Essential tremor (ET) is the most common movement disorder. It starts at a mean age of 45 years and affects ∼4% of those aged > 40 years, and the prevalence increases with age. The prevalence of ET varies widely among studies because of different criteria used in making the diagnosis. It affects both males and females. ET is a chronic and slowly progressive disorder with both upper extremities most commonly affected. It is postural and kinetic in nature and can be disabling and affect the quality of life. Family aggregation is noted in more than half of the patients and seems to follow an autosomal dominant pattern of inheritance. Linkage of genes on chromosomes 3q13 (ETM1) and 2p24.1 (ETM2) to ET and their clinical significance need to be further investigated. Environmental factors such as β-carboline alkaloids, which include harmine and harmane, may also play a role in the development of ET.
Essential tremor is diagnosed on the basis of its clinical features compiled through a detailed medical history regarding tremor, family history, social history (alcohol, caffeine, and drug use), and medications (eg, β-agonists, corticosteroids, valproic acid, amphetamines, thyroid hormones, lithium, neuroleptic agents, tricyclic antidepressants), as well as a thorough physical examination. The tremor typically starts from either hands or forearms (∼95%) or less commonly from one hand (usually dominant) in 10–15% of cases with upper extremity involvement as the initial presentation. The tremor can be postural, occurring with outstretched arms, or kinetic, occurring during action such as finger-to-nose movement, pouring and drinking water from a cup, writing, or drawing Archimedean spirals. With more advanced age, the tremor will be slower but have greater amplitude, which can be more disabling. Other parts of the body can be affected in isolation or concomitantly with hand tremor, such as head (34%), legs (30%), voice (12%), chin, tongue, or trunk. The patient may present with head shaking (no-no) or nodding (yes-yes), a shaky or trembling voice, or an unsteady gait (eg, tandem gait disturbance). Ethanol reduces tremor in two-thirds of cases with prompt improvement within 15 minutes. Many tremor scales are available for assessing severity, for example, the tremor rating scale from the Washington Heights–Inwood Genetic Study of Essential Tremor (score 0–5) and the Fahn-Tolosa-Marin tremor rating scale (score 0–40). In Table 44-7, the classic phenomena of essential tremor are described and contrasted with features of tremor resulting from other physiologic and pathologic causes.
Table 44–7.Clinical and differential diagnosis of tremors. ||Download (.pdf) Table 44–7.Clinical and differential diagnosis of tremors.
|Tremor ||Clinical Features ||Diagnostic Tests and Management |
|Essential tremor ||An 8–12-Hz tremor is seen in young adults and a 6–8-Hz tremor in elderly people; there are negative neurologic signs with normal muscle tone and coordination, worsening with stress, fatigue, and voluntary movement; improves with alcohol ingestion ||Only for differential diagnosis or atypical presentations |
|Enhanced physiologic tremor ||High frequency, 10–12 Hz, lower amplitude; involves hands; occurs under various conditions, eg, stress, fatigue, hypoglycemia, thyroid and adrenal gland disorders, alcohol withdrawal, and medication use; no other neurologic signs; responsive to offending medication or toxin reduction or removal, treatment of endocrine disorders, and stress management ||Chemistry profile (glucose, liver function tests); thyroid function tests; review of medications; propranolol prior to stressful events may help |
|Parkinsonism ||Late age onset; asymmetric; slow (4–6 Hz), high amplitude, rest tremor biplanar; pill-rolling; possible action tremor; worse under stress, better with voluntary movement; unaffected by alcohol; onset in hands or legs; additional parkinsonian symptoms ||See text |
|Cerebellar tremor ||Intentional tremor on the ipsilateral side of the body; 3–4 Hz; positive ataxia; dysmetria; nystagmus; other cerebellar signs ||Appropriate imaging and other tests |
|Orthostatic tremor ||Occurs exclusively while standing (13–18 Hz); late onset; rare family history; tremor limited to legs and paraspinal muscles ||Response to gabapentin, pramipexole, and clonazepam |
|Neuropathic tremor ||Associated with peripheral nerve pathology, eg, hereditary neuropathies, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy; not responsive to propranolol or other therapy || |
|Psychogenic tremor ||Variable tremor; intermittent; somatization in past history; tremor changes with voluntary movement of contralateral limb ||Electrophysiologic testing |
|Wilson disease ||Postural or intentional, wing-beating tremor (4–6 Hz); ascites, jaundice, signs of hepatic disease; intracorneal ring-shaped pigmentation; rigidity, muscle spasms; mental symptoms ||Liver function tests; serum ceruloplasmin; urine copper; slit-lamp examination for Kayser-Fleischer rings |
|Task-specific intention tremors ||Involves skilled, highly learned motor acts, eg, writing, sewing, playing musical instrument (5–7 Hz) ||Treatment: botulinum toxin injection; surgery effective; oral medicine less effective |
B. Laboratory and Other Tests
Routine laboratory tests such as thyroid function; liver function; electrolytes, including calcium, magnesium, and phosphorous; and blood glucose level may be ordered. Other lab tests or imaging studies should be ordered according to each clinical scenario. In patients whose tremor started before age 40 years, blood and urine should be checked to rule out Wilson disease. Physiologic studies such as electromyography and accelerometry are available in specialized labs. They are not part of the routine evaluation but can assist with atypical tremor diagnosis and measure tremor severity and its influence on patients by assessing frequency, rhythmicity, and amplitude of the tremor.
Essential tremor is not as benign as once believed. It can cause substantial physical, cognitive, and psychosocial disability. Patients may lose or have to quit their jobs owing to the uncontrollable tremor and memory and other cognitive impairments. Activities of daily living, as simple as drinking and eating, are significantly affected. The impact of ET on the patient’s physical, psychologic, and social health status needs to be assessed from the patient’s point of view. The health-related quality-of-life (QoL) evaluation for ADL abilities is also essential to management.
Nonmotor, cognitive-neuropsychological presentations of ET also contribute to the patient’s health status and may influence functional disability. Depression, anxiety, low vigor, mild executive dysfunction, possible mild cognitive impairment, and personality changes are some of the nonmotor manifestations of ET. Patients with late onset are more likely to have dementia. A disease-specific questionnaire, for example, the Quality of Life (QoL) in Essential Tremor Questionnaire, will assist in a comprehensive evaluation of ET to improve management and QoL.
The goal of ET treatment is to decrease functional disability and improve the patient’s health status and QoL. Treatment may be initiated when symptoms are present. Both pharmacologic and surgical approaches are available. The response to medical treatment varies; some patients may not benefit from any medications or have only a partial response. Propranolol and primidone are recommended as initial therapy in ET, either alone or in combination (Table 44-8). More recent studies do not report sufficient evidence to support or refute the use of antipsychotics (clozapine and olanzapine), pregabalin, or zonisamide in ET. Levetiracetam and 3,4-diaminopyridine are not recommended for limb tremor in ET, based on 2001 evidence-based guideline update from the American Academy of Neurology. In medically refractory cases, deep-brain stimulation (DBS) of the thalamus and unilateral thalamotomy (level C) have shown moderate to marked improvement of tremor in most patients. DBS of the ventral intermediate (VIM) thalamic nucleus (level C) has fewer adverse events than thalamotomy and the flexibility for adjustment but is more expensive.
Table 44–8.Pharmacotherapy for essential tremor. ||Download (.pdf) Table 44–8.Pharmacotherapy for essential tremor.
|Class/Drug ||Usual Daily Dosage ||Clinical Use and Side Effects |
60–800 mg/d (divided TID)
Optimal: 160–320 mg/d
Long-acting: 80–320 mg/d
Well tolerated; titrate every 3–7 d
Fatigue, mild to moderate bradycardia and reduced blood pressure, exertional dyspnea, depression
50–750 mg/d (divided TID)
Maximum 400 mg/d
Tolerance may develop
Sedation, fatigue, unsteadiness, vomiting, acute toxic reaction, ataxia, vertigo
Drowsiness, nausea, dizziness, unsteadiness
Dizziness, ataxia, somnolence, depression, nausea, weight loss, paresthesia
Sedation and cognitive slowing; potential for abuse
Efficacy varies; 26–71% improvement
Withdrawal following abrupt discontinuance
Botulinum toxin injection (Ca)
For hand tremor
For head tremor
For voice tremor
50–100 units per arm
0.6–15 units (uni- or bilateral)
Produces focal weakness; reduces tremor effectively but may not improve function; postinjection pain
Significant clinical improvement but no statistical significance
Physical or occupational therapy with lightweight training of wrists may help improve hand stability and function.
Essential tremor is a slowly progressive disorder with a potential 7% increase in tremor amplitude each year. More than two-thirds of patients report significant changes in their daily living and socializing, and approximately 15% are seriously disabled, more notably men, in a longitudinal, prospective study. Complications secondary to difficulty in ambulating, falls, pneumonia, and other functional disabilities may have contributed to the increased mortality.
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TIC Disorders: Tourette Syndrome
ESSENTIALS OF DIAGNOSIS
Two or more motor tics and one or more vocal tics are present (not necessarily concurrent).
The tics occur many times a day nearly every day over >1 year without a tic-free period of > 3 consecutive months.
Disease onset before age 18 years.
Other causes of tics ruled out (eg, substance uses, stimulants, Huntington disease, CNS infection, stroke).
Tourette syndrome (TS) is a serious, chronic neuropsychiatric disorder. It affects 4–6 per 1000 children. The mean age of onset is ∼5 years with males 4–5 times more than females. Both genetic (likely complex inheritance) and environmental factors (eg, stress, postinfection autoimmune disease, intrauterine exposure, fetal or neonatal hypoxia) play a role in the development of TS.
Tics are sudden, brief (0.5–1-second), uncontrollable, repetitive, nonrhythmic, stereotyped, and purposeless movements (motor tics) or vocalizations (vocal tics). Tics can be either simple, such as blinking, grimacing, head jerking, shoulder shrugging, and throat clearing, or other meaningless utterances/noises, or more coordinated and purposeful complex features, such as jumping, kicking, abdomen thrusting, stuttering, echolalia (involuntary repetition of other people’s words), echopraxia (imitating others’ gestures), and coprolalia (speaking obscenities). Ninety percent of patients with TS have premonitory sensations, or unpleasant somatosensory urges (burning, tingling, itching, or pain) preceding tics. They are relieved by the execution of tics. Tics typically start early, at 3–5 years of age, and peak around 9–12 years; the severity improves at the end of adolescence. Simple and transient tics are common in children, with 6–20% affected.
Tics are the only positive findings on neurologic examination in TS. They usually start in the upper body, especially the eyes or other parts of the face, in the form of simple motor or vocal tics. As TS gradually progresses, the tics can involve other parts of the body such as the extremities and torso, where they will become complex in nature and vary in type and combination, severity, and location. The phenotype of TS involves not only tics but also behavioral components and commonly associated comorbidities (Table 44-9). Frustrated or embarrassed by the involuntary and sometimes disabling tics, together with the misconception of family and others that tics can be controlled, patients may develop anxiety, depression, or even social withdrawal, which impairs academic and social performance. Comorbid conditions include obsessions such as repeatedly counting, hand washing, or touching, and the need to scratch out a word. A comprehensive physiopsychosocial evaluation (eg, Yale Global Tic Severity Scale, Global Assessment of Functioning, Health-Related Quality of Life Scale, Child Behaviour Checklist, or Youth Self-Report) is necessary for children with tics. Comorbid ADHD may impact cognitive performance. A neuropsychological assessment may be considered. Coping strategies for the patient, family, and teachers need to be explored.
Table 44–9.Tourette syndrome phenotype and comorbidities. ||Download (.pdf) Table 44–9.Tourette syndrome phenotype and comorbidities.
|Tic Component ||Simple or Complex Features |
|Socially inappropriate behaviors || |
Coprophenomena (coprolalia, mental coprolalia, copropraxia)
Echophenomena (echolalia, echopraxia)
Paliphenomena (palilalia, palipraxia) spitting, hitting and kicking, self-injury
|Compulsive behaviors ||Forced touching, repetitive looking at objects, other ritualized behaviors |
|Comorbidities || |
Learning disability (20%a)
Problems with executive planning, organization, and social problem solving
B. Laboratory and Other Test Findings
Tourette syndrome is a clinical diagnosis based on a thorough personal and family history, physical examination, and close observation of the disease process. Laboratory tests, EEG, and brain imaging studies (CT, MRI, or PET) may be considered to rule out infections or other neurologic conditions that can either cause tics or mimic tics.
Other medical conditions that may cause tics or be misdiagnosed as tics need to be ruled out before starting treatment. Tics may be mistaken for other hyperkinetic movement disorders such as chorea, myoclonus, dystonia, tardive dyskinesia, seizure, periodic limb movements of sleep, and restless leg syndrome. Tics can also be caused by other medical conditions such as stroke, infections, dystonia, essential tremor, and dementia.
The goal of TS treatment is to control disabling symptoms and comorbidities; improve academic, occupational, or social performance and quality of life; and support patient and family. It is important to prioritize treatment to the most bothersome symptoms and to achieve symptom control to the level at which the patient can function. Patients and families need to realize that complete resolution of symptoms is difficult to achieve. TS with mild symptoms that do not interfere with the patient’s daily functioning can be followed clinically without medical treatment.
α2-Agonists are the current first-line treatment (see Table 44-10 for these and other treatment recommendations). They may help reduce tics by ∼30% and can improve comorbid ADHD symptoms. They are preferred to antipsychotics because they do not cause tardive dyskinesia or weight gain. Neuroleptics (haloperidol, pimozide, fluphenazine, and risperione) are the most effective in treating TS, but are usually reserved as second-line medications for moderate to severe TS because of their side effects, including weight gain and diabetes. They can reduce the severity of tics by 25–50%. Acute dystonic reactions may occur with initiation of these agents. Anticholinergics can be added to decrease their risk. Tardive dyskinesia may develop during neuroleptic treatment and is not always reversible after treatment is discontinued. Pergolide, tetrabenazine, and topiramate are also effective in decreasing tics. Stimulants or SSRIs may be started for attention deficit hyperactivity behaviour (ADHD), obsessive compulsive disorder (OCD), and other comorbidities.
Table 44–10.Pharmacotherapy for Tourette syndrome. ||Download (.pdf) Table 44–10.Pharmacotherapy for Tourette syndrome.
|Class/Drug ||Usual Daily Dosage ||Clinical Use and Adverse Effects |
|α-Agonists || ||First-line agents |
|Clonidine (oral, transdermal) (Aa) || |
0.05 mg at bedtime, increased by 0.05 mg every few days to a maximum of 0.2 mg TID
Most patients respond to 1 tablet (0.1 mg) TID
Initial treatment of TS
Sedation, orthostatic hypotension and constipation
Withdrawal: taper over 7–10 d
|Guanfacine ||0.5 mg at bedtime; maximum 1 mg TID ||Fewer side effects; well tolerated |
|Antipsychotics (dopamine receptor blockers) || || |
Second-line agents; may be added to α-agonist or monotherapy
First-line agents: for patients with severe tics
Acute dystonic reaction
|Risperidone(Aa) ||0.25 mg at bedtime; maximum 2 mg BID || |
Sedation and weight gain
Less risk of tardive dyskinesia
|Olanzapine(Ba) ||1.25 mg at bedtime; maximum 5 mg BID ||Similar to risperidone |
|Haloperidol(Aa) ||0.25–2 mg/d || |
Used when atypical antipsychotics listed above are ineffective
|Pimozide(Aa) ||0.5 mg at bedtime; maximum 3 mg BID ||Prolonged QTc interval, ventricular arrhythmia |
|Fluphenazine ||0.5 mg at bedtime; maximum 3 mg TID ||Safer than haloperidol; more controlled studies needed |
5 mg daily; maximum 20 mg TID
25 mg at bedtime; maximum 200 mg daily
0.25 mg at bedtime; maximum 1 mg TID
|Alternative to antipsychotics; safe and effective; weight loss |
B. Behavioral Therapy and Counseling
Habit reversal therapy through awareness training and competing response practice is as effective as antipsychotics and supportive therapy. Assertiveness training, cognitive therapy, relaxation therapy, and habit reversal therapy are widely used to improve patients’ social functioning and the undesirable behaviors associated with tics. Education should be provided to the family and at school to create a supportive and understanding environment and decrease misconceptions and intolerance.
Botulinum toxin injection and deep-brain stimulation are available for medically refractory tics.
Tics typically wax and wane, with the most severe tics occurring between 8 and 12 years of age. Many patients will experience significant improvement by the end of adolescence. However, if tics persist into adulthood (20%), TS can cause severe behavioral and social dysfunction.
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Restless LegS Syndrome (RLS)
Restless leg syndrome (RLS) is a chronic neurologic movement disorder with a prevalence of 5–10% in the adult population; it affects approximately 2% of children aged 8–17 years. It affects 12 million people in the United States, with a 2:1 female predominance, and it is also more severe in females. Primary RLS is idiopathic and occurs sporadically, but it demonstrates a strong genetic component with familial inheritance (60%). Pathogenesis of RLS is related to low brain iron and may involve the subcortical dopaminergic system. Several genes for RLS have been identified. Secondary RLS can be associated with other medical conditions such as anemia, thyroid problems, diabetes, kidney failure, peripheral neuropathy, ADHD, fibromyalgia, rheumatoid arthritis, Sjögren’s syndrome, cyanocobalamin deficiency, folic acid deficiency, and pregnancy. Medications that can aggravate RLS symptoms include antinausea drugs (prochlorperazine, metoclopramide), anticonvulsants (phenytoin, droperidol), antipsychotic drugs (haloperidol), tricyclic and SSRI antidepressants, and over-the-counter (OTC) cold and allergy medications.
Diagnosis of RLS is based on a detailed history, including symptoms, medications, family history, and a thorough neurologic evaluation. Its typical presentation includes unpleasant sensations due to paresthesias and dysesthesias (burning, itching, tingling, cramping, or aching) deep in the legs (calves), which subside only with voluntary movement of the legs. The sensation may present on only one side of the body and may move to another part of the body. The motor restlessness occurs with the urge to relieve the sensation, and the patient may move voluntarily with repetitive stereotypical movements such as pacing, rocking, and stretching. Patients with RLS usually have sleep disturbances, such as difficulty falling asleep or maintaining sleep, leg movement during sleep, and daytime fatigue. PLMS and PLMW are stereotyped, repetitive movements with dorsiflexion of the ankles or big toes. Abnormal physical findings and positive test results may be due to associated conditions in secondary RLS. Smoking, alcohol consumption, poor sleep hygiene, and fatigue may aggravate symptoms of RLS.
B. Laboratory and Other Test Findings
A complete blood count, ferritin iron level, electrolytes, glucose level, thyroid hormone, and kidney function should be ordered. PLMS can be assessed and monitored by the International Restless Leg Syndrome scale (IRLS). Polysomnography is not routinely ordered. It may be considered when the presentation is not diagnostic for RLS, there is suboptimal response to treatment, or other nocturnal conditions such as sleep apnea are suspected.
Among the many medical conditions that need to be differentiated from RLS, polyneuropathy is the most commonly encountered. The sensory symptoms of polyneuropathy do not improve with movement, and there will be positive findings from the neurologic examination, nerve biopsy, and neurophysiologic examination. The differential diagnosis includes nocturnal leg cramps, obstructive sleep apnea syndrome, intermittent claudication, pathophysiologic insomnia, Tourette syndrome, and orthostatic tremor.
The goal of RLS treatment is to minimize the unpleasant sensations and motor restlessness, reduce sleep disturbance, and improve quality of life.
Identify any conditions that may cause or aggravate RLS, such as offensive medications, smoking, and excessive alcohol consumption. Give iron supplementation when ferritin is low and vitamin supplementation. Monitor kidney function. A healthy lifestyle will help alleviate RLS with moderate daily exercise, leg movement and massage, and hot baths. Cognitive behavioral and exercise therapy are under investigation.
Medications should be started when patients are experiencing daily symptoms that are affecting their quality of life. The nonergot dopamine agonists (DAs) ropinirole and pramipexole are the medications of choice for primary RLS (high evidence). DAs are 70–90% effective in relieving symptoms. They can be administered 1–3 hours before the onset of symptoms, and their effect is immediate. Adverse effects include nausea, peripheral edema, daytime somnolence, and impulsivity. Levodopa (high evidence) is fast-acting and can be taken 1–2 hours before symptoms start. However, augmentation, worsening of RLS symptoms from ongoing treatment, may develop with long-term use or high doses (>200 mg) of dopaminergic medications, especially carbidopa/levodopa. It is recommended for treatment of intermittent RLS. Levodopa is less favored as an initial medication than DAs because of its motor side effect as well as the augmentation.
There is ample evidence that gabapentin enacarbil, the prodrug of gabapentin, is effective in RLS treatment. There is insufficient evidence to support the use of gabapentin, pregabalin, opioids, carbamazepine, and clonidine. Oral iron treatment may reduce RLS symptoms in patients with iron deficiency or refractory RLS (minimal evidence). Benzodiazepines are effective in improving sleep quality but not periodic leg movement (PLM).
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Chorea is an irregular, rapid, involuntary jerky movement that flows randomly to any part of the body. Multiple etiologies, such as Huntington disease (see next section), vascular disorders, electrolyte imbalance, medications (antiparkinsonian, anticonvulsants, cocaine, neuroleptics), infection (HIV, encephalitis), and autoimmune disorders (SLE, Sydenham chorea), have been identified as causing chorea by affecting the basal ganglia. Chorea usually affects the hands, feet, face (eg, nose wrinkling), and trunk. Laboratory tests may be ordered to differentiate the causes, such as throat culture and streptococcal blood antigen for Sydenham chorea, liver function tests, complement levels, ANA, antiphospholipid antibody titers, TSH, and electrolytes. Brain CT, MRI, and PET scan may also aid in diagnosis.
Huntington’s disease (HD) is an adult-onset (ages 35–50 years), autosomal-dominant progressive neurodegenerative disorder caused by a mutation with CAG repeats in the IT15 gene on chromosome 4. It affects approximately 1 in 10,000 people. Dopamine and glutamate neurotransmitters are thought to be affected. It is characterized by chorea, cognitive decline, and psychiatric impairment. Its clinical features include chorea, gait disturbance, dysarthria and dysphagia, eye movement disorders, and associated cognitive and behavioral disorders (dementia, depression, OCD, suicidal ideation). The Unified Huntington Disease Rating scale (UHDRS) measures the motor, cognitive, behavioral and functional impairment in HD and have been used to evaluate clinical progression in research. Its application in clinical settings needs further investigation. Imaging studies may show abnormalities such as putamen atrophy on MRI, enlarged ventricles on CT, and decreased glucose and oxygen metabolism in caudate nuclei on PET. Genetic confirmatory testing may be offered to patients with clear symptoms of HD and a family history of HD. Testing for fatal HD in individuals without symptoms but with a documented family history can cause enormous stress and emotional concerns. Genetic counseling before and after the test regarding implications of possible results and potential family, social, and ethical issues is important for informed decision making and patient and family support. Individuals who have a positive test result will experience a gradually increasing sense of hopelessness as the onset of the disease approaches. Some will suffer severe depression with suicidal ideation. They will demonstrate increased avoidance behaviors, and close monitoring is warranted.
Treatment is mainly symptomatic to control chorea, behavioral comorbidities (by means of antidepressants), and potential complications (rhabdomyolysis, local trauma from falls, and aspiration pneumonia). Tetrabenazine, a monoamine-depleting agent, is the only FDA-approved drug for HD. It is likely effective in chorea control. Its serious side effects include depression, parkinsonism, prolonged QT interval, and neuroleptic malignant syndrome. Amantadine and nabilone (a synthetic cannabinoid) may be effective in decreasing HD chorea. Riluzole, with antiglutamatergic and antiexcitotoxic effects, is moderately effective at a higher dose, 200 mg/d. Liver function and suicidal thoughts need to be monitored. There is no sufficient date to support the use of clozapine, coenzyme Q10, donepezil, or creatine. Supportive management and a multidisciplinary approach, including speech and physical and occupational therapy, are important in maintaining patients’ quality of life. Patients can be referred to several national support groups and organizations, including the Huntington Disease Society of America (http://www.hdsa.org) and the Hereditary Disease Foundation (http://www.hdfoundation.org/home.php).
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