11th August 2024

Idiopathic Parkinson’s disease

Overview of idiopathic Parkinson’s disease

Idiopathic Parkinson’s disease (PD) is characterised by the presence of Lewy bodies in the dopaminergic cells of the substantia nigra resulting in the death of those cells over time. It is more commonly seen in men, with an average age of onset of age of 65 years and a prevalence of 1% in the over 60s.

Symptoms frequently start unilaterally, and all three components of the triad may not be present. Over time, postural instability and gait disturbance develop along with speech and swallowing difficulties, hypomimia and micrographia, and non-motor symptoms such as depression, autonomic dysfunction, sleep disturbance and dementia. The rate at which the symptoms progress varies greatly, with most patients having a near-normal life expectancy. The biggest cause of death in the PD population is pneumonia, with dysphagia greatly contributing to this.

Idiopathic PD is normally a clinical diagnosis, but where there is uncertainty a dopamine transporter (DaT) scan can be performed. This has a good negative predictive value, with a negative result almost ruling out idiopathic PD or a Parkinson’s plus syndrome (unless too early in the disease course). However, a positive DaT scan does not necessarily indicate PD. In young patients, other movement disorders should be considered and investigated, including Wilson’s and Huntington’s diseases.

The next two sections will cover pharmacological management of the symptoms of idiopathic PD. It is important to note that non-pharmacological management is also incredibly important, including speech and language therapy, counselling, psychological support, physiotherapy and occupational therapy.

Pharmacological management of motor symptoms

Treatment is to manage symptoms; at present we do not have a way to slow disease progression. The aim is to minimise the frequency and severity of ‘off’ periods, when patients feel their movements slowing and becoming increasingly difficult to initiate.

Diagnosis and treatment initiation should only be done by those with expertise in movement disorders. The first-line therapy depends on whether motor symptoms are affecting the patient’s quality of life. NICE suggests the following:

Some further information about the above medications is as follows:

• Levodopa is nearly always combined with a decarboxylase inhibitor, either carbidopa or benserazide (as co-careldopa and co-beneldopa respectively), to prevent its conversion to dopamine in the peripheral circulation. This increases the amount of levodopa that reaches the CNS and reduces side effects.
• Dopamine agonists include ropinirole, rotigotine and pramipexole. Apomorphine is a liquid dopamine agonist preparation, which is fast acting and can help with the management of off periods.
• MAO B inhibitors reduce the breakdown of dopamine within the CNS and include selegiline, rasagiline and safinamide.
• COMT is an enzyme that breaks down levodopa, and its inhibitors prolong the activity of the levodopa. Examples include entacapone and tolcapone. They can only be used as an adjunct to levodopa.

Other treatment options include:

• Amantadine: considered if medication-induced dyskinesia is not managed by alternative agents. Side effects include ataxia, slurred speech, confusion, dizziness and livedo reticularis.
• Deep brain stimulation: can be considered when medical therapy alone is ineffective or insufficient.

A summary of the potential harms and benefits of the main drugs used in idiopathic PD is as follows:

* Excessive sleepiness, hallucinations and impulse control disorders

** Not included in NICE guideline tables but added here for completeness

The side effect profiles are similar across the four main treatments (levodopa, dopamine agonists, MAO B and COMT inhibitors) but vary in severity. Hallucinations, impulse control disorders, psychosis and dyskinesias are related to increased dopamine activity and are most severe with dopamine agonists. Side effects common to all drug classes mentioned in Table 2 and sometimes due to the Parkinson’s disease itself, include dry mouth, nausea and low blood pressure (most commonly orthostatic),

• MAO B inhibitors are mostly well tolerated, although they have been known to cause serotonin syndrome, especially if taken alongside SSRIs or other drugs that increase serotonin, and these should therefore be avoided.
• COMT inhibitors can cause gastrointestinal upset; tolcapone therapy requires careful monitoring due to the risk of hepatotoxicity.
• Psychotic symptoms (hallucinations or delusions) can occur with all treatments and can also occur later on due to the disease itself. Hallucinations are most commonly visual, like in Lewy body dementia. They do not always need treatment if well tolerated. If needed, the offending medication can be reduced, and if there is no cognitive impairment, quetiapine can be considered. Clozapine is an alternative if standard treatment is ineffective. NICE recommends that olanzapine should NOT be offered due to its possible worsening of motor symptoms.
• Impulse control disorders may manifest as gambling, hypersexuality, binge eating or obsessive shopping, and can develop at any time in the disease course. Risk factors include high alcohol consumption, smoking and history of impulsive behaviours. If these develop, the NICE recommendation is to reduce the dose of the dopamine agonist or, if this is not sufficient, the medication may need to be discontinued.
• Excessive sleepiness can be related to the disease itself or dopamine agonists. If this develops the patient must not drive and needs to inform DVLA. It is also important to consider any hazards at work. If reducing the medication is not possible then modafinil can be considered.

The pharmacological response threshold increases as the disease progresses and thus patients require increasing doses of levodopa and additional agents for symptom control. This reduces the therapeutic window between a sufficient motor response and dyskinesia, resulting in increasing difficulty managing ‘off’ periods and dyskinesias later in the disease course. Gait freezing can also develop, even when other motor symptoms are well controlled.

Another important side effect is neuroleptic malignant syndrome. This can occur on abrupt withdrawal of medication or in patients initiated on antipsychotic treatment. This is important to consider when patients develop poor absorption, for example secondary to diarrhoea or vomiting, or if they become unable to take their medication orally due to confusion or an unsafe swallow. Levodopa is a medication that is particularly at risk of poor absorption. In such cases either an NG tube can be considered or the oral medication can be converted into the equivalent dose as a dopamine agonist patch. If anti-emetics are required, domperidone is the medication of choice in idiopathic PD, as it does not cross the blood-brain barrier and therefore does not cause extrapyramidal side effects.

Management of other symptoms

Along with the traditional motor symptoms managed with the dopamine treatments above, there are other motor and non-motor symptoms of PD which require different treatment.

Other motor symptoms include:

• REM sleep disorders: loss of the normal paralysis during this sleep phase, which may result in violent, powerful movements, which may cause harm to the patient or those with whom they share a bed. It can be due to the disease process itself or secondary to medication. If it is due to the latter, the offending medication should ideally be discontinued; if this is not an option or does not work, clonazepam or melatonin can be trialled. Note that REM sleep disorders are not the same disease process as sleepwalking or night terrors common in childhood, which occur in the non-REM sleep phase.
• Restless leg syndrome.
• Nocturnal akinesia: reduced or absent movement overnight, hindering re-positioning and ultimately causing pain and sleep impairment. Thus, it is important to use long-acting forms of dopamine overnight.
• Dysphagia: impaired swallowing in PD is multifactorial. It causes two major complications: an inability to meet nutritional requirements and a risk of aspiration. Patients may eventually need a gastrostomy, although this does not eliminate the risk of salivary aspiration and some patients may decide to risk feed for pleasure alongside the gastrostomy.
• Sialorrhea (drooling): thought to be due to increased saliva secretion, an inability to maintain saliva in the mouth due to head drooping and hypomimia, and impaired saliva clearance. Treatment involves behaviour modification (such as frequent conscious swallowing), dopamine treatment, glycopyrronium bromide and botox injections.

Psychiatric symptoms include:

• Depression: the aetiology of depression in PD is not well understood but it occurs in around 35% of patients and is likely often multifactorial. NICE recommends psychosocial interventions first, such as a physical activity programme, a peer support group, a guided self-help programme or CBT (cognitive behavioural therapy). If these do not help then antidepressant medication such as an SSRI can be trialled.
• Dementia: there are two dementias associated with lewy body deposition – PD dementia and Lewy body dementia. In PD dementia, cognitive impairment is a late sign usually occurring many years after the motor symptoms have developed. In Lewy body dementia, cognitive impairment is an early symptom with motor symptoms developing after or at the same time, and progressing together. Management of these conditions is similar to other dementias such as Alzheimer’s and involves cognitive therapies along with medications.

Autonomic symptoms:

• Constipation: often occurs early and is likely multifactorial, partly due to autonomic dysfunction.
• Gastroparesis: affects >70% of individuals with PD. Although often asymptomatic, it is of particular importance in regards to levodopa treatment as delayed absorption causes delayed onset of action.
• Bladder dysfunction: can present as either an overactive bladder/urge incontinence, nocturia or less commonly urinary retention. Retention increases the risk of a urinary tract infection, which is an important cause of acute neurological deterioration. Overactive bladder can be treated with anticholinergic agents.
• Orthostatic hypotension: more commonly seen in later stages of the disease. Unfortunately, PD medication can precipitate or worsen hypotension. The advice is to stop possible contributing medications such as antihypertensives and diuretics, avoid dehydration and optimise cardiac function. If lifestyle measures are not sufficient then midodrine is first line and fludrocortisone is second line.
• Sexual dysfunction: erectile dysfunction or ejaculation difficulties in men and loss of lubrication and involuntary urination in women. Sexual counselling is important. Sildenafil and apomorphine can be used in erectile dysfunction. Other important factors that contribute to sexual dysfunction include hypersexuality from dopaminergic treatment and the effect low mood has on sexual drive and arousal.

A key miscellaneous symptom is that of:

• Olfactory dysfunction: impaired smell often precedes motor symptoms.