20.3 — Parkinson's Disease

By the time the first symptom appears, around 60 to 80 percent of the dopamine neurons in the substantia nigra have already died.

Which tells you two things. The brain has enormous reserve — it compensates for the loss of most of a nucleus before anything is noticeable. And the disease has been running for years, probably decades, before diagnosis.

And treatment works. Levodopa produces a response so consistent that its absence casts doubt on the diagnosis, and people treated well can function for many years.

What is happening

Dopamine neurons in the substantia nigra — a small pigmented nucleus in the midbrain — progressively die (Chapter 11.4).

They project to the basal ganglia, which are central to selecting and initiating movement (Chapter 11.5).

Losing dopamine there means movements are harder to start, smaller, and slower — which is exactly what the symptoms describe.

And the pathological hallmark is the Lewy body — an aggregate of misfolded alpha-synuclein inside neurons (Chapter 1.3).

Braak's staging proposed that the pathology begins in the lower brainstem and the olfactory system, and ascends over years — which fits the observation that loss of smell and REM sleep behaviour disorder frequently precede motor symptoms by a decade or more.

And a genuinely interesting hypothesis: some cases may begin in the gut. Alpha-synuclein pathology is found in the gut nerves, and it has been proposed to spread up the vagus nerve (Chapter 11.7). Supporting evidence includes a lower incidence in people who have had the vagus cut for ulcer surgery. It remains a hypothesis rather than established.

The symptoms

The motor triad:

Bradykinesia — slowness, and it is required for the diagnosis.

Not simply moving slowly, but progressive reduction in amplitude with repetition — which is what a clinician is testing when they ask you to tap finger and thumb repeatedly and watch the movement shrink.

In life it looks like: small handwriting that gets smaller across a line; reduced arm swing on one side; a quieter, more monotonous voice; reduced facial expression; and difficulty with fine tasks like buttons.

Tremor — at rest.

Typically 4 to 6 Hz, in one hand initially, classically described as pill-rolling.

And the crucial distinction: it is present at rest and improves with movement — the opposite of the intention tremor of cerebellar disease and of essential tremor (Chapter 11.4).

Around 20 to 30 percent never have tremor, which is a common reason for delayed diagnosis.

Rigidity — increased tone throughout the range, described as lead-pipe, or cogwheel when combined with tremor.

Postural instability — later, and it is the feature most responsible for falls.

And the asymmetry matters. Parkinson's starts on one side and remains asymmetric for years. Symmetrical parkinsonism from the outset suggests something else.

The non-motor symptoms, which are frequently more disabling and consistently under-treated:

Loss of smell — in around 90 percent, frequently years before motor symptoms.

REM sleep behaviour disorder — acting out dreams, sometimes violently, because the paralysis that normally accompanies REM sleep fails. Over 80 percent of people with it eventually develop a synucleinopathy — Parkinson's or a related condition — often more than a decade later. It is the strongest known predictor.

Constipation — extremely common and often preceding diagnosis by years.

Depression and anxiety — affecting around 40 percent, and part of the disease rather than only a reaction to it, because the same neurotransmitter systems are affected.

Cognitive impairment — mild in many, progressing to dementia in a substantial proportion over 10 to 20 years.

Postural hypotension, urinary urgency, sexual dysfunction, fatigue, pain, and drooling.

Diagnosis

Clinical. There is no definitive test.

Bradykinesia plus tremor or rigidity, with supportive features and no red flags.

DaTscan — imaging the dopamine transporter — distinguishes Parkinson's from essential tremor and drug-induced parkinsonism, and does not distinguish Parkinson's from the other degenerative parkinsonian syndromes.

And the levodopa response is itself diagnostic. A clear, sustained response supports the diagnosis; its absence argues strongly against it.

The conditions that mimic it, and each has a distinguishing feature:

Essential tremor — present with action rather than at rest, often symmetrical, often improved by alcohol, and frequently with a family history. Much commoner than Parkinson's.

Drug-induced parkinsonism — from antipsychotics, metoclopramide and prochlorperazine, which block dopamine receptors (Chapter 11.2). Symmetrical, and reversible on stopping — though recovery can take months. It is a common and entirely avoidable misdiagnosis.

Vascular parkinsonism — predominantly lower body, with a stepwise history.

Progressive supranuclear palsy — early falls, and impaired vertical eye movement.

Multiple system atrophy — early and severe autonomic failure.

Dementia with Lewy bodies — dementia within a year of the motor symptoms, with visual hallucinations and marked fluctuation.

Normal pressure hydrocephalus — the "wet, wobbly, wacky" triad, and it is treatable with a shunt (Chapter 11.10).

Treatment

Levodopa — the precursor of dopamine.

And it exists because of a specific pharmacological problem: dopamine cannot cross the blood–brain barrier and levodopa can, using an amino acid transporter (Chapter 11.10).

It is given with a decarboxylase inhibitor — carbidopa or benserazide — which blocks conversion in the body but cannot itself cross the barrier. So the dopamine is made only where it is wanted, and the peripheral side effects are largely avoided.

It is the most effective treatment by a wide margin, and its introduction in the late 1960s was described by Oliver Sacks in Awakenings.

And a practical point: protein competes with levodopa for the same transporter, so taking it with a large protein meal reduces absorption. Taking it 30 to 60 minutes before food improves the response.

Long-term motor complications, and these are the central problem of Parkinson's management.

Wearing off — the benefit no longer lasting until the next dose.

Dyskinesias — involuntary writhing movements, occurring at peak drug levels. They are caused by the treatment rather than the disease, and patients frequently prefer them to being immobile.

On-off fluctuations — abrupt, sometimes unpredictable switching between mobile and immobile states.

These affect a majority within 5 to 10 years, and they relate to both disease progression and pulsatile drug delivery.

Which is why continuous delivery — infusions and long-acting formulations — is used in advanced disease.

Other drugs:

Dopamine agonists — acting directly on the receptor. Fewer dyskinesias, and more neuropsychiatric side effects.

And one of those deserves emphasis, because it destroys lives and is frequently not warned about.

Impulse control disorders — pathological gambling, compulsive shopping, hypersexuality and binge eating — occur in around 15 percent of people on dopamine agonists, and considerably more with higher doses and younger age.

Patients and families must be warned explicitly, because the person affected frequently does not recognise it, and the financial and relationship damage can be severe and irreversible. It resolves on reducing or stopping the drug.

MAO-B inhibitors — reducing dopamine breakdown. Modest benefit, useful early.

COMT inhibitors — extending levodopa's duration.

Amantadine — the only drug that reduces dyskinesias.

Apomorphine — injected or infused, for rapid rescue from off periods.

Deep brain stimulation — electrodes implanted in the subthalamic nucleus or globus pallidus, connected to a pulse generator.

For patients with motor fluctuations who still respond to levodopa. It substantially reduces off time and dyskinesias, and can allow drug reduction. It does not slow the disease and does not help the non-motor symptoms.

And focused ultrasound — a non-invasive alternative producing a precise lesion without surgery, currently mainly used for tremor.

Non-drug treatment, and the evidence is better than it is usually given credit for:

Exercise. And this is the one intervention with evidence of a disease-modifying effect — high-intensity aerobic exercise has slowed progression in trials, and it improves balance, gait and mood regardless.

Physiotherapy with cueing strategies. Freezing of gait — feet feeling stuck to the floor — responds to visual and auditory cues: stepping over a line, marching to a rhythm, or a laser line projected from a walking stick. It is a striking demonstration that the movement circuits are intact and the internal initiation is what has failed.

Speech and language therapy — specific programmes such as LSVT LOUD produce measurable improvement in voice volume, and swallowing assessment matters because aspiration pneumonia is a leading cause of death.

Occupational therapy.

Living with it

It is progressive, and it varies enormously. Some people remain well controlled for 15 to 20 years.

And life expectancy is only modestly reduced with modern treatment, which is not the impression most people have on diagnosis.

The non-motor symptoms deserve as much attention as the motor ones, and they are consistently under-asked-about: depression, constipation, sleep, blood pressure on standing, and pain.

Medication timing is critical, and this matters practically in hospital: Parkinson's medication must be given on time, not on the ward drug round schedule. Delays of even an hour can leave someone immobile, and missed doses in hospital are a recognised and preventable harm.

And dopamine-blocking antiemetics must be avoided — metoclopramide and prochlorperazine will worsen the disease markedly. Domperidone and ondansetron are the safe alternatives, and this is one of the most important things for a patient or family member to know.

What is being worked on

Disease-modifying treatment remains the goal, and nothing has yet succeeded.

Approaches under investigation: alpha-synuclein antibodies and aggregation inhibitors; repurposed drugs including exenatide, a GLP-1 agonist, which showed promise in a phase 2 trial; gene therapy; and cell replacement using stem cell-derived dopamine neurons, which is in early trials.

And there is a genuine possibility of earlier intervention, because the prodromal features — loss of smell, REM sleep behaviour disorder, constipation — identify people years before motor symptoms. If a disease-modifying treatment is found, that population is where it would be used.

What the next page fixes

Chapter 20.4 covers dementia — the most feared diagnosis in later life, what is and is not known about it, and the substantial proportion of risk that is modifiable.