Movement disorders are a cluster of motor disturbances arising from the dysfunction of basal ganglia and, in some cases, from other parts of the nervous system, for example, brainstem, cortex, spinal cord, cerebellum, and peripheral nervous system. Patients suffering from movement disorders have normal muscle strength and sensation, but their normal voluntary motor activities are influenced or impaired by the 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. Movement disorders can be classified into the following categories based on their clinical manifestations: tremor, chorea and choreoathetosis, dystonia, myoclonus, tics, and ataxia. They demonstrate less movement, hypokinesia or akinesia, or excessive movement, hyperkinesia, or both (Table 43-1). The goal of this chapter is to provide clinical information regarding the diagnosis, management, and recent findings for the most commonly encountered movement disorders. Nonmotor features of movement disorders are also discussed in an effort to improve comprehensive care and patients’ quality of life.

Essentials of Diagnosis

At least two of the first three cardinal motor features, which are unilateral, and absence of a secondary cause:

• Bradykinesia.
  
• 4-6 Hz rest tremor.
  
• Muscular rigidity.
  
• Postural instability (late presentation).

General Considerations

Parkinson disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer disease but remains the only neurodegenerative disease for which symptoms can be effectively controlled medically. It affected about 340,000 individuals older than 50 years in the United States, according to the estimate of Dorsey et al (2005). In the United States, the prevalence of PD is estimated at 128 per 100,000 in individuals in their fifties, 550 per 100,000 in those in their sixties or seventies, and 958 per 100,000 in those older than 80 years. The number is expected to grow in the next 25 years, with the projected number being 610,000 in 2030 in the United States (Dorsey et al, 2007). The number of individuals with PD older than 50 years in Western Europe’s five most and the world’s 10 most populous nations was between 4.1 and 4.6 million in 2005 and will double to between 8.7 and 9.3 million by 2030 (Dorsey et al, 2007).

Numerous hypotheses, for example, environmental, genetic, inflammatory process, defects in mitochondrial function or oxidative stress, have been explored to explain the process of the neurodegeneration but without a definitive conclusion. Aging is the biggest risk factor associated with PD. About 95% of PD cases are idiopathic and occur in people older than 50 years. Recent research shows a 1.5-2 times higher incidence in males. Other risk factors include pesticides or herbicides in association with rural living and exposure to well water, and head trauma. The remaining 5% are early onset and occur in familial clusters. An individual may have a doubled risk if there is a family history in a first-degree relative. Five genes, two of which are alpha-synuclein (dominant) and parkin (autosomal recessive), have been located for familial forms of PD.

Pathogenesis

PD results from the loss of dopaminergic projections neurons in the substantia nigra (SN). It is a progressive and degenerative process. Patients will become symptomatic when 60%-80% of SN dopaminergic neurons 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 neuroprotection of the dopaminergic neurons in SN, supplementation of levodopa (L-dopa), or decreased metabolism/ degradation of dopamine.

Lewy bodies, typical alpha-synuclein immunoreactive intracytoplasmic eosinophilic inclusions in neurons, are neuropathologic confirmation of the clinical diagnosis. PD may also involve other CNS, peripheral, and enteric nervous systems, with Lewy bodies located in olfactory nucleus, amygdala, brainstem, and neocortex, the vagal nerve nucleus, and the sympathetic nervous system. Lewy bodies are also associated with Alzheimer disease, Down syndrome, and other neurologic diseases.

Prevention

The insidious onset and wide variety of possible etiologies make PD difficult to identify and to initiate effective preventive care. The role of sex hormones, such as estrogen and testosterone, as well as other hormones, such as growth hormone, in neuroprotection has been under investigation with uncertain clinical value. Based on a study by Haaxma et al, 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 factors 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 neuroinflammatory destruction of dopaminergic neurons and in decreasing the risk of PD development.

Clinical Findings

Symptoms and Signs

The diagnosis of PD is based on its characteristic cardinal motor manifestations not caused by infections or by primary visual, vestibular, cerebellar, proprioceptive, or other neurodegenerative disorders. 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.

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 or initiation of movement or the sudden stopping of movement. Patients may make short, shuffling steps with decreased arm swing or have an expressionless mask-like face, freezing gait, or difficulty turning in bed. They cannot make a rapid repetitive movement, 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 with standing, known as postural instability, which will increase the risk of falls. Other clinical presentations include hypophonia, difficulty swallowing, muscle spasm, and micrographia.

Nonmotor Symptoms

PD is no longer considered a pure motor disorder. The nonmotor symptoms may begin unnoticeably long before the motor signs start. When treating the cardinal motor symptoms, we need to be attentive to the nonmotor symptoms affecting patients’ emotional, cognitive, behavioral, and general health. Clinical evidence shows that nonmotor symptoms may precede motor signs by 4-20 years. Recognizing these premotor symptoms may aid in 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 43-2. The significance of these nonmotor features in early diagnosis of PD requires further investigation.

Some research has shown that olfactory impairment precedes motor features of PD and may be used to identify people either at risk for developing PD or in a presymptomatic stage of PD. Depression is commonly seen in PD patients. According to some studies, depression may precede PD by decades; patients who have depression also are at higher risk of developing PD.

Cognitive and Psychiatric Symptoms

Psychosis happens 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 (higher risks) can cause 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 its common clinical manifestation. Auditory hallucinations are less frequent and typically co-occur with visual hallucinations. Vivid dreaming, illusions, or delusions may also occur. Lewy body deposition is associated with dementia in PD.

Laboratory Findings

Genetic tests should be considered in patients with a family history or early onset of PD before age 40 years. Other laboratory tests are based on each patient’s condition, such as for malnutrition and dehydration.

Imaging Studies

CT and MRI can be ordered for atypical clinical presentations to rule out other intracranial pathologic processes, for example, normal-pressure hydrocephalus (NPH) and vascular or other causes of parkinsonism. Positron emission tomography (PET) or single photon emission computed tomography (SPECT), functional MRI, and other MRI modalities may have a role in early detection of preclinical PD and in monitoring disease progression. SPECT is useful in differentiating PD from essential tremors when they appear asymmetrically and at rest. Transcranial sonography (TCS) can differentiate PD from progressive supranuclear palsy (PSP) and multisystem atrophy (MSA) by detecting hyperechogenicity of the substantia nigra.

Differential Diagnosis

It is important to differentiate PD from other parkinsonian syndromes (see Table 43-1) in order to effect 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 underlying neurodegenerative conditions are relatively uncommon and have characteristic clinical presentations and different neurologic imaging findings. PSP is the most common Parkinson-plus syndrome. It is characterized by a downgaze 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. The detailed clinical presentation of Parkinson-plus syndromes is not discussed in this chapter.

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. Examples include falls and injuries, weight loss, malnutrition and risk of aspiration, cognitive deterioration and depression, speech, worsening of vision, and loss of smell. The risk of osteoporosis may double in PD. Table 43-2 lists common clinical complications.

Motor complications, dyskinesias, and motor fluctuations usually start 4-6 years after initiation of treatment. They are thought 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 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, to delay the onset of and control motor symptoms, and to maintain patients’ independent functions; in more advanced PD, the goals are to maximize medication effectiveness, to manage motor complications from levodopa, and to control complications due to PD progression. Nonmotor symptom treatment should be started early and monitored throughout the disease process.

Pharmacotherapy

When to start PD therapy is a collaborative decision relying on effective communication among 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. Recent research shows the beneficial effects of starting neuroprotective treatment as soon as the diagnosis has been made. This approach may protect dopaminergic neurons and slow disease progression.

Motor Symptom Therapy

Levodopa 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 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. Dopamine agonists can be used as the first-line PD treatment preferably in patients younger than 65 years, who can better tolerate their psychiatric side effects. Together with levodopa, they increase dopamine levels in the brain and reduce motor fluctuation. Compared with bromocriptine, a dopamine agonist, levodopa has a demonstrated advantage in motor function, better cognitive function and less dementia, and overall quality of life. Both drugs have similar mortality rates and effects on motor fluctuation. Many patients have benefited from the irreversible monoamine oxidase (MAO)-B inhibitors selegiline and rasagiline. In some laboratory experiments, they have shown potential cognitive enhancement and neuroprotective features. The extended MAO-B blockage from selegiline may make daily dosing of selegiline unnecessary for motor symptom control. 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. The fear of motor complications may delay the use of levodopa and result in under-treatment of PD. Table 43-3 lists the common antiparkinsonian medications.

Pergolide was withdrawn from the market in 2007 owing to 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.

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 that when some nonmotor or premotor symptoms are identified. The MAO-B inhibitors selegiline and rasagiline, levodopa, and coenzyme Q10 may possess neuroprotective properties, but more evidence is needed. Antioxidant (vitamin E) has not shown protective effects. How to identify at-risk patients and diagnose PD early to start preventive or protective treatment also need to be addressed.

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. To adjust levodopa dosage, discontinue nighttime use of antiparkinsonian drugs, or discontinue dopamine agonists for sleep disturbance. Clonazepam may be started. 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 lastly 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 have worse extrapyramidal adverse effects. Cholinesterase inhibitors (except rivastigmine), for example, donepezil, galantamine, and tacrine, have shown inconsistent results and may worsen PD or have other side effects. Electroconvulsive therapy (ECT) should be used as the 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.

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. 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.