# 17 - 447 Tremor, Chorea, and Other Movement Disorders

### 447 Tremor, Chorea, and Other Movement Disorders

Parkinson’s disease
Nonpharmacologic intervention
Pharmacologic intervention
Neuroprotection —? Rasagiline
Functional disability
No
Yes
PART 13
Neurologic Disorders
Dopamine agonists
MAO-B inhibitor
Levodopa
Combination therapy
Levodopa/dopamine
agonist/COMT
Inhibitor/MAO-B Inhibitor
Surgery/CDS
FIGURE 446-7  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). (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 low doses of levodopa particularly in 
the elderly and those with more advanced disease. A monoamine oxidase type B 
(MAO-B) inhibitor may be preferred in mildly affected patients because of their good 
safety profile and the potential for a disease-modifying effect. Some prefer dopamine 
agonists for younger patients with functionally significant disability as they have 
a reduced risk of inducing motor complications. All patients eventually require 
levodopa, but it is generally recommended to employ polypharmacy using low doses 
of multiple drugs to avoid side effects associated with high doses of any one agent 
and minimize the risks of levodopa-induced motor complications. (4) Management of 
motor complications: motor complications are typically approached with combination 
therapy to try and reduce dyskinesia and enhance the “on” time. When medical 
therapies cannot provide satisfactory control, surgical therapies such as deep brain 
stimulation (DBS) or continuous infusion of levodopa/carbidopa or apomorphine 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 CW Olanow et al: Neurology 72:S1, 2009.)
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 recom­
mended for all patients.
A decision tree that considers the various treatment options and 
decision points for the management of PD is provided in Fig. 446-7.
■
■FURTHER READING
Balestrino R, Schapira AHV: Parkinson disease. Eur J Neurol 27:27, 
2020.
Ben-Shlomo Y et al: The epidemiology of Parkinson’s disease. Lancet 
403:283, 2024.
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.

Bloem BR et al: Parkinson’s disease. Lancet 397:2284, 2021.
Marras C et al: Nomenclature of genetic movement disorders: Rec­
ommendations of the International Parkinson and Movement Disor­
der Society task force. Mov Disord 32:724, 2017.
Morris HR et al: The pathogenesis of Parkinson’s disease. Lancet 
403:293, 2024.
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.
Postuma RB et al: MDS clinical diagnostic criteria for Parkinson’s 
disease. Mov Disord 12:1591, 2015.
Schapira AHV et al: Non-motor features of Parkinson disease. Nat 
Rev Neurosci 18:446, 2017.
Siderowf A et al: Assessment of heterogeneity among participants in 
the Parkinson’s Progression Markers Initiative cohort using alphasynuclein seed amplification: A cross-sectional study. Lancet Neurol 
22:407, 2023.

Tremor, Chorea, and Other 
Movement Disorders
C. Warren Olanow*, Christine Klein
HYPERKINETIC MOVEMENT DISORDERS
Hyperkinetic movement disorders are characterized by involuntary 
movements unaccompanied by weakness. The major clinical features 
are summarized in Table 447-1. The term is somewhat arbitrary and 
potentially misleading as hypokinetic disorders such as Parkinson’s 
disease (PD) are often accompanied by tremor, while hyperkinetic 
disorders such as dystonia may be manifest as slow or restricted move­
ment because of severe muscle contractions. Nonetheless, the terms 
continue to be used by convention. The major hyperkinetic movement 
disorders and the diseases with which they are associated are consid­
ered in this section.
TREMOR
■
■CLINICAL FEATURES
Tremor is defined as an involuntary, rhythmic, oscillatory movement 
of a body part with alternating contraction 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 
or intention 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 and histori­
cal 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 
genetic, secondary, or idiopathic origins.
Essential tremor (ET) is characterized by a tremor that typically 
occurs while trying to sustain a posture and/or an action tremor that 
is noted when reaching toward a target. This contrasts with the resting 
tremor of PD (Chap. 446), which is characterized by a predominant 
resting tremor and is less pronounced with action. Cerebellar dys­
function is characterized by a kinetic tremor (brought out by trying 
to touch an object) and is usually associated with hypotonia and past 
pointing. Healthy individuals can have a physiologic tremor that 
typically manifests as a mild, high-frequency (10–12 Hz), postural, or 
*Deceased.

TABLE 447-1  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, semi-purposeful, graceful, dance-like 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), jerk-like, 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.
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 asso­
ciation with lifting a weight, anxiety, fatigue, a metabolic disturbance 
(e.g., hyperthyroidism, electrolyte abnormalities), drugs (e.g., valpro­
ate, lithium), or toxins (e.g., caffeine, smoking, alcohol). Treatment is 
initially directed at control of any underlying disorder, and if necessary, 
it can often be improved with a beta blocker.
■
■ESSENTIAL TREMOR
ET is the most common movement disorder, affecting ~1% of the 
population and 5% of those over 60 years (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 bilat­
eral 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, along with mild ataxia, 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 ~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 been described. The differential diagnosis includes 
dystonic tremor (see below) or PD. PD can usually be differentiated 
from ET because the former tends to be present primarily at rest and to 
be suppressed by a voluntary action. Further, PD is typically associated 
with bradykinesia with progressive slowing of sequential movements 
(sequence effect), rigidity, gait, postural instability, and other parkinso­
nian features. However, the examiner should be aware that PD patients 
may have a postural tremor and ET patients may develop a rest tremor, 
but these typically only begin after a latency of a few seconds (emergent 
tremor). In contrast to the micrographia of PD, ET patients have rela­
tively large handwriting with evidence of tremor in writing samples. 
The examiner must be careful to identify tremor when assessing tone 
in order to distinguish the interruption of movement associated with 
tremor from the cogwheel rigidity found in PD.
■
■ETIOLOGY AND PATHOPHYSIOLOGY
The etiology and pathophysiology of ET are not known. Approximately 
50% of ET patients have a positive family history with an autosomal 
dominant pattern of inheritance. Linkage studies have detected pos­
sible loci in large ET families. Expansion of a GGC repeat in the 

human-specific NOTCH2NLC gene has been found to be associated 
with ET, but no independently confirmed causative gene has been 
identified to date. It is likely that there are several as yet undiscovered 
genes underlying ET that have thus far escaped detection because of 
the heterogeneity of the syndrome and the high frequency of ET in the 
population, likely resulting in a large number of phenocopies (i.e., fam­
ily members with a similar clinical syndrome but not carrying the same 
causative mutation). The cerebellum and inferior olives have been 
implicated as possible sites of an altered “tremor pacemaker” based 
on the presence of cerebellar signs in ~10% of ET patients, as well as 
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, suggesting a neuro­
degenerative disease, but these findings remain controversial, and the 
precise pathologic correlate of ET remains to be defined. Interest has 
also focused on the possibility that ET is caused by degeneration of 
GABAergic cerebellar neurons with defects in neurotransmission. It is 
likely that multiple causes of ET will ultimately be identified.

CHAPTER 447
■
■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 
~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 as necessary 
(125–250 mg three times daily) to avoid sedation, nausea, and dizzi­
ness. 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 effec­
tive for severe and drug-resistant cases. More recently, focal ultrasound 
(a procedure that does not require surgery) has also been shown to be 
an effective therapy against tremor in some cases of ET.
Tremor, Chorea, and Other Movement Disorders
DYSTONIA
■
■CLINICAL FEATURES
Dystonia is a movement disorder characterized by sustained or inter­
mittent synchronous muscle contractions of agonist and antagonist 
muscles causing abnormal, often repetitive, painful movements and 
postures. Dystonic movements are typically patterned and twisting 
and may be associated with a “dystonic” tremor. This tremor can usu­
ally be distinguished from ET as the tremor is most pronounced when 
the body part is moved in the direction of the dystonia and relieved 
when the body part is moved in the direction opposite to the dysto­
nia. Dystonia can range from minor contractions affecting only an 
individual muscle group (focal) to severe and disabling contractions 
with involvement of multiple muscle groups (i.e., multifocal, seg­
mental, or generalized). Nonmotor features such as pain, depression, 
anxiety, and impaired sleep can be associated with, or even precede 
onset of, the dystonia. The frequency of dystonia is estimated to be 
about 30 per 100,000 but is likely to be higher because many cases are 
not recognized or correctly diagnosed. 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 contractions). Dystonia 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 combina­
tion of phenotypic and etiologic features, the older terms are no longer

TABLE 447-2  Monogenic Forms of Isolated and Combined Dystonia
DESIGNATION AND 
PHENOTYPIC SUBGROUP
ADDITIONAL DISTINGUISHING FEATURES
FORM OF DYSTONIA
GENE
TOR1A
DYT-TOR1A
Childhood or adolescent onset, generalized
AD
Isolateda
    
 
  
KMT2B
DYT-KMT2B
Early onset, generalized, mild syndromic features
AD
THAP1
DYT-THAP1
Adolescent onset, cranial or generalized
AD
ANO3
DYT-ANO3
Adult onset, focal or segmental
AD
GNAL
DYT-GNAL
Mostly adult onset, focal or segmental
AD
VPS16
DYT-VPS16
Frequent cervical and laryngeal dystonia
AD or AR
EIF2AK2
DYT-EIF2AK2
Childhood or adolescent onset, focal to generalized
AD or AR
 
PRKRA
DYT-PRKRA
Generalized
AR
 
HPCA
DYT-HPCA
Childhood onset
AR
 
AOPEP
DYT-AOPEP
Frequent cervical and laryngeal dystonia
AR
Combinedb
Dystonia plus 
parkinsonism 
GCH1
DYT-GCH1
Dopa-responsive
AD
 
TAF1
DYT-TAF1
Neurodegeneration
XL
PART 13
Neurologic Disorders
 
 
ATP1A3
DYT-ATP1A3
Rapid onset
AD
 
Dystonia plus 
myoclonus 
SGCE
DYT-SGCE
Alcohol responsive
AD
 
KCTD17
DYT-KCTD17
Childhood onset
AD
aKMT2B pathogenic variants may present with mild syndromic features. bSelected examples.
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; XL, X-linked.
recommended. A Movement Disorder Society Task Force recom­
mended classifying dystonia along the same 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, action-specific [diurnal and paroxys­
mal]), 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 it may be secondary to other causes, such as trauma 
and stroke. Genetic features used for classification include mode of 
inheritance or identification of a specific pathogenic gene variant. 
More than 200 genes have been linked to different types of dystonia, 
primarily childhood-onset and generalized forms. These include forms 
in which dystonia is the only disease manifestation with the exception 
of tremor (“isolated dystonia”) and forms in which dystonia co-occurs 
with another movement disorder such as parkinsonism, myoclonus, 
or other neurologic and/or nonneurologic manifestations (“combined 
dystonia”) and may not even be the dominant clinical feature. This 
group represents the most heterogeneous class in terms of clinical 
expression. A list of confirmed monogenic mutations associated with 
isolated or combined dystonias is provided in Table 447-2.
■
■ISOLATED DYSTONIAS
Focal, Multifocal, and Segmental Dystonia 
Adult-onset, focal 
dystonia is by far the most frequent form of isolated dystonia. Women 
are affected about twice as often as men, with the exception of writer’s 
cramp, which occurs more frequently in men than in women. Focal 
dystonia typically presents in the fourth to sixth decade. The major 
clinical phenotypes are: (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 radicu­
lopathy and even myelopathy. (2) Blepharospasm—dystonic contrac­
tion of the eyelids resulting in increased blinking and eye closure that 
can interfere with reading, watching television, working on a com­
puter, and driving. This can sometimes be so severe as to cause func­
tional blindness. (3)  Oromandibular dystonia (OMD)—contractions 
of muscles of the lower face, lips, tongue, and jaw (opening or clos­
ing). Meige’s syndrome is a combination of OMD and blepharospasm 
that predominantly affects women aged >60 years. (4) Spasmodic 

MODE OF 
INHERITANCE
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 handwrit­
ing (writer’s cramp), playing a musical instrument (musician’s cramp), 
or putting in golf (the yips). The vast majority of patients with focal 
dystonia have cervical dystonia (~40%) or blepharospasm (~15%). 
Focal hand or leg dystonia (~10%), musician’s dystonia (~3%), spas­
modic dysphonia (~2%), and OMD (~1%) are much less common. 
Focal dystonias can extend to involve other body regions (~30% of 
cases) and are frequently misdiagnosed as psychiatric or orthopedic 
in origin. Their cause is usually not known. They are rarely mono­
genic (~1%); autoimmunity and trauma have been suggested as other 
possible etiologies. Focal dystonias are often associated with a highfrequency tremor that can resemble ET. Dystonic tremor can usually be 
distinguished from ET because it tends to occur in the direction of the 
dystonic contraction and disappears when the dystonia is relieved (i.e., 
turning the head in the opposite direction of the dystonia).
Generalized Dystonia  
Generalized dystonia is often hereditary 
and, unlike focal dystonia, typically has an age of onset in childhood or 
adolescence. There are currently at least 10 well-established genes that, 
when mutated, can cause mostly isolated, segmental or generalized 
dystonia: ANO3, AOPEP, EIF2AK2, GNAL, HPCA, KMT2B, PRKRA, 
THAP1, TOR1A, and VPS16. The AOPEP, HPCA, and PRKRA patho­
genic mutations are recessively inherited, while others (e.g., EIF2AK2 
and VPS16) can be either dominantly or recessively inherited. Accord­
ing 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.
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 estab­
lished 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 affect other body parts, 
but the face and neck are typically spared. Rare carriers of two mutated 
alleles have been described and are characterized by a severe neurode­
velopmental syndrome and arthrogryposis.

Missense mutations in KMT2B (lysine methyltransferase 2B) are 
another relatively frequent cause of early-onset generalized dystonia, 
which may be accompanied by other syndromic features, including 
intellectual disability, microcephaly, psychiatric features, dysmorphia, 
or skin lesions. The majority of the mutations occur de novo. KMT2B 
mutations may account for up to 10% of early-onset generalized dysto­
nia, but further validation is warranted, and placement into the group 
of isolated versus complex dystonias is currently under debate.
Mutations in the THAP1 gene (THAP domain containing apoptosisassociated protein 1) 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. While DYT-Tor1A and DYTKMT2B typically respond well to deep brain stimulation (DBS) of the 
globus pallidus internus bilaterally, the DBS response is much more 
variable in carriers of pathogenic variants in the THAP1 gene.
Mutations in the ANO3 gene (anoctamin 3) 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 dys­
tonia and myoclonic jerks.
Mutations in the GNAL gene (guanine nucleotide-binding protein 
subunit alpha L) are a rare cause of cervical or cranial dystonia, with 
a few patients developing generalized dystonia. The mean age of onset 
is in the thirties.
Pathogenic variants in the VPS16 gene can be inherited in a recessive 
or dominant fashion, with the latter mode of inheritance being more 
common. Currently, >30 carriers of ~20 different, often truncating, 
heterozygous pathogenic variants have been described. The median 
age of onset is 14 years. Dystonia tends to generalize and is typically 
isolated, although more complex phenotypes have also been described.
Pathogenic missense variants in EIF2AK2, coding for the eukaryotic 
translation initiation factor 2-alpha kinase 2, cause dystonia with a 
median age at onset of 6 years and onset often in the limbs followed by 
generalization. There is a recurrent missense variant (p.Gly130Arg) in 
most patients. The EIF2AK2 protein is one of the kinases responsible 
for eIF2a phosphorylation and is thus linked to the same pathway as 
PRKRA.
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 with childhood onset.
The median age at onset of carriers of recessively inherited, bial­
lelic, and typically truncating pathogenic variants in the AOPEP gene 
is 20 years, with frequent onset in the hands. Most patients progress to 
isolated, 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 (e.g., parkinsonism 
or myoclonus) or with other neurologic and/or nonneurologic features.
Dopa-responsive dystonia (DRD; also known as Segawa syndrome) 
is caused by mutations in the GCH1 gene (GTP cyclohydrolase-1) that 
encodes for the rate-limiting enzyme in the biosynthesis of dopamine 
via the biopterin pathway. It manifests as a childhood-onset form of 
dystonia with diurnal fluctuations, and it 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 single-photon 
emission computed tomography. Younger patients are frequently 
misdiagnosed as having cerebral palsy, mistaking dystonia for spastic­
ity, and it is important that young-onset forms of dystonia should be 
tested with levodopa to exclude the possibility of DRD. To date, >100 
different mutations have been reported with a penetrance of ~50% and 
incidence 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 the levodopa biosynthesis, there is a life­
long and dramatic response to levodopa therapy. Importantly, since 
dopamine terminals do not degenerate and the dopamine neuronal 
network is anatomically preserved, fluctuations in dopamine levels can 
be avoided, and accordingly, these patients do not develop dyskinesia 
with chronic levodopa treatment.

X-linked dystonia-parkinsonism (Lubag) presents with a combined 
form of dystonia and parkinsonism that is found exclusively in patients 
of Filipino origin due to a founder effect that seems to be fully pen­
etrant. The typical presentation is a focal (cranial) dystonia 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. Sixty-five percent of the age-at-onset variability 
is explained by the variable length of a hexameric repeat expansion 
within the retrotransposon and genotypes at three single-nucleotide 
polymorphisms in the MSH3 and PMS1 genes acting as age-at-onset 
modifiers.
CHAPTER 447
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, physi­
cal 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 clini­
cal 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.
Tremor, Chorea, and Other Movement Disorders
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 gene (sarcoglycan epsilon), 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 inher­
ited from the father due to the epigenetic effect of maternal imprinting 
of SGCE. KCTD17 mutations are another recently identified cause of 
myoclonus-dystonia.
A number of additional monogenic causes have been suggested for 
isolated and combined forms of dystonia but still await independent 
confirmation. Table 447-2 provides a list of the confirmed monogenic 
forms of isolated and combined dystonias.
Diagnostic Considerations 
In the largest group of combined 
dystonias, dystonia is a part of a more complex syndrome that is char­
acterized by multiple different clinical manifestations of the disease. 
Most frequently, they are hereditary, such as Wilson’s disease (WD), 
Lesch-Nyhan syndrome, corticobasal ganglionic disorders, and a 
variety of other neurologic, neurometabolic, neurodevelopmental, and 
mitochondrial disorders. Dystonia may also develop as a consequence 
of drugs or toxins. 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 (e.g., caudate/putamen) and 
occasionally in the globus pallidus, 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 follow­
ing peripheral nerve injury and be associated with features of complex 
regional pain syndrome (Chap. 19). A psychogenic origin is respon­
sible 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 pathophysi­
ologic basis of dystonia is not completely known. Physiologically, dys­
tonia 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 char­
acterized 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. 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 most types of 
dystonia, as 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 DBS of specific 
regions of the globus pallidus may ameliorate dystonia. The dopa­
mine system has been specifically implicated because dopaminergic 
therapies can both induce and treat some forms of dystonia in different 
circumstances. However, no specific pathology has been consistently 
identified that underlies dystonia.

PART 13
Neurologic Disorders
TREATMENT
Dystonia
Treatment of acute dystonia should include the immediate with­
drawal of any precipitating agent. A variety of drug therapies may 
be beneficial including diphenhydramine, benztropine, benzodiaz­
epines, or dopamine agonists.
Treatment of chronic dystonia is for the most part symptomatic 
except in rare cases where correction of a primary underlying con­
dition is possible. WD should be ruled out, particularly in young 
patients with dystonia. Levodopa should be tried in all cases of 
childhood-onset dystonia to test for DRD. High-dose anticholin­
ergics (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 at 
all, 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 (discussed 
below). 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 tar­
dive dystonia. Clonazepam and diazepam are sometimes effective.
Botulinum toxin is 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 trouble­
some, particularly if injections involve the neck and swallowing 
muscles. No systemic side effects are encountered with the doses 
typically used, but benefits are transient, and repeat injections are 
typically required at 2- to 4-month intervals. Some patients fail 
to respond after having experienced an initial benefit. This has 
been attributed to the development of neutralizing antibodies, but 
improper muscle selection, injection technique, and inadequate 
dose should be excluded. A new long-acting formulation of botu­
linum toxin (daxibotulinumtoxinA-l) that provides benefits for up 
to 6 months has recently been approved in the United States for the 
treatment of cervical dystonia.

Surgical therapy is a consideration for patients with severe gener­
alized dystonia who are not responsive to other treatments. Periph­
eral 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 dysto­
nia. This represents a major therapeutic advance because previously 
there was no consistently effective therapy, especially for patients 
with generalized dystonia and 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 (weeks to 
months). Better results are typically obtained in younger patients 
with shorter disease duration and in those with certain monogenic 
forms, such as DYT-Tor1A. DBS may also be valuable for patients 
with focal and secondary dystonias, although results are less consis­
tent. Neurophysiologic studies suggest that DBS acts by suppressing 
theta oscillations in the basal ganglia network that correlate with the 
dystonia. Adverse effects of DBS in dystonia patients include pares­
thesia, dysarthria, gait disturbance, and mood change. Dyskinesia 
can occur with stimulation of the subthalamic nucleus (STN), while 
bradykinesia and impaired coordination have been reported with 
stimulation of the globus pallidus pars interna (GPi). Focal ultra­
sound is being assessed as a possible alternative to surgical therapy. 
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 poten­
tially 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. In severe cases, anesthesia with muscle 
paralysis may be required.
CHOREAS
■
■HUNTINGTON’S DISEASE
Huntington’s disease (HD) is a progressive, fatal, highly penetrant 
autosomal dominant disorder characterized by motor, behavioral, ocu­
lomotor, 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, nonpat­
terned, semi-purposeful, involuntary choreiform movements, and for 
this reason was formerly referred to as Huntington’s chorea. However, 
dysarthria, gait disturbance, parkinsonism, oculomotor abnormalities, 
behavioral disturbance, and cognitive impairment with dementia are 
also common clinical 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 known as the West­
phal variant. Eye movement abnormalities may be an early manifesta­
tion of HD. These include slowed and reduced amplitude saccades with 
intrusions in smooth pursuit movements and impaired convergence. 
HD patients eventually develop behavioral and cognitive disturbances, 
and the majority progress to dementia. Depression with suicidal ten­
dencies, aggressive behavior, and psychosis can be prominent features. 
HD patients may also develop non-insulin-dependent diabetes mellitus

A
B
FIGURE 447-1  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).
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 ventricles, can be readily visualized on magnetic resonance 
imaging (MRI) (Fig. 447-1), 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 magnetic resonance spectroscopy. 
Genetic testing can be used to confirm the diagnosis and to detect atrisk individuals in the family, but it must be performed in conjunction 
with trained counselors because advising patients of positive results 
can worsen depression and even generate suicidal reactions. Indeed, 
genetic counseling is a requirement in some regions. The neuropa­
thology of HD consists of prominent neuronal loss and gliosis in the 
caudate nucleus and putamen; similar changes can also be widespread 
in the cerebral cortex. Intraneuronal inclusions containing aggregates 
of ubiquitin and the mutant protein huntingtin are found in the nuclei 
of some affected neurons.
In anticipation of developing neuroprotective therapies, an inten­
sive effort has been made to define the earliest stage of HD. Subtle 
motor impairment, cognitive alterations, and imaging changes can be 
detected in at-risk individuals who later 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 a mutation in which there is an increase in the num­
ber 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. Inter­
mediate forms of the disease with 36–39 repeats are described in some 
patients, typically with less severe clinical involvement and reduced 
penetrance (i.e., not every mutation carrier develops the disease). 
These clinic-genetic observations have recently been incorporated into 
a new research classification of HD. Carriers of a fully penetrant (>40 
repeats) allele are defined as having stage 0 HD, irrespective of their 
affected status. These developments are meant to facilitate the inclu­
sion of at-risk individuals or those in the earliest disease stages into 
clinical trials.

CHAPTER 447
Tremor, Chorea, and Other Movement Disorders
Expansion of repeat length 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 postnatal somatic gene expansion that occurs 
over time as well as genetic modifiers of disease progression, for exam­
ple, in the FAN1 and MSH3 genes, the latter overlapping with X-linked 
dystonia-parkinsonism. New-onset gene expansion in patients with no 
family history is rare.
The Huntingtin gene encodes the highly conserved cytoplasmic pro­
tein huntingtin (HTT), which is widely distributed in neurons through­
out the central nervous system (CNS). Mutated HTT RNA is toxic and 
disrupts transcription, impairs immune and mitochondrial function, 
and is aberrantly modified posttranslationally. Genome-wide asso­
ciation 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 the accumula­
tion and aggregation of toxic proteins in HD, like Alzheimer’s disease 
(Chap. 442) and PD (Chap. 446), may be critical to the disease process 
and reflect a prion-like disorder (Chap. 449; see also Chap. 435). 
Models of HD with striatal pathology can be induced in multiple trans­
genic 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. These relevant animal models can 
be helpful in assessing potential therapeutic agents. Interestingly, when 
correcting the neurotransmitter deficit present in HD mice in the very 
first week of life, disease development can be prevented.
TREATMENT
Huntington’s Disease
Although the gene for HD was identified >30 years ago, there is still 
no disease-modifying therapy for this disorder, and clinically mean­
ingful symptomatic treatment is limited. Current treatment involves 
a multidisciplinary approach, with medical, neuropsychiatric, and 
social approaches, as well as genetic counseling for patients and their 
families. Dopamine-blocking agents such as tetrabenazine and val­
benazine have been approved to treat the choreiform movements 
but can be associated with secondary parkinsonism as an adverse 
event. Deuterated tetrabenazine (Austedo) and a long-acting version 
of deuterated tetrabenazine have also been approved as treatments 
for chorea in HD. Deuteration interferes with the metabolism of

tetrabenazine and avoids the high maximum concentration (Cmax), 
which is thought to contribute to adverse effects. In clinical trials, 
deuterated tetrabenazine has been shown to have fewer dose-related 
side effects and less parkinsonism than tetrabenazine and, therefore, 
can be administered in higher doses with potentially superior clini­
cal 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. There are currently no therapies approved for 
treating the more disabling motor features of HD, but large-scale 
platform studies are ongoing, which are assessing a variety of differ­
ent therapeutic approaches using a common placebo group. Depres­
sion 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), que­
tiapine (50–600 mg/d), and risperidone (2–8 mg/d).

PART 13
Neurologic Disorders
A neuroprotective therapy that slows or stops disease progres­
sion is the major unmet medical need. Some strategies are designed 
to reduce the formation or accumulation of mutant HTT. These 
largely focus on inhibiting mRNA synthesis either by blocking 
transcription (zinc finger motif protein), preventing posttranscrip­
tional processes, promoting early mRNA degradation (antisense 
oligonucleotides [ASO]), or inhibiting translation with short inter­
fering RNA. The most advanced of these experimental therapeu­
tic approaches investigated intrathecal administration of an ASO 
in patients with early HD in a randomized, placebo-controlled, 
double-blind clinical trial. While a dose-dependent reduction in 
concentrations of mutant HTT was observed and there were no 
side effects, the study was terminated early because no clinical 
benefit was detected. Drugs that enhance mitochondrial func­
tion and increase the clearance of defective mitochondria are also 
being tested as possible disease-modifying therapies. Other inves­
tigative approaches include immunotherapy, dietary supplements 
(resveratrol), lipid-lowering medication (fenofibrate), anaplerotic 
therapy (triheptanoin), and DBS of the GPi. A promising therapy 
is the sigma 1 receptor agonist pridopidine. Various clinical trials 
have suggested that the drug may provide benefit with respect to 
total motor function and total functional capacity, particularly in 
patients with relatively mild disease. Double-blind studies are cur­
rently underway. Preliminary clinical trials testing cell-based thera­
pies (stem cells and fetal striatal cells) have been initiated, aimed at 
replacing damaged striatal neurons, but efficacy and safety of these 
procedures have not yet been determined. Experimentally, there 
is great interest in the potential of using CRISPR (gene editing) 
techniques to target and destroy or prevent the formation of mutant 
Huntingtin RNA and to reduce accumulation of the abnormal pro­
tein. Numerous other molecular and gene-based approaches are 
being evaluated to interfere with the formation and promote the 
clearance of the toxic protein, and many clinical studies are antici­
pated to begin within the next few years.
HUNTINGTON’S DISEASE–LIKE DISORDERS
A group of rare inherited conditions that can mimic HD, designated 
HD-like (HDL) disorders, have also been identified. HDL-1, -2, and 
-4 are autosomal dominant conditions that typically present in adult­
hood. 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. 449). Thus, HDL-1 is properly considered a 
prion disease. Patients exhibit onset of personality change in the third 
or fourth decade, followed by chorea, rigidity, myoclonus, ataxia, and 
epilepsy. HDL-2 manifests in the third or fourth decade 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 regulat­
ing transcription; this condition is identical to spinocerebellar ataxia 
(SCA) 17 (Chap. 450), and most patients present with ataxia rather 
than chorea. Like in HD, a certain range of repeat expansions in the 
TBP gene is associated with reduced penetrance, whereby penetrance 
was recently identified to be full when a variant in the Stub1 gene is 
present in conjunction with the repeat expansion. Mutations of the 
C9Orf72 gene associated with frontotemporal dementia and amyo­
trophic lateral sclerosis (Chaps. 443 and 448) have also been reported 
in some individuals with an HDL phenotype.
■
■OTHER CHOREAS
Chorea can be seen in a number of other 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 combina­
tion with dystonia and developmental delay. Characteristic perioral 
movements are a hallmark of the disorder. Notably, patients respond 
well to caffeine.
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 selfmutilating 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 transcrip­
tion factor 1 and a late-onset benign senile chorea (BHC2) have also 
been reported. It is important to do genetic testing in these patients to 
ensure that they 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’s 
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. 153) and is thought to 
be autoimmune in nature. It is characterized by the acute onset of 
choreiform movements and behavioral disturbances. With the reduc­
tion 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, and is usually self-limited. Treatment is gener­
ally 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) recep­
tor antibody–positive encephalitis, following herpes simplex virus 
encephalitis, and in paraneoplastic syndromes associated with antiCRMP-5 or anti-Hu antibodies (Chap.  99). Systemic lupus erythe­
matosus (Chap. 368) is the most common systemic disorder that is 
associated with chorea. The chorea may last for only a few days but 
can be long-lasting and persist for years. Chorea can also be seen 
with hyperthyroidism, autoimmune disorders including Sjögren’s syn­
drome, infectious disorders including HIV, metabolic alterations, and 
polycythemia rubra vera. Chorea has been described following openheart surgery in the pediatric population. It may also occur in associa­
tion with many medications (especially anticonvulsants, cocaine, CNS 
stimulants, estrogens, and lithium). In particular, chorea is commonly 
seen as a side effect of chronic levodopa treatment in patients with PD 
(Chap. 446).

■
■BALLISM/HEMIBALLISMUS
Ballism is a violent form of choreiform movement composed of wild, 
flinging, large-amplitude movements most frequently affecting proxi­
mal limb muscles on one side of the body (hemiballism). The move­
ments may only affect 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 help­
ful, 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 STN, but in 30–40% of 
cases, the lesion is found in the putamen, thalamus, or parietal cortex. 
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 purpose­
less 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 dis­
abling. 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 vocaliza­
tions (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 (ADHD), and obsessive-compulsive disorder. 
Patients may experience personality disorders, self-destructive behav­
iors, 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. Genome-wide linkage studies have suggested 
Slit, Trk-like 1, and histidine decarboxylase (HDC) genes as conferring 
genetic risk for TS. The risk of a family with one affected child having a 
second one with TS is ~25%. The pathophysiology of TS is not known, 
but alterations in dopamine neurotransmission, opioids, and secondmessenger systems have been proposed.
TREATMENT
Tics and Tourette’s Syndrome
There is no cure for tics or TS. Patients with mild disease often only 
require education and counseling (for themselves and family mem­
bers). 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 to help control tics is indicated when the tics are 
disabling and interfere with quality of life and social interactions. 
Therapy is individualized, and few treatment regimens have been 
properly evaluated in double-blind trials. Some physicians use the 
α-agonist clonidine, starting at low doses and gradually increas­
ing 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 only requires once-daily dosing. Other physicians prefer 
to use neuroleptics, but treatment can be complicated by tardive 
dyskinesia and weight gain. 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 hal­
operidol, fluphenazine, pimozide, or tiapride can be tried because 
the risk of tardive dyskinesia in young people is relatively low. Tet­
rabenazine and deuterated tetrabenazine may be recommended but 
are associated with depression. The dopamine D1 antagonist ecopi­
pam was reported to provide benefits without serious side effects in 
a controlled trial of short duration in TS. Antiepileptic drugs such 
as topiramate may provide benefit for some patients. Botulinum 
toxin injections can be effective in controlling focal tics that involve 
small muscle groups. There is also interest in the potential value of a 
wrist device that delivers electrical pulses and has been reported to 
reduce the frequency and severity of tics in an open-label study. The 
potential value of closed-loop DBS targeting the anterior portion 
of the internal capsule, the GPi, or the thalamus is currently being 
explored for severely affected patients. A large-scale public database 
and registry for DBS in TS has been established. Behavioral fea­
tures, and particularly anxiety and compulsions, can be a disabling 
feature of TS and should be treated as appropriate. Behavioral and 
speech therapies are also occasionally employed but have not been 
formally tested. ADHD medications such as methylphenidate are 
sometimes used to increase attention and concentration but may 
also exacerbate tics.

CHAPTER 447
Tremor, Chorea, and Other Movement Disorders
MYOCLONUS
Myoclonus is a brief, rapid (<100 ms), shock-like, jerky movement 
consisting of single or repetitive muscle discharges that can occur with 
or without a pattern and with a variable frequency. Myoclonic jerks can 
be focal, multifocal, segmental, or generalized and can occur sponta­
neously, in association with voluntary movement (action myoclonus), 
or in response to an external stimulus (reflex myoclonus). Myoclonic 
jerks can be severe and interfere with normal movement or benign 
and of no clinical consequence, as is commonly observed in normal 
people who can experience myoclonic jerks when waking up or falling 
asleep (hypnagogic jerks). Negative myoclonus consists of a brief loss 
of muscle activity (e.g., asterixis in hepatic failure). Palatal myoclonus 
(or palatal tremor) involves contractions of the soft palate and may be 
associated with an audible click that can be disturbing to the patient 
and family members. This is usually idiopathic and benign but can 
be related to a lesion in the cerebellum or brainstem. Myoclonus may 
also occur consequent to injury to a peripheral or cranial nerve (e.g., 
hemifacial spasm).
Myoclonic jerks differ from tics in that they are typically not 
repetitive, are not suppressible, and can severely interfere with normal 
voluntary movement. They can be associated with abnormal neuronal 
discharges in cortical, subcortical, brainstem, or spinal cord regions, 
particularly in cases related to 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 clini­
cal features: prominent myoclonus, prominent myoclonus 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 majority

of patients. The frequent association with epilepsy suggests that a brief 
epileptic-like discharge could underlie myoclonus in some situations.

Myoclonic epilepsy is a disorder comprised of myoclonus and epi­
lepsy. It can be associated with other focal neurologic deficits, has a 
variable but progressive course, and may ultimately be fatal. The most 
common form of action myoclonus of cortical origin with general­
ized epilepsy is myoclonic epilepsy or Unverricht-Lundborg disease 
(EPM-1). Ataxia may also be a feature. This is an autosomal recessive 
disease caused by pathogenic variants in the CSBT gene. Other causes 
are Lafora body epilepsy or progressive myoclonic epilepsy (PME2) caused by mutations in the EPM2A or NHLRC1 genes. Neuronal 
ceroid lipofuscinosis (Batten’s disease) is another consideration. 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, lightninglike movements that are frequently alcohol sensitive. Mutations in the 
epsilon-sarcoglycan gene have been associated with myoclonus seen in 
association with dystonia (myoclonus-dystonia).
PART 13
Neurologic Disorders
The precise cause of myoclonus is not known but, in some cases, is 
thought to be due to overexcitability or impaired inhibition of cortical 
or peripheral nerve stimuli related to a particular movement. Imaging 
studies are seeking to define the altered connectivity in neuronal cir­
cuits that underlies myoclonus.
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 in which a cortical origin for the myoclonic dis­
charges has been identified (e.g., postanoxic myoclonus, progressive 
myoclonic epilepsy). In some cases, combinations of drugs may 
prove helpful. The serotonin precursor 5-hydroxytryptophan (plus 
carbidopa) may be useful in cases of postanoxic myoclonus. DBS 
can be highly effective in myoclonus-dystonia. Botulinum toxin 
has been used successfully in some patients with focal myoclonus, 
palatal myoclonus, and hemifacial spasm. Some patients with hemi­
facial spasm have also been reported to benefit from neurosurgical 
decompression of the involved facial nerve.
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 gastro­
esophageal disorders (e.g., metoclopramide [Reglan]) are neurolep­
tic agents and can 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 and are associated with cognitive side effects, and 
there is concern that such treatment might actually increase the risk of 
developing a tardive syndrome.
■
■ACUTE
Dystonia is the most common acute hyperkinetic drug reaction 
(see above). 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), 

diphenhydramine, benzodiazepines (lorazepam, clonazepam, or diaz­
epam), or dopamine agonists. The abrupt onset of severe spasms may 
occasionally be confused with a seizure; however, there is no loss of 
consciousness, and no automatisms, electroencephalogram abnormali­
ties, 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. In rare cases, the airway may be affected and must be 
protected.
■
■SUBACUTE
Akathisia is the most common reaction in this category. Akathisia 
consists of motor restlessness with a need to move that is alleviated 
by movement. It is most frequently associated with use of neuroleptic 
drugs and generally starts within 2 weeks of initiating therapy. It can 
also be seen with calcium channel blockers, antiemetics, cocaine, and 
sedatives. The cause is not known but is thought to relate to blocking 
the dopaminergic system. Therapy consists of lowering the dose or 
removing the offending agent. When this is not possible, symptoms 
may be ameliorated with benzodiazepines, anticholinergics, beta 
blockers, or dopamine agonists. Treatment is generally effective, but in 
chronic cases, it may become associated with anxiety, depression, and 
even suicide.
■
■TARDIVE SYNDROMES
These disorders develop months to years after initiation of a neu­
roleptic agent. Tardive dyskinesias (TD) are most common and 
typically present with choreiform 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, 
TDs remit within 3 months of stopping the drug, and most patients 
gradually improve over the course of several years. However, abnor­
mal movements may also develop, persist, or worsen after stopping 
the offending agent. The movements are often mild and more upset­
ting to the family than to the patient, but in some cases, they can 
be severe and disabling, particularly in the context of an underlying 
psychiatric disorder. Second-generation or atypical antipsychotics 
(e.g., clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and 
aripiprazole) are thought to be associated with a lower risk of causing 
TD in comparison to traditional antipsychotics, although they do not 
eliminate this risk. Younger patients have a lower risk of developing 
neuroleptic-induced TD, whereas the elderly, females, and those with 
underlying organic cerebral dysfunction are at greater risk. Chronic 
neuroleptic use is associated with increased risk of TD, and the U.S. 
Food and Drug Administration has specifically 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 and atypical neuroleptics should be the preferred 
agent whenever possible, although there are now questions as to the 
risk of TD with atypical neuroleptics as well. In all patients on these 
agents, the need for continued use should be regularly evaluated. The 
cause of TD is not known with certainty, but it is thought to be related 
to hypersensitivity of dopamine receptors following the use of dopa­
mine D2–blocking agents. This concept is based on observations that 
acute discontinuation can lead to accentuation of TD, while higher 
doses of these agents or the introduction of more potent neuroleptics 
can alleviate symptoms (at least transiently). Another hypothesis is 
that structural changes at the receptor level due to toxic effects of the 
neuroleptic may be causative. It has also been suggested that there 
may be a genetic predisposition in individuals who develop TD.
Treatment primarily consists of tapering and withdrawal of the 
offending agent. If the patient is receiving a traditional antipsychotic, 
and withdrawal is not possible, replacement with an atypical antipsy­
chotic (e.g., clozapine) should be tried. Abrupt cessation of a neurolep­
tic should be avoided because acute withdrawal can induce worsening. 
TD can persist after withdrawal of antipsychotics and can be difficult 
to treat. Tetrabenazine, a vesicular monoamine transporter type 2 
(VMAT-2) inhibitor that blocks storage of dopamine, has been used 
to treat TD but is short-acting and is associated with a dose-related

new onset or worsening of parkinsonian features. Valbenazine, an 
ester of tetrabenazine, has been approved for the treatment of tardive 
dyskinesia in a dose of 80 mg/d based on efficacy in double-blind trials, 
but it is associated with sleepiness and QT prolongation. Deuterated 
tetrabenazine has also been approved for this indication. Deuteration 
provides a longer half-life with lower Cmax, reducing risk of parkinso­
nian side effects. It can be individually titrated and permits the use 
of higher doses with lower risk of side effects. In open-label studies, 
benefits have also been reported with valproic acid (750–3000 mg/d), 
anticholinergics, and botulinum toxin injections. Other approaches 
include baclofen (40–80 mg/d) and clonazepam (1–8 mg/d). In some 
refractory cases, pallidal DBS may be an option.
Chronic neuroleptic exposure can also be associated with a tardive 
dystonia, with preferential involvement of axial muscles and charac­
teristic rocking movements of the trunk and pelvis. Gray coloration of 
skin can be a clue that the patient is receiving a neuroleptic in patients 
for whom the cause of the dystonia is not obvious. 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, and renal fail­
ure with 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 apomor­
phine or levodopa subcutaneously) may be required. Treatment may 
need to be undertaken in an intensive care setting and include sup­
portive 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 other drugs can be associated with hyperkinetic move­
ment disorders. Some examples include phenytoin (chorea, dystonia, 
tremor, myoclonus), carbamazepine (tics and dystonia), tricyclic 
antidepressants (dyskinesias, tremor, myoclonus), fluoxetine (myoclo­
nus, chorea, dystonia), oral contraceptives (dyskinesia), β-adrenergics 
(tremor), buspirone (akathisia, dyskinesias, myoclonus), digoxin, 
cimetidine, diazoxide, lithium, methadone, and fentanyl (dyskinesias). 
And as described in an earlier chapter (Chap. 446), treatment of PD 
with levodopa can be associated with dyskinetic movements; these are 
typically choreiform, but dystonia and myoclonus may also occur.
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 dyski­
nesias (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.

PKDs are characterized by brief, self-limited attacks induced by the 
onset of movement such as running but also occasionally by unex­
pected 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 disor­
der 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 phe­
nytoin is advised when the attacks are frequent and interfere with daily 
life activities and is effective in ~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 ori­
gin, but this has not been established.

CHAPTER 447
Tremor, Chorea, and Other Movement Disorders
PNKD involves attacks of generalized dyskinesias precipitated by 
alcohol, caffeine, stress, or fatigue. In comparison to PKD, the epi­
sodes 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. Treat­
ment may not be required if the condition is mild and self-limited. 
Most patients with PNKD do not benefit from anticonvulsant drugs, 
but these should be tried, and some may respond to clonazepam or 
other benzodiazepines.
PED is characterized by a combination of chorea, athetosis, and 
dystonia in excessively exercised body regions, with the legs being 
most frequently affected. They are frequently familial. A single attack 
lasts from a few minutes to an hour and occurs after prolonged physi­
cal exercise. In addition to the movement disorder, several patients 
have other disease manifestations between episodes such as epilepsy, 
hemolytic anemia, and migraine. The SLC2A1 (solute carrier family 2 
member 1) gene, previously linked to GLUT1 (glucose transporter of 
the blood-brain barrier) deficiency syndrome, can also cause parox­
ysmal PED. Treatment includes avoiding prolonged physical exercise. 
Whereas anticonvulsants and most medications are typically not effec­
tive, a ketogenic diet may be an effective therapeutic option.
Other (rare) forms of paroxysmal dyskinesia are caused by 
pathogenic variants in the ECHS1, GLDC, KCNMA1, SCN8A, and 
TMEM151A genes.
RESTLESS LEGS SYNDROME
Restless legs syndrome (RLS) is a neurologic disorder that affects ~10% 
of the adult population (it is rare in Asians). It was first described in the 
seventeenth century by the English physician Thomas Willis but has 
only recently been appreciated to be 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 
are often mild but can cause significant morbidity in some individuals.
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 ~80% 
of patients, RLS is associated with periodic leg movements (PLMs) 
during sleep and occasionally while awake. These involuntary move­
ments 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 sleepi­
ness. RLS is also commonly associated with depression, anxiety, and 
hypertension.

The mean age of onset in familial forms is in the third decade, 
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 neuropathy. There is an association with 
abnormalities of iron metabolism, possibly because low iron can result 
in reduced dopamine levels. Diagnosis is made on clinical grounds 
but can be supported by polysomnography and the demonstration of 
PLMs. Recent studies suggest that age, sex, and genetic markers can 
be used to accurately predict who is likely to develop RLS in 90% of 
cases. The neurologic examination is normal. Secondary causes of 
RLS should be excluded, and ferritin levels, glucose, and renal func­
tion should be measured. The pathogenesis is thought to be associated 
with an alteration in dopamine function, which may be peripheral or 
central, but this has not been specifically defined. Primary RLS is often 
familial and has a strong genetic component; however, no causative 
gene has yet been identified. Genome association studies have identi­
fied >150 variants associated with RLS risk, with the strongest candi­
dates in the PTPRD, BTBD9, and MEIS1 genes. Interestingly no genetic 
linkage to iron has been identified.
PART 13
Neurologic Disorders
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 symptoms 
and emergence during the day) or rebound (reappearance sometimes 
with worsening of symptoms at a time related to the drug’s short halflife). Augmentation can also be seen with chronic use of drugs such as 
dopamine agonists, particularly if higher doses are employed. Other 
drugs that have been reported to be effective in individual cases include 
anticonvulsants, analgesics, and opiates, but these are not commonly 
employed. Tonic motor activation (TOMAC) is a nonpharmacologic 
approach to RLS that has not responded to drug therapy and has 
recently been approved in the United States. The treatment involves 
electrical stimulation of the peroneal nerves during the night and is 
reported to be effective and to improve sleep quality. Management of 
secondary RLS should be directed to correcting the underlying disor­
der (e.g., iron replacement for anemia).
OTHER DISORDERS THAT MAY PRESENT 
WITH A COMBINATION OF PARKINSONISM 
AND HYPERKINETIC MOVEMENTS
■
■WILSON’S DISEASE (SEE ALSO CHAP. 427)
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 Ger­
man physicians Kayser and Fleischer separately noted the characteris­
tic association of corneal pigmentation (Kayser-Fleischer rings) along 
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 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 character­
istic (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 his­
tory of psychiatric disturbances, including depression, mood swings, 
and overt psychosis. Kayser-Fleischer (KF) rings are seen in virtually 
all patients with neurologic features and 80% of those with hepatic pre­
sentations. 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, particularly when arising 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, puta­
men, globus pallidus, substantia nigra, and red nucleus on T2-weighted 
MRI scans. However, the 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 diagnosis.
In the absence of treatment, the course is progressive and leads 
to severe neurologic dysfunction and early death in most 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 treating this disease. 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 co-administration of pyridoxine. 
Tetrathiomolybdate blocks the absorption of copper and can be used 
instead of penicillamine. Trientine tetrahydrochloride 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. Gene therapy studies that 
involve an infusion of a working copy of the ATP7B gene into the liver 
are being investigated clinically, while preclinical studies are testing the 
novel chelator methanobactin.
■
■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 a progressive neurologic 
disorder with a variety of clinical features including parkinsonism, 
dystonia, neuropsychiatric abnormalities, and retinal degeneration. 
Cognitive disorders and cerebellar dysfunction may also be seen. Pre­
sentation is usually in childhood, but adult cases have been described. 
Multiple genes have been identified. Pantothenate kinase-associated 
neurodegeneration (PKAN), formerly known as Hallervordan-Spatz 
disease, is caused by a mutation in the PANK2 gene and is the most 
common form of NBIA, accounting for ~50% of cases. Onset is usu­
ally 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 some 
basal ganglia regions is normal, and excess iron accumulation may 
occur in the basal ganglia as a nonspecific secondary consequence of