This document discusses atypical parkinsonism (AP), which accounts for 15-20% of all cases of parkinsonism. It begins by classifying AP into primary, multisystem degenerations, hereditodegenerative, and secondary types. It then focuses on the major AP syndromes - Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), and Corticobasal Degeneration (CBD). For PSP and MSA, it provides details on clinical presentation, diagnostic criteria, investigations, pathology, and treatment approaches. The document emphasizes the importance of differentiating AP from Parkinson's disease to allow for accurate prognosis and management of patients.
2. OUTLINE
Classifications
Red flag signs
AP- syndromic approach
Diagnostic criteria
Phenotypic spectrum
Atypical AP or mimickers
Investigations
Novel biomarkers
Treatment
Future trends
3. INTRODUCTION
Common problem in neurology outpatient
departments
Wide variety of sporadic / heredodegenerative
syndromes
Aetiologies vary widely
80-85% -IPD
Differentiation from other syndromes
Very important in prognostication and management
11. IDIOPATHIC PD
UK Brain Bank Criteria
bradykinesia and at least one of the following: rest
tremor, rigidity, or postural instability.
12. RED FLAGS
Symmetric bradykinesia and rigidity
Absence of tremor
Prominent myoclonus
Limb apraxia
Alien limb phenomena
Impaired down gaze
Facial dystonia
Early loss of postural reflexes
L- dopa induced facial dyskinesias
Ataxia
Stridor
Early dysphagia
Spasticity
Early dementia or hallucinations
Early and prominent dysautonomia
15. PATHOPHYSIOLOGY
Accurate diagnosis is necessary to understand
pathogenesis
Two proteins mainly
Alpha synuclein
- Pre synaptic protein
- Aggregates in cell body & neurons – lewy body &
lewy neuritis- PD & DLBD
- glial cytoplasmic inclusion in MSA
16.
17.
18. TAUPATHY
4 repeat tau accumalates
NFT & in glia
Psp- astrocytic tufts
CBD- astrocytic plaques
19.
20.
21. PROGRESSIVE SUPRANUCLEAR PALSY
Steele et al—1964
5% of parkinsonian pts
Prevalence—4.9 / 100,000
Incidence 1.7 (50-59yrs) to 14.7(80-89yrs)
Commonly misdiagnosed as PD
Insidious onset
No pathologic proven cases have begun before the
age of 40.
22. Tauopathy-4-repeat t, 4R tauopathy).
always sporadic, few familial cases-
- MAPT (microtubuli associated protein t) gene mtn.
Mitochondrial dysfunction & oxidative stress -
pathophysiology of PSP
24. Reduced blink rate and closure of eyelids due to eyelid
dystonia or levator inhibition ( apraxia of eyelid
opening)
square wave-jerks
on doll’s eye maneuver, there is improved range, as
vestibulo-ocular reflex is preserved
Subcortical-type dementia
Typical facies- “surprised look”
25.
26.
27. NINDS–SPSP DIAGNOSTIC CRITERIA FOR PSP
Possible PSP
Mandatory inclusion criteria:
gradually progressive disorder
onset age 40 or later
Either vertical supranuclear palsy or both slowing of
vertical saccades
postural instability with falls within a year of disease onset
no evidence of other diseases that could explain the
foregoing features, as indicated by exclusion criteria
28. Mandatory exclusion criteria:
recent history of encephalitis
alien limb syndrome
cortical sensory deficits
focal frontal or temporoparietal atrophy
hallucinations or delusions unrelated to
dopaminergic therapy
cortical dementia of Alzheimer type
prominent, early cerebellar symptoms
unexplained dysautonomia
29. Supportive features:
symmetrical akinesia or rigidity
proximal more than distal
abnormal neck posture
especially retrocollis
poor or absent response of parkinsonism to levodopa
early dysphagia and dysarthria
early onset of cognitive impairment including two or
more of: apathy, impairment in abstract thought,
decreased verbal fluency, utilisation or imitation
behaviour, or frontal release signs
30. Probable PSP
Mandatory inclusion criteria
gradually progressive disorder
onset age 40 or later
vertical supranuclear palsy
prominent postural instability with falls within a year
of disease onset
no evidence of other diseases that could explain
the foregoing features, as indicated by exclusion
criteria
32. PHENOTYPIC SPECTRUM OF PROGRESSIVE
SUPRANUCLEAR PALSY
typical PSP phenotype- Richardson syndrome
PSP-p = PD at least at the initial stages, with asymmetric
parkinsonism, rest-tremor, better levodopa response, longer
mean survival
pure akinesia with gait freezing (PSP-PAGF)
corticobasal syndrome (PSP-CBS),
frontotemporal dementia (PSP-FTD), progressive nonfluent
aphasia
no clinical sign to predict PSP pathologic abnormality
accurately in the non-RS phenotypes
33. INVESTIGATIONS
clinical diagnosis
MRI-
midbrain atrophy
Superior cerebellar peduncle atrophy.
“morning glory flower sign” and the “hummingbird sign” are
quite specific but show low sensitivity (50% and 68.4%,
respectively
(DATscan) is abnormal in PD and all AP syndromes
34. differentiate with PD, [123]meta-iodobenzylguanidine
(MIBG) and 123I-iodobenzamide (IBZM) SPECT may be
useful
MIBG is abnormal in PD because of postganglionic
sympathetic denervation, but is typically normal in PSP.
IBZM SPECT assessing the postsynaptic receptors is
abnormal in PSP and normal in PD
IBZM SPECT is abnormal in all APs and therefore
cannot differentiate between PSP and other AP
Novel diagnostic approaches and biomarkers
- csf tau protein
-neurofilament light chain
35.
36.
37. PATHOLOGY
Neurofibrillary tangles are present in these areas.
Tufted astrocytes (Gallyas-positive) -hallmark
feature of PSP that differentiates other 4R
tauopathies such as CBD (astrocytic plaques
38.
39. RX
no effective symptomatic or neuroprotective treatments
A trial of levodopa (up to 1 g/d) and amantadine (up to 450 mg/d)
Botulinum toxin injections can be used to treat levator inhibition.
Serotonin reuptake inhibitors (SSRIs) may be used for apathy with no
clear benefit.
A small study with Coenzyme Q10- no RCT study
Recent large, double-blind studies with GSK-3b inhibitors (Tideglusib,
Davunetide) have failed to show any clinical effect.
Tideglusib reduced the rate of brain atrophy in one study.
Supportive measures such as physiotherapy, walking aids, speech
therapy and PEG
40. MULTIPLE SYSTEM ATROPHY :
Sporadic neurodegenerative disorder clinically any
combination of parkinsonian, autonomic, cerebellar, or
pyramidal signs
Pathologically–
cell loss, gliosis, and glial cytoplasmic inclusions in
several CNS structures.
MSA is an a-synucleinopathy
usually a sporadic disease; however, rarely, familial
cases - mutations in COQ2 gene
41. Epidemiology :
prevalence of MSA in four studies ranged from 1·9
to 4·9 cases per 100 000 people.
similar to those of other well-known
neurodegenerative disorders such as Huntington’s
disease and motor neuron disease.
no single environmental factor shown to increase
or to reduce risks of MSA
42. Clinical presentation :
affects both men and women
the sixth decade of life progresses with a mean
survival of 6–9 years.
substantial variation of disease progression with
survival of more than 15 yrs.
main features –
autonomic failure
Parkinsonism
cerebellar ataxia
pyramidal signs in any combination.
43. TWO MAJOR MOTOR PRESENTATIONS
distinguished clinically–
Parkinsonian features predominate in 80% of
patients (MSA-P subtype),
cerebellar ataxia is the main motor feature in 20%
of patients (MSA-C subtype).
Both similar survival times.
patients with MSA-P have a more rapid functional
deterioration than those with MSA-C
44. MSA-P-associated parkinsonism :
progressive akinesia and rigidity
jerky postural tremor and tremor at rest.
orofacial or craniocervical dystonia associated with a
characteristic quivering high-pitched dysarthria.
Postural stability is compromised early on in the
disease course
recurrent falls at disease onset are unusual in
contrast to psp.
45. 90% of the MSA-P pts- unresponsive to levodopa in
the long term.
50% have levodopa-induced dyskinesia affecting
orofacial and neck muscles, without motor benefit.
fully developed clinical picture of MSA-P evolves
within 5 years of disease onset, allowing a clinical
diagnosis during follow-up.
47. MSA-C :
gait ataxia
limb kinetic ataxia
scanning dysarthria,
cerebellar oculomotor disturbances.
Most patients develop additional non-cerebellar
symptoms and signs
may be indistinguishable from other patients with
idiopathic late onset cerebellar ataxia
48. Dysautonomia :
urogenital and orthostatic dysfunction.
Early erectile dysfunction is nearly universal in men
with MSA
Female- genital insensitivity
urinary incontinence or retention are common early
in the course or as presenting symptoms
49. CONSENSUS STATEMENT FOR THE CLINICAL
DIAGNOSIS OF MSA
clinical domains,
features
criteria used in the diagnosis of MSA
50. Autonomic and urinary dysfunction :
Features
1. Orthostatic hypotension
2. Urinary incontinence or incomplete bladder emptying
Criteria
Reduction of least 30mmHg or in diastolic blood pressure
by at least 15 mm Hg after 3 min of standing
urinary incontinence (persistent, involuntary partial or
total bladder emptying, accompanied by erectile
dysfunction in men) or both
51. Parkinsonism :
A. Features
1. Bradykinesia
2. Rigidity
3. Postural instability (not caused by primary visual,
vestibular, cerebellar, or proprioceptive dysfunction) 4.
Tremor (postural, resting or both)
B. Criteria
Bradykinesia plus at least one of features 2–4
52. Cerebellar dysfunction :
A. Features
1. Gait ataxia
2. Ataxic dysarthria
3. Limb ataxia
4. Sustained gaze-evoked nystagmus
Criteria
Gait ataxia plus at least one of features 2–4
53. Corticospinal tract dysfunction
A. Features
1. Extensor plantar responses with hyper-reflexia
Criteria
Corticospinal tract dysfunction in MSA: no
corticospinal tract features are used in defining the
diagnosis of MSA
prominent and severe spasticity should raise
suspicion for an alternative diagnosis
54. Consensus statement: exclusion criteria for the
diagnosis of MSA :
History
Symptomatic onset under 30 years of age
Family history of a similar disorder
Systemic disease or other identifiable causes
Hallucinations unrelated to medication
DSM IV criteria for dementia
Prominent slowing of vertical saccades or vertical
supranuclear gaze palsy
Evidence of focal cortical dysfunction such as aphasia,
alien limb syndrome, and parietal dysfunction
Laboratory investigation- Metabolic, molecular genetic
and imaging evidence of an alternative cause of
features
55. DIAGNOSTIC CLINICAL APPROACH
Motor signs
Parkinsonism poorly responsive to levodopa
Cerebellar ataxia
Pyramidal signs
Early instability and falls Within 3 years of disease
onset
Rapid progression (wheelchair sign) despite
dopaminergic treatment within 5 years of disease
onset
56. Orofacial dystonia or dyskinesias
Atypical spontaneous or levodopa induced
dystonia
dyskinesia mainly affecting orofacial muscles,
[resembling risus sardonicus of cephalic tetanus]
Axial dystonia -Pisa syndrome (subacute axial
dystonia with a severe tonic lateral flexion of the
trunk, head, and neck)
early severe camptocormia
Disproportionate antecollis -Chin on chest, neck
can only be passively and forcibly extended to its
normal position with difficulty; despite severe
chronic neck flexion, flexion elsewhere is minor.
57.
58. Jerky tremor
Irregular myoclonic postural or action tremor of the hands
or fingers
Dysarthria-
- Atypical quivering, irregular and severely hypophonic or
slurring high pitched dysarthria,
- tends to develop earlier and be more severe than in PD
notable dysphagia
59. Non-motor signs
Severe dysautonomia
Abnormal respiration
Nocturnal (harsh or strained, high pitched inspiratory
sounds) or diurnal inspiratory stridor,
involuntary deep inspiratory sighs and gasps, sleep
apnoea
snoring increased from premorbid level
newly arisen REM sleep behaviour disorder
Emotional incontinence
60. “RED FLAGS’’
RBD and autonomic failure- pre motor stage
Early falls and postural instability can be seen- look for
eye signs & fronto-subcortical dysfunction for PSP
L-dopa induced oro facial dystonia- MSA
Raynaud phenomenon is a common in MSA
Freezing of gait may be prominent, early, and severe,
causing diagnostic difficulties -PSP -PAGF phenotype
dementia, it is considered a non supporting feature for
the diagnosis of MSA
frank, prominent, early dementia should lead the clinician
to other diagnoses.
61. Investigations
Autonomic function tests
Cardiovascular function test-within in 2-3 ys
Bladder function tests
standard urine analysis will exclude infection.
The residual volume –usg,cystometry ,UDS
62. IMAGING
MRI
- Hot cross burn sign- mcp/pons- MSA-c
- Putaminal rim- MSA-p
- DAT scan
- abnormal in all MSA, PSP, and PD
- MIBG scintigraphy
- abnormal in PD, normal in MSA
IBZM SPECT is normal in PD,abnormal in MSA (but
also in PSP and CBD)
63.
64. NOVEL BIOMARKERS
Mollenhauer and colleagues-
CSF mean a-synuclein levels , not total t, or Ab42 levels
differentiated PD and MSA from neurologic controls (70%
sensitivity, 53% specificity)
a-synuclein and phosphorylated t/total t could differentiate
PD from MSA -sensitivity of 90% & specificity of 71%
Flt3 ligand, a cytokine
PD and MSA with a sensitivity of 99% and a specificity of
95%.
67. CORTICOBASAL DEGENERATION :
sixth to eighth decades of life,
onset of symptoms at mean age 63 years (SD 7·7)
. sporadic disease
4–6% of parkinsonism,
68. Clinical presentations
Five initial presentations
The most common presentation (55%) -“useless
arm” (ie, a rigid, dystonic, akinetic, or apraxic arm),
gait disorder (27%)
prominent sensory symptoms
isolated speech disturbance
behavioural disturbance
71. DIAGNOSTIC CRITERIA FOR CORTICOBASAL
DEGENERATION
Inclusion criteria (one of A or B)
A) Rigidity (easily detectable without reinforcement) and
one cortical sign:
apraxia (more than simple use of limb as object;
absence of cognitive or motor deficit sufficient to explain
disturbance)
cortical sensory loss (preserved primary sensation,
asymmetric)
alien-limb phenomenon (more than simple levitation)
B) Asymmetric rigidity, dystonia (focal in limb; present at
rest at onset),
focal reflex myoclonus (spreads beyond stimulated digits
72. Exclusion criteria
Early dementia (will exclude some patients with
corticobasal degeneration)
Early vertical gaze palsy
Rest tremor
Severe autonomic disturbances
Sustained responsiveness to levodopa
Lesions on imaging studies indicate another
pathological process
73. PROPOSED CRITERIA FOR THE DIAGNOSIS OF
CORTICOBASAL DEGENERATION
Core features
Insidious onset and progressive course
No identifiable cause (eg, tumour, infarct)
EPS – one of the follow
-focal or asymmetric appendicular rigidity
-lacking prominent and sustained l-dopa response
-focal or asymmetric appendicular dystonia
Cortical dysfunction - at least one of the following
: focal or asymmetric ideomotor apraxia
alien-limb phenomena
cortical sensory loss visual or sensory hemineglect
constructional apraxia
focal or asymmetric myoclonus
apraxia of speech or nonfluent aphasia
74. Supportive investigations
Variable degrees of focal or lateralised cognitive
dysfunction,
with relative preservation of learning and memory
on neuropsychometric testing
Focal or asymmetric atrophy on CT or MRI imaging,
typically in perifrontal cortex
Focal or asymmetric hypoperfusion on SPECT or
PET, typically maximal in parietofrontal cortex with
or without basal ganglia involvement
75. NEUROPATHOLOGICAL CRITERIA
Core features
Focal cortical neuronal loss
Substantia nigra neuronal loss
Cortical and striatal Gallyas/tau-positive neuronal and
glial lesions, especially astrocytic plaques and threads, in
both white and grey matter
Supportive features
Cortical atrophy, commonly with superficial spongiosis
Ballooned neurons, in atrophic cortices
Tau-positive oligodendroglial coiled bodies
76. PHENOTYPIC SPECTRUM OF CORTICOBASAL
DEGENERATION
Classic CBD phenotype- CBS
CBD- present with FTD,RS,PPA,PCA
AD,PSP,FTD present with CBS
Symmetrical bilateral CBS- AD pathology/RS
Early onset PSP – CBD pathology
For which proposed clinical criteria applied
77. INVESTIGATIONS
Imaging
asymmetric frontal, and parietal cortical atrophy becomes
evident with dilatation of the lateral ventricle
EEG –
-normal at first
- show asymmetric slowing that is maximum over the
hemisphere contralateral to the more affected limb
Dopamine transporter SPECT- abnormal
- differentiate them from those with Alzheimer’s and Pick’s
diseases (in whom this scan is typically normal) early in
the course of the disease.
81. DEMENTIA WITH LEWY BODIES
Central feature (essential for a diagnosis of possible
or probable DLB)
Dementia -progressive cognitive decline of sufficient
magnitude to interfere with normal social or
occupational function.
Prominent or persistent memory impairmen- not occur
in the early stages ,usually evident with progression.
Deficits on tests of attention, executive function, and
visuospatial ability may be especially prominent.
82. CORE FEATURES (TWO CORE FEATURES ARE SUFFICIENT FOR
A DIAGNOSIS OF PROBABLE DLB, ONE FOR POSSIBLE DLB)
Fluctuating cognition with pronounced variations in
attention and alertness
Recurrent visual hallucinations that are typically well
formed and detailed
Spontaneous features of parkinsonism
83. SUGGESTIVE FEATURES
REM sleep behavior disorder
Severe neuroleptic sensitivity
Low dopamine transporter uptake in basal ganglia
demonstrated by SPECT or PET imaging
(If one or more of these is present in the presence of one
or more core features, - probable DLB .
In the absence of any core features, one or more
suggestive features is sufficient for possible DLB.
Probable DLB should not be diagnosed on the basis of
suggestive features alone.)
84. SUPPORTIVE FEATURES (COMMONLY PRESENT BUT NOT
PROVEN TO HAVE DIAGNOSTIC SPECIFICITY)
Repeated falls and syncope
Transient, unexplained loss of consciousness
Severe autonomic dysfunction, e.g., orthostatic hypotension, urinary
incontinence
Hallucinations in other modalities
Systematized delusions
Depression
Relative preservation of medial temporal lobe structures on CT/MRI
scan
Generalized low uptake on SPECT/PET perfusion scan with reduced
occipital activity
Abnormal (low uptake) MIBG myocardial scintigraphy
Prominent slow wave activity on EEG with temporal lobe transient
sharp waves
85. A DIAGNOSIS OF DLB IS LESS LIKELY
If -CVA evident as focal neurologic signs or on brain
imaging
In the presence of any other physical illness or brain
disorder sufficient to account in part or in total for the
clinical picture
If parkinsonism only appears for the first time at a stage
of severe dementia
86. TEMPORAL SEQUENCE OF SYMPTOMS
diagnosed when dementia occurs before or concurrently
with parkinsonism (if it is present).
Parkinson disease dementia (PDD) - dementia that occurs
in the context of well-established Parkinson disease.
In research studies in which distinction needs to be made
between DLB and PDD, the existing 1-year rule between
the onset of dementia and parkinsonism - DLB continues
to be recommended.
87. CLINICAL MANAGEMENT
Motor parkinsonism-
-Levodopa at low doses & titrate up.
-Anticholinergics should be avoided.
Neuropsychiatric symptoms.--cholinesterase inhibitors
(CHEIs) or atypical antipsychotic
88.
89.
90.
91.
92. “ATYPICAL” ATYPICAL PARKINSONISM
Misdiagnosis PD with AP , as well as FTD,AD,PPA
Mimickers of Atypical PD
Eg:
SCAS/ FTAX- mimic MSA
Neimann Pick C,CTX,prion d/s,mitochondrial- mimic AP
phenotype
- Age of onset
- Tempo of progression
- Family history
- Clinical exam + associated features
93.
94. SUMMARY
Careful clinical examination
Expanding phenotypic spectrum of AP & expanding
pathological spectrum of classic AP phenotypes –
diagnostic challenge
AP mimickers
Investigations may be supportive, but their sensitivity
and specificity are low.
There are currently no biomarkers available.
There are currently no neuroprotective treatments
available.
symptomatic and supportive treatments with usually no
sustained effect.
Further research required