1. Dr Helen Ling Queen Square Brain Bank for Neurological Disorders Institute of Neurology University College London Clinical aspects of MSA 2 nd UK MSA Research Meeting

2. 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 sign Stridor MSA-P: Rapidly progressive parkinsonism Poor L-dopa response Postural instability <3yrs of onset Cerebellar signs Dysphagia <5yrs of onset MRI: atrophy of putamen, pons, cerebellum FDG-PET: hypometabolism in putamen, brainstem, cerebellum MSA-C: Parkinsonism MRI / FDG-PET findings DAT-SPECT: reduced uptake Definite MSA:

3. MSA-P ‘Red flag’ features supportive of MSA: Rapid progression (wheelchair) Antecollis L-dopa induced fixed orofacial dystonia Severe dysarthrophonia Jerky action tremor Polyminimyoclonus Others: Cold hands, Raynaud’s phenomenon REM sleep behaviour disorder (early sign) New snoring, sleep apnoea Inspiratory stridor/sighs Pisa syndrome Emotional incontinence (MSA & PSP)

4. MSA-C Differential diagnosis: Idiopathic late onset cerebellar ataxia Spinocerebellar ataxia 2, 3, 6 Fragile X premutation (FXTAS) Primary progressive multiple sclerosis

6. PAFPremotor MSA RBD-+ ED++ UD++ OH++ RD/Stridor-+ Smell+- / + Pure Autonomic Failure Vs. Premotor MSA

7. 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)

8. 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)

9. Independent predictors of disease duration in MSA Milestones of disease progression and total disease course Early autonomic dysfunction Older age of onset Not admitted to residential care 53% of 83 MSA cases developed autonomic dysfunction within 2 years

10. MSA ‘Variants’ Classical: MSA-P MSA-C Long Duration MSA Minimal Change MSA MSA with Cognitive Impairment

11. Case 1 (UK)Case 2 (UK)Case 3 (UK)Case 4 (Canada)Mean Age at onset6250484350.8 Disease duration 1517191817 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 Ataxic gait and limbs dysmetria (14) “Red flags” latency (latency in years) 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

12. 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

14. Pathological findings: Neuronal loss in substantia nigra & locus coeruleus Glial cytoplasmic inclusions - widespread

15. Y Asi, H Ling, I Petrovic et al. Manuscript under review. Minimal Change MSA

18. Case 1 (UK)Case 2 (UK)Case 3 (UK)Case 4 (Canada) Age at onset62504843 Disease duration15171918 Cognitive impairment (latency in years) No MCI (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

19. 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

20. 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