3. Common problem in neurology OPD
Wide variety of sporadic / heredodegenerative syndromes
80-85% -IPD
Differentiation from other syndromes
important in prognostication and management
5. Progressive Supranuclear Palsy
Multiple System Atrophy [(Shy-Dragger syn.) SND (MSAP) OPCA (MSAC)]
Corticobasal Degeneration
Dementia with Lewy Body Disease
6. 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
11. Steele et al—1964
5% of parkinsonian pts
male-to-female ratio is 1.5:1
Commonly misdiagnosed as PD
diagnosis is purely clinical
always sporadic, few familial cases-
12. The usual interval from initial symptom occurrence to the need for a cane or a walker is
3.1 years,
confinement to a chair or bed is 8.2 years.
median disease duration of 9.7 years
13. Postural Instability & EP Features :
Falls—backward
Rigidity –axial
Hypophonic
Widely based ataxic
Frontal release signs
Pseudobulbar palsy
L-DOPA UNRESPONSIVENESS
14. early signs- Slow vertical saccades and square wave jerks
Reduced blink rate and apraxia of eyelid opening
on doll’s eye maneuver, there is improved range
Subcortical-type dementia
Typical facies- “surprised look”
advanced PSP - Complete ophthalmoparesis
16. Possible PSP(highly sensitive)
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
17. 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
NINDS–SPSP DIAGNOSTIC CRITERIA FOR PSP
18. 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
NINDS–SPSP DIAGNOSTIC CRITERIA FOR PSP
19. Probable PSP(highly specific)
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
NINDS–SPSP DIAGNOSTIC CRITERIA FOR PSP
20. Definite PSP
Mandatory inclusion criteria:
Clinically probable or possible PSP and
histopathological evidence of typical PSP
NINDS–SPSP DIAGNOSTIC CRITERIA FOR PSP
22. INVESTIGATIONS
Clinical diagnosis
MRI-
midbrain atrophy(appearance of a flat or concave profile -68% sensitivity and an 89%
specificity
Superior cerebellar peduncle atrophy.
“morning glory flower sign” and the “hummingbird sign” – Highly specific(100%) low
sensitivity (50% and 68.4%)
magnetic resonance parkinsonism index (MRPI) - sensitivity of 100%
and specificity of 99·2–100·0% for PSP-RS.
pons:midbrain ratio-
23. oPET – lowered glucose metabolism in the midbrain ,caudate, Thalamus of PSP
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
(DATscan) is abnormal in PD and all AP syndromes
INVESTIGATIONS
25. PATHOLOGY
Neurofibrillary tangles are present in reticular formation and ocular motor nuclei.
Tufted astrocytes (Gallyas-positive) -feature of PSP that differentiates other
tauopathies such as CBD (astrocytic plaques)
27. -CSF tau protein- CSF phospho-tau and total tau concentrations lower than AD
- 2–5 times increased neurofilament light chain concentrations in PSP
Novel diagnostic approaches and biomarkers
28. Treatment
No effective symptomatic or neuroprotective treatments
A trial of levodopa (up to 1 g/d) and amantadine (up to 450mg/d)
Botulinum toxin injections can be used to treat levator inhibition,rigiditY, dystonia
Serotonin reuptake inhibitors (SSRIs) may be used for apathy with no clear benefit.
Supportive measures such as physiotherapy, walking aids, speech therapy and PEG
29. A small study with Coenzyme Q10- no RCTstudy
Recent large, double-blind studies with GSK-3b inhibitors (Tideglusib,
Davunetide) - failed.
Tideglusib reduced the rate of brain atrophy in onestudy.
30. Sporadic neurodegenerative disorder clinically any combination of parkinsonian,
autonomic, cerebellar, or pyramidal signs
MSA is an a-synucleinopathy
usually a sporadic disease; however, rarely, familial cases - mutations in COQ2
gene
Prevalence of MSA - ranged from 1·9 to 4·9 cases per 100 000 people.
31. Clinical presentation :
Affects both men and women
sixth decade of life
mean survival of 6–9 years.(upto 15yrs)
Main features –
Autonomic failure
Parkinsonism
Cerebellar ataxia
Pyramidal signs in any combination.
32. Distinguished clinically–
1. Parkinsonian features predominate in 80% of patients (MSA-P
subtype),
2. Cerebellar ataxia is the main motor feature in 20% of patients (MSA-C
subtype).
Both similar survival times.
MSA-P - more rapid functional deterioration
33. progressive akinesia and rigidity
jerky postural tremor and tremor at rest.
orofacial or craniocervical dystonia
recurrent falls at disease onset are unusual .
90% of the MSA-P pts- unresponsive to levodopa in the long term.
34. gait ataxia
scanning dysarthria
cerebellar oculomotor disturbances.
may be indistinguishable from other patients with idiopathic late onset cerebellar
ataxia
35. Dysautonomia :
urogenital and orthostatic dysfunction.
Early erectile dysfunction is nearly universal in men with MSA
Female- genital insensitivity
urinary incontinence or retention are common
36. Autonomic and urinary dysfunction :
Features
1. Orthostatic hypotension(68% of patients)
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
37. Parkinsonism :initial feature in 46% of patients with MSA-P
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
38. Cerebellar dysfunction :initial feature in 5%
A. Features
1. Gait ataxia
2. Ataxicdysarthria
3. Limb ataxia
4. Sustained gaze-evoked nystagmus
Criteria
Gait ataxia plus at least one of features 2–4
39. Corticospinal tract dysfunction
A. Features
1. Extensor plantar responses with hyper-reflexia
Criteria
no corticospinal tract features are used in defining the diagnosis of MSA
prominent and severe spasticity should raise suspicion for an
alternative diagnosis
40. exclusion criteria:
Symptomatic onset <30 years/>75YRS of age
Family history of a similar disorder
Systemic disease or other identifiable causes
Hallucinations unrelated to medication
Dementia
41. exclusion criteria:
Prominent slowing of vertical saccades or vertical supranuclear gaze palsy
Evidence of focal cortical dysfunction
Laboratory investigation- Metabolic, molecular genetic and imaging evidence of an
alternative cause of features
42. Possible MSA
A sporadic, progressive, adult (>30y) with onset disease* characterized by the following:
Parkinsonism or cerebellar syndrome
At least 1 feature of autonomic or urogenital dysfunction
At least 1 additional feature
Probable MSA
A sporadic, progressive, adult (>30y) with onset disease* characterized by the following:
Autonomic failure involving urinary dysfunction
Poorly levodopa-responsive parkinsonism or
cerebellar dysfunction
43. Definitive MSA
A sporadic, progressive, adult (>30y) with onset disease pathologically confirmed by
presence of high density GCIs in association with degenerative changes in
striatonigral and olivopontocerebellar pathways
44. Pyramidal signs
Orofacial dystonia or dyskinesias
dyskinesia mainly affecting orofacial muscles
Axial dystonia -Pisa syndrome (subacute axial dystonia with a severe
tonic lateral flexion of the trunk, head, and neck)
early severe camptocormia
MSA - Additional features
45. Jerky tremor
Dysarthria- Atypical, irregular and severely hypophonic
Dysphagia within 5 years of motor onset
Neuropsychiatric features - • Depression (41%) • Hallucinations (5·5%)
• Dementia (4·5%) • Insomnia (19%)
• Daytime sleepiness (17%) • Restless legs (10%)
MSA - Additional features
46. Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum
Hypometabolism on FDG-PET in putamen, brainstem, or cerebellum
48. Investigations
Autonomic function tests
Cardiovascular function test-within in 2-3 ys
Standard urine analysis will exclude infection.
The residual volume –usg,cystometry ,UDS
MSA
49. IMAGING
MRI
- Hot cross burn sign- mcp/pons- MSA-c
- Putaminal rim- MSA-p
The slight hyperintensity of the lateral margin of the putamen on T2-
weighted MRI is a characteristic finding in patients with MSA involving the
extrapyramidal system
Trace (D)-DW MRI -MSA-P-anterior putamen
MSA-C-cerebellum and middle cerebellar peduncle
51. .
- 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)
PET- The caudateputamen index- lower in patients with MSA than in PD
52. CSF mean a-synuclein levels from PD (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%.
COQ2, a gene that encodes coenzyme Q10,
59. Inclusion criteria (one of A orB)
A) Rigidity (easily detectable without reinforcement) and one cortical sign:
apraxia
cortical sensory loss
alien-limb phenomenon
B) Asymmetric rigidity, dystonia (focal in limb; present at rest at onset),
focal reflex myoclonus (spreads beyond stimulated digits
60. Exclusion criteria
Early dementia (will exclude some patients)
Early vertical gaze palsy
Rest tremor
Severe autonomic disturbances
Sustained responsiveness to levodopa
Lesions on imaging studies indicate another
pathological process
61. 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
investigations
63. Imaging
asymmetric frontal, and parietal cortical atrophy becomes evident with dilatation
of the lateral ventricle(temporal/parietal cortex (the latter pattern is seen in
dementia of the Alzheimer type)
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.
64. FDG-PET
- Asymmetric reduction in fronto parietalregions
LP & jejunal biopsy- Whipple disease
65. The R2 component of the blink reflex recovery cycle (R2 BRRC) appears to be a useful tool
to distinguish progressive supranuclear palsy (PSP) from corticobasal degeneration (CBD)
4-repeat-tau aggregates - neocortex in CBD, brainstem in PSP
66. TREATMENT
L-dopa trial (upto 1 gm/d)/Amantadine- PD symptoms
Valproate, Levetiracetam- myoclonus
Botox inj- dystonic hand
antioxidants or vitamin E if the patient has memory loss
Palliative rx
67. Dementia -not occur in the early stages ,usually evident with progression.
Deficits on tests of attention, executive function, and visuospatial ability may
be especially prominent.
68. Two core features are sufficient for a diagnosis of probable, one for
possible DLB
Fluctuating cognition with pronounced variations in attention and
alertness
Recurrent visual hallucinations that are typically well formed and detailed
features of parkinsonism
69. REM sleep behavior disorder
Severe neuroleptic sensitivity
Low dopamine transporter uptake in basal ganglia demonstrated by
SPECT or PET imaging
one or more of these + one or more core features, - probable DLB .
In the absence of any core features, one or more
suggestive features - possible DLB.
Probable DLB should not be diagnosed on the basis of suggestive features alone.
70. Repeated falls and syncope, Transient unexplained loss of consciousness
Severe autonomic dysfunction
Hallucinations in other modalities
Depression
Relative preservation of medial temporal lobe structures on CT/MRI scan
Generalized low uptake on SPECT/PET perfusion scan with reduced
occipital activity
Prominent slow wave activity on EEG with temporal lobe transient sharp waves
71. 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
72. 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.
the 1-year rule between the onset of dementia and parkinsonism – DLB .
74. SPECT & PET - decreased occipital lobe blood flow – DLB > AD
relative preservation of the posterior cingulate gyrus (cingulate island
sign) - DLB > AD
SPECT scanning studies in DLB patients :
Visual hallucinations - Were related to hypoperfusion of the parietal and occipital
association cortices
Misidentifications - Were related to hypoperfusion of the limbic-paralimbic structures
Delusions - Were related to hyperperfusion of the frontal cortices
75. CSF
Tau – DLB < AD
beta amyloid are lower than normal in DLB, AD
LBCRS - Lewy body composite risk score - help determine whether Lewy body
pathology is contributing to dementia.
76. Motor parkinsonism-mild hallucinations and agitation may not require medical
treatment.
-Levodopa at low doses & titrate up.
-Anticholinergics should be avoided.
Neuropsychiatric symptoms.--cholinesterase inhibitors (CHEIs) or atypical
antipsychotic ,
modafinil initially had a positive effect , but didn't last long.
memantine improves cognitive function and neuropsychiatric features in
patients with DLB.
82. SUMMARY
Careful clinical examination
AP mimickers
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
87. magnetic resonance
parkinsonism index (MRPI) -(P / M) x (MCP / SCP)
MCP = width of middle cerebellar peduncle
SCP = width of superior cerebellar peduncle
P = area of pons in midsagittal plane
M = area of midbrain in midsagittal plane
A value of more than 13.55 indicates an abnormal result, and
strongly suggests that these patients will go on to develop PSP.
88. Misdiagnosis PD with AP , as well as FTD,AD,PPA
Mimickers of AtypicalPD 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