niall quinn - rcp london
TRANSCRIPT
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