Chapter 44: Movement Disorders

Movement disorders (MDs) are a broad spectrum of motor and nonmotor disturbances arising from the dysfunction of subcortical motor control circuitry, including basal ganglia and thalamus, as well as other parts of the nervous system, involving the cortex, cerebellum, central, and peripheral autonomic nervous system. Patients suffering from MDs have normal muscle strength and sensation, but their normal voluntary motor activities are influenced or impaired by involuntary movement, alteration in muscle tone or posture, and loss of coordination or regulation—either facilitation or inhibition—of pyramidal motor activities as a result of malfunction. MDs can be classified into the following categories on the basis of their clinical manifestations: tremor, chorea and choreoathetosis, dystonia, myoclonus, tics, and ataxia. MDs include less movement (hypokinesia or akinesia), or excessive movement (hyperkinesias), or both (Table 44-1).

General Considerations

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer’s disease but remains the only neurodegenerative disease for which symptoms can be effectively controlled medically. It affects 1% of the global population aged 65 years and may double in 2030 with aging of the population. Numerous hypotheses have been explored to explain the process of the neurodegeneration, such as the effects of environment, genetics, or inflammatory processes, or defects in mitochondrial function, or oxidative stress, but without a definitive conclusion. Aging is the greatest risk factor associated with PD. Approximately 95% of PD cases are idiopathic/sporadic and occur in people aged >50 years. The incidence of PD is 1.5–2 times higher in males. Other risk factors include head trauma and exposure to pesticides or herbicides in association with rural living or exposure to well water. Five genes, including the best studied leucine-rich repeat kinase 2 (LRRK2, autosomal-dominant) and parkin (autosomal-recessive), may be the cause of 2–3% of PD. New genetic foci have been identified or investigated. An individual may have a doubled risk if there is a family history in a first-degree relative.

Pathogenesis

More recent studies of functional brain imaging in PD and other MDs have identified, circuit disorders in PD, including increased metabolic activity in the putamen/globus pallidus, thalamus, pons, cerebellum, and sensorimotor cortex, with relatively reduced premotor and parietal association cortex activity. PD results from the loss of dopaminergic projection neurons and axons in the substantia nigra (SN) and striatum. It is a progressive and degenerative process. Patients will become symptomatic when ∼30% of DAergic SN neurons or 50–60% of their axon terminals are impaired or dead and there is a 20–50% dopamine decrease in the striatum. One side of the SN is usually more severely affected than the other, which results in more prominent symptoms on one side of the body. The treatment of PD aims at supplementation of levodopa (l-dopa), or decreased metabolism/degradation of dopamine. Neuroprotection of the dopaminergic neurons in SN is still under investigation.

Lewy bodies, typical α-synuclein (αSyn) immunoreactive intracytoplasmic eosinophilic inclusions in neurons, are a neuropathologic hallmark of PD. PD may also involve other CNS, peripheral, and enteric nervous systems, with Lewy bodies located in the olfactory nucleus, amygdala, brainstem, neocortex, vagal nerve nucleus, and the sympathetic nervous system. αSyn is also found in the intramural enteric nervous system, skin, retina, submandibular gland, cardiac nervous system, and other visceral organ nervous systems. Lewy bodies are also associated with Alzheimer’s disease, Down syndrome, and other neurologic diseases.

Clinical Findings

A. Symptoms and Signs

The diagnosis of PD is based on its characteristic cardinal motor manifestations, not by infections or primary visual, vestibular, cerebellar, proprioceptive, or other neurodegenerative disorders. The patients’ excellent and sustained response to dopaminergic treatment supports the diagnosis. The most common initial finding is an asymmetric resting tremor in an upper extremity. The cardinal signs may eventually become bilateral after several years but will remain more prominent on one side of the body. Early referral to PD specialists is crucial when a patient has atypical or secondary parkinsonism.

1. Cardinal motor signs

Resting tremors are the presenting symptoms in 50–70% of patients, with hands, fingers, forearms, and feet most frequently affected. The tremors are a characteristic oscillating or pill-rolling movement of one hand at a regular rhythm (4–6 Hz). They diminish during sleep and voluntary movement. Other parts of the body such as the jaw or face may also be affected. Bradykinesia refers to slow movement, the initiation of movement, or the sudden stopping of movement. Patients may make short, shuffling steps with a decreased arm swing or manifest an expressionless masklike face, freezing gait, or difficulty turning in bed. They cannot perform rapid repetitive movements, such as tapping the fingers or heels repeatedly. Rigidity or increased muscle tone in the affected limb manifests as a “lead pipe” with continuous resistance or “cogwheel type” movement with passive flexion or extension of the elbow. Patients with PD may experience impaired balance and postural reflexes when standing, known as postural instability, which will increase the risk of falls. Other clinical presentations include hypophonia, difficulty swallowing, muscle spasm, and micrographia.

2. Nonmotor symptoms

PD is no longer considered a pure motor disorder. The nonmotor symptoms may begin subtly, long before the motor signs start. They affect patients’ emotional, cognitive, behavioral, and general health. Recognizing these premotor symptoms may aid in the early diagnosis of PD, so preventive measures and treatment can be started early to achieve more favorable results. The major nonmotor/premotor features are listed in Table 44-2. The significance of these nonmotor features in early diagnosis of PD requires further investigation.

Olfactory impairment precedes motor features of PD by many years in most patients with PD. Olfactory testing should be considered in order to differentiate PD from progressive supranuclear palsy and corticobasal degeneration. It is not currently recommended for diagnosing PD. It is not specific, but may be used to identify people either at risk for developing PD or in a presymptomatic stage of PD.

3. Cognitive and psychiatric symptoms

Dementia may affect a third of patients in late PD. Lewy body deposition is associated with dementia in PD. It can be a result of medications with anticholinergic property, or other medical conditions that can affect patients’ mental status, such as infection, dehydration, or intracranial bleeding. Once detected, it should be treated with rivastigmine or donepezil because of their small but significant effect on the improvement in cognitive scales and activities of daily living. Polypharmacy should be assessed and avoided. A withdrawal of anticholinergic medications, including amantadine, dopamine agonists, and MAO-B inhibitors, may be needed. Major depression is seen in ~17% and milder depression in another ~35% of PD patients. The somatic and cognitive symptoms in PD, such as psychomotor retardation, or anhedonia resulting from inability to perform usual activities, overlap with that of depression, which makes it difficult to diagnose. The Hamilton Depression Rating Scale (Ham-D) or the Montgomery-Asberg Depression Rating Scale (MADRS) should be used in conjunction with a structured patient interview in all circumstances to eliminate DSM exclusion criterion.

Psychosis occurs late (10 years after the diagnosis) in the disease process. These symptoms are often the side effects of antiparkinsonian medications. Both dopaminergic and dopamine receptor agonists pose a higher risk for psychosis, which is independent of dosage and treatment duration. Other underlying disease processes, for example, dementia, advanced age, depression, insomnia, and preexisting psychiatric conditions (which usually occur early in PD), are also risk factors for psychosis. Visual hallucinations are the most common clinical manifestation. Auditory hallucinations are less frequent and typically occur concomitantly with visual hallucinations. Vivid dreaming, illusions, or delusions may also occur. Quetiapine and clozapine are effective in treating psychotic symptoms in PD.

B. Laboratory Findings

Genetic tests should be considered in patients with a family history or early onset of PD before age 40 years.

C. Imaging Studies

Researchers have been trying to identify changes in brain structural and functional imaging studies to assist PD diagnosis, especially in the premotor stage. Early diagnosis is critical in redefining the importance of neuroprotective treatment. Routine use of imaging studies is currently not recommended for PD diagnosis.

The dopamine transporter ligand ioflupane with single-photon emission computed tomography scanning, (123) I-FP-CIT SPECT, was approved by the FDA in 2011 for use in differentiating PD from essential tremor and for evaluating parkinsonian syndromes. It cannot differentiate PD from secondary etiologies of parkinsonism.

Both CT and MRI can be ordered for atypical clinical presentations to rule out other intracranial pathologic processes; examples are midbrain atrophy in possible progressive supranuclear palsy, cerebellar/brainstem atrophy/gliosis in possible multisystem atrophy (MSA), normal-pressure hydrocephalus (NPH), and vascular or other causes of parkinsonism. MRI measurement of iron deposition transcranial sonography (TCS) can differentiate PD from progressive supranuclear palsy and MSA by detecting hyperechogenicity of the substantia nigra.

Differential Diagnosis

It is important to differentiate PD from other parkinsonian syndromes (see Table 44-1) in order to produce a favorable response to antiparkinsonian treatment. An imaging study of the brain is usually required to rule out other parkinsonian syndromes if a patient has an atypical presentation, such as being unresponsive to levodopa, early falls in the disease course, symmetric signs without tremor, rapid disease process, and early dysautonomia. Patients with secondary parkinsonism may have a positive medication or medical history. Parkinson-plus syndromes related to underlying neurodegenerative conditions are relatively uncommon and have characteristic clinical presentations and different neurologic imaging findings. Progressive supranuclear palsy is the most common Parkinson-plus syndrome. It is characterized by a downward-gaze palsy, minimal tremor, and severe postural instability with frequent falls starting during the first year of the disease process. Corticobasal ganglionic degeneration (CBGD) demonstrates asymmetric symptoms but also severe limb apraxia and dystonia.

Complications

Both motor and nonmotor clinical features of PD cause progressive disability that interferes with daily activities in all age groups and at all stages of the illness. The frequent reasons for hospitalization include motor disturbances, reduced mobility, lack of adherence to treatment, inappropriate use, falls, fractures, and pneumonia. Other potential complications of PD include weight loss, malnutrition and risk of aspiration, cognitive deterioration and depression, problem with speech, worsening of vision, and loss of smell. The risk of osteoporosis may double in PD. Table 44-2 lists common nonmotor symptoms and complications.

Motor complications, dyskinesias, and motor fluctuations usually start 4–6 years after initiation of treatment. They are assumed to be induced by pulsatile plasma levodopa levels. Dyskinesias are involuntary movements that can present as choreiform movements, dystonia, and myoclonus. Patients with motor fluctuations may experience a sudden loss of levodopa effects and switch from an “on” symptom-controlled period to an “off” symptomatic period, an end-dose “wearing-off” effect, and “freezing” during “on” periods.

Treatment

Treatment of PD is aimed at cardinal symptom control, disease process modification, nonmotor manifestation treatment, and management of motor and nonmotor complications in late stages of PD. Although no treatment has been shown conclusively to slow down progression of the disease, several pharmacologic and surgical therapies are available to control patients’ symptoms.

The goals of treatment vary depending on the disease stage. In early PD, treatment goals are to modify the disease process, delay and control motor symptoms, and maintain patients’ independent functions; in more advanced PD, the goals are to maximize medication effectiveness, manage motor complications from levodopa, and control complications due to PD progression. Nonmotor symptom treatment should be started early and monitored throughout the disease process.

A. Pharmacotherapy

When to start PD therapy is a collaborative decision relying on effective communication between the physician, patient, and family. A variety of factors will be considered, such as the degree of impairment and its effect on the patient’s daily life and employment, the patient’s understanding of PD, and the patient’s attitude toward medications. The traditional wait and watch approach, to start treatment when the patient begins to experience functional impairment, has been challenged.

1. Motor symptom therapy

Levodopa with a dopa decarboxylase inhibitor (DDI) is the most effective medication for PD symptom control and has a more favorable safety profile compared with other regimens, especially in older patients. However, the motor complications, such as dyskinesia, motor fluctuation, or hypertonia, appearing several years after initiation of levodopa, can compromise its effects and limit its long-term use.

Strategies to extend levodopa treatment and minimize motor complications have been explored, such as continuous administration of intravenous levodopa or administration via duodenal infusion (effective but not clinically applicable). Sustained-release levodopa has not been shown to decrease motor complications. Adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa reduces “off” periods by limiting dopamine metabolism and prolonging levodopa half-life. Domperidone can be used for nausea and vomiting, which are common side effects of levodopa. There is no sufficient evidence to support the concerns of neurotoxicity from chronic use of l-dopa in vivo and postmortem studies. The fear of the side effects and motor complications may delay the use of levodopa and result in undertreatment of PD, but alternative medications may be used as first-line treatment to reduce dyskinesias.

Dopamine agonists (DAs) are used by many physicians as the first monotherapy to control PD motor symptoms, especially in younger patients. DAs have shown significant improvement in the Unified Parkinson Disease Rating Scale (UPDRS) in early PD with fewer motor side effects, but their other side effects (Tables 44-3, 44-4, and 44-5) have limited its use especially in those aged > 65 years or those with alcohol, OCD, or mood disorders. Together with levodopa, they increase dopamine levels in the brain and reduce motor fluctuation. Compared with bromocriptine, levodopa has a demonstrated advantage in motor function, disability scores, and physical dysfunction, but may have no significant difference in mortality, dyskinesias, motor fluctuations, and dementia. Ergoline DAs, including bromocriptine, pergolide, lisuride, and cabergoline, are almost never used now because they are associated with moderate to severe cardiac valvulopathy, and pleural, pericardial, and retroperitoneal serosal fibrosis.

Early use of the irreversible monoamine oxidase (MAO-B) inhibitors has shown effectiveness in some clinical trials in controlling motor symptoms, and providing disease-modifying, levodopa-sparing relief when used simultaneously with a dopamine agonist, and less functional decline. MAO-B inhibitors, alone or together with a dopamine agonist, are preferred by some physicians to initiate PD treatment, but they have demonstrated conflicting effectiveness on motor fluctuation. Table 44-5 lists the common antiparkinsonian medications.

Pergolide was withdrawn from the market in 2007 because of its potential serious side effect of heart valve damage. The rotigotine patch was recalled in the United States in April 2008 secondary to the formation of rotigotine crystals, which decrease the delivery and thus the efficacy of the medication.

2. Neuroprotective/disease-modifying therapy

Neuroprotective treatment should be the final goal of PD treatment. Ideally, it should be started as soon as the diagnosis of PD has been made or even before the nonmotor or premotor symptoms are identified. The insidious onset and wide variety of possible etiologies renders PD difficult to identify and prevent. There is insufficient evidence to support the neuroprotective or modifying effects of the MAO-B inhibitors selegiline and rasagiline. There is little or no evidence to substantiate the disease-modifying effects of vitamins, anti-inflammatory medications, nutritional supplements, or CoQ10. How to identify at-risk patients and diagnose PD early to start preventive or protective treatment, which is under investigation, also needs to be addressed.

3. Nonmotor symptom therapy

Medications and other management methods are chosen based on each specific symptom or problem, such as SSRI antidepressants for depression and baclofen for pain and spasm control. For patients with cognitive impairment, antiparkinsonian medications such as anticholinergics, dopamine agonists, amantadine, and selegiline may need to be decreased or discontinued. Cholinesterase inhibitors may be considered for dementia and fludrocortisone or midodrine for orthostatic hypotension. Sleep disturbance may improve with adjusting levodopa dosage, discontinuing nighttime use of antiparkinsonian drugs, discontinuing dopamine agonists, or starting clonazepam. Methylphenidate may help improve gait and decrease the risk of falls.

The first step in controlling psychosis is to decrease the dosage of antiparkinsonian medication or gradually remove some medications in the order of anticholinergics, selegiline, amantadine, dopamine receptor agonists, COMT, and finally, levodopa (switch to short-acting). Antipsychotic agents are considered if the patient still has symptoms. The atypical antipsychotic agents clozapine and quetiapine have fewer extrapyramidal and prolactin-elevating adverse effects. Other second-generation antipsychotic medications, such as ziprasidone, risperidone, and olanzapine, and the third-generation antipsychotic aripiprazole are not recommended because they may be not as effective or may have worse extrapyramidal adverse effects. Cholinesterase inhibitors (except rivastigmine), such as donepezil, galantamine, and tacrine, have shown inconsistent results and may worsen PD or have other side effects. Electroconvulsive therapy (ECT) should be used as a last resort for psychiatric disorders or depression when medications are not effective. By stimulating the D₃ dopamine receptors in the mesolimbic pathways, ropinirole has been shown to control motor symptoms and mood fluctuation, including depression and anxiety in patients with motor fluctuations.

B. Surgical Intervention

Surgery is an effective treatment option in more advanced PD. Subthalamic nucleus (STN) deep-brain stimulation (DBS) is effective in improving motor function and alleviating motor complications. It is reserved for motor complications from levodopa treatment. Potential neurorestoration with dopaminergic or stem cell replacement may also bring hope in controlling dopamine deficiency–related disabilities. Other options such as thalamotomy and pallidotomy are effective in controlling motor complications but can cause destructive lesions.

C. Ancillary Treatment and Supportive Measures

Psychological counseling and therapy, such as cognitive-behavioral therapy, supportive therapy, and coping skill development, may help patients with psychiatric manifestations.

Supportive treatment is important in terms of maintaining function and general health. It includes allied health interventions; occupational therapy; physical therapy; and speech, swallowing, and voice therapy. Physical exercise is a very important component in PD treatment. It can improve PD patients’ motor performance as well as their learning, memory, and mental health. It may repair or reverse the neurochemical damage through facilitating synaptogenesis and neurotrophy. To provide support to the family and caregivers is also crucial. Information regarding PD and other resources should be provided to caregivers. Patients and their families can be referred to various support groups, including the American Parkinson Disease Association (http://www.apdaparkinson.com), the National Parkinson Foundation (http://www.parkinson.org), and the Michael J. Fox Foundation for Parkinson Research (http://www.michaeljfox.com). Other websites providing PD information include the Worldwide Education and Awareness for Movement Disorder and the Movement Disorder Society (http://www.movementdisorders.org/).

Prevention

The role of hormones (ie, estrogen, testosterone, or growth hormone) in neuroprotection has been under investigation with uncertain clinical value. Haaxma et al. (2007) reported that estrogen may play a role in the lower prevalence of PD, delayed and milder symptoms, and slower progression of PD in females. Some potential protective factor have been identified in some studies, such as caffeine and smoking. Smoking, however, is not an option, for obvious reasons. Nonsteroidal anti-inflammatory drugs (NSAIDs) may have a potential role in preventing the neuroinflammatory destruction of dopaminergic neurons and decreasing the risk of PD development.

Prognosis and Disease Process Monitoring

Parkinson disease is a chronic and progressive disease with a mean survival of >10 years. Older age at onset and the presence of rigidity or hypokinesia as initial symptoms predict a more rapid rate of motor progression, as do other associated morbidities such as stroke, auditory deficits, visual impairments, gait disturbances, and male sex.

Caring for PD patients involves a long-term assessment of disease progress and monitoring for the effects and adverse effects of treatment in order to modify the management plan as needed. Clinical rating scales can be used to evaluate the patients’ function, satisfaction, and severity of motor and nonmotor symptoms. The Unified Parkinson Disease Rating Scale (UPDRS) is widely used and contains six sections to assess mood and cognition; activities of daily living in both “on” and “off” states; motor abilities; complications of therapy; disease severity; and global function, including level of disability, mood, and both disease- and treatment-related manifestations of PD. Other monitoring/evaluating instruments include the Parkinson Psychosis Rating Scale (PPRS), Mini-Mental State Examination (MMSE), and the Parkinson Disease Quality of Life questionnaire (PDQL), to name only a few.

Tremor is a rhythmic oscillation of one part of the body from regular contractions of reciprocally innervated antagonistic muscles. It is the most common movement disorder. Tremor can occur at rest, when body parts are held in a fixed posture (postural), or during certain actions (intentional). Table 44-6 lists different types of tremor due to different physiologic or pathologic etiologies.

General Considerations

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.

Clinical Findings

A. Symptoms and Signs

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.

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.

Nonmotor Complications

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.

Treatment

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.

Physical or occupational therapy with lightweight training of wrists may help improve hand stability and function.

Prognosis

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.

TIC Disorders: Tourette Syndrome

General Considerations

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.

Clinical Findings

A. Symptoms and Signs

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.

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.

Differential Diagnosis

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.

Treatment

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.

A. 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.

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.

C. Other Therapies

Botulinum toxin injection and deep-brain stimulation are available for medically refractory tics.

Prognosis

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.

Restless LegS Syndrome (RLS)

General Considerations

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.

Clinical Findings

A. Symptoms and Signs

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.

Differential Diagnosis

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.

Treatment

The goal of RLS treatment is to minimize the unpleasant sensations and motor restlessness, reduce sleep disturbance, and improve quality of life.

A. Nonpharmacotherapy

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.

B. Pharmacotherapy

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

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

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).

Dystonia

Dystonia is characterized by sustained, directional, uncoordinated, or simultaneous agonist and antagonist muscle contractions, which result in repetitive twisting movements or abnormal postures with a body part flexed or twisted along its longitudinal axis. The same group of muscles are repeatedly involved. The excessive random movements are worsened with intentional movements and improve at rest. Dystonic movements can be triggered by specific actions such as hand cramps with writing, called task-specific dystonia; they can extend beyond the commonly affected body parts, called overflow dystonia. Mirror movements may be seen in unaffected extremities when repetitive tasks, such as writing or finger sequences, are performed in the most affected body side; in a more severe form than action dystonia, they can occur at rest, called rest dystonia. Finally, the movements become fixed postures or positions, referred to as permanent contractures. A sensory trick (geste antagonistique) is a phenomenon of dystonic movements. Patients may suppress dystonic movements by touching affected or adjunctive body parts. In primary dystonia, this is the only neurologic abnormal finding and is associated with a genetic cause in autosomal dominant fashion (such as DYT phenotypes). It is considered a neurodevelopmental circuit disorder of the cortical, subcortical, and cerebellar pathways. Early-onset (<26 years) primary dystonia usually affects an extremity. Late-onset (>26 years) primary dystonia affects the neck or cranial muscles and tends to remain focal. Secondary dystonia is associated with an exogenous etiology such as drug use, head trauma, infection, and hypoxia. Other abnormal neurologic examination findings are present, for example, HD, PD, neurodegeneration, Wilson disease, CNS tumor, and stroke. Dopa-responsive dystonia (DRD, Segawa syndrome) is a childhood-onset dystonia plus parkinsonism that responds to levodopa.

The diagnosis of dystonia is based on history, typical clinical presentation, and neurologic examination. Dopamine transporter (DAT) scans are typically normal in primary dystonia. MRI of the brain and appropriate laboratory investigations (eg, serum ceruloplasmin, CSF analysis, ANA, ESR, and metabolic panels) can help assess secondary dystonia. Genetic testing for early-onset dystonia may be considered. Genetic counseling should be provided to patients and family before and after the testing.

Treatment of dystonia is aimed at underlying causes and symptom control. Botulinum toxin injection is the first choice for most focal dystonias. Other symptomatic treatments include oral medication (benzodiazepines, dopamine agonists or dopaminergic agents, anticholinergics, or baclofen); and surgery, such as DBS, epidural premotor stimulation or peripheral denervation. Early-onset dystonia should have a trial of levodopa for possible DRD. Physical therapy such as stretching exercises and sensory tricks may be used to help maintain range of motion or interrupt muscle twisting.

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Myoclonus

Myoclonus refers to sudden, quick, jerklike, involuntary spasmodic movements of a muscle or a group of muscles. Positive myoclonus is due to involuntary muscular contractions; negative myoclonus (asterixis) is due to sudden brief loss of muscle tone. It is not preceded by an urge to move and not suppressible. It is not interrupted by a geste antagoniste such as in dystonia. They can be focal, segmental, axial, or generalized; arrhythmic, rhythmic, or oscillatory. Based on etiology, myoclonus can be classified into four categories. Physiologic myoclonus is a normal and benign movement that occurs commonly, such as hiccups, hypnic jerks, anxiety-induced or exercise-induced jerks, and benign infantile myoclonus with feeding. The movements are usually self-limited and not disabling. Essential myoclonus is a multifocal movement disorder, which can be sporadic or hereditary in an autosomal dominant pattern (associated with dystonia). Even though myoclonic movements are the one abnormal clinical finding on neurologic examination, they occur more frequently at any time, affecting patients’ daily lives. Epileptic myoclonus occurs with seizure activities and demonstrates EEG and electromyographic changes. Secondary (symptomatic) myoclonus is the most common type of myoclonus (∼70%) and occurs as the result of central or peripheral nervous system insult or damage from a wide variety of medical conditions, which can be metabolic (inborn errors of metabolism, Hashimoto encephalopathy) or neurodegenerative (PD, HD), or due to trauma or infection; medications (eg, anesthetic agents, opiates, and anticonvulsants), or toxin exposure (pesticides, gases). Electrophysiologic studies (EEG-EMG), MRI and transcranial magnetic stimulation (TMS) can be employed for the diagnosis and to evaluate origin of myoclonus at cortical, subcortical, spinal, and peripheral levels. Laboratory investigations and genetic testing should be ordered on the basis of suspected underlying conditions. Treatment of myoclonus is aimed at the secondary causes such as removal medications or correction of metabolic imbalances. Evidence for symptomatic treatment is disappointing. Different medications are used according to the level of the nervous system involved, such as levetiracetam and piracetam, which are first choices for cortical myoclonus; clonazepam is used in subcortical and spinal myoclonus; botulinum toxin injection is used for peripheral myoclonus. Other medications have been used to control myoclonus, such as trihexyphenidyl, rituximab, ACTH, valproic acid, and primidone. DBS may be effective in certain cases of myoclonus.