Parkinsons Disease

Epidemiology

Pathogenesis

Clinical features

Treatment

Progressive Supranuclear Palsy

Epidemiology

Pathology

Clinical

Imaging

Treatment

Corticobasal Degeneration

Pathology

Clinical

Imaging

Treatment

Multiple Systems Atrophy

Definition

Epidemiology

Pathogenesis

Clinical

Imaging

Other atypical parkinsonism

Scans without evidence of dopamine deficiency (SWEDDS)

Parkinsons Disease

Epidemiology

• Peak age of onset 60’s
• Range 35-85
• Familial clusters represent ~5%
• Generally if onset <45yrs
• Risk factors
• Family history
• Male gender
• Head injury
• Exposure to pesticides
• Consumption of well water
• Rural living
• Protective factors
• Coffee
• Smoking
• NSAIDs
• HRT

Pathogenesis

· Loss of dopamine containing neurones in striatum – particularly substantia nigra pars compacta

• Usually 50%-70% loss by time of diagnosis
• >90% by death
• Presence of Lewy bodies in many neurones
• This occurs first in anterior olfactory nuclei and lower brainstem
• Ascending involvement to include SNpc
• Round dense eosinophilic intracytoplasmic bodies with pale halo’s
• Alpha-synuclein
• Main protein in Lewy bodies

Dopamine pathways

· Cortex stimulates striatum (putamen +caudate)

• Signal is then ‘gated’ down either direct (D1 receptor) or indirect pathway (D2 receptor)
• Usually dopaminergic input from Substantia nigra pars compacta inhibits indirect and stimulates direct pathway, the opposite occur when SNpc is not functioning.
• The result is increased inhibition of thalamic outputs back to the cortex.

Genetics

Monogenic forms

· Recessive and dominant forms

· Recessive forms earlier onset and generally more benign

• LRRK2 is probably most common ~1% of PD
• Indistinguishable from standard disease

Locus	Gene	Protein	Function	Inheritance	Comments
PARK1	SNCA	Alpha-Synuclein	Uncertain; ? vesicle trafficking	AD	Typical presentation
PARK2	PRKN	Parkin	E3 ubiquitin ligase	AR	Starts early and has a more benign course
PARK4	SNCA	Alpha-Synuclein (triplication or duplication)	Uncertain; ? vesicle trafficking	AD
PARK5	UCH-L1	UCH-L1 (Ubiquitin carboxy-terminal hydroxylase L1)	Proteosomal processing	AD
PARK6	PINK1	PINK1	Mitochondrial kinase	AR	Starts early and has a more benign course
PARK7	PARK7	DJ-1	Oxidative stress response	AR	Rare
PARK8	LRRK2	Dardarin	Cytosolic kinase	AD	Typical presentation
	VPS35			AD
	RAB32			AD	Rare.

Complex forms

· GBA1 mutations

o Strong risk factor (“Like autosomal dominant with very low penetrance”)

· Cumulative burden of rare variants

o Multiple minor variants (often in the same genes as monogenic forms)

o Looking at combinations of high risk SNPs can identify patients with up to 4x risk.

Clinical features

1. Tremor
1. Present in 85%
2. Usu. Unilateral
3. 4-6Hz
4. Pill-rolling
5. Starts distally, spreads proximally and then to ipsilateral leg before crossing to other side
2. Rigidity
1. Plastic quality
2. Superimposed tremor causes cog-wheeling
3. Dystonia’s can occur due to disease
3. Bradykinesia
1. Impaired fine motor control
2. Micrographia
3. Bulbar bradykinesia results in hypophonia, sialorrhoea
4. Postural instability
1. Tends to be a late feature
2. Short shuffling steps and tendancy to turn en bloc
3. Festinating gait
4. Stooped posture
5. Poor arm swing

Sleep

REM sleep behaviour disorder

Excessive daytime sleepiness

Insomnia

Restless legs syndrome

Cognitive (see below)

Memory

Concentration

Apathy

Psychiatric (see below)

Depression

Anxiety

Hallucinations

Gastrointestinal

Swallowing

Constipation

Urinary

Urgency

Nocturia

Visual

Impaired convergence

Impaired colour vision

Other

Anosmia

Excessive sweating and seborrhoea

Neuropsychiatric Symptoms

• Depression
• Anxiety
• Cognitive impairment/Dementia
• Incidence of dementia 6x
• Nearly 80% at 8 years
• Overall 30% of PD pts have dementia
• MDS task force 8-point checklist to diagnose PD-dementia
• Psychotic symptoms
• Significant spectrum across the disease (see chart below)
• Early:
1. Minor illusions:
1. ‘Standard’ Illusions – Objects are mis-interpreted as other objects (e.g. seeing the branch of a tree as a cat)
2. Pareidolia – faces are seen in formless visual object (e.g. in the clouds or wallpaper patterns).
3. Diplopia, selective - seeing two of a particular object in an otherwise normal background.
4. Presence – a feeling that someone is nearby. Or a persisting experience of someone who has just left the room (palinparousia)
5. Passage - a person, animal or object is seen briefly passing in the peripheral visual field.
• Middle
1. Hallucinations with preserved insight
2. Non-visual hallucinations – auditory, tactile, olfactory
• Late
1. Hallucinations without insight
2. Delusions
• Early, predominantly visual hallucinations are probably present in ~25% (large range with different studies)
• Presence of hallucinations is a risk factor for developing dementia (OR 3x)
• Can be due to disease or treatment
• Management – see below
• Reference: The psychosis spectrum in Parksinson disease. Nature Rev Neuro Feb 2017.

Medications effects

• Motor fluctuations
• Wearing-off phenomenon
• Probably due to lack of storage of dopamine in neurones in advanced disease, patients become very sensitive to plasma levels of dopamine
• Dyskinesia
• Involuntary movement that occur as a direct result of levodopa
• Occurs in 30-40% of patients treated for 5 years
• Choreiform movements, however ballistic movements can occur in severe form.
• Dystonia
• A more sustained abnormal movement than dyskinesia

Management Summary

See Specific medications for more information on specific agents.

Drug		SE
Dopamine agonist	Less motor fluctuations and dyskinesias Longer acting Less control of non-motor symptoms, Effective for bradykinesia and gait disturbance but not tremor Relatively expensive	Nausea Postural hypotension Psychiatric symptoms Daytime sedation Occasional sleep attacks Impulse control disorders (?15%)
Non-ergot alkaloids
Ropinorole (ReQuip)
Pramipexole (Sifrol, Aimipex, Simpral)	Std release: 125mcg tds double every week up to 1.5mg tds Extended release: 375mcg one week 750mcg one week 1.5mcg one week then titrate up by 750mcg weekly to max 4.5mcg	Sleep attacks	Std release 125mcg, 30 [0] 250mcg, 100 [5] 1000mcg, 100 [5] Extended Release 375mcg, 30 [5] 750mcg 1.5mg 2.25mg 3mg 3.75mg 4.5mg
Rotigotine (Neupro)	Patch Start with 2mg patch, increase by 2mg/week	Patch site reaction in ~40%	2mg/24hours, 28 [5] 4mg, 28 [5] 6mg, 28 [5] 8mg, 28 (Non-PBS)
Ergot		Less sleep attacks
Pergolide (Permax)		Valvular heart disease
Carbergoline
Bromocriptine		Pulmonary and retroperitoneal fibrosis
Apomorphine	S/C pump administration
Levodopa based	Best symptom control but complicated by late SE’s Improves bradykinesia and rigidity more than tremor (Carbidopa inhibits dopa decarboxylase) Always take before food. Dose	Short term: Nausea, vomiting, gastritis Postural hypotension Long term: Motor fluctuations Dyskinesias Neuropsychiatric - Hallucinations - Delirium - Hypersezuality Sleep relates - Nightmares, vivid dreams - Fragmented sleep Drowsiness
Carbidopa/Levodopa (Sinemet and Sinemet CR)	Sinemet CR – increase dose by 10-30%
Carbidopa/Benserazide (Madopar or MadoparHBS)	HBS – may require 50% increase dose.
Carbidopa/Levodopa/ Entacapone (Stalevo)
MAOB Inhibitors		Insomnia (May be useful to stimulate drowsy patients) Anorexia, weight loss Possible impulse control disorder
Selegiline	Weak May be used as monotherapy or to alleviate tremor or levodopa wearing off 10mg od OR 5mg bd OR 1.25mg od buccal.
Rasagiline (Azilect)	1mg once daily ADAGIO trial suggested possible neuroprotective action
COMT Inhibitors	Decrease degradation of levodopa (inhibit COMT), increase effective dose by 30% Increase ‘on’ time 1-2hours	GIT Can worsen dyskinesias Same as levopdopa
Entacapone
Tolcapone		Hepatic and haematologic SE
Anticholinergics	Used as adjunct to levodopa Useful to control tremor and rigidity – NO effect on bradykinesia. Can reduce drug induced dyskinesia’s by 70%	Often aggravate confusion and psychosis Nausea Headaches Oedema Erythema Livedo reticularis Dry mouth, constipation, urinary retention.
Benztropine (Cogentin)
Benhexol
Biperiden
Orphenadrine
Trihexyphenidyl (Artane)
Other
Amantadine (Symmetrel)	Domapinergic and anti-cholinergic properties Good for akinesia and rigidity but not as good for tremor Used to alleviate drug induced dyskinesias Dose: 100mg daily (up to 300mg in some people) Reduce in renal impairment	Autonomic Psychiatric Some anticholinergic effect	100mg, 100, [5]
Domperidone	Can be used to help with symptoms on initiation of dopamine agonists

Levodopa Equivalent Doses

Drug	Conversion factor	Equivalence to 100mg Levodopa (mg)
Immediate release L-dopa	X 1	100
Controlled release L-dopa	X 0.75	133
Entacapone (or Stalevo®)	LD x 0.33	303
Tolcapone	LD x 0.5	200
Duodopa®	X 1.11	90
Pramipexole (as salt)	X 100	1
Ropinirole	X 20	5
Rotigotine	X 30	3.3
Selegiline-Oral	X 10	10
Selegiline – sublingual	X 80	1.25
Rasagiline	X 100	1
Amantadine	X 1	100
Apomorphine	X 10	10

Specific symptoms

• Tremor – anti-cholinergic
• Drug induced dyskinesia – amantadine
• Freezing (off periods) - apomorphine

· Psychotic symptoms/hallucinations

o Consider reducing medication that may be worsening

o Clozapine effective, but risk of side effects

o Quetiapine – no proven efficacy

o Olanzapine – no proven efficacy

o Rivastigmine – reduction in agitation component, no reductio in hallucinations

o Pimavanserin – some evidence of benefit.

	LD	DA	Amantadine	MAOB	Anticholinergic
Effective for:			Dyskinesia		Tremor Rigidity
Not effective:					Bradykinesia
SE:
Dyskinesias	+++	+/-	-		-
Hallucinations	++	+++	++		++
Hypotension	++	+++			?
Drowsiness	+	++

·

When to initiate treatment:

• PDLIFE study – UK study which suggested delayed treatment resulted in unnecessary suffering

• Reasons to delay:

o ?Levodopa toxicity – it has been proposed that levodopa may be toxic to dopamine neurones, this is not backed up by the current evidence.

o Levodopa dyskinesia

• Studies:

o REAL-PET – Ropinirole vs Levodopa

- Motor scores better with Levodopa, less dyskinesia with ropinirole and possibly less degeneration (as measured by PET)

o CALM-PD – Pramipexole vs Levodopa

- Same as REAL-PET

o ELLDOPA – Early vs late Levodopa (2004 NEJM)

- 150mg, 300mg, 600mg or placebo

- Most improvement with higher doses

- Patients came off drug at end of trial, did not return to the same severity as placebo patients.

Specific medications

Levodopa

Dosing

• Initial 50-100mg/day given TDS

• Maximum 2g daily

• Side effects can be minimised by taking with food

• Domperidone 20mg tds can help relieve some peripheral symptoms

• Controlled release

o Only advantage is in treating nocturnal problems

o Reduced bioavailability, slower onset

• Combined with COMT

o STRIDE-PD study

o Increased rate of dsykinesa’s

o Trend to improved motor scores (not significant)

Side effects

• Short term:

o Nausea, vomiting, gastritis

o Postural hypotension

o Drowsiness

• Long term:

o Motor fluctuations

- Wearing off

- Random on/off

- Delayed on

- Drug resistant off

- Early morning akinesia

- Freezing

- Diphasic dyskinesia

o Dyskinesias

o Neuropsychiatric

- Hallucinations

- Delirium

- Hypersexuality

o Sleep relates

- Nightmares, vivid dreams

- Fragmented sleep

o Non-motor (off period related)

- Pain, akathisia, restless legs

- Sweating, tachycardia

Dopamine Agonists

Side effects

Nausea (Similar rate to LD)

Drowsiness

Side effect	Comparison to Levodopa
Nausea	Similar
Oedema	More
Orthostatic hypotension	Similar
Drowsiness	More
Sleep disorders (incl. “narcolepsy”)	More
Neuropsychiatric Hallucinations	More (10-20% vs 3-4%)
Motor fluctuations	Less
Dopamine dysregulation syndrome Punding Impulse control disorders	More

Specific agents:

Non-ergot alkaloids
Ropinorole (ReQuip)
Pramipexole (Sifrol)	Initial 125mcg tds Maintenance 500mcg tds Maximum 1.5mg tds Slow release (ER) Initial 375mg daily Maintenance 750mcg daily Maximum 4.5mg daily
Rotigotine (Neupro)	Patch
Ergot		Less sleep attacks
Pergolide (Permax)		Valvular heart disease
Carbergoline
Bromocriptine		Pulmonary and retroperitoneal fibrosis
Apomorphine	S/C pump administration

MAO inhibitors

· Rasagiline trialled in LARGO study (Lancet 2005) vs entacapone or placebo in patients with motor fluctuations.

o Rasagiline (1mg daily) better than placebo and equally effective as entacapone at reducing motor fluctuations.

o Minimal side effects. 5% with worsening dyskinesia

Progressive Supranuclear Palsy

• Also known as Steele Richardson Olszewski syndrome

Epidemiology

• Prevalence 5/100,000
• Accounts for 4% of patients with Parkinsons syndromes.
• Generally sporadic, rare familial cases
• Men >women
• Age 50-70years

Pathology

• Tau protein accumulation – neurofibrillary tangles
• Loss of dopaminergic neurons

Clinical

• Vertical supranuclear palsy
• Affects downward gaze first
• Followed by variable degree of upward and horizontal gaze palsy
• Eyes still move with dolls head manoeuvre and Bell’s reflex – hence supranuclear
• Postural instability and frequent falls
• Truncal rigidity
• Bradykinesia and rigidity
• Apathy, disinhibition, dysphoria, and anxiety are common
• Prominent stare
• Furrowed brow
• The rest tremor of PD is rare in PSP
• A pseudobulbar palsy with associated dysarthria and dysphagia ~ 80 % .
• A frontal lobe-like dementia syndrome ~80%
• Head tilted back (rather than flexed as in PD) – due to nuchal muscle tone.

Prognosis

• The overall course is relentlessly progressive, with death occurring at a median of six years after onset.

Imaging

MRI

• Midbrain atrophy (superior colliculus)

o Concave upper surface

o ‘penguin’ or ‘hummingbird’ sign

o Midbrain to pons measurements and ratio (Massey et al. Neurology 80, May 14 2013)

- Measure across ellipses placed over midbrain and pons

- Midbrain width <9.35mm (normal ~11.5mm)

• Sn 83%, Sp 100%

- Ratio <0.52 (normal ~0.63)

• Sn 67%, Sp 100%

o Axial scans – widened interpeduncular angle, abnormal concavity of the midbrain tegmentum

• Enlarged 3^rd ventricle

• Prominent perimesencephalic cisterns

• Atrophy of

o Superior cerebellar peduncles

o Quadrigeminal plate

PET

• FDG – hypometabolism in the midbrain and medial frontal regions

• DAT – decreased caudate and putamen

Treatment

• The response to levodopa in PSP is typically poor, but about 20 percent of patients have some improvement initially or in the early stages of the disease.
• Life expectancy ~7years (i.e. 50% of that of PD)

Corticobasal Degeneration

• Rare
• Onset 50s-60s
• Sporadic

Pathology

• Tauopathy

Clinical

• asymmetric progressive apraxia,
• rigidity, dystonia, bradykinesia, and myoclonic jerks
• with or without cortical sensory loss
• "alien limb" phenomenon, consisting of involuntary purposeful movements of a hand or limb, is a characteristic sign.
• Progresses to become bilateral over 2–5 years
• Leads to total incapacity with, ultimately, paraplegia in flexion.
• A significant number of cases present with frontotemporal dementia or progressive aphasia, followed by asymmetric cortical sensory signs, including abnormalities of graphesthesia and astereognosis

Imaging

• Brain MRI - focal cortical loss in the contralateral superior frontal and parietal lobes
• with corresponding hypometabolic changes on PET scan
• hyperintense signal abnormalities in white matter and sometimes atrophy of the corpus callosum.

Treatment

• Treatment is largely ineffective

Multiple Systems Atrophy

Definition

• Three conditions grouped together:

o Olivopontocerebellar atrophy

o Striatonigral degeneration

o Shy-Drager/ Progressive autonomic failure

Epidemiology

• Median onset 50years
• Prognosis 6-9years life expectancy
• Most patients wheelchair bound in 5 years
• Prevalence 4-5/100,000

Pathogenesis

• Characterized by the presence of alpha-synuclein positive glial cytoplasmic inclusions (similar to Lewy bodies)
• Different distribution to PD and DLB
• Substantia nigra, putamen, inferior olives, pontine nuclei, pigmented nuclei of the brainstem, intermediolateral nucleus of the spinal cord, and the cerebellum

Clinical

• Parkinsons features (90%) with dysfunction of either:

o Cerebellar (~55%)

o Corticospinal/pyramidal (50%)

o Autonomic (~75%)

• Compared to Parkinson’s Disease MSA:

o Features tend to present more symmetrically

o Often no tremor

o Early instability and falls

o Most wheelchair bound in 5 yrs

o Early hypokinetic dysarthria

o Distal myoclonus

o Short lived response to levodopa with early dyskinesias

o Autonomic features

- Orthostatic hypotension

- Incontinence

- Impotence

- Cold hands and feet with bluish discoloration

• Suggested red flags to distinguish from PD:

o Early instability

o Rapid progression

o Abnormal postures

- Pisa syndrome (sustained lateral flexion with some rotation)

- Disproportionate anterocollis

- Contractures of the hands or feet

o Bulbar dysfunction

o Respiratory dysfunction

- Diurnal or nocturnal inspiratory stridor and inspiratory sighs

o Emotional incontinence

• Corticospinal features:

o Spasticity (especially of the arms)

o Psuedobulbar palsy

• Cerebellar signs:

o Especially a wide based ataxic gait

Clinically divided into 2 major forms:

• MSA-P

o Prominent parkinsonism at onset

o Previously ‘striatonigral degeneration’

• MSA-C

o Prominent cerebellar signs at onset

o Previously olivopontocerebellar atrophy

o Heterogenous phenotype

o Some fall more into the category of spinocerebellar ataxia’s

Imaging

• In MSA-C

o Prominent atrophy of the (best seen on T1)

- Cerebellum,

- Pons

- Medulla (olivary eminence)

- Resultant enlarged 4^th ventricle

- Concavity of MCPs

o Cruciform hyperintensity in the pons (on T2/FLAIR)

- ‘Hot-cross bun sign’

o ADC map shows elevated signal in pons, middle cerebellar peduncles, cerebellar white matter, dentate nuclei

• In MSA-P,

o Decreased T2 signal and volume loss in the putamen

o Hyperintensity in the putamen – particularly the lateral edge/dorsolateral rim

- N.B a thin, smooth, slit-like hyperintense line along the lateral putamina is a normal finding at 3.0T.

o GRE/SWI shows significantly higher iron deposition in the putamen compared to controls

Other atypical parkinsonism

Scans without evidence of dopamine deficiency (SWEDDS)

• Typically asymmetric arm tremor – resting and isolated

• No decremental breakdown or bradykinesia

o Though movement may be slow

• Dominant tremor action (not rest)

• Head tremor more prominent (than PD)

• Dystonic tremor more common

• Writing tremor more common

• Normal dopamine scan