Which possible adverse effects are associated with the use of dopamine replacement drugs

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Approach Considerations

The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long as possible while minimizing adverse effects. Studies demonstrate that a patient's quality of life deteriorates quickly if treatment is not instituted at or shortly after diagnosis. [44]

Symptomatic and neuroprotective therapy

Pharmacologic treatment of Parkinson disease can be divided into symptomatic and neuroprotective (disease modifying) therapy. At this time, there is no proven neuroprotective or disease-modifying therapy.

Levodopa, coupled with carbidopa, a peripheral decarboxylase inhibitor (PDI), remains the gold standard of symptomatic treatment for Parkinson disease. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the systemic circulation, allowing for greater levodopa distribution into the central nervous system. Levodopa provides the greatest antiparkinsonian benefit for motor signs and symptoms, with the fewest adverse effects in the short term; however, its long-term use is associated with the development of motor fluctuations (“wearing-off”) and dyskinesias. Once fluctuations and dyskinesias become problematic, they are difficult to resolve.

Monoamine oxidase (MAO)-B inhibitors can be considered for initial treatment of early disease. These drugs provide mild symptomatic benefit, have excellent adverse effect profiles, and, according to a Cochrane review, have improved long-term outcomes in quality-of-life indicators by 20-25%. [45]

Dopamine agonists (ropinirole, pramipexole) provide moderate symptomatic benefit and delay the development of dyskinesia compared with levodopa. Proactively screen patients receiving oral dopamine agonists for adverse events. A review of the Cochrane and PubMed databases from 1990 to 2008 found that these agents caused a 15% increase in adverse events such as somnolence, sudden-onset sleep, hallucinations, edema, and impulse control disorders (eg, pathologic gambling, shopping, and Internet use; hypersexuality; and hoarding). [46] Note that patients may be reluctant to mention these events or may not attribute them to their treatment.

Symptomatic anti-Parkinson disease medications usually provide good control of motor signs of Parkinson disease for 4-6 years. After this, disability often progresses despite best medical management, and many patients develop long-term motor complications, including fluctuations and dyskinesias. Additional causes of disability in late disease include postural instability (balance difficulty) and dementia. Thus, symptomatic therapy for late disease requires different strategies.

Neuroprotective therapy aims to slow, block, or reverse disease progression; such therapies are defined as those that slow underlying loss of dopamine neurons. Although no therapy has been proven to be neuroprotective, there remains interest in the long-term effects of MAO-B inhibitors. Other agents currently under investigation include creatine and isradipine.

The younger the patient, the more emphasis the authors place on long-term considerations to guide early treatment. Young patients have a longer life expectancy and are more likely to develop motor fluctuations and dyskinesias. For older patients and those with cognitive impairment, less emphasis is placed on long-term considerations; instead, the focus is on providing adequate symptomatic benefit in the near term, with as few adverse effects as possible.

For patients who have motor fluctuations and dyskinesias that cannot be adequately managed with medication manipulation, surgery is considered. The principal surgical option is deep brain stimulation (DBS), which has largely replaced neuroablative lesion surgeries. Levodopa/carbidopa intestinal gel infusion is available in some countries and is in clinical trials in others, including the United States. [12]

Nonmotor symptoms

It is now recognized that in Parkinson disease, nonmotor symptoms may be as troublesome as, or more troublesome than, motor symptoms. Nonmotor symptoms can be categorized as autonomic, cognitive/psychiatric, and sensory [47] and may include depression, dementia, hallucinations, rapid eye movement (REM) sleep behavior disorder (RMD), orthostatic hypotension, and constipation. Nonmotor symptoms can also fluctuate, especially depression, pain, numbness, paresthesia/dysesthesia, akathisia, and restless-legs syndrome. Recognition of nonmotor symptoms of Parkinson disease is essential for appropriate management. [47]

Screen Parkinson disease patients for depression, and treat it when present. An evidence-based guideline from the American Academy of Neurology (AAN) reports that physician recognition of depression is low in Parkinson disease, at less than 30% of clinically proven cases. There are many factors that confound its diagnosis in these patients; and depression has the single largest effect on the quality of life of patients with Parkinson disease. [26, 48]

In 2010, the AAN released guidelines on the treatment of nonmotor symptoms of Parkinson disease. Recommendations included the following [49] :

• Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction

• Polyethylene glycol may be considered to treat constipation

• Modafinil should be considered for patients who subjectively experience excessive daytime somnolence

• For insomnia, evidence is insufficient to support or refute the use of levodopa to improve objective sleep parameters that are not affected by motor symptoms; evidence is also insufficient to support or refute the use of melatonin for poor sleep quality

• Levodopa/carbidopa should be considered to treat periodic limb movements of sleep in Parkinson disease, but there are insufficient data to support or refute the use of nonergot dopamine agonists to treat this condition or that of restless-legs syndrome

• Methylphenidate may be considered for fatigue (note: methylphenidate has the potential for abuse and addiction)

• Evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence, anxiety, and RMD

Symptomatic Therapy, Early Disease

Medications commonly used for symptomatic benefit of motor symptoms in early Parkinson disease include levodopa, monoamine oxidase (MAO)-B inhibitors, and dopamine agonists.

Levodopa

Levodopa, coupled with a peripheral dopa decarboxylase inhibitor such as carbidopa, remains the standard of symptomatic treatment for Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short term. However, long-term use of levodopa is associated with the development of fluctuations and dyskinesias. Once fluctuations and dyskinesias become problematic, they are difficult to resolve. These adverse effects are the reason to consider delaying the initiation of levodopa if other alternatives are able to control symptoms.

Levodopa/carbidopa is introduced at a low dose and escalated slowly. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the systemic circulation, allowing for greater levodopa delivery into the central nervous system.

Currently available levodopa preparations in the United States include levodopa/carbidopa immediate-release (IR) tablets (Sinemet), levodopa/carbidopa controlled-release (CR) tablets (Sinemet CR), and levodopa/carbidopa orally disintegrating tablets (Parcopa). The orally disintegrating tablet is bioequivalent to oral levodopa/carbidopa IR, but it dissolves on the tongue without the need to swallow it with water. The orally disintegrating tablet is not absorbed in the mouth but travels in the saliva to absorption sites in the proximal small bowel (where other levodopa preparations are also absorbed).

Levodopa/carbidopa is also available in combination with entacapone, a catechol-O-methyltransferase (COMT) inhibitor. When entacapone is given in conjunction with levodopa and carbidopa, plasma levels of levodopa are higher and more sustained than after administration of levodopa and carbidopa alone. Levodopa/carbidopa/entacapone is useful in advanced Parkinson disease in patients with motor fluctuations. In the STRIDE-PD (STalevo Reduction In Dyskinesia Evaluation) study, patients with early Parkinson disease treated with levodopa/carbidopa/entacapone (Stalevo) developed more dyskinesia than patients treated with levodopa/carbidopa; therefore, levodopa/carbidopa/entacapone is not recommended for treatment of early disease. [50]

Levodopa in combination with a dopa decarboxylase inhibitor is started at a low dose and slowly titrated to control clinical symptoms. Most patients experience a good response on a daily levodopa dosage of 300–600 mg/day (usually divided 3 or 4 times daily) for 3–5 years or longer. Doses higher than those necessary to control symptoms adequately should be avoided, because higher doses increase the risk for the development of dyskinesia. [51] If nausea occurs, the levodopa dose can be taken immediately following a meal. Additional measures to alleviate nausea include adding extra carbidopa or introducing domperidone (available outside the United States). Other side effects include dizziness and headache. In elderly patients, confusion, delusions, agitation, hallucinations, and psychosis may be more commonly seen.

MAO-B inhibitors

MAO-B inhibitors, such as selegiline and rasagiline, may be used for early symptomatic treatment of Parkinson disease. These medications provide mild symptomatic benefit, have excellent adverse effect profiles, and may improve long-term outcomes. These characteristics make MAO-B inhibitors a good choice as initial treatment for many patients. When the MAO-B inhibitor alone is not sufficient to provide good control of motor symptoms, another medication (eg, a dopamine agonist or levodopa) can be added.

Selegiline is indicated as adjunctive therapy (5 mg every morning; maximum, 10 mg/day) in the treatment of Parkinson disease in patients being treated with levodopa/carbidopa. Rasagiline is indicated for the treatment of the signs and symptoms of Parkinson disease as initial monotherapy (1 mg/day) and as adjunctive therapy (0.5-1.0 mg/day) to levodopa. Potential side effects include nausea, headaches, and dizziness.

Dopamine agonists

Initial treatment with a dopamine agonist, to which levodopa can be added as necessary, is associated with fewer motor fluctuations and dyskinesias than levodopa alone in prospective, double-blind studies. Subsequent analyses of these studies indicate that the benefit of dopamine agonists in delaying motor symptoms is due to their ability to delay the need for levodopa/carbidopa. [52, 53] Commonly used dopamine agonists include pramipexole and ropinirole.

Dopamine agonists provide symptomatic benefit that is comparable to that with levodopa/carbidopa in early disease, but these agents lack sufficient efficacy to control signs and symptoms by themselves in more advanced disease. Dopamine agonists provide moderate symptomatic benefit and rarely cause fluctuations and dyskinesias by themselves, but they have more adverse effects than levodopa, including sleepiness, hallucinations, edema, and impulse control disorders. However, these adverse effects resolve upon lowering the dose or discontinuing the medication.

Dopamine agonists are commonly reserved for younger individuals (< 65-70 years) who are cognitively intact. When the dopamine agonist (with or without an MAO-B inhibitor) no longer provides good control of motor symptoms, levodopa can be added. However, dopamine agonists may provide good symptom control for several years before levodopa is required.

For patients aged 65-70 years, the authors make a judgment based on general health and cognitive status. The more robust and cognitively intact the patient, the more likely the authors are to treat with a dopamine agonist before levodopa and add levodopa/carbidopa when necessary. For patients with cognitive impairment and those older than 70 years—who may be prone to adverse effects, such as hallucinations, from dopamine agonists—and for those likely to require treatment for only a few years, the authors may elect not to use a dopamine agonist and instead depend on levodopa/PDI (peripheral decarboxylase inhibitor) as primary symptomatic therapy.

When introducing a dopamine agonist, it is important to start at a low dose and escalate slowly. The dose should be titrated upward until symptoms are controlled, the maximum dose is reached, or adverse effects emerge.

The most common adverse effects of dopamine agonists are nausea, orthostatic hypotension, hallucinations, somnolence, and impulse control disorders. Nausea can usually be reduced by having the patient take the medication after meals. Domperidone, a peripheral dopamine agonist available outside the United States, is very helpful in relieving refractory nausea.

Patients on dopamine agonists should be routinely asked about sleepiness, sudden onset of sleep, and impulse control disorders such as pathologic gambling, shopping, internet use, and sexual activity. These adverse effects typically resolve with reduction in dose or discontinuation of the medication. Patients should be warned not to drive if they are experiencing undue sleepiness. They should also be warned about the possibility of impulse control disorders and the need to let their physician know if such an effect occurs.

Anticholinergic agents

Anticholinergic agents can be used for patients who have disability due to tremor that is not adequately controlled with dopaminergic medication, but these are not first-line drugs, because of their limited efficacy and the possibility of neuropsychiatric side effects. Anticholinergic medications provide good tremor relief in approximately 50% of patients but do not meaningfully improve bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication but not another, a second anticholinergic agent usually can be tried if the first is not successful. These medications should be introduced at a low dose and escalated slowly to minimize adverse effects, which include memory difficulty, confusion, and hallucinations. Adverse cognitive effects are relatively common, especially in elderly persons.

One of the most commonly used anticholinergic is trihexyphenidyl. The initial dose of trihexyphenidyl should be low and gradually increased. It is recommended to begin therapy with a single 1-mg dose. Dosage can be titrated by 1 mg each week or so, until a total of 4-6 mg is given daily or until satisfactory control is achieved. Some patients may require higher doses. Benztropine (Cogentin) is also commonly used, with an initial dose of 0.5-1 mg daily at bedtime. Dose can be titrated at weekly intervals in increments of 0.5 mg to a maximum of 6 mg/day.

Amantadine

Amantadine is an antiviral agent that has antiparkinsonian activity. Its mechanism of action is not fully understood, but amantadine appears to potentiate CNS dopaminergic responses. It may release dopamine and norepinephrine from storage sites and inhibit the reuptake of dopamine and norepinephrine. Amantadine may offer additional benefit in patients experiencing maximal or waning effects from levodopa.

Amantadine is commonly introduced at a dose of 100 mg per day and slowly increased to an initial maintenance dose of 100 mg 2 or 3 times daily. The most concerning potential side effects of amantadine are confusion and hallucinations. Common side effects include nausea, headache, dizziness, and insomnia. Less frequently reported side effects include anxiety and irritability, ataxia, livedo reticularis, peripheral edema, and orthostatic hypotension.

In a small, double-blind crossover study, amantadine was found to ameliorate pathologic gambling associated with Parkinson disease. [54] However, in a large cross-sectional study, amantadine was associated with a higher prevalence of impulse control disorders, including gambling. [55] Thus, further research is needed to understand the role of amantadine as a treatment or cause of impulse control disorders in patients with Parkinson disease.

Symptomatic Therapy, Advanced Disease

Motor fluctuations

Patients initially experience stable, sustained benefit through the day in response to levodopa. However, after several months to years, many patients notice that the benefit from immediate-release (IR) levodopa/carbidopa wears off after 4-5 hours. Over time, this shortened duration of response becomes more fleeting, and clinical status fluctuates more and more closely in concert with peripheral levodopa concentration. Ultimately, benefit lasts only about 2 hours. The time when medication is providing benefit for bradykinesia, rigidity, and tremor is called "on" time, and the time when medication is not providing benefit is called "off" time.

Treating motor fluctuations in the absence of peak-dose dyskinesia is relatively easy. Several different strategies, either alone or in combination, can be used to provide more sustained dopaminergic therapy. Possible strategies include the following:

• Adding a dopamine agonist, catechol-O -methyltransferase (COMT) inhibitor, monoamine oxidase (MAO)-B inhibitor, or selective adenosine antagonist

• Dosing levodopa more frequently

• Increasing the levodopa dose

• Adding intermittent levodopa inhaled doses

• Switching from immediate-release (IR) to sustained-release (CR) levodopa/carbidopa or levodopa/carbidopa/entacapone

• Continuous intrajejunal infusion of a carbidopa/levodopa enteral suspension [56]

In January 2015, the FDA approved a carbidopa/levodopa enteral suspension (Duopa) that is infused into the jejunum by a portable pump. The efficacy of the enteral suspension to decrease off-time and increase on-time was shown in a multicenter, international study. From baseline to 12 weeks, mean off-time decreased by 4.04 hours for 35 patients allocated to the levodopa/carbidopa intestinal group compared with a decrease of 2.14 hours for 31 patients allocated to immediate-release oral levodopa/carbidopa (p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11 hours in the intestinal gel group and 2.24 hours in the immediate-release oral group (p=0.0059). [56]

Safinamide (Xadago), a MAO-B inhibitor, was approved by the FDA in March 2017 as add-on treatment for patients with Parkinson disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. It is the first new chemical entity approved in the United States in more than 10 years. Approval was based on 2 phase-III trials that included nearly 1200 patients who had PD with motor fluctuations. Results showed that safinamide as add-on treatment to levodopa/carbidopa provided a significant reduction in off-time and a significant increase in on-time without troublesome dyskinesia in patients experiencing motor fluctuations. [57, 58]

Levodopa inhaled (Inbrija), a dopamine agonist, was approved in December 2018 for intermittent treatment of "off" episodes in patients who are already treated with oral carbidopa/levodopa. The inhaled dosage form bypasses the digestive system, thereby providing a quick onset of action as soon as 10 minutes. Approval was based on the phase 3 SPAN-PD trial (N = 339). The change at week 12 in UPDRS III score was -9.83 for patients receiving the 84-mg dose compared with -5.91 for the group taking placebo (P = 0.009). [59]

Istradefylline (Nourianz), a selective adenosine A2A antagonist, was approved by the FDA in August 2019 as adjunctive treatment to levodopa/carbidopa in adults with PD experiencing “off” episodes. Approval was based on four randomized, placebo-controlled trials (n=1143) in patients stabilized on levodopa/carbidopa with or without other medications for their Parkinson disease. Results showed statistically significant decreases in OFF time in the istradefylline treatment groups compared with placebo. [60, 61, 62]  

Unless limited by the emergence of peak-dose symptoms such as dyskinesia or hallucinations, dopaminergic therapy should be increased until off-time is eliminated. Once-daily formulations of the dopamine agonists ropinirole and pramipexole are now available. These medications appear to provide efficacy and safety similar to the IR formulations that are administered 3 times daily. [63]

Dyskinesia

By several months to years after the introduction of levodopa, many patients develop peak-dose dyskinesia consisting of choreiform, which is twisting/turning movements that occur when levodopa-derived dopamine levels are peaking. At this point, increasing dopamine stimulation is likely to worsen peak-dose dyskinesias, and decreasing dopamine stimulation may worsen Parkinson disease motor signs and increase off time. The therapeutic window lies above the threshold required to improve symptoms (on threshold) and below the threshold for peak-dose dyskinesia (dyskinesia threshold). The therapeutic window narrows over time because of a progressive decrease in the threshold for peak-dose dyskinesia.

Although many patients prefer mild dyskinesia to off time, the clinician should recognize that dyskinesias can be sufficiently severe to be troublesome to the patient, either by interfering with activities or because of discomfort. Asking patients how they feel during both off time and time with dyskinesia is important in titrating medication optimally. Having patients fill out a diary may be helpful; the diary should be divided into half-hour time periods on which the patient denotes whether they are off; on without dyskinesia; on with non-troublesome dyskinesia; or on with troublesome dyskinesia (see the following image). The goal of medical management is to minimize off time and time on with troublesome dyskinesia. Stated another way, the goal is to maximize on time without troublesome dyskinesia.

Treatment of motor fluctuations with dyskinesia

The treatment of patients with both motor fluctuations and troublesome peak-dose dyskinesia can be difficult. The goal of treatment in this situation is to provide as much functional time throughout the day as possible. This is accomplished by maximizing on time without troublesome dyskinesia. An attempt is made to reduce both off time and time with troublesome or disabling dyskinesia. Unfortunately, a decrease in dopaminergic therapy may increase off time, and an increase in dopaminergic therapy may worsen peak-dose dyskinesia.

For patients on the levodopa/carbidopa CR formulation, switching to levodopa/carbidopa IR often provides a more consistent and predictable dosing cycle and allows finer titration. In general, smaller levodopa doses are administered more frequently. A dose should be sought that is sufficient to provide benefit without causing troublesome dyskinesia. The time to wearing-off then determines the appropriate interdose interval. The extreme of this strategy is using liquid levodopa, a solution with which the dose can be titrated finely and administered every hour.

COMT inhibitors inhibit the peripheral metabolism of levodopa to 3-O -methyldopa (3-OMD), thereby prolonging the levodopa half-life and making more levodopa available for transport across the blood-brain barrier over a longer period. Because of the potential risk of hepatotoxicity with tolcapone (Tasmar), liver function test monitoring is required, and this medication should be used only in patients who are experiencing motor fluctuations on levodopa that cannot be adequately controlled with other medications. If dyskinesia occurs, the levodopa dose should be reduced. In patients who already have dyskinesia, the levodopa dose often is reduced by 30-50% at the time tolcapone is introduced.

Entacapone (Comtan) is a COMT inhibitor that does not cause hepatotoxicity; liver function tests are not required with this medication. Levodopa/carbidopa/entacapone (Stalevo) is currently available as a drug combination for Parkinson disease.

Another COMT inhibitor, opicapone (Ongentys), was approved in April 2020. It is taken PO once daily at bedtime. Approval was based on the BIPARK-1 and BIPARK-2 phase 3 clinical studies (n ~1000). A significant reduction of daily OFF time and dyskinesia with opicapone 50 mg was observed compared with placebo (P < 0.0001). [64]  

Similarly, dopamine agonists can be added to levodopa to try to smooth the response. If the patient has both fluctuations and dyskinesias on levodopa, adding a dopamine agonist is likely to decrease the disease severity and could delay dyskinesias and motor fluctuations; then, an attempt can be made to lower the levodopa dose.

The FDA approved amantadine (Gocovri) extended-release (ER) capsules for the treatment of dyskinesia in Parkinson disease patients receiving levodopa-based therapy, with or without concomitant dopaminergic medications. Amantadine ER, previously known as ADS-5102, is the first drug FDA-approved for this indication.

The safety and efficacy of amantadine ER was seen in two Phase 3 controlled trials in Parkinson disease patients with dyskinesia. In the Easy LID trial, amantadine ER-treated patients had statistically significant and clinically relevant reductions in dyskinesia as per the Unified Dyskinesia Rating Scale (UDysRS) total score vs. placebo at Week 12 (37% vs. 12%). In the Easy LID 2 trial, amantadine ER-treated patients had a 46% reduction in UDysRS compared with 16% in the placebo arm. For both studies, treatment with amantadine ER increased functional time daily (ON time without troublesome dyskinesia) for patients at Week 12 (3.6 hours and 4.0 hours, respectively) vs. placebo (0.8 hour and 2.1 hours, respectively). [65, 66]

This should be considered for patients who have clinically relevant dyskinesia and who appear likely to be able to tolerate this medication. Results from the 3-month, parallel-group, washout AMANDYSK (AMANtadine for DYSKinesia) study showed that amantadine treatment maintained its antidyskinetic effect over several years in patients with Parkinson disease and levodopa-induced dyskinesia. [67, 68]

The principal side effects of amantadine are hallucinations and confusion, so the drug is usually not appropriate for patients with preexisting cognitive dysfunction.

For patients who have motor fluctuations and dyskinesia that cannot be adequately managed with medication manipulation, surgery is considered.

Tremor

Levodopa/carbidopa, dopamine agonists, and anticholinergics each provide good benefit for tremor in approximately 50-60% of patients. If a patient is experiencing troublesome tremor and if symptoms are not controlled adequately with one medication, another should be tried. If the tremor is not controlled adequately with medication, surgical therapy may be considered at any time during the disease.

Bradykinesia

A study published in Neurology found that laser shoes can improve freezing episodes in patients with PD. The shoes are specially designed to emit a laser beam on the ground ahead, providing a visual cue to the patient and a target to aim for. In the study, the shoes cut freezing episodes and their overall duration by 49.5% when patients were off medication and 37.7% when patients were on medication. [69]

Putative Neuroprotective Therapy

Neuroprotective therapies are defined as those that slow underlying loss of neurons. Currently, no proven neuroprotective therapies exist for Parkinson disease. If a neuroprotective therapy were available for Parkinson disease, it would be administered from the time of diagnosis onward. At the current time, the greatest interest in possible neuroprotection resides with the monoamine oxidase (MAO)-B inhibitors, selegiline, and rasagiline. Other agents of interest include creatine and isradipine. Clinical trials have not provided support for neuroprotective effects for vitamin E or coenzyme Q10.

Selegiline

Selegiline (Eldepryl, Zelapar) is an irreversible inhibitor of MAO-B. In humans, brain dopamine is metabolized by MAO-B, and the blockade of this enzyme will reduce the metabolism of dopamine. Selegiline was shown conclusively to delay the need for levodopa therapy in early Parkinson disease, in the DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) study. [70, 71] The Parkinson Study Group evaluated the ability of selegiline and tocopherol to delay progression of clinical disability in early Parkinson disease by randomizing 800 patients to receive selegiline (10 mg/day) or placebo and tocopherol (2000 IU/day) or placebo. Patients who received selegiline, with placebo or with tocopherol, experienced a significant delay in the need for levodopa therapy. Patients who received placebo required levodopa at a projected median of 15 months from enrollment, whereas those who received selegiline required levodopa ataprojectedmedianof24monthsafterenrollment.Tocopherolhadnoeffectonprogression of disability. [70, 71]

Because selegiline was observed to provide a small but statistically significant symptomatic (early) benefit, it is not possible to determine whether a neuroprotective effect contributed to the delay in need for levodopa in the DATATOP study. [70, 71]

In another study, patients with early Parkinson disease who received selegiline over a 7-year period experienced less clinical progression and required less levodopa than patients receiving placebo. [72] In this study, patients with early Parkinson disease were randomized to selegiline or placebo, and levodopa was added as needed. After 5 years, patients who were treated with placebo had Unified Parkinson Disease Rating Scale (UPDRS) scores that were 35% higher (worse) than those treated with selegiline, even as they were receiving 19% higher doses of levodopa. [72] This is a striking finding, considering that as monotherapy in early disease, selegiline provides only modest symptomatic improvement.

Selegiline is the medication that first garnered wide interest as a possible neuroprotective agent for Parkinson disease. Laboratory investigations continue to provide evidence that selegiline affords a neuroprotective effect for dopamine neurons independent of MAO-B inhibition. Selegiline was reported to protect dopamine cells in mice from MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity, even when the agent was administered after a delay sufficient to allow the oxidation of MPTP to MPP+ (1-methyl-4-phenylpyridinium), [73] an effect that cannot be attributed to MAO-B inhibition.

In cell-culture systems, selegiline's neuroprotective effect is mediated by new protein synthesis. Selegiline induces transcriptional events that result in increased synthesis of antioxidant and antiapoptotic proteins. Evidence indicates that one of selegiline's metabolites, desmethylselegiline, is the active agent for neuroprotection. It is possible that selegiline's amphetamine metabolites may interfere with its neuroprotective actions.

Rasagiline

Rasagiline (Azilect) is also an MAO-B inhibitor that exhibits neuroprotective effects in cell culture and animal models. Possible disease-modifying effects of rasagiline were studied in 2 large, delayed-start studies. In such studies, subjects are randomized to treatment with active study medication or to placebo followed by active study medication. This creates 2 phases within the study. In phase I, one group is on placebo, and the other is on active study medication; in phase II, both groups are receiving active study medication. If phase II is long enough to allow full wash-in of symptomatic effects, any differences between the groups at the end of the study should be due to enduring benefits (ie, disease modification) that accrue only to the group that received active study medication during phase I.

Stated another way, in a delayed-start design, half of the subjects in the study take the trial drug from day 1 and the other half take placebo. However, halfway through the study, the placebo group is switched from placebo to the trial drug. If the drug is truly beneficial in slowing progression of the disease, those that started the trial on placebo should never catch up, in terms of disease progression, to those who were given the trial drug from the beginning of the study.

ADAGIO and TEMPO studies

In October 2011, the US Food and Drug Administration’s (FDA’s) Peripheral and Central Nervous System Drugs Advisory Committee voted against approval of an indication for disease-modifying effects for rasagiline. The advisory committee determined that the 2 delayed-start rasagiline studies did not provide compelling evidence that rasagiline slows progression of Parkinson disease. These trials were the ADAGIO (Attenuation of Disease progression with Azilect Given Once-daily) [74, 75] and TEMPO (Rasagiline in Early Monotherapy for Parkinson's Disease Outpatients) [76, 77] studies, which are discussed below.

In the TEMPO study, patients were randomized to treatment with rasagiline 1 mg/day for 12 months; rasagiline 2 mg/day for 12 months; or placebo for 6 months, followed by rasagiline 2 mg/day for 6 months. [76] Rasagiline administered at a dosage of 1 or 2 mg/day for the first 6 months resulted in improved Unified Parkinson Disease Rating Scale (UPDRS) scores relative to placebo; there was also a higher proportion of patients with treatment responses in the active treatment groups than in the placebo group. [76] In addition, both of the rasagiline groups showed significant differences, compared with the placebo group, in the motor and activities of daily living (ADL) subscales of the UPDRS and in the Parkinson Disease Quality of Life (PDQUALIF) scale. [76]

Over the 12 months of the TEMPO study, patients who were initially treated with placebo had a greater progression in clinical symptomatology as assessed by UPDRS scores than did patients who were treated with rasagiline for the full 12 months. This finding suggested that there was an effect over and above a simple symptomatic effect and potentially consistent with a disease-modifying effect. [78] When the TEMPO investigators looked at the long-term (6.5-year follow-up period) outcome of early rasagiline therapy relative to late therapy in early Parkinson disease, patients in the early rasagiline treatment group—who received the drug from the beginning of the TEMPO study—had significantly less worsening of their total UPDRS scores than patients in the delayed-start group, even as investigators added other antiparkinson medications as needed. [77]

In the large and rigorous delayed-start study called ADAGIO, patients with early Parkinson disease were randomized to rasagiline 1 mg/day for 18 months; rasagiline 2 mg/day for 18 months; placebo for 9 months, followed by rasagiline 1 mg/day for 9 months; or placebo for 9 months, followed by rasagiline 2 mg/day for 9 months. Results demonstrated that rasagiline at 1 or 2 mg/day was associated with a slower rate of worsening in the active drug groups, relative to the placebo groups. [75] Over 18 months, rasagiline 1 mg/day started early resulted in less worsening in mean total UPDRS score than when it was started late. However, for the groups that received rasagiline 2 mg/day, there was no difference at 18 months between the early-start and delayed-start groups. [75]

Based on their findings, the ADAGIO investigators concluded that early treatment with rasagiline at a dose of 1 mg/day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg/day did not. [75] They speculated that the effect of the 2-mg dose on symptoms may have masked any disease-modifying effects in patients with mild Parkinson disease; they also noted that it was possible that results with 1 mg/day were false positive, rather than the results with 2 mg/day being false negative. [75]

Thus, there remains interest as to whether selegiline and rasagiline improve long-term outcome for Parkinson disease patients, but this is not definitively proven, and the mechanism is unclear.

Levodopa

Clinical trial data suggest that levodopa therapy in early Parkinson disease can potentially slow progression or has a prolonged effect on the symptoms of the disease. [79] However, neuroimaging studies also indicate that loss of nigrostriatal dopamine nerve terminals may be accelerated or the dopamine terminals may be modified with use of levodopa. [79] In a study by Parkkinen et al that evaluated whether chronic levodopa use accelerates pathologic cerebral processes in parkinsonism, the investigators did not find such a progression based on nigral neuronal count and Lewy body pathology. [80] Nonetheless, the lowest dose that is necessary to maintain good function should be used to avoid motor complications. [23] Additional research is needed to determine whether levodopa accelerates, slows, or has no effect on disease progression.

Dopamine agonists

Dopamine agonists have been used to provide symptomatic relief in early Parkinson disease. In vivo experiments have demonstrated that the ergot and nonergot dopamine agonists protect cultured cells from death due to oxidative damage. Clinical data in patients with early Parkinson disease provide neuroimaging results that suggest a possible neuroprotective effect. [79, 81] Various studies have been conducted with ropinirole and pramipexole; however, definitive neuroprotection cannot be confirmed on the basis of these studies. [82, 83]

Deep Brain Stimulation

Deep brain stimulation (DBS) has become the surgical procedure of choice for Parkinson disease for the following reasons:

• It does not involve destruction of brain tissue

• It is reversible

• It can be adjusted as the disease progresses or adverse events occur

• Bilateral procedures can be performed without a significant increase in adverse events

Deep brain stimulation, a form of stereotactic surgery, has made a resurgence in the treatment of Parkinson disease largely because long-term complications of levodopa therapy result in significant disability over time. A better understanding of basal ganglia physiology and circuitry and improvements in surgical techniques, neuroimaging, and electrophysiologic recording have allowed surgical procedures to be performed more accurately and with lower morbidity.

Surgery for movement disorders previously involved predominantly destructive lesioning of abnormally hyperactive deep brain nuclei; however, the observation that high-frequency electrostimulation in the ventral lateral nucleus (VL) of the thalamus eliminates tremors in patients undergoing thalamotomy led to investigation of long-term DBS as a reversible alternative to lesioning procedures.

Continued refinement of the knowledge of basal ganglia circuitry and Parkinson disease pathophysiology has narrowed the focus of movement disorder surgery to 3 key gray-matter structures: the thalamus, the globus pallidus, and the subthalamic nucleus (STN). Currently, the STN is the most commonly targeted site for Parkinson disease. (See the following image.)

DBS surgery includes subthalamic nucleus (STN) stimulation, globus pallidus interna (GPi) stimulation, and thalamic deep brain stimulation (see the following images). The UK National Collaborating Centre for Chronic Conditions notes the following indications for STN and GPi in patients with Parkinson disease [23] :

• The presence of motor complications refractory to medical therapy

• The absence of significant comorbidities in a biologically fit individual

• The absence of significant mental health problems (eg, depression, dementia)

• Response to levodopa

A key to patient selection is that appropriate patients still experience a good response to levodopa, but that response cannot be adequately maintained through the day or is complicated by excessive dyskinesia.

Thalamic DBS has been used in patients with predominantly severe and disabling tremor. [23] However, this surgery is now rarely used in patients with Parkinson disease, because it has been shown that other symptoms continue to progress, causing significant disability that is not controlled by thalamic DBS.

Recent landmark studies have demonstrated the effectiveness of STN and GPi DBS for appropriate Parkinson disease patients. [84] In a randomized, controlled trial of 255 patients enrolled in the Veterans Affairs (VA) Cooperative Studies Program (CSP) trial for patients with advanced Parkinson disease, bilateral DBS (STN and GPi) was more effective than best medical therapy in improving on time without troublesome dyskinesia, motor function, and quality of life at 6 months; however, DBS was associated with an increased risk of serious adverse events. [85] In the same study, when the 2-year outcomes of 147 patients who received STN DBS and 152 patients who received GPi DBS were compared, motor function and adverse events were not significantly different between the 2 sites. [86] However, those who received STN DBS had a greater reduction in dopaminergic medications, and individuals who received GPi DBS had significantly less depression. [86]

Investigators from the EARLYSTIM Study Group reported that relative to medical therapy alone, STN DBS in conjunction with medical therapy offers benefits earlier in the course of PD, before the appearance of severe disabling motor complications. [87, 88] Moreover, subthalamic stimulation plus medical therapy was superior to medical therapy alone on several key measures of quality of life and motor function. However, 54.8% of the patients in the DBS group suffered serious adverse events, compared to 44.1% of those in the medical-therapy group [87, 88] ; 17.7% of patients suffered serious adverse events related to surgical implantation or the neurostimulation device.

A study by Foltynie assessed 79 consecutive patients who underwent bilateral subthalamic nucleus DBS at the National Hospital for Neurology and Neurosurgery using an MRI-guided surgical technique without microelectrode recording. [89] At a median follow-up period of 12-14 months, a mean improvement of 27.7 points (standard deviation, 13.8) was noted in the off-medication motor part of the Unified Parkinson Disease Rating Scale (UPDRS III), equivalent to a mean improvement of 52%. Significant improvements in dyskinesia duration, disability, and pain were noted. This suggests that in well-selected patients with Parkinson disease, image-guided STN DBS without microelectrode recording can lead to substantial improvements in motor disability and improvements in quality of life, with very low morbidity.

A randomized trial by Moreau et al assessed the effectiveness of the drug methylphenidate in improving gait disorders and freezing of gait in patients with advanced Parkinson disease without dementia who also received subthalamic nucleus stimulation (STN). Eighty-one patients from 13 movement disorders departments in France were randomly assigned to methylphenidate or placebo for 90 days. Compared with patients in the placebo group, patients in the methylphenidate group used fewer steps at 90 days. These results suggest methylphenidate may improve gait hypokinesia and freezing although further study is needed to determine long-term risks. [90]

There is evidence that long-term motor improvement from STN DBS is sustained overall. However, axial signs progressively decline over time and contribute to a waning of the initial benefit of this procedure. [91]

Although not specifically approved by the Food and Drug Administration (FDA) for pain, STN DBS may be effective in improving specific types of pain related to Parkinson disease, [92, 93] such as musculoskeletal pain [92, 94] and dystonic pain. However, there is a risk of postoperative deterioration of somatic pain exacerbated by Parkinson disease and radicular/peripheral neuropathic pain due to lumbar spine diseases. Patients with central pain have had a poor response to STN DBS. [92]

STN DBS may result in either a favorable or an unfavorable outcome in patients with Parkinson disease and impulse control and related disorders. [95] Although there may be resolution or improvement of impulse control disorders following STN DBS, the procedure may also induce, exacerbate, reveal, or have no effect on these conditions. [95]

In 2017, the FDA approved the Vercise DBS system to treat symptoms of Parkinson disease. The device is a rechargeable implantable pulse generator with a potential battery life of 15 years. It has been available in Europe since 2012. [96]

(See Deep Brain Stimulation forParkinson Disease for a more extensive discussion of deep brain stimulation in this setting, including mechanisms of action, advantages and disadvantages, and stages of the procedure.)

Neuroablative Lesion Surgeries

Lesion surgeries involve the destruction of targeted areas of the brain to control the symptoms of Parkinson disease. Lesion surgeries for Parkinson disease have largely been replaced by deep brain stimulation (DBS). During neuroablation, a specific deep brain target is destroyed by thermocoagulation. A radiofrequency generator is used most commonly to heat the lesioning electrode tip to the prescribed temperature in a controlled fashion.

Thalamotomy and pallidotomy

Thalamotomy involves destruction of a part of the thalamus, generally the ventralis intermedius (VIM), to relieve tremor. The VIM nucleus is considered the best target for tremor suppression, with excellent short- and long-term tremor suppression in 80-90% of patients with Parkinson disease. Thalamotomy has little effect on bradykinesia, rigidity, motor fluctuations, or dyskinesia. When rigidity and akinesia are prominent, other targets, including the globus pallidus interna (GPi) and subthalamic nucleus (STN), are preferred.

Svenillson and Leksell described ventral posterior pallidotomy in the 1960s [97] ; however, their report was largely overlooked. The original pallidotomy target was in the medial and anterodorsal part of the nucleus. This so-called medial pallidotomy effectively relieved rigidity but inconsistently improved tremor. Leksell subsequently moved the target to the posteroventral and lateral GPi, resulting in sustained improvement in as many as 96% of patients. In 1992, Laitinen et al reported reduced tremor, rigidity, akinesia, and levodopa-induced dyskinesia in 38 patients treated with pallidotomy, prompting a reappraisal of the procedure performed with more modern techniques. [98]

Pallidotomy involves destruction of a part of the GPi. Pallidotomy studies have demonstrated significant improvements in each of the cardinal symptoms of Parkinson disease (tremor, rigidity, bradykinesia), as well as a significant reduction in dyskinesia.

The most serious and frequent (3.6%) adverse effect of pallidotomy is a scotoma in the contralateral lower-central visual field. This complication occurs when the GPi lesion extends into the optic tract, which lies immediately below the GPi. The risk of visual-field deficit is reduced greatly by accurate delineation of the ventral GPi border by microelectrode recording. Less frequent complications (< 5%) include injury to the internal capsule, facial paresis, and intracerebral hemorrhage (1-2%). Abnormalities of speech, swallowing, and cognition may also be observed.

Bilateral pallidotomy is not recommended because complications are relatively common and include speech difficulties, dysphagia, and cognitive impairment.

Subthalamotomy

Hyperactivity of the excitatory STN projections to the GPi is a crucial physiologic feature of Parkinson disease. Subthalamotomy involves destruction of a part of the STN. Although lesioning the STN usually has been avoided because of the concern about producing hemiballismus, results obtained by experimental lesions of the STN in animals and humans suggest that subthalamotomy may be performed safely and may reverse parkinsonism dramatically. Subthalamotomy studies have shown significant improvements in the cardinal features of Parkinson disease, as well as the reduction of motor fluctuations and dyskinesia.

Preoperative Evaluation

Good surgical outcomes begin with careful patient selection and end with attentive, detail-oriented postoperative care. The authors believe that this level of care is best provided by a multidisciplinary team that includes a movement disorder neurologist, a neurosurgeon who is well-versed in stereotactic technique, a neurophysiologist, a psychiatrist, and a neuropsychologist. Additional support from neuroradiology and rehabilitation medicine is essential.

First, a neurologist with expertise in movement disorders evaluates the patient. Patient selection is particularly important for successful subthalamic nucleus (STN) deep brain stimulation (DBS), because a number of factors determine positive surgical outcome. [99, 100] These can be summarized as follows:

• A diagnosis of Parkinson disease

• Positive response to levodopa

• Absence of atypical parkinsonian features

• Advanced disease, virtually unmanageable with dopaminergic medications

• Relatively young age; however, advanced age (>75 years) is not an absolute contraindication to surgery (if a patient otherwise meets the selection criteria for a procedure and the quality of life is predicted to improve substantially, surgery should be offered)

• No significant cognitive impairment

• Absence of active psychiatric disease

• Good social support and access to programming

Potential surgical candidates are then evaluated by the neurosurgeon, who determines whether the patient is indeed a surgical candidate and decides which procedure(s) would benefit the patient most. Close collaboration between the neurologist and the neurosurgeon aids the decision-making process, minimizing patient confusion and stress. If the neurologist and neurosurgeon agree that the patient is a good surgical candidate, further workup includes the following:

• Brain magnetic resonance imaging (MRI) to rule out comorbid conditions and to assess the degree of brain atrophy; significant atrophy may increase the risk of perioperative hemorrhage

• Detailed neuropsychological testing to rule out cognitive impairment, which can be worsened by the surgical procedure

A psychiatrist with expertise in psychiatric complications of movement disorders may be consulted to rule out active psychiatric disease and screen for relevant past psychiatric history that may pose a contraindication to surgery (eg, major depression, suicidality).

A fluorodopa positron emission tomography (PET) scan may be performed in the unusual circumstance of diagnostic uncertainty. A medical evaluation is performed to determine the patient's general fitness for surgery.

Surgery is reserved for patients with disabling motor fluctuations and dyskinesia or disabling tremor that cannot be adequately controlled with medications. Key points to consider are as follows:

• Ablative surgery such as thalamotomy, pallidotomy, and subthalamotomy have largely been replaced by DBS

• Thalamic DBS is offered to the minority of patients with Parkinson disease who have predominant and disabling tremor (more commonly, this procedure is performed on patients with disabling essential tremor)

• Bilateral STN DBS (or globus pallidus interna [GPi] DBS) is offered to patients with advanced Parkinson disease with disabling motor fluctuations and/or dyskinesia or disabling tremor that cannot be adequately controlled by medications; outcomes have been shown to be similar after STN and GPi DBS

• Before surgery, the patient should be informed that these procedures do not cure Parkinson disease and that progression is expected

Neural Transplantation

Neural transplantation is a potential treatment for Parkinson disease, because the most significant neuronal degeneration is site and type specific (ie, dopaminergic); the target area is well defined (ie, striatum); postsynaptic receptors are relatively intact; and the neurons provide tonic stimulation of the receptors and appear to serve a modulatory function.

Transplantation of autologous adrenal medullary cells and fetal porcine cells has not been found to be effective in double-blind studies and has been abandoned. Although open-label studies of fetal dopaminergic cell transplantation yielded promising results, 3 randomized, double-blind, sham-surgery–controlled studies found no net benefit. In addition, some patients receiving these transplants developed a potentially disabling form of dyskinesia that persisted even after withdrawal of levodopa. Features such as gait dysfunction, freezing, falling, and dementia are likely due to nondopaminergic pathology and hence are unlikely to respond to dopaminergic grafts. [101]

Lewy body–like inclusions have been found in grafted nigral neurons in long-term transplant recipients; these inclusions stained positively for alpha-synuclein and ubiquitin and had reduced immunostaining for dopamine transporter, suggesting that Parkinson disease may affect grafted cells. [14]

Human retinal pigment epithelial cells produce levodopa, and retinal pigment epithelial cells in gelatin microcarriers have been implanted into the putamen in preliminary studies. A phase II double-blind, randomized, multicenter, sham-surgery–controlled study of this technique has been completed. [102, 103] Parkinson disease patients received no benefit from this procedure compared to sham surgery. In addition, in one case study, postmortem examination in a patient who died 6 months after surgical implantation of 325,000 retinal pigment epithelial cells found only 118 surviving cells. [104]

Gene Therapy

Several studies have demonstrated the safety of gene therapy as a treatment for Parkinson disease, and larger studies have been initiated to examine the efficacy of this procedure. Three investigational strategies that use gene transfer for targeted protein expression are as follows [105] :

• Improving dopamine availability to the striatum using more continuous delivery,

• Reducing STN activity with local induction of gamma-aminobutryic acid (GABA) expression

• Protection/restoration of nigrostriatal neuronal function with trophic factor expression

A double-blind, phase II, randomized, controlled trial of gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) in Parkinson patients aged 30-75 years suggested mild efficacy. Further studies are ongoing. [106]

Management of Psychiatric Comorbidities

Dementia

Although no specific therapy exists for dementia, the American Academy of Neurology evaluated the evidence regarding the use of cholinesterase inhibitors in Parkinson disease dementia. [107] Based on their review, they suggested that rivastigmine (Exelon) and donepezil (Aricept) are probably effective in treating Parkinson disease dementia. Anticholinergic drugs used for the treatment of motor symptoms of Parkinson disease may exacerbate memory impairment. When possible, avoid these medications.

Depression

Depression is one of the most common nonmotor symptoms of Parkinson disease, occurring in approximately 35% of patients. [108, 109] This condition is more common in patients with Parkinson disease than in the general elderly population and in those with chronic conditions such as osteoarthritis. Depression in Parkinson disease has a profound impact on quality of life and is associated with reduced function, cognitive impairment, and increased caregiver stress.

A systematic review of prevalence studies of depression in Parkinson disease found that 17% of patients present with major depression, 22% with minor depression, and 13% with dysthymia [110] Moreover, multiple studies have found that a history of depression is a risk factor for the subsequent development of Parkinson disease. [111]

Imaging, cerebrospinal fluid, and autopsy studies indicate that depression in Parkinson disease is associated with dysfunction of basal ganglia dopaminergic circuits that project to the frontal lobes, as well as noradrenergic limbic and brainstem structures. [109] Whether serotonin (5-HT) dysfunction plays a role in depression in PD is unclear.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used medications to treat depression in Parkinson disease in clinical practice. However, several randomized controlled trials, systematic reviews, and meta-analyses have suggested that SSRIs may be no more effective than placebo in this situation. [48, 109, 112]

Positive results in randomized clinical trials have been demonstrated for nortriptyline (a tricyclic antidepressant [TCA] with serotoninergic and adrenergic activity), desipramine (a predominantly noradrenergic reuptake inhibitor TCA), venlafaxine (a serotonin-noradrenaline uptake inhibitor), citalopram (an SSRI), and paroxetine (an SSRI). [109] For example, in Parkinson disease patients that were diagnosed with depressive disorder or operationally-defined subsyndromal depression, venlafaxine extended release or paroxetine significantly reduced scores on the Hamilton Rating Scale for Depression compared to placebo. Both venlafaxine and paroxetine were well tolerated and did not worsen motor function. [113]

There is a suggestion that noradrenergic or dual action (noradrenergic/serotoninergic) antidepressants may be more effective for treating depression in Parkinson disease than SSRIs. However, whether this is an artifact of clinical-trials methodology is not yet clear, and more research is necessary.

Antiparkinsonian medications can also exert an antidepressant effect. In a large, randomized trial, pramipexole (mean daily dose, 2.18 mg) significantly reduced depression scores relative to placebo. [114] The monoamine oxidase (MAO)-B inhibitor selegiline was also demonstrated to provide an antidepressant effect in patients with early Parkinson disease who were not clinically depressed. [115]

Preliminary studies suggest that repetitive transcranial magnetic stimulation (rTMS) may be effective for depression in Parkinson disease, but more research is required. Electroconvulsive therapy (ECT) can be considered for refractory moderate to severe depression.

Psychotic symptoms (hallucinations or delusions)

Antiparkinsonian drugs can trigger psychosis in patients with Parkinson disease. In Parkinson disease patients with psychosis, antiparkinsonian medications other than levodopa should be withdrawn in an effort to resolve psychosis while maintaining motor control with levodopa. In individuals with only mild hallucinations that are well tolerated, active antipsychotic treatment may not be necessary.

Pimavanserin (Nuplazid) was approved in April 2016 for treatment of hallucinations and delusions associated with Parkinson disease psychosis. It is the first drug to be approved for this condition. It is a selective serotonin inverse agonists (SSIA). It not only preferentially targets 5-HT2A receptors, but also avoids activity at dopamine and other receptors commonly targeted by antipsychotics. Efficacy was shown in a 6-week clinical trial (n=199), where it was shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor Parkinson disease symptoms (p=0.001). [116]

Use of some other typical antipsychotics can exacerbate motor symptoms of Parkinson disease and should be avoided. [23]

Quetiapine is the atypical neuroleptic agent most commonly used by movement-disorder experts, because it rarely exacerbates motor symptoms and blood monitoring is not required. However, its efficacy has not been confirmed in clinical trials. Quetiapine is used in Parkinson disease at doses much lower than those used in schizophrenia. It is usually introduced at a dose of 25 mg at bedtime and can be increased to 50 mg or more at bedtime as necessary.

Clozapine can also be used, but blood monitoring is required due to its potential for agranulocytosis and other severe side effects. [23, 117] For this reason, clozapine is usually reserved for patients who are not adequately controlled with quetiapine. Other atypical neuroleptics generally have more potential to worsen Parkinson disease motor symptoms than quetiapine and clozapine.

Anxiety

The 2010 American Academy of Neurology (AAN) practice parameter on the treatment of nonmotor symptoms in Parkinson disease found insufficient evidence to support or refute the treatment of anxiety in Parkinson disease with levodopa. [49] However, SSRIs and venlafaxine (Effexor, Effexor XR) may be beneficial. Buspirone is well tolerated but has not been studied in this population. Benzodiazepines can be considered, but adverse effects such as cognitive impairment, somnolence, and balance problems may be concerning. Behavior modification techniques can play an important role in the treatment of anxiety. [118]

Impulse behaviors

Cognitive-behavioral therapy (CBT) can help control impulse behaviors in PD. In a study of 45 patients with idiopathic PD and associated impulse control behaviors that had not responded to standard treatment, CBT significantly improved symptom severity, neuropsychiatric disturbances, and depression and anxiety levels. Of the 45 patients, 17 were randomly assigned to a 6-month wait list for CBT along with standard medical care and 28 were randomized to CBT starting immediately. Among the 28 patients in the treatment group, 58% completed all 12 sessions of CBT and 88% completed at least 6. Three-quarters of those receiving the treatment had improved symptom severity compared with only about a third of those who did not receive the therapy. [119, 120]

In a placebo-controlled pilot study of 50 patients with idiopathic PD who developed impulse control disorder (ICD) symptoms while receiving dopamine agonist treatment, Papay and colleagues found that the opioid antagonist naltrexone improved ICD symptoms, as measured on a PD-specific rating scale. [121, 122]

Naltrexone was administered at 50 mg daily for 4 weeks and then increased to 100 mg daily for 4 weeks in nonresponders. The difference in response rate on the Clinical Global Impression-Change (CGI-C) scale between the naltrexone (54.5%) and placebo (34.8%) groups was not significant (P = 0.23). Estimated changes on the patient-completed Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) from baseline to week 8, however, significantly favored naltrexone: a change of 14.9 points for naltrexone vs 7.5 points for placebo (P = 0.04). Nausea and headache were the most common side effects of naltrexone treatment. [121, 122]

Sleep disturbances

Benzodiazepines can be helpful in the treatment of rapid eye movement (REM) sleep behavior disorder (RBD), and obstructive sleep apnea (OSA) can be treated with positive airway pressure with either continuous pressure or bilevel pressure. Sleep hygiene techniques include avoiding stimulants/fluids near bedtime, avoiding heavy late-night meals, and following a regular sleep schedule. [118, 123] It is advised that patients with Parkinson disease and sudden-onset sleep avoid driving and take precautions against potential occupational hazards. [23]

The 2010 AAN practice parameter found insufficient evidence to support or refute beneficial effects from the treatment of RBD in Parkinson disease. Other sleep disorders may benefit from treatment. Levodopa/carbidopa should be considered to treat periodic limb movements of sleep. Modafinil may improve patients’ subjective perceptions of excessive daytime somnolence (EDS), and methylphenidate may be considered in patients with fatigue. [49]

Exercise and Physical Therapy

Exercise therapy in patients with Parkinson disease using a variety of physiotherapy interventions may play a role in improving gait, balance and flexibility, aerobic capacity, initiation of movement, and functional independence. Studies generally have suggested improvement in functional outcomes, but the observed benefits were small in magnitude and were not sustained following discontinuation of the exercise. [83]

A systematic review of 33 randomized trials involving 1518 patients evaluated various physiotherapy interventions, including general physiotherapy, exercise, treadmill training, cueing, dance and martial arts. There were significant improvements for walking speed, walking endurance and step length, mobility (the Timed Up & Go test), and balance. Unified Parkinson’s Disease Rating Scale (UPDRS) scores were also improved with physiotherapy. There was no benefit observed for falls or patient-rated quality of life, and there was no evidence that one type of physiotherapy was superior to others. [124]

There has been a resurgence of interest in the potential benefit of exercise in Parkinson disease, including a possible neuroprotective effect. [125] Vigorous exercise in mid-life is associated with a reduced risk of subsequent Parkinson disease. In animal models, vigorous exercise provides a protective effect against a variety of toxins that cause parkinsonism. In addition, in healthy people, serum brain-derived neurotrophic factor (BDNF) increases after exercise, in proportion to the intensity of the activity. In Parkinson disease, BDNF levels in the substantia nigra are reduced, and in animal models of Parkinson disease, BDNF provides a neuroprotective effect. This is an area of active research.

Speech Therapy

The laryngeal manifestations of Parkinson disease often lead to decreased participation in the activities of daily living because of an inability to communicate effectively. During the course of the disease, 45-89% of patients report speech problems, and more than 30% find speech problems to be the most debilitating part of the disease.

Medications and surgery cannot effectively treat the laryngeal manifestations of Parkinson disease. For this reason, speech therapy plays a key role in the disease's vocal treatment regimen. Speech therapy is effective in treating the laryngeal manifestations of Parkinson disease, but despite the significant number of patients with vocal symptoms, only an estimated 3-4% of patients with Parkinson disease undergo speech therapy.

The Lee Silverman Voice Treatment (LSVT) is a program designed to increase vocal intensity in patients with Parkinson disease. The treatment focuses on a simple set of tasks that are practiced intensively, 4 sessions per week during a 4-week period, resulting in maximization of phonatory and respiratory functions. The goal of LSVT is to improve vocal performance for 6-24 months without interval intervention. LSVT focuses on maximizing vocal effort ("think loud, think shout") and maximizing sensory perception of vocal effort and loudness by therapists. Therapists who quantify results give constant feedback to patients during sessions and encourage patients to self-monitor and internally calibrate their loudness. After LSVT, patients with Parkinson disease speak at a normal volume and with a healthy voice quality despite the need to "think loud, think shout."

In studies with a 2-year follow-up, patients who received LSVT maintained or improved vocal intensity compared with pretreatment levels. Glottal incompetence and swallowing ability both improved after LSVT, without any significant change in supraglottal hyperfunction. Preliminary positron emission tomography (PET) scans after LSVT training in patients with Parkinson disease show reduced activity in the globus pallidus, an effect similar to pallidotomy. LSVT may also stimulate coordination of motor output beyond the phonatory system in the form of increased orofacial expression.

Other therapies have been suggested for the treatment of the vocal symptoms in Parkinson disease, but most data so far support LSVT as the most promising therapy for Parkinson disease laryngeal symptoms. Alternative methods of delivering therapy that do not involve 16 face-to-face sessions with a therapist are currently being studied. These methods incorporate webcam delivery of LSVT (eLOUD) and software programs that patients can perform at home. These technologically enhanced methods, when used to replace half of the face-to-face sessions, have documented outcomes that are equivalent to classic LSVT. The hope is that such alternatives will be implemented to allow a less transportation-intensive therapy course for the patient and to allow follow-up review of the LSVT techniques as needed.

A systematic review of clinical trials of speech and language therapy in Parkinson disease identified 3 randomized controlled trials that included 61 patients. The authors concluded that although improvements were noted, they were not able to conclusively confirm or refute the benefit of speech and language therapy in Parkinson disease due to the small number of patients in these trials, methodologic limitations, and possible publication bias. [126]

Dietary Considerations

Proper nutritional support is essential for patients with Parkinson disease, including adequate dietary fiber to prevent the common problem of constipation. Patients recently diagnosed with Parkinson disease are often confused regarding dietary protein, because they receive conflicting information.

Levodopa is absorbed via a large neutral amino acid active carrier system and therefore competes with dietary proteins for absorption; this effect is generally relatively small and is not clinically important for most patients, especially those with early or moderate disease. However, as the disease progresses and patients become more and more sensitive to maintaining relatively narrow therapeutic serum concentrations of levodopa, this effect can become clinically relevant. These patients usually have significant motor fluctuations. Some report that when they are "on" and they eat a meal including protein, they turn "off." Others find that if they eat a protein meal, their next levodopa dose does not kick in. These patients may benefit from a low protein or a protein redistributed diet.

In a low-protein diet, the total daily protein intake is spread more or less equally over the day. In a protein-redistributed diet, individuals only consume food very low in protein during the day and then eat a high-protein meal in the evening. Unfortunately, these diets are difficult to follow; dietary consultation may be beneficial for patients in whom such diets are considered.

For patients with early and moderate Parkinson disease, the considerations are quite different. As with patients with more advanced Parkinson disease, patients with early and moderate Parkinson disease will get the most complete and consistent absorption of levodopa by taking their levodopa doses a half hour or more before meals or 1 hour or more after meals. However, most patients with early or moderate disease will not notice a difference in clinical benefit, whether they take their levodopa with meals or apart from meals.

Even if there is some reduction in clinical benefit when levodopa is taken with meals, this can be mitigated by increasing the levodopa dose, if necessary. In patients with early disease, the primary concern regarding levodopa is typically nausea, which is less likely to occur if they take their levodopa dose at the completion of meals. Therefore, in early Parkinson disease, it is common to instruct patients to take their levodopa after meals to reduce the likelihood of nausea as the dose is titrated to clinical effect.

Some studies have shown mild motor benefit with Mucuna pruriens (cowhage, velvet bean), which contain levodopa, and Vicia faba (broad or fava bean) may have short-term benefits. [83] However, additional studies are needed.

Vitamin E and coenzyme Q10 have not been shown to have a neuroprotective effect in Parkinson disease, [70, 127] and they are not currently recommended as dietary supplements for this condition.

Consultations

Generally, patients with Parkinson disease are best treated and monitored by a neurologist or movement disorder specialist. Depending on the patient, consultations may include the following:

• Neurosurgeon

• Psychiatrist

• Urologist

• Physiatrist

• Nutritionist

• Otolaryngologist

• Gastroenterologist

• Speech therapist

Neurosurgical consultation may be appropriate in patients with tremor, dyskinesias, motor fluctuations, or dystonia refractory to medical treatment. However, patients with dementia or significant psychiatric or behavioral problems are not candidates for current neurosurgical treatments for Parkinson disease.

Psychiatric consultation may be required to control mood disorders and psychiatric symptoms, especially in patients with refractory depression or psychosis.

A urologist is consulted for evaluation and treatment of urinary frequency, urgency, incontinence, or erectile dysfunction.

A physiatrist, physical therapist, or occupational therapist may be able to improve the patient's ability to perform activities of daily living, reduce pain, and avoid fractures and compression neuropathies from falls. Botulinum injections for limb dystonia can be very helpful and are administered by specially trained physiatrists or neurologists.

A nutritionist can help ensure adequate energy intake, particularly when low-protein diets are needed to avoid adverse effects of levodopa.

An otolaryngologist can offer vocal fold bulking procedures in the form of vocal fold injection or Gore-Tex thyroplasty as a possibility in treating refractory true vocal fold bowing. Bilateral injections to medialize the vocal fold can offer improvement, unless the patient is already aphonic due to advanced disease. Bilateral collagen, gel, fat, and hydroxyapatite injections have been used for this purpose. [128] Articulatory problems can persist, and the result of surgery can be disappointing.

A gastroenterologist and a speech therapist may be needed to evaluate dysphagia, a common complication in patients with more advanced Parkinson disease. Excessive sialorrhea can be treated with botulinum toxin injections into the salivary glands, usually administered by neurologists or otolaryngologists. In some patients, a gastrostomy may be needed to maintain adequate nutrition.

Long-Term Monitoring

Patients with Parkinson disease must have regular follow-up care to ensure adequate treatment of motor and behavioral abnormalities. Once patients are stable on a medication regimen, provide follow-up care at least every 3-6 months, and periodically adjust medication dosages as necessary. Patients also need to be monitored for adverse events, including somnolence, sudden-onset sleep, impulse control disorders, and psychosis. In addition, patients should be evaluated and treated for emergence of clinically relevant nonmotor symptoms, including dementia, psychosis, sleep disorders, and mood disorders.

Future Treatments for Parkinson Disease

Future treatments for Parkinson disease are covered in Future Treatments for Parkinson’s Disease: Surfing the PD Pipeline. This article provides a discussion of new therapies in clinical development that may alleviate motor features or slow disease progression, including A2a antagonists, levodopa formulations, other antiparkinsonian medications, antidyskinesia medications, and gene therapy. [129]

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Author

Robert A Hauser, MD, MBA Professor of Neurology, Molecular Pharmacology and Physiology, Director, USF Parkinson's Disease and Movement Disorders Center, National Parkinson Foundation Center of Excellence, Byrd Institute, Clinical Chair, Signature Interdisciplinary Program in Neuroscience, University of South Florida College of Medicine

Robert A Hauser, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Society of Neuroimaging, International Parkinson and Movement Disorder Society

Disclosure: Received consulting fee from Cerecor for consulting; Received consulting fee from L&M Healthcare for consulting; Received consulting fee from Cleveland Clinic for consulting; Received consulting fee from Heptares for consulting; Received consulting fee from Gerrson Lehrman Group for consulting; Received consulting fee from Indus for consulting; Received consulting fee from University of Houston for consulting; Received consulting fee from AbbVie for consulting; Received consulting fee from Adama.

Coauthor(s)

Kelly E Lyons, PhD Research Professor of Neurology, Director of Research and Education, Parkinson’s Disease and Movement Disorder Center, University of Kansas Medical Center

Kelly E Lyons, PhD is a member of the following medical societies: American Academy of Neurology, International Parkinson and Movement Disorder Society

Disclosure: Received honoraria from Novartis for speaking and teaching; Received honoraria from Teva Neuroscience for speaking and teaching; Received honoraria from St Jude Medical for board membership.

Theresa A McClain, RN, MSN, ARNP-BC Advanced Registered Nurse Practitioner and Investigator, Parkinson’s Disease and Movement Disorders Center, University of South Florida College of Medicine

Theresa A McClain, RN, MSN, ARNP-BC is a member of the following medical societies: Sigma Theta Tau International

Disclosure: Received consulting fee from Teva for consulting; Received consulting fee from Schering Plough for consulting; Received consulting fee from Biotie for consulting; Received consulting fee from Novartis for consulting.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Aquestive, Bioserenity, Ceribell, Eisai, Jazz, LivaNova, Neurelis, Neuropace, Nexus, SK life science, Stratus, Sunovion, UCB
Serve(d) as a speaker or a member of a speakers bureau for: Aquestive, Bioserenity, Ceribell, Eisai, Jazz, LivaNova, Neurelis, Neuropace, Nexus, SK life science, Stratus, Sunovion, UCB
Received research grant from: Cerevel, LivaNova, Greenwich (Jazz), SK biopharmaceuticals, Takeda, Xenon.

Acknowledgements

Ron L Alterman, MD Associate Professor of Neurosurgery, Mount Sinai School of Medicine; Consulting Surgeon, Department of Neurosurgery, Mount Sinai School of Medicine, Elmhurst Hospital, and Walter Reed Army Medical Center

Ron L Alterman, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Neurological Surgeons, Congress of Neurological Surgeons, Medical Society of the State of New York, and New York County Medical Society

Disclosure: Nothing to disclose.

Heather S Anderson, MD Assistant Professor, Staff Neurologist, Department of Neurology, Alzheimer and Memory Center, University of Kansas Medical Center

Heather S Anderson, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Jeff Blackmer, MD, FRCP(C) Associate Professor, Medical Director, Neurospinal Service, Division of Physical Medicine and Rehabilitation, The Rehabilitation Centre, University of Ottawa Faculty of Medicine; Executive Director, Office of Ethics, Canadian Medical Association

Jeff Blackmer, MD, FRCP(C) is a member of the following medical societies: American Paraplegia Society, Canadian Association of Physical Medicine and Rehabilitation, Canadian Medical Association, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Thomas L Carroll, MD Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Tufts University School of Medicine and Director, The Center for Voice and Swallowing, Tufts Medical Center

Thomas L Carroll, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Bronchoesophagological Association, American Laryngological Association, and American Medical Association

Disclosure: Merz aesthetics inc. Consulting fee Speaking and teaching

Richard J Caselli, MD Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale

Richard J Caselli, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, American Neurological Association, and Sigma Xi

Disclosure: Nothing to disclose.

Arif I Dalvi, MD Director, Movement Disorders Center, NorthShore University HealthSystem, Clinical Associate Professor of Neurology, University of Chicago Pritzker Medical School

Arif I Dalvi, MD is a member of the following medical societies: European Neurological Society and Movement Disorders Society

Disclosure: Nothing to disclose.

Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida

Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society

Disclosure: Nothing to disclose.

Stephen T Gancher, MD Adjunct Associate Professor, Department of Neurology, Oregon Health Sciences University

Stephen T Gancher, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, and Movement Disorders Society

Disclosure: Nothing to disclose.

Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA Professor of Neurology, University of Central Florida College of Medicine; Director of Cognitive Neurology, Director of Stroke Program, James A Haley Veterans Affairs Hospital

Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA is a member of the following medical societies: American Academy of Neurology, American Headache Society, American Heart Association, and American Society of Neuroimaging

Disclosure: Nothing to disclose.

Daniel H Jacobs MD, FAAN, Associate Professor of Neurology, University of Florida College of Medicine; Director for Stroke Services, Orlando Regional Medical Center

Daniel H Jacobs is a member of the following medical societies: American Academy of Neurology, American Society of Neurorehabilitation, and Society for Neuroscience

Disclosure: Teva Pharmaceutical Grant/research funds Consulting; Biogen Idex Grant/research funds Independent contractor; Serono EMD Royalty Speaking and teaching; Pfizer Royalty Speaking and teaching; Berlex Royalty Speaking and teaching

Robert M Kellman, MD Professor and Chair, Department of Otolaryngology and Communication Sciences, State University of New York Upstate Medical University

Robert M Kellman, MD is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Medical Association, American Neurotology Society, American Rhinologic Society, American Society for Head and Neck Surgery, Medical Society of the State of New York, and Triological Society

Disclosure: GE Healthcare Honoraria Review panel membership; Revent Medical Honoraria Review panel membership

Milton J Klein, DO, MBA Consulting Physiatrist, Heritage Valley Health System-Sewickley Hospital and Ohio Valley General Hospital

Milton J Klein, DO, MBA is a member of the following medical societies: American Academy of Disability Evaluating Physicians, American Academy of Medical Acupuncture, American Academy of Osteopathy, American Academy of Physical Medicine and Rehabilitation, American Medical Association, American Osteopathic Association, American Osteopathic College of Physical Medicine and Rehabilitation, American Pain Society, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Kat Kolaski, MD Assistant Professor, Departments of Orthopedic Surgery and Pediatrics, Wake Forest University School of Medicine

Kat Kolaski, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine and American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

Jose G Merino, MD Medical Director, Suburban Hospital Stroke Program

Jose G Merino, MD is a member of the following medical societies: American Heart Association and American Stroke Association

Disclosure: Nothing to disclose.

Arlen D Meyers, MD, MBA Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine

Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck Society

Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation Unrestricted gift Unknown; Axis Three Corporation Ownership interest Consulting; Omni Biosciences Ownership interest Consulting; Sentegra Ownership interest Board membership; Syndicom Ownership interest Consulting; Oxlo Consulting; Medvoy Ownership interest Management position; Cerescan Imaging Honoraria Consulting; GYRUS ACMI Honoraria Consulting

Lorraine Ramig, PhD Professor, Department of Speech Language Hearing Sciences, University of Colorado at Boulder; Senior Scientist, National Center for Voice and Speech (NCVS); Adjunct Professor, Department of Biobehavior, Columbia University Teacher's College

Disclosure: Nothing to disclose.

Alan D Schmetzer, MD Professor Emeritus, Interim Chairman, Vice-Chair for Education, Associate Residency Training Director in General Psychiatry, Fellowship Training Director in Addiction Psychiatry, Department of Psychiatry, Indiana University School of Medicine; Addiction Psychiatrist, Midtown Mental Health Cener at Wishard Health Services

Alan D Schmetzer, MD is a member of the following medical societies: American Academy of Addiction Psychiatry, American Academy of Clinical Psychiatrists, American Academy of Psychiatry and the Law, American College of Physician Executives, American Medical Association, American Neuropsychiatric Association, American Psychiatric Association, and Association for Convulsive Therapy

Disclosure: Eli Lilly & Co. Grant/research funds Other

Roy Sucholeiki, MD Director, Comprehensive Seizure and Epilepsy Program, The Neurosciences Institute at Central DuPage Hospital

Roy Sucholeiki, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, and American Neuropsychiatric Association

Disclosure: Nothing to disclose.

Margaret M Swanberg, DO Assistant Professor of Neurology, Uniformed Services University; Chief of Neurobehavior Service, Walter Reed Army Medical Center; Assistant Chief, Department of Neurology, Walter Reed Army Medical Center

Margaret M Swanberg, DO is a member of the following medical societies: American Academy of Neurology and American Neuropsychiatric Association

Disclosure: Nothing to disclose.

Michele Tagliati, MD Associate Professor, Department of Neurology, Mount Sinai School of Medicine; Division Chief of Movement Disorders, Mount Sinai Medical Center

Michele Tagliati, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, and Movement Disorders Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

B Viswanatha, MBBS, MS, DLO Professor of Otolaryngology (ENT), Chief of ENT III Unit, Sri Venkateshwara ENT Institute, Victoria Hospital, Bangalore Medical College and Research Institute; PG and UG Examiner, Manipal University, India and Annamalai University, India

B Viswanatha, MBBS, MS, DLO is a member of the following medical societies: Association of Otolaryngologists of India, Indian Medical Association, and Indian Society of Otology

Disclosure: Nothing to disclose.

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