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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 ...
 Neuroregressive /neurodegenerative disorders are a
group of heterogeneous diseases which results from
specific genetic, ...
 Dementia, used for neurodevelopmental regression in
children, is associated with loss of memory, ability to
think, under...
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 ve...
 Major component of the CNS having a grey –brown color(due
to capillary blood vessels & neurinal cell bodies)
 Consists ...
 The grey matter includes regions of the brain involved in
 muscle control,
 sensory perception such as seeing and hear...
Gray matter Disease White matter Disease
Processing center Represents networking between these
centers
Primarily involve n...
Differentiating
features
White matter
disorders
Gray matter
disorders
Age of onset Usually late(childhood) Usually early(i...
Differentiating
features
White matter
disorders
Gray matter
disorders
Cerebellar signs Early,prominent late
Fundal examina...
 Gray matter: fits, decrease HMF
 EEG: early abnormality
 MRI Brain: cortical atrophy
 White matter: blindness ,Gait d...
 Basal Ganglia :Dystonia,Involantary movements
 Spinocerebellar degeneration: Ataxia
Classification of neurodegenerative
brain disease
Inherited Acquired
Focal
manifestations
Both
White
matter
Gray matter
Me...
Acquired causes
 Infections
 SSPE
 Progressive Rubella
Syndrome
 Chronic HIV
 Metabolic
 Chronic lead poisoning
 Hy...
Inherited causes
 Gray matter involvement:seizure,dementia, visual loss, intellectual
impairment. Spike & sharp waves in ...
 B. Gray matter diseases involvement without visceromegaly
 Rett Syndrome
 Neuronal curoid lipofuscinosis
 Menke’s kin...
 Spasticity , optic atrophy, ataxia ,peripheral neuropathy .Seizure , dementia
are the late manifestations. Slow waves in...
 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 At...
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
hypoglycemia
and lactic
acidosis/
ci...
Typical facies
MPS Zellweger syndrome
Diagnosis is usually made between 6
and 24 mo of age with evidence of
hepatosplenome...
Difficulty in feeding, FTT,
Cherry red spot,
hypotonia, death by 3yr
• loss of motor skills,
increased startle
reaction, c...
< 2 yr without hepatomegaly
KRABBE DISEASE
• The infantile form of Krabbe disease is rapidly
progressive and patients present in early infancy with
ir...
RETT SYNDROME
• Development normal until 1 yr of age, when regression of
language and motor milestones and acquired microc...
MAPLE SYRUP URINE DISEASE
• This form has the most severe clinical manifestations.
Affected infants who are normal at birt...
PHENYLKETONURIA
• The affected infant is normal at birth.
• Mental retardation may develop gradually and may
not be eviden...
2-5 years
Myoclonus,
Myoclonic epilepsy,
Ataxia,
Raggaed red fibre in
muscle
hypotonic extremit
absent deep
tendon reflexe...
Acquired causes
SSPE
The initial clinical manifestations include personality changes, aggressive
behavior, and impaired cognitive function...
Chronic HIV
Onset: 2 month t0 five yr after exosure.
Progressive loss of developmental milestones , microcephaly, dementia...
History
 History of present illness:
 Onset/Age of onset
 Fits ,Clumsiness or difficulty in gait
 Deterioration of HMF...
 Birth history:
 Term/preterm
 Postnatal complications
 Meningitis
 Head trauma
 kernicterus
 Developmental history:
 Detailed development history- decide whether there is delayed
development milestones or regress...
 Classically , the loss of previously acquired
milestones(regression) marks the onset of most
Neurodegenerative brain dis...
Clinical examination
 General physical examination
 Dysmorphism: Zellweger syndrome, Neonatal adrenal
leukodystrophy, co...
 Skin & hair ( Hartnup Diseases-pellagra like skin rash, Menkes
disease-kinky hair)
 Examination of the spine- for assoc...
Neurological examination
 Higher mental function, signs of raised ICP
 Speech, memory
 Cranial nerves
 Gait
 Motor sy...
Eye examination
 Optic atrophy(white matter- due to demyelination)
 Retinal degeneration(gray matter)- as the retinal
re...
DECIDE
 REGRESSION AND NOT DELAY
 AGE ABOVE 2 YEARS OR LESS THAN 2 YEARS
 VISCEROMEGALY
 NEUROPATHY
 GRAY OR WHITE MA...
Investigations- to identify the underlying diagnosis
& examining the associated complications
 Complete Blood picture-pan...
 Special tests:
 Lactate & pyruvate levels, Lysosomal enzyme level
 WBCs, Fibroblast enzyme level
 Wilson’s disease-se...
 Urine
 Reducing substances, Organic acids,24 hr (MPS)
 Imaging
 Skull & Vertebrae, Long bones
 CT/MRI
 Biopsy
 Ski...
ROLE OF MRI
 The abnormalities of metabolic disease are
characteristically bilateral and symmetrical.
 Assessment on mri...
 Pathognomonic imaging patterns are seen in
 X-linked adrenoleukodystrophy (ALD),
 Alexander's disease
 Neonatal maple...
 Respiratory chain tend to be multisystem diseases.
 In the brain they may result in multiple cerebral
infarcts in nonva...
Dystosis multplex
Elongated (J-
shaped) sella. The
vault shows an
overall ground-
glass opacity
The ribs are broad,
and th...
Inferior hook
(arrowhead) on
the body of L2
with a mild
kyphosis.
Bilateral hip
subluxation with
long femoral
necks and co...
 Diagnosis
 Important for genetic counseling
 Outcome
 Invariably fatal
Management
 Directed towards the treatment of the underlying
disorder, other associated features and complications
 Supp...
Specific treatment
Neurodegenerative
disorders
Specific treatment modality
Krabbe leukodystrophy Bone marrow transplantati...
Counseling the families and educating the public about these
potentially preventable disorders is very important.
Neurodeg...
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
NEURODEGENERATIVE DISORDER OF CHILDHOOD
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NEURODEGENERATIVE DISORDER OF CHILDHOOD

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neurodegenerative disease in children

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NEURODEGENERATIVE DISORDER OF CHILDHOOD

  1. 1. Moderator : Dr. D. Devi , Asso prof, Dept of paediatrics, SMCH Presented by: Dr. Samiul Ahsan Hussain PGT, Paediatrics
  2. 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. 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. 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. 5. Gray matter & White matter Striations seen in white mater
  6. 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. 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. 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. 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. 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. 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. 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. 13.  Basal Ganglia :Dystonia,Involantary movements  Spinocerebellar degeneration: Ataxia
  14. 14. Classification of neurodegenerative brain disease Inherited Acquired Focal manifestations Both White matter Gray matter Metabolic Infections
  15. 15. Acquired causes  Infections  SSPE  Progressive Rubella Syndrome  Chronic HIV  Metabolic  Chronic lead poisoning  Hypothyroidism  Vit B12 & E deficiency  Drugs (anticonvulsant)
  16. 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. 17.  B. Gray matter diseases involvement without visceromegaly  Rett Syndrome  Neuronal curoid lipofuscinosis  Menke’s kinky hair disease
  18. 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. 19.  B. Acquired causes/ Demyelinating  Multiple sclerosis  Schilder’s disease  Devic disease
  20. 20.  Basal Ganglia  Wilson's disease  Dystonia muscular Deformans  Huntington’s Disease  Spinocerebellar  Friedrich’s Ataxia  Ataxia Telangiectasia
  21. 21. Classification according to age
  22. 22. An approach to a child with regression of milestones
  23. 23.  Divide the babies according to age.  Look for organomegaly.
  24. 24. <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
  25. 25. 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
  26. 26. 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
  27. 27. < 2 yr without hepatomegaly
  28. 28. 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
  29. 29. 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
  30. 30. 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.
  31. 31. 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
  32. 32. 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
  33. 33. Acquired causes
  34. 34. 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.
  35. 35. 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.
  36. 36. 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
  37. 37.  Birth history:  Term/preterm  Postnatal complications  Meningitis  Head trauma  kernicterus
  38. 38.  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
  39. 39.  Classically , the loss of previously acquired milestones(regression) marks the onset of most Neurodegenerative brain disease with subsequent progressive neurological deterioration
  40. 40. 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
  41. 41.  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
  42. 42. 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
  43. 43. 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
  44. 44. DECIDE  REGRESSION AND NOT DELAY  AGE ABOVE 2 YEARS OR LESS THAN 2 YEARS  VISCEROMEGALY  NEUROPATHY  GRAY OR WHITE MATTER DISEASE
  45. 45. 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
  46. 46.  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
  47. 47.  Urine  Reducing substances, Organic acids,24 hr (MPS)  Imaging  Skull & Vertebrae, Long bones  CT/MRI  Biopsy  Skin, Bone marrow, nerve, brain
  48. 48. 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 )
  49. 49.  Pathognomonic imaging patterns are seen in  X-linked adrenoleukodystrophy (ALD),  Alexander's disease  Neonatal maple syrup urine disease
  50. 50.  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
  51. 51. Dystosis multplex Elongated (J- shaped) sella. The vault shows an overall ground- glass opacity The ribs are broad, and the clavicles short and broad
  52. 52. 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
  53. 53.  Diagnosis  Important for genetic counseling  Outcome  Invariably fatal
  54. 54. 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.
  55. 55. 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
  56. 56. 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

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