This document discusses progressive supranuclear palsy (PSP). It begins by classifying PSP and outlining its diagnostic criteria and phenotypes. Key signs of PSP include early vertical supranuclear gaze palsy, postural instability with falls, and poor response to levodopa. Investigations like MRI, PET, and CSF analysis can aid in diagnosis. Pathology involves tau neurofibrillary tangles in brainstem nuclei. There is no effective treatment, only supportive and symptomatic measures. The document also briefly discusses multiple system atrophy (MSA) and corticobasal degeneration (CBD).

1. Dr. RAHI KIRAN.B
SR NEUROLOGY
GOVT MEDICAL COLLEGE, KOTA

2.  Classification
 Red flag signs
 Diagnostic criteria
 Phenotypic spectrum
 Investigations
 Novel biomarkers
 Treatment
 Future trends

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

9. SYNUCLEINOPATHY TAUPATHY

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,

53. TREATMENT
 Symptomatic
 PD- L-dopa/ dopa agonists- cranio cervical dystonia postural hypotension
Amantidine- gait disturbances
 Orthostatic hypotension-
high salt, fludrocortisone,midodrine
 Urinary dysfunction
- UDS
-Neurogenic bladder- Oxybutinin or Tolderotidne
 Erectile dysfunction-
- sildenafil
-intracavernosal inj. Or penile implants

54.  Depession
- SSRI/TCA
Promising studies
- Rasagiline
- Intrarterial/IV - autologous stem cells
- Future trials
- Alpha synuclein targeting antibodies
TREATMENT

55. Sixth to eighth decades of life - mean age 63 years
. Sporadic disease , 4–6% of parkinsonism.

56. 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

57. Motor (asymmetric)
Limb clumsiness
Bradykinesia/Akinesia
Rigidity
Tremor (action/postural)
Myoclonus
Limb dystonia
Blepharospasm
Choreoathetoid movements
Speech abnormalities
Gait disorder

58. Higher cortical functions
 Apraxia
 Dementia
 Alien-limb phenomenon
 Aphasia
 Frontal-lobe-release signs
 Cortical sensory abnormalities
 Depression
 apathy
 Anxiety Irritability
 Disinhibition, Delusions,Obsessive compulsive disorder

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

62. PHENOTYPIC SPECTRUM
 Classic CBD phenotype- CBS
 CBD- a/w FTD,PSP,PPA

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 .

73.  less hippocampal atrophy - 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.

79.  prion hypothesis - recently

81.  davunetide , tideglusib - failed
 droxidopa - orthostatic hypotension – failed
 losartan - supine hypertension - failed

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

83. THANK YOU

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