Parkinsonism-plus syndromes

Presenter - Dr Danish Ahammed P K

Introduction
• Parkinson-plus syndrome (PPS), also called atypical parkinsonism, refers to
a group of neurodegenerative movement disorders that resemble idiopathic
Parkinson's disease (PD) with certain distinguishing clinical and
pathophysiological features.
Components
Progressive
Multiple system
supranuclear
atrophy (MSA)
palsy (PSP)

Corticobasal
Lewy body
degeneration dementia (LBD)
(CBD)
Multiple System Atrophy
neurodegenerative
disorder manifested
by

dysautonomia

• various
parkinsonism combinations
and ataxia
 Predominantly
Cerebellar MSA
parkinsonian MSA (MSA-C)
(MSA-P)

Old term Old term

striatonigral olivopontocerebellar
degeneration. atrophy
 EPIDEMIOLOGY
Prevalence
• 4–5 per 100,000

mean age at onset

• 54 years
Autonomic Features
• bladder dysfunction (89%), • sleep apnea (37%)
• urinary incontinence(44%) • nocturnal stridor (30%)
• urinary retention (26%),
• bowel dysfunction (77%)
• constipation (46%)
• fecal incontinence (27%)
• orthostatic hypotension (75%),
• sexual dysfunction (64%)
• RBD (54%),
• sweating dysfunction (40%)
•
Clinical Manifestations
• MSA-P usually - symmetrical parkinsonism, often without tremor, with early
instability and falls.
• Most patients become wheelchair bound within 5 years after onset
• more autonomic
• MSA C - prominent cerebellar signs, especially wide-based ataxic gait
Red flags - high diagnostic specificity

• (1) Early instability,

• (2) Rapid progression,
• (3) Abnormal postures - includes Pisa syndrome, disproportionate
anterocollis, and/or contractures of hands or feet
• (4) Bulbar dysfunction (includes severe dysphonia, dysarthria, and/or
dysphagia),
• (5) Respiratory dysfunction (includes diurnal or nocturnal inspiratory stridor
and/or inspiratory sighs)
• (6) Emotional incontinence (includes inappropriate crying and/or laughing)
• >/= 2 / 6 red-flag categories can be used as additional criteria for the
diagnosis of probable MSA-P.
Antecollis in MSA and Parkinson’s disease has been suggested
to be caused by neck extensor myopathy, imbalanced rigidity of
the anterior and posterior neck muscles, or dystonia.
Other characteristic features
• Early hypokinetic dysarthria,
• Distal myoclonus,
• Cold hands and feet with bluish discoloration of the distal extremities
Reich, S. G. (2003). The cold hands sign in
MSA. Neurology, 60(4), 719–719.
doi:10.1212/01.wnl.0000028966.139
 autonomic symptoms
Autonomic symptoms
(particularly sexual
years or even onset of motor
dysfunction) and decades symptoms
RBD
• More autonomic symptoms at baseline and more progression to global
anhidrosis than patients with PD.

• About 10% of patients originally diagnosed with pure autonomic failure

eventually transition to MSA
Diagnostic Tests
• Clinical tests of autonomic dysfunction - Testing of cardiovascular
reflexes such as heart rate variability at rest and during forced respiration, as
well as blood pressure changes during head-up tilt, may help establish a clinical
diagnosis of MSA.
• A lack of responsiveness of growth hormone to clonidine challenges
• Denervation on rectal sphincter electromyography (EMG)
 MRI Brain

Axial T2 (A) and coronal T2*(B) images of a MSA-P patient, depict bilateral low signal intensity of the posterolateral
segment of putamen with an irregular high signal intensity rim along their lateral borders ("hyperintense putaminal rim"
sign)-yellow arrows
MRI Brain

hot-cross bun sign - Cruciform hyperintensity within the pons,

Movement disorder society criteria for the diagnosis of MSA
Supportive clinical features:
• Rapid progression within 3 years of motor onset,
• moderate-to-severe postural instability within 3 years of motor onset,
• craniocervical dystonia induced or exacerbated by L-dopa in the absence of
limb dyskinesia,
• severe speech impairment within 3 years of motor onset,
• severe dysphagia within 3 years of motor onset,
• unexplained Babinski sign,
• jerky myoclonic postural or kinetic tremor,
• postural deformities, stridor, inspiratory sighs,
• cold discolored hands and feet, erectile dysfunction (below age of 60 years
for clinically probable MSA), pathologic laughter or crying
*Exclusion criteria:
• Substantial and persistent beneficial response to dopaminergic medications,
• unexplained anosmia on olfactory testing,
• fluctuating cognition with pronounced variation in attention and alertness and
early decline in visuoperceptual abilities,
• recurrent visual hallucinations not induced by drugs within 3 years of disease
onset,
• dementia according to DSM-V within 3 years of disease onset,
• downgaze supranuclear palsy or slowing of vertical saccades,
• brain MRI findings suggestive of an alternative diagnosis (e.g., PSP, multiple
sclerosis, vascular parkinsonism, symptomatic cerebellar disease, etc.),
PET -PMP :subcortical
acetyl cholinesterase
(AChE) activity was
significantlymore
decreased in MSA-P and
PSP than in PD

possibly reflecting
greater impairment in
the pontine cholinergic
group (PPN)greater gait
disturbances in the early
stages ofthese two
disorders compared to PD
MSA: (a) medial view of the left cerebral hemisphere showing severe atrophy of the pontine base (asterisk);cerebellar
vermis atrophy and discoloration; (b) coronal section of the left cerebral hemisphere showing atrophy and dark brown
discoloration of the posterior putamen (arrow); (c) neuronal loss in substantia nigra with neuromelanin containing
macrophages (arrows); (d) fiber tracts in the pontine base have numerous oligodendroglial inclusions (GCIs) with a-
synuclein immunohistochemistry; (e) neurons in the pontine base have neuronal cytoplasmic inclusions (arrows) with
a-synuclein immunohistochemistry (note also the dystrophic neurites).
Management
Mainly Symptomatic.

Parkinsonism -
• First Line - Levodopa - Only 1/3 rd responsive.
• Trial - up to 2 g total daily dose of levodopa (titratedfrom 100 to 300 mg 3-4
times daily) for at least 3 months
• may worsen orthostatic hypotension
 Alternatives - Dopamine agonists
 Amantadine, up to 300 mg in 3 divided doses
• DBS -Not recommended
• RBD - First line - clonazepam 0.5 to 2 mg at
night with lower doses often quite effective.
• In case of apnea - second-line agent -
melatonin at a starting dose of 3 mg

• OSA - 37 to 65% of MSA patients - CPAP

• First described in 1964 by Steele, Richardson, and Olszewski as a progressive

axial rigidity
vertical
illness characterized by
supranuclear
ophthalmoplegia
pseudobulbar
palsy

mild dementia

4R tauopathy - accumulation of the tau isoform with

four repeats in the microtubule-binding domain
Epidemiology
• third most common cause of parkinsonism,
• prevalence -1.39 to 6.4 per 100,000. Men >women.
Clinical Features
• begins with a gait disorder and falling in the sixth to seventh decades of life.
• akinetic rigid state with symmetrical signs and prominent axial rigidity

flexed posture of patients with PD, extended trunk or retrocolic neck posture
Procerus sign - A characteristic facial appearance features a wide-eyed stare, furrowing of the forehead
with frowning expression
• Pseudobulbar palsy - dysarthria and dysphagia with spasticity, hypokinesia,
and ataxia and often leading to “silent” aspiration.
• Frontal lobe features are common- executive dysfunction early in the disease
course;
 concrete thought,
 difficulty shifting set,
 decreased verbal fluency,
 personality changes such as impulsivity
 and poor judgment
 progressive
advanced stages true dementia
apathetic state
• Applause sign - manifested by persistence of applauding by the patient
beyond the number of claps performed by the examiner.
• highly correlated with impairments in executive, visuospatial, and language
function as well as measures of disease severity

•
neuro-ophthalmological findings
• Abnormal vertical saccades compared to horizontal saccades, is one of the
earliest ophthalmological signs of PSP
• vertical saccades are more impaired in an upward rather than downward
direction.
• square wave jerks - inappropriate saccades that take the eye off the target,
followed by a nearly normal intersaccadic interval (approximately 200 msec),
and then a corrective saccade that brings the eye back to the target
• blepharospasm with or without apraxia of eyelid opening
• Gait - broad-based with knee extension, and instead of turning en bloc they
tend to pivot on their toes and sometimes even cross their legs, which
contributes to frequent falls
• Atypical - pure akinesia manifested by severe motor blocks while walking
(freezing).
Course - rapidly progressive; by the fourth year of illness, half
of patients need assistance for walking and have troublesome dysarthria
and visual symptoms. Dysphagia becomes prominent shortly thereafter.
Clinical Diagnosis of Progressive Supranuclear Palsy:
The Movement Disorder Society Criteria
MRI - midbrain atrophy

“hummingbird” sign - midsagittal MRI Mickey Mouse” signs on axial MRI.

• midbrain-pons area ratio • magnetic resonance parkinsonism
Index

< 52%

incorporates the ratio of middle cerebellar peduncle (MCP) and superior cerebellar
peduncle (SCP) width in addition to the midbrain-pons area ratio
• Other MRI Signs -
• atrophy or increased signal in the red nucleus,
• third ventricle dilation,
• atrophy of the frontal or temporal lobes.
• Pathological findings - neuronal loss, gliosis,neurofibrillary
tangles, and granulovacuolar degeneration in neurons of the
brainstem.
• Tufted astrocytes in the motor cortex and the striatum
• globose neurofibrillary tangle, made up of hyperphosphorylated 4
repeat tau protein filaments
• Other biomarkers -
• neurofilament light chain concentrations in the CSF and blood show promise
as a potential biomarker
An analysis of 103 pathologically confirmed consecutive
cases of PSP,

Richardson syndrome PSP-P,

• typical features • clinical features overlap with PD
• more benign course
• less tau pathology
• 4R-tau/3R-tau ratio isolated from • quarter of all patients with PSP
the pons : (2.84) • 1.63
Treatment

Levodopa
• provide temporary improvement • usually does not improve
in bradykinesia in approximately dysarthria, gait, or balance
40% of patients problems.

• Amitriptyline - helpful in improving pseudobulbar affect and emotional

incontinence

• Botulinum toxin injections - treat blepharospasm or retrocolic neck

posture in PSP.

• Poor Prognosis - Median duration of survival of approximately 8

years.
Corticobasal Degeneration
• Introduction -
• 1967, Rebeiz et al - described three patients with akinetic
rigidity, apraxia, dystonia, tremor, and aphasia, who at autopsy had pale
achromatic ballooned neurons similar to those seen in Pick disease.
• 1989 - Termed as corticodentatonigral degeneration with neuronal
achromasia
• since became known simply as corticobasal degeneration
clinical diversity of CBD
• classical CBS phenotype
• primary progressive aphasia,
• a frontal-dysexecutive-spatial syndrome
• Richardson-like syndrome
Epidemiology
• Incidence - 0.6–0.9/100,000/year
• 4–6% of patients with Parkinsonism.
• prevalence of 4.9–7.3 per 100.000
• Mean age at disease onset -64 years
Clinical Features
• predominantly motor disease, with heterogeneous
clinical presentations.
• parkinsonism with strikingly asymmetrical rigidity,
• asymmetrical dystonia,
• myoclonus,
• Apraxia- loss of the ability to execute or carry out skilled
movements and gestures, despite having the desire and the
physical ability to perform them
• alien limb,
• cortical sensory loss.
• They may also present with primary progressive
aphasia and may evolve into global dementia
Pathology
• neuronal and glial hyper-
phosphorylated microtubule
associated 4R tau protein.
• widespread cortical pathology than
PSP
• initially affects the dorsolateral
prefrontal cortex and basal ganglia
circuits, with more posterior regions
affected as the disease progresses

astrocytic plaques pathognomonic of CBD Tufted PSP NFT

Astrocyte
DIAGNOSTIC CRITERIA
MRI Brain
• asymmetrical and often focal cortical atrophy with widening of the sylvian
and interhemispheric fissures and dilation of frontal, parietal, and temporal
sulci
asymmetrical hypometabolism in the thalamus and motor cortex
Treatment
• Parkinsonism - levodopa, - poor and only transient response
• Dystonia - botulinum toxin,
• Clonazepam - first choice treatment for myoclonus

• prognosis - poor, with a reported median survival after onset of about 7

years.
Dementia with Lewy Bodies
• second most prevalent degenerative dementia after AD.
• progressive dementia characterized especially by fluctuating cognitive
impairment, prominent disruption of attention and visuospatial abilities, visual
hallucinations, and parkinsonism
• RBD and depression are also very common.
• behavioral symptoms are typically present at least 1 year prior to the onset
of motor (parkinsonian) features .
• Patients with DLB are extremely sensitive to dopamine receptor antagonists
and experience severe parkinsonism when treated with neuroleptics.
 Histopathology
• progressive accumulation and aggregation of the synaptic protein alpha
synuclein (α-syn) as Lewy bodies and Lewy neurites, in the brainstem,
limbic and neocortical regions

Dementia with Lewy bodies

neuropathology. Lewy body in a
neuron of the substantia nigra (A), in a
pyramidal cell of CA1 area of the
hippocampus (B), and in cingulated
cortex (C) (arrows). Lewy body (arrow)
and Lewy neurites (arrowheads) in the
substantia nigra (D). Cortical Lewy
bodies (E,F).
Revised criteria for the clinical diagnosis of
probable and possible dementia with Lewy
bodies (DLB) - Fourth consensus report of the
DLB Consortium
• A Study by Harper et al., in 2016 showed that medial temporal lobe atrophy
differentiated AD from DLB with a sensitivity of 64% and specificity of 68% .

DLB AD
greater subcortical involvement in DLB Greater cortical grey matter atrophy in
AD than DLB
Treatment
Cognitive symptoms
• Cholinesterase inhibitors - both donepezil and rivastigmine
• benefit on cognitive function in DLB > AD
• efficacy of memantine in DLB is less clear, though increasingly memantine is
used in addition to a cholinesterase inhibitor in clinical practice
Neuropsychiatric symptoms
• non-pharmacologic interventions - caregiver training,
• physical activities,
• social stimulation
• environmental modification
• Antipsychotic medications - should be avoided in DLB
• potential for severe neuroleptic sensitivity reactions.
• profound changes in conscious state which can be fatal and occur in
around 50% of people with DLB
• Despite limited efficacy, quetiapine, is the generally preferred option by
• severe neuropsychiatric disturbances due to the perceived less risk of
parkinsonism
Motor symptoms
• Physical therapy, Fall prevention strategies.
• Levodopa - shown to benefit around 30% of DLB patients with motor
symptoms but the response is typically less pronounced compared to PD.
• increased risk of psychosis, including hallucinations.
• dopamine agonists - can substantially worsen psychotic symptoms and
exacerbate confusion, and should be avoided.

• RBD - melatonin is an effective and generally well-tolerated option

• Clonazepam and pramipexole are second-line treatment options for RBD, but
the potential side effects of drowsiness and confusion limit their use in DLB
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