Case 22.4 – Parkinsons & MND

History:

Motor symptoms (cardinal features):

• Tremor:
  • Character: resting tremor (improves with action)?
  • Frequency: 4-6 Hz "pill-rolling"
  • Distribution: asymmetric, starting in one limb?
  • Exacerbating/relieving factors
• Bradykinesia (slowness of movement):
  • Difficulty with fine motor tasks (buttons, writing - micrographia)
  • Reduced arm swing when walking
  • Difficulty turning in bed
  • Reduced facial expression (hypomimia)
  • Reduced blink rate
• Rigidity:
  • Limb stiffness
  • Muscle aches/pains
• Postural instability:
  • Balance problems, falls (usually later feature)
  • Difficulty with turning

Other motor features:

• Gait disturbance: Shuffling, festinating (accelerating forward), freezing episodes
• Speech changes: Quiet (hypophonia), monotonous
• Swallowing difficulties: Dysphagia (later feature)
• Handwriting: Small (micrographia)

Non-motor symptoms (very common, often under-recognized):

• Autonomic: Constipation, urinary urgency/frequency, erectile dysfunction, orthostatic hypotension
• Sleep disturbances: REM sleep behavior disorder, excessive daytime sleepiness, restless legs, insomnia
• Neuropsychiatric: Depression, anxiety, apathy, hallucinations (especially with medications), dementia (late)
• Sensory: Anosmia (loss of smell - often precedes motor symptoms), pain (shoulder, back)
• Cognitive: Executive dysfunction, slowed processing

Onset and progression:

• Age of onset (peak 60s; young-onset <50 years suggests genetic causes)
• Which symptoms appeared first?
• Rate of progression (PD is slowly progressive)
• Asymmetry (PD typically asymmetric initially)

Response to levodopa (if already tried):

• Good response strongly supports diagnosis of PD
• Poor/no response suggests alternative diagnosis (Parkinson-plus syndromes)

Red flags (suggest alternative diagnosis):

• Early falls, early dementia, early dysautonomia
• Rapid progression
• Symmetrical onset
• Lack of tremor
• Poor/absent levodopa response
• Eye movement abnormalities (PSP)
• Cerebellar signs
• Upper motor neuron signs (pyramidal)
• Hallucinations early in disease (suggest DLB)

Past medical and drug history:

• Medications that can cause parkinsonism: antipsychotics (especially typical), metoclopramide, prochlorperazine
• Vascular risk factors (vascular parkinsonism)
• Head injury, encephalitis

Family history:

• Parkinson's disease (5-10% have family history)
• Young-onset PD more likely genetic

Examination:

Observe:

• Resting tremor (observe hands at rest)
• Reduced facial expression (hypomimia, "mask-like facies")
• Reduced blink rate
• Posture: stooped, flexed

Bradykinesia:

• Finger tapping: Ask patient to tap index finger and thumb together rapidly - look for slowing, reduced amplitude, freezing
• Hand opening/closing: Rapid repeated movements - progressive slowing
• Pronation/supination: Rapid alternating movements of forearms
• Foot tapping: Tap foot on ground rapidly
• Look for decrement in speed and amplitude with repetition

Tremor:

• Resting tremor (4-6 Hz, "pill-rolling")
• Asymmetric (at least initially)
• Re-emergent tremor: tremor reappears after brief delay when arms held outstretched
• Improves with action (distinguish from essential tremor, which worsens with action)
• Exacerbated by distraction/mental stress (e.g., serial 7s)

Rigidity:

• Lead-pipe rigidity: Uniform resistance throughout passive movement of limb
• Cogwheel rigidity: Ratchet-like resistance (combination of tremor + rigidity)
• Test by passive flexion/extension of wrist and elbow, with patient relaxed
• Reinforcement maneuver: ask patient to move opposite limb to enhance rigidity

Postural instability:

• Pull test: Stand behind patient, warn them, pull backwards on shoulders - inability to recover balance or need >2 steps to recover is abnormal
• NOTE: This is a later feature; early falls suggest alternative diagnosis

Gait:

• Shuffling, small steps
• Reduced arm swing (often asymmetric)
• Difficulty initiating gait, turning (requires multiple small steps)
• Festination (accelerating forward, difficulty stopping)
• Freezing (sudden inability to move feet)

Other signs:

• Glabellar tap: Repeated tapping between eyebrows - persistent blinking (Myerson's sign) - seen in PD but not specific
• Hypophonia: Quiet, monotonous speech
• Micrographia: Ask patient to write - small, cramped handwriting

Exclude atypical features/Parkinson-plus syndromes:

• Eye movements: Supranuclear gaze palsy (PSP), saccadic intrusions
• Cerebellar signs: Ataxia, dysmetria, nystagmus (MSA-C)
• Pyramidal signs: Brisk reflexes, extensor plantars (not typical of PD)
• Dysautonomia: Orthostatic hypotension, urinary retention (MSA)
• Cognitive impairment: Early dementia (DLB, PSP)

The differential diagnosis of parkinsonism includes:

1. IDIOPATHIC PARKINSON'S DISEASE (PD) - most common (~80%)

• Slowly progressive
• Asymmetric onset
• Resting tremor common (but 30% have minimal tremor)
• Good response to levodopa
• Non-motor symptoms (anosmia, constipation, REM sleep behavior disorder) may precede motor symptoms by years

2. DRUG-INDUCED PARKINSONISM

• Caused by dopamine receptor blockers
• Common culprits:
  • Antipsychotics: Especially typical (haloperidol, chlorpromazine); atypicals less likely but risperidone/amisulpride can cause
  • Antiemetics: Metoclopramide, prochlorperazine
  • Others: Calcium channel blockers (rarely - cinnarizine, flunarizine), valproate, lithium
• Usually symmetric
• Tremor less prominent
• Should improve within weeks to months of stopping offending drug (but can take >6 months)

3. VASCULAR PARKINSONISM ("lower body parkinsonism")

• Due to small vessel cerebrovascular disease
• Affects lower limbs predominantly (gait disturbance)
• Upper limbs relatively spared
• Tremor uncommon
• Stepwise progression
• MRI shows extensive white matter changes, lacunar infarcts
• Poor response to levodopa

4. ATYPICAL PARKINSONIAN DISORDERS ("Parkinson-Plus Syndromes")

a) Progressive Supranuclear Palsy (PSP):

• Supranuclear vertical gaze palsy (especially downward gaze; later becomes horizontal too)
• Early postural instability and falls (within first year)
• Axial rigidity > limb rigidity (extended rather than flexed posture)
• Frontal dementia, personality change, apathy
• Tremor uncommon
• Poor/transient response to levodopa
• Rapidly progressive

b) Multiple System Atrophy (MSA):

• Parkinsonism PLUS autonomic failure and/or cerebellar signs
• Two subtypes:
  • MSA-P: Predominant parkinsonism
  • MSA-C: Predominant cerebellar ataxia
• Autonomic features (prominent and early): Severe orthostatic hypotension, urinary retention/incontinence, erectile dysfunction, constipation
• Tremor less common; rigidity often symmetric
• Laryngeal stridor (can be life-threatening)
• Poor/minimal response to levodopa
• Rapid progression (survival ~6-10 years)

c) Dementia with Lewy Bodies (DLB):

• Dementia precedes or occurs within 1 year of parkinsonism
• Fluctuating cognition
• Visual hallucinations (early, recurrent, well-formed)
• REM sleep behavior disorder
• Severe sensitivity to antipsychotics
• Parkinsonism usually symmetric, tremor less prominent
• Variable response to levodopa; may worsen hallucinations

d) Corticobasal Degeneration (CBD):

• Highly asymmetric, progressive parkinsonism
• Limb apraxia, "alien limb" phenomenon
• Cortical sensory loss
• Myoclonus
• Cognitive impairment (frontal, language)
• Poor response to levodopa

5. OTHER CAUSES

Essential Tremor:

• Action/postural tremor (not resting tremor)
• Bilateral, symmetric
• Head tremor common (not typical in PD)
• Improves with alcohol
• Family history common
• NO bradykinesia or rigidity

Wilson's Disease:

• Young onset (\<40 years)
• Parkinsonism, dystonia, wing-beating tremor
• Psychiatric features
• Kayser-Fleischer rings (copper deposition in cornea)
• Liver disease
• Low ceruloplasmin, high urinary copper
• TREATABLE - must not miss!

Normal Pressure Hydrocephalus:

• Triad: Gait disturbance, cognitive impairment, urinary incontinence
• "Magnetic" gait (feet appear stuck to floor)
• Potentially reversible with shunting

Other rare causes:

• Post-encephalitic parkinsonism (historical - encephalitis lethargica epidemic)
• Toxins: Carbon monoxide, manganese, MPTP
• Brain tumors, subdural hematoma
• Repeated head trauma ("punch-drunk syndrome")

UK PD BRAIN BANK CLINICAL DIAGNOSTIC CRITERIA (simplified):

Step 1: Diagnosis of Parkinsonian syndrome

• Bradykinesia PLUS at least one of: Resting tremor, Rigidity, Postural instability

Step 2: Exclusion criteria (suggest alternative diagnosis)

• Repeated strokes, repeated head injury
• Encephalitis
• Neuroleptic treatment at onset
• More than one affected relative
• Sustained remission
• Strictly unilateral after 3 years
• Supranuclear gaze palsy
• Cerebellar signs
• Early severe autonomic involvement
• Early severe dementia
• Babinski sign
• Cerebral tumor or hydrocephalus on imaging
• Negative response to large doses of levodopa

Step 3: Supportive criteria (3+ required for definite PD)

• Unilateral onset
• Rest tremor
• Progressive disorder
• Persistent asymmetry
• Excellent response to levodopa (70-100%)
• Severe levodopa-induced chorea
• Levodopa response for ≥5 years
• Clinical course ≥10 years

Parkinson's disease is a CLINICAL diagnosis. There is no definitive diagnostic test. Investigations are mainly to exclude alternative diagnoses.

In most cases of typical PD, NO investigations are required if:

• Classic clinical features (asymmetric, rest tremor, bradykinesia, rigidity)
• Gradual onset and progression
• Good response to levodopa
• No atypical features

Investigations to consider:

1. MRI Brain:

• Usually NORMAL in idiopathic PD
• Useful to exclude:
  • Vascular parkinsonism (multiple infarcts, white matter disease)
  • Normal pressure hydrocephalus
  • Structural lesions (tumor, subdural)
  • Atypical parkinsonian disorders (may show specific patterns of atrophy)
• Consider if: Young onset, atypical features, rapid progression, poor levodopa response

2. DaTscan (Dopamine Transporter SPECT imaging):

• Assesses integrity of dopaminergic nerve terminals in basal ganglia
• ABNORMAL (reduced uptake) in:
  • Idiopathic PD
  • Atypical parkinsonian disorders (PSP, MSA, CBD)
  • Dementia with Lewy bodies
• NORMAL in:
  • Essential tremor
  • Drug-induced parkinsonism
  • Vascular parkinsonism
  • Psychogenic/functional parkinsonism
• Useful when: Diagnostic uncertainty between PD vs essential tremor vs drug-induced parkinsonism
• Limitation: Cannot distinguish PD from atypical parkinsonian disorders

3. Blood tests (to exclude secondary causes):

• Ceruloplasmin and serum copper: To exclude Wilson's disease (ESSENTIAL in patients <40 years)
• FBC, U&Es, LFTs, TFTs: General screen
• Vitamin B12: Deficiency can mimic/worsen symptoms
• Syphilis serology (if clinically indicated)

4. Autonomic function tests:

• Tilt table testing, heart rate variability
• Useful if suspecting MSA (severe early autonomic failure)

5. Olfactory testing:

• Anosmia (loss of smell) is very common in PD (\>90%)
• Preserved smell suggests alternative diagnosis (PSP, MSA, vascular, drug-induced)
• Not routinely used clinically but can be helpful diagnostically

6. Genetic testing:

• NOT routinely recommended
• Consider if:
  • Young onset (\<50 years), especially <40 years
  • Strong family history (multiple affected relatives)
  • Specific ethnic backgrounds (e.g., LRRK2 mutations in Ashkenazi Jews, North African Arabs)
• Common genes: LRRK2, PRKN (parkin), PINK1, DJ-1, SNCA (rare)

7. Therapeutic trial of levodopa:

• Not strictly an "investigation" but clinically very useful
• Give adequate dose (e.g., co-careldopa 25/100 three times daily) for adequate duration (4-6 weeks minimum)
• Good response (≥30% improvement) strongly supports PD diagnosis
• Poor/absent response suggests atypical parkinsonism

Summary: When to investigate?

• Young onset (\<40 years): MRI brain, Wilson's screen (ceruloplasmin, copper), consider genetic testing
• Atypical features (red flags): MRI brain, consider DaTscan, autonomic testing
• Diagnostic uncertainty (PD vs essential tremor vs drug-induced): DaTscan
• Typical late-onset PD with good levodopa response: Often no investigations needed

MEDICAL MANAGEMENT OF PARKINSON'S DISEASE

General Principles:

• Treatment is symptomatic (no disease-modifying therapies available)
• Individualized approach based on age, symptoms, disability, patient preference
• Initiate treatment when symptoms affect quality of life or function
• No need to treat if minimal symptoms and patient not bothered

1. DOPAMINERGIC MEDICATIONS

a) Levodopa (with carbidopa or benserazide):

• MOST EFFECTIVE symptomatic treatment for PD
• Levodopa is converted to dopamine in brain; carbidopa/benserazide are peripheral decarboxylase inhibitors (reduce peripheral conversion, reduce side effects)
• Preparations:
  • Co-careldopa (Sinemet): Levodopa + carbidopa (ratios: 12.5/50, 25/100, 25/250)
  • Co-beneldopa (Madopar): Levodopa + benserazide
  • Also available: Modified-release preparations, dispersible preparations
• Efficacy: Improves ALL cardinal motor features (tremor, rigidity, bradykinesia)
• Initial dose: Start low (e.g., 25/100 three times daily), increase gradually
• Side effects:
  • Nausea, vomiting (give with food; use domperidone if needed - NOT metoclopramide)
  • Postural hypotension
  • Hallucinations, confusion (dose-related, especially in elderly)
• Long-term complications:
  • Motor fluctuations: "Wearing-off" (symptoms return before next dose), unpredictable "on-off" fluctuations
  • Dyskinesias: Involuntary movements (chorea) at peak dose; occur in ~40% after 4-6 years
• Strategy: Traditionally delayed in younger patients to reduce long-term motor complications, but current evidence suggests early use is acceptable if symptoms warrant; use lowest effective dose

b) Dopamine Agonists (DAs):

• Directly stimulate dopamine receptors
• Options:
  • Ergot-derived (rarely used now): Bromocriptine, cabergoline (risk of cardiac valvulopathy, pulmonary/retroperitoneal fibrosis)
  • Non-ergot (preferred):
    • Ropinirole (oral): Short-acting
    • Pramipexole (oral): Short-acting
    • Rotigotine (transdermal patch): Useful if swallowing problems
    • Apomorphine (subcutaneous injection): Rescue therapy for "off" periods
• Efficacy: Less effective than levodopa but useful as monotherapy in early PD or adjunct to levodopa
• Advantages: May delay motor complications (dyskinesias, wearing-off); longer half-life than levodopa
• Side effects:
  • Similar to levodopa: nausea, postural hypotension, hallucinations
  • Impulse control disorders: Pathological gambling, hypersexuality, compulsive shopping, binge eating (~15% of patients) - WARN patients and families!
  • Excessive daytime sleepiness, sudden onset of sleep (caution with driving)
  • Peripheral edema
  • Patch site reactions (rotigotine)

c) MAO-B Inhibitors:

• Inhibit monoamine oxidase B (enzyme that breaks down dopamine)
• Options:
  • Selegiline (oral): Older agent
  • Rasagiline (oral): Once daily, possibly neuroprotective (controversial)
• Use: Monotherapy in early PD (mild benefit) or adjunct to levodopa (reduces wearing-off)
• Side effects: Generally well tolerated; nausea, headache, insomnia (if taken late in day)
• Caution with antidepressants (risk of serotonin syndrome - especially SSRIs)

d) COMT Inhibitors:

• Inhibit catechol-O-methyltransferase (enzyme that breaks down levodopa)
• Options: Entacapone, tolcapone (tolcapone rarely used - hepatotoxicity risk)
• Use: ONLY as adjunct to levodopa (prolongs levodopa effect, reduces wearing-off)
• Side effects: Diarrhea, urine discoloration (orange), dyskinesias (may need to reduce levodopa dose)

e) Amantadine:

• Weak dopaminergic effect; NMDA antagonist
• Use: Mild benefit for motor symptoms; BEST for reducing dyskinesias
• Side effects: Livedo reticularis (skin mottling), ankle edema, confusion

2. ANTICHOLINERGICS:

• Examples: Trihexyphenidyl (benzhexol), procyclidine
• Use: Mainly for tremor in younger patients
• Side effects: Dry mouth, constipation, urinary retention, confusion, memory impairment, hallucinations
• AVOID in elderly (high risk of confusion, falls)
• Rarely used now due to side effects

TREATMENT APPROACH:

Early PD / Younger patients (\<65-70 years):

• If functional impairment: Consider dopamine agonist OR MAO-B inhibitor OR levodopa (choice based on patient factors, tolerability)
• Traditionally, levodopa delayed to reduce long-term motor complications, but no longer dogmatic

Early PD / Older patients (\>70 years):

• Levodopa usually first-line (better efficacy, motor complications less problematic as shorter life expectancy)

Advanced PD with motor complications:

• Optimize levodopa dosing (smaller, more frequent doses; add modified-release preparations)
• Add adjunct therapies: Dopamine agonist, MAO-B inhibitor, COMT inhibitor
• Amantadine for dyskinesias
• Consider advanced therapies (see below)

3. MANAGEMENT OF NON-MOTOR SYMPTOMS:

Depression/Anxiety:

• SSRIs (citalopram, sertraline), SNRIs (venlafaxine)
• CBT, psychological support

Psychosis/Hallucinations:

• Review and reduce dopaminergic medications if possible
• Quetiapine: Low-dose (off-label use; limited evidence)
• Clozapine: Effective but requires blood monitoring (agranulocytosis risk)
• Pimavanserin: Specific for PD psychosis (not available in all countries)
• AVOID typical antipsychotics (worsen parkinsonism)

Orthostatic Hypotension:

• Review medications (reduce dopaminergics, antihypertensives if possible)
• Non-pharmacological: Increase fluid/salt intake, compression stockings, head-up tilt sleeping
• Midodrine, fludrocortisone

Constipation:

• Increase fiber, fluids, exercise
• Laxatives (macrogol, senna)

Urinary symptoms:

• Exclude UTI
• Anticholinergics for urgency/frequency (but caution - cognitive side effects)
• Alpha-blockers for hesitancy/retention

REM Sleep Behavior Disorder:

• Clonazepam, melatonin
• Safety measures (remove dangerous objects from bedroom)

Sialorrhea (drooling):

• Glycopyrrolate, botulinum toxin injections to salivary glands

4. SURGICAL MANAGEMENT

Deep Brain Stimulation (DBS):

Mechanism:

• Implantation of electrodes into specific brain targets (subthalamic nucleus - STN, or globus pallidus interna - GPi) connected to pacemaker-like device
• High-frequency electrical stimulation modulates abnormal neuronal activity

Indications:

• Idiopathic PD with motor complications (fluctuations, dyskinesias) despite optimal medical therapy
• Good response to levodopa (DBS does NOT work if levodopa doesn't work)
• No significant cognitive impairment or major psychiatric disorder
• Typically age <70 years (but case-by-case)
• Disease duration usually >5 years

Efficacy:

• Significant improvement in motor fluctuations (increases "on" time)
• Reduces dyskinesias
• Allows reduction in medication dose
• Improves quality of life
• Does NOT cure PD; disease continues to progress

Complications:

• Surgical: Hemorrhage (~2%), infection, hardware complications
• Stimulation-related: Speech/cognitive changes, mood changes (especially STN-DBS), gait disturbance
• Requires ongoing programming adjustments

Other surgical options (rarely used):

• Pallidotomy, thalamotomy (ablative procedures - largely replaced by DBS)

5. ADVANCED THERAPIES (for advanced PD with refractory motor fluctuations):

Apomorphine infusion:

• Continuous subcutaneous infusion of dopamine agonist
• Reduces "off" time

Levodopa-carbidopa intestinal gel (LCIG/Duodopa):

• Continuous infusion of levodopa gel directly into duodenum via PEG-J tube
• Provides stable levodopa levels
• Reduces motor fluctuations

6. NON-PHARMACOLOGICAL MANAGEMENT (ESSENTIAL!):

• Physiotherapy: Gait training, balance, exercise (improves motor function, reduces falls)
• Occupational therapy: ADL support, home modifications, adaptive equipment
• Speech and language therapy: For dysarthria, dysphagia
• Exercise: Regular aerobic exercise beneficial for motor and non-motor symptoms
• Dietitian: Nutritional support, swallowing advice
• PD nurse specialist: Education, medication management, holistic care
• Psychological support: For patient and carers
• Driving assessment: DVLA notification required (UK)
• Palliative care: In advanced disease

Hereditary ataxias are a group of genetic disorders characterized by progressive cerebellar dysfunction leading to ataxia (incoordination), often with other neurological features.

CLASSIFICATION:

1. AUTOSOMAL DOMINANT CEREBELLAR ATAXIAS (ADCAs) = Spinocerebellar Ataxias (SCAs)

General features:

• Usually adult onset (but variable)
• Progressive ataxia
• Over 40 different genetic subtypes (SCA1, SCA2, SCA3, etc.)
• Most caused by CAG repeat expansions (polyglutamine diseases)

Common subtypes:

SCA3 (Machado-Joseph disease) - most common worldwide:

• Ataxia, parkinsonism, dystonia, peripheral neuropathy, external ophthalmoplegia
• Variable phenotype

SCA1:

• Ataxia, pyramidal signs, peripheral neuropathy
• Relatively rapid progression

SCA2:

• Ataxia, slow saccades, peripheral neuropathy, parkinsonism

SCA6:

• Pure cerebellar syndrome (ataxia, dysarthria, nystagmus)
• Later onset, slower progression
• Mutation in calcium channel gene (not polyglutamine)

SCA7:

• Ataxia PLUS progressive visual loss (retinal degeneration)

Clinical features (vary by subtype):

• Cerebellar: Gait ataxia, limb ataxia, dysarthria, nystagmus
• Extra-cerebellar:
  • Pyramidal signs (spasticity, hyperreflexia)
  • Extrapyramidal signs (parkinsonism, dystonia, chorea)
  • Peripheral neuropathy
  • Ophthalmoplegia, slow saccades
  • Cognitive impairment
  • Retinal degeneration (SCA7)

Genetic features:

• Anticipation: Earlier onset and more severe in subsequent generations (especially with paternal transmission)
• CAG repeat length correlates with age of onset and severity

2. AUTOSOMAL RECESSIVE CEREBELLAR ATAXIAS:

Friedreich's Ataxia - most common autosomal recessive ataxia:

• Genetics: GAA repeat expansion in FXN gene (frataxin); autosomal recessive
• Onset: Childhood/adolescence (usually before age 25)
• Clinical features:
  • Progressive ataxia (gait, then limb, then speech)
  • Absent reflexes (peripheral neuropathy, dorsal column degeneration)
  • Extensor plantar responses (pyramidal tract involvement)
  • Pes cavus, scoliosis
  • Cardiomyopathy (~90% - main cause of death)
  • Diabetes mellitus (~10-20%)
  • Optic atrophy (some patients)
• Investigations:
  • Genetic testing (GAA repeat expansion)
  • ECG, echocardiogram (cardiomyopathy screening - essential!)
  • MRI: Spinal cord atrophy; cerebellum may be normal or mildly atrophic
  • Nerve conduction studies: Axonal sensory neuropathy
• Management:
  • No disease-modifying treatment
  • Cardiac monitoring and treatment (ACE inhibitors, beta-blockers)
  • Physiotherapy, occupational therapy
  • Orthopedic management (scoliosis)
  • Diabetes management

Ataxia-telangiectasia:

• Childhood-onset ataxia
• Telangiectasias (dilated blood vessels in eyes, skin)
• Immunodeficiency (recurrent infections)
• Increased cancer risk
• Elevated alpha-fetoprotein

Ataxia with vitamin E deficiency (AVED):

• Resembles Friedreich's ataxia clinically
• Low vitamin E levels
• TREATABLE with vitamin E supplementation

Other rare causes:

• Abetalipoproteinemia, Refsum disease, cerebrotendinous xanthomatosis (all treatable - important not to miss!)

3. X-LINKED ATAXIAS:

• Fragile X-associated tremor/ataxia syndrome (FXTAS): Late-onset (\>50 years) tremor and ataxia in male carriers of fragile X premutation

INVESTIGATION OF HEREDITARY ATAXIA:

• MRI brain and spine: Cerebellar and spinal cord atrophy
• Genetic testing:
  • If family history/autosomal dominant: SCA gene panel
  • If early onset/recessive: Friedreich's ataxia gene testing first, then broader panel
• Blood tests:
  • Vitamin E level (AVED - treatable!)
  • Alpha-fetoprotein (ataxia-telangiectasia)
  • Lipid profile (abetalipoproteinemia)
  • Creatine kinase (may be elevated in some SCAs)
• Nerve conduction studies: Peripheral neuropathy
• ECG/echocardiogram: Especially if Friedreich's suspected

GENERAL MANAGEMENT:

• No cure for most hereditary ataxias
• Supportive care: Physiotherapy, occupational therapy, speech therapy
• Treatment of complications (cardiomyopathy, diabetes, scoliosis)
• Genetic counseling
• A few are treatable (AVED, abetalipoproteinemia, Refsum, cerebrotendinous xanthomatosis) - important to identify!

MOTOR NEURONE DISEASE (MND) / AMYOTROPHIC LATERAL SCLEROSIS (ALS)

Motor neurone disease is a progressive neurodegenerative disorder affecting upper and lower motor neurons, leading to progressive weakness and wasting.

PATHOLOGY:

• Degeneration of:
  • Lower motor neurons: Anterior horn cells (spinal cord), motor nuclei of brainstem (cranial nerves)
  • Upper motor neurons: Motor cortex, corticospinal tracts
• Cause unknown (~90% sporadic; ~10% familial)

EPIDEMIOLOGY:

• Incidence: ~2 per 100,000/year
• Peak onset: 50-70 years
• Slightly more common in men
• Rapidly progressive; median survival 3-5 years from symptom onset
• Prognosis worse with: Bulbar onset, older age, rapid progression

CLINICAL FEATURES:

Lower Motor Neuron (LMN) signs:

• Weakness
• Muscle wasting (atrophy)
• Fasciculations (spontaneous muscle twitching)
• Hyporeflexia or areflexia (in affected limbs)
• Hypotonia

Upper Motor Neuron (UMN) signs:

• Weakness (without wasting initially)
• Spasticity (increased tone)
• Hyperreflexia
• Extensor plantar responses (Babinski sign)
• Brisk jaw jerk
• Pseudobulbar palsy (if bulbar UMN involvement - see below)

KEY DIAGNOSTIC FEATURE: Combination of UMN AND LMN signs in the SAME region

TYPES OF MND:

1. AMYOTROPHIC LATERAL SCLEROSIS (ALS) - Classical MND (~60-70%)

• BOTH UMN and LMN signs in limbs
• May have bulbar involvement
• Most common presentation
• Example: Wasting and fasciculations (LMN) in hands, with brisk reflexes and extensor plantars (UMN)

2. PROGRESSIVE BULBAR PALSY (PBP) (~20-25%)

• Predominant bulbar (brainstem motor nuclei) involvement
• Can have LMN (bulbar palsy) or UMN (pseudobulbar palsy) features, or both
• Bulbar palsy (LMN):
  • Flaccid, fasciculating tongue
  • Dysarthria (nasal, slurred speech)
  • Dysphagia (difficulty swallowing)
  • Nasal regurgitation
  • Reduced/absent gag reflex
• Pseudobulbar palsy (UMN):
  • Spastic tongue (small, slow)
  • Dysarthria (strained, strangled quality - "Donald Duck speech")
  • Dysphagia
  • Brisk jaw jerk, increased gag reflex
  • Emotional lability (pathological laughing/crying)
• Limb involvement usually follows
• Worst prognosis (respiratory complications, aspiration)

3. PROGRESSIVE MUSCULAR ATROPHY (PMA) (~5-10%)

• ONLY LMN signs (no UMN signs)
• Limb weakness and wasting
• Better prognosis than ALS
• Many eventually develop UMN signs (reclassified as ALS)

4. PRIMARY LATERAL SCLEROSIS (PLS) (~1-3%)

• ONLY UMN signs (no LMN signs)
• Progressive spastic paraparesis or tetraparesis
• Slowest progression
• Best prognosis
• Diagnosis requires absence of LMN signs for >4 years

FEATURES PRESERVED IN MND (important - help differentiate from mimics):

• NO sensory loss (sensory neurons spared)
• NO sphincter disturbance (bladder/bowel function preserved until late)
• NO eye movement abnormalities (extraocular muscles spared)
• Cognition usually preserved (but ~15% develop frontotemporal dementia; ~50% have mild cognitive/behavioral changes)

DIAGNOSIS (EL ESCORIAL CRITERIA - revised):

• Requires evidence of:
  • LMN degeneration (clinical, electrophysiological, or pathological)
  • UMN degeneration (clinical)
  • Progressive spread within a region or to other regions
• PLUS absence of other causes (imaging, electrophysiology)
• Body divided into 4 regions: Bulbar, cervical, thoracic, lumbosacral
• Diagnostic certainty increases with number of regions involved

INVESTIGATIONS:

1. Electromyography (EMG) and Nerve Conduction Studies (NCS):

• ESSENTIAL for diagnosis
• EMG: Shows LMN features (fibrillations, fasciculations, chronic denervation with reinnervation) in multiple regions
• NCS: Motor conduction may be reduced (axonal loss) but sensory conduction NORMAL (helps exclude other conditions)

2. MRI brain and spine:

• Usually normal in MND
• Main purpose: EXCLUDE structural causes of weakness (cord compression, syrinx, MS, etc.)
• May show corticospinal tract signal change (T2 hyperintensity)

3. Blood tests (to exclude mimics):

• FBC, ESR, CRP
• TFTs, calcium
• Vitamin B12
• Creatine kinase (may be mildly elevated in MND)
• Anti-GM1 antibodies (multifocal motor neuropathy with conduction block)
• Paraneoplastic antibodies (if rapid onset)
• HIV, Lyme, syphilis serology (if indicated)

4. Lumbar puncture:

• Usually not needed unless diagnostic doubt
• CSF normal in MND

5. Respiratory function tests:

• FVC (forced vital capacity), sniff nasal inspiratory pressure
• Important for monitoring and planning ventilatory support

6. Genetic testing:

• Consider if family history or young onset
• C9orf72 repeat expansion (most common familial cause)
• SOD1, TARDBP, FUS mutations

DIFFERENTIAL DIAGNOSIS (MND mimics):

• Cervical myelopathy with radiculopathy: Can have UMN + LMN signs; MRI spine diagnostic
• Multifocal motor neuropathy with conduction block (MMN): Pure LMN; treatable with IV immunoglobulin; anti-GM1 antibodies; conduction block on NCS
• Kennedy's disease (spinobulbar muscular atrophy): X-linked; bulbar + limb LMN signs; gynecomastia; genetic test (CAG repeat in androgen receptor gene)
• Inclusion body myositis: Progressive muscle weakness; may mimic MND but is a myopathy
• Myasthenia gravis: Fatigable weakness; can cause bulbar symptoms; positive antibodies; improves with edrophonium
• Syringomyelia/syringobulbia
• Multiple sclerosis
• Paraneoplastic syndromes

MANAGEMENT OF MND:

1. Disease-modifying treatments (limited efficacy):

• Riluzole:
  • Glutamate antagonist
  • Extends survival by ~2-3 months on average
  • Does NOT reverse weakness
  • Dose: 50mg twice daily
  • Monitor LFTs
• Edaravone:
  • Free radical scavenger
  • May slow progression in some patients
  • IV infusion; not widely available

2. Symptomatic management (ESSENTIAL - improves quality of life):

Respiratory:

• Monitor respiratory function (FVC)
• Non-invasive ventilation (NIV): Prolongs survival and improves quality of life; offer when FVC \<50% or symptoms of respiratory insufficiency
• Discussions about invasive ventilation/tracheostomy (patient preference)

Nutrition/Dysphagia:

• Speech and language therapy assessment
• Modified diet, thickened fluids
• PEG (gastrostomy) feeding tube: If significant dysphagia or weight loss; ideally before FVC \<50% (safer procedure)

Communication:

• Speech therapy
• Communication aids (text-to-speech devices, eye-gaze technology)

Spasticity:

• Baclofen, tizanidine, gabapentin
• Physiotherapy

Sialorrhea (drooling):

• Anticholinergics (glycopyrrolate)
• Botulinum toxin to salivary glands

Thick secretions:

• Carbocysteine
• Suction devices

Emotional lability:

• Amitriptyline, SSRIs

Pain:

• Analgesia, physiotherapy, muscle relaxants

3. Multidisciplinary care (CRITICAL):

• Neurology, respiratory medicine
• MND specialist nurse
• Physiotherapy, occupational therapy, speech therapy
• Dietitian
• Palliative care (early involvement)
• Psychological support for patient and family
• Equipment provision (wheelchair, communication aids, home adaptations)

4. Advance care planning:

• Discussions about wishes for ventilatory support, resuscitation
• Advance directives, lasting power of attorney
• Place of care preferences

5. End-of-life care:

• Palliative care involvement
• Symptom control (dyspnea - opioids, benzodiazepines; pain; secretions)
• Emotional and spiritual support

PROGNOSIS:

• Median survival: 3-5 years from symptom onset
• ~50% die within 3 years; ~20% survive >5 years; ~10% survive >10 years
• Better prognosis: Younger age, limb onset (vs bulbar), PMA/PLS subtypes
• Worse prognosis: Older age, bulbar onset, rapid progression, FVC \<50%
• Most common cause of death: Respiratory failure