Differentials
Common
Transient idiopathic dystonia of infancy
History
onset usually before 6 months of age, typical posturing of an upper limb with forearm pronation and wrist hyperflexion, usually resolved by 2 years of age, development normal, some may be permanent with attenuation during sleep, others posturing usually observed during relaxation or in specific positions[134][135]
Exam
physical and neurologic exam are normal
1st investigation
- diagnosis is clinical:
no tests are required to confirm diagnosis, but specific tests to rule out the diseases in the differential diagnosis are necessary (e.g., electroencephalogram and MRI of the brain and cervical spine)
Benign paroxysmal torticollis of infancy
History
Exam
between the attacks, the physical and neurologic exams are normal
1st investigation
- genetic testing for FHM1 gene mutation:
abnormal gene may or may not be present
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Congenital torticollis
History
either a palpable mass (olive) or tightness in the sternocleidomastoid (SCM) at birth or develops in first 2 months, usually history of breech presentation/difficult delivery, increased risk of associated abnormalities (e.g., clubfoot, developmental dysplasia of hip, cranial plagiocephaly)
Exam
1st investigation
- ultrasound of SCM:
more hyperechogenic than with normal appearance
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Primary paroxysmal kinesigenic dyskinesia (PKD)
History
brief attacks of involuntary choreoathetotic movement, triggered by voluntary movements, may involve a sensory aura, no loss of consciousness, can be associated with benign familial infantile epilepsy in the same individual or family; responds well to very low-dose carbamazepine, particularly in those with PRRT2 mutations; infantile-onset PKD: no clear trigger, poor response to antiepileptic drugs[143][144][145]
Exam
physical and neurologic exams normal between attacks
1st investigation
- genetic testing (such as gene panel including PRRT2):
often positive (especially in autosomal-dominant families with a history of benign infantile epilepsy)
Drug-related dystonia
History
history of drug exposure before the appearance of dystonia
Exam
neurologic exam in the acute setting demonstrates dystonia, mostly generalized, but after discontinuing the offending drug and applying the appropriate treatment, the neurologic exam becomes normal
1st investigation
- stop the offending drug:
complete disappearance of dystonia
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Other investigations
- serum level of drug (if concern about exposure in utero):
detection of the offending drug in newborn
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Dyskinetic cerebral palsy
History
dystonia and choreoathetosis, obstetric/perinatal history may indicate high risk for perinatal hypoxia, typically arms affected more than legs, extrapyramidal syndromes often associated with marked reduction in speech production, may have relatively preserved intelligence, dystonia can occur several years later[156]
Exam
dystonic-type hypertonicity, persistent or obligatory primitive reflexes, upper motor neuron signs, abnormal oromotor patterns, oculomotor abnormalities, delayed postural reactions, abnormalities of movement, gross and fine motor delay
1st investigation
- MRI of the brain:
selective injury to the basal ganglia
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Post-traumatic dystonia
History
history of trauma causing primary cerebral insults or secondary processes during recovery, usually hemidystonia, often refractory to medications, contralateral posteroventral pallidotomy may significantly improve hemidystonia, latency from insult to dystonia usually 2.8 years, may be longer after perinatal injury[158][159][160]
Exam
systemic and neurologic exams are abnormal depending on the nature of the insult, hemidystonia is usually seen
1st investigation
- MRI of the brain:
selective injury to the basal ganglia
More
Other investigations
Nonfatal drowning
History
history of nonfatal drowning, deficits affecting new learning, memory, attention, executive functions, visuospatial functions, and language, dysphagia, dysarthria, seizure or Balint syndrome (ocular apraxia, optic ataxia, hemispatial neglect)
Exam
initially: generalized hypotonia, decerebrate/decorticate posturing to painful stimuli, inability to react to people/environment, inability to gaze/eye follow, generalized dystonia with opisthotonus and torsion spasms; later: vegetative state, visual agnosia, prosopagnosia, optic ataxia, severe spasticity; during the hospital course: other complications, for example, status dystonicus
1st investigation
- MRI of the brain:
during the first week post injury: bilateral signal abnormalities in the globus pallidus, caudate nucleus, putamen, gray-white matter junction, parieto-occipital cortical gray matter
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Other investigations
Primary stereotypies
History
more common in boys, stereotypies (e.g., body rocking, thumb sucking, nail biting, hair twisting, head banging, head rolling, arm flapping, self-masturbation) usually occur with excitement, stress, boredom, usually a sense of pleasure by performing the movement
Exam
normal exam
1st investigation
- None:
no tests required unless secondary stereotypies are considered
Other investigations
Secondary stereotypies
History
history of neurologic problems (e.g., autistic syndromes, intellectual disability, congenital blindness or deafness, epileptic automatism, Rett syndrome, neuroacanthosis), stereotypies (e.g., body rocking, thumb sucking, nail biting, hair twisting, head banging, head rolling, arm flapping, self-masturbation) usually with excitement, stress, boredom, usually a sense of pleasure by performing the movement
Exam
abnormal findings depending on the etiology
1st investigation
- MRI:
abnormal result depending on etiology
- electroencephalogram:
abnormal result depending on etiology
Other investigations
- hearing test:
abnormal result depending on etiology
- vision test:
abnormal result depending on etiology
- metabolic tests:
abnormal result depending on etiology
- genetic workup:
abnormal result depending on etiology
Secondary infantile torticollis (SIT)
History
varies depending on the etiology of SIT, history of trauma, fever and infection is very important
Exam
Klippel-Feil syndrome: short neck, low hair line, and Sprengel deformity (congenital failure of descent of the scapula, decreased range of motion in the cervical spine); ocular abnormalities; fever, lethargy, neck stiffness in infants with infectious cause
1st investigation
- choice of tests based on findings from history and clinical exam:
test results depend on underlying cause
More
Other investigations
- plain radiograph of cervical spine:
findings may include vertebral body segmentation anomalies such as Klippel-Feil malformation, spondyloepiphyseal dysplasia, subluxation of the atlanto-axial or atlanto-occipital joint
More - CT of the cervical spine:
findings may include vertebral body segmentation anomalies such as Klippel-Feil malformation, spondyloepiphyseal dysplasia, subluxation of the atlanto-axial or atlanto-occipital joint
More - MRI of the brain and the cervical spine:
cerebellar tumors, Chiari malformations, cortical dysplasia, cerebral injury or cervical spinal cord tumors
More - full ophthalmologic evaluation:
congenital nystagmus, 4th cranial nerve palsy
More - full workup for GERD:
positive for gastroesophageal reflux disorders
More - electroencephalogram:
test results depend on underlying cause
More - electroretinography:
test results depend on underlying cause
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Seizure
History
features include symmetric tonic posturing (both partial and generalized-onset seizures), usually unresponsiveness during event, ictal events exactly the same each episode, not stopped by restraining limb in which event occurs, postictal drowsiness after event, events usually last seconds to minutes[102]
Exam
1st investigation
- electroencephalogram (EEG):
normal or abnormal partial or generalized-onset epileptic activities
Other investigations
Uncommon
Primary paroxysmal nonkinesigenic dyskinesia (PNKD)
History
attacks are combinations of dystonia, chorea, athetosis, ballismus; precipitated by hunger, fatigue, exercise, excitement, stress, but not voluntary movements; normal between attacks; poor response to antiepileptic drugs; frequency of attacks from 20 times daily to twice per year;[146][147] patients with inherited paroxysmal movement disorder (PxMD)-PNKD due to PNKD gene mutations typically have a family history of affected relatives with caffeine- and alcohol-triggered attacks, normal exam between attacks, and response to benzodiazepines[26]
Exam
physical and neurologic exams normal between attacks
1st investigation
- diagnosis is clinical:
no tests are required to confirm diagnosis but specific tests to rule out differential diagnoses are necessary (e.g., electroencephalogram, MRI of the brain, and metabolic workup); the diagnosis may be strongly suspected from the history and clinical exam
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Alternating hemiplegia of childhood (AHC)
History
onset a few months of age; screaming, restlessness, may be oculomotor abnormalities; later recurrent attacks of flaccid, unilateral/bilateral hemiplegia; typically resolving with sleep but recurring on awakening; dystonic events often independent to hemiplegia; seizures might be problematic in later stage[22][148]
Exam
transient oculomotor abnormalities, unilateral/bilateral nystagmus, unilateral/bilateral flaccid hemiplegia, dystonic stiffening, autonomic symptoms, persistent hypotonia, choreoathetosis, semiflexed posture, cognitive and developmental delay
1st investigation
- electroencephalogram:
normal between attacks, contralateral slowing during the attack
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DYT-TOR1A (primary torsion dystonia)
History
Exam
dystonia, especially in the distal lower limb, is the predominant finding, progression to a generalized form is usually seen in follow-up neurologic exams
1st investigation
- MRI of the brain:
normal
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Dopa-responsive dystonia (Segawa syndrome, dystonia-parkinsonism with diurnal fluctuation)
History
more frequent form: dystonia of one limb, spreading to the other extremities in several years, diurnal fluctuations, typically responds well to levodopa; rarer form: dystonic posturing of limbs, severe motor developmental delay, hypokinesia, rigidity, disturbances of sleep-wake cycle, response to levodopa may be slow/partial; atypical presentations may occur[29][151][152][153][154][155]
Exam
dystonia is most striking finding, diurnal fluctuations and progression of dystonia may be observed during repeated or follow-up neurologic exams
1st investigation
- diagnostic therapeutic trial with levodopa:
dramatic improvement versus slow and partial improvement
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Other investigations
Paroxysmal exercise-induced dyskinesia glucose transporter 1 (GLUT1)
History
may have generalized epilepsy (absence and/or tonic-clonic type) onset usually at a mean age of 2 years but can start after birth; weekly episodes of gait-inhibiting dystonia, predominantly of legs, lasting 15 minutes; attacks triggered by physical exertion or stress, relieved by eating and ketogenic diet; dystonia starts after 2 years of age and improves slowly over years; associated symptoms include choreoathetosis and dysautonomia; clinical course is mild compared with the classic severe forms of GLUT1 deficiency[27]
Exam
interictal neurologic and cognitive abilities normal for most patients[27]
1st investigation
- MRI of the brain:
normal
- interictal electroencephalogram:
normal or shows generalized epileptic discharges on a normal background
- fasting cerebrospinal fluid: serum glucose ratio:
may be mildly decreased
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Other investigations
- genetic testing:
heterozygous mutations of the SLC2A1 gene
Dopamine transporter deficiency syndrome (DYT/PARK-SLC6A3, infantile parkinsonism-dystonia)
History
neonatal onset of irritability and feeding difficulties with early infantile progressive developmental delay;[34] complex dystonia with parkinsonism and/or chorea; additional features can include axial hypotonia, extraocular movement abnormalities such as saccade initiation failure and ocular flutter, eyelid myoclonus, developmental delay, and attention deficit hyperactivity disorder; possibility of recurrent status dystonicus and oculogyric crises
Exam
neurologic exam, by 4 months of age, demonstrates parkinsonism (mask-like facies, bradykinesia, rigidity) followed by dystonia, hypotonia, oculomotor, and pyramidal tract signs[34]
1st investigation
- MRI of the brain:
normal
- cerebrospinal fluid studies for biogenic amine metabolites:
markedly elevated homovanillic acid (HVA), normal 5-hydroxyindoleacetic acid (5-HIAA), HVA:5-HIAA ratio >4.0
Other investigations
- ioflupane single-photon emission computed tomography (DaTScan):
absent or reduced uptake
- genetic testing:
biallelic pathogenic loss-of-function mutations in SLC6A3
Kernicterus
History
history of neonatal jaundice and prolonged hyperbilirubinemia; risk factors of hyperbilirubinemia include prematurity, sepsis, acidosis, Rhesus disease, and inherited red blood cell disorders including glucose-6-phosphate dehydrogenase deficiency
Exam
usually athetoid cerebral palsy with movement disorders (e.g., dystonia, athetosis, and sometimes spasticity), ataxia, incoordination, impaired upgaze, stained deciduous teeth, dysarthria, impaired hearing
1st investigation
- MRI of the brain:
signal abnormalities in the globus pallidus, sometimes the subthalamic nucleus; may be other lesions in the putamen, cortex, or periventricular leukomalacia if other comorbid conditions (e.g., hypoxic-ischemic, strokes, encephalitis, intraventricular hemorrhage)
More
Other investigations
Glutaric aciduria type I (glutaryl-CoA dehydrogenase [GCDH] deficiency)
History
mild motor delay, hypotonia, or focal seizure/generalized convulsions, vomiting, lethargy after an acute infectious illness, immunization, or surgical intervention; followed by psychomotor regression, dystonic or choreoathetotic movements
Exam
in the acute encephalopathic crisis phase: hypotonia, irritability, dystonia, lethargy; later: developmental delay, hypotonia, dystonia, macrocephaly, skeletal deformities, joint dislocations[163]
1st investigation
- tandem mass spectrometry-based neonatal screening program:
glutarylcarnitine value above the cut-off (value set by each laboratory); screening may be the initial test, if available; all other tests may be ordered together as part of a workup
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Other investigations
- CT and/or MRI of the brain:
increase of subarachnoid spaces with frontotemporal atrophy, hypodensity and hyperintensity of the caudate and putamen (CT and on T2 MRI, respectively), bitemporal arachnoid cysts, chronic subdural effusions, subdural hemorrhages
More - urinary organic acid analysis:
increased levels of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, glutarylcarnitine
More - GCDH deficiency assay in leukocytes or fibroblasts:
low or deficient enzyme activity
More - GCDH gene mutation analysis:
biallelic disease-causing mutations
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Methylmalonic acidemia
History
lethargy, developmental delay/regression, convulsions, recurrent vomiting, difficulty with feeding, exacerbations during catabolic states; occasionally: acute dystonic syndrome, progressive symptoms[111]
Exam
yellowish hair, developmental delay/regression, dystonia, lethargic in catabolic state; in some cases: hair loss, hepatomegaly, microcephaly, optic atrophy, cataract, spasticity, ataxic or stiff gait, motor weakness with muscular atrophy, peripheral neuropathies
1st investigation
Other investigations
- CT and/or MRI of the brain:
abnormal signals in globus pallidus, substantia nigra, red nucleus, and cerebral white matter, diffuse cerebral atrophy
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Lesch-Nyhan syndrome
History
aggressive and self-injurious behavior in most, automutilation frequently affecting fingers, mouth, buccal mucosa, abnormal movements predominantly dystonia, orange-colored crystalline material in the diapers may occur[41]
Exam
developmental delay, decreased growth, hypotonia, dystonia, and evidence of self-injurious behavior (mutilated fingers, mouth, and buccal mucosa), gouty arthritis and tophi
1st investigation
Infantile GM2 gangliosidosis (Tay-Sachs and Sandhoff disease)
History
initially: excessive startle response; later: slowing in motor development, inability to learn to sit, loss of other motor skills (e.g., rolling, head control), decrease in vocalizations, loss of awareness of environment, loss of vision
Exam
axial hypotonia, increased extremity tone, hyperreflexia, startle response, macular cherry-red spot; later: severe cognitive impairment, decerebrate posturing, blindness, inability to respond to most stimuli; Sandhoff disease: mild hepatosplenomegaly, bony deformities
1st investigation
- MRI of the brain:
increased T2 signals in basal ganglia and white matter, decreased T2 signals in thalami, later cerebral atrophy with widening of the cerebral sulci and ventriculomegaly, increased T1 signals in basal ganglia, thalamus, and cerebral cortex
More
Other investigations
- biopsy of skin, conjunctiva, and rectal mucosa for electron microscopy evaluation:
storage of membranous cytoplasmic bodies, or other electron-dense material[168]
- beta-hexosaminidase A and B enzyme activity in serum leukocytes:
low activity
More - mutation analysis in the corresponding genes:
biallelic pathogenic mutations in the relevant gene
Mitochondrial encephalomyopathies
History
Exam
hypotonia and developmental delay, other relevant systemic and neurologic findings depending on type of mitochondrial encephalopathy
1st investigation
- lactate and pyruvate in blood and cerebrospinal fluid:
increased levels, increased lactate/pyruvate ratios
More - MRI and CT of the brain:
delayed myelination in early phase, basal ganglia calcifications, leukoencephalopathy with cysts or stroke-like lesions extending past grey-white matter boundaries, symmetric signal abnormalities in deep gray matter (e.g., brainstem, basal ganglia, diencephalon, cerebellum), cerebral and cerebellar atrophy, increased lactate peak on magnetic resonance spectroscopy of lesional areas
More
Other investigations
- muscle biopsy:
abnormal
More - automated auditory brainstem responses:
hearing test passed or failed
More - brainstem auditory-evoked responses:
sensorineural hearing loss
More - full audiology evaluation:
may demonstrate pattern of sensorineural hearing loss
- genetic testing:
pathogenic mutations either in the mitochondrial genome or in nuclear-encoded mitochondrial genes
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Biotin-thiamine-responsive basal ganglia disease (DYT-SLC19A3)
History
acute or subacute encephalopathic episodes with dystonia, seizures, weakness, and spasticity triggered by fever or other stressors such as surgery or mild trauma; there is also an early infantile presentation with Leigh-like presentation or with infantile spasms; excellent response to biotin and thiamine[46]
Exam
dystonia, cogwheel rigidity, spasticity, seizures, sometimes external ophthalmoplegia, supranuclear facial palsy, dysphagia, cerebellar involvement, hemiparesis or quadriparesis; laboratory investigations may be entirely normal or only show high lactate during acute encephalopathic crisis
1st investigation
- MRI of the brain:
in acute period, bilateral symmetric edematous T2-hyperintense basal ganglia lesions primarily affecting the caudate and putamen and usually sparing the globus pallidus; in chronic period, MRI shows atrophy
More
Other investigations
- therapeutic trial of oral biotin and oral/intravenous thiamine:
typical response within days
- genetic testing:
biallelic pathogenic mutations in SLC19A3
Dopamine-serotonin vesicular transport disease
History
onset with hypotonia, poor head control, then dystonia and parkinsonism; dystonia includes persistent, paroxysmal, with walking, and oculogyric crises; other features may include tremor, chorea, myoclonus, other eye movement abnormalities, ataxia, hyporeflexia, developmental delay, epilepsy, and autonomic dysfunction
Exam
severe bradykinesia, dyskinesias including facial dyskinesias, limb tremors, alternating limb dystonias while walking; axial hypotonia, variable appendicular tone
1st investigation
- MRI of the brain:
normal
Acquired paroxysmal kinesigenic dyskinesia (PKD)
History
history of etiology (e.g., head trauma, perinatal hypoxic injury, cerebral infarcts and hemorrhages, focal seizures, encephalitis, hypoparathyroidism, thyrotoxicosis, hypoglycemia, hypocalcemia)
Exam
positive findings relevant to the cause, other findings include weakness, hemiparesis, seizures in addition to the PKD
1st investigation
- EEG:
test results depend on underlying cause
- MRI of the brain:
test results depend on underlying cause
- metabolic workup:
test results depend on underlying cause (e.g., hypoparathyroidism, thyrotoxicosis, hypoglycemia, hypocalcemia)
More
Other investigations
Acquired paroxysmal nonkinesigenic dyskinesia (PNKD)
History
may be history of etiology (e.g., cerebrovascular accident, infections, trauma, kernicterus, basal ganglia calcifications, and cranial radiation hypoparathyroidism, hypoglycemia)
Exam
abnormal exams depending on the etiology
1st investigation
- electromyogram:
test results depend on underlying cause
- MRI of the brain:
test results depend on underlying cause
- metabolic workup:
test results depend on underlying cause
More - lumbar puncture:
test results depend on underlying cause
Other investigations
Neurodegeneration with brain iron accumulation (NBIA), including pantothenate kinase-associated neurodegeneration (PKAN)
History
Exam
corticospinal tract signs, rigidity, dysarthria, abnormal movements such as choreoathetosis and dystonia, bilateral pigmentary retinopathy
1st investigation
- MRI of the brain:
in PKAN, the "eye of the tiger" sign: a low-signal intensity (iron accumulation) ring surrounding a central high signal intensity region (necrosis) in the globus pallidus
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Other investigations
- genetic testing:
positive for pathogenic mutations
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Leukodystrophies/hypomyelinating disorders
History
Exam
dystonias including focal limb and hemidystonias, oculogyric crises, choreoathetosis, perioral dyskinesias, rigidity; ataxia and other cerebellar findings, pyramidal signs including spasticity; dysarthria, dysphonia, swallowing impairment
1st investigation
- MRI of the brain:
diffuse cerebral hypomyelination and atrophy
More
Other investigations
- genetic testing:
pathogenic mutation in one of several genes associated with Pelizaeus-Merzbacher disease, other hypomyelinating leukodystrophy, tRNA synthetase genes, BCAP31
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Aicardi-Goutieres syndrome (AGS)
History
subacute or acute presentation after several months of normal development with irritability, inconsolable crying, intermittent sterile pyrexias, loss of skills; neonatal onset: jittery, poor feeding, neonatal seizures; some patients with ADAR mutations have acute or subacute dystonia
Exam
peripheral spasticity, truncal hypotonia, pyramidal tract signs, extrapyramidal signs, dystonias often of upper limbs or buccal-lingual dyskinesia, encephalopathy, acquired microcephaly; may have normal to severely reduced/absent vision, seizures, startle reaction to sudden noise; chilblains or generalized mottling are suggestive features but not present in all patients; newborns: hepatosplenomegaly
1st investigation
- CT of the brain:
intracranial calcifications in basal ganglia, dentate nuclei of cerebellum, deep white matter, and in periventricular area alongside ventricular wall, white matter hypodensities mainly around ventricular horns, temporal lobe swelling followed by atrophy, early global cerebral atrophy
More - genetic testing:
pathogenic (mostly loss-of-function) mutations in genes associated with AGS: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11, and RNU7-1, including biallelic null mutations in TREX1 and SAMHD1
More
Other investigations
- cerebrospinal fluid (CSF) analysis:
lymphocytosis (10-50 cells/mm³ in most patients but can be normal), increased interferon alfa (3-75 IU/mL in most patients; normal <2 IU/mL)
More - MRI of the brain:
hypointensity on T1-weighted images, hyperintensity on T2-weighted images of white matter, temporal lobe swelling followed by atrophy, early global cerebral atrophy; can have extensive bitemporal cystic lesions, significant thinning of brainstem, cerebellar atrophy with enlarged ventricles and sulci, progression over time; patients with the acute/subacute dystonia phenotype of ADAR mutation instead show bilateral striatal necrosis
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