This document provides an overview of Parkinson plus syndromes, which are degenerative disorders that present with parkinsonism but have distinguishing features from idiopathic Parkinson's disease. It discusses several conditions in detail, including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD). For each, it covers clinical presentation, diagnostic criteria, investigations, pathology, treatment approaches, and future research directions. The document aims to help clinicians differentiate these syndromes from Parkinson's disease and each other for accurate prognostication and management of patients.

1. PARKINSON PLUS SYNDROME
DR SWAPNIL SAMADHIYA
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