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, • 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 pressure monitoring

Night period

Neurogenic orthostatic and supine 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 ( + 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 , (mestinon, EPO, )

• Urinary dysfunction , (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.