Moderator : Dr. D. Devi ,

Asso prof, Dept of paediatrics, SMCH

Presented by: Dr. Samiul Ahsan Hussain

PGT, Paediatrics

INTRODUCTION

The hallmark of neurodegenerative disease is regression and progressive deterioration of neurologic

function with loss of speech , vision, hearing or locomotion a/w

seizure, feeding difficulties and impairment of intellect.

Neuroregressive /neurodegenerative disorders are a

group of heterogeneous diseases which results from

specific genetic, biochemical defect, chronic viral

infection, toxic substances

Involves both the gray matter and white matter

Dementia, used for neurodevelopmental regression in

children, is associated with loss of memory, ability to

think, understand and recognize along with personality

changes or distressing behaviour

Gray matter & White matter

Striations seen in white mater

Contains mostly myelinated axons

Appears pinkish white to the naked eye (myelin is

composed largely of lipid tissue veined with capillaries)

A 20 year-old male has a 176,000 km of myelinated

axons in his brain while that of a female is 149,000 km

connect various grey matter areas (the locations of nerve

cell bodies) of the brain to each other, and carry nerve

impulses between neuron

White matter

Major component of the CNS having a grey –brown color(due

to capillary blood vessels & neurinal cell bodies)

Consists of

neuronal cell bodies( in contrast to white matter)

neuropil (dendrites and unmyelinated axons )

glial cells (astroglia and oligodendrocytes) & capillaries.

Gray matter

The grey matter includes regions of the brain involved in

muscle control,

sensory perception such as seeing and hearing,

memory, emotions, and speech.

Gray matter Disease White matter Disease

Processing center Represents networking between these

centers

Primarily involve neurons± histologic

evidence of abnormal metabolic

products--> neuronal death and

secondary axon degeneration

Myelin is disrupted either destruction

of normal myelin or biochemically

abnormal myelin production

Differentiatingfeatures

White matterdisorders

Gray matterdisorders

Age of onset Usually late(childhood) Usually early(infancy)

Head size May have megaenchepaly Usually microcepaly

Seizures Late , rare Early, severe

Cognitive functions Initially normal Progressive dementia

Peripheral neuropathy Early demyelination Late, axonal loss

Spasticity Early, severe Later, progressive

Reflexes Absent(neuropathy) or exaggerated(long tracts)

Normal or exaggerated

Differentiatingfeatures

White matterdisorders

Gray matterdisorders

Cerebellar signs Early,prominent late

Fundal examination May show optic atrophy Retinal degeneration

EEG Diffuse delta slowing Epileptic form discharges

EMG Slowed nerve conduction velocity

Usually normal

Evoked potentials(VEP, ABR)

Prolonged or absent Usually normal

ERG Normal Abnormal

EEG=electroencephalogram, EMG= electomyography , VEP=visualevoked potential, ABR= auditory brain stem response,ERG= electroretinogram

Gray matter: fits, decrease HMF

EEG: early abnormality

MRI Brain: cortical atrophy

White matter: blindness ,Gait disturbances ,Motor signs-

Spasticity ,optic atrophy ,ataxia , papilledema

EEG: late abnormality

MRI Brain: Demyelination

Nerve conductance + Evoke potentials

Classification

Basal Ganglia :Dystonia,Involantary movements

Spinocerebellar degeneration: Ataxia

Classification of neurodegenerative brain disease

Inherited Acquired

Focal manifestations

Both

White matter

Gray matter Metabolic

Infections

Acquired causes

Infections

SSPE

Progressive Rubella

Syndrome

Chronic HIV

Metabolic

Chronic lead poisoning

Hypothyroidism

Vit B12 & E deficiency

Drugs (anticonvulsant)

Inherited causes Gray matter involvement:seizure,dementia, visual loss, intellectual

impairment. Spike & sharp waves in EEG

A. Gray matter involvement with visceromegaly

GM1 Gangliosides-Infantile , generalized , juvenile

Sandholf disease (GM2)

Niemann pick Disease( Sphingolipid storage disease)

Sialidosis

MPS

Gaucher disease( Sphingolipid storage disease)

B. Gray matter diseases involvement without visceromegaly

Rett Syndrome

Neuronal curoid lipofuscinosis

Menke’s kinky hair disease

Spasticity , optic atrophy, ataxia ,peripheral neuropathy .Seizure , dementia

are the late manifestations. Slow waves in EEG

A. Leukodystrophies

Metachromatic leukodystrophy

Krabbe disease

Adrenoleukodystrophy

Alexander disease ,

Cannavan disease,

P.Merzbacker disease

White matter involvement

B. Acquired causes/ Demyelinating

Multiple sclerosis

Schilder’s disease

Devic disease

Basal Ganglia

Wilson's disease

Dystonia muscular

Deformans

Huntington’s Disease

Spinocerebellar

Friedrich’s Ataxia

Ataxia Telangiectasia

Classification according to age

An approach to a child with regression of milestones

Divide the babies according to age.

Look for organomegaly.

<2 year with hepatomegaly

Jaundice, vomiting, lethargy, irritability, and convulsions

hypoglycemiaand lactic acidosis/

cirrohosis

Typical facies OTHER

Fructose intolerance /Galactosemia

GSD TYPE 1 t0 4

MPS/Zellwegersyndrome

TSD/NPD/

GD Type 2

biochemglycogensynthesikz6.jpg

vongierke-glucose-

metabolism.jpg

Typical faciesMPS Zellweger syndrome

Diagnosis is usually made between 6 and 24 mo of age with evidence of hepatosplenomegaly, coarse facial features, corneal clouding, large tongue, prominent forehead, joint stiffness, short stature, and skeletal dysplasia .

• Typical facial appearance (high forehead, unslanting palpebral fissures, hypoplastic supraorbital ridges, and epicanthal folds ),

• severe weakness and hypotonia, neonatal seizures, and eye abnormalities (cataracts, glaucoma, corneal clouding, brushfield spots, pigmentaryretinopathy, and nerve dysplasia).

• More than 90% show postnatal growth failure

Difficulty in feeding, FTT, Cherry red spot,

hypotonia, death by 3yr

• loss of motor skills, increased startle reaction, cherry red spots .

• norma until 4–5 mo of age when decreased eye contact and an exaggerated startle response to noise (hyperacusis) are noted.

increased tone, strabismus, . Failure to

thrive and stridor caused by laryngospasm are

typical

NEIMANN–PICK DISEASE

Tay-Sachs disease Gaucher disease

Gucher cell, glucocerebrosida

se

Vacuolated histocytes,

sphingomyelinase

CRS, Hexoseaminida

se, Mutation analysis

< 2 yr without hepatomegaly

KRABBE DISEASE

• The infantile form of Krabbe disease is rapidly progressive and patients present in early infancy with irritability, seizures, and hypetonia.

• Optic atrophy is evident in the 1st yr of life, and mental development is severely impaired.

• MRI: diffuse demyelination of cerebral hemisphere• Delayed motor nerve conduction velocity• Increase CSF protein• Beta Galactosidase• krabbe disease.jpg

RETT SYNDROME

• Development normal until 1 yr of age, when regression of language and motor milestones and acquired microcephaly become apparent

• The hallmark of Rett syndrome is repetitive hand-wringing movements and a loss of purposeful and spontaneous use of the hands; these features may not appear until 2–3 yr of age.

• Autistic behavior is a typical finding in all patients.• Generalized tonic-clonic convulsions occur • Feeding disorders and poor weight gain are common

MAPLE SYRUP URINE DISEASE

• This form has the most severe clinical manifestations. Affected infants who are normal at birth develop poor feeding and vomiting in the 1st wk of life; lethargy and coma may ensue within a few days.

• Physical examination reveals hypertonicity and muscular rigidity with severe opisthotonos. Periods of hypertonicity may alternate with bouts of flaccidity.

PHENYLKETONURIA

• The affected infant is normal at birth.

• Mental retardation may develop gradually and may not be evident for the 1st few months.

• Older untreated children become hyperactive, with purposeless movements, rhythmic rocking, and athetosis

2-5 yearsMyoclonus,

Myoclonic epilepsy,Ataxia,

Raggaed red fibre in muscle

hypotonic extremitabsent deep

tendon reflexes,Inability to walk

Ataxia/Involuntary movements/infections / cancer Dysarthria

MERRF MLD AT

Acquired causes

SSPE

The initial clinical manifestations include personality changes, aggressive behavior, and impaired cognitive function. Myoclonic seizures soon dominate the clinical picture. Later, generalized tonic-clonic convulsions, hypertonia, and choreoathetosis become evident, followed by progressive bulbar palsy, hyperthermia, and decerebrate postures.

• Chronic lead poisoning

• loss of short-term memory or concentration, depression, nausea, abdominal pain, loss of coordination, and numbness and tingling in the extremities.] Fatigue, problems with sleep, headaches, stupor, slurred speech, and anemia are also found in chronic lead poisoning.

• A "lead hue" of the skin with pallor• ]Burton line• Children with chronic poisoning may refuse to play or may

have hyperkinetic or aggressive behavior disorders.

Chronic HIV

Onset: 2 month t0 five yr after exosure.Progressive loss of developmental milestones , microcephaly, dementia and spastcity is characteristics

Hypothyrodism

Asymtomatic at birthWide open posterior frontanalare, constipation , jaundice,poor temperature control, and umbilical hernia, large tongue, edema of eyes , hands and feet.

History History of present illness:

Onset/Age of onset

Fits ,Clumsiness or difficulty in gait

Deterioration of HMF

Ataxia or imbalance

Headache,Blindness,Vomiting, deafness

Change in personality and behaviour

Deteriorance in school performance

Increased startle response or hyperacusis

Birth history:

Term/preterm

Postnatal complications

Meningitis

Head trauma

kernicterus

Developmental history:

Detailed development history- decide whether there is delayed

development milestones or regression of milestones

Family history:

H/o of consanguinity

Family history of neurological disorder

Early or unexplained death

Nature of the neurological manifestations should be clarified

Classically , the loss of previously acquired

milestones(regression) marks the onset of most

Neurodegenerative brain disease with subsequent

progressive neurological deterioration

Clinical examination

General physical examination

Dysmorphism: Zellweger syndrome, Neonatal adrenal

leukodystrophy, coarse facial features(MPS)

OFC –microcepaly (gray matter disease)

Megaenchepaly – certain white mater disorder(Cannavan &

Alexander)

Jaundice

Enlarged tongue

Skin & hair ( Hartnup Diseases-pellagra like skin rash, Menkes

disease-kinky hair)

Examination of the spine- for associated complications (scoliosis)

Contractures of joints

Systemic examination:

Hepatosplenomegaly

Chest deformity

Cardiomyopathy

Neurological examination Higher mental function, signs of raised ICP

Speech, memory

Cranial nerves

Gait

Motor system:

Tone-hypo/ hypertonia,Deep tendon reflexes

Motor spasticity

Sensory loss /neuropathy

Abnormal /involuntary movements

Eye examination Optic atrophy(white matter- due to demyelination)

Retinal degeneration(gray matter)- as the retinal

receptors are neuronal cells): Cherry red spot, retinitis

pigmentosa

Cataracts

Telengiectasias

K.F ring

DECIDE REGRESSION AND NOT DELAY

AGE ABOVE 2 YEARS OR LESS THAN 2 YEARS

VISCEROMEGALY

NEUROPATHY

GRAY OR WHITE MATTER DISEASE

Investigations- to identify the underlying diagnosis

& examining the associated complications

Complete Blood picture-pancytopenia, vacuolated

lymphocytes,acanthocytes

ABGs-metabolic acidosis(organic acidopathies, urea cycle

defects, mitochondrial encephalopathies)

S/E (Anion gap), for adrenal

insufficiency(adrenoleukodystrophy)

Ammonia level,LFTs,RFTs

Special tests:

Lactate & pyruvate levels, Lysosomal enzyme level

WBCs, Fibroblast enzyme level

Wilson’s disease-serum ceruloplasmin level, serum copper

Amino acids

Urinary organic acids

Uric acid level

Urine

Reducing substances, Organic acids,24 hr (MPS)

Imaging

Skull & Vertebrae, Long bones

CT/MRI

Biopsy

Skin, Bone marrow, nerve, brain

ROLE OF MRI The abnormalities of metabolic disease are

characteristically bilateral and symmetrical.

Assessment on mri should include analysis of grey and white matter structures.

Calcification is much better assessed on ct.

Inherited hypomyelination (pelizaeus merzbacher)

Pathognomonic imaging patterns are seen in

X-linked adrenoleukodystrophy (ALD),

Alexander's disease

Neonatal maple syrup urine disease

Respiratory chain tend to be multisystem diseases.

In the brain they may result in multiple cerebral infarcts in nonvascular territories.

Leigh's disease : Bilateral typically symmetrical signal change is seen within the brainstem, deep cerebellargrey matter, subthalamic nuclei and basal ganglia

Dystosis multplexElongated (J-

shaped) sella. The vault shows an overall ground-

glass opacity

The ribs are broad, and the clavicles short and broad

Inferior hook (arrowhead) on the body of L2

with a mild kyphosis.

Bilateral hip subluxation with

long femoral necks and coxa

valga

proximal pointing of the second to fifth

metacarpals

Diagnosis

Important for genetic counseling

Outcome

Invariably fatal

Management

Directed towards the treatment of the underlying

disorder, other associated features and complications

Supportive :The treatable complications :

feeding difficulties, Gastoresophageal reflux

spasticity, drooling

skeletal deformities, and recurrent chest infections

epilepsy, sleep disorder, behavioral symptoms

A multidisciplinary approach(pediatrics, neurology, genetics, orthopedics, physiotherapy, and occupational therapy.

Specific treatmentNeurodegenerativedisorders

Specific treatment modality

Krabbe leukodystrophy Bone marrow transplantation

Metachromatic leukodystrophy

Bone marrow transplantation

Adrenoleukodystrophy Glyceryl trioleate and trierucate,steroids for adrenal insufficiency, diet low in VLCFA, bone marrowtransplantation

Mucopolysaccharidosis Bone marrow transplantation,recombinant human α-L-iduronidase

Menkes kinky hair syndrome Copper sulfate

Counseling the families and educating the public about these

potentially preventable disorders is very important.

Neurodegenerative

disorders

Specific treatment modality

Mitochondrial encephalopathies Nicotinamide, riboflavin,

dichloroacetate, L-carnitine, CoQ10

Wilson disease D- penicillamine, trietine, zinc acetate,

liver transplantation

Refsum disease Reduction of phytanic acid intake

Lesch-Nyhan disease Allopurinol

Fabry’s Disease Recombinant human α galactosidase A