Atypical parkinsonism
Wassilios Meissner
Service de neurologie et CMR atrophie multisystématisée, CHU de Bordeaux Institut des Maladies Neurodégénératives, Université Bordeaux 2, CNRS UMR 5293 Parkinsonism
?
If it’s not PD, what else could it be? No Yes
Parkinson’s disease Atypical parkinsonism
Progressive Corticobasal Multiple system Lewy body supranuclear degeneration atrophy (MSA) dementia palsy (PSP) (CBD) MSA - clinical signs
• Asymmetrical parkinsonism, weak l-dopa response • Cerebellar dysfunction • Autonomic failure • Pyramidal tract signs • Rapid progression (« wheel chair sign » ≤ 5 years) GCIs in MSA
Lewy bodies in PD
Spillantini et al., 1997; Lashuel et al., 2013 MSA - motor signs
• L-dopa induced orofacial dyskinesias (risus sardonicus) • Axial dystonia (Pisa syndrome, camptocormia)
• Disproportional antecollis • Early postural instability with falls • “Jerky tremor” • Early dysphagia and/or dysarthria MSA - non motor signs
• Emotional instability • Autonomic failure - OH, urinary dysfunction, constipation, Raynaud syndrome • Sleep disturbances - RBD, respiratory, stridor
Consensus diagnosis criteria
• Diagnosis of MSA-P and MSA-C with 3 degrees of certitude • Inclusion of additional signs (clinical, imaging)
Gilman et al., 2008 Paraclinical investigations - MRI
• Hypersignal of lateral putaminal border • Hypointensity of postero-latéral putamen (T2, T2*) • Hypersignal of middle cerebellar peduncles (PCM) • “Hot cross bun sign” • Atrophy of cerebellum, pons and PCM Urinary dysfunction - differences between PD and MSA
Sakakibara et al., 2001 Hahn and Ebersbach, 2004 Pathophysiology of cardiovascular autonomic failure
Freeman, 2008 Evaluation of cardiovascular autonomic failure MIBG SPECT
PD MSA
MIBG uptake is reduced in PD indicating postganglionic denervation.
Braune et al., 1999 Evaluation of cardiovascular autonomic failure Ambulatory blood pressure monitoring
Night period
Neurogenic orthostatic hypotension and supine hypertension in chronic CV autonomic failure.
Courtesy Dr A. Pavy-Le-Traon, Toulouse Evaluation of cardiovascular autonomic failure Ewing test 1. Deep respiration
Pavy-Le Traon and Valensi, 2008
2. Standing test (blood pressure + 30/15 index) Physiological response Neurogenic orthostatic hypotension BP HR
Wieling, 1997 Courtesy Dr A. Pavy-Le-Traon, Toulouse Treatments
• Motor signs L-dopa, amantadine DBS = no Focal dystonia (limbs): botulinum toxin
• Orthostatic hypotenion Nonpharmacologic interventions Midodrine, fludrocortisone (mestinon, EPO, droxidopa)
• Urinary dysfunction Anticholinergics, (alpha-adrenergic antagonists) Desmopressine Intermittent catheterization Active immunization against α-synuclein with Affitope® PD01 and PD03 in MSA
Tailored Antibodies
Original
Mimotope / AFFITOPE®
http://www.sympath-project.eu Progressive supranuclear palsy
Clinical signs • Axial parkinsonism, weak l-dopa response • Early postural instability and falls • Vertical gaze palsy • Early cognitive dysfunction (apathy, executive dysfunction)
Intraglial tau inclusions
Burn et al., 2002 Clinical spectrum of PSP
Williams and Lees, 2009 Clinical spectrum of PSP
Williams and Lees, 2009 New consensus diagnosis criteria
Hoeglinger et al., 2017 New consensus diagnosis criteria
Hoeglinger et al., 2017 Paraclinical investigations - MRI
Control PSP MSA
• Midbrain atrophy (diameter<17mm) • “Mickey mouse sign” • “Hummingbird sign” • “Morning glory sign” • Pallidal and putaminal atrophy • Atrophy of sup. cerebellar peduncle
Schrag et al, 2001; Oba et al., 2005 Paraclinical investigations - MRI
Index midbrain/pons
For an index < 0.015, sensitivity and specificity are 100% for the diagnosis of PSP.
Oba et al., 2005 Paraclinical investigations - pTau PET
Kepe et al., 2013 Treatment pipeline
Two large trials have started in 2017 and test the efficacy of antibodies directed against tau protein. Corticobasal degeneration
Clinical signs • Asymmetrical parkinsonism, weak l-dopa response • Myoclonus, distal dystonia • Apraxia, aphasia, cortical sensory deficit • “Alien hand syndrome” Intraneuronal and intraglial inclusions of tau protein
Mahapatra et al, 2004 The clinical phenotypes of CBD
Armstrong et al., 2013 Paraclinical investigations – MRI
Koyama et al, 2007 Take home messages
• The differential diagnosis between atypical parkinsonian disorders can be difficult in early disease. Recent progress in imaging provides help in some cases.
• Screening for red flag signs is key. They can sometimes emerge after several years.
• Treatments are available for some symptoms, while disease-modifying strategies remain an unmet need.