REVIEW

Multiple System Atrophy of the Cerebellar Type: Clinical State of the Art David J. Lin, MD, Katherine L. Hermann, BA, and Jeremy D. Schmahmann, MD* Ataxia Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA

ABSTRACT:

Multiple system atrophy (MSA) is a late-onset, sporadic neurodegenerative disorder clinically characterized by autonomic failure and either poorly levodopa-responsive parkinsonism or cerebellar ataxia. It is neuropathologically defined by widespread and abundant central nervous system a-synuclein– positive glial cytoplasmic inclusions and striatonigral and/or olivopontocerebellar neurodegeneration. There are two clinical subtypes of MSA distinguished by the predominant motor features: the parkinsonian variant (MSA-P) and the cerebellar variant (MSA-C). Despite recent progress in understanding the pathobiology of MSA, investigations into the symptomatology and natural history of the cerebellar variant of the disease have been limited. MSA-C presents a unique challenge to both clinicians and researchers alike. A key question is how to distinguish early in the disease course between

Multiple system atrophy (MSA) is a late-onset, sporadic neurodegenerative disorder characterized by autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal tract signs in various combinations.1-3 The estimated incidence is 0.6 cases per 100,000 person-years, increasing to 3 cases per 100,000 person-years after age 50 years.4-6 The mean age of onset is approximately 54 years, and survival ranges

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*Correspondence to: Dr. Jeremy D. Schmahmann, Department of Neurology, Massachusetts General Hospital, 175 Cambridge Street, Suite 340, Boston, MA 02114-3117; [email protected]

Funding agencies: This study was supported by the National Ataxia Foundation, the National Organization for Rare Disorders, the Birmingham Foundation, and the Mindlink Foundation. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 15 October 2013; Revised: 27 December 2013; Accepted: 27 January 2014 Published online 24 February 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25847

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MSA-C and other causes of adult-onset cerebellar ataxia. This is a particularly difficult question, because the clinical framework for conceptualizing and studying sporadic adult-onset ataxias continues to undergo flux. To date, several investigations have attempted to identify clinical features, imaging, and other biomarkers that may be predictive of MSA-C. This review presents a clinically oriented overview of our current understanding of MSA-C with a focus on evidence for distinguishing C 2014 MSA-C from other sporadic, adult-onset ataxias. V International Parkinson and Movement Disorder Society

K e y W o r d s : multiple system atrophy; cerebellum; ataxia; idiopathic late-onset cerebellar ataxia; sporadic adult-onset ataxia of unknown etiology

from 7 to 9 years.7,8 The defining pathology of MSA consists of widespread neurodegeneration in striatonigral and olivopontocerebellar structures accompanied by distinctive glial cytoplasmic inclusions formed by fibrillized a-synuclein.9-12 There are two clinical subtypes of MSA based on the predominant motor feature present at the time of clinical presentation: poorly levodopa (L-dopa)– responsive parkinsonism (MSA-P) or cerebellar ataxia (MSA-C).1 The majority of investigations into the clinical course of MSA have focused on MSA-P rather than on MSA-C, perhaps reflecting the epidemiological bias that MSA-P is at least two times more prevalent than MSA-C in North America and Europe.13-15 In addition, studying MSA-P in the differential diagnosis of Parkinson’s disease (PD) seems only natural given the shared a-synuclein neuropathology.16 Specific investigations into the symptomatology and natural history of MSA-C are much more limited. One of the most important and as yet unanswered questions for the neurologist evaluating a patient with

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ataxia is how to differentiate MSA-C from other adult-onset cerebellar ataxias. Here, we review the current literature on MSA-C with a focus on early diagnosis.

Multiple System Atrophy: A Moving Target MSA has been difficult to study in part because its nosology has changed markedly over time. In 1900, Dejerine and Thomas introduced the term olivopontocerebellar atrophy (OPCA) in a clinical description of two patients with ataxia, dysarthria, akinesia, rigidity, brisk leg reflexes, and urinary incontinence with pathologic findings of atrophy in the olives, pons, and cerebellum.17 Over subsequent years, a number of authors, including Shy and Drager, recognized an association between autonomic dysfunction, postural hypotension, and pathology involving the striatonigral and olivopontocerebellar systems.18-20 By the 1960s, neurologists used OPCA, idiopathic orthostatic hypotension, Shy-Drager syndrome, and striatonigral degeneration to describe separate clinical and pathologic entities, when, in fact, these terms may have all described the same disease. Recognizing this confusing multiplicity, Graham and Oppenheimer proposed the term multiple system atrophy in 1969.21 The major catalyst in shaping our understanding of and clinical context for MSA has been the elucidation of the underlying neuropathology. Whereas the neurodegeneration in MSA primarily affects the substantia nigra, the sensorimotor striatum, dopaminergic terminals in the putamen, the inferior olive, the pontine nuclei, and the cerebellar vermis, it also noticeably affects other brainstem nuclei and the intermediolateral cell column of the spinal cord.22 In 1989, Papp and colleagues reported the presence of widespread filamentous glial cytoplasmic inclusions in the brains of patients with MSA.9 The subsequent discovery that asynuclein, a neuronal presynaptic protein, is a major component of these inclusions10-12,23 linked MSA to the family of a-synucleinopathies, which include PD and dementia with Lewy bodies.24,25 It should be noted that MSA-C and MSA-P share the common neuropathology of glial a-synuclein inclusions. Moreover, although it currently continues to be useful to divide these two presentations of MSA for diagnosis and symptom-alleviating interventions, targeted asynuclein treatments in the future may make this clinical division less relevant. Diagnostic criteria for MSA have undergone many changes in the past two decades. When Niall Quinn proposed the first diagnostic classification of MSA in 1989, he defined two subtypes of MSA—the striatonigral degeneration (SND) type with predominant parkinsonism and the OPCA type with predominant cerebellar features—and three levels of diagnostic certainty—possible, probable, and definite (requiring

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post-mortem confirmation).2 In 1999, Gilman and colleagues reported the results from a consensus conference on the diagnosis of MSA.26 Definite MSA now required neuropathologic examination of glial cytoplasmic inclusions. The clinical criteria established autonomic, parkinsonian, cerebellar, and corticospinal domains and, within each domain, defined criteria for the diagnosis of possible and probable MSA. The SND and OPCA subtypes were reclassified as MSA-P (predominant parkinsonism) and MSA-C (predominant cerebellar), respectively. In 2008, the consensus criteria were revised to incorporate new pathologic and imaging data and for the sake of simplification (Table 1).1 Although MSA has classically been described as a sporadic disorder (there may be a putative causative role of environmental toxins in MSA27), recent studies describing multiplex families with the disorder point to a potential genetic contribution to the disease.28-30 One study using whole-genome sequencing found that functionally impaired variants of COQ2 were associated with an increased risk of multiple system atrophy in both multiplex families as well as patients with sporadic disease.31

The Differential Diagnosis of MSA-C Establishing a diagnosis of MSA-C post-mortem is straightforward, as is clinical diagnosis late in the disease course. However, differentiating MSA-C early in its disease course from other causes of adult-onset cerebellar ataxia represents one of the more complex challenges in clinical neurology. A detailed consideration of all potential causes of adult-onset cerebellar ataxia is beyond the scope of this review (see Klockgether 201032 and Manto et al. 201233 for full reviews). Adult-onset ataxias can be classified into acquired (including toxins, tumors, and infections), genetic (eg, spinocerebellar ataxias), and sporadic etiologies. In the majority of patients, a complete disease-course history, family history, and neurological examination accompanied by first-line investigations, including brain magnetic resonance imaging (MRI), will help to narrow the differential diagnosis considerably and to differentiate these other disorders from MSA-C (Table 2). The challenge arises, however, in considering cases of a pure or predominantly cerebellar ataxia coming on in adulthood with no family history or apparent inciting event. This is so-called sporadic degenerative ataxia, of which one subgroup is the pathologic entity MSA-C. The other subgroup is idiopathic late-onset cerebellar ataxia (ILOCA), also known as sporadic adult-onset ataxia of unknown etiology (SAOA). Idiopathic late-onset cerebellar ataxia Anita Harding coined the term idiopathic late onset cerebellar ataxia (ILOCA) in 1981 to label cases of

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TABLE 1. Current consensus criteria for multiple system atrophya Definite MSA Autopsy-confirmed case with neuropathologic evidence of widespread and abundant CNS a-synuclein–positive glial cytoplasmic inclusions in association with striatonigral and/or olivopontocerebellar neurodegeneration Probable MSA Sporadic, progressive, adult-onset (age >30 years) disease characterized by  Autonomic failure involving 䊊 Urinary incontinence (with erectile dysfunction in males); OR 䊊 Orthostatic blood pressure drop of at least 30 points systolic or 15 points diastolic within 3 minutes after standing from a recumbent position AND one of the following predominant motor features  Poorly levodopa-responsive parkinsonism (defined as bradykinesia with rigidity, tremor, or postural instability); OR  A cerebellar syndrome consisting of gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction Possible MSA Sporadic, progressive, adult-onset (age >30 years) disease characterized by  Parkinsonism (defined as bradykinesia with rigidity, tremor, or postural instability); OR  A cerebellar syndrome consisting of gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction AND at least one of the following symptoms that suggest autonomic dysfunction, including otherwise unexplained  Urinary urgency  Urinary frequency or incomplete bladder emptying  Erectile dysfunction in males  Significant orthostatic blood pressure drop not meeting the criterion for probable MSA AND at least one of the following additional features for MSA-P or MSA-C  MSA-P or MSA-C 䊊 Babinski sign with hyper-reflexia 䊊 Stridor  MSA-P 䊊 Rapidly progressive parkinsonism 䊊 Poor response to levodopa 䊊 Postural instability within 3 years of motor onset 䊊 Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction 䊊 Dysphagia within 5 years of motor onset 䊊 Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum 䊊 Hypometabolism on FDG-PET in putamen, brainstem, or cerebellum  MSA-C 䊊 Parkinsonism (bradykinesia and rigidity) 䊊 Atrophy on MRI of putamen, middle cerebellar peduncle, or pons 䊊 Hypometabolism on FDG-PET in putamen 䊊 Presynaptic nigrostriatal dopaminergic denervation on SPECT or PET a

See Gilman et al, 2008.1 MSA, multiple system atrophy; CNS, central nervous system; MSA-P, parkinsonian variant of multiple system atrophy; MSA-C, cerebellar variant of multiple system atrophy; FDG-PET, 18F-fludeoxyglucose-positron emission tomography; MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography.

progressive cerebellar ataxia with onset after age 20 years in the absence of a history of “alcoholism, hypothyroidism, chronic anticonvulsant ingestion, or malignancy.” Harding characterized the clinical features of 36 patients who met these criteria and found, in addition to ataxia, a diverse range of extracerebellar symptoms, including urinary dysfunction, abnormal reflexes, and dementia.60 Since Harding’s description of ILOCA, the field has advanced considerably. With increased understanding of the clinical classification, genetics, and pathobiology of different cerebellar ataxias, over time, studies have retrospectively differentiated the causes of what were previously regarded as idiopathic ataxias. Many patients once diagnosed with ILOCA have now been reclassified into one of many of the spinocerebellar ataxias (SCAs), fragile X-associated tremor ataxia syndrome (FXTAS), Friedreich’s ataxia, autosomal reces-

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sive cerebellar ataxia type 1 (ARCA1), or MSA.56,61-65 Recent genetic confirmation of apparently sporadic disorders such as Gordon-Holmes syndrome,57 Perrault syndrome,58 Wolfram syndrome,59 and novel SYNE 1 gene disorders (spectrin repeat containing, nuclear envelope 1; Schmahmann et al., unpublished data) confirm that the sculpting out from ILOCA of the ataxias with genetic underpinnings continues to be a work in progress. Indeed, it is presently unclear whether what remains of the non-MSA sporadic ataxias represents a distinct disease entity or a collection of diseases for which we have not yet identified the cause. A continuing line of inquiry has attempted to characterize the clinical, imaging, and pathologic features of patients with adult-onset ataxia for which no apparent cause can be identified.62,65-70 Additional terms have now been applied to this group. For example,

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TABLE 2. The differential diagnosis of adult-onset cerebellar ataxia Diagnosis

Acquired cerebellar ataxia Toxins32 Alcohol Vitamin B1 deficiency Chemotherapy Others Immune-mediated Paraneoplastic cerebellar degeneration Anti-GAD ataxia Gluten ataxia Post-infectious cerebellitis Hashimoto’s thyroiditis Other Superficial siderosis44,45

Other Hereditary cerebellar ataxia Spinocerebellar ataxias46-48

Fragile X-associated tremor/ataxia syndrome (FXTAS)49-52 Friedreich’s ataxia (FRDA)53,54

Autosomal recessive cerebellar ataxia type 1 (ARCA 1)55 Ataxia with oculomotor ataxia type 2 (AOA2)56 Other recently identified genetic syndromes that present in adulthood with ataxia as a central clinical feature Sporadic cerebellar ataxia Multiple system atrophy (MSA)

Idiopathic late-onset cerebellar ataxia (ILOCA)

Features

Gait and limb ataxia; can lead to vitamin B1 deficiency Deficiency can cause Wernicke’s encephalopathy 5-Fluorouracil is a common cause Lead, lithium, amiodarone, toluene; cessation of the toxin usually improves symptoms Most common with small cell lung cancer, breast cancer, ovarian cancer, and Hodgkin’s lymphoma; onset of ataxia is usually subacute, but the clinical course is rapidly progressive34 Occurs as part of a polyglandular immune syndrome, more commonly in women and often associated with diabetes35 Reported associations between cerebellar ataxia and antigliadin antibodies as well as celiac disease36; recent studies have called these findings into question37,38 Often follows infection with Epstein-Barr virus; history of infection and short latency to progression is distinctive; can lead to permanent ataxia39,40 Association with ataxia described in case reports41 Lhermitte-Duclos gangliocytoma,42 Langerhans cell histiocytosis43; there are cases in our clinic and others of steroid-responsive ataxias with a presumptive immune basis for which no antibody or underlying tumor has been identified Slowly evolving progressive cerebellar ataxia, hearing loss, and pyramidal tract signs, often with impaired sense of smell and cognitive decline; reflects chronic CNS hemorrhage from repeated subarachnoid bleeding or other vascular abnormalities leading to deposition of free iron and hemosiderin along the pial and subpial structures of the brain Cerebellar tumors, infections, Creutzfeld-Jacob disease, and vascular injury all can lead to adultonset ataxia Group of 31 dominantly inherited ataxias with several underlying mutational mechanisms; although positive family history is expected, some of the SCAs (most notably SCA6 and SCA17) can present as sporadic disorders Carriers of FMR1 (fragile site mental retardation 1 gene) permutation (55-200 repeats); presents with progressive cerebellar ataxia accompanied by intention tremor, mild parkinsonism, and autonomic dysfunction Autosomal recessive, GAA trinucleotide repeat disorder caused by a transcriptional defect of the frataxin gene; clinical presentation characterized by dysmetria, dysathria, distal extremity weakness, and sensory neuropathy accompanied by diabetes, cardiomyopathy, and scoliosis; typically presents in young people with a mean age of onset at age 10 years, but adult-onset FRDA can resemble SCA Recessively inherited SYNE 1 (synaptic nuclei expressed gene 1) gene disorder with high incidence in French-Canadian population; slowly progressive and purely cerebellar, manifesting in adulthood Disorder of the senataxin gene; presents in early adulthood with peripheral neuropathy, choreiform movements, and mild intellectual decline Gordon Holmes syndrome,57 Perrault syndrome58 (Lieber et al., unpublished data), Wolfram syndrome,59 and SYNE 1 gene disorders (Schmahmann and Mootha, unpublished data); currently, these disorders are not testable in commercial laboratories, but will likely become increasingly recognized once whole-exome sequencing is readily available Characterized by autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal tract signs in various combinations; MSA is divided into two subtypes based on the predominant motor feature present at the time of clinical presentation: poorly levodopa-responsive parkinsonism (MSA-P) or cerebellar ataxia (MSA-C); the current Consensus Criteria for MSA were released in 2008 and contain three levels of diagnostic certainty: definite, probable, and possible MSA (see Table 1) Cerebellar ataxia of unknown cause with onset in adulthood. This term is typically used to refer to cases in which family history is negative, acquired causes have been ruled out, commercially available genetic tests are negative, and/or the patient does not meet consensus criteria for a diagnosis of possible or probable MSA; many other terms have been used in the literature to describe the same group of patients, including sporadic adult onset ataxia of unknown etiology (SAOA) (see Table 3)

Anti-GAD, anti-glutamic acid decarboxylase; CNS, central nervous system; SCA, spinocerebellar ataxia.

Abele and colleagues coined the term “sporadic adult onset ataxias of unknown etiology” (SAOA) to denote a non-genetic, adult-onset, sporadic ataxia distinct

from MSA.71 Currently, ILOCA, SAOA, and a host of other terms (Table 3) are used to refer to this same group of patients. In this review, we use the terms

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TABLE 3. Terms used in the literature to denote sporadic ataxia with onset in adulthood and without a readily identifiable cause Year Citeda

Term

Olivopontocerebellar atrophy (OPCA)17 Sporadic OPCA72 Idiopathic late-onset cerebellar ataxia (ILOCA)60 Idiopathic cerebellar ataxia of late onset (IDCA)70 Idiopathic cerebellar ataxia (IDCA), purely cerebellar form (IDCA-C) or with extracerebellar features (IDCA-P)73 Sporadic adult onset ataxia of unknown etiology (SAOA)71 Sporadic cerebellar ataxia73 Idiopathic late-onset pure cerebellar ataxia63 Idiopathic sporadic late-onset chronic progressive cerebellar ataxia65

1900 1982 1981 1998 2004

2007 2004 2005 2009

a

Does not necessarily indicate first usage in the literature.

ILOCA, SAOA, and others interchangeably, referring to the terminology used in the article of reference. Regardless of the terminology, we are referring to patients who have adult-onset ataxia for which no apparent cause can be identified. ILOCA (or SAOA) represents the greatest diagnostic dilemma for MSA-C. Abele and colleagues report that the median age of onset of SAOA is 56 years,62 very similar to MSA-C, which also presents in the mid-50s. SAOA also presents with a number of extra-cerebellar symptoms that overlap with features of MSA, including erectile dysfunction, bladder urgency, dysphagia, snoring, restless leg syndrome, and rapid eye movement sleep behavior disorder.71 Two independent studies found that adult patients presenting with idiopathic (at the time of presentation) sporadic ataxia evolved to develop MSA approximately 30% of the time (29% in one study62 and 33% in the other74). However, the natural histories of the two diseases are quite different. Patients with MSA become dependent on walking aids after 5 years and have an average survival of 7 to 9 years.32 In contrast, half of the patients with SAOA can still walk after 12 years, and their lifespan reportedly is most likely to be normal.62,74

Evidence for Differentiating MSA-C From ILOCA Clinical features Which clinical features are unique to MSA-C, and which can be used to separate MSA-C from ILOCA patients? Urinary symptoms, including frequency, urgency, and incontinence, are hallmarks of the autonomic dysfunction of MSA but can be difficult to disentangle from common age-related urologic or gynecologic issues, such as stress incontinence, uterine prolapse, atrophic urethritis, bladder contractile dysfunction, and benign prostatic hyperplasia (in men),

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all of which can lead to similar symptoms. Studies of urethral and sphincter electromyography (EMG) in cohorts of patients with MSA-C found evidence for denervation and reinnervation of motor units, consistent with degeneration of Onuf’s nucleus.75 The conclusion was that sphincter EMG is a potential clinical tool for confirming the diagnosis of MSA-C and for mapping disease progression.76 A limitation of these studies was the absence of a control group. To this point, more recent studies point to the poor sensitivity and specificity of sphincter EMG in distinguishing MSA from both PD as well as other cerebellar ataxias.77-81 A few studies have compared the frequency of specific clinical symptoms in MSA-C versus ILOCA patients. Abele and colleagues observed that the presence of muscular rigidity, tremor, dysphagia, and bladder dysfunction was significantly more frequent in patients with MSA-C than in patients with unexplained ataxia. Decreased and absent reflexes were more predominant in patients with unexplained ataxia.62 Burk and colleagues reported that, compared with patients who had idiopathic cerebellar ataxia with extracerebellar features (IDCA-P), patients who had MSA had significantly more rigidity, akinesia, and autonomic dysfunction and had less spontaneous nystagmus.82 Two recent reviews discussed the non-motor or extra-motor clinical features of MSA, such as urinary dysfunction, stridor, constipation, dysphagia, dystonia, cognitive impairment, and sleep disturbances.83,84 The recognition that the non-motor manifestations often precede the cerebellar or parkinsonian motor features of MSA has led some to label these manifestations as premotor signs and symptoms. However, ILOCA also presents with extra-motor features,71 many of which overlap with those observed in MSA-C. Imaging Identifying robust, objective, and specific imaging markers for MSA has long been of interest.85 Abnormalities associated with MSA seen on conventional MRI include atrophy of the putamen, pons, middle cerebellar peduncles, and cerebellum and accompanying T2-weighted signal hypointensities and hyperintensities visualized in each of these brain regions. For a recent comprehensive review on neuroimaging studies in MSA, see Brooks and Seppi 2009.86 Two specific findings often cited as hallmarks for MSA are T2-weighted, slit-like, marginal hyperintensity in the putamen (aka putaminal hyperintense rim)87,88 and the hot-cross bun sign, consisting of a cruciform pattern of hyperintensity in the basis pontis visible on T2-weighted and proton density-weighted MRI.89-91 However, neither of these findings is pathognomonic. A hyperintense putaminal rim is a nonspecific finding that

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can occur in healthy adults.92 The hot-cross bun sign reflects the general process of degeneration and gliosis of pontocerebellar fibers, irrespective of the underlying pathologic process,93 and can be seen with relatively high frequency in the SCAs.94 In addition, both pontine and putaminal signal changes emerge well after symptom onset in MSA-C, limiting their role in early diagnosis.95 Studies using neuroimaging markers to differentiate MSA-C from ILOCA are limited, and the majority of imaging studies either consider MSA-C and MSA-P together or compare MSA with parkinsonian syndromes.86,96 Burk and colleagues compared MRI findings from patients who had MSA-C with those from patients who had IDCA-P (patients with cerebellar ataxia plus additional extracerebellar features who did not fulfill formal criteria for MSA). They found that, although both MSA-C and IDCA-P patients had substantial cerebellar atrophy, atrophy in the brainstem and middle cerebellar peduncles along with corresponding signal hyperintensities was significantly more pronounced and frequent in the MSA-C group.73,82 Advanced imaging techniques, such as fluorodeoxyglucose-positron emission tomography (FDG-PET), magnetic resonance spectroscopy (MR spect), and diffusion-weighted imaging, also have been investigated as diagnostic tools for MSA. Gilman and colleagues used FDG-PET to compare regional glucose metabolism between patients who had MSA and patients who had sporadic or dominantly inherited OPCA, which they defined as cerebellar degeneration with no clinical evidence of autonomic or extrapyramidal involvement. The authors found that whereas patients who had dominantly inherited OPCA had significantly decreased glucose metabolism in the brainstem and cerebellum compared with controls, patients who had MSA and sporadic OPCA had decreased metabolism in those areas as well as in the putamen, thalamus, and cerebral cortex.97 These conclusions are difficult to interpret given the changes in diagnostic classification of MSA and OPCA that would lead to different patient cohorts today—the sporadic OPCA patients would now most likely be reclassified with MSA or ILOCA, and those diagnosed with dominantly inherited OPCA most likely represent a collection of patients with different SCAs. Prakash and colleagues compared diffusion tensor imaging metrics of white matter integrity in patients with different types of ataxia, including MSA-C, SCA, and sporadic OPCA. They observed that the average fractional anisotropy of white matter tracts in the inferior, middle, and superior cerebellar peduncles was significantly lower in MSA-C compared with the other ataxia syndromes.98 Multiple groups have examined the use of MR spect for differentiating MSA-C from other ataxias. MR spect characteristics that have shown promise

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in the identification of MSA include cerebellar lactate,99 N-acetylaspartate and choline,100 as well as brainstem myo-inositol, creatine, glutamate, and glutamine.101 Notably, all of those studies compared MSA only with the SCAs. Biomarkers Some investigators have attempted to develop serum and cerebrospinal fluid (CSF) biomarkers for MSA. Arginine growth hormone stimulation testing, an endocrinologic test designed to probe the functionality of central noradrenergic pathways, had previously been shown to distinguish MSA from ILOCA and PD in an Italian cohort with very promising sensitivity and specificity (>90% respectively).102,103 However, a subsequent study conducted in a North American cohort failed to replicate those results.104 Abdo and colleagues observed that increased levels of the CSF proteins neurofilament light chain and tau and decreased levels of the neurotransmitter metabolite 3-methoxy-4-hydroxyphenylethyeleneglycol could accurately differentiate MSA-C from ILOCA.105 Notably, a comparison of CSF a-synuclein was not mentioned in their study. Hirohata and colleagues combined CSF samples from patients with MSA, PD, dementia with Lewy bodies, SCA, and tension-type headache with recombinant a-synuclein to test which CSF environments were more favorable to in vitro a-synuclein fibril formation. They found that CSF from patients with MSA promoted a-synuclein fibril formation more strongly than PD CSF, SCA CSF, or CSF from patients with tension-type headache; and they concluded that the CSF environment in patients with MSA is particularly favorable to a-synuclein aggregation.106 It is difficult to interpret the ramifications of this study.

Current Therapeutic Options Although clinical trials of potential MSA therapies are in progress, there are as yet no definitive treatments for this devastating disease.107,108 Currently, medical treatment is limited to alleviating individual symptoms. The two main targets of symptomatic treatment are parkinsonism and dysautonomia. There is no effective therapy for the progressive cerebellar ataxia of MSA-C.109 Although the parkinsonism of MSA is classically defined as poorly L-dopa–responsive, clinical series have documented some L-dopa response in up to 40% of patients. The benefit of L-dopa is transient in most patients, lasting only a few years and leaving over 90% of patients L-dopa–unresponsive in the long term.13,110-112 Approximately half of patients who are treated with L-dopa develop L-dopa–induced dyskinesias, which often involve the face, jaw, and neck.110,113 Dopamine agonists, including bromocriptine, pergolide,

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and lisuride, have been tried in MSA with more limited success.74,111 The treatment of orthostatic hypotension in MSA-C decreases fall risk and can dramatically improve quality of life, especially in patients who are symptomatic. Nonpharmacologic options include adequate fluid intake, high salt diet, and compression stockings. Pharmacologic agents, including pyridostigmine (a cholinesterase inhibitor that exerts its action of improving ganglionic transmission primarily when the patient is standing), fludrocortisone (a mineral corticoid that promotes sodium retention), and midodrine (a vasoactive a-agonist), are first-line options for orthostatic hypotension.114-116 Droxidopa, a norepinephrine precursor, has also been used with success in the treatment of the neurogenic orthostatic hypotension associated with MSA.117-119 Urinary incontinence can be treated with anticholinergic agents such as oxybutynin or tolterodine,120 but often at the expense of inducing urinary retention and other anticholinergic side effects. At the late stages of the disease, patients are counseled on intermittent self-catheterization or even permanent indwelling catheter for frank incontinence. Other clinically important issues amenable to intervention include pathologic laughing or crying, which respond to selective serotonin reuptake inhibitors as well as dextromethorphan/quinidine; rapid eye movement sleep behavior disorder treated successfully with benzodiazepines; excessive salivation managed with scopolamine patch or glycopyrrolate; tremor, which may improve with anti-parkinsonian medications, beta blockers, primidone, and trihexyphenidyl; and constipation that needs close medical supervision.108,109,121 Physical, speech, and occupational therapies are critical resources for helping to improve strength, mobility, speech, swallowing, and general quality of life for patients with MSA.

Animal Models of MSA and the Promise of Future Therapies Several animal models have been developed to recapitulate the clinical and pathophysiological characteristics of MSA. For a recent review of animal models of MSA, please see Fernagut and Tison 2012.22 The first animal models used stereotoxic injections of neurotoxins into the nigral and striatal systems of rats to recapitulate the L-dopa–unresponsive parkinsonism in MSA.122-125 The strength of these stereotoxic models is that they allow for the correlation of specific degrees of striatal and nigral degeneration to characteristic dopaminergic-unresponsive motor phenotypes. However, they are also limited in that they do not reproduce the pathology and resulting symptomatology outside of the basal ganglia. The identification of a-synuclein inclusions in oligodendrocytes as the pathophysiological hallmark of

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MSA has allowed for the development of transgenic mouse models, which express human wild-type a-synuclein under the control of various oligodendroglialspecific promoters.126-129 The power of genetic mouse models is that they allow for the ongoing investigation of the pathophysiologic link between a-synuclein and neurodegeneration. However, the current genetic models do not seem to reproduce the full severity or extent of neurodegeneration seen in human disease. Animal models of MSA provide an invaluable platform to evaluate potential treatments. Potential pharmacotherapies that have shown promise in mouse models include myeloperoxidase inhibition,130 erythropoietin,131 rasagiline,132 and antidepressants.133 Mesenchymal stem cells are being evaluated as a potential neuroprotective and immunomodulatory strategy,134,135 and their success has informed recent human clinical trials.136,137 Hasegawa and colleagues recently demonstrated the promise of SIRT2 inhibition as a potential therapeutic strategy for MSA in vitro.138 Indeed, with a deeper understanding of the pathophysiology of a-synuclein and neurodegeneration, the promise of targeted pharmacotherapy reaching the clinic for patients with MSA is bright.

Limitations and Future Directions MSA, whether of the parkinsoninan or cerebellar variety, is now an established neuropathological diagnosis—a synucleinopathy with glial cytoplasmic inclusions and a characteristic pattern of brain pathology and atrophy. The consensus criteria for MSA are clinically useful and have helped to advance the care and education of patients with this relentlessly debilitating disorder. The clinical differentiation of MSA-C, particularly in the early stage, from other adult-onset, apparently spontaneously occurring ataxias remains uncertain; and, in this domain, the field is still evolving. Metabolic and morphometric biomarkers in MSA are promising, but these are not yet generalizable to the clinic, because the pilot studies used to evaluate them have small sample sizes, and the control groups used are widely variable. The most critical shortcoming that limits the conclusions of the clinical, imaging, and biomarker-based studies to date is the lack of pathologic confirmation of the MSA-C and non-MSA-C diagnoses. Many of the alternate diagnoses, including ILOCA and IDCAP, also exhibit extra-cerebellar and autonomic features and, thus, have a large degree of clinical overlap with MSA-C. In fact, it is currently unclear whether MSA-C, ILOCA, and IDCA-P represent fundamentally different clinicopathologic entities or whether they represent different severities on the same disease spectrum. Systematically comparing clinical features in pathologically proven groups of patients is necessary

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and essential to address this limitation and to advance the field going forward. A number of unanswered and important questions remain. Are there faster and slower forms of MSA-C, and can these timelines be predicted from clinical or biomarker phenotypes? Does MSA-C always involve the autonomic nervous system, or, like striatonigral degeneration of old, can the cerebellar variant occur in the absence of autonomic failure? Is ILOCA truly a sporadically presenting, non-MSA-C disease, or are some apparent ILOCA cases merely the earliest manifestation of a slowly evolving form of MSA-C? At this time, MSA-C remains the clinician’s challenge, relying on the history, examination, and special investigations to narrow the list of possible diagnoses and arrive at a working hypothesis for the cause of the cerebellar ataxia. Further analyses of the neurological presentations, long-term outcomes, post-mortem confirmation, and potential biomarkers in patients with MSA-C are needed to enhance the accuracy of the clinical diagnosis and provide more certainty in differentiating this disorder from non-MSA-C ataxias. New insights into the neurobiology of a-synuclein139 and the identification of potential targets for therapeutic intervention in molecular pathophysiology of MSA31 mandate accurate and early diagnosis.

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