differential diagnosis of cerebral palsy

1. MIMICS OF CEREBRAL PALSY
D Kalpana
Sr. Consultant Pediatric Neurologist
KIMSHEALTH hospitals, Trivandrum

2. WHAT IS CEREBRAL
PALSY
• disorders of movement and
posture,
• causing activity limitation
• Due to non-progressive
disturbances that occurred
in the developing fetal or
infant brain.
• often accompanied by
disturbances of sensation,
cognition, communication,
perception, and/or by a
seizure disorder
Rosenbaum 2005

3. CP is not a clinical diagnosis
No common pathology or aetiology
Even when there is antecedent cause like prematurity or
perinatal asphyxia, it can have a metabolic or genetic cause
cause
All children with a diagnosis of cerebral palsy should be
investigated and followed up.
• A specific diagnosis identifies treatable causes early.
• Helps in prognostication
• Aids in genetic counselling
• Can be included in the emerging genetic treatment trials
• AVOID LITIGATION REGARDING NEGLIGENCE IN
MANAGEMENT.
R Gupta and R E Appleton;Cerebral palsy:not always what it seems Arch Dis Childhood 2001

4. Carr and Cogil:Mimics of cerebral palsy: Pediatrics and Child health 2016
RED FLAGS IN THE DIAGNOSIS OF
CEREBRAL PALSY
• History and examination
– No risk factors for CP
– Positive family history or consanguinity
– History of developmental regression after normal
attainment of early motor milestones, such as independent
sitting and walking
– Dysmorphic features
– Fluctuating neurologic signs
– Episodic decompensation
– Dyskinetic or ataxic cerebral palsy
– Persisting hypotonia
– Eye movement abnormalities
– Neurocutaneous markers
– Organomegaly

5. RED FLAGS IN THE DIAGNOSIS OF
CEREBRAL PALSY cont….
• Imaging
– Normal neuroimaging
– Structural abnormalities
– Cerebellar atrophy
– Typical radiologic findings of metabolic disorder
• Glutaric aciduria
• Maple syrup urine disease
– If scan shows findings which are NOT concordant
with the clinical history

6. DEVELOPMENTAL REGRESSION
• one of the cardinal features of neurodegenerative or
metabolic disorders.-
• In many cases there will be a mild developmental delay
initially, and regression starts later only
• In severe CP or severe degenerative disease baby may
not attain any milestone
• In cerebral palsy also, transient regression occurs
– following severe infection
– with epileptic encephalopathy
– due to fixed contractures, dislocation of joints
• Definite regression in all the milestones is the key

7. DYSMORPHIC FEATURES
Angelman syndrome Fragile X syndrome

8. HEAD SIZE
• Microcephaly
– HIE
– Lissencephaly
– Schizencephaly
– Intrauterine infections
– Aicardi Goutiere syndrome
– Krabbe’s disease
– Rett syndrome
• Macrocephaly
– Alexander
– Canavan
– Storage diseases
– Vander Knapp disease

9. SKIN CHANGES
Icthyosis in Sjogren Larssen
syndrome
Seborrheic dermatitis in
botinidase deficiency

10. HYPOPIGMENTED SKIN AND HAIR
Hypopigmented skin and hair
Global developmental delay
Hypotonia with brisk reflexes
Seizures
Menkes disease

11. HYPOPIGMENTED SKIN AND
HAIR
Trichothiodystrophy

12. HYPOPIGMENTED SKIN AND
HAIR
Cataract
Myocardial dysfunction
Immunodeficiency
Hypotonia with retained DTR
Global developmental delay
Vici syndrome
homozygous mutations in the KIAA1632/mEPG51 gene

13. HYPERTRICHOSIS
20 month old with mild delay development, stagnation, ataxia,
tremor, hypertrichosis,MR brain involvement of brain stem and
subthalamic nucleus
Leigh syndrome due to SURF1 mutation

14. SELF MUTILATION
Child with dystonic cerebral palsy
h/o constant rubbing of lips with the
hand
Death of maternal uncle at 6 yrs of
age
s. Uric acid 12 mg%
Leisch Nyhan syndrome

15. EYE ABNORMALITIES
• Cataract – galactosemia, Aicardi Goutieres syndrome
• Telengiectasia – ataxia telangiectasia
• Retinitis pigmentosa – Refsum, SCA2 &7
• Pendular nystagmus- PMD
• Ophthalmoplegia – Leigh’s disease
• Oculogyric spasm – neurotransmitter diseases –
AADC, Infantile parkinsonism dystonia

16. PENDULAR NYSTAGMUS
American academy of neurology: teaching video
Pelizaeus Merzbacher disease

17. OPHTHALMOPLEGIA AND NYSTAGMUS
Leigh’s syndrome

18. FLUCTUATING SYMPTOMS
• Characteristic diurnal fluctuation is seen in dopa
responsive dystonia and other neurotransmitter
diseases
• GLUT1 deficiency manifests as seizures or
dystonia manifesting at the time of fasting. Even
EEG changes aggravate with fasting.
• Episodic decompensation in response to fever or
protein rich diet is characteristic of organic
aciduria, urea cycle defects etc
• Vanishing white matter disease shows
deterioration with fever or trauma

19. NEUROIMAGING
• Common imaging findings in CP due to perinatal asphyxia
– Periventricular leukomalacia
– Cystic encephalomalacia
– Intraventricular Hemorrhage(porencephalic cyst)
– Basal ganglia and thalamus injury (status marmoratus)
– Globus pallidus involvement in BIND
– Acute infarct (arterial or venous)
– Normal MRI in 10 %
• At least one imaging should be done in all cases of
cerebral pasy

20. NEUROIMAGING
• Genetic tests are indicated in
– Normal imaging
– Structural malformations
– Specific pattern in certain genetic/metabolic
conditions
• Glutaric aciduria – Bat’s wing appearance
• Maple syrup urine disease – myelin splitting edema
• Hypomyelination in PMD and related disorders
• Dilated and tortuous vessels in Menke’s disease
• Basal ganglia calcification and cysts – Aicardi Goutiere
syndrome

21. NORMAL NEUROIMAGING
• Occur in about 10% of cerebral palsy cases
• Think about
– Hereditary spastic paraplegia
– Neurotransmitter diseases
– Creatine deficiency disorders – MRS will reveal the
diagnosis

22. STRUCTURAL MALFORMATIONS

23. IMAGING
Aicardi Goutieres syndrome
Bilirubin induced neurological disease
Methyl malonic acidemia
Symmetrical Globus Pallidus T2
hyperintensity
CT head- symmetrical BG
calcification and cystic changes in
white matter

24. VAN DER KNAAPS DISEASE
• Siblings with large head
• Delay in development
• Progressive spasticity
• Ataxia
• Dysarthria
• Occasional seizures
Megalencephalic leukoencephalopathy with subcortical cysts

25. HYPOMYELINATION AND DYSMYELINATION
Hypomyeliination -
PMD
Dysmyelination
Symmetrical not involving U fibres – MLD
Symmetrical anteriorly dominant involving U
fibres – Alexanders disease

26. GLUTARIC ACIDURIA TYPE1
• Large head
• Hypotonia followed by
dystonia
• Episodic fluctuation
• Characteristic MRI brain
• Riboflavin
• Carnitine
• Protein restricted diet
BATS WING APPEARANCE

27. OTHER INVESTIGATIONS
• Investigations should be focused – to get the maximum yield
• Thrust should be for treatable/curable conditions
• Plan costly investigations after MRI – as we can get useful clues
• Metabolic testing –
– if there is family history
– History of recurrent encephalopathy
– Suggestive MRI findings
– Abnormal odour, failure to thrive, fast breathing.
(ABG, glucose, ammonia, lactate, pyruvate, urinary ketones, uric acid
Urine organic acids,TMS for aminoacid, organic acids, fatty acid oxidation
disorders)
• Thyroid function tests – T3, T4,TSH
• Enzyme assay
• Genetic tests

28. GENETIC TESTS
• In dysmorphism
– Karyotype
– FISH for specific deletions
– Chromosomal microarray
• Trinucleotide repeat sequencing – fragile X,SCA
• Clinical exome sequencing
• Whole exome sequencing
• Whole genome sequencing
Now a days genetic testing is having the highest yield
and is relatively cheaper

29. MIMICS OF SPASTIC CP
• Spinal dysraphism – Imaging of spine
• Hereditary spastic paraplegia- pure or complicated
• Arginase deficiency – s.ammonia
• Sjogren Larssen syndrome
• Biotinidase and multiple carboxylase deficiency –
seborrheic dermatitis and alopecia
• Leukodystrophy – Nerve conduction studies, imaging
genetics

30. HEREDITARY SPASTIC PARAPLEGIA
• Mild developmental delay with spasticity
• Spasticity may be noted by 2 or 3 years
• Very slowly progressive
• Pure type – spasticity severe than degree of weakness
– SPG 3a, SPG 4,SPG11(associated with thin corpus callosum)
• Complicated type – associated with seizures, dysarthria,
learning problems and peripheral neuropathy
• Regression, +/-neuropathy with normal MRI or with thin
corpus callosum
• Examine both parents for spasticity or hyperreflexia even
if asymptomatic

31. SJOGREN LARSSEN SYNDROME
• Often born preterm
• Spastic diplegia or quadriplegia
• MRI brain – bilateral periventricular T2
hyperintensity
• Ichthyosis over legs and flexures
• Macula crystallina
• Mutation in ALDH3A2 gene
Nagappa M, Bindu PS, Chiplunkar S, Gupta N, Sinha S, Mathuranath PS, et al. Child Neurology: Sjögren-
Larsson syndrome. Neurology. 2017 Jan 3;88(1):e1–4.

32. WITH PROMINENT DYSTONIA OR CHOREA
• DOPA responsive dystonia- CSF neurotransmitters
• Mitochondrial disease- serum/CSF lactate, MRS
• Lesch Nyhan- s. urate
• Glutaric aciduria – imaging, urine organic acids
• GLUT 1A deficiency – CSF glucose/s.glucose ratio
• Rett’s syndrome- MECP2 mutation
• Neurodegeneration with brain iron accumulation-
imaging
Genetic tests

33. NEUROTRANSMITTER DISEASES
• Lower limb spasticity
• Dystonia
• Diurnal fluctuation
• ? Trial of l- dopa in all
children with spasticity with
or without dystonia
• AD
• GTP cyclohydrolase
deficiency
• Tyrosine hydroxylase
deficiency
• Sepiapterin reductase
deficiency
– Dystonia
– Oculogyric crises
– Diurnal fluctuation
• Aromatic aminoacid
decarboxylase deficiency
• VMAT2(infantile dystonia
parkinsonism 2) –DOPA
agonist responsive
Dopa responsive dystonia (Segawa) Other Dopa responsive syndromes

34. ALLAN-HERNDON-DUDLEY SYNDROME
• 2 male children in the
family affected
• Prominent dystonia
• S TSH – low
• S.T4 – low
• S.T3 – very high
• No response to thyroxin
• Monocarboxylate
transporter 8 deficiency
• X linked recessive

35. OCULOGYRIC SPASM
Infantile dystonia parkinsonism type 2 VMAT 2 mutation

36. AUTOSOMAL RECESSIVE
METHHEMOGLOBINEMIA TYPE2

37. ATAXIA
• Angelmans – FISH, deletion/duplication/methylation
• Jouberts – imaging, associated findings
• Friedreich’s ataxia- trinucleotide repeat
• Ataxia telangiectasia – S.AFP,immunoglobulin
• Spinocerebellar ataxia – SCA 2&7- trinucleotide repeat
• Cockayne syndrome – photosensitivity, microcephaly
• Pelizaeus-Merzbacher disease –clinical, imaging
• Non-ketotoc hyperglycinaemia – CSF glycine
• Maple syrup urine disease –imaging, urine organic acids

38. TREATABLE CAUSES OF CEREBRAL PALSY
• Glut 1 deficiency – Ketogenic diet
• Biotinidase and holocarboxylase synthetase
deficiency – biotin
• Urea cycle defect – protein restricted diet, sodium benzoate,
phenyl acetate
• Methyl malonic academia – protein restriction, vitamin
B12
• Glutaric aciduria- riboflavin, carnitine, lysine restricted
diet
• Neurotransmitter disease – L Dopa and Dopa agonists

39. PRACTICE POINTS
• Be mindful of ‘Red Flags’ when reviewing a child with
CP.
• MRI scan changes can evolve over time, so imaging
should be repeated if the child shows unusual
progression of symptoms or signs.
• MRI scan features NOT concordant with the clinical
history think of another underlying condition.
• A trial of levodopa should still be considered in all
children presenting with dystonia, where causation is
not established.
Carr LJ, Coghill J, Mimics of cerebral palsy, Paediatrics and Child Health (2016)

40. HOW THE DIAGNOSIS IS MADE?
• Concentrate on atypical/unique findings in history, physical
examination and imaging.
• Do an extensive literature search
• Investigations should be focused.
• Careful follow up may reveal the nature of the disease.
• Accept mistakes and learn from mistakes
• Take each case as a challenge and get excited in getting the
correct diagnosis. Half hearted attempts are going to fail.
• Never miss treatable causes

41. The clinical diagnosis of cerebral palsy should
not be changed, whatever the cause.
The diagnosis of cerebral palsy makes the children eligible for all the
support services including financial support
Registry available in many countries.Monitoring of children becomes
easy
Many of these diseases are slowly progressive and need support
The International Cerebral Palsy Genomics Consortium 2018
Very few have a definitive treatment