This document summarizes information about multiple system atrophy (MSA). MSA is a neurodegenerative disorder characterized by autonomic failure and motor symptoms. It has an estimated incidence of 0.6-0.7 per 100,000 people per year. Common features include parkinsonism in at least 90% of patients, orthostatic hypotension, and urinary dysfunction in over 80% of cases. The document discusses the types of tremors seen in MSA, respiratory issues like stridor, and prognostic factors like the presence of urinary incontinence which are associated with shorter survival times.

1. Didattica integrativa
31 Maggio 2016
Dott.ssa Giulia Giannini
Tutor: Dott.ssa Giovanna Calandra Buonaura

2.  Neurodegenerative disorder characterized by
autonomic failure with motor involvement of
parkinsonism and/or cerebellar ataxia
 Estimated mean incidence 0,6-0,7 per 100.000 per
year
 Estimated prevalence 3,9 to 4,9 per 100.000 cases
per 100.000 per year, increasing to 7,8 per 100.000
among persons older than 40 years of age

3. Gilman et al. Neurology 2008; 71: 670-6

4. Parkinsonism or
cerebellar syndrome
Parkinsonism
Cerebellar syndrome
Gilman et al. Neurology 2008; 71: 670-6

5. 203 pts reported in 108 articles
35 cases UK Brain Bank

6. 19 centers, 437 pts
12 centers, 87 pts

7. 15 centers, 141 pts

8. 12 centers, 175 pts

10.  Parkinsonism (rigidity, bradykinesia, and postural
instability) occurs in at least 90% of all patients
with MSA
 Often symmetrical akinetic-rigid picture without
tremor
 The motor findings are sometimes asymmetrical
(35-40%)
 Parkinson-like “pill-rolling” rest tremor is unusual,
whereas irregular postural and action tremor with
superimposed jerks is seen in as many as 50% of
patients with MSA

11.  Rest Tremor
 Frequency ranging from
25% to 43%
 More common in MSA-P than in
MSA-C (32-44% vs. 17-26%)
 Pill-rolling rest tremor is
rarely (8-11%)
 Postural Tremor
 The most common tremor
variant among MSA
(28-67%)
 More common in
MSA-P than in MSA-C
(47-55% vs. 22%)

13.  Jerky irregular tremor/ Minipolymyoclonus
Jerky/ irregular
tremor
Myoclonus
Wenning et al. 1994 20% of MSA-P 31% of patients (45% in
MSA-P vs. 33% in MSA-C)
Rodriguez et al. 1994 23/24 MSA-C patients
Gouider-Khouja et al.
1995
55% of MSA-P 16.6% of MSA-P
Wenning et al. 1995 29% of patients

16. o 9 out 11 MSA-P patients presented abnormal, small-amplitude,
nonrhythmic movements of the fingers or hands when holding a
posture or at the beginning of an action;
o Involvement of proximal arm segments, leading to larger jerks,
occurred only occasionally
o During maintenance of a posture, external stimuli such as
cutaneous pinprick with a sharpened object or passive sudden
stretch elicited reflex jerks in all 9 patients
o Neurophysiological investigations have demonstrated that jerky
postural tremor in MSA consists of small-amplitude irregular
oscillations with no predominant peak in the fast Fourier frequency
spectrum analyses
Minipolymyoclonus

17. o Jerky tremor, defined as “irregular postural or action tremor of the
hands and/or fingers with stimulus-sensitive myoclonus” is a
feature that appears more often in MSA-P than in PD (47.4% vs.
5.9% of patients, respectively)
o Supporting feature of MSA (94.1% specificity, p value <0.001)

18.  Variant atypical or jerky components have been
reported
 the classic parkinsonian (pill-rolling) rest tremor
is only present in a minority of patients
 Pill-rolling rest tremor supports a diagnosis of
PD.
 Intention tremor points away from PD but is
typical in MSA, especially MSA-C (up to 45% of
patients).
 Tremor of the legs, head, chin, lips, and tongue
can be found in PD but are all uncommon in MSA.

22. 16 MSA-P vs. 31 PD
patients

24. 28.6% annual increase of UPDRS-III scores in MSA
 (0.6%-4.1% in PD)

32. o Speech is more severely affected in MSA than in PD
o Speech impairment in MSA patients is probably multifactorial, related
to laryngeal dysfunction, akinesia/rigidity of lips/tongue and palate,
and respiratory dysfunction
o As well as the low volume monotony of parkinsonism, a croaky,
quivering, irregular, severely hypophonic or slurring dysarthria is often
characteristic

33.  Intentional Tremor
 Frequency ranging from
11% to 39%
 More common in MSA-C
than in MSA-P
(33-45% vs. 11-28%)

37. Objective: to prospectively investigate the frequency of dystonia and
its relation to levodopa treatment in a group of 24 patients with MSA
(18 MSA-P, 6 MSA-C)
Dystonia before levodopa treatment
Dystonia 11 (46%) patients
Anterocollis 6 (25%) patients, 4 MSA-P and 2 MSA-C
Unilateral limb dystonia 5 (21%) patients, 4 MSA-P and 1 MSA-C
o 12 (80%) MSA-P patients developed dyskinesias after the initiation of
levodopa therapy (on avarage 2.3 years after therapy)
o Levodopa induced dyskinesias were predominantly or purely dystonic
o Most patients had peak dose craniocervical dystonia

43.  Symptomatic dysautonomia is present in 95-99%
 OH symptoms (43-75%), documented OH (56.7-78%),
syncope (19-41.4%)
 Urinary symptoms (83-96%) Urge incontinence (55-87%),
incomplete bladder emptying (72-83%),
 Erectile dysfunction (93-96% male patients)
 Constipation (58-87%)
 Sudomotor disturbances (anhidrosis)

44. 121 MSA patients

45. Early stage=
detrusor hyper-
reflexia with
bladder neck
incompetence due
to abnormal
urethral sphincter
dysfunction (urge
incontinence)
Late stage=
reduced detrusor
hyper-reflexia ,
bladder become
atonic increasing
post-micturition
residual-urine
volumes

46.  Probable MSA: a decrease of blood pressure within 3 min of
standing by at least 30 mm Hg systolic or 15 mm Hg diastolic
 Possible MSA: significant orthostatic blood pressure decline that
does not meet the level required in probable MSA
 Orthostatic hypotension is a sustained reduction of systolic blood
pressure of at least 20 mmHg or diastolic blood pressure of 10
mmHg within 3 min of standing or head-up tilt to at least 60 on a tilt
table. Orthostatic hypotension is a clinical sign and may be
symptomatic or asymptomatic (Freeman et al. 2011)

48. Controllo, 65 anni, maschio
MSAp, 74 anni, maschio

51. Lipp et al 2009
Iodice et al 2012

52.  Reduced sleep efficiency and fragmented sleep
 RBD
 Stridor
 OSAS (new or increased snoring is a red flag)
 Other sleep-related breathing disorders: central
apnea, tachypnea and paradoxical breathing

54. OR of pRBD in MSA vs. PD  3.29

56. RBD

59.  A harsh high-pitched respiratory sound,
almost always occurring during inspiration
due to a laryngeal narrowing
 Typically in MSA occurs during sleep
 One of the additional features for the
diagnosis of possible MSA
 Stridor prevalence (12-41%)
 Higher diagnostic positive predicted value
than clinical diagnosis at first visit (PPV:
100%; CI-34-100)
Inspiratory sights

62.  Abnormal sleep structure in MSA patients,
with reduced NREM deep sleep and
decreased sleep efficiency.
 Patients with stridor, already tachypnoic
during Wake, MSA patients had a significant
increase in breathing rate from Wake to
NREM and REM sleep.

67. The best compromise score is 11 or more out 17,
with a sensitivity of 90.3% and specificity of 92.6%

68. The repeat analysis using the features that were recorded within
the first 5 years after onset of symptoms, identified four
variables as significant predictors with the following
Weightings:
- autonomic features present (2),
- poor initial response to levodopa (2),
- early fluctuations (2),
- initial rigidity (2).
A patient could therefore score between 0 and 8:
a cut off of >4 results in a sensitivity of 87.1% and
specificity of 70.5%.

69. 57 probable MSA-P vs. 116 with probable PD
matched for age, sex and disease duration

70. 98.3% specificity and 84.2% sensitivity
PPV of 96% and NPV of 92.7% if red flags from 2 or more categories were present
When applying these criteria to patients with possible MSA-P, 76.5% of them
would have been correctly diagnosed as probable MSA-P
(16 months earlier than with criteria)

72.  Cerebellar onset: SCA 1,2,3,6,7,12,17;
fragile-X-associated tremor ataxia syndrome;
sporadic adult-onset ataxia of unknown origin
 Parkinsonian onset: PD o MSA?
 Autonomic onset: PAF o MSA o PD?

73. o Esordio P
Test l-Dopa
Test NPS
o Esordio C
SPECT DatScan
Indagini genetiche
(SCA, X-fragile)
RM encefalo

74. o RBD VPSG
o Stridor
o Disturbi respiratori VPSG
Laringoscopia

75. Autonomic Onset
OH test
RCV
Scintigrafia
miocardica
con MIBG
OH neurogena
Holter PA
Valutazione residuo
vescicale
Prove urodinamiche

76.  FDG-PET
 Biopsia di cute
 Ricerca Ab. per escludere Sd paraneoplastiche
 EMG sfinterica
 RCV con prelievo di catecolamine
 RCV con test farmacologici

78. Univariable regression analysis adjusted for sex and age at symptom onset
identified
- diagnosis of MSA-P ( HR 1,84, 95% CI 1,05–3,25, p=0,034),
- presence of urinary incontinence (HR 2,45, 1,19–5,04, p=0,015),
- presence of incomplete bladder emptying (HR 2,16, 1,08–4,34, p=0,030),
- presence of pyramidal signs (1,60, 0,92–2,79, p=0,099),
- presence of hyperreflexia (2,62, 0,94–2,81, p=0,085),
- higher baseline scores for the UMSARS activities of daily living subscale
(1.04, 1.01–1.07, p=0.021)
as predictors of shorter survival at p<0・1 (the cutoff criterion).
Median survival from symptom
onset as
determined by Kaplan-Meier
analysis was
9.8 years (95% CI 8,1–11,4)
Cox regression model adjusted for age at symptom onset and sex
identified a diagnosis of MSA-P (HR 2.08, 95% CI 1.09–3.97, p=0.026) and the
presence of incomplete bladder emptying (2.10, 1.02–4.30, p=0.044)
as the strongest predictors of shorter survival.

79. Participants with severe
symptomatic autonomic failure
at diagnosis (n=62) had a worse
prognosis than those without
severe disease (n=113):
8·0 years, 95% CI 6·5–9·5 vs 10·3
years, 9·3–11·4 (p=0·021).

84. VARIABLE n Unadjusted HR (95% CI) p-value
Age at disease onset 136 1.01 (0.98-1.04) 0.431
Sex
Female 48 0.93 (0.63-1.37) 0.701
Male 88 1.0 (reference)
Clinical phenotype
MSA-P 68 0.92 (0.64-1.34) 0.676
MSA-C 68 1.0 (reference)
Symptom of disease onset
Autonomic 78 1.48 (1.00-2.20) 0.049
Cerebellar 47 0.91 (0.61-1.36) 0.655
Parkinsonism 44 1.02 (0.69-1.52) 0.910
Symptom of autonomic onset
OH / Symptomatic OH 32 1.56 (0.99-2.45) 0.056
Urinary dysfunction 92 1.0 (reference)
Stridor (VPSG)
Yes 42 1.20 (0.80-1.81) 0.386
No 78 1.0 (reference)
NA 16

85. Survival analysis in patients
with and without stridor
Survival analysis in patients with
early and late stridor onset
p= 0.3467 p= 0.0209
At the multivariable COX model the early stridor onset remained
an independent predictor of mortality (HR= 3.21, p= 0.006)

86. Grazie per
l’attenzione !!!