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Mimics of cerebral palsy
SYMPOSIUM: CEREBRAL PALSY
Mimics of cerebral palsy
When to question a diagnosis of CP The pathology of CP is not progressive but the clinical manifestations will evolve as the child matures. As a child grows, muscles often become ‘tighter’ (or lose length) and this can lead to the development of contractures and impact on function. Most clinicians will have seen children with CP who ‘go off their feet’ in adolescence. Also subtle sensory or cognitive difficulties may not be immediately apparent. Such features may lead to the question whether this is part of the natural history of CP or if the condition itself is progressive. GMFCS levels are helpful in enabling longitudinal prediction of how motor development is likely to progress in a child with CP.
Lucinda J Carr Joanna Coghill
Abstract Cerebral palsy (CP) is the commonest cause of movement disorder in childhood, with an incidence of around 1 in 400 live births. Many other conditions can masquerade as CP in their clinical presentation, particularly in the early stages. Neuroimaging is often a helpful tool in discriminating CP from other conditions, where characteristic patterns of damage and/or developmental changes are described. However, epidemiological reports consistently report that imaging is normal in up to 15% of children with established CP. Such cases need to be carefully distinguished from other metabolic and genetic conditions, which may also show normal imaging or only slowly evolving change. This article highlights features that may point to an underlying genetic or metabolic disease rather than the static insult that defines causation in CP and suggests an approach to examination and investigation.
Confirming the diagnosis of CP In the absence of a clear aetiology further questions and investigations need to be considered. Red flags in history and examination will confirm the need for further investigation (Table 2). Establishing an accurate diagnosis of CP is imperative for the child as it enables doctors and families to: understand the child’s health status and predict natural history; offer early intervention and treatment; remove the doubt and fear of ‘not knowing’; offer accurate genetic counselling to child and family; prevent further (unnecessary) investigation; identify and secure benefits and support in raising a child with CP; inform registers/epidemiological studies of prevalence.
Keywords cerebral palsy; genetic conditions; metabolic disorders; neuroimaging; ‘red flags’
Introduction In developed countries the incidence of cerebral palsy (CP) is estimated at 1 in 400 live births. CP remains the most common cause of movement disorders in childhood. CP is an umbrella term describing a permanent disorder of movement and posture caused by an insult to the developing brain, either through damage or developmental anomaly. Although, by definition, we are primarily dealing with a motor disorder in CP, other associated factors are often present and this is captured in the revised definition from 2006: namely that ‘The motor disorders of CP are often accompanied by disturbances of sensation, cognition, communication, perception, and/or behaviour and/or a seizure disorder’. The aetiology of CP can be best defined as prenatal, perinatal and postnatal (Table 1). It is then classified by the predominant motor type and distribution. The incidence of predominant motor type in CP is reported as 70% spasticity, 15% extrapyramidal or dyskinetic (which includes both dystonia and choreoathetosis), 10% mixed and 5% ataxic. In clinical practice it is very rare to see absolutely pure spasticity or dystonia and indeed if present, may raise the possibility of an alternative diagnosis. Standardised assessment measures such as the Gross Motor Function Classification System (GMFCS) and Manual Ability Scale (MACs) can be helpful in defining a child’s functional ability.
Neuroimaging An MRI brain scan is the investigation of choice to confirm the diagnosis of CP. Scans are most likely to show abnormality once myelination is advanced so ideally once over 18 months of age, but this is not a reason to defer if there is any uncertainty about the diagnosis. Normal scan: Systematic reviews of neuroimaging in CP (which include CT and MRI scans) find that up to 17% of children with a clinical diagnosis of CP do not show any abnormality on scan. The yield is higher with MRI but still over 10% of scans are normal in children who clinically present as CP. If the MRI brain scan is normal then further metabolic and genetic tests should be performed, guided by the phenotype of the child. Imaging should also be extended to the spine if appropriate. Scan changes may evolve over time so imaging should be repeated if there is a history of progression of symptoms or signs. Abnormal scan: This often provides the confirmation of typical and expected features of CP with damage or brain maldevelopment. If scan features are NOT concordant with the clinical history this may suggest another underlying condition. It is easier to refine further tests by first defining the neurological nature of a child’s motor disorder. They can usually be placed into one of three groups on the basis of clinical examination and history: spastic motor disorders, dyskinetic (extrapyramidal) motor disorders or ataxic disorders (see Table 3).
Lucinda J Carr MD FRCPCH is a Consultant Paediatric Neurologist based at Neuroscience Department, Great Ormond Street Hospital, London, UK. Conflicts of interest: none declared. Joanna Coghill MRCPCH MSc PgCert Med Ed. is Locum Consultant in Paediatric Neurodisability, Great Ormond Street Hospital, London, UK. Conflicts of interest: none declared.
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SYMPOSIUM: CEREBRAL PALSY
Classification of aetiology of CP Prenatal C
C
C C C
Perinatal
Maternal TORCH infections or medical illness Antepartum haemorrhage, Pregnancyrelated hypertension Chorioamnionitis Drugs and toxins Intrauterine growth restriction
C C
C C
Postnatal
Prematurity; around 43% of children with CP Intrapartum catastrophes such as asphyxia, cord prolapse or uterine rupture, (less than 10%). Infection (HIV, Group B Strep) Metabolic disturbances e (jaundice, hypoglycaemia
C C C C C
Traumatic brain injury Hypoxia CNS infections Metabolic disturbance Cerebrovascular accident
Table 1
unilateral, as with perinatal stroke and on rare occasions progressive signs are seen, such as in Rasmussen’s encephalitis. However with an underlying genetic or metabolic cause, signs are usually bilateral and symmetrical. There are a number of other conditions which may result in bilateral spasticity:
‘Red Flags’ where another diagnosis should be considered History
Examination
No risk factors for CP Regression of skills Fluctuation in motor function Pure neurological signs Positive family history
Dysmorphic Optic atrophy/retinopathy Pes cavus Evolving sensory signs
Spinal dysraphism This describes a spectrum of disorders where closure of the neural tube is defective in early foetal life, leading to anomalous development of the spinal cord. Open spina bifida is part of this spectrum but more often the skin is closed. The cord may become ‘tethered’ to the vertebral column or subcutaneous tissues by a thickened filum terminale, fibrous band, dermal sinus tract, diastematomyelia, or a lipoma and so cause traction to the neural elements. Brain MRI scan is normal but the spine characteristically shows a low lying conus medullaris below L2 level or the presence of a lipoma or dermal tract. In childhood, spinal dysraphism can cause progressive gait abnormalities, particularly during periods of rapid growth (5e15
Table 2
Spastic motor disorders Spasticity is defined as dynamic hypertonus (i.e. elicited as a muscle ‘catch’ or clonus with rapid movement of the limb). In CP, spasticity is usually seen along with other features of an upper motor neuron syndrome, namely co-existing distal weakness, loss of selective muscle control and hyperreflexia. Spasticity may be
Alternative diagnoses and investigations in suspected CP by motor type Spasticity C C C C C C
Spinal Dysraphism HSP Leukodystrophy Arginase deficiency Sjorgen Larsson syndrome Biotinidase/Folate deficiency
Dyskinetic C C C C C C C
Spasticity C C C C C C C C C
HSP Genetics Nerve conduction/EMG White cell enzymes Very long chain fatty acids Plasma ammonia Plasma amino acids ALDH3A2 gene CSF lactate, folate & neurotransmitters Serum biotinidase and folate
Ataxia
DOPA responsive dystonia Mitochondrial disease Lesch Nyhan Wilson’s disease Glutaric aciduria GLUT 1A Neurodegeneration with brain iron accumulation
Dyskinetic C C C C C C C C
C C C C C C C C
Anglemans Jouberts Friedreich’s ataxia Ataxia telangiectasia Cockayne syndrome Pelizaeus-Merzbacher disease Non-ketotoc hyperglycinaemia Maple syrup urine disease
Ataxia
CSF neurotransmitters Genetics MECP2 (Retts) Plasma/CSF lactate and glucose Respiratory chain enzymes in muscle Serum urate Serum/urine Copper Caeruloplasmin Urine organic acids
C C C C C
Genetics Nerve conduction DNA fragility AFP Plasma amino acids
Table 3
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SYMPOSIUM: CEREBRAL PALSY
years). Neurological findings are variable but often comprise asymmetric weakness of the legs, with mixed upper and lower motor neuron signs. Arms are unaffected. The presence of scoliosis, patchy numbness of the legs and bowel and bladder incontinence may be additional features. About one third of cases will have cutaneous manifestations over the lower back, such as a hairy patch or haemangioma. Urgent neurosurgical assessment is recommended since if left untreated, neurological progression may continue.
Main types of Leukodystrophy Metochromatic Leukodystrophy (MLD)
Hereditary spastic paraplegia (HSP) Inheritance in this group of genetic disorders may be autosomal dominant, autosomal recessive or X linked. Over 70 genotypes are described, with an estimated prevalence of around 2e10 cases per 100,000. There is a spectrum of presentation from early childhood into adult life. HSP may be relatively static or slowly progressive and result in significant disability. HSP is divided into two clinical groups both of which are accompanied with normal MRI scans of brain and spine in almost all cases: a) Uncomplicated’ or ‘pure’ HSP where symmetrical spastic weakness of the legs is the main feature, often accompanied by some urinary urgency and decreased vibration sense in the toes. This is usually accompanied by hyperreflexia in the legs and extensor plantar responses. Pure HSP is most often due to dominant mutations in Spastin (SPG4), Atlastin (SPG3A) or NIPA1 (SPG6) genes thus a positive family history of abnormal gait and examination of both parents for hypertonia and hyperreflexia can be informative. However, despite there being high genetic penetrance, the age of onset of symptoms can vary widely within families so parental signs are not always reliable. b) Complicated HSP has more generalised systemic abnormalities such as learning difficulties, dysarthria, seizures, peripheral neuropathy and sometimes muscle atrophy.
C
Krabbe’s disease
C
C
C
Canavan’s disease
C
C
C
Alexander disease
Leukodystrophies These disorders are characterised by disruption of the growth or maintenance of the myelin sheath which results in degeneration of the white matter in the brain and sometimes spinal cord and peripheral nerves. This leads to characteristic findings on MRI scans and nerve conduction studies. Individual conditions (see Table 4) have specific clinical and radiological features but they share the common features of neuroregression with loss of gross and fine motor skills, usually with rigidity and pathological tendon reflexes (increased or absent). Feeding difficulties, seizures and loss of vision and hearing usually develop in the later stages. Alongside this is cognitive decline, indeed with many of the juvenile presentations, altered behaviour and declining school performance is often the first clue. With early onset leukodystrophy, life expectancy is severely curtailed and children rarely survive beyond childhood. Progression is slower in Juvenile and Adult onset forms and they may survive for many years but become increasingly dependent. When symptoms arise in infancy an initial diagnosis of CP is often given but ongoing global deterioration and feeding difficulties should raise doubts. The diagnosis is suggested by the characteristic evolution of an MRI brain scan, with characteristic patterns of dysmyelination in each of the leukodystrophies (see case 1). Timely diagnosis is crucial since bone marrow transplant or stem cell transplant may be offered in mild or pre-
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C
C
C
C
Adreno-leukodystrophy (ALD)
C
C
C
Autosomal recessive, Arylsulfatase A (ASA) deficiency more than 50% late infantile form: onset 15e24 months, regression in gait and speech, before global deterioration. Hypotonia followed by rigidity. C 30% Juvenile onset at 3e10 years. Adult onset more than 16 years with psychiatric illness or dementia Diagnosis: MRI Brain scan. White cell enzyme screen confirms low ASA. Metachromatic granules in urine. Genetic testing. Demyelinating polyneuropathy Autosomal recessive, galactocerebrosidase deficiency Usually onset c 3e6months: increasing irritability, stiffness, feeding difficulties and reduced interaction optic atrophy Diagnosis: MRI Brain scan. White cell enzyme screen confirms low enzyme. Genetic testing. Demyelinating polyneuropathy. Autosomal recessive, N-acetylaspartate amidohydrolase (NAA) deficiency Usually presents in infancy as development regresses with hypotonia, irritability and macrocephaly Diagnosis: MRI Brain scan. low NAA in urine /CSF. Genetics Spontaneous inheritance, Glial fibrillary acidic protein deficiency Usually presents less than 2 years with developmental delay, spasticity and macrocephaly Diagnosis: MRI Brain scan. Genetics X-linked, affecting ATP binding cassette transporters Childhood cerebral onset form c 4e10 years, toe walking and ‘diplegic pattern’ with emerging learning/ behavioural difficulties. Diagnosis: MRI Brain scan. Raised Very Long Chain Fatty Acid levels. Genetics. Monitor Adrenal function.
Table 4
symptomatic stages of MLD and ALD (often the siblings of an index case). Metabolic disorders An underlying metabolic disorder should be suspected if there is a history of relapsing encephalopathy, often provoked by intercurrent illness or high protein intake. A complete list of these rare
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SYMPOSIUM: CEREBRAL PALSY
Case 1 A girl was born at term to non-consanguineous parents with normal neonatal period. She began walking at 13 months but her gait failed to mature. By 20 months of age, parents reported deterioration in her gross and fine motor skills as well as feeding difficulties. At 2 years of age, she stopped walking independently. Assessment revealed some drooling. There was the impression of mild weakness without hypertonia and no deep tendon reflexes could be elicited.
Key investigations Initial MRI scan was performed outside the UK at 2 years of age. This was initially reported to show white matter damage of immaturity. Repeat MRI brain scan 6 months later showed progressive diffuse abnormal white matter signal. Figure 1 showing progressive diffuse and confluent white matter signal.
Figure 1 MRI Brain scans taken at a) 2 years b) 2 years six months showing progressive diffuse and confluent white matter signal.
EMG study showed severe demyelinating neuropathy affecting sensory and motor nerves in upper and lower limbs. CSF protein 255 mg/dL (normal range 20e50). Leucocyte enzymes: Arylsulphatase A 1.0 nmol/hr/mg (normal range 22e103). Urine confirmed presence of metachromatic granules. Mutation in ARSA gene on genetic testing. Diagnosis: Metochromatic leucodystrophy.
disorders is beyond the scope of this article but some of the more common mimics of motor CP are considered below.
retinal examination. Diagnosis is confirmed by low fatty aldehyde dehydrogenase levels in blood and genetic testing demonstrates mutation in ALDH3A2 gene.
Arginase deficiency: this autosomal recessive disorder of the urea cycle, results in raised arginine levels and inconsistent elevation of ammonia concentration. Children usually present around 3 years of age with progressive spastic paraparesis. Regression of cognitive skills typically follows, with failure to thrive in the context of seizures and tremor. Diagnosis is confirmed by measuring arginase levels in cultured skin fibroblasts.
Disorders of vitamin metabolism and nutritional deficiencies Biotinidase deficiency: children with biotinidase deficiency are unable to recycle the vitamin Biotin (B7). Neurological features include seizures, hypotonia, ataxia, developmental delay, disturbed vision and hearing and cutaneous abnormalities (such as alopecia and skin rashes). Older children with profound biotinidase deficiency may exhibit weakness, spastic paresis and optic atrophy. Blood tests confirm low biotinidase levels. Prompt treatment with oral biotin is vital, since neurological signs are usually irreversible. Many countries now offer neonatal screening.
Sjorgen Larsson syndrome: a rare recessive disorder caused by disruption of fatty acid oxidation which results in nonprogressive congenital ichthyosis, spastic paraplegia and cognitive delay, particularly affecting speech. MRI scan shows leukoencephalopathy. Crystalline maculopathy is often found on
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SYMPOSIUM: CEREBRAL PALSY
progressive generalized dystonia, often associated with evolving MRI changes (Figure 2), which typically affect basal ganglia and brain stem. Retinopathy, renal tubulopathy and peripheral neuropathy may also be present. Raised plasma and CSF lactate levels, along with raised alanine levels are further evidence of mitochondrial dysfunction. The gold standard tests are of analysis of muscle histology and respiratory chain enzyme analysis with exome sequencing of mitochondrial and nuclear DNA.
Primary cerebral folate deficiency: this results from several disorders of folate transport and metabolism. Clinical characteristics include lower limb spasticity, postnatally acquired microcephaly and developmental delay often with autism, epilepsy, ataxia and dyskinesia. The diagnosis is confirmed by demonstrating low levels of 5-methyl tetrahydrofolate in CSF neurotransmitter measurement in the context of normal peripheral serum folate. Treatment with folinic acid in early childhood may result in improvement.
Lesch Nyhan syndrome: this X-linked disorder is caused by mutations in the HPRT1 gene with a lack of hypoxanthine phosphoribosyl-transferase 1 and failure to recycle purines. As a result, uric acid progressively accumulates in body tissues to cause renal calculi and gouty arthritis. Affected children are delayed in sitting and most never walk. Within the first few years, extrapyramidal and pyramidal signs emerge (a mixture of dystonia, choreoathetosis, opisthotonus and spasticity with hyperreflexia and extensor plantar reflexes). Between ages two and three years, persistent self-injurious behaviours develop with biting of fingers, hands, and lips being a hallmark of the disease. Diagnostic features are of raised urinary urate-tocreatinine ratio (more than 2.0) and low enzyme activity in blood. Mutation analysis confirms the diagnosis.
Extrapyramidal/dyskinetic motor disorders Dyskinetic CP is characterized by abnormal movements or postures due to defective coordination of movement and/or regulation of muscle tone. It is generally subdivided into dystonic and hyperkinetic forms. In dystonia, movements are slow and sustained, sometimes with spasms whereas in hyperkinetic CP, they are slow and writhing (athetoid) or rapid jerky (choreiform) movements. There is often some associated spasticity. Typically children with dyskinetic CP are initially hypotonic, usually over the first few months but sometimes into the second year of life. Around 75% of affected children will have a history of adverse events around delivery (e.g. hypoxia or bilirubin encephalopathy). In the dystonic child with no risk factors and a normal MRI scan of brain and spine, it is important to consider other causes of dystonia (genetic and metabolic).
Wilson’s disease: this autosomal recessive condition is caused by mutations in ATP7B gene and as a result, copper accumulates in body tissues, particularly brain and liver. In around 50% of cases this results in neurological or psychiatric symptoms with Parkinsonism, tremor, ataxia and dyskinesia along with emotional lability and impulsiveness. Liver disease occurs in the remainder (usually with hepatic encephalopathy or fulminant liver failure). Other affected organs include eyes (Keyser Fleischer rings), kidneys (renal tubular acidosis) and heart (cardiomyopathy). Diagnosis is suggested by abnormal liver function tests sometimes with prolonged prothrombin time, low levels of serum copper and ceruloplasmin and raised 24-hour copper excretion. MRI changes evolve with increasing symptoms, showing high signal in basal ganglia on T2 weighted images Liver biopsy is the gold standard diagnostic test.
Genetic dystonia Dopa responsive dystonia (DRD): this condition is characterized by a history of dystonia with diurnal fluctuation, so that gait worsens through the day and is improved by sleep. The commonest cause for this is a mutation in GTP cyclohydrolase gene which is dominantly inherited but of low penetrance. Only 30 e40% of people carrying the gene will develop the condition. The dystonia usually shows a dramatic and sustained response to small doses of levodopa. GTP cylcohydrolase is a rate limiting enzyme in the synthesis of tetrahydrobiopterin (BH4) and analysis of neurotransmitter levels in CSF typically shows low levels of neopterin and BH4 and the dopamine metabolite homovanillic acid. Recessive forms of DRD are less common and may show only a partial response to trials of levodopa treatment. DRD is not entirely excluded by normal CSF neurotransmitters. Gene analysis and a trial of levodopa should still be considered in all children presenting with dystonia, where causation is not established.
GLUT1 deficiency: this disorder results from mutations in the SLC2A1 gene, which facilitates glucose transportation across the blood brain barrier. As a result, CSF glucose levels are low and can cause seizures in infancy with acquired microcephaly and developmental impairment. It can also cause both paroxysmal and persistent movement disorders, most often dyskinetic in nature, with dystonic gait or choreoathetosis or ataxia. Diagnosis is confirmed by demonstrating a low CSF to plasma glucose concentration (typically less than 0.4) and mutations in SLC2A1 gene. Although it can be dominantly inherited most mutations occur de novo.
Rett syndrome: this is caused by mutations in MECP2 gene or CDKL5 gene and almost exclusively presents in girls, initially with developmental delay and hypotonia, but gradually characteristic midline hand stereotypies emerge. These become more intrusive around 1e4 years and there is more generalised regression, often with marked irritability. In the later stages dystonia and spasticity develops. Acquired microcephaly, seizures and paroxysmal breathing pattern suggest the diagnosis which is confirmed by genetic analysis.
Glutaric aciduria type 1 (GA1): GA1 is caused by mutations in the GCDH gene, responsible for production of the enzyme glutaryl-CoA dehydrogenase. This metabolises the amino acids lysine, hydroxylysine, and tryptophan; in GA1 their intermediate breakdown products build up to abnormal levels, especially at times of stress. Affected children often have macrocephaly, secondary to subdural effusions and early hypotonia with mild
Metabolic dystonia Mitochondrial disease: mitochondrial disorders have protean clinical manifestations and can be difficult to confidently exclude. Clinical clues are of episodic encephalopathy and
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SYMPOSIUM: CEREBRAL PALSY
Figure 2 Evolving MRI brain changes in Mitochondrial Disorder. T2 images from an MRI scan taken at 5 years 8 months and repeated 3 years later at 8 years 8 months demonstrating increasing signal in basal ganglia and brain stem.
progressive cerebellar ataxia with poor balance and coordination and intention tremor.
developmental delay. Presentation is often with acute metabolic crises with exacerbation of symptoms particularly dystonia. Analysis of urine organic acids and genetic analysis confirms the diagnosis. Neonatal blood spot screening has recently been introduced so that early treatment can be offered before the potentially devastating effects of acute decompensation.
Genetic conditions Angelman syndrome: this results from disruption of UBE3A gene, which is usually due to maternally inherited deletions. Typically, it presents with apparent ataxia and severe developmental delay (particularly in expressive language). Children often have a happy demeanour and have acquired microcephaly and seizures. The EEG shows a characteristic pattern with large amplitude slowspike waves. Genetic testing confirms the diagnosis.
Neurodegeneration with Brain Iron Accumulation (NBIA) (Case 2): in these conditions, iron accumulates in the basal ganglia, which is associated with progressive dystonia, spasticity, Parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Ten different conditions are recognized, each with specific genetic mutations. The age of onset and rate of progression varies even within each disorder.
Joubert syndrome: over six underlying genotypes are now recognized to cause this specific ciliopathy. It results in congenital brain malformation of the cerebellar vermis and brainstem, which can be seen in the axial plane of MRI scan as a “molar tooth” sign. Clinically children present with ataxia and developmental delay with oculomotor apraxia. There is often a history of hyperpnoea intermixed with central apnoea in the neonatal period. Renal cysts and retinopathy often develop in later life.
Ataxic disorders There should be caution with the diagnosis ataxic CP since several genetic and metabolic disorders can mimic this in their early stages. In CP, predominant features are those of non-
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SYMPOSIUM: CEREBRAL PALSY
Case 2 A girl was born at 25 weeks gestation with a birth weight of 710 g. She was the third child of consanguineous parents with no relevant family history. Small bilateral intraventricular haemorrhages were noted. Early developmental milestones were delayed but she made good progress. At 7 years of age she could walk with a frame, hold a pen and count to 20. She showed good understanding of language and used several single words. She fed well. Following dental treatment at 8 years she deteriorated dramatically with drooling, feeding difficulties and gradual loss of speech. She evolved dystonic posturing spreading to all 4 limbs and disturbing sleep. By 9 years, she became aphasic and required nasogastric feeds. She showed persistent dystonic posturing of legs and hands with tongue protrusion (Figure 3). Key investigations MRI
Figure 3 MRI Brain scan shows lack of cerebral white matter bulk with thinning of the corpus callosum. The cerebellum is small and atrophic. There is bilateral pallidal iron deposition. Loss of response on electroretinogram. Acanthocytes found on blood film. Genetic testing confirms homozygous mutation in PANK2 gene. Diagnosis: initially Bilateral spastic CP GMFCS111 secondary to prematurity. Later regression due to Pantothenate kinase-associated neurodegeneration (PKAN).
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plantar responses can develop. Sensory examination is abnormal with abnormal proprioception and vibration sense. The most serious risk of Vitamin B12 deficiency is Subacute Combined Degeneration of the spinal cord, which may also involve brain, optic nerves and peripheral nerves. Typical symptoms are of tingling of fingers and toes, before deterioration of gait, weakness and fatigue. Low B12 and folate levels with megaloblastic anaemia are found on blood tests. Nerve conduction studies show a sensory neuropathy. It can result from malabsorption or pernicious anaemia. Vitamin E deficiency may be associated with anaemia and retinopathy. It usually results from fat malabsorption, usually in the context of systemic disorders such as cystic fibrosis, but also occurs in abetalipoproteinemia.
Friedreich ataxia: this is the most common form of hereditary ataxia, affecting about one in every 50,000 individuals and caused by loss of function in the frataxin gene. Symptoms typically begin between the ages of 5 and 15 years (although sometimes not until late adult life), with progressive gait ataxia often with pes cavus and loss of proprioception and tendon reflexes. Cerebellar signs evolve with past pointing and dysarthria. Many people with Friedreich’s ataxia develop scoliosis and later diabetes, hearing and vision loss. Hypertrophic cardiomyopathy usually develops and limits life expectancy. Ataxia telangiectasia: in this autosomal recessive multisystem disorder, first symptoms are usually of ataxia as the child begins to walk and are associated with abnormal head thrusting (a result of oculomotor apraxia). It is slowly and steadily progressive with dystonia often seen in later stages. Immunodeficiency and risk of malignancy are additional features. Diagnosis is established by characteristic MRI changes (cerebellar atrophy and increased white matter signal changes on T2-weighted images). Blood tests show elevated levels of alpha-fetoprotein and absent or low level of immunoglobulin A. Radiation studies show excessive chromosomal fragility and DNA sequencing confirms mutation of the ATM gene.
Conclusion A careful history, clinical examination and neuroimaging are essential when considering a diagnosis of CP. The genetic and metabolic mimics of CP discussed are all individually rare so a focused approach is needed; based on clinical clues and targeted investigations. The opinion of a neurologist and geneticist can be invaluable in guiding investigations further when a CP diagnosis doesn’t fit. A correct diagnosis has huge implications in terms of prognosis, specific treatments and genetic counselling. A
Cockayne syndrome: this recessive condition results from defective DNA nucleotide excision repair, secondary to mutations in ERCC gene. Criteria required for the diagnosis include poor growth with microcephaly and progressive neurological degeneration with ataxia and tremor. Other common manifestations include sensorineural hearing loss, cataracts, pigmentary retinopathy and cutaneous photosensitivity.
FURTHER READING Carr LJ. Clinical presentation of cerebral palsy in cerebral palsy: Science and clinical practice. In: Dan B, Mayston M, Paneth N, Rosenbloom L, eds. MacKeith Press, Nov 2014. Gupta R, Appleton RE. Cerebral palsy: not always what it seems. Arch Dis Child 2001; 85: 356e60. Huntsman R, Lemire E, Norton J, Dzus A, Blakley P, Hasal S. The differential diagnosis of spastic diplegia. Arch Dis Child 2015; 100: 500e4.
Pelizaeus-Merzbacher disease: mutations in the PLP1 gene are inherited in an X-linked recessive pattern and result in dysmyelination on MRI scan. Classic Pelizaeus-Merzbacher disease is the more common type and within the first year of life, affected boys demonstrate hypotonia with motor delay. The consistent finding of pendular nystagmus is an important clue to the diagnosis. As the child matures nystagmus diminish but other movement disorders develop, including spasticity, ataxia and chorea.
Acknowledgements Acknowledgement to Dr Kling Chong Consultant Paediatric Neuroradiologist, Great Ormond Street Hospital, London WC1N3JH for help with MRI images.
Metabolic conditions Non-ketotic hyperglycinaemia: this most commonly presents as a neonatal encephalopathy with intractable seizures and hiccoughs. However it can present later with cerebellar ataxia. CSF amino acids confirm raised glycine levels.
Personal practice points Maple syrup urine disease: this is caused by disordered metabolism of branch chain amino acids. It classically presents in the neonatal period on introduction of milk feeds however there are rare intermittent forms which can present later with episodic encephalopathy associated with ataxia or dystonia. At such time, sweat and urine will smell of maple syrup. Ketosis and high levels of branch chain amino acids are found.
C
C
C
Disorders of vitamin metabolism and nutritional deficiencies Apparent ataxia can occur if proprioception is abnormal and this can be mistaken as CP; as sometimes seen in B12 and vitamin E deficiency disorders. If untreated progressive spastic-ataxic gait associated with loss of lower limb tendon reflexes and upgoing
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C
C
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Be mindful of ‘Red Flags’ when reviewing a child with CP and consider referral on for more specialist neurogenetic/metabolic opinion. Remember that MRI scan changes can evolve over time, so imaging should be repeated if the child shows unusual progression of symptoms or signs. If MRI scan features are NOT concordant with the clinical history this may suggest another underlying condition. A trial of levodopa should still be considered in all children presenting with dystonia, where causation is not established. Ataxic CP is rare and has several genetic and metabolic mimics in early childhood.
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Please cite this article in press as: Carr LJ, Coghill J, Mimics of cerebral palsy, Paediatrics and Child Health (2016), http://dx.doi.org/10.1016/ j.paed.2016.04.017
Mimics of cerebral palsy
When to question a diagnosis of CP The pathology of CP is not progressive but the clinical manifestations will evolve as the child matures. As a child grows, muscles often become ‘tighter’ (or lose length) and this can lead to the development of contractures and impact on function. Most clinicians will have seen children with CP who ‘go off their feet’ in adolescence. Also subtle sensory or cognitive difficulties may not be immediately apparent. Such features may lead to the question whether this is part of the natural history of CP or if the condition itself is progressive. GMFCS levels are helpful in enabling longitudinal prediction of how motor development is likely to progress in a child with CP.
Lucinda J Carr Joanna Coghill
Abstract Cerebral palsy (CP) is the commonest cause of movement disorder in childhood, with an incidence of around 1 in 400 live births. Many other conditions can masquerade as CP in their clinical presentation, particularly in the early stages. Neuroimaging is often a helpful tool in discriminating CP from other conditions, where characteristic patterns of damage and/or developmental changes are described. However, epidemiological reports consistently report that imaging is normal in up to 15% of children with established CP. Such cases need to be carefully distinguished from other metabolic and genetic conditions, which may also show normal imaging or only slowly evolving change. This article highlights features that may point to an underlying genetic or metabolic disease rather than the static insult that defines causation in CP and suggests an approach to examination and investigation.
Confirming the diagnosis of CP In the absence of a clear aetiology further questions and investigations need to be considered. Red flags in history and examination will confirm the need for further investigation (Table 2). Establishing an accurate diagnosis of CP is imperative for the child as it enables doctors and families to: understand the child’s health status and predict natural history; offer early intervention and treatment; remove the doubt and fear of ‘not knowing’; offer accurate genetic counselling to child and family; prevent further (unnecessary) investigation; identify and secure benefits and support in raising a child with CP; inform registers/epidemiological studies of prevalence.
Keywords cerebral palsy; genetic conditions; metabolic disorders; neuroimaging; ‘red flags’
Introduction In developed countries the incidence of cerebral palsy (CP) is estimated at 1 in 400 live births. CP remains the most common cause of movement disorders in childhood. CP is an umbrella term describing a permanent disorder of movement and posture caused by an insult to the developing brain, either through damage or developmental anomaly. Although, by definition, we are primarily dealing with a motor disorder in CP, other associated factors are often present and this is captured in the revised definition from 2006: namely that ‘The motor disorders of CP are often accompanied by disturbances of sensation, cognition, communication, perception, and/or behaviour and/or a seizure disorder’. The aetiology of CP can be best defined as prenatal, perinatal and postnatal (Table 1). It is then classified by the predominant motor type and distribution. The incidence of predominant motor type in CP is reported as 70% spasticity, 15% extrapyramidal or dyskinetic (which includes both dystonia and choreoathetosis), 10% mixed and 5% ataxic. In clinical practice it is very rare to see absolutely pure spasticity or dystonia and indeed if present, may raise the possibility of an alternative diagnosis. Standardised assessment measures such as the Gross Motor Function Classification System (GMFCS) and Manual Ability Scale (MACs) can be helpful in defining a child’s functional ability.
Neuroimaging An MRI brain scan is the investigation of choice to confirm the diagnosis of CP. Scans are most likely to show abnormality once myelination is advanced so ideally once over 18 months of age, but this is not a reason to defer if there is any uncertainty about the diagnosis. Normal scan: Systematic reviews of neuroimaging in CP (which include CT and MRI scans) find that up to 17% of children with a clinical diagnosis of CP do not show any abnormality on scan. The yield is higher with MRI but still over 10% of scans are normal in children who clinically present as CP. If the MRI brain scan is normal then further metabolic and genetic tests should be performed, guided by the phenotype of the child. Imaging should also be extended to the spine if appropriate. Scan changes may evolve over time so imaging should be repeated if there is a history of progression of symptoms or signs. Abnormal scan: This often provides the confirmation of typical and expected features of CP with damage or brain maldevelopment. If scan features are NOT concordant with the clinical history this may suggest another underlying condition. It is easier to refine further tests by first defining the neurological nature of a child’s motor disorder. They can usually be placed into one of three groups on the basis of clinical examination and history: spastic motor disorders, dyskinetic (extrapyramidal) motor disorders or ataxic disorders (see Table 3).
Lucinda J Carr MD FRCPCH is a Consultant Paediatric Neurologist based at Neuroscience Department, Great Ormond Street Hospital, London, UK. Conflicts of interest: none declared. Joanna Coghill MRCPCH MSc PgCert Med Ed. is Locum Consultant in Paediatric Neurodisability, Great Ormond Street Hospital, London, UK. Conflicts of interest: none declared.
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Classification of aetiology of CP Prenatal C
C
C C C
Perinatal
Maternal TORCH infections or medical illness Antepartum haemorrhage, Pregnancyrelated hypertension Chorioamnionitis Drugs and toxins Intrauterine growth restriction
C C
C C
Postnatal
Prematurity; around 43% of children with CP Intrapartum catastrophes such as asphyxia, cord prolapse or uterine rupture, (less than 10%). Infection (HIV, Group B Strep) Metabolic disturbances e (jaundice, hypoglycaemia
C C C C C
Traumatic brain injury Hypoxia CNS infections Metabolic disturbance Cerebrovascular accident
Table 1
unilateral, as with perinatal stroke and on rare occasions progressive signs are seen, such as in Rasmussen’s encephalitis. However with an underlying genetic or metabolic cause, signs are usually bilateral and symmetrical. There are a number of other conditions which may result in bilateral spasticity:
‘Red Flags’ where another diagnosis should be considered History
Examination
No risk factors for CP Regression of skills Fluctuation in motor function Pure neurological signs Positive family history
Dysmorphic Optic atrophy/retinopathy Pes cavus Evolving sensory signs
Spinal dysraphism This describes a spectrum of disorders where closure of the neural tube is defective in early foetal life, leading to anomalous development of the spinal cord. Open spina bifida is part of this spectrum but more often the skin is closed. The cord may become ‘tethered’ to the vertebral column or subcutaneous tissues by a thickened filum terminale, fibrous band, dermal sinus tract, diastematomyelia, or a lipoma and so cause traction to the neural elements. Brain MRI scan is normal but the spine characteristically shows a low lying conus medullaris below L2 level or the presence of a lipoma or dermal tract. In childhood, spinal dysraphism can cause progressive gait abnormalities, particularly during periods of rapid growth (5e15
Table 2
Spastic motor disorders Spasticity is defined as dynamic hypertonus (i.e. elicited as a muscle ‘catch’ or clonus with rapid movement of the limb). In CP, spasticity is usually seen along with other features of an upper motor neuron syndrome, namely co-existing distal weakness, loss of selective muscle control and hyperreflexia. Spasticity may be
Alternative diagnoses and investigations in suspected CP by motor type Spasticity C C C C C C
Spinal Dysraphism HSP Leukodystrophy Arginase deficiency Sjorgen Larsson syndrome Biotinidase/Folate deficiency
Dyskinetic C C C C C C C
Spasticity C C C C C C C C C
HSP Genetics Nerve conduction/EMG White cell enzymes Very long chain fatty acids Plasma ammonia Plasma amino acids ALDH3A2 gene CSF lactate, folate & neurotransmitters Serum biotinidase and folate
Ataxia
DOPA responsive dystonia Mitochondrial disease Lesch Nyhan Wilson’s disease Glutaric aciduria GLUT 1A Neurodegeneration with brain iron accumulation
Dyskinetic C C C C C C C C
C C C C C C C C
Anglemans Jouberts Friedreich’s ataxia Ataxia telangiectasia Cockayne syndrome Pelizaeus-Merzbacher disease Non-ketotoc hyperglycinaemia Maple syrup urine disease
Ataxia
CSF neurotransmitters Genetics MECP2 (Retts) Plasma/CSF lactate and glucose Respiratory chain enzymes in muscle Serum urate Serum/urine Copper Caeruloplasmin Urine organic acids
C C C C C
Genetics Nerve conduction DNA fragility AFP Plasma amino acids
Table 3
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years). Neurological findings are variable but often comprise asymmetric weakness of the legs, with mixed upper and lower motor neuron signs. Arms are unaffected. The presence of scoliosis, patchy numbness of the legs and bowel and bladder incontinence may be additional features. About one third of cases will have cutaneous manifestations over the lower back, such as a hairy patch or haemangioma. Urgent neurosurgical assessment is recommended since if left untreated, neurological progression may continue.
Main types of Leukodystrophy Metochromatic Leukodystrophy (MLD)
Hereditary spastic paraplegia (HSP) Inheritance in this group of genetic disorders may be autosomal dominant, autosomal recessive or X linked. Over 70 genotypes are described, with an estimated prevalence of around 2e10 cases per 100,000. There is a spectrum of presentation from early childhood into adult life. HSP may be relatively static or slowly progressive and result in significant disability. HSP is divided into two clinical groups both of which are accompanied with normal MRI scans of brain and spine in almost all cases: a) Uncomplicated’ or ‘pure’ HSP where symmetrical spastic weakness of the legs is the main feature, often accompanied by some urinary urgency and decreased vibration sense in the toes. This is usually accompanied by hyperreflexia in the legs and extensor plantar responses. Pure HSP is most often due to dominant mutations in Spastin (SPG4), Atlastin (SPG3A) or NIPA1 (SPG6) genes thus a positive family history of abnormal gait and examination of both parents for hypertonia and hyperreflexia can be informative. However, despite there being high genetic penetrance, the age of onset of symptoms can vary widely within families so parental signs are not always reliable. b) Complicated HSP has more generalised systemic abnormalities such as learning difficulties, dysarthria, seizures, peripheral neuropathy and sometimes muscle atrophy.
C
Krabbe’s disease
C
C
C
Canavan’s disease
C
C
C
Alexander disease
Leukodystrophies These disorders are characterised by disruption of the growth or maintenance of the myelin sheath which results in degeneration of the white matter in the brain and sometimes spinal cord and peripheral nerves. This leads to characteristic findings on MRI scans and nerve conduction studies. Individual conditions (see Table 4) have specific clinical and radiological features but they share the common features of neuroregression with loss of gross and fine motor skills, usually with rigidity and pathological tendon reflexes (increased or absent). Feeding difficulties, seizures and loss of vision and hearing usually develop in the later stages. Alongside this is cognitive decline, indeed with many of the juvenile presentations, altered behaviour and declining school performance is often the first clue. With early onset leukodystrophy, life expectancy is severely curtailed and children rarely survive beyond childhood. Progression is slower in Juvenile and Adult onset forms and they may survive for many years but become increasingly dependent. When symptoms arise in infancy an initial diagnosis of CP is often given but ongoing global deterioration and feeding difficulties should raise doubts. The diagnosis is suggested by the characteristic evolution of an MRI brain scan, with characteristic patterns of dysmyelination in each of the leukodystrophies (see case 1). Timely diagnosis is crucial since bone marrow transplant or stem cell transplant may be offered in mild or pre-
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C
C
C
C
Adreno-leukodystrophy (ALD)
C
C
C
Autosomal recessive, Arylsulfatase A (ASA) deficiency more than 50% late infantile form: onset 15e24 months, regression in gait and speech, before global deterioration. Hypotonia followed by rigidity. C 30% Juvenile onset at 3e10 years. Adult onset more than 16 years with psychiatric illness or dementia Diagnosis: MRI Brain scan. White cell enzyme screen confirms low ASA. Metachromatic granules in urine. Genetic testing. Demyelinating polyneuropathy Autosomal recessive, galactocerebrosidase deficiency Usually onset c 3e6months: increasing irritability, stiffness, feeding difficulties and reduced interaction optic atrophy Diagnosis: MRI Brain scan. White cell enzyme screen confirms low enzyme. Genetic testing. Demyelinating polyneuropathy. Autosomal recessive, N-acetylaspartate amidohydrolase (NAA) deficiency Usually presents in infancy as development regresses with hypotonia, irritability and macrocephaly Diagnosis: MRI Brain scan. low NAA in urine /CSF. Genetics Spontaneous inheritance, Glial fibrillary acidic protein deficiency Usually presents less than 2 years with developmental delay, spasticity and macrocephaly Diagnosis: MRI Brain scan. Genetics X-linked, affecting ATP binding cassette transporters Childhood cerebral onset form c 4e10 years, toe walking and ‘diplegic pattern’ with emerging learning/ behavioural difficulties. Diagnosis: MRI Brain scan. Raised Very Long Chain Fatty Acid levels. Genetics. Monitor Adrenal function.
Table 4
symptomatic stages of MLD and ALD (often the siblings of an index case). Metabolic disorders An underlying metabolic disorder should be suspected if there is a history of relapsing encephalopathy, often provoked by intercurrent illness or high protein intake. A complete list of these rare
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Case 1 A girl was born at term to non-consanguineous parents with normal neonatal period. She began walking at 13 months but her gait failed to mature. By 20 months of age, parents reported deterioration in her gross and fine motor skills as well as feeding difficulties. At 2 years of age, she stopped walking independently. Assessment revealed some drooling. There was the impression of mild weakness without hypertonia and no deep tendon reflexes could be elicited.
Key investigations Initial MRI scan was performed outside the UK at 2 years of age. This was initially reported to show white matter damage of immaturity. Repeat MRI brain scan 6 months later showed progressive diffuse abnormal white matter signal. Figure 1 showing progressive diffuse and confluent white matter signal.
Figure 1 MRI Brain scans taken at a) 2 years b) 2 years six months showing progressive diffuse and confluent white matter signal.
EMG study showed severe demyelinating neuropathy affecting sensory and motor nerves in upper and lower limbs. CSF protein 255 mg/dL (normal range 20e50). Leucocyte enzymes: Arylsulphatase A 1.0 nmol/hr/mg (normal range 22e103). Urine confirmed presence of metachromatic granules. Mutation in ARSA gene on genetic testing. Diagnosis: Metochromatic leucodystrophy.
disorders is beyond the scope of this article but some of the more common mimics of motor CP are considered below.
retinal examination. Diagnosis is confirmed by low fatty aldehyde dehydrogenase levels in blood and genetic testing demonstrates mutation in ALDH3A2 gene.
Arginase deficiency: this autosomal recessive disorder of the urea cycle, results in raised arginine levels and inconsistent elevation of ammonia concentration. Children usually present around 3 years of age with progressive spastic paraparesis. Regression of cognitive skills typically follows, with failure to thrive in the context of seizures and tremor. Diagnosis is confirmed by measuring arginase levels in cultured skin fibroblasts.
Disorders of vitamin metabolism and nutritional deficiencies Biotinidase deficiency: children with biotinidase deficiency are unable to recycle the vitamin Biotin (B7). Neurological features include seizures, hypotonia, ataxia, developmental delay, disturbed vision and hearing and cutaneous abnormalities (such as alopecia and skin rashes). Older children with profound biotinidase deficiency may exhibit weakness, spastic paresis and optic atrophy. Blood tests confirm low biotinidase levels. Prompt treatment with oral biotin is vital, since neurological signs are usually irreversible. Many countries now offer neonatal screening.
Sjorgen Larsson syndrome: a rare recessive disorder caused by disruption of fatty acid oxidation which results in nonprogressive congenital ichthyosis, spastic paraplegia and cognitive delay, particularly affecting speech. MRI scan shows leukoencephalopathy. Crystalline maculopathy is often found on
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progressive generalized dystonia, often associated with evolving MRI changes (Figure 2), which typically affect basal ganglia and brain stem. Retinopathy, renal tubulopathy and peripheral neuropathy may also be present. Raised plasma and CSF lactate levels, along with raised alanine levels are further evidence of mitochondrial dysfunction. The gold standard tests are of analysis of muscle histology and respiratory chain enzyme analysis with exome sequencing of mitochondrial and nuclear DNA.
Primary cerebral folate deficiency: this results from several disorders of folate transport and metabolism. Clinical characteristics include lower limb spasticity, postnatally acquired microcephaly and developmental delay often with autism, epilepsy, ataxia and dyskinesia. The diagnosis is confirmed by demonstrating low levels of 5-methyl tetrahydrofolate in CSF neurotransmitter measurement in the context of normal peripheral serum folate. Treatment with folinic acid in early childhood may result in improvement.
Lesch Nyhan syndrome: this X-linked disorder is caused by mutations in the HPRT1 gene with a lack of hypoxanthine phosphoribosyl-transferase 1 and failure to recycle purines. As a result, uric acid progressively accumulates in body tissues to cause renal calculi and gouty arthritis. Affected children are delayed in sitting and most never walk. Within the first few years, extrapyramidal and pyramidal signs emerge (a mixture of dystonia, choreoathetosis, opisthotonus and spasticity with hyperreflexia and extensor plantar reflexes). Between ages two and three years, persistent self-injurious behaviours develop with biting of fingers, hands, and lips being a hallmark of the disease. Diagnostic features are of raised urinary urate-tocreatinine ratio (more than 2.0) and low enzyme activity in blood. Mutation analysis confirms the diagnosis.
Extrapyramidal/dyskinetic motor disorders Dyskinetic CP is characterized by abnormal movements or postures due to defective coordination of movement and/or regulation of muscle tone. It is generally subdivided into dystonic and hyperkinetic forms. In dystonia, movements are slow and sustained, sometimes with spasms whereas in hyperkinetic CP, they are slow and writhing (athetoid) or rapid jerky (choreiform) movements. There is often some associated spasticity. Typically children with dyskinetic CP are initially hypotonic, usually over the first few months but sometimes into the second year of life. Around 75% of affected children will have a history of adverse events around delivery (e.g. hypoxia or bilirubin encephalopathy). In the dystonic child with no risk factors and a normal MRI scan of brain and spine, it is important to consider other causes of dystonia (genetic and metabolic).
Wilson’s disease: this autosomal recessive condition is caused by mutations in ATP7B gene and as a result, copper accumulates in body tissues, particularly brain and liver. In around 50% of cases this results in neurological or psychiatric symptoms with Parkinsonism, tremor, ataxia and dyskinesia along with emotional lability and impulsiveness. Liver disease occurs in the remainder (usually with hepatic encephalopathy or fulminant liver failure). Other affected organs include eyes (Keyser Fleischer rings), kidneys (renal tubular acidosis) and heart (cardiomyopathy). Diagnosis is suggested by abnormal liver function tests sometimes with prolonged prothrombin time, low levels of serum copper and ceruloplasmin and raised 24-hour copper excretion. MRI changes evolve with increasing symptoms, showing high signal in basal ganglia on T2 weighted images Liver biopsy is the gold standard diagnostic test.
Genetic dystonia Dopa responsive dystonia (DRD): this condition is characterized by a history of dystonia with diurnal fluctuation, so that gait worsens through the day and is improved by sleep. The commonest cause for this is a mutation in GTP cyclohydrolase gene which is dominantly inherited but of low penetrance. Only 30 e40% of people carrying the gene will develop the condition. The dystonia usually shows a dramatic and sustained response to small doses of levodopa. GTP cylcohydrolase is a rate limiting enzyme in the synthesis of tetrahydrobiopterin (BH4) and analysis of neurotransmitter levels in CSF typically shows low levels of neopterin and BH4 and the dopamine metabolite homovanillic acid. Recessive forms of DRD are less common and may show only a partial response to trials of levodopa treatment. DRD is not entirely excluded by normal CSF neurotransmitters. Gene analysis and a trial of levodopa should still be considered in all children presenting with dystonia, where causation is not established.
GLUT1 deficiency: this disorder results from mutations in the SLC2A1 gene, which facilitates glucose transportation across the blood brain barrier. As a result, CSF glucose levels are low and can cause seizures in infancy with acquired microcephaly and developmental impairment. It can also cause both paroxysmal and persistent movement disorders, most often dyskinetic in nature, with dystonic gait or choreoathetosis or ataxia. Diagnosis is confirmed by demonstrating a low CSF to plasma glucose concentration (typically less than 0.4) and mutations in SLC2A1 gene. Although it can be dominantly inherited most mutations occur de novo.
Rett syndrome: this is caused by mutations in MECP2 gene or CDKL5 gene and almost exclusively presents in girls, initially with developmental delay and hypotonia, but gradually characteristic midline hand stereotypies emerge. These become more intrusive around 1e4 years and there is more generalised regression, often with marked irritability. In the later stages dystonia and spasticity develops. Acquired microcephaly, seizures and paroxysmal breathing pattern suggest the diagnosis which is confirmed by genetic analysis.
Glutaric aciduria type 1 (GA1): GA1 is caused by mutations in the GCDH gene, responsible for production of the enzyme glutaryl-CoA dehydrogenase. This metabolises the amino acids lysine, hydroxylysine, and tryptophan; in GA1 their intermediate breakdown products build up to abnormal levels, especially at times of stress. Affected children often have macrocephaly, secondary to subdural effusions and early hypotonia with mild
Metabolic dystonia Mitochondrial disease: mitochondrial disorders have protean clinical manifestations and can be difficult to confidently exclude. Clinical clues are of episodic encephalopathy and
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SYMPOSIUM: CEREBRAL PALSY
Figure 2 Evolving MRI brain changes in Mitochondrial Disorder. T2 images from an MRI scan taken at 5 years 8 months and repeated 3 years later at 8 years 8 months demonstrating increasing signal in basal ganglia and brain stem.
progressive cerebellar ataxia with poor balance and coordination and intention tremor.
developmental delay. Presentation is often with acute metabolic crises with exacerbation of symptoms particularly dystonia. Analysis of urine organic acids and genetic analysis confirms the diagnosis. Neonatal blood spot screening has recently been introduced so that early treatment can be offered before the potentially devastating effects of acute decompensation.
Genetic conditions Angelman syndrome: this results from disruption of UBE3A gene, which is usually due to maternally inherited deletions. Typically, it presents with apparent ataxia and severe developmental delay (particularly in expressive language). Children often have a happy demeanour and have acquired microcephaly and seizures. The EEG shows a characteristic pattern with large amplitude slowspike waves. Genetic testing confirms the diagnosis.
Neurodegeneration with Brain Iron Accumulation (NBIA) (Case 2): in these conditions, iron accumulates in the basal ganglia, which is associated with progressive dystonia, spasticity, Parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Ten different conditions are recognized, each with specific genetic mutations. The age of onset and rate of progression varies even within each disorder.
Joubert syndrome: over six underlying genotypes are now recognized to cause this specific ciliopathy. It results in congenital brain malformation of the cerebellar vermis and brainstem, which can be seen in the axial plane of MRI scan as a “molar tooth” sign. Clinically children present with ataxia and developmental delay with oculomotor apraxia. There is often a history of hyperpnoea intermixed with central apnoea in the neonatal period. Renal cysts and retinopathy often develop in later life.
Ataxic disorders There should be caution with the diagnosis ataxic CP since several genetic and metabolic disorders can mimic this in their early stages. In CP, predominant features are those of non-
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Case 2 A girl was born at 25 weeks gestation with a birth weight of 710 g. She was the third child of consanguineous parents with no relevant family history. Small bilateral intraventricular haemorrhages were noted. Early developmental milestones were delayed but she made good progress. At 7 years of age she could walk with a frame, hold a pen and count to 20. She showed good understanding of language and used several single words. She fed well. Following dental treatment at 8 years she deteriorated dramatically with drooling, feeding difficulties and gradual loss of speech. She evolved dystonic posturing spreading to all 4 limbs and disturbing sleep. By 9 years, she became aphasic and required nasogastric feeds. She showed persistent dystonic posturing of legs and hands with tongue protrusion (Figure 3). Key investigations MRI
Figure 3 MRI Brain scan shows lack of cerebral white matter bulk with thinning of the corpus callosum. The cerebellum is small and atrophic. There is bilateral pallidal iron deposition. Loss of response on electroretinogram. Acanthocytes found on blood film. Genetic testing confirms homozygous mutation in PANK2 gene. Diagnosis: initially Bilateral spastic CP GMFCS111 secondary to prematurity. Later regression due to Pantothenate kinase-associated neurodegeneration (PKAN).
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plantar responses can develop. Sensory examination is abnormal with abnormal proprioception and vibration sense. The most serious risk of Vitamin B12 deficiency is Subacute Combined Degeneration of the spinal cord, which may also involve brain, optic nerves and peripheral nerves. Typical symptoms are of tingling of fingers and toes, before deterioration of gait, weakness and fatigue. Low B12 and folate levels with megaloblastic anaemia are found on blood tests. Nerve conduction studies show a sensory neuropathy. It can result from malabsorption or pernicious anaemia. Vitamin E deficiency may be associated with anaemia and retinopathy. It usually results from fat malabsorption, usually in the context of systemic disorders such as cystic fibrosis, but also occurs in abetalipoproteinemia.
Friedreich ataxia: this is the most common form of hereditary ataxia, affecting about one in every 50,000 individuals and caused by loss of function in the frataxin gene. Symptoms typically begin between the ages of 5 and 15 years (although sometimes not until late adult life), with progressive gait ataxia often with pes cavus and loss of proprioception and tendon reflexes. Cerebellar signs evolve with past pointing and dysarthria. Many people with Friedreich’s ataxia develop scoliosis and later diabetes, hearing and vision loss. Hypertrophic cardiomyopathy usually develops and limits life expectancy. Ataxia telangiectasia: in this autosomal recessive multisystem disorder, first symptoms are usually of ataxia as the child begins to walk and are associated with abnormal head thrusting (a result of oculomotor apraxia). It is slowly and steadily progressive with dystonia often seen in later stages. Immunodeficiency and risk of malignancy are additional features. Diagnosis is established by characteristic MRI changes (cerebellar atrophy and increased white matter signal changes on T2-weighted images). Blood tests show elevated levels of alpha-fetoprotein and absent or low level of immunoglobulin A. Radiation studies show excessive chromosomal fragility and DNA sequencing confirms mutation of the ATM gene.
Conclusion A careful history, clinical examination and neuroimaging are essential when considering a diagnosis of CP. The genetic and metabolic mimics of CP discussed are all individually rare so a focused approach is needed; based on clinical clues and targeted investigations. The opinion of a neurologist and geneticist can be invaluable in guiding investigations further when a CP diagnosis doesn’t fit. A correct diagnosis has huge implications in terms of prognosis, specific treatments and genetic counselling. A
Cockayne syndrome: this recessive condition results from defective DNA nucleotide excision repair, secondary to mutations in ERCC gene. Criteria required for the diagnosis include poor growth with microcephaly and progressive neurological degeneration with ataxia and tremor. Other common manifestations include sensorineural hearing loss, cataracts, pigmentary retinopathy and cutaneous photosensitivity.
FURTHER READING Carr LJ. Clinical presentation of cerebral palsy in cerebral palsy: Science and clinical practice. In: Dan B, Mayston M, Paneth N, Rosenbloom L, eds. MacKeith Press, Nov 2014. Gupta R, Appleton RE. Cerebral palsy: not always what it seems. Arch Dis Child 2001; 85: 356e60. Huntsman R, Lemire E, Norton J, Dzus A, Blakley P, Hasal S. The differential diagnosis of spastic diplegia. Arch Dis Child 2015; 100: 500e4.
Pelizaeus-Merzbacher disease: mutations in the PLP1 gene are inherited in an X-linked recessive pattern and result in dysmyelination on MRI scan. Classic Pelizaeus-Merzbacher disease is the more common type and within the first year of life, affected boys demonstrate hypotonia with motor delay. The consistent finding of pendular nystagmus is an important clue to the diagnosis. As the child matures nystagmus diminish but other movement disorders develop, including spasticity, ataxia and chorea.
Acknowledgements Acknowledgement to Dr Kling Chong Consultant Paediatric Neuroradiologist, Great Ormond Street Hospital, London WC1N3JH for help with MRI images.
Metabolic conditions Non-ketotic hyperglycinaemia: this most commonly presents as a neonatal encephalopathy with intractable seizures and hiccoughs. However it can present later with cerebellar ataxia. CSF amino acids confirm raised glycine levels.
Personal practice points Maple syrup urine disease: this is caused by disordered metabolism of branch chain amino acids. It classically presents in the neonatal period on introduction of milk feeds however there are rare intermittent forms which can present later with episodic encephalopathy associated with ataxia or dystonia. At such time, sweat and urine will smell of maple syrup. Ketosis and high levels of branch chain amino acids are found.
C
C
C
Disorders of vitamin metabolism and nutritional deficiencies Apparent ataxia can occur if proprioception is abnormal and this can be mistaken as CP; as sometimes seen in B12 and vitamin E deficiency disorders. If untreated progressive spastic-ataxic gait associated with loss of lower limb tendon reflexes and upgoing
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C
C
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Be mindful of ‘Red Flags’ when reviewing a child with CP and consider referral on for more specialist neurogenetic/metabolic opinion. Remember that MRI scan changes can evolve over time, so imaging should be repeated if the child shows unusual progression of symptoms or signs. If MRI scan features are NOT concordant with the clinical history this may suggest another underlying condition. A trial of levodopa should still be considered in all children presenting with dystonia, where causation is not established. Ataxic CP is rare and has several genetic and metabolic mimics in early childhood.
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