Dr. Monica Juneja*
Professor of Pediatrics, Maulana Azad Medical College.
Email: firstname.lastname@example.org *
Cerebral Palsy (CP) is an umbrella term that defines a group of non-progressive, but often changing, syndromes of motor impairment secondary to lesions and anomalies of developing brain. CP is neither a specific disease not a pathological or etiological entity. A suggestive gestational or perinatal history much increases the probability of cerebral palsy, but many metabolic conditions mimic asphyxia during the neonatal period and also many neurodegenerative or metabolic disorders have a slow rate of progression and can be misdiagnosed as cerebral palsy. Thus a child presenting after an unremarkable gestational and perinatal experience, especially during the second or subsequent years of life, presents a challenging diagnostic problem.
Among the disorders that mimic cerebral palsy are
neurodegenerative disorders and some other commonly seen disorders like recovering asphyxia. Most asphyxiated infants, whether they show fetal distress, low Apgar scores at one minute, or even early neonatal clinical changes, show no permanent effects on their development, although in their first few months there may be a delay and recovering neurological signs. Some of these have been labeled as CP. Transient dystonia mimicking spastic diplegia can be seen in some preterms who get labeled as CP but they become normal by 12-15 months of age. The diagnosis in these children can be made only retrospectively.
Transient dystonia mimicking spastic diplegia can be seen in some preterms who get labeled as CP but they become normal by 12-15 months of age.
Children who are Bottom Shufflers also my not walk till 2 to 2.5 of age. Some infants "just stand up" without using transitional modes of mobility; about one third of babies never crawl. Although these 'Normal Variations' can be associated with hypotonia and in rare cases may be adopted by infants with cerebral palsy, they are most frequently not associated with any permanent deficits. These normal variations can be differentiated by the absence of other questionable or abnormal signs.
Children with GDD (Global Developmental Delay) also have motor delay and hypotonia and are often initially diagnosed as CP. Erb's palsy has also been misdiagnosed as Cerebral Palsy on some occasions.
Apart from these causes which are relatively common, some neurodegenerative diseases may progress so slowly in the initial phases or lead to such severe damage at birth that they may be mistaken for a static encephalopathy. Although CP refers solely to the motor dysfunction in these children, other signs like seizures, mental retardation, blindness, and deafness are seen at greater frequency in children with CP as well as in children with neurodegenerative diseases, which explains why some patients with these disorders can be misdiagnosed as CP.
The most common type of CP exhibits hypertonia or spasticity, less common types of CP are choreoathetoid, and ataxic. The latter group of symptoms is associated with alternative disorders more often than with CP. Although most infants with CP may start with hypotonia in the neonatal period, eventually this is replaced with hypertonia in most patients. In children in whom the hypotonia persists, consideration of alternative explanations for this motor impairment should be undertaken.
The most common type of CP exhibits hypertonia or spasticity, less common types of CP are choreoathetoid, and ataxic.
The latter group of symptoms is associated with alternative disorders more often than with CP.
Table: Common Neurodegenerative Disorders and Neurometabolic Disorders
Which are Mimics of Cerebral Palsy:
- Conditions presenting with true muscle weakness, which is not seen in cerebral palsy although hypotonia and poor motor planning often give the impression of apparent weakness:
- Muscular dystrophies: Duchenne and Becker types
- Infantile neuro-axonal dystrophy
- Mitochondrial cytopathies
- Cerebral white matter diseases may present in the first year with hypotonia and developmental delay, with spasticity and metal retardation occurring later.
- Conditions with significant dystonia or involuntary movements:
- DOPA responsive dystonia
- Hallervordan Spatz Disease
- Pyruvate dehydrogenase deficiency
- Glutaric aciduria type I
- Leigh syndrome
- Juvenile neuronal ceroid lipofuscinosis
- Rett syndrome
- Pelizaeus-Merzbacher disease
- 3-methylcrotonyl Co-enzymeA carboxylase deficiency
- Lesch Nyhan Syndrome
- Conditions with predominant diplegia or quadriplegia:
- Arginase deficiency
- Metachromatic leukodystrophy
- Hereditary progressive spastic paraplegia
- Holocarboxylase synthetase deficiency
- Prenatal iodine deficiency ("neurological cretinism")
- Conditions with ataxia (Ataxic CP is Rare)
- Angelman syndrome
- Niemann-Pick disease type C
- Ataxia-telangiectasia (Louis-Barr syndrome)
- Ponto-cerebellar hypoplasia or atrophy
- Chronic/adult GM2 gangliosidosis
- Mitochondrial cytopathy (NARP mutation)
- Posterior fossa tumours
- X-linked spino-cerebellar ataxia
- Conditions with significant bulbar and oral-motor dysfunction:
Worster-Drought syndrome, also known as the bilateral Perisylvian or Opercular syndrome causes Pseudobulbar palsy and presents with swallowing difficulties and anarthria/severe dysarthria resulting from severe central disturbance of volitional control of the facio-linguo-glosso-pharyngeal masticatory. muscles with preserved emotional movements. It is often accompanied by spastic diplegia of variable severity, as well as learning disability, seizures and behavior problems. MRI shows B/L abnormal wide and deep sylvian fissure, exposure of insulae due to failure/absence of opercularisation of central sulcus, cortical dysplasias and polymicrogyria on T1 weighted sequence.
Conditions with apparent muscle weakness:
Profound Hypotonia seen in children with CP in first year of life is mistaken as weakness but children with CP don't have weakness and also they have exaggerated DTRs. Clonus in lower limbs and extensor plantars.
- Hypotonia and Brisk DTRs:
- Evolving CP
- Metachromatic Leukodystrophy
- Infantile NAD
- Ponto-cerebellar Atrophy
- Delayed Walking with Tiptoe gait:
- Duchenne's Muscular Dystrophy
- (Weakness, Normal/decreased DTRs, Increased CPK)
- Spastic Diplegia (Brisk Reflexes, Clonus, Extensor Plantars)
- Mitochondrial Myopathies
- (Multi-system involvement, ? Family history, Increased serum Lactate and pyruvate).
Profound Hypotonia seen in children with CP in first year of life is mistaken as weakness but children with CP don't have weakness and also they have exaggerated DTRs.
Conditions with significant dystonia or involuntary movements:
Dystonia and choreoathetosis are not very common in CP, typically occurring following a short but profound period of hypotension and hypoxia in the perinatal period.
DOPA responsive Dystonia: It mimics Athetoid or Dyskinetic CP. Dystonia, usually affects the legs which may worsen throughout the day and occurs in early childhood. It shows dramatic response to low doses of Levodopa. The characteristic worsening during the day may not be seen in all thus a trial of Levodopa must be given to all children presenting with dystonia.
- Hallervordan-Spatz Disease: It is an Autosomal Recessive disorder characterized by dystonia, parkinsonism, iron accumulation in the brain and is caused by mutations in PANK2 gene in many patients. Classic cases (PANK2 positive) usually present before 6 yrs (between 6 months to 12 years) of age with gait or postural difficulties. Predominant symptoms are dystonia, dysarthria, rigidity and Choreoathetosis. Early dystonia often involves Cranial and limb musculature with axial dystonia leading to severe arching predominating later. Pyramidal signs and cognitive decline can be seen in 25-30%. Retinitis pigmentosa is common. Majority become on ambulatory 10-15 yrs after the onset. MRI of brain shows 'Eye of the Tiger Sign' on T2 weighted images.
Thus a trial of Levodopa must be given to all children presenting with dystonia
Glutaric Aciduria I: It is an A/R disorder due to deficiency of Glutaryl-CoA Dehydrogenase coded by a gene on chromosome 19p13.2. The disorder is characterized by microencephalic macrocephaly, which may be present at birth, and dystonia, choreoathetosis, which may present gradually or abruptly in 2-18 months of life. Subdural Hematomas and Retinal Hemorrhages may be associated and lead to suspicion of non-accidental injury. Acute episodes of ketoacidosis, hypoglycemia and hyperammonemia also occur. Accurate diagnosis requires metabolic testing, including urine organic acid analysis and, plasma acylcarnitine analysis. Urine organic acid analysis characteristically reveals elevated glutaric and 3-hydroxyglutaric acids (the latter metabolite is pathognomonic). MRI shows combination of Fronto-operculo-temporal hypoplasia and communicating hydrocephalus. Putamen is consistently involved. It is treated with low protein diet, riboflavin (100 mg) and Carnitine (50-100 mg/kg/d), and symptomatic treatment of dystonia as well as treatment of acute infections.
- Lesch-Nyhan Syndrome:This disorder is caused by deficiency of Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency. Orange urate crystals in nappies may be the first recognized sign. In majority patients, delayed development is the earliest abnormality, mean age at presentation being 6 months. Hypotonia becomes apparent in the first yr of life and choreoathetoid movements develop between 8-12 months, but are eventually masked by progressive spasticity in all limbs. Pyramidal signs are usually manifest by 1 yr of age. Self-mutilation, the most characteristic feature, manifests anytime from 8 mo to teenage, but there may be cases without self mutilation or delayed mutilation who may be misdiagnosed as CP. This diagnosis should be ruled out in all males with CP who have no history of perinatal distress, by documenting increased urinary Uric Acid/Creatinine ratio, as Sr. Uric Acid levels may not be raised in all cases. Definitive diagnosis is by documentation of HGPRT deficiency in skin fibroblasts.
Self-mutilation, the most characteristic feature, manifests anytime from 8 mo to teenage, but there may be cases without self mutilation or delayed mutilation who may be misdiagnosed as CP.
Pyruvate Dehydrogenase Complex Deficiency: It is X-linked Dominant condition caused by mutations in E1a gene. The most severely affected children of both sexes present with 'Neonatal form'. They manifest on first days with extreme hypotonia, lethargy, weak sucking, and respiratory difficulties with apnea. Seizures are seen in 1/3rd patients. MRI shows partial/complete absence of Corpus Callosum, Cavitating lesions in the cerebral white matte, severe cortical atrophy and B/L low density lesions in the putamen. There is marked increase of Lactate in both blood and CSF. Some patients including the heterozygous symptomatic females present with 'Early infantile Form', between 3-6 months. They live for many years and have microcephaly, quadriplegia, dystonia, peripheral neuropathy, optic atrophy, ophthalmoplegia, and seizures; MRI shows symmetric lesions in brainstem, basal ganglion, thalamus and Cerebellum. Significant increased lactate levels are present in CSF but not always in blood. (These children may be labeled as CP if CSF lactate is not measured).
- Rett Syndrome: RS is a common neurodevelopmental problem seen in 1:10,000 females till 12 yrs age, thus it is one of commonest genetic cause of severe MR in females. These girls have apparently normal pre-perinatal period and normal development for first few months. The disorder is characterized by choreoathetosis, spasticity, autistic traits, seizures, an abnormal respiratory pattern, acquired microcephaly and loss of purposeful hand functions. They have characteristic and almost continuous hand wringing, hand washing movements. 90-90% of these girls have mutations in MECP2 gene.
Rett Syndrome is one of commonest genetic cause of severe MR in females.
It is slowly progressive X-linked Leukodystrophy resulting from deficiency of myelin protein, 'Proteolipid protein'. Affected boys present with a pendular nystagmus (never seen in CP) in first months of life, Inspiratory stridor and pyramidal and extrapyramidal manifestations. Diagnosis is by MRI which shows notably delayed myelination, abnormal a VEP and DNA analysis.
Conditions with predominant diplegia or quadriplegia:
- Adrenoleukodystrophy: It is an X-linked disorder characterized by progressive CNS demyelination and adrenal insufficiency. The female carriers can also be symptomatic. The onset in most cases is between 3-10 yrs of age with cognitive disturbances, hyperactivity, dysarthria and occasionally a psychotic behavior. Centrally originating hemianopsia, progressive visual loss and hearing loss are usual. There is progressive spasticity often with ataxia. Seizures occur in 1/3 rd cases. After 1-2 yrs of onset, many have deteriorated to a vegetative state. MRI shows demyelination predominantly in B/L parieto-occipital regions with a caudorostral progression. Contrast enhancement is seen in the periphery of demyelination zone. There is clinical/biochemical evidence of Adrenal Insufficiency in great majority of cases as typical Addison's disease or isolated focal/diffuse melanoderma. Diagnosis is made by demonstration of abnormally high levels of saturated VLCFAs in plasma, RBCs, WBCs using GC/MS or other techniques.
- Arginase Deficiency: It is an A/R disorder of Urea Cycle involving the last step of the cycle, resulting in Arginaemia and intermittent moderate increase in plasma Ammonia concentrations. Clinically these children present with developmental delay, manifesting in 96% by 5 yrs, somatic growth delay and recurrent vomiting in 80-85%, progressive spastic diplegia, more commonly, and spastic quadriplegia are seen in majority. Spastic Diplegia is manifest in 30-50% by 2 3 yrs of age. Seizures are also common. Many patient learn to self restrict protein in diet. MRI shows Cerebral Atrophy in> 50% and Cerebellar atrophy in ~ 20%. Three to fourfold elevation of plasma arginine concentration above the upper limit of normal is highly suggestive of the diagnosis, but in some cases with borderline levels the test should be repeated with protein load if the suspicion of Arginase deficiency is high. Hyperammonemia is an inconstant feature. Most affected individuals have no detectable arginase enzyme activity (usually < 1% of normal) in red blood cell extracts. ARG1 is the only gene known to be associated with arginase deficiency and can be tested in clinical patients.
- Metachromatic Leukodystrophy as the classic late infantile form presents with delay or deterioration in walking/standing with frequent falls and progressive ataxia by 3 yrs of age. On examination these patients have a combination of Pyramidal signs and features of peripheral Neuropathy; most commonly spasticity, extensor plantars but depressed DTRs. Higher mental functions and vision is normal though a non-paralytic squint is common. After 6-18 months, there is progressive loss of milestones and patients develop spastic quadriplegia with axial hypotonia dysarthria, drooling, dysphagia and loss of HMFs along with visual failure and decerebrate/decorticate posturing in the last stages. NCVs show mark slowing, proteins are raised in CSF. MRI shows hyperintense signal in periventricular and central white matter, initially in occipitoparietal region progressing caudo-rostrally but there is no contrast enhancement. Diagnosis is by showing marked increase in urinary sulfatide levels, decreased Arylsulfatase A levels in WBCs and cultured fibroblasts. Sural Nerve biopsy/conjunctival biopsy show pathognomic deposits of sulfatides in Schwann cells and macrophages. Prenatal Diagnosis is also possible.
This Leukodystrophy caused by a deficiency of galactocerebroside ß-galactosidase, presents usually by 3-6 months of life with marked irritability, feeding problems and vomiting. There is marked rigidity progressively involving limbs, trunk and neck. Tonic opisthotonic posturing/spasms are induced by many stimuli. Pyramidal signs which are seen initially are replaced later by hypotonia and depressed DTRs. Blindness appears later. NCV shows slowing, CSF protein is raised. The centrum semiovale, periventricular white matter, and deep gray matter demonstrate high signal intensity at T2-weighted MR imaging, foci of symmetric altered attenuation are seen in the thalami and caudate.
- Holocarboxylase Synthetase deficiency:
Holocarboxylase links activated Biotin to the Carboxylases; its deficiency is thus a disorder of Biotinylation. The disease usually becomes apparent in the first weeks of life or even at birth with severe metabolic acidosis. Most have breathing abnormalities such as hyperpnoea/apneic spells, hypotonia/hypertonia, lethargy, coma, anorexia and vomiting. Seizures are common. A red scaly skin rash is seen in more than half, rarely there is alopecia. All patients respond dramatically to Biotin (10 mg/d) with resolution of skin rash and organic aciduria. Prenatal maternal treatment may be useful. Diagnosis is made by finding raised Serum lactate, 3 Methylcrotonylglycine and 3 Hydroxyisovaleric acid in blood and urine.
- Hereditary Spastic Paraplegia: These are a group of inherited disorders in which there is only or primarily slowly progressive paraplegia related to B/L lesions of Pyramidal tracts. Pure HSP is an Autosomal Dominant condition with onset from infancy to eighth decade. Most patients present with difficulty in walking/gait disturbances, other sign and symptoms are stiffness of legs, premature wear of footwear and urinary disturbances. In childhood onset HSP, there is commonly a history of delayed walking. As up to 25% of patients can be asymptomatic, it is important do careful clinical evaluation of family members. Apart from presence of pyramidal signs, there is a characteristic marked discrepancy between often severe spasticity and mild/absent weakness. Upper limb involvement is relatively uncommon and usually consists of mild hyperreflexia. Diminished Vibration and Joint Position sense in lower limbs may be seen in 10-65%. Pes cavus and mild distal atrophy in lower limbs is seen in patients with illness of more than 10 yrs duration. There is no involvement of cranial nerves/corticobulbar tracts. Complicated HSP are A/R diseases, some may be very rare. They are associated with optic atrophy, retinopathy, extrapyramidal disease, amyotrophy, dementia, ataxia, MR, epilepsy, ichthyoids (sjogren-larson syndrome) etc. NCV, EMG, CSF studies are usually normal in pure HSP. MRI may show atrophy of spinal cord.
- Neurological Cretinism: Cretinism occurs in areas of Iodine deficiency. Maternal thyroxin has been shown to cross the placenta and it is now envisaged that neurological cretinism is predominantly caused by maternal hypothyroidism due to iodine deficiency therefore iodine repletion must occur by three months of pregnancy to prevent neurological cretinism. In the Neurologic form apart from mental deficiency, deafness is very common and may be severe in = 50% of cases. All totally deaf cretins are mute and many with some hearing have no intelligible speech. Strabismus is also commonly associated. The motor disorder shows a characteristic proximal spasticity of both lower and upper extremities and the trunk with markedly exaggerated deep tendon reflexes at the knees, adductors and biceps, with characteristic sparing of the feet and hands function so that most cretins can walk. This observation is very useful in differentiating cretinism from other forms of cerebral palsy. They are not much shorter than rest of the population, unlike the myxedematous type. The hypothyroidism is either of slight degree or subclinical.
The motor disorder shows a characteristic proximal spasticity of both lower and upper extremities and the trunk with markedly exaggerated deep tendon reflexes at the knees, adductors and biceps, with characteristic sparing of the feet and hands
Other disorders like isolated sulfite oxidase deficiency, Molybdenum co-factor deficiency, Cytochrome oxidase deficiency and 2-Methyl-3hydroxybutyryl-CoA Dehydrogenase (MHBD) deficiency may present with microcephaly, spastic diplegia / quadriplegia, Mental Retardation. MRI picture may also show features suggestive of HIE.
Conditions with ataxia
Ataxia Telangiectasia: AT is a rare A/R neurodegenerative disorder seen in 1 in 20,000-100,000 population caused by a mutation in the ATM gene on chromosome 11q22-23, which seems to be important for cell cycle control and DNA repair. All children with AT present with gait ataxia due to Cerebellar ataxia and choreoathetosis in the first 2-3 yrs of life; oculomotor apraxia and dysarthria also manifest by school age. In some patients there is evidence of peripheral neuropathy but pyramidal signs are rare. Most characteristic features are ocular and cutaneous telangiectasias which appear between 4-7 yrs of age; although in some cases they may never occur.
Most characteristic features are ocular and cutaneous telangiectasias which appear between 4-7 yrs of age.
These children also have frequent sinopulmonary infections and atrophic LNs & Tonsillo-adenoids. The disease progresses very slowly and children may not seem to deteriorate in function until the early school years. Death is usual in 2 nd decade. The risk for malignancy is 60-180 times the normal population. Diagnosis is by demonstrating elevated Serum AFP (also CEA) found in 95% of cases. Defects in cellular and humoral immunity are not constant, most common being absence or low levels of IgA and IgG2, MRI shows Cerebellar atrophy. ATM mutations can be detected in more than 95%.
Diagnosis is by demonstrating elevated Serum AFP (also CEA) found in 95% of cases.
Angelman Syndrome: AS is a neurodevelopmental disorder characterized by severe learning difficulties, ataxia, seizures, dysmorphic facies and typical behavior phenotype. It is seen in 1 in 15000 populations and is caused by variety of genetic abnormalities in chromosome 15q11-13 region. All AS patients have severe mental retardation; they sit unsupported by 12 months and walk between 18 mos to 7 yrs. The gait is slow, stiff legged and ataxic and the arms are held raised and flexed at elbows and wrist, but ataxia may be mild in some cases. Muscle tone is abnormal with truncal hypertonic limbs with brisk reflexes. The most characteristic is the behavioral phenotype, which is present in all the cases. It consists of easily provoked paroxysms of laughter beginning in first few weeks of life and almost all patients are happy and smile frequently. They are very hyperactive and love to play in water. Dysmorphism manifests as prominent chin,
deep set eyes, wide mouth and microcephaly with a flat occiput. Seizures are present in more than 80%, usually starting in first 3 yrs. Some children with AS speak more than 10 words but most are severely speech impaired. Thus none of these features are constant and seen in all except the behavioral phenotype. EEG shows characteristic changes that are important for diagnosis but EEG may need to be repeated.
It consists of easily provoked paroxysms of laughter beginning in first few weeks of life and almost all patients are happy and smile frequently. They are very hyperactive and love to play in water.
Juvenile Niemann Pick Disease - Type C: It is an A/R disorder due to defect in intracellular processing of exogenous cholesterol leading to the accumulation of unesterified cholesterol and glycolipids in the lysosomes. In the juvenile form, symptoms appear between 3 rd and 8 th year in 70% of cases with dysarthria, Cerebellar ataxia, dystonia and choreoathetosis. The neurologic hallmark is supranuclear gaze palsy of vertical eye movements, usually a constant finding after 7 yrs of age. Seizures occur in one third of cases. Mental regression occurs late. There is moderate enlargement of spleen and to a lesser degree of liver in most cases. There are no retinal changes, visual failure or dysmorphism. NCV, CSF, skeletal survey are normal. BMA shows Sea Blue Histiocytes, MRI frequently shows cerebellar atrophy.
The neurologic hallmark is supranuclear gaze palsy of vertical eye movements, usually a constant finding after 7 yrs of age.
Mitochondrial Cytopathies especially causing Neurogenic Muscle weakness, Ataxia and retinitis Pigmentosa (NARP) my also be misdiagnosed as familial CP. Possibility of this mtDNA defect should be kept in children with mild non-progressive neurological dysfunction akin to CP, particularly with Pigmentary Retinopathy, especially if they have relatives with neurological /ophthalmological disease. Muscle Biopsy and serum lactate may be normal. CSF lactate is increased; mitochondrial DNA analysis establishes the diagnosis. Thus once a diagnosis of Cerebral Palsy has been made on the basis of signs and symptoms, each child should undergo appropriate evaluation to determine if it is of prenatal, perinatal, or postnatal in origin. It is important that all children with CP are kept under follow up and should be referred to pediatric neurologist/geneticist when:
- No obvious cause is identified.
- There is any evidence of regression.
- There is a positive family history of CP.
- There is presence of ataxia, involuntary movements/oculomotor findings.
The diagnosis of these disorders which can mimic CP is important because some of these may be treatable and accurate prognosis for the child can be given. Also Genetic counseling including prenatal testing can be offered whenever it is available.
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