Neurology JC023: Unsteady Gait: Cerebellar Lesions, Movement Disorders, Parkinsonism Flashcards
Physiology of gait
3 levels of gait control:
1. Upper level (**Gait execution)
- Premotor cortex
- Motor cortex
- Regulatory system: **Extrapyramidal system (e.g. Basal ganglia)
- Middle level (Subcortical centres: **Synergy of gait)
- Midbrain locomotor region (MLR)
- Spinal locomotor network (SLN)
- Regulatory system: **Cerebellar system - Lower level (Force production)
- Peripheral nervous system
- Musculoskeletal system
- Regulatory system: Spinal reflex pathways (Vestibular + ***Proprioceptive inputs)
Regulatory system: **Postural control + **Balance
Gait disorders
- Apraxic gait
- **Motor cortex + Extrapyramidal system affected (Diffuse problem)
- **Difficulty initiating walking, 行行下唔行 - Parkinsonian gait
- ***Extrapyramidal system affected
- Hypokinetic gait, Small steps, Turn slowly - Ataxic gait
- **Cerebellar system + Spinal reflex pathways affected
- **Wide based, Truncal unsteadiness - Hemiplegic / Diplegic / Spastic gait
- Upper level of gait centre affected (e.g. Stroke) - Antalgic gait
- Musculoskeletal system affected (∵ pain) - Waddling gait
- Musculoskeletal system affected
Causes of Gait disorders
- Motor deficits
- UMN (spasticity)
- LMN (amytrophy = muscular wasting)
- Muscular disorders - Movement disorders (Extrapyramidal disease)
- Sensory ataxia
- Cerebellar ataxia
- Vestibular disorders
- Parkinsonian syndromes
- Normo-pressure hydrocephalus
Revision: Cerebellum
Cerebellum:
- Coordination / Fine-tuning of voluntary movements
- Control of equilibrium + muscle tone
- Responsible for ***ipsilateral side
Vermis / Other paramedian structures:
- **Truncal stability
- **Gaze fixation
- ***Gait
—> rely on integration of Sensory (Vision) + Vestibular + Motor (Proprioception) signals input
Cerebellar disorders
Ataxia (共濟失調症):
- ***loss of coordination
- irregularity / disorderliness
- may result from:
1. Cerebellar disorders
2. Impaired sensory feedback (Sensory ataxia)
- Limb ataxia / Ataxic gait
- Dysmetria + Tremor + Dysdiadochokinesia
- hard to test if weakness / sensory impairment
- muscle tone is reduced but often not apparent - Scanning dysarthria (***specific for cerebellar disorder)
- Explosive dysarthria (incoordination of speech / respiration —> speech volume / rate vary from word to word) + Cerebellar speech (slow + slurred) - Nystagmus
- vestibulocerebellar pathway affected —> Ocular Dysmetria (jerkiness of smooth-pursuit eye-movements with disrupted fixation)
- **Gaze-evoked + **Horizontal
- unilateral lesion: fast-phase of nystagmus is towards the ***affected side - Dysmetria
- errors in range + force of movements —> under / over-shooting of target: Finger-nose, Heel-shin test - Dysdiadochokinesia
- decomposition of fine repetitive movements
- NOT specific for cerebellar disorders
- can be seen in ALL neurological conditions affecting motor control of limb - Hypotonia
- Intention / Kinetic tremor
- exaggerated by maximising range of movement tested - ***Pendular tendon reflexes
Etiologies of Cerebellar disorders
Children:
- Congenital maldevelopment (Arnold-Chiari malformation, Dandy-Walker syndrome)
- Metabolic disorders
- **Infections (Chicken pox encephalitis)
- **Tumours (Medulloblastoma, Cystic astrocytoma)
- Hereditary degenerative disorders
Adult:
- Hereditary degenerative disorders (AD Spinocerebellar ataxias, Recessive Friedreich’s ataxia)
- Alcoholism
- **Cerebrovascular disease
- **Multiple sclerosis
- **Metabolic disorders (e.g. Hypothyroidism)
- **Drug overdose (e.g. Anticonvulsant, Antihistamine)
- ***Tumours (direct involvement / paraneoplastic syndrome)
Ataxic gait
Result of Incoordination of movements + Unsteady balance of trunk
Features:
- **Wide based (to maintain balance)
- **Truncal unsteadiness (when asked to walk tandem)
- **Tendency to Jerk sideway
- **Walk relatively quickly
- Irregular length / synergy
- Greatly exacerbated during rapid postural adjustments e.g. Turning corners
- may combine with other gait disorders (e.g. Spastic gait in MS, High-stepping gait in Tabes dorsalis)
Hemiplegic gait
- Arm adducted
- Internally rotated at shoulder
- ***Flexed at elbow
- Pronation of forearm
- ***Flexion of wrist and fingers
- Leg slightly flexed at hip
- ***Extended at knee
- Plantar flexion
- ***Inversion at foot
Apraxic gait / Gait apraxia
- ***Difficulty initiating walking
- Disorganised walking skills
- ***Shuffling small steps
- BUT ***arm swing and posture are normal (vs PD: reduced arm swing, stooping posture)
Cerebellum vs Basal ganglia
Cerebellum: Rapid (ballistic movement)
Basal ganglia: Slow (ramp, smooth movement)
1. Caudate nucleus
2. Putamen
3. Globus pallidum
4. Substantia nigra
Extrapyramidal disorders (aka Movement disorders)
Disorders of Basal ganglia:
- affect slow (ramp) rather than rapid (ballistic) movements
Basal ganglia motor loop:
- complex network consisting of multiple nuclei
- D1: excitatory pathway
- D2: inhibition pathway
- normally balance out each other, imbalance: Movement disorders
Dyskinesia / Hyperkinetic disorders (Defect in D2 inhibition pathway)
- Chorea (舞蹈症)
- Ballismus (芭蕾舞症)
- Athetosis (手足徐動症), Choreoathetosis
- Dystonia (肌張力不全症)
- Tremor (顫抖症)
- Myoclonus (肌躍症)
- Tics (肌抽搐症)
Akinesia / Hypokinetic disorders (Defect in D1 excitatory pathway)
- Parkinsonism
Chorea (舞蹈症)
Lesion in Striatum / related structures
Features:
- **Irregularity + **Randomness + Excessive + **Spontaneous + Jerky + Non-repetitive
- At different parts of body in random sequence
- **No weakness
- Gait: Tendency to sway + jerk
- ***Muscle tone ↓
- Patient may mask it by Quasi-purposive (seemingly on purpose)
- Irregular + Explosive speech
Causes:
- Huntington’s disease
- Cerebral palsy
- **Kernicterus (excessive bilirubin)
- Rheumatic fever (Sydenham’s chorea, reactivate as **Chorea gravidarum during pregnancy)
- SLE
- Structural lesions (e.g. Tumour, AV malformation)
- ***Wilson’s disease
(- Can be secondary to PD due to high Levodopa dose)
Hemiballismus (單側芭蕾舞症) / Ballismus (芭蕾舞症)
Exaggerated form of Chorea / Proximal chorea
Etiology:
- Stroke —> Lesion affect **Contralateral Basal ganglia / Subthalamic nucleus unilaterally —> **Contralateral Hemiballismus
Features:
- Irregular, Non-repetitive
- ***Violent excursions of affected limbs (∵ proximal muscles affected)
Treatment:
- ***Tetrabenazine (block Dopamine reuptake)
Prognosis:
- usually disappear several weeks after onset
Athetosis (手足徐動症)
Etiology:
- **Neonatal cerebral hypoxia
- **Kernicterus
Features:
1. ***Abnormal limb posturing
- Shoulder: Adducted + Internally rotated
- Elbow: Semi-flexed
- Wrist / MCP joints: Flexed
- IP joints: Extended
- ***Slow, coarse, twisting writhing movements of extremities
- Flexion / Extension of wrist, fingers, elbow
- Retraction, Internal rotation at shoulder - Patient may grasp affected limb with normal hand to ***restrain movement
- UMN signs may present
- Lower limb less affected
Dystonia (肌張力不全症)
Frozen Athetosis
***Abnormal posturing
Etiology (reversible):
- Focal brain lesion (involving Basal ganglia, Rostral midbrain)
- Wilson’s disease
- Drug-induced dystonia
Features:
- **Excessive muscular tone + contraction of antagonistic muscle groups
—> Sustained postural distortion of limbs + trunk (扭麻花, painful)
—> may be distorted by Repetitive spasmodic twisting movements
- **Posture / Action / Task-specific
- Sporadic / Familial
Types:
1. Focal Dystonia (more common)
- **Cervical dystonia (Spasmodic torticollis)
- **Blepharospasm
- Foot dystonia
- Writer’s cramp
- Generalised dystonia
Treatment:
- **Anticholinergics
- Levodopa
- **Benzodiazepines
- Botox local injection
Tremor (顫抖症)
- ***Rhythmic oscillating movement of a segment of limb / head
- ***Alternating / Synchronous contraction of antagonistic pair muscles —> Rhythmic oscillating movement
- Fixed periodicity
- Waveforms / Amplitudes can vary
3 types:
1. Resting tremor (esp. Parkinsonian)
2. Postural tremor
3. Intention / Kinetic tremor (esp. Cerebellar)
(4. Essential tremor)
Parkinsonian tremor:
- 4-6Hz
- in relaxed + supported limb
- occur when affected body parts are **at rest
- **subside with action
Postural tremor:
- enhanced physiologic (8-12 Hz) tremor on outstretched hand:
—> anxiety, exercises, sleep deprivation, drugs, alcohol, thyrotoxicosis, heavy metal poisoning
Cerebellar Kinetic tremor:
- ***3-6 Hz
- Terminal accentuation / Terminal dysmetria: ↑ in tremor towards target
- Past-pointing
- Treatment: No
- Pathology in Red nucleus: Severe Resting + Kinetic tremor
Physiological tremor:
- 8-12 Hz
- more obvious with old age, anxiety, thyrotoxicosis
Essential tremor:
- 5-10 Hz
- **action-induced
- resemble **exaggerated physiological tremor
- **not well-defined etiology
- worsen by stress / age
- some have positive family history (Benign essential tremor)
- alcohol can improve transiently
- Treatment: **β-blocker, ***Primidone (barbiturate)
Myoclonus (肌躍症)
Very wide DDx
Features:
- **Sudden, Brief shock-like muscle contractions
- Variable intensity
- Repetitive / Paroxysmal jerk
- **Simple movement (not complex e.g. chorea / athetosis)
- ***Less rhythmic + Visible pauses (vs Tremor)
Types:
1. Focal (involving only a few muscles)
- Basal ganglia disorders (neck, arm, shoulder)
- Generalised
- types: - Physiological (nocturnal, hiccups)
- Essential
- ***Epileptic
- Symptomatic
- Abnormal Cerebral cortex activities
—> Epilepsy syndromes
—> Neurodegenerative diseases e.g. AD, CJD
—> Mitochondrial diseases
—> Cerebral anoxia
- Spinal cord disorders
Treatment:
- Depend on etiological diagnosis / specific disease syndrome
- **Benzodiazepines
- Piracetam
- **Anticonvulsant e.g. Na Valproate
Differentials of myoclonus
- ***Epilepsy with myoclonus seizures
- ***Secondary myoclonus
- ***Dystonia myoclonus / chorea-related
- Basal ganglia disorders
- Stiff-person syndrome
- Essential myoclonus
- Periodic movements of sleep
- Brainstem, spinal myoclonus
Tics (肌抽搐症)
Etiology:
- **Gilles de la Tourette’s syndrome
- **Compulsive behaviour
- Obsessive ruminations
- ADHD
Features
- **Brief, Rapid
- **Coordinated movements, **Stereotypic (vs Chorea: irregular, random)
- Repeated at irregular intervals
- Ability of **voluntary suppression, but ***inner urge to make movement (vs Chorea: involuntary)
- Can be trivial
- Not uncommon
Persistent multiple simple tics:
- begin before 15 yo
- associated with vocal tics
- complete remission can occur in adulthood
Chronic multiple motor + vocal tics:
- Gilles de la Tourette’s syndrome
- **Male
- Treatment: **Clonidine (α2 agonist), ***Haloperidol (typical antipsychotic)
Prognosis:
- Symptoms begin in childhood, Worst during late adolescence
- Resolve spontaneously after 20 yo (majority)
Drug-induced movement disorders
- Acute dystonic reactions
- ***Anti-dopaminergic drugs (in young patients after a few hours) (Prochloperazine, Metoclopramide)
- Cranial, Cervical, Axial muscles
- Oculogyric crisis
Treatment:
- **IV Anticholinergics (Procyclidine, Benztropine, Diphenhydramine)
- **Benzodiazepines
- Tardive dyskinesia:
- Elderly taking long-term antipsychotic
- may be due to Dopamine receptor ***hypersensitivity
- Continuous stereotypic oro-lingual movements
—> Lip-smacking
—> Chewing
—> Rolling of tongue in mouth, pushing against cheek, periodic protrusion
- Gait unaffected
Treatment:
- Difficult
- Withdrawal (abruptly may paradoxically cause Tardive dyskinesia)
(Extrapyrimidal symptoms of Anti-psychotics:
1. Akathisia
2. Dystonia
3. Parkinsonism
4. Tardive dyskinesia)
Parkinson’s disease
A Clinicopathological entity
Etiology:
- Mostly **Sporadic (only a few Familial)
- Idiopathic degeneration of **Substantia nigra
- Presence of Intraneuronal ***Lewy bodies on microscopy
Parkinsonism:
- Clinical features of PD (reflecting loss of dopaminergic neurons)
Pathology:
- Loss of neurons in Substantia nigra (Melanin-containing, Dopaminergic)
- Loss of neurons in Brainstem, Pallidum, Putamen
- Lewy bodies inclusions (PD)
Parkinsonian syndromes:
- big family of syndromes that present with Parkinsonism
- PD one of them (but commonest Parkinsonian syndrome)
Other causes of Parkinsonism
- Secondary parkinsonism
- **Antipsychotic (i.e. Neuroleptics e.g. Phenothiazine) / Other dopamine-depleting drugs (e.g. Metoclopramide)
- **Wilson’s disease (must be excluded in early-onset Parkinsonism)
- Lithium
- Toxins: MPTP, CO poisoning, Cu, Mn
- Trauma (e.g. Punch drunk syndrome)
- Microvascular disease (HT, Atherosclerotic)
- **Normal pressure hydrocephalus
- Post-encephalitis lethargica
- AD, **Lewy body dementia, CJD
- Leucodystrophies
- Hallevorden-Spatz disease
- Westphal variant of Huntington’s disease
- Denatao-rubro-pallido-luysian atrophy
- Guam variant of motor neuron disease - Other neurodegenerative disease involving Basal ganglia
- **Diffuse Lewy body disease
- **Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)
- ***Multiple system atrophy
- Corticobasal ganglionic degeneration
—> called Parkinsonism “Plus” syndromes (have other features apart from Parkinsonism ∵ more widespread disease process)
Epidemiology of PD
- 80% of Parkinsonian syndromes
- Prevalance: 160/100,000 population
- Incidence: 20/100,000 per year
- 1% population >65 yo
- Onset: 40-70 yo, peak in ***6th decade
- Onset before 30 yo: ~1%
- Onset before 50 yo: ~10%
- M:F = 3:2
Natural history of PD
- Degenerative condition
- Insidious onset
- Gradual progression
- Average survival from onset ***13 years
- Mortality rate 2-5x of age-matched population
***“Hoehn and Yahr” staging
Stage 1: Unilateral (3 years)
Stage 2: Bilateral (6 years)
Stage 3: Bilateral + Postural imbalance (7 years)
Stage 4: Severe, need help (9 years)
Stage 5: Chair / Bedbound (14 years)
Risk factors of PD
Likely multi-factorial
1. Aging
- Nigral cells 425,000 reduced to 200,000 by 80 yo (30% of age-matched subject to start with —> early emergence of motor dysfunction)
- Genetics
- family history
- specific mutation - Environment (less clear)
***Clinical features of PD
Parkinsonism (TRAP):
1. Resting Tremor
- Resting (↓ with action, ↑ with rest)
- Begins in hand / foot
- Flexion + Extension of **fingers (usually little movement above wrists)
- Exacerbated by stress
- **Coarse (4-6 Hz)
- ***“Pill-rolling”
- Rigidity
- ↑ Resistance to passive movements (Lead-pipe / Cogwheel) (vs Spasticity: distribution + velocity-dependent)
- ↑ Muscle tone equal in flexor / extensor
- Uniform throughout range of movement
- **Cogwheel rigidity (combination of Tremor + Hypertonia)
- **Fatigue, muscle ache (∵ sustained muscle contraction) - Akinesia / Bradykinesia
- Slowness in voluntary movements
- **↓ Automatic movements (e.g. Arm swinging)
- Gait disturbance
—> Flexed, Stooping posture
—> Slow
—> **↓ Arm swing
—> Poor foot clearance
—> Poor gait initiation
—> **Small steps, Shuffling (Marche a petit)
—> Turning difficulty
—> Falls
—> Difficulty in initiation —> then advances rapidly with small steps to catch up with shift in centre of gravity (Festinating gait)
- Lack of facial expression + blinking (Facial amimia)
- Clumsiness in rapid repetitive movements (Dysdiadochokinesia)
- Blepharospasm, sustained blink responses (Myerson’s sign)
- Small hand writing (**Micrographia)
- ***↓ Voice, monotonous speech - Postural instability
- Tendency to fall backwards (***Retropulsion)
Other S/S apart from Motor symptoms:
1. Psychiatric
- Panic, Anxiety
- Depression
- Paranoia, Hallucinations (more prone to SE of anti-parkinsonian drugs)
- Sensory
- Paresthesia
- Pain - Autonomic dysfunction
- Tachycardia
- Sweating
- Constipation
- Belching
- SOB
- Postural hypotension
- ***Detrusor instability - Cognitive decline
- Slowness in thought
- Poor memory
- Lack of motivation
Clinical red flags to differentiate Parkinsonism Plus vs PD
- ***Rapid progression, early instability and falls
- ***Poor treatment response to Levodopa (PD has excellent response to Levodopa)
- ***Early + prominent dementia
- **Pyramidal signs, Cerebellar signs, Autonomic dysfunction, **Gaze palsy
- Young onset with strong family history
Diagnosis of PD
Clinical diagnosis:
- **Klawans principle: Presence of S/S of PD + without S/S not consistent with PD
- ∵ **NO reliable in-life markers
UK PD Society Brain Bank Clinical Diagnostic Criteria
Step 1: Diagnosis of Parkinsonian syndrome (S/S of PD)
- Bradykinesia
- >=1 of following
—> Muscle rigidity
—> 4-6 Hz rest tremor
—> Postural instability not caused by primary visual, vestibular, cerebellar, proprioceptive dysfunction
Step 2: Exclusion criteria for PD (without S/S not consistent with PD)
- S/S with Parkinsonism Plus syndrome
Step 3: Supportive prospective positive criteria for PD (only 80% specificity)
- Progressive disorder
- Persistent asymmetry affect side of onset most
- Excellent response (70-100%) to Levodopa
- Severe Levodopa-induced chorea
- Levodopa response >=5 years
- Clinical course of >=10 years
Other investigations:
1. DaT (Dopamine transporter) scan (123I-β-CIT and 123I-FP-CIT SPECT)
2. 18F-dopa, 11C-Raclopride PET scan
—> can still be positive in Parkinsonism Plus syndromes
- TC-US midbrain for Fe deposition in SNc (substantia nigra pars compacta)
- MRI (DWI, DTI, ADC map)
Genetics of PD
- Sporadic
- Positive family Hx: Double risk of PD
- > 10 genetic loci implicated in Parkinsonian syndromes: PARK, SNCA, LRRK etc. (although most of them related to Parkinsonism Plus syndromes)
- Gene mutation: **α-synuclein, **Parkin
- ***LRRK2 associated with
1. Familial PD
2. Sporadic late-onset cases (0.5-2%)
Treatment of PD
NOT exist in PD:
1. Restorative therapy (reverse disease process)
2. Neuroprotective therapy (arrest / slow down disease progression)
Only available in PD:
3. Symptomatic / Palliative therapy
- Dopaminergic (replenish dopamine deficiency from Nigral cell degeneration)
- Anti-inhibitory
Drug therapy:
- ***Levodopa + Carbidopa (peripheral DOPA decarboxylase inhibitor) (Gold standard)
Early stage:
- **Anticholinergic (Benzhexol)
- **MAO-BI (Selegiline)
Adjunct:
- **Dopamine agonists (Bromocriptine, Ropinirole, Apomorphine, Pergolide)
- **COMT inhibitor (Entacapone, Tolcapone)
- Amantadine
Surgery:
- **Pallidotomy
- **Thalamotomy
- ***Deep brain stimulation
- Cell transplantation
Others:
- Physical therapy
- Daily living aid
***Dopaminergic therapy
- Levodopa
- converted to Dopamine in remaining Nigral cell
- combined with peripheral Dopa-decarboxylase inhibitor / Transferase inhibitor —> achieve higher CNS concentration
- Problems with long term use:
—> **Loss of efficacy (only for ~5 years, ∵ gradual loss of dopaminergic terminals)
—> Drug-induced **Choreiform Dyskinesia (Motor fluctuations, End-of-dose wearing off, Unpredictable on-off response)
—> **Psychiatric complications (Hallucinations, Psychosis)
—> Can add **Atypical antipsychotics with low propensity for inducing extrapyramidal SE (e.g. Clozapine, Olanzepine, Quetiapine) - MAOI (Monoamine oxidase B inhibitor)
- ↓ breakdown of dopamine - Dopamine receptor agonist
- ↑ sensitivity of dopamine receptor
Anti-inhibitory therapy
Surgical treatment
1. Lesioning specific D2 nuclei e.g. Pallidotomy, Thalamotomy
- Down-regulate D2 inhibitory pathway
- Deep brain stimulation (current)
- Overdrive pacing of STN (subthalamic nucleus) with electrodes —> blockade effect
Treatment flow of PD
Early disease, impaired ADL
—> **Tremor predominant: Selegiline, Anticholinergic, Levodopa
—> **Other features dominant: Selegiline, Amantadine, Dopamine agonist, Levodopa
—> Good response: Lowest dose that maintains control
—> Poor / No response: ↑ Dose, Consider other diagnosis
Moderate impairment of ADL
—> Levodopa
—> Wearing off: Smaller + more frequent doses, Carbidopa Levodopa, Add Dopamine agonist, COMT inhibitor (Entacapone)
—> **Dyskinesia: ↓ Dose, Add Amantadine
—> **Non-motor adverse effects: ↓ Dose, Add Quetiapine, Clozapine
Consider surgical options for severe, pharmacologically unaddressable detriments
Other structures affected by PD
Apart form Substantia nigra pars compacta
- Ventral tegmental area
- Locus ceruleus
- Raphe nuclei
- Substantia innominate
- Intermediolateral column
- Olfactory bulb
Parkinsonism
- Occurs in all ethnicities groups
- related to aging
- clinical signs
Other notes
Other notes
Huntington’s disease
- Manifest 30-50 yo
- Chorea —> Dementia
Pathophysiology:
- Neuronal loss in **Striatum + **Cerebral cortex
Genetics:
- **Autosomal dominant
- **Chromosome 4, repeat GAG
Behavioural problems:
- personality change
- affective disorders
- frank psychosis
Prevalence: 5-10 / 100,000
MRI / CT:
- Cortical + Caudate atrophy
Treatment:
- No cure
- ***Symptomatic (Haloperidol: atypical antipsychotic)
Clinical features:
- Marching the knee reflex
Prognosis:
- Death within 10-12 years
Wilson’s disease (Hepatolenticular degeneration)
- ***Autosomal recessive
- Defect in copper-transporting ATPase coded on chromosome 13 (ATP7B gene) + Low Ceruloplasmin / Cannot incorporate Cu
—> **Cu accumulation in Liver + **Basal ganglia
—> Neurological manifestations in childhood / young adulthood
—> Dyskinesia / Parkinsonism / Psychiatric problems
Features:
- Kayser-Fleischer rings (Cerebral involvement)
Prognosis:
- Untreated: die from **Cirrhosis / **Neurological complications within 10 years
Treatment:
- ***Penicillamine (Cu chelation)
- Liver transplantation (Cu removal)
Prevention:
- Family screening to detect presymptomatic cases —> treat with ZnSO4
