In most realms of neurologic disease, localization is the first step toward differential diagnosis. In assessing movement disorders, however, the first step is to accurately characterize the type of abnormal movement(s) present, each of which has its own differential diagnosis. Movement disorders are broadly classified as either hyperkinetic (increased movement: tremor, chorea, myoclonus, dystonia, tics) or hypokinetic (decreased movement: bradykinesia as is seen in parkinsonism) (Table 23–1).

Tremor refers to rhythmic oscillation (i.e., shaking) of one or more parts of the body. Tremor can be characterized by (Table 23–2):

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  Body part(s) affected by tremor

  
  
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  Frequency: speed of oscillation of tremor

  
  
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  Amplitude: distance of excursion of tremor

  
  
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  The state(s) of the body part in which the tremor is observed—rest, posture, and/or action:

  
  
  
  
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    Rest tremor emerges when the affected body part is inactive

    
    
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    Postural tremor is observed when a posture is sustained against gravity (e.g., the arms and hands outstretched)

    
    
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    Kinetic or action tremor occurs with movement, and can be further characterized by whether the tremor is the same throughout the range of movement or worsens as the affected limb approaches a target (intention tremor).

Enhanced Physiologic Tremor

Enhanced physiologic tremor is the augmentation of a baseline tremor that is present in everyone but usually not apparent. This can be brought out or accentuated by emotional states (e.g., anxiety, fear), metabolic states (e.g., hypoglycemia, hyperthyroidism), endocrine conditions (e.g., hyperthyroidism), or caffeine.

Essential Tremor

Essential tremor is a condition that causes tremor in isolation without associated symptoms (i.e., no bradykinesia or rigidity as is seen in Parkinson’s disease), and can be either familial or sporadic. Essential tremor almost always involves the hands, is most often symmetric (although may begin asymmetrically and remain asymmetric in some patients), and can also involve the voice and/or head (nodding “yes,” “no,” or side-to-side). The tremor is typically present with sustained posture and with action, but is typically absent at rest except in very severe cases. The frequency and amplitude may differ between patients but are generally constant within an individual patient, although the severity of tremor may worsen over time. Some patients report amelioration with alcohol. There are two peaks in age of onset in the 20s and 60s.

Symptomatic treatment for disabling essential tremor is with beta blockers (commonly propranolol) and/or primidone. Propranolol should be avoided if the patient has asthma or is already on other cardiac medications. Primidone can be sedating. Benzodiazepines, topiramate, gabapentin, and/or botulinum toxin can be considered if first-line medications are ineffective or not tolerated. In patients who have disabling essential tremor refractory to medical therapy, deep brain stimulation (of the ventral intermediate [VIM] nucleus of the thalamus) may be considered.

Parkinsonian Tremor

The tremor of Parkinson’s disease or other parkinsonian syndromes is generally present at rest and resolves with intentional action. The tremor may also reemerge with sustained posture of the affected limb(s) (see “Tremor in Parkinson’s Disease” below).

Cerebellar Tremor

Cerebellar tremor is an oscillating action tremor, generally absent at rest, but worse at the extremes of movements where precision is required (see Ch. 8).

Rubral (Holmes) Tremor

Rubral (Holmes) tremor is a tremor caused by disruption of the superior cerebellar peduncle, which is the cerebellar output pathway to the motor system by way of the red nucleus and ventrolateral (VL) nucleus of the thalamus (see “Superior Cerebellar Peduncles: Output Back to the Brain” in Ch. 8). Rubral tremor is typically a slow tremor present at rest that augments with posture and movement. The most common lesion location is in the midbrain where the superior cerebellar peduncle meets the red nucleus. Given this localization in the midbrain, associated contralateral hemiparesis, contralateral ataxia, and/or ipsilateral cranial nerve 3 palsy may be present (see “CN 3: The Oculomotor Nerve” in Ch. 11).

Orthostatic Tremor

Orthostatic tremor is a rapid tremor of the legs that occurs only with standing and resolves upon sitting or walking. Clonazepam is generally used for treatment.

Myoclonus refers to rapid jerking movements. Myoclonus should not be confused with clonus, which is rhythmic contraction–relaxation seen in association with hyperreflexia with upper motor neuron lesions (see “Upper Motor Neuron Lesions Versus Lower Motor Neuron Lesions” in Ch. 4). Myoclonus generally affects a whole muscle, leading to obvious movement of a part of the body (distinguishing myoclonus from fasciculations, which are twitches of a few muscle fibers visible as movements beneath the skin). Asterixis is sometimes referred to as “negative myoclonus,” a sudden loss of tone causing a jerking movement.

Myoclonus can be seen in a wide range of conditions:

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  Normal/physiologic: e.g., myoclonus while falling asleep (hypnic jerks)

  
  
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  Epilepsy syndromes: e.g., juvenile myoclonic epilepsy, myoclonic epilepsy with ragged red fibers (MERRF) and Unverricht-Lundborg disease

  
  
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  Non-epileptic primary neurologic diseases

  
  
  
  
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    Dementias: particularly Creutzfeldt-Jacob disease and corticobasal degeneration, but can occur in any neurodegenerative dementia (e.g., Alzheimer’s disease) (see Ch. 22)

    
    
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    Paraneoplastic: opsoclonus-myoclonus syndrome associated with neuroblastoma in children and anti-Ri antibodies in adults (most commonly seen with breast and lung cancers in adults) (see “Opsoclonus-Myoclonus” in Ch. 24)

    
    
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    Encephalitis: infectious (e.g., herpes simplex virus, subacute sclerosing panencephalitis) or inflammatory (e.g., Hashimoto’s encephalopathy)

  
  
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  Systemic conditions affecting the brain: postanoxic brain injury, renal failure, electrolyte abnormalities

  
  
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  Medications including selective serotonin reuptake inhibitors (SSRIs), dopamine agonists, amantadine, antiepileptics, opiates, and antibiotics (e.g., cephalosporins)

  
  
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  Benzodiazepine withdrawal

  
  
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  Spinal cord disease causing segmental myoclonus or propriospinal myoclonus (see below)

The term essential myoclonus is used when myoclonus is present in isolation; this may be idiopathic or genetic.

Myoclonus of cortical origin tends to affect the face and hands, whereas subcortical and brainstem myoclonus more commonly affect the proximal muscles. Cortical myoclonus may be triggered by action or touch; brainstem myoclonus may be triggered by startle. Myoclonus of spinal origin may be segmental (affecting a particular muscle or muscle group) or propriospinal (causing abdominal myoclonus that may lead to torso flexion).

Palatal myoclonus causes the patient to hear clicking sounds. This may be idiopathic (essential palatal myoclonus) or due to a lesion in the Guillain-Mollaret triangle: dentate nucleus of cerebellum→contralateral red nucleus (via the superior cerebellar peduncle)→ipsilateral inferior olive→contralateral dentate nucleus (i.e., back to dentate nucleus where the triangle began [via the inferior cerebellar peduncle]).

Diffuse myoclonus may be seen in the acute period after anoxic brain injury (myoclonic status epilepticus), and is often associated with a poor prognosis. Lance-Adams syndrome refers to the emergence of action-induced myoclonus seen during recovery after anoxic brain injury. In Lance-Adams syndrome, there is no myoclonus at rest, but attempted action triggers myoclonic jerks of the active limb(s).

Treatment of Myoclonus

When there is a clear reversible underlying cause of myoclonus (e.g., renal failure), this should be treated. Any potentially causative medications should be discontinued if possible. For symptomatic control of myoclonus, levetiracetam, valproate, and clonazepam can be used.

Chorea refers to dancelike movements (same etymologic root as choreography). Chorea exists on a continuum with athetosis (slow sinuous movements) and ballism (larger amplitude often more violent-appearing movements). Sometimes choreiform movements may be subtle, appearing as “fidgeting” and disguised by incorporation into voluntary movements. Chorea may be seen in the following conditions:

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  Hereditary neurologic diseases

  
  
  
  
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    Huntington’s disease

    
    
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    Dentatorubral-pallidoluysian atrophy (DRPLA)

    
    
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    Neuroacanthocytosis

    
    
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    Pantothenate kinase–associated neurodegeneration (PKAN)

    
    
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    Some of the spinocerebellar ataxias (SCA 2, SCA 3, SCA 17)

    
    
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    Wilson’s disease

  
  
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  Structural lesion of the basal ganglia

  
  
  
  
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    Tumor

    
    
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    Infection: toxoplasmosis has a predilection for the basal ganglia

    
    
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    Stroke: stroke in the subthalamic nucleus is associated with contralateral hemiballismus

  
  
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  Systemic diseases

  
  
  
  
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    Immune-mediated

    
    
    
    
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      Sydenham’s chorea (poststreptococcal/rheumatic fever)

      
      
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      Lupus

      
      
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      Antiphospholipid antibody syndrome

      
      
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      Paraneoplastic syndrome: anti-Hu or anti-CRMP5 (collapsin response mediator protein 5) antibodies

    
    
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    Metabolic: hyperthyroidism, hyperglycemia

    
    
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    Polycythemia vera

  
  
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  Pregnancy: chorea gravidarum

  
  
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  Medications: dopaminergic therapy for Parkinson’s disease, oral contraceptives

  
  
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  Drugs: cocaine

  
  
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  Congenital: choreoathetotic cerebral palsy

Sydenham’s Chorea

Sydenham’s chorea occurs months following infection with group A beta-hemolytic streptococcus in children. The other features of rheumatic fever (carditis and arthritis) are not always present. Accompanying behavioral changes including obsessive-compulsive disorder are common. Anti-streptolysin O is often checked but can be normal when chorea emerges months after rheumatic fever. Symptoms usually resolve over months, but some practitioners utilize steroids in severe cases. Sydenham’s chorea may recur, so penicillin prophylaxis is often administered until adulthood.

Hereditary Causes of Chorea

The most common hereditary cause of chorea is Huntington’s disease. Rarer hereditary causes of chorea include neuroacanthocytosis, McLeod syndrome, and pantothenate kinase–associated neurodegeneration.

Huntington’s Disease

Huntington’s disease is an autosomal dominantly inherited condition causing chorea and neuropsychiatric symptoms (e.g., dementia, depression, psychosis). Additional examination findings include motor impersistence of the tongue (inability to keep the tongue protruded such that it darts in and out of the mouth) and slowed or absent saccades. Neuroimaging may demonstrate caudate atrophy. Definitive diagnosis is made by genetic testing, and requires genetic counseling of the patient and family since the disease is dominantly inherited. Huntington’s disease is caused by a CAG repeat in the huntingtin gene (chromosome 4), and increasing repeat length leads to the phenomenon of anticipation such that the disease presents at an earlier age of onset in subsequent generations. Treatment is largely supportive and symptomatic. The most effective treatment for chorea is tetrabenazine, which acts to decrease presynaptic dopamine release. If this is ineffective or there is concurrent psychosis, antipsychotics are used.

A juvenile form of Huntington’s disease (Westphal variant) is characterized by parkinsonism rather than chorea.

Dentatorubral-Pallidoluysian Atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominantly inherited condition caused by a CAG repeat in the atrophin 1 gene (chromosome 12), leading to degeneration of all of the structures listed in the name of the disease: dentate nucleus (dentato), red nucleus (rubral), globus pallidus (pallido), and the subthalamic nucleus (also known as the body of Luys). The adult-onset form of the disease (onset after age 20) is characterized by ataxia, chorea, and dementia. The juvenile-onset form of the disease (onset before age 20) causes seizures, myoclonus, ataxia, and mental retardation (without chorea). Neuroimaging in DRPLA demonstrates cerebellar atrophy, brainstem atrophy (most prominent in the anterior pons), and subcortical white matter abnormalities. The disease is most common in Japan, although a variant has been described in an African-American family in North Carolina (Haw River syndrome).

Neuroacanthocytosis