Parkinson's Disease

 Parkinsonism is a clinical syndrome characterized primarily by bradykinesia, with associated increased tone (rigidity), tremors and the loss of postural reflexes. There are many causes but the most common is Parkinson's disease. 

Parkinson's disease is a neurodegenerative disease, causing relentlessly progressive symptoms, with incidence rising with age.

Age has a critical influence on incidence and prevalence, the latter rising to 300 - 500/100,000 after 80 years of age. Average age of onset is about 60 years and fewer than 5% of patients present under the age of 40.

Genetic factors are increasingly recognised and several single genes causing parkinsonism have been identified, although they account for a very small proportion of cases overall. Having a first-degree relatives with Parkinson's disease confers a 2-3 times increased risk of developing the disorder. It is progressive and incurable with the variable prognosis. While motor symptoms are the most common presenting features, non motor are symptoms (particularly cognitive impairment, depression and anxiety) become increasingly prominent as the disease progresses, and significantly reduce quality of life.

Pathophysiology

In most patients the cause remains unknown, although in few cases mutations in several genes have been identified. The discovery that methyl-phenyl-tetrahydropyridine (MTPT) caused severe parkinsonism in young drug users suggested that Parkinson's disease might be due to an environmental toxin but none has begin convincingly identified.

The pathological hallmarks of Parkinson's disease are:

1. depletion of the pigmented dopaminergic neurones in the substantia nigra

2. Presence of Alpha synuclein and the otherpother inclusions in nigral cells (lewy bodies)

Lewy bodies are also found in basal ganglia, brain stem and cortex, and increase which disease progression. Parkinson disease is recognised as a synucleinopathy alongside multiple system atrophy and dementia with lewy bodies. The loss of dopaminergic neurotransmission is responsible for many of the clinical features.

Clinical Features

Non-motor symptoms:

1. reduction in sense of smell (hyposmia) 

2. Anxiety/ depression

3. Constipation 

4. REM sleep behavioral disturbance (RBD)

Non motor symptoms may precede the development of typical motor features by many years but patients really present at the early stage.

These features become increasingly common and disabling as Parkinson's disease progresses. Cognitive impairment, including dementia, is the symptoms most likely to impair quality of life for patients and their carers. Dementia frequency ranges from 30 % to 80% depending on definitions and the length of follow-up. Other distressing non-motor symptoms include neuropsychiatric features (anxiety, depression, apathy, hallucination / psychosis), sleep disturbance and hypersomnolence, fatigue, pain, sphincter disturbance and constipation, sexual problems (erectile failure, loss of libido or hypersexuality), drooling and weight loss.

Motor symptoms:

1.  Bradykinesia -leading to classic symptoms  such as increasingly small handwriting (microghraphia), difficulty tying shoelaces, or buttoning clothes, and difficulty rolling over in bed.

2. Tremor - Early feature but may not present in at least 20% of people with Parkinson's disease.

It isUis typically unilateral rest tremor affecting limbs, jaw and chin but not the head. In some patients, tremors remains the dominant symptoms for many years.

 3. Rigidity - Causes stiffness and a flexed posture.

4. Loss of postural reflexes- Although postural righting reflexes are impaired early on in the diseases, falls tend not to occur until later. 

5. As the disease advances speech becomes softer and indistinct.

 Although features are initially unilateral, gradually bilateral involvement evolves with time. Cognition is spared in early disease; if impaired, it should trigger consideration of alternative diagnosis, such as dementia with lewy bodies.

Investigations

The diagnosis is clinical.

 Structural imaging - CT or MRI is usually normal for age, and thus rarely helpful, although it may support a suspected vascular cause parkinsonism.

 Functional dopaminergic imaging SPECT or PET is abnormal, even in the early stages, but does not differentiate between the different forms of degenerative parkinsonism, and so is not specific of Parkinson's disease.

In younger patients, specific investigation may be appropriate (e.g. exclusion of Huntington's or Wilson's disease). Some patients with family histories may wish to consider genetic testing, although the role of genetic counselling is uncertain at present.

Management

Drug therapy

Drug treatment for Parkinson's disease remains symptomatic rather than curative, and there is no evidence that any of the currently available drugs are neuroprotective. Levodopa(LD) remains the most effective treatment available,but other agents include dopamine agonist, anticholinergics, inhibitors of monoamine oxidase (MOI)- B and catechol-O-methyltransferase and amantadine.

Levodopa is the most effective, best tolerated and cheapest drug. Many motor symptoms such as tremor, freezing, falling, head drop and abnormal flexion are quite resistant to treatment. Some non-motor symptoms such as anxiety or depression may respond to drug or non drug treatment.

In UK, rivastigmine is licensed for use in Parkinson's disease- associated dementia, although its effect is modest. Many other non-motor symptoms are resistant to treatment. Drugs for Parkinson's disease should not be stopped abruptly, as this can precipitate malignant hyperthermia.

Levodopa: 

Levodopa is the precursor to dopamine. When administered orally, more than 90% is decarboxylated to dopamine peripherally in gastrointestinal tract and blood vessels, and only a small proportion reaches the brain. The peripheral conversion is responsible for the high frequency of adverse effect. To avoid this levodopa is combined with Dopa decarboxylase inhibitor; the inhibitor does not cross the blood- brain barrier, thus avoiding unwanted decarboxylation- blocking in the brain. Two DDIs, carbidopa and bensarazide are available as combination preparations with levodopa (Sinemet and Madopar, respectively).

Levodopa is the most effective for relieving akinesia and rigidity, tremor response is often less satisfactory and it has no effect on many motor (posture, freezing) and non- motor symptoms. Failure of a akinesia/ rigidity to respond to levodopa (1000 mg/day) should prompt reconsideration of the diagnosis. Although controlled release version of Levodopa exist, these are usually reserved for use overnight, as their variable bioavailability make them difficult to use throughout the day. Madopar is also available as that dispersible tablet for more rapid- onset effect.

Adverse effects:

1. Postural hypotension 

2. Nausea and vomiting, which may be offset by domperidone

3. Exacerbate or Trigger hallucination

4. Abnormal LD seeking behaviour (Dopamin dysregulation syndrome).

As Parkinson's disease progresses, the response to levodopa becomes less predictable in many patients, leading to motor fluctuations. This end-of-dose deterioration is due to progressive loss of the dopamine storage capacity by dwindling numbers of striatonigral neurons.

Levodopa-induced involuntary movements (dyskinesia) may occur as:

• Peak dose phenomenon, or
•  biphasic phenomenon (occurring during both the build-up and wearing-off phases)

Most complex fluctuation present as sudden, unpredictable changes is response, in which

• Off-phase: Periods of Parkinsonism, alternates with
• On-phase: Improved mobility but with dyskinesia