SDL 23 - Parkinson’s Disease BMS16091064 Jonathan

Introduction
This common disease, characterised by abnormalities in posture and movement was
first described by James Parkinson in 1817. In his words, it was characterized by
“involuntary tremulous motion, with lessened muscular power, in parts not in action
and even when supported; with a propensity to bend the trunk forward, and to pass
from a walking to a running pace, the senses and intellect being uninjured.” Strangely,
his essay contained no reference to rigidity or to slowness of movement and it stressed
unduly the reduction in muscular power.

The natural history of the disease is of interest. As a rule, it begins between 45 and 70
years of age, with the peak age of onset in the sixth decade. It is infrequent before 30
years of age, and most series contain a somewhat larger proportion of men. Trauma,
emotional upset, overwork, exposure to cold, “rigid personality,” and so on, were
among many factors that had been suggested over the years as predisposing to the
disease but there is no evidence to support any such claims. Idiopathic Parkinson

disease is observed in all countries, all ethnic groups, and all socioeconomic classes,
although the incidence in African Americans is lower than in whites. There may be an
increased incidence in rural compared to urban areas, attributed tentatively and not
consistently, to exposure to pesticides. In Asians, the incidence is one-third to
one-half that in whites. The disease is frequent in North America, where there are
approximately 1 million affected patients, constituting about 1 percent of the
population over the age of 65 years. The incidence in European countries where vital
statistics are kept, is similar. A possible relationship to repeated cerebral trauma and
to the “punch-drunk” syndrome (dementia pugilistica; chronic traumatic
encephalopathy) has been particularly problematic and is unresolved despite several
celebrated cases (Lees); certainly most cases do not have this exposure. A protective
effect of smoking and coffee drinking has emerged in some epidemiologic studies but
the magnitude of effect is marginal.
Clinical Features
Non-motor symptoms, including reduction in sense of smell (hyposmia),
anxiety/depression, constipation and REM sleep behavioural disturbance (RBD), may
precede the development of typical motor features by many years but patients rarely
present at this stage.

The motor symptoms are almost always initially asymmetrical. The hallmark is
bradykinesia, leading to classic symptoms such as increasingly small handwriting
(‘micrographia’), difficulty tying shoelaces or buttoning clothes, and difficulty rolling
over in bed. Tremor is an early feature but may not be present in at least 20% of
people with PD.

It is typically a unilateral rest tremor affecting limbs, jaw and chin but not the head.
In some patients, tremor remains the dominant symptom for many years. Rigidity
causes stiffness and a flexed posture. Although postural righting reflexes are impaired
early on in the disease, falls tend not to occur until later. As the disease advances,
speech becomes softer and indistinct. There are a number of abnormalities on
neurological examination.

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

Non-motor symptoms
While non-motor symptoms may precede the onset of more typical symptoms by
many years, for most patients these features become increasingly common and
disabling as PD progresses.

Cognitive impairment, including dementia, is the symptom most likely to impair

quality of life for patients and their carers. Estimates of dementia frequency range
from 30% to 80%, depending on definitions and length of follow-up.

Other distressing non-motor symptoms include neuropsychiatric features (anxiety,

depression, apathy, hallucinosis/psychosis), sleep disturbance and hypersomnolence,
fatigue, pain, sphincter disturbance and constipation, sexual problems (erectile failure,
loss of libido or hypersexuality), drooling and weight loss.
Pathology

The pathological hallmarks of PD are depletion of the pigmented dopaminergic

neurons in the substantia nigra and the presence of α-synuclein and other protein
inclusions in nigral cells (Lewy bodies). The loss of dopaminergic neurotransmission
is responsible for many of the clinical features.

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 of
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 for PD. In younger patients, specific
investigations may be appropriate (e.g. exclusion of Huntington’s or Wilson’s
diseases). 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 PD 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
agonists, anticholinergics, inhibitors of monoamine oxidase (MAOI)-B and
catechol-O-methyl-transferase (COMT), and amantadine. Debate continues about
when and what treatment should be started. In general, most specialists recommend
initiating treatment when symptoms are impacting on everyday life although some
favour treatment as soon as the diagnosis is made. Whether it is best to start with LD,
a dopamine agonist or MAOI-B remains unclear but most accept that the most
effective, best-tolerated and cheapest drug is LD. 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 treatments. In the UK, rivastigmine is licensed for use in PD-associated
dementia, although its effect is modest. Many other non-motor symptoms are resistant
to treatment. Drugs for PD should not be stopped abruptly, as this can precipitate
malignant hyperthermia.

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

LD-induced involuntary movements (dyskinesia) may occur as a peak-dose

phenomenon or as a biphasic phenomenon (occurring during both the build-up and
wearing-off phases). More complex fluctuations present as sudden, unpredictable
changes in response, in which periods of parkinsonism (‘off’ phases) alternate with
improved mobility but with dyskinesias (‘on’ phases). Motor complication
management is difficult; wearing-off effects may respond to increased dose or
frequency of LD or the addition of a COMT inhibitor (see below). More complex
fluctuations may be improved by the addition of dopamine agonists (including
continuous infusion of apomorphine), use of intraintestinal LD via a percutaneous
endoscopic jejunostomy, or deep brain stimulator implantation.

Dopamine receptor agonists

Originally introduced in the hope of delaying the initiation of LD and thus delaying
motor complications, several dopamine agonists are available, and may be delivered
orally, transdermally or subcutaneously. The ergot-derived agonists are no longer
recommended because of rare but serious fibrotic effects. With the exception of
apomorphine, all the agonists are considerably less effective than LD in relieving
parkinsonism, have more adverse effects (nausea, vomiting, disorientation and
hallucinations, impulse control disorders) and are more expensive. Their role in the
management of PD (monotherapy or adjunctive) remains uncertain, and evidence
suggests that their usefulness as initial monotherapy is short-lasting.

MAOI-B inhibitors
Monoamine oxidase type B facilitates breakdown of excess dopamine in the synapse.
Two inhibitors are used in PD: selegiline and rasagiline. The effects of both are
modest, although usually well tolerated. Neither is neuroprotective, despite initial
hopes.

COMT inhibitors
Catechol-O-methyl-transferase (along with dopa decarboxylase) is involved in
peripheral breakdown of LD. Two inhibitors are available: entacapone and tolcapone
(which also inhibits central COMT). Entacapone has a modest effect and is most
useful for early wearing-off. It is available either as a single tablet taken with each
LD/DDI dose, or as a combination tablet with LD and DDI. The more potent
tolcapone is less used because of rare but serious hepatotoxicity.

Amantadine
This has a mild, usually short-lived effect on bradykinesia and is rarely used unless
patients are unable to tolerate other drugs. It is more commonly employed as a
treatment for LD-induced dyskinesias, although again benefit is modest and
short-lived. Adverse effects include livedo reticularis, peripheral oedema, delirium
and other anticholinergic effects.

Anticholinergic drugs These were the main treatment for PD prior to the
introduction of LD. Their role now is limited by lack of efficacy (apart from an effect
on tremor sometimes) and adverse effects, including dry mouth, blurred vision,
constipation, urinary retention, delirium and hallucinosis, as well as long-term
concerns regarding cognitive impairment. Several anticholinergics are available,
including trihexyphenidyl (benzhexol) and orphenadrine.

Physiotherapy, occupational therapy and speech therapy

Patients at all stages of PD benefit from physiotherapy, which helps reduce rigidity
and corrects abnormal posture. Occupational therapists can provide equipment to help
overcome functional limitations, such as rails for stairs and the toilet, and bathing
equipment. Speech therapy can help where dysarthria and dysphonia interfere with
communication, and advice may also be provided to those with dysphagia. As with
many complex neurological disorders, patients with PD should ideally be managed by
a multidisciplinary team, including PD specialis nurses.