Different parkinsonism syndromes compared with Idiopathic Parkinson's disease

1. PARKINSON PLUS SYNDROME
DR VAIBHAV KUMAR SOMVANSHI
SR NEUROLOGY
GMC KOTA

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

3. INTRODUCTION
• Common problem in neurology OPD
• Wide variety of sporadic / heredodegenerative syndromes
• 80-85% -IPD
• Differentiation from other syndromes
• Important in prognostication and management

5. PARKINSONISM PLUS
• Progressive Supranuclear Palsy
• Multiple System Atrophy [(Shy-Dragger syn.), SND (MSA P),
OPCA (MSA C)]
• Corticobasal Degeneration
• Dementia with Lewy Body Disease

7. PROGRESSIVE SUPRANUCLEAR PALSY
• 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

8. • 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

9. • Postural Instability & EP Features :
• Falls—backward
• Rigidity –axial
• Hypophonic
• Widely based ataxic
• Frontal release signs
• Pseudobulbar palsy
• L-DOPA UNRESPONSIVENESS

10. • 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

12. NINDS PSP DIAGNOSTIC CRITERIA
• 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

13. • 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

14. • 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

15. • 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

16. • Definite PSP
• Mandatory inclusion criteria:
• Clinically probable or possible PSP and
• Histopathological evidence of typical PSP

18. 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

19. MAGNETIC RESONANCE
PARKINSONISM INDEX (MRPI)
P = area of pons in midsagittal plane
MCP = width of middle cerebellar peduncle
(P / M) x (MCP / SCP)
M = area of midbrain in midsagittal plane
SCP = width of superior cerebellar peduncle
value more than 13.55 abnormal ,
strongly suggests will develop PSP.

20. • PET – 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
• DAT scan is abnormal in PD and all AP syndromes

23. PATHOLOGY
• Spares the cortex and involves the basal ganglia,dentate,
pontine, and oculomotor nuclei.
• Abnormal tau hyperphosphorylation and deposition. Tau is
encoded by MAPT and normally functions to stabilize
microtubules.
• Neurofibrillary tangles are present in reticular formation and
ocular motor nuclei.
• Tufted astrocytes -feature of PSP that differentiates other
tauopathies such as CBD (astrocytic plaques,colloid bodies)

25. NOVEL DIAGNOSTIC APPROACH AND
BIOMARKERS
• CSF tau protein- CSF phospho-tau and total tau concentrations
lower than AD
• 2–5 times increased neurofilament light chain concentrations
in PSP

26. TREATMENT
• 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,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

27. • A small study with Coenzyme Q10- no RCT study
• Recent large, double-blind studies with (glycogen synthase
kinase)GSK-3b inhibitors (Tideglusib,Davunetide) ,prevent
hyperphosphorylation of tau- failed.
• Tideglusib reduced the rate of brain atrophy in one study.

28. MULTIPLE SYSTEM ATROPHY
• Sporadic neurodegenerative disorder clinically any combination
of parkinsonian, autonomic, cerebellar, or pyramidal signs.
• MSA is an alpha-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

29. 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

30. TWO MAJOR MOTOR MANIFESTATIONS
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

31. MSA-P
• 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.

32. MSA-C
• Gait ataxia
• Scanning dysarthria
• Cerebellar oculomotor disturbances.
• May be indistinguishable from other patients with idiopathic
late onset cerebellar Ataxia

33. • Dysautonomia
• Urogenital and orthostatic dysfunction.
• Early erectile dysfunction is nearly universal in men with MSA
• Female- genital insensitivity
• Urinary incontinence or retention are common

34. CONSENSUS STATEMENT FOR CLINICAL
DIAGNOSIS OF MSA
• 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

35. • 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

36. • Cerebellar dysfunction :initial feature in 5%
• 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

37. • 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

38. • 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

39. • 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

40. • 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

41. • 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

42. 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

43. MSA ADDITIONAL FEATURES
• 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

44. • 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%)

46. Investigations
• Autonomic function tests (table tilt,24 hr ambulatory bp,heart
rate monitoring,baroreflex sensitivity,qsart,gastric emptying
study,psg)
• Cardiovascular function
• Standard urine analysis will exclude infection.
• The residual volume –USG,Cystometry ,UDS

47. 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
• MSA-C-cerebellum and middle cerebellar peduncle

49. INVESTIGATIONS
• 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 caudate putamen index- lower in patients with MSA than in
PD

50. TREATMENT
• Symptomatic
• PD- l-dopa/ dopa agonists- cranio cervical dystonia postural
hypotension
• Amantidine- gait disturbances
• Orthostatic hypotension- high salt, fludrocortisone,
midodrine,droxidopa,pyridostigmine
• Urinary dysfunction- oxybutinin
• Erectile dysfunction– sildenafil, Intracavernosal inj. Or penile
implants

51. Depression
• SSRI/TCA
Promising studies
• Rasagiline
• Intrarterial/IV - autologous stem cells
Future trials
• Alpha synuclein targeting antibodies

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

53. • Clinical 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

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

55. • Higher cortical functions
• Apraxia
• Dementia
• Alien-limb phenomenon
• Aphasia
• Frontal-lobe-release signs
• Cortical sensory abnormalities
• Depression
• Apathy
• Anxiety irritability
• Disinhibition, delusions,obsessive compulsive disorde

56. DIAGNOSTIC CRITERIA
• Inclusion criteria (one of A or B)
• 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)

57. • 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

58. PHENOTYPIC SPECTRUM

59. • Imaging
• MRI
• Asymmetric frontal, and parietal cortical atrophy becomes
evident with dilatation of the lateral ventricle
(temporal/parietal cortex (the later pattern is seen in
dementia of the alzheimer type)

60. • 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.
FDG-PET
• Asymmetric reduction in fronto parietal regions

61. • 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
Eur J Neurol.sciacca g et al, 2018 Aug;25(8):1100-e85. doi:
10.1111/ene.13673. Epub 2018 Jun 12.

62. TREATMENT
• L-dopa trial (upto 1 gm/d)
• Amantadine(450 mg/d)
• Valproate, levetiracetam- myoclonus
• Botox inj- dystonic hand
• Antioxidants or vitamin E if the patient has memory loss
• Palliative rx

63. DEMENTIA WITH LEWY BODY
• 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.

64. CORE FEATURES
• 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

65. SUGGESTIVE FEATURES
• 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

66. SUPPORTIVE FEATURES
• 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

67. 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.
• The 1-year rule between the onset of dementia and
parkinsonism – DLB .

68. INVESTIGATIONS
• MRI BRAIN
-diffuse cerebral atrophy with relative preservation of occipital
and mesial temporal lobes compared to alzheimer disease.
• SPECT & PET
-decreased occipital lobe blood flow – DLB > AD
-relative preservation of the posterior cingulate gyrus
(cingulate island sign) - DLB > AD

69. • 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

70. • 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.

72. CLINICAL MANAGEMENT
• Motor parkinsonism-mild hallucinations and agitation may not
require medical treatment.
• Levodopa at low doses & titrate up.
• Anticholinergics should be avoided,worsen cognition,psychosis
• Neuropsychiatric symptoms.--Cholinesterase inhibitors atypical
antipsychotic
• Memantine improves cognitive function and neuropsychiatric
features in patients with DLB.
• Recently Pimavenserin selective 5 HT2 inverse agonist phase 3
trial promisi ng conrolling psychosis

76. RECENT TRIAL
• Davunetide , Tideglusib - failed
• Droxidopa - orthostatic hypotension –FDA approved
• Losartan - supine hypertension - failed

77. CLINICAL FEATURES TAUPATHY SYNUCLEOPATHY
Age of onset 7th 6th
Initial symptoms Postural &gait disorder Tremor & bradykinesia
Family history - +/-
Multi infarct state +/- -
Dementia +/- +/-
Downgaze ophthalmoparesis + -
Eyelid abnormalities + +/-
Pseudobulbar palsy + +/-
Gait Wide,stiff,unsteady Slow
shuffling,narrow,festinating
Rigidity Axial(neck) Generalised
Facial expression Astonished,worried Hypomimia
Tremor at rest - +/-
Dystonia + +/-

78. Corticobulbar signs +/- -
Symmetry of findings + -
Weight loss - +
Improvement with DA drugs _ +
Levodopa induced dyskinesias _ +

86. 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. REFERENCES
• Eur J Neurol.sciacca g et al, 2018 Aug;25(8):1100-e85.
doi:10.1111/ene.13673. Epub 2018 Jun 12.
• Litvan I, Hauw JJ, Bartko JJ, et al. Validity and reliability of the
preliminary NINDS neuropathologic criteria for progressive
supranuclear palsy and related disorders.JNeuropathol Exp Neurol
1996;55(1):97Y105
• Strowd RE, Cartwright MS, Okun MS, et al.
• Pseudobulbar affect: prevalence and quality of life impact in
movement disorders.J Neurol 2010;257(8):1382Y1387.
doi:10.1007/s00415-010-5550-3
• Bradley's Neurology in Clinical Practice,7th ed
• Uptodate.com

88. Thank you