Chapter 23: Movement Disorders

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):

• Body part(s) affected by tremor

• Frequency: speed of oscillation of tremor

• Amplitude: distance of excursion of tremor

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

  • Rest tremor emerges when the affected body part is inactive

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

  • 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:

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

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

• Non-epileptic primary neurologic diseases

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

  • 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)

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

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

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

• Benzodiazepine withdrawal

• 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:

• Hereditary neurologic diseases

  • Huntington’s disease

  • Dentatorubral-pallidoluysian atrophy (DRPLA)

  • Neuroacanthocytosis

  • Pantothenate kinase–associated neurodegeneration (PKAN)

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

  • Wilson’s disease

• Structural lesion of the basal ganglia

  • Tumor

  • Infection: toxoplasmosis has a predilection for the basal ganglia

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

• Systemic diseases

  • Immune-mediated

    • Sydenham’s chorea (poststreptococcal/rheumatic fever)

    • Lupus

    • Antiphospholipid antibody syndrome

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

  • Metabolic: hyperthyroidism, hyperglycemia

  • Polycythemia vera

• Pregnancy: chorea gravidarum

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

• Drugs: cocaine

• 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

Neuroacanthocytosis is an autosomal recessively inherited condition characterized by chorea, oral dystonias (causing biting of the tongue and lips as well as swallowing difficulties), neuropsychiatric symptoms, seizures, tics, neuropathy, and/or parkinsonism with characteristic acanthocytes on blood smear (red cells with “spikes”).

McLeod Syndrome

McLeod syndrome is an X-linked condition similar to neuroacanthocytosis, but may also be associated with myopathy and cardiomyopathy, and is less likely to have the oral dystonias characteristic of neuroacanthocytosis.

Pantothenate Kinase–Associated Neurodegeneration

Pantothenate kinase–associated neurodegeneration (PKAN), formerly called Hallervorden-Spatz disease, is an autosomal recessive disorder that is an example of a group of rare disorders classified as neurodegeneration with brain iron accumulation (NBIA). Patients with PKAN demonstrate both extrapyramidal features and pyramidal features. The characteristic MRI) signature is the “eye of the tiger sign” on T2-weighted imaging: T2 hyperintensity of the center of the globus pallidus interna surrounded by hypointensity (Fig. 23–1).

Dystonia refers to involuntary sustained (or paroxysmally sustained) postures of one or more body parts due to muscle contraction that often leads to twisting movements/postures of the affected limb(s). Tremor may accompany dystonia in some cases. Patients may describe maneuvers whereby touching the dystonic region lessens the dystonia, called a sensory trick (or geste antagoniste).

Dystonia can present in several ways:

• Dystonia may occur in isolation or as part of a syndrome with multiple additional features

• Dystonia may be focal (confined to one body part), segmental (confined to one limb), multifocal (more than one limb but not generalized), or generalized

• Dystonia may or may not be task-specific (e.g., writer’s cramp or musician’s dystonia)

• Dystonia may be primary (idiopathic or genetic) or may be secondary to:

• Structural lesions of the basal ganglia: e.g., infarct, trauma, neoplastic, or infectious. (Such lesions often lead to hemidystonia [i.e., dystonia on one side of the body.])

• Drugs: e.g., acute dystonic reaction with dopamine-blocking antiemetics

Focal Dystonias

Torticollis (Cervical Dystonia)

Torticollis is a common dystonia that causes neck twisting (torticollis), forward flexion (anterocollis), extension (retrocollis), or tilting to one side (laterocollis). Sensory tricks that may ameliorate the symptoms include touching the chin or neck. A head tremor may be associated. Botulinum toxin injection is first-line treatment.

Task-Specific Dystonias

Task-specific dystonias emerge only during the provocative activity: for example, writing in writer’s cramp or playing a musical instrument in musician’s dystonia (which may affect the hands or mouth depending on the instrument).

Blepharospasm

Blepharospasm is dystonia of the periorbital muscles leading to involuntary bilateral closure of the eyes. When disabling, botulinum toxin injected into the orbicularis oculi may be effective.

Genetic Dystonias

An ever-increasing list of genetic dystonias (numbered DYT[x]; e.g., DYT1, DYT25) is emerging with different gene loci, inheritance patterns, geographic distribution, and clinical phenotype. Some of these syndromes cause an isolated dystonia, while others are accompanied by other movement disorders such as parkinsonism (DYT3, DYT5, DYT 12) or myoclonus (DYT11, DYT15). Some of the more common genetic dystonias include:

• DYT1: an autosomal dominantly inherited childhood-onset dystonia that begins in one limb and subsequently generalizes, and is more common in patients of Ashkenazi Jewish heritage.

• DYT3: an X-linked syndrome affecting Filipino men in which both dystonia and parkinsonism are present.

• DYT5 (Segawa syndrome): an autosomal dominantly inherited childhood-onset disorder in which dystonia of the lower extremities arises later in the day and may be absent after rest. Since the condition responds well to levodopa therapy it is sometimes referred to as dopa-responsive dystonia.

Acute Dystonic Reactions

Acute dystonic reactions are medication-induced dystonias that can affect any region of the body including the limbs, the eyes (oculogyric crisis), the neck (torticollis), the tongue, or the mouth. The most commonly implicated drugs are antidopaminergic agents such as antipsychotics and antiemetics. Acute dystonic reactions may occur after the first dose or within days of initiation of the offending medication. Treatment is with benztropine or diphenhydramine and discontinuation of the medication.

Tics

Tics are brief movements (motor tics) or vocalizations (phonic tics, which can include anything from grunts, sniffs, or throat clearing to fully-formed words). Tics are generally preceded by a premonitory urge, able to be suppressed, and accompanied by a sense of relief after they occur. Tics can present in several ways:

• Tics can occur transiently (<1 year) in children (transient motor tics; transient phonic tics)

• Tics can occur as part of Tourette’s syndrome, a primary tic disorder (see “Tourette’s Syndrome” below)

• Tics can occur secondary to:

  • Drugs, including cocaine, antipsychotics, antiepileptics

  • Developmental disorders, including autism, fragile X syndrome

  • Neurodegenerative conditions, including neuro- acanthocyotsis

Tourette’s Syndrome

Tourette’s syndrome is a disorder in which tics are the primary feature. For diagnosis of Tourette’s syndrome, both motor and phonic tics must have occurred for over 1 year beginning before age 18 (although most cases present at a much younger age), with changes in types of tics over time. Obsessive-compulsive disorder and/or attention deficit–hyperactivity disorder may co-occur with Tourette’s syndrome, and so patients should be screened for these conditions. Some cases resolve spontaneously in the transition to adulthood, whereas others persist. Treatment involves behavioral therapies, and if severely disabling, antipsychotics (pimozide, haloperidol, or fluphenazine), tetrabenazine (reduces presynaptic dopamine release), or clonidine may be used.

Sterotypies

Sterotypies are repetitive purposeless movements, such as the rocking or spinning seen in patients with autism or the hand wringing seen in patients with Rett syndrome.

Parkinson’s disease (PD) is a neurodegenerative disease with the core features of tremor, bradykinesia, rigidity, and postural instability. Additional motor features include decreased facial expression (hypomimia), decreased blink rate, small handwriting (micrographia), stooped posture, shuffling gait with reduced arm swing, festination (increasingly rapid small steps), difficulty turning when walking, and difficulty turning over in bed. The constellation of some or all of these motor features is referred to as parkinsonism. In addition to idiopathic PD, other causes of parkinsonism include:

• Medications: most commonly antipsychotics and antiemetics (see “Drug-Induced Parkinsonism” below)

• Cerebrovascular disease (vascular parkinsonism)

• Toxins, including manganese and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) (MPTP may contaminate the illicit synthetic opioid MPPP [1-methyl-4-phenyl-propionoxypiperidine].)

• Metabolic conditions such as extrapontine myelinolysis

• Neurodegenerative diseases aside from idiopathic PD, called the Parkinson-plus syndromes (see “Parkinson-Plus Syndromes” below):

  • Multiple systems atrophy (MSA)

  • Progressive supranuclear palsy (PSP)

  • Corticobasal syndrome (CBS)

  • Dementia with Lewy bodies (DLB)

Parkinson’s Disease

Clinical Features of Parkinson’s Disease

Tremor, bradykinesia, and rigidity typically begin unilaterally in patients with idiopathic Parkinson’s disease, but usually become bilateral as the disease progresses (although commonly remains asymmetric). Some patients may have a tremor-predominant form of the disease without much rigidity or gait dysfunction, some patients may have no tremor at all and have predominant bradykinesia and rigidity (akinetic-rigid form), and some patients may have predominant postural instability and gait dysfunction. The tremor-predominant form of PD may have a more benign course than other forms of the disease.

Although most cases of Parkinson’s disease are idiopathic/sporadic, familial forms are associated with mutations in a growing number of genes including LRRK2 (autosomal dominant) and parkin (PARK2; autosomal recessive with onset in youth).

Tremor in Parkinson’s disease—The tremor of PD is most commonly a tremor of the hand(s) that is present at rest and resolves with movement, but may also reemerge after sustained posture (e.g., holding the arms and hands out straight). The tremor may be pill-rolling (flexion movements of the fingers and thumb giving the impression that the patient is rolling a pill in the hand), but this is not always the case. Rest tremor may emerge when distracting the patient, for example, by asking the patient to perform serial seven subtractions. The tremor typically presents unilaterally and, although it may become bilateral throughout the course of the disease, it often remains asymmetric in its severity. Tremor of the jaw may also be present, but tremor of the head (as is seen in essential tremor) is not typically a feature of Parkinson’s disease.

Bradykinesia in Parkinson’s disease—Bradykinesia denotes slowing of movements. This may be evident in observing the patient’s normal activities, and can be elicited on examination by testing finger tapping, foot tapping, or repeated pronation–supination movements (“as if screwing in a light bulb”). These movements should be tested one side at a time to avoid entrainment, which may mask asymmetries.

Rigidity in Parkinson’s disease—The side(s) of the body with tremor and/or bradykinesia may be noted to have cogwheel rigidity, whereby a joint appears to “click” through the passive range of motion rather than move smoothly when moved slowly through the range of motion by the examiner. This can be brought out by the technique of reinforcement, asking the patient to make circles or other repeated movements with the hand on the side opposite the limb being evaluated for rigidity. In idiopathic PD, rigidity is commonly asymmetric, affecting the limb(s) with tremor more so than the others. Axial rigidity can be evaluated for by moving the patient’s neck passively through its range of motion.

Postural instability in Parkinson’s disease—Postural instability tends to emerge later in the course of Parkinson’s disease (although it may be present earlier in the course of progressive supranuclear palsy; see “Progressive Supranuclear Palsy” below). Postural instability can be assessed using the pull test to look for retropulsion. The examiner stands behind the patient with the patient’s back to the examiner, preferably with a wall behind the examiner to break a fall should one occur. The examiner then explains that she or he will be pulling briskly on the patient’s shoulders and that the patient should maintain balance however necessary. After a brisk, forceful tug on the patient’s shoulders, the patient’s response is observed. Normally, a patient with intact postural stability will maintain balance with no steps or one or two steps backward. In a patient with postural instability due to parkinsonism, the patient will exhibit retropulsion, requiring several (more than three) small steps to regain balance, or in severe cases, the patient will simply fall backward.

Gait in Parkinson’s disease—Gait in PD is generally slow with small shuffling steps (marche à petit pas). Arm swing is usually diminished (usually more prominently on the side of greater tremor and/or rigidity). Turning is often difficult, requiring a number of small steps to turn. Some patients may start walking slowly and then accelerate with increasingly rapid small steps (festination). In advanced PD, some patients may develop freezing of gait, freezing in place and unable to proceed. Freezing may be able to be overcome by a visual stimulus (e.g., a line on the ground).

Other signs in Parkinson’s disease—When tapping slowly and rhythmically between the eyes, normal individuals will blink several times and then stop blinking. Patient’s with Parkinson’s disease may not extinguish the blink response and continue to blink with each tap, called Myerson’s sign or the glabellar sign.

Nonmotor aspects of Parkinson’s disease—Nonmotor features of PD include fatigue, depression, anxiety, dementia, autonomic dysfunction (including constipation, orthostatic hypotension, urinary dysfunction), decreased sense of smell, and REM sleep behavior disorder (RBD). In RBD, patients act out their dreams, which often involve kicking, punching, and/or running. RBD and olfactory dysfunction may precede the onset of Parkinson’s disease by years, and RBD is associated with a high risk of future development of a neurodegenerative disorder (most commonly synucleinopathies such as PD, multiple systems atrophy, and dementia with Lewy bodies). Dementia is typically not present at onset of parkinsonian symptoms in idiopathic PD. If dementia and parkinsonism arise concurrently, dementia with Lewy bodies should be considered (see “Dementia with Lewy Bodies” in Ch. 22). Autonomic dysfunction is usually a more prominent feature in multiple systems atrophy as compared to in PD.

Diagnosis and Differential Diagnosis of Parkinson’s Disease

Parkinson’s disease is a clinical diagnosis. A tremor-predominant presentation must be distinguished from essential tremor, drug-induced tremor, physiologic tremor, and hyperthyroidism. Asymmetry of tremor and accompanying bradykinesia and rigidity on the side of tremor are suggestive of PD. Early falls and/or impaired vertical gaze with parkinsonism suggest progressive supranuclear palsy (PSP). Early and severe autonomic dysfunction with parkinsonism suggests multiple system atrophy (MSA). Dementia and hallucinations arising before or concurrently with parkinsonism suggest dementia with Lewy bodies (DLB). Improvement in symptoms with levodopa is also suggestive of PD, although some Parkinson-plus syndromes may have an initial response to levodopa. When there is clinical ambiguity, a dopamine transporter SPECT (single photon emission computed tomography) scan can be used to look for asymmetric decreased activity in the basal ganglia. However, dopamine transporter SPECT only distinguishes a neurodegenerative parkinsonian syndrome from “not a neurodegenerative parkinsonian syndrome” (i.e., it does not distinguish between PD, multiple systems atrophy, progressive supranuclear palsy, and corticobasal syndrome). Dopamine transporter SPECT can be useful in a patient in whom there is a question of PD versus essential tremor (if the latter presents asymmetrically, as it sometimes does) or PD versus drug-induced parkinsonism (see “Drug-Induced Parkinsonism” below).

Treatment of Parkinson’s Disease

Pharmacologic treatment of PD is symptomatic, and therefore should begin when the disease begins to interfere with activities of daily living. For example, if the patient has a mild tremor in the nondominant hand that the patient does not feel is bothersome, treatment is not necessarily required. The available medications for PD include:

• Levodopa: given combined with carbidopa. Carbidopa inhibits peripheral dopamine breakdown, increasing the amount of levodopa that enters the CNS and decreasing peripheral side effects such as nausea.

• Dopamine agonists: pramipexole and ropinirole are the most commonly used agents in this category (pergolide is no longer in use due to cardiac valvular toxicity).

• Catecholamine O-methyl transferase (COMT) inhibitors: entacapone and tolcapone are used with carbidopa-levodopa to potentiate its effect (tolcapone can rarely cause hepatotoxicity and so entacapone is more commonly used).

• Anticholinergics: trihexyphenidyl is used predominantly for tremor.

• Monoamine oxidase B (MAO-B) inhibitors: selegiline and rasagiline.

• Amantadine: particularly useful in the treatment of dopamine replacement–induced dyskinesias (see “Treatment-induced dyskinesias in Parkinson’s disease” below)

In addition, exercise (aerobic and tai chi), speech therapy (for hypophonia if present), and psychiatric care (if depression, anxiety, or psychosis is present) are all important aspects of supportive care for PD.

Dopamine replacement with levodopa or a dopamine agonist is first-line therapy when the disease begins to become disabling. Levodopa is more effective than dopamine agonists and causes fewer initial side effects, but may be associated with a higher risk of subsequent motor complications (dyskinesias) than dopamine agonists. Side effects of dopamine agonists include daytime somnolence, peripheral edema, psychosis, hallucinations, and impulse control disorders (including hypersexuality, pathologic gambling). Side effects of levodopa include dizziness and nausea, which may be ameliorated by taking the medication with food (although this can decrease the absorption of the medication if the medication is taken with a high-protein meal).

Some practitioners suggest that younger patients should initially be treated with dopamine agonists, whereas patients who develop the disease later in life should begin immediately on levodopa. Advocates of this strategy prefer dopamine agonists in younger patients since these patients will likely survive longer with the disease and be prone to later treatment-related motor complications with levodopa. Given the efficacy of levodopa, however, some practitioners start directly with this medication in patients even if they are younger. As the disease progresses, nearly all patients with PD will ultimately require levodopa.

COMT inhibitors potentiate the effects of carbidopa-levodopa and can be added to this medication as the disease advances and response to levodopa decreases, a phenomenon called wearing off.

Anticholinergic medications such as trihexyphenidyl are most effective for tremor, and may be used in patients in whom tremor is the predominant disabling feature. Due to anticholinergic side effects such as confusion, this medication is often avoided in older adults.

MAO-B inhibitors and amantadine provide only minor symptomatic benefits and are sometimes used in early disease. Some data suggest a possible neuroprotective effect of rasagiline, but this is debated. Amantadine may also be useful in patients who develop dyskinesias (see “Treatment-induced dyskinesias in Parkinson’s disease” below).

Regimens involving multiple agents are inevitably necessary as the disease progresses, and must be individualized for each patient (Fig. 23–2). As the dopaminergic pathways continue to degenerate, the effect of levodopa may wear off quickly between doses (off states), requiring higher doses and/or increased dose frequency to maintain symptomatic relief (on states). Taking levodopa on an empty stomach may increase efficacy (although may also increase nausea). Additional strategies at this stage include adding a COMT inhibitor to potentiate the effect of levodopa, adding an MAO-B inhibitor, and/or adding a dopamine agonist. If a COMT inhibitor or a dopamine agonist is added, a dose reduction in levodopa may be necessary.

Treatment-induced dyskinesias in Parkinson’s disease—Degeneration of the dopaminergic pathway leads to hypersensitivity to dopamine replacement, which can cause dyskinesias (usually involuntary choreoathetoid movements). Dyskinesias usually arise after about 5 years of levodopa therapy (as mentioned above, this is part of the rationale given by some clinicians in delaying initiation of levodopa in younger patients). Dyskinesias can be treated with addition of amantadine or with lowering of levodopa dose, but this can lead to a “rock and hard place” scenario between the patient being “off” (parkinsonian) and “on” but dyskinetic. At this point, deep brain stimulation may be considered.

Deep brain stimulation in the treatment of Parkinson’s disease—Deep brain stimulation (DBS) is performed by surgical implantation of stimulating leads in the subthalamic nucleus (STN) or globus pallidus interna (GPi) connected to a stimulator that is placed in the soft tissue of the chest. The parameters of the stimulator can be adjusted by an external programming device. DBS increases the amount of time the patient spends in the “on” state without dyskinesias. Patients will not improve beyond their best response to levodopa and will still require medications, although often levodopa dosing can be decreased, which may account in part for the reduction in dyskinesias.

DBS only ameliorates motor symptoms, and generally does not lead to improvement in non-motor aspects of PD. Patients with cognitive impairment or psychiatric disease are generally not considered candidates for DBS. Surgical complications of DBS include intracerebral hemorrhage and intracranial infection, although these are not common occurrences. Hardware complications can occur due to lead breakage or migration. In addition to PD, DBS can also be considered in essential tremor and dystonia, although it is not currently used in Parkinson-plus disorders.

Drug-Induced Parkinsonism

Parkinsonism can be induced by dopamine-blocking agents, most commonly:

• Antipsychotics: more common with typical/first-generation antipsychotics, but can occur with atypical/second-generation antipsychotics

• Dopamine antagonist antiemetics: metoclopramide, prochlorperazine

• The rarely used antihypertensives reserpine and alpha-methlydopa

Drug-induced parkinsonism can also be seen rarely with antiepileptics (most commonly valproic acid, although this more commonly causes isolated tremor rather than parkinsonism).

In drug-induced parkinsonism, bradykinesia and rigidity are typically symmetric but can present asymmetrically as in PD. Tremor may be at rest, postural, or both. Symptoms generally emerge within months of starting the offending medication but can also emerge with change of dosage later in the course of medication treatment. Other associated drug-induced movement disorders such as tardive dyskinesia and akathisia may also be present (see “Tardive Dyskinesia” below), although drug-induced parkinsonism may be present in isolation. Treatment is ideally discontinuation of the offending medication when possible. If ongoing antipsychotic treatment is necessary for the underlying disorder, clozapine can be considered (although this requires monitoring of complete blood cell count [CBC] due to risk of developing agranulocytosis with this medication). Most cases of drug-induced parkinsonism are reversible, although this can take months. If a patient requires a particular typical or atypical antipsychotic for the underlying psychiatric condition and cannot be on a lower dose or changed to another medication, anticholinergic medication (e.g., benztropine) may be used as symptomatic treatment. Dopamine replacement is generally ineffective.

An important diagnostic consideration in older patients who develop parkinsonian symptoms while on antipsychotic medications or dopamine-blocking antiemetics is whether idiopathic PD is emerging or being in some way “unmasked” by antidopaminergic therapy. In such patients— especially if there is no improvement with removal of the offending agent—dopamine transporter imaging can be useful since this will be normal in drug-induced parkinsonism but abnormal in PD (or any Parkinson-plus syndrome).

Parkinson-Plus Syndromes

The Parkinson-plus syndromes (also called atypical parkinsonism) are neurodegenerative diseases that cause parkinsonism but also have additional features not seen in Parkinson’s disease. The Parkinson-plus syndromes include multiple systems atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB) (see Table 23–3). With the exception of CBS, parkinsonism is typically symmetric at onset compared to the unilateral onset typically seen in Parkinson’s disease.

Multiple Systems Atrophy

Multiple systems atrophy (MSA) is a disease characterized by parkinsonism and/or cerebellar dysfunction accompanied by autonomic dysfunction. Two variants of the disease are recognized, which are named based on their predominant feature: MSA-P (P for parkinsonism; formerly called striatonigral degeneration) and MSA-C (C for cerebellar; formerly called olivopontocerebellar atrophy). Parkinsonian features, when present, are typically symmetric at onset (as compared to asymmetric in Parkinson’s disease), and tend to progress more rapidly than in Parkinson’s disease. Tremor is not a predominant feature, and when present is most commonly an action tremor as opposed to the rest tremor typically seen in Parkinson’s disease (although rest tremor can occur in MSA). Autonomic dysfunction in MSA can manifest as orthostatic hypotension, urinary incontinence, and/or erectile dysfunction. These autonomic features may also be seen in Parkinson’s disease and dementia with Lewy bodies, but are typically milder in those diseases.

Additional features of MSA can include anterocollis (forward flexed posture of the neck), Pisa syndrome (head, neck, and trunk flexion to one side like the leaning tower of Pisa), hyperreflexia and/or Babinski’s sign(s), dysarthria and/or dysphagia, nocturnal stridor, pseudobulbar affect (uncontrolled laughing and/or crying), and/or Raynaud’s phenomenon. Although parkinsonian features may initially respond to levodopa in some patients with MSA leading to diagnostic consideration of Parkinson’s disease, this response is generally not sustained, and levodopa may worsen orthostatic hypotension.

In MSA-C, MRI may reveal the “hot cross bun” sign (resembling a plus sign in a circle) in the pons due to degeneration of the crossing corticopontocerebellar fibers destined for the middle cerebellar peduncles (Fig. 23–3). MRI abnormalities may also be present in the putamen, and atrophy may be seen in the putamen, middle cerebellar peduncle, pons, and/or cerebellum; these structures may also demonstrate hypometabolism on PET. Dopamine transporter imaging may be abnormal (decreased uptake in basal ganglia), but this can occur in any neurodegenerative parkinsonian syndrome and does not distinguish between them. Treatment is supportive.

Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is characterized by gait dysfunction (leading to falls) and oculomotor dysfunction (most commonly problems with vertical gaze). The first symptom is usually falls, commonly backward. The vertical gaze palsy characteristic of the disease may not be present initially, leading to initial diagnostic consideration of Parkinson’s disease. However, tremor is rare in PSP, and most of the rigidity in PSP is axial (neck and back) rather than in the extremities as is commonly seen in Parkinson’s disease. Patients have difficulty looking up and down voluntarily, but since the problem is supranuclear (hence the name of the disease), vertical eye movements can be elicited with vertical oculocephalic maneuvers (since the cranial nerve 8—medial longitudinal fasciculus [MLF]—cranial nerves 3, 4, and 6 pathways are intact; see “Supranuclear Versus Nuclear Lesions Affecting Eye Movements” in Ch. 11). Before vertical gaze palsy develops, slowing of vertical saccades compared to horizontal saccades may be noted. Downgaze palsy is more specific for the disease, since decreased upward gaze can be seen in many neurodegenerative disorders as well as in normal elderly patients. Cognitive and behavioral changes are often present early in the disease.

Other features of PSP include dysarthria and/or dysphagia, a startled/surprised appearance of the face, retrocollis, and ocular motor findings including square-wave jerks (saccadic intrusions away from the point of focus), eyelid opening apraxia (difficulty reopening the eyes after closure), and failure to suppress the vestibulo-ocular reflex (see “The Vestibulo-Ocular Reflex” in Ch. 12). The clap sign (inability to clap only three times and then stop; i.e., patient keeps clapping due to motor perseveration) is often associated with PSP, but can be present in any neurodegenerative disease.

Neuroimaging can reveal midbrain atrophy without pontine atrophy, resulting in a “hummingbird” appearance of the brainstem in midsagittal view (Fig. 23–4A). However, the brainstem in this view looks like a bird even in normal patients, and the pattern of midbrain atrophy in PSP may be more easily identifiable in the axial plane as a “carving out” of the space between the cerebral peduncles creating a “Mickey Mouse” appearance (Fig. 23–4B). As in MSA, levodopa may be helpful initially but often is not, and any response is often mild and transient compared to Parkinson’s disease. Therefore, treatment is supportive.

Corticobasal Syndrome and Corticobasal Degeneration

Corticobasal syndrome (CBS) refers to a clinical phenotype, and corticobasal degeneration (CBD) refers to a pathologic diagnosis (based on a specific anatomic distribution of tau pathology). The clinical phenotype of CBS can be caused by CBD pathology, but also by Alzheimer’s disease (AD) pathology, progressive supranuclear palsy (PSP) pathology, frontotemporal dementia (FTD) pathology, or mixed pathology. CBD pathology can give rise to clinical syndromes of CBS, PSP, FTD, an AD-like picture, or a mixed phenotype.

Symptoms of CBS are typically asymmetric (like Parkinson’s disease, but unlike MSA and PSP), and the affected side may demonstrate both cortical findings (such as myoclonus, apraxia, sensory neglect, and/or the alien limb phenomenon [involuntary purposeful limb movements]) and subcortical findings (such as parkinsonism, dystonia). Dementia, dysarthria, and eye movement abnormalities (saccadic breakdown of smooth pursuit and/or slowed saccades) may be present. Neuroimaging may reveal asymmetric parietal cortical atrophy (most pronounced contralateral to the affected limb) and PET may demonstrate asymmetric decreased cortical and basal ganglia metabolism. Treatment is supportive.

Dementia With Lewy Bodies

In dementia with Lewy bodies (DLB), parkinsonism (usually symmetric) is accompanied by dementia, hallucinations, and fluctuations in level of arousal/mental state. Unlike Parkinson’s disease dementia, in which the motor features of parkinsonism precede the development of dementia by years, in DLB, dementia and parkinsonism usually arise concurrently. (For further discussion of DLB, see “Dementia With Lewy bodies” in Ch. 22.)

Tardive Dyskinesia

Long-term use of dopamine blocking agents over months to years can lead to tardive dyskinesias: involuntary choreoathetotic movements most commonly involving the mouth and/or tongue (although they can occur in any part of the body). Tardive tremors, dystonias, and akathisia (restlessness) can also occur. The typical (first-generation) antipsychotics are the most common culprits, although tardive dyskinesia can be caused by atypical (second-generation) antipsychotics. Tardive dyskinesia can also occur after discontinuation of antipsychotics, especially when stopped abruptly. Prolonged metoclopramide use can also cause tardive syndromes.

Treatment of tardive dyskinesia is by withdrawing the offending agent by slow taper, although symptoms may persist for months or even years. However, in many patients, antipsychotic drug withdrawal may be contraindicated from a psychiatric perspective. Ideally, such patients should be switched to an atypical antipsychotic, or if already on one, to clozapine or quetiapine, which carry the lowest risk of tardive dyskinesia. Clozapine requires regular monitoring of CBC due to risk of agranulocytosis. When a patient requires ongoing antipsychotic medications that cannot be changed or lowered in dose from the psychiatric perspective, tetrabenazine or a benzodiazepine may be initiated, or trihexyphenidyl may be utilized for the treatment of tardive tremor. Deep brain stimulation may be used in severe cases not responsive to medications. Ideally, tardive dyskinesia can be prevented by avoiding long-term use of typical antipsychotic agents when possible.

Restless Leg Syndrome

In restless leg syndrome (RLS), patients feel unpleasant sensations in the legs (such as crawling, aching) causing a desire to move, and moving the legs relieves the sensation. This typically occurs at night in bed, or when resting late in the day. RLS should not be confused with periodic limb movements of sleep (PLMS), which are actual movements of the limbs during sleep. PLMS are commonly present in patients with RLS, but many people have PLMS without RLS. PLMS is more likely to be noted by the bed partner (since the patient is asleep), whereas RLS is noted by the patient.

Most cases of RLS are idiopathic, but an important reversible cause for which to evaluate is iron deficiency anemia. When RLS is due to iron deficiency anemia, symptoms often respond to iron replacement. Pregnancy and diabetes are predisposing factors to RLS (although evaluation for iron deficiency should be performed in such patients as well). It is also important to evaluate for an underlying neuropathy, which may produce similar symptoms or coexist with RLS.

First-line treatment for disabling RLS symptoms is with dopamine agonists, although gabapentin or pregabalin can also be used. With long-term dopamine agonist use, symptoms may worsen in severity and timing (i.e., beginning earlier in the day), a phenomenon called augmentation. Levodopa carries greater risk of augmentation than dopamine agonists, and so it should not be the initial agent used for treatment of RLS. If augmentation occurs, patients can be switched from one agonist to another or from dopamine agonists to gabapentin or pregabalin. In patients who do not respond to any of these drug classes, opioids may be effective.

Stiff Person Syndrome

In stiff person syndrome, patients develop muscle stiffness and spasm first in the axial muscles, and later in the proximal extremity muscles. Stiffness is generally apparent in how the patient walks, and palpable paraspinal muscle rigidity is present on examination. EMG, if performed, will reveal continuous muscle activity. The syndrome may be a sporadic autoimmune syndrome (associated with anti–glutamic acid decarboxylase [GAD] antibodies and often accompanied by other autoimmune diseases such as type 1 diabetes) or paraneoplastic (associated with anti–amphiphysin antibodies). Therefore, patients with stiff person syndrome should be evaluated for underlying malignancy. Treatment is with diazepam and immunomodulatory therapy (usually steroids and/or intravenous immunoglobulin [IVIg]).

Hemifacial Spasm

Hemifacial spasm is a condition in which there are paroxysmal contractions of half of the face. Neuroimaging may reveal a vascular loop compressing the facial nerve. Botulinum toxin is a highly effective treatment, but some patients respond to carbamazepine. Microvascular decompression of the facial nerve may be considered in refractory cases.

Faciobrachial Dystonic Seizures

An important differential diagnosis to consider in patients with hemifacial spasm is faciobrachial dystonic seizures. These are very brief episodes in which there is momentary dystonic posturing of one side of the face and the ipsilateral arm, which may occur many times per day (or even per hour) after onset. This entity is important to recognize as it is associated with anti-LGI1 (leucine-rich, glioma inactivated 1) antibodies. Faciobrachial dystonic seizures often precede the development of limbic encephalitis associated with anti-LGI1 antibodies, and development of limbic encephalitis may be prevented by early treatment with steroids upon recognition of faciobrachial dystonic seizures (Irani et al., 2011; Irani et al., 2013). This is one of the autoimmune encephalitides that is most commonly not associated with an underlying malignancy, although it may rarely be associated with thymoma or small cell lung cancer (see “Paraneoplastic Syndromes of the Nervous System” in Ch. 24).

Wilson’s Disease

Wilson’s disease is an autosomal recessive disease that affects the liver and brain, presenting in childhood or early adulthood. Many of the neurologic manifestations are movement disorders, which can include parkinsonism, tremor, dystonia, ataxia, and/or chorea. The classic tremor of Wilson’s disease is a wing-beating tremor elicited by having the patient sustain the arms elevated with elbows flexed (like wings). Cognitive and psychiatric symptoms are common. Seizures may occur. A pathognomonic ocular finding, the Kayser-Fleischer ring (a dark ring encircling the periphery of the iris), is almost always present in patients with neurologic manifestations of the disease. The diagnosis can usually be made by decreased serum ceruloplasmin and increased urinary copper on 24-hour urine collection, but liver biopsy may be necessary if these tests are inconclusive. Treatment with copper chelation (D-penicillamine or trientine) can be highly effective. In cases refractory to such treatments, liver transplantation may be considered.