Dr Helen Ling

Queen Square Brain Bank for Neurological DisordersInstitute of Neurology

University College London

Clinical aspects of MSA

2nd UK MSA Research Meeting

Possible MSA:Sporadic, progressive, >30y.o.:-Parkinsonism with poor L-dopa response or cerebellar syndrome-Autonomic failure (urinary symptoms/ED or OH)

Probable MSA:Possible + ≥ 1 additional features:

Additional features (probable):Babinski signStridor

MSA-P:Rapidly progressive parkinsonismPoor L-dopa responsePostural instability <3yrs of onsetCerebellar signsDysphagia <5yrs of onsetMRI: atrophy of putamen, pons, cerebellumFDG-PET: hypometabolism in putamen, brainstem, cerebellum

MSA-C:ParkinsonismMRI / FDG-PET findingsDAT-SPECT: reduced uptake

Definite MSA:

MSA-P

‘Red flag’ features supportive of MSA:Rapid progression (wheelchair)

AntecollisL-dopa induced fixed orofacial dystonia

Severe dysarthrophoniaJerky action tremorPolyminimyoclonus

Others:Cold hands, Raynaud’s phenomenon

REM sleep behaviour disorder (early sign)New snoring, sleep apnoea

Inspiratory stridor/sighsPisa syndrome

Emotional incontinence (MSA & PSP)

MSA-C Differential diagnosis:Idiopathic late onset cerebellar ataxia

Spinocerebellar ataxia 2, 3, 6Fragile X premutation (FXTAS)

Primary progressive multiple sclerosis

PAF Premotor MSA

RBD - +

ED + +

UD + +

OH + +

RD/Stridor - +

Smell + - / +

Pure Autonomic Failure Vs. Premotor MSA

Prospective f/u of MSA patients for 2 years:

N = 141 (38% MSA-C); moderately severe

Mixed parkinsonism and cerebellar signs in majority of cases

Mean age of onset = 56.2 years

Median survival = 9.8 years (95% CI 8.1 – 11.4)

Unified MSA Rating Scales (UMSARS)

Prospective f/u of MSA patients for 2 years:

N = 141 (38% MSA-C); moderately severe

Mixed parkinsonism and cerebellar signs in majority of cases

Mean age of onset = 56.2 years

Median survival = 9.8 years (95% CI 8.1 – 11.4)

Unified MSA Rating Scales (UMSARS)

Independent predictors of disease duration in MSA

Milestones of disease progression and total disease course

Early autonomic dysfunctionOlder age of onset

Not admitted to residential care

53% of 83 MSA cases developed autonomic dysfunction within 2

years

MSA ‘Variants’

Classical:MSA-PMSA-C

Long Duration

MSA

Minimal Change

MSA

MSA with Cognitive

Impairment

Case 1 (UK) Case 2 (UK) Case 3 (UK) Case 4 (Canada) Mean

Age at onset 62 50 48 43 50.8

Disease duration 15 17 19 18 17

Initial presentation

Parkinsonism

(Lt hand rest tremor)

Parkinsonism

(Lt hand slowness)

Parkinsonism

(Lt hand rest tremor)

Parkinsonism

(Rt foot and hand tremor)

 

Latency to autonomic dysfunction

11 years

(UI)

9 years

(UI)

11 years

(UR)

14 years

(OH)11.3

Cerebellar symptoms (latency in years)

No No No Ataxic gait and limbs dysmetria

(14) 

“Red flags” latency

(latency in years)

Antecollis (8)

Antecollis (8)

Inspiratory stridor (6)

Dysarthria (10)

Antecollis (9)

Dysphagia (9)

Inspiratory stridor (14)

Dysphagia (16)

Myoclonus (17)

9

I Petrovic, H Ling, Y Asi et al. Mov Disord. 2012

MSA-P with slow progression: A diagnostic catch

Clinical characteristics:

Late onset autonomic dysfunction

All had Ldopa-induced generalised choreiform dyskinesia despite limited motor benefit

MSA-P with slow progression: A diagnostic catch

I Petrovic, H Ling, Y Asi et al. Mov Disord. 2012

Slow progression MSA

Classic MSA

Pathological findings:

• Neuronal loss in substantia nigra & locus coeruleus

• Glial cytoplasmic inclusions - widespread

Y Asi, H Ling, I Petrovic et al. Manuscript under review.

Minimal Change MSA

Case 1 (UK) Case 2 (UK) Case 3 (UK) Case 4 (Canada)

Age at onset 62 50 48 43

Disease duration 15 17 19 18

Cognitive impairment (latency in years)

No NoMCI (12)

Dementia (17)MCI (15)

Petrovic et al. MDJ 2012, Asi and Ling et al, 2014 under review

MSA-P with slow progression:

2 out of 4 cases had cognitive impairment

Summary:

• Diagnostic accuracy of MSA - 75%

• Early autonomic dysfunction and older age of onset are

poor prognostic factors

• A subgroup of MSA-P may have very long disease duration

for up to 19 yrs and autonomic dysfunction only occurs in

the second decade

• Minimal change MSA – a unique subgroup which may

represent early MSA pathology

• Cognitive impairment can be a feature in up to 30% of cases

Acknowledgements

• Janice Holton• Yasmine Asi• Igor Petrovic• Andrew Lees• Niall Quinn• Zeshan Ahmed• Tetsutaro Ozawa• Tamas Revesz• Henry Houlden• John Hardy• Nadia Magdalinou• Atbin Djamshidian• Alastair Noyce

• Sean O'Sullivan• Luke Massey• Linda Parsons• Susan Stoneham• Robert Courtney• Kate Strand• Iliyana Komsiyska• Tammaryn Lashley• Queen Square Brain Bank• Patients and family

Acknowledgements