parkinsonismi (atipici ?): inquadramento clinico · parkinsonismi (atipici ?): inquadramento...
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Parkinsonismi (Atipici ?):inquadramento clinico
Seminario UNIVA, 3 Luglio 2013, Lamezia Terme
Paolo BaroneCenter for Neurodegenerative Diseases
University of Salerno, Italy
Segni che suggeriscono un parkinsonismo atipico
Motori• instabilità precoce con cadute• rapida progressione• risposta alla levo-dopa assente,
povera, non mantenuta• segni piramidali• segni cerebellari• disartria e disfagia precoci
Oculomotori• paralisi sopranucleare• rallentamento dei saccadici• difficoltà ad iniziare i saccadici
Cognitivo-comportamentali• demenza precoce• allucinazioni visive non indotte da
trattamento• aprassia• disturbi corticali sensitivi
Vegetativi• disturbi vegetativi precoci non
imputabili al trattamento (ipotensione ortostatica, impotenza, disturbi urinari)
Parkinsonismi Atipici: criteri diagnostici
• MSA: Gilman et al. - J. Neurol. Sci. 1999-
Gilman et al- Neurology 2008
• PSP: Litvan et al. - Neurology 1996
• CBD: Litvan et al. - Neurology 1997
• DLBD: McKeith et al. - Neurology 2005
Classification of parkinsonian syndromes in a community
• Idiopathic PD ~ 85% of all PS cases
• Drug-induced parkinsonism (DIP) 7% - 9%
• MSA-P ~ 2.5%
• PSP ~ 2.0%
• Vascular parkinsonism ~ 3%
• PS due to MPTP, CO, Mn, recurrent head trauma is extremely rare
• No new cases of postencephalitic parkinsonism since l960s
PD 422
MSA 75
PSP 69
Other 123
Queen square BRAIN BANK (UK): 1989-1999
Total parkinsonian brains = 689
Patologie Rare: problema di denominazione
MSA Schrag et al 1999
• Prevalenza 4.4 10-5
• Incidenza 0.5 10-5/yr
PSP Schrag et al 1999
• Prevalenza 6.4 10-5
• Incidenza 1.14 10-5/yr
Quadro anatomo-patologico
che dovrebbe definire
un gruppo di malattie (ed in vivo ?)
Un segno/sintomo che definisce
una malattia (patognomonico ?)
DCB
Adams et al 1961
SND
Dejerine & Thomas 1900
OPCA
Graham & Oppenheimer 1969
MSA = OPCA = SDS = SND
Spillantini et al 1998
MSA =
α-Synucleino-
pathie
Papp, Kahn,
Lantos 1989
GCI
Shy & Drager 1960
SDS
Fattori di rischio per MSA
• Maggior rischio di MSA per esposizione occupazionale a:– Solventi organici
– Monomeri plastici
– Pesticidi
– Metalli (Nee et al, 1991)
• Abitudine al fumo meno comune negli MSA rispetto ai controlli (Vanacore et al, 2000)
• Genetica– Limitata al Giappone (?)
Homozygous mutation (M78V-V343A/M78V-V343A) and
compound heterozygous mutations (R337X/V343A) in COQ2
in multiplex families
Caratteristiche cliniche della MSA
Parkinsonismo 80% Rigidità Acinesia asimmetrica Tremore a riposo Distonie
Segni cerebellari 40% Coordinazione Atassia marcia Tremore intenzionale Nistagmo
Disturbi vegetativi 96% Impotenza Incontinenza urinaria Ritenzione urinaria Ipotensione posturale Sincopi ricorrenti
Segni piramidali 54% Iperreflessia
Babinski
Dysautonomia Parkinsonism L-Doparesponse(duration)
Ataxia Babinski Hyper-reflexia
Europe 78% 87% 38% (3) 63% 28% 43%
Austria 67% 95% 32% (3) 92% 38% 38%
Denmark 87% 100% 40% (3.5) 53% 27% 33%
England 87% 85% 27% (3) 84% 48% 56%
France 86% 90% 18% (3) 71% 30% 59%
Germany 80% 86% 26% (4) 71% 14% 25%
Israel 78% 86% 55% (3) 56% 59% 37%
Italy 88% 100% 45% (2) 58% 33% 73%
Portugal 46%* 100% 45% (2) 39% 15% 62%
Spain 74% 49%* - 71% 14% 34%
Sweden 87% 80% 67% (5.5) 40% 7% 13%
Clinical presentation in Europe
• Retrospective study
• Mean FU: 2.5 ys
MSA-C MSA-P MSA
N of patients 119 23 142
Autonomic failure 85.7% 82.6% 85.2%
Neurogenic bladder 69.7% 82.6% 71.8%
Orthostatic
hypotension
71.4% 52.2% 68.3%
Cerebellar ataxia 94.1% 52.2% 87.3%
Parkinsonism 15.1% 100% 28.9%
Pyramidal signs 18.5% 8.7% 16.9%
MSA-C MSA-P MSA
N of patients 119 23 142
Autonomic failure 100% 100% 100%
Neurogenic bladder 90.8% 87% 90.1%
Orthostatic
hypotension
90.8% 73.9% 88%
Cerebellar ataxia 100% 69.6% 95.1%
Parkinsonism 42% 100% 51.4%
Pyramidal signs 71.4% 47.8% 67.6%
Neurological findings at first examination Neurological findings at the latest follow-up
Wenning et al, submitted
The Natural History of Multiple System atrophy: A prospective study by the European MSA Study Group
141 MSA patientsMean disease duration: 5.5 ysFollow-up: 2 ys
Annualized D Baseline – Last follow-up
UMSARS Score points Percent change
UMSARS I (ADL) 5.8 (5.9) 28.3%
UMSARS II (ME) 8.7 (8.3) 41.5%
UMSARS Total 14 (12.2) 32.2%
Shorter disease duration and absent levodopa response predicted rapid UMSARS progression
MSA-P and incomplete bladder emptying were strong predictors of shorter survival
Caveat: La disautonomia nell’ MSA può comparire
molto tardivamente
Petrovic et al, Mov Disord 2012
(4 casi di MSA confermati antomo-patologicamente)
0
10
20
30
40
50
60
70
80
90
100
Falls Cognitive
dysfunction
Visual
Sypmtoms
Dysphagia Speech
disturbance
Asymmetric
onset
First 2 years Throughout disease
Frequency of symptoms reported in 103
cases of PSP
0
10
20
30
40
50
60
70
80
90
100
BradyK Tremor Rigidity Impa ired
Postura l
Ref lexes
SNGP Abnorma l
pursuits/
saccades
Limb
dystonia
Pyramida l
signs
L-dopa
response
Dyskinesia
F irst 2 yea rs Throughout disease
Frequency of clinical signs in 103 cases
of PSP
n=25 n=18
0.0
0.2
0.4
0.6
0.8
1.0
2N4R 2N3R 1N4R 1N3R 0N4R 0N3R
Series1 Series2
Richardson’s syndrome vs. PSP-P:
Tau isoforms
R-τ RS PSP-P
2N 4R
2N 3R
1N 4R
1N 3R
0N 4R
0N 3R *
*
*
* p<0.05 RS PSP-P
Typical and “atypical” PSP
Four clinical phenotypes were identified
• Richardson’s syndrome PSP-RS
• Parkinsonism PSP-P
• Pure akenesia with gait freezing PSP-PAGF
• Progressive non-fluent aphasia PSP-PNFA
SPM clearly demonstrated a bilateral frontotemporal hypoperfusion
involving the IFG and the STG. In this patient, a significant
hypoperfusion was also detected in the rectal gyrus of both
cerebral hemispheres.
Supranuclear Palsy (the sign) is
observed in:
• Richardson’s syndrome PSP-RS
• Frontotemporal Lobar Degeneration (MAPT, PGRN, C9ORF72, Dynactin )
• PARK9 (Kufor-Rakeb)
• SYNJ 1
• Cerebrotendinous xanthomatosis (CYP27A1)
• Gaucher’s Disease (GBA)
• Niemann-Pick-C (NPC)
• Various Mitochondrial disorders
• Prion disease (PRNP)
• Whipple Disease
• Cerebrovascular disorders
More typical features in bold
CASO 1, donna di 77 anni
-Esordio a 72 anni con rigidità e dolenzia al braccio dx; A 74 anni cadute
CASO 2, donna di 68 anni
- Esordio a 65 anni con disturbo del linguaggio. Progressione negli anni e comparsa di
sindrome parkinsoniana bradicinetico-rigida.
CASO 3, Donna, 63 anni
- Esordio a 59 anni con rallentamento motorio generalizzato e “limitazione funzionale” del
braccio dx
CASO 4, Donna, 59 anni
- Esordio 9 mesi prima con distonia, movimenti involontari e alterato controllo del braccio sin.
CASO 5, Donna, 74 anni
- Esordio 1 mese prima con alterazione del linguaggio, delle funzioni cognitive e della marcia