Parkinson’s Disease- Treatment Update 2019

Introduction

Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disease whose cardinal features are tremor, bradykinesia and rigidity. Nonmotor features such as dementia, psychosis and autonomic dysfunction (excessive sweating, bladder frequency/urgency, orthostasis) often become the more disabling features as the disease progresses. Treatment significantly decreases morbidity and mortality; however, no treatment to date has been definitively shown to impact the underlying disease process.^[1] Medications providing the most benefit are directed at replenishing dopamine within the brain.

Goals of Therapy

• Improve functioning and quality of life
• Minimize acute and long-term side effects of medications
• Instill a positive outlook, despite the chronic, progressive nature of PD

Investigations

• The clinical diagnosis of PD can be made with confidence if the classic features of a unilateral or asymmetric resting tremor plus bradykinesia and rigidity are present. The patient’s earliest complaints may include fatigue, loss of smell, sleep disorders, general slowness, poor handwriting and a tremulous feeling in one arm, without obvious tremor.
• Early postural instability, autonomic dysfunction, early and prominent dementia, impaired eye movements, rapid progression and poor response to dopaminergic therapy are not features of early PD, and if present suggest a different diagnosis.
• Perform imaging studies in young patients or those with atypical features. Exclude Wilson disease in young patients by performing a serum ceruloplasmin, a slit-lamp examination and a 24-hour urine for copper.
• Exclude drug-induced parkinsonism. The most common drug causes include first- and second-generation antipsychotic agents and central dopamine-blocking antiemetics, e.g., metoclopramide and prochlorperazine.

Therapeutic Choices

Nonpharmacologic Choices

• Provide patient education via books, websites and local and national Parkinson societies (all available through Parkinsons Canada).
• Stress importance of staying active and having a regular exercise routine. To improve motor and nonmotor symptoms, the exercise program should include aerobic, strength, balance and gait training e.g., dance, tai chi, yoga.
• Encourage awareness of the important roles of allied health professionals such as speech, physical and occupational therapists,and home care as the disease becomes more advanced.
• Some patients may benefit from surgery;

Surgery

Recognition that there is a limit to the medical management of Parkinson’s has brought about a resurgence of surgical treatments. Two main surgical procedures have been shown to be effective: lesioning procedures and deep brain stimulation (DBS). Surgical treatment of Parkinson’s mainly targets the thalamus (improves tremor), globus pallidus (improves dyskinesia and bradykinesia) and the subthalamic nucleus (improves bradykinesia, tremor and dyskinesia).Lesioning procedures such as pallidotomy and thalamotomy are performed rarely. DBS is the surgical treatment of choice in patients with advanced disease in whom medications can no longer control motor symptoms, though use of subthalamic DBS in patients with early motor complications has shown promise. It is important for patients to understand that these surgeries are not a cure; functioning will increase only to the level of their best “on” times, and postural instability does not improve. Poor cognition is a contraindication to these procedures.

Pharmacologic Choices

Levodopa

Levodopa is converted to dopamine within presynaptic dopaminergic neurons. Although used alone when first discovered, it is now combined with a DOPA decarboxylase inhibitor (carbidopa or benserazide) to inhibit peripheral transformation to dopamine, thus enhancing distribution to the brain, reducing the amount of levodopa required for optimal therapeutic benefit and minimizing acute side effects such as nausea and vomiting.

There is theoretical concern that levodopa could be toxic to already damaged dopaminergic neurons through a mechanism involving excess oxidative stress. There is little evidence for this from in vitro studies, in vivo animal models or human studies.

Over time, many Parkinson’s patients develop symptoms such as dysarthria, gait disorders, postural instability and cognitive dysfunction that are poorly responsive to levodopa therapy. The cause is mainly disease-related degeneration of nondopaminergic neuronal systems, and not that levodopa has become ineffective for the initial symptoms for which it was started.

Though initially effective, in many patients levodopa therapy is eventually complicated by motor fluctuations and dyskinesia; these complications develop in up to 50% of patients after 5 years.In the early stages of Parkinsons, patients enjoy a long-lasting response following a single dose of levodopa. With disease progression and longer-term treatment, patients begin to experience motor fluctuations, such as end-of-dose “wearing off” of effectiveness or periods of fluctuating response known as “on-off” phenomena, and a variety of patterns of dyskinesia such as peak-dose dyskinesia (occurring during the peak effect of the dose), diphasic dyskinesia (occurring at the beginning and/or end of a dosing interval) and off-period dystonia (painful spasms, usually of the feet, occurring upon morning rising or when a dose is wearing off). There is also increasing recognition that nonmotor symptoms such as excessive perspiration, anxiety, cognitive changes and shortness of breath do occur and can fluctuate with the motor features of the disease.

The pathophysiology of motor complications is not completely understood, but the leading theory suggests they are related to pulsatile stimulation of dopamine receptors resulting from intermittent dosing and levodopa’s short plasma half-life.

Factors shown to increase the risk of levodopa-induced dyskinesia include higher doses of levodopa, longer duration of treatment, severity of the underlying nigral degeneration and a younger age at disease onset.Delaying the use of levodopa to preserve its effectiveness and minimize adverse effects, especially in young-onset patients, has been the standard of practice in many movement disorder centres; however, this approach is being questioned as the risks and benefits of delayed versus earlier treatment appear to be less clear, and the use of levodopa in younger patients is increasing. Slow-release preparations of levodopa benefit patients having difficulty with wearing off, although good randomized trials are lacking; there is no evidence that initiating treatment with controlled-release levodopa provides an advantage over immediate-release formulations.Other strategies to minimize pulsatile stimulation of dopamine, such as combining levodopa with a catechol-O-methyl transferase (COMT) inhibitor, have not delayed onset of motor fluctuations, and may actually increase the risk of dyskinesia.

For individuals whose motor fluctuations are not controlled with oral/transdermal medications, intrajejunal levodopa/carbidopa infusion therapy is now available in Canada. This gel formulation is supplied in cartridges and administered through a percutaneous gastrostomy connected to a wearable external pump. The patient’s levodopa levels are thus more stable throughout the day, which may reduce motor fluctuations.

Dopamine Agonists

Bromocriptine, pramipexole and ropinirole are effective as monotherapy in the early stages of the disease, and as adjunctive therapy with levodopa for patients with more advanced motor complications. Pergolide was withdrawn from the Canadian market in 2007 because of its association with cardiac valvulopathy; it is now available through Health Canada’s Special Access Programme for patients who meet specific criteria. Rotigotine, available as a transdermal patch formulation, has been shown to be effective in reducing Parkinson disease symptoms Transdermal delivery results in stable plasma concentrations (which avoids pulsatile stimulation of dopamine receptors), offers an alternative for patients wishing to reduce oral medications and may result in improved adherence.

Compared with levodopa, dopamine agonists are associated with fewer motor complications in the first 5 years of the disease, but it is unclear whether this translates into benefits in the long term when these problems become more significant. Although all clinical trials demonstrate a lower efficacy compared with levodopa, this difference does not seem to affect quality-of-life scores in early disease.Because of the lower incidence of motor complications, dopamine agonists had been typically used as initial therapy in younger patients, then levodopa would be added in the case of poor tolerance or inadequate benefit, or later because of waning efficacy of the dopamine agonist; however, this strategy is being re-examined and the use of levodopa in younger patients is rising.

Because bromocriptine can cause pulmonary fibrosis, the newer, non-ergot dopamine agonists (pramipexole and ropinirole) are better choices. Daytime sleepiness or sudden irresistible attacks of sleep can occur with all of the dopamine replacement medications, including levodopa, but occur more frequently with dopamine agonists compared with levodopa.Impulse control disorders such as hypersexual behaviour or pathologic gambling occur in up to 50% of patients taking dopamine agonists. It is important to discuss these significant side effects with your patient. Additional difficulties with dopamine agonists, compared with levodopa, include more GI upset, orthostatic hypotension and psychiatric reactions (hallucinations and confusion); in addition, supplementary levodopa is almost always required for supervening disability after varying periods of time. For these reasons, there has been a shift away from using dopamine agonists.

Apomorphine subcutaneous injection is the first member of a new category of Parkinson rescue medications to be approved in Canada. It is indicated for use during an off-episode that has not responded to adjustments to other medications. The onset of action is 10 minutes, with a duration of action of approximately 90 minutes. There is a significant risk of GI upset at the initiation of treatment that requires 2 days of pretreatment with domperidone. The initial dose is administered under medical supervision, typically in an outpatient clinic, in order to determine an appropriate starting dose and to assess for adverse effects, particularly orthostatic hypotension.

Monoamine Oxidase B Inhibitors

Early clinical evaluations of selegiline, an irreversible inhibitor of monoamine oxidase B (MAO-B), suggested that it might slow the progression of PD. Evidence now indicates that it does not have a substantial neuroprotective effect, and most of the apparent benefit during the first year of treatment is likely due to its mild effects on symptoms. In addition, it does not delay the development of dyskinesia or fluctuations associated with chronic levodopa therapy. A second, more potent MAO-B inhibitor, rasagiline, is now available as initial treatment to improve motor symptoms and for patients with more advanced disease to help with wearing off. Studies have suggested it may slow disease progression but this remains controversial.

Amantadine

Amantadine provides mild-to-modest improvement in about two-thirds of early Parkinson’s patients and improves levodopa-induced dyskinesia in the later stages of the disease. Its exact mechanism of action is unclear but it may release dopamine from the presynaptic terminals or block its reuptake. Amantadine is an N-methyl-D-aspartate (NMDA) antagonist, which may account for some of its antiparkinsonian efficacy. The blockade of NMDA receptors confers a neuroprotective effect in some animal models of parkinsonism, and it has been suggested that amantadine improves survival in PD patients; however, this is unproven. Amantadine is not recommended as a drug of first choice in the early management of PD. It may be considered in patients whose dyskinesias are not adequately managed by modifying existing therapy. It is easy to use and usually well tolerated; leg edema, erythema and livedo reticularis (a reversible condition characterized by a bluish, mottled appearance of the skin, mainly of the lower extremities) are the most common adverse events. In patients with cognitive deficits, amantadine can increase confusion and should not be used.

Anticholinergics

Anticholinergic drugs such as benztropine, ethopropazine and trihexyphenidyl have been used in the treatment of PD for decades, since before the availability of levodopa. Their major putative effect is on tremor, with little or no effect on bradykinesia; however, this has not been well studied. They can be used as monotherapy or as adjuncts to dopaminergic therapy. Their many side effects (e.g., dry mouth, urinary retention, constipation) limit their use, especially in the elderly, and they are not recommended as drugs of first choice.They should not be used in patients with dyskinesias and/or motor fluctuations.

Catechol-O-Methyl Transferase Inhibitors

Catechol-O-methyl transferase (COMT), an enzyme that helps metabolize levodopa, is found in both the brain and in the peripheral nervous system. COMT inhibitors such as entacapone help prevent peripheral metabolism of levodopa, which increases its availability to the brain, and have no effect if not used in conjunction with levodopa. Despite some studies showing additional improvement in activities of daily living, in nonfluctuating patients their use should be limited to patients with wearing off. Most of their side effects relate to increased dopaminergic activity in the brain, e.g., dyskinesia and, less often, confusion/hallucinations. Because of this, levodopa dosage may have to be reduced by up to 30% when a COMT inhibitor is initiated. Tolcapone was the first COMT inhibitor to be approved in Canada, but because of associated hepatotoxicity, it is now available only through Health Canada’s Special Access Programme for use in exceptional cases. Entacapone is not associated with liver toxicity, but other potential side effects are diarrhea (often weeks to months after initiation) and a harmless orange/brown discoloration of the urine that patients need to be warned about.

Treatment of Nonmotor Issues of Parkinson’s

Depression is common in Parkinson’s, but keep in mind that a lack of facial expression in a patient with PD does not necessarily indicate sadness or depression. SSRIs and tricyclic antidepressants (TCAs) have been the mainstay of therapy for depression in patients with PD, with an increasing number of studies showing improvement with a wide variety of antidepressants.TCAs should be used cautiously because their anticholinergic effects are more likely to induce delirium, especially in memory-impaired patients; they may also aggravate orthostatic hypotension, which can increase the risk of falls.

Psychosis and dementia are also common in Parkinson’s , typically in patients with more advanced disease. All medications used to treat motor symptoms can contribute to psychosis in a dose-related fashion. There is no need to treat hallucinations/delusions if they are well tolerated by the patient/caregivers. As the disease progresses, Parkinson’s medications often need to be reduced or withdrawn because of worsening of the patient’s cognitive status. Usually, anticholinergics are withdrawn first, then selegiline, rasagiline, amantadine, dopamine agonists and COMT inhibitors, until only levodopa remains. At that point, reducing the dose of levodopa is an option. Review other (non-PD) medications carefully to ensure they are not also contributing to the psychosis. For patients in whom an optimum balance cannot be found by adjusting Parkinson’s medications, antipsychotics are sometimes used. All antipsychotics have some potential to reduce control of movement disorders. The second-generation (atypical) antipsychotic clozapine appears to have the lowest risk and has shown clear benefit in randomized controlled trials for management of psychotic symptoms in patients with Parkinson’s . Quetiapine has not shown consistent benefit in clinical trials, yet is often tried first to avoid the blood monitoring requirements with clozapine use.Avoid olanzapine as it has not been shown to be effective and is poorly tolerated.

Cholinesterase inhibitors (e.g., donepezil, rivastigmine) have a modest impact on improving dementia, but careful observation for deterioration in motor function is required.

Autonomic dysfunction causes many issues, such as orthostatic hypotension, which tends to increase as the disease progresses. If conservative measures (e.g., increasing salt intake and hydration, avoiding alcohol) are not helpful, then adding domperidone, midodrine and/or fludrocortisone can be considered. Urinary urgency and incontinence can be treated with anticholinergic drugs; options with less blood-brain penetration (e.g., darifenacin, trospium) or the newer nonanticholinergic agents (e.g., mirabegron) that are less likely to cause confusion are preferred. Sildenafil, tadalafil and vardenafil can all be used for erectile dysfunction. Constipation requires continuous monitoring and treatment, as it is an almost universal problem. Limit drugs that have any anticholinergic effect. Ensure the patient has proper hydration with a high fibre diet and exercise before considering treatments like polyethylene glycol, lactulose or fibre supplements such as psyllium. OnabotulinumtoxinA, administered by a specialist, has been shown to be efficacious for the symptomatic control of sialorrhea; other medication options are typically poorly tolerated by patients with PD.

Therapeutic Tips in Parkinson’s

• Symptomatic treatment is not necessary in the early stage of PD when symptoms are noticed but not troublesome. All drugs have the potential to cause side effects that would outweigh their benefits at this stage of the disease.
• Start medication at low doses and titrate slowly, especially in the elderly, to minimize the acute side effects of medications.
• When levodopa or a dopamine agonist are initiated, domperidone (10–20 mg 30 minutes prior to each dose) can be helpful in minimizing gastric upset or orthostatic hypotension. Observational studies suggest that domperidone use may be associated with an increased risk of ventricular arrhythmia and sudden cardiac death in patients with PD who have a history of cardiovascular disease. This was observed in high risk patients at doses over 4 times a day.
• Levodopa may be taken with food early in therapy to ease nausea; it may be taken on an empty stomach in more advanced disease to help manage motor fluctuations.
• Individualize patient management based on the severity of disease, level of disability, cost, patient’s preference and patient’s age.
• Refer patients with dyskinesia and/or motor fluctuations to a health-care professional with specialist expertise in PD before modifying therapy.
• Optimizing the management of nonmotor difficulties and including the assistance of allied health professionals is important for maximizing a patient’s quality of life
• Impulse control disorders can develop in Parkinson’s patients under any dopaminergic therapy; patients taking dopamine agonists, with a history of previous impulsive behaviours and/or a history of alcohol consumption and/or smoking are at increased risk.
• Parkinsonism-hyperpyrexia syndrome (similar to neuroleptic malignant syndrome) is a potentially fatal complication of Parkinson’s treatment usually associated with abrupt reduction or discontinuation of dopaminergic drugs. Hyponatremia is also a risk factor. Medications should be reduced or withdrawn slowly. “Drug holidays” to reduce motor complications are not a recommended practice.
• Pregnancy and breastfeeding are uncommon considerations among patients with Parkinson’s . Expert consultation should be sought where possible; amantadine should be avoided.

References available upon request