neurodegenerative disease in children

1. Moderator : Dr. D. Devi ,
Asso prof, Dept of paediatrics, SMCH
Presented by: Dr. Samiul Ahsan Hussain
PGT, Paediatrics

2. 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.

3.  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

4.  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

5. Gray matter & White matter
Striations seen in white mater

6.  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

7.  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

8.  The grey matter includes regions of the brain involved in
 muscle control,
 sensory perception such as seeing and hearing,
memory, emotions, and speech.

9. 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

10. Differentiating
features
White matter
disorders
Gray matter
disorders
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

11. Differentiating
features
White matter
disorders
Gray matter
disorders
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=visual
evoked potential, ABR= auditory brain stem response,
ERG= electroretinogram

12.  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

13.  Basal Ganglia :Dystonia,Involantary movements
 Spinocerebellar degeneration: Ataxia

14. Classification of neurodegenerative
brain disease
Inherited Acquired
Focal
manifestations
Both
White
matter
Gray matter
Metabolic
Infections

15. Acquired causes
 Infections
 SSPE
 Progressive Rubella
Syndrome
 Chronic HIV
 Metabolic
 Chronic lead poisoning
 Hypothyroidism
 Vit B12 & E deficiency
 Drugs (anticonvulsant)

16. 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)

17.  B. Gray matter diseases involvement without visceromegaly
 Rett Syndrome
 Neuronal curoid lipofuscinosis
 Menke’s kinky hair disease

18.  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

19.  B. Acquired causes/ Demyelinating
 Multiple sclerosis
 Schilder’s disease
 Devic disease

20.  Basal Ganglia
 Wilson's disease
 Dystonia muscular
Deformans
 Huntington’s Disease
 Spinocerebellar
 Friedrich’s Ataxia
 Ataxia Telangiectasia

21. Classification according to age

25. An approach to a child with
regression of milestones

26.  Divide the babies according to age.
 Look for organomegaly.

27. <2 year with hepatomegaly
Jaundice, vomiting,
lethargy, irritability,
and convulsions
hypoglycemia
and lactic
acidosis/
cirrohosis
Typical facies OTHER
Fructose
intolerance
/Galactosemia
GSD TYPE 1 t0 4
MPS/
Zellweger
syndrome
TSD/
NPD/
GD Type 2
biochemglycogen
synthesikz6.jpg
vongierke-
glucose-
metabolism.jpg

28. Typical facies
MPS 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, pigmentary
retinopathy, and nerve dysplasia).
• More than 90% show postnatal
growth failure

29. 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

30. < 2 yr without hepatomegaly

31. 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

32. 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

33. 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.

34. 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

35. 2-5 years
Myoclonus,
Myoclonic epilepsy,
Ataxia,
Raggaed red fibre in
muscle
hypotonic extremit
absent deep
tendon reflexes,
Inability to walk
Ataxia/
Involuntary movements
/infections / cancer
Dysarthria
MERRF MLD AT

36. Acquired causes

37. 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.

38. Chronic HIV
Onset: 2 month t0 five yr after exosure.
Progressive loss of developmental milestones , microcephaly, dementia and
spastcity is characteristics
Hypothyrodism
Asymtomatic at birth
Wide open posterior frontanalare, constipation , jaundice,poor temperature
control, and umbilical hernia, large tongue, edema of eyes , hands and feet.

40. 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

41.  Birth history:
 Term/preterm
 Postnatal complications
 Meningitis
 Head trauma
 kernicterus

42.  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

43.  Classically , the loss of previously acquired
milestones(regression) marks the onset of most
Neurodegenerative brain disease with subsequent
progressive neurological deterioration

44. 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

45.  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

46. 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

47. 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

48. DECIDE
 REGRESSION AND NOT DELAY
 AGE ABOVE 2 YEARS OR LESS THAN 2 YEARS
 VISCEROMEGALY
 NEUROPATHY
 GRAY OR WHITE MATTER DISEASE

49. 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

50.  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

51.  Urine
 Reducing substances, Organic acids,24 hr (MPS)
 Imaging
 Skull & Vertebrae, Long bones
 CT/MRI
 Biopsy
 Skin, Bone marrow, nerve, brain

52. 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
)

54.  Pathognomonic imaging patterns are seen in
 X-linked adrenoleukodystrophy (ALD),
 Alexander's disease
 Neonatal maple syrup urine disease

59.  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 cerebellar
grey matter, subthalamic nuclei and basal ganglia

61. Dystosis multplex
Elongated (J-
shaped) sella. The
vault shows an
overall ground-
glass opacity
The ribs are broad,
and the clavicles
short and broad

62. 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

64.  Diagnosis
 Important for genetic counseling
 Outcome
 Invariably fatal

65. 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.

66. Specific treatment
Neurodegenerative
disorders
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
marrow
transplantation
Mucopolysaccharidosis Bone marrow transplantation,
recombinant human α-L-iduronidase
Menkes kinky hair syndrome Copper sulfate

67. 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