Atypical Parkinsonian Disorders Irene Litvan, M.D. Tasch Professor in PD Research University of California San Diego, USA Disclosures • Member of Advisory Board of: – Pfizer, TEVA, MERZ, ACADIA • Consultant: – Biotie & UCB • Research: – Michael J Fox Foundation, NIH, CurePSP, CBD Solutions, TEVA, Parkinson Study Group Outline • Definition • Clinical Features of APD • Diagnosis of PSP, MSA, CBD and VaD • Laboratory Studies • Management Early & accurate diagnosis is important for: • appropriate management • prognosis • clinical research PARKINSONIAN DISORDERS NEURODEGENERATIVE ATYPICAL DISORDERS SPORADIC SECONDARY LEWY BODY DISEASE FAMILIAL FAMILIAL SCA DLB CBD PSP MSA FTD-PRGR FTD-UI PD FTDP-17 FTDP-C9ROF72 PSP, progressive supranuclear palsy; CBD, corticobasal degeneration; MSA, multiple system atrophy; DLB, dementia with Lewy bodieES; FTDP-17, Frontotemporal dementia associated with parknsonism and chromosome 17 abnormalities; FTD-PRG, frontotemporal dementia with progranulin mutatations; FTD-UI, Frontotemporal dementia with Ubiquitin Inclusions; PD, Parkinson’s disease; SCA, spinocerebellar atrophies Tau α-synuclein TDP-43 Ataxin/Tatabox-Binding Protein Clinicopathologic studies show: • 50-70% of the patients with CBD are never diagnosed by their primary neurologists • Only 75% of the PSP pts are ever clinically diagnosed by specialists • Diagnosis: at half course of the disease Nelson et al., 2010; Lopez et al., 1999; Litvan et al., 1997; Litvan et al. 1998 Atypical Parkinsonism • Akinesia (Hypokinesia &/or Bradykinesia) with either: • Tremor • Rigidity or • Postural & gait instability with • Atypical features for PD (green flags for APD) Green Flags for APD • Limited L-dopa response • Early postural instability/falls • Rapid progression (wheelchair sign) • Supranuclear gaze palsy / saccade abnormalities • Early or severe autonomic features • Cerebellar signs • Early prominent dysphagia/dysarthria • Lower motor neuron / Pyramidal signs • Ideomotor apraxia, aphasia or sensory neglect • Early hallucinations unrelated to Rx • Early cortical or severe frontal dementia L-dopa response Parkinsonism Levodopa Response Present Good & Maintained Present but less optimal PD DLB MSA Absent SCA 2, 17 PSP CBD TDP-43 proteinopathies SCA 3 MSA If L-dopa responsive & no family history: α-synucleinopathy Falls Latency to Falls Onset Short Intermediate PSP (6 months) MSA (2 yrs Wenning et al., 1999 Long CBD (3 years) DLB (4 years) PD (10 years) (Means) Wheelchair sign Possible NINDS/SPSP (PSP-RS) • Gradually progressive disorder • Onset age 40 or later • No evidence of other disease that could explain features OR Supranuclear vertical gaze palsy Slowing of saccades + Prominent postural instability with falls within 1st year of onset Litvan et al., 1996 Less common PSP phenotypes • PSP-Parkinsonism (less than 1/3) • Pure Akinesia • Frontal Dementia • CBS Williams 2008; 2007; O’Sullivan et al., 2008; Kaat et al, 2007; Litvan et al., 1996; 2003; Bergeron et al., 1997; Nakamura & Imai 1997; Imai 1993, 1996 Corticobasal Syndrome CBS Present CBD PSP TDP-43 Absent AD/CJD DLB PD MSA Boeve et al, 1999;Boeve 2000; Chand et al., 2006; Kelley et al., 2007; Spina et al., 2007; Guerreiro et al, 2008;Le Ber et al., 2008; Lopez de Munain et al., 2008; Spina et al., 2010 Oculomotor Disturbances Saccades Abnormal Slow Hypometric SWJ PSP Delayed Initiation ---CBD Normal Hypermetric Nystagmus ---MSA ---PD ---DLB Supranuclear Gaze Palsy Tsuboi et al., 2003 Steele et al., 1992 MSA: Two major presentations • Gradually progressive disorder • Onset age 30 or later • Autonomic failure: - Orthostatic Hypotension - Urinary problems: urgency, frequency, nocturia, and urge incontinence - Erectile disturbances & Parkinsonism (MSA-P) Akinesia, rigidity, tremor, post. Inst. or Cerebellar (MSA-C) Gait/limb ataxia, speech problem Autonomic Dysfunction Present Early MSA Severe DLB Intermediate Absent Late PD Mild PSP CBD FTD-P FTD-TDP43 Urinary Disturbances Neurogenic Bladder Early/Intermediate Peripheral Bladder MSA Late? Spastic/Overactive Bladder MSA PSP PD CBS PD Kabay et al 2009; Brusa et al, 2007; Palleschi et al., 2006; Sakakibara et al., 1993; 2004; Stochi et al., 1997 Urinary Disturbances Latency to Urinary Disturbances Short MSA (1 year) Intermediate DLB (3 yrs) PSP (4.5 yrs) Long CBD (6 yrs) PD (12 yrs) Wenning et al., 1999 MSA-P • Parkinsonism benefits from L-Dopa in 30% of pts • Orofacial/craniocervical dyskinesias/dystonia in 50% • All problems to develop may take 5 years • Differential diagnosis with PSP & PD MSA-C • Gait ataxia • Cerebellar tremor • Scanning speech • Usually develop non-cerebellar problems • Differential diagnosis with idiopathic late onset cerebellar ataxia Cerebellar Disturbances Cerebellar Features Present Axial PSP MSA Absent Limbs SCA MSA PD DLB CBD FTDP 17 FTD-TDP 43 SCA Differences between PSP and MSA • Early, severe autonomic dysfunction • Cerebellar limb and speech dysfunction • Supranuclear gaze palsy/slowing of saccades Vascular Parkinsonism • 2.5-5% of all cases of parkinsonism • Secondary Parkinsonism due to ischemic CVD • Lower body parkinsonism • Postural instability and falls; short shuffling wider base of stance & variable stride length (parkinsonian-ataxic gait) • Frequent pyramidal signs • Early subcortical dementia. • Diffuse white matter lesions and/or strategic subcortical infarcts Work-up: MRI “Hot-cross bun sign” Schrag et al., 2000 Work-up: MRI Oba et al., 2005 • AP-midbrain atrophy ≤13.4 (Warmuth-Metz et al. 2001) or ≤17mm • Dilation of 3rd ventricle Superior cerebellar peduncle atrophy PSP PSP Normal Normal Normal PSP Paviour et al., 2005 MRI in CBD Litvan, unpublished, Tokumaru et al., 2009 Vascular Parkinsonism The underlying anatomic distribution explains the symptomatology & radiological findings Supranuclear vertical palsy T807 Management • Interdisciplinary team approach • Pharmacologic • Motor: Dopaminergic (e.g., Sinemet®, dopamine agonists) • Orthostatic hypotension: Na, fludrocortisone, midrodrine, droxidopa • Neurogenic bladder: (e.g., solifenacin) • Antidepressants • Non-Pharmacologic • Physical Therapy/Weighted walkers • Swallowing techniques (i.e., thickeners, PEG) • Speech therapy / amplifiers • Occupational Therapy • Supportive Therapy/Education • Social Worker Conclusions • Atypical parkinsonian disorders have a spectrum of symptoms/signs, should not be lumped, management and prognosis varies • Symptom duration, knowledge of the various disease presentations and an increased index of suspicion improves diagnostic accuracy • No biological markers, diagnosis relies on clinical features and pathology, but imaging may support the diagnosis Thank you! 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