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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;
dr.huntsman@usask.ca
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 exors and hamstrings can
result in a crouch gait, which makes prolonged
walking difcult, 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 identied 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,
uctuations 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 (gure 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 exion 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;0:15. doi:10.1136/archdischild-2014-307443

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Huntsman R, et al. Arch Dis Child 2014;0:15. 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 ndings or metabolic/genetic evaluation. BCAA, branch chain aminoaciduria; BITW, benign idiopathic toe walking; CSF, cerebrospinal uid; 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 deciency.

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Review
dystonic posturing of the ankle often uctuates. 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 reexes
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 uid 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 (45 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 identied 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 fth decade, a juvenile
form ( JPLS) can occur with onset in the rst 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 reexes, 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 CharlevoixSaguenay is the
most prevalent. Initially described in Quebec, a worldwide distribution is now recognised. To date, ve 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 classied 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 ndings including hydrocephalus, developmental
delay, retinopathy and pigmentary skin lesions.18 19 Most cases
Huntsman R, et al. Arch Dis Child 2014;0:15. 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 lum 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
hyporeexia. However, some can present with lower limb spasticity resulting from spinal cord ischaemia. Associated ndings
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 exion of the spine.28
The diagnosis of tethered cord syndrome is conrmed 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 lum 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-bres. 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.3336 Sjogren
Larsson syndrome, a leukodystrophy due to decient activity of the
fatty aldehyde dehydrogenase component of fatty alcohol:NAD+
oxidoreductase, typically presents in the rst 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 conrmed 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
deciency) can cause slowly progressive lower limb spasticity
with periventricular cerebral white matter abnormalities mimicking spastic diplegia.3841 Diagnosis is made by testing the
cerebrospinal uid: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 ndings can range from normal to diffuse cerebral atrophy.
Diagnosis is made with plasma amino acid and ammonia
proles.

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 deciency 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 conrmed by measuring decreased
levels of 5-methyltetrahydrofolate in the cerebrospinal uid.
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 reexes, 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 decits. 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 rmly 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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