Treatment Strategies For Parkinson’s Disease Must Evolve With The Predominant Problem At Each Stage Of The Disease.
Idiopathic Parkinson’s disease (IPD) is a common, progressive, neurodegenerative disease that affects 1 per cent of the population aged over 60. IPD is a complex disease, which manifests in different ways over the course of disease, so treatment strategies must evolve with the predominant problem at each stage of the disease.
IPD is a progressive, neurodegenerative disease characterised by cardinal motor features: Rest tremor, rigidity, bradykinesia, postural instability, flexed posture, and freezing. A wide range of non-motor symptoms are described in IPD, including fatigue, sleep disturbance, drooling of saliva, urinary dysfunction, skin changes, postural hypotension, and neuropsychiatric problems, including cognitive impairment, anxiety, depression, apathy, and psychosis. IPD is highly heterogenous, with clinical manifestations varying widely between patients and over the time course of the disease. As a result of this, a range of therapeutic options must be considered to optimise function and quality of life for people with IPD.
Diagnosis of IPD is based on clinical assessment and therefore estimates of incidence and prevalence vary, depending on the diagnostic criteria and epidemiologic methods used. IPD is the second-most common neurodegenerative disease of ageing (Alzheimer’s disease is the most common) with a prevalence of 0.3 per cent in the general population, rising to 1 per cent in people over 60 years of age. Prevalence and incidence of IPD is 1.5-to-2 times higher in men than women, which may be related to the effect of oestrogen on striatal dopamine levels.
DIAGNOSTIC CRITERIA FOR IPD
Despite increasing interest in biochemical and imaging biomarkers, IPD remains a clinically defined entity. Due to the heterogeneity of IPD presentations and clinical overlap between IPD and other neurodegenerative Parkinsonisms (ie, DLB, MSA, CBS, and PSP), it is impossible to make a diagnosis of IPD with certainty during life. Therefore, several diagnostic criteria have been proposed to aid the clinical diagnosis of IPD; the most recent guidelines from the Movement Disorders Society Clinical Diagnostic Criteria were published in 2015. These guidelines allow for a diagnosis of ‘clinically established PD’ based on the presence of Parkinsonism (defined as the presence of bradykinesia with either rest tremor, rigidity, or both), the absence of exclusion criteria or red flags, and the presence of two supportive criteria, while ‘probable PD’ can be diagnosed in the presence of red flags that are counterbalanced by supportive criteria. One notable alteration made by these criteria is the removal of early cognitive impairment as an exclusionary criterion and the inclusion of the category of ‘PD (Lewy body dementia subtype)’ to accommodate DLB.
The correlation between clinical diagnostic criteria and pathological diagnosis at autopsy remains imperfect, and it is hoped that in future, biochemical biomarkers may provide insight into pathological processes while patients are living.
TREATMENT OF EARLY-TO-MODERATE STAGE IPD
Treatment of IPD is complicated. Some patients will have a tremor-predominant phenotype, some prominent postural and gait abnormalities, and some will have a mixed phenotype with additional non-motor features. The individual response to dopaminergic therapy varies, as does the tolerability of medications. All patients with PD require an individualised approach to management with multidisciplinary input, including physiotherapy, occupational therapy, speech and language therapy, general practice and neurology/medicine for the elderly expertise. Patients may also require support from psychology, psychiatry, gastroenterology, and neurosurgical services.
Exercise plays an important role in maintaining strength and mobility in PD. Regular, consistent exercise is likely to be more effective than targeted, intense bursts. Speech and language therapy, in particular Lee Silverman Voice Treatment (LSVT), may help with hypophonia.
Pharmacological options in early-to-moderate stage disease include anticholinergics, monoamine oxidase B inhibitors (MAOB-I), dopamine agonists (DA), and levodopa treatment.
Where tremor is the predominant or only troublesome symptom, anticholinergic treatment may be helpful, but this has limited impact on non-tremor symptoms and its attendant side-effects of dry mouth, constipation, sexual dysfunction and confusion can be difficult to tolerate, particularly in older patients or those with early cognitive involvement.
Monoamine oxidase B (MAO-B) inhibitors such as selegiline and rasagiline give a minor symptomatic benefit and may be sufficient in very early disease. There is some evidence to support a neuroprotective effect of MAO-B inhibition, but interpretation of these trials is complicated by the long-lasting symptomatic effect of the medications.
Dopamine agonists are the second-most symptomatically effective treatment and offer the advantage, especially in younger patients, of postponing use of levodopa and the complications of prolonged levodopa use, such as dyskinesia and motor fluctuations. The use of dopamine agonists is complicated by side-effects, including hypersomnolence, orthostatic hypotension, and impulse control disorders. Dopamine agonists are available in modified-release preparations that allow them to be taken once per day or via a topical patch.
Exogenous levodopa, the immediate precursor to dopamine, is the most powerful drug available to counter the motor symptoms of PD. Levodopa has a short half-life, of approximately 90 minutes, and is usually given three-to-four times per day. Common early side-effects include nausea and light-headedness, while prolonged use is associated with the development of dyskinesias and motor fluctuations.
Symptoms consistent with REM sleep behaviour disorder (RBD) are a common finding in IPD. RBD can precede the motor symptoms on IPD by many years (so-called prodromal PD). Treatment is indicated when symptoms are disruptive of sleep or if there is a risk of the patient injuring themselves or their bed partner. Melatonin starting at 2mg od and increasing in 2mg increments or clonazepam 0.5mg nocte may be helpful.
Prolonged use of levodopa to treat the symptoms of Parkinsonism results in treatment-associated complications such as motor fluctuations and dyskinesias. Risk factors for the development of these complications include younger age at onset, high levodopa dose, low body weight, use of entacapone in addition of levodopa, female gender, and more severe UPDRS score.
‘Wearing off’ describes the gradual return of Parkinsonism with falling plasma concentration of levodopa. Problematic variations include ‘sudden offs’ (rapid onset of ‘off’ symptoms), ‘random offs’ (return of symptoms is unpredictable), or ‘super offs’ (severe ‘off’ symptoms occurring at the start of the day). Motor symptoms during ‘off’ periods are also associated with non-motor symptoms, which may include pain, depression, anxiety, drenching sweats, abdominal bloating, and dyspnoea.
Dyskinesia in IPD typically refers to choreiform movements associated with higher levodopa levels. Although patients complain of dyskinesia less than they do of ‘offs’ (indeed, movements may be entirely unnoticed by the patient), dyskinesia can be uncomfortable, exhausting, and socially embarrassing. Diphasic dyskinesia, or dyskinesia-improvement-dyskinesia (D-I-D) syndrome, refers to dyskinesias which develop as the patient enters the ‘on’ phase, then abate as the levodopa levels increase and recur as the patients enters the ‘off’ phase. Diphasic dyskinesias may respond to higher doses of levodopa.
In treating worsening motor symptoms, it is worthwhile first to consider complicating factors which may be exacerbating the symptoms. Food, especially protein, can interfere with the absorption of levodopa, so it is important to check that medication is being taken on an empty stomach (usually 30 minutes before or 60 minutes after a meal). Constipation may reduce the efficacy of dopaminergic treatment and should be treated. Pain, depression, poor or disturbed sleep, and concomitant illness or infection can exacerbate symptoms of PD.
Various strategies may be tried to achieve more consistent levels of plasma levodopa and reduce wearing-off. Increasing frequency of dosing may be tried, but this frequently leads to more rapid fluctuations and is unlikely to yield sustained benefits. The addition of a COMT (catechol-o-methyl transferase) inhibitor such as entacapone inhibits the peripheral breakdown of levodopa and prolongs its effects, however this may increase the likelihood of peak dose complications, such as confusion and dyskinesia. The addition of a MAO-B inhibitor or a dopamine agonist (already in place in this case) may be considered, but their utility may be limited by associated side-effects.
Amantadine may be useful in treating peak-dose dyskinesia, although its utility may be limited by side-effects, including confusion and hallucinations.
Continuous administration of dopaminergic medications may help to ameliorate fluctuations in response. Apomorphine is a potent dopamine agonist which may be given via a continuous subcutaneous pump. This treatment can reduce the number of ‘off’ periods but potential complications include nausea, vomiting and hypotension, as well as hallucinations, delusions and impulsive behaviours.
Continuous infusion of carbidopa/levodopa gel via a PEG tube with a jejunal extension (PEG-J) is an additional strategy which may help to ameliorate motor fluctuations.
For selected patients with troublesome motor fluctuations, dyskinesia, and/ or treatment-resistant tremor and good cognitive function, deep brain stimulation (DBS), typically targeting the subthalamic nucleus or globus pallidus pars interna, is a potentially useful therapeutic strategy. Patient selection is key to delivering good outcomes. Criteria include five years of duration of PD (to allow time for features of atypical Parkinsonism to emerge and assess response to dopaminergic medications); dopamine responsiveness (>30 per cent improvement in UPDRS); absence of dementia and depression; good cognitive function; and few comorbidities. Recently, there has been interest in using DBS earlier in the disease course, hoping to achieve improved quality of life and motor symptom control with lower doses of levodopa. Potential complications include dysarthria, worsening gait, cognitive dysfunction, and intracranial haemorrhage. Since January 2022, this procedure is available in Ireland and is accessed through the National DBS Service at the Mater Misericordiae University Hospital, Dublin, with surgeries taking place in Beaumont Hospital, Dublin.
KEY LEARNING POINTS
- IPD is a common, progressive, neurodegenerative disease which affects 1 per cent of the population over 60.
- Key clinical symptoms of IPD include Parkinsonism (tremor, bradykinesia, and rigidity), as well as a broad range of non-motor symptoms.
- IPD is a complex disease which manifests in different ways over the course of disease.
- Treatment strategies must evolve with the predominant problem at each stage of the disease.
- In advanced disease, a range of therapeutic options, including continuous administration of dopamine agonists and levodopa, may be considered.
- DBS treatment for symptoms such as motor fluctuations, refractory tremor, and disabling dyskinesias is now available in Ireland through the National DBS service.