Parkinson’s Disease

Therapeutics Core Knowledge

Key Points

Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting 1% of the population over 65.
Characterised by bradykinesia, resting tremor, rigidity and postural instability.
Non-motor features (psychiatric, cognitive, autonomic) contribute significantly to impaired quality of life.
Neuronal loss in the substantia nigra leads to dopamine deficiency in the striatum.
Levodopa remains the most potent oral treatment, though motor fluctuations (on–off) occur with long-term use.
Dopamine agonists are alternatives, but carry risks of impulse control disorders.

Fig. 32.1 Summary of Pathophysiological Processes:

Ageing

Genetic factors

Oxidative stress

Protein aggregation

Mitochondrial dysfunction

Inflammation

Synaptic dysfunction

Impaired trafficking

Result: CELL DEATH

Environment & Genetics

Environmental factors like pesticide exposure, rural living, and well water drinking are associated with increased PD risk. Conversely, tobacco smoking and coffee drinking have been linked to a reduced risk (Bellou et al., 2016). Genetics play a role in a minority of cases, with mutations in the α-synuclein and GBA genes being strong risk factors.

Pathophysiology

PD is defined by neuronal loss in the substantia nigra and the presence of Lewy bodies (eosinophilic inclusion bodies). The Braak hypothesis proposes that α-synuclein pathology may start in the lower brainstem (dorsal vagal nucleus) or olfactory bulb, explaining why sense of smell and bowel issues often precede motor symptoms.

Clinical Features

Motor Features

Bradykinesia (slowness of movement) is a prerequisite for diagnosis. Other cardinal signs are a pill-rolling resting tremor, cogwheel rigidity, and postural instability. Patients often show a stooped posture, reduced arm swing, and micrographia (small handwriting).

Non-motor Features

Autonomic: Postural hypotension and chronic constipation.
Psychiatric: Depression (40% of patients), paranoia, and hallucinations (often drug-induced).
Cognitive: Dementia develops in up to 80% of patients long-term (Hely et al., 2008).
Sleep: REM sleep behavioural disorder (acting out dreams).

Differential Diagnosis

Essential Tremor (ET) is commonly confused with PD but lacks bradykinesia. Other "Parkinson-plus" syndromes include Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA). Drug-induced Parkinsonism (caused by neuroleptics or antiemetics like prochlorperazine) is potentially reversible.

Schizophrenia

Caroline Parker

Key Points

Lifetime prevalence is 1 in 100 people; up to 10% commit suicide.
Positive symptoms (hallucinations, delusions) usually respond to antipsychotics.
Negative symptoms (apathy, social withdrawal) are more resistant to medication.
Second-generation (atypical) antipsychotics generally avoid EPSE but cause weight gain and diabetes.
Clozapine is the most effective drug but requires mandatory blood monitoring for neutropenia.

Classification & Symptoms

Kraepelin initially called it ‘dementia praecox’. Bleuler later introduced ‘schizophrenia’ to describe the split between emotions and intellect. It is categorized by:

Positive Symptoms: Hallucinations (mostly auditory), delusions (thought insertion), and thought disorder.
Negative Symptoms: Apathy, social withdrawal, and lack of drive.

Causes & Models

The Dopamine Hypothesis suggests overactivity at D2 receptors causes psychosis. The Developmental Model points to structural brain abnormalities during fetal development. Environmental triggers include urban living, childhood trauma, and substance misuse.

Fig. 30.1 Classification of Antipsychotics:

First Gen (Typical): Haloperidol, Chlorpromazine

Second Gen (Atypical): Olanzapine, Risperidone

Partial Agonist: Aripiprazole

Refractory Gold Standard: Clozapine

Side Effects

EPSE: Parkinsonism, Akathisia (restlessness), and Acute Dystonia (sustained muscle contraction).
Tardive Dyskinesia: Rhythmic involuntary movements of the tongue/face; often irreversible.
Metabolic: Significant weight gain and diabetes risk, especially with Olanzapine and Clozapine.
NMS: Neuroleptic Malignant Syndrome – a serious emergency with fever, rigidity, and autonomic instability.

Clozapine & Refractory Illness

Clozapine is indicated after failing two other antipsychotics. It carries a risk of agranulocytosis (low white blood cells) and requires titration to avoid tachycardia and seizures. Augmentation with sulpiride or amisulpride is sometimes used if response is inadequate.

Epilepsy

Gonçalo Cação and Josemir W. Sander

Key Points

An epileptic seizure is a transient paroxysm of uncontrolled neuronal discharges.
Incidence is highest in the first two decades and in late life (due to stroke).
60–70% of people become seizure-free on treatment.
SUDEP: Sudden unexpected death in epilepsy is a risk for those with frequent convulsions.
Diagnosis is primarily clinical, supported by EEG and MRI.

Pathophysiology

The hallmark is rhythmic, repetitive hyper-synchronous discharge of neurones. These discharges can be localized (focal) or involve the whole cortex (generalised). Neurones switch from normal low-frequency patterns to high-frequency bursts.

Clinical Manifestations

Generalised Seizures

Tonic-clonic: Stiffening (tonic) followed by jerking (clonic). Often followed by confusion/sleep.
Absence: Brief (seconds) behavioural arrest/staring; common in children.
Myoclonic: Sudden, brief, shock-like jerks, usually in the morning.
Atonic: Sudden loss of muscle tone causing a "drop attack."

Focal Seizures

Divided into Focal Aware and Focal with Impaired Awareness. Symptoms depend on the brain area affected (e.g., lip smacking, déjà vu, or localized jerking). These may evolve into bilateral tonic-clonic seizures.

NICE Management Summary (2014)

Emergency Treatment: Buccal midazolam is first-line for prolonged seizures in the community. Rectal diazepam is an alternative. Intravenous lorazepam is used in hospitals.

Diagnosis: Should be made urgently by a specialist. Diagnosis is clinical; EEG classifies the syndrome but does not "prove" epilepsy if the history is weak.

Women: Must receive counseling on contraception (interaction with AEDs) and the risks of sodium valproate in pregnancy.

Diagnosis & Treatment

MRI is essential for identifying structural causes like tumours or cortical dysplasia. EEG helps classify the seizure type. Treatment aims for seizure freedom using a single drug (monotherapy) to minimize side effects. If two drugs fail, the patient is considered "refractory" and should be referred for surgery evaluation.