The differential diagnosis of spastic diplegiaRichard Huntsman,1 Edmond Lemire,2 Jonathon Norton,3 Anne Dzus,4

Patricia Blakley,5 Simona Hasal1

1Division of PediatricNeurology, Department ofPediatrics, University ofSaskatchewan, Saskatoon,Saskatchewan, Canada2Division of Medical Genetics,Department of Pediatrics,University of Saskatchewan,Saskatoon, Saskatchewan,Canada3Division of Neurosurgery,Department of Surgery,University of Saskatchewan,Saskatoon, Saskatchewan,Canada4Division of PediatricOrthopedics, Department ofSurgery, University ofSaskatchewan, Saskatoon,Saskatchewan, Canada5Division of DevelopmentalPediatrics, Department ofPediatrics, University ofSaskatchewan, Saskatoon,Saskatchewan, Canada

Correspondence toDr Richard J Huntsman,Division of Pediatric Neurology,Department of Pediatrics,University of Saskatchewan,103 Hospital Drive, Saskatoon,Saskatchewan S7N-0W8,Canada;dr.huntsman@usask.ca

Received 28 August 2014Revised 25 October 2014Accepted 29 October 2014

To cite: Huntsman R,Lemire E, Norton J, et al.Arch Dis Child PublishedOnline First: [please includeDay Month Year]doi:10.1136/archdischild-2014-307443

ABSTRACTSpastic diplegia is the most common form of cerebralpalsy worldwide. Many disorders mimic spastic diplegia,which can result in misdiagnosis for the child withresultant negative treatment and family counsellingimplications. In this paper, the authors provide a briefreview of spastic diplegia and the various disorders inthe differential diagnosis. We also provide a diagnosticalgorithm to assist physicians in making the correctdiagnosis.

INTRODUCTIONSpastic diplegia is a form of cerebral palsy (CP)where spasticity predominates in the lower extrem-ities with minimal upper extremity involvement.It is strongly associated with prematurity.1 It is themost common subtype comprising 34% of all chil-dren in a multinational European CP study.2 Spasticparaplegia refers to lower limb spasticity due to aspinal cord lesion.Although the causative cerebral lesion is static,

children with spastic diplegia typically go through aprogression of abnormalities of tone, posture andgait. Standing and walking are acquired late withequinovarus posturing of the ankles due to spasti-city of the calf muscles.3 As the child ages, progres-sive spasticity of the hip flexors and hamstrings canresult in a crouch gait, which makes prolongedwalking difficult, thus giving the appearance ofneurological deterioration.4

The most common cerebral lesion encounteredwith spastic diplegia is periventricular leukomalacia(PVL) characterised by bilateral necrosis of thefrontal and parietal periventricular white matter.5

The topographical distribution of the corticospinaltracts in the frontal periventricular regions resultsin the diplegic pattern of motor impairment.6 Theimaging features of PVL include enlarged scallopedlateral ventricles, periventricular gliosis, loss ofwhite matter and thinning of the corpus callosum.7

PVL is identified in approximately 75% of all chil-dren with spastic diplegia.2 6

Excluding slowly progressive neurological disor-ders from a diagnosis of CP can be challenging asboth frequently share similar patterns of motorimpairment.8 In a highly consanguineous SouthAsian population in Northern England, the numberof children diagnosed with CP was almost threetimes that expected, indicating that genetic orinherited metabolic disorders accounted for a highpercentage of these diagnoses.9

The American Academy of Neurology recom-mends that routine metabolic and genetic testingnot be performed unless there are features atypicalof CP on history and physical examination. All chil-dren diagnosed with CP should have neuroimaging,

preferably with MRI. If the MRI is normal, thenmetabolic or genetic screening should be consid-ered especially if the history does not support thediagnosis of CP.10

Clinical features that should alert the physicianto an alternate diagnosis to spastic diplegia wouldinclude; absence of premature birth, parental con-sanguinity, family history of CP, bulbar dysfunction,fluctuations in degree of motor impairment, boweland bladder dysfunction and severe cognitiveimpairment. In our own experience, the diagnosisof CP tends to persist even though the clinical fea-tures suggest an alternate diagnosis.In this paper, the authors aim to provide a clin-

ical review of those conditions that can mimicspastic diplegia and provide a diagnostic algorithmto aid in making the correct diagnosis (figure 1).

IDIOPATHIC TOE WALKINGBenign idiopathic (habitual) toe walking is theabnormal persistence of toe walking after 2 years ofage in the absence of any cause. Its presence can beassociated with abnormal language developmentand autism.11 Despite weight bearing on the ballsof their feet, the gait otherwise looks well coordi-nated and these children can walk and run atnormal velocities.11 Apart from some tightness inthe calf muscles and heel cords, the neurologicalexam is normal and most children are able to walkwith a heel strike. Familial toe walking has beenwell described and a positive family history stronglysupports this diagnosis.12 Normal gait is attained inalmost all children with daily stretching, splintingand occasionally casting. Surgical intervention israrely required.11

Idiopathic toe walkers attain walking at a normalage, while those with spastic diplegia are usually lateto start and have tight hamstrings and a reducedrange of popliteal angles during goniometry. Duringgait analysis, the idiopathic toe walker will typicallyexhibit knee hyperextension while the child withspastic diplegia will have abnormal knee flexion inthe terminal swing phase of the gait cycle. Additionof dynamic electromyography to the gait analysiscan further aid in the differentiation.11

DYSTONIADystonia is a hyperkinetic movement disorder withcontinuous contraction of agonist and antagonistmuscle groups causing sustained posturing of thetrunk or limbs. Clinically, dystonia can usually bedifferentiated from spasticity by the presence ofrigidity throughout the entire range of movementof the affected limbs and the lack of a spastic catch.Transient dystonic toe walking typically presents

in early infancy with asymmetrical toe walking assoon as the child starts to ambulate. The degree of

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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 asopposed to MRI findings or metabolic/genetic evaluation. BCAA, branch chain aminoaciduria; BITW, benign idiopathic toe walking; CSF, cerebrospinal fluid; DRD, dopa-responsive dystonia; HSP, hereditaryspastic 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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dystonic posturing of the ankle often fluctuates. On examin-ation, there is rigidity with resistance to passive movement ofthe ankle in all directions. Unlike spasticity, this rigidity doesnot change with leg position or with velocity of the passivemovement. Dystonic toe walking eventually resolves afterseveral months.13

Dopa-responsive dystonia (DRD) is an uncommon primary dys-tonia with a median age of onset of 6 years. It is frequently mis-diagnosed as spastic diplegia.14 It usually presents with asymmetriclower limb rigidity that gradually generalises by early adulthood.At the time of presentation, most children have bilateral limb rigid-ity and equinovarus foot posturing. Lower limb tendon reflexesare brisk with ankle clonus, but the plantar response is usuallynormal. Occasionally a striatal toe can be seen. The most strikingfeature of DRD is marked diurnal variation of symptoms withworsening of symptoms as the day progresses and near completeresolution after sleep. This diurnal variation attenuates with ageand is no longer seen by adulthood.15 Other features that suggestDRD are tremor and parkinsonism with decreased velocity ofrapid repetitive hand movements.16

Most cases are due to a mutation in the gene (GCH1) thatencodes the enzyme guanosine-5-triphosphate cyclohydrolase I(GTPCH1) on chromosome 14q22.2. Inherited in an auto-somal-dominant fashion, the penetrance rate is 35%–100%with a female predilection.17 GTPCH1 is the enzyme respon-sible for the synthesis of tetrahydrobiopterin (BH4), an essentialcofactor for the enzyme tyrosine hydroxylase that converts tyro-sine to levodopa.15 Rare cases of autosomal-recessive DRD dueto homozygous mutations in the genes that code for GTPCH1and tyrosine hydroxylase are seen. In cases associated withGCH1 mutations, cerebrospinal fluid analysis shows decreasedlevels of dopamine metabolites.16 Genetic analysis is able todetect up to 90% of mutations in the GCH1 gene.17 Treatmentwith low-dose levodopa/carbidopa (4–5 mg/kg/day of levodopa)will result in a marked resolution of symptoms with minimalside effects.15 A therapeutic challenge with levodopa/carbidopashould be considered in any child whose diagnosis of spasticdiplegia is uncertain due to the dramatic improvement in symp-toms seen in children with DRD after a short period oftreatment.14

HEREDITARY MYELOPATHIESThe inherited myelopathies include hereditary spastic paraplegia(HSP) and primary lateral sclerosis (PLS). Onset in childhoodoften results in a misdiagnosis of spastic diplegia.18

HSP is characterised by progressive spasticity and weakness ofthe lower extremities without bulbar and upper extremityinvolvement. To date, over 50 different gene loci associatedwith HSP have been reported. HSP can be inherited in anautosomal-dominant, autosomal-recessive, X-linked recessive ormaternally inherited pattern. Affected genes are involved in thephysiological maintenance of axons within the corticospinaltracts.19 HSP can be classified as pure or complex depending onthe presence of other neurological or systemic features. Patientswith pure HSP will have slowly progressive lower limb spasticity.Urinary dysfunction from hypertonic bladder is common. Mostpatients have decreased proprioception and vibration sense dueto involvement of the posterior columns.19 Lower limb spasti-city begins at any age and progression is gradual without acuteexacerbations or remissions.18 Complicated HSP has a similarclinical presentation along with other neurological and non-neurological findings including hydrocephalus, developmentaldelay, retinopathy and pigmentary skin lesions.18 19 Most cases

of HSP are pure and inherited in an autosomal-dominantfashion.20

Because of its slowly progressive course, HSP should be con-sidered in any child with a diagnosis of spastic diplegia whereno underlying cause is found.20 In children, the most commonforms of HSP are SPG3A and SPG4 due to mutations in theatlastin-1 and spastin genes, respectively. Both are autosomaldominant with a predominantly pure presentation. Genes havebeen identified for 41 different forms of HSP.

PLS is a rare disorder characterised by progressive spasticitystarting in the lower extremities which eventually involves theupper extremities and bulbar muscles due to corticospinal tractdegeneration. Sensory pathways are not affected; therefore, pro-prioception and somatosensory evoked potentials (SSEP) arenormal. While onset is typically in the fifth decade, a juvenileform ( JPLS) can occur with onset in the first decade withaffected patients and wheelchair users with severe bulbar dys-function by the second decade.21 JPLS is autosomal recessiveand secondary to a mutation in the ALS2 (alsin) gene that isalso implicated in autosomal-recessive amyotrophic lateral scler-osis.22 A rare severe infantile variant called infantile-onsetascending HSP is also caused by mutations in ALS2.23

HEREDITARY ATAXIAS WITH LOWER LIMB SPASTICITYThere are multiple hereditary progressive ataxias includingFriedreich ataxia and the hereditary spastic-ataxias. All are asso-ciated with cerebellar atrophy on neuroimaging. Children withFriedreich ataxia typically have absent lower limb reflexes, dis-tinguishing it from spastic diplegia.24

The hereditary spastic-ataxia syndromes comprise a raregroup of disorders characterised by slowly progressive lowerlimb spasticity and ataxia. Childhood onset is common. Ofthese, autosomal-recessive ataxia of Charlevoix–Saguenay is themost prevalent. Initially described in Quebec, a worldwide dis-tribution is now recognised. To date, five other hereditaryspastic ataxias with childhood onset have been described in iso-lated kinships worldwide. Most of these are autosomal recessivewith the exception of an autosomal-dominant form described inNewfoundland.25

TETHERED CORD SYNDROMETethered cord syndrome results from stretching of the caudalelements of the spinal cord and is frequently associated withoccult spinal dysraphisms such as thickened filum terminale andspinal lipoma. These are frequently associated with overlyingcutaneous and vertebral abnormalities.26 Neurological dysfunc-tion in tethered cord syndrome results from traction-inducedoxidative dysfunction in neural elements of the lumbosacralspinal cord.27

Most children with tethered cord syndrome present withweakness of the lower extremities with muscle atrophy andhyporeflexia. However, some can present with lower limb spasti-city resulting from spinal cord ischaemia. Associated findingssuch as back pain, urinary incontinence and patchy sensory dis-turbances are frequently associated.26 In infants and young chil-dren, pain typically manifests as irritability and is aggravated byperforming tasks causing flexion of the spine.28

The diagnosis of tethered cord syndrome is confirmed withimaging of the lower spine showing a low lying conus medul-laris below the level of L2 vertebral body. MRI is the imagingmodality of choice allowing visualisation of the entire spinalcord and filum terminale along with associated vertebral ele-ments.28 Lower limb SSEPs can document physiological evi-dence of spinal cord dysfunction. Early recognition and surgical

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intervention of tethered cord syndrome may result in improvedoutcomes especially with regards to pain and prevention offurther motor decline.29

LEUKODYSTROPHIESThe leukodystrophies are genetically determined disordersaffecting myelin development within the central nervoussystem.30 The clinical presentation of the leukodystrophies typ-ically follows a period of normal development with progressivebilateral spasticity. Behavioural and cognitive decline also occur,which differs from spastic diplegia where cognitive delay, ifpresent, tends to be mild and is static.31 MRI often reveals sym-metrical dysmyelination with increased T2 signal intensity in theperiventricular cerebral white matter with sparing of the subcor-tical U-fibres. The pattern of cerebral dysmyelination seen onMRI can be helpful in determining the aetiology of theleukodystrophy.32

Several leukodystrophies such as Krabbe Disease, MetachromaticLeukodystrophy and Juvenile Onset Alexander Disease havelate-onset forms with predominant lower limb spasticity. The spas-ticity can be slowly progressive with cognitive function remainingintact, resulting in the appearance of a static process.33–36 Sjogren–Larsson syndrome, a leukodystrophy due to deficient activity of thefatty aldehyde dehydrogenase component of fatty alcohol:NAD+

oxidoreductase, typically presents in the first year of life with ich-thyosis, developmental delay and lower limb spasticity. The pres-ence of ichthyosis and moderate to severe developmental delaydifferentiates this disorder from spastic diplegia. Cerebral MRIreveals abnormal T2 changes throughout the frontal and parietalwhite matter. Diagnosis can be confirmed with enzyme or geneticanalysis.30

DISORDERS OF AMINO AND ORGANIC ACID METABOLISMAND UREA CYCLE DEFECTSSeveral inherited disorders of amino and organic acid metabol-ism have been associated with the development of slowly pro-gressive lower limb spasticity that can be mistaken for spasticdiplegia.37 Clinical suspicion of these disorders should be raisedwhen the patient has a history of relapsing encephalopathy inthe face of catabolic stress provoked by illness or high proteinintake.

Among the disorders of amino acid metabolism, bothlate-onset non-ketotic hyperglycinaemia and disorders of branchchain amino acid metabolism (in particular, Maple Syrup UrineDisease and 2-methyl-3-hydroxybutyryl-CoA dehydrogenasedeficiency) can cause slowly progressive lower limb spasticitywith periventricular cerebral white matter abnormalities mim-icking spastic diplegia.38–41 Diagnosis is made by testing thecerebrospinal fluid:plasma glycine ratio in the case of non-ketotic hyperglycinaemia and urine organic acid analysis in thebranch chain aminoacidopathies.

Both argininaemia and triple H syndrome are urea cycledefects that can mimic spastic diplegia.42 43 Cerebral MRI find-ings can range from normal to diffuse cerebral atrophy.Diagnosis is made with plasma amino acid and ammoniaprofiles.

DISORDERS OF VITAMIN METABOLISM AND NUTRITIONALDEFICIENCIESChildren with inherited disorders of vitamin metabolism canpresent with a clinical picture similar to spastic diplegia.Primary cerebral folate deficiency can result from several disor-ders of folate transport and metabolism. Clinical characteristicsinclude lower limb spasticity, deceleration of head growth and

developmental delay often with autism, epilepsy, ataxia and dys-kinesia. The diagnosis is confirmed by measuring decreasedlevels of 5-methyltetrahydrofolate in the cerebrospinal fluid.Treatment with folinic acid in early childhood may result inimprovement of symptoms.44

An inherited disorder affecting vitamin E metabolism andtransport results in a progressive spastic-ataxic gait associatedwith loss of lower limb tendon reflexes, upgoing plantarresponses and impaired proprioception. Dysarthria and gazepalsies may also occur. Diagnosis is made by measuring serumvitamin E levels, and response to vitamin E supplementation isfavourable.45

Tropical paraplegia causes lower limb spasticity without asso-ciated sensory deficits. While most cases are due to chronichuman T-lymphotropic virus 1 infection, some cases such askonzo and lathyrism seen in Africa and the Indian subcontinentresult from excessive consumption of foods containing neuro-toxic substances.45

CONCLUSIONRecent advances in neuroimaging and molecular genetics haveimproved the diagnosis of many neurological disorders that maymimic spastic diplegia. Correctly identifying these conditionsrests firmly with the recognition that the patient has features onhistory and physical examination atypical of spastic diplegia anda strong index of suspicion that an alternate diagnosis may beresponsible.

The authors reemphasise the importance of obtaining theexpertise of a paediatric neurologist and medical geneticist withexpertise in metabolic disease as part of the multidisciplinaryteam involved in the diagnosis and care of these children.46

While the disorders discussed in the preceding section and diag-nostic algorithm are not an exhaustive differential diagnosis ofspastic diplegia, it is hoped that an awareness of these diagnosticpossibilities will help the clinician to recognise the possibility ofan underlying condition that has treatment or genetic implica-tions 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

Patricia Blakley and Simona HasalRichard Huntsman, Edmond Lemire, Jonathon Norton, Anne Dzus,

published online November 18, 2014Arch Dis Child 

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