Atypical parkinsonism

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1 Atypical parkinsonism Wassilios Meissner Service de neurologie et CMR atrophie multisystématisée, CHU de Bordeaux Institut des Maladies Neurodégénératives, Université Bordeaux 2, CNRS UMR 5293

2 Parkinsonism? No Yes If it s not PD, what else could it be? Parkinson s disease Atypical parkinsonism Multiple system atrophy (MSA) Progressive supranuclear palsy (PSP) Corticobasal degeneration (CBD) Lewy body dementia

3 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

4 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

5 MSA - non motor signs Emotional instability Autonomic failure - OH, urinary dysfunction, constipation, Raynaud syndrome Sleep disturbances - RBD, respiratory, stridor

6 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

7 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

8 Urinary dysfunction - differences between PD and MSA Sakakibara et al., 2001 Hahn and Ebersbach, 2004

9 Pathophysiology of cardiovascular autonomic failure Freeman, 2008

10 Evaluation of cardiovascular autonomic failure MIBG SPECT PD MSA MIBG uptake is reduced in PD indicating postganglionic denervation. Braune et al., 1999

11 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

12 Evaluation of cardiovascular autonomic failure Ewing test 1. Deep respiration 2. Standing test (blood pressure + 30/15 index) Physiological response Neurogenic orthostatic hypotension BP HR Pavy-Le Traon and Valensi, 2008 Wieling, 1997 Courtesy Dr A. Pavy-Le-Traon, Toulouse

13 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

14 Active immunization against α-synuclein with Affitope PD01 and PD03 in MSA Tailored Antibodies Original Mimotope / AFFITOPE

15 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

16 Clinical spectrum of PSP Williams and Lees, 2009

17 Clinical spectrum of PSP Williams and Lees, 2009

18 New consensus diagnosis criteria Hoeglinger et al., 2017

19 New consensus diagnosis criteria Hoeglinger et al., 2017

20 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

21 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

22 Paraclinical investigations - ptau PET Kepe et al., 2013

23 Treatment pipeline Two large trials have started in 2017 and test the efficacy of antibodies directed against tau protein.

24 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

25 The clinical phenotypes of CBD Armstrong et al., 2013

26 Paraclinical investigations MRI Koyama et al, 2007

27 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.

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