24: Parkinson Disease & Essential Tremor

Parkinson disease (PD) is the second most common chronic progressive neurodegenerative disorder, after Alzheimer disease. It affects an estimated 1% of people older than age 65 years and up to 3% older than age 85 years, or approximately 1.5 million people in the United States and more than 5 million people worldwide. With the aging of the world’s population, and with age being the strongest risk factor for PD, incidence is expected to rise dramatically in coming decades. By 2050, some researchers project more than 2.5 million cases in the United States.

PD is generally considered a disease of the older adult, but it can affect younger age groups. The mean age of onset is about age 60–65 years. Several key points should be emphasized about the care of older PD patients. The differential diagnosis of parkinsonian symptoms in patients older than the age of 75 years is mostly limited to either idiopathic PD or secondary parkinsonism, as onset of atypical etiologies is rare in this age group. Older PD patients often present with an akinetic-rigid syndrome, more nonmotor symptoms, and less tremor. Levodopa is the drug of choice in patients older than age 70 years, as dopamine agonists (such as pramipexole and ropinirole), amantadine, and anticholinergics are poorly tolerated in this age group.

The clinical presentation of PD was first described by James Parkinson in his 1817 “Essay on Shaking Palsy.” It was not until the 20th century that the pathologic hallmarks of PD, α-synuclein-positive Lewy bodies and dopaminergic cell loss of the substantia nigra, were described. It is estimated that by the time the first symptoms emerge, 60% of substantia nigra neurons have already died. Neurochemically, this results in dopamine depletion in the nigrostriatal pathway. Physiologically, this leads to inhibition of the thalamus and reduced excitation of the motor cortex, manifesting as the cardinal motor features of PD (bradykinesia and rigidity).

A fundamental shift in our understanding of PD pathology has occurred in recent years. It has long been known that the pathology spreads beyond the substantia nigra as PD progresses, which explains much of the disabling nonmotor features of advanced PD, such as dementia, depression, and autonomic failure. However, we now know that even before any motor symptoms occur, pathology has spread through specific areas of the olfactory system, lower brainstem, and peripheral nervous system. This “premotor” phase of PD can manifest as hyposmia, sleep disorders, mood disorders, and constipation. In summary, from the earliest to the most advanced stages, PD pathology occurs in a much wider distribution of the central and peripheral nervous systems than previously thought, making PD much more than just a movement disorder.

The mechanisms of neurodegeneration in idiopathic PD are not well understood but likely include complex interactions between environmental factors and genetic predisposition. Environmental risk factors remain elusive, although exposure to pesticides, agricultural occupation, and rural place of residence are known to be risk factors. Cigarette smoking and coffee consumption are possible protective factors.

Genetics play a role. There are now up to 18 genes or loci (designated as the PARK loci) that cause or predispose people to PD. Although some of these genes account for the 5% to 10% of PD that seems to be inherited in a mendelian pattern, some also contribute to a higher percentage of “sporadic” PD that has more complex modes of inheritance. Perhaps more importantly, discovering the function of these genes in neurons has helped elucidate several important mechanisms of pathogenesis in PD overall.

PD has an insidious onset and gradually progresses, leading to increasing disability over time. The cardinal motor features include resting tremor, bradykinesia, rigidity, and gait impairment/postural instability, although the latter usually arises later in the disease. Nonmotor features are also prominent, and increasingly become the main source of disability as the disease progresses.

PD remains a clinical diagnosis. Bradykinesia plus 1 of the other cardinal manifestations must be present to diagnose idiopathic PD. Other clinical features that are supportive of the diagnosis are asymmetric presentation and a strong response to dopaminergic medications. Approximately 20% of PD cases present without tremor. Diagnostic accuracy increases to over 90% in patients followed by movement disorders specialists.

Symptoms & Signs

Rest tremor is the most common presenting symptom of PD. It usually attenuates with use of the affected limb. However, action tremor is fairly common and should not steer the clinician away from a PD diagnosis if other parkinsonian features are present. In early stages, the tremor may only appear when the patient is distracted (while talking or walking) and the patient may even be able to suppress it with concentration. With progression, tremor becomes more constant, more common with actions, and higher in amplitude, impairing many activities of daily living (ADLs). On examination, tremor is a rhythmic, oscillatory, involuntary movement. Parkinsonian tremor is asymmetric, relatively slow (frequency 3–6 Hz), and tends to have a prominent pronation–supination component to it (as opposed to flexion–extension), frequently giving the tremor a “pill-rolling” quality. Examiners should observe tremor at rest, with different postures and actions, including handwriting and drawing spirals. If there is no obvious tremor, distracting tasks should be given to patients to elicit mild tremor.

Bradykinesia is defined as a slowness or lack of movement. It manifests as loss of dexterity and difficulty initiating and maintaining the amplitude and velocity of movement. ADLs, like eating and dressing, will take more time to complete. It is often described by patient as “weakness,” although strength is actually intact. Many of the common complaints of the PD patient are direct manifestations of bradykinesia including small handwriting (micrographia), loss of facial expression (hypomimia), quiet monotone speech (hypophonia), and slower walking with shorter steps. To elicit bradykinesia, the examiner asks the patient to perform rapid repetitive movements (such as finger taps, hand openings and closings, and heel stomps), as quickly and largely as possible. Examining handwriting and having the patient draw spirals can reveal micrographia. It is also important to take note of lack of spontaneous movements, such as blink rate, expression in speech, hand gestures while speaking, or the amount of shifting one’s position.

Rigidity is subjectively experienced by the patient as “stiffness,” and when severe enough, can lead to painful aching or cramping. Patients may experience musculoskeletal complaints (such as painful, frozen shoulder), and it is common for a patient to seek care from an orthopedic surgeon or rheumatologist before a neurologist. Rigidity is defined as the increased resistance that is felt as the examiner passively moves a body part about a joint to assess muscle tone. The increase in tone should be constant, independent of the speed or direction of the passive movement. This even increase in tone has been termed lead pipe rigidity, as opposed to the variable resistance felt when examining spasticity. When tremor is superimposed on rigidity, a ratcheting sensation can be sensed, giving the rigidity a “cogwheeling” component.

Postural instability and gait dysfunction are less prominent at presentation. In early PD, mild gait impairment can manifest as subtly shortened stride length, decreased arm swing, and stooped posture. In moderate PD, the gait becomes more shuffling, posture stooped, and patients turn en bloc, requiring several steps to make a turn. In advanced PD, festination (a sense that the body wants to hasten forward) or freezing of gait (the inability to take effective steps) can occur. Freezing of gait is especially sensitive to anything that requires more attention of the patient, including initiating gait, narrow spaces or doorways, turns, or even carrying something. Postural instability can be assessed with the “pull test.” More than 3 corrective steps backward is considered abnormal. This should be done only by experienced examiners with caution, as patients can have surprising lack of postural reflexes, and may even need to be caught by the examiner. Gait dysfunction is not as responsive to treatment, can lead to falls and loss of mobility, and many patients end up wheelchair-bound.

A diverse range of nonmotor symptoms are increasingly being recognized as characteristic of PD. Patients frequently describe hyposmia, constipation, dream enactment, and mood symptoms years before the appearance of any movement disorder. However, as the disease progresses to moderate and advanced stages, additional nonmotor problems lead to significant disability. In fact, nonmotor symptoms most strongly correlate with decreased quality of life (QOL) in PD. Cognitive and behavioral impairment is almost universal in PD, with earlier stages showing mild impairment in attention, visual–spatial, and executive function. Memory and language are relatively spared. In advanced stages, dementia and psychosis (especially visual hallucinations and delusions) are common. A majority of patients with PD have depression and anxiety at some point. The autonomic nervous system is greatly affected in PD, with constipation, gastroparesis, orthostatic hypotension, urinary urgency, erectile dysfunction, and sweating dysregulation. With the exception of constipation, autonomic complaints usually do not become prominent or disabling until later in the course, when incontinence and severe orthostatic hypotension can lead to severe disability. Sleep can be disturbed with dream enactment, insomnia and sleep apnea, contributing to excessive daytime sleepiness and fatigue.

Patient Examination

The physical examination should include a complete neurologic examination. Extraocular eye movements, motor strength, sensory, and cerebellar examinations should be normal. The extrapyramidal examination is the central focus of the examination of a PD patient. Part III of the Unified PD Rating Scale (UPDRS) is the best validated, standardized, objective tool that the clinician can routinely use in examining a patient. In using the UPDRS, the clinician carefully examines facial expression, speech, tremor, rapid repetitive tasks, muscle tone, gait, and balance. Details about the objective findings related to the cardinal features of PD are discussed in the section above.

Laboratory Findings

At this time, there are no laboratory tests or imaging studies that can confirm the diagnosis of PD. However, PD is not a diagnosis of exclusion. To the contrary, only when certain red flags come to the attention of the clinician (especially lack of response to dopaminergic therapy) is it necessary to rule out atypical and secondary causes of parkinsonism. Genetic testing is commercially available for certain PARK gene mutations. Routine testing for these genes is not yet recommended, and for the most part, clinical use of genetic testing remains restricted to settings where there is a strong family history, or when onset occurs before the age of 40 years.

Imaging Tests

The FDA has approved the use of DaTSCAN (¹²³I-ioflupane, a ligand that uses single-photon emission computed tomography [SPECT] imaging to detect presynaptic dopamine transporters) in trying to distinguish PD from essential tremor. PD patients (but also some atypical parkinsonism patients) will have a decreased DaT signal in the basal ganglia. However, DaTSCAN should not be considered a routine test, as it is no more sensitive or specific than examination by a movement disorders neurologist. Advanced functional imaging techniques remain a research tool for the vast majority of situations. Routine MRI of the brain is usually normal in early stages of PD. Only in settings when the diagnosis remains in question is an MRI ordered to investigate secondary or atypical parkinsonism.

Idiopathic PD is the most common cause of parkinsonism. It is important to think of secondary or atypical causes when certain red flags are seen; namely symmetric presentation, lack of tremor, and the presence of atypical features that are rarely seen early in PD. The strongest alert is a lack of response to higher doses of dopaminergic medications (more than 1000–1500 mg/day of levodopa).

The 2 most common etiologies of secondary parkinsonism are vascular and drug induced. These are especially important to consider in older adults, as atypical parkinsonian syndromes rarely have onset after the age of 75 years. In fact, when exposure to dopamine-blocking drugs can be ruled out by history, idiopathic PD and vascular parkinsonism account for the vast majority of cases in older patients.

Vascular parkinsonism can result from chronic ischemic damage or multiple infarcts in the brain. Patients often present with a symmetric akinetic-rigid syndrome. Findings tend to be more severe in the legs, and gait is prominently affected. Vascular parkinsonism occasionally responds to dopaminergic medications, but not as robustly as with PD.

Drug-induced parkinsonism results from exposure to dopamine receptor blocking agents, most commonly antiemetics and antipsychotics (both typical and atypical) or dopamine depleters (such as reserpine or tetrabenazine). In older adults, parkinsonian features can persist for months after the offending dopamine receptor blocking agent has been discontinued. Other secondary causes of parkinsonism are more rare (Table 24–1).

Atypical parkinsonism results from neurodegenerative disorders that lead to parkinsonism. They are also termed “Parkinson Plus” syndrome as they are associated with disabling features, such as autonomic failure, early falls, and early dementia, not usually seen in early PD. These early disabling atypical features, the lack of response to medications, and the rapid progression of these illnesses combine to give these diseases a poor prognosis. Table 24–2 lists the signs for these disorders.

A common challenge in the differential diagnosis is distinguishing between the tremor of PD and that of essential tremor (ET). The action tremor of ET tends to be more symmetric, higher frequency, and more extension–flexion as opposed to the asymmetric lower frequency, pronation–supination tremor of PD. The diagnosis can be especially difficult when one considers that a minor amount of rigidity and bradykinesia can occasionally be seen in ET. ET patients should not have the anosmia, rapid eye movement (REM) sleep behavior disorder, and more significant parkinsonism seen in PD.

PD, historically viewed as a movement disorder, is now recognized as a complex condition with diverse clinical manifestations, including neuropsychiatric and other nonmotor features. As PD progresses, it can affect many parts of the central and peripheral nervous system, leading to diverse complications. Autonomic dysfunction can lead to drooling, bloating, gastroparesis, constipation, urinary dysfunction, incontinence, erectile dysfunction, temperature dysregulation and orthostatic hypotension which can lead to syncope. Two major sources of morbidity and mortality are dysphagia and gait dysfunction. Dysphagia can lead to aspiration or choking. Postural instability and freezing of gait can lead to injurious falls or the many complications associated with immobility. Sleep dysfunction, somnolence, and fatigue are extremely common in PD. When prominent, cognitive–behavioral dysfunction is a major source of disability and are the PD symptoms most associated with poor QOL. Furthermore, patients with advanced PD experience complications from its treatment as well.

Motor Fluctuations and Dyskinesia

Complications of dopaminergic therapy are significant sources of disability in moderate stage PD patients. “Wearing off” is managed in two ways; shortening the interval between doses, or adding a catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO) inhibitor. Dyskinesia can be managed either by slightly reducing the amount of levodopa at each dose or by adding amantadine. If the patient is taking a long-acting (controlled-release) formulation of levodopa multiple times a day, an unpredictable “stacking effect” may contribute to dyskinesia, and conversion to a short-acting levodopa regimen should be considered. Deep brain stimulation (DBS), especially globus pallidus interna (GPi)-DBS, can have a robust antidyskinetic effect. Because management of complications is complex, and because DBS can alleviate both problems in some patients, prompt referral to a neurologist is strongly recommended for advanced treatment options.

Dementia and Psychosis

Dementia occurs in a majority of patients with advanced PD. First, look for medications that contribute to sedation and/or confusion (eg, dopamine agonists, amantadine, muscle relaxants, pain medications, and anticholinergic medications for tremor and bladder symptoms). Cholinesterase inhibitors (eg, donepezil, galantamine, rivastigmine) can be beneficial for attention, bradyphrenia, and psychotic features like visual hallucinations. To treat psychosis, address medications first (eg, lowering dopaminergic medications or consider using quetiapine and clozapine). All other typical and atypical antipsychotics are contraindicated in PD, especially in older adults. Always rule out general medical issues, such as infections, especially if there is a component of delirium.

Depression

Selective serotonin reuptake inhibitors (SSRIs) are first-line agents for depression in PD, but serotonin-norepinephrine reuptake inhibitors (SNRIs) may address a broader spectrum of neurotransmitter deficits in PD. However, few clinical trials provide evidence for the choice among antidepressants in PD. Care should be taken to avoid drug interactions with MAO inhibitors like selegiline.

Orthostatic Hypotension

Medications that contribute to orthostatic hypotension should be reduced if possible. Consider antihypertensives, which are frequently no longer needed as PD progresses. Dopaminergic drugs can also exacerbate hypotension. Salt in the diet can be liberalized, and water intake encouraged. The head of the bed should be raised above 30 degrees. Eating small, frequent meals can avoid splanchnic dilatation. Hot weather, hot liquids, and hot showers should be avoided. Pharmacotherapy, such as fludrocortisone and/or midodrine is sometimes used when the above measures fail, but cause complications in older patients and should be used with caution.

Gastrointestinal Complications/Constipation

Dysphagia must be monitored closely and patients should be promptly referred for swallowing evaluation when present. Drooling can respond to careful administration of botulinum toxin to the salivary glands. Constipation is practically universal in PD. Hydration, exercise, and a healthy, high-fiber diet should be encouraged. Stool softeners and laxative agents (eg, docusate and Senokot) should be taken daily.

Falls

Falls are a major source of injury, morbidity, and mortality in PD, and patients with postural instability need to be closely monitored for falls and referred promptly to physical therapy for gait and balance evaluation and management.

Referral Guidelines

Consider referring patients to a neurologist or movement disorders specialist when: (a) the diagnosis is in question; (b) a patient is not responding to standard therapies; (c) the patient has unacceptable side effects; (d) complications occur from PD or its treatments; or (e) surgical interventions are considered.

Nonpharmacologic Therapy

Care of the PD patient requires a multidisciplinary team approach, including important aspects such as patient education, exercise, diet, and rehabilitation services. Patients and their families should be educated about the natural history of PD and available treatments and resources. Support groups are particularly valuable. As the disease progresses and new symptoms and complications arise, treatment regimens can become complex. Patients will need to learn to differentiate among symptoms related to PD, medication side effects, or other conditions. Exercise improves mood, strength, balance, flexibility, and mobility. A combination of aerobic, strengthening, and flexibility exercises can maintain functional status. A well-balanced healthy diet and adequate hydration can prevent constipation and orthostatic hypotension. Furthermore, protein restriction may be necessary in some patients, as amino acids compete with levodopa for absorption, thus blocking its therapeutic effect. Involving a nutritionist may be vital, especially as weight loss and disuse atrophy can occur and are associated with poor outcomes. Physical, occupational, speech, and swallowing rehabilitation therapies aimed at improving daily function and QOL can be effective at all stages. Emotional and psychological needs of the patient and family should also be addressed through counseling of a chaplain, psychiatrist, psychologist, or other mental health provider.

Pharmacotherapy

PD is an incurable illness, with no treatments proven to slow disease progression. However, PD is somewhat unique among neurodegenerative disorders in that it benefits from a diverse range of effective symptomatic treatments such as dopaminergic medications. The primary goal of pharmacotherapy is to reduce symptoms to maintain independence, functional status, and QOL and reduce disability. A common misconception among patients (and clinicians) is that medications will “only last for so long” once started. This now discredited belief has led to an all-too-common practice of delaying treatment as long as possible. Treatment should be initiated and tailored to adequately reduce symptoms whenever patients are bothered by their symptoms, and certainly when functional status, independence or mobility is threatened. Many PD patients, especially young-onset and tremor/motor-predominant patients, can lead highly functional lives for many years with optimized treatment regimens. However, as the disease progresses, complications of dopaminergic medications, such as dyskinesia and motor fluctuations, occur and regimens can become complex. Especially in older adults, medications can exacerbate nonmotor symptoms, such as visual hallucinations, behavioral problems, orthostasis, and somnolence, and reductions may be necessary at the cost of decreased motor benefit.

Levodopa—

Levodopa is the most effective and well-established drug in the treatment of PD. Converted by DOPA-decarboxylase into dopamine, it provides dopaminergic replacement. It ameliorates tremor, bradykinesia and rigidity, thus reducing morbidity and disability. Axial features of PD such as speech and gait impairment are frequently less responsive to levodopa and other dopaminergic medications. Furthermore, in advanced PD, postural instability, speech impairment, autonomic dysfunction, dementia and psychiatric problems are not responsive to levodopa. Although levodopa does not slow the progression of PD pathology, life expectancy in PD has drastically improved today compared to the prelevodopa era.

Levodopa provides a robust and consistent improvement of motor features, and keeps patients highly functional for years. However, the vast majority of advanced patients will eventually experience motor complications, namely motor fluctuations and dyskinesia, manifest as inconsistent response to levodopa. In the earlier stages, patients experience “wearing off,” where the duration of effect of each levodopa dose progressively shortens, and requires shorter intervals between doses. Later on, more unpredictability occurs, with some doses completely failing to “kick in,” and others abruptly losing effect. Dyskinesias are involuntary hyperkinetic movements that occur at “peak-dose” levodopa levels. They are most commonly choreiform (abnormal twisting, writhing, dance-like movements) but can also be dystonic (pulling into more sustained and often painful postures).

Other side effects of levodopa include nausea, vomiting, lightheadedness, dizziness, somnolence, and, in more advanced patients, hallucinations and confusion. Peripheral decarboxylase inhibitors, such as carbidopa are always included in formulations of levodopa to reduce the gastrointestinal side effects by preventing peripheral conversion of levodopa to dopamine. Isolated carbidopa can be added to prevent the nausea experienced with standard levodopa formulations. Levodopa is generally a well-tolerated medication and most side effects can be avoided if started slowly and gradually titrated up to an effective dose. It should be taken on empty stomach at least 30–45 minutes before or after meals, to avoid protein blocking of absorption of levodopa. Long-acting formulations of levodopa (eg, Sinemet CR) are helpful for bedtime dosing as they can reduce nocturnal return of PD symptoms, but daytime use of these formulations can exacerbate complications.

Dopamine agonists—

Dopamine agonists directly stimulate dopamine receptors in the striatum (the postsynaptic target of nigral neurons). The older ergot derivatives such as bromocriptine and pergolide are not used in clinical practice because of serious side effects such as heart valve damage. Newer nonergot agonists, such as pramipexole, ropinirole, and transdermal rotigotine, have replaced them. Dopamine agonists are effective as monotherapy in reducing cardinal motor features of PD. However, within 2–5 years, most patients will require the addition of levodopa. Dopamine agonists are also used as adjunctive therapy with levodopa when motor complications occur. As they are longer-acting, they can reduce the severity of “wearing off,” and as they cause less dyskinesia than levodopa, they are sometimes used in order to attempt a decreased levodopa dose.

Dopamine agonists are poorly tolerated in older adults. Although side effects are similar to levodopa (nausea, vomiting, orthostatic hypotension, somnolence, dizziness, psychiatric symptoms, hallucinations), they occur more commonly and more severely, especially in older adults. Serious consideration should be given before starting a dopamine agonist in patients older than 70 years of age because of the side effects of somnolence, cognitive impairment, and psychosis. Dopamine agonists also have additional side effects, including impulse control disorder, that are rarely seen with levodopa. Patients on dopamine agonists should be educated about and frequently screened for compulsive gambling, eating, and shopping, hypersexuality, and other impulsive behaviors.

Other pharmacotherapies—

Levodopa and dopamine agonists are the 2 main drug classes used as monotherapy in PD. Other PD drugs have minimal symptomatic benefits when used alone and serve as adjunctive therapy when motor complications occur. As most patients require these medications when they have entered the more complicated moderate to advanced stage of PD, one should consider consulting a neurologist before initiating these agents. COMT inhibitors (entacapone and tolcapone) and MAO-B inhibitors (selegiline and rasagiline) block the enzymatic breakdown of levodopa and are used to decrease motor fluctuations (“wearing off”) by extending the duration of benefit of each dose of levodopa. Amantadine is the only medication with proven effectiveness for reducing dyskinesia. It reduces tremor and freezing of gait in some patients as well. Amantadine has dopamine agonist and anticholinergic properties, commonly exacerbates somnolence, cognitive impairment and psychosis, and has limited use in older adults. Similarly, anticholinergic medications like trihexyphenidyl can be effective at reducing tremor, dyskinesia, and dystonia, but older patients have low tolerance for their cognitive and autonomic impairment. These drugs should not be considered options in the geriatric population.

Surgical Therapies

In many patients, medications become progressively less effective in relieving PD symptoms consistently, especially after the onset motor fluctuations or dyskinesia. Some of these patients may benefit from surgical therapies. Candidacy for these interventions is complex. The ideal candidate is a patient who has a clear diagnosis of PD, continued good response to medications in the “on” state, suffers from disabling motor complications despite optimal medical management, is healthy enough to tolerate a neurosurgical intervention, has relatively intact cognition and does not suffer from a significant or uncontrolled mood disorder. There is no firm age-limit, but patients older than age 70 years are generally considered higher risk, and those older than age 80 years are rarely operated on.

Stereotactic lesioning—

Pallidotomy (lesioning of the GPi) is effective in treating the cardinal features of PD and can drastically reduce levodopa-induced dyskinesias. Similarly, thalamotomy can reduce tremor. However, these lesioning procedures are irreversible, not adjustable, and bilateral procedures that are associated with dysphagia, dysarthria, and cognitive impairment. Consequently, today these procedures are mostly used only in situations where DBS is not feasible.

Deep brain stimulation—

DBS of subthalamic nucleus (STN) or GPi has mostly replaced stereotactic lesioning procedures. Although more expensive, DBS has the advantages of being nondestructive, reversible, and programmable. Bilateral procedures are better tolerated. The DBS system is a 4-contact lead implanted into each hemisphere of the brain by stereotactic technique. The leads are connected to a pulse generator in the chest wall by subcutaneous extension wires. Clinicians program the device for optimal benefit to avoid side effects by adjusting the amplitude, pulse width, frequency and polarity of stimulation, and by changing the configuration of active contacts on each lead. Patients can also make some adjustments at home.

DBS of both targets can alleviate the cardinal features of PD, motor fluctuations, and dyskinesia. Both targets are effective at treating tremor, rigidity, and bradykinesia, especially in the limbs. However, as with medications, axial symptoms such as gait and speech are less responsive to DBS. In fact, DBS can make speech, falls, cognition, and behavioral symptoms worse, especially in high-risk patients. It is important to have extensive discussion with patients and their families before surgery to make sure that the symptoms that bother them the most (ie, their goals of treatment) match those that can be reliably alleviated by DBS. The largest recent randomized clinical trial found these 2 targets to have similar effectiveness and safety. However, STN-DBS has higher risk of falls and cognitive and mood side effects.

DBS has higher risk of infection and hardware problems than ablative procedures. Some side effects, such as speech impairment, spasticity, and mood changes, can result from stimulation of neighboring structures in the brain. Adjusting stimulation parameters often alleviates these stimulation-induced side effects.

Caring for patients with advanced PD presents many challenges, and the prospect of having a chronic progressive debilitating disease is frightening. Patients can benefit from PD treatments for years and become disabled by nonmotor symptoms without effective treatments. Furthermore, PD drug doses frequently need to be lowered because of exacerbation of nonmotor symptoms, worsening, in turn, their motor symptoms.

A palliative care approach can be beneficial and is underutilized in advanced PD. PD has a variable, slow, and prolonged course, making accurate prognosis difficult. However, some trends predict an unfavorable prognosis. Onset of PD in older age, prominent nonmotor features, and prominent akinetic-rigid syndrome with gait dysfunction are associated with more rapid progression and poor outcomes; whereas younger-onset PD, lack of nonmotor features, and tremor predominance are associated with slower progression.

Palliative care, unlike hospice, is not limited to a particular prognosis. PD causes disability, suffering, and caregiver strain. Applying palliative care principles at every stage is important.

Addressing advanced directives and involving an attorney or estate planner for financial and legal issues (eg, establishing power of attorney) is important. Although it may be difficult to initiate end-of-life discussions, it is important to hear a PD patient’s wishes, when they are still able to share them. A palliative care approach does not preclude life-prolonging therapies, but proactively focuses on relief of suffering from pain, depression, anxiety, and other psychosocial stressors for both patients and caregivers.

Family Caregiver Alliance (provides information on support groups, hiring caregivers, and issues of long-term care). http://www.caregiver.org

National Parkinson Foundation, Inc. (provides information on educational programs, support groups, treatment options, and publications). http://www.parkinson.org

“We Move” Foundation (a useful central information resource). http://www.wemove.org

Unified Parkinson’s Disease Rating Scale (UPDRS). http://www.mdvu.org/library/ratingscales/pd/updrs.pdf

General Principles in Older Adults

ET is the most common movement disorder, affecting 4% of adults 40 years of age and older. Age and family history are the strongest risk factors. It has been referred to as familial tremor, but a significant percentage of ET patients do not have a family history. The term “benign” ET, used to differentiate it from tremors associated with PD and other neurodegenerative diseases, has fallen out of use, as the tremor itself can be quite disabling. There is also recent controversy regarding considering ET as a neurodegenerative disorder or a condition of normal aging of the nervous system.

Clinical Findings

ET is characterized by a postural-kinetic tremor, although rest tremor can occur. It often involves the arms, but commonly involves the head and voice as well. It is unusual for ET to be prominent in the legs, lips or chin. Bilateral involvement is the general rule but it can be asymmetric. An isolated head tremor can occur, but these cases are considered variants of cervical dystonia. ET progresses slowly and remains mild in majority of cases. In fact, some estimate that less than 10% of people with ET seek medical attention. ET worsens with anxiety, stress and caffeine intake, and is frequently reduced by alcohol, although this can be true for all forms of tremor.

ET is a clinical diagnosis, usually made by a thorough history and examination. Other than the tremor, neurologic examination should be normal, except for possible subtle findings such as hearing loss and subtle cerebellar signs.

Differential Diagnosis

The differential diagnosis includes parkinsonism, with a resting tremor and other signs. Action tremors are also found in dystonia and Wilson disease, but these conditions are associated with other neurologic abnormalities and occur in a younger population. Secondary causes of postural and kinetic tremor should only be considered with unusual presentations of tremor. Tobacco and caffeine use, as well as certain medications (see Table 24–1), may result in an enhanced physiologic tremor that can closely mimic ET. Tremor can be seen with alcohol or sedative withdrawal, and can occur as part of a somatoform disorder or conversion disorder. Psychogenic tremors are usually interrupted on examination by distracting the patient.

Complications

ET can result in significant functional impairment and social embarrassment. ET has significant effects on functional status, especially on ADLs and IADLs, like feeding, dressing, manual work, and household chores. Furthermore, ET can have significant psychological impact as it worsens in social situations and can result in early retirement, social isolation, and increased level of care. Tremor is not the only neurologic manifestation of ET. Recent studies show patients with additional findings, such as subtle cerebellar dysfunction (difficulty with tandem gait, slight incoordination), mild cognitive deficits, anxiety, and hearing loss. ET is also associated with a higher risk of PD and may be associated with an increased risk of dementia.

Treatment

All current treatments for ET are solely symptomatic. The goal of treatment is not to eradicate all tremor, but to improve function and reduce social embarrassment. If the tremor is mild and nondisabling, treatment may not be required. Stress reduction and caffeine avoidance can ameliorate tremor, and can be sufficient in mild ET. Alcohol may reduce tremor, but regular use is not recommended because of rebound tremor and long-term effects, including a higher rate of alcoholism in ET patients. Occupational therapists can provide adaptive utensils and devices that can improve QOL. All medications for tremor can cause side effects and should be started at low doses and gradually increased until satisfactory control or intolerable side effects occur. Severe, refractory or atypical cases should be referred to a specialist for management including consideration for DBS.

Pharmacotherapy

First-line agents—

Propranolol and primidone have the most evidence of efficacy in treating ET, reducing tremor by approximately 50% to 70% of patients. Propranolol is a nonselective β-blocker that crosses the blood–brain barrier, and the only agent approved by the FDA for ET. The average effective dose is 120 mg/day, up to 320 mg if tolerated. Mild ET can be treated with as-needed doses. Sustained-release preparations are equally effective. Potential side effects include bronchoconstriction, bradycardia, hypotension, lightheadedness, fatigue, impotence, and depression. Other β blockers are less effective than propranolol. Primidone is structurally similar to barbiturates. Most patients respond to about 250 mg daily. Adverse effects include sedation, dizziness, ataxia, confusion, and depression. Response to treatment and side effects guide dose adjustments. Combining propranolol and primidone may provide additive benefit.

Second-line agents—

Gabapentin or topiramate are antiseizure drugs that can be added to first-line agents if tremor control is unsatisfactory. Gabapentin is well tolerated, with typical effective dose around 1200 mg daily. Common side effects include sedation, dizziness, and unsteadiness. Topiramate is effective at doses above 100 mg twice daily. Its use is limited because of cognitive side effects, reduced appetite, weight loss, and paresthesia. Zonisamide is an alternative to topiramate, and is better tolerated and dosed daily. Benzodiazepines are occasionally used to control tremor, but common side effects (eg, sedation, cognitive dysfunction, hypotension, respiratory inhibition and abuse potential) limit their use. Calcium-channel blockers, theophylline, carbonic anhydrase inhibitors, isoniazid, clonidine, and phenobarbital have yielded contradictory results and are not recommended as first- or second-line agents.

Other pharmacotherapies—

The use of botulinum toxin type A to treat limb tremor has been disappointing, and its use should only be considered in rare refractory cases. However, neck injections can be quite effective in reducing head tremor. A high risk of dysphagia limits its use for voice tremor.

Surgical Therapies

There is extensive evidence that unilateral thalamotomy or thalamic (ventral intermediate [VIM]) DBS is effective in treating patients with disabling, medication-refractory ET. Dysarthria, dysequilibrium, and cognitive impairment may occur after thalamotomy. DBS appears to be associated with fewer adverse events and bilateral intervention is better tolerated. The decision to use either procedure depends on individual patient circumstance, perioperative risks, and access availability to ongoing stimulator monitoring and adjustments.