Parkinson's plus syndromes

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