5 Movement and Neurodegenerative Disorders 5.1 Approach to Movement Disorders 5.1.1 Approach to Abnormal Movements Ref: Davidson Ch26, Neurology in Practice Ch8, JC23, JC Teaching clinic, Maudsley’s guidelines Ch2 Movement disorders are divided into: □ Hyperkinetic disorders: , chorea/choreoathetosis, tics, ballismus, myoclonus, dystonia, stiff-person syndrome □ Hypokinetic disorders: Parkinsonism, catatonia Note that functional movement disorders (common) may mimic any syndrome patterns A. Tremor Tremor: alternating contractions of antagonistic muscle groups causing involuntary rhythmic oscillation of body parts Types of tremor: □ Rest tremor: occurs in supported body parts w/o ms activation Test: observe with body part supported, ↑by mov’t in other body parts and ↓by its own mov’t □ Postural tremor: occurs when maintaining certain posture Test: observe by extending UL horizontally, pointing at objects, sitting erect w/o support, standing, protruding tongue □ Kinetic tremor: occurs during voluntary movement → Simple kinetic tremor: tremor roughly the same throughout course of a voluntary movement → Intention tremor: crescendo increase as affected body part approaches its target → Task-specific tremor: occurs during specific task, eg. primary writing tremor

Example Features Comments - Low-amplitude, high frequency (10-12Hz) tremor - Not evident in normal circumstances - Exacerbation of physiologic tremor Physiological - Postural tremor, occurs upon maintaining posture is the commonest cause of action - Symmetrical and distal in distribution tremor tremor - Should seek a primary medical - ↑ by anxiety, emotional stress, drugs (eg. β2-agonist and other catecholaminergic drugs, lithium, antidepressants), cause first in action tremor alcohol/opioid withdrawal, thyrotoxicosis, fever

- Variable amplitude, high-frequency (8-10Hz) tremor - Prev 300/100k (up to 5%) - 30-70% FHx +ve, AD inheritance Essential - Postural and kinetic tremor, NOT at rest - Typically affects bilateral arms (not LL) and head - Usually a/w insidious onset tremor - May be alleviated by alcohol but not ↑ by caffeine - Mx: propranolol, primidone, benzodiazepine (1st line), DBS of - NOT a/w other Parkinsonian and cerebellar features ventromedial nucleus of thalamus

- Coarse, low-frequency (3-4Hz) tremor - May be first manifestation of Parkinsonian - Resting tremor, dampened during volition idiopathic PD - Typically starts at unilateral UL and spread to other limbs - Anticholinergics may be used as tremor - Classically described as ‘pill-rolling’ tremor initial Tx in tremor-dominant PD in - Associated with rigidity and bradykinesia young pt

Cerebellar - Coarse, low-frequency (4-6Hz) tremor - Intention tremor, maximal approaching end of movement / tremor - Associated with other cerebellar features

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B. Choreiform Movements Chorea: sudden, unpredictable quasipurposive involuntary fidgety/jerky movement □ ↑ by voluntary movement, stress, anxiety; ↓ during sleep : slower, coarser, more writhing movement, esp affecting distal parts of limbs □ Often occurs together with athetosis (choreoathetosis) Ballism: involuntary movement that are proximal and large amplitude with a flinging/kicking character □ Most often unilateral (hemiballism) □ Classically a/w contralateral subthalamic nucleus stroke

Aetiology: all choreiform movements result from a disruption in basal ganglia circuitry resulting in imbalance between indirect and direct pathways → localizes to basal ganglia □ Inherited: Huntington’s disease, Wilson’s disease, neuro-acanthocytosis... □ Vascular: basal ganglia stroke □ Inflammatory: Sydenham chorea, SLE, vasculitis □ Neoplastic: BG tumours, paraneoplastic chorea □ Drugs: neuroleptics, levodopa, DA, antihistamines, amphetamines, digoxin, OC pills □ Infectious: AIDS, neurosyphilis, cerebral malaria... □ Metabolic: kernicterus, polycythaemia vera, hypoparathyroidism, chorea gravidorum (in pregnancy)… Diagnosis: Hx, neurological/CVS exam + slit-lamp examination Mx: tetrabenazine and clonazepam for symptomatic Tx

C. Tics Tics: abrupt stereotyped repetitive movements involving discrete muscle groups □ Can mimic normal coordinated movements, vary in intensity and lack rhythm → Motor tics, eg. eye-blinks, head tossing, shoulder shrugs, facial grimaces → Phonic tics, eg. barks, grunts, throat-clearing noises □ May be temporarily inhibited by will power and usually disappear by sleep Causes: □ Primary tics: no underlying structural lesions, usually onset in childhood and resolves after 20y → Transient tic disorder: last <1y, occurs in normal children → Gilles de la Tourette syndrome: otherwise unexplained motor + phonic tics with onset <21y □ Secondary tics should be suspected if tics begin abruptly, are persistent or are problematic → Eg. dopaminergic drugs, stimulants, neuroleptics, other inherited diseases Mx: behavioural Tx as mainstay (response to drug Tx unsatisfactory in general)

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D. Myoclonus Myoclonus: brief, repetitive, involuntary sudden ‘shock-like’ jerks of muscle groups □ Results from focal discharge from cortex (majority), subcortical or spinal cords Causes: □ Physiological: hypnic (during sleep transitions), anxiety-related, exercise-related □ Essential myoclonus: myoclonus as primary symptom, non-progressive Hx □ Epileptic myoclonus: a/w seizure syndrome, eg. juvenile myoclonic epilepsy □ Symptomatic (secondary) myoclonus: → Focal CNS lesions, eg. post-stroke, CNS tumour → Metabolic and toxic encephalopathies, eg. due to cerebral anoxia, organ failure, hypoNa, hypoGly → Neurodegenerative diseases, eg. CJD, Alzheimer’s disease, CBD → Metabolic storage diseases → Progressive myoclonic epilepsy (with progressive cognitive decline, seizures, and death) Mx: clonazepam, piracetam, sodium valproate as symptomatic relief

E. Dystonia Dystonia: sustained/intermittent involuntary muscle contractions in antagonistic muscle groups causing abnormal movements or distorted postures □ Dystonic movements are typically patterned, twisting and may be tremulous, i.e. dystonic tremor Classification: □ Focal: a group of muscles, eg. blepharospasm, oromandibular dystonia, cervical dystonia □ Segmental: contiguous groups of muscles, eg. craniobrachial dystonia, Meige syndrome □ Multifocal: ≥2 non-contiguous groups of muscles □ Generalized, eg. idiopathic torsion dystonia Clinical features: □ Context: initiated/worsened by voluntary action, fatigue, stress and emotional states → occurs at rest in late stages □ Alleviation by sensory tricks (geste antagoniste, eg. touching face), sleep and relaxation □ Hypertrophy of involved muscles progressing into fixed muscle contractures in late stages □ Involvement: LL onset in early onset vs facial, neck or UL onset in late onset Aetiology: pathogenesis unknown, probably involve dopaminergic and cholinergic systems □ Idiopathic torsion dystonia: dystonia as only feature w/o other neurological deficits → Hereditary: early onset (<21y), LL focal onset becoming generalized, eg. DYT1-TOR1A → Sporadic: adult onset (>21y), UL, facial or cervical onset w/o generalization □ Secondary dystonia, esp when a/w ↓cognition, pyramidal/extrapyramidal features, , sensory loss → Brain injury, eg. cerebral palsy, head injury → Neurodegenerative diseases, eg. Parkinsonism, spinocerebellar ataxia, Huntington’s disease → Drug-induced, eg. anticonvulsants, CCB, Das, levodopa, neuroleptics □ Pseudodystonia, eg. AAJ subluxation, stiff-person syndrome, bone/ligamentous injury, posterior fossa tumour, psychogenic dystonia Dx: clinical + r/o alternative causes, esp when a/w atypical features Mx: treat underlying cause + symptomatic Tx □ Pharmacotherapy: levodopa (if young-onset), anticholinergic/BZD (if adult-onset) □ Botox injection: Tx of choice for focal dystonia, combined w/ Rx in systemic/segmental dystonia → MoA: IM injection → presynaptic NMJ blockage → ↓ACh release → ‘chemodenervation’ → S/E: injection site reaction, muscle atrophy, ptosis, lower facial weakness, ↑lacrimation (generally reversible) - Page 96 of 179 -

F. Neuroleptic-induced Movement Disorders

Type Features Treatment Subjectively unpleasant state of inner restlessness A/w strong desire/compulsion to move ↓ or change antipsychotic Propranolol Akathisia Stereotypic motor behaviours, eg. constant crossing/uncrossing leg, foot stamping when seated, rocking Benztropine motion of trunk, wrining of hands Benzodiazepine Occurs in 25% pt within hours-weeks Involuntary contractions of major muscle groups Anticholinergics, eg. Acute eg. oculogyric crisis (eyes rolling upwards), torticollis (H&N benztropine, diphenhydramine dystonia twisted to the side), dysphagia, laryngospasm (rare) Change antipsychotics Occurs in 10% pt (esp children/young M) within hours Botox injection Drug-induced Tremor, rigidity and bradykinesia ↓ or change antipsychotic Parkinsonism Occurs in ~20% pt within days-weeks Benztropine Delayed onset of abnormal movements Eg. bucco-lingual-masticatory ↓ or change antipsychotic Tardive (commonest) i.e. complex chewing/tongue popping mov’t STOP anticholinergics64 dyskinesia Eg. piano-playing fingers, body rocking Eg. torticollis (i.e. tardive dystonia) Tetrabenazine Occurs in 5% pt/yr within months-years

5.1.2 Approach to Abnormal Gait Ref: Neurology and Neurosurgery Illustrated P. 192, JC23 A. Physiology of Gait Normal gait depends on: □ Normal muscles: hip flexion, knee flexion, ankle dorsiflexion □ Corodination to ensure fluidity □ Antigravity reflexes to maintain erect posture

Characterized by: □ Erect posture □ Moderately sized steps □ Medial malleoli of tibia tracing a straight line

64 Anticholinergics are usually ineffective and may even exacerbate TD in some cases. - Page 97 of 179 -

Physiological control of gait: Tasks Components Centres - Initiation: - Start + end Premotor Motor cortices Locomotor - Pattern, eg. direction, speed, stepping surface - Synergy: subcortical centres - Maintaining rhythm Mesencephalic locomotor region (MLR) Spinal locomotor network (SLN) - Regulatory: - Orientation w.r.t. environment Postural Basal ganglia control and and gravity Cerebellum balance - Maintaining equilibrium Vestibular/proprioceptive input

Anatomy of gait control: □ Higher control: premotor cortex, motor cortex → Motor cortex □ Pyramidal tract □ Pattern generator: → MLR generates drive → SLN allows rhythm generation and pattern formation □ Reticulospinal tract □ Effector: spinal reflex pathways □ Regulation: → Extrapyramidal system → upper level (initiation) → Cerebellar system → middle level (synergy) → Spinal reflex pathways → lower level (effector) arises from pathologies involving any part of the gait control pathway B. Abnormal Gaits 1. Plegic gaits Hemiplegic gait: □ Cause: unilateral arm + leg □ Features: mimicks ancient reflexive gait → Arm: adducted and internally rotated at shoulder, flexed at elbow, pronation of forearm, flexion of wrist and fingers → Leg: - Abduction and circumduction at hip to prevent dragging - Knee extended, foot plantarflexed and inversion at foot Paraplegic gait □ Cause: spastic □ Features: scissor-like posture → Strong adduction at hips → Two legs perform circumduction - Page 98 of 179 -

2. Parkinsonian (festinating) gait Cause: Parkinsonism (extrapyramidal damage) Features: □ Flexed, stopping posture □ Bradykinesia: hesitation in starting, freezing □ Festination: initial hesitance → leans forward to initiate walking → hurries in shuffling steps to ‘catch-up’ on himself

3. Apraxic (Frontal) gait Cause: bilateral frontal lobe or hemispheric diseases Features: □ Wide-based gait □ Poor initiation – leg appear stuck to the floor □ Tendency to fall backwards

4. Ataxic Gait Cerebellar ataxia: ‘drunken’ gait □ Wide-based □ Jerk and unsure steps varying in size □ Trunk sways forward □ May only be detectable in tandem gait in mild cases : ‘stomping’ gait □ Gait appear normal with eyes open □ Feet appear to ‘stamp’ on ground → to enhance proprioceptive input

5. ‘LMN’ gaits Neuropathic (steppage) gait □ Cause: LMN weakness of pretibial and peroneal muscles (dorsiflexors) □ Features: → Leg lifted high for toe clearance → Toes touch ground before heels Myopathic (waddling) gait: □ Cause: proximal myopathy → bilateral hip adductor weakness → inability to fix pelvis during walking □ Features: ‘waddling gait’ → Bilateral dropping of pelvis → Appears as swaying buttocks : □ Cause: pain with weight bearing □ Feature: → Shortened stance relative to swing phase

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5.1.3 Approach to Cerebellar Syndrome Ref: Neurology and Neurosurgery Illustrated P. 180-183, 250 Cases in Clinical Medicine Case 46, JC21-22 Anatomy: □ Vestibulocerebellum → Site: flocculonodular lobe → Fx: vestibular reflexes (VOR, VSR) □ Spinocerebellum → Site: vermis and intermediate zones → Fx: error-detector of truncal/paraxial muscles and distal muscles respectively □ Cerebrocerebellum → Site: hemisphere → Fx: motor planning esp for rapidly alt. movements Results in ipsilateral abnormalities Clinical evaluation checklist: Midline lesions cause ocular and balance abnormalities Hx of falls, gait instability □ Nystagmus: horizontal or vertical nystagmus Hx of clumsiness and difficulty □ : wide-based cerebellar gait, Romberg –ve with fine coordinated movement □ LL : heel-shin test Scanning dysarthria Hemispheric lesions cause abnormalities in limb coordination Rebound, rapidly alternating □ Limb ataxia: UL dysmetria, intention tremor, mov’t, finger-nose test , rebound, gait ataxia Heel-shin test, Romberg test, □ Scanning dysarthria: same emphasis put on each syllable tandem gait D/dx of cerebellar ataxia: Nystagmus, ocular dysmetria, fundoscopy for optic neuritis □ Sensory loss or motor weakness Pendular reflexes □ Sensory ataxia (proprioceptive deficit) □ Vestibular pathologies (also present with persistent vertigo) Aetiology: grouped by temporal course Acute Subacute Chronic progressive Vascular Autoimmune Congenital Cerebellar ischaemia Chiari malformation Cerebellar haemorrhage Miller-Fisher syndrome Dandy-Walker syndrome Drugs and toxins SLE, Behcet’s, coeliac… Cerebellar agenesis Antiepileptics, eg. phenytoin Paraneoplastic degeneration Hereditary Chemo, eg. cytarabine, 5FU SCLC, gyne, breast, lymphoma Spinocerebellar ataxia Alcohol Neoplastic, esp CPA tumours Friedreich’s ataxia Infectious Metabolic Wilson’s disease Meningoencephalitis Chronic alcoholism Mitochondrial diseases ADEM Wernicke encephalopathy Neurodegenerative Vitamin E deficiency Multiple system atrophy Hypothyroidism PSP Evaluation: □ R/o alternative causes, eg. sensory ataxia due to DM neuropathy

□ Basic bloods: CBC, L/RFT, ESR/CRP, TFT, vit B12 and E, serum Cu, serum lactate □ Neuroimaging (esp MRI) ± LP □ Genetic testing for hereditary if appropriate - Page 100 of 179 -

5.2 Parkinsonism and Parkinson’s Disease Parkinson’s disease (PD): idiopathic degeneration of substantia nigra with intraneuronal Lewy bodies □ A clinicopathological entity, major (80%) cause of parkinsonism □ Cf parkinsonism = syndrome of clinical features seen in PD □ Cf Parkinsonian syndromes including other diseases w/ similar S/S → Eg. progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD) → Present with Parkinsonism + other S/S 5.2.1 Parkinsonism Tremor: presenting symptom in ~70-80% idiopathic PD Classic quad of □ Course: develops early in the disease but may ↓ in later stages due to Parkinsonism: bradykinesia and rigidity - Tremor □ Character: characteristically unilateral resting tremor - Rigidity → Context: ↓with purposeful action, ↑with rest and stress - Akinesia → Amplitude/rate: coarse (4-6Hz) - Postural instability → Classically ‘pill-rolling’ (thumb moving rhythmically backwards and forwards on palm of hand) → May also involve legs, lips, jaw, tongue (but not the head) Rigidity: occurs in ~75-90% idiopathic PD □ Course: begins unilaterally and spreads contralaterally □ Character: → ‘Cogwheel’ or ‘lead-pipe’ rigidity (↑with passive movement cf spasticity) → Predominantly flexors → flexed/stooped posture □ A/w: fatigue, muscle ache Akinesia or bradykinesia: present at onset in ~80% idiopathic PD, major cause of disability □ Slowness in initiating voluntary movement with hesitance □ Arms: starts distally → ↓manual dexterity of fingers → gradual ↑ difficulty to perform simple tasks (eg. buttoning) □ Legs: difficulty in getting out of chair with shuffling gait □ Face: → ‘Masked’ facies with lack of facial expression and blinking → Monotonous speech → Slowness in swallowing → drooling of saliva □ Clinical tests: → Finger tapping: ask pt to tap fingers in turn onto a surface repeatedly and quickly with both hands → slow and clumsy → Twiddling: rotating hands around each other in front of body → slow and clumsy Postural instability: □ Cause: loss of postural reflexes → imbalance and tendency to falls □ Occurs early on in the disease but falls usually occur in the later stages (consider d/dx if occur early) → Loss of independent ADL → the most disabling feature □ Test: propulsion/retropulsion when in standing position → loss of ability to balance

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A. Clinical Evaluation General inspection: □ Mask-like facies □ Stooped posture with little spontaneous movement □ Tremor: unilateral resting pill-rolling Neurological examination □ Tone: cogwheel or lead-pipe rigidity (best felt at wrists) □ Gait: → Difficulty in starting/ending/turning (bradykinesia) → ‘Festinating’ gait: small shuffling steps - ↓arm swing and poor foot clearance → Improve with visual input (eg. put lines on ground) Other tests: □ Glabellar tap: tap on glabella with middle finger/tendon hammer repeatedly → Normal → stop blinking after a few taps → Continuous blinking → PD or frontal lobe disease (Myerson’s sign) □ Finger tapping: ask pt to tap fingers in turn onto a surface repeatedly and with both hands → clumsiness and slowness □ Twiddling: rotating hands around each other in front of body → slowness and clumsiness □ Writing: characteristic micrographia when asked to write address □ Speech: ask pt to read out a long passage → Monotonous tremulous speech with ↓volume, ↓speed, ↓modulation, frequent pausing, tremored, indistinct → Palilalia: repetition of the end of a word □ Propulsion and retropulsion → instability Signs to r/o other d/dx: □ UMN and cerebellar signs for MSA □ Vertical gaze palsy for PSP □ Tardive dyskinesia for drug-induced parkinsonism

B. Differential Diagnosis Idiopathic Parkinsonism (Parkinson’s disease, PD): commonest, 80% of cases Parkinsonian-plus syndromes: □ Multisystem atrophy (MSA) □ Progressive supranuclear palsy (PSP, Steele-Richardson-Olzewski syndrome) □ Corticobasal degeneration (CBD)

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Secondary (symptomatic parkinsonism): □ Post-encephalitic, eg. encephalitis lethargica (not present anymore) □ Drug-induced, eg. neuroleptics, dopamine-depleting/anti-dopaminergic drugs, lithium, antihistamines □ Toxic: MPTP65, manganese66, CO poisoning67, rotenone □ Chronic head trauma, eg. ‘punch-drunk’ syndrome □ Neoplastic, eg. parasagittal meningioma Inherited neurodegenerative diseases: □ Wilson’s disease □ Hallervorden-Spatz syndrome: neurodegeneration with brain iron accumulation □ Familial olivopontocerebellar atrophy Pseudoparkinsonism: □ Cerebral arteriosclerotic disease: stepwise deterioration, LL>UL involvement □ Normal pressure hydrocephalus

Parkinsonism should be differentiated from: □ Essential tremor: tremor only present on posture and movement (cf PD resting tremor) □ Cerebellar tremor: tremor only present on intention □ Akinetic form of Huntington’s chorea (see below)

5.2.2 Parkinson’s disease (PD) Epidemiology: □ Burden: prevalence 160/100k (1% of pop’n >65y/o), incidence 20/100k/y □ Demographics: M:F = 3:2, onset 40-70y, peak in 6th decade (~1% cases before 30y, ~10% before 50y) □ RFs: aging, genetics (2× risk if FHx+, a/w PA R K , SNCA, LRRK68), environmental Aetiology: idiopathic, neurodegenerative in nature, likely multifactorial Pathology: □ Depletion of dopaminergic neurones in substantia nigra □ Intraneuronal Lewy bodies (eosinophilic inclusion bodies) in BG → may spread to cerebral cortex in later stages → PD-related dementia Pathophysiology: □ Motor symptoms: degeneration of nigrostriatal pathway → ↓dopamine input to striatum → balance shifted towards indirect pathway → bradykinesia, rigidity □ Cognitive symptoms: degeneration of mesocortical/mesolimbic dopaminergic pathways □ Autonomic dysfunction: dopamine depletion in hypothalamus □ Dementia: degeneration of cholinergic nucleus A. Clinical Features Parkinsonism: TRAP that is initially asymmetrical with late impairment of postural reflexes

65 MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is a prodrug to the neurotoxin MPP+, found as an impurity in heroin. This substance destroys the dopaminergic neurones in the substantia nigra of the brain, resulting in permanent Parkinsonism. 66 Manganese may accumulate in basal ganglia in liver dysfunction. 67 CO poisoning affects basal ganglia due to its high metabolic activity. 68 LRRK2 gene is associated with both familial and sporadic late-onset cases (0.5-2%). - Page 103 of 179 -

Non-motor symptoms: may precede TRAP for many years but become ↑prominent with progression □ Neuropsychiatric: → Depression (>50%): a/w serotonergic deficiency, can consider SSRI → Anxiety: common, can consider BDZ → PD-psychosis: common in late stages, can be due to levodopa/DA and the disease itself - Eg. frightening nightmares, vivid dreams/illusions, overt mania, visual hallucinations, delusions □ PD-dementia (10-15%): worsened by anticholinergics, consider AChR inhibitors □ Autonomic: → Postural hypotension: dizziness and falls, worsened by levodopa/DA → consider ↓dose → Constipation: common, consider high-fibre diet, bulk/osmotic laxative, ↑fluid intake/exercise → ↑sweating: a/w seborrheic dermatitis, may respond to levodopa □ Other features: fatigue, pain, sleep disturbance (eg. hypersomnolence), sexual problems (erectile failure, loss of libido, hypersexuality)

Clinical course: insidious onset with gradual progression over 10-15 years □ Untreated → ↓UPDRS69 motor score 8-9%/y □ Mortality rate 2-5× general population matched for age □ Average survival from onset = 13y (often die from complications eg. pneumonia) ‘Hoen and Yahr’ staging (under UPDRS) in PD: Stage Description Mean time from dx 1 Unilateral involvement, minimal/no functional disability 3y 2 Bilateral/midline involvement w/o impaired balance 6y 3 Bilateral involvement with mild-to-moderate disability and impaired 7y postural reflexes but physically independent 4 Severely disabling but still able to walk/stand unassisted 9y 5 Chair-/bed-bound if unassisted 14y

2. Diagnosis Parkinson’s disease is a clinical diagnosis based on □ Presence of S/S of PD (A + ≥1 of TRP) □ Absence of S/S not consistent with PD Note that initial presentation is seldom full-blown and therefore diagnosis of PD requires repeated re-examination over time until clearly PD or signatures of other processes emerge

69 UPDRS = unified Parkinson’s disease rating scale. It consists of six parts: (1) evaluation of mentation, behaviour and mood; (2) self-evaluated ADL; (3) clinician-scored motor evaluation; (IV) complications of therapy; (V) Hoehn and Yahr stages; (VI) Schwab and England ADL scale. - Page 104 of 179 -

Diagnostic criteria:

(1) Diagnosis of PD (2) Exclusion criteria (3) Supportive prospective - Bradykinesia - Hx of repeated strokes with stepwise progression of positive criteria PD features - ≥1 of the following: - Hx of repeated head injury - Progressive disorder Muscular rigidity - Hx of definite encephalitis - Persistent asymmetry - Oculogyric crises 4-6Hz rest tremor - Antipsychotic Tx at onset affecting side of onset most Postural instability - ≥1 affected relative - Excellent response - Sustained remission (70-100%) to levodopa not caused by - Strictly unilateral after 3y primary visual, - Supranuclear gaze palsy - Severe levodopa-induced vestibular, - Cerebellar signs chorea cerebellar or - Early severe autonomic involvement - Early severe dementia with disturbances of memory, - Levodopa response ≥5y proprioceptive language and praxis - Clinical course ≥10y dysfunction - Babinski sign

Consider alternative diagnosis when: □ Onset/course: sudden onset, rapid progression, young onset with strong FHx of other ds □ Clinical pattern: early and prominent dementia, early frequent falls, early incontinence, no tremor in presence of significant bradykinesia □ S/S of other causes: pyramidal/cerebellar signs/autonomic dysfx (MSA), gaze palsy (PSP), cortical signs/ (CBD) □ Retrospective: poor treatment response to levodopa (PD usually excellent response)

Neuroimaging: considered for atypical cases □ CT/MRI: usually normal for age → r/o alternative cause □ Dopaminergic SPECT/PET: ↓dopamine activity in basal ganglia → Does not differentiate between different forms of degenerative Parkinsonism Other Ix: □ Specific Ix to r/o secondary/alternative causes in young patients □ Genetic testing if early onset with +ve FHx 3. Treatment NO CURE! → symptomatic only Treatment approach: □ General: PT, OT □ Dopamine-based Rx for motor S/S □ Psychotropics for non-motor S/S Initial treatment: (NICE 2017) □ Levodopa if motor S/S impact on QoL □ Any of following if no effect on QoL → Levodopa-based Tx → Dopamine agonist (DA) → MAO-B inhibitor → (Anticholinergics) if young-onset, prominent dystonia and tremor Adjunctive treatment to levodopa if developing dyskinesia or motor fluctuation despite optimal LD □ Options: dopamine agonist, MAO-B inhibitor, COMT inhibitor Surgical Tx considered for pharmacologically refractory cases

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Levodopa-based Tx, eg. sinemet (levodopa + carbidopa), madopar (levodopa + beserazide) □ MoA: → Levodopa is precursor of dopamine → decarboxylated into dopamine → replenishes inadequate dopamine in striatum → Peripheral DOPA deCOase inhibitor cannot pass BBB → ↓peripheral decoration of levodopa → ↓peripheral S/E + ↑central availability □ Effect: most effective drug, more vs akinesia, rigidity □ S/E: postural hypotension, nausea, vomiting, hallucinations, addiction (dose-related) Problems of long-term levodopa therapy: □ Loss of efficacy (natural progression of PD → ↓dopaminergic neurone reserve) □ Motor fluctuations: occurs in prolonged levodopa treatment → ↓predictability to response → First presents as peak-dose phenomenon with end-of-dose wearing off70 of effect → Later become unpredictable alterations between periods of - ‘On’ episodes with positive response to levodopa - ‘Off’ episodes with re-emergence of symptoms (or even acute ‘freezing’) → Mx: - Adjunctive Tx by DA, COMT inhibitor, MAO-B inhibitors When titrating Rx for PD, remember that dyskinesia (‘on’) - SC apomorphine: potent DA, rescue Tx for ‘off’ episodes is often more tolerable than □ Dyskinesia: mixture of chorea and dystonia freezing (‘off’). → Peak-dose dyskinesia at max dose (more common) → Diphasic dyskinesia in between ‘on’ and ‘off’ → Mx: amantadine, clozapine

Dopamine agonist (DA), eg. rotigotine (skin patch), pramipexole, ropinirole, apomorphine □ MoA: direct agonist at dopamine receptors □ Use: as monotherapy (‘levodopa-sparing) or as adjunct □ S/E: N/V, postural hypotension, headache, confusion, agitation, depression, hallucination, ↑dyskinesia MAO-B inhibitor (MAOI), eg. selegiline, rasagiline □ MoA: inhibitor of monoamine oxidase → ↓DA breakdown □ Use: as monotherapy (less efficacious cf LD/DA) or adjunct □ S/E: insomnia, skin rash Catechol-O-methyltransferase (COMT) inhibitor, eg. entacapone □ MoA: ↓methylation of dopamine and levodopa → ↑duration of action of levodopa □ S/E: dyskinesia, urine discolouration, diarrhoea Amantadine: □ MoA: unknown, likely a/w NMDA receptor blockade □ Use: treatment of LD-induced

70 Wearing off phenomenon refers to a re-emergence of Parkinsonism at the end of the dosing interval. - Page 106 of 179 -

Anticholinergics, eg. orphenidrine, benzhexol (Artane), benztropine □ MoA: inhibitor muscarinic cholinergic fibres in striatum → ↓inhibition □ Use: initial therapy in young-onset pt w/ prominent dystonia and tremor □ S/E: dry mouth, blurred vision, urinary retention, confusion, memory loss, psychosis

Surgical therapy: □ Destructive neurosurgery: → Thalamotomy for control of medi8cally intractable tremor → Pallidotomy for control of LD-induced dyskinesias, rigidity, bradykinesia, tremor □ Deep brain stimulation (DBS): produces same effects as permanent lesioning → Principle: electrical stimulation → induce a functional inhibition → Site: usually at subthalamic nucleus or globus pallidus internum (indirect pathway) → Indication: medically refractory tremor or motor fluctuation

5.2.3 Parkinson plus syndromes Multiple system atrophy (MSA): □ Epidemiology: prevalence 2-5/100k (less common than PD), mean onset 54y, M:F = 1:1 □ Pathology: glial inclusion and myelin degeneration in various sites, eg. BG, pontine nuclei, cerebellum… □ Clinical features: Parkinsonism + autonomic failure + cerebellar ataxia + pyramidal signs → Motor involvement71: Parkinsonism-dominant (MSA-P) vs cerebellar-dominant (MSA-C) - Parkinsonism: akinesia, rigidity, postural instability, irregular jerky postural/action tremor, prominent camptocormia/anterocollis72 - Cerebellar ataxia: gait ataxia, limb ataxia, ataxic dysarthria, gaze-evoked nystagmus - Pyramidal S/S → Dysautonomia: urinary dysfunction, symptomatic orthostatic hypotension, early ED → Others: REM sleep behaviour disorders (eg. vivid or acting out dreams), relatively preserved cognition (cf PD) □ Dx: clinically by poor response to levodopa □ MRI: non-specific, suggestive features include → Hyperintense lateral putaminal rim → Hot crossed bun sign: ↑T2W cross within pons due to degeneration of transverse pontocerebellar fibres □ D/dx from PD: little response to levodopa, presence of jerky postural tremor, ataxia, pyramidal signs and autonomic failure □ Mx: trial of levodopa (some do better than w/o), otherwise symptomatic □ Prognosis: faster than idiopathic PD → Dysautonomia in 2.5y, wheelchair-bound in 3.5-5y, bedridden in 5-8y, death in 6-10y

71 MSA-P and MSA-C subtypes were called striatonigral degeneration and olivopontocerebellar atrophy before but were now grouped under MSA. Shy-Drager syndrome was a histological entity referring to MSA with Parkinsonism + pronounced autonomic failure. 72 Camptocormia refers to severe anterior flexion of spine. Anterocollis refers to patterned, repetitive muscle contractions resulting in neck flexion. - Page 107 of 179 -

Progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski syndrome): □ Epidemiology: commonest of atypical parkinsonism, 3-7/100k prevalence, average onset 54y □ Pathology: midbrain + cerebral cortical atrophy a/w tau neurofibrillary tangle inclusions □ Clinical features: → Early postural instability: stiff and broad-based gait, instability with frequent falls → Supranuclear gaze palsy: slowed vertical saccades followed by limitation of saccadic range - Often starts in downgaze but gradually spreads to other directions - Doll’s eye (oculocephalic) reflex characteristically intact (indicates ‘supranuclear’ location) → Parkinsonism: bradykinesia, axial > limb rigidity, ± pyramidal signs (1/3) → Frontal features, eg. impaired abstract thoughts, ↓verbal fluency, disinhibition, personality changes □ Dx: core clinical features + supportive clinical features + supportive imaging features → Core features: (1) oculomotor dysfx (2) postural instability (3) akinesia (4) cognitive dysfx → Supportive clinical features: (1) LD resistance (2) hypokinetic spastic dysarthria (3) dysphagia (4) photophobia → Supportive imaging features: (1) predominant midbrain atrophy/hypometabolism (2) postsynaptic striatal daopminergic degeneration □ CT/MRI: generalized + brainstem atrophy esp midbrain → Hummingbird (penguin silhouette) sign: prominent midbrain atrophy with relatively preserved pons □ Mx: supportive (no symptomatic Tx available) □ Prognosis: rapid and relentless, dependent in 3-4y, death in 6-9y

Corticobasal degeneration (CBD): □ Epidemiology: 5-7/100k, avg onset 61-64y, sporadic □ Pathology: asymmetric frontoparietal atrophy a/w tau NFTs inclusions □ Clinical features: cortical features + Parkinsonian features → Cortical: dementia, behavioural changes, limb apraxia, aphasia, cortical sensory loss, ‘alien limb’ syndrome73 → Asymmetric Parkinsonism: limb rigidity, bradykinesia, postural instability, abnormal gait, limb dystonia → Others: ocular gaze palsy, myoclonus, athetosis □ Dx: clinically by compatible clinical features w/ poor response to LD □ Neuroimaging: focal atrophy involving posterior frontal and parietal regions w/ dilatation of lateral ventricles □ Mx: supportive □ Prognosis: variable, median survival 5.5-7.9y

Lewy body dementia (LBD): sometimes considered a Parkinson plus syndrome □ Early dementia: typical presenting symptom in LBD (cf PD) □ Core clinical features: should have ≥2 → Cognitive fluctuations (60-80%): fluctuations in cognition and levels of alertness → Visual hallucinations (~2/3): can vary from extremely complex to simple → REM sleep disorders: dream enactment behaviours → Parkinsonism: typically more bilaterally symmetric and milder than in PD, less tremor

73 Alien limb phenomenon occurs in 30-50% of pt with CBD and is described as a feeling that the limb does not belong to the subject or that it has a will of its own. - Page 108 of 179 -

5.3 Huntington’s Disease Aetiology: □ Genetics: AD disorder due to ↑CAG trinucleotide repeats in Huntingtin □ Pathology: loss of medium spiny neurones in striatum → ↓↓indirect pathway → dyskinesia Epidemiology: mean age of onset = 40, prevalence 4-8/100k Clinical features: □ Neurological: classically chorea → Chorea: ↑ with stress and walking, disappears during sleep → Loss of voluntary motor control: progressive, gradually causes dysarthria, dysphagia → Parkinsonism: usually in late stage - ‘Akinetic form (Westphal variant)’: presents with parkinsonism rather than chorea □ Psychiatric: chronic atypical depressive states, psychosis, abnormal emotional states □ Cognitive: dementia, poor judgment, inflexibility of thought, ↓concentration… Dx: □ Genetic testing □ Hung-up knee jerk (‘marching the knee’): slowness in relaxation after knee jerk → repeated tapping results in rising of leg Mx: □ No cure: progressive and fatal in 10-15y □ Symptomatic treatment: → Chorea: neuroleptics (risperidone/sulpride), tetrabenazine → Psychiatric: benzodiazepines (clonazepam), antidepressants □ Supportive care

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5.4 Dementia and Dementia Syndromes Ref: Neurology and Neurosurgery illustrated P. 125-132, Neurology in Practice Ch11, UpToDate 5.4.1 Approach to Dementia Dementia: clinical syndrome of impaired cognitive function in multiple domains but with preserved consciousness Diagnostic criteria by DSM-5: □ Evidence of decline from a previous level of performance in ≥1 of the following cognitive domains: → Learning and memory, language, executive function, complex attention, perceptual motor, social cognition □ The cognitive deficits interfere with independence in everyday activities. At a minimum, assistance should be required with complex instrumental activities of daily living, such as paying bills or managing medications. □ Not fully explained by delirium or other mental disorder Causes: important to note that 10-15% dementia can be reversed □ Neurodegenerative diseases: → Pure dementias: Alzheimer’s disease (60-80%), frontotemporal dementia (~5%) → Dementia plus syndromes: dementia with Lewy bodies (~10%), PD-related dementia, corticobasal degeneration, progressive supranuclear palsy, Huntington’s disease… □ Vascular dementia (10-20%): multi-infarct dementia □ Infections: CJD, syphilis, HIV, PML, AIDS-dementia complex, SSPE □ Structural: NPH, frontal tumours, corpus callosum tumours, 3rd ventricle tumours □ Trauma: chronic SDH, punch-drunk encephalopathy

□ Metabolic: Wernicke encephalopathy, B12 deficiency, thyroid disease, heavy metal poisoning

Clinical features of dementia: □ Cognitive impairment: deficits in 6 cognitive domains as above □ Behavioural and psychological symptoms of dementia (BPSD): pacing, shouting, sexual disinhibition, aggression, apathy, depression, delusions, hallucinations □ Neurological S/S: pyramidal and extrapyramidal signs, movement ds… □ Functional impairment: difficulties in basic or instrumental ADL (required in dx of dementia) Classification of dementia by site: Anterior dementia (frontal, motor cortex) Posterior dementia (parietal, temporal cortices) S/S: behavioural changes, disinhibition, S/S: memory loss, language disturbance w/ antisocial behaviour, irresponsibility… relatively preserved behaviour Includes: FTD, NPH, Huntington’s disease Includes: Alzheimer’s disease Cortical dementia Subcortical dementia S/S: higher cortical dysfx, eg. dysphasia, S/S: apathy, forgetfulness (recognition>recall, agnosia, apraxia, acalculia, true amnesia improved by prompting), impaired coordination, Includes: Alzheimer’s disease, FTD other neurological signs and movement ds Includes: PD, PSP, CJD, HD… Mild cognitive impairment (MCI): cognitive impairment NOT meeting criteria for dementia □ Considered the transitional state between normal cognition and dementia → 10-15%/y progress to dementia in >65y □ Classification: amnesic MCI vs non-amnesic MCI vs multi-domain MCI □ Mx: not well-defined

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Clinical evaluation: □ Cognitive testing: MMSE, MoCA… to establish dx □ Hx: pay attention to → Rate of cognitive decline → Degree of ADL impairment (necessary for dx) → Hx of relevant ds, eg. stroke RFs, head injury → Any features of psychiatric illness, eg. depression → FHx of dementia and age of onset □ P/E: → General exam for any underlying systemic ds → Neurological examination for any focal sgns suggestive of dementia-plus syndromes → Primitive reflexes: pout reflex, glabellar reflex, grasp reflex, palmomental reflex □ Ix: (* included in NICE 2010 guidelines as minimum Ix)

→ CBC, serum B12 and B9 for folate or B12 def* → TFT for hypothyroidism* → RFT, Ca, and Glc for hypercalcaemia, Cushing’s or Addison’s disease* → CT/MRI for any structural brain lesions* → PET/SPECT for diagnosis of dementia syndromes → Vasculitic screen, ESR for vasculitis; LFT for hepatic encephalopathy; VDRL for neurosyphilis; LP for chronic meningitis or neurosuphilis; EEG for CJD and metabolic encephalopathy; copper studies for Wilson’s disease - Page 111 of 179 -

D/dx: □ Depression can cause pseudodementia (account for 10% of presumed dementia) □ Oligophrenia: longstanding poverty of intellect □ Isolated disorder of higher fx, eg. dysphasia, visual agnosia □ Delirium: acute confusional state w/ fluctuating consciousness Mx: □ Treat reversible causes, eg. NPH, thyroid disorders □ Supportive Mx: psychosocial support, day or institutional care □ Symptomatic Mx, eg. neuroleptics for confusion, aggressive behaviour and paranoia 5.4.2 Alzheimer’s Disease Alzheimer’s disease (AD): commonest cause (50-70%) of dementia Epidemiology: □ Burden: 47M worldwide, 2% in 65-69y, 2× every 5y after 65y □ RFs: age, FHx of dementia (↑10-30% risk, up to 30% familial) and vascular RFs74 Pathogenesis: unclear □ Genetics: → Early onset AD (i.e. <65y, <1%): AD inheritance pattern, a/w APP, PSEN1 and PSEN2 (highly penetrant) → Late onset AD (i.e. >65y): genetic basis more complex, a/w APOE (less penetrant) □ Histology: plaques and tangles most often affecting temporal lobes → Neuritic plaques: degenerated axons and synaptic structures clustered around central core of amyloid beta peptides → Neurofibrillary tangles:intracellular paired helical filamentous materials derived from tau protein □ Gross features: ↓hippocampal volume, medial temporal lobe atrophy ± generalized atrophy Clinical features: usually presents w/ memory deficit followed by other deficits

74 Pathogenic mechanisms linking vascular RFs to AD pathogenesis are unclear. They may involve brain cholesterol metabolism but cerebrovascular disease and AD frequently co-exist in the form of mixed dementia. - Page 112 of 179 -

□ Memory impairment: anterograde recent episodic amnesia75 □ Parietal cortical symptoms: aphasia, apraxia, agnosia □ Executive dysfunction, eg. planning, reasoning, task completion □ Anosmia: often occurs early but usually neglected □ Neuropsychiatric symptoms: apathy, social disengagement, irritability, agitation, aggression, wandering, psychosis □ ± other neurological deficits, eg. pyramidal and extrapyramidal features Clinical course: relentlessly progressive, 7-10 average life expectancy → bedbound and incontinent at terminal stages Evaluation: clinical diagnosis □ Cognitive testing: MoCA preferred76 □ Neuroimaging: → Structural (MRI): unilateral/bilateral perihippocampal atrophy (early), generalized atrophy (late) → Functional: ↓metabolism in parietotemporal and hippocampal regions □ Genetic testing for FHx+ early onset cases D/dx: □ Vascular dementia: Hx, S/S and imaging evidence of stroke □ LBD: early prominent VH, cognitive fluctuations □ FTD: early personality, behavioural and executive fx deficits Mx: □ Cholinesterase inhibitors, eg. donepezil (Aricept), galantamine (Reminyl), rivastigmine (Exelon) → Indication: early to moderately advanced AD → MoA: ↓ACh breakdown at synapses → ↑cholinergic transmission → Effect: modest improvement in cognition, neuropsychiatric symptoms, ADLs, delay deterioration for ~18 months → S/E: GI upset (diarrhoea, N/V), weight loss □ NMDA antagonists, eg. Memantine (Ebixa) → Indication: moderate to advanced dementia → MoA: block excitatory Glu transmission by NMDAr → ↓excitotoxicity (esp in vascular dementia) → Effect: modest benefit in advanced dementia, may have synergistic effect with cholinesterase inhibitor → S/E: uncommon, dizziness, confusion/hallucinations (rare) □ Antioxidants, eg. vitamin E, selegiline → Indication: mild to moderate AD → Effect: modest benefit but S/E prominent for selegiline □ Supportive Tx: → Behavioural Tx, eg. provide emotional support, adhere to daily routines… → Antipsychotics and anxiolytics for behavioural disturbances and neuropsy S/S

75 Both declarative semantic and recent memory are heavily dependent on medial temporal lobe structures whereas semantic memory (neocortical temporal regions), procedural (subcortical structures), immediate (sensory association, prefrontal) and distant (neocortex) memory are supported by other structures. 76 MoCA has better sensitivity for executive and language dysfunction. - Page 113 of 179 -

5.4.2 Vascular Dementia Vascular dementia (VaD): dementia arising from multiple infarcts and chronic ischaemia □ Accounts for ~15% of all dementia □ RFs: vascular RFs, i.e. HTN, stroke, IHD, peripheral vascular disease Pathophysiology: can result from the following mechanisms □ Large artery infarcts: usually cortical but may also be subcortical □ Small artery (lacunar) infarcts: exclusively subcortical (BG, thalamus, IC, cerebellum, brainstem) □ Chronic subcortical ischaemia: affects periventricular white matter

Clinical features: stepwise deterioration w/ usually preserved insight in the following syndromes Cortical syndrome Subcortical syndrome Medial frontal: executive dysfunction, abulia, apathy Focal: focal motor signs, early apraxic or Parkinsonian Left parietal: aphasia, apraxia, agnosia gait, unsteadiness and falls, pseudobulbar palsy Right parietal: hemineglect, confusion, agitation, Neuropsy: personality and mood changes, apathy, visuospatial and constructional apraxia depression, emotional incontinence, relatively mild memory deficits Medial temporal: anterograde amnesia Autonomic: early urinary frequency or urgency

Evaluation: □ Clinical: Hachinski score for distinguishing from AD □ Neuroimaging: → White matter lesions → Old cortical or subcortical infarcts □ Vascular imaging for underlying atherosclerotic changes and embolic source

Mx: □ RF management77: healthy lifestyle, HTN, DM, statins, aspirin □ Pharmacological therapy: anticholinesterase and NMDA receptor antagonists78 □ Supportive: behavioural Tx, pain control, antidepressants, anxiolytics, antipsychotics

77 Apart from lifestyle changes, most of the RF management interventions are probably more effective in preventing further stroke events than dementia. 78 Evidence for use of these drugs in VaD is limited, but they are often used due to well-known co-association between AD and VaD and the clinical difficulty in differentiating between the two. - Page 114 of 179 -

5.4.4 Frontotemporal Dementia (FTD) Frontotemporal dementia (FTD, Pick’s disease): dementia characterized by disturbances in behaviour, personality and language accompanied by focal degeneration of frontal and/or temporal lobes Epidemiology: □ Burden: 3.5/100k/y in UK, common cause of early onset dementia □ Demographics: average onset 58y, unusual before 40 or after 70y Pathophysiology: □ Genetics: highly heritable (40% FHx for dementia/psy ds), ~10-25% AD inheritance, a/w C9ORF72, MAPT, GRN □ Gross pathology: frontotemporal lobar atrophy □ Microscopic pathology: microvaculolation and neuronal loss w/ swollen neurones, a/w either tau inclusions (i.e. Pick’s bodies, ~1/2) or other inclusions (eg. ubiquitin) Divided into two subtypes: Behavioural variant FTD (bvFTD) Primary progressive aphasia (PPA) Disinhibition, eg. public urination Early, progressive language Apathy and loss of empathy disturbance Clinical Variants include non-fluent, features Hyperorality: puts excessive food in mouth Compulsive behaviour, eg. perseveration, semantic and lopogenic variants ritualistic behaviour Other domains are relatively spared

Imaging

Focal atrophy in orbitofrontal, medial frontal, anterior cingulate, anterior insula cortices and Typically with asymmetric amygdala frontotemporal atrophy affecting the left Psychiatric disorders, eg. depression Cerebrovascular disease D/dx Dementia with Lewy bodies Slow-growing mass lesions, eg. Early onset Alzheimer’s disease brain tumour Associated motor syndromes: FTD may be a/w following motor syndromes □ Motor neurone disease: a/w bvFTD □ Corticobasal degeneration: often frontal-dominant → may present initially as bvFTD or svPPA □ Progressive supranuclear palsy: a/w bvFTD

Mx: symptomatic only □ Neurobehehavioural features: SSRI, trazodone, atypical antipsychotics □ Cognitive dysfunction: NO available treatment □ Parkinsonism: generally NOT responsive to dopaminergic agents

Prognosis: progress faster than AD, avg survival = 8-10y (shorter for bvFTD)

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5.4.5 Dementia with Lewy Bodies (DLB) Dementia with Lewy bodies (DLB): commonest degenerative dementia after AD (4-30%) □ Demographics: avg onset 75y, M>F = 4:1 Pathophysiology: □ Genetics: majority sporadic (a/w GBA mutation), familial form a/w SNCA duplication/triplication □ Pathology: Lewy bodies (round, eosinophilic, intracytoplasmic neuronal inclusions composed of phosphorylated alpha-synuclein) found in deep cortical layers throughout the brain (esp in anterior frontal/temporal lobes, cingulate and insula)79 Clinical features: cortical + subcortical dementia □ Dementia: characterized by early impairments in attention and executive and visuospatial function (memory affected late) □ Core clinical features: must have ≥2 → Cognitive fluctuations (60-80%): described as episodes of ‘blanking out’, daytime drowsiness or bizarre behaviour interspersed with periods of near-normal function → Visual hallucinations (67%): occurs early in the illness, may range from simple (shapes/colours) to complex (images of people or animals) → REM sleep behaviour disorders (85%): dream enactment behaviour, eg. vocalization, complex motor behaviour → Parkinsonism (70-90%): usually more bilaterally symmetric and milder than in PD □ Supportive features: → Antipsychotic sensitivity (30-50%): acute irreversible Parkinsonism, LOC ± NMS towards antipsychotics → Repeated falls, syncopes/transient LOCs, autonomic dysfunction, hypersomnia, hyposmia → Other hallucinations, systematized delusions, apathy/anxiety/depression

Diagnosis: clinical + supportive Ix □ MRI: preserved medial temporal lobe structures (cf AD) □ SPECT/PET: generalized ↓perfusion and ↓metabolism (most marked in occipital areas) D/dx: □ PD-dementia: differentiation arbitrary, generally dementia occurs in well-established Parkinsonism in PDD whereas dementia occurs with or before Parkinsonism in DLB □ Other dementia + superimposed delirium: r/o systemic causes of fluctuating clinical features □ NPH: no psychiatric symptoms, sleep disorder and dysautonomic features

Treatment: symptomatic (no disease-modifying Tx available) □ Cognition and neuropsychiatric S/S: cholinesterase inhibitor, atypical antipsychotics80 (only when severe), SSRI for depression □ REM sleep behaviour disorder: melatonin □ Parkinsonism: levodopa Prognosis: gradual deterioration, average lifespan 7.7y

79 Similar to PD, Lewy bodies are found in basal ganglia. This explains why many patients with DLB have Parkinsonism and why many PD patients develop DLB features in later stages. 80 Only very low doses of atypical antipsychotics should be considered in DLB due to antipsychotic sensitivity phenomenon mentioned above. - Page 116 of 179 -