Differential Diagnosis in Neurology

14.3. Hyperkinetic Disorders

General Categories of Hyperkinetic Disorders

• Tremor
• Myoclonus
• Tardive dyskinesia
• Ballism
• Chorea
• Athetosis
• Dystonia
• Paroxysmal dyskinesias
• Akathisic movements
• Tics

Tremor

• General considerations:
  • Definition:
    • Involuntary movement
    • Rhythmic
    • Oscillatory about a fixed point
    • Due to alternating or synchronous contractions of agonist and antagonist muscles
    • May occur at rest or with movement or on holding a static posture
• Differential Diagnosis:
  • Physiologic
  • Pathologic:
    • Parkinson's Disease
    • Parkinsonian syndrome
    • Physiologic tremor (exaggerated)
    • Tremor of peripheral nerve origin
    • Benign essential tremor
    • Dystonic tremor
    • Drugs
    • Cerebellar disease
    • Midbrain ("rubral") tremor
    • Psychogenic tremor
    • Wilson's disease
    • Toxins
    • Metabolic

Physiologic Tremor

• General considerations:
  • Mechanical reflex component
  • 8–12 Hz entrainment of motor units
  • May not be seen with unaided eye
  • Enhanced by:
    • Fatigue
    • Anxiety
    • Thyrotoxicosis
    • Narcotic withdrawal
    • Hyperglycemia
    • Pheochromocytoma
    • Alcohol withdrawal
    • Catecholamine excess
    • Steroids
    • Caffeine
    • Theophylline
  • Absent at rest
  • Present with maintained posture
  • Activated by severe muscle fatigue

Pathologic Tremors

Resting Tremor

• General considerations:
  • 3.5–7 Hz
  • Disappears or is markedly attenuated with intention
  • Characteristic of basal ganglia diseases

Parkinson's Disease Tremor

• General considerations:
  • VIM nucleus of the motor thalamus is the thalamic oscillator (burst neurons that fire at the same frequency as the tremor)
  • Proprioceptive feedback from displaced joints sustains the tremor
• Clinical features:
  • Head tremor is rare:
    • Up and down when present
    • Lips and jaw are more prominent in PD than in other conditions
  • Pronation-supination of the forearm; rhythmic, thumb and finger movements of a metacarpophalangeal flexed hand ("pill rolling" character)
  • Frequently asymmetrical at onset
  • Postural kinetic component; has a latent period when the hands are out stretched; essential tremor does not
  • Chin, jaw and tongue may be affected
  • Severe late stage patients may demonstrate postural kinetic and intention tremor
  • Walking may increase the hand tremor

Postural Kinetic Tremor

• General considerations:
  • 6–11 Hz frequency
  • Occurs in the antigravity muscles of the extremities and trunk
  • Associated head titubation, jaw tremor and involvement of the voice

Benign Essential Tremor

• General considerations:
  • Family history is obtained in 17–70%
  • Increased incidence of Parkinson's disease
  • Affects men and women equally
  • AD form; two loci:
    • Chromosome 3q13 (Icelandic; Tajiks)
    • HS1-BP3 gene
• Clinical features:
  • Seen with maintenance of a specific posture
  • Rare at rest
  • Kinetic
  • A few patients may only demonstrate it with a fixed posture
  • Usually abduction-adduction or flexion–extension of the hand; rarely pronation-supination
  • Most often monosymptomatic
  • May be associated with:
    • Poor fine hand movements
    • Balance and gait disturbance
  • Rarely affects the jaw (distinguishing point from PD)
  • Rarely associated dystonia
  • Malignant hyperthermia (rare)
  • Migraine
  • Fragile X-pre-mutations (have essential tremor)
  • HS1-BP3 gene:
    • Head tremor more common in women than men
  • Head tremor:
    • Vertical yes-yes (rare)
    • Horizontal no-no is usual (PD is vertical head tremor when present)
    • Usually associated with hand tremor
  • Frequency is 4–10 Hz
  • Slowly progressive
  • Late stages:
    • Tremor of the voice, palate and tongue
  • Handwriting:
    • Rounded letters are produced with sharp angularity
    • Large letters
  • Age: frequency declines; amplitude increases
  • Responds to alcohol, gabapentin; benzodiazepine, primidone; beta adrenergic blockade

Clinical Tremor Variants

• General considerations:
  • Orthostatic tremor
• Clinical features:
  • Rapid irregular and asynchronous tremor of the legs and trunk induced by standing
  • Onset: middle aged or elderly patients
  • Unsteadiness in the legs with fear of falling
  • Loss of extensor tone in the legs
  • Difficulty in initiating gait
  • Pain in the legs when standing
  • Wide based stance but walk normally
  • Signs and symptoms abolished with sitting
  • 13–18 Hz burst firing in antigravity muscles
  • Tremor may occur in the trunk and cranial musculature
  • Isometric contracture of muscles may induce tremor (16 Hz) during the supine posture
  • Asymptomatic hypertrophy of thigh and calves (rare)
  • Described with pontine lesions
  • It is a task specific tremor
• Primary writing tremor:
  • Affects writing in isolation
  • No associated (or minimal) postural or kinetic component
  • Possibly initiated by hand position
  • 1/3 of patients have family history of the disorder
• Isolated voice tremor:
  • May be associated with spasmodic dysphonia
• Kinetic predominant head tremor
• Combined resting and postural tremor

Wilson's Disease

• General considerations:
  • AR; chromosome 13q 14–21
  • 75% present with liver signs and symptoms, psychiatric manifestations or tremor may be early features
  • Hepatitis and cirrhosis present prior to CNS manifestations
  • Nephropathy: amino acidosis, phosphaturia, uricosuria (low serum uric acid), increased urine copper
• Clinical features:
  • Kayser–Fleischer ring (copper deposition on Descemet's membrane
    • Seen upper limbus of blue-eyed patients
    • Seen in 100% of patients with CNS manifestations
  • Associated neurologic signs:
    • Dystonia
    • Chorea
    • Myoclonus
    • Gait disturbance
    • Dysarthria
    • Seizures
    • Parkinsonism
    • Cerebellar signs
• Pathology:
  • Atrophy of putamen primarily; some in globus pallidus
  • Glial modification
  • Diffuse atrophy of cerebellum and cerebral cortex
  • Opalski cells

Dystonic Tremor

• In context of sustained abnormal contracture
• "Jerking" tremor-like movement:
  • With intention
  • Passive movement of the dystonic muscles
  • Pain in distribution of the affected segment
  • Frequently of peripheral origin (chronic regional pain syndrome); most often mistaken for dystonia of central origin. Allodynia of the affected part is often present.

Intention (Kinetic or Action Tremor)

• General considerations:
  • Most commonly seen with cerebellar disease
  • Oscillation during the terminal 1/3 of a specific movement which decreases as the target is approached.
• Clinical features:
  • Specific cerebellar lesions cause specific patterns of tremor:
    • Lateral cerebellar hemispheric lesion (dentate-superior cerebellar peduncle) extremity tremor
    • Tremor of the head and trunk vermian or fastigial lesions
    • Postural tremors (6–10 Hz) cerebellar outflow tremor:
      • Involvement of the superior cerebellar peduncle near the red nucleus has been termed a "rubral" tremor. Clinical observation in some patients is that the tremor is more severe with lesions near the red nucleus ("rubral tremor"); 2–5 Hz
      • A tremor may be seen with involvement of the cerebellum at any level
• Usual pathologies:
  • Midbrain Rubral Tremor:
    • Sequelae of severe head trauma
    • Coma
    • Lesions close to the red nucleus interrupt the dentato-thalamo-rubral pathway
    • Delayed onset after the coma (weeks to months)
  • Stroke Involving:
    • Interpeduncular artery (top of the basilar)
    • Thalamoperforate artery (P1) branch of the posterior cerebral artery (PCA)
    • Medial posterior choroidal (PCA)

Tremor of Peripheral Nerve Origin

• Often following trauma (CRPS I/II)
• Exaggerated physiological tremor
• Increased by sympathetic stimulation
• 2–8 Hz frequency
• Possible spindle mechanism (sympathetics innervate muscle spindles)
• Kinetic and postural
• Weeks to months after injury

Drugs that Cause Tremor

• Amphetamines
• Alcohol withdrawal
• Antihistamines
• Anticholinergics
• Lithium
• Valproate
• Epinephrine
• Caffeine
• Adrenocorticoids
• Theophylline
• Thyroid
• Beta adrenergic agonists
• Neuroleptics
• Calcium channel blockers (nimodipine, flunarizine)
• Lidocaine
• Amiodarone
• Nicotine

Neuroleptic Tremors

• Postural
• Bilateral
• Associated with parkinsonism
• Beta 2 adrenergic agonists
• Lithium tremors:
  • Rest
  • Postural
  • Kinetic
  • 3–15 Hz
• Valproic Acid:
  • Resting, kinetic, postural tremors
• Tricyclic antidepressants:
  • Postural and kinetic tremors
  • Associated with chorea and myoclonus
  • 10% respond to Inderal
• Ethanol withdrawal:
  • Generalized tremor
  • 7–14 Hz
  • Increased by activity and emotional stress
• Nicotine:
  • Increases amplitude of physiological tremor

Metabolic Causes of Tremor

• Uremia
• Thyrotoxicosis
• Hypocalcemia
• Hypomagnesemia
• Hypophosphatemia

Toxic Causes of Tremor

• Mercury poisoning
• Ethylene oxide
• Carbon monoxide
• Heat stroke (kills Purkinje cells)

Psychogenic Tremor

• Abrupt onset
• Sporadic course
• Spontaneous remission
• Clinical inconsistencies
• Unresponsive to drugs
• Changing characteristics
• Lessens with distractibility
• Increases with attention
• Responds to placebo

Chorea

• General characteristics:
  • Definition: Sudden, irregular unpredictable brief involuntary irregular movements of the extremities, facial or truncal musculature.
  • Specific muscles involved depend on the illness
    • Huntington's more truncal than appendicular while Sydenham's is more appendicular than truncal
  • May occur at rest or with intention, in this instance they may be masked as semi purposeful (parakinesia)
  • The movements may be unilateral or bilateral, cease in sleep and are exacerbated by stress
  • Associated with increased or decreased tone
  • Hyperpronation of the upper extremity with extension
  • Intermittent contracture of grip (milk-maids hand)
  • Difficulty sustaining movement (inability to maintain the extruded tongue)
  • Facial grimacing and interruption of smooth breathing patterns are characteristic

Causes of Chorea

Hereditary

• Huntington's Disease
• Hereditary non-progressive chorea
• Neuroacanthocytosis
• Wilson's disease
• Ataxia telangiectasia
• Lesch–Nyhan Syndrome
• Hallervorden–Spatz Disease (PANK-2)
• Pelezuis Merzbacher disease
• Paroxysmal kinesogenic choreoathetosis
• DRPLA
• Familial abetalipoproteinemia
• Aceruloplasmalemia
• Abetalipoproteinemia
• DHL 1 (Huntington like acanthocytosis)
• Alzheimer's (late)
• Ferritonapthy

Huntington's Disease

• General characteristics:
  • AD
  • Varies in different populations
  • Between 4–7/100,000 people
  • Low frequency less than 1/100,000:
    • Finland
    • Japan
    • Black population of the USA
  • Chromosome 4:
    • CAG repeat (37–86) range for disease
  • Inverse correlation with CAG repeat length:
    • Age of onset
    • Age of death
    • Rate of progression
    • Other clinical features:
      • Correlation strongest with early >late onset disease
  • Sporadic HD:
    • Expansion from a large repeat in an unaffected male patient
    • Intermediate alleles
    • Unstable expansion
  • No variance of repeat length in different tissues:
    • Repeat size altered in gametogenesis:
      • Highest in spermatogenesis:
      • Juvenile onset with paternal transmission
    • Polyglutamine tract in Huntington gene is translated:
      • Binds to glyceraldehydes 3-phosphate dehydrogenase (GAPD)
• Clinical presentation:
  • Variable onset:
    • Juvenile (4–19 years of age)
    • Early (20–34 years of age)
    • Midlife (35–49 years of age)
    • Late onset is greater than 50 years of age
    • 10% present as juvenile
    • 25% present as late onset
  • Anticipation:
    • Progressive increase in the length of the tandem repeat
    • Longest tandem repeats associated with the earliest onset
    • Late onset disease/maternal transmission
• Clinical patterns:
  • Hyperkinetic:
    • Most common form
    • Chorea first clinical manifestation
    • Usual form:
      • Middle or late onset disease
      • Variable rate of progression
    • Hyperreflexic
    • Hypotonic
    • Lurching gait
    • Choreatic eye movements
    • Dementia:
      • Frontal lobe features
      • Choreatic movements may precede or follow the dementia
  • Juvenile or early onset disease (Westphal variant):
    • Inheritance of the gene from an affected father
    • Rapid clinical progression
    • Some patients:
      • Neuropsychological disturbance > movement disorders
    • Bradykinesia
    • Rigidity
    • Seizures
    • Movements persist through sleep
    • Differential diagnosis of akinetic rigid HD
      • Wilson's disease
      • Juvenile Parkinsonism
      • Neuroaxonal dystrophy
      • Metabolic storage disorders
  • Late state Disease:
    • Uncommunicative:
      • Orolingual chorea
      • Cognitive dysfunction
      • Rigidity
      • Dystonia
      • Dysphagia (aspiration pneumonia)
      • Duration of disease:
      • Shorter in patients with:
        • Juvenile
        • Early onset disease
• Laboratory evaluation:
  • CT:
    • Enlarged lateral ventricles (box car ventricles)
    • Flattening or absence of the caudate nucleus
    • PET studies:
      • Hypometabolism of the caudate and putamen nuclei

Differential Diagnosis of Huntington Chorea

• Sydenham's chorea:
  • Earlier age of onset
  • Self limited
  • Euphoria but no dementia
  • May be familial
  • Rheumatic heart disease
  • Unilateral (hemichorea) in 50%
  • Apparent flaccid paralysis (chorea mollis)
• Chorea with SLE:
  • More acute onset
  • Chorea:
    • More localized
    • Periodic
• Neuroleptic chorea (tardive dyskinesia):
  • Stereotypic movements (repetitive)
  • Oral Lingual buccal dyskinesia (most characteristic)
  • Gait is normal; lurching in HD
• Alzheimer's/Pick complex:
  • Mental disorder may be similar
  • Language involvement
  • No aphasia in early HD
  • Myoclonus >chorea
• Neuroacanthocytosis:
  • Mild chorea
  • Tics
  • Tongue biting
  • Peripheral neuropathy
  • Increased serum CPK
  • Red cell acanthocytes
• Hereditary non-progressive chorea:
  • Begins in childhood
  • Does not progress
  • No dementia or personality disorder

Infectious/Immunologic/Hematologic

• Sydenham chorea
• Encephalitis
• SLE
• Behçet's disease
• Subacute sclerosing pan encephalitis
• Lyme's disease
• Neurosyphilis
• Polycythemia vera

Drug Induced

• Levodopa
• D2 agonists
• Anti-convulsants (phenytoin)
• Neuroleptics
• Metoclopramide
• Steroids
• Amphetamines

Metabolics/Endocrine/Toxins

• Chorea gravidarum
• Hyperthyroidism/hypothyroidism
• Birth control pills (BCP)
• Hyperglycemia nonketotic encephalopathy
• Hypoparathyroidism
• Hypo or hypercalcemia
• Hypernatremia
• Renal failure
• Mercury poisoning
• Carbon monoxide poisoning
• Cocaine "crack dancing"

Vascular

• Hemichorea/hemiballism (STN lesion)
• Periarteritis nodosa
• Polycythemia vera
• Primary cardiolipin syndrome
• Congophilic angiopathy

Other

• Senile chorea
• Essential chorea
• Paraneoplastic striatal encephalitis

Neuroacanthocytosis

• General characteristics:
  • Molecular basis of chorea-acanthocytosis:
    • Chromosome 9q21: VPS1 13 A gene
    • Two splice variants are formed the longer variant of which is associated with chorea
    • AD chorea acanthocytosis:
      • JPH3; an expansion of CTG/CAG repeats within the junctophilin 3 gene in chromosome 16 q 24.3
    • Rare acanthocytosis noted in Hallervorden–Spatz disease; PANK 2 gene
• Clinical features:
  • Mean age of onset (32 and range 8–62 years of age)
  • Major movement disorder is chorea
  • Progressive disorder
  • Other movement abnormalities include:
    • Chorea most prominent sign
    • Dystonia (lingual action dystonia)
    • Tics (motor and phonic)
    • Parkinsonism (akinetic rigid)
    • Initial lip and tongue biting
  • Associated features:
    • Cognitive decline
    • Psychiatric disturbances
    • Dysphagia (secondary to oral facial lingual dystonic movements)
    • Dysarthria
    • Seizures (grand mal usually) occur in 50% of patients
    • Vertical ophthalmoparesis
    • Amyotrophy of extremities
    • Axonal neuropathy
    • Absent reflexes
  • Genetically heterogeneous: some patients have associated:
    • Abetalipoproteinemia
    • McLeod Syndrome

McLeod Syndrome

• General characteristics:
  • Male carriers of the McLeod blood group
• Clinical features:
  • Onset between 18–61 years (mean of 35 years)
  • One third present with choreatic movements
  • 20% present with seizures and 40% develop them during the course of the illness
  • Differential point between chorea acanthocytosis and the McLeod syndrome:
    • Less or no lip or tongue biting or branchial symptoms and involuntary in salivation in the McLeod syndrome
  • Absent deep tendon reflexes
  • 50% develop muscle weakness
  • Frequent dilated cardiomyopathy
  • 1/3 of patients have non-symptomatic hepatosplenomegaly
  • Frontal subcortical dementia is seen
• Laboratory evaluation:
  • Elevated CK level up to 4000 units
  • No specific immunohistochemistry staining for XK and Kell antigens of the sarcoplasmic membranes
  • Erythrocyte acanthocytosis with compensated hemolysis

Huntington's Disease Variant (HD Like 2 Acanthocytosis)

• General characteristics:
  • CTG/CAG repeat expansion within the junctophilin gene (JPH3) on chromosome 16 q 24.3 repeats that are pathologic are 41–58
  • Junctophilin-3 the encoded protein may regulate calcium and appears to be important in membrane structure
• Clinical features:
  • Onset occurs in the third to fourth decades
  • May present with chorea or Parkinsonism
  • Frequent dystonia
  • Feeding dystonia or oral facial dyskinesia with mutilation are not prominent
  • No multisystem organ involvement
  • Frontal subcortical dementia is prominent
• MRI evaluation:
  • Generalized atrophy of the basal ganglia
  • Advanced cortical atrophy (some patients)
  • White matter changes in several case reports
• Pathology
  • Striatal atrophy
  • Putamen and globus pallidus are involved

Familial Hypobetalipoproteinemia Type 1

• General characteristics:
  • AD:
    • FHBL2 gene on chromosome 3p 22–p 22.1
  • Obligate heterozygotes for FHB1 have hypocholesterolemia but no neurological deficits
  • Majority of familial hypobetalipoproteinemia patients have no known gene defect
  • Fat malabsorption occurs due to absent apolipoprotein B and inability to form chylomicrons
  • Neurologic disease is secondary to vitamin E deficiency
• Clinical features:
  • Acanthocytosis
  • Retinitis pigmentosa
  • Dorsal column degeneration
  • Proximal myopathy
  • Fat malabsorption
  • Decreased cholesterol levels

Abetalipoproteinemia (Bassen Kornzweig Disease)

• General characteristics:
  • AR:
    • Enzyme encoded is microsomal triglyceride transfer protein
• Clinical features:
  • Progressive neuropathy (large fiber)
  • Proximal myopathy
  • Dorsal column dysfunction; loss of vibration and deep tendon reflexes
  • Ataxia
  • Decreased cognition in approximately 1/3 of patients
  • Decreased [18F fluro] fluorodopa uptake in the putamen cell membrane and caudate nuclei
  • RBC acanthocytes:
    • Decreased fluidity of the red blood cell membrane
    • Altered lipid composition

Genetic Differential Diagnosis of Neuroacanthocytosis that Demonstrate Chorea

• HD (adult); AD; IT 15 gene
• HDL 1 – AD; PRNP gene
• HDL2 – AD; JPH3 – gene
• HDL 4 – AD
• SCA 3 – AD; 14; FTL 1 gene
• SCA 17 – AD – TBP gene
• DRPLA – AD – DRPL gene
• Neuro ferritinopathy – AD – FTL (ferritin light chain gene)
• Benign hereditary chorea – AD – TITF
• Wilson's disease – AR; ATP71
• Hallervorden – Spatz – AR; PANK2 gene
• Karak syndrome – AR; X-gene
• McLeod Syndrome – X – XK, X gene
• Lubag (Filipino dystonia Parkinsonism – X; DYT3
• Lesch-Nyhan Syndrome – X; HPRT gene
• Chorea acanthocytosis – AR; VPS 13 gene
• HARP – Part of the PANK-2 spectrum of disease

Unusual Diseases with Chorea as a Manifestation

Neuroferritinopathy (Adult Onset Basal Ganglial Disease)

• General characteristics:
  • AD
  • Mutation of the ferritin light chain gene; affects protein folding and stability
  • Mutations
• Clinical features:
  • Onset in the third to sixth decade
  • Spectrum of presentation:
    • Chorea
    • Dystonia
    • Akinetic rigid syndrome
• Pathology:
  • Ferritin and iron precipitates in the basal ganglia

Karak Syndrome

• General characteristics:
  • AR or X-link recessive
    • Gene possibly involved in iron sequestrations
• Clinical features:
  • May present with ataxia
  • Evolves to basal ganglia features suggestive of Hallervorden Spatz disease

HARP (Hypoprebetalipoprotemia)

• General characteristics:
  • Part of the pantothenate kinase spectrum of disease
  • Homozygous nonsense mutation in the PANK 2 gene
• Clinical features:
  • Hyperprebetalipoproteinemia
  • Retinitis pigmentosa
  • Pallidal degeneration with a clinical spectrum similar to patients with PANK 2

Hereditary Aceuroplasminemia

• General characteristics:
  • AR; loss of function mutation in the ceruloplasmin gene
  • Ceruloplasmin function:
    • Rate of iron flux from CNS and systemic cells
  • Hepatic iron accumulation
  • Increased iron stores in hepatocytes, reticuloendothelial cells
  • Beta cells of the pancreas are affected with consequent diabetes mellitus
• Clinical features:
  • Present in adult hood
  • Peripheral retinal degeneration
  • Dystonia
  • Dementia
  • Dysarthria
• Laboratory evaluation:
  • Microcytic anemia
  • Elevated serum ferritin
  • Absence of serum ceruloplasmin ferroxidase
• MRI evaluation:
  • Increased Fe⁺⁺ noted in the basal ganglia (decreased signal on T2 weighted images)
  • Involvement of the cerebral cortex

Lesch Nyhan Syndrome (HPRT)

• General characteristics:
  • X-linked; deficiency of hypoxanthine-phosphoribosyl transferase
  • Kelly Seqniller variant
    • Hyperuricemia with no CNS signs
• Clinical features:
  • Choreoathetosis
  • Biting of the lower lip
  • Spasticity
  • Mental retardation
  • Nephrolithiasis
• Laboratory evaluation:
  • Hyperuricemia

Benign Hereditary Chorea

• General characteristics:
  • Chromosome 14q
• Clinical features:
  • Early childhood onset
  • Most severe symptoms occur in the second decade
  • Does not progress after adolescence
  • Normal life expectancy
  • Some improvement with age
  • Distal extremities are affected

Dentato-Rubral-Pallidal Atrophy (DRPLA)

• General characteristics:
  • Autosomal dominant; most prevalent in Japan
  • Haw River Disease in southern USA
  • CAG repeat; overlap with SCA 15 and 17 SCA locus:
    • Expanded trinucleotide repeat of the coding region of the gene which translate polyglutamine stitches that cause:
      • Nuclear aggregates
• Clinical features:
  • Age of onset is the fourth decade (may range from second to seventh):
    • Early onset form:
      • Myoclonus, epilepsy, mental retardation
    • Late onset:
      • Ataxia, choreoathetosis, dementia, parkinsonism
      • Dystonia
      • Postural kinetic and intention tremor
• Pathology:
  • Atrophy of globus pallidus, subthalamic nuclei, substantia nigra, inferior olive and thalamus
  • Cerebral white matter involvement (one patient)
  • Corneal endothelial cell loss

Hemichorea

• General characteristics:
  • Structural lesions of the contralateral subthalamic nucleus, thalamus, or caudate nucleus
  • May be on the spectrum of hemiballism
• Clinical features:
  • Chorea may involve contralateral part of the body and spare the face
  • Usually seen in middle aged patients
  • Abrupt onset
• Pathology:
  • Hemorrhage
  • Tumor (rare)
  • Complication of thalamotomy

Chorea of Cardiac Surgery (Post Pump Chorea)

• General characteristics:
  • Usually seen in children
  • Risk factors:
    • Prolonged pump time
    • Circulatory arrest
    • Deep hypothermia

Choreoathetoid Encephalopathy after Cardiac Surgery

• General characteristics:
  • Seen after congenital heart surgery
  • Possibly due to vasoconstriction of the cerebral circulation (due to alkalosis during re-warming)
• Clinical features:
  • Choreoathetosis
  • Oro-facial dyskinesias
  • Hypotonia
  • Pseudobulbar palsy

Sydenham's Chorea

• General characteristics:
  • Following streptococcal infection with consequent rheumatic fever and heart valve involvement. Mitral>aortic
  • Familial tendency
  • Rarely occurs without heart disease
  • Adult recrudescence:
    • Associated with increased anti-streptolysin titer (ASO titer)
    • Jaccoud's arthritis (adults)
    • Generalized chorea
  • May resolve spontaneously in 3–6 months
• Clinical features:
  • Behavioral abnormalities (hyperactivity)
  • "Milk maids" hands; inability to sustain a movement
  • Incoordination
  • May have a grand mal onset:
    • Usually begins abruptly (worsening over 2–4 weeks)
  • Quick semi purposeful movements:
    • Jerking movements of the arms and legs
    • Decreased ability to walk
    • Involuntary movements of facial musculature with dysarthria
  • "Warner" hand
    • Flexed wrist; extended fingers
  • Chorea may recur:
    • First time during pregnancy (chorea gravidarum)
    • While taking oral contraceptives
  • Primarily distal extremities involved
  • Choreiform tongue movements

Paroxysmal Kinesigenic Dyskinesia (Paroxysmal Kinesigenic Choreoathetosis)

• General characteristics:
  • AD; several loci; chromosome 1 p and 2 q
  • Some family members may have infantile convulsions
• Clinical features:
  • Attacks initiated by sudden movement or startle; last seconds to minutes
  • Hyperventilation may induce attacks
  • Movements may be preceded by paresthesias, crawling sensations or anxiety
  • Movements consist of dystonic posture, ballism, chorea, athetosis or various combinations
  • May affect speech and cause falls
  • Movements habituate
  • Acquired etiologies:
    • Head trauma
    • Demyelinating disease
    • PSP
    • Putaminal and thalamic infarction
    • Hypoparathyroidism with basal ganglia calcifications
    • Hyperglycemia
    • Vascular malformation
  • Respond (90%) to anticonvulsants

Paroxysmal Non-Kinesigenic Dyskinesia (Paroxysmal Dystonic Choreoathetosis)

• General characteristics:
  • AD; chromosome 2 q 26–31; calcium channelopathy
• Clinical features:
  • Attacks last minutes to hours
  • Occur spontaneously at rest
  • Dystonia, chorea, athetosis, ballism and speech arrest; combinations of these movements may occur
  • Preceded by paresthesias, stiffness and occasionally formications
  • Triggered by stress, fatigue, caffeine, alcohol
  • Frequency is less than PKC
• Pathology:
  • Familial
  • Some patients linked to chromosome 2 q:
    • Migraine prevalent in these patients
    • Diazepam drug of choice
  • Hypoparathyroidism
  • Perinatal encephalopathy
  • Basal ganglia calcification
  • Infantile hemiplegia
  • Head trauma
  • Thyrotoxicosis
  • HIV infection
  • Anoxia
  • Brain tumor

Variants of Kinesigenic Dyskinesia

• General characteristics:
  • Paroxysmal exertion induced dyskinesia
• Clinical features:
  • Induced by prolonged exercise
  • Legs affected greater than arms

Paroxysmal Hypnogenic Dyskinesia

• Clinical features:
  • Involuntary movements only occur during sleep

SCA 7

• General characteristics:
  • AD
• Clinical features:
  • Myokymia
  • Nystagmus
  • Extraocular muscle dysfunction
  • Vertigo
  • Ataxia and tremor

Chorea in SLE

• General characteristics:
  • Occurs in 20% of SLE patients
  • Often associated with the SLE anticoagulant
• Clinical features:
  • Appears in younger patients
  • Lasts days to years
  • May be sole manifestation of the disease
  • Episodic

Chorea Gravidarum

• General characteristics:
  • Usually starts after six weeks of pregnancy
  • May recur with each pregnancy
  • May be triggered by birth control pills in those that have chorea in pregnancy

Senile Chorea

• General characteristics:
  • Choreic movements begin insidiously
  • Mild signs; involve the limbs
  • Rare, lingual facial movements
  • Slow progression

Tardive Dyskinesia

• General characteristics:
  • Usual cause is dopamine receptor antagonists or neuroleptic medication
  • Most common drugs:
    • Metoclopramide
    • Amoxapine
    • Perphenazine
    • Amitriptyline
    • Stelazine
    • Promethazine
  • Dopamine receptor dysfunction in the motor loop that synapses in the face area of the putamen may be causative
  • Abnormal movements occur:
    • During drug treatment
    • After drug withdrawal
    • May be permanent
  • Usually 3 months of exposure is required
  • Exacerbation of movements may occur with drug withdrawal; increasing the dose may dampen movements
• Clinical features:
  • Orofacial dyskinesia; the buccolingual masticatory syndrome (BLM):
    • Rhythmical involuntary movements of the tongue, face, mouth or jaw
    • Choreiform movements of the extremities
    • Distal athetosis
    • Abnormalities of gait, trunk and posture
    • Axial dystonias:
      • Patients>50 years of age
      • May coexist with buccal lingual masticatory (BLM) and choreoathetosis
      • Neck flexion and lordosis
      • Pelvic rocking and thrusting
    • Respiratory dyskinesia with involuntary chest and diaphragmatic movements
    • Often accompanied by tardive akathisia:
      • Inner compulsion to move
      • Restlessness
      • Uncomfortable sensations of the body as a whole or specific body parts

Tardive dyskinesia variants

• Tardive dystonia:
  • Accompanied by tardive akathesia or tardive dyskinesia
  • Sustained and torsional movements
  • Facial dystonia (blepharospasm) with or without facial grimacing
  • Jaw deviations protrusion or sustained opening or jaw closure (striking in DYT3 or Lubag)
  • Dystonic neck posturing (retrocollis)
• Tardive dyskinesia variants:
  • Generalized chorea
  • Tardive akathisia
  • Tardive tics
  • Tardive dystonia
  • Tardive myoclonus
• Tardive dyskinesia accompaniments:
  • Respiratory dyskinesia
  • Body rocking
  • Pelvic thrusting

Differential Diagnosis of Tardive Dyskinesia

• Tardive dyskinesia (TD) follows the long term use of all neuroleptic medication:
  • Two years of use
  • Some patients acquire the syndrome in six months
  • Phenothiazines
  • Butyrophenones
  • Anti-emetic drugs
• Schizophrenic patients (drug naïve):
  • Stereotyped and repetitive movements
  • Complex involuntary hyperkinetic dyskinesia
  • Isolated tics
• Orofacial dyskinesia in normal patients:
  • Elderly
  • Early senile dementia
• Huntington's disease:
  • Protrusion of tongue is abnormal; it usually is normal in BLM
• Wilson's Disease
• Withdrawal emergent dyskinesia:
  • Usually seen in children
  • Dyskinesias that occur transiently after withdrawal of neuroleptics
• Unilateral striatal lesions may cause bilateral oral buccal dyskinesia

Abdominal Dyskinesia

• General characteristics:
  • Continuous sinuous rhythmic movements of the abdominal wall

Differential Diagnosis of Abdominal Dyskinesia

• Abdominal trauma
• Propriospinal myoclonus
• During emergent withdrawal from neuroleptics

Ballismus

• General characteristics:
  • Rapid large amplitude flinging movements of an extremity
  • Proximal girdle muscles are primarily involved
  • At least 2/3 of the corpus Luysii or its efferents must be destroyed
  • Usual artery that is infarcted is the thalamoperforate artery from the P1 segment of the PCA. Infarction of the anterior choroidal artery (carotid) and the interpeduncular artery from the top of the basilar or posterior communicating artery may be causative.
  • Rarely ballismus may occur from striatal, cortical or thalamic lesions
• Clinical features:
  • Proximal limb girdle involvement
  • Face is usually spared
  • Sudden onset
  • Patients may restrain their arm under a belt or tie it down
  • Often associated with hemichorea particularly if there is a metabolic cause (hyperosmotic state)
  • Exhausting for patients; ceases during sleep
  • May be seen bilaterally
  • Ceases during sleep

Differential Diagnosis of Ballismus

• Ischemic infarct of the contralateral STN
• hemorrhage of the basal ganglia; hypertensive or due to a vascular malformation
• Rare causes:
  • Abscess
  • HIV
  • Basal ganglia calcification
  • Levodopa therapy
  • Parkinson's disease surgery
  • head trauma
  • Tuberculosis
  • Demyelinating disease (ADEM >MS)

Akathisia

• General characteristics:
  • Definition: the subjective sensation of restlessness associated with an inability to stay still. Movement relieves the sensation.
• Clinical features:
  • Complex stereotyped movements of the extremities and trunk
  • Shifting weight, crossing and uncrossing legs, rocking back and forth
  • Vocalizations; moaning, humming, or groaning
  • Acute akathisia occurs with initiation of medicine
  • Chronic treatment (tardive akathisia); increased by drug withdrawal
  • Movements are present throughout the day

Differential Diagnosis of Akathisia

• Dopamine antagonists
• Neuroleptic treatment
• Parkinsonism/Parkinson's disease
• Post encephalitic Parkinsonism
• Tourette syndrome
• Huntington's Disease
• Obsessive compulsive disease (OCD)
• Myriadit (jumping Frenchman of Quebec)
• TIC disorders
• Oromandibular dystonia

Differential Diagnosis of Orofacial Dyskinesia

• Associated clinical signs
  • Drug induced (primarily D2 antagonists):
    • Levodopa (associated chorea)
    • Triphenyl hexedine (dry mouth)
    • Antihistamines (neck muscle dystonia)
    • Stelazine (most potent by milligram)
    • Tricyclic antidepressants (those with basic phenothiazine structure)
  • Huntington's disease:
    • Associated dementia and choreatic eye movements
  • Hepatocellular degeneration:
    • Setting of chronic liver failure
    • Dysarthria
    • Falling backwards
  • Cerebellar infarction:
    • PICA
    • Salt and pepper facial pain
  • Edentulous patients:
    • Multiple "rodent like" mouthing movements
  • Dystonia:
    • Meige's syndrome:
      • Dramatic associated blepharospasm
    • Tardive dystonia:
      • Associated choreiform movements
  • Tics:
    • Associated complex stereotyped extremity movements
  • Tremor:
    • Up-down head tremor; slight side to side jaw tremor; a prominent chin tremor
  • ET (essential tumor) (side to side head tremor)
  • Cerebellar tremor of neck and jaw:
    • Associated postural kinetic tremor of body >extremity intention tremor
  • Myoclonus (facial)
  • Hemifacial spasm:
    • Large facial fasciculations
    • Risus sardonicus branch of VIIth nerve may be first affected muscle
  • Myokymia:
    • Seen around the soft tissues of the eye (often not evident)
  • Facial nerve synkinesia:
    • Jaw winking
    • Mentalis muscle often most severely affected
    • Deep ipsilateral nasolabial fold
  • Bruxism:
    • Associated TMJ joint disease with atrophic masseter muscles
  • Epilepsia partialis continua:
    • Thumb involvement at the same rhythm of eye blinking
    • Cortical nystagmus to the contralateral side

Hemifacial Spasm

• General characteristic:
  • Definition: brief irregular, clonic twitches that may build up to a sustained contracture of facial muscles that usually lasts for seconds, but may continue for minutes.
• Clinical features:
  • Movements may begin around the eye and later spread to the lower facial muscles
  • Persists in sleep
  • Approximately 15% of patients have bilateral involvement
  • Contractions are dyssynchronous
  • Rarely bilateral

Differential Diagnosis of Hemifacial Spasm

• Aberrant branch of AICA (or the artery itself) that intermittently compresses the VIIth nerve:
  • Especially likely if the patient is aware of a postural trigger
• Bell's palsy
• Neoplasm of the CPA angle
• Cranial dystonia
• Tic

Athetosis

• General characteristics:
  • Definition: slow writhing involuntary large amplitude that primarily involve the distal extremity muscles. Facial and axial muscles may also be involved in severe cases.
• Clinical features:
  • Associated episodic hypertonic muscle contractions of affected muscle groups
  • Abnormal movements may be unilateral or bilateral
  • Often associated with facial grimacing and dysarthria
  • Mixed with chorea and dystonia

Differential Diagnosis of Athetosis

• Congenital anoxia with bilateral damage ot the globus pallidus, red nucleus, mid brain tegmentum and descending periventricular corticospinal pathways
• Kernicterus
• Wilson's Disease
• Stroke or tumor that involves the striatum and spares the cortex
• Severe recovered head trauma
• Post anoxia from hanging

Pseudoathetosis

• General characteristic:
  • "Finger playing" sinuous movements of the outstretched upper extremity fingers
  • Updrift
  • Proprioceptive deficits

Differential Diagnosis of Pseudoathetosis

• Large fiber 20–22 μm fiber (proprioceptive and vibratory sensation loss)
• Large neuron dorsal root ganglion cell loss:
  • Sjögren's syndrome
  • Cis-platinum
  • Syphilis (dorsal root entry zone)
  • Paraneoplastic
  • Autoimmune (Richter's variant of GBS)
• Dorsal column and nuclear lesions:
  • If from posterior medullary artery infarction there may be large flinging movements of the arms
  • Loss of vibratory sense; the only other lesion that produces this is in the sensory thalamus (VPL)