Approach to neurodegenerative disorders new praman

1. Approach to
Neurodegenerative
Disorders
By
Dr Praman Kushwah
Guide : Dr Pradeep Pazare

2. Scenario 1
• 7-year-old boy presented with inability to hold
materials, and coarse skin since age of 5 years . The
patient was apparently well until about 5 years ago
when he was noticed not to be able to hold materials
due to stiffening of the wrist fold. He was also unable
to express “self needs” (toilet needs). There was also
the problem of talking incoherently and other
problems such as protrusion of abdomen and short
stature.

3. Scenario 2
A 6½ year child was brought to ER with complaints of seizures
,impaired vision ,hearing and behavioral changes of 1 month
duration. Hx of consanguinity positive. Birth history uneventful
.Patient neonatal period and developmental milestones normal.
He was apparently of normal health a few months back when he
developed hyper pigmentation of lips, buccal mucosa and nails,
and body associated with vomiting.
Now child has presented with right focal fits, becoming
generalized and deterioration of previously normal functions of
hearing ,vision and intelligence.

4. Learning Objectives
1. Familiarization with broad classification of
neurodegenerative disease
2. To be able to approach a child with a
neurodegenerative process
3. Familiarize with common prototypes of each
broad group.
4. Various investigations
5. Management

5. Definition
Neurodegenerative disease is regression
and progressive deterioration of neurologic
function with loss of speech, vision, hearing ,
or locomotion , often associated with seizures,
feeding difficulties, and impairment of
intellect .

6. • 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

8. • The age of onset, rate of progression, and
principal neurologic findings determine
whether the disease affects primarily the
white or the gray matter.

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 exaggerated(long tracts) or
Absent(neuropathy)
Normal or exaggerated in
late stage

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= electromyography ,
VEP = visual evoked potential , ABR = auditory brain stem response,
ERG= electro-retino-gram

12. Appearance of
Signs
White matter Gray matter
Early 1. Spasticity
2. Optic atrophy
3. Ataxia
4. Peripheral neuropathy
1. Intellectual deterioration
2. Seizures
3. Retinal involvement (Cherry
red spot/Retinitis
pigmentosa )
4. Extra-pyramidal
Late 1. Seizure
2. Intellectual deterioration
1. Spasticity
2. Babinski’s sign
To Remember

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

14. Gray matter
Cortical
Basal gangliaCerebellum
Non storage
storage
Without HSMWith HSM
1. GM1 Gangliosides
2. Sandholf disease (GM2)
3. Niemann pick Disease
4. Sialidosis
5. MPS
6. Gaucher disease
1. Tay Sach disease (GM2)
2. Rett Syndrome
3. Neuronal ceroid lipofuscinosis
4. Menke’s kinky hair disease
acquired genetic
1. SSPE
2. HIV
3. Progressive Rubella
Encephalopathy
1. Leigh
2. Menke’s
Friedrich’s Ataxia
Ataxia Telangiectasia
1. Wilson's disease
2. Dystonia muscular Deformans
3. Huntington’s Disease

15. White matter
DemyelinatingHypomyelinating / Dysmyelinating
1. Multiple sclerosis
2. Schilder’s disease
3. Devic disease
MicrocephalyNormal size headMacrocephaly
Leukodystrophies
1. Metachromatic
leukodystrophy
2. Adrenoleukodystrophy
1. Alexander disease
2. Cannavan disease
1. Krabbe disease

16. Approach
~ The most important component of diagnostic
approach continues to be a thorough history and physical
examination.

17. • Step 1: Is to decide whether it is a
Neurodegenrative disorder?

18. Clues to suspect
1. Positive family history
2. Parental consanguinity
3. Affection of CNS with PNS
4. Presence of neurocutaneous stigmata
5. Dysmorphic features
6. Unusual smell to urine and skin
7. Skeletal abnormalities

19. Rule out other treatable condition
• Inflammatory conditions – presence of fever
• Tumors – Associated with raised ICP
• Vascular – Lesion has an arterial territory
involvement
• Endocrinal condition – e.g. hypothyroidism
developing myopathy

20. History
 History of present illness:
1. Onset/Age of onset
2. Any precipitating factor
3. Course – progressive / static / improving
4. Fits ,Clumsiness or difficulty in gait
5. Deterioration of Higher Motor Functions
6. Ataxia or imbalance
7. Headache , Blindness , Vomiting , deafness
8. Change in personality and behaviour
9. Deterioration in school performance
10. Increased startle response or hyperacusis

21. Below 2 years:
Failure to thrive, seizures, and inability to sit and stand at
1 year and to speak in short sentences at 2 years.
School-aged child:
Regresses in language skills and withdraws socially.
Older children and adolescents:
Gait difficulties and loss of vision and intellectual abilities.

22. Prenatal and Perinatal histories:
They help determine whether the disorder is congenital or
whether it began at some later time.
Development Hx:
Feeding, sleep, motor milestones, expressive and receptive
language, behavior, social attainments.
Family History:
Tells mode of inheritance, previous affected siblings, even
when the diagnosis seems to be unrelated such as neonatal
sepsis, sudden infant death.

23. Physical examination

24. Head
Macrocephaly Microcephaly
1. Tay sachs disease
2. Alexander
3. Canavan’s disease
4. Sandhoff’s disease
5. Glutaricaciduria type I
6. MPS
7. MLSC
1. Krabbes disease
2. Neuronal ceroid lipofuscinosis
3. Rett syndrome

26. Facial Dysmorphism
1. Mucopolysaccharidosis
2. Zellwegwer syndrome
3. Menke’s disease
4. GM1 gangliosidosis

27. Hair Abnormalities
1. Biotinidase deficiency
(hair loss)
2. Cockayne’s syndrome
(aging process including
grey hair)
3. Menkes syndrome
(fine silvery wiry hair)
4. Mucopolysaccharidoses
(coarse hair)

28. Skin
• Persistant large mongolian spots
1. GM1 Gangliosidosis
2. MPS
3. Nieman Pick
• Hyperpigmentation
1. Adrenoleukodystrophy

29. •Angiokeratomas
1. Fabry ‘s

30. •Cornea
1. MPS
2. Wilson disease
Eyes

31. •Retinitis Pigmentosa
1. Mitochondrial
Encephalomyopathies
2. Neuronal ceroid lipofuscinosis
3. Peroxisomal disorder
4. MPS
5. Pantothenate kinase asso.
neurodegeneration
6. Abetalipoproteinemia
Eyes

32. 1. GM1 gangliosidosis
2. Niemann-Pick disease,
3. Tay-Sachs
•Cherry-Red Spot

33. Cataract
1. Galactosemia
2. Zellweger
3. Wilson

34. • Optic Atrophy
1. Metachromatic leukodystrophy
2. Krabbe
3. Canavan
4. GM2 Gangliosidosis juvenile type

35. Ears
• Exaggerated startle response
1. Tay- Sachs disease
2. Krabbe’ s disease
• Hearing Loss
1. MPS
2. ALD
3. Mitochondrial disorders

36. • Hepatosplenomegaly
1. MPS
2. GM1 gangliosidosis
3. Gaucher
4. Niemann-Pick

37. • Hernia
1. MPS
2. GM1
gangiosidoses

38. Step 2: Whether degeneration has involved
gray matter or white matter?

39. Appearance of
Signs
White matter Gray matter
Early 1. Spasticity
2. Optic atrophy
3. Ataxia
4. Peripheral neuropathy
1. Intellectual deterioration
2. Seizures
3. Retinal involvement (Cherry
red spot/Retinitis
pigmentosa )
4. Extra-pyramidal
Late 1. Seizure
2. Intellectual deterioration
1. Spasticity
2. Babinski’s sign
EEG 1. Late Abnormality 1. Early Abnormality
MRI 1. Demylenating 1. Cortical atrophy

40. Step3:consider common D/D based on age
of onset and presence or absence of
certain physical findings.
Screen for remendiable process
1.Rule out hydrocephalus
2.Rule out Hypothyriodism

41. • Divide the babies according to age.
• Look for organomegaly.

43. Regression in a child below two years
• The infant lacks visual interest or socialization
• has poor head control and inability to use
hands
• developmental retardation
• severe hypotonia especially with feeding
difficulties and/or vomiting
• failure to thrive

45. < 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
Taysachdisease/
Niemann PD/
Gaucher D

46. Typical facies
MPS Zellweger syndrome
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 .

47. MPS

48. 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
Increased tone,
strabismus, . failure to
thrive and stridor caused
by laryngospasm are
typical
Neimann–pick disease Tay-sachs disease Gaucher disease
Gucher cell ,
glucocerebrosida
e
Vacuolated
histocytes,
sphingomyelinase
CRS,
hexoseaminidase

50. Algorithm for the differential diagnosis of leukodystrophies with onset in the first year of life.
MRS, magnetic resonance spectroscopy; NAA, N-acetyl aspartate; MLC, megalencephalic
leukoencephalopathy with subcortical cysts; PLP22, proteolipid protein 22; PMD, Pelizaeus-
Merzbacher disease.

51. Algorithm for the differential diagnosis of leukodystrophies in childhood with onset
after the first year of life

52. < 2 yr without hepatomegaly
RETT syndrome : girls
with deceleration of
head growth , loss of
hand skills and hand
wringing , impaired
language skills , gait
apraxia.
Canavan disease:
white matter disease
with macrocephaly
Phenylketonuria :
light pigmentation ,
eczema , seizures
Maple syrup urine
disease : poor
feeding , tremors ,
myoclonus and
opisthotonus .
Menky kinky hair
disease: hypertonia ,
irritability and seizures
, abnormal hair .
KRABBE disease:
irritability , extensor
posturing , optic
atrophy and
blindness .

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

54. 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

55. 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.

56. 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

57. MLD
• child initially appears awkward and frequently
falls
• Within the next several months, the child can
no longer stand, and deterioration in
intellectual function becomes apparent
• child appears dull and apathetic
• Within 1 yr from the onset of the disease, the
child is unable to sit unsupported, and
progressive decorticate postures develop

59. • White matter disease  Metachromatic leukodystrophy
• Myoclonus with myoclonic
epilepsy,ataxia,ragged red fibres in
muscle (grey matter disease)
 MERRF
• Ataxia, dysarthria , involuntary
movements/infections/cancer.
(basal ganglia disease)
 Ataxia telengiectasia.
• Chorea (basal ganglia disease)  Huntington disease
• Liver disease, kayser feisher ring,
deterioration of cognition is late
 Wilson disease
• White matter, behaviour problems
, deteriorating school
performance , quadriperesis
 Adrenoleukodystrophy

60. 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

62. ADRENOLEUCODYSTROPHY
• caused by accumulation of very long
chain fatty acids in neural tissue and
adrenals due to mutations in the ABCD1
gene
• Generalized seizures are common in the
early stages
• Upper motor neuron signs include
spastic quadriparesis and contractures,
ataxia, and marked swallowing
disturbances
• adrenal insufficiency characterized by
abnormal skin pigmentation
• CT scans and MRI studies of patients
indicate periventricular demyelination

63. Ataxia-telangiectasia
• Most common of the degenerative ataxias
• Ataxia beginning at about age 2 yr and
progressing to loss of ambulation by
adolescence
• Mutations in the ATM gene located at
11q22-q23.
• Oculomotor apraxia of horizontal gaze
• May present with chorea rather than ataxia
• Telangiectasia becomes evident by mid-
childhood and is found on the bulbar
conjunctiva, over the bridge of the nose,
and on the ears
• Abnormalities of immunologic function
that lead to frequent sinopulmonary
infections

64. Pantothenate kinase associated
neurodegeneration
• Formerly Hallervorden-spatz syndrome
• Chorea, dystonia, parkinsonian features, pyramidal tract
features; MR abnormalities with decreased T2 signal in the
globus pallidus and substantia nigra, “eye of the tiger” sign;
sometimes acanthocytosis.

65. Acquired causes

66. 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.

67. 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.

68. Investigations
1. Imaging:
2. Radiographs:
3. Urine and blood assay for plasma ammonia, blood lactate and pyruvate,
plasma amino acids:
4. Specific investigations are done based on clues obtained from preceding
investigations

69. 1. Serology: HIV, SSPE
2. Urine copper, serum ceruloplasmin: Wilson disease
3. Urine MPS: mucopolysaccharidosis
4. Enzyme analysis: lysosomal storage disorders,
biotinidase deficiency
5. Urine organic acids: organic acidemias
6. Very long-chain fatty acids (VLCFA) and plasmalogen
levels: peroxisomal disorders
7. Mutation testing: this can be undertaken if the
diagnosis is quite certain and the test is available

70. 5. Electrophysiological test
6. Histopathological and ultrastructural information from
selected biopsies
1. Bone marrow: storage cells are seen in Niemann-Pick disease,
Gaucher disease
2. Conjunctival, skin, rectal biopsy: Neuronal ceroid lipofuscinosis
3. Hair microscopy: Menkes Disease

72. Management
• Firstly, never miss out a treatable cause of
neuroregression like hydrocephalus, HIV
infection, hypothyroidism, lead toxicity, etc. It
must be remembered that many NDD are
amenable to treatment

73. •Supportive Measures
It is never wise or correct to say that the disease is
“untreatable”.
Something can almost always be done to help the child.
Supportive treatment may add significantly to the quality of life
of a child with neurodegenerative disorder.
Measures to reduce spasticity, control seizures, control pain,
improve nutrition, prevent constipation, prevent bed sores, and
to enhance mobility, all contribute to the quality of life of the
patient and indirectly to the quality of life of the parents and any
unaffected siblings

74. • 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

76. Prognosis
• The prognosis in NDD depends on the underlying disorder. In general an
earlier onset of disease predicts a poorer outcome. However, several late
onset diseases can also rapidly progress, e.g. adrenoleukodystrophy ages
•
• Always keep the treatable causes in mind and exclude them systematically,
based on the clinical presentation.
• While managing these children, always focus on issues, which make the
child’s life comfortable, e.g. control seizures, spasticity, adequate nutrition
and skin care, etc.

77. • Prenatal diagnosis is available by
determination of enzyme activity and/or the
specific family mutations in chorionic villi or
cultured amniotic fluid cells

78. Scenario 1
• 7-year-old boy presented with inability to hold materials, and
coarse skin, 5 years ago. The patient was apparently well until
about 5 years ago when he was noticed not to be able to hold
materials due to stiffening of the wrist fold. He was also unable to
express “self needs” (toilet needs). There was also the problem of
talking incoherently and other problems such as protrusion of
abdomen and short stature.
• He was born of an uneventful pregnancy. No significant
antenatal,natal and postnatal risk factors and developmental
history unremarkable.

79. On examination
• Occipito-frontal circumference of 59 cm (macrocephaly).
• Coarse skin, coarse facies frontal bossing, Capud quadratum, widely
spaced teeth. Thick skin.
• Claw and shortened fingers (bradydactyly) with painless nodules.
• Mildly pale, anicteric and acyanosed.
• Distended abdomen, and liver was 12cm bcm, With tip of spleen
palpable.
• Other findings showed pectus carinatum and transmitted breath sound
with no cardiovascular anomaly.

80. Clawed and short fingers,
with nodules on the wrist
Disproportionate short trunk
and thick skin

82. • Gait was noted to be clumsy and stiff. Range of motion in all
extremities was limited, and the arms and legs were slightly flexed.
Investigations revealed the following:
• Full blood count (FBC) and Serum electrolyte, urea and creatinine
were within normal range for age.
• Blood film : Anisopoikilocytosis, microcytosis, hypochromia with
pencil cells (showing iron deficiency).
• Urate: creatinine ratio – 0.48 (0.27–0.91)
• Urinary mucopolysaccharide – 12.1 mg (0.0–12.9 mg)

83. Scenario 2
A 6½ year child was brought to ER with complaints of seizures ,impaired
vision ,hearing and behavioral changes of 1 month duration. Hx of
consanguinity positive. Birth history uneventful .Patient neonatal period and
developmental milestones normal.
He was apparently of normal health a few months back when he developed
hyper pigmentation of lips, buccal mucosa and nails, and body associated
with vomiting.
Now child has presented with right focal fits, becoming generalized and
deterioration of previously normal functions of hearing ,vision and
intelligence.

84. General examination revealed an alert, normally nourished boy, with diffuse
hyper pigmentation more marked over lips ,toe and finger nails. He was
groping for objects while walking implying impaired vision. He talked
irrelevantly at times and laughed unprovoked.
His CVS, RESP and abdominal examination was unremarkable.
Power and Tone in all muscles and sensory examination was normal.
Fundoscopy normal.
Visual acuity testing revealed right homonymous hemianopia.
Ct scan brain showed hypodense areas over parieto-occipital areas consistent
with cerebral white matter degeneration.

85. What is the diagnosis?
• Adrenoleukodystrophy
• Peroxisomal disease and biochemically characterized by the
accumulation of very long chain saturated fatty acids (VLCFA)
What is the treatment?
• Only supportive rx

86. Brain MRI of an 8-year-old boy who
developed declining school
performance, clumsiness, and
visual impairment at age 5 years.
His symptoms became
progressively worse over time .
Physical exam showed cognitive
impairment and hyperreflexia .
Plasma levels of very-longchain
fatty acids were increased,
confirming a diagnosis of ??

87. a 6-month-old girl with poor head
control, hypotonia, and macrocephaly.
Axial T2- weighted image (A) shows
hyperintense signal in all of the white
matter. MRS reveals a markedly
elevated N-acetyl aspartate peak (white
arrow) consistent with -??
Canavan disease

88. a 2-month-old girl who presented with
irritability and developmental arrest.
Cerebrospinal fluid protein was markedly
elevated at 216 mg/dL. CT shows
symmetric hyperdensities in the bilateral
lateral thalami, putamen, and adjacent
white matter. MRI shows hypointense
signal in the corresponding regions
(arrows). Galactocerebrosidase enzyme
activity was undetectable --??
Krabbe

89. a 2-year-old girl who initially had normal
development but did not achieve
walking. Examination showed absent
reflexes, and nerve conduction studies
were consistent with a generalized
polyneuropathy. Urine sulfatides were
elevated and arylsulfatase A activity was
low, consistent with --??
late-infantile MLD

90. Take home message
1. A precise history confirms regression of developmental milestones, and
neurological examination localizes processes within nervous system.
2. Outcome of a neurodegenerative condition is usually fatal and available
therapies are often limited in effect.
3. It is important to make correct diagnosis so that Genetic Counseling may
be offered and Prevention Strategies can be implemented.
4. Onset of inherited disease can occur at any age.
5. BMT and other novel therapies may prevent the progression of disease
in certain presymptomatic individuals.

91. References
• Nelson textbook of Pediatrics 20th edition
• Fenichel Pediatric Neurology
• Recent advances in pediatrics
• Training Module for Childhood neurological diseases AIIMS
New Delhi
• Clinical approach to children with suspected
neurodegenerative disorders - Neurosciences 2002; Vol. 7 (1):
2-6

92. Thank You