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Multiple System Atrophy Tasneem Peeraully, MBBS, BSc1

Medical School, Newark, New Jersey Semin Neurol 2014;34:174–181.

Abstract

Keywords

► ► ► ►

dysautonomia atypical parkinsonism ataxia synucleinopathy

Address for correspondence Tasneem Peeraully, MBBS, BSc, Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Doctors Office Center, Suite 8100, 90 Bergen Street, Newark, NJ 07103 (e-mail: [email protected]).

Multiple system atrophy (MSA) is a rare adult-onset synucleinopathy associated with dysautonomia and the variable presence of poorly levodopa-responsive parkinsonism and/or cerebellar ataxia. Other clinical symptoms that can be associated with MSA include hyperreflexia, stridor, sleep apnea, and rapid eye movement sleep behavior disorder (RBD). Mean survival from time of diagnosis ranges between 6 to 10 years, and definitive diagnosis is made on autopsy with demonstration of oligodendroglial cytoplasmic inclusions consisting of fibrillar α-synuclein. Magnetic resonance imaging (MRI) may be positive for cruciform T2 hyperintensity within the pons (the “hot cross bun sign”), volume loss in the pons and cerebellum, and T2 signal loss in the dorsolateral putamen with hyperintense rim on fluid attenuated inversion recovery (FLAIR) sequencing. Although most cases are sporadic, genetic polymorphisms have been identified both in familial and sporadic cases of MSA, and influence observed phenotypes. Treatment is symptomatic, with both pharmacological and nonpharmacological strategies. There are currently no consensus guidelines on management. Current and future research is aimed at identifying biomarkers and developing disease-modifying therapies.

Multiple system atrophy (MSA) is a rare, adult-onset, neurodegenerative disorder, characterized by autonomic dysfunction and variable combinations of parkinsonism and cerebellar ataxia. Pathologically, there is widespread presence of oligodendroglial cytoplasmic inclusions (GCI) composed of α synuclein within the central nervous system (CNS).1–3 Early in the course of disease, it may be difficult to distinguish between MSA and Parkinson disease (PD). However, MSA follows a different clinical course, and is associated with distinct underlying pathology and neuroimaging findings. Accurate diagnosis is therefore important in strategizing therapy and counseling patients and caregivers.

Epidemiology The annual incidence of multiple system atrophy ranges from 0.6 to 3 per 100,000 people.4–6 One series reported a higher incidence of multiple system atrophy in women than men (4.8 vs. 1.7 per 100,000), whereas another reported no

Issue Theme Atypical Parkinsonian Disorders; Guest Editors, Yvette Bordelon, MD, PhD, and Carlos PorteraCailliau, MD, PhD

difference.7,8 The prevalence ranges from 3.4 to 5 per 100,000 people.6,7,9 Multiple system atrophy is associated with a history of high exposure to exogenous toxins, including organic solvents, plastic monomers and additives, pesticides and metals.9 Low education level, daily consumption of meat, and occupational history of working in factories or plants are also associated with increased risk, whereas there is an inverse relationship with smoking.10,11

Pathophysiology In MSA, there is a combination of neuronal cell loss, gliosis, and demyelination within the CNS. Striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA) are pathological variations in MSA correlating with the clinical subtypes MSA-P (parkinsonian) and MSA-C (cerebellar), respectively. In SND, there is prominent involvement of the dorsolateral striatum, ventrolateral globus pallidus, and substantia nigra.12 Olivopontocerebellar atrophy is characterized

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DOI http://dx.doi.org/ 10.1055/s-0034-1381737. ISSN 0271-8235.

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1 Department of Neurology and Neurosciences, Rutgers New Jersey

by degeneration of Purkinje cells, particularly in the cerebellar vermis, as well as the inferior olives. Other areas affected include the mesocortical and mesolimbic pathways, caudal raphe nucleus, locus ceruleus, pontine micturition center, pedunculopontine nucleus, intermediate reticular formation, medullary autonomic nuclei, corticospinal tract, intermediolateral cell column, Onufrowicz nucleus, sympathetic ganglia, and adrenergic fibers.13 Increased accumulation of intracellular ferritin and reduced export of iron from the basis pontis, and to a lesser extent, the putamen can lead to oxidative stress and mitochondrial dysfunction.14,15 Subcortical and frontal cortical atrophy and changes in frontal metabolism are linked to frontal executive impairment.16,17 Alpha-synuclein comprises the major component of both oligodendroglial and neuronal inclusions in MSA. There is debate whether MSA is a primary glial disorder, triggering neurodegeneration, or a combined primary oligodendrogliopathy and neuronal synucleinopathy. Glial cytoplasmic inclusions (GCIs) are common to both MSA phenotypes.1 In addition to α synuclein, numerous other components of GCIs have been identified, including ubiquitin, 4R tau, DJ-1, LRRK2, and parkin.18 Glial cytoplasmic inclusions are primarily found in the pons, medulla, putamen, substantia nigra pars compacta, cerebellum, and preganglionic autonomic structures.19 Duration of illness, clinical subtype, and degree of neuronal degeneration correlate well with the density and distribution of GCIs, but not α synuclein positive neuronal inclusions.20,21 Single-nucleotide polymorphisms in the SNCA gene coding for α synuclein have been linked to an increased risk of developing MSA.22,23 Genes for interleukin 1-α and β, interleukin 8, TNF α, α-1-antichymotrypsin gene, apolipoprotein E4 and tau have also been associated with MSA.22 Despite the presence of LRRK2 in GCIs, to date no genetic mutations in LRRK2 have been associated with MSA. Putative risk variants of genes involved in oxidative stress are SLC1A4, SQSTM1, and EIF4EBPI.24 Upregulation of microRNA miR-96 posttranscriptional regulators, with resultant downregulation of target solute carrier genes, SLC1A1 and SLC6A6 have recently been described in MSA.25 Decreased expression of SLC1A1, a cellmembrane high-affinity glutamate transporter, may lead to excitotoxicity and neurodegeneration. Mutations in the COQ2 gene have been identified both in familial and sporadic cases of MSA.26 COQ2 encodes a coenzyme involved in the biosynthesis of coenzyme Q10. The presence of a common variant (V343A) and multiple rare variants in COQ2 confer susceptibility to sporadic MSA with a higher ratio of MSA-C to MSA-P. The V343A variant of COQ2 is detected in Japanese but not Western populations, concordant with greater predominance of OPCA pathology in the Japanese compared with European or North American populations (40% and 17%, respectively).27–29

Signs and Symptoms Autonomic dysfunction is a key feature, necessary for the diagnosis of MSA.30 Erectile dysfunction is experienced by 97% of men, with urinary dysfunction occurring in 83% of all patients.31,32 Urgency from neurogenic detrusor overactivity is an early symptom. Symptoms of orthostatic hypotension

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occur in 75% of cases, and may include syncopal episodes, postural lightheadedness, and pain in the neck and shoulders known as “coat-hanger ache.”33 Other symptoms of dysautonomia are postprandial hypotension, supine hypertension, anhydrosis with thermoregulatory disturbance, constipation, and poor lacrimation and salivation. Parkinsonism occurs in 90% of MSA cases overall. Even within disease subtypes there is significant symptomatic overlap. Seventy-six percent of patients with MSA-C have parkinsonism, and 54% with MSA-P have cerebellar symptoms.34 Tremor is present in up to 80% of MSA patients, and tends to be more common in MSA-P.35 Patients may have more than one tremor type. Postural tremor is most frequently seen, occurring in 50%. Minipolymyoclonus, continuous generalized myoclonus of tiny amplitude resembling an irregular tremor, may be apparent. A jerky myoclonic action tremor can also be seen. Although resting tremor is present in a third, only 10% demonstrate the typical 3 to 6 Hz “pillrolling” tremor of PD. Cerebellar dysfunction is present in 70% of MSA cases, with any combination of intention tremor, gait and appendicular ataxia, sustained gaze-evoked nystagmus, hypometric saccades, and dysarthria. Rapid eye movement sleep behavior disorder (RBD) is reported in 70% of MSA patients, and detected in 90% undergoing polysomnography.36 Central and obstructive sleep apnea tends to occur in the later stages of the disease, and can be associated with sudden death.37 Laryngeal dystonia can produce stridor.38 Pyramidal signs, including hyperreflexia and upgoing plantar responses, are seen in 45% of patients with MSA-P and 57% with MSA-C.34 Dystonia occurs in 46% of levodopa-naïve patients, most commonly in MSA-P.39 Facial dystonia is a characteristic levodopa-induced complication in MSA. Abnormalities of posture include antecollis, camptocormia, and Pisa syndrome, of which antecollis is most common, seen in 25% of patients. Oculomotor findings include square wave jerks, slowing of saccades, diminished vestibulo-ocular reflex suppression, internuclear ophthalmoplegia, and reduced vertical gaze. Extremities may be cold and violaceous, giving rise to the “cold hands” and “cold feet” signs. Contractures of the hands or feet and emotional lability are also considered supportive features of MSA. Frontal lobe-related functions are impaired in 41%, with more verbal retrieval difficulties in MSA-P and more impairment in controlling attention and learning new verbal information in MSA-C.40 Unlike PD and pure autonomic failure, hyposmia is very mild or absent in MSA.41

Studies Neurodiagnostic studies may be instrumental in differentiating MSA from other parkinsonian disorders, and supportive neuroimaging findings may contribute to diagnostic criteria.30 In MSA-P, T2 magnetic resonance imaging (MRI) sequencing demonstrates putaminal atrophy with lateral rim putaminal hyperintensity, and diffusion-weighted imaging shows increased putaminal apparent diffusion coefficient values.42,43 Atrophy and hyperintensity of the medulla, middle cerebellar peduncles, pons, inferior olives, and cerebellum Seminars in Neurology

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are more commonly seen in MSA-C.44 The “hot cross bun” sign, cruciform T2 hyperintensity within the pons, is characteristic although not specific for MSA.45 Autonomic testing reveals abnormalities early in the course of disease in MSA compared with PD. Urine residual volume of greater than 100 mL increases the likelihood of a diagnosis of MSA.30 External anal sphincter denervation on electromyogram, reflecting loss of neurons in the Onufrowicz nucleus, is sensitive, but not specific for MSA.46 Myocardial MIBG uptake on cardiac MIBG scintigraphy is usually preserved in MSA, as preganglionic neurons are affected. This is in comparison to PD, in which uptake is decreased due to postganglionic denervation.47 Cerebrospinal fluid axonal markers, including neurofilament light chain, heavy chain, and tau, are increased in MSA-P compared with PD.48 DJ-1 is significantly higher in MSA than PD. A combination of DJ-1 and tau proteins can distinguish MSA from PD with 82% sensitivity and 81% specificity.49

Diagnostic Criteria Definitive diagnosis of MSA requires histopathological confirmation of widespread and abundant GCI in the CNS

and degeneration of striatonigral or olivopontocerebellar structures. Clinical criteria for the diagnosis of probable and possible MSA are shown in ►Table 1.30 The designation of probable MSA requires rigorously defined autonomic failure, whereas possible MSA requires parkinsonism or cerebellar ataxia, at least one feature of dysautonomia, and either another clinical feature or a neuroimaging abnormality. Features suggesting an alternative diagnosis to MSA include classic pill-rolling tremor, significant neuropathy, hallucinations not induced by medications, onset after age 75 years, family history of ataxia or parkinsonism, dementia, and radiologic white matter lesions characteristic of multiple sclerosis.

Clinical Course The mean age at onset is 53 to 65 years, although onset can range from the fourth to ninth decade.6,8,32,34,50 Median survival is 6 to 10 years, with 1- and 5-year survival rates of 74% and 28%, respectively.4,6 Nonmotor features may precede motor symptoms and signs by several years. Erectile dysfunction is most commonly the earliest feature in men, preceding urinary symptoms and orthostatic hypotension in

Table 1 Clinical criteria for the diagnosis of multiple system atrophy (MSA) Diagnostic categories

Clinical criteria

Probable

Sporadic, progressive disorder with age at onset 30; Autonomic failure: • Urinary incontinence (with erectile dysfunction in males) or an orthostatic decrease of blood pressure within 3 min of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic with either poorly levodopa-responsive parkinsonism (MSA-P) • Bradykinesia with rigidity, tremor, or postural instability or a cerebellar syndrome (MSA-C) • Gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction

Possible

Sporadic, progressive disorder with age at onset 30 with either parkinsonism or a cerebellar syndrome and at least one feature suggesting autonomic dysfunction • Otherwise unexplained urinary urgency, frequency or incomplete bladder emptying, erectile dysfunction in males, or significant orthostatic blood pressure decline not meeting requirements for probable MSA and at least 1 additional feature: MSA-P or MSA-C: • Babinski sign or hyperreflexia •Stridor MSA-P: • Rapidly progressive parkinsonism • Poor response to levodopa • Postural instability within 3 y of motor onset • Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction • Dysphagia within 5 y of motor onset • Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum • Hypometabolism on FDG-PET in putamen, brainstem, or cerebellum MSA-C: • Parkinsonism (bradykinesia and rigidity) • Atrophy on MRI of putamen, middle cerebellar peduncle, or pons • Hypometabolism on FDG-PET in putamen • Presynaptic nigrostriatal dopaminergic denervation on SPECT or PET

Abbreviations: FDG-PET, fluorodeoxyglucose positron emission tomography; MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography. Source: Adapted from Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670–676. Seminars in Neurology

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58% and 91% of cases, respectively.51,52 Urinary disturbances are present in more than 80% at the time of diagnosis, and precede orthostatic hypotension in 76% of cases. Rapid eye movement sleep behavior disorder can be a very early feature, with more than 80% eventually developing a synucleinopathy at a mean interval of 14 years from onset of RBD symptoms.53 Although one retrospective review revealed no significant difference in survival between MSA-P and MSA-C, a prospective study has identified the strongest predictors of shorter survival as a diagnosis of MSA-P and incomplete bladder emptying.34,44 Urinary incontinence, pyramidal signs, hyperreflexia, and higher baseline scores on the activities of daily living (ADL) subscale of the Unified MSA Rating Scale (UMSARS) confer a poor prognosis. Unilateral or bilateral vocal fold paralysis is associated with decreased survival, although the presence of stridor does not confer an adverse prognosis.54 Among patients surviving more than 15 years, cardiovascular autonomic dysfunction occurs late, with a mean latency of 9.4 years from onset.50 Disease onset before age 55 also predicts longer survival.44 Yearly progression, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) motor assessment, is 28% in MSA versus 4% in PD.55 Rates of progression are greater over the first year from symptom onset for both motor and ADL subscales of the UMSARS, with 45% and 32% progression, respectively, over the first 12 months, compared with 17.2% and 11.2% from months 12 to 24.34 Clinical milestones include falling more than once a day, wheelchair dependency, nasogastric tube or gastrostomy placement, urinary catheterization, and unintelligible speech.52 Ninety-five percent of MSA patients reach their first milestone at 5 years from diagnosis. Mean time to death after the first milestone is 2 years if early autonomic symptoms are present, and 3.4 years in the absence of early autonomic symptoms. Frequent falls and urinary catheterization are the most common milestones, occurring in 59% and 60% of cases, respectively. End-stage MSA is characterized by loss of ambulation and wheelchair dependency, occurring at 7 years after onset, followed by unintelligible speech, severe dysphagia, and residential care. Mortality is usually linked to aspiration resulting from dysphagia.

Treatment There are currently no therapies approved by the Food and Drug Administration for MSA. With the exception of midodrine for neurogenic orthostatic hypotension, there are no clinical trials meeting scientific evidence standards proving efficacy of any treatments for MSA. In the absence of consensus guidelines, symptomatic management is mostly based on precedent (►Table 2).56 Only 30% respond to levodopa, and those that do generally experience only a short-lived benefit, lasting 3.5 years on average.34 High doses (> 1000 mg/d) are often required for symptomatic relief, but the dose may be limited by side effects, including hypotension, hallucinations, and nausea. Dopamine agonists are generally less effective and less well

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tolerated than levodopa, but some patients may show improvement. Amantadine and paroxetine may improve motor function, although the benefit is also usually short-lived.57,58 In a small placebo-controlled trial, MSA patients randomized to receive recombinant human growth hormone demonstrated a nonsignificant trend of less worsening of UPDRS and UMSARS total scores at 12 months.59 Botulinum toxin injections can alleviate neck or limb dystonia in MSA, but may cause or exacerbate dysphagia. Midodrine, a peripherally acting α-adrenergic agonist, has been shown to be effective for the treatment of neurogenic orthostatic hypotension in randomized, placebo-controlled studies.60–62 However, midodrine aggravates supine hypertension in a dose-dependent manner. Pyridostigmine, a parasympathomimetic and a reversible cholinesterase inhibitor, can ameliorate orthostatic hypotension without worsening supine hypertension.63 Sildenafil is efficacious in the treatment of erectile dysfunction in multiple system atrophy, although it can exacerbate hypotension.64 Though clonazepam is effective for managing RBD, melatonin or zopiclone can also be used, particularly if there is comorbid obstructive sleep apnea.65 Exercise is increasingly recognized as a critical component of treatment in neurodegenerative diseases to induce neuroplasticity.66 Deep brain stimulation is currently contraindicated in MSA. Transient symptomatic benefit was reported in two patients who were clinically diagnosed with PD, in whom the diagnosis of MSA was made at autopsy.67 Both patients had levodopa-responsive parkinsonism, but required gradually increasing doses. Deep brain stimulation of the pedunculopontine nucleus remains under investigation to improve walking and balance in PD and atypical parkinsonism, although data have yet to be confirmed.68 A team of health care professionals, including a neurologist, physical therapist, speech therapist, occupational therapist, and social worker, is the key to optimizing the care of MSA patients. Preparing advance directives and the decision to contact hospice services are topics that should be broached early on. Private foundations providing information for MSA patients and their caregivers are listed in ►Table 3.

Treatment Trial Underway Droxidopa is an investigational drug for the management of neurogenic orthostatic hypotension. It is converted peripherally and centrally into norepinephrine. It is taken up into adrenergic terminals and released in response to baroreflex signaling. A phase 3 trial is planned to look at durability of drug effect.69

Open-Label Studies Intra-arterial and intravenous (IV) delivery of mesenchymal stem cells resulted in a significantly smaller increase in total and motor UMSARS scores compared with the placebo group. However, brain MRIs revealed ischemic lesions in those receiving intra-arterial infusion. Small single-arm open label trials of subarachnoid cord blood mononuclear cells injection and IV immunoglobulin have been reported, but the improvement in UMSARS scores Seminars in Neurology

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Table 2 Symptomatic therapies for multiple system atrophy (MSA) Clinical feature

Pharmacological treatments

Nonpharmacological treatments

Parkinsonism

Levodopa Dopamine agonists (pramipexole, ropinirole, rotigotine) Rasagiline Amantadine Paroxetine

Physical therapy: Range of motion, gait, and balance

Orthostatic hypotension

Midodrine Fludrocortisone Pyridostigmine

Compression stockings/ abdominal binder Fluid and salt intake

Cerebellar tremor

Clonazepam Baclofen Propranolol Amantadine

Limb ataxia

Buspirone Gabapentin

Urinary retention

Self-catheterization

Urinary incontinence

Anticholinergics (oxybutynin, tolterodine, solifenacin, trospium, fesoterodine, darifenacin) Desmopressin Botulinum toxin to detrusor muscle

Dystonia

Botulinum toxin Baclofen Benzodiazepines (clonazepam, diazepam, lorazepam) Anticholinergics (trihexyphenidyl)

Erectile dysfunction

Sildenafil Intracavernosal injection of papaverine or PGE1 Subcutaneous apomorphine

Stridor

Botulinum toxin injection of the vocal cords Prophylactic tracheostomy

Sleep apnea

Continuous positive airway pressure Adaptive seroventilation

RBD

Clonazepam Melatonin Zopiclone

Depression and anxiety

SSRIs Citalopram Levodopa

Cognitive dysfunction

Cholinesterase Inhibitors (donepezil, rivastigmine, galantamine) Memantine

Drooling

Anticholinergics Botulinum toxin injection to salivary glands

Electroconvulsive therapy Psychological support

Abbreviations: SSRIs, selective serotonin reuptake inhibitors. Source: Adapted from Flabeau O, Meissner WG, Tison F. Multiple system atrophy: current and future approaches to management. Ther Adv Neurol Disord 2010;3(4):249–263.

need to be confirmed by large double-blind randomized controlled studies.70,71

Failed Trials in Multiple System Atrophy Lithium is poorly tolerated in MSA patients. A study testing the safety and tolerability of lithium in MSA found a high number of adverse events in those assigned to take lithium, Seminars in Neurology

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resulting in the trial being stopped.72 Riluzole had no significant effect on survival or rate of functional deterioration in MSA in a 36-month double-blind randomized placebocontrolled trial.73 Although rifampicin inhibited formation of α-synuclein fibrils in a mouse model of MSA, a clinical trial of rifampicin in MSA found no disease-modifying benefit.74 An interim analysis of the effect of rifampicin on rates of disease

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Table 3 Private foundations for multiple system atrophy (MSA) Foundation

Website

Joseph G. Fortier Foundation for Multiple System Atrophy - MSA

http://movingtodayformsa.org

The Multiple System Atrophy (MSA) Coalition®

http://www.multiple-system-atrophy.org/index.htm

CurePSP: Foundation for PSP l CBD & Related Brain Diseases

http://www.curepsp.org

CURE M.S.A. (Multiple System Atrophy)

https://www.facebook.com/curemsa.now

Brain Support Network

http://www.brainsupportnetwork.org

Multiple System Atrophy Trust founded by Sarah Matheson

http://www.msatrust.org.uk

Conclusions/Future Directions Multiple system atrophy is a neurodegenerative synucleinopathy with pathology, clinical course, and response to treatment distinct from PD. Diagnosis has been refined by new criteria and greater recognition of the underlying pathology. Advances are being made in understanding environmental and genetic risk factors. Current symptomatic treatments may provide some benefit, but must be individualized. A validated clinical rating scale is available, and the pace of MSA research has recently accelerated. There is an ongoing quest for diagnostic and treatment biomarkers. International multicenter clinical trials are needed for the development of consensus guidelines for the standard of care in MSA. Further research on symptomatic and diseasemodifying therapies is eagerly anticipated.

8 Stefanova N, Bücke P, Duerr S, Wenning GK. Multiple system

atrophy: an update. Lancet Neurol 2009;8(12):1172–1178 9 Vanacore N, Bonifati V, Fabbrini G, et al; European Study Group on

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progression, as measured by rates of change of UMSARS 1 scores, met futility criteria and resulted in study termination. In a 46-week randomized study, rasagiline had no significant effect over placebo in patients with MSA-P, as assessed using UMSARS scoring.75 Similarly, a 48-week randomized controlled study failed to show a clinical effect of minocycline on symptom severity in MSA-P patients.76

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Multiple System Atrophy

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Multiple system atrophy.

Multiple system atrophy (MSA) is a rare adult-onset synucleinopathy associated with dysautonomia and the variable presence of poorly levodopa-responsi...
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