Parkinson Disease

Parkinson disease is a progressive neurodegenerative disorder. Pathologically it features loss of dopaminergic neurons in the substantia nigra pars compacta and intraneuronal accumulation of misfolded alpha-synuclein within Lewy bodies.

The core clinical triad is bradykinesia, rigidity and rest tremor, with postural instability later in the course. It is the commonest neurodegenerative movement disorder and the second commonest neurodegenerative condition overall after Alzheimer disease.

The disease progresses gradually over years to decades. Non-motor symptoms are a substantial burden and frequently precede the motor features by years. In advanced disease they often contribute as much as, or more than, the motor symptoms to overall disease burden and quality of life impact.

Pathophysiology

• Progressive loss of dopaminergic neurons in the substantia nigra pars compacta disrupts dopaminergic input to the striatum. This causes dysfunction of the basal ganglia motor circuitry and the characteristic motor features.
• Motor symptoms generally do not appear until a substantial proportion (approximately fifty to sixty percent) of the dopaminergic neuron population has been lost, reflecting functional compensatory reserve.
• Alpha-synuclein pathology follows a characteristic, though variable, pattern of progressive spread through the nervous system. Some evidence supports an initial site in the peripheral autonomic nervous system or olfactory system. Spread then goes through the brainstem to the substantia nigra and, in more advanced disease, to widespread cortical structures.
• This is a proposed pathological correlate for the often early non-motor symptoms (including anosmia and constipation) that precede the classical motor features by years. It is an area of substantial research interest because of its potential relevance to earlier detection and intervention.
• The cause of sporadic Parkinson disease is incompletely understood. It reflects a complex interplay of genetic susceptibility and environmental factors, with relative contribution varying considerably between individuals.
• Several specific genetic mutations are identified in familial forms. More common genetic variants confer modest increased risk in the sporadic population.

• The core diagnostic motor triad is:
  • Bradykinesia: slowness of movement with progressive decrement in amplitude on repetitive action. This distinguishes genuine parkinsonian bradykinesia from simple general slowness.
  • Rigidity: increased resistance to passive movement, classically "cogwheel" when combined with tremor, or "lead pipe" in its absence.
  • Rest tremor: characteristically a pill-rolling tremor, most prominent at rest and diminishing or disappearing with voluntary movement. This distinguishes it from the action or postural tremor typical of essential tremor.
• Postural instability (impaired postural reflexes with falls risk) typically emerges later in the course.
• Motor symptoms characteristically begin asymmetrically, with one side affected before, and generally more than, the other. This supports the diagnosis and helps distinguish idiopathic Parkinson disease from several atypical parkinsonian syndromes (Parkinson plus syndromes), which more typically present with symmetrical involvement from an earlier stage.
• Non-motor symptoms are a major, often underappreciated component of disease burden. They include hyposmia or anosmia (frequently an early, sometimes presymptomatic feature preceding motor onset by years) and constipation.
• Rapid eye movement sleep behaviour disorder involves loss of the normal muscle atonia during rapid eye movement sleep, so the individual physically acts out their dreams. When it occurs in isolation, it is a strong, well established predictor of subsequent Parkinson disease or a related synucleinopathy.
• Other non-motor features are depression and anxiety, and autonomic dysfunction (including orthostatic hypotension, urinary dysfunction, and sexual dysfunction).
• Cognitive impairment can progress to major neurocognitive disorder in advanced disease (Parkinson disease dementia). It shares substantial clinical and pathological overlap with dementia with Lewy bodies. The two labels are generally distinguished by the timing of motor onset relative to cognitive decline, rather than by any fundamental difference in pathology.
• With progression, particularly with longer term dopaminergic medication, characteristic motor complications frequently develop. These are motor fluctuations ("wearing off" of medication benefit before the next scheduled dose) and dyskinesia (involuntary, often choreiform movements, a treatment related complication rather than a direct feature of the disease). See medication for Parkinson disease.

• Diagnosis is predominantly clinical. It rests on the core motor features (bradykinesia with either rigidity or rest tremor) meeting established diagnostic criteria, together with supportive features: asymmetric onset and a clear, sustained, robust response to dopaminergic treatment.
• Carefully exclude "red flag" features that suggest an alternative, atypical parkinsonian syndrome (see Parkinson plus syndromes).
• Structural neuroimaging (magnetic resonance imaging) is generally normal in idiopathic Parkinson disease. It is performed mainly to exclude alternative structural causes of parkinsonism (including vascular parkinsonism or, rarely, a structural lesion), not to confirm the diagnosis, which remains clinical.
• Dopamine transporter imaging (a radiolabelled tracer with single photon emission computed tomography, commonly termed a DaTscan) can support the diagnosis in genuine diagnostic uncertainty.
• It distinguishes degenerative parkinsonism (Parkinson disease and the Parkinson plus syndromes, both showing reduced tracer uptake from nigrostriatal dopaminergic neuronal loss) from non-degenerative causes of tremor or parkinsonism (including essential tremor and drug induced parkinsonism, both showing normal, preserved uptake).
• It cannot distinguish between the degenerative parkinsonian syndromes, which share the same pattern of reduced dopaminergic tracer uptake.
• A therapeutic trial of dopaminergic medication (typically levodopa), with assessment of the clinical response, provides valuable supportive information. Genuine idiopathic Parkinson disease generally shows robust, sustained motor improvement, in contrast to the more limited, less sustained response in several atypical parkinsonian syndromes.

• Pharmacological management of motor symptoms is the cornerstone of symptomatic treatment (see medication for Parkinson disease). Levodopa, generally combined with a peripheral decarboxylase inhibitor to reduce peripheral conversion and adverse effects, is the most effective single agent for motor symptom control.
• Other agent classes (dopamine agonists, monoamine oxidase B inhibitors, and others) are used according to disease stage, patient age, and clinical circumstances.
• Non-pharmacological management is an essential, integral component across the disease course. It includes regular, structured physical exercise, with accumulating evidence of benefit for motor function and potentially for disease modification (an area of substantial research interest).
• It also includes physiotherapy (particularly gait and balance training, and fall prevention), occupational therapy, and speech and language therapy (addressing dysarthria and, in more advanced disease, dysphagia).
• Managing non-motor symptoms is an essential component of care. This includes treating depression and anxiety by standard principles, managing orthostatic hypotension by the relevant autonomic dysfunction principles, and treating constipation.
• Pay specific attention to sleep disturbance, including rapid eye movement sleep behaviour disorder. This can be managed effectively with clonazepam or melatonin where clinically significant, including where dream enactment risks injury to the patient or bed partner.
• Advanced therapy options include deep brain stimulation (typically targeting the subthalamic nucleus or globus pallidus internus), continuous levodopa-carbidopa intestinal gel infusion, and subcutaneous apomorphine infusion.
• Consider these in selected patients with advanced disease and significant motor fluctuations or dyskinesia not controlled by optimised oral medication (see medication for Parkinson disease).
• Full, multidisciplinary, longitudinal management underpins effective long term care over the typically prolonged course. It includes regular neurology follow up, allied health and psychosocial support, and proactive attention to both motor and non-motor aspects, which are of increasingly recognised equal importance.