Multiple system atrophy

 

Contributors

Robert Fekete MD, author. Dr. Fekete of Baylor College of Medicine has no relevant financial relationships to disclose.

 

Joseph Jankovic MD, editor. Dr. Jankovic, Director of the Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, has received research support from Advanced Neuromodulation Systems, Allergan, Boehringer Ingelheim, Ceregene, Chitern International, EMD Serono, Impax Pharmaceuticals, Ipsen Limited, Medtronic, Merz Pharmaceuticals, Neurogen, Novartis, Ortho-McNeil, and Teva. He has served as a consultant for Allergan, EMD Serono, Lundbeck, Merz Pharmaceuticals, and Teva.

 

Former author(s)

Lawrence I Golbe MD

 

Publication dates

Originally released October 4, 1993; last updated June 7, 2010; expires June 7, 2013

 

Synonyms

Shy-Drager syndrome

 

Historical note and nomenclature

  Like many heterogeneous disorders, multiple system atrophy was described piecemeal over a period of decades and engenders nosologic controversy. The sporadic form of "olivopontocerebellar atrophy," a term often applied to the cerebellar-predominant variety of multiple system atrophy, was first described by Dejerine and Thomas (Dejerine and Thomas 1900). A dysautonomia-predominant type was described much later (Shy and Drager 1960), as was the parkinsonism-predominant variety, striatonigral degeneration (van der Eecken et al 1960; Adams et al 1964; Adams and Salam-Adams 1986). No less historic a contribution was the observation that all varieties of multiple system atrophy share a specific glial cytoplasmic inclusion (Papp et al 1989) and that these inclusions are principally composed of alpha-synuclein (Gai et al 1998; Dickson et al 1999).

  The current classification scheme based on the first consensus statement on the diagnosis of multiple system atrophy divides the disorder into a parkinsonian type (MSA-P) and a cerebellar type (MSA-C) (Gilman et al 1999). These terms replaced the striatonigral degeneration, sporadic olivopontocerebellar atrophy, and Shy-Drager syndrome designations. In the second consensus statement in 2008, definite, probable, and possible multiple system atrophy diagnostic criteria were introduced (Gilman et al 2008).

Clinical manifestations

    Parkinsonism (rigidity, bradykinesia, and postural instability) occurs in at least 90% of all 3 types of multiple system atrophy (Wenning et al 1994). Unlike Parkinson disease, however, multiple system atrophy rarely receives sustained benefit from levodopa and exhibits rest tremor in fewer than 10% of cases (compared with 60% to 70% in Parkinson disease). The progression of parkinsonian motor features of multiple system atrophy, as measured by the motor score (Part III) of the Unified Parkinson's Disability Rating Scale, averages 28% per year, whereas untreated early Parkinson disease progresses less than 4% per year (Seppi 2005).

  Autonomic insufficiency is a more prominent part of most cases of multiple system atrophy than of Parkinson disease. Cerebellar features are early and important in many patients and predominate in some. Parkinsonism predominates in others. Because there is considerable pathologic and clinical overlap among the 3 varieties of multiple system atrophy, there is no need for formal criteria differentiating them. A few patients with multiple system atrophy have isolated dysautonomia, cerebellar dysfunction, or parkinsonism (Wenning et al 1994).

  Rapid eye movement behavioral disorder occurs in 69% of patients by history and in 90% of patients by polysomnography (Plazzi et al 1997). The condition occurs earlier and more intensely than in Parkinson disease (Iranzo et al 2005), and its violent, even aggressive motor outbursts can injure the patient or bed partner.

  Even more dangerous is obstructive sleep apnea, which occurs in the later stages and may produce sudden death (Munschauer et al 1990). It may be related either to central alveolar hypoventilation caused by loss of brainstem ventilatory drive centers or to obstructive sleep apnea caused by laryngeal dystonia (Vetrugno et al 2007b) producing upper airway obstruction (Iranzo 2005).

  Less frequent or severe features of multiple system atrophy include emotional lability, pyramidal signs, contractures, a tendency to lean laterally while seated (the “Pisa syndrome”), supranuclear ophthalmoplegia, antecollis, an irregular or jerky myoclonic action tremor that is of cortical origin (Okuma 2005), large-amplitude myoclonus, respiratory stridor, polyneuropathy, amyotrophy, distal cyanosis, and Raynaud phenomenon. Dementia occurs no more commonly than in Parkinson disease (Quinn et al 1989; Tison et al 1996). There is often a mild normocytic/normochromic anemia that may be caused by loss of sympathetic stimulation of renal erythropoietin production (Winkler et al 2001).

  Most prominent among the dysautonomic findings is orthostatic hypotension, but other important defects are postprandial hypotension, supine hypertension, anhidrosis with thermoregulatory disturbance, poor lacrimation and salivation, constipation, and impotence. Bladder emptying function may also be severely impaired. This usually starts with urgency, but later in the course of many cases, simulates prostatic enlargement in men and stress incontinence in women (Beck et al 1994).

  Olfactory function remains preserved in multiple system atrophy as tested via the University of Pennsylvania Smell Identification Test (UPSIT) (Goldstein et al 2008).

  Gastrointestinal symptoms, pain, urinary problems, and postural instability due to orthostatic hypotension are reported more frequently in multiple system atrophy than in Parkinson disease, progressive supranuclear palsy, or corticobasal degeneration (Colosimo et al 2010). MSA-P shows a wider involvement of cognitive dysfunction than MSA-C, possibly associated with prefrontal dysfunction (Kawai et al 2008). MSA-P patients have reduced verbal retrieval, whereas MSA-C patients have difficulties learning new information (Balas et al 2010).

Clinical vignette

  A 57-year-old right-handed bookkeeper, on disability, complained of a 6-year history of autonomic symptoms as exemplified by urinary urgency as well as urge incontinence. About 4 years ago, she developed a staggering “drunk” gait, dysarthria, and difficulty with balance. She had multiple falls due to loss of balance. She had no history of lightheadedness. About a year ago, she developed right upper extremity rest tremor as well as REM behavior disorder. She had been taking carbidopa-levodopa, without any response. Her MRI showed cerebellar atrophy.

  On physical examination, there was mild saccadic pursuit with saccadic hypometria. Gait was both broad-based and shuffling. There was mild dysmetria on finger-to-nose testing, which was worse on the left side. The patient also had bradykinesia in the bilateral upper extremities, which was worse on the right side, as well as rigidity, which was worse in the right upper extremity. She was diagnosed with probable MSA-C as the cerebellar features were most prominent.

Etiology

  One study has shown an association of multiple system atrophy with various exogenous exposures such as solvents, pesticides, metals, and components of plastics (Vanacore et al 2001). Another showed an association with farming experience (Vanacore et al 2005). There appears to be an inverse association with smoking, as occurs in Parkinson disease, which is independent of the farming association (Vanacore et al 2000; 2005). In a population of Korean patients, the risk of multiple system atrophy was independent of participation in agriculture (Cho et al 2008a). A greater than expected exposure of patients to occupational toxins and frequent occurrence of minor dysautonomic symptoms in their relatives suggest that multiple system atrophy may be caused by a hereditary predisposition to an exogenous chemical toxicant (Nee et al 1991).

  Fewer than 1% of patients have a family history of progressive supranuclear palsy (Soma et al 2006). A hint of a specific genetic factor is the unconfirmed association of multiple system atrophy with a specific allele in the genes for interleukin 1-beta (Nishimura et al 2002) and alpha-1-antichymotripsin (Furiya et al 2005). No mutations have been found in LRRK2, the gene presently considered to be the most commonly mutated in Parkinson disease (Tan et al 2006), although LRRK2 was found to co-localize with glial cytoplasmic inclusions in laboratory studies (Jellinger and Lantos 2010). Single nucleotide polymorphisms at the SNCA locus, which codes for alpha-synuclein, have been associated with increased risk for developing multiple system atrophy (Scholz et al 2009). Scholz and colleagues propose that instead of direct amino acid sequence alteration, differences in expression of the SNCA gene may contribute to the development of multiple system atrophy.

Pathogenesis and pathophysiology

  The hallmark of multiple system atrophy pathology is the presence of glial cytoplasmic inclusions (Trojanowski and Revesz 2007; Yoshida 2007; Jellinger 2010). Glial cytoplasmic inclusions are most consistently present in the external and internal capsules, the central tegmental tract, and the white matter of the cerebellar cortex (Armstrong et al 2007). A case with abundant glial cytoplasmic inclusions, but not fulfilling diagnostic criteria for multiple system atrophy, has been reported (Parkkinen et al 2007). Of unknown significance is a case of hypoparathyroidism with basal ganglia calcifications in addition to multiple system atrophy pathology and phenotype. Massive lipid laden macrophage infiltration of the pontocerebellar fibers was described in 1 case (Yokoyama et al 2007).

  Glial cytoplasmic inclusions include hyperphosphorylated alpha-synuclein, ubiquitin, LRRK2, as well as other proteins (Jellinger and Lantos 2010). Phosphorylated alpha-synuclein at serine 87 and 129 has been detected in multiple system atrophy brains, but not in controls (Paleologou 2010). On the other hand, a series of 58 patients with multiple system atrophy was negative for alpha-synuclein mutations (Lincoln et al 2007). In an animal model of multiple system atrophy, alpha-synuclein knockout mice appeared to be resistant to 3-nitropropionic acid-induced neuronal loss and dendritic pathology (Ubhi et al 2010).

  Dysfunction of the ubiquitin proteasome system has been reported in multiple system atrophy (Bukhatwa et al 2010). Phosphorylation of DARPP32, a major substrate of cdk5, may be involved in the formation of oligodendrocyte glial cytoplasmic inclusions (Honjo et al 2008). Reduction in LRRK2 expression in oligodendroglia is associated with increased neuronal loss in multiple system atrophy, but parkin immunoreactivity has been seen in only a small proportion of glial cytoplasmic inclusions (Huang et al 2008). An oligodendroglial protein, p25alpha, which interacts with myelin basic protein, migrates to glial cytoplasmic inclusions (Song et al 2007). NUB1, a synphilin-1-interacting protein, is found in the intracytoplasmic inclusions of both neuronal and oligodendroglial cells, neuronal nuclear inclusions, and swollen neurites (Tanji et al 2007). HtrA2/Omi, a mitochondrial proapoptotic serine protease that is released into the cytosol, has been found in glial and neuronal cytoplasmic inclusions in multiple system atrophy brains (Kawamoto et al 2008).

  In MSA-P, there is cell type-specific neuronal loss, with calcineurin-positive medium spiny neurons depleted in the posterior putamen as compared to choline acetyltransferase positive neurons (Sato et al 2007a). A subsequent study showed that in the caudal and dorsolateral putamen, calbindin-positive neurons are more affected than calcineurin-positive neurons (Sato et al 2007b).

  Lewy body pathology has been found in submandibular glands of Parkinson disease and incidental Lewy body disease patients, but not in multiple system atrophy patients (Del Tredici et al 2010).

  A rare association of multiple system atrophy with Alzheimer disease has been described (Rusina et al 2007). Alpha-synuclein and phosphorylated tau co-localize in certain brain regions in cases of combined multiple system atrophy and Alzheimer disease (Terni et al 2007). Blood brain barrier dysfunction has been found to correlate with disease severity in multiple system atrophy (Song et al 2010).

  Transcranial magnetic stimulation with triple stimulation technique detects corticospinal tract involvement in multiple system atrophy (Eusebio et al 2007). Median nerve somatosensory evoked potential measurement shows slowing of the central sensory conduction time as the disease progresses (Miyatake et al 2010). Microvessel degeneration has been found in medullary autonomic nuclei (Miller et al 2007).

  High levels of CSF axonal biomarkers are found in MSA-P. Neurofilament light chain, heavy chain, and tau are significantly increased in MSA-P (all p < 0.0001), whereas noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol levels are significantly decreased in MSA-P (p < 0.0001) as compared to Parkinson disease (Abdo et al 2007a). No difference in biomarkers has been found between MSA-C and MSA-P (Abdo et al 2007b). CSF hypocretin (orexin) levels are normal (Martinez-Rodriguez et al 2007). Although neurofilament light chain can differentiate between Parkinson disease and atypical parkinsonism, it cannot differentiate between multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration (Constantinescu et al 2010).

  Neuronal cell loss has been reported in the Onufrowicz nucleus and the intermediolateral cell column, as well as a portion of the intermediate reticular formation, dorsal motor nucleus of vagus, nucleus ambiguus, caudal raphe nucleus, arcuate nucleus, pontine micturition center, and locus ceruleus (Ozawa 2007). Rostral raphe neurons are relatively preserved in multiple system atrophy, in contrast to diffuse Lewy Body disease (Benarroch et al 2007). The pedunculopontine nucleus has also been implicated in multiple system atrophy (Nandi et al 2008). Multiple system atrophy patients have neurogenic orthostatic hypotension and decreased baroreflex function, with a relatively preserved cardiac sympathetic innervation (Imrich et al 2008; Tada et al 2009). A relatively high frequency of cardiac ectopy has been found (Goldstein 2010). Autonomic dysfunction can be exacerbated by medical treatment of other symptoms (Ziemssen and Reichmann 2010). Resting baroreflex sensitivity has been shown to be lower in a group of 35 patients with multiple system atrophy (Friedrich et al 2008). Postsynaptic sympathetic nerves in the epicardium are affected in multiple system atrophy (Orimo 2008a; Orimo et al 2008b), but the changes are less prominent than in Parkinson disease or diffuse Lewy Body disease (Ozawa 2007). Awake ventilatory response to hypercapnia and hypoxia appears to be affected later in the disease course than baroreflex function (Lipp et al 2010). In a group of patients with multiple system atrophy who suffered sudden death as compared to multiple system atrophy patients who died from well-established causes, depletion of serotonergic neurons in the ventrolateral medulla and nucleus raphe obscurus was present (Tada et al 2009). Neurons in the intermediolateral cell column, as well as catecholaminergic neurons in the ventrolateral medulla, were affected equally in both groups.

  Growth hormone release in response to arginine is impaired in multiple system atrophy, but not in Parkinson disease (Ozawa 2007). This response to arginine can also differentiate MSA-P from progressive supranuclear palsy (Pellecchia et al 2008). The clonidine stimulation test for growth hormone release has higher sensitivity and specificity for differentiating MSA-P and Parkinson disease. A combination of clonidine and arginine tests could further enhance sensitivity and specificity (Zhang et al 2010).

  In a study, multiple system atrophy patients were found to have pupillary sympathetic dysfunction from an early stage, whereas in Parkinson disease patients, it tended to gradually accelerate at a more advanced stage of the disease (Yamashita et al 2010). Pupillography may distinguish multiple system atrophy from Parkinson disease (Reimann et al 2010). In multiple system atrophy patients, pupillary sympathetic sensitivity has been correlated with the severity of orthostatic hypotension during a head-up tilt test and with the elevation of systolic blood pressure during a noradrenaline infusion test (Yamashita et al 2010).

  Blunted heart rate (Freilich et al 2010) and electroencephalographic changes during period limb movements of sleep have been observed in multiple system atrophy (Vetrugno et al 2007a). Skin sympathetic dysfunction has been demonstrated via impaired vasodilator response to local heating (Yamanaka et al 2007).

  In an electromyography study, the mean duration of motor unit potentials recorded from the external anal sphincter was significantly longer in patients with multiple system atrophy and progressive supranuclear palsy compared with motor unit potentials recorded from patients with Parkinson disease (P < 0.005 for both) (Winge et al 2010).

  Chronic orthostatic hypotension in multiple system atrophy patients leads to structural remodeling of veins and reduced venous compliance, which actually serves to counteract excessive venous pooling in the lower extremities (Lipp et al 2007).

Epidemiology

  At a large referral center, 100 patients with multiple system atrophy reported a median age at onset of 53 years (range 33 to 76 years) (Wenning et al 1994), whereas another registry reported a mean age at onset of 60 years (SD=9; range 34 to 83 years) (Stefanova et al 2009). In Jellinger's unpublished series of 600 autopsied brains from patients with parkinsonian disorders, multiple system atrophy occurred in 5.1% (Quinn et al 1989). The sexes appear to be affected equally (Stefanova et al 2009). The incidence in the 50- to 99-year age group has been measured at 3.0 new cases per 100,000 person-years (Bower et al 1997), and the prevalence in a medically based series in London was 4.4 per 100,000 population (Schrag et al 1999), about 3% of that of Parkinson disease. The annual incidence of new cases is about 0.6 per 100,000 population (Vanacore et al 2001; Stefanova et al 2009). The crude incidence of MSA-P in northern Sweden is 2.1 per 100,000 (Linder et al 2010). Multiple system atrophy of the cerebellar type comprises 29% of the cases of sporadic, adult-onset ataxia (Abele et al 2002).

  Also see the clinical summary: Epidemiology of movement disorders.

Prevention

  Not applicable.

Differential diagnosis

  Clinical and imaging findings of sporadic adult-onset ataxia of unknown etiology have some overlap with multiple system atrophy (Abele et al 2007). Although multiple system atrophy is considered a sporadic disease, 4 families, one of which had a consanguineous marriage, were reported with familial cases of multiple system atrophy phenotype with autonomic failure, parkinsonism, and cerebellar ataxia (Hara et al 2007). These patients were negative for spinocerebellar ataxia types 1, 2, 3, 6, 7, 12, 17, dentatorubral-pallidoluysian atrophy, and alpha-synuclein mutations.

  Spinocerebellar ataxia type 2 may present with a parkinsonian or cerebellar phenotype and should be considered in the differential diagnosis, especially if an autosomal dominant inheritance pattern is established (Lastres-Becker et al 2008; Yomono et al 2010). Spinocerebellar ataxia type 3 has also been reported with a multiple system atrophy phenotype (Wullner et al 2007). Aprataxin mutations leading to ataxia with oculomotor apraxia can also have an overlapping phenotype with MSA-C (Baba et al 2007). An SCA17 case with progressive ataxia, autonomic dysfunction, parkinsonism, supranuclear gaze palsy, and cognitive impairment has been reported (Lin et al 2007). A series of 199 patients with a clinical diagnosis of multiple system atrophy was negative for SCA12 (Cho et al 2008b).

  “Red flags” with greater than 95% specificity for MSA-P as opposed to Parkinson disease include postural instability within 3 years of disease onset and resulting recurrent falls, wheelchair dependency within 10 years of onset, Pisa syndrome (prolonged episodes of lateral trunk flexion), disproportionate antecollis (van de Warrenburg et al 2007), contractures of hands or feet excluding Dupuytren disease, diurnal inspiratory stridor, nocturnal inspiratory stridor, inspiratory sighs, severe dysphonia, severe dysarthria, severe dysphagia, and emotional incontinence (Kollensperger et al 2008). Laryngeal abductor paralysis (Nagata et al 2007), generally occurring in advanced stages of multiple system atrophy, has also been reported in the early stages (Deguchi et al 2007b). It may lead to nocturnal sudden death (Egami et al 2007). “Cold hand sign,” with poor circulatory return after blanching, is a clue for multiple system atrophy with poorly understood pathophysiology (Pietzarka et al 2010). Lower limb tremor, although a possible presentation of Parkinson disease, may be suspicious for multiple system atrophy (Hellmann et al 2010). Symmetric symptoms, which were reported in 48% of a cohort of MSA-P patients, should also increase suspicion for this disorder when evaluating Parkinson disease patients (Gomez-Esteban et al 2010). Emotional incontinence exhibited by inappropriate laughter or crying has also been reported in 36% of a series of MSA-C patients (Parvizi et al 2007).

  The presence of excessive square-wave jerks, mild to moderate hypometria of saccades, impaired vestibulo-ocular reflex suppression, spontaneous nystagmus, or positioning downbeat nystagmus may be oculomotor clues to the presence of multiple system atrophy, whereas the presence of clinically slow saccades or moderate to severe gaze restriction argues against multiple system atrophy (Anderson et al 2008). Of note, hypometric saccades have been reported in Parkinson disease (Armstrong 2008). Ocular jaw synkinesia, described in Parkinson disease, is not seen in MSA-P (Salazar et al 2010).

  Differentiation of MSA-P from the subset of Parkinson disease patients with prominent autonomic failure is a profound diagnostic challenge. In a prospective study of multiple system atrophy and Parkinson disease patients, scores on self-report questionnaires of autonomic symptoms as well as on clinical assessments of autonomic function were similar in the 2 groups (Lipp et al 2009). The pattern of anhidrosis is different in the 2 groups. Intact quantitative sudomotor axon testing in anhidrotic areas confirmed a preganglionic lesion in multiple system atrophy patients, whereas Parkinson disease patients had anhidrosis due to a peripheral lesion (Lipp et al 2009).

  Although progressive supranuclear palsy parkinsonism (PSP-P) shares many features with multiple system atrophy, autonomic dysfunction is uncommon in this disorder and can help distinguish it from multiple system atrophy (Williams and Lees 2010).

  Corticobasal degeneration may be confused with multiple system atrophy, but the former is highly asymmetric and always shows important apraxia and cortical sensory loss. The multiple system atrophy with a predominance of dysautonomia may be confused with progressive autonomic failure. However, the dysautonomic features in multiple system atrophy typically start with bladder and erectile dysfunction, proceeding to thermoregulatory difficulty and orthostatic hypotension, and finally to ventilatory dysrhythmias. Progressive autonomic failure, on the other hand, begins with thermoregulatory and blood pressure dysregulation; bladder dysfunction occurs last, and ventilatory arrhythmias do not occur (Mabuchi 2005).

  In a large series of patients carrying a diagnosis of multiple system atrophy of the cerebellar type, 4% (3 of 76 patients) had a mutation in the FMR1 gene, suggesting that fragile-X-associated tremor-ataxia syndrome should be considered in the differential diagnosis (Kamm et al 2005).

  Multi-infarct states may mimic multiple system atrophy and many other degenerative disorders but are usually identified by vascular lesions on MRI scan, arteriosclerotic risk factors, and a history of stepwise progression. Additionally, a rare case of multiple system atrophy masking symptoms of multiple sclerosis has been reported (Finke et al 2010). Cases of pure autonomic failure do not have the additional parkinsonian or cerebellar signs of multiple system atrophy on physical examination.

Diagnostic workup

  MRI will help rule out a multi-infarct state or normal-pressure hydrocephalus as a cause of dopa-unresponsive parkinsonism and will also rule out an anatomical lesion of the cerebellum.

  The “hot cross bun” sign is a hyperintensity in the pons on T2 MRI images of MSA-C (Albuquerque et al 2007; Shrivastava 2007). Of note, the “hot cross bun” sign has also been observed in spinocerebellar ataxia types 2 and 3, parkinsonism secondary to vasculitis, and variant Creutzfeldt-Jacob disease (Burk et al 2001; Muqit et al 2001; Brooks and Seppi 2009; Soares-Fernandes et al 2009).

  Putaminal atrophy can differentiate multiple system atrophy from Parkinson disease (Brooks and Seppi 2009; Seppi and Poewe 2010). Signal loss in dorsolateral putamen on T2 MRI sequences with the presence of a hyperintense lateral rim in fluid attenuated inversion recovery (FLAIR) sequences has a specificity of 0.97 for discriminating between multiple system atrophy and Parkinson disease (von Lewinski et al 2007). Although specificity is high, sensitivity of these signs on 1.5 Tesla MRI in early stages of the disease is suboptimal (Brooks and Seppi 2009; Seppi and Poewe 2010). Hyperintense putaminal rim on 3 Tesla T2 images by itself may be a nonspecific finding (Brooks and Seppi 2009; Seppi and Poewe 2010). Fractional anisotropy and apparent diffusion coefficient changes are present prior to these MRI signs and may be used to differentiate multiple system atrophy from Parkinson disease (Ito et al 2007).

  “Pointers” raising the possibility of multiple system atrophy also include hyperintensity of the middle cerebellar peduncle, pons, and cerebellum (Seppi and Poewe 2010). Susceptibility weighted MRI (Gupta et al 2010) as well as magnetic resonance spectroscopy (Guevara et al 2010) may help in differentiating between multiple system atrophy and Parkinson disease.

  Hypometabolism on fluorodeoxyglucose positron emission tomography (FDG-PET) in the brainstem, cerebellum, or putamen, as well as presynaptic nigrostriatal dopaminergic denervation in SPECT or PET, are included in the diagnostic criteria (Gilman et al 2008). A variety of investigational techniques have potential for the differentiation of multiple system atrophy and Parkinson disease, as well as between the subtypes of multiple system atrophy. In PET testing, putamen to substantia nigra ratios and putamen to caudate ratios of 6-[18F]fluorodopa-derived activity as well as cardiac 6-[18F]fluorodopamine-derived activity separate Parkinson disease from multiple system atrophy (Goldstein et al 2008; Kwon et al 2008). Also, 123I-Ioflupane scanning can be used to differentiate multiple system atrophy from Parkinson disease (Punal Rioboo et al 2007). Reduction in AChE activity as measured by [(11)C] N-methylpiperidin-4-yl propionate PET has been seen in the thalamus (-27%) and the posterior lobe of cerebellar cortex (-36%) in patients with MSA-C (Hirano et al 2008). A fully automated, voxel-based FDG-PET method has been shown to differentiate multiple system atrophy from Parkinson disease and controls (Eckert et al 2007). Substantia nigra hyperechogenicity on transcranial sonography, seen in Parkinson disease, was observed less frequently in Japanese patients with multiple system atrophy (Okawa et al 2007). Transcranial sonography could also distinguish between Parkinson disease and atypical parkinsonism patients in a German population (Walter et al 2007). Of note, 10% of the population has been found to have abnormal echogenicity of the substantia nigra (Woitalla et al 2010). Differences in cardiac and whole body metaiodobenzylguanidine (MIBG) imaging are seen between multiple system atrophy and Parkinson disease (Marini et al 2010).

  Voxel-based morphometry as well as tractography are not appropriate for the diagnostic workup of individual patients, but they offer important research insights (Brooks and Seppi 2009). Morphometric measurement of midbrain and pons can distinguish MSA-P and progressive supranuclear palsy (Cosottini et al 2007). Additionally, putamen/caudate volume ratios on MRI scans can also differentiate between multiple system atrophy and Parkinson disease (Shin et al 2007). Voxel-based morphometry and relaxometry comparison of MSA-P and MSA-C shows infratentorial differences, namely, stronger reduction of gray matter in the cerebellum and white matter in the brainstem, as well as reduction of the relaxation rate R2 in the cerebellum and brainstem (Minnerop et al 2007). MSA-P does not show any changes in the superior cerebellar peduncle (Kataoka et al 2008). On tractography-based analysis, MSA-C cases display decreased fractional anisotropy and volume as well as increased apparent diffusion coefficient values in the middle cerebellar peduncle, compared to controls (Taoka et al 2007). Diffusion tensor imaging indexes correlate with severity of orthostatic hypotension and disease duration in MSA-C (Tha et al 2010). MSA-C can be differentiated from Parkinson disease via computer-assisted statistical analysis of brain perfusion SPECT images (Waragai et al 2007). Three-dimensional fractal analysis (Wu et al 2010) and voxel-based morphometry (Nanri et al 2010) can also show cerebellar volume loss in MSA-C. 11C-raclopride PET scanning using both D2 receptor binding potential and cerebral influx ratio can distinguish MSA-P and Parkinson disease patients better than current striatal D2 receptor-only analysis (Van Laere et al 2010).

  Nerve conduction and EMG studies may show subclinical polyneuropathy in multiple system atrophy. External urethral sphincter EMG shows denervation in almost all patients with multiple system atrophy (Paviour et al 2005), but not in Parkinson disease or in other cerebellar degenerations (Kirby et al 1986; Wenning et al 1997). The ability of this procedure to distinguish multiple system atrophy from Parkinson disease has, however, been disputed (Giladi et al 2000) and false positives arise from many nonneurologic causes of sphincter denervation such as multiparity or pelvic surgery.

  A set of diagnostic criteria proposed by Quinn (Quinn 1989) was modified and operationalized by a Consensus Conference in 1999. The criteria from the Second Consensus Conference are outlined here (Gilman et al 2008).

  A validated disability rating scale is available (Wenning et al 2004).

 

Table 1. Multiple System Atrophy Diagnostic Criteria

 

Definite multiple system atrophy	Requires neuropathologic finding of widespread and abundant central nervous system glial cytoplasmic inclusions that are positive for alpha-synuclein, in association with neurodegeneration in striatonigral or olivopontocerebellar structures.
Probable multiple system atrophy	A sporadic, progressive adult-onset (after age 30) disease characterized by autonomic failure involving urinary incontinence plus erectile dysfunction in males, or an orthostatic decrease of blood pressure within 3 minutes of standing by at least 30 mmHg systolic or 15 mmHg diastolic, and   • poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor, or postural instability) or   • a cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction).
Possible multiple system atrophy	A sporadic, progressive adult-onset (after age 30) disease characterized by parkinsonism or a cerebellar syndrome and   • at least 1 feature suggesting autonomic dysfunction otherwise unexplained urinary urgency, frequency, or incomplete bladder emptying; erectile dysfunction in males; or significant orthostatic hypotension decline that does not meet the level requirements in probable multiple system atrophy, and   • at least 1 additional feature from Table 2.

 

(Gilman et al 2008)

 

Table 2. Additional Diagnostic Criteria for Possible Multiple System Atrophy

 

Possible MSA-P or MSA-C	• Babinski sign with hyperreflexia • Stridor
Possible MSA-P	• Rapidly progressive parkinsonism • Poor response to levodopa • Postural instability within 3 years of motor onset • Gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction • Dysphagia within 5 years of motor onset • Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum • Hypometabolism on FDG-PET in putamen, brainstem, or cerebellum
Possible MSA-C	• Parkinsonism • Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum • Hypometabolism on FDG-PET in putamen • Presynaptic nigrostriatal dopaminergic denervation in SPECT or PET

 

(Gilman et al 2008)

Prognosis and complications

  As a heterogeneous group, autopsy-proven cases of multiple system atrophy survived a mean of 8.0 years in an autopsy series (Hughes et al 1992). A meta-analysis of 433 cases gave a mean survival of only 6.2 years (Ben-Shlomo et al 1997), with no difference between the parkinsonian type and cerebellar type. In a large series, median intervals from onset to the need for gait assistance was 3 years, to wheelchair confinement 5 years, to a bedbound state 8 years, and to death 9 years (Watanabe et al 2002). In the final stage, all 3 variants will produce a rigid, bradykinetic state leading eventually to a bed-bound existence with aphagia and its complications. Levodopa may induce disabling confusion and psychosis and may cause dyskinesias without concomitant motor benefit (Hughes et al 1992). Sudden death is over 7 times as common in patients with dysautonomic predominance than in other forms of multiple system atrophy (Tada et al 2007).

Management

  Available treatments are primarily symptomatic (Esper and Factor 2007). Although estimates vary, about 30% to 40% of multiple system atrophy patients may be responsive to levodopa (Constantinescu et al 2007). Facial dystonia occurs more frequently than limb dyskinesias with levodopa therapy. Levodopa therapy may worsen orthostatic hypotension (Wenning et al 2005; Constantinescu et al 2007). Treatment may be initiated with carbidopa/levodopa 25/100 0.5 to 1 tablet twice a day and increased every few days to efficacy or side effects. Patients with multiple system atrophy may require and tolerate far larger dosages than patients with Parkinson disease. High-dose levodopa therapy has been found to be nontoxic in a transgenic mouse multiple system atrophy model (Stefanova et al 2007a). Ancillary antiparkinsonian agents have not added importantly to the efficacy of levodopa, but adequate studies are lacking.

  Treatment of symptomatic orthostatic hypotension starts with sodium and volume repletion, unless the patient is at risk of congestive heart failure or renal insufficiency. Patients with multiple system atrophy and dysautonomia should be informed that the frequent recommendation to minimize dietary sodium does not necessarily apply to them. Drinking 350 mL of tap water once daily in the early morning demonstrated a benefit in treating orthostatic hypotension in a group of multiple system atrophy patients without any adverse effects (Deguchi et al 2007a). Four hundred and fifty milliliters of clear water ingestion was confirmed to have a pressor effect in another study of orthostatic insufficiency, but eating clear soup seemed to have a postprandial hypotensive effect (Z'graggen et al 2010).

  Ancillary measures such as pressure stockings to increase central venous volume and elevating the head of the bed 6 inches to increase renin secretion may also be attempted, but often prove uncomfortable. It is also useful to avoid extreme heat with its reflex peripheral vasodilation and to avoid overeating and straining at stool, which increase vagal activity.

  The mineralocorticoid fludrocortisone may be started at 0.1 mg daily and increased to a maximum of 4 tablets per day in 2 divided doses, given with fluid repletion. Midodrine, an alpha-adrenergic agonist, is a good alternative (Jankovic et al 1993). Treatment starts with 2.5 mg 3 times a day increasing to 10 mg 3 times a day. Supine hypertension is an uncommon but important adverse effect that may be lessened by raising the head of the bed. If these drugs are unsuccessful, inhibition of vasodilator prostaglandin synthesis may be initiated with indomethacin 25 mg 3 times a day with meals increasing to 50 mg 3 times a day. Alternatives include the alpha-adrenergic agonist clonidine 0.1 mg twice a day increasing to 0.3 mg twice a day, and the peripheral vasoconstrictors ephedrine starting at 25 mg 3 times a day and propranolol starting at 20 mg twice a day.

  Pyridostigmine has recently been found to ameliorate the hypotension of multiple system atrophy without causing supine hypertension, at least after a single 60 mg dose (Singer et al 2006).

  Urinary frequency or incontinence may respond to a peripherally acting anticholinergic agent such as oxybutynin 5 to 10 mg at bedtime, tolterodine 2 mg at bedtime, or propantheline 15 to 30 mg at bedtime, if the pathophysiology is detrusor hyperreflexia. However, anticholinergic treatment may worsen the constipation of multiple system atrophy. The impotence of multiple system atrophy may respond to yohimbine 5.6 mg 1 to 3 times daily (Robertson and Davis 1995). Sildenafil, although efficacious, often exacerbates the orthostatic hypotension of multiple system atrophy (Hussain et al 2001).

  The hallucinations caused by dopaminergic therapeutic agents usually respond to clozapine 6.25 to 50 mg or quetiapine 25 to 75 mg at bedtime. These must be used cautiously in patients with hypotension. All patients receiving clozapine must be monitored for agranulocytosis with weekly white blood cell counts.

  There is no known treatment for the ataxia of multiple system atrophy, olivopontocerebellar atrophy type.

  Rapid eye movement behavior disorder usually responds well to clonazepam 0.5 mg at bedtime. Patients with multiple system atrophy have a higher risk of obstructive sleep apnea (Gama et al 2010). Central apnea due to degeneration of pontomedullary respiratory centers may be masked by untreated obstructive sleep apnea (Suzuki et al 2010). Nocturnal stridor (Tanaka et al 2007) due to vocal cord paralysis and possible excessive adductor activation (Vetrugno et al 2007b) is treated with continuous positive airway pressure (CPAP) (Shiba et al 2007).

  Laryngoscopy under anesthesia may be useful for evaluating upper airway obstruction in multiple system atrophy (Shimohata et al 2007). Tremulous arytenoid movements are a marker of severity of glottic stenosis, which worsens as the disease progresses (Ozawa et al 2010). If stridor occurs during wakefulness or CPAP is not tolerated, tracheostomy should be considered (Iranzo 2007). Sudden death may occur in a subset of patients, even with tracheostomy (Tada et al 2009). Gastrostomy and tube feeding may be necessary in later stages of the disease (Nagaoka et al 2010).

  Deep brain stimulation of the internal pallidum remains ineffective for multiple system atrophy and may even be harmful (Lambrecq et al 2008). Intravenous immunoglobulin therapy has no effect on multiple system atrophy (Nanri et al 2009).

  Nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to inhibit the formation of alpha-synuclein fibrils, which are involved in the pathogenesis of multiple system atrophy, and could serve as a potential drug development target for multiple system atrophy treatment (Hirohata et al 2008). Fibril formation is also inhibited by nicotine (Ono et al 2007). Suppression of microglial activation is another potential research target (Stefanova et al 2007b). The Unified Multiple System Atrophy Rating Scale (UMSARS) has been evaluated as an outcome measure to be used in therapeutic trials (Wenning et al 2005; May et al 2007). Pontine and cerebellar atrophy rates on MRI can also serve as outcome measures (Paviour et al 2007). The PDQ-39 questionnaire, a disease-specific quality of life instrument for patients with Parkinson disease, has only limited validity in multiple system atrophy (Schrag et al 2007a). A multiple system atrophy health-related quality of life scale (MSA-QoL) has been reported to have good potential for use in clinical trials (Schrag et al 2007b). A prospective, 48-week, randomized, double-blind, multinational study failed to show a clinical effect of minocycline on symptom severity (Dodel et al 2010). More studies of the serotonergic system may also provide important insights due to reports of serotonergic depletion in ventrolateral medulla as well as a possible motor symptoms benefit from paroxetine (Friess et al 2006; Tada et al 2009).

Pregnancy

  No information was provided by the author.

Anesthesia

  Patients with any form of parkinsonism should avoid neuroleptic tranquilizers. Hypotension may be aggravated by opiates or other sedatives. The dysphagia of some patients with multiple system atrophy dictates careful postoperative airway management.

ICD codes

ICD-9:

Other degenerative diseases of the basal ganglia: 333.0

 

ICD-10:

Other specified degenerative diseases of basal ganglia: G23.8

Associated disorders

Obstructive sleep apnea

Rapid eye movement behavioral disorder

Related summaries

Advanced Parkinson disease

Epidemiology of movement disorders

Myoclonus

Neurochemical and functional imaging of movement disorders

Obstructive sleep apnea

Parkinson disease

Rapid eye movement sleep behavior disorder

Sleep disorders associated with parkinsonism

Differential diagnosis

Parkinson disease

progressive supranuclear palsy

corticobasal degeneration

fragile-X-associated tremor-ataxia syndrome

multi-infarct states

spinocerebellar ataxia

pure autonomic failure

Demographics

For more specific demographic information, see the Epidemiology, Etiology, and Pathogenesis and pathophysiology sections of this clinical summary.

 

Age

19-44 years

45-64 years

65+ years

 

Population

None selectively affected.

 

Occupation

None selectively affected.

 

Sex

male=female

 

Family history

None

 

Heredity

None

References cited

Abdo WF, Bloem BR, Van Geel WJ, Esselink RA, Verbeek MM. CSF neurofilament light chain and tau differentiate multiple system atrophy from Parkinson's disease. Neurobiol Aging 2007a;28(5):742-7.

 

Abdo WF, van de Warrenburg BP, Kremer HP, Bloem BR, Verbeek MM. CSF biomarker profiles do not differentiate between the cerebellar and parkinsonian phenotypes of multiple system atrophy. Parkinsonism Relat Disord 2007b;13(8):480-2.

 

Abele M, Burk K, Schols L, et al. The aetiology of sporadic adult-onset ataxia. Brain 2002;125(Pt 5):961-8.

 

Abele M, Minnerop M, Urbach H, Specht K, Klockgether T. Sporadic adult onset ataxia of unknown etiology : a clinical, electrophysiological and imaging study. J Neurol 2007;254(10):1384-9.

 

Adams RD, Salam-Adams M. Striatonigral degeneration. In: Vinken PJ, Bruyn GW, Klawans HL, editors. Extrapyramidal disorders. Handbook of clinical neurology. Vol. 49. Amsterdam: Elsevier, 1986:205-12.

 

Adams RD, van Bogaert L, van der Eecken H. Striato-nigral degeneration. J Neuropathol Exp Neurol 1964;23:584-608.

 

Albuquerque AV, Freitas MR, Cincinatus D, Harouche MB. Clinical-radiological correlation. Report of two cases. Arq Neuropsiquiatr 2007;65(2B):512-5.

 

Anderson T, Luxon L, Quinn N, Daniel S, Marsden CD, Bronstein A. Oculomotor function in multiple system atrophy: clinical and laboratory features in 30 patients. Mov Disord 2008;23(7):977-84.

 

Armstrong RA. Visual signs and symptoms of Parkinson's disease. Clin Exp Optom 2008;91(2):129-38.

 

Armstrong RA, Cairns NJ, Lantos PL. A quantitative study of the pathological changes in white matter in multiple system atrophy. Neuropathology 2007;27(3):221-7.

 

Baba Y, Uitti RJ, Boylan KB, et al. Aprataxin (APTX) gene mutations resembling multiple system atrophy. Parkinsonism Relat Disord 2007;13(3):139-42.

 

Balas M, Balash Y, Giladi N, Gurevich T. Cognition in multiple system atrophy: neuropsychological profile and interaction with mood. J Neural Transm 2010;117(3):369-75.

 

Beck RO, Betts CD, Fowler CJ. Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases. J Urology 1994;151:1336-41.

 

Benarroch EE, Schmeichel AM, Sandroni P, Parisi JE, Low PA. Rostral raphe involvement in Lewy body dementia and multiple system atrophy. Acta Neuropathol 2007;114(3):213-20.

 

Ben-Shlomo Y, Wenning GK, Tison F, Quinn NP. Survival of patients with pathologically proven multiple system atrophy: a meta-analysis. Neurology 1997;48:384-93.

 

Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 1997;49:1284-8.

 

Brooks DJ, Seppi K; Neuroimaging Working Group on MSA. Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov Disord 2009;24(7):949-64.

 

Bukhatwa S, Zeng BY, Rose S, Jenner P. A comparison of changes in proteasomal subunit expression in the substantia nigra in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Brain Res 2010;1326:174-83.

 

Burk K, Skalej M, Dichgans J. Pontine MRI hyperintensities ("the cross sign") are not pathognomonic for multiple system atrophy (MSA). Mov Disord 2001;16(3):535.

 

Cho JW, Jeon BS, Jeong D, et al. Association between parkinsonism and participation in agriculture in Korea. J Clin Neurol 2008a;4(1):23-8.

 

Cho JW, Kim SY, Park SS, Jeon BS. Spinocerebellar ataxia type 12 was not found in Korean Parkinsonian patients. Can J Neurol Sci 2008b;35(4):488-90.

 

Colosimo C, Morgante L, Antonini A, et al. Non-motor symptoms in atypical and secondary parkinsonism: the PRIAMO study. J Neurol 2010;257(1):5-14.

 

Constantinescu R, Richard I, Kurlan R. Levodopa responsiveness in disorders with parkinsonism: a review of the literature. Mov Disord 2007;22(15):2141-8.

 

Constantinescu R, Rosengren L, Johnels B, Zetterberg H, Holmberg B. Consecutive analyses of cerebrospinal fluid axonal and glial markers in Parkinson's disease and atypical Parkinsonian disorders. Parkinsonism Relat Disord 2010;16(2):142-5.

 

Cosottini M, Ceravolo R, Faggioni L, et al. Assessment of midbrain atrophy in patients with progressive supranuclear palsy with routine magnetic resonance imaging. Acta Neurol Scand 2007;116(1):37-42.

 

Deguchi K, Ikeda K, Sasaki I, et al. Effects of daily water drinking on orthostatic and postprandial hypotension in patients with multiple system atrophy. J Neurol 2007a;254(6):735-40.

 

Deguchi K, Ikeda K, Shimamura M, et al. Assessment of autonomic dysfunction of multiple system atrophy with laryngeal abductor paralysis as an early manifestation. Clin Neurol Neurosurg 2007b;109(10):892-5.

 

Dejerine J, Thomas A. L'atrophie olivopontocerebelleuse. Nouv Iconogr Salpet 1900;13:330-70.

 

Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease. Acta Neuropathol 2010;119(6):703-13.

 

Dickson DW, Liu WK, Hardy J, et al. Widespread alterations in alpha-synuclein in multiple system atrophy. Am J Pathol 1999;155:1241-51.

 

Dodel R, Spottke A, Gerhard A, et al. Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord 2010;25(1):97-107.

 

Eckert T, Van Laere K, Tang C, et al. Quantification of Parkinson's disease-related network expression with ECD SPECT. Eur J Nucl Med Mol Imaging 2007;34(4):496-501.

 

Egami N, Inoue A, Osanai R, Kitahara N, Kaga K. Vocal cord abductor paralysis in multiple system atrophy: a case report. Acta Otolaryngol Suppl 2007;(559):164-7.

 

Esper CD, Factor SA. Current and future treatments in multiple system atrophy. Curr Treat Options Neurol 2007;9(3):210-23.

 

Eusebio A, Azulay JP, Witjas T, Rico A, Attarian S. Assessment of cortico-spinal tract impairment in multiple system atrophy using transcranial magnetic stimulation. Clin Neurophysiol 2007;118(4):815-23.

 

Finke C, Siebert E, Plotkin M, Wenning GK, Reuter U. Multiple system atrophy masking multiple sclerosis. Clin Neurol Neurosurg 2010;112(1):59-61.

 

Freilich S, Goff EA, Malaweera AS, et al. Sleep architecture and attenuated heart rate response to arousal from sleep in patients with autonomic failure. Sleep Med 2010;11(1):87-92.

 

Friedrich C, Rudiger H, Schmidt C, et al. Baroreflex sensitivity and power spectral analysis in different extrapyramidal syndromes. J Neural Transm 2008;115(11):1527-36.

 

Friess E, Kuempfel T, Modell S, et al. Paroxetine treatment improves motor symptoms in patients with multiple system atrophy. Parkinsonism Relat Disord 2006;12(7):432-7.

 

Furiya Y, Hirano M, Kurumatani N, et al. alpha-1-Antichymotrypsin gene polymorphism and susceptibility to multiple system atrophy (MSA). Brain Res Mol Brain Res 2005;138:178-81.

 

Gai WP, Power JH, Blumbergs PC, Blessing WW. Multiple-system atrophy: a new alpha-synuclein disease? Lancet 1998;352:547-8.

 

Gama RL, Tavora DG, Bomfim RC, Silva CE, de Bruin VM, de Bruin PF. Sleep disturbances and brain MRI morphometry in Parkinson's disease, multiple system atrophy and progressive supranuclear palsy - a comparative study. Parkinsonism Relat Disord 2010;16(4):275-9.

 

Giladi N, Simon ES, Korczyn AD, et al. Anal sphincter EMG does not distinguish between multiple system atrophy and Parkinson's disease. Muscle Nerve 2000;23:731-4.

 

Gilman S, Low PA, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999;163(1):94-8.

 

Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71(9):670-6.

 

Goldstein DS. Cardiac ectopy in chronic autonomic failure. Clin Auton Res 2010;20(2):85-92.

 

Goldstein DS, Holmes C, Bentho O, et al. Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy. Parkinsonism Relat Disord 2008;14(8):600-7.

 

Gomez-Esteban JC, Tijero B, Ciordia R, et al. Factors influencing the symmetry of Parkinson's disease symptoms. Clin Neurol Neurosurg 2010;112(4):302-5.

 

Guevara CA, Blain CR, Stahl D, Lythgoe DJ, Leigh PN, Barker GJ. Quantitative magnetic resonance spectroscopic imaging in Parkinson's disease, progressive supranuclear palsy and multiple system atrophy. Eur J Neurol 2010. [Epub ahead of print]

 

Gupta D, Saini J, Kesavadas C, Sarma PS, Kishore A. Utility of susceptibility-weighted MRI in differentiating Parkinson's disease and atypical parkinsonism. Neuroradiology 2010. [Epub ahead of print]

 

Hara K, Momose Y, Tokiguchi S, et al. Multiplex families with multiple system atrophy. Arch Neurol 2007;64(4):545-51.

 

Hellmann MA, Melamed E, Steinmetz AP, Djaldetti R. Unilateral lower limb rest tremor is not necessarily a presenting symptom of Parkinson's disease. Mov Disord 2010;25(7):924-7.

 

Hirano S, Shinotoh H, Arai K, et al. PET study of brain acetylcholinesterase in cerebellar degenerative disorders. Mov Disord 2008;23(8):1154-60.

 

Hirohata M, Ono K, Morinaga A, Yamada M. Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. Neuropharmacology 2008;54(3):620-7.

 

Honjo Y, Shirakashi Y, Kawamoto Y, Akiguchi I. Anti-DARPP32 antibody-immunopositive inclusions in the brain of patients with multiple system atrophy. Clin Neuropathol 2008;27(5):309-16.

 

Huang Y, Song YJ, Murphy K, et al. LRRK2 and parkin immunoreactivity in multiple system atrophy inclusions. Acta Neuropathol 2008;116(6):639-46.

 

Hughes AJ, Colosimo C, Kleedorfer B, Daniel SE, Lees AJ. The dopaminergic response in multiple system atrophy. J Neurol Neurosurg Psychiatry 1992;55:1009-13.

 

Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ. Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson's disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry 2001;71:371-4.

 

Imrich R, Eldadah BA, Bentho O, et al. Attenuated pre-ejection period response to tyramine in patients with cardiac sympathetic denervation. Ann N Y Acad Sci 2008;1148:486-9.

 

Iranzo A. Management of sleep-disordered breathing in multiple system atrophy. Sleep Med 2005;6(4):297-300.

 

Iranzo A. Sleep and breathing in multiple system atrophy. Curr Treat Options Neurol 2007;9(5):347-53.

 

Iranzo A, Santamaria J, Rye DB, et al. Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD. Neurology 2005;65:247-52.

 

Ito M, Watanabe H, Kawai Y, et al. Usefulness of combined fractional anisotropy and apparent diffusion coefficient values for detection of involvement in multiple system atrophy. J Neurol Neurosurg Psychiatry 2007;78(7):722-8.

 

Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: a double-blind placebo-controlled study with midodrine. Am J Med 1993;95(1):38-48.

 

Jellinger KA, Lantos PL. Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update. Acta Neuropathol 2010;119(6):657-67.

 

Kamm C, Healy DG, Quinn NP, et al. The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group. Brain 2005;128:1855-60.

 

Kataoka H, Tonomura Y, Taoka T, Ueno S. Signal changes of superior cerebellar peduncle on fluid-attenuated inversion recovery in progressive supranuclear palsy. Parkinsonism Relat Disord 2008;14(1):63-5.

 

Kawai Y, Suenaga M, Takeda A, et al. Cognitive impairments in multiple system atrophy: MSA-C vs MSA-P. Neurology 2008;70(16 Pt 2):1390-6.

 

Kawamoto Y, Kobayashi Y, Suzuki Y, et al. Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with alpha-synucleinopathies. J Neuropathol Exp Neurol 2008;67(10):984-93.

 

Kirby R, Fowler C, Gosling F, Bannister R. Urethro-vesical dysfunction in progressive autonomic failure with multiple system atrophy. J Neurol Neurosurg Psychiatry 1986;49:554-62.

 

Kollensperger M, Geser F, Seppi K, et al. Red flags for multiple system atrophy. Mov Disord 2008;23(8):1093-9.

 

Kwon KY, Choi CG, Kim JS, Lee MC, Chung SJ. Diagnostic value of brain MRI and 18F-FDG PET in the differentiation of Parkinsonian-type multiple system atrophy from Parkinson's disease. Eur J Neurol 2008;15(10):1043-9.

 

Lambrecq V, Krim E, Meissner W, Guehl D, Tison F. [Deep-brain stimulation of the internal pallidum in multiple system atrophy.] Rev Neurol (Paris) 2008;164(4):398-402.

 

Lastres-Becker I, Rub U, Auburger G. Spinocerebellar ataxia 2 (SCA2). Cerebellum 2008;7(2):115-24.

 

Lin IS, Wu RM, Lee-Chen GJ, Shan DE, Gwinn-Hardy K. The SCA17 phenotype can include features of MSA-C, PSP and cognitive impairment. Parkinsonism Relat Disord 2007;13(4):246-9.

 

Lincoln SJ, Ross OA, Milkovic NM, et al. Quantitative PCR-based screening of alpha-synuclein multiplication in multiple system atrophy. Parkinsonism Relat Disord 2007;13(6):340-2.

 

Linder J, Stenlund H, Forsgren L. Incidence of Parkinson's disease and parkinsonism in northern Sweden: a population-based study. Mov Disord 2010;25(3):341-8.

 

Lipp A, Sandroni P, Ahlskog JE, Maraganore DM, Shults CW, Low PA. Calf venous compliance in multiple system atrophy. Am J Physiol Heart Circ Physiol 2007;293(1):H260-5.

 

Lipp A, Sandroni P, Ahlskog JE, et al. Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure. Arch Neurol 2009;66(6):742-50.

 

Lipp A, Schmelzer JD, Low PA, Johnson BD, Benarroch EE. Ventilatory and cardiovascular responses to hypercapnia and hypoxia in multiple-system atrophy. Arch Neurol 2010;67(2):211-6.

 

Mabuchi N, Hirayama M, Koike Y, et al. Progression and prognosis in pure autonomic failure (PAF): comparison with multiple system atrophy. J Neurol Neurosurg Psychiatry 2005;76:947-52.

 

Marini C, di Poggio MB, Pomposelli E, et al. Whole body and cardiac metaiodobenzylguanidine kinetics in Parkinson disease and multiple system atrophy: implications for the diagnostic role of imaging. Clin Nucl Med 2010;35(5):311-6.

 

Martinez-Rodriguez JE, Seppi K, Cardozo A, et al. Cerebrospinal fluid hypocretin-1 levels in multiple system atrophy. Mov Disord 2007;22(12):1822-4.

 

May S, Gilman S, Sowell BB, et al. Potential outcome measures and trial design issues for multiple system atrophy. Mov Disord 2007;22(16):2371-7.

 

Miller VM, Kalaria RN, Hall R, Oakley AE, Kenny RA. Medullary microvessel degeneration in multiple system atrophy. Neurobiol Dis 2007;26(3):615-22.

 

Minnerop M, Specht K, Ruhlmann J, et al. Voxel-based morphometry and voxel-based relaxometry in multiple system atrophy-a comparison between clinical subtypes and correlations with clinical parameters. Neuroimage 2007;36(4):1086-95.

 

Miyatake S, Mochizuki H, Naka T, et al. Brain volume analyses and somatosensory evoked potentials in multiple system atrophy. J Neurol 2010;257(3):419-25.

 

Munschauer FE, Loh L, Bannister R, Newsom-Davis J. Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomic failure. Neurology 1990;40:677-9.

 

Muqit MM, Mort D, Miskiel KA, Shakir RA. "Hot cross bun" sign in a patient with parkinsonism secondary to presumed vasculitis. J Neurol Neurosurg Psychiatry 2001;71(4):565-6.

 

Nagaoka U, Shimizu T, Matsukura T, Takeda M. [Nutritional problems in multiple system atrophy--necessity of early tube feeding and caloric restriction at the advanced stage.] Rinsho Shinkeigaku 2010;50(3):141-6.

 

Nagata T, Kamei H, Furuya K, Fujii N, Noda K, Iwaki T. [Pathological study on abducent paralysis of the vocal cord in a patient having multiple system atrophy with nasogastric intubation.] Rinsho Shinkeigaku 2007;47(6):340-3.

 

Nandi D, Jenkinson N, Stein J, Aziz T. The pedunculopontine nucleus in Parkinson's disease: primate studies. Br J Neurosurg 2008;22 Suppl 1:S4-8.

 

Nanri K, Koizumi K, Mitoma H, et al. Classification of cerebellar atrophy using voxel-based morphometry and SPECT with an easy Z-score imaging system. Intern Med 2010;49(6):535-41.

 

Nanri K, Okita M, Takeguchi M, et al. Intravenous immunoglobulin therapy for autoantibody-positive cerebellar ataxia. Intern Med 2009;48(10):783-90.

 

Nee LE, Gomez MR, Dambrosia J, Bale S, Eldridge R, Polinsky RJ. Environmental-occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation. Clin Auton Res 1991;1(1):9-13.

 

Nishimura M, Kawakami H, Komure O, et al. Contribution of the interleukin-1beta gene polymorphism in multiple system atrophy. Mov Disord 2002;17(4):808-11.

 

Okawa M, Miwa H, Kajimoto Y, et al. Transcranial sonography of the substantia nigra in Japanese patients with Parkinson's disease or atypical parkinsonism: clinical potential and limitations. Intern Med 2007;46(18):1527-31.

 

Okuma Y, Fujishima K, Miwa H, Mori H, Mizuno Y. Myoclonic tremulous movements in multiple system atrophy are a form of cortical myoclonus. Mov Disord 2005;252:91-6.

 

Ono K, Hirohata M, Yamada M. Anti-fibrillogenic and fibril-destabilizing activity of nicotine in vitro: implications for the prevention and therapeutics of Lewy body diseases. Exp Neurol 2007;205(2):414-24.

 

Orimo S. [Clinical and pathological study on early diagnosis of Parkinson's disease and dementia with Lewy bodies.] Rinsho Shinkeigaku 2008a;48(11):831-4.

 

Orimo S, Uchihara T, Nakamura A, et al. Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson's disease. Brain 2008b;131(Pt 3):642-50.

 

Ozawa T. Morphological substrate of autonomic failure and neurohormonal dysfunction in multiple system atrophy: impact on determining phenotype spectrum. Acta Neuropathol 2007;114(3):201-11.

 

Ozawa T, Shinoda H, Tomita M, Shimohata T, Nakayama H, Nishizawa M. Tremulous arytenoid movements predict severity of glottic stenosis in multiple system atrophy. Mov Disord 2010. [Epub ahead of print]

 

Paleologou KE, Oueslati A, Shakked G, et al. Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J Neurosci 2010;30(9):3184-98.

 

Papp M, Kahn J, Lantos P. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 1989;94:79-100.

 

Parkkinen L, Hartikainen P, Alafuzoff I. Abundant glial alpha-synuclein pathology in a case without overt clinical symptoms. Clin Neuropathol 2007;26(6):276-83.

 

Parvizi J, Joseph J, Press DZ, Schmahmann JD. Pathological laughter and crying in patients with multiple system atrophy-cerebellar type. Mov Disord 2007;22(6):798-803.

 

Paviour DC, Price SL, Lees AJ, Fox NC. MRI derived brain atrophy in PSP and MSA-P. Determining sample size to detect treatment effects. J Neurol 2007;254(4):478-81.

 

Paviour DC, Williams D, Fowler CJ, Quinn NP, Lees AJ. Is sphincter electromyography a helpful investigation in the diagnosis of multiple system atrophy? A retrospective study with pathological diagnosis. Mov Disord 2005;20(11):1425-30.

 

Pellecchia MT, Longo K, Manfredi M, et al. The arginine growth hormone stimulation test in bradykinetic-rigid parkinsonisms. Mov Disord 2008;23(2):190-4.

 

Pietzarka K, Reimann M, Schmidt C, et al. The cold hand sign in multiple system atrophy: skin perfusion revisited. J Neural Transm 2010;117(4):475-9.

 

Plazzi G, Corsini R, Provini F, et al. REM sleep behavior disorders in multiple system atrophy. Neurology 1997;48:1094-7.

 

Punal Rioboo J, Varela Lema L, Serena Puig A, Ruano-Ravina A. [Effectiveness of 123I-ioflupane (DaTSCAN) in the diagnosis of Parkinsonian syndromes. A systematic review.] Rev Esp Med Nucl 2007;26(6):375-84.

 

Quinn N. Multiple system atrophy--the nature of the beast. J Neurol Neurosurg Psychiatry 1989;Suppl:78-89.

 

Quinn NP, Luthert P, Honavar M, Marsden CD. Pure akinesia due to Lewy body Parkinson's disease: a case with pathology. Mov Disord 1989;4(1):85-8.

 

Reimann M, Schmidt C, Herting B, et al. Comprehensive autonomic assessment does not differentiate between Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. J Neural Transm 2010;117(1):69-76.

 

Robertson D, Davis TL. Recent advances in the treatment of orthostatic hypotension. Neurology 1995;45:S26-32.

 

Rusina R, Bourdain F, Matej R. [Multiple system atrophy and Alzheimer's disease: a case report of a rare association of two neuro-degenerative disorders.] Rev Neurol (Paris) 2007;163(12):1239-41.

 

Salazar G, Casas E, Oliveras D, Rando A, Sergio P. Ocular-jaw synkinesia in normal, Parkinson's disease, and multiple system atrophy subjects: Clinical and electrophysiological findings. Clin Neurophysiol 2010;121(1):94-7.

 

Sato K, Kaji R, Matsumoto S, Goto S. Cell type-specific neuronal loss in the putamen of patients with multiple system atrophy. Mov Disord 2007a;22(5):738-42.

 

Sato K, Kaji R, Matsumoto S, Nagahiro S, Goto S. Compartmental loss of striatal medium spiny neurons in multiple system atrophy of parkinsonian type. Mov Disord 2007b;22(16):2365-70.

 

Scholz SW, Houlden H, Schulte C, et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 2009;65(5):610-4.

 

Schrag A, Ben-Shlomo Y, Quinn NP. Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 1999;354:1771-5.

 

Schrag A, Jenkinson C, Selai C, Mathias C, Quinn N. Testing the validity of the PDQ-39 in patients with MSA. Parkinsonism Relat Disord 2007a;13(3):152-6.

 

Schrag A, Selai C, Mathias C, et al. Measuring health-related quality of life in MSA: the MSA-QoL. Move Disord 2007b;22(16):2332-8.

 

Seppi K, Poewe W. Brain magnetic resonance imaging techniques in the diagnosis of parkinsonian syndromes. Neuroimaging Clin N Am 2010;20(1):29-55.

 

Seppi K, Yekhlef F, Diem A, et al. Progression of parkinsonism in multiple system atrophy. J Neurol 2005;20:158-63.

 

Shiba K, Isono S, Nakazawa K. Paradoxical vocal cord motion: a review focused on multiple system atrophy. Auris Nasus Larynx 2007;34(4):443-52.

 

Shimohata T, Shinoda H, Nakayama H, et al. Daytime hypoxemia, sleep-disordered breathing, and laryngopharyngeal findings in multiple system atrophy. Arch Neurol 2007;64(6):856-61.

 

Shin HY, Kang SY, Yang JH, Kim HS, Lee MS, Sohn YH. Use of the Putamen/Caudate Volume Ratio for Early Differentiation between Parkinsonian Variant of Multiple System Atrophy and Parkinson Disease. J Clin Neurol 2007;3(2):79-81.

 

Shrivastava A. The hot cross bun sign. Radiology 2007;245(2):606-7.

 

Shy GM, Drager GA. A neurological syndrome associated with orthostatic hypotension: a clinical-pathological study. Arch Neurol 1960;2:511-27.

 

Singer W, Sandroni P, Opfer-Gehrking TL, et al. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol 2006;63:513-8.

 

Soares-Fernandes JP, Ribeiro M, Machado A. "Hot cross bun" sign in variant Creutzfeldt-Jakob disease. AJNR Am J Neuroradiol 2009;30(3):E37.

 

Soma H, Yabe I, Takei A, Fujiki N, Yanagihara T, Sasaki H. Heredity in multiple system atrophy. J Neurol Sci 2006;240:107-10.

 

Song SK, Lee SK, Lee JJ, et al. Blood-brain barrier impairment is functionally correlated with clinical severity in patients of multiple system atrophy. Neurobiol Aging 2010. [Epub ahead of print]

 

Song YJ, Lundvig DM, Huang Y, et al. p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol 2007;171(4):1291-303.

 

Stefanova N, Bücke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol 2009;8(12):1172-8.

 

Stefanova N, Kollensperger M, Hainzer M, Cenci A, Poewe W, Wenning GK. High dose levodopa therapy is not toxic in multiple system atrophy: experimental evidence. Mov Disord 2007a;22(7):969-73.

 

Stefanova N, Reindl M, Neumann M, Kahle PJ, Poewe W, Wenning GK. Microglial activation mediates neurodegeneration related to oligodendroglial alpha synucleinopathy: implications for multiple system atrophy. Mov Disord 2007b;22(15):2196-203.

 

Suzuki M, Saigusa H, Shibasaki K, Kodera K. Multiple system atrophy manifesting as complex sleep-disordered breathing. Auris Nasus Larynx 2010;37(1):110-3.

 

Tada M, Kakita A, Toyoshima Y, et al. Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death. Brain 2009;132(Pt 7):1810-9.

 

Tada M, Onodera O, Tada M, et al. Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy. Arch Neurol 2007;64:256-60.

 

Tan EK, Skipper L, Chua, et al. Analysis of 14 LRRK2 mutations in Parkinson's plus syndromes and late-onset Parkinson's disease. Mov Disord 2006;21:997-1001.

 

Tanaka H, Nishio H, Sasanabe R, Shiomi T. [A case of multiple systemic atrophy (MSA) analyzed by acoustic sound for nocturnal inspiratory stridor.] Nihon Kokyuki Gakkai Zasshi 2007;45(8):604-8.

 

Tanji K, Mori F, Kakita A, et al. Immunohistochemical localization of NUB1, a synphilin-1-binding protein, in neurodegenerative disorders. Acta Neuropathol 2007;114(4):365-71.

 

Taoka T, Kin T, Nakagawa H, et al. Diffusivity and diffusion anisotropy of cerebellar peduncles in cases of spinocerebellar degenerative disease. Neuroimage 2007;37(2):387-93.

 

Terni B, Rey MJ, Boluda S, et al. Mutant ubiquitin and p62 immunoreactivity in cases of combined multiple system atrophy and Alzheimer's disease. Acta Neuropathol 2007;113(4):403-16.

 

Tha KK, Terae S, Yabe I, et al. Microstructural white matter abnormalities of multiple system atrophy: in vivo topographic illustration by using diffusion-tensor MR imaging. Radiology 2010;255(2):563-9.

 

Tison F, Wenning GK, Volonte MA, Poewe WR, Henry P, Quinn NP. Pain in multiple system atrophy. J Neurol 1996;243:153-6.

 

Trojanowski JQ, Revesz T; Neuropathology Working Group on MSA. Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 2007;33(6):615-20.

 

Ubhi K, Rockenstein E, Mante M, et al. Alpha-synuclein deficient mice are resistant to toxin-induced multiple system atrophy. Neuroreport 2010. [Epub ahead of print]

 

Vanacore N, Bonifati V, Fabbrini G, et al. Smoking habits in multiple system atrophy and progressive supranuclear palsy. European Study Group on Atypical Parkinsonisms. Neurology 2000;54(1):114-9.

 

Vanacore N, Bonifati V, Fabbrini G, et al. Epidemiology of multiple system atrophy. ESGAP Consortium. European Study Group on Atypical Parkinsonisms. Neurol Sci 2001;22:97-9.

 

Vanacore N, Bonifati V, Fabbrini G, et al. Case-control study of multiple system atrophy. Mov Disord 2005;20:158-63.

 

van der Eecken H, Adams RD, van Bogaert L. Striopallidal-nigral degeneration. A hitherto undescribed lesion in paralysis agitans. J Neuropathol Exp Neurol 1960;19:159-61.

 

van de Warrenburg BP, Cordivari C, Ryan AM, et al. The phenomenon of disproportionate antecollis in Parkinson's disease and multiple system atrophy. Mov Disord 2007;22(16):2325-31.

 

Van Laere K, Clerinx K, D'Hondt E, de Groot T, Vandenberghe W. Combined striatal binding and cerebral influx analysis of dynamic 11C-raclopride PET improves early differentiation between multiple-system atrophy and Parkinson disease. J Nucl Med 2010;51(4):588-95.

 

Vetrugno R, D'Angelo R, Cortelli P, Plazzi G, Vignatelli L, Montagna P. Impaired cortical and autonomic arousal during sleep in multiple system atrophy. Clin Neurophysiol 2007a;118(11):2512-8.

 

Vetrugno R, Liguori R, Cortelli P, et al. Sleep-related stridor due to dystonic vocal cord motion and neurogenic tachypnea/tachycardia in multiple system atrophy. Mov Disord 2007b;22(5):673-8.

 

von Lewinski F, Werner C, Jorn T, Mohr A, Sixel-Doring F, Trenkwalder C. T2(*)-weighted MRI in diagnosis of multiple system atrophy: a practical approach for clinicians. J Neurol 2007;254(9):1184-8.

 

Walter U, Dressler D, Probst T, et al. Transcranial brain sonography findings in discriminating between parkinsonism and idiopathic Parkinson disease. Arch Neurol 2007;64(11):1635-40.

 

Waragai M, Yamada T, Matsuda H. Evaluation of brain perfusion SPECT using an easy Z-score imaging system (eZIS) as an adjunct to early-diagnosis of neurodegenerative diseases. J Neurol Sci 2007;260(1-2):57-64.

 

Watanabe H, Saito Y, Terao S, et al. Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 2002;125(Pt 5):1070-83.

 

Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. Clinical features and natural history of multiple system atrophy: an analysis of 100 cases. Brain 1994;117:835-45.

 

Wenning GK, Geser F, Poewe W. Therapeutic strategies in multiple system atrophy. Mov Disord 2005;20 Suppl 12:S67-76.

 

Wenning GK, Kraft E, Beck R, et al. Cerebellar presentation of multiple system atrophy. Mov Disord 1997;12:115-7.

 

Wenning GK, Tison F, Seppi K, et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord 2004;19:1391-402.

 

Williams DR, Lees AJ. What features improve the accuracy of the clinical diagnosis of progressive supranuclear palsy-parkinsonism (PSP-P)? Mov Disord 2010;25(3):357-62.

 

Winge K, Jennum P, Lokkegaard A, Werdelin L. Anal sphincter EMG in the diagnosis of parkinsonian syndromes. Acta Neurol Scand 2010;121(3):198-203.

 

Winkler AS, Marsden J, Parton M, Watkins PJ, Chaudhuri KR. Erythropoietin deficiency and anaemia in multiple system atrophy. Mov Disord 2001;16:233-9.

 

Woitalla D, Braak H, Tredici KD, et al. [Transcraniel ultrasound in the differential diagnosis of Parkinson's disease.] Fortschr Neurol Psychiatr 2010;78 Suppl 1:S25-30.

 

Wu YT, Shyu KK, Jao CW, et al. Fractal dimension analysis for quantifying cerebellar morphological change of multiple system atrophy of the cerebellar type (MSA-C). Neuroimage 2010;49(1):539-51.

 

Wullner U, Schmitz-Hubsch T, Abele M, Antony G, Bauer P, Eggert K. Features of probable multiple system atrophy patients identified among 4770 patients with parkinsonism enrolled in the multicentre registry of the German Competence Network on Parkinson's disease. J Neural Transm 2007;114(9):1161-5.

 

Yamanaka Y, Asahina M, Mathias CJ, Akaogi Y, Koyama Y, Hattori T. Skin vasodilator response to local heating in multiple system atrophy. Mov Disord 2007;22(16):2405-8.

 

Yamashita F, Hirayama M, Nakamura T, et al. Pupillary autonomic dysfunction in multiple system atrophy and Parkinson's disease: an assessment by eye-drop tests. Clin Auton Res 2010;20(3):191-7.

 

Yokoyama T, Hasegawa K, Horiuchi E, Yagishita S. Multiple system atrophy (MSA) with massive macrophage infiltration in the ponto-cerebellar afferent system. Neuropathology 2007;27(4):375-7.

 

Yomono HS, Kurisaki H, Hebisawa A, Sakiyama Y, Saito Y, Murayama S. [Autopsy case of SCA2 with Parkinsonian phenotype.] Rinsho Shinkeigaku 2010;50(3):156-62.

 

Yoshida M. Multiple system atrophy: alpha-synuclein and neuronal degeneration. Neuropathology 2007;27(5):484-93.

 

Z'graggen WJ, Hess CW, Humm AM. Acute fluid ingestion in the treatment of orthostatic intolerance - important implications for daily practice. Eur J Neurol 2010. [Epub ahead of print]

 

Zhang K, Zeng Y, Song C, Fu Y, Wan Q. The comparison of clonidine, arginine and both combined: a growth hormone stimulation test to differentiate multiple system atrophy from idiopathic Parkinson's disease. J Neurol 2010. [Epub ahead of print]

 

Ziemssen T, Reichmann H. Cardiovascular autonomic dysfunction in Parkinson's disease. J Neurol Sci 2010;289(1-2):74-80.

 

**References especially recommended by the author or editor for general reading.