Parkinsonismi (Atipici ?):inquadramento clinico

Seminario UNIVA, 3 Luglio 2013, Lamezia Terme

Paolo BaroneCenter for Neurodegenerative Diseases

University of Salerno, Italy

Le sindromi parkinsoniane

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 (?)

parahydroxybenzoate-polyprenyl transferase

CoQ10

2013

Homozygous mutation (M78V-V343A/M78V-V343A) and

compound heterozygous mutations (R337X/V343A) in COQ2

in multiplex families

Impaired variants in COQ2 are associated

with an increased risk of sporadic disease

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

European MSA-SG Registry

Clinical presentation

Age at disease onsetWenning et al, Brain 1994

Colosimo, Nat Rev Neurol 2011

Glass PG et al, Mov Disord 2012

L’iposmia può differenziare MSA e PD

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

Gilman et al, J Neural Transm 2005

• 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

Risposta alla levodopa nell’MSA

Colosimo et al, 2005

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

Wenning et al, submitted

Caveat: La disautonomia nell’ MSA può comparire

molto tardivamente

Petrovic et al, Mov Disord 2012

(4 casi di MSA confermati antomo-patologicamente)

Petrovic et al, Mov Disord 2012

Clarke D et al, Curr Opin Ophthalmol. 2012

Movimenti oculari nei parkinsonismi

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

Richardson’s syndrome vs. PSP-P:

Disease duration

p=0.446

p<0.001

Age at death 72.2 75.2 p=0.032

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

CONTROL

CONTROLCONTROL

Quadri et al, 2013

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

Case #1: diagnosis

Case #2: diagnosis

“My left hand goes first...”

“Is your hand moving?”

“No...”

Case #3: diagnosis

Case #4: diagnosis

Case #5: diagnosis

Case #5: diagnosis

CORTICO BASAL SYNDROME

(Boeve BF, 2011)

Stamelou, Mov Disord 2013

Aerts MB et al, Practical Neurology 2012

Stamelou, Mov Disord 2013

Stamelou, Mov Disord 2013

Lee W et al, Mov Disord 2012

Lipp et al, Arch Neurol 2009

Lipp et al, Arch Neurol 2009

68 MSA patientsFollow-up: 10 months

Damon-Perriere et al, 2012

Pinkhardt EH et al, J Neurol 2009

Target

Saccadi anticipatorie

Rappresenta il rapporto tra il

movimento reale e quello aspettato

(quanto è più vicino al volare unitario,

tanto più il movimento è continuo)