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The differential diagnosis of spastic diplegia Richard Huntsman,1 Edmond Lemire,2 Jonathon Norton,3 Anne Dzus,4 Patricia Blakley,5 Simona Hasal1 1
Division of Pediatric Neurology, Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 2 Division of Medical Genetics, Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 3 Division of Neurosurgery, Department of Surgery, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 4 Division of Pediatric Orthopedics, Department of Surgery, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 5 Division of Developmental Pediatrics, Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Correspondence to Dr Richard J Huntsman, Division of Pediatric Neurology, Department of Pediatrics, University of Saskatchewan, 103 Hospital Drive, Saskatoon, Saskatchewan S7N-0W8, Canada; [email protected] Received 28 August 2014 Revised 25 October 2014 Accepted 29 October 2014
To cite: Huntsman R, Lemire E, Norton J, et al. Arch Dis Child Published Online First: [ please include Day Month Year] doi:10.1136/archdischild2014-307443
ABSTRACT Spastic diplegia is the most common form of cerebral palsy worldwide. Many disorders mimic spastic diplegia, which can result in misdiagnosis for the child with resultant negative treatment and family counselling implications. In this paper, the authors provide a brief review of spastic diplegia and the various disorders in the differential diagnosis. We also provide a diagnostic algorithm to assist physicians in making the correct diagnosis.
INTRODUCTION Spastic diplegia is a form of cerebral palsy (CP) where spasticity predominates in the lower extremities with minimal upper extremity involvement. It is strongly associated with prematurity.1 It is the most common subtype comprising 34% of all children in a multinational European CP study.2 Spastic paraplegia refers to lower limb spasticity due to a spinal cord lesion. Although the causative cerebral lesion is static, children with spastic diplegia typically go through a progression of abnormalities of tone, posture and gait. Standing and walking are acquired late with equinovarus posturing of the ankles due to spasticity of the calf muscles.3 As the child ages, progressive spasticity of the hip flexors and hamstrings can result in a crouch gait, which makes prolonged walking difficult, thus giving the appearance of neurological deterioration.4 The most common cerebral lesion encountered with spastic diplegia is periventricular leukomalacia (PVL) characterised by bilateral necrosis of the frontal and parietal periventricular white matter.5 The topographical distribution of the corticospinal tracts in the frontal periventricular regions results in the diplegic pattern of motor impairment.6 The imaging features of PVL include enlarged scalloped lateral ventricles, periventricular gliosis, loss of white matter and thinning of the corpus callosum.7 PVL is identified in approximately 75% of all children with spastic diplegia.2 6 Excluding slowly progressive neurological disorders from a diagnosis of CP can be challenging as both frequently share similar patterns of motor impairment.8 In a highly consanguineous South Asian population in Northern England, the number of children diagnosed with CP was almost three times that expected, indicating that genetic or inherited metabolic disorders accounted for a high percentage of these diagnoses.9 The American Academy of Neurology recommends that routine metabolic and genetic testing not be performed unless there are features atypical of CP on history and physical examination. All children diagnosed with CP should have neuroimaging,
preferably with MRI. If the MRI is normal, then metabolic or genetic screening should be considered especially if the history does not support the diagnosis of CP.10 Clinical features that should alert the physician to an alternate diagnosis to spastic diplegia would include; absence of premature birth, parental consanguinity, family history of CP, bulbar dysfunction, fluctuations in degree of motor impairment, bowel and bladder dysfunction and severe cognitive impairment. In our own experience, the diagnosis of CP tends to persist even though the clinical features suggest an alternate diagnosis. In this paper, the authors aim to provide a clinical review of those conditions that can mimic spastic diplegia and provide a diagnostic algorithm to aid in making the correct diagnosis (figure 1).
IDIOPATHIC TOE WALKING Benign idiopathic (habitual) toe walking is the abnormal persistence of toe walking after 2 years of age in the absence of any cause. Its presence can be associated with abnormal language development and autism.11 Despite weight bearing on the balls of their feet, the gait otherwise looks well coordinated and these children can walk and run at normal velocities.11 Apart from some tightness in the calf muscles and heel cords, the neurological exam is normal and most children are able to walk with a heel strike. Familial toe walking has been well described and a positive family history strongly supports this diagnosis.12 Normal gait is attained in almost all children with daily stretching, splinting and occasionally casting. Surgical intervention is rarely required.11 Idiopathic toe walkers attain walking at a normal age, while those with spastic diplegia are usually late to start and have tight hamstrings and a reduced range of popliteal angles during goniometry. During gait analysis, the idiopathic toe walker will typically exhibit knee hyperextension while the child with spastic diplegia will have abnormal knee flexion in the terminal swing phase of the gait cycle. Addition of dynamic electromyography to the gait analysis can further aid in the differentiation.11
DYSTONIA Dystonia is a hyperkinetic movement disorder with continuous contraction of agonist and antagonist muscle groups causing sustained posturing of the trunk or limbs. Clinically, dystonia can usually be differentiated from spasticity by the presence of rigidity throughout the entire range of movement of the affected limbs and the lack of a spastic catch. Transient dystonic toe walking typically presents in early infancy with asymmetrical toe walking as soon as the child starts to ambulate. The degree of
Huntsman R, et al. Arch Dis Child 2014;0:1–5. doi:10.1136/archdischild-2014-307443
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Huntsman R, et al. Arch Dis Child 2014;0:1–5. doi:10.1136/archdischild-2014-307443
Figure 1 Demonstrating proposed diagnostic algorithm of child with presumed diagnosis of spastic diplegic cerebral palsy. The algorithm is weighted towards the clinical assessment of the child as opposed to MRI findings or metabolic/genetic evaluation. BCAA, branch chain aminoaciduria; BITW, benign idiopathic toe walking; CSF, cerebrospinal fluid; DRD, dopa-responsive dystonia; HSP, hereditary spastic paraplegia; PLS, primary lateral sclerosis; PVL, periventricular leukomalacia; TCS, tethered cord syndrome; TDTW, transient dystonic toe walking; UCD, urea cycle defect; 5-MTFH, 5-methytetrahydrofolate deficiency.
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Review dystonic posturing of the ankle often fluctuates. On examination, there is rigidity with resistance to passive movement of the ankle in all directions. Unlike spasticity, this rigidity does not change with leg position or with velocity of the passive movement. Dystonic toe walking eventually resolves after several months.13 Dopa-responsive dystonia (DRD) is an uncommon primary dystonia with a median age of onset of 6 years. It is frequently misdiagnosed as spastic diplegia.14 It usually presents with asymmetric lower limb rigidity that gradually generalises by early adulthood. At the time of presentation, most children have bilateral limb rigidity and equinovarus foot posturing. Lower limb tendon reflexes are brisk with ankle clonus, but the plantar response is usually normal. Occasionally a striatal toe can be seen. The most striking feature of DRD is marked diurnal variation of symptoms with worsening of symptoms as the day progresses and near complete resolution after sleep. This diurnal variation attenuates with age and is no longer seen by adulthood.15 Other features that suggest DRD are tremor and parkinsonism with decreased velocity of rapid repetitive hand movements.16 Most cases are due to a mutation in the gene (GCH1) that encodes the enzyme guanosine-5-triphosphate cyclohydrolase I (GTPCH1) on chromosome 14q22.2. Inherited in an autosomal-dominant fashion, the penetrance rate is 35%–100% with a female predilection.17 GTPCH1 is the enzyme responsible for the synthesis of tetrahydrobiopterin (BH4), an essential cofactor for the enzyme tyrosine hydroxylase that converts tyrosine to levodopa.15 Rare cases of autosomal-recessive DRD due to homozygous mutations in the genes that code for GTPCH1 and tyrosine hydroxylase are seen. In cases associated with GCH1 mutations, cerebrospinal fluid analysis shows decreased levels of dopamine metabolites.16 Genetic analysis is able to detect up to 90% of mutations in the GCH1 gene.17 Treatment with low-dose levodopa/carbidopa (4–5 mg/kg/day of levodopa) will result in a marked resolution of symptoms with minimal side effects.15 A therapeutic challenge with levodopa/carbidopa should be considered in any child whose diagnosis of spastic diplegia is uncertain due to the dramatic improvement in symptoms seen in children with DRD after a short period of treatment.14
of HSP are pure and inherited in an autosomal-dominant fashion.20 Because of its slowly progressive course, HSP should be considered in any child with a diagnosis of spastic diplegia where no underlying cause is found.20 In children, the most common forms of HSP are SPG3A and SPG4 due to mutations in the atlastin-1 and spastin genes, respectively. Both are autosomal dominant with a predominantly pure presentation. Genes have been identified for 41 different forms of HSP. PLS is a rare disorder characterised by progressive spasticity starting in the lower extremities which eventually involves the upper extremities and bulbar muscles due to corticospinal tract degeneration. Sensory pathways are not affected; therefore, proprioception and somatosensory evoked potentials (SSEP) are normal. While onset is typically in the fifth decade, a juvenile form ( JPLS) can occur with onset in the first decade with affected patients and wheelchair users with severe bulbar dysfunction by the second decade.21 JPLS is autosomal recessive and secondary to a mutation in the ALS2 (alsin) gene that is also implicated in autosomal-recessive amyotrophic lateral sclerosis.22 A rare severe infantile variant called infantile-onset ascending HSP is also caused by mutations in ALS2.23
HEREDITARY ATAXIAS WITH LOWER LIMB SPASTICITY There are multiple hereditary progressive ataxias including Friedreich ataxia and the hereditary spastic-ataxias. All are associated with cerebellar atrophy on neuroimaging. Children with Friedreich ataxia typically have absent lower limb reflexes, distinguishing it from spastic diplegia.24 The hereditary spastic-ataxia syndromes comprise a rare group of disorders characterised by slowly progressive lower limb spasticity and ataxia. Childhood onset is common. Of these, autosomal-recessive ataxia of Charlevoix–Saguenay is the most prevalent. Initially described in Quebec, a worldwide distribution is now recognised. To date, five other hereditary spastic ataxias with childhood onset have been described in isolated kinships worldwide. Most of these are autosomal recessive with the exception of an autosomal-dominant form described in Newfoundland.25
TETHERED CORD SYNDROME HEREDITARY MYELOPATHIES The inherited myelopathies include hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). Onset in childhood often results in a misdiagnosis of spastic diplegia.18 HSP is characterised by progressive spasticity and weakness of the lower extremities without bulbar and upper extremity involvement. To date, over 50 different gene loci associated with HSP have been reported. HSP can be inherited in an autosomal-dominant, autosomal-recessive, X-linked recessive or maternally inherited pattern. Affected genes are involved in the physiological maintenance of axons within the corticospinal tracts.19 HSP can be classified as pure or complex depending on the presence of other neurological or systemic features. Patients with pure HSP will have slowly progressive lower limb spasticity. Urinary dysfunction from hypertonic bladder is common. Most patients have decreased proprioception and vibration sense due to involvement of the posterior columns.19 Lower limb spasticity begins at any age and progression is gradual without acute exacerbations or remissions.18 Complicated HSP has a similar clinical presentation along with other neurological and nonneurological findings including hydrocephalus, developmental delay, retinopathy and pigmentary skin lesions.18 19 Most cases Huntsman R, et al. Arch Dis Child 2014;0:1–5. doi:10.1136/archdischild-2014-307443
Tethered cord syndrome results from stretching of the caudal elements of the spinal cord and is frequently associated with occult spinal dysraphisms such as thickened filum terminale and spinal lipoma. These are frequently associated with overlying cutaneous and vertebral abnormalities.26 Neurological dysfunction in tethered cord syndrome results from traction-induced oxidative dysfunction in neural elements of the lumbosacral spinal cord.27 Most children with tethered cord syndrome present with weakness of the lower extremities with muscle atrophy and hyporeflexia. However, some can present with lower limb spasticity resulting from spinal cord ischaemia. Associated findings such as back pain, urinary incontinence and patchy sensory disturbances are frequently associated.26 In infants and young children, pain typically manifests as irritability and is aggravated by performing tasks causing flexion of the spine.28 The diagnosis of tethered cord syndrome is confirmed with imaging of the lower spine showing a low lying conus medullaris below the level of L2 vertebral body. MRI is the imaging modality of choice allowing visualisation of the entire spinal cord and filum terminale along with associated vertebral elements.28 Lower limb SSEPs can document physiological evidence of spinal cord dysfunction. Early recognition and surgical 3
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Review intervention of tethered cord syndrome may result in improved outcomes especially with regards to pain and prevention of further motor decline.29
LEUKODYSTROPHIES The leukodystrophies are genetically determined disorders affecting myelin development within the central nervous system.30 The clinical presentation of the leukodystrophies typically follows a period of normal development with progressive bilateral spasticity. Behavioural and cognitive decline also occur, which differs from spastic diplegia where cognitive delay, if present, tends to be mild and is static.31 MRI often reveals symmetrical dysmyelination with increased T2 signal intensity in the periventricular cerebral white matter with sparing of the subcortical U-fibres. The pattern of cerebral dysmyelination seen on MRI can be helpful in determining the aetiology of the leukodystrophy.32 Several leukodystrophies such as Krabbe Disease, Metachromatic Leukodystrophy and Juvenile Onset Alexander Disease have late-onset forms with predominant lower limb spasticity. The spasticity can be slowly progressive with cognitive function remaining intact, resulting in the appearance of a static process.33–36 Sjogren– Larsson syndrome, a leukodystrophy due to deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol:NAD+ oxidoreductase, typically presents in the first year of life with ichthyosis, developmental delay and lower limb spasticity. The presence of ichthyosis and moderate to severe developmental delay differentiates this disorder from spastic diplegia. Cerebral MRI reveals abnormal T2 changes throughout the frontal and parietal white matter. Diagnosis can be confirmed with enzyme or genetic analysis.30
DISORDERS OF AMINO AND ORGANIC ACID METABOLISM AND UREA CYCLE DEFECTS Several inherited disorders of amino and organic acid metabolism have been associated with the development of slowly progressive lower limb spasticity that can be mistaken for spastic diplegia.37 Clinical suspicion of these disorders should be raised when the patient has a history of relapsing encephalopathy in the face of catabolic stress provoked by illness or high protein intake. Among the disorders of amino acid metabolism, both late-onset non-ketotic hyperglycinaemia and disorders of branch chain amino acid metabolism (in particular, Maple Syrup Urine Disease and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency) can cause slowly progressive lower limb spasticity with periventricular cerebral white matter abnormalities mimicking spastic diplegia.38–41 Diagnosis is made by testing the cerebrospinal fluid:plasma glycine ratio in the case of nonketotic hyperglycinaemia and urine organic acid analysis in the branch chain aminoacidopathies. Both argininaemia and triple H syndrome are urea cycle defects that can mimic spastic diplegia.42 43 Cerebral MRI findings can range from normal to diffuse cerebral atrophy. Diagnosis is made with plasma amino acid and ammonia profiles.
DISORDERS OF VITAMIN METABOLISM AND NUTRITIONAL DEFICIENCIES Children with inherited disorders of vitamin metabolism can present with a clinical picture similar to spastic diplegia. Primary cerebral folate deficiency can result from several disorders of folate transport and metabolism. Clinical characteristics include lower limb spasticity, deceleration of head growth and 4
developmental delay often with autism, epilepsy, ataxia and dyskinesia. The diagnosis is confirmed by measuring decreased levels of 5-methyltetrahydrofolate in the cerebrospinal fluid. Treatment with folinic acid in early childhood may result in improvement of symptoms.44 An inherited disorder affecting vitamin E metabolism and transport results in a progressive spastic-ataxic gait associated with loss of lower limb tendon reflexes, upgoing plantar responses and impaired proprioception. Dysarthria and gaze palsies may also occur. Diagnosis is made by measuring serum vitamin E levels, and response to vitamin E supplementation is favourable.45 Tropical paraplegia causes lower limb spasticity without associated sensory deficits. While most cases are due to chronic human T-lymphotropic virus 1 infection, some cases such as konzo and lathyrism seen in Africa and the Indian subcontinent result from excessive consumption of foods containing neurotoxic substances.45
CONCLUSION Recent advances in neuroimaging and molecular genetics have improved the diagnosis of many neurological disorders that may mimic spastic diplegia. Correctly identifying these conditions rests firmly with the recognition that the patient has features on history and physical examination atypical of spastic diplegia and a strong index of suspicion that an alternate diagnosis may be responsible. The authors reemphasise the importance of obtaining the expertise of a paediatric neurologist and medical geneticist with expertise in metabolic disease as part of the multidisciplinary team involved in the diagnosis and care of these children.46 While the disorders discussed in the preceding section and diagnostic algorithm are not an exhaustive differential diagnosis of spastic diplegia, it is hoped that an awareness of these diagnostic possibilities will help the clinician to recognise the possibility of an underlying condition that has treatment or genetic implications for the patient and their families. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
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ADC Online First, published on November 18, 2014 as 10.1136/archdischild-2014-307443 Review
The differential diagnosis of spastic diplegia Richard Huntsman,1 Edmond Lemire,2 Jonathon Norton,3 Anne Dzus,4 Patricia Blakley,5 Simona Hasal1 1
Division of Pediatric Neurology, Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 2 Division of Medical Genetics, Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 3 Division of Neurosurgery, Department of Surgery, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 4 Division of Pediatric Orthopedics, Department of Surgery, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 5 Division of Developmental Pediatrics, Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Correspondence to Dr Richard J Huntsman, Division of Pediatric Neurology, Department of Pediatrics, University of Saskatchewan, 103 Hospital Drive, Saskatoon, Saskatchewan S7N-0W8, Canada; [email protected] Received 28 August 2014 Revised 25 October 2014 Accepted 29 October 2014
To cite: Huntsman R, Lemire E, Norton J, et al. Arch Dis Child Published Online First: [ please include Day Month Year] doi:10.1136/archdischild2014-307443
ABSTRACT Spastic diplegia is the most common form of cerebral palsy worldwide. Many disorders mimic spastic diplegia, which can result in misdiagnosis for the child with resultant negative treatment and family counselling implications. In this paper, the authors provide a brief review of spastic diplegia and the various disorders in the differential diagnosis. We also provide a diagnostic algorithm to assist physicians in making the correct diagnosis.
INTRODUCTION Spastic diplegia is a form of cerebral palsy (CP) where spasticity predominates in the lower extremities with minimal upper extremity involvement. It is strongly associated with prematurity.1 It is the most common subtype comprising 34% of all children in a multinational European CP study.2 Spastic paraplegia refers to lower limb spasticity due to a spinal cord lesion. Although the causative cerebral lesion is static, children with spastic diplegia typically go through a progression of abnormalities of tone, posture and gait. Standing and walking are acquired late with equinovarus posturing of the ankles due to spasticity of the calf muscles.3 As the child ages, progressive spasticity of the hip flexors and hamstrings can result in a crouch gait, which makes prolonged walking difficult, thus giving the appearance of neurological deterioration.4 The most common cerebral lesion encountered with spastic diplegia is periventricular leukomalacia (PVL) characterised by bilateral necrosis of the frontal and parietal periventricular white matter.5 The topographical distribution of the corticospinal tracts in the frontal periventricular regions results in the diplegic pattern of motor impairment.6 The imaging features of PVL include enlarged scalloped lateral ventricles, periventricular gliosis, loss of white matter and thinning of the corpus callosum.7 PVL is identified in approximately 75% of all children with spastic diplegia.2 6 Excluding slowly progressive neurological disorders from a diagnosis of CP can be challenging as both frequently share similar patterns of motor impairment.8 In a highly consanguineous South Asian population in Northern England, the number of children diagnosed with CP was almost three times that expected, indicating that genetic or inherited metabolic disorders accounted for a high percentage of these diagnoses.9 The American Academy of Neurology recommends that routine metabolic and genetic testing not be performed unless there are features atypical of CP on history and physical examination. All children diagnosed with CP should have neuroimaging,
preferably with MRI. If the MRI is normal, then metabolic or genetic screening should be considered especially if the history does not support the diagnosis of CP.10 Clinical features that should alert the physician to an alternate diagnosis to spastic diplegia would include; absence of premature birth, parental consanguinity, family history of CP, bulbar dysfunction, fluctuations in degree of motor impairment, bowel and bladder dysfunction and severe cognitive impairment. In our own experience, the diagnosis of CP tends to persist even though the clinical features suggest an alternate diagnosis. In this paper, the authors aim to provide a clinical review of those conditions that can mimic spastic diplegia and provide a diagnostic algorithm to aid in making the correct diagnosis (figure 1).
IDIOPATHIC TOE WALKING Benign idiopathic (habitual) toe walking is the abnormal persistence of toe walking after 2 years of age in the absence of any cause. Its presence can be associated with abnormal language development and autism.11 Despite weight bearing on the balls of their feet, the gait otherwise looks well coordinated and these children can walk and run at normal velocities.11 Apart from some tightness in the calf muscles and heel cords, the neurological exam is normal and most children are able to walk with a heel strike. Familial toe walking has been well described and a positive family history strongly supports this diagnosis.12 Normal gait is attained in almost all children with daily stretching, splinting and occasionally casting. Surgical intervention is rarely required.11 Idiopathic toe walkers attain walking at a normal age, while those with spastic diplegia are usually late to start and have tight hamstrings and a reduced range of popliteal angles during goniometry. During gait analysis, the idiopathic toe walker will typically exhibit knee hyperextension while the child with spastic diplegia will have abnormal knee flexion in the terminal swing phase of the gait cycle. Addition of dynamic electromyography to the gait analysis can further aid in the differentiation.11
DYSTONIA Dystonia is a hyperkinetic movement disorder with continuous contraction of agonist and antagonist muscle groups causing sustained posturing of the trunk or limbs. Clinically, dystonia can usually be differentiated from spasticity by the presence of rigidity throughout the entire range of movement of the affected limbs and the lack of a spastic catch. Transient dystonic toe walking typically presents in early infancy with asymmetrical toe walking as soon as the child starts to ambulate. The degree of
Huntsman R, et al. Arch Dis Child 2014;0:1–5. doi:10.1136/archdischild-2014-307443
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Huntsman R, et al. Arch Dis Child 2014;0:1–5. doi:10.1136/archdischild-2014-307443
Figure 1 Demonstrating proposed diagnostic algorithm of child with presumed diagnosis of spastic diplegic cerebral palsy. The algorithm is weighted towards the clinical assessment of the child as opposed to MRI findings or metabolic/genetic evaluation. BCAA, branch chain aminoaciduria; BITW, benign idiopathic toe walking; CSF, cerebrospinal fluid; DRD, dopa-responsive dystonia; HSP, hereditary spastic paraplegia; PLS, primary lateral sclerosis; PVL, periventricular leukomalacia; TCS, tethered cord syndrome; TDTW, transient dystonic toe walking; UCD, urea cycle defect; 5-MTFH, 5-methytetrahydrofolate deficiency.
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Review dystonic posturing of the ankle often fluctuates. On examination, there is rigidity with resistance to passive movement of the ankle in all directions. Unlike spasticity, this rigidity does not change with leg position or with velocity of the passive movement. Dystonic toe walking eventually resolves after several months.13 Dopa-responsive dystonia (DRD) is an uncommon primary dystonia with a median age of onset of 6 years. It is frequently misdiagnosed as spastic diplegia.14 It usually presents with asymmetric lower limb rigidity that gradually generalises by early adulthood. At the time of presentation, most children have bilateral limb rigidity and equinovarus foot posturing. Lower limb tendon reflexes are brisk with ankle clonus, but the plantar response is usually normal. Occasionally a striatal toe can be seen. The most striking feature of DRD is marked diurnal variation of symptoms with worsening of symptoms as the day progresses and near complete resolution after sleep. This diurnal variation attenuates with age and is no longer seen by adulthood.15 Other features that suggest DRD are tremor and parkinsonism with decreased velocity of rapid repetitive hand movements.16 Most cases are due to a mutation in the gene (GCH1) that encodes the enzyme guanosine-5-triphosphate cyclohydrolase I (GTPCH1) on chromosome 14q22.2. Inherited in an autosomal-dominant fashion, the penetrance rate is 35%–100% with a female predilection.17 GTPCH1 is the enzyme responsible for the synthesis of tetrahydrobiopterin (BH4), an essential cofactor for the enzyme tyrosine hydroxylase that converts tyrosine to levodopa.15 Rare cases of autosomal-recessive DRD due to homozygous mutations in the genes that code for GTPCH1 and tyrosine hydroxylase are seen. In cases associated with GCH1 mutations, cerebrospinal fluid analysis shows decreased levels of dopamine metabolites.16 Genetic analysis is able to detect up to 90% of mutations in the GCH1 gene.17 Treatment with low-dose levodopa/carbidopa (4–5 mg/kg/day of levodopa) will result in a marked resolution of symptoms with minimal side effects.15 A therapeutic challenge with levodopa/carbidopa should be considered in any child whose diagnosis of spastic diplegia is uncertain due to the dramatic improvement in symptoms seen in children with DRD after a short period of treatment.14
of HSP are pure and inherited in an autosomal-dominant fashion.20 Because of its slowly progressive course, HSP should be considered in any child with a diagnosis of spastic diplegia where no underlying cause is found.20 In children, the most common forms of HSP are SPG3A and SPG4 due to mutations in the atlastin-1 and spastin genes, respectively. Both are autosomal dominant with a predominantly pure presentation. Genes have been identified for 41 different forms of HSP. PLS is a rare disorder characterised by progressive spasticity starting in the lower extremities which eventually involves the upper extremities and bulbar muscles due to corticospinal tract degeneration. Sensory pathways are not affected; therefore, proprioception and somatosensory evoked potentials (SSEP) are normal. While onset is typically in the fifth decade, a juvenile form ( JPLS) can occur with onset in the first decade with affected patients and wheelchair users with severe bulbar dysfunction by the second decade.21 JPLS is autosomal recessive and secondary to a mutation in the ALS2 (alsin) gene that is also implicated in autosomal-recessive amyotrophic lateral sclerosis.22 A rare severe infantile variant called infantile-onset ascending HSP is also caused by mutations in ALS2.23
HEREDITARY ATAXIAS WITH LOWER LIMB SPASTICITY There are multiple hereditary progressive ataxias including Friedreich ataxia and the hereditary spastic-ataxias. All are associated with cerebellar atrophy on neuroimaging. Children with Friedreich ataxia typically have absent lower limb reflexes, distinguishing it from spastic diplegia.24 The hereditary spastic-ataxia syndromes comprise a rare group of disorders characterised by slowly progressive lower limb spasticity and ataxia. Childhood onset is common. Of these, autosomal-recessive ataxia of Charlevoix–Saguenay is the most prevalent. Initially described in Quebec, a worldwide distribution is now recognised. To date, five other hereditary spastic ataxias with childhood onset have been described in isolated kinships worldwide. Most of these are autosomal recessive with the exception of an autosomal-dominant form described in Newfoundland.25
TETHERED CORD SYNDROME HEREDITARY MYELOPATHIES The inherited myelopathies include hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). Onset in childhood often results in a misdiagnosis of spastic diplegia.18 HSP is characterised by progressive spasticity and weakness of the lower extremities without bulbar and upper extremity involvement. To date, over 50 different gene loci associated with HSP have been reported. HSP can be inherited in an autosomal-dominant, autosomal-recessive, X-linked recessive or maternally inherited pattern. Affected genes are involved in the physiological maintenance of axons within the corticospinal tracts.19 HSP can be classified as pure or complex depending on the presence of other neurological or systemic features. Patients with pure HSP will have slowly progressive lower limb spasticity. Urinary dysfunction from hypertonic bladder is common. Most patients have decreased proprioception and vibration sense due to involvement of the posterior columns.19 Lower limb spasticity begins at any age and progression is gradual without acute exacerbations or remissions.18 Complicated HSP has a similar clinical presentation along with other neurological and nonneurological findings including hydrocephalus, developmental delay, retinopathy and pigmentary skin lesions.18 19 Most cases Huntsman R, et al. Arch Dis Child 2014;0:1–5. doi:10.1136/archdischild-2014-307443
Tethered cord syndrome results from stretching of the caudal elements of the spinal cord and is frequently associated with occult spinal dysraphisms such as thickened filum terminale and spinal lipoma. These are frequently associated with overlying cutaneous and vertebral abnormalities.26 Neurological dysfunction in tethered cord syndrome results from traction-induced oxidative dysfunction in neural elements of the lumbosacral spinal cord.27 Most children with tethered cord syndrome present with weakness of the lower extremities with muscle atrophy and hyporeflexia. However, some can present with lower limb spasticity resulting from spinal cord ischaemia. Associated findings such as back pain, urinary incontinence and patchy sensory disturbances are frequently associated.26 In infants and young children, pain typically manifests as irritability and is aggravated by performing tasks causing flexion of the spine.28 The diagnosis of tethered cord syndrome is confirmed with imaging of the lower spine showing a low lying conus medullaris below the level of L2 vertebral body. MRI is the imaging modality of choice allowing visualisation of the entire spinal cord and filum terminale along with associated vertebral elements.28 Lower limb SSEPs can document physiological evidence of spinal cord dysfunction. Early recognition and surgical 3
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Review intervention of tethered cord syndrome may result in improved outcomes especially with regards to pain and prevention of further motor decline.29
LEUKODYSTROPHIES The leukodystrophies are genetically determined disorders affecting myelin development within the central nervous system.30 The clinical presentation of the leukodystrophies typically follows a period of normal development with progressive bilateral spasticity. Behavioural and cognitive decline also occur, which differs from spastic diplegia where cognitive delay, if present, tends to be mild and is static.31 MRI often reveals symmetrical dysmyelination with increased T2 signal intensity in the periventricular cerebral white matter with sparing of the subcortical U-fibres. The pattern of cerebral dysmyelination seen on MRI can be helpful in determining the aetiology of the leukodystrophy.32 Several leukodystrophies such as Krabbe Disease, Metachromatic Leukodystrophy and Juvenile Onset Alexander Disease have late-onset forms with predominant lower limb spasticity. The spasticity can be slowly progressive with cognitive function remaining intact, resulting in the appearance of a static process.33–36 Sjogren– Larsson syndrome, a leukodystrophy due to deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol:NAD+ oxidoreductase, typically presents in the first year of life with ichthyosis, developmental delay and lower limb spasticity. The presence of ichthyosis and moderate to severe developmental delay differentiates this disorder from spastic diplegia. Cerebral MRI reveals abnormal T2 changes throughout the frontal and parietal white matter. Diagnosis can be confirmed with enzyme or genetic analysis.30
DISORDERS OF AMINO AND ORGANIC ACID METABOLISM AND UREA CYCLE DEFECTS Several inherited disorders of amino and organic acid metabolism have been associated with the development of slowly progressive lower limb spasticity that can be mistaken for spastic diplegia.37 Clinical suspicion of these disorders should be raised when the patient has a history of relapsing encephalopathy in the face of catabolic stress provoked by illness or high protein intake. Among the disorders of amino acid metabolism, both late-onset non-ketotic hyperglycinaemia and disorders of branch chain amino acid metabolism (in particular, Maple Syrup Urine Disease and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency) can cause slowly progressive lower limb spasticity with periventricular cerebral white matter abnormalities mimicking spastic diplegia.38–41 Diagnosis is made by testing the cerebrospinal fluid:plasma glycine ratio in the case of nonketotic hyperglycinaemia and urine organic acid analysis in the branch chain aminoacidopathies. Both argininaemia and triple H syndrome are urea cycle defects that can mimic spastic diplegia.42 43 Cerebral MRI findings can range from normal to diffuse cerebral atrophy. Diagnosis is made with plasma amino acid and ammonia profiles.
DISORDERS OF VITAMIN METABOLISM AND NUTRITIONAL DEFICIENCIES Children with inherited disorders of vitamin metabolism can present with a clinical picture similar to spastic diplegia. Primary cerebral folate deficiency can result from several disorders of folate transport and metabolism. Clinical characteristics include lower limb spasticity, deceleration of head growth and 4
developmental delay often with autism, epilepsy, ataxia and dyskinesia. The diagnosis is confirmed by measuring decreased levels of 5-methyltetrahydrofolate in the cerebrospinal fluid. Treatment with folinic acid in early childhood may result in improvement of symptoms.44 An inherited disorder affecting vitamin E metabolism and transport results in a progressive spastic-ataxic gait associated with loss of lower limb tendon reflexes, upgoing plantar responses and impaired proprioception. Dysarthria and gaze palsies may also occur. Diagnosis is made by measuring serum vitamin E levels, and response to vitamin E supplementation is favourable.45 Tropical paraplegia causes lower limb spasticity without associated sensory deficits. While most cases are due to chronic human T-lymphotropic virus 1 infection, some cases such as konzo and lathyrism seen in Africa and the Indian subcontinent result from excessive consumption of foods containing neurotoxic substances.45
CONCLUSION Recent advances in neuroimaging and molecular genetics have improved the diagnosis of many neurological disorders that may mimic spastic diplegia. Correctly identifying these conditions rests firmly with the recognition that the patient has features on history and physical examination atypical of spastic diplegia and a strong index of suspicion that an alternate diagnosis may be responsible. The authors reemphasise the importance of obtaining the expertise of a paediatric neurologist and medical geneticist with expertise in metabolic disease as part of the multidisciplinary team involved in the diagnosis and care of these children.46 While the disorders discussed in the preceding section and diagnostic algorithm are not an exhaustive differential diagnosis of spastic diplegia, it is hoped that an awareness of these diagnostic possibilities will help the clinician to recognise the possibility of an underlying condition that has treatment or genetic implications for the patient and their families. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
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The differential diagnosis of spastic diplegia Richard Huntsman, Edmond Lemire, Jonathon Norton, Anne Dzus, Patricia Blakley and Simona Hasal Arch Dis Child published online November 18, 2014
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