneration: (ABM,TBM, gangliosidosis, hematoma sclerosis,

Cranioskeltal - Canavan ds, Torch) MPS, Neurofibroma

Hemolytic

dysplasia Alexander Ds, Subdural Hypopara- Anemia

Hydrocephalus MLD effusion/ thyroidism

Megalencephaly Gray Matter: empyema

Porencephaly Tay Sach

Large Head may result from increased CSF space (Hydrocephalus); Increased brain Volume( Megalencephaly); Subdural Fluid ( Hygroma, empyema, hematoma); Abnormal Storage (Gray/WhiteMatter disease) or due to thick skull related abnormalities( Hemolytic anemia-HA, Achondroplasia,Osteopetrosis-OP)

Two important groups of condition with large head is megalencephaly and hydrocephalus: Bycareful history and physical examination we can differentiate them easily (Table II)

Congenital: Degenerative Infectious: Metabolic: Space

Occu -

pation

Misc

Benign/Familial

Achondroplasia

Cranioskeltal -

dysplasia

Hydrocephalus

Megalencephal

y

Porencephaly

White Matter

degeneration

: Canavan ds,

Alexander Ds,

MLD

Gray Matter:

Tay Sach

Hydrocephalu

s (ABM,TBM,

Torch)

Subdural

effusion/

empyema

GM1

gangliosidosis

, MPS,

Hypopara-

thyroidism

Tumors,

subdural

hematom

a

Tuberous

sclerosis,

Neurofibrom

a

Hemolytic

Anemia

27

OFC(cm3)

Body weight in grm

Table-II : Difference between Megalencephaly and Hydrocephalus:

Features Megalencephaly Hydrocephalus:

Shape of Skull N rounded/dolico Triangular/Unduly rounded

Temporal fossa Normal depression Bulging

Skin of scalp Normal Thin and stretched

Scalp vein Normal Distended

Scalp hair Normal Sparse

AF Normal / Tense Tense, lack pulsation

Sutural separation Late and mild Prominent separation

MacEwans Sign Rare Positive after AF closure

Tran illumination Negative Positive

Clinical approach to a child with large head: A reasonable history with detailed physical examinationand meticulous follow up of the case is important in reaching a clinical diagnosis.

History:

A history suggestive of intrauterine infection is important. Prenatal large head is suggested by dystocia.Developmental delay and neuroregression are seen in neuro degenerative/ neurometabolic disease.History of fever with seizure(CNS infection), recurrent blood transfusion (HA ) and any previous surgeryare important

Examination: Head is examined for OFC, abnormal shape, skin and hair, abnormal vein, anterior andother fontanel.

AF: size, shape, sutures, other fontanel, bruit and trans illumination

Early diagnosis by head index: (Nishe):

Normal: 10+1 (constant from birth to 18mo)

Cephalic Index:

<76=Dolichocephaly; 76-80=Mesocephaly; >80=Brachycephaly

Dynes Formula to calculate OFC from the length of the child in <1yr

+9.5 +/-2.5

————————

2

Clinical Features: depends on age at onset, duration, rate at which the ICT is raised and pre-existingconditions

_

Maximum breadth X 100

Max imum Length

Length in CM+9.5 +2.5

2

_

Features Megalencephaly Hydrocephalus:

Shape of Skull

Temporal fossa

Skin of scalp

Scalp vein

Scalp hair

AF

Sutural separation

MacEwans Sign

Tran illumination

N rounded/dolico

Normal depression

Normal

Normal

Normal

Normal/Tense

Late and mild

Rare

Negative

Triangular/Unduly rounded

Bulging

Thin and stretched

Distended

Sparse

Tense, lack pulsation

Prominent separation

Positive after AF closure

Positive

28

Asymptomatic, Vomiting, drowsiness, FTT, shrill cry, delayed motor milestones(0-2yrs)

Forehead is disproportionately large, lending an inverted triangular appearance

Skull is thin and sutures are separated. Look for cranial bruit over vertex, eye and temples with the bell ofstethoscope. Earliest sign: Separated squamo parietal suture beyond the first month

Cranial nerve: Optic atrophy due to compression of opticN/ chiasm by enlarged 3rd ventricle

6th N palsy, sunset sign, ptosis, nystagmus, divergent strabismus

Setting sun sign due to pressure of enlarged 3rd ventricle on mesencephalic tectum pressing on verticalgaze centre

Spasticity in lower limb. Later opishotonus posture

Cracked pot sign (MacEwen’s sign) Scalp veins are dilated, AF tense

Unilateral or bilateral 6th N palsy, nystagmus, ptosis and diminished papillary reflex

Parachute reflex may fail to develop

Spasticity in LL due to stretching of corticospinal tracts(myelin disruptin and cellular loss), mild ULinvolvement also(spastic diplegia)

Psedobulbar palsy-difficulty in sucking, feeding and phonation and result in regurgitation, drooling andaspiration

Laryngeal stridor due to vagal Nerve stretching or infarction of Vagal nuclei in the medulla

Bobble Head Doll syndrome characterized by 2-4 oscillations/second-due to pressure by 3rd ventricle onmedial aspect dorsomedial thalamic nucleus

Psychomotor retardation

Endocrine changes due to abnormal pituitary-hypothalamic axis-obesity, DI, delayed or precocious puberty,gigantism, hypothyroidism

Shrill brief pitched cry-due to cortico bulbar deficits together with a change in acoustic properties ofsinuses and calvarium

Investigation and treatment depends up on the primary aetiolgy

29

APPROACH TO NEUROMETABOLIC DISORDERP.A. MOHAMMED KUNJU

Most neurometabolic disorders (NMD) are multiorgan dysfunctions that usually involve the nervoussystem also. So a sound general pediatric knowledge is also required for the accurate diagnosis of NMD.They are diverse groups of disorders that results in acute, sub acute or chronic-progressive deteriorationof the functions of the nervous system.

Generally, NMDs are inherited in an autosomal recessive manner. Knowing just the exceptions will helpone in remembering the inheritance pattern.

Exceptions of Carbohydrate metabolism XLR — phosphorylase kinase deficiency

Exceptions of Lipidoses – XLR; Fabry’s disease

Exceptions of Protein XLR - Lesch-Nyhan syndrome

Exceptions of MPS – XLR; - Hunter

Exceptions of Urea cycle disorder -XLR – ornithine transcarbamylase deficiency

Autosomal dominant - e.g., acute intermittent porphyria, familial hypercholesterolemia.

Clinical classification of NMDs

1. NEUROMETABOLIC DISEASES CLASSIFICATION

• ACUTE ENCEPHALOPTHY (Due to accumulation of small molecules)

– Presents early in life

– SYMPTOMS:

• Recurrent vomiting

• Poor feeding

• Lethargy

• Dehydration

• Seizures

• Coma

– Rapidly progressive course

• CHRONIC ENCEPHALOPATHY ( Due to accumulation of large molecules)

• Late infancy, children, adolescents

• SYMPTOMS: Depends on grey matter(GM) or white matter(WM) involvement

30

• GM

– Dementia

– Seizures

– Affection of other organ systems

• WM

– Spasticity

– Ataxia

– Visual or hearing loss

• Gradually progressive

ACUTE ENCEPHALOPATHY

• CONDITIONS:

• Organic aciduria

• Aminoacidopathies eg. MSUD.

• Lactic acidosis

• Urea cycle disorders

• Systemic carnitine deficiency.

• Non ketotic hyperglycinemia ( Glycine encephalopathy)

• Sulfite oxidase deficiency

• Clinical picture is uniform

• Diagnosis rests on laboratory tests

RED FLAGS

• In the setting of an acute encephalopathy, intractable seizures or seizures occurring in sibships,consider an NMD in parallel with more common disorders, especially if fever is not a majorsymptom. However, in newborns, infections & hypoglycemia/ hypocalcaemia must be excludedand a trial of IV calcium and glucose must be given in all patients before embarking on detaileddiagnostic evaluations.

Following is a step wise approach for a baby presenting with acute encephalopathy

– Blood and urine are tested, Blood gases (acidosis) lactate, Ammonia, sugar (hypoglycemia)& Urine Ketones.

31

– Abnormal metabolites may not be present during stable periods or in samples obtainedafter the acute illness is over.

Clinical features of acute encephalopathy are present thenà Clinical features of acute encephalopathy

Clinical features of acute

encephalopathy

• *Organic acidemias can be differentiated by looking for presence of ketosis.

• If ketosis is present with abnormal urine odor consider MSUD (maple syrup) & Isovalericacademia (sweaty feet ) , & without urine odor -Methyl malonic academia & Propionicacademia

• Organic Acidemias with ketosis & skin manifestations like alopecia is multiple carboxylasedeficiency.

• Organic acidemias without ketosis are Glutaric academia & Acyl CoA dehydrogenase.deficiency

Rule out infections, hypoglycemia, Hypocalcaemia

METABOLIC DISORDER

Obtain plasma ammonia

High Normal

Obtain blood pH &CO2

No Acidosis

Urea cycle disorders

Acidosis

Organic acidemias*

No acidosis

Aminoacidopathies Or galactosemia

Obtain blood

pH & CO2

32

• Final confirmation of acute encephalopathy is possible by

– Detection of organic acid, amino acid, & sulfites in urine

– Detection of specific enzyme deficiency or DNA analysis in WBC and fibroblasts

– Clinical distinction between various diseases coming under each category is not possible

– Histologic evaluation of affected tissues such as skin, liver, brain, heart, kidney, and skeletalmuscle may help but not fool proof.

Resistant seizures are features of vitamin-responsive disorders (e.g., pyridoxine dependency states andfolinic acid metabolism, biotin-responsive MCD), and are a prominent feature in Glycine encephalopathy(nonketotic hyperglycinemia), sulfite oxidase deficiency, and congenital malabsorption of magnesium.

Congenital lactic acidosis and central hypotonia are features of deficiencies of pyruvate carboxylase(PC) and pyruvate dehydrogenase (PDH) and disorders of the Krebs cycle and mitochondrialencephalopathies (Lactate/pyruvate ratio (Normal : <20:1) increased in mitochondrial encephalopathies;normal in PDHC deficiency)

Increase in lactate with ketoacidosis

Without myopathy (Alper’s with liver failure & Leigh’s with out liver failure)

With myopathy (specific mitochondrial diseases – KSS, MELAS & MERRF)

Recurrent hypoglycemia in the glycogen storage disorders (GSD) affecting the liver and in defectsof FAO (consequent to over utilization); which are often associated with signs of cardiac involvement(cardiomyopathy, arrhythmias)

Sample collection

1.Plasma or serum lactate, pyruvate, albumin, triglycerides, uric acid, quantitative amino acids, organicacids, acylcarnitines, (1-2 mL in EDTA or and for molecular study in heparin tube, on ice)

2. Urine amino acids, Acyl Glycine, organic acids, and/or orotic acid (5-10 mL, freeze immediately)

Increase in lactate with ketoacidosis

With myopathy Without myopathy

Specific Mitochondrial diseases – KSS , MELAS & MERRF

With liver failure

Alper’s

With out liver failure

Leigh’s

ACUTE ENCEPHALOPATHY

33

3. Cerebrospinal fluid (CSF) lactate, pyruvate, organic acids, neurotransmitters, and/or disease-specificmetabolites collected at the same time as plasma (1-2 mL)

Routine urine metabolic screen will help in screening

Emergency treatment of acute encephalopathy

• ABC must be established first. Give appropriate antibiotics.

• Initial treatment of NMDs is to correct the metabolic abnormalities. Start empirical treatment byclinical clues.

• Eliminate potentially harmful protein or sugars. Stop all oral intakes.

• Treat hypoglycemia and prevent catabolism.

Correct hypoglycemia.

Dextrose will improve most conditions.

Add insulin, 0.2-0.3 IU/kg, as needed to maintain normoglycemia.

Add electrolytes at maintenance concentrations with appropriate adjustments to correctdyselectrolytemia.

• Treat acute acidosis;

pH <7.0-7.2, Give bicarbonate 0.35-0.5 mEq/kg/h up to 1-2 mEq/kg/h (controversial). For intractableacidosis, consider hemodialysis.

• Significant hyperammonemia

Ø Sodium phenyl acetate and sodium benzoate ((Ammonul 100 mg/mL) - Loading: 250 mg /kgIV over 90-120 min followed by 250 mg/kg/d IV over 24 h through central line

Ø Arginine (210 mg/kg/d IV over 90 min followed by infusion of 210 mg/kg/d over 24 h or viaNG tube) is an essential amino acid in patients with some urea cycle defects.

Ø For ammonia > 500-600 mcg/dL, hemodialysis, if not available, peritoneal dialysis or doublevolume exchange transfusion can be performed.

Ø IV L-carnitine (100mg/kg) in life-threatening situations associated with primary metabolicacidosis or hyperammonemia.

Disorder Ferric

chloride

DNPH Sugar Nitroprusside CTAB

PKU + + - - -

Galactosemia - - + - -

Organic aciduria + + - - -

Aminoaciduria - + - - -

Homocystinuria - - - + -

MPS - - - - +

34

Ø

• Pyridoxine/Biotin for seizures unresponsive to conventional anticonvulsants.

CHRONIC ENCEPHALOP ATHY

Chronic NMDs has to be considered as a group of progressive disorders collectively called as isneurodegenerative disorders.

They could result from.

• Genetic disorders

• Biochemical defects

• Chronic viral infections

• Toxins

• Idiopathic

When to suspect that there is neurodegeneration?

A precise history will definitely give the clue. There will be a decline in the neurological function and thedisease keeps worsening as time goes on. But the single most important clue is regression of developmentalmile stones. However a CP like presentation with atypical neurological features and systemic manifestationsalso must be a situation for directed investigation for neurometabolic disorder.

Pathological Classification

• Gray matter disease

• White matter disease

• Basal Ganglia disease

• Spinocerebellar disease

• Peroxisomal disorders

• Mitochondrial disorders

They also can be categorized according to the age of presentation & with liver enlargement or withoutliver enlargement

After a thorough clinical examination directed neuroimaging techniques and specific biochemicalmolecular diagnostic tests can be utilized for the diagnosis of neurodegenerative disorders

Approach

Neurometabolic disease = Diffuse affection à Psychomotor retardation

Restricted affection à Progressive neurological deficit

Eg. Progressive ataxic syndrome, Paraplegia, Peripheral Neuropathy

STEP. I Is it progressive or static?

I a. Clues to suspect static encephalopathy

A. History: High risk factors eg. Prematurity, Asphyxia, Birth trauma

B. Constellation of signs: Group of congenital stigmata

» Suggest malformation of brain

» Chromosomal anomaly

35

Pitfalls in diagnosing static encephalopathy

– Degenerative diseases with slow evolution may mimic static encephalopathy in infancy

II a. Clues to suspect progressive

• Positive family history

• Parental consanguinity

• Affection of CNS with PNS

• Presence of neurocutaneous stigmata

• Dysmorphic features

• Unusual smell to urine & skin

• Skeletal abnormalities

• Somatic involvement (Hepatosplenomegaly & dysostosis multiplex.)

• Pitfalls in diagnosing degenerative diseases:

• Child with hypertonia may turn over early with subsequent delay in milestones

• Extra pyramidal movements like dystonia may appear late in static encephalopathy

STEP. II - FIND OUT SITE/SITES OF AFFECTION

Central / peripheral; Central+ peripheral;

By noting selectivity of regression

Global deterioration (Regression of motor, social, adaptive & language milestones) = Central

= Cognitive regression (Dementia dominant)

Regression only in one milestone (Eg: motor)

Pure motor regression

UMN lesion

Spinal Cord lesion ( Hereditary spastic paraplegia)

LMN lesion (Hypotonia with absent reflexes)

• Anterior horn cell disease ( SMA)

• Muscle disease( Pompe)

• Polyneuropathy (+/- Sensory)

STEP. III - Rule out other treatable conditions

– Inflammatory conditions

– Tumors

– Vascular

– Endocrine disorders

– Recurrent seizures

When to suspect degenerative /metabolic diseases?

• Gradually progressive

• Symmetrical affection

36

• No Inflammatory response/no raised ICT

• Positive family history

• Recurrent coma and vomiting

• Recurrent ataxia or spasticity

• Mental retardation without congenital anomalies

• Associated somatic manifestations

• WHAT TO LOOK FOR IN THE EXAMINATION

• Developmental assessment

• Unusual posturing or involuntary movements

• Dysmorphic features

• Hair & skin

• Neurocutaneous lesions

• Micro or macrocephaly

• Examination of eye

• Examination of motor system

• Hepatosplenomegaly

• Skeletal change

GREY OR WHITE MATTER DISEASE?

FORMULATING THE DIAGNOSIS

Non progressive Central motor disorder (CP)

Features are in history. Positive risk factors in antenatal, Natal, Postnatal and behavioral softsigns that include colicky behavior, feeding problems and irregular sleep patterns. Physical examinationmay not yield specific findings. So look for associated findings that may help in rehabilitation.

Neurodevelopmental examination shows delayed milestones or disordered sequence of motormilestones and abnormalities of tone (either hypotonia or poor control of head or a stiffness and rigidity.)

In reflex behavior, a combination of delay in disappearance of primitive reflexes and delay inappearance of postural reflexes or incomplete expression is also a powerful predictor of cerebral palsy.Diagnosis of specific type of CP can be done by 1 to 2 years.

Progressive Central Disorder

When there is delay or regression in development, the pregnancy and birth history is normal withpositive family history and consanguinity, progressive central disorder must be thought of.

Progressive disorders can be clinically grouped as grey or white matter disease

Differentiating features are as follows

Table APPEARANCE

OF SIGNS

GREY MATTER WHITE MATTER

Intel.deterior. Spasticity

37

EARLY

Seizures

P. neuropathy

Retinal invol.

Optic atrophy

Extrapyramidal

Ataxia

LATE

Spasticity Intel. Deterior.

Babinski sign Seizures

Approach to these disorders is given in the algorithm.

Among them, a progressive lipidosis may be considered when there are positive eye grounds andhepato-splenomegaly. A Hurler phenotype should be considered in a situation where dysmorphic featurescombined with dysostosis multiplex are seen.

Non-Specific progressive disorders or gray or white matter should be considered where the historyis normally in association with marked subsequent developmental delay. Pelizaeus - Merzbacher diseasemay masquerade as cerebral palsy. The give away clue is peculiar rhythmic eye movements.

White matter disorders can be differentiated by the imaging finding

Images of WM disorders are shown in power point slides

Since the demonstration of the Dopa sensitive dystonia (Segawa syndrome), L-dopa has beentried in some of the cases of congenital cerebral palsy where choreo athetotic rigidity is seen. A markedimprovement suggests the possibility of Dopa responsive dystonia.

Peripheral progressive disorder

Myasthenia gravis and congenital myasthenia, muscular dystrophy and a spectrum of intrinsicmuscle disease along with spinal muscular atrophy are considered in this group. Congenital myotonicdystrophy is to be considered in children thought to be having cerebral palsy. A maternal myotonia andmyopathic facies with history of fetal wastage are the diagnostic clues.

Pure NMD in this group are Pompe disease, Refsum disease etc

Determine

Static Progressive

Central Eg.CP

Peripheral Eg Benign congenital Hypotonia

Central Eg.Tay sachs

Peripheral Eg SMA

Central + Peripheral Eg MLD

Secondary Systemic Malnutrition Endocrinopathy

Cognitive/ Motor delay

38

Grey Matter (GM) Degenerations

Progressive

White Matter (WM) Degenerations

Dementia, Seizure, Retinal

Spasticity, ataxia, Optic atrophy

With HSM Without HSM

With CNS Affection

With CNS + PNS Affection

Grey Matter Degenerations with HSM

With dysmorphism With out

dysmorphism

GM1 Gangliosidosis (generalzd) MPS

Multiple sulfatase deficiency Mannosidosis Fucosidosis I cell disease Zellweger Syndrome

Gaucher’s Niemann-Pick Sandhoff

Severe swallowing problem Opisthotonus

With multifocal seizures

GM1 Gangliosidosis Sialidosis Zellweger’s Lowe’s

Without seizures

Corneal clouding

MPSMucolipidosisMannosidosisMultiplesulfatasedeficiencyFucosidosis

39

Megalencephaly No Megalencephaly Blindness

Grey Matter Without HSM

With cherry red spot

With out cherry red spot

Tay-Sach’s Sialidosis

Tay-Sach’s Sialidosis

NCL. Menke’s Alpers

Abnormal hair

Menke’s NCL

White Matter Degenerations

CNS Affection CNS &PNS Affection

Canavan disease Alexander disease Adrenoleucodystrophy Palizeus –Merzbacher

MLD Krabbe (opisthotonus) Neuroaxonal dystrophy Adrenomyeloneuropathy

Macrocephaly No Macrocephaly

Canavan’s dis. Alexander’s

Visual loss

Palizeus-Merzbacher Adrenoleucodystrophy

Abnl Eye movt.

40

Other presentations

• Psychomotor retardation with connective tissue involvement Homocystinuria.

INVESTIGATIONS

A careful history and physical examination can help more than all the investigations put together.

Exercise prudence in the investigations. Some children need little or no testing as part of evaluation formotor delay; others may require an extensive search.

Karyotyping, EEG, brain electrical activity mapping, brain imaging studies (CT, MRI, PET ) and metabolicscreening may be utilized in appropriate situations

Following are some points in deciding on the investigations

1. Although brain imaging may not be required routinely, in the following situations it will be ofhelp: an unexpected change in behavior, head circumferences, motor status, cognitive abilities, neurologicexamination, or seizure frequency.

2. Based on the extremely low prevalence of IEM, metabolic screening does not need to be aroutine part of an evaluation. If there is a history if intermittent episodes of vomiting and lethargy, failureto thrive, progressive loss of skilled or a plateau in milestone acquisition, an unusual body odor, or asuggestive family history, metabolic screening studies should be performed.

3. In peripheral (motor unit) disorders, muscle enzyme studies, electromyography and nerveconduction studies, Neostigmine test and muscle or nerve biopsy will help in differentiating muscle,nerve, anterior horn cell and for myoneural junction disease.

Diagnostic (Molecular) testing: When a pattern of disease and its tissue localization are identifiedother laboratory testing can be employed to make a specific diagnosis, and direct treatment.

Tissue characterization test are

A. Muscle biopsy

B. Histochemistry : Diagnosis by specific morpholgic features Mitochondrial disease

C. Immunohistochemistry: Absent or reduced staining for specific protein

Emery-Dreifuss muscular dystrophy

Duchenne muscular dystrophy

D. Biochemistry: Absent or reduced enzyme function

Myophosphorylase deficiency

E. Nerve biopsy

Vasculitis; Metachromatic leukodystrophy

F. Antibodies in serum or CSF: May define specific immune neuromuscular disorders

4. Genetic testing: Defines specific hereditary disorders

Usually with symmetric weakness if facilities are available

Hexosaminidase A (multisystem disorder)

Spinal muscular atrophy (SMN /survival motor Neuron) deletion)

Bulbo-spinal muscular atrophy (Androgen receptor triplet repeat)

The age of onset of symptoms is often a helpful guide in deciding which progressive degenerative disorders

41

should be considered.

In occasional situation one has to consider a combination of cerebral and motor unit hypotonia.

They are

1. Acid maltase deficiency

2. Familial dysautonomia

3. Infantile neuroaxonal dystrophy

4. MLD & Krabbe

5. Mitochondrial disorders

6. Neonatal myotonic dystrophy

7. Giant axonal neuropathy

8. Perinatal asphyxia secondary to motor unit disease.

9. Fukuyama type congenital muscular dystrophy

10.

Following syndromic groups will help in identification of other diseases.

Myoclonus Ataxia dementia syndrome

1. Lafora body disease. Onset in adolescent

2. NCL Retinal degen

3. Baltic Myoclonus

4. MERRF ragged red fibre

5. Late Gaucher’s Slow saccades,

6. Sialidosis Cherry red spot

Progressive EPS( Extrapyramidal symptoms )syndromes

Mineraldeposit !!)

1. (Copper) Wilson KF ring

2. (Iron)Hallervorder-spatz Similar to wilson, myoclonus, MRI “ eye of tiger”

3. (Calcium) Fahr syndrome (Familial Basal ganglia calcification syndrome)

4. (Uric acid) Lesch Nyhan Self mutilation

3. Chediac - Higashi Mainly Neuropathy

4. Juvenile PD Parkinson feature, L DOPA response

5. Segawa syndrome Diurnal fluctuation

6. Dystonia Musculorum deformans

7. Juvenile dystonic lipidosis. Sea blue hystiocytes

Intermittent ataxic syndrome

1. Hartnup disease

2. Urea cycle disorders

42

3. Pyruvate decarboxylase & dehydrogenase deficiency.

4. Intermittent MSUD

Stroke like presentation

1. MELAS syndrome

2. 5, 10-methylene tetrahydrofolate reductase deficiency (common)

3. Fabry’s disease (1:80,000 to 1:117,000)

4. Ethylmalonic-adipicaciduria (rare)

5. Ornithine transcarbamylase deficiency (1:70,000)

6. Chédiak-Higashi syndrome (rare)

7. Homocystinuria

Treatment

There is currently no known treatment or cure for most (or perhaps all) causes of children withmotor delay. But all options are not that gloomy.

Physical, occupational, and speech therapies are often recommended and used, with very goodresults. Appliances like KAFO are sometimes used for weak limb muscles. Hypotonic/ hypertonic, infantmay need extra stimulation. Toddlers and children with speech difficulties may benefit greatly by usingsign language within the family until speech has become intelligible by the family.

Prognosis

The outcome in any particular case depends largely on the nature of the underlying disease.Typicallythe hypotonia does not get much worse, and sometimes improves. Usually, life expectancy is not seriouslythreatened in peripheral/central non progressive disorders. As of today in progressive disorders nothingmuch can be offered. Recently a few cases with dysmyelinative features, trial of steroids have yieldedunexpected and dramatic positive out come. So we recommend a course of steroid in children with MRI/ CT evidence of dysmyelination. Similarly in children with CP, no response with physiotherapy warrantsa trial of Levodopa since some of these cases may be dopa responsive dystonia.

References

1. Fernandes J, Saudubray JM, Van den Berghe G: Inborn Metabolic Diseases: Diagnosis and Treatment.Springer; 4th, rev. ed. edition (October 19, 2006).

2. Hoffman GF, Nyhan WL, Zschocke J: Inherited Metabolic Diseases. Philadelphia: LippincottWilliams & Wilkins; 2002

3. Lyon G ,Kolodny E H , Pastores G M Neurology of Hereditary Metabolic Disease of Children)McGraw-Hill Professional; 3 edition (April 24, 2006)

4. William L. Nyhan,Bruce A. Barshop , Pinar T. Ozand; Atlas of Metabolic Diseases (A HodderArnold Publication)(2nd Edition) Hodder Arnold Publication; 2 edition , 2005

5. Joe T. R. Clarke. A Clinical Guide to Inherited Metabolic Diseases

Cambridge University Press; 3 edition ,2006)

43

MLDCANAVANSymmetric demyelination that spares

the subcortical U fibers Symmetric demyelination that involvessubcortical U fibers

KRABBE DISEASEWhite Matter Dysmyelination with High density basal ganglia

44

ADRENOLEUKODYSTROPHY

Occipital white matter most involved(also callosal splenium)Frontal white matter most involved

ALEXANDER DISEASE

45

PATTERN OF NEUROMUSCULAR DISORDERSS. MINI

Neuromuscular disorders encompass a group of disorders which affect the peripheral nervoussystem at various levels. The diagnosis is made easy if the patterns of disease process are recognisedfrom history and physical examination.

Weakness in neuromuscular disorders is of LMN type. i.e. The weak muscles are flabby, hypotonic,usually wasted, tendon jerks are often diminished or absent. Presence of fasciculation points towardsLMN type of weakness.

Detection of Clinical patterns of NM disorders

A. Functional pattern

• Motor: weakness, muscle size, abnormal movements (fasciculation, polyminimyoclonus)

• Sensory: Positive symptoms like paraesthesia or negative symptoms (sensory loss) seen inneuropathy. Positive sensory symptoms are seen in acquired neuropathy.

• Autonomic disturbances: fluctuations in heart rate, BP, hypo/hyperhydrosis, trophic changes as inPolyradiculoneuropathy /neuropathy

B. Anatomical pattern

a. Arms vs legs vs Cranial:

• Cranial involvement: Myasthenia gravis, Myotonic dystrophy, ophthalmoplegia in mitochondrialdisorders, bifacial involvement in GBS and FSHD

• Leg involvement: most of the neuropathies and muscle diseases.

• Upper limb weakness: FSHD presents with weakness of shoulder girdle muscles before involvementof lower limbs.

b. Proximal vs distal weakness

The general rule is that the neuropathies result in distal weakness where as muscle disorders andneuromuscular junction disorders result in proximal weakness. However, there can be exceptions.

• When there is radicular involvement (GBS, CIDP) weakness can be more pronounced proximally.

• Certain muscle diseases can produce predominantly distal weakness eg. Myotonic dystrophy, distalmyopathy like Bethlem and Myoshi disease etc.

C. Symmetric Vs asymmetric

• Neuropathies can be symmetric ( Polyneuropthy) or asymmetric (eg traumatic mononeuropathy,vasculitis leading to mononeuritis multiplex etc)

• Neuromuscular junction disorders: often symmetrical

• Muscle disorders; Symmetrical; but in FSHD there can be asymmetry

• Selective involvement of certain muscles supplied by the same nerve/ roots: Muscular dystrophyeg. In DMD, sternal head of the pectoralis major is more affected than the clavicular head.

Temporal pattern:

• Acute: Poliomyelitis, GBS, Traumatic neuritis, viral/ bacterial myositis

• Sub acute: Inflammatory myopathy, Neuromuscular junction disorders

46

• Chronic: muscular dystrophy, Hereditary sensory motor neuropathy

• Episodic presentation: Periodic paralysis

• Diurnal variation : NM junction disorders

Anatomical Localisation

Anterior horn cells:

• Weakness can be acute and patchy (Poliomyelitis) or chronic and proximal (SMA).

• Affected muscles are flabby/hypotonic and wasted.

• Tendon jerks are diminished or absent.

• Fasciculation may be evident in weak muscles.

Poly radiculoneuropahy:

• weakness is symmetrical usually & often more pronounced proximally

• Acute onset in GBS, and sub acute to chronic progression in CIDP

• Tendon jerks are absent or diminished (may be retained in axonal forms of GBS)

• Affected muscles are wasted.

• Autonomic disturbances can occur

• Fasciculations can be seen in chronic cases

Neuropathy:

• The weakness is distal

• The involvement can be single nerve (traumatic neuropathy) or patchy involvement of multiplenerves (mononeuritis as in vasculitis) or symmetrical (poly neuropathy). The weakness is in nervedistribution

• Lower limbs are usually affected earlier than upper limbs. But upper limb involvement may beseen early in some conditions like Neuritic Hansen’s disease

• Ankle jerks are lost initially in polyneuropathy.

• Trophic changes

Neuromuscular junction disorders

• Weakness can be patchy (ptosis or ophthalmoplegia alone) or generalized.

• Proximal muscles are affected.

• Usually there is no wasting, even though some types of congenital myasthenia (usually manifestsin adulthood) like slow channel disease may be associated with muscle wasting.

• Tendon jerks are normal

Muscle diseases

• Weak muscles are hypotonic and wasted usually.

• Gait is waddling and Gower’s sign may be positive.

• Muscle hypertrophy (pseudo/true) may be seen in some conditions like X- linked muscular dystrophy,LGMD, Myotonia congenita.

• The muscles which are usually hypertrophied in DMD include gastrocnemius, vastus lateralis,

47

infraspinatous, deltoid, masseter and tongue muscles. . Calf hypertrophy can occur in some LGMDsand SMA type III also.

• The tendon jerks are diminished in proportion to the degree of weakness, the ankle jerks are retainedtill the late stages.

• Contractures are very prominent in some conditions like Emery- Driefuss muscular dystrophy &congenital muscular dystrophy. Ankle contractures and ilio tibial band contractures can be seen inDMD also.

• The pattern of muscle weakness is usually symmetrical. Hip girdle muscles are affected oftenearlier than shoulder girdle in muscular dystrophy like DMD, LGMD etc. But in FSHD theinvolvement can be asymmetrical and weakness begins in scapular muscles. Beevor sign may bepositive in FSHD.

• Weakness is more distal in Myotonic muscular dystrophy and distal myopathy.

• Myotonia can be clinically elicited by around five years of age in conditions like myotonic musculardystrophy, myotonia congenita etc

• Muscle tenderness is seen in viral myositis, pyomyositis or inflammatory myopathy.

• Other systemic involvement may provide clue to diagnosis. CNS involvement can be seen incongenital muscular dystrophy, Mitochondrial disorders etc. Multiple system involvement can occurwith Myotonic dystrophy and mitochondrial myopathy. Skin manifestations like Gottrons papulesand heliotrope rash in Dermatomyositis. Cardiac involvement (cardiomyopathy/ conductiondisorders) in DMD, Becker muscular dystrophy, some LGMD, Emery- Driefuss muscular dystrophy,Myotonic dystrophy, Mitochondrial myopathy, Pompe etc.

48

New Born with seizures New Born with seizures -- ApproachApproach

Dr.Vinayan.K.PDr.Vinayan.K.P

Professor

Division of Pediatric Neurology

Department of Neurology

Amrita Institute of Medical Sciences

Cochin, Kerala

EpidemiologyEpidemiology

� Highest incidence of seizures in lifespan

�1.5-3.0 per 1000 live term births

�50-150 per 1000 live preterm births

� Incidence as a function of birth weight

�57.5 per l000 in infants < 1500 grams

�2.8 per 1000 in infants 2500 to 3999 grams

� An epileptic seizure is a transient occurrence of signs and symptoms due to abnormal , excessive or synchronous neuronal activity in the brain.

� Only a symptom/ sign: not a disease

Se izure

Neonatal brain is prone to seizure Neonatal brain is prone to seizure --Why?Why?

� GABA is excitatory on the young neurons� Major inhibitory systems have delayed

maturation� There is an excess of excitatory glutamate

synapses

� Imbalance of excitation and inhibition--->seizures

EpilepsyEpilepsy

� A disorder of brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic , cognitive , psychological and social consequences of this condition.

� The definition of epilepsy requires occurrence of at least one epileptic seizure

Seizures in the new bornSeizures in the new born

Stereotypic, paroxysmal spell of altered neurologic function (behavior, motor, and/or autonomic function)

� �epileptic�

� �non-epileptic�

� Acute symptomatic seizures !

Neonatal SeizuresNeonatal Seizures

� first 28 days in term infants

�44 weeks of gestation in preterm infants

EtiologyEtiology

Hypoxic-ischemic encephalopathy

Intracranial hemorrhage

Cerebral infarction

Cerebral malformations

Meningitis/septicemia

Metabolic

Hypoglycemia

Hypocalcemia

30-53%

7-17%

6-17%

3-17%

2-14%

0.1-1.5%

4-22%

NEWBORN WITH SEIZURES- APPROACHVINAYAN K.P

49

Approach to etiologyApproach to etiology

0-3 DAYS

>3DAYS

PREMATURE

FULL TERM

Hypoxic-ischemic Encephalopathy

+ + + + + + +


+ + + + +

Intracranial infection + + + + + +

Developmental defects + + + + + +

Hypoglycemia + + +

Hypocalcaemia + + + +

Other metabolic + +

Epileptic syndromes + + +

Clinical approachClinical approach

� with encephalopathy

� no encephalopathy

Classification of Neonatal SeizuresClassification of Neonatal Seizures

� Clinical

� Electroencephalographic

Clinical ClassificationClinical Classification

� Subtle

� Tonic

� Clonic

� Myoclonic

Clinical ClassificationClinical Classification

Subtle seizures

� More in preterm than in term� Eye deviation (term)� Blinking, fixed stare (preterm)� Repetitive mouth and tongue

movements� Apnea� Pedaling and tonic posturing of limbs

Neonatal seizures behave differently!Neonatal seizures behave differently!

� The immature brain cannot sustain a synchronized, generalized seizure.

� The lack of myelin � restricts conduction

Electroencephalographic ClassificationElectroencephalographic Classification

� Epileptic

� Non-epileptic

� Electrical seizures without clinical activity

��EpilepticEpileptic�� seizureseizure

� Generated by hypersynchronousdischarges of a critical mass of cortical neurons

� Not provoked by tactile stimulation

� Not suppressed by restraint of involved limb or repositioning of the infant

� Consistently associated with EEG activity

50

��NonNon--epilepticepileptic�� seizureseizure

� brainstem release phenomena (reflex)

� provoked by stimulation

� suppressed by restraint or repositioning

� no electrical signature

Focal clonicUnifocalMultifocalHemiconvulsiveAxial

Focal tonicAsymmetrical truncal posturingLimb posturingSustained eye deviation

Myoclonic

Generalized

Focal

Spasms

Flexor

Extensor

Mixed extensor/flexor

“Epileptic” seizure

��NonNon--epilepticepileptic�� seizureseizure

Myoclonic

GeneralizedFocal

Fragmentary

Generalized tonic

Flexor

ExtensorMixed extensor/flexor

Motor automatisms

Oral-buccal-lingual movements

Ocular signsProgression

movementsComplex purposeless

movements

Classification of Neonatal Seizures

ELECTROENCEPHALOGRAPHIC SEIZURE

CLINICAL SEIZURE COMMON UNCOMMON

Subtle +*Clonic

Focal +Multifocal +

TonicFocal +Generalized +

MyoclonicFocal, multifocal +Generalized +

---------------------------------------------------------------------------------------------------------------

*Only specific varieties of subtle seizures are commonly associated with simultaneous

Electroencephalographic seizure activity.

��NormalNormal�� neonatal activity mistaken for neonatal activity mistaken for seizureseizure

Awake or Drowsy

� roving eye movements

� sucking, puckering mouth movements not associated with tonic eye deviation

Sleep

� fragmentary myoclonic jerks

� isolated, generalized myoclonic jerk wakes

JITTERJITTER

� Tremor is the characteristic finding

� No associated abnormality of gaze or eye movement

� No associated autonomic changes

� Stimulus-sensitive

� Movements cease with passive limb flexion

Benign Neonatal ConvulsionsBenign Neonatal Convulsions

� Familial & non familial

� 5th day fits

� Familial � autosomal dominant

� K channel mutations

� Seizure semiology varied

� No specific EEG patterns

� Prognosis excellent

Neonatal epileptic syndromesNeonatal epileptic syndromes

� Benign neonatal convulsions

� Catastrophic neonatal epilepsies

�Cerebral malformations

�Metabolic syndromes

51

Neonatal Epileptic Neonatal Epileptic

encephalopathies with suppression encephalopathies with suppression burst patternburst pattern

� Early infantile epileptic encephalopathy

( EIEE) of Ohtahara

� Early myoclonic encephalopathy of Aicardi

EIEE (Ohtahara)

� Tonic spasms

� Cerebral malformations

� Suppression burst

� Poor outcome

EMEE(Aicardi)

� Massive and erratic

myoclonus

� Metabolic disorders

� Suppression burst

� Poor outcome

Laboratory Studies to Evaluate Neonatal Laboratory Studies to Evaluate Neonatal SeizuresSeizures

Complete blood count, differential, platelet count;

� Blood glucose , BUN, Ca, P, Mg, electrolytes

� Blood oxygen and acid-base analysis

� Blood, CSF and other bacterial cultures

� CSF analysis

� EEG

� Neuroimaging

Prognosis of Neonatal SeizuresPrognosis of Neonatal Seizures

2 major factors

� EEG

� Underlying neurological disease

Prognosis of Neonatal seizures in Prognosis of Neonatal seizures in

relation to EEGrelation to EEG

EEG BACKGROUND NEUROLOGICAL SEQUELAE(%)

Normal: 10

Severe abnormalities 90

Moderate abnormalities ~50

Laboratory Studies to Evaluate Neonatal Laboratory Studies to Evaluate Neonatal

SeizuresSeizures

Clinical Suspicion of Specific Disease

� TORCH antibody titers, and viral cultures

� Blood and urine metabolic studies

� Blood and urine amino and organic acid screen

Why to treat neonatal seizures?Why to treat neonatal seizures?

� interfere with important supportive measures

� ? cause of brain injury

TreatmentTreatment

Identify the underlying cause:

hypoglycemia Dextrose

hypocalcemia Calcium gluconate

hypomagnesemia Magnesium sulfate

pyridoxine deficiency Pyridoxine

meningitis antibiotics

52

Drug therapy for neonatal seizures

Standard Therapy

AED Initial Dose Maintenance Dose Route

Phenobarbital 20mg/kg 3 to 5 mg/kg per day lV, lM, PO

Phenytoin 20 mg/kg 5-8 mg/kg per day lV, POª

Fosphenytoin 20 mg/kg phenytoin 5-8 mg/kg per day lV, lM

equivalentsLorazepam² 0.05 to 0.1 mg/kg Every 8 to 12 hours

lVDiazepam²´ 0.25 mg/kg Every 6 to 8 hours

lV

Determinants of duration of AED Determinants of duration of AED

therapytherapy

� Neonatal neurological examination

� Cause of neonatal seizure

� Electroencephalogram

Duration of anticonvulsant therapyDuration of anticonvulsant therapy

� No definite evidence based guidelines

� Normal neurological examination -discontinue therapy

� Neurological examination persistently abnormal

�consider etiology and obtain EEG

� continue AED

� re-evaluate in 1-3 months

Duration of anticonvulsant therapyDuration of anticonvulsant therapy

First visit after discharge

Neurological examination

�Normal: discontinue AED�Persistently abnormal : obtain EEG

� No seizure activity on EEG: discontinue AED

Conclusion & take home messageConclusion & take home message

� Seizure manifestations differ in the neonate

� Associated with high morbidity and mortality

� Multiple etiologies demand an aggressive work-up

53

CLINICAL FEATURES OF AUTISMP.A. MOHAMMED KUNJU

Definition

“A condition presenting in early childhood characterized by marked abnormalities incommunication and social interactions and a restricted and socially atypical range of interests.”

PERVASIVE DEVELOPMENTAL DISORDER ( DSM IV)

Severe qualitative deficits in all the 3 of the following:

1) Behavioral domains.

2) Social interaction.

3) Language communication & play.

Stereotypes, preservations and narrow range of interest & activities

1) Classic autism- as defined before

2) Asperger’s syndrome: non-retarded, often clumsy kids with no speech delay and with deficientsociability and narrow range of interests.

3) PDD not otherwise specified (PDD-NOS). Autistic behavior that do not fulfill the othervarieties.

4) Heller’s disintegrative disorder. Previously normal kids who undergo massive regressionbetween 2 & 10 yr ->acquired autism + dementia. But no schizophrenia or degenerative brain disease.

5) Rett’s syndrome: girls with acquired microcephaly, infantile regression, lack of hand use,stereotypes like hand wringing

CRITERIA FOR AUTISTIC DISORDER ( DSM 4)

Triad of autism

• Impaired socialization,

• Impaired communication

• Repetitive behavior

A TOTAL OF 6 OR MORE MANIFESTATIONS FROM 1, 2, 3

1) QUALITATIVE SOCIAL INTERACTION IMPAIRMENT ( AT LEAST 2 OF 4)

a) Nonverbal Behavior: Poor Eye to Eye Gaze, Abnormal Facial Expression, Body Postures &Gestures to regulate social interactions

b) Failure to develop peer relationship

c) Lack of spontaneous seeking for sharing enjoyment etc with others

d) Lack of Social or Emotional Reciprocity

54

2)QUALIT ATIVE IMP AIRMENT OF COMMUNICA TION ( AT LEAST 1)

a) For those with adequate speech marked impairment in the ability to initiate or sustain aconversation with others.

b) Stereotyped/ idiosyncratic language

c) Lack of make believe play or social imitative play appropriate to age

d) Delay in / lack of development of spoken language

3) RESTRICTIVE AND STEREOTYPED PATTERNS OF BEHAVIOR, INTERESTS ANDACTIVITIES ( A T LEAST 1 BEHAVIORAL MANIFEST ATION) encompassing preoccupationwith one or more restricted, repetitive and stereotyped patterns of interest that is abnormal either inintensity or focus

Inflexible adherence to specific nonfunctional routine or rituals

Stereotyped motor mannerism (hand or finger flapping or complex whole body mannerism)

Persistent preoccupation with parts of objects

COMMUNICATION DEFICITS IN AUTISM.

Delay or loss of speech by 1yr

• Language deviations

• Pronomial reversals

• Phonology: word deafness

• Prosody: sing song intonation, high pitched voice, monotonous or robotic speech

• Syntax: agrammatical

• Semantics: word retrieval problems, echolalia, narrow range of topics, impaired comprehensionof questions, jokes

• Pragmatics: impaired interpretation of tone of voice, body posture, facial expression, gazeavoidance, nonstop queries. failure to answer, failure to initiate, pursue or terminate talking

But the spectrum can be so much varied to near normal to severely retarded.

AUTISM- PLA Y

The best index to check autism in young kids- look at how they play ( usually by 2 yrs normal kidsplay well with toys).; Fascination of “non-toy” objects

Don’t know to play/ pretend play

Imaginative playing not seen

COGNITIVE DYSFUNCTION IN AUTISM

75% mentally retarded

Poor creativity

Poor insight

Poor verbal skills. better nonverbal skills.

SENSORIMOTOR SYMPTOMS IN AUTISM

Generalized hypotonia, clumsiness, apraxia, toe walking

• Body Movement

55

– Choreoathetotic movements

– Stereotypies

– Motor tics

– Hand Flapping

– Spinning

Motor stereotypes- limbs & vocal

Self injurious behavior due to ^ endorphins

Epilepsy ~ 30%.

Instruments for Diagnosis of ASD

Interview with family:Autism Diagnostic Interview (ADI)

Assessment of child:Autism Diagnostic Observation Schedule (ADOS)

Observation of child:Childhood Autism Rating Scales (CARS)

Clinical diagnosis based on the DSM IV

Early Diagnosis at 6 months

Subtle differences

Decreased vocalization

Somewhat passive

Motor delays (low muscle tone)

No obvious social concerns/Eye contact & reciprocal social smiling absent.

•Proctodeclarative Pointing

•Use of index finger to indicate item of interest to another person

•Absence = predictive of Autism

Assessed by interview of family

at 12 months

• Poor visual tracking

• Quiet, lack social babbling

• Decreased social behaviors (smiling, response to game of peek-a-boo)

• Lack basic imitation skills

• Extreme reactivity

Fall in head circumference in Rett syndrome Hand washing movement in Rett syndrome

56

• Atypical sensory-oriented behaviors

Play with non toy objects

Fragile X Syndrome

Repetitive behaviors –repeated rolling o paper

57

APPROACH TO A FIVE YEAR OLD WHO PRESENTSWITH ONE MONTH HISTORY OF ATAXIA

MARY IYPE

The child could be having a sub acute progression of one of the causes of acute ataxia, or the firstepisode of a recurrent ataxia or the beginning of a progressive ataxia. The history and examinationshould be directed with all these causes in mind with a heightened awareness of the treatable causes. Asmany of the causes as possible in the list should be ruled out so that the investigations can be tailored tothe needs of the patient. In cases where the etiology cannot be pinpointed the genetic diseases have to beinvestigated for.

Causes of acute ataxia in a 5yr old

1. Infections

Cerebellar abscess

Viral cerebellitis (varicella, coxsackie, mumps, EBV, polio)

Bacterial (diphtheria, pertussis, typhoid)

2. Toxins / Metabolic

Alcohol / antiepileptic drugs

Heavy metal poisoning

Hartnup disease / MSUD

Organic & aminoacidurias

3. Posterior fossa tumors

4. Trauma - Cerebellar hemorrhage /Posterior fossa Subdural hemorrhage

5. Migraine - Basilar

6. Vascular - Embolism / Thrombosis / AVM (rare)

7. Hydrocephalus

8. Demyelination – Brainstem encephalitis

9. Paraneoplastic – Neuroblastoma (Opsoclonus myoclonus syndrome

10. Conversion hysteria.

Causes of Recurrent Ataxia

A] Migraine;

Basilar.

Benign paroxysmal vertigo.

B] Multiple sclerosis.

C] Pseudoataxia “ Epileptic Ataxia”.

D] Genetic/Metabolic disorders;

Dominant recurrent ataxia.

Episodic ataxia type 1 “paroxysmal ataxia and myokymia”.

58

Episodic ataxia type 2 “Acetazolamide-Responsive Ataxia” .

Pyruvate decarboxylase deficiency.

Hartnup disease.

Maple syrup urine disease, juvenile form

Causes of Chronic Ataxia

Nonprogressive:

1) Head trauma.

2) Ataxic cerebral palsy:

3) Kernicterus

4) Hypoglycemia

5) Congenital malformations:

A. Cerebellar aplasias.

Cerebellar hemisphere aplasia/hypoplasia

Cerebellar vermis aplasia/hypoplasia

B. Craniovertebral junction anomalies

Arnold-Chiari malformation.

Basilar impression.

Progressive:

1) Brain tumor:

Cerebellar astrocytoma

Cerebellar hemangioblastoma “Von Hippel-Lindau disease”

Medulloblastoma

Ependymoma

Pontine glioma

Frontal lobe

2) Genetic

Autosomal dominant

Spinocerebellar degenerations

SCA types 5 and 7

Autosomal recessive

Abetalipoproteinemia

Ataxia telangiectasia

Friedreich’s ataxia

Ataxia with episodic dystonia

Ataxia with Isolated Vitamin E Deficiency

Cerebellar ataxia due to Coenzyme Q10 deficiency

59

Cerebrotendinous Xanthomatosis

Ataxia without oculomotor apraxia

Maple syrup urine disease

Ramsay Hunt syndrome

Lysosomal storage disease

Juvenile GM2 gangliosidosis

Juvenile sulfatide lipidosis

Marinesco-Sjorgen syndrome

Nieman Pick variant

Neuronal Ceroid Lipofuscinosis

Refsum disease

Mitochondrial disorders

Hartnup disease

X-linked inheritance

Adrenoleukodystrophy

Leber optic neuropathy

With adult onset dementia

With deafness

With deafness and loss of vision

3. Endocrine

Hypothyroidism

Treatable Causes

1. Metabolic:

Acute thiamin (B1) deficiency,

Chronic vitamin B12 and E deficiencies

Autoimmune thyroiditis

2. Toxic (drug induced):

3. Paraneoplastic.

4. Other autoantibodies: e.g. Anti-gliadin antibodies ( the most common, treated with gluten-free diet and anti-immune therapy- steroids, plasmapheresis, IVIG, Methotrexate, and others.

5. Treatable genetic ataxias

A. Recurrent:

Dominant recurrent ataxia.

Episodic ataxia type 1 “paroxysmal ataxia and myokymia”

Episodic ataxia type 2 “Acetazolamide-Responsive Ataxia”

Pyruvate decarboxylase deficiency

60

Hartnup disease.

Maple syrup urine disease, juvenile form.

Chronic

Abetalipoproteinemia

Friedreich’s ataxia.

Ataxia with Isolated Vitamin E Deficiency

Cerebellar ataxia due to Coenzyme Q10 deficiency

Cerebrotendinous Xanthomatosis

Hartnup disease.

Maple syrup urine disease

Ramsay Hunt syndrome.

Appr oach to diagnosis

Neurological and medical history, including drug and toxin exposures

Family history of neurological problems.

Neurological and medical examinations.

Blood tests to rule out specific deficiencies and toxins.

Urine screen for mercury exposure.

Brain Imaging: Magnetic Resonance Image (MRI) or Computed Tomogram (CT)

Possible neuroimaging of the spinal cord.

Electrophysiologic testing: Electromyography (EMG) and nerve conduction velocity testingif there are signs or symptoms of peripheral nerve dysfunction.

Treatment

First of all, search for treatable causes of ataxia. Since there is no universal treatment for ataxia,treatment of the underlying cause in those instances in which there is a treatable etiology is obligatory.

Treat known causes, diet, replacement therapies, and Detoxification therapy.

Improve performance using symptom-specific drugs and retraining of nerve pathways.

Improve activities of daily living and quality of life.

Slow up disease progression using anti-oxidants and neuroprotective drugs.

Gene therapy and stem cell therapy.

Baclofen in low doses may reduce leg spasticity. GABAergic agents such as clonazepam, beta-blockers such as propranolol, or Primidone may reduce the prominence of some cerebellar tremors.

Give health education toward remaining in good general health by engaging in regular physicaland mental exercise, eating and sleeping well, and avoiding injury from taking too much medicine,falling, or developing aspiration pneumonia. A primary care physician is essential for coordination ofhealth care available for patients, encouragement of preventive health management, education of patientsabout avoidance of risks, and to guide the use of medications.

A few clinical examples

61

1. A five year old girl who was previously well with normal milestones, coping well atschool was admitted with acute onset of unsteady gait, confusion, refusing to speak. She gave a precedinghistory of vesicular rash. fever and malaise. The rash erupted 10 days prior to admission. There werecrops of vesicles over the trunk and limbs. Cerebellar signs were florid and the patient was mildlyencephalopathic. The CT scan of the brain was normal and CSF was normal.

Post varicella cerebellitis with encephalitis.

2. A 5 year old boy referred from a Taluq hospital was previously well, with one monthhistory of fatigue, loss of weight, dizziness, poor balance. The mother reported slurred speech, “drunken”gait, and poor handwriting. He was previously right-handed but was now using his left hand only. He wasnot dysmorphic had no skin lesions or neurocutaneous syndromes. Systemic examination was normal.He was alert and responsive. There were no signs of meningeal Irritation. His cranial nerves were normal.He had symmetric cerebellar signs with a broad-based ataxic gait. CT Brain showed a posterior fossalesion; highly calcified vermal and right cerebellar hemisphere mass – A medulloblastoma.

3. A girl, aged 5 yrs from Nedumangadu, referred to the Paediatric Neuro Clinic with an 7 yrold similarly affected brother gave one month history of red eyes, poor balance, frequent falls, with anabnormal thrust of the head which was becoming progressively worse. Her milestones were normal andshe was intellectually normal and had marked gait ataxia. Examination revealed symmetric cerebellarsigns, scanning and staccato speech, some dystonic posturing of trunk and arms, apraxic movement ofeyes and conjunctival telangiectasia.

CT showed marked cerebellar atrophy.

Ataxia Telangiectasia

4. A five year old male, presented with a month’s history of bumping into things & fallingover regularly. His mother had noticed deformity of feet and assumed this was the cause of the problem.He was referred to the Physical medicine department from where he was referred back. His maternalgrandmother had 2 siblings with weakness, who became wheelchair-bound and died in their mid 20’s.He had a normal systemic examination. He had distal muscle wasting, significant pes cavus bilaterallywith hammer toes. Tone was globally reduced with rounded back but no kyphoscoliosis. He had grade 5/5 power proximally and 3/5 distally. Reflexes were globally absent and plantars equivocal. He had gloveand stocking sensory loss for pain and temperature and proprioception was intact.

The child had a dysarthric speech bilaterally symmetric mild cerebellar signs, a high steppingbroad based ataxic gait. CT Brain & MRI of the brain were normal. Cardiac assessment was normal.Nerve conduction studies showed an axonal sensory peripheral neuropathy

Blood investigation showed a homozygous expansion in the frataxin gene

Friedreich’s Ataxia

Notes on a few diseases

Friedreich’s Ataxia

Diagnostic criteria for Friedreich’s Ataxia

- onset before 20 years

- autosomal recessive inheritance

- combined involvement :

Peripheral nerves

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Cerebellar tracts

Pyramidal tracts

Posterior columns

CNS Clinical Features: (variable)

Cerebellar

• Progressive Ataxia (2-16years, more marked in legs, wide based gait)

• Progressive cerebellar speech

• Titubation

• Nystagmus

• Corticospinal involvement

• Weakness & distal wasting calf and hand muscles

• Positive Babinski reflex

• Absent knee & ankle reflexes (may be present initially) Posterior column

• Vibratory & proprioception loss

• Positive Romberg test Peripheral nerves

• Distal sensory loss

Associated Clinical Features:

Talipes-equino-varus

Pes cavus (early onset/birth)

Claw hand deformity

Spastic bladder

Cranial nerve involvement

Kyphoscoliosis

Cardiomyopathies – common, HOCM, progression to intractable CCF

Arrhythmias

Diabetes (abnormal glucose tolerance and insulin resistance)

Prognosis: (variable)

Most wheelchair bound by mid-twenties

Disease may become static and survival into sixties is possible

Mortality occurs due to respiratory problems 2° to severe scoliosis

Ataxia Telangiectasia

This rare, progressive childhood disease causes degeneration in the brain and other body systems.Signs and symptoms usually appear by age 10. The disease causes immune system breakdown(immunodeficiency disease), which increases susceptibility to other diseases. It affects various organs.

Telangiectasias are tiny red “spider” veins that may appear in the corners of the child’s eyes or onthe ears and cheeks. Although they’re characteristic of the disease, the affected child may or may not

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develop them. Delayed development of motor skills, poor balance and slurred speech are typically thefirst indications of the disease. Recurrent sinus and respiratory infections are common. About 1 in 5children with ataxia-telangiectasia develops leukemia or lymphoma. Death occurs in teens or early twenties.

Points

Autosomal recessive - Chromosome 11q22-q23

Defect of DNA repair

Clinical features:

- Progressive ataxia

- Abnormal eye movements

- Dystonic posturing hands & feet

- Choreoathetosis

- Cerebellar speech

- Oculocutaneous telangiectasia

- Learning disability

- Immune abnormalities

- Increased incidence of malignancies

Ataxia - Onset at 2-4 years, progresssive

- Initially truncal

Oculomotor apraxia

- Impaired upward gaze

- Concomitant eye blinking

- Poor saccadic eye movements

- Jerking head movements

Telangiectasia

- Onset 2-6 years

- Bulbar conjunctivae

- Ears, neck, antecubital & popliteal fossae

Skin - Café-au-lait spots, vitiligo

Sclerodermoid changes

Immune deficiency:

- Cellular (thymic hypoplasia, ¯ tonsils, adenoids, spleen,

Lymph nodes, lymphopaenia)

- Humoral (¯ synthesis immunoglobulins with recurrent sinopulmonary infections withbronchiectasis)

IgG, IgA, IgE - IgM

Other clinical features

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Mild polyneuropathy

Hypotonia, reduced reflexes

¯ Muscle bulk & weakness

Intellectual fall off

Defect in DNA repair, sensitivity to ionising radiation,

increased risk of malignancy especially ALL/gliomas.

The Spinocerebellar ataxias that could have onset by five years age.

1. SCA type 7

SCA7 is a rare form of autosomal dominantSCA in all populations. The age of onset of the symptomsranges widely, from infancy, to the fifth or sixth decade. SCA7 is characterized by abnormalities in colorvision and central visual acuity, due to a macular pigmentary degeneration. The cerebellar signs of gaitunsteadiness, incoordination and dysarthria soon progress to a bedridden state. Rate of progression dependson age of onset. In the infantile-onset form there is rapidly progressive cerebellar and brainstemdegeneration and visual loss may be difficult to ascertain before death. Otherwise retinal degeneration isprogressive and leads to blindness. When visual symptoms appear at or before adolescence, blindnesscan occur within a few years. Ataxia progresses to wheelchair confinement in 5-10 years. The retinaldegenerative component distinguishes this hereditary ataxia from other forms of SCA. The diagnosis ofSCA7 is established by the demonstration of an expansion in one CAG repeat alleles in the SCA7 locusgreater than 36 repeats in an ataxia patient.

2. SCA type 14

SCA14 was described in a single four-generation Japanese kindred with autosomal dominant cerebellarataxia. The age of onset ranges from 3 to 42 years of age. Initial symptoms are ataxia of gait in manycases. However, in several individuals with an earlier onset initial signs include an irregular tremulousnessof the neck and axial musculature, described as intermittent axial myoclonus, followed soon afterward bymild ataxia. Progression of disease is usually slow. Other findings on examination included gaze-evokednystagmus, saccadic visual pursuits, upper and lower limb ataxia, dysarthria, and reduced Achilles reflexes. Neuroimaging studies reveal cerebellar atrophy. The gene for SCA14 encoded the protein kinase Cgamma. The diagnosis is established by demonstration of one of several mutations indentified as pathogenicin this gene.

FAQs

Can a patient with ataxia recover completely?

Recovery depends on the cause of ataxia. If the cause can be completelytreated for example, in the case of low thyroid hormone levels or sometumours, then the person can recover completely from the ataxia.

3. Is vertigo and ataxia the same?

No. Vertigo is a feeling that either one’s body or the environment is spinningwhereas ataxia is a condition where the patient mainly lacks coordination.Vertigo occurs when the inner ear or its associated structures are affected.

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STATUS EPILEPTICUSS. MINI

Status epilepticus (SE) is the most common neurological emergency associated with high mortalityand morbidity. The underlying aetiology is a major determinant of the outcome of SE. The key to themanagement of a patient with SE includes prompt recognition and institution of early and appropriateanticonvulsant therapy in order to terminate seizures, thereby preventing the homodynamic, systemicand neurological embarrassment. Simultaneously an attempt is begun to determine the underlying aetiologyand provide specific treatment.

Definition of SE

The current operational definition of SE is continuous seizures lasting for more than five minutes or twoor more discrete seizures between which there is incomplete recovery of consciousness. The duration ofseizures for defining SE has been progressively brought down from 30 minutes to five minutes based onthe observations that majority of seizures which do not remit within 10 minutes are unlikely to ceasewithout medical intervention, the risk of refractoriness and complications increase as the duration ofseizures increase and neuronal injury starts within minutes of seizure onset itself.

Classification

Based on the aetiology, SE can be classified as

A. Provoked SE

a. Febrile SE: occurring in a previously neurologically normal child in the age group of 6months to 5 years during febrile illness (temperature >380 C) in the absence of a definedCNS infection

b. Acute symptomatic SE occurring within a week of an acute CNS illness / insult like CNSinfections, trauma, stroke, anoxia etc

c. Remote symptomatic SE with an acute precipitant

B. Unprovoked

a. Remote symptomatic SE occurring without an acute provocation in a patient with a previousCNS insult which occurred more than a week prior to the occurrence of SE

b. Progressive symptomatic SE (3%) SE developing in a patient with an underlying,progressive CNS disorder like neurodegenerative disorders, neurocutaneous syndromesetc

C. Cryptogenic SE: (15%) : No apparent cause

Based on clinical presentation:

A. Generalized SE

1. GTC SE

2. Tonic SE

3. Clonic SE

4. Absence SE

5. Myoclonic SE

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B. Focal SE

1. EPC of Kojevnikov

2. Aura continua

3. Limbic SE

4. Hemiconvulsive status with hemiparesis

The term nonconvulsive SE is falling out of favour. ILAE reclassifies this as Focal SE. It includesabsence SE and complex partial SE. The EEG shows continuous generalized electrographic seizures

Aetiology of SE

Data on the aetiology of SE vary according to the origin of the reports and the classification used.

Principal aetiologies of SE in children include

1. CNS infections—meningitis, encephalitis, brain abscess, tuberculoma etc. Common viruses whichcan precipitate SE include HSV, HHV 6&7, EBV, Influenza A, Enterovirus, Echo virus, Adeno virus,Parvo B19, RSV and Flavi viruses. The other infectious causes include bacteria like pneumococcus, H.influenza and meningococcus, malaria, tuberculosis, mycoplasma etc.

2. Acute anoxic insult

3. Metabolic—hypoglycaemia including ketotic hypoglycemia, IEM, Reye syndrome, electrolyteimbalance

4. CNS trauma /hemorrhage/tumors

5. Drug intoxication (eg antipsychotics, INH, dimenhydrinate, neem oil, antihyperglycemic agents),poisoning (camphor)

6 Patients with diagnosed epilepsy on irregular treatment, sleep deprivation, intercurrent infections

7. Febrile SE which are not directly due to CNS infections

When a child presents with fever and status, the possibilities are

1. CNS infections

2. Systemic infections leading to FSE or systemic infection provoking SE in a child who is alreadydiagnosed to have epilepsy. Or it may the 1st manifestation of epilepsy where fever has reduced thethreshold for seizures and precipitated SE,

3. Fever may follow SE itself due to prolonged muscular activity and metabolic changes.

Clinical phases of CSE

1. Premonitory stage: confusion, myoclonic jerks, serial seizures

2. Incipient stage (0-5’): Early (5-29 minutes)

3. Late/established stage (30-60 minutes)

4. Refractory stage (more than 60minutes): unresponsive to 1st & 2nd line therapy

5. Postictal stage

Super-refractory SE defined as refractory SE that has continued or recurred despite 24 hours of generalanaesthesia

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Nonconvulsive SE

Overt and subclinical epileptic seizures are not uncommon in critically ill patients in the intensive careunit (ICU), following incomplete treatment of status epilepticus

Pathophysiology

This includes activation of neurons with intrinsic burst generation, failure or loss of inhibition surroundingabnormally firing neurons, spread, synchronization & maintenance of discharges and progressive timedependent pharmaco resistance & imbalance between excitatory & inhibitory neurotransmitters.

Management of Status epilepticus

A. Prehospital management: It appears that early pharmacological treatment is the key to terminatingseizures and improving the overall outcome. This recognition led to the out of-hospital administration ofbenzodiazepines by paramedics/parents to patients with SE. Studies have shown that this shortens theduration of SE. The agents that are recommended include benzodiazepines.

1. Rectal diazepam gel (0.5mg/kg)

2. Midazolam by buccal/ intranasal/intramuscular route (0.15-0.2mg/kg)

3. Intranasal lorazepam

Intranasal midazolam: has high bioavailability. It is preferred over buccal route when there is excessivesalivation. The maximum plasma concentration is reached within 10 minutes of intranasal administration.Compared to rectal diazepam, intranasal midazolam is socially more acceptable. Absorption throughintranasal route can be limited in upper respiratory infection. During transportation, patient needs to bepositioned properly to avoid risks from aspiration.

B. Management of SE in hospital

Any patient seen convulsing in emergency department should be considered as having SE and managedaccordingly. Every ICU should have a protocol for management of SE.

Objectives of treatment are

(1) Support of vital functions

(2) Termination of seizures and prevention of recurrence by maintenance therapy

(3) Identification and treatment of causal/ precipitating factors

The key to the management of SE is using the appropriate medications in appropriate dose without losingtime. The failure to control seizures is often due to inadequate doses of medicines administered throughless optimal routes. Ideally all anticonvulsant medications should be given intravenously. In case ofdelay in establishing IV access, buccal/ intranasal /intramuscular midazolam & intramuscular Fosphenytoincan be tried to save time. The adverse effects of anticonvulsants are often due to rapid infusion rate ratherthan the total dose administered. So one has to stick on to the recommended infusion rates to avoidadverse effects and delay in administration of total recommended dose.

1. Support of vital functions

1. Get a brief and clear history from a reliable attendant. Note the time of onset of seizures .Checkwhether the patient is in active seizures or not. Do a quick, screening systemic and neurologicalexamination.

2. Assess airway, breathing and circulation at each step. Place pulse oxymeter. Assess respiratoryrate and effort, heart rate, oxygenation and temperature.

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3. Position : left lateral to prevent aspiration unless patients need assisted ventilation

4. Maintain air way patency. If chin lift is unsuccessful, place oral airway

5. Gentle oral suction with large bore sucker

6. Continuous nasogastric tube aspiration to prevent emesis and aspiration.

7. Supplemental oxygen (100%). If oxygenation cannot be maintained by bag and mask ventilationor if respiratory efforts are poor, proceed to rapid sequential incubation and ventilation.

8. Check for bed side glucose. If hypoglycaemic, administer 2ml/kg of 25 % dextrose or 5 ml/kg of10% dextrose.

9. Administer antipyretics if indicated.

10. Establish IV access and send blood for lab investigations ( Blood glucose, electrolytes includingCalcium, Magnesium, RFT, LFT, blood cultures ,complete blood counts)

11. Ideally AED level has to be checked if patient is already on medications

12. Toxicological analysis when indicated.

13. Carefully monitor for and treat hypotension, hypoxia, hyperthermia & hypoglycaemia throughout the ICU stay

2. Terminating seizures

First line medications

This includes benzodiazepines. Diazepam, lorazepam and midazolam are equally effective in terminationseizures.

a. Lorazepam is the preferred drug as it is less lipophilic, less protein bound ,has less volume ofdistribution (CNS levels are maintained for longer period) and shorter elimination half life. Because ofhigh lipid solubility, diazepam is rapidly redistributed to peripheral fat stores and this leads to higherchance of seizure recurrence. The dose of lorazepam is 0.1 mg/kg at an infusion rate of 2 mg/min (maximumof 4 mg). The reconstituted solution loses potency rapidly and hence refrigeration is required. Wait for 3-5 minutes before administering second line medications.

Dose of Diazepam: 0.2-0.3mg/Kg

Dose of midazolam: ) 0. .2mg/kg IV

Second line medications

This includes IV Fosphenytoin /phenytoin, Phenobarbitone, sodium Valproate, levetiracetam

Fosphenytoin is a water soluble prodrug of phenytoin and gets converted to phenytoin within 15minutes of intravenous administration. Time to reach peak brain concentration is similar to phenytoin. Itis administered as Phenytoin equivalents (PE units). 75 mg Fosphenytoin equivalent to 50mg phenytoin.The standard loading dose is 20 PE units / kg of at an infusion rate of not more than 3 PE units / Kg/min( or not > 7 min to administer a loading dose of 20 PE /Kg). A second dose of 10 PE units/kg (for a totalof 30 PE units/kg, maximum of 1500mg /day) is often given if the first loading dose fails to stop clinicalseizures. . Advantages of Fosphenytoin over phenytoin include lower risk of cardiac dysfunction withrapid infusion, lower rates of phlebitis and less severe tissue necrosis if the medication extravasates fromthe vein during infusion. It can be infused at a significantly faster rate than phenytoin.

Phenytoin is used if Fosphenytoin is not available. The loading dose of phenytoin is 20 mg/ KgIV infusion at a rate1 mg/kg/min. Prepare phenytoin in 0.9% saline (maximum concentration of 10mg/

69

ml). Avoid dextrose containing IVF for reconstituting phenytoin. Propylene glycol (40%) contained inthe preparation can lead to cardiac arrhythmias and hypotension. High alkaline pH (12) leads to phlebitis,purple glove syndrome. If seizures continue, additional 5 mg/kg can be infused (maximum 1000g/day).Phenytoin has less respiratory & CNS depression than Phenobarbitone. The maintenance dose is 1.5 mg/kg/dose tid.

Sodium Valproate is the second line drug of choice for myoclonic and absence SE. It is an alternative tophenytoin in generalized convulsive SE in patients allergic to phenytoin and in those with pre-existingcardiac arrhythmias. It has also been tried as the as 3rd line drug in SE It is non sedating and has no risk ofrespiratory depression. The risk of hypotension is less. Loading dose is 20-40 mg/kg bolus in dextrose-containing solutions at rate of up to 6 mg/kg/min. Maintenance dose is 15-20mg/kg tid or infusion at arate of 1mg/kg/min. Valproate is contraindicated in suspected Reyes syndrome, liver disease, mitochondrialdisorders and when there is thrombocytopenia or platelet dysfunction. Caution should be exercised inchild less than 2 years, especially with previous neurological abnormalities. The major but rare adverseeffects are pancreatitis, hyperammonemic encephalopathy and coagulopathy.

Phenobarbitone can be used as the second line AED especially in newborns. The loading dose is15-20 mg/kg IV infusion in normal saline at a rate 1mg/kg/min. Risk of respiratory depression more ifbenzodiazepine used as 1st line therapy. Patients may require ventilator support.

Levetiracetam is a new generation anticonvulsant that has been tried in SE in several case series (openlabel trials). It has a different mechanism of action than conventional AEDs and has better side effectprofile. The dose is 20-30 mg/kg IV bolus of over 15 minutes followed by 20mg/kg /dose at eight hourlyintervals. It is safe in mitochondrial disorders and hepatic diseases. It may rarely produce neuropsychiatriccomplications and neutropenia.

Treatment of refractory status (3rd line drugs)

Commonly used agents include continuous IV infusion of midazolam, propofol or barbiturates(pentobarbital, high dose Phenobarbitone or thiopental infusion). The aim is to achieve burst suppressionin EEG and continuous EEG monitoring is required.

Midazolam: It has a rapid onset of action, short half life, stability in aqueous solution, and lower incidenceof cardiovascular depression than thiopental and propofol. Even though the initial response seems to begood, nearly half of the patients tend to develop break through seizures during continuous infusion. Thisis because of the rapid development of tachyphylaxis which necessitates continuous escalation of dose.Loading dose is 0.15- 0.2 mg/kg followed by infusion at a rate of 1-10 µg/kg/minute. Increase the dose by1 µg/kg/minute every 15 minutes. The goal is to achieve burst suppression in EEG. Maintain same dosefor 24 hrs once seizures are controlled. Wean by 1 µg/kg/minute every 2hrs. If seizures recur, maintain onthe dose that achieved burst suppression previously.

Propofol : Propofol is a short-acting, nonbarbiturate, anesthetic agent possessing anticonvulsant properties.Although the exact anticonvulsant mechanism is unknown, it appears to be a GABA

A agonist similar to

benzodiazepines and barbiturates. Advantages of propofol compared with traditional barbiturate anestheticagents include somewhat better cardiovascular tolerability and a more favorable pharmacokinetic profile,allowing rapid induction and elimination. Seizures have been associated with both the induction andwithdrawal of propofol. So propofol should be reduced slowly under careful, continuous EEG monitoring.

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A loading dose of 3 to 5 mg/kg is given slowly, followed by an infusion of 1 to 10 mg/kg / hour. Propofolhas been associated with hypotension, bradycardia, hyperlipidemia, rhabdomyolysis ,severe metabolicacidosis and renal failure in children (propofol infusion syndrome) ,as well as a variety of neuroexcitatoryadverse events such as opisthotonus, muscle rigidity, and choreoathetoid movements. The risk of propofolinfusion syndrome is more when it is used at a higher infusion rate of 8mg/kg/hour and during prolongedinfusion (> 48 hours). Risk is more especially when used in combination with steroids or catecholamines.

Anesthetic Barbiturates

Pentobarbital and thiopental are much shorter acting than phenobarbital. Thiopental is

rapidly metabolized to pentobarbital. Both agents are highly lipid soluble and will

accumulate in fat stores, leading to prolonged elimination. The dose of thiopentone is 3-5 mg/kg loadingdose followed by continuous infusion at a rate of 1-5 mg/kg/hour. The dose of pentobarbitone is 5-15mg/kg bolus followed by 0.5-10mg/kg/hour. Adverse effects are hypotension, hypoventilation/apnea, andcardiac depression.

Newer Generation AEDs

Topiramate : 10mg/kg orally thr’ NG tube followed by 2 more doses of 5mg /kg /dose at 12 hourinterval

Lacosamide Case reports show that IV lacosamide may be effective in terminating seizures in SE . However,the experience in children is limited to recommend its usage at present.

Ketamine: acts as neuroprotective agent and simultaneously controls seizures by blocking Glycine-activated NMDA receptors. It has no cardiac depressant action and does not produce hypotension. 1-2mg/kg IV bolus, maximum rate of infusion is 7.5mg/kg/hr

Lidocaine Non sedating agent, 1.5-2 mg/kg bolus followed by continuous infusion 3-14mg/kg/hour.

Inhalational Anaesthetics: halothane, desflurane, isoflurane etc. Hypotension is a frequent complication.Concentrations and duration of use have not been

standardized, and it is not yet clear whether patients would ultimately benefit from their use.

Role of Immunotherapy: The rationale is that many of the episodes without known cause might be dueto overt immunologic disease. There is literature evidence that status epilepticus can be due to anti-NMDA-receptor antibodies and that this is not a very rare condition. Treatment is usually attempted withhigh-dose methylprednisolone (1 g prednisolone per day), and then followed if there is no response, byone or two courses of intravenous immunoglobulin (IVIG).

Hypothermia: hypothermia to 30–350C achieved using endovascular cooling for 20-60 hrs in patientsreceiving barbiturate or benzodiazepine anesthesia has been tried for superrefractory SE..

Epilepsy surgery: has role in medically refractory status epilepticus due to focal lesions

C. Evaluation for and treatment of underlying cause

Empirical treatment should be initiated with intravenous broad spectrum antibiotics (3rd generationcephalosporins and Vancomycin) and acyclovir when the possibility of a CNS infection cannot be excluded.Blood cultures should be sent prior to starting antibiotics. Once the child is stable, brain imaging andCSF study can be done to confirm CNS infection in indicated cases. Specific treatment can be modifiedbased on CSF report .However, one has to remember that SE itself can produce rise in body temperatureand CSF pleocytosis (usually< 12 cells/mm3).If the child had respiratory symptoms, consider starting IVAzithromycin and Oseltamavir. Antimalarials may also be considered if cerebral malaria is suspected.

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Correct electrolyte disturbances. Avoid hyperglycaemia also as it is associated with poor neurologicaloutcome. Treat fever aggressively with antipyretics.

Continuation of AED: Once seizures are controlled maintenance dose of anticonvulsants should becontinued in case of symptomatic seizures and those who already are diagnosed to have epilepsy. FebrileSE has to be managed aggressively like SE due to other causes. However, in a previously normal childpresenting with febrile SE, there is no literature evidence at present to recommend long term anticonvulsanttherapy.

Suggested Reading

1. Clinical update: childhood convulsive status epilepticus; Rod C Scott: Lancet Vol 370 September 1, 2007

2. Comparative Efficacy and Safety of Antiepileptic Drugs for the Treatment of Status Epilepticus; Steve S.Chung, Journal of Pharmacy Practice 2007 20: 137

3. Management of Prolonged Seizures and Status Epilepticus in Childhood: A Systematic Review KalliopiSofou, J Child Neurol 2009 24: 918

4. The mortality and morbidity of febrile seizures; Manoj Chungath and Simon Shorvon; Nature clinicalpractice Neurology November 2008 vol 4 no 11

5. Practice Parameter: Diagnostic assessment of the child with status epilepticus (an evidence-based review);J.J. Riviello, Jr et al. Neurology; 2006;67:1542–1550

6. What is the evidence to use new intravenous AEDs in status epilepticus? Eugen Trinka; Epilepsia, 52(Suppl. 8):35–38, 2011

1-3 min ABC, IV line, Blood sampling, Quick exam, IV

dextrose pupush/ Pyridoxine

5-15 min IV Lorazepam 0. 1mg/kg at 2mg/min

Maximum dose 4mg

15-35 min Phenytoin 20 mg/kg / Fosphenytoin 20 PE/kg

35-45 min

Repeat

Phenytoin/Fosphphen

VPA/ Pheno/ Levi

Rapid sequential Intubation

Thio /Pento / Midazolam / Propofol infusion

Flow Chart: Management of SE

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Hemiplegia in children, even though rare, is often alarming to the parents as well as to thePediatrician. There are many causes for acute hemiplegia in children.

Differential Diagnosis of Acute Focal Neurological Deficit

Epilepsy: post-ictal Todd’s paralysis or a focal inhibitory seizure

Complicated migraine

Focal cerebral ischemia


Cerebral abscess

Encephalitis (herpes simplex virus)

Meningitis(pyogenic/TB)

Brain tumor

Alternating hemiplegia of childhood

ADEM

MELAS

Hypertensive encephalopathy (PRES)

Todd’s paralysis is common in children with febrile seizures as well as seizure disorder. If theweakness has developed following a seizure observation for 2-3 hours is advisable. But proceed withinvestigations if the weakness persists.

Familial hemiplegic migraine is relatively rare in children, imaging is often essential if it is the firstepisode.

A sick child with fever, vomiting, seizures , altered sensorium and hemiparesis with or withoutmeningeal signs may have intracranial infections.

ADEM often presents subacutely, but acute presentation is not rare. If the child also has atxia, opticneuritis or spinal cord involvement (multiaxial involvement)diagnosis is easy.

Brain tumours have a subacute progressive course, but can present acutely if there is hemorrhage intothe tumour or sudden obliteration of CSF pathways.

Mitochondrial encephalopathy with lactic acidosis and stroke like episodes presents with hemiparesisin a child with developmental delay and or ataxia. The imaging findings does not confirm to a vascularterritory.

ACUTE HEMIPLEGIA IN CHILDREND. KALPANA

Epilepsy: post-ictal Todd’s paralysis or a focal inhibitory seizure

Complicated migraine

Focal cerebral ischemia


Cerebral abscess

Encephalitis (herpes simplex virus)

Meningitis(pyogenic/TB)

Brain tumor

Alternating hemiplegia of childhood

ADEM

MELAS

Hypertensive encephalopathy (PRES)

Differential Diagnosis of Acute Focal Neurological Deficit

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Alternating hemiplegia of childhood presents as recurrent hemiparesis in infancy with completerecovery is considered as a migraine equivalent.

Stroke is defined as an acute onset of focal neurological deficit lasting more than 24 hrs of presumedvascular origin (WHO). > 50 % of children with acute arterial stroke are diagnosed > 12 hours afteronset. The clinical findings are subtle and differential diagnosis are many.10% of children with Arterialischemic stroke have had a ‘missed’ preceding stroke or TIA .Stroke can be ischemic or hemorrhagic.Ischemic stroke is again divided into arterial and venous, Unlike in adults, where ischemic strokeconstitutes 80% of cases. ischemic and hemorrhagic stroke occur with almost equal frequency inchildren, The causes of stroke are also different-non atherosclerotic vasculopathies, abnormalities ofcoagulation, heart disease and sickle cell anemia dominate the list. In adults 80% of strokes aresecondary to atherosclerosis.

Seizures are also more common in childhood stroke. Focal seizures are often the presenting symptomin neonatal stroke.

Evaluation:

1. To confirm the diagnosis/differential diagnosis.

2. To identify the predisposing factors.

To confirm the diagnosis:

• MRI Brain with contrast or CT Scan if MRI not possible.

– can detect infarcts, hemorrhage, demyelination, tumours, encephalitis

• CSF Study in suspected intracranial infections

• EEG

• SERUM/CSF Lactate. – if MELAS is suspected

To identify the predisposing factors

• Hb and peripheral smear for sickle cell anemia, Iron deficiency anemia is found to beassociated with increased stroke incidence

• PT,APTT,- in hemorrhagic stroke

• X ray chest, ECG, ECHO

• ESR, ANA, dSDNA.

• Contrast MR Angiography of intracranial and neck vessels in acute ischemic stroke and AVM

• MR Venogram in venous sinus thrombosis

• Profile of prothrombotic factors

t Protein C

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t Protein S

t Factor 5 Leyden

• Carotid Doppler

• Digital substraction angiography – If MRA negative and dissection/aneurysm is suspected.

Management(AHA guidelines2008)

1. Supportive measures for AIS should include

t Control of fever, maintenance of normal oxygenation, control of systemichypertension, and normalization of serum glucose levels. (Class I, Level ofEvidence C)

t It is reasonable to treat dehydration and anemia in children with stroke.

t Prophylactic administration of antiepileptic medications in children withischemic stroke is not necessary. (Class III, Level of Evidence C)

2. Specific treatment

• Sickle cell disease : Acute management of ischemic stroke due to SCD should includeoptimal hydration, correction of hypoxemia, and correction of systemic hypotension.(Class I, Level of Evidence C). Periodic transfusions to reduce the percentage of sicklehemoglobin are effective for reducing the risk of stroke in children 2 to 16 years of agewith abnormal TCD results due to SCD and are recommended. (Class I, Level ofEvidence A)

• Cervicocephalic arterial dissection: LMW Heparin followed by oral anticoagulation for3-6 months

• Congenital heart disease producing embolic stroke:

t Low molecular weight heparin followed by oral anticaglulation for at least ayear.

t Definitive surgical management of heart disease other than PFO

t Resection of myxoma

t Aspirin for PFO alone

• Anticoagulation with LMWH is useful for long-term anticoagulation of children with asubstantial risk of recurrent cardiac embolism, cerebral venous sinus thrombosis,dissection and selected hypercoagulable states. (Class I, Level of Evidence C)

• The administration of LMWH or UFH may be considered in children for up to 1 weekafter an ischemic stroke pending further evaluation to determine the stroke’s etiology.(Class IIb, Level of Evidence C)

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• Anticoagulation with warfarin is reasonable for the long-term anticoagulation ofchildren with a substantial risk of recurrent cardiac embolism, CCAD, CVST, orselected hypercoagulable states. (Class IIa, Level of Evidence C)

• Aspirin is a reasonable option for the secondary prevention of AIS in children whoseinfarction is not due to SCD and in children who are not known to have a high risk ofrecurrent embolism or a severe hypercoagulable disorder. (Class IIa, Level of EvidenceC)

• Thrombolytic Therapy for Childhood Stroke

t Thrombolytic therapy with tPA may be considered in selected children withCVST. (Class IIb, Level of Evidence C)

t Until there are additional published safety and efficacy data, tPA is notrecommended for AIS outside of a clinical trial. (Class III, Level of Evidence C)

3. Modifying Stroke Risk Factors in Children

• to treat iron deficiency because it may increase the risk of AIS in conjunction with otherrisk factors. (Class IIa, Level of EvidenceC)

• dietary improvement, the benefits of exercise, and the avoidance of tobacco products.

4. Evaluation and Treatment of Hemorrhage in Children:

• Children with a severe coagulation factor deficiency should receive appropriate factorreplacement therapy, and children with less severe factor deficiency should receivefactor replacement following trauma. (Class I, Level of Evidence A)

• congenital vascular anomalies should be identified and corrected whenever it isclinically feasible. Similarly, other treatable hemorrhage risk factors should becorrected. (Class I, Level of Evidence C)

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APPROACH TO HEADACHE IN CHILDRENM. SHAHANAZ AHAMED

This section will be covering first an understanding of pediatric headaches followed by thediagnostic as well as management options. .

We will not be dealing with the nosology, detailed IHS Classification, controversies betweenclassification & clinical experiences.

Approach is derived more from real clinical experience than from literature & complexities of criteria arenot dealt with.

What is Pediatrician’s role?

1. Knowledge regarding common headaches & clinical features

2. Awareness regarding red flags.

3. Awareness of migraine variants.

4. Differentiate from epilepsy by close history taking

5. Imaging & referral when in doubt.

PAEDIATRIC HEADACHE can be broadly classified into

• Primary Headaches

• Secondary Headaches

Primary headaches are those in which there is no underlying pathology and the pain arises from intrinsicprocesses

Primary Headaches Secondary Headaches

•Migraine 1.Head & neck trauma

•Tension 2.Vascular disorder

•Cluster 3.ICSOLs

•Others 4.Substance abuse

5.Infection

6.Disorders of Craniofacial structures

7.Homeostasis disorders

8.Psychiatric disorders

9.Cranial neuralgias & facial pains

Prevalence of headache

• 37-51% in 7 yr

• 57-82% in 15 yr

Recurrent headache

• 2.5% of 7yr

• 15% in 15 yr old

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Before puberty boys are more affected than girls. After puberty girls are affected more than boys. Meanage of onset of migraine is 7.2 yrs for boys & 10.9 yrs for girls

Prevalence of tension type headache is 10-23%

HEADACHE SYNDROMES

• ACUTEà GENERALISED & LOCALIZED

• ACUTE RECURRENT- Migraine

• CHRONIC PROGRESSIVE -ICSOL

• CHRONIC NON PROGRESSIVE -Tension Headache

ACUTE GENERALISED ACUTE LOCALISED ACUTE RECURRENT

•Fever Migraine

•Systemic infection Sinusitis Migraine variants

•CNS infection Otitis Cluster

•Toxins-Lead,CO2 Ocular Paroxysmal hemicrania

•Post seizure Dental disease After seizure

•Electrolyte imbalance Trauma Trigeminal neuralgia

•Hypertension Occipital neuralgia Exertional

•Hypoglycemia TM joint dysfunction

•Post LP

•Trauma

•Embolic

•Vascular thrombosis

•Haemorrhage

•Collagen disease

•Exertional

CHRONIC PROGRESSIVE CHRONIC NON PROGRESSIVE

•Tumour •Tension headache

•Pseudo tumour cerebri •Malingering

•Brain abscess •Conversion

•Subdural Haematoma •After concussion

•Hydrocephalus •Depression

•Vasculitis •Anxiety

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•Hypertension •Adjustment reaction

•Hemicrania continua

RED FLAGS in Headache

• Progressive headache

• Recent onset worsening /change in nature of pre existing headache

• Development of neuro deficits/seizures

• Early morning headache

• Transient obscuration of vision.

• Persistent vomiting

• Sudden peaking of the first headache(SAH,ICH)

• Weight loss ,fever ,systemic symptoms

MIGRAINE- IHS classification

• Migraine without aura

• With aura

• Childhood periodic syndromes which are precursors of migraine

• Retinal migraine

• Complications of migraine

• Probable migraine

Migraine variants

• Migraine attack accompanied by or manifested by transient neurological symptoms

• Symptoms may occur just before, during or after headache. Sometimes headache may be absent orvery mild.

1. Hemiplegic Migraine

2. Basilar Migraine

3. Ophthalmoplegic migraine

4. Benign paroxysmal vertigo

5. Benign paroxysmal torticollis of infancy

6. Confusional migraine

7. Alice in wonderland syndrome

8. Cyclic vomiting

9. Abdominal migraine

10. Retinal Migraine

COMPLICATIONS OF MIGRAINE

• Chronic migraine or Transformed migraine

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• Status migrainosus(>72 hrs)

• Persistent aura without infarction(aura>1 week)

• Migrainous infarction (Aura>60mts with infarct in scan)

• Migralepsy (migraine triggered seizures occurring within 60mts of migraine attack)

Alternating hemiplegia is now viewed as a metabolic disorder & ophthalmoplegic migraine is considereda cranial neuralgia

Cyclic vomiting syndrome

It is characterized by recurrent unprovoked intense vomiting episodes > 4/hour which last for 1-2 dayscoming every 2-4 wks

Children are healthy between attacks & there is family history of migraine

Age of onset is 5yrs & outgrow by 10 yrs

DD include intestinal obstruction, raised ICP, Epilepsy, UCD, Organic acidemias

Treatment-Antiemetics, IVF

Abdominal migraine

It is characterized by recurrent episodes of midline epigastric pain lasting 1-72 hrs. Pain is of moderate tosevere intensity associated with flushing, pallor, nausea, vomiting

Differentials include GIT & GUT conditions & abdominal epilepsy

Benign paroxysmal vertigo of childhood

Abrupt brief episodes of unexplained unsteadiness with nystagmus

Attacks occur in clusters & typically get relieved with sleep

Children later tend to develop migraine esp. basilar M

DDs- Epilepsy, (CPS) ENT problems& CNS problems should be ruled out

Confusional migraine

Affected children become agitated restless, disoriented & occasionally combative for minutes to hours

Later they may have an inability to communicate,frustration, confusion,loss of orientation to time & maynot recall headache phase at all

DDs –Encephalitis, Epilepsy, Intoxication, Metabolic disorders, Vasculitis, TIA etc

Migraine in MR/Devpt delay

Developmentally abnormal children may show repeated cycling of quiet withdrawn behaviour withpallor ,regurgitation,vomiting & desire to rest

The DD in this setting includes GERD, Hydrocephalus, epilepsy etc

Tension type headache

Its nature is a pressure/tightening type feeling around the head/felt in bifrontal +/-bioccipital region

No nausea & vomiting and there will be either photophobia /phonophobia ;not both

Assd symptoms such as tiredness,sleep disturbances & light headedness may be common

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Drug of choice is Amitryptiline

Ophthalmoplegic migraine

Now classified as a cranial neuralgia

Ophthalmoparesis appears during/ after the headache which is usually retroorbital, mild to moderate inintensity

Partial oculomotor involvement with pupillary sparing is common

Abducen & trochear nerves may be involved

Postulated Mechanism is by ischemia /inflammation/demyelination

MRI may show enhancement of affected nerve & treatment is by steroids.

Migraine prophylaxis should be used to prevent sequelae

Occipital neuralgia

Stabbing pain in the upper neck /occipital region precipitated by head rotation/neck flexion & may occurpost traumatically

Examination shows point tenderness,C2 distribuition sensory changes,limitation of neck motion.

Treatment is by analgesics, cervical collar ,Physiotherapy & Muscle relaxants.

Cluster headache

Criteria is at least five attacks of severe unilateral orbital

pain lasting 15mts to 3hrs with a sense of restless

agitation accompanied by ipsilateral conjunctival injection,

lacrimation ,nasal congestion, rhinorrhea, eyelid edema

forehead sweating, miosis or ptosis

—Attacks occur once every 24 hrs

Treatment is by O2 inhalation , DHT/sumatriptan/Steroids

Prophylaxis is by Steroids initially Later we can try Verapamil/valproate/Lithium/Methysergide/ergotamine

Paroxysmal hemicrania

Cluster like syndrome characterised by intense attacks of periorbital pain lasting only 5-30 mts butoccuring upto dozens of times /day

No assd lacrimation/rhinorrhea

Exquisite response to indomethacin(25-50mg/day)

Other rar e HEADACHES

1)Primary stabbing headache

( Icepick headache)

Brief attacks of stabbing pain in the ophthalmic division of trigeminal nerve without autonomic features.

2)Primary cough headache- Shortlasting & we have to rule out Chiari malformation

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3)Primary exertional HA- Similar to migraine ,lasts mts to 48 hrs

Post traumatic headache

Acute post traumatic Headache is an indication for urgent neuroimaging

Footballer,s migraine may occur immediately after relatively minor head trauma while playing football& after Road Traffic Accidents

Clinical Features include confusion ,language disorders,agitation

Chronic post traumatic HA

CF span the spectrum from tension type, migraine,chronic daily headache,Occipital neuralgias etc

Associated complaints of post concussive syndrome may be present

Treatment is by analgesics & relaxation therapies+ preventive therapy for 3-6 months

Appr oach to paediatric headache

A well taken history

A thorough physical examination

Ancillary investigations

What to ask?

1. Onset of headache

Sudden –Subarachnoid haemorrhage,

Gradual-migraine

Assd with fever- Viral fever,Sinusitis, Meningitis,Other systemic infection,

2. If recurrent headache

Recent onset- Think of ICSOL,Initial attacks of migraine

Long duration- Primary headaches like migraine

3. Site of headache

Bifrontal- Sinusitis, Migraine,

Bitemporal –Migraine

Periorbital- Cluster,Paroxysmal hemicrania Ophthalmoplegic migraine

Pain in eyes & frontal region with tearing-Glaucoma,Cluster, SUNCT

Strictly unilateral- Cluster,SUNCT

Migraine is also predominantly unilateral

Occipital- Migraine variant,SAH,Cervicogenic headache, Occipital neuralgia

Vertex headache-sellar tumours,Sphenoid sinusitis, Psychogenic

4. Nature of headache

Pounding /throbbing—migraine,cluster

Piercing periorbital pain –paroxysmal hemicrania

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Sudden pricking –Ice pick headache

Aching – Tension HA

Tight feeling around head- Tension ,Depression

5. Any aura?

Binocular visual impairment with scotoma is most common phenomenon

Any spots ,colours,lights in the visual field?

Any dimness of vision,fogging of vision?

Any net formation with lines of light?

Any flashes of light ,stars of light,black spots?

Black spots which are surrounded by flashes of light which move in visual field

Any micropsia ,macropsia ,metamorphosia?

Any visual field defects –hemianopia,quadrantanopia?

Photopsia- Bright blinding episodes

Teichopsia-Objects appear far away

6. Aura vs seizure

Migraine Aura usually has a slow migratory/spreading quality ; while a partial seizure aura is rapid

Elementary visual phenomena are seen in migraine vs complex aura in ComplexPartial Seizures.

There is characteristic return of function in the first affected area/field while symptoms are ongoing inthe later affected areas-not seen in seizure /Ischemia

Biphasic progression with positive followed by negative symptoms(lightsà scotoma)

7. Aura

Elementary visual phenomena like these originate from the occipital lobe while formed visual hallucinationsoriginate from the temporal lobe in complex partial seizures.

Any paraesthesia /numbness/weakness felt in the perioral region/limbs.

Any double vision,field defect, dysarthria, ataxia,vertigo felt before the headache

8. Associated complaints

Photophobia, phonophobia, irritability(migraine)

Unilateral nasal block, tearing, conjunctival congestion (cluster)

Does the patient want to sleep (migraine) /want to move about (cluster) during the headache,

Is there any nausea/vomiting(migraine)

Timing, relieving/aggravating factors

Does the pain appear in the morning?

(Raised ICT,Depression,Some cases of migraine)

Is the pain relieved by sleep(Migraine)

Is the pain aggravated by sleep(ICSOL,BIH)

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Is there any recent rapid gain in weight,use of VitA(ferradol),Steroids,etc(BIH)

9. Any assd medical complaints

Any neck pain with radiation to arm (Cervicogenic HA)

Feverà systemic/CNS infections

Any dental pain,

Nasal block with URI, Purulent discharge from noseà

Vacuum headache, sinus headache

EXAMINA TION

Depressed look (Depression,THA)

Bradycardia- Cushing,s reflex

Hypertension & radiofemoral delay-coarctation

Sinus tenderness-Sinusitis

Caries tooth- Dental infection

Fundus –To look for papilloedema,Glaucomatous disc

Eye- Glaucoma ,Corneal clouding, any KPs, Synechiae(Uveitis)

CVS examination in cases of migraine with syncope

CNS examination for neurodeficits

INVESTIGA TION

Investigations especially imaging is not routinely indicated in the case of primary headache. But oneshould not be miserly in this aspect.

CT Scan: This is a very useful investigation to rule out any underlying causes of head ache like ICSOL.Calcification ,haemorrhage, bony lesions are better seen on CT

MRI SCAN: MRI gives much more anatomic details,

• detects small lesions,

• good imaging of posterior fossa, Brainstem,

• pituitary hypothalamic area ,

• CP angle ,Cranial nerves etc

Depending on the clinical diagnostic possibilities we can order any one of these

Recommendations for neuroimaging

1. Obtaining a neuroimaging study on a routine basis is not indicated in children with recurrentheadaches & a normal neurological examination

2. Neuroimaging should be considered in children with

-Recent onset of severe headache

-Change in the type of headache

-Neurologic dysfunction

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3. Neuroimaging should be considered in children with

-an abnormal neurological examination i.e.

focal findings, raised ICP, significant alteration in consciousness

-and the coexistence of seizures

Other investigation in relevant cases include

1. Blood routine esp ESR to r/o significant illnesses like malignancy, collagen diseases ,infections etc

2. Peripheral smear to r/o leukaemia,Thrombocytopenia

3. Mantoux test ,Chest x-ray

4. X-ray of paranasal sinuses/CT scan PNS for sinusitis

5. Ophthalmological work up for refractive error, Glaucoma

6. MR venogram in Chronic venous sinus thrombosis /Pseudotumour cerebri

7. Vasculitic work up in indicated cases

8. Serum antibodies or PCR for infectious organism

EEG in Headache

Headache as a symptom/aura of epilepsy is very rare.

You have to distinguish clearly between a headpain & other complaints like head numbness, vertiginousfeeling etc when the child complaints of headache

EEG becomes important

1. In migraine with syncope

2. Migraine with sensory or motor aura or transient neuro deficits

3. Abdominal migraine vs Abdominal epilepsy

4. Occipital epilepsy coexisting with migraine

Even in migraine you get occasional spikes in the occipital region in the eeg

Treatment

For secondary causes of headache treatment of the cause will relieve the headache.

Treatment of migraine

Treatment of acute attack & Prophylaxis

Drugs used in acute attack

Analgesics like Paracetamol (15-20mg/kg)

Mefenamic acid (8mg/kg/dose) Ibuprofen(10mg/kg)

Paracetamol+ domperidone combination

Naproxen+ domperidone combn(2.5-5 mg/kg/dose)

Triptans-Rizatriptan(5mg) in 7-12 yr,Sumatriptan in adolescents , Naratriptan 1mg,2.5mg

They should be administered as early as possible to have maximum effect.

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If administered at the onset of headache triptans can abort the attack

Drugs used for prophylaxis

1. Proponalol

2. Amitryptiline

3. Flunarizine

4. Imipramine

5. Cyproheptadine

6. Divalproex sodium

7. Valproate

8. Topiramate

9. Nimodipine

10. Levetiracetam

Proponalol

Proponalol is the drug of 1st choice

Begin with 1mg/kg/day in single/ 2 ddoses can be increased to 4mg/kg/day for full response

Most patient have good response with 1mg/kg in my experience

Should be given preferably in the morning after food as a single dose.Timed release preparations arepreferred

Night dose may interfere with sleep and cause nightmares in some

Avoid proponalol in Children with bronchial asthma,Cardiac arrhythmias,Recurrent nasal allergy.

Heart rate decrease upto 75% can be allowed during dose titration

Other beta blockers Metoprolol(2-6mg/kg)Atenolol(2-6mg/kg)

Amitryptilline

A very useful drug which is useful in a variety of conditions and situations

1. Migraine

2. Migraine with occipital headache

3. Post traumatic headache

4. Tension headache

5. Childhood depression with Headache

6. Headache with other psychosomatization

7. Patients in whom Proponalol cannot be used

Dosage:- 0.25 mg/kg/day as a single night time dose 30-45 mts before going to bed

Can be increased upto 1mg/kg/day without much adve effects.

Strengths- 10 mg,25mg,50mg tab

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Flunarizine

Calcium channel blocker specifically used in the treatment of migraine

It produces daytime sedation and fatigue which are trouble some in many cases

Can be used to assess the migrainous nature of the episode in certain confusing situations

Safe in children & adults & very good response in several cases.

Usual dosage is 5mg for 10-20 kg range,7.5 mg for 20-30 kg and 10 mg for higher body weights.Availableas 5mg,10 mg tab

Imipramine

It has a similar mechanism of action & is useful when there is nocturnal enuresis in the same child.

One thing I have noticed when using TAD is that a patient who does not respond to one drug may havegood response to another drug in the same class.

If the child has additional problem of obsessive compulsive behaviour clomipramine can be used.

Cyproheptadine

It is an antihistaminic drug with antimigraine & appetite stimulating action at hypothalamic level

This is particularly useful in situations when the mother complaints of decreased appetite,constipation &when there is coexisting nasal /other allergy so that proponalol & amitryptiline cannot be used .

Antimigraine action is weaker compared to the other drugs.

Major side effect is sedation

Available as drops, syrup 1mg/ml ,2mg/5ml, 2 & 4mg tab

Usual dosage is 1-2 (Max-8mg)mg at night time

Divalpr oex sodium

This is primarily an antiepileptic drug containing 50:50 amount of valproic acid & sodium valproate.

Used in the maintenance treatment of epilepsy as an extended release preparation

It has got moderate antimigraine action & also mood stabilizing action.

It is particularly useful in situations where there is a confusion between epilepsy & migraine & you getsuspicious/borderline findings in EEG

It is available in strengths of 125,250,500 , 750mg & 1gm as an ER preparation to be given at night time.

Topiramate

This is an antiepileptic drug with broad spectrum & several mechanisms of action

It has got additional antimigraine action & neuroprotective action

Dose – 2-6 mg/kg/day in 2 div doses

Its disadwantage is in the cognitive side effects with decreased memory, naming difficulty,& renal stoneformation .So don’t give to a child with good academics

Other adverse effects include paraesthesia,fatigue & nausea

Nimodipine

Calcium channel blocker & cerebral vasodilator used in the trt of SAH

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Acts by preventing the vasoconstrictive phase of migraine

Moderate efficacy & not commonly used in children

Review of studies show flunarizine to be the most effective among these

GENERAL MEASURES

1. Ensuring good sleep hygiene

2. Regular graded exercise

3. Avoid dietary triggers like cheese, chocolate, nuts, MSG, aspartame, processed meats

4. Do not skip breakfast, take 3 regular meals,drink plenty of water

5. Reduce caffeine use,Avoid analgesic overuse

CHRONIC HEADACHES

1. Chronic daily headache

2. Chronic migraine

3. Chronic tension type

4. New daily persistent headache

5. Hemicranium continuum

Chronic deaily headache

Defined as Headache longer than 4 months during which the patient has more than 15 headaches /monthwith the headaches lasting more than 4 hours/day

New daily persistent headache

Represents a unique entity in that the chronic headache started abruptly denovo without any h/o previousheadache syndrome

Hemicranium continuum

This is uncommon in children & represents a cluster variant with daily or continuous unilateral pain withconjunctival congestion, lacrimation, rhinorrhea & ptosis

It is responsive to indomethacin

Secondary causes of CDH

• Neoplasm,

• Pseudotumour cerebri

• Subdural haematoma

• Hydrocephalus

• Glaucoma

• Chronic sinusitis

• Malocclusion, Temporomandibular dysfunction

• Psychologic,Medicolegal headache

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Treatment of primary CDH

Reassurance & Inv to r/o secondary causes

Prophylactic drugs

Breaking the vicious cycle of analgesic overuse

Avoidance of triggers, exercise, Relaxation therapy, YOGA

Identifying & rectifying problems at school, family & social life & counseling

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MOVEMENT DISORDERS IN CHILDRENAND ADOLESCENTS

P A MOHAMMED KUNJU

The extrapyramidal system

STRUCTURE:

� Centers:

� The corpus striatum, the substantia nigra, thalamic and subthalamic nuclei

� Inter connections: the above centers are interconnected with: The cerebral cortex, thecerebellum, the reticular formation, the cranial nerve nuclei (particularly the vestibular nerve)and the spinal cord

Functions

� Regulation of voluntary motor activity

� Control of the muscle tone

� Maintenance of emotional and associative movements

Disturbance

It is now clear that in many extrapyramidal disorders there are specific changes inneurotransmitter profile rather than discrete anatomical lesions

1. Disturbance in the control of voluntary motor activity resulting in involuntary movementswhich may be of two main types:

� Rhythmic and regular as in parkinsonism

� Dysrhythmic and irregular as in chorea, athetosis and dystonia

2. Disturbance in the normal muscle tone resulting in hypertonia (rigidity)

3. Disturbance in the maintenance of emotional and associated movements resulting inbradykinesia (mask face, infrequent blinking and loss of swinging during walking)

Movement disorders

Akinetic-rigid syndromes

Idiopathic Parkinson’s disease

Drug-induced parkinsonism (e.g. phenothiazines)

Postencephalitic parkinsonism

Childhood akinetic-rigid syndrome

Dyskinesias

Essential tremor

Chorea

Hemiballismus

Myoclonus Dystonias

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Tic or ‘habit spasms’

Classification by Movement

Hyperkinetic Isokinetic Hypokinetic

Dystonia Spasticity Rigidity

Athetosis Ataxia Bradykinesia

Chorea

Myoclonus

Tremor

Ballism

Tics

Stereotypies

Though dystonia is a common symptom in neurology it is being recognized less frequently bypediatricians.

Definition ; Dystonia can be defined as syndromes of sustained muscle contractions frequently causingtwisting and repetitive movements or abnormal postures.

Dystonia is a disorder both of posture and movement.1 The factor which distinguishes myoclonus,chorea, athetosis and dystonia would be the variable speed of movement; fastest being myoclonus, 50ms to 100 ms and slowest one being dystonia, which may last at least a second.2-3

Dystonia evolves in a focal manner and during voluntary activity-‘action dystonia’.

Pathophysiology

• Decreased mean neuronal firing in GPi and GPe

• Decreased thalamic inhibition by pallidumàExcessive cortical stimulation

CLASSIFICATION

The dystonias are classified according to their (1) distribution (2) age of onset, (3) type of onset, and(4) etiology.

Distribution

Focal

When dystonia is confined to anyone single region

Ocular muscles: Blepharospasm

Tongue: Lingual dystonia

Vocal cord: Dystonic dysphonia

Mouth: Oromandibular dystonia

Neck:. Torticollis

Hand: Writer’s cramp.

Segmental

When focal dystonia spreads to contiguous area Cranial: Face and neck

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Axial: Neck and trunk

Brachial: Arm and trunk

Crural: One leg and trunk; both legs with or without trunk.

Gneralized- crural

With any other segmental involvement.

Focal or segmental dystonia may progress &become generalized if : (a) childhood or adolescent onset(b) beginning in the lower limbs

Hemidystonia

When one side of the body is involved

Type of dystonia

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Type of Onset 1-7

It is broadly divided in to 4 groups 1. Acute dystonia2.Tardive dystonia 3.paroxysmal dystonia, an4Chronic non progressive /progressive dystonia

1.Acute Dystonia

Acute Dystonia arise from neuroleptic drugs ,exposure to toxins, infections, and certain familialdisorders. Acute reactions can appear soon after starting treatment with phenothiazine,or evenpromethazine (phenergan) . Manifestations include bizarre postures of face ( Sustained grimacing)eyes (oculogyric crisis), jaw (trismus, mandibular dystonia), tongue lingual dystonia :necek(torticollis), trunk (scoliosis, lordosis, kyphosis and opisthotonos Limbs (torsion spasm). These may beconfused with seizure , tetany or encephalitis if a proper history of drug ingestion is not obtained.

The acute dystonic reactions may be the result of excess dopaminergic activity. Response to treatmentof acute dystonia is often dramatic. anticholinergic drugs like diphenhydramine or promethazine willreverse the Acute Dystonia with in minutes. We have seen transient dyskinesia in asthmatic patientsreceiving theophylline. Interaction of theophylline and hypoxemia with other factors may induce this

Tardive dystonia is a separate entity from acute dystonic reactions in that it is persistent, does notshow response to intravenous diphenhydramine or anticholinergics. Another striking feature is thedistribution of dystonic movement. Generalized dystonia is more :- in younger individuals whereas inolder subjects it has a more restricted distribution.

Paroxysmal dystonia

A group of interesting disorders which may be confused with seizures.

1. Familial paroxysmal dystonic choreoathetosis: This rare bizarre paroxysmal movements occurringin an autosomal dominant manner .8 Each attack is characterized by (a) painful spasm of affectedmusculature (b) choreoathetosis, and (c) return to normality.

II. Paroxysmal kinesigenic dystonia: Sudden movement or startle and stress will precipitate an attack.These patients can avert an attack by avoiding abrupt movement and sensory stimuli

III. Exercise induced paroxysmal dystonia: Lance and Plant et al have described a paroxysmaldystonicchoreoathetosis, which is seen after continued exercise or by sensory stimuli but not after a sudden

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movement.9,10

IV. Paroxysmal hypnogenic dystonia: Certain varieties of dystonia may be brought on by sleep. Inaddition to the idiopathic variety we have seen paroxysmal dystonias due to. intracranial tumor,hyperthyroidism and transient ischemic attacks.

Treatment;Paroxysmal kinesigenic choreoathetosis responds to phenytoin. Other varieties may respondto clonazepam, L-tryptophan and carbamazepine.

Chronic Non-progressive/Progressive Dystonias

Etiology

Dystonias are divided into two types on the basis of etiology as follows (i) Primary dystonia and (ii)Secondary dystonia.

Primary dystonia

Idiopathic Torsion Dystonia (lTD)/ Dystonia Musculorum Deformans (DMD)1-7 Autosomaldominant dystonia gene is found to be located on chromosome 9q34. usual age of onset is 5-15 yearswith dystonia of legs and within·5-10 yrs disease reach to maximum level of disability. At that timethey are twisted axially with contorted oromandibular, neck,trunk and limb musculature.

Dopa-responsive dystonia; these group of patients with dystonia respond dramatically to a very lowdosage of levodopa.

Features include onset of dystonia before the age of 16 ,onset in the legs or with gait, and often havingfeatures of parkinsonism. Inheritance is AD. Since the demonstration of dopa-sensitive dystonic states,L-dopa has been tried in some of the cases of the congenital cerebral palsy where choreoathetoticrigidity is seen.

Diurnal dystonia (Segawa syndrome)

Rrelatively free of dystonic movements and postures in the morning and be afflicted severely in thelate afternoon. Segawa had described this type of dystonia12 and we have seen many with similarinvolvement and who showed dramatic response to L dopa. . The disease is caused by a GTPcyclohydrolase 1 (GCH) deficiency

Secondary Dystonias

Secondary dystonia can be due to congenital, hereditary, metabolic, vascular, infection, degeneration,demyelination, tumor, drugs, toxins, etc.

Useful clinical pointers to suggest a secondary dystonia:

1.History to suggest involvement of other organ systems, e.g. liver (Wilson’s disease), multiple system(systemic lupus erythematosus-SLE).

2.coexistant neurological signs indicating involvement of higher mental, retinal, pyramidal, or lowermotor neuron function.

3.H/O exposure to antipsychotic drugs, toxins, injury or cerebrovascular disorders Treatable dystonicconditions like Wilson’s disease, tardive dystonias, etc. has to be considered first.

Treatment

{a) drugs .;Trihexy phenidyl ,dopamine agonists, baclofen, clonazepam, carbamazepine and clonidine).b.local administration of botulinum toxin for focal dystonias, (c) surgical methods, and

d)Psychological methods

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Athetosis- Slow sinuous writhing distal movements of the hands and fingers, sometimes the toes, andmuscles around the mouth

Pathophysiology of Athetosis-Unknown -Probably related to the abnormal corticostriatal-

pallidal-thalamo-cortical circuits affected in dystonia

� Hallmarks of Athetosis-Onset @ 1-5yrs.

� Often mentally normal

� Athetosis impedes motor function

� Doesn’t progress

� Doesn’t cause contractures

Etiology

Cerebral palsy;(hyperbilirubinemia, HIE status marmoratus); Open heart operations;Drug reaction(Tigabine), Wilson’s disease.

Chorea -involuntary,purposeless/quasipurposive, jerky, dance-like movements

Pathophysiology of Chorea

� Inhibition or destruction of the subthalamic nucleus à

� decreases excitation of GPi (globus pallidum internii)

� decreases inhibition of thalamus

� increases excitation of cortex

Treatments-

Haloperidol;risperidon;Valproate; Steroids-

� Ballism-Extremity flailing, Hyper-chorea

� Destruction of the subthalamic nucleus

Ataxia

characterized by failure of muscular

coordination. Poor limb control;Poor target accuracy;Poor balance

Pathophysiology; The cerebellum integrates sensory information from multiple spinal segments thatreceive information from proprioceptors throughout the body. It modifies motor commands based onongoing dynamics of the limb and rest of the body.

TRemor

Definition: Regular Rhythmic Repetitive to & fro oscillatory movements

Types:

Writers cramps –Before and after

Botox injn

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Resting tremor

Postural tremor

Intention tremor

Action tremor

Causes:

Essential (familial);exaggerated physiological –hypoglycemia; hyperthyroidism;

Medications (bronchodilators, AEDs,stimulants steroids)

Damage to red nucleus

Wilson’s disease

Rigidity

A form of hypertonia in which resistance to passive movement is present at low speeds,does notdepend on the speed, and does not exhibit a speed or threshold angle.

Hallmarks of Rigidity

Associated with diseases with a primary failure of dopamine production:

Juvenile Parkonson’s disease-rigidity, bradykinesia, (not tremor in kids)

Dopa-responsive dystonia

EP cerebral palsy

Tics -Stereotyped, repetitive, often complex movements

“Probably the most common MD in children.”

Tics increase or appear with ADHD treatment

Types

Simple - blink or sniff.

Complex - gesticulating or uttering

Transient tics - less than 12 months,

Chronic motor or vocal tics lasts at least 1 year,

Tourette syndrome -

Criteria requires the (1) combination of motor and vocal tics, (2) duration of at least 1 year,(3) onsetbefore the age of 18 ; exclusion of other causes (direct physiologic effects of a substance [eg, stimulantdrugs] or a general medical condition [eg, Huntington disease or postviral encephalitis]).+ comorbiddisorders- OCD, ADHD, or behavioral problems.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).

Abrupt onset of tics or OCD after infection with group A b-hemolytic streptococcus (GAS) inprepubertal children, with motoric hyperactivity and adventitious movements but not frank chorea

Treatment of Tics: conventional neuroleptic meds Haloperidol(0.25 mg to 3–5 mg/day,

qd to tid) pimozide (0.5 mg to 6–8 mg/day,qd to tidLarap 1, 2mg tabs) , Risperidone(0.25 mg to 6 mg/day,) Clonidine(0.025 mg to 0.1 mg tid) Clonazepam, Tetrabenazin(12.5 mg to 75 mg/day-Revocon25mg tab).

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Stereotypies- repeated, purposeless movements

Two groups:

o Primary ,indicating a physiologic basis, and

o Secondary , for those associated with other neurodevelopmental problems

o Secondary (in the Presence of Other Pathology)

o Pervasive developmental disability-Autism,Rett syndrome

o Mental retardation

o Sensory deprivation: -congenital blindness/deafness,

o Inborn errors of metabolism: -Lesch-Nyhan syndrome

o Genetic: Neuroacanthocytosis

o Tics are different from Stereotypies- Can be reproduced voluntarily;Patient has partialcontrol;Do not interfere with voluntary activity

Drug-Induced Movement Disorders

o Acute dystonia,

o Chorea

o Parkinsonism

o Akathisia- (Inability to sit still )

o Treatment emergent dyskinesia,

o Withdrawal emergent dyskinesia,-( Chorea and myoclonus appearing after abruptlydiscontinuing or decreasing the dose of neuroleptic drugs. )

o Neuroleptic malignant syndrome – Hyperthermia, Rigidity, Autonomic dysfunction , Elevatedcreatinine kinase

o Others –tremor; tics

Treatment of DIMDs

� DIMDs with neuroleptics and antipsychotics:

Anticholinergics, AMPT, Reserpine, Tetrabenazine, Vit E.

� DMIDs with ADHD treatment:

◊Add clonidine to methylphenidate.

� DMIDs with SSRIs:

◊Treatment is reduction or elimination of the medication.

CBT will sometimes be more effective.

References

1. Thyagarajan D Recent Advances. J Clin Neuroscience 1999; 6:1-8.

2. Kunju P A M Extrapyramidal disorders. In Gupte S (Ed): Recent Advances in Pediatrics. Jaypee;New Delhi: 1994 ;4; 140-66.

3. In Kennards C(Ed): Recent Advance in Clinical Neurology. Edinburgh: Churchill

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Livingstone 1988 175-200.

4. Butler IJ Movement disorders of children. Pediatr Clin North Am’1992; 39: 727-42.

5. Behrman RE, Kliegman RM, Jenson HB(Eds): Nelson Textbook of pediatrics Harcourt Asia PteLtd, 2007; 1839-43.

6. Fauci,Isselbacher KJ, Wilson JD, Martin JB, Kasper DL Hauser SL, Longo DL: Harrison’sprinciples of internal medicine

17 th edn. New York: McGraw-Hill, 2007; 114, 2356-63.

7. Swash M, Oxbury J(Eds): Clinical Neurology, 1st edn. Edinburgh: Churchill Livingstone 19911456-70

8. Mount LA, Reback Seizure Familial paroxysmal choreoathetosis. Arch Neurol Psychiatry 1990;44: 841-47

9. Lance N Familial paroxysmal dystonic choreoathetoses and its differentiation from relatedsyndromes. Ann Neurol 1977;2;285-93

10. Plant GL, Earl CJ, Marsden CD. Familial paroxysmal dystonia induced by exercise. J Neurolneurosurg psych 1984; 47: 2’75-79.

11. fahn Seizure .Clinical variants of idiopathic torsion dystonia. J Neurol Neurosurg Psychiatry-special supplement 1989 52;96-100

12. segawa Extrapyramidal disorders in childhood. Current Opinion Neurol Neurosurg 1993; 6: 387-92.

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TREATMENT OF NEUROGENETIC DISORDERSSANKAR VH

Genetic diseases result from inherited abnormalities in the body systems concerned with normaldevelopment and physiological homeostasis. While “cure” of such diseases by ablating their primarycauses is seldom achievable, alternative approaches are in place to control or prevent effects of theseillnesses. Furthermore, the provision of supportive care to the patient as well as counseling and supportto the family is also part of the management of these patients.

Therapy of genetic diseases can be viewed in a biological model starting from the clinical phenotypeand working back to the molecular level (Figure 1). Therapy at the clinical phenotype includes variousmedical and surgical measures advised in genetic diseases which ameliorate the symptoms of the patient.Anticonvulsants for seizures in a patient with neurometabolic disorders and beta blockers in Marfansyndrome to prevent or delay dilatation of the aortic root are examples of this approach. In this review wediscussed modalities like metabolic correction, hematopoietic stem cell transplantation, enzymereplacement therapy, and gene therapy.

Metabolic therapy

Therapy at this level often involves nutritional and pharmacological approaches which will preventtoxicity due to metabolite excess or deficiency.

Modalities of metabolic therapy includes

· Substrate Restriction

· Alternative pathways to remove toxic metabolites

· Replacement of deficient products

· Metabolic Inhibitors

Dietary alterations designed to restrict intake of a particular substrate may be effective if thepathophysiology involves accumulation of a toxic precursor or metabolite. Dietary restriction ofphenylalanine in phenylketonuria is an effective treatment to prevent mental retardation. In addition tosubstrate restriction it is often necessary to replace the deficient end product like tyrosine inphenylketonuria. Early detection and treatment of galactosemia with restriction of galactose will reducethe mortality and lifelong restriction will prevent development of cataract and cognitive impairment. Butrecent evidences suggest that the persons can develop mild learning disabilities and ovarian failure eventhough strict galactose restriction was practiced. Specific diets are available commercially for thesemetabolic disorders but it is very expensive. Some modification of routine Indian diet may be tried basedon content of different nutrients but the desirable fine control is very difficult to achieve.

In some metabolic disorders the offending metabolite can be converted to a less harmful substancewhich can be easily excreted. Classical example is urea cycle disorders where excess ammonia is centralto the pathogenesis of various symptoms. Administration of benzoate, phenyl acetate or phenyl butyratewill lead to conjugation of these with glycine and glutamine respectively forming hippurate and phenyl

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acetyl glutamine. These conjugates are readily excreted in urine, thereby providing a way to eliminateexcess nitrogen.

Replacement of the reaction product is the most logical approach to the management of inheritedmetabolic diseases in which the symptoms of the diseases are due to deficiency of the product. In glycogenstorage disease (GSD I) the symptoms are due to hypoglycemia secondary to deficient hepatic glycogenconversion in fasting state. Cornstarch, a slowly digsted glucose polymer acts as timed release source ofglucose will help these patients to prevent episodes of hypoglycemia.

In disorders where alternate pathway overflows lead to formation of toxic metabolite, toxicitycan be reduced by inhibiting a prior step in the pathway by some inhibitors. This may lead to accumulationof prior metabolite which may be better tolerated if this approach is to be successful. In gout allopurinolis used which inhibits xanthine oxidase, thereby uric acid accumulation is prevented. The prior metabolitexanthine is better tolerated than uric acid since xanthine is water soluble. Another outstanding exampleof effective therapy with an enzyme inhibitor is use of 2-2-nitro 4 trifluromethyl benzoyl 1-3cyclohexandione (NTBC) which inhibit 4-hydroxy phenyl pyruvate dioxygenase in type I hereditarytyrosinemia dramatically changing the prognosis in affected patients.

Stem cell transplantation (SCT)

For past two decades stem cell transplantation has been used as effective therapy for variousgenetic diseases. Stem cells are characterized by their self-renewability and high plasticity. There aredifferent types of stem cells: adult stem cells (ASCs) maintain the tissue homeostasis as they are alreadypartially committed. In contrast embryonic stem cell (ESCs) are pluripotent and can generate all committedcell types. Fetal stem cells (FSCs) are derived from placenta and fetal tissues and have higher expansionpotential compared to ASCs. Umbilical cord stem cells (UCB SCs) are biologically analogous to theiradult counterpart but better immunological tolerance.

SCT acts in one of the three ways in treating genetic diseases.

· By directly replacing diseased marrow or blood cells operating within the blood systems; forexample in hemoglobinopathies like thalassemia.

· By replacing phagocytic cells of the monocyte/ macrophage lineage which operate in solid organs;for example in osteopetrosis.

· By acting as a source of indwelling enzyme therapy in metabolic disease; for example in Hurlersyndrome (MPS 1).

Hemopoetic stem cell transplantation (HSCT) was usually performed using donor bone marrowfrom siblings with identical HLA match. Major obstacle in HSCT is the availability of HLA matcheddonor. Recently the choice of donors were widened to include parents who are only half matched for theirchild’s tissue type (haploidentical). However, risks remain substantially higher in the more mismatchedtransplants. Altogether, graft survival has been reported in 75% of matched sibling donor transplants and38% of unrelated donors in large series. Umbilical cord blood (UCB) is a viable alternative and preliminaryresults reported encouraging results. A significant determinant of outcome after UCB is the nucleatedcell dose per kilogram of recipient weight.

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Pre-transplant “conditioning therapy” to both eradicate patient’s marrow and to suppress rejectionreaction is an important determinant of successful HSCT. This carries many short and long term sideeffects like endocrine and growth problems. Recently reduced intensity nonmyeloablative preparatoryregime was used in some indolent form of metabolic diseases. Another major challenge during HSCT isintercurrent infections during immunosupression. Graft versus host disease (GVHD) is another majorconcern after HSCT due to allogenic recognition of patient tissue by donor T-cells. The role of bonemarrow graft engineering (T cell depletion) and cell dose of nucleated cells (CD34 cells) will reducerates of GVHD, but at the price of increased infections and more frequent graft rejections. As a screeningtool for graft acceptance, donor/recipient chimaerism can be monitored accurately in most patients byPCR methods. Comprehensive multidisciplinary team approach is important in managing patient onHSCT.

Evaluation of the true long term effects of HSCT is very difficult to asses since most diseaseshave a wide spectrum of clinical phenotype. Moreover benefit varies between organ systems.Reticuloendothelial organs like liver and spleen often shrink quickly as enlarged macrophages take upthe enzyme easily. However central nervous system improvement is slower because of the turnover ofmicroglia and their replacement by donor derived cells. Unfortunately the impact of HSCT on bonedisease like dysostosis multiplex in mucopolysaccharidoses is little, presumably because of poor penetrationinto mesenchymal tissue. Timing of HSCT is also important for good results. In MetachromaticLeukodystrophy HSCT is recommended in presymptomatic patient where neurophysiologic functionsand independence in activities of daily living remains good. In case of X-linked adrenoleukodystrophyHSCT must be reserved for those who have early but definite evidence of cerebral disease as determinedby MRI. In Krabbe disease where neurodegenaration is very early, HSCT should be done in neonatal lifeitself.

HSCT is a proven effective therapy for Hurler syndrome (MPS type 1). Engraftment after HSCTin Hurler disease patients leads to rapid reduction in glycosaminoglycans (GAG) substrates in liver,tonsils, conjunctiva, CSF and urine. Obstructive airway symptoms, hepatosplenomegaly corneal cloudingare dramatically reduced, hydrocephalus prevented or stabilized and hearing improves in many children.Dysostosis multiplex shows much poorer response because of poor penetration of enzyme intomesenchymal tissue. It is critical to perform the transplant as early as possible, ideally before 18 monthsof age when intellectual function is relatively well preserved. The optimal neurological outcome afterHSCT in children with Hurler syndrome are likely to occur when the child is less than 2 years of age andhas a Mental development index (MDI) more than 70 before HCT. In Gauchers disease HCT is notcurrently recommended as first line of treatment since enzyme replacement therapy (ERT) is effectivewith low morbidity.

Stem cell therapy is also tried in neurodegenerative conditions like Parkinon’s diseases,Huntington’s disease and amyotrophic lateral sclerosis (ALS). Several studies have emphasized safety,the donor’s cell survival, and the functional efficiency. However complications like post-graft subduralhematoma are reported. Subarachanoid injections of immature nervous cells and hematopoeitic tissuesuspension, in patients with brain stroke, have significantly improved the functional activity withoutserious side effects. Myoblast transplantation in Duchenne Muscular Dystrophy (DMD) is a safe procedurewith no local or systemic side effects.

Various innovative methods have been tried in HSCT to improve the outcome. Insertion of genesfor specific lysosomal hydrolyses or for the ALD protein into autologous hematopoietic stem cells and

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transplantation of these cells is theoretically attractive. To correct skeletal manifestations of storagedisorders co transplantation of mesenchymal stem cells which may differentiate into chondrocytes andosteoblasts is novel approach. In rapidly progressive infantile form of neurodegenerative disorders likeKrabbe disease, intrauterine HCT may be worth exploring but the major limitation of this approach is thelow levels of donor cell engraftment. Improvement in HCT techniques and the development of novelstem cells will significantly impact the safety and efficacy of therapy as well as expand the list of candidatediseases.

Enzyme replacement therapy

The enzyme replacement therapy have been witnessed remarkable advances in the last decade.The first successful treatment of Gauchers disease by enzyme replacement therapy was developed byBrady and colleagues in 1974. The breakthrough development in ERT is identification of mannose 6-phosphate receptor mediated pathway that helps in targeted delivery of the enzymes to lysosomes. Anothercrucial observation was that only a very small percentage increase in intracellular activity (1-5%) wasrequired to correct storage disorder. Main obstacles were a good animal model suitable for preclinicaltrials and purification of enzyme in sufficient quantities. Both hurdles were eventually overcome bytechnological advances.

At present enzyme replacement therapy has become standard treatment for patients with type I(non neuronopathic) Gauchers disease (CEREDASE, CEREZYME) . The aim of ERT is to achievereversal of the clinical symptoms and prevent irreversible organ damage. The current indications includethe presence of symptomatic bone diseases, severe anemia, a tendency to bleed due to thrombocytopeniawhether or not associated with coagulopathy, hepatic infiltration with liver dysfunction and pulmonaryinvolvement. Neurological manifestations associated with Gauchers disease type II will not respond toERT and its use in these patients is deemed inappropriate. The response to ERT is generally excellentirrespective of the degree of the disease, although inter individual variability exists. The cases of poorresponse are rare and possibly improved by splenectomy. However there are some bad prognostic factorslike persistent hypersplenism, hepatic cirrhosis and pulmonary hypertension. Dosage is to be determinedon individual basis and optimum dosage frequency remains controversial. Usual recommended dosage is30-60 units/ kg/ two weeks with later dose adjustments. Several teams have reported the interest in lowdosages (5IU/Kg) administered two to three times weekly which shows equal clinical and hematologicalimprovement. The response will be evident in first year itself with correction of thrombocytopenia andanemia. Hepatomegaly will decrease by 30-40% and splenomegaly will decrease by 50-60%. ERT isusually well tolerated except with immediate hypersensitivity reactions. Recombinant enzyme(CEREZYME) has less adverse effects than plasma derived enzyme (CEREDASE). Even though duringthe last 10 years, worldwide experience with ERT in over 3000 patients with type I Gaucher disease hasclearly documented its safety and effectiveness, the cost is prohibitive for common usage in clinicalpractice especially in developing country like India. An estimated cost for treating a 10 Kg child withGaucher disease is approximately rupees 1 lakh per month.

In addition to Gauchers diseases ERT is approved for Fabrys diseases (FABRYZYME),Mucopolysaccharidoses type I (LARONIDASE), Pompes Disease (MYOZYME), Hurler syndrome(ELAPRASE) and MPS type VI(GALSULFASE). In case of Pompes disease, the MYOZYME transfusionis given at a dose of 20mg/kg in every two weeks. The results of ERT vary considerably from disease todisease. Important considerations are the age of onset, rapidity of progression and presence or absence ofneurological involvement. There is no conclusive evidence that ERT crosses blood brain barrier. Even

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intrathecal administration of enzymes had no beneficial effects. Although there is experimental datademonstrating that enzyme given directly intracerebrally is taken up by neurons, such an approach is notlogistically possible.

There are several issues that should be answered in near future concerning ERT. Novel technologiesneed to be developed to deliver the therapeutic enzyme effectively to the target tissues like skeletalmuscles in Pompes diseases and mesenchymal tissues in MPS. The development of severity score indicesthat can be used to quantify the benefit of ERT is also important. Most important concern regarding ERTin developing country like India is the prohibitive cost of the enzyme preparation for most of the neededpopulation.

Small molecules as therapeutic agents

More recently another potential therapeutic option such as chaperon mediated enzyme enhancementtherapy (EET) was tried in genetic disorders. In EET low molecular weight pharmacological chaperonsare used to rescue misfolded or unstable proteins, thereby increasing protein function. In contrast torecombinant lysosomal enzymes these hydrophobic molecules might cross blood brain barrier and diffusethrough connective tissue matrices to reach the target site. The use of pharmacological chaperones likegalactose to treat lysosomal storage disorders has been validated in the cardiac variant of Fabrys disease.Limitation of this therapy is that it is likely to be effective only in those patients in whom the mutationdoes not inactivate the catalytic site.

Another novel approach to treatment is substrate reduction therapy31[31]. The imino sugar N-butyldeoxynojirimycin (NB-DNJ) has been shown to inhibit ceramide specific glucosyltransferase, whichcatalyses the first step in glycosphingolipid biosynthesis. This results in inhibition of biosynthesis of allglucosylceramide based glycosphingolipid leading reduction of storage material in different tissues. Sinceanimal experiments showed significant reduction in storage material in CNS and clinical improvement,clinical trials in patients with Gaucher disease type I was done. The results showed a response in variousdisease parameters. However it is unlikely that NB-DNJ will have a role in all sphingolipid disorders(e.g. Niemann-Pick disease type A). This type of therapy will deplete all glucosylceramide basedglycosphingolipid, which may cause additional side effects.

Gene Therapy

Gene therapy is a potentially definitive treatment for diseases that have a genetic etiology. Thisrequires the targeted transfer of exogenous genetic material into human cells and the subsequent regulatedexpression of the corresponding gene product. Gene therapy trials are going on for single gene disorderslike cystic fibrosis, multifactorial disorders like coronary artery disease and HIV infections. Despite itspromise, gene therapy is not sufficiently developed for clinical use due to several reasons.

· The optimum dose of vector and its passenger gene necessary to achieve therapeutic outcome isnot established

· The specificity of transgene delivery

· The control of transgene expression

· The adequate margin of safety

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t Adenoviral vector in OTC deficiency – mortality

t Retroviral vector in SCID deficiency- leukemia

· The interaction between the novel gene therapy with established safe therapy

Additional clinical and basic research is needed to evaluate the future role gene therapy in clinicalpractice. RNA interference (RNAi) is a conserved biologic response to double-stranded RNA that resultsin sequence specific silencing of target gene expression. It has the potential to revolutionize the treatmentof genetic disorders where gene expression has to be silenced like viral infections and malignancy.

Summary

Technical experience for more than two decades has shown that SCT may benefit some but not allpatients with genetic disorders. Despite rapid technological improvements, there are still many shortterm risks and potential long term adverse effects secondary to SCT. The rapid emergence of alternatetherapies like enzyme replacement therapy (ERT) should be evaluated. ERT is a reality for Gaucherdisease, Pompes disease Fabrys disease, MPS I and MPS VI. Unfortunately these tend to be extremelyexpensive to be used in routine clinical practice especially in developing countries like India. Somespecific targeted pharmacological therapies were also identified. It is hoped that gene therapy caneventually replace all of these modalities. However, additional clinical and basic research is needed todetermine the future role of gene therapy. Even though rapid advances are occurring in treatment ofgenetic disorders, we should never forget preventive aspects like screening and prenatal diagnosis ofgenetic disorders.

Legends for illustration

Figure 1:

The different levels of therapy in genetic disorders considering the biological model

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DIETARY MANAGEMENT OF MEDICALLY REFRACTORYEPILEPSYSHEFFALI GULATI

Background: Food has a variety of nutrients like protein, fat, carbohydrates (sugars and starches), fiber,vitamins and minerals. Carbohydrates, fats and proteins provide us with energy. Normally, our body usescarbohydrates as the major source of energy.

A ketogenic diet is used for some forms of childhood epilepsy. It is usually started after the seizuresremain uncontrolled on anticonvulsant medications. Fat has high ketogenic potential, protein has mixedpotential and glucose has anti ketogenic effect. Ketosis is not harmful for the body. It is in fact an alternativebrain fuel and is believed to stabilize neuronal membranes for seizure reduction.

In this regimen, strict adherence to prescribed diet has to be followed to be effective. Diet calculated canbe divided into three major meals based on homemade stuff. Half of the patients respond to the diet tosome extent and one third respond very well. Once seizures are controlled drug therapy may be taperedgradually. Most children are more alert and active on dietary therapy

Conditions where ketogenic diet (KD) has been found successful

Refractory epilepsy: Of all patients with epilepsy, approximately 20%–30% will develop medicallyrefractory epilepsy. Refractory epilepsy may be defined as seizures persisting daily or more than 7 perweek despite the adequate trials of at least three tolerated and appropriately chosen anti-epileptic drugsincluding one newer antiepileptic drug (either alone or in combination). All seizure types have beendocumented to respond to this therapy including absence, complex partial, atonic, myoclonic, mixedepilepsies, including severe myoclonic epilepsy of infancy (Dravet Syndrome) and myoclonic-astaticepilepsy. The Ketogenic diet can effectively treat epilepsy in individuals from infancy through adulthood.

Also used in some specific metabolic problems: GLUT1 deficiency syndrome and pyruvate dehydrogenasedeficiency (PDHD); Tuberous sclerosis; Rett Syndrome; Infantile spasms who are refractory tocorticosteroids and other medications

Other Conditions where ketogenic diet has been tried include Brain tumor, Alzheimer disease,Parkinson’s disease, Autism, Stroke, Traumatic brain injury and Narcolepsy

Contraindications to ketogenic diet: Fatty acid oxidation defects, Porphyria, Known surgical focus,

Inability to maintain adequate nutrition, Parental reluctance to initiate or erratic compliance.

Clinical suspicion about an inborn error of metabolism includes developmental delay, cardiomyopathy,hypotonia, exercise intolerance, myoglobinuria, and easy fatigability. The presence of one of those clinicalfeatures suggests that the child should be tested to rule out an inborn error of metabolism prior to KDinitiation.

After adequate counseling and Pre-diet preparation ketogenic diet is initiated.Diet Initiation:

Diet initiation can be either after hospital admission especially in younger children or home based. Thediet is started with a full calorie, ketogenic ratio i.e. ratio of fat: protein+ carbohydrate by weight of 1:1.

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This is built up over a period of 4 days to 3:1 in children younger than 18 months, and 4:1 in childrenolder than 18 months. Blood sugars, urine ketones, serum electrolytes, weight, and intake-output aremonitored. The child is discharged by the fourth or fifth day after admission. Calcium and multivitaminsupplementation are to be added. The antiepileptic drugs which the child was receiving are continued inaddition to the diet in sugar free formulations.

Side effects

Short term: nausea, vomiting, behavioral changes, initial lethargy

Long-term: such as possible renal stones, growth faltering (compensatory growth spurt resumes oncediet is discontinued)

Discontinuation of Ketogenic diet

Timing and method is to be individualized by decreasing ratios. At least 3 Months trial should be givenbefore one thinks of giving up if unsuccessful and should be used for 2-3 years if successful. It may berequired for longer period and even lifelong for few specific metabolic conditions

Other dietary therapies include modified atkins diet and low glycemic index diet

Modified Atkins diet

It is less restrictive diet than ketogenic diet. Carbohydrates intake is restricted to 10 grams/ day. Use offats (e.g. cream, butter, oils, ghee) is encouraged. proteins (cheese, fish, eggs, chicken, soya products)and clear fluids are also unrestricted.

Low glycemic index diet:

Glycemic index (GI) is a system for classifying carbohydrate foods, according to how fast they raiseblood-sugar levels. The higher the GI value of a food, the faster the rise in blood glucose. The glycemicindex classify foods into three categories; high GI foods with GI more than 70, intermediate GI foodswith GI between 55 and 69, and low GI foods with GI 55 or less.

Low glycemic index diet, compared to the classic ketogenic diet, allows for a relatively liberal totalcarbohydrate intake but restricts foods to those that produce relatively little elevation in blood glucose(GI <55). By limiting the quantity of carbohydrates consumed and restricting sources of carbohydrates tolow-GI foods, the low glycemic index treatment (LGIT) is designed to prevent dramatic postprandialincreases in blood glucose. LGIT had been found to be effective in reducing seizure frequency in childrenwith refractory epilepsy.

AIIMS experience

Ketogenic Diet:

In a prospective study of introducing ketogenic diet using non fasting protocol, 27 children aged 6 monthsto 5 years were enrolled of which 55% remained on KD at 6 months, and 37% remained on it at 1 year.48% (13 of 27) had >50% reduction in seizures and four children (15 %) were seizure free at 6 months.At 1 year, 37% had >50% reduction in seizures and five children (18.5%) were seizure free.

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In another randomized controlled trial, 38 children (19 in each group) aged 6 months to 5 years withrefractory epilepsy were randomized to receive either a 4:1 or 2.5:1 ketogenic ratio diet. At three months,11 children (58%) in the 4:1 group and 12 (63%) in the 2.5:1 group had more than 50% reduction inseizures (p = 0.78). Five children (26%) in the 4:1 group and four (21%) in 2.5:1 group became seizurefree. Thus, 2.5:1 ratio KD is possibly as effective as 4:1 KD in controlling seizures and has fewer adverseeffects.

Modified Atkin’s diet:

In a prospective, open label, uncontrolled study, we have found that after three months of modifiedAtkin’s diet, six out of 13 children with refractory infantile spasms were spasm free. The time to spasmfreedom after diet initiation ranged from two days to two months.

In another randomized controlled trial, 102 children aged 2 to 14 years with refractory epilepsy wererandomized to receive either modified Atkin’s diet or no diet therapy. At three months of follow up, 30 %of patients in diet group had > 90% seizure reduction as compared to only 7.7% in control group. 52% ofpatients in diet group had > 50% seizure reduction as compared to only 11.5% in control group.

Low glycemic index diet:

We are enrolling patients currently in a randomized controlled trial at our Institute titled “Efficacy of lowglycemic index diet therapy in children with refractory epilepsy - A randomized controlled trial”

Suggested Reading

1. Lee PR, Kossoff EH. Dietary treatments for epilepsy: management guidelines for the general practitioner.Epilepsy Behav. 2011 Jun;21(2):115-21. Epub 2011 Apr 21.

2. Kessler SK, Neal EG, Camfield CS, Kossoff EH. Dietary therapies for epilepsy: Future research.Epilepsy Behav. 2011 Sep;22(1):17-22. Epub 2011 Mar 26

3.. Raju KN, Gulati S, Kabra M, Agarwala A, Sharma S, Pandey RM, Kalra. V Efficacy of 4:1 (classic)versus 2.5:1 ketogenic ratio diets in refractory epilepsy in young children: A randomized open labeledstudy. Epilepsy Res. 2011 May 26. [Epub ahead of print]

4.. Sharma S, Gulati S, Kalra V, Agarwala A, Kabra M. Seizure control and biochemical profile on theketogenic diet in young children with refractory epilepsy—Indian experience. Seizure. 2009; 18(6):446-9. Epub 2009 May 7.

5 Sharma S, Sankhyan N, Gulati S, Agarwala A. Use of the modified Atkins diet in infantile spasmsrefractory to first-line treatment. Seizure. 2011 Sep 13. [Epub ahead of print]

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The role of the clinician in the diagnosis and treatment of a weak child is as important today as it was inthe 19th century. Fundamental tools are a detailed medical history & a carefully performed physicalexamination. The clinical assessment has three possible immediate outcomes: Reassurance; determinenatural history of the process; arrange for further diagnostic procedures.

Neuromuscular disorders can be due to disorder anywhere in the motor unit which is illustrated inFigure 1 below. The anterior horn cell involvement can produce spinal muscular atrophy, Amyotrophiclateral sclerosis; Nerve involvement can produce various neuropathies; neuromuscular junctioninvolvement can produce myasthenia gravis, congenital myasthenic syndromes; muscle fiber involvementcan produce various dystrophies, myotonic syndromes, and can be due to mitochondrial, congenital,metabolic or autoimmune disorders.

Figure1: Motor Unit

Weakness is a symptom of all motor unit disorders. Table 1 enumerates key features to differentiatebetween these disorders.

Table 1: Key features to differentiate between motor unit disorders

APPROACH TO NEUROMUSCULAR DISORDERSSHEFFALI GULATI

Site of involvement

Proximal (P) Vs Distal (D) involvement

Muscle stretch reflexes

Electrophysiological studies

Muscle biopsy

Anterior horn cell P = D Absent Evidence of denervaion, fasciculations

Type grouping

Nerve D > P Depressed/Absent Abnormal nerve conduction studies, Denervation potentials on EMG

Denervation pattern

Neuromuscular junction

Variable Normal Repetitive nerve stimulation – abnormal decrement/increment

Normal

Muscle P > D Depressed Low amplitude short duration polyphasic MUAPs on EMG

Usually characteristic

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While approaching a child with a suspected neuromuscular disorder, one should consider followingquestions in one’s mind:

• What is the clinical pattern?

• Any involvement outside skeletal muscle?

• Disease course?

• Mode of inheritance?

• Means for securing a diagnosis?

• Treatment options available?

Initial history should include complaints of the patient, age at onset, symptoms at presentation,course of disease, family history. Mode of inheritance can be variable: It is X- Linked recessive in Duchennemuscular dystrophy, Becker muscular dystrophy, Charcot-Marie-Tooth; Autosomal dominant inFacioscapulohumeral muscular dystrophy, central core disease; autosomal recessive insarcoglycanopathies, congenital muscular dystrophies, to name a few. It is essential to establish a detailedpedigree which we commonly miss in our clinics.

Examination should be complete and should include: Gower’s sign, valley sign, waddling gait,scapular winging, facial weakness, tongue/ calf hypertrophy, contractures, ophthalmoplegia, ptosis,myotonia, cardiac, respiratory or CNS involvement. Various phenotypes are easily recognizable likeDuchenne- Becker muscular dystrophy, Emery- Dreifuss Muscle dystrophy, Facioscapulohumeraldystrophy, myotonic dystrophy, Charcot- Marie- tooth, spinal muscular atrophy. Depending upon patternof muscle involvement, facial or ocular involvement, contractures or wasting, cardiac/ respiratoryinvolvement, rate of progression we can form an initial clinical impression.

Laboratory evaluation: Traditional diagnostic tests include nerve conduction studies,electromyography (EMG) and open muscle biopsy. Recently there has been lot of advances in molecularneurogenetics.

Tissue involvement can be assessed by Electrodiagnostic testing: Electromyography, repetitivenerve stimulation, and nerve conduction testing; imaging; serum creatine kinase(CK) and muscle biopsy.On muscle biopsy diagnosis is made by specific morphologic features, immunohistochemistry (absent orreduced staining for specific protein) and histochemistry (absent or reduced enzyme function). Otherdiagnostic tests include nerve biopsy, antibodies in serum or CSF (may define specific immuneneuromuscular disorders)and genetic testing (defines specific hereditary disorders)

Electrophysiology has certain cardinal rules:

• Electromyography and Nerve conduction studies are an extension of the clinical examination

• Whenever in doubt: think about technical factors; re-examine the patient

• Always think of clinical-electrophysiologic correlation

Goals of electrophysiology include: Localization of the lesion: Nerve/ neuromuscular junction/muscle; Underlying nerve pathophysiology: fiber type involved/ pathology; Assessment of severity;Assessment of temporal course. It helps us to distinguish neuropathic Vs myopathic pattern, neuromuscularjunction blocks, myotonic discharges, decremental response, assess nerve conduction velocities (motor& sensory) and sensory potentials

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Muscle imaging

Various techniques are available: Ultrasound; Computerized tomography; Magnetic resonance imaging.It is potentially useful to select site of muscle biopsy(especially in inflammatory); to demonstrate someselectivity; to follow up disease progression

Creatine kinase

It has much inter-individual variability. If elevated suggests muscular dystrophy

CK may be very high in:

• Hereditary : Duchenne & Becker dystrophy, Limb girdle dystrophies, Miyoshi DistalMyopathy, Acid maltase deficiency

• Chronic acquired disorders: Inflammatory Myopathies (Except: Inclusion body myositis),Hypothyroid

• Acute muscle damage (Highest CK): Rhabdomyolysis, Trauma ,Injection

Muscle biopsy

Selection of muscle to biopsy:

• Chronic disease: Muscle with moderate, but not severe, weakness

• Acute disease: Muscle with severe or moderate weakness

• Best specific muscles: Deltoid; Biceps; Quadriceps

• MRI can be used to select pathological muscle site in difficult cases

• Avoid: Muscles that were site of EMG, injections,or trauma ( Biopsy: left side; EMG:right side)

How to read a muscle biopsy?

• Are muscle fibers abnormal?

• Is the pathologic process:

à Neurogenic or Myopathic?

à Acute or Chronic?

à Producing specific diagnostic features?

• What is the distribution of the pathology?

• Are there diagnostic features?

à Is there inflammation or excess cellularity?

à Is there storage material?

à Is there pathology in structures other than muscle fibers?

Muscle biopsy stains

§ Morphology: Hematoxylin and eosin; Verhof van Giesson (VvG); Modified Gomoritrichrome

§ Fiber Typing: Myofibrillar ATPase; ATPase pH 9.4/pH 4.6./pH 4.3

§ Enzymes: Oxidative: NADH-TR, Succinate dehydrogenase,Cytochrome oxidase

§ Enzymes: Glycolytic: Myophosphorylase, Phosphofructokinase, Amylopectinase

§ Enzymes: Hydrolytic: Acid phosphatase, Non-specific esterase,Acetylcholinesterase,Alkaline phosphatase

§ Storage material: PAS, Alcian blue, Sudan black B, Oil red O

§ Other: Congo red, Myoadenylate deaminase, Methyl green pyronine, Acridine orange,Von Kossa

§ Fixed muscle: H & E

Immunohistochemistry

§ Extracellular molecules

à Laminins: Laminin á2 (Merosin)

§ Sarcolemma-related proteins

à Dystrophin: 3 Antibodies used, vs C-terminal, Rod & N-terminal domains ofdystrophin; Western blot: Useful for detecting reduced size/ different sizes/ reducedamount of dystrophin

§ Cytoplasmic proteins: Soluble & Myofibrillar

à Calpain-3 ( western blot)

§ Nuclear proteins

à Emerin

Western blotting

On muscle specimen, is a semi-quantitative method; detects reduction of protein level or size/ weightabnormalities; For a limited number of proteins: Calpain, Dysferlin useful; Dystrophin, Sarcoglycans(αβχδ)

Electron microscopy

Not routinely performed; expensive, time-consuming; especially useful in congenital myopathies, storagemyopathies, mitochondrial myopathies, protein aggregating myopathies

Nerve biopsy

§ The whole sural nerve is biopsied (rather than only 1 fascicle).

§ The nerve is viewed in frozen or paraffin embedded, and in plastic, sections

§ Teased fibers: Distinguish axonal from demyelinating pathology

§ Ultrastructural analysis is available

§ Diagnoses to look for on a nerve biopsy: Inflammatory; Demyelinating Disorders;Hereditary Disorders; Systemic Disease; Toxic

Antibodies

§ Myasthenia Gravis: Anti-Acetylcholine Receptor(IgG); Anti-Striational(IgG): WithThymoma

§ Lambert-Eaton Myasthenic Syndrome: Anti-P-type Calcium Channel (IgG)

§ Myositis associated antibodies

§ Antibodies associated with connective tissue disorders

§ Disorders of the nerve

à Monoclonal antibodies (M-proteins): Serum or urine

à Cryoglobulins: if detected, test for Monoclonal antibodies; Hepatitis C; CollagenVascular Screen

Molecular diagnostic methods available

§ Chromosomes ( FISH)

§ DNA ( Restriction fragments; PCR; sequencing; denaturing techniques; protein truncationtest)

§ mRNA (Northern blot; microarray expression analysis)

§ Protein ( Immunohistochemistry; enzyme functional assays; western blot)

Genetic studies

Mutational diversity of a gene: Duplication; Deletion; Point mutation; Null mutation; Missense mutation;Triplet expansion; Out of frame or in frame

Suggested Protocol of Investigations in NM disorders

§ DMD/ BMD: DNA; M Biopsy

§ LGMD: DNA; M Biopsy; EMG/ NCS

§ EDMD: DNA; M Biopsy; EMG/ NCS

§ FSHMD: DNA;EMG/ NCS

§ MyD: DNA;EMG/ NCS

§ Periodic paralysis/ myotonias: DNA;EMG/ NCS

§ Metabolic myopathies: M Biopsy; DNA; EMG/ NCS

§ Congenital myopathies: EMG/ NCS; M Biopsy; DNA

§ DM/PM: MRI; M Biopsy; EMG/ NCS

§ Indeterminate proximal weakness: EMG/ NCS; RMNS; M Biopsy/ DNA

§ SMA:DNA; EMG/ NCS; M Biopsy

§ CIDP: EMG/ NCS; CSF analysis

§ GBS(AIDP): CSF analysis; EMG/ NCS

§ HMSNs: EMG/ NCS; DNA

§ Neuromuscular transmission disorders: EMG/ NCS; RMNS; antibodies

Suggested Reading

1. Fenichel GM. The hypotonic infant. In: Clinical Pediatric Neurology, A signs and symptomsapproach, sixth edition. Elsevier 2010. P 153.

2. Riggs JE, Bodensteiner JB, Schochet SS. Congenital myopathies/dystrophies. Neurol ClinN Am 2003;21:779-794.

3. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne musculardystrophy, part 1: diagnosis and pharmacological and psychosocial management. Lancet Neurol.2010;9:77-93.

4. Straub V, Bushby K. The childhood limb-girdle muscular dystrophies. Semin Pediatr Neurol2006;13:104-114.

5. Bromberg MB. An Approach to the Evaluation of Peripheral Neuropathies. Semin Neurol2010; 30:350–355.

6. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet 2008;371:2120-33.

PEDIATRIC NEUROLOGICAL EXAMINATIONN. ANAND

The extent of neurological examination will depend on the age of the child. Observation of thechild during interaction with the parents, while playing, behavior during the interviews is of extremeimportance and more informative than the examination of cranial nerves, tone or gradation of power.

HIGHER MENTAL FUNCTIONS

A - Appearance

B - behaviour

C - consciousness,cooperation

D - delusion

E - emotional state

G - gnosis or memory-immediate,recent ,remote memory

I - intelligence-(FACT)F-fund of knowledge,A-abstract thinking, C-calculation,T-thought process

S – speech

Examination of cranial nerves

1. Olfactory nerve – anosmia – commonly seen in upper respiratory infections , following fracture ofthe base of skull, frontal lobe tumor

2. Optic nerve-

visual acuity- at 5-6 yr of age snellens chart is useful,pre school -E chart

poor vision in darkness (nyctalopia ) seen in vitamin A def,retinitis pigmentosa

Visual field is assessed by confrontation method .

color vision by ishihara chart

Fundus –look for papilledema seen in increased intracranial pressure conditions such asmeningitis,intracranial tumors,severe hypertension,obstructive hydrocephalus

Also look for Optic atrophy which can be primary or secondary . in primary disc is pale yellowwith sharp margins.in secondary disc appears filled up grayish with irregular and indistinct margins.

Other signs to elicit are cherry red spot in IEM ,chorioretinitis in intrauterine infections

3. Oculomotor, trochlear,abducent nerves

Assess the movement of eyeball in all cardinal positions

In paralysis of 3rd nerve there will be ptosis, opthalmoplegia. Look for conjugate deviation of theeyes (a cortical irritative lesion causes conjugate deviation of eye to the opposite side CIA ) (acortical destructive lesion causes conjugate deviation of eyes to he same side as the lesion)

Examine for diplopia if there is gaze palsy with no diplopia it is supranuclear gaze palsy lesion wilbe in cortex or midbrain .

Asses the dolls eye response if present indicate a intact brain stem . check for abnormal chaoticmovements of eye (opsoclonus ) seen in neuroblastoma or viral infections.

4. Trigeminal nerve - asses the sensory distribution of the face . motor function assessed byexamination of masseters,pterygoid and temporalis during mastication

5. Facial nerve - LMN facial involves upper and lower face equally, decreased voluntary movementof the lower face with flattening of the nasolabial angle on the same side indicates a upper motorneuron lesion .

6. VIII th nerve - hearing should be assessed in all cerebral palsy cases

7. Glossopharyngeal nerve – look for gag response

8. Vagus nerve – unilateral lesions produce palatal paralysis,bilateral lesions produce respiratorydistress

9. Accessory nerve – paralysis and atrophy of the sternomastoid and trapezius muscle occurs formlesion of this nerve . seen in motor neuron disease ,myotonic dustrophy,myasthenia gravis

10. Hypoglossal nerve – innervates tongue . malfunction produces wasting ,wekness, fasciculationsof the tongue . seen in infantile SMA ,congenital anomalies in the region of foramen magnum.

Examination of motor system

§ Posture of the child

§ Bulk of muscle- size, shape , symmetry of muscle is assessed .Atrophy is more marked in LMNlesions Hypertrophy with weakness is seen in Duchenne muscular dystrophy. Weakness associatedfasciculation are seen in spinal muscular atrophy.

§ Tone of muscles –in infants tone is assessed by measuring the amiel-tyson angles.

In children look for spasticity as in cerebral palsy,hypotonia as in floppy infant, muscle disorders

Spastic cerebral palsy-quadriplegic type –all limbs are affected.if lower limbs are more involvedthan upper limbs it is spastic diplegia

§ Power of muscles – is graded according to the Medical RESEARCH COUNCIL (MRC)scale.Weakness is moreor equal on(proximal –distalmuscle groups) when it is central disorder or anteriorhorn cell disease .if it is a peripheral nerve disorder weakness is more of distal distridution.In muscledisease weakness is more of proximal . in neuromuscular junction disease weakness is same on proximaland distal muscle groups.

§ Face involvement is a predominant feature of neuromuscular junction disorder,variableinvolvement in muscle disease,late involvement in anterior horn cell disease, not involved in central andperipheral nerve disease.

§ Coordination of movements –assesed by finger nose test ,heel knee test, past pointing

Other signs of cerebellar dysfunction such as dysarthria,nystagmus,ataxic gait

§ Involuntary movements –in extrapyramidal cerebral palsy (choreo athetoid,dystonic) involuntarymovements occur after 2yrs of life.involuntary movements like chorea occurs in rheumatic fever .slowbizarre involuntary movements lasting for more than 30seconds (dystonia occurs inextrapyramidal cerebralpalsy).drug induced dystonic reaction (occulogyric crisis) can occur following over dosage ofmetoclopramide.

§ Examination of reflexes-in UMN lesions DTR is exaggerated(look for patellar, ankle clonus),LMN lesions it will be absent. Exaggerated jaw jerk is a feature of quadriplegic cerebral palsy.In anteriorhorn cell disease reflexes are absent,decreased in muscle/peripheral nerve diseases and normal inneuromuscular junction disorders.

One point which help in differentiating congenital hemiplegia from acquired is the reflexes;congenital hemiplegia superficial reflexes are retained but in acquired hemiplegia it will be absent.

Assesment of primitive reflexes is important as persistence of primitive reflexes is an early markerof cerebral palsy.

§ Examination of sensory system – a detailed sensory testing is important when we are suspecting aspinal cord lesion such as a myelomeningocoele(asses the anal sphincter tone ), transverse myelitis.

§ Signs of meningeal irritation – commonly seen in meningitis

Neck rigidity can also occur in subarachnoid hemorrhage,tetanus,meningism,local painful lesions.

§ Examination of skull & spine - elicit cracked-pot sign if there is hydrocephalus.

auscultate for cranial bruit in arteriovenous malformation .

transiilumination of skull in case of macrocephaly.

Look for spinal dysraphisms - cutaneous manifestations such as a hemangioma,pit,lump,hairy patchorsinuses

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