Niall Quinn

Professor of Clinical Neurology

UCL IoN & NHNN Queen Square London UK

“Decade of the basal ganglia”

1960 Shy Drager syndrome

1961 Striatonigral degeneration

1961 Birkmeyer & Hornykiewicz; Barbeau : L-dopa

1964 Steele-Richardson-Olszewski : PSP

1967 Hoehn & Yahr

1967 Cotzias : L-dopa

1968 Rebeiz : CBD

1969 Graham & Oppenheimer : MSA

MSA - neuropathology

Cell loss &/or gliosis in:-

striatum (mainly posterior putamen)

substantia nigra, locus coeruleus

inferior olives

pontine nuclei, middle cerebellar peduncles

cerebellar Purkinje cells

intermediolateral cell columns, Onuf’s nucleus

plus

-synuclein positive

oligodendroglial cytoplasmic inclusions (GCIs)

1989 Papp-Lantos bodies J Neurol Sci 94: 79-100

1998 GCIs stain positive for

alpha-synuclein Spillantini et al Neurosci Lett 251: 205-8

Is MSA primarily a glial disease ?

1989 - First set of diagnostic criteria for MSA

2008 - Second consensus criteria

Probable MSA

Autonomic failure

plus

Poorly levodopa- or Cerebellar syndrome

responsive parkinsonism

Gilman S et al. Second consensus statement on the diagnosis of

multiple system atrophy Neurology 2008; 71: 670–676

2008 - Second consensus criteria

Possible MSA

MSA-P MSA-C Parkinsonism Cerebellar syndrome

plus plus

Autonomic dysfunction Autonomic dysfunction

plus one of : Cerebellar syndrome Parkinsonism

Rapidly progressive parkinsonism

Postural instability in 3 years

Dysphagia in 5 years

Poor levodopa response

Stridor

Pyramidal signs

--------------------------------------------------

MRI atrophy of:

Putamen/MCP/pons/brainstem/cerebellum Putamen/mcp/pons

FDG hypometabolism in:

Putamen/brainstem/cerebellum Putamen

SPECT/PET

igrostriatal DA denervation

MCP=middle cerebellar peduncle

Clinical features

MSA

Survival - median 7-9 (max 19) years

Aetiology - unknown, very rarely familial,

no alpha-syn genetic abnormalities found

Prevalence – approx 5/100,000

(versus 150/100,000 for PD)

i.e. 1 for every 30 PD

Age ranges (years)

81-85

76-80

71-75

66-70

61-65

56-60

51-55

46-50

41-45

36-40

31-35

Missing

Co

un

t

70

60

50

40

30

20

10

0

Age at onset

NNIPPS

PSP (n=363) : 63.5 years

MSA (n=403) : 57.4 years

EMSA-SG

MSA (n=361) : 57.4 years

PSP MSA

(n=363) (n=403)

Falls and <1 year 50% 23%

instability <3 years 79% 45%

Falls or <1year 59% 33%

instability <3 years 82% 60%

NNIPPS study

Bensimon G et al.

Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study

Brain 2009: 132 ;156–171

Autonomic failure NHNN NAMSA-SG EMSA-SG

n=100 n=87 n=412

OH - - 71%

Symptomatic

OH

68%

- 57%

Syncope 15% (x 3) 41% 30%

Incontinence 71% 88% 76%

Retention 27% - -

Incomplete

emptying

- 80% 54%

MED 95% 93% 86%

PARKINSONISM CEREBELLAR PYRAMIDAL URINARY

YRS BEFORE

DIAGNOSIS

IMPOTENCE AUTONOMIC

Genitourinary dysfunction in multiple system atrophy

Beck RO et al. Genitourinary

dysfunction in multiple system

atrophy: clinical features and

treatment in 62 cases. J Urol.

1994;151(5):1336-41.

WOMEN

MEN

Parkinsonism in 100 cases of clinically diagnosed MSA

Total 91%

Akinesia/rigidity 91%

Tremor absent in 34%

present in 66%

at rest 29%

classical pill-rolling 9%

postural 47%

action 20%

(more than 1 type may be present in 1 patient)

Wenning at al Brain 1994; 117: 835-845

Levodopa response in MSA-P

Initial Best Last

Excellent 20% 29% 13%

or good

Moderate 80% 71% 87%

or poor

2008 Second consensus criteria -

a problem with probable MSA

Autonomic failure

plus

Poorly levodopa- or Cerebellar syndrome

responsive parkinsonism

But - many MSA patients show

reasonable response early on

Cerebellar signs in 100 cases of clinically

diagnosed MSA

Limb ataxia 47%

Intention tremor 13%

Gait ataxia 37%

(Postural instability 93%)

Nystagmus 25%

Pyramidal signs in 30%

but : no frank pyramidal weakness

no scissoring of gait

RBD Common in both MSA & PD (more in MSA),

so unhelpful in separating MSA-P from PD,

but may help separate MSA-C from other cerebellar

AF (OH) Common in both MSA & PD (more in MSA),

so less helpful in separating MSA-P from PD,

but may help separate MSA-C from other cerebellar

Olfaction Typically normal in MSA, but impaired in PD

• Orofacial dystonia

• Disproportionate antecollis

• Camptocormia +/or Pisa syndrome

• Contractures

• Inspiratory sighs

Supporting features :-

• Severe dysphonia

• Severe dysarthria

• New/increased snoring

• Cold hands/ feet / nose/ ears

• Pathological laughter/crying

• Jerky myoclonic tremor

EMSA-SG “red flags” versus PD

• Early instability*

• Rapid progression*

• Pisa syndrome / disproportionate antecollis

• Stridor / sighs

• Severe dysphonia / dysarthria / dysphagia*

• Emotional incontinence*

2 out of 6 : specificity 98.3%, sensitivity 84.5%

* also features of PSP

Kollensperger M et al. Red flags for Multiple System Atrophy. Movement Disorders 2008; 23: 1093–1099

• Classic pill-rolling tremor

• Clinically significant neuropathy

• Hallucinations not induced by drugs

• Onset after age 75

• Family history of ataxia/parkinsonism

• Dementia (DSM)

• White matter lesions suggesting MS

Non-supporting features :-

“Red flags”

“Wheelchair sign”

Clinically diagnosed MSA = 169

Path confirmed MSA = 126

(PPV: 75%)

Other path Dx:

PD = 23 (14%)

PSP = 10 (6%)

CBD = 0

VaD = 3

Others = 7

Path confirmed MSA = 165

Correct clinical diagnosis = 128

(Sensitivity: 77%)

Other clinical Dx:

PD = 22 (13%)

PSP = 9 (5%)

CBS = 1

Others = 5

Diagnostic accuracy of MSA is about 75%

Queen Square Brain Bank Archival

Collection 1989 – 2013 (Total = 1870 cases)

Courtesy of Helen Ling, QSBB

When DLB, PD and PSP masquerade as MSA :

an autopsy study of 134 patients

83 (62%) had correct MSA diagnosis at autopsy

51 (38%) had non-MSA :-

19 DLB

8 PD

15 PSP

9 others

(2 CBD, 2 vasc P, 5 misc)

Koga S et al Neurology 2015; 85: 404-412

Female, age 45, seen May 2015

3 yrs – UTIs, urgency, nocturia, incontinence & increased RV,

RBD, unsteady, falls

1 year – Freezing of gait, increased snoring, inspiratory sighs,

dysarthria, dysphagia, limb rigidity, finger twitching

Abn DaT, normal MRI

Current- Pads day & night, double micturition

Falls once a week

On rising, unsteady and dizzy, no vertigo , no syncope,

occ blurred vision / coathanger symptom

O/E - Quivering strained high-pitched hypophonic speech,

saccadic pursuit, antecollis, Pisa syndrome, hand myoclonus,

poor circulatory return, bilateral d/d/kinesis & dysmetria in

arms, heel-shin ataxia, marked akinesia & rigidity, extensor

plantars

Current:- Pads day & night, double micturition

Falls once a week

45 yo woman

April 2015 – Admitted to hospital for autonomic tests :-

Standard battery

Postprandial study

Plasma adrenaline and noradrenaline

24-hr ambulatory BP and HR profile

Conclusion :-

“She has evidence of autonomic failure and at this stage,

although PD with AF cannot be excluded, the clinical

features and autonomic findings do not exclude MSA

Ideal to review her in 3 or 4 months”

Investigations (1)

• Measure BP lying & after 3mins standing

(actually part of the physical exam)

• Measure post-micturition residual volume

• MRI brain scan – mainly to exclude other things

• These are usually the only investigations needed!

Normal MSA PSP

Putamen:

Lateral hyperintense slit

Posterior hypointensity

Atrophy

Pons:

“Hot cross bun”, MCP hyperintensity

(Ideally do T2* and DWI if you can)

Investigations (2)

• DaT scan - only in some MSA-C cases

• OH /AFTs alone can’t separate PD+AF from MSA+AF

but may help separate MSA-C from SAOA

• Sphincter EMG - abnormal result unhelpful in MSA-P vs PD

but may be helpful in MSA-C vs other crerebellar

• MIBG scan - typically normal in MSA, abn. in PD

• (FDG-PET)

“MSA speech”

Very characteristic

“Diagnosis over the telephone”

Typically croaky, quivery (partly myoclonic),

strained, high-pitched

& (sometimes severely) hypophonic

Slurred in MSA-C

Management I

Parkinsonism L-D, (?agonist), amantadine

STN stim*, grafts don’t help

Spasticity Baclofen

Bladder Peripheral a/cholinergics, i.s.c.

Impotence Sildanefil etc

Postural faintness High salt intake, head-up tilt at night,

elastic support stockings, etc

Fludrocortisone/ephedrine/midodrine

/L-threo-DOPS

Stridor CPAP/cord lateralization/tracheostomy

Antecollis Prismatic spectacles, (botulinum toxin)

Myoclonus Clonazepam/valproate/levetiracetam

Depression / Tricyclic/SSRI

emotional incontinence

* Only if levodopa-responsive

Management II

Dietician Diet

Speech & swallowing Advice, amplifiers,

therapist communication aids,

+ n/g tube or PEG

Continence nurse

Occupational therapist Home visit

Physiotherapist Wheelchair assessment

Palliative care MSA Trust helpline & nurses