TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS

NEURO2

 tends to occur in association with anxiety, fatigue, a

Contents
metabolic disturbance (e.g., hyperthyroidism, electrolyte
I. Tremor
abnormalities), drugs (e.g., valproate, lithium), or toxins
II. Dystonia
(e.g., caffeine, smoking, alcohol)
III. Choreas
 treatment is initially directed at control of any underlying
IV. Tics
disorder and, if necessary, can often be improved with a
V. Myoclonus
beta blocker
VI. Drug-Induced Movement Disorders
VII. Paroxysmal Dyskinesias
ESSENTIAL TREMOR
VIII. Restless Legs Syndrome (RLS)
 epidemiology
IX. Other Disorders that May Present with a Combination of
 most common movement disorder, affecting ~5% of the
Parkinsonism and Hyperkinetic Movements
population (an estimated 5–10 million persons in the US or
X. Psychogenic (Functional) Disorders
Western Europe)
 can present in childhood but dramatically increases in
HYPERKINETIC MOVEMENT DISORDERS prevalence in those aged >70 years
 hyperkinetic movements disorders are characterized by  tremor involves:
involuntary movements unaccompanied by weakness  head in ~30%
 voice in ~20%
 tongue in ~20%
 face/jaw in ~10%
 lower limbs in ~10%
 multiple body parts in at least 50%
 tremor characteristic
 high-frequency tremor (6–10 Hz) that predominantly
affects the upper extremities
 most often manifest as a postural or action tremor and, in
severe cases, can interfere with functions such as eating
and drinking
 typically bilateral and symmetric but may begin on one
side and remain asymmetric
 severe ET: intention tremor with overshoot and slowness of
movement suggesting the possibility of a cerebellar origin
 tremor is characteristically improved by alcohol and
worsened by stress
TREMOR  subtle impairment of coordination or tandem walking may be
present, and disturbances of hearing, cognition, personality,
CLINICAL FEATURES mood, and olfaction have been described, but usually the
 tremor: alternating contractions of agonist and antagonist neurologic examination is normal aside from tremor
muscles in an oscillating, rhythmic manner  differential diagnosis
 rest tremor: tremor most prominent at rest  dystonic tremor
 postural tremor: tremor on assuming a posture  PD:
 kinetic tremor: tremor on actively reaching for a target - tremor stops at the onset of a voluntary action and is
 action tremor: tremor on carrying out a movement typically associated with bradykinesia with progressive
 tremor may also be characterized based on distribution, slowing of sequential movements (sequence effect),
frequency, amplitude, and related neurologic dysfunction rigidity, gait and postural instability, and other
 Parkinson’s disease (PD): resting tremor parkinsonian features
 essential tremor (ET): tremor that typically occurs while trying - PD patients may have a postural tremor and ET
to sustain a posture coupled with an action tremor patients may develop a rest tremor, and that these
 cerebellar dysfunction: kinetic tremor associated with typically begin after a latency of a few seconds
hypotonia and past pointing (emergent tremor)
 normal individuals can have a physiologic tremor that typically - in contrast to the micrographia of PD, ET patients have
manifests as a mild, high-frequency (10–12 Hz), postural or relatively large handwriting with evidence of the effect
action tremor typically affecting the upper extremities of tremor
 this tremor is usually of no clinical consequence and often - the examiner must also differentiate the effect of
is only appreciated with an accelerometer or under stress tremor when assessing tone in ET to distinguish this
 enhanced physiologic tremor (EPT): from the cogwheel rigidity found in PD
 seen in up to 10% of the population

ETIOLOGY ANG PATHOPHYSIOLOGY

Page | 1
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2

 etiology and pathophysiology are not known  can range from focal minor contractions affecting only an
 ~50% have a positive family history with an autosomal individual muscle group to severe and disabling
dominant pattern of inheritance involvement of multiple muscle groups
 no independently confirmed causative genes have been  often brought out by voluntary movements (action
identified to date dystonia) and can extend to involve other muscle groups
 cerebellum and inferior olives have been implicated as possible and body regions not required for a given action
sites of a “tremor pacemaker” based on the presence of (overflow)
cerebellar signs (in 10% of patients) and increased metabolic  can be aggravated by stress and fatigue and attenuated by
activity and blood flow in these regions in some patients relaxation and sensory tricks such as touching the affected
 some pathologic studies have described cerebellar body part (geste antagoniste)
pathology with a loss of Purkinje cells and axonal  classification
torpedoes, but these findings are controversial  a Movement Disorder Society Task Force charged with
 precise pathologic correlate of ET remains to be defined redefining dystonia recommends classifying dystonia
along two main axes: clinical and etiologic
TREATMENT  on clinical grounds, dystonia can be categorized by:
 many cases are mild and require no treatment other than - age of onset (infancy, childhood, adolescence, early
reassurance and late adulthood
 occasionally, tremor can be severe and interfere with eating, - body distribution (focal, segmental, multifocal, and
writing, and activities of daily living generalized)
 this is more likely to occur as the patient ages and is often - temporal pattern (static or progressive, action-specific
associated with a reduction in tremor frequency [diurnal and paroxysmal])
 beta blockers and primidone are the standard drug therapies - association with additional features
for ET and help in about 50% of cases  clinical description along these lines enables formulating
 propranolol (20–120 mg daily, given in divided doses) specific dystonia syndromes (e.g., early-onset generalized
- usually effective at relatively low doses, but higher isolated dystonia)
doses may be needed in some patients  etiology
- contraindicated in patients with bradycardia or asthma  primarily reflects genetic abnormalities, although
- hand tremor tends to be most improved, while head occasionally there may be other causes such as trauma and
tremor is often refractory stroke
 primidone  genetic features used for classification include mode of
- can be helpful but should be started at low doses (12.5 inheritance or identification of a specific genetic defect
mg) and gradually increased (125–250 mg tid) to avoid  in the past three decades, more than 200 genes have been
sedation, nausea, and dizziness linked to different, mainly childhood-onset and
 gabapentin and topiramate: have reported benefits but these generalized forms of dystonia which includes:
drugs have not been widely employed - isolated dystonia: dystonia is the only disease
 botulinum toxin injections: may be helpful for limb or voice manifestation except for tremor
tremor, but treatment can be associated with muscle weakness - combined dystonia: dystonia co-occurs with another
 surgical therapies targeting the ventro-intermediate (VIM) movement disorder such as parkinsonism or
nucleus of the thalamus: can be very effective for severe and myoclonus
drug-resistant cases - complex dystonia: dystonia is only one of several
 focal ultrasound clinical manifestations and may be a less prominent or
 does not require surgery even inconsistent feature
 has been shown to be an effective therapy  most of the genetic forms belong to the latter phenotypic
group, which also represents the most heterogeneous
DYSTONIA class in terms of clinical expression

ISOLATED DYSTONIAS
CLINICAL FEATURES
Focal (Multifocal, Segmental) Dystonia
 dystonia: movement disorder characterized by sustained or
 adult-onset, focal dystonia is by far the most frequent form of
intermittent muscle contractions of antagonist muscles causing
isolated dystonia, with women being affected about twice as
abnormal often repetitive movements and postures
often as men
 epidemiology
 focal dystonia typically presents in the fourth to sixth decade
 frequency is estimated to be 16 per 100,000 (~50,000
and can be focal, multifocal, or segmental
cases in the US) but is likely to be much higher because
 the major clinical phenotypes are as follows:
many cases are not recognized
(1) Cervical dystonia—dystonic contractions of neck muscles
 dystonia characteristics
causing the head to deviate to one side (laterocollis), twist
 dystonic movements are typically patterned and twisting
(torticollis), move in a forward direction (anterocollis), or
and may be associated with a “dystonic tremor”
move in a backward direction (retrocollis). Muscle

Page | 2
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2
contractions can be painful and occasionally can be
complicated with 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 so severe as 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).
 epidemiology
 frequency:
- cervical dystonia (~50%)
- blepharospasm (~20%)
- focal hand or leg dystonia (~5%)
- spasmodic dysphonia (~2%)
- musician’s dystonia (~3%)
- OMD (~1%)
 etiology
 focal dystonias can extend to involve other body regions
(about 30% of cases) and are frequently misdiagnosed as
psychiatric or orthopedic in origin
 cause is usually not known, but genetic factors,
autoimmunity, and trauma have been suggested
 differential diagnosis
 ET
- 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
 often hereditary in nature and generally has an age of onset in
childhood or adolescence
 four well established genes for isolated dystonia: TOR1A,
THAP1, ANO3, and GNAL
 according to the recommendations of the International
Parkinson’s Disease and Movement Disorder Society,
confirmed monogenic forms are classified according to
absence or presence of accompanying clinical features and
preceded by a “DYT” prefix, e.g., DYT-TOR1A
 these genetic forms are all inherited in an autosomal
dominant fashion and found in <5% of dystonia patients
 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)
 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 progress to other body
parts, but typically spare the face and neck
 mutations in the THAP1 gene (THAP domain containing,
apoptosis associated protein 1)
 have been linked to adolescent-onset dystonia with mixed
phenotype
 about 100 different mutations have been reported in
THAP1
 typically manifest with dysphonia or writer’s cramp
beginning in late childhood or adolescence
 over the course of the disease, dystonia spreads to other
body parts with prominent craniocervical involvement
 mutations in the ANO3 gene (anoctamin 3)
 first reported in patients with predominantly craniocervical
dystonia with a broad range of ages of onset
Page | 3
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2

 while many missense variants can be found in healthy  biallelic mutations in the PRKRA (protein activator of
individuals, a pathogenic role of ANO3 mutations has interferon-induced protein kinase EIF2AK2) gene
recently been supported by the description of additional  linked to a dystonia-parkinsonism syndrome and mostly
families with dystonia and myoclonic jerks due to the same missense mutation that seems to result
 mutations in the GNAL gene (guanine nucleotide-binding from a shared founder
protein subunit alpha L)  includes early-onset generalized dystonia, often with
 rare cause of cervical or cranial dystonia with a mean age laryngeal dystonia, tongue protrusion, prominent
of onset in the thirties oromandibular involvement, dysphagia, and retrocollis
 about 30 different GNAL mutations have been reported in  Parkinsonian features are mild (or even absent) and do not
dystonia patients respond to levodopa therapy
 missense mutations in KMT2B (lysine methyltransferase 2B)  mutations in the ATP1A3 (ATPase Na+/K+ transporting
 recently identified and confirmed to be a cause of an early- subunit alpha 3) gene
onset generalized dystonia which may be accompanied by  present with a characteristic, sudden onset usually in
other syndromic features including intellectual disability, adolescence or young adulthood, often triggered by high
microcephaly, psychiatric features, dysmorphia, or skin fever, physical exertion, or emotional stress
lesions  dystonic symptoms frequently show a rostrocaudal
 majority of the mutations occurred de novo gradient with a strong involvement of the bulbar region
 KMT2B mutations may account for up to 10% of early- and are often accompanied by bradykinesia as a
onset generalized dystonia parkinsonian feature
 have also been linked to a variety of clinical syndromes
Combined Dystonia (pleiotropy) including epileptic or hemiplegic attacks,
 several other well-established genes have been described for ataxia, cognitive decline, and other neurological disorders,
combined forms of dystonia in which dystonia occurs in often with a more severe course and an earlier age at
conjunction with a different movement disorder, such as onset
parkinsonism or myoclonus  myoclonic-dystonia
 dopa-responsive dystonia (DRD) or Segawa syndrome  characterized by action-induced, alcohol-responsive
 caused by mutations in the GCH1 gene (GTP myoclonic jerks predominantly involving the upper body
cyclohydrolase-1) that encodes for the rate-limiting half
enzyme in the biosynthesis of dopamine via the biopterin  onset is usually in childhood or adolescence
pathway  many individuals develop psychiatric features such as
 manifests as a childhood-onset form of dystonia with depression, anxiety-related disorders, and alcohol
diurnal fluctuations and is important to recognize as the dependence
condition dramatically responds to low doses of levodopa  primarily related to mutations in the SGCE gene
 parkinsonism can be a major, or even the only finding, and (sarcoglycan epsilon) which codes for the ε member of the
there may be a presynaptic dopaminergic deficit as sarcoglycan family
evidenced by SPECT  about 80 different mutations have been reported in SGCE
 to date, more than 100 different mutations have been including deletions of the entire gene
reported with a penetrance of around 50% which is - the latter type of mutation often also involves loss of
considerably higher in women compared to men adjacent genes leading to additional clinical features
 recessively inherited (biallelic) mutations in GCH1 result in such as joint problems
a much more severe clinical phenotype with  SGCE mutations are incompletely penetrant and only
developmental delay and infantile onset. manifest when inherited from the father due to the
 due to the enzymatic defect in the levodopa biosynthesis, epigenetic effect of maternal imprinting of SGCE
there is a lifelong and dramatic response to levodopa  several additional monogenic causes have been suggested for
therapy isolated and combined forms of dystonia but still await
 indeed, all young onset forms of dystonia should be tested independent confirmation
with levodopa to exclude the possibility of DRD
 X-linked dystonia-parkinsonism (Lubag) COMPLEX DYSTONIAS
 combined form of dystonia and parkinsonism that is found  complex dystonias: dystonia is one part of a syndrome with
exclusively in patients of Filipino origin due to a founder multiple different disease manifestations
effect and seems to be fully penetrant  etiology
 patients usually develop focal (cranial) dystonia first that  hereditary (most frequent cause)
rapidly generalizes and, after 5–10 years, is gradually - Wilson’s disease (WD)
replaced by a form of L-dopa-unresponsive parkinsonism - Huntington’s disease (HD)
 exact mutation is not yet known but several variants in a - Lesh Nyhan syndrome
disease haplotype segregate with the disease and a - corticobasal ganglionic disorders
retrotransposon insertion in the TAF1 (TATA-Box Binding - other neurologic, neurometabolic, and mitochondrial
Protein Associated Factor 1) gene has been suggested as disorders
the most likely disease cause

Page | 4
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2
 drugs or toxins (previously referred to as secondary
dystonias)
- may be acute or chronic
- most seen with neuroleptic drugs or after chronic
levodopa treatment in PD patients
 discrete lesions in the striatum, and occasionally in the
pallidum, thalamus, cortex, and brainstem
- due to infarction, hemorrhage anoxia, trauma, tumor,
infection, or toxins such as manganese or carbon
monoxide
- dystonia often assumes a segmental distribution, but
may be generalized when lesions are bilateral or
widespread
 peripheral nerve injury: features of complex regional pain
syndrome
 psychogenic: typically present with fixed, immobile
dystonic postures
PATHOPHYSIOLOGY OF DYSTONIA
 pathophysiologic basis of dystonia is not completely known
 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)
 there is derangement of the basic physiological 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.
 dopamine system has also been implicated; dopaminergic
therapies can both induce and treat some forms of dystonia in
different circumstances
 no specific pathology has been consistently identified
TREATMENT: DYSTONIA
 symptomatic except in rare cases where correction of a
primary underlying condition is possible
 Wilson’s disease should be ruled out in young patients with
dystonia
 levodopa: should be tried in all cases of childhood-onset
dystonia to test for DRD
 high-dose anticholinergics (e.g., trihexyphenidyl 20–120 mg/d):
 may be beneficial in children
 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
 benefits are usually modest
 side effects: sedation, weakness, and memory loss
 intrathecal infusion of baclofen:
 more likely to be useful, particularly for leg and trunk
dystonia
 benefits are frequently not sustained
 complications: infection, seizures, and coma
 tetrabenazine (usual starting dose is 12.5 mg/d and the
average treating dose is 25–75 mg/d): use may be limited by
sedation and the development of parkinsonism
 neuroleptics:
 can improve as well as induce dystonia
 not recommended because of their potential to induce
parkinsonism and other movement disorders, including
tardive dystonia
 clonazepam and diazepam: rarely effective
 botulinum toxin:
 preferred treatment for patients with focal dystonia,
particularly where involvement is limited to small muscle
groups such as in blepharospasm, torticollis, and
spasmodic dysphonia
 acts by blocking the release of acetylcholine at the
neuromuscular junction, leading to reduced dystonic
muscle contractions
 treatment can be complicated by excessive weakness that
can be troublesome, particularly if it involves neck and
swallowing muscles
 two serotypes of botulinum toxin are currently available (A
and B); both are effective, and it is not clear that there are
advantages of one over the other
 no systemic side effects are encountered with the doses
typically used
 benefits are transient, and repeat injections are required at
2–5 month intervals
- some patients fail to respond after having experienced
an initial benefit which has been attributed to antibody
formation; improper muscle selection, injection
technique, and inadequate dose should be excluded
 surgical therapy:
 alternative for patients with severe dystonia who are not
responsive to other treatments
 peripheral procedures (rhizotomy and myotomy): 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
- 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 and often occur after a relatively longer
latency (weeks to months) than in PD
- better results are typically obtained in younger
patients with shorter disease duration
- recent studies suggest that DBS may also be valuable
for patients with focal and secondary dystonias,
although results are less consistent
 supportive treatments (physical therapy and education) should
be a part of the treatment regimen
 dystonic storm
Page | 5
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2

 rare but potentially fatal condition that can occur in  in younger patients (~10% of cases), it can present as an
response to a stress situation such as surgery or a systemic akinetic-rigid or parkinsonian syndrome (Westphal variant)
infection in patients with pre-existing dystonia  patients eventually develop behavioral and cognitive
 consists of the acute onset of generalized and persistent disturbances, and the majority progress to dementia
dystonic contractions that can involve the vocal cords or  depression with suicidal tendencies, aggressive behavior,
laryngeal muscles, leading to airway obstruction and psychosis can be prominent features
 patients may experience rhabdomyolysis with renal failure  patients may also develop noninsulin-dependent diabetes
and should be managed in an ICU with airway protection if mellitus and neuroendocrine abnormalities (e.g.,
required hypothalamic dysfunction)
 treatment can be instituted with one or a combination of  diagnosis
anticholinergics, diphenhydramine, baclofen,  clinical diagnosis can be strongly suspected in cases of
benzodiazepines, and dopaminergic agents chorea with a positive family history, but genetic testing
 spasms may be difficult to control, and anesthesia with provides the ultimate confirmation of the diagnosis
muscle paralysis may be required  disease predominantly affects the striatum but progresses
to involve the cerebral cortex and other brain regions
CHOREAS  MRI:
- visualizes the progressive atrophy of the head of the
caudate nucleus (Fig. 428-1) but the putamen can be
HUNTINGTON’S DISEASE
equally or even more severely affected
 HD is a progressive, fatal, highly penetrant autosomal
- more diffuse cortical atrophy can be seen in the
dominant disorder characterized by motor, behavioral,
middle and late stages of the disease
oculomotor, and cognitive dysfunction
 MR spectroscopy:
 disease is named for George Huntington, a family physician
- supportive
who described cases on Long Island, New York, in the
- reduced metabolic activity in the caudate nucleus and
nineteenth century
putamen
 epidemiology
- reduced brain metabolites
 onset is typically between the ages of 25 and 45 years
 genetic testing:
(range, 3–70 years)
- can be used to confirm the diagnosis and to detect at-
 prevalence of 2–8 cases per 100,000
risk individuals in the family
 average age at death of 60 years
- must be performed with caution and in conjunction
 prevalent in Europe, North America, South America, and
with trained counselors, because positive results can
Australia but is rare in African blacks and Asians
worsen depression and generate suicidal reactions
 manifestations
 neuropathology
 characterized by rapid, nonpatterned, semi-purposeful,
 prominent neuronal loss and gliosis in the caudate nucleus
involuntary choreiform movements (formerly referred to as
and putamen; similar changes are also widespread in the
Huntington’s chorea)
cerebral cortex
 dysarthria, gait disturbance, oculomotor abnormalities,
 intraneuronal inclusions containing aggregates of ubiquitin
behavioral disturbance, and cognitive impairment with
and the mutant protein huntingtin are found in the nuclei
dementia are also common features
of affected neurons
 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,
Etiology
bradykinesia, and myoclonus
 functional decline is often predicted by progressive weight
loss despite adequate calorie intake

Page | 6
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2

 caused by an increase in the number of polyglutamine (CAG)  antidepressant and antianxiety drugs:
repeats (>40) in the coding sequence of the huntingtin gene  for depression and anxiety
located on the short arm of chromosome 4  patients should also be monitored for mania and suicidal
 the larger the number of repeats, the earlier the disease ideations
manifests  atypical antipsychotics:
 intermediate forms of the disease with 36–39 repeats are  clozapine (50–600 mg/d), quetiapine (50–600 mg/d) and
described in some patients, typically with less severe risperidone (2–8 mg/d)
clinical involvement  for psychosis
 acceleration of the process tends to occur, particularly in  no adequate treatment for cognitive and motor decline
males, with subsequent generations having larger numbers  neuroprotective therapy that slows or stops disease
of repeats and earlier age of disease onset, a phenomenon progression is the major unmet medical need
referred to as anticipation  drugs that enhance mitochondrial function and increase
 the gene encodes the highly conserved cytoplasmic protein the clearance of defective mitochondria are being tested
huntingtin, which is widely distributed in neurons throughout as possible disease-modifying therapies
the central nervous system (CNS), but whose function is largely  other investigative approaches:
unknown  antiglutamate agents
 mitochondrial dysfunction has been demonstrated in the  dopamine stabilizers
striatum and skeletal muscle of symptomatic and pre-  caspase inhibitors
symptomatic individuals  neurotrophic factors
 fragments of the mutant huntingtin protein can be toxic,  anti-inflammatory agents
possibly by translocating into the nucleus and interfering with  transplantation of fetal striatal cells or stem cells
transcriptional regulation of proteins  DBS of the globus pallidus pars interna (GPi)
 neuronal inclusions found in affected regions in HD may  the potential to block/edit the mutant huntingtin gene with
represent a protective mechanism aimed at segregating and small interfering RNAs (siRNAs) or CRISPR/ cas9 technology is
facilitating the clearance of these toxic proteins an exciting area of research that is currently being investigated
 protein accumulation and aggregation may be critical to the as a possible future therapy
disease process and reflect a prion-like disorder
 models of HD with striatal pathology can be induced in HUNTINGTONT’S DISEASE-LIKE (HDL) DISORDERS
transgenic animals that express the mutant gene and by  group of rare inherited conditions that can mimic HD
excitotoxic agents such as kainic acid and 3-nitropropionic acid  HDL-1, 2, and 4 are autosomal dominant conditions that
which promote calcium entry into the cell and cytotoxicity typically present in adulthood
 HDL-1
Treatment  due to expansion of an octapeptide repeat in PRNP, the
 there is still no disease-modifying therapy for this disorder and gene encoding the prion protein
symptomatic treatment is limited  properly considered a prion disease
 current treatment involves a multidisciplinary approach, with  patients exhibit onset of personality change in the third or
medical, neuropsychiatric, social, and genetic counselling for fourth decade, followed by chorea, rigidity, myoclonus,
patients and their families ataxia, and epilepsy
 dopamine-blocking agents may control the choreatic  HDL-2
movements  manifests in the third or fourth decade with a variety of
 tetrabenazine (a presynaptic dopamine depleting agent): movement disorders, including chorea, dystonia, or
approved for the treatment of chorea; can cause secondary parkinsonism and dementia
parkinsonism  most patients are of African descent
TM
 deuterated tetrabenazine (Austedo )  acanthocytosis can sometimes be seen in these patients,
- approved as a treatment for chorea in HD and this condition must be distinguished from
- deuteration interferes with the metabolism of neuroacanthocytosis
tetrabenazine and avoids a high Cmax  caused by an abnormally expanded CTG/CAG trinucleotide
- in clinical trials, it has been shown to have fewer dose- repeat expansion in the junctophilin-3 (JPH3) gene
related side effects than tetrabenazine, and therefore  pathology: intranuclear inclusions immunoreactive for
can be administered in higher doses with potentially ubiquitin and expanded polyglutamine repeats
superior clinical benefits  HDL-4
 neuroleptics:  most common condition in this group
 generally not recommended because of their potential to  caused by expansion of trinucleotide repeats in TBP, the
induce other troubling movement disorders and because gene that encodes the TATA box-binding protein involved
HD chorea tends to be self-limited and is usually not in regulating transcription
disabling  identical to spinocerebellar ataxia (SCA), and most patients
 may be used in patients with severe and disabling chorea present primarily with ataxia rather than chorea
 no medications have been developed that interfere with the
nonchoreic aspects of motor dysfunction in HD

Page | 7
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2

 mutations of the C9Orf72 gene associated with amyotrophic  following open-heart surgery in the pediatric population
lateral sclerosishave also been reported in some individuals  medications (anticonvulsants, cocaine, CNS stimulants,
with an HDL phenotype estrogens, lithium)
 chorea is commonly seen in association with chronic
OTHER CHOREAS levodopa treatment
 chorea can be seen in several additional disorders related to  paraneoplastic syndromes associated with anti- CRMP-5 or
genetic mutations or other disease states anti-Hu antibodies
 it is important to ensure that patients with these types of
choreas do not have HD HEMIBALLISMUS
 mutations in the ADCY5 (adenylate cyclase 5) gene  ballism: violent form of choreiform movement composed of
 an increasingly recognized and probably relatively wild, flinging, large-amplitude movements
common cause of hereditary childhood-onset chorea,  hemiballism: most common; proximal limb muscles on one
often in combination with dystonia and developmental side of the body are affected
delay in some cases  monoballism: only one limb is affected
 characteristic perioral movements are a hallmark of the  paraballism: both upper and lower limbs are affected
disorder  movements may be so severe as to cause exhaustion,
 chorea-acanthocytosis (neuroacanthocytosis) dehydration, local injury, and, in extreme cases, death
 progressive and typically fatal autosomal recessive  hemiballismus is a common feature of the paroxysmal
disorder that is characterized by chorea coupled with red dyskinesias
cell abnormalities on peripheral blood smear  etiology
(acanthocytes)  most common cause is a partial lesion (infarct or
 the chorea can be severe and associated with self- hemorrhage) in the subthalamic nucleus (STN)
mutilating behavior, dystonia, tics, seizures, and a  in 30–40% of cases the lesion is found in the putamen,
polyneuropathy thalamus, or parietal cortex
 mutations in the VPS13A gene encoding chorein  treatment
 phenotypically similar X-linked form of the disorder in older  usually self-limiting and tends to resolve spontaneously
individuals who have reactivity with Kell blood group antigens after weeks or months
(McLeod syndrome)  dopamine-blocking drug: can be very helpful
 benign hereditary chorea of childhood (BHC1) due to  pallidotomy or DBS of the GPi: can be effective in extreme
mutations in the gene for thyroid transcription factor 1 cases; abolish the involuntary movements
 late-onset benign senile chorea (BHC2)
 infections and degenerative disorders TICS
 vascular diseases and hypo- and hyperglycemia  tic: brief, rapid, recurrent, and seemingly purposeless
 Sydenham’s chorea (originally called St. Vitus’s dance) stereotyped motor contraction
 more common in females  motor tics
 typically seen in childhood (5–15 years) - can be simple, with movement only affecting an
 often develops in association with prior exposure to group individual muscle group (e.g., blinking, twitching of the
A streptococcal infection and is thought to be nose, jerking of the neck), or complex, with
autoimmune in nature coordinated involvement of multiple muscle groups
 characterized by the acute onset of choreiform movements (e.g., jumping, sniffing, head banging, and echopraxia
and behavioral disturbances [mimicking movements])
 chorea generally responds to dopamine-blocking agents,  phonic (or vocal) tics
valproic acid, and carbamazepine, but is self-limited, and - can also be simple (e.g., grunting) or complex (e.g.,
treatment is generally restricted to those with severe echolalia [repeating other people’s words], palilalia
chorea [repeating one’s own words], and coprolalia
 chorea may recur in later life, particularly in association [expression of obscene words])
with pregnancy (chorea gravidarum) or treatment with sex  sensory tics
hormones - composed of unpleasant focal sensations in the face,
 N-methyl-D-aspartate (NMDA) receptor antibody–positive head, or neck
encephalitis following herpes simplex virus encephalitis  can be mild and of little clinical consequence or severe and
 systemic lupus erythematosus: disabling to the patient
 most common systemic disorder that is associated with  may present in adulthood and can be seen in association with
chorea a variety of disorders, including PD, HD, trauma, dystonia,
 chorea can last for days to years drugs (e.g., levodopa, neuroleptics), and toxins
 hyperthyroidism
 autoimmune disorders (Sjögren’s syndrome)
 infectious disorders (HIV)
 metabolic alterations TOURETTE’S SYNDROME (TS)
 polycythemia rubra vera

Page | 8
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2
 TS is a neurobehavioral disorder named after the French
neurologist Georges Gilles de la Tourette
 predominantly affects males
 prevalence is estimated to be 0.03–1.6%, but it is likely that
many mild cases do not come to medical attention
 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:
 anxiety
 depression
 attention deficit hyperactivity disorder
 obsessive-compulsive disorder
 patients may experience personality disorders, self-destructive
behaviors, difficulties in school, and impaired interpersonal
relationships
Etiology and Pathophysiology
 etiology
 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
 risk of a family with one affected child having a second is
about 25%
 pathophysiology
 not known
 alterations in dopamine neurotransmission, opioids, and
second-messenger systems have been proposed
 some may be the consequence of an autoimmune
response to β-hemolytic streptococcal infection (pediatric
autoimmune neuropsychiatric disorder associated with
streptococcal infection [PANDAS]); however, this entity
remains controversial
TREATMENT: TICS
 patients with mild disease often only require education and
counselling (for themselves and family members)
 drug treatment is indicated when the tics are disabling and
interfere with quality of life
 therapy is individualized, and there is no singular treatment
regimen that has been properly evaluated in double-blind
trials
 clonidine:
 α-agonist
 start at low doses and gradually increase the dose and
frequency until satisfactory control is achieved
 guanfacine (0.5–2 mg/d):
 α-agonist that is preferred by some because it only
requires once-a-day dosing
 neuroleptics:
 preferred by some physicians prefer to use
 atypical neuroleptics are usually used initially (risperidone,
olanzapine, ziprasidone) because they are thought to be
associated with a reduced risk of tardive dyskinesia
- if not effective, low doses of classical neuroleptics such
as haloperidol, fluphenazine, pimozide, or tiapride can
be tried because the risk of tardive dyskinesia in young
people is relatively low
 tetrabenazine and deuterated tetrabenazine: currently being
evaluated
 botulinum toxin injections: can be effective in controlling focal
tics that involve small muscle groups
 DBS targeting the anterior portion of the internal capsule, the
GPi, or the thalamus: potential value of currently being
explored
 behavioral features, and particularly anxiety and compulsions,
can be a disabling feature and should be treated
MYOCLONUS
 myoclonus: brief, rapid (<100 ms), shock-like, jerky movement
consisting of single or repetitive muscle discharges
 myoclonic jerks can be focal, multifocal, segmental, or
generalized and can occur spontaneously
 action myoclonus: myocolonic jerks in association with
voluntary movement
 reflex myoclonus: myocolonic jerks in response to an external
stimulus
 negative myoclonus: 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
 pathogenesis: 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
 combination of action myoclonus (cortical origin) with ataxia
and generalized epilepsy:
 myoclonic epilepsy or Unverricht-Lundborg disease (EPM-
1)
- most common
- can have a variable but often progressive course
- an autosomal recessive disease caused by mutations in
the CSBT gene
 Lafora body epilepsy or progressive myoclonic epilepsy
(PME-2) caused by mutations in in the EPM2A gene or the
NHLRC1 gene
Page | 9
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2

 ceroid lipofuscinosis
 mitochondrial disorders and neurodegenerative disorders SUBACUTE
affecting the cerebellum (i.e., SCAs): in patients with less  akathisia is the most common reaction in this category which
severe or absent epilepsy consists of motor restlessness with a need to move that is
 essential myoclonus: relatively benign familial condition alleviated by movement
characterized by multifocal, very brief, lightning-like  treatment
movements that are frequently alcohol-sensitive  removing the offending agent
 mutations in the epsilon-sarcoglycan gene: associated with  symptoms may be ameliorated with benzodiazepines,
myoclonus seen in association with dystonia (myoclonic- anticholinergics, beta blockers, or dopamine agonists
dystonia)
TARDIVE SYNDROMES
TREATMENT: MYOCLONUS  develop months to years after initiation of the neuroleptic
 primarily consists of managing the underlying condition or agent
removing an offending agent  tardive dyskinesias (TD)
 pharmacologic therapy  most common
 one or a combination of GABAergic agents such as  typically present with choreiform and/or dystonic
valproic acid (800–3000 mg/d), piracetam (8–20 g/d), movements involving the mouth, lips, and tongue
clonazepam (2–15 mg/d), levetiracetam (1000–3000 mg/d),  in severe cases, the trunk, limbs, and respiratory muscles
or primidone (500–1000 mg/d): may be associated with may also be affected
striking clinical improvement in chronic cases (e.g.,  movements are often mild and more upsetting to the
postanoxic myoclonus, progressive myoclonic epilepsy) in family than to the patient, but they can be severe and
which a cortical origin for the myoclonic discharges has disabling, particularly in the context of an underlying
been identified psychiatric disorder
 serotonin precursor 5-hydroxytryptophan (plus carbidopa):  younger patients have a lower risk
may be useful in some cases of postanoxic myoclonus  risk factors:
- elderly
DRUG-INDUCED MOVEMENT DISORDERS - females
- underlying organic cerebral dysfunction
 group of movement disorders is primarily associated with
- chronic use (US FDA has warned that use of
drugs that block dopamine receptors (neuroleptics) or central
metoclopramide for >12 weeks increases the risk of
dopaminergic transmission
TD)
 associated drugs:
 atypical antipsychotics (e.g., clozapine, risperidone,
 drugs widely used in psychiatry
olanzapine, quetiapine, ziprasidone, and aripiprazole) are
 drugs used in the treatment of nausea or vomiting (e.g.,
associated with a lower risk of causing TD in comparison to
prochlorperazine [Compazine])
traditional antipsychotics
 drugs used in the treatment of gastroesophageal disorders
 because TD can be permanent and resistant to treatment,
(e.g., metoclopramide)
antipsychotics should be used judiciously; atypical
 hyperkinetic movement disorders 2° to neuroleptic drugs can
neuroleptics should be the preferred agent when possible,
be divided into those that present acutely, subacutely, or after
and the need for continued use should be regularly
prolonged exposure (tardive syndromes)
monitored
 prognosis
ACUTE
- TD remit within 3 months of stopping the drug in
 dystonia is the most common acute hyperkinetic drug reaction
approximately one-third of patients
which is typically generalized in children and focal in adults
- most patients gradually improve over the course of
(e.g., blepharospasm, torticollis, or OMD)
several years
 treatment
 treatment
 parenteral administration of anticholinergics (benztropine
- stopping the offending agent
or diphenhydramine), benzodiazepines (lorazepam,
 abnormal movements may develop or worsen
clonazepam, or diazepam), or dopamine agonists
 if the patient is receiving a traditional
 differential diagnosis
antipsychotic, and withdrawal is not possible,
 seizure: abrupt onset of severe spasms may be confused
replacement with an atypical antipsychotic should
with seizure, however, there is no loss of consciousness,
be tried
automatisms, or postictal features typical of epilepsy
 abrupt cessation of a neuroleptic should be
 exposure to CNS stimulants such as methylphenidate,
avoided because acute withdrawal can induce
cocaine, or amphetamines: presents with acute onset of
worsening
chorea, stereotypic behavior, and tics
 TD can persist after withdrawal of antipsychotics
and can be difficult to treat.
- Valbenazine (IngrezzaTM)
 ester of tetrabenazine

Page | 10
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2

 has recently been approved for the treatment - propranolol, diazepam, diphenhydramine,
based on results of efficacy in double blind trials chlorpromazine, or cyproheptadine
 associated with sleepiness and QT prolongation - supportive measures
 acts as a vesicular monoamine transporter type 2  drugs associated with parkinsonism and other hyperkinetic
(VMAT-2) inhibitor and blocks storage of movement disorders:
dopamine DRUG MOVEMENT DISORDER
- deuterated tetrabenazine: use is being studied phenytoin chorea, dystonia, tremor, myoclonus

- benefits in open label studies have been reported with carbamazepine tics, dystonia
tricyclic antidepressants dyskinesias, tremor, myoclonus
valproic acid (750–3000 mg/d), anticholinergics, or
fluoxetine myoclonus, chorea, dystonia
botulinum toxin injections
oral contraceptives dyskinesia
- other approaches that have been tried include
β-adrenergics tremor
baclofen (40–80 mg/d) or clonazepam (1–8 mg/d) buspirone akathisia, dyskinesias, myoclonus
- in some cases, the abnormal movement is refractory to digoxin, cimetidine, diazoxide, dyskinesias
therapy lithium, methadone, and fentanyl
 tardive dystonia
 there is preferential involvement of axial muscles and PAROXYSMAL DYSKINESIAS
characteristic rocking movements of the trunk and pelvis
 paroxysmal dyskinesias: group of rare disorders characterized
 can be more troublesome than tardive dyskinesia and
by episodic, brief involuntary movements that can manifest as
frequently persists despite stopping medication
various types of hyperkinetic movements, including chorea,
 treatment: valproic acid, anticholinergics, and botulinum
dystonia, tremor, myoclonus, and ballism
toxin may occasionally be beneficial, but patients are
 three main types:
frequently refractory to medical therapy
(1) paroxysmal kinesigenic dyskinesia (PKD): involuntary
 tardive akathisia, tardive TS, and tardive tremor
movements are triggered by sudden movement
syndromes
(2) paroxysmal nonkinesigenic dyskinesias (PNKD): attacks are
 rare but may also occur after chronic neuroleptic exposure
not induced by movement,
 neuroleptic malignant syndrome (NMS)
(3) exertion-induced dyskinesia (PED): rare; attacks are induced
 characterized by the acute or subacute onset of muscle
by prolonged exercise
rigidity, elevated temperature, altered mental status,
 PKD
hyperthermia, tachycardia, labile blood pressure, renal
 characterized by brief, self-limited attacks induced by
failure, and markedly elevated creatine kinase levels
movement onset such as running but also occasionally by
 symptoms typically evolve within days or weeks after
unexpected sound or photic stimulation
initiating the drug
 attacks may affect one side of the body, last seconds to
 can also be precipitated by the abrupt withdrawal of
minutes at a time, and recur several times a day
dopaminergic medications in PD patients
 usually manifest as a mixed hyperkinetic movement
 treatment
disorder with dystonic posturing of a limb, ballismus, and
- immediate cessation of the offending antipsychotic
chorea, which may also become generalized
drug
 about 70% report sensory symptoms such as tingling or
- dopaminergic agent (e.g., a dopamine agonist or
numbness of the affected limb preceding the attack by a
levodopa), dantrolene, or a benzodiazepine
few milliseconds
 patch (delivering rotigotine SC) or an infusion
 etiology: most commonly familial with an autosomal
pump (delivering apomorphine SC): may be the
dominant pattern of inheritance and mutations in the
best approach in very severe cases when oral
proline-rich transmembrane protein 2 (PRRT2) gene, but
intake is not possible
may also occur 2° to various brain disorders such as
- may need to be undertaken in an intensive care setting
multiple sclerosis or hyperglycemia
and include supportive measures such as:
 epidemiology: more frequent in males (4:1), and the onset
 control of body temperature (antipyretics and
is typically in the first or second decade of life
cooling blankets)
 prognosis: evolution is relatively benign, and there is a
 hydration
trend toward resolution of the attacks over time
 electrolyte replacement
 treatment
 control of renal function and blood pressure
- low-dose anticonvulsant therapy (carbamazepine,
 drugs that have serotonin-like activity (tryptophan, MDMA or
phenytoin):
“ecstasy,” meperidine) or that block serotonin reuptake can
 advised when the attacks are frequent and
induce a rare, but potentially fatal, serotonin syndrome that is
interfere with daily life activities
characterized by confusion, hyperthermia, tachycardia, and
 effective in about 80% of patients
coma as well as rigidity, ataxia, and tremor
 PNKD
 myoclonus is often a prominent feature, in contrast to
 involve attacks of generalized dyskinesias precipitated by
NMS, which it resembles in other respects
alcohol, caffeine, stress, or fatigue
 treatment

Page | 11
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2

 episodes have a relatively longer duration (minutes to  primary RLS

hours) and are less frequent (one to three per day)  has a strong genetic component
 etiology  several loci have been associated with an autosomal
- inherited as an autosomal dominant condition with dominant pattern of inheritance, although penetrance may
high (~80%) but incomplete penetrance be variable and no specifically causative gene has been
- missense mutation in the myofibrillogenesis regulator identified to date
(PNKD) gene has been identified in several families  mean age of onset in familial forms is 27 years, although
 recognition of the condition and elimination of the pediatric cases are recognized
underlying precipitating factors, where possible, are the  severity of symptoms is variable
first priorities  secondary RLS
 treatment  may be associated with pregnancy or a range of
- may not be required if the condition is mild and self- underlying disorders, including anemia, ferritin deficiency,
limited renal failure, and peripheral neuropathy
- tetrabenazine, neuroleptics, dopamine-blocking  pathogenesis: disordered dopamine function, which may
agents, propranolol, clonazepam, and baclofen may be be peripheral or central, possibly in association with an
helpful abnormality of iron metabolism
- most patients do not benefit from anticonvulsant  diagnosis
drugs, but some may respond to clonazepam or other - made on clinical grounds but can be supported by
benzodiazepines polysomnography and the demonstration of PLMs
 PED - neurologic examination is normal
 etiology: SLC2A1 (solute carrier family 2 member 1) gene, - secondary causes of RLS should be excluded, and
previously linked to GLUT1 (glucose transporter of the ferritin levels, glucose, and renal function should be
blood brain barrier) deficiency syndrome, has been measured
identified to also cause paroxysmal PED  treatment
 attacks are characterized by a combination of chorea,  most RLS sufferers have mild symptoms that do not
athetosis, and dystonia in excessively exercised body require specific treatment
regions with the legs being most frequently affected  general measures to improve sleep hygiene and quality
 a single attack lasts from a few minutes to an hour and should be attempted first
occurs after prolonged physical exercise  low doses of dopamine agonists, e.g., pramipexole (0.25–
 several patients have other disease manifestations such as 0.5 mg), ropinirole (1–2 mg), or patch rotigotine (2–3 mg),
epilepsy, hemolytic anemia, and migraine taken 1–2 h before bedtime: if symptoms remain intrusive;
 treatment: ketogenic diet is an effective therapeutic generally effective
option  levodopa:
- may also be effective
RESTLESS LEGS SYNDROME (RLS) - more likely to be associated with augmentation
(spread and worsening of restlessness and its
 neurologic disorder that affects ~10% of the adult population
appearance earlier in the day) or rebound
(it is rare in Asians)
(reappearance sometimes with worsening of
 can cause significant morbidity in some individuals
symptoms at a time related to the drug’s short half-
 was first described in the seventeenth century by the English
life)
physician Thomas Willis, but has only recently been recognized
 dopamine agonists: augmentation can also be seen
as being a bona fide movement disorder
particularly if higher doses
 four core symptoms required for diagnosis:
 other drugs that can be effective:
 an urge to move the legs usually caused or accompanied
- anticonvulsants
by an unpleasant sensation in the legs
- analgesics
 symptoms that begin or worsen with rest
- opiates
 partial or complete relief by movement
 management of secondary RLS should be directed to
 worsening during the evening or night
correcting the underlying disorder (e.g., iron replacement
 symptoms most commonly begin in the legs, but can spread to
for anemia)
or even begin in the upper limbs
 unpleasant sensation is often described as a creepy-crawly
feeling, paresthesia, or burning OTHER DISORDERS THAT MAY PRESENT WITH A
 in about 80% of patients, RLS is associated with periodic leg COMBINATION OF PARKINSONISM AND HYPERKINETIC
movements (PLMs) during sleep and occasionally while awake MOVEMENTS
 these involuntary movements are usually brief, lasting no
more than a few seconds, and recur every 5–90 s WILSON’S DISEASE
 restlessness and PLMs are a major cause of sleep disturbance  WD: autosomal recessive inherited disorder of copper
in patients, leading to poor-quality sleep and daytime metabolism
sleepiness

Page | 12
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2
 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
 etiology: caused by mutations in the ATP7B gene encoding a
P-type ATPase
 epidemiology
 worldwide prevalence of ~1 in 30,000, with a mutation
carrier frequency of 1 in 90
 manifestations
 manifests with neurologic, psychiatric, and liver disorders,
alone or in combination
 about half of patients (especially younger patients)
manifest with liver abnormalities; 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
- tremor
 usually in the upper limbs, bilateral, and
asymmetric
 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:
- parkinsonism with bradykinesia
- dystonia (particularly facial grimacing)
- dysarthria
- 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
- seen virtually in all patients with neurologic features
and 80% of those with hepatic presentations
- represent the deposition of copper in Descemet’s
membrane around the cornea
- consist of a characteristic grayish rim or circle at the
limbus of the cornea and are best detected by slit
lamp examination
 neuropathology: neurodegeneration and astrogliosis in the
basal ganglia, particularly in the striatum
 diagnosis
 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
- generalized brain atrophy in established cases
- ~50% have signal hypointensity in the caudate head,
putamen, globus pallidus, substantia nigra, and red
nucleus on T2-weighted MRI scans
- correlation of imaging changes with clinical features is
not good
 liver biopsy with demonstration of high copper levels and
genetic testing remain: gold standard for the diagnosis
 treatment
 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
- frequently used to increase copper excretion
- 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; can
be used instead of penicillamine
 trientine and zinc: useful drugs for maintenance therapy
- adherence to maintenance therapy is a major
challenge in long-term care
 liver transplant: for patients with advanced hepatic disease
 research is looking into the potential role of organ-specific
chelators
 prognosis:
 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
 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
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION
(NBIA)
 NBIA: group of inherited disorders characterized by iron
accumulation in the basal ganglia
 manifestations
 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
 presentation is usually in childhood, but adult cases have
been described
 etiology
 multiple genes have been identified to date
 numerous gene mutations have been described associated
with iron accumulation including mutations in PLA2G6,
C19orf12, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17
 antothenate kinase–associated neurodegeneration (PKAN)
 formerly known as Hallervorden-Spatz disease
 caused by a mutation in the PANK2 gene
 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
Page | 13
TREMOR, CHOREA, AND OTHER MOVEMENT DISORDERS
NEURO2

 MRI: characteristic low signal abnormality in the center of
the globus pallidus on T2-weighted scans caused by iron
accumulation known as the “eye of the tiger” sign
 differential diagnosis
 iron accumulation in specific basal ganglia regions is
normal
 excess iron accumulation may occur in the basal ganglia
region as a consequence of neurodegeneration associated
with multiple causes unrelated to a defect in iron
metabolism
PSYCHOGENIC (FUNCTIONAL) DISORDERS
 comorbid psychiatric problems such as anxiety, depression,
and emotional trauma may be present but are not
necessary for the diagnosis of a psychogenic movement
disorder to be made
 treatment
 identify and treat underlying psychiatric problems (many
patients with psychogenic movement disorders have no
obvious psychiatric pathology)
 psychotherapy and hypnosis: may be of value for patients
with conversion reaction
 cognitive behavioral therapy: may be helpful for patients
with somatoform disorders
 prognosis: patients with hypochondriasis, factitious disorders,
and malingering have a poor prognosis

 virtually all movement disorders including tremor, tics,

dystonia, myoclonus, chorea, ballism, and parkinsonism can be
psychogenic in origin
 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)
 can occur as an isolated entity or in association with an
underlying organic problem
 epidemiology:
 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: acute onset with a pattern of abnormal
movement that is inconsistent with a known movement
disorder
 diagnosis:
 diagnosis can often be made based on clinical features
alone, and unnecessary tests or medications can be
avoided
 based on the nonorganic quality of the movement, the
absence of findings of an organic disease process, and
positive features that specifically point to a psychogenic
illness such as variability and distractibility
- for example, the magnitude of a psychogenic 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 an organic tremor where the
magnitude is increased with distraction and tends to
be reduced when observed
 other positive include a tremor frequency that is variable
or that entrains with the frequency of a designated
movement in the contralateral limb, or a response to
placebo interventions
 associated features:
- nonanatomic sensory findings, give-way weakness,
astasia-abasia (an odd, gyrating gait or posture)
- multiple somatic complaints with no underlying
pathology (somatoform disorder)

Page | 14