17.2 Movement Disorders & Cognitive Impairment
Key Takeaways
- Parkinson's disease is diagnosed clinically by bradykinesia (progressive decrement in amplitude and speed during repetitive movements) combined with asymmetric 4–6 Hz resting tremor or lead-pipe/cogwheel rigidity, driven by loss of dopaminergic neurons in the substantia nigra pars compacta and alpha-synuclein Lewy bodies.
- Levodopa combined with a dopa-decarboxylase inhibitor (co-careldopa or co-beneldopa) is the most potent motor therapy, but precipitates motor fluctuations ('wearing off') and peak-dose dyskinesias within 3–5 years; dopamine agonists (pramipexole, ropinirole) carry a high risk of impulse control disorders (gambling, hypersexuality) and somnolence.
- Atypical parkinsonian syndromes (Parkinson-Plus) are distinguished by early atypical signs: vertical supranuclear gaze palsy and early backward falls in PSP (hummingbird sign); severe autonomic failure, cerebellar ataxia, and stridor in MSA (hot cross bun sign); asymmetric alien limb and cortical sensory loss in CBD.
- Dementia with Lewy Bodies (DLB) presents with fluctuating cognition, detailed visual hallucinations, spontaneous parkinsonism, and REM sleep behaviour disorder; administration of typical or atypical neuroleptics can precipitate fatal neuroleptic malignant syndrome or irreversible extrapyramidal collapse.
- Alzheimer's disease features early episodic memory failure with medial temporal atrophy, treated with acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine; monitor for bradycardia) or memantine (NMDA receptor antagonist); frontotemporal dementia presents before age 65 with prominent personality changes, disinhibition, and knife-blade frontotemporal atrophy.
Movement disorders and neurodegenerative dementias represent a major domain in MRCP(UK) Part 1. Candidates must master clinical diagnostic criteria for Parkinson's disease, the pharmacology and long-term complications of dopaminergic medications, the distinguishing features of Parkinson-Plus syndromes, and the differential diagnosis and evidence-based pharmacotherapy of neurodegenerative cognitive disorders.
1. Parkinson's Disease: Neuropathology & Clinical Phenotype
Neuropathology & Pathogenesis
- Dopaminergic Depletion: Progressive degeneration of pigmented neuromelanin-containing dopaminergic projection neurons within the substantia nigra pars compacta (SNpc), causing profound loss of striatal dopamine in the putamen and caudate nucleus. Motor symptoms manifest when approximately 60–70% of SNpc neurons are lost.
- Histopathological Hallmark: Intraneuronal Lewy bodies—eosinophilic cytoplasmic inclusions composed of aggregated, misfolded α-synuclein and ubiquitin.
- Braak Staging Hypothesis: Pathology originates decades before motor symptoms in the enteric nervous system and olfactory bulb, ascending via the vagus nerve to the medulla, pons, and midbrain (SNpc), before finally invading the cerebral cortex.
Clinical Diagnostic Criteria (UK Brain Bank Criteria)
Diagnosis requires the presence of bradykinesia PLUS at least one of the following three cardinal motor signs:
- Bradykinesia (Essential / Sine Qua Non): Slowness of movement initiation and progressive reduction in speed and amplitude during repetitive movements (e.g. finger tapping, hand opening/closing, foot tapping).
- Muscular Rigidity: Resistance to passive joint movement throughout the entire range of motion ("lead-pipe rigidity"), or with superimposed tremor ("cogwheel rigidity"). Rigidity is reinforced by voluntary movement of the contralateral limb (Froment's manoeuvre).
- Resting Tremor: Characteristic 4–6 Hz "pill-rolling" tremor, asymmetric at onset, present at rest, suppressed during purposeful voluntary movement, and reinforced during mental calculation (e.g. counting backwards) or walking.
- Postural Instability: Late finding in idiopathic PD (impaired postural recovery on the pull test); early postural instability with falls (<1–2 years) strongly indicates an atypical parkinsonian syndrome.
Classical Examination & Motor Features
- Cranial Signs: Masked facies (hypomimia), reduced blink rate, hypophonia (quiet monotone speech), drooling of saliva (sialorrhoea from impaired swallowing).
- Motor & Gait: Micrographia (handwriting becoming progressively smaller and cramped), festinant shuffling gait with reduced unilateral arm swing, difficulty initiating gait (freezing), hesitation, and en bloc turning (requiring multiple steps to turn).
- Glabellar Tap Reflex (Myerson's Sign): Repetitive tapping on the forehead between the eyebrows fails to extinguish blinking (normal subjects habituate after 3–5 taps).
Non-Motor Features (Often Predating Motor Signs)
- Hyposmia / Anosmia: Present in >90% of patients, frequently predating motor deficits by 5–10 years.
- REM Sleep Behaviour Disorder (RBD): Loss of normal motor atonia during REM sleep, causing vivid, violent dream-enactment behaviours (kicking, punching); strong predictor of phenoconversion to an α-synucleinopathy.
- Autonomic Dysfunction: Severe intractable constipation, orthostatic hypotension, erectile dysfunction, and urinary urgency/frequency.
- Neuropsychiatric Symptoms: Depression, anxiety, apathy, cognitive slowing (bradyphrenia), and late visual hallucinations.
2. Medical Pharmacotherapy of Parkinson's Disease
| Drug Class & Agents | Mechanism of Action | Clinical Role & Indications | Characteristic Toxicities & High-Yield Exam Pearls |
|---|---|---|---|
| Levodopa + DDCI<br>(Co-careldopa / Co-beneldopa) | Metabolic precursor of dopamine; crosses blood-brain barrier via LNAA transporter. Co-formulated with peripheral dopa-decarboxylase inhibitor (carbidopa or benserazide) | Most efficacious motor agent; first-line therapy, especially in elderly patients (>65 years) or those with significant motor impairment | - Nausea, vomiting, postural hypotension<br>- Long-term motor complications (at 3–5 years): End-of-dose "wearing-off", unpredictable "on-off" fluctuations, and peak-dose dyskinesias (choreoathetosis) |
| Dopamine Receptor Agonists<br>(Pramipexole, Ropinirole, Rotigotine patch) | Non-ergot direct agonists at striatal D2 and D3 dopamine receptors | First-line monotherapy or adjunct, often favoured in younger patients (<65 years) to postpone levodopa motor complications | - Impulse Control Disorders (ICDs) in 15–20%: pathological gambling, hypersexuality, binge eating, punding (driven by D3 stimulation in nucleus accumbens)<br>- Excessive daytime somnolence & sudden sleep attacks (driving warning)<br>- Peripheral ankle oedema, hallucinations |
| Ergot-Derived Dopamine Agonists<br>(Cabergoline, Bromocriptine) | Direct dopamine receptor stimulation with ergot alkaloid structure | Rarely used due to severe fibrotic complications | - Fibrotic reactions via 5-HT2B agonism: Retroperitoneal, pulmonary/pleural, and cardiac valvular fibrosis (requires baseline and serial echocardiography, ESR, creatinine, CXR) |
| MAO-B Inhibitors<br>(Rasagiline, Selegiline, Safinamide) | Irreversibly inhibit central monoamine oxidase type B, preventing dopamine degradation in the striatum | Mild symptomatic benefit as monotherapy in early disease, or adjunct to reduce "wearing-off" | - Minimal cheese reaction risk at therapeutic doses (MAO-A spared)<br>- Insomnia, headache, nausea, postural hypotension |
| COMT Inhibitors<br>(Entacapone, Opicapone, Tolcapone) | Inhibit catechol-O-methyltransferase, preventing peripheral degradation of levodopa to 3-OMD, extending levodopa half-life | Adjunct strictly combined with levodopa to smooth out motor fluctuations and "wearing-off" | - Entacapone harmlessly discolours urine reddish-brown<br>- Diarrhoea (can be severe/delayed)<br>- Tolcapone causes fatal acute hepatic failure (rarely used, requires intensive LFT monitoring) |
| NMDA Antagonist<br>(Amantadine) | Weak uncompetitive NMDA receptor antagonist; promotes dopamine release | Used primarily as add-on therapy to suppress levodopa-induced dyskinesias | - Livedo reticularis (mottled purplish skin discolouration), ankle oedema, confusion, hallucinations |
| Anticholinergics<br>(Trihexyphenidyl, Orphenadrine) | Central muscarinic receptor antagonists | Useful for prominent resting tremor in younger patients (<60 years) | - Confusion, memory impairment, acute urinary retention, dry mouth, blurred vision, acute angle-closure glaucoma; contraindicated in elderly |
3. Atypical Parkinsonian Syndromes (Parkinson-Plus)
The Parkinson-Plus syndromes are neurodegenerative conditions that present with parkinsonism but exhibit distinct clinical, pathological, and neuroimaging features with poor response to levodopa:
| Diagnostic Feature | Progressive Supranuclear Palsy (PSP) | Multiple System Atrophy (MSA) | Corticobasal Degeneration (CBD) | Vascular Parkinsonism |
|---|---|---|---|---|
| Underlying Neuropathology | 4-repeat (4R) Tauopathy; neurofibrillary tangles in basal ganglia and brainstem | α-Synucleinopathy; glial cytoplasmic inclusions in oligodendrocytes | 4-repeat (4R) Tauopathy; astrocytic plaques and ballooned cortical neurons | Multiple subcortical lacunar strokes and arteriolosclerotic leukoaraiosis |
| Cardinal Clinical Manifestations | - Early backward falls (<1 year)<br>- Vertical supranuclear gaze palsy (downward saccades impaired first)<br>- Axial rigidity > limb rigidity<br>- Retrocollis (neck extension)<br>- Profound frontal apathy | - Early severe autonomic failure (orthostatic BP drop >= 30/15 mmHg, urinary incontinence, erectile dysfunction)<br>- Cerebellar ataxia (MSA-C) or parkinsonism (MSA-P)<br>- Laryngeal stridor (risk of sudden death) | - Marked asymmetric presentation<br>- Limb apraxia (ideomotor)<br>- Alien limb phenomenon<br>- Cortical sensory loss (astereognosis)<br>- Focal dystonia, myoclonus | - "Lower-body parkinsonism"<br>- Wide-based "magnetic" gait<br>- Upright posture, preserved arm swing<br>- Sparing of facial expression<br>- Absence of resting tremor |
| Ocular Motor Signs | Impaired downward voluntary saccades; preserved doll's head (oculocephalic) reflex | Nystagmus, broken smooth pursuit, normal vertical saccades | Ocular motor apraxia | Normal ocular motility |
| Levodopa Responsiveness | Poor or transient (<20%) | Poor or absent (<10%); can trigger severe orofacial dystonia | Poor or absent | Minimal or absent |
| Diagnostic Neuroimaging (MRI) | Midbrain tegmental atrophy with preserved pons: "Hummingbird" or "Penguin" sign on sagittal T1; "Mickey Mouse" sign on axial midbrain | Atrophy of pons, middle cerebellar peduncles; "Hot cross bun" sign on axial T2; hyperintense putaminal rim | Asymmetric frontoparietal cortical atrophy contralateral to the more affected limb | Extensive bilateral subcortical and periventricular white matter T2/FLAIR hyperintensities |
4. Neurodegenerative Dementia Subtypes
| Dementia Subtype | Primary Pathology | Distinctive Clinical Phenotype | Neuroimaging & Biomarkers | Guideline-Directed Management |
|---|---|---|---|---|
| Alzheimer's Disease | Extracellular β-amyloid (Aβ42) plaques and intracellular hyperphosphorylated tau neurofibrillary tangles | Insidious onset; early prominent impairment of episodic memory (repeating questions, misplacing items), progressing to executive dysfunction, visuospatial disorientation, dysnomia, and apraxia | MRI: Bilateral medial temporal lobe and hippocampal atrophy.<br>CSF: Decreased Aβ42, increased total tau and phospho-tau | Acetylcholinesterase inhibitors (AChEIs): Donepezil, Rivastigmine, Galantamine (mild-to-moderate). Memantine (NMDA antagonist; moderate-to-severe). Perform baseline ECG: AChEIs cause bradycardia/heart block |
| Dementia with Lewy Bodies (DLB) | Intraneuronal α-synuclein Lewy bodies in cortex, limbic structures, and brainstem | Classic core tetrad:<br>1. Fluctuating cognition with marked variations in attention/alertness<br>2. Recurrent well-formed visual hallucinations (people, animals)<br>3. Spontaneous motor parkinsonism (within 1 year of cognitive onset)<br>4. REM sleep behaviour disorder | ¹²³I-FP-CIT SPECT (DaTscan) reveals reduced striatal dopamine transporter uptake.<br>MRI: Relative preservation of medial temporal lobes | AChE inhibitors (donepezil, rivastigmine) highly effective for hallucinations and cognitive fluctuations.<br>CRITICAL CONTRAINDICATION: Severe neuroleptic sensitivity; avoid typical/atypical antipsychotics (risk of fatal rigidity/NMS) |
| Vascular Dementia | Cerebrovascular disease: multiple cortical infarcts, strategic lacunes, or subcortical ischemic leukoaraiosis | Stepwise cognitive decline, temporal link to stroke/TIA events; prominent early executive dysfunction (planning, processing speed), preserved recognition memory; focal pyramidal signs | MRI: Extensive periventricular white matter hyperintensities, multi-infarct status, lacunes | Intensive vascular risk factor reduction: antihypertensives, high-intensity statin, antiplatelet therapy, smoking cessation, diabetes management |
| Frontotemporal Dementia (Pick's Disease) | 3R/4R tau inclusions (Pick bodies) or TDP-43 proteinopathies | Early onset (<65 years).<br>- Behavioural variant (bvFTD): Personality changes, social disinhibition, apathy, loss of empathy, dietary hyperorality (craving sweets), compulsive stereotypies.<br>- Language variants: Primary progressive aphasia | MRI: Marked, circumscribed, asymmetric "knife-blade" atrophy of frontal and anterior temporal lobes | Supportive, behavioral strategies, SSRIs for compulsions/hyperphagia.<br>AChE inhibitors are INEFFECTIVE and may worsen agitation |
A 64-year-old retired bank manager with a 2-year history of Parkinson's disease attends the movement disorder clinic with his wife. He was commenced on oral ropinirole 9 months ago with good improvement in his unilateral resting tremor and bradykinesia. His wife privately expresses profound distress, disclosing that over the last 4 months, her husband has secretly gambled away over £45,000 on online roulette platforms, despite having never previously gambled. She also notes that he spends up to 8 hours each night compulsively sorting and reorganizing hardware tools in the shed (punding). When questioned, the patient acknowledges the behaviour but feels an irresistible compulsion to continue. He has no prior psychiatric history. What is the pharmacological mechanism primarily responsible for this patient's behavioural disturbance?
A 71-year-old retired civil engineer is brought to the neurology clinic by his family due to walking difficulties and recurrent unexplained falls. His symptoms began 10 months ago with unprovoked backward falls ('falling like a timber'), requiring two visits to the emergency department for facial contusions. Over the last 4 months, his family noticed that he has become progressively slower in his thinking, emotionally blunted, and has difficulty feeding himself because he cannot look down at the plate without bending his entire neck forward. On examination, he exhibits a wide-based, stiff gait, marked symmetrical axial and neck rigidity that exceeds limb rigidity, and an upright, hyperextended posture. Eye examination reveals profoundly restricted voluntary downward saccades, while voluntary horizontal gaze is mildly slowed. When the oculocephalic manoeuvre (doll's head reflex) is performed, full vertical and horizontal ocular excursions are smoothly elicited. Sagittal T1-weighted MRI of the brain demonstrates prominent midbrain tegmentum atrophy with preservation of the pons ('hummingbird' or 'penguin' sign). What is the most likely diagnosis?
A 75-year-old woman is admitted to the medical assessment unit with a 9-month history of fluctuating mental state and cognitive decline. Her daughter reports that on some days she is alert and engaged, whereas on other days she is profoundly confused, somnolent, and disorientated. For the past 4 months, the patient has described recurrent, highly detailed, non-threatening visual hallucinations of small children and animals playing in her living room. On neurological examination, she has a Montreal Cognitive Assessment (MoCA) score of 18/30. Motor examination reveals mild bilateral symmetrical cogwheel rigidity at the wrists and mild bradykinesia with reduced arm swing, although no tremor is observed. Due to agitation and distress regarding unfamiliar hospital surroundings, she is administered a single low dose of haloperidol (1 mg orally). Within 12 hours, she develops severe generalized muscle rigidity, mutism, fever of 39.4°C, blood pressure of 178/104 mmHg, and heart rate of 124 beats/min. Serum creatine kinase is markedly elevated at 9,200 U/L (reference <170). What underlying neurodegenerative disorder best explains this patient's presentation and adverse response?