3399Parkinson’s Disease CHAPTER 435

Sleep disturbances are common in PD patients, with many

experiencing fragmented sleep with excess daytime sleepiness.

Restless leg syndrome, sleep apnea, and other sleep disorders also

occur with increased frequency and should be treated as appropriate. REM behavior disorder (RBD) is a syndrome composed of

violent movements and vocalizations during REM sleep, possibly

representing acting out of dreams due to a failure of motor inhibition that typically accompanies REM sleep (Chap. 31). Many PD

patients have a history of RBD preceding the onset of the classic

motor features of PD by many years, and most cases of RBD eventually go on to develop an α-synucleinopathy (PD or MSA). Low

doses of clonazepam (0.5–1 mg at bedtime) are usually effective

in controlling this problem. Consultation with a sleep specialist

and polysomnography may be necessary to identify and optimally

treat sleep problems. Excess daytime sleepiness can be problematic

for PD patients, and therapies such as Xyrem that are effective in

narcolepsy are currently being evaluated in PD.

NONPHARMACOLOGIC THERAPY

Gait dysfunction with falling is an important cause of disability in

PD. Dopaminergic therapies can help patients whose gait is worse

in “off ” times, but there are currently no specific therapies for gait

dysfunction. Canes and walkers may become necessary to increase

stability and reduce the risk of falling. An effective therapy for gait

impairment is an important unmet need in PD.

Freezing, where patients suddenly become stuck in place for seconds to minutes as if their feet were glued to the ground, is a major

cause of falling. Freezing may occur during “on” or “off ” periods.

Freezing during “off ” periods may respond to dopaminergic therapies, but there are no specific treatments for on-period freezing and

the mechanism is not well understood. Some patients will respond

to sensory cues such as marching in place, singing a song, or stepping over an imaginary line or obstacle.

Speech impairment is another source of disability for many

advanced PD patients. Speech therapy programs may be helpful, but

benefits are generally limited and transient.

Exercise has been shown to maintain and even improve function

for PD patients, and active and passive exercises with full range of

motion reduce the risk of arthritis and frozen joints. Some laboratory studies suggest the possibility that exercise might also have

neuroprotective effects, but this has not been confirmed in PD

patients. Exercise is generally recommended for all PD patients.

It is less clear that any specific type of physical therapy or exercise

programs such as tai chi or dance offer any specific advantage. It is

important for patients to maintain social and intellectual activities

to the extent possible. Education, assistance with financial planning,

social services, and attention to home safety are important elements

of the overall care plan. Information is available through numerous

PD foundations and on the Internet but should be reviewed with

physicians to ensure accuracy. The needs of the caregiver should

not be neglected. Caring for a person with PD involves a substantial

work effort and there is an increased incidence of depression among

caregivers. Support groups for patients and caregivers may be useful.

CURRENT MANAGEMENT OF PD

The management of PD should be tailored to the needs of the

individual patient, and there is no single treatment approach that

is universally accepted and applicable to all individuals. Clearly, if

an agent could be demonstrated to have disease-modifying effects,

it should be initiated at the time of diagnosis. Indeed, recent studies

suggest that dopamine terminal degeneration may be complete

within 4 years of diagnosis. Epidemiologic and pathologic studies

suggest that constipation, RBD, and anosmia may represent premotor features of PD and, along with imaging of the dopamine system,

could permit diagnosis and the initiation of a disease-modifying

therapy even prior to the onset of the classical motor features of the

disease. However, no therapy has been conclusively proven to be a

disease-modifying agent as yet, although rasagiline 1 mg per day met

all three prespecified primary endpoints consistent with a diseasemodifying effect. For now, physicians must use their judgment in

deciding whether or not to introduce a drug such as rasagiline for

its possible disease-modifying effects based on available preclinical

and clinical information.

The next important issue to address is when to initiate symptomatic therapy and which agent to use. Several studies suggest

that it may be best to start therapy at the time of diagnosis in order

to preserve beneficial compensatory mechanisms and possibly

provide functional benefits with improved quality of life even in

the early stage of the disease. Levodopa remains the most effective

symptomatic therapy for PD, and some recommend starting it

immediately using low doses (≤400 mg/d), as motor complications

have now clearly been shown to be dose-related. Others, however,

prefer to delay introduction of levodopa treatment, particularly

in younger patients, in order to reduce the risk of inducing motor

complications. An alternate approach is to begin with an MAO-B

inhibitor and/or a dopamine agonist, and reserve levodopa for later

stages when these drugs no longer provide satisfactory control. In

making this decision, the age, degree of disability, and side effect

profile of the drug must all be considered. In patients with more

severe disability, the elderly, and those with cognitive impairment,

significant comorbidities, or in whom the diagnosis is uncertain,

most physicians would initiate therapy with levodopa. Regardless

of initial choice, most patients ultimately require polypharmacy

(combination of levodopa, an MAO-B inhibitor, and a dopamine

agonist) in order to minimize the total daily levodopa dose and

reduce the risk of motor complications. While it is important to

use low doses of each agent to reduce the risk of side effects, it

is important not to deny patients levodopa when they cannot be

adequately controlled with alternative medications. It is important

to discuss the risks and benefits of the different therapeutic options

with patients so that they have informed opinions as to whether

they wish to start therapy and if so which drug to start.

If motor complications develop, patients can initially be treated

by adjusting the frequency and dose of levodopa or by combining

lower doses of levodopa with a dopamine agonist, a COMT inhibitor, or an MAO-B inhibitor. More recently the A2A antagonist

istradefylline has been approved in the United States as an additional medical therapy for treating “off ” periods. Amantadine is the

only drug that has been demonstrated to treat dyskinesia without

worsening parkinsonism, but benefits may decline over time and

there are important side effects related to cognitive function. In

advanced cases where patients suffer motor complications that cannot be adequately controlled with medical therapies, it may be necessary to consider a surgical procedure such as DBS or Duodopa,

but as described above, these procedures have their own set of complications. The use of DBS in early PD patients has been advocated

by some, but there is considerable skepticism about this approach

considering the costs and potential side effects, when inexpensive,

well-tolerated, and effective medical alternatives are available. Continuous intraintestinal infusion of levodopa/carbidopa intestinal gel

(Duodopa) offers similar benefits to DBS, but also requires a surgical intervention with potentially serious complications. Continuous infusion of apomorphine is a treatment option that does not

require surgery but is associated with potentially troublesome skin

nodules. Well-controlled comparative studies of these approaches

are awaited. There are ongoing efforts aimed at developing systems

that provide continuous delivery of levodopa or a long-acting formulation of levodopa that mirror the pharmacokinetic properties

of a levodopa infusion. Such a formulation might provide all of

the benefits of levodopa without motor complications and avoid

the need for polypharmacy and surgical intervention. Treatment

for the nonmotor features of PD should be instituted as deemed

appropriate, and exercise therapy is recommended for all patients.

A decision tree that considers the various treatment options and

decision points for the management of PD is provided in Fig. 435-7.

3400 PART 13 Neurologic Disorders

Functional disability

Parkinson’s disease

Surgery/CDS

Combination therapy

Levodopa/dopamine

agonist/COMT

Inhibitor/MAO-B Inhibitor

Nonpharmacologic intervention Pharmacologic intervention

Neuroprotection —? Rasagiline

Yes

Levodopa

No

Dopamine agonists

MAO-B inhibitor

FIGURE 435-7 Treatment options for the management of Parkinson’s disease

(PD). Decision points include: (1) Introduction of a neuroprotective therapy: no

drug has been established to have or is currently approved for neuroprotection or

disease modification, but there are several agents that have this potential based

on laboratory and preliminary clinical studies (e.g., rasagiline 1 mg/d, coenzyme

Q10 1200 mg/d, the dopamine agonist ropinirole, and pramipexole). (2) When to

initiate symptomatic therapy: There is a trend toward initiating therapy at the time

of diagnosis or early in the course of the disease because patients may have some

disability even at an early stage, and there is the possibility that early treatment

may preserve beneficial compensatory mechanisms; however, some experts

recommend waiting until there is functional disability before initiating therapy. (3)

What therapy to initiate: many experts favor starting with a monoamine oxidase type

B (MAO-B) inhibitor in mildly affected patients because of the good safety profile

of the drug and the potential for a disease-modifying effect; dopamine agonists for

younger patients with functionally significant disability to reduce the risk of motor

complications; and levodopa for patients with more advanced disease, the elderly,

or those with cognitive impairment. Recent studies suggest the early employment

of polypharmacy using low doses of multiple drugs to avoid side effects associated

with high doses of any one agent. (4) Management of motor complications: motor

complications are typically approached with combination therapy to try to reduce

dyskinesia and enhance the “on” time. When medical therapies cannot provide

satisfactory control, surgical therapies such as DBS or continuous infusion of

levodopa/carbidopa intestinal gel can be considered. (5) Nonpharmacologic

approaches: interventions such as exercise, education, and support should be

considered throughout the course of the disease. CDS, continuous dopaminergic

stimulation; COMT, catechol-O-methyltransferase. (Reproduced with permission

from CW Olanow et al: The scientific and clinical basis for the treatment of Parkinson

disease (2009). Neurology 72(21 Suppl 4):S1, 2009.)

Hollenbach JA et al: A specific amino acid motif of HLA-DRB1

mediates risk and interacts with smoking history in Parkinson’s disease. Proc Natl Acad Sci U S A 116:7419, 2019.

Kieburtz K et al: A new approach to the development of diseasemodifying therapies for PD; treating another pandemic. Mov Disord

36:59, 2021.

Marras C et al: Nomenclature of genetic movement disorders: Recommendations of the International Parkinson and Movement Disorder Society task force. Mov Disord 32:724, 2017.

Obeso JA et al: Past, present and future of Parkinson’s disease: A special

essay on the 200th Anniversary of the Shaking Palsy. Mov Disord

32:1264, 2017.

Olanow CW, Prusiner SB: Is Parkinson’s disease a prion disorder?

Proc Natl Acad Sci 106:12571, 2009.

Olanow CW et al: A double-blind delayed-start study of rasagiline in

early Parkinson’s disease. N Engl J Med 361:1268, 2009.

Olanow CW et al: Scientific and clinical basis for the treatment of

PD—2009. Neurology 72:S1, 2009.

Postuma RB et al: MDS clinical diagnostic criteria for Parkinson’s

disease. Mov Disord 12:1591, 2015.

Schapira AH et al: Slowing of neurodegeneration in Parkinson’s

disease and Huntington’s disease: Future therapeutic perspectives.

Lancet 384:545, 2014.

Schapira AHV et al: Non-motor features of Parkinson disease. Nat

Rev Neurosci 18:435, 2017.

Verschuur CVM et al: Randomized delayed-start trial of levodopa in

Parkinson’s disease. N Engl J Med 380:315, 2019.

HYPERKINETIC MOVEMENT DISORDERS

Hyperkinetic movement disorders are characterized by involuntary

movements unaccompanied by weakness (Table 436-1). This term is

somewhat arbitrary and potentially misleading as hypokinetic disorders

such as Parkinson’s disease (PD) are often accompanied by tremor,

which is a hyperkinetic feature, and hyperkinetic disorders such as dystonia may manifest slow or restricted movement because of the severe

muscle contractions. Nonetheless, the terms continue to be used because

of convention. The major hyperkinetic movement disorders and the

diseases with which they are associated are considered in this section.

TREMOR

■ CLINICAL FEATURES

Tremor is defined as an involuntary, rhythmic, oscillatory movement

of a body part with alternating contractions of agonist and antagonist

muscles. It can be most prominent at rest (rest tremor), on assuming

a posture (postural tremor), on actively reaching for a target (kinetic

tremor), or on carrying out a movement (action tremor). Tremor may

also be characterized based on its distribution, frequency, amplitude,

and related neurologic dysfunction. Tremor is classified along two axes:

Axis 1 covers the clinical characteristics, including historical features

(age at onset, family history, temporal evolution), tremor characteristics (body distribution, activation condition), associated signs (systemic, neurologic), and laboratory tests (electrophysiology, imaging).

Axis 2 relates to the etiology of the tremor and distinguishes acquired,

genetic, or idiopathic origins.

PD (Chap. 427) is characterized by a predominant resting tremor,

essential tremor (ET) characterized by a tremor that typically occurs

while trying to sustain a posture coupled with an action tremor, and

436 Tremor, Chorea, and Other

Movement Disorders

C. Warren Olanow, Christine Klein

■ FURTHER READING

Ascherio A, Schwarzschild MA: The epidemiology of Parkinson’s

disease: Risk factors and prevention. Lancet Neurol 15:1257, 2016.

Berg D et al: MDS research criteria for prodromal Parkinson’s disease.

Mov Disord 12:1600, 2015.

Blauwendraat C et al: The genetic architecture of Parkinson’s disease. Lancet Neurol 19:170, 2020.

Dorsey ER et al: Projected number of people with Parkinson disease

in the most populous nations, 2005 through 2030. Neurology 68:384,

2007.

Höglinger GU et al: Clinical diagnosis of progressive supranuclear

palsy: The Movement Disorder Society criteria. Movement Disorder

Society-endorsed PSP Study Group. Mov Disord 32:853, 2017.

3401Tremor, Chorea, and Other Movement Disorders CHAPTER 436

linked loci in large ET families. Recently, expansion of GGC repeat in

the human-specific NOTCH2NLC gene has been found to be associated with ET, but no independently confirmed causative genes have

been identified to date. It is likely that there are undiscovered genes for

ET that have escaped detection to date because of the heterogeneity of

the syndrome and the high population frequency of ET likely resulting

in a large number of phenocopies, (i.e., family members with a similar

clinical syndrome, but not carrying the causative mutation). The cerebellum and inferior olives have been implicated as possible sites of a

“tremor pacemaker” based on the presence of cerebellar signs in about

10% of ET patients, and increased metabolic activity and blood flow in

these regions in some patients. Some pathologic studies have described

cerebellar pathology with a loss of Purkinje cells and axonal torpedoes,

but these findings are controversial, and the precise pathologic correlate of ET remains to be defined. It is likely that multiple causes of ET

will ultimately be identified.

■ TREATMENT

Many cases are mild, do not cause any functional impairment, and

require no treatment other than reassurance. Occasionally, tremor

can be severe and interfere with eating, writing, and activities of daily

living. This is more likely to occur as the patient ages and is often

associated with a reduction in tremor frequency. Beta blockers and primidone are the standard drug therapies for ET and are useful in about

50% of cases. Propranolol (20–120 mg daily, given in divided doses)

is usually effective at relatively low doses, but higher doses may be

needed in some patients. The drug is contraindicated in patients with

bradycardia or asthma. Hand tremor tends to be most improved, while

head tremor is often refractory. Primidone can be helpful but should

be started at low doses (12.5 mg) and gradually increased (125–250 mg

tid) to avoid sedation, nausea, and dizziness. Benefits have also been

reported with gabapentin and topiramate, but these drugs have not

been widely employed. Botulinum toxin injections may be helpful

for limb or voice tremor, but treatment can be associated with muscle

weakness. Surgical therapies targeting the ventro-intermediate (VIM)

nucleus of the thalamus can be very effective for severe and drug-resistant cases. Recently, focal ultrasound (which is a procedure that does

not require surgery) has also been shown to be an effective therapy

against tremor in ET.

DYSTONIA

■ CLINICAL FEATURES

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions of agonist/antagonist muscles causing

abnormal, often repetitive movements and postures. Dystonic movements are typically patterned and twisting and may be associated with

a “dystonic” tremor in which the tremor is most pronounced when the

body part is moved in the direction of the dystonia. Dystonia is often

initiated or worsened by voluntary action and associated with overflow

muscle activation. Dystonia can range from focal minor contractions

affecting only an individual muscle group to severe and disabling

involvement of multiple muscle groups. The frequency is estimated to

be 16 per 100,000 (~50,000 cases in the United States) but is likely to be

much higher because many cases are not recognized. Dystonia is often

brought out by voluntary movements (action dystonia) and can extend

to involve other muscle groups and body regions not required for the

intended action (overflow). It can be aggravated by stress and fatigue

and attenuated by relaxation and sensory tricks such as touching the

affected body part (geste antagoniste).

Historically, dystonia has been described as primary or secondary.

However, because of a confusing and not always congruent combination of phenotypic and etiologic features, the older terms are no longer

recommended. A Movement Disorder Society Task Force charged

with redefining dystonia recommends classifying dystonia along the

same main axes as ET: clinical and etiologic. On clinical grounds,

dystonia can be categorized by age of onset (infancy, childhood, adolescence, early and late adulthood), body distribution (focal, segmental,

multifocal, and generalized), temporal pattern (static or progressive,

TABLE 436-1 Hyperkinetic Movement Disorders

Tremor Rhythmic oscillation of a body part due to intermittent muscle

contractions

Dystonia Involuntary, patterned, sustained, or repeated muscle

contractions often associated with twisting movements and

abnormal posture

Athetosis Slow, distal, writhing, involuntary movements with a

propensity to affect the arms and hands (this represents a

form of dystonia with increased mobility)

Chorea Rapid, semipurposeful, graceful, dancelike nonpatterned

involuntary movements involving distal or proximal muscle

groups. When the movements are of large amplitude and

predominant proximal distribution, the term ballism is used.

Myoclonus Sudden, brief (<100 ms), jerklike, arrhythmic muscle twitches

Tic Brief, repeated, stereotyped muscle contractions that can

often be suppressed for a short time. These can be simple

and involve a single muscle group or complex and affect a

range of motor activities.

cerebellar dysfunction characterized by a kinetic tremor (brought out

by trying to touch an object) and is usually associated with hypotonia

and past pointing. Normal individuals can have a physiologic tremor

that typically manifests as a mild, high-frequency (10–12 Hz), postural,

or action tremor typically affecting the upper extremities. This tremor

is usually of no clinical consequence and often is only appreciated with

an accelerometer or under stress. An enhanced physiologic tremor

(EPT) can be seen in up to 10% of the population, and tends to occur

in association with anxiety, fatigue, a metabolic disturbance (e.g.,

hyperthyroidism, electrolyte abnormalities), drugs (e.g., valproate, lithium), or toxins (e.g., caffeine, smoking, alcohol). Treatment is initially

directed at control of any underlying disorder and, if necessary, can

often be improved with a beta blocker.

■ ESSENTIAL TREMOR

ET is the most common movement disorder, affecting ~5% of the

population (an estimated 5–10 million persons in the United States

or Western Europe). It can present in childhood but dramatically

increases in prevalence in those aged >70 years. ET is characterized

by a high-frequency tremor (6–10 Hz) that predominantly affects the

upper extremities. The tremor is most often manifest as a postural or

action tremor and, in severe cases, can interfere with functions such

as eating and drinking. It is typically bilateral and symmetric but may

begin on one side and remain asymmetric. Patients with severe ET can

have an intention tremor with overshoot and slowness of movement

suggesting the possibility of a cerebellar origin. Tremor involves the

head in ~30% of cases, voice in ~20%, tongue in ~20%, face/jaw in

~10%, and lower limbs in ~10%. Multiple body parts are involved in at

least 50% of cases. The tremor is characteristically improved by alcohol

and worsened by stress. Usually the neurologic examination is normal

aside from tremor, but subtle impairment of coordination or tandem

walking may be present, and disturbances of hearing, cognition, personality, mood, and olfaction have also been described. The differential

diagnosis includes dystonic tremor (see below) or PD. PD can usually

be differentiated from ET because the former stops at the onset of a

voluntary action and is typically associated with bradykinesia with progressive slowing of sequential movements (sequence effect), rigidity,

gait and postural instability, and other parkinsonian features. However,

the examiner should be aware that PD patients may have a postural

tremor and ET patients may develop a rest tremor, but that these typically only begin after a latency of a few seconds (emergent tremor). In

contrast to the micrographia of PD, ET patients have relatively large

handwriting with evidence of the effect of tremor. The examiner must

also differentiate the effect of tremor when assessing tone in order to

distinguish the tremor of ET from the cogwheel rigidity found in PD.

■ ETIOLOGY AND PATHOPHYSIOLOGY

The etiology and pathophysiology of ET are not known. Approximately

50% of cases have a positive family history with an autosomal dominant pattern of inheritance. Linkage studies have detected possibly

3402 PART 13 Neurologic Disorders

action-specific [diurnal and paroxysmal]), and association with additional features. Clinical description along these lines enables formulating specific dystonia syndromes (e.g., early-onset generalized isolated

dystonia). From an etiologic point of view, dystonia primarily reflects

genetic abnormalities, although occasionally there may be other causes

such as dystonia following trauma and stroke. Genetic features used

for classification include mode of inheritance or identification of a

specific genetic defect. More than 200 genes have been linked to different, mainly childhood-onset and generalized forms of dystonia. These

include forms in which dystonia is the only disease manifestation with

the exception of tremor (“isolated dystonia”), forms in which dystonia

co-occurs with another movement disorder such as parkinsonism or

myoclonus (“combined dystonia”), and disorders in which dystonia

is one of several clinical manifestations and may be a less prominent

or even inconsistent feature (“complex dystonia”). Most of the genetic

forms belong to the latter phenotypic group, which also represents the

most heterogeneous class in terms of clinical expression.

■ ISOLATED DYSTONIAS

Focal, Multifocal, and Segmental Dystonia Adult-onset, focal

dystonia is by far the most frequent form of isolated dystonia, with

women being affected about twice as often as men. Focal dystonia typically presents in the fourth to sixth decade of life. The major clinical

phenotypes are as follows: (1) Cervical dystonia—dystonic contractions

of neck muscles causing the head to deviate to one side (laterocollis),

twist (torticollis), move in a forward direction (anterocollis), or move in a

backward direction (retrocollis). Muscle contractions can be painful and

occasionally can be complicated by a secondary cervical radiculopathy.

(2) Blepharospasm—dystonic contractions of the eyelids with increased

blinking that can interfere with reading, watching television, working

on a computer, and driving. This can sometimes be severe enough

to cause functional blindness. (3) Oromandibular dystonia (OMD)—

contractions of muscles of the lower face, lips, tongue, and jaw (opening

or closing). Meige’s syndrome is a combination of OMD and blepharospasm that predominantly affects women aged >60 years. (4) Spasmodic

dysphonia—dystonic contractions of the vocal cords during phonation,

causing impaired speech. Most cases affect the adductor muscles and

cause speech to have a choking or strained quality. Less commonly, the

abductors are affected, leading to speech with a breathy or whispering

quality. (5) Limb dystonias—these can be present in either arms or legs

and are often brought out by task-specific activities such as handwriting

(writer’s cramp), playing a musical instrument (musician’s cramp), or

putting in golf (the yips). The vast majority of patients with this class

of dystonia have cervical dystonia (~50%) or blepharospasm (~20%).

Focal hand or leg dystonia (~5%), spasmodic dysphonia (~2%), musician’s dystonia (~3%), or OMD (~1%) are much less common. Focal

dystonias can extend to involve other body regions (about 30% of cases)

and are frequently misdiagnosed as psychiatric or orthopedic in origin.

Their cause is usually not known. They are rarely monogenic (~1%);

autoimmunity and trauma have been suggested as other possible etiologies. Focal dystonias are often associated with a high-frequency tremor

that can resemble ET. Dystonic tremor can usually be distinguished

from ET because it tends to occur in conjunction with the dystonic

contraction and disappears when the dystonia is relieved (e.g., turning

the head in the opposite direction of the dystonia).

Generalized Dystonia Generalized dystonia is often hereditary in

nature and, unlike focal dystonia, typically has an age of onset in childhood or adolescence. There are currently at least seven well-established

genes that, when mutated, can cause a generalized dystonia; TOR1A,

THAP1, ANO3, GNAL, KMT2B, PRKRA, and HPCA. While PRKRA

and HPCA mutations are recessively inherited, all others are transmitted in an autosomal dominant fashion. According to the recommendations of the International Parkinson’s Disease and Movement Disorder

Society, monogenic forms of dystonia are classified according to the

absence or presence of accompanying additional clinical features and

preceded by a “DYT” prefix, e.g., DYT-TOR1A. These genetic forms

are primarily inherited in an autosomal dominant fashion and are

found in <5% of dystonia patients. Further, not all mutation carriers

develop generalized dystonia; about 35% remain unaffected despite

harboring a pathogenic mutation (reduced penetrance), and rarely they

present with dystonia that remains focal or segmental in nature.

Mutations in the TOR1A gene (torsin family 1 member A—formerly

known as the DYT1 gene) are the most common cause of early-onset

generalized dystonia. The first, and currently the only clearly established mutation, is a 3-base pair deletion in the TOR1A gene. The

mutation is frequently found among Ashkenazi Jewish patients due to

a founder effect. Mutation carriers usually present with dystonia in an

extremity in childhood that later progresses to other body parts, but

typically spares the face and neck. Rare carriers of two mutated alleles

have been described and are characterized by a severe neurodevelopmental syndrome and arthrogryposis.

Mutations in the THAP1 (THAP domain containing, apoptosis associated protein 1) gene have been linked to adolescent-onset dystonia

with mixed phenotype. About 100 different mutations have been

reported in THAP1. Mutations typically manifest with dysphonia or

writer’s cramp beginning in late childhood or adolescence. Over the

course of the disease, dystonia can spread to other body parts with

prominent craniocervical involvement.

Mutations in the ANO3 (anoctamin 3) gene were first reported in

patients with predominantly craniocervical dystonia with a broad

range of ages of onset. While a large number of missense variants can

be found in healthy individuals, a pathogenic role of ANO3 mutations

has been confirmed by the description of additional families with dystonia and myoclonic jerks.

Mutations in the GNAL (guanine nucleotide-binding protein subunit

alpha L) gene are a rare cause of cervical or cranial dystonia, with a

few patients developing a generalized dystonia. Mean age of onset is in

the thirties. About 30 different GNAL mutations have been reported in

dystonia patients.

In addition to the above, missense mutations in KMT2B (lysine

methyltransferase 2B) have been confirmed to be a cause of an earlyonset generalized dystonia that may be accompanied by other syndromic features including intellectual disability, microcephaly, psychiatric

features, dysmorphia, or skin lesions. The majority of the mutations

occurred de novo. KMT2B mutations may account for up to 10% of

early-onset generalized dystonia, but further validation is warranted,

and placement into the group of isolated vs complex dystonias is currently under debate.

The vast majority of PRKRA mutation carriers develop a generalized

dystonia, frequently with laryngeal involvement. Likewise, all patients

described to carry HPCA mutations are characterized by generalized

dystonia.

■ COMBINED DYSTONIAS

A number of other well-established genes have been described that are

associated with combined forms of dystonia in which dystonia occurs

in conjunction with a different movement disorder, such as parkinsonism or myoclonus.

Dopa-responsive dystonia (DRD; also known as Segawa syndrome)

is caused by mutations in the GCH1 (GTP cyclohydrolase-1) gene that

encodes the rate-limiting enzyme in the biosynthesis of dopamine

via the biopterin pathway. It is manifest as a childhood-onset form of

dystonia with diurnal fluctuations and is important to recognize as the

condition dramatically responds to low doses of levodopa. Parkinsonism can be a major, or even the only, finding, and there may be a presynaptic dopaminergic deficit as evidenced by SPECT. To date, more

than 100 different mutations have been reported with a penetrance

of around 50%, which is considerably higher in women compared to

men. Recessively inherited (biallelic) mutations in GCH1 result in a

much more severe clinical phenotype with developmental delay and

infantile onset. Due to the enzymatic defect in levodopa biosynthesis,

there is a lifelong and dramatic response to levodopa therapy. Younger

patients are frequently misdiagnosed as having cerebral palsy, and

all young-onset forms of dystonia should be tested with levodopa to

exclude the possibility of DRD. Importantly, since the dopamine neuronal network is anatomically preserved, these patients do not develop

dyskinesia with chronic levodopa treatment.

3403Tremor, Chorea, and Other Movement Disorders CHAPTER 436

X-linked dystonia-parkinsonism (Lubag) is a combined form of

dystonia and parkinsonism that is found exclusively in patients of

Filipino origin due to a founder effect and seems to be fully penetrant.

Patients usually develop focal (cranial) dystonia first that rapidly

generalizes and, after 5–10 years, is gradually replaced by a form of

L-dopa-unresponsive parkinsonism. A retrotransposon insertion in

the TAF1 (TATA-box binding protein associated factor 1) gene is the

cause of the disease, and 50% of the age-at-onset variability is explained

by the variable length of a hexameric repeat expansion within the

retrotransposon.

Mutations in the ATP1A3 (ATPase Na+/K+ transporting subunit

alpha 3) gene present with a characteristic, sudden-onset dystonia usually in adolescence or young adulthood, often triggered by high fever,

physical exertion, or emotional stress. Dystonic symptoms frequently

show a rostrocaudal gradient with a strong involvement of the bulbar

region, often accompanied by parkinsonian features such as bradykinesia. In addition, mutations in ATP1A3 have been linked to a variety

of clinical syndromes (pleiotropy), including epileptic or hemiplegic

attacks, ataxia, cognitive decline, and other neurologic disorders, often

with a more severe course and an earlier age at onset.

Myoclonic-dystonia is characterized by action-induced, alcoholresponsive myoclonic jerks predominantly involving the upper body

half. Onset is usually in childhood or adolescence. Many individuals

also develop psychiatric features such as depression, anxiety-related

disorders, and alcohol dependence. The disorder is primarily related

to mutations in the SGCE (sarcoglycan epsilon) gene, which codes for

the ε member of the sarcoglycan family. About 80 different mutations

have been reported in SGCE including deletions of the entire gene. The

latter type of mutation often also involves loss of adjacent genes leading

to additional clinical features such as joint problems. SGCE mutations

are incompletely penetrant and only manifest when inherited from the

father due to the epigenetic effect of maternal imprinting of SGCE.

Another recently identified cause of myoclonus-dystonia is KCTD17

mutation.

A number of additional monogenic causes have been suggested for

isolated and combined forms of dystonia but still await independent

confirmation. Table 436-2 provides a list of the confirmed monogenic

forms of isolated and combined dystonias.

■ COMPLEX DYSTONIAS

In the complex dystonias, dystonia is a part of a syndrome that is characterized by multiple different clinical manifestations of the disease.

Most frequently, they are hereditary such as Wilson’s disease (WD),

Huntington’s disease (HD), Lesh Nyhan syndrome, corticobasal ganglionic disorders, and a variety of other neurologic, neurometabolic,

and mitochondrial disorders. Complex dystonias may also develop as

a consequence of drugs or toxins (previously referred to as secondary

dystonias). Drug-induced dystonia may be acute or chronic and is most

commonly seen with neuroleptic drugs or after chronic levodopa treatment in PD patients. Dystonia can also be observed following discrete

lesions in the striatum, and occasionally in the pallidum, thalamus,

cortex, or brainstem due to infarction, hemorrhage anoxia, trauma,

tumor, infection, or toxins such as manganese or carbon monoxide. In

these cases, dystonia often assumes a segmental distribution but may

be generalized when lesions are bilateral or widespread. More rarely,

dystonia can develop following peripheral nerve injury and be associated with features of complex regional pain syndrome (Chap. 17).

A psychogenic origin is responsible for some cases of dystonia; these

typically present with fixed, immobile dystonic postures (see below).

■ PATHOPHYSIOLOGY OF DYSTONIA

Even in cases with a known dystonia gene mutation, the pathophysiologic basis of dystonia is not completely known. The phenomenon

is characterized by co-contracting synchronous bursts of agonist and

antagonist muscle groups with recruitment of muscle groups that are

not required for a given movement (overflow). Dystonia is characterized by derangement of the basic physiologic principle of action selection, leading to abnormal recruitment of inappropriate muscles for a

given action with inadequate inhibition of this undesired motor activity.

Physiologically, loss of surround inhibition is observed at multiple levels

of the motor system (e.g., cortex, brainstem, spinal cord) accompanied

by increased cortical excitability and reorganization. Attention has

focused on the basal ganglia as the site of origin of at least some types

of dystonia because there are alterations in blood flow and metabolism

in these structures. Further, lesions of the basal ganglia (particularly the

putamen) can induce dystonia, and surgical ablation or deep brain stimulation (DBS) of specific regions of the globus pallidus may ameliorate

dystonia. The dopamine system has also been implicated, because dopaminergic therapies can both induce and treat some forms of dystonia in

different circumstances. Interestingly, no specific pathology has been

consistently identified to underlie dystonia.

TREATMENT

Dystonia

Treatment of dystonia is for the most part symptomatic except in

rare cases where correction of a primary underlying condition is

possible. Wilson’s disease should be ruled out, particularly in young

patients with dystonia. Levodopa should be tried in all cases of

TABLE 436-2 Confirmed Monogenic Forms of Isolated and Combined Dystoniaa

FORM OF DYSTONIA GENE LOCUS NAME

DESIGNATION AND

PHENOTYPIC SUBGROUPa

ADDITIONAL DISTINGUISHING

FEATURES MOI

Isolated TOR1A DYT1 DYT-TOR1A Childhood or adolescent-onset,

generalized

AD

THAP1 DYT6 DYT-THAP1 Adolescent-onset, cranial or

generalized

AD

ANO3 DYT24 DYT-ANO3 Adult-onset, focal or segmental AD

GNAL DYT25 DYT-GNAL Mostly adult-onset, focal or segmental AD

KMT2Bb DYT28 DYT-KMT2B Early-onset, generalized, mild

syndromic features

AD

Combined Dystonia plus

parkinsonism

GCH1 DYT5a DYT-GCH1 Dopa-responsive AD

TAF1 DYT3 DYT-TAF1 Neurodegeneration XL

PRKRA DYT16 DYT-PRKRA Dystonia with mild parkinsonism AR

ATP1A3 DYT12 DYT-ATP1A3 Rapid-onset AD

Dystonia plus

myoclonus

SGCE DYT11 DYT-SGCE Psychiatric disease AD

a

According to C Marras et al: Mov Disord 31:436, 2016. b

Several, but not all, patients show syndromic features; DYT-KMT2B may thus be better placed with the complex

dystonias.

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; MOI, mode of inheritance; XL, X-linked.

3404 PART 13 Neurologic Disorders

childhood-onset dystonia to test for DRD. High-dose anticholinergics (e.g., trihexyphenidyl 20–120 mg/d) may be beneficial in children, but adults can rarely tolerate high doses because of side effects

related to cognitive impairment and hallucinations. Oral baclofen

(20–120 mg) may also be helpful, but benefits, if present, are usually

modest, and side effects of sedation, weakness, and memory loss

can be problematic. Intrathecal infusion of baclofen is more likely

to be useful, particularly for leg and trunk dystonia, but benefits

are frequently not sustained, and complications can be serious and

include infection, seizures, and coma. Tetrabenazine is another

consideration; the usual starting dose is 12.5 mg/d and the average

treating dose is 25–75 mg/d, but its use may be limited by sedation

and the development of parkinsonism. Parkinsonian side effects

can be minimized with deuterated tetrabenazine. Neuroleptics can

both improve and induce dystonia, but they are typically not recommended because of their potential to induce parkinsonism and

other movement disorders, including tardive dystonia. Clonazepam

and diazepam are sometimes effective.

Botulinum toxin has become the preferred treatment for patients

with focal and segmental dystonia, particularly where involvement is

limited to small muscle groups such as in blepharospasm, torticollis,

and spasmodic dysphonia. Botulinum toxin acts by blocking the

release of acetylcholine at the neuromuscular junction, leading to

reduced dystonic muscle contractions. However, treatment with botulinum toxin can be complicated by excessive weakness that can be

troublesome, particularly if it involves neck and swallowing muscles.

No systemic side effects are encountered with the doses typically

used, but benefits are transient, and repeat injections are required at

2- to 5-month intervals. Some patients fail to respond after having

experienced an initial benefit. This has been attributed to development of neutralizing antibodies, but improper muscle selection,

injection technique, and inadequate dose should be excluded.

Surgical therapy is an alternative for patients with severe dystonia who are not responsive to other treatments. Peripheral procedures such as rhizotomy and myotomy were used in the past to

treat cervical dystonia but are now rarely employed. DBS of the

pallidum can provide dramatic benefits for some patients with various forms of hereditary and nonhereditary generalized dystonia.

This represents a major therapeutic advance because previously

there was no consistently effective therapy, especially for patients

with severe disability. Benefits tend to be obtained with a lower frequency of stimulation than used in PD or ET, and often occur only

after a relatively long latency. Better results are typically obtained

in younger patients with shorter disease duration and in those

with certain monogenic forms, such as DYT-Tor1A. Recent studies

suggest that DBS may also be valuable for patients with focal and

secondary dystonias, although results are less consistent. Supportive

treatments such as physical therapy and education should be a part

of the treatment regimen for all types of dystonia.

Physicians should be aware of dystonic storm, a rare but potentially fatal condition that can occur in response to a stress situation

such as a surgical procedure or a systemic infection in patients with

preexisting dystonia. It consists of the acute onset of generalized

and persistent dystonic contractions that can involve the vocal

cords or laryngeal muscles, leading to airway obstruction. Patients

may experience rhabdomyolysis with renal failure and should

be managed in an intensive care unit with airway protection if

required. Treatment can be instituted with one or a combination

of anticholinergics, diphenhydramine, baclofen, benzodiazepines,

and dopaminergic agents. Spasms may be difficult to control, and

anesthesia with muscle paralysis may be required.

CHOREAS

■ HUNTINGTON’S DISEASE

HD is a progressive, fatal, highly penetrant autosomal dominant disorder characterized by motor, behavioral, oculomotor, and cognitive

dysfunction. The disease is named for George Huntington, a family

physician who described cases on Long Island, New York, in the nineteenth century. Onset is typically between the ages of 25 and 45 years

(range, 3–70 years) with a prevalence of 2–8 cases per 100,000 and

an average age at death of 60 years. It is prevalent in Europe, North

America, South America, and Australia but is rare in African blacks

and Asians. HD is characterized by rapid, nonpatterned, semipurposeful, involuntary choreiform movements, and for this reason was

formerly referred to as Huntington’s chorea. However, dysarthria, gait

disturbance, oculomotor abnormalities, behavioral disturbance, and

cognitive impairment with dementia are also common features; thus

the condition is currently referred to as Huntington’s disease. In the

early stages, chorea tends to be focal or segmental, but progresses over

time to involve multiple body regions. With advancing disease, there

tends to be a reduction in chorea and the emergence of dystonia, rigidity, bradykinesia, and myoclonus. Functional decline is often predicted

by progressive weight loss despite adequate calorie intake. In younger

patients (~10% of cases), HD can present as an akinetic-rigid parkinsonian syndrome (Westphal variant). HD patients eventually develop

behavioral and cognitive disturbances, and the majority progress to

dementia. Depression with suicidal tendencies, aggressive behavior, and psychosis can be prominent features. HD patients may also

develop non-insulin-dependent diabetes mellitus and neuroendocrine

abnormalities (e.g., hypothalamic dysfunction). A clinical diagnosis of

HD can be strongly suspected in cases of chorea with a positive family

history, but genetic testing provides the ultimate confirmation of the

diagnosis.

The disease predominantly affects the striatum but progresses

to involve the cerebral cortex and other brain regions. Progressive

atrophy of the head of the caudate nucleus, which forms the lateral

margin of the lateral ventricle, can be visualized on MRI (Fig. 436-1),

but the putamen can be equally or even more severely affected. More

diffuse cortical atrophy can be seen in the middle and late stages of the

disease. Supportive studies include reduced metabolic activity in the

caudate nucleus and putamen, and reduced brain metabolites on MR

spectroscopy. Genetic testing can be used to confirm the diagnosis and

to detect at-risk individuals in the family but must be performed with

caution and in conjunction with trained counselors, because positive

results can worsen depression and even generate suicidal reactions.

Indeed, genetic counseling is a requirement in some regions. The neuropathology of HD consists of prominent neuronal loss and gliosis in

the caudate nucleus and putamen; similar changes are also widespread

in the cerebral cortex. Intraneuronal inclusions containing aggregates

of ubiquitin and the mutant protein huntingtin are found in the nuclei

of affected neurons.

In anticipation of developing neuroprotective therapies, there has

been an intensive effort to define the premanifest stage of HD. Subtle

motor impairment, cognitive alterations, and imaging changes can be

detected in at-risk individuals who later go on to develop the manifest

form of the disease. Defining the rate of progression of these features

is paramount for future studies of putative disease-modifying therapies

designed to slow the rate of disease progression and the development

of cumulative disability.

■ ETIOLOGY

HD is caused by an increase in the number of polyglutamine (CAG)

repeats (>40) in the coding sequence of the huntingtin gene located on

the short arm of chromosome 4. The larger the number of repeats, the

earlier the disease is manifest. Intermediate forms of the disease with

36–39 repeats are described in some patients, typically with less severe

clinical involvement. Acceleration of the process tends to occur, particularly in males, with subsequent generations having larger numbers

of repeats and earlier age of disease onset, a phenomenon referred to

as anticipation. There is also evidence of somatic gene expansion that

occurs over time.

The huntingtin gene encodes the highly conserved cytoplasmic

protein huntingtin (HTT), which is widely distributed in neurons

throughout the central nervous system (CNS). Mutated HTT RNA

is toxic. Mutant HTT disrupts transcription, impairs immune and

mitochondrial function, and is aberrantly modified post-translationally.

3405Tremor, Chorea, and Other Movement Disorders CHAPTER 436

FIGURE 436-1 Huntington’s disease. A. Coronal fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging shows enlargement of the lateral ventricles

reflecting typical atrophy (arrows). B. Axial FLAIR image demonstrates abnormal high signal in the caudate and putamen (arrows).

Genome-wide association studies have nominated DNA repair pathways as modifiers of somatic instability and disease course in HD.

Fragments of the mutant HTT can also be toxic, possibly by translocating into the nucleus and interfering with transcriptional regulation

of proteins. Neuronal inclusions found in affected regions in HD may

represent a protective mechanism aimed at segregating and facilitating the clearance of these toxic proteins. There is also interest in the

possibility that protein accumulation and aggregation in HD, like

Alzheimer’s disease (Chap. 431) and PD (Chap. 435), may be critical

to the disease process and reflect a prion-like disorder (Chap. 438; see

also Chap. 424). Models of HD with striatal pathology can be induced

in multiple transgenic animals that express the mutant gene and by

excitotoxic agents such as kainic acid and 3-nitropropionic acid, which

promote calcium entry into the cell and cytotoxicity.

TREATMENT

Huntington’s Disease

Although the gene for HD was identified more than 25 years ago,

there is still no disease-modifying therapy for this disorder, and

symptomatic treatment is limited. Current treatment involves a

multidisciplinary approach, with medical, neuropsychiatric, social,

and genetic counseling for patients and their families. Dopamine-blocking agents may control the choreatic movements.

Tetrabenazine (a presynaptic dopamine-depleting agent) has been

approved for the treatment of chorea but can cause secondary

parkinsonism. Deuterated tetrabenazine (Austedo) has also been

approved as a treatment for chorea in HD. Deuteration interferes

with the metabolism of tetrabenazine and avoids a high Cmax,

which is thought to contribute to adverse effects. In clinical trials,

deuterated tetrabenazine has been shown to have fewer dose-related

side effects than tetrabenazine and therefore can be administered

in higher doses with potentially superior clinical benefits. Neuroleptics are generally not recommended because of their potential to

induce other troubling movement disorders and because HD chorea tends to be self-limited and is usually not disabling. These drugs

may be used, however, in patients with severe and disabling chorea.

Depression and anxiety can be major problems, and patients should

be treated with appropriate antidepressant and antianxiety drugs

and monitored for mania and suicidal ideations. Psychosis can

be treated with atypical antipsychotics such as clozapine (50–600

mg/d), quetiapine (50–600 mg/d), and risperidone (2–8 mg/d).

A neuroprotective therapy that slows or stops disease progression is the major unmet medical need in HD. Strategies to

reduce mutant HTT focus on inhibiting mRNA synthesis either by

blocking transcription (zinc finger motif protein), preventing posttranscriptional processes, and promoting early mRNA degradation

(antisense oligonucleotides; ASO) or inhibiting translation with

short-interfering RNA. The most advanced of these experimental

therapeutic approaches investigated intrathecal administration of

an ASO in patients with early HD in a randomized, placebocontrolled, double-blind phase 1–2a clinical trial. While a dosedependent reduction in concentrations of mutant HTT was

observed and there were no side effects, the study was prematurely

terminated, presumably because no clinical benefit was detected.

Drugs that enhance mitochondrial function and increase the clearance of defective mitochondria are also being tested as possible

disease-modifying therapies. Other investigative approaches include

immunotherapy, dietary supplements (Resveratrol), lipid-lowering

medication (Fenofibrate), and anaplerotic therapy (Triheptanoin),

and DBS of the globus pallidus pars interna (GPi). Perhaps most

promising at this time is the sigma 1 receptor agonist pridopidine.

While previous 6-month trials with this drug showed no significant

benefit with respect to total motor function, significant benefits

were observed in total functional capacity after 1 year, particularly

in patients with relatively mild disease. Double-blind studies are

currently underway.

HUNTINGTON’S DISEASE-LIKE DISORDERS

A group of rare inherited conditions that can mimic HD, designated

HD-like (HDL) disorders, has also been identified. HDL-1, 2, and 4

are autosomal dominant conditions that typically present in adulthood.

HDL-3 is recessively inherited, presents in early childhood, and differs

markedly from HD and the other HDLs. HDL-1 is due to expansion

of an octapeptide repeat in PRNP, the gene encoding the prion protein (Chap. 438). Thus HDL-1 is properly considered a prion disease.

Patients exhibit onset of personality change in the third or fourth

decade of life, followed by chorea, rigidity, myoclonus, ataxia, and

epilepsy. HDL-2 manifests in the third or fourth decade of life with a

variety of movement disorders, including chorea, dystonia, or parkinsonism and dementia. Most patients are of African descent. Acanthocytosis can sometimes be seen in these patients, and this condition

must be distinguished from neuroacanthocytosis (below). HDL-2 is

caused by an abnormally expanded CTG/CAG trinucleotide repeat

expansion in the junctophilin-3 (JPH3) gene. The pathology of HDL-2

consists of intranuclear inclusions immunoreactive for ubiquitin and

expanded polyglutamine repeats. HDL-4, the most common condition

in this group, is caused by expansion of trinucleotide repeats in TBP,

the gene that encodes the TATA box-binding protein involved in regulating transcription; this condition is identical to spinocerebellar ataxia

3406 PART 13 Neurologic Disorders

(SCA) 17 (Chap. 439), and most patients present primarily with ataxia

rather than chorea. Mutations of the C9Orf72 gene associated with

amyotrophic lateral sclerosis (Chap. 437) have also been reported in

some individuals with an HDL phenotype.

■ OTHER CHOREAS

Chorea can be seen in a number of additional disorders related to

genetic mutations or other disease states.

Among the hereditary forms of childhood-onset chorea, mutations

in the NKX2-1 gene cause a benign hereditary chorea. Mutations in the

ADCY5 (adenylate cyclase 5) gene are an increasingly recognized and

relatively common cause of childhood-onset chorea, often in combination with dystonia and developmental delay. Characteristic perioral

movements are a hallmark of the disorder.

Chorea-acanthocytosis (neuroacanthocytosis) is a progressive and

typically fatal autosomal recessive disorder that is characterized

by chorea coupled with red cell abnormalities on peripheral blood

smear (acanthocytes). The chorea can be severe and associated with

self-mutilating behavior, dystonia, tics, seizures, and a polyneuropathy.

Mutations in the VPS13A gene encoding chorein have been described.

A phenotypically similar X-linked form of the disorder has been

described in older individuals who have reactivity with Kell blood

group antigens (McLeod syndrome). A benign hereditary chorea of

childhood (BHC1) due to mutations in the gene for thyroid transcription factor 1 and a late-onset benign senile chorea (BHC2) have also

been reported. It is important to ensure that patients with these types

of choreas do not have HD.

Chorea may also occur in association with a variety of infections

and degenerative disorders as well as vascular diseases and hypo- and

hyperglycemia. Sydenham’s chorea (originally called St. Vitus’ dance)

is more common in females and is typically seen in childhood

(5–15 years). It often develops in association with prior exposure to

group A streptococcal infection (Chap. 148) and is thought to be

autoimmune in nature. It is characterized by the acute onset of choreiform movements and behavioral disturbances. With the reduction in

the incidence of rheumatic fever, the incidence of Sydenham’s chorea

has fallen, but it can still be seen in developing countries. The chorea

generally responds to dopamine-blocking agents, valproic acid, and

carbamazepine, but is self-limited, and treatment is generally restricted

to those with severe chorea. Chorea may recur in later life, particularly

in association with pregnancy (chorea gravidarum) or treatment with

sex hormones. Several reports have documented cases of chorea associated with N-methyl-D-aspartate (NMDA) receptor antibody–positive

encephalitis (Chap. 94) following herpes simplex virus encephalitis,

and in paraneoplastic syndromes associated with anti-CRMP-5 or

anti-Hu antibodies (Chap. 90). Systemic lupus erythematosus

(Chap. 356) is the most common systemic disorder that is associated

with chorea. The chorea can last for days to years. Chorea can also be

seen with hyperthyroidism, autoimmune disorders including Sjögren’s

syndrome, infectious disorders including HIV disease, metabolic alterations, and polycythemia rubra vera. Chorea has also been described

following open-heart surgery in the pediatric population and in association with many medications (especially anticonvulsants, cocaine, CNS

stimulants, estrogens, and lithium). Chorea is commonly seen as a side

effect of chronic levodopa treatment in patients with PD (Chap. 435).

■ BALLISM/HEMIBALLISMUS

Ballism is a violent form of choreiform movement composed of wild,

flinging, large-amplitude movements most frequently affecting proximal limb muscles on one side of the body (hemiballism). The movements may affect only one limb (monoballism) or, more exceptionally,

both upper or lower limbs (paraballism). The movements may be so

severe as to cause exhaustion, dehydration, local injury, and, in extreme

cases, death. Fortunately, dopamine-blocking drugs can be very helpful, and importantly, hemiballismus is usually self-limiting and tends to

resolve spontaneously after weeks or months. The most common cause

is a partial lesion (infarct or hemorrhage) in the subthalamic nucleus

(STN), but in 30–40% of cases the lesion is found in the putamen, thalamus, or parietal cortex. Hemiballismus is also a common feature of

the paroxysmal dyskinesias (see below). In extreme cases, pallidotomy

or DBS of the GPi can be effective and abolish the involuntary movements. Interestingly, surgically induced lesions and DBS of the STN in

PD patients are usually not associated with hemiballismus.

TICS

A tic is a brief, rapid, recurrent, stereotyped, and seemingly purposeless motor contraction. Motor tics can be simple, with movement only

affecting an individual muscle group (e.g., blinking, twitching of the

nose, jerking of the neck), or complex, with coordinated involvement

of multiple muscle groups (e.g., jumping, sniffing, head banging, and

echopraxia [mimicking movements]). Phonic (or vocal) tics can also

be simple (e.g., grunting) or complex (e.g., echolalia [repeating other

people’s words], palilalia [repeating one’s own words], and coprolalia

[expression of obscene words]). Patients may also experience sensory

tics, composed of unpleasant focal sensations in the face, head, or neck.

These can be mild and of little clinical consequence or severe and disabling. Tics may present in adulthood and can be seen in association

with a variety of disorders, including PD, HD, trauma, dystonia, drugs

(e.g., levodopa, neuroleptics), and toxins.

■ TOURETTE’S SYNDROME

Tourette’s syndrome (TS) is a neurobehavioral disorder named after

the French neurologist Georges Gilles de la Tourette. It predominantly

affects males, and the prevalence is estimated to be 0.03–1.6%, but it

is likely that many mild cases do not come to medical attention. TS is

characterized by multiple motor tics often accompanied by vocalizations (phonic tics). Patients characteristically can voluntarily suppress

tics for short periods of time, but then experience an irresistible urge

to express them. Tics vary in intensity and may be absent for days or

weeks only to recur, occasionally in a different pattern. Tics tend to

present between ages 2 and 15 years (mean 7 years) and often lessen or

even disappear in adulthood, particularly in males. Associated behavioral disturbances include anxiety, depression, attention deficit hyperactivity disorder, and obsessive-compulsive disorder. Patients may

experience personality disorders, self-destructive behaviors, difficulties

in school, and impaired interpersonal relationships.

Etiology and Pathophysiology TS has a high heritability and

is thus thought to be a genetic disorder, but no specific monogenic

cause has yet been identified. Current evidence supports a complex

inheritance pattern with an important contribution of de novo, likely

gene-disrupting variants. Four likely risk genes with multiple de novo

damaging variants in unrelated probands include WWC1, CELSR3,

NIPBL, and FN1. The risk of a family with one affected child having

a second is about 25%. The pathophysiology of TS is not known, but

alterations in dopamine neurotransmission, opioids, and secondmessenger systems have been proposed.

TREATMENT

Tics

Patients with mild disease often only require education and counseling (for themselves and family members). In a high proportion

of patients, the severity of tics wanes in adult life, becoming less

of a medical problem, thus arguing for conservative management

if possible during the first decades of life. Drug treatment is indicated when the tics are disabling and interfere with quality of life

and social interactions. Therapy is individualized, and there is

no singular treatment regimen that has been properly evaluated

in double-blind trials. Some physicians use the α-agonist clonidine, starting at low doses and gradually increasing the dose and

frequency until satisfactory control is achieved. Guanfacine

(0.5–2 mg/d) is an α-agonist that is preferred by some because it

requires only once-daily dosing. Other physicians prefer to use

neuroleptics. Atypical neuroleptics are usually used initially (risperidone, olanzapine, ziprasidone) because they are thought to be

associated with a reduced risk of tardive dyskinesia. If they are not

effective, low doses of classical neuroleptics such as haloperidol,

3407Tremor, Chorea, and Other Movement Disorders CHAPTER 436

fluphenazine, pimozide, or tiapride can be tried because the risk

of tardive dyskinesia in young people is relatively low. Tetrabenazine and deuterated tetrabenazine are currently being evaluated.

Botulinum toxin injections can be effective in controlling focal tics

that involve small muscle groups. Behavioral features, and particularly anxiety and compulsions, can be a disabling feature of TS

and should be treated as appropriate. The potential value of DBS

targeting the anterior portion of the internal capsule, the GPi, or

the thalamus is currently being explored and a large-scale public

database and registry for DBS in TS has been established.

MYOCLONUS

Myoclonus is a brief, rapid (<100 ms), shocklike, jerky movement consisting of single or repetitive muscle discharges. Myoclonic jerks can

be focal, multifocal, segmental, or generalized and can occur spontaneously, in association with voluntary movement (action myoclonus),

or in response to an external stimulus (reflex myoclonus). Negative

myoclonus consists of a brief loss of muscle activity (e.g., asterixis

in hepatic failure). Myoclonic jerks can be severe and interfere with

normal movement or benign and of no clinical consequence as is commonly observed in normal people when waking up or falling asleep

(hypnagogic jerks).

Myoclonic jerks differ from tics in that they are not typically

repetitive, can severely interfere with normal voluntary movement,

and are not suppressible. They can arise in association with abnormal neuronal discharges in cortical, subcortical, brainstem, or spinal

cord regions, particularly in association with hypoxemia (especially

following cardiac arrest), encephalopathy, and neurodegeneration.

Reversible myoclonus can be seen with metabolic disturbances (renal

failure, electrolyte imbalance, hypocalcemia), toxins, and many medications. Hereditary myoclonus syndromes can be grouped into three

classes based on clinical features: prominent myoclonus syndromes,

prominent myoclonus syndromes combined with another prominent

movement disorder, and disorders that usually present with other phenotypes but can also manifest as a prominent myoclonus syndrome.

An additional movement disorder is seen in nearly all myoclonus

syndromes, most commonly ataxia or dystonia. Furthermore, cognitive decline and epilepsy are present in the vast majority of patients.

The most common form of action myoclonus of cortical origin with

ataxia and generalized epilepsy is myoclonic epilepsy type 1 (EPM-1)

or Unverricht-Lundborg disease, which can have a variable but often

progressive course. This is an autosomal recessive disease caused by

mutations in the CSBT gene. Other causes are Lafora body epilepsy

or progressive myoclonic epilepsy (PME-2) caused by mutations in

the EPM2A gene or the NHLRC1 gene and ceroid lipofuscinosis. In

patients with less severe or absent epilepsy, mitochondrial disorders

and neurodegenerative disorders affecting the cerebellum (i.e., SCAs)

should be considered. Essential myoclonus is a relatively benign familial condition characterized by multifocal, very brief, lightning-like

movements that are frequently alcohol-sensitive. Mutations in the

epsilon-sarcoglycan gene have been associated with myoclonus seen in

association with dystonia (myoclonic-dystonia).

TREATMENT

Myoclonus

Treatment primarily consists of managing the underlying condition

or removing an offending agent. Pharmacologic therapy involves

one or a combination of GABAergic agents such as valproic acid

(800–3000 mg/d), piracetam (8–20 g/d), clonazepam (2–15 mg/d),

levetiracetam (1000–3000 mg/d), or primidone (500–1000 mg/d).

Treatment may be associated with striking clinical improvement in

chronic cases (e.g., postanoxic myoclonus, progressive myoclonic

epilepsy) in which a cortical origin for the myoclonic discharges

has been identified. The serotonin precursor 5-hydroxytryptophan

(plus carbidopa) may be useful in some cases of postanoxic myoclonus. DBS can be highly effective in myoclonus dystonia.

DRUG-INDUCED MOVEMENT DISORDERS

This important group of movement disorders is primarily associated

with drugs that block dopamine receptors (neuroleptics) or central

dopaminergic transmission. These drugs are widely used in psychiatry, but it is important to appreciate that drugs used in the treatment

of nausea or vomiting (e.g., prochlorperazine [Compazine]) or gastroesophageal disorders (e.g., metoclopramide) are neuroleptic agents

and can also cause these disorders. Hyperkinetic movement disorders

secondary to neuroleptic drugs can be divided into those that present

acutely, subacutely, or after prolonged exposure (tardive syndromes).

Dopamine-blocking drugs can also be associated with a reversible

parkinsonian syndrome for which anticholinergics are often concomitantly prescribed, but these drugs are not effective antiparkinsonian

agents, they are associated with cognitive side effects, and there is concern that this may increase the risk of developing a tardive syndrome.

■ ACUTE

Dystonia is the most common acute hyperkinetic drug reaction. It is

typically generalized in children and focal in adults (e.g., blepharospasm, torticollis, or OMD). The reaction can develop within minutes

of exposure and can be successfully treated in most cases with parenteral administration of anticholinergics (benztropine or diphenhydramine), benzodiazepines (lorazepam, clonazepam, or diazepam), or

dopamine agonists. The abrupt onset of severe spasms may occasionally be confused with a seizure; however, there is no loss of consciousness, automatisms, EEG abnormalities, or postictal features typical of

epilepsy. The acute onset of chorea, stereotypic behavior, and tics may

also be seen, particularly following exposure to CNS stimulants such as

methylphenidate, cocaine, or amphetamines.

■ SUBACUTE

Akathisia is the most common reaction in this category. It consists of

motor restlessness with a need to move that is alleviated by movement.

Therapy consists of removing the offending agent. When this is not

possible, symptoms may be ameliorated with benzodiazepines, anticholinergics, beta blockers, or dopamine agonists.

■ TARDIVE SYNDROMES

These disorders develop months to years after initiation of the neuroleptic agent. Tardive dyskinesias (TD) are most common, and typically

present with choreiform and/or dystonic movements involving the

mouth, lips, and tongue. In severe cases, the trunk, limbs, and respiratory muscles may also be affected. In approximately one-third of

patients, TD remit within 3 months of stopping the drug, and most

patients gradually improve over the course of several years. However, abnormal movements may also develop, persist, or worsen after

stopping the offending agent. The movements are thought to be often

mild and more upsetting to the family than to the patient, but they

can be severe and disabling, particularly in the context of an underlying psychiatric disorder. Atypical antipsychotics (e.g., clozapine,

risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) are

associated with a lower risk of causing TD in comparison to traditional

antipsychotics. Younger patients have a lower risk of developing neuroleptic-induced TD, whereas elderly people, females, and those with

underlying organic cerebral dysfunction have been reported to be at

greater risk. Chronic use is associated with increased risk of TD, and

specifically, the U.S. Food and Drug Administration has warned that

use of metoclopramide for >12 weeks increases the risk of TD. Because

TD can be permanent and resistant to treatment, antipsychotics should

be used judiciously, atypical neuroleptics should be the preferred agent

when possible although there are now questions as to the risk of TD

with atypical neuroleptics as well, and continued use should be regularly monitored and cease when possible.

Treatment primarily consists of stopping the offending agent. If the

patient is receiving a traditional antipsychotic, and withdrawal is not

possible, replacement with an atypical antipsychotic (e.g., clozapine)

should be tried. Abrupt cessation of a neuroleptic should be avoided

because acute withdrawal can induce worsening. TD can persist after

withdrawal of antipsychotics and can be difficult to treat. Valbenazine

3408 PART 13 Neurologic Disorders

(Ingrezza) is an ester of tetrabenazine that is approved for the treatment of TD based on results of efficacy in double-blind trials, but it is

associated with sleepiness and QT prolongation. It acts as a vesicular

monoamine transporter type 2 (VMAT-2) inhibitor and blocks storage

of dopamine. Deuterated tetrabenazine is also being studied for this

indication. Benefits in open-label studies have been reported with

valproic acid (750–3000 mg/d), anticholinergics, or botulinum toxin

injections. Other approaches that have been tried include baclofen

(40–80 mg/d) or clonazepam (1–8 mg/d). In some cases, where the

abnormal movement is refractory to therapy, pallidal DBS may be a

treatment option.

Chronic neuroleptic exposure can also be associated with tardive

dystonia, with preferential involvement of axial muscles and characteristic rocking movements of the trunk and pelvis. Tardive dystonia can

be more troublesome than tardive dyskinesia and frequently persists

despite stopping medication. Valproic acid, anticholinergics, and botulinum toxin may occasionally be beneficial, but patients are frequently

refractory to medical therapy. Tardive akathisia, tardive TS, and tardive

tremor syndromes are rare but may also occur after chronic neuroleptic

exposure.

Neuroleptic medications can also be associated with a neuroleptic

malignant syndrome (NMS). NMS is characterized by the acute or

subacute onset of muscle rigidity, elevated temperature, altered mental

status, hyperthermia, tachycardia, labile blood pressure, renal failure,

and markedly elevated creatine kinase levels. Symptoms typically

evolve within days or weeks after initiating the drug. NMS can also be

precipitated by the abrupt withdrawal of dopaminergic medications in

PD patients. Treatment involves immediate cessation of the offending

antipsychotic drug and the introduction of a dopaminergic agent (e.g.,

a dopamine agonist or levodopa), dantrolene, or a benzodiazepine. In

very severe cases, when oral intake is not possible, a patch (delivering

rotigotine subcutaneously) or an infusion pump (delivering apomorphine subcutaneously) may be the best approach to provide dopaminergic treatment. Treatment may need to be undertaken in an intensive

care setting and include supportive measures such as control of body

temperature (antipyretics and cooling blankets), hydration, electrolyte

replacement, and control of renal function and blood pressure.

Drugs that have serotonin-like activity (tryptophan, MDMA or

“ecstasy,” meperidine) or that block serotonin reuptake can induce a

rare, but potentially fatal, serotonin syndrome that is characterized

by confusion, hyperthermia, tachycardia, and coma as well as rigidity,

ataxia, and tremor. Myoclonus is often a prominent feature, in contrast

to NMS, which it resembles in other respects. Patients can be managed

with propranolol, diazepam, diphenhydramine, chlorpromazine, or

cyproheptadine as well as supportive measures.

A variety of drugs can also be associated with parkinsonism and

other hyperkinetic movement disorders. Some examples include phenytoin (chorea, dystonia, tremor, myoclonus), carbamazepine (tics and

dystonia), tricyclic antidepressants (dyskinesias, tremor, myoclonus),

fluoxetine (myoclonus, chorea, dystonia), oral contraceptives (dyskinesia), β-adrenergics (tremor), buspirone (akathisia, dyskinesias,

myoclonus), and digoxin, cimetidine, diazoxide, lithium, methadone,

and fentanyl (dyskinesias).

PAROXYSMAL DYSKINESIAS

Paroxysmal dyskinesias are a group of rare disorders characterized by

episodic, brief involuntary movements that can manifest as various

types of hyperkinetic movements, including chorea, dystonia, tremor,

myoclonus, and ballism. There are three main types: (1) paroxysmal

kinesigenic dyskinesia (PKD), where the involuntary movements are

triggered by sudden movement, (2) paroxysmal nonkinesigenic dyskinesias (PNKD), where the attacks are not induced by movement, and

(3) rare cases of paroxysmal exertion-induced dyskinesia (PED), where

attacks are induced by prolonged exercise.

PKD is characterized by brief, self-limited attacks induced by

movement onset such as running but also occasionally by unexpected

sound or photic stimulation. Attacks may affect one side of the body,

last seconds to minutes at a time, and recur several times a day. They

usually manifest as a mixed hyperkinetic movement disorder with

dystonic posturing of a limb, ballismus, and chorea, which may also

become generalized. PKD is most commonly familial with an autosomal dominant pattern of inheritance and mutations in the proline-rich

transmembrane protein 2 (PRRT2) gene, but may also occur secondary

to various brain disorders such as multiple sclerosis or hyperglycemia.

PKD is more frequent in males (4:1), and the onset is typically in the

first or second decade of life. About 70% report sensory symptoms

such as tingling or numbness of the affected limb preceding the attack

by a few milliseconds. The evolution is relatively benign, and there

is a trend toward resolution of the attacks over time. Treatment with

low-dose anticonvulsant therapy such as carbamazepine or phenytoin

is advised when the attacks are frequent and interfere with daily life

activities and is effective in about 80% of patients. Some clinical features of PKD (abrupt and short-lasting attacks preceded by an “aura”),

the association with true seizure episodes, and its favorable response

to anticonvulsant drugs have led to speculation that it is epileptic in

origin, but this has not been established.

PNKD involves attacks of generalized dyskinesias precipitated by

alcohol, caffeine, stress, or fatigue. In comparison with PKD, the episodes have a relatively longer duration (minutes to hours) and are less

frequent (one to three per day). PNKD is inherited as an autosomal

dominant condition with high (~80%) but incomplete penetrance. A

missense mutation in the myofibrillogenesis regulator (PNKD) gene

has been identified in several families. Recognition of the condition

and elimination of the underlying precipitating factors, where possible,

are the first priorities. Tetrabenazine, neuroleptics, dopamine-blocking

agents, propranolol, clonazepam, and baclofen may be helpful. Treatment may not be required if the condition is mild and self-limited.

Most patients with PNKD do not benefit from anticonvulsant drugs,

but some may respond to clonazepam or other benzodiazepines.

The SLC2A1 (solute carrier family 2 member 1) gene, previously

linked to GLUT1 (glucose transporter of the blood-brain barrier)

deficiency syndrome, has been identified to also cause paroxysmal

PED. The attacks in this disorder are characterized by a combination

of chorea, athetosis, and dystonia in excessively exercised body regions

with the legs being most frequently affected. A single attack lasts from a

few minutes to an hour and occurs after prolonged physical exercise. In

addition to the movement disorder, several patients have other disease

manifestations between episodes such as epilepsy, hemolytic anemia,

and migraine. A ketogenic diet is an effective therapeutic option.

RESTLESS LEGS SYNDROME

Restless legs syndrome (RLS) is a neurologic disorder that affects ~10%

of the adult population (it is rare in Asians) and can cause significant

morbidity in some individuals. It was first described in the seventeenth century by the English physician Thomas Willis but has only

recently been recognized as a bona fide movement disorder. The four

core symptoms required for diagnosis are: an urge to move the legs

usually caused or accompanied by an unpleasant sensation in the legs;

symptoms that begin or worsen with rest; partial or complete relief by

movement; and worsening during the evening or night.

Symptoms most commonly begin in the legs but can spread to,

or even begin in, the upper limbs. The unpleasant sensation is often

described as a creepy-crawly feeling, paresthesia, or burning. In about

80% of patients, RLS is associated with periodic leg movements (PLMs)

during sleep and occasionally while awake. These involuntary movements are usually brief, lasting no more than a few seconds, and recur

every 5–90 s. The restlessness and PLMs are a major cause of sleep

disturbance, leading to poor-quality sleep and daytime sleepiness.

Primary RLS has a strong genetic component; however, no causative gene has been identified. Genome association studies have

identified variants associated with RLS risk, the strongest candidates

in the PTPRD, BTBD9, and MEIS1 genes. The mean age of onset in

familial forms is in the third decade of life, although pediatric cases

are recognized. The severity of symptoms is variable. Secondary RLS

may be associated with pregnancy or a range of underlying disorders,

including anemia, ferritin deficiency, renal failure, and peripheral

3409Tremor, Chorea, and Other Movement Disorders CHAPTER 436

neuropathy. The pathogenesis probably involves disordered dopamine

function, which may be peripheral or central, possibly in association

with an abnormality of iron metabolism. Diagnosis is made on clinical

grounds but can be supported by polysomnography and the demonstration of PLMs. The neurologic examination is normal. Secondary

causes of RLS should be excluded, and ferritin levels, glucose, and renal

function should be measured.

Most RLS sufferers have mild symptoms that do not require specific

treatment. General measures to improve sleep hygiene and quality

should be attempted first. If symptoms remain intrusive, low doses

of dopamine agonists, e.g., pramipexole (0.25–0.5 mg), ropinirole

(1–2 mg), or patch rotigotine (2–3 mg), taken 1–2 h before bedtime are

generally effective. Levodopa may also be effective but is more likely to

be associated with augmentation (spread and worsening of restlessness

and its appearance earlier in the day) or rebound (reappearance sometimes with worsening of symptoms at a time related to the drug’s short

half-life). Augmentation can also be seen with dopamine agonists,

particularly if higher doses are employed. Other drugs that can be

effective include anticonvulsants, analgesics, and opiates. Management

of secondary RLS should be directed to correcting the underlying disorder; for example, iron replacement for anemia.

OTHER DISORDERS THAT MAY PRESENT

WITH A COMBINATION OF PARKINSONISM

AND HYPERKINETIC MOVEMENTS

■ WILSON’S DISEASE (SEE ALSO CHAP. 415)

Wilson’s disease (WD) is an inherited autosomal recessive disorder of

copper metabolism that produces neurologic, psychiatric, and liver

manifestations, alone or in combination. It is caused by mutations

in the ATP7B gene encoding a P-type ATPase. The disease was first

described by the English neurologist Kinnier Wilson at the beginning

of the twentieth century, although at around the same time the German

physicians Kayser and Fleischer separately noted the characteristic

association of corneal pigmentation with hepatic and neurologic features. WD has a worldwide prevalence of ~1 in 30,000, with a mutation

carrier frequency of 1 in 90. About half of WD patients (especially

younger patients) present with liver abnormalities. The remainder

present with neurologic disease (with or without underlying liver

abnormalities), and a small proportion have hematologic or psychiatric

problems at disease onset.

Neurologic onset usually manifests in the second decade of life with

tremor, rigidity, and dystonia. The tremor is usually in the upper limbs,

bilateral, and asymmetric. Tremor can be on intention or occasionally

at rest and, in advanced disease, can take on a wing-beating characteristic (a flapping movement when the arms are held outstretched with

the fingers opposed). Other features can include parkinsonism with

bradykinesia, dystonia (particularly facial grimacing), dysarthria, and

dysphagia. More than half of those with neurologic features have a history of psychiatric disturbances, including depression, mood swings,

and overt psychosis. Kayser-Fleischer (KF) rings are seen virtually in

all patients with neurologic features and 80% of those with hepatic presentations. KF rings represent the deposition of copper in Descemet’s

membrane around the cornea. They consist of a characteristic grayish

rim or circle at the limbus of the cornea and are best detected by slitlamp examination. Neuropathologic examination is characterized by

neurodegeneration and astrogliosis in the basal ganglia, particularly

in the striatum.

WD should always be considered in the differential diagnosis of

a movement disorder in the first decades of life. Low levels of blood

copper and ceruloplasmin and high levels of urinary copper may be

present, but normal levels do not exclude the diagnosis. Brain imaging

usually reveals generalized brain atrophy in established cases, and

~50% have signal hypointensity in the caudate head, putamen, globus pallidus, substantia nigra, and red nucleus on T2-weighted MRI

scans. However, correlation of imaging changes with clinical features

is not good. Liver biopsy with demonstration of high copper levels and

genetic testing remain the gold standard for the diagnosis.

In the absence of treatment, the course is progressive and leads

to severe neurologic dysfunction and early death in the majority of

patients, although a small proportion experience a relatively benign

course. Treatment is directed at reducing tissue copper levels and maintenance therapy to prevent reaccumulation. There is no clear consensus

on optimal treatment, and patients should be managed in a unit with

expertise in WD. Penicillamine is frequently used to increase copper

excretion, but may lead to a worsening of symptoms in the initial stages

of therapy. Side effects are common and can to some degree be attenuated by coadministration of pyridoxine. Tetrathiomolybdate blocks

the absorption of copper and can be used instead of penicillamine.

Trientine and zinc are useful drugs for maintenance therapy. Effective

treatment can reverse the neurologic features in most patients, particularly when started early. However, some patients may still progress,

especially those with hepatocerebral disease. KF rings tend to decrease

after 3–6 months and disappear by 2 years. Adherence to maintenance

therapy is a major challenge in long-term care. Patients with advanced

hepatic disease may require a liver transplant, and the potential role of

organ-specific chelation therapy is under investigation.

■ NEURODEGENERATION WITH BRAIN

IRON ACCUMULATION

Neurodegeneration with brain iron accumulation (NBIA) represents a

group of inherited disorders characterized by iron accumulation in the

basal ganglia. Clinically, they can manifest as progressive neurologic

disorders with a variety of clinical features including parkinsonism,

dystonia, neuropsychiatric abnormalities, and retinal degeneration.

Cognitive disorders and cerebellar dysfunction may also be seen. Presentation is usually in childhood, but adult cases have been described.

Multiple genes have been identified. Pantothenate kinase–associated

neurodegeneration (PKAN), formerly known as Hallervorden-Spatz

disease, is caused by a mutation in the PANK2 gene, and is the most

common form of NBIA, accounting for about 50% of cases. Onset is

usually in early childhood and is manifest as a combination of dystonia,

parkinsonism, and spasticity. MRI shows a characteristic low signal

abnormality in the center of the globus pallidus on T2-weighted scans

caused by iron accumulation and known as the “eye of the tiger” sign.

Numerous other gene mutations have been described associated with

iron accumulation including PLA2G6, C19orf12, FA2H, ATP13A2,

WDR45, FTL, CP, COASY, and DCAF17. One must be cautious, however, not to assume that all cases with iron accumulation in the basal

ganglia represent an NBIA, because iron accumulation in specific basal

ganglia regions is normal, and excess iron accumulation may occur in

the basal ganglia as a nonspecific secondary consequence of neurodegeneration unrelated to a defect in iron metabolism.

FUNCTIONAL (PSYCHOGENIC) DISORDERS

Virtually all movement disorders including tremor, tics, dystonia,

myoclonus, chorea, ballism, and parkinsonism can be psychogenic

in origin. The term functional neurological symptom disorder (FND)/

conversion disorder has been suggested to replace the term psychogenic

disorder in order to remove the criterion of psychological stress as a

prerequisite for diagnosis; however, the terminology remains controversial and both terms are used. A diagnosis can be made by identifying neurologic signs that are specific to FNDs without reliance on

psychological stressors or suggestive historical clues. Tremor affecting

the upper limbs is the most common psychogenic movement disorder.

Psychogenic movements can result from a somatoform or conversion

disorder, malingering (e.g., seeking financial gain), or a factitious

disorder (e.g., seeking psychological gain). Functional movement disorders are relatively common (estimated to be 2–3% of patients seen

in a movement disorder clinic), more frequent in women, disabling

for the patient and family, and expensive for society. Clinical features

suggesting a functional or psychogenic movement disorder include an

acute onset with a pattern of abnormal movement that is inconsistent

with the phenotype of a known movement disorder. Diagnosis is based

on the nonorganic quality of the movement, the absence of findings

of an organic disease process, and positive features that specifically

3410 PART 13 Neurologic Disorders

point to a functional illness such as variability and distractibility. For

example, in a functional or psychogenic disorder, the magnitude of

tremor is increased with attention and diminishes or even disappears

when the patient is distracted by being asked to perform a different

task or is unaware that he or she is being observed. This is the opposite

of what is seen with an organic tremor where the magnitude of tremor

is increased with distraction and tends to be reduced when observed.

Other positive features suggesting a psychogenic problem include variable tremor frequency, entrainment of frequency with the frequency of

a designated movement in the contralateral limb such as tapping, and

a response to placebo interventions. Associated features can include

nonanatomic sensory findings, give-way weakness, astasia-abasia

(an odd, gyrating gait or posture) (Chap. 26), and multiple somatic

complaints with no underlying pathology (somatoform disorder).

Comorbid psychiatric problems such as anxiety, depression, and emotional trauma may be present but are not necessary for the diagnosis,

which is why some prefer to call the movement disorder functional

rather than psychogenic. Functional movement disorders typically

occur as an isolated entity but may also be seen in association with an

underlying organic problem. The diagnosis can usually be made based

on history and clinical features alone, and unnecessary tests or medications can be avoided. If there are underlying psychiatric problems,

they should be identified and treated, but as noted many patients with

functional movement disorders have no obvious psychiatric pathology.

Treatment of FND starts with explaining the diagnosis to the patient

in a nonthreatening manner, but many are resistant to accepting this

diagnosis. Psychological therapies (especially cognitive-behavioral)

are the method of choice. An increasing role of physiotherapy has

recently been recognized; comorbid depression, anxiety, and pain may

be treated pharmacologically. Patients with hypochondriasis, factitious

disorders, and malingering have a poor prognosis.

■ FURTHER READING

Albanese A et al: Therapeutic advances in dystonia. Mov Disord

30:1547, 2015.

Balint B, Bhatia KP: Dystonia: An update on phenomenology, classification, pathogenesis and treatment. Curr Opin Neurol 27:468, 2014.

Bhatia KP et al: Consensus statement on the classification of tremors

from the task force on tremor of the International Parkinson and

Movement Disorder Society. Mov Disord 33:75, 2018.

Billnitzer A, Jankovic J: Current management of tics and Tourette

syndrome: Behavioral, pharmacologic, and surgical treatments. Neurotherapeutics 17:1681, 2020.

Espay AJ et al: Essential pitfalls in “essential” tremor. Mov Disord

32:325, 2017.

Espay AJ et al: Current concepts in diagnosis and treatment of functional neurological disorders. JAMA Neurol 75:1132, 2018.

Kieburtz K et al: Huntington’s disease: Current and future therapeutic

prospects. Mov Disorders 33:1033, 2018.

Krack P et al: Current applications and limitations of surgical treatments for movement disorders. Mov Disord 32:36, 2017.

Maras C et al: Nomenclature of genetic movement disorders: Recommendations of the International Parkinson and Movement Disorder

Society task force. Mov Disord 32:724, 2017.

Mestre TA: Recent advances in the therapeutic development for Huntington disease. Parkinsonism Relat Disord 59:125, 2019.

Pan L, Feigin A: Huntington’s disease: New frontiers in therapeutics.

Curr Neurol Neurosci Rep 21:10, 2021.

Tabrizi SJ et al: Targeting Huntingtin expression in patients with Huntington’s disease. N Engl J Med 380:2307, 2019.

Van Der Veen S et al: Nomenclature of genetically determined myoclonus syndromes: Recommendations of the International Parkinson

and Movement Disorder Society Task Force. Mov Disord 34:1602,

2019.

AMYOTROPHIC LATERAL SCLEROSIS (ALS)

ALS is the most common progressive motor neuron disease. It is a

prime example of a neurodegenerative disease and is arguably the most

devastating of the neurodegenerative disorders.

■ PATHOLOGY

The pathologic hallmark of motor neuron degenerative disorders is

death of lower motor neurons (consisting of anterior horn cells in

the spinal cord and their brainstem homologues innervating bulbar

muscles) and upper, or corticospinal, motor neurons (originating in

layer five of the motor cortex and descending via the pyramidal tract

to synapse with lower motor neurons, either directly or indirectly via

interneurons) (Chap. 24). Although at its onset ALS may involve selective loss of function of only upper or lower motor neurons, it ultimately

causes progressive loss of both categories of motor neurons. Indeed,

in the absence of clear involvement of both motor neuron types,

the diagnosis of ALS is questionable. In a subset of cases, ALS arises

concurrently with frontotemporal dementia (Chap. 432); in these

instances, there is degeneration of frontotemporal cortical neurons and

corresponding cortical atrophy.

Other motor neuron diseases involve only particular subsets of

motor neurons (Tables 437-1 and 437-2). Thus, in bulbar palsy and spinal muscular atrophy (SMA; also called progressive muscular atrophy),

the lower motor neurons of brainstem and spinal cord, respectively,

are most severely involved. By contrast, pseudobulbar palsy, primary

lateral sclerosis (PLS), and hereditary spastic paraplegia (HSP) affect

only upper motor neurons innervating the brainstem and spinal cord.

In each of these diseases, the affected motor neurons undergo

shrinkage, often with accumulation of the pigmented lipid (lipofuscin)

that normally develops in these cells with advancing age. In ALS, the

motor neuron cytoskeleton is typically affected early in the illness.

Focal enlargements are frequent in proximal motor axons; ultrastructurally, these “spheroids” are composed of accumulations of neurofilaments and other proteins. Commonly in both sporadic and familial

ALS, the affected neurons demonstrate ubiquitin-positive aggregates,

typically associated with the protein TDP43 (see below). Also seen is

proliferation of astroglia and microglia, the inevitable accompaniment

of all degenerative processes in the central nervous system (CNS).

The death of the peripheral motor neurons in the brainstem and

spinal cord leads to denervation and atrophy of the corresponding

muscle fibers. Histochemical and electrophysiologic evidence indicates

that in the early phases of the illness denervated muscle can be reinnervated by sprouting of nearby distal motor nerve terminals, although

reinnervation in this disease is considerably less extensive than in most

other disorders affecting motor neurons (e.g., poliomyelitis, peripheral

neuropathy). As denervation progresses, muscle atrophy is readily

recognized in muscle biopsies and on clinical examination. This is

the basis for the term amyotrophy. The loss of cortical motor neurons

results in thinning of the corticospinal tracts that travel via the internal capsule (Fig. 437-1) and pyramidal tracts in the brainstem to the

lateral and anterior white matter columns of the spinal cord. The loss

of fibers in the lateral columns and resulting fibrillary gliosis impart

a particular firmness (lateral sclerosis). A remarkable feature of the

disease is the selectivity of neuronal cell death. By light microscopy,

the entire sensory apparatus and cerebellar structures that control the

coordination of movement remain intact. Except in cases of frontotemporal dementia, the components of the brain required for cognitive

processing are also preserved. However, immunostaining indicates that

neurons bearing ubiquitin, a marker for degeneration, are also detected

437 Amyotrophic Lateral

Sclerosis and Other Motor

Neuron Diseases

Robert H. Brown, Jr.