PERSPECTIVES OPINION
Nonmotor presentations of multiple system atrophy Carlo Colosimo Abstract | Multiple system atrophy (MSA) is a neurodegenerative disease characterized clinically by a combination of parkinsonian, cerebellar, autonomic and pyramidal features. Recent data show that the MSA clinical spectrum is wider than was originally thought, and may include various nonmotor symptoms that arise at disease onset. These symptoms include urinary disorders, erectile dysfunction in men, orthostatic hypotension, sleep disruption, stridor, and severe constipation. Neurologists and other specialists must be made aware that this relatively common neurodegenerative disease can manifest with nonmotor symptoms well before patients develop any overt motor disorder. The importance of recognizing such symptoms should not be underestimated, being crucial for understanding the disease prognosis, avoiding unnecessary tests and procedures, and planning any therapeutic intervention. Colosimo, C. Nat. Rev. Neurol. 7, 295–298 (2011); published online 22 February 2011; doi:10.1038/nrneurol.2011.5
Introduction The term multiple system atrophy (MSA) was introduced by Graham and Oppenheimer in 1969 to denote a sporadic neurodegenera tive disease clinically characterized by any given combination of parkinsonian, cere bellar, pyramidal and autonomic symptoms and signs, and pathologically by cell loss and gliosis in the basal ganglia, olivoponto cerebellar system and spinal cord.1 Cases of MSA were previously referred to as olivo pontocerebellar atrophy, Shy–Drager syn drome or striatonigral degeneration.2–4 A summary of the clinicopathological corre lations between the widespread pathology and the myriad of clinical manifestations of MSA is provided in Table 1. The diagnosis of MSA is based on the char acteristic picture of progressive multisystem neurological involvement. MRI evidence of structural changes in the basal ganglia, brain stem and cerebellum is useful for confirming clinical suspicions of MSA, but is poorly sen sitive in the early disease stages. Parkinson disease (PD), other atypical parkinsonian Competing interests The author declares an association with the following company: Teva Pharmaceutical Industries. See the article online for full details of the relationship.
disorders (for example, progressive supra nuclear palsy or corticobasal degeneration), and late-onset sporadic cerebellar ataxia are the main differential diagnoses of MSA. The aim of this article is to highlight, with the help of three illustrative cases, the wide range of nonmotor symptoms through which MSA can initially manifest.
Classic features of MSA MSA affects both men and women and has an estimated prevalence of four to five cases per 100,000 individuals. 5 Natural
history studies in white populations have shown that parkinsonian symptoms— usually poorly responsive to levodopa— predominate in 80% of patients (MSA‑P),2 whereas cerebellar ataxia is the main feature in approximately 20% of patients (MSA‑C). By contrast, in Japan the disease shows an apparent predominance of the MSA‑C subtype,6 possibly indicating ethnic varia tions in genetic predisposition, or simply an effect of case selection bias in surveys carried out in specialized ataxia clinics. In 1989, Papp and colleagues reported widespread glial cytoplasmic inclusions (GCIs) in the brains of patients with MSA, regardless of the clinical presentation (par kinsonism or cerebellar ataxia).7 The fact that GCIs were not found in patients with other neurodegenerative disorders lent further support to the idea that such cases all belonged to the same disease entity, characterized by neuronal multisystem degeneration related to a specific oligo dendroglial inclusion pathology.5,8 In the late 1990s, α‑synuclein immunostaining was recognized as the most sensitive marker of inclusion pathology in MSA, being superior to the previously used ubiquitin immunostaining. 9 The consis tent finding of pathological α‑synuclein as the main component of GCIs has led MSA to be classified as a synucleinopathy, prompting extensive basic science research on this and related proteins, aimed at a better understanding of the pathogenesis of this disease.8
Table 1 | Clinicopathological correlations* Site of α‑synuclein pathology
Clinical features
Substantia nigra
Akinesia, rigidity, dysarthria
Striatum
Akinesia, rigidity, dysarthria, dystonia, no response to levodopa, dysexecutive syndrome
Olivopontocerebellar system
Ataxia, oculomotor disorders, dysarthria
Peduncolopontine nucleus
Rapid eye movement sleep behavior disorder, postural instability
Catecholaminergic rostral ventrolateral medulla nuclei, intermediolateral columns of the thoracolumbar cord
Orthostatic hypotension
Onuf’s and inferior intermediolateral sacral nuclei
Bladder, rectal and sexual dysfunction
Primary motor cortex
Pyramidal signs
Nucleus ambiguus
Stridor
Rostral medullary raphe nuclei
Impaired skin vasomotor activity
*The table summarizes the putative clinicopathological correlations in multiple system atrophy.
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PERSPECTIVES Box 1 | Nonmotor symptoms in MSA The following nonmotor symptoms have been observed as presenting features of MSA: ■■ Urinary incontinence or retention ■■ Erectile failure (in men) ■■ Syncope due to orthostatic hypotension ■■ Rapid eye movement sleep behavior disorder ■■ Stridor due to bilateral laryngeal abductor paralysis ■■ Fecal incontinence and constipation ■■ Fluent aphasia* ■■ Hypohidrosis or hyperhidrosis* *Based only on occasional reports and to be confirmed. Abbreviation: MSA, multiple system atrophy.
Nonmotor symptoms of MSA Regardless of the predominant motor dis order of MSA, the first manifestations of the condition are often nonmotor symptoms (Box 1). A similar phenomenon has been suggested in PD.10 In a series of 22 patients clinically affected by MSA and actively followed in our center, a thorough medical history revealed that the disease manifested with nonmotor symptoms before the occur rence of any motor disorder in at least seven cases (31.8%). The initial symp toms were genitourinary (unexplained frequency and urge incontinence, erectile dysfunction in men) in five cases, stridor in one case, and symptomatic orthostatic hypotension in the remaining case. The widespread occurrence of specific markers of neurodegeneration—that is, GCIs—in several areas of the CNS implicated in the control of diverse bodily functions accounts for the complex clinical picture observed in MSA.11
Genitourinary dysfunction Genitourinary dysfunction (Box 2) in a patient with parkinsonism should always alert the clinician to a possible diagnosis of MSA, while bearing in mind the frequent confounding problem of prostate enlargement in elderly men. Bladder dysfunction in MSA differs from that in PD: although frequency and urgency are common in both disorders, constant urge or stress incontinence with con tinuous leakage are not typical features of PD, and tend to occur only in advanced stages of the disease, if at all. Conversely, early urinary incontinence, consisting of involuntary partial or total bladder emptying, is a typical char acteristic of patients affected by MSA.12 In addition, in men, erectile dysfunction is a widespread symptom often associated with bladder dysfunction in MSA. Retrospective studies strongly suggest that erectile dysfunc tion in men with MSA can appear as early as 5–10 years before other clinical symptoms.13 Orthostatic hypotension Orthostatic hypotension (Box 3, Figure 1) is a key characteristic of autonomic dys function associated with MSA. Orthostatic hypotension is defined as an orthostatic fall in systolic blood pressure of >20 mmHg or in diastolic blood pressure of >10 mmHg.14 Although orthostatic hypotension occurs at varying degrees of severity in PD and other parkinsonian syndromes, an early finding of orthostatic hypotension is more likely to suggest MSA. Patients who have MSA can initially remain asymptomatic despite large decreases in systolic and diastolic blood pres sure. When symptomatic, orthostatic ����������������� hypo tension manifests with postural faintness, aching neck and shoulders, and changes in visual perception, leading, in more-advanced stages of the disease, to repeated syncope and even sudden death.2,14
Box 2 | Nonmotor presentations of MSA: genitourinary dysfunction At the age of 46 years, an otherwise healthy businessman started to experience rapid eye movement sleep behavior disorder, as reported by his wife who had noticed the symptoms at night. He subsequently developed difficulty in achieving an erection, and developed urge incontinence 3 years later. He consulted various urologists, who prescribed symptomatic therapy but were unable to make a more accurate diagnosis on the basis of his clinical picture. At the onset of the urinary disorders, the patient had also noticed paracervical aching pain on standing. In a subsequent visit, he was found to have orthostatic hypotension, as confirmed by cardiovascular autonomic testing, which demonstrated a drop in systolic blood pressure of 55 mmHg (from 125/75 mmHg to 70/50 mmHg) not accompanied by an appropriate increase in heart rate. Following the emergence of a slight hand tremor, scanning dysarthria and gait unsteadiness, the patient was eventually seen by a neurologist, who—after a normal MRI scan—diagnosed probable MSA of the cerebellar type (MSA-C). Abbreviation: MSA, multiple system atrophy.
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Sleep disruption Nearly all patients with MSA have some form of sleep disruption, a problem that usually starts early in the disease course. In particular, more than two-thirds of patients with MSA experience rapid eye movement (REM) sleep behavior disorder (RBD). 15 This form of parasomnia is characterized by loss of normal skeletal muscle atonia during REM sleep, enabling patients to physically enact their dreams, which are often vivid or unpleasant. Partners commonly report vocalizations (shouting, talking) and abnor mal movements (arm or leg jerks, violent movements that sometimes result in falling out of bed). Isolated RBD is suggested to be a possible early symptom of MSA, before the occurrence of any motor impairment, in 30% of cases. RBD and other sleep dis orders are more common in patients with MSA than in those with PD matched for disease duration.15 Patients with MSA also manifest with nocturnal inspiratory stridor (due to laryngeal abductor paralysis; Box 4) and obstructive sleep apnea, which can cause sudden death. Stridor occurs in approxi mately one-third of all patients with MSA and may be the presenting feature in ≈4% of cases.16 Stridor accompanied by central respiratory failure can present in early MSA as severe respiratory insufficiency, frequently necessitating tracheostomy. 17 Recognizing stridor as a feature of MSA is clinically relevant, both because it is a negative prognostic indicator, and because patients presenting with laryngeal abduc tor paralysis and stridor but without other neurological symptoms are usually seen initially by general physicians or otolaryngologists. Gastrointestinal and other disorders Gastrointestinal disorders are other common manifestations of parkinsonian syndromes. The disorder most frequently observed in MSA is constipation, which in particularly severe cases can lead to pseudoobstructive phemonena. 18 Constipation in MSA most probably results from slow colonic transit, decreased phasic rectal contraction and weak abdominal strain, whereas fecal incontinence results from a weak anal sphincter owing to denervation. These dysfunctions seem to arise from both the CNS and PNS, which together regulate the lower gastrointestinal tract. Other possible—though unusual—early nonmotor manifestations of MSA are sudomotor 19 and language disorders.20 www.nature.com/nrneurol
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PERSPECTIVES Conclusions and final considerations The wide range of symptoms through which MSA can manifest is, unfortunately, not fully covered in the published clinical diag nostic criteria for this disease,21,22 includ ������� ing those published in 2008 as the second consensus statement on MSA.23 The various sets of criteria all acknowledge the constella tion of nonmotor disorders present in MSA, and place particular emphasis on those related to autonomic failure, but each also includes the mandatory presence of a motor disorder (parkinsonism and/or cerebellar ataxia) as a prerequisite for the diagnosis of this disease.
On the basis of these considerations, neurolo gists should be aware that even patients without any overt motor disorder might have initial manifestations of this not uncommon neurodegenerative disease. This reflection applies even more so to other spe cialists, such as urologists, cardiologists, oto laryngologists and gastroenterologists, who may be the first physicians to see patients with MSA who have yet to develop the full-blown form of this devastating disease. MSA remains an intractable illness with a median survival of 7–8 years from its initial diagnosis. Patients should, however, be able to take advantage of accurate, early diagnosis
Box 3 | Nonmotor presentations of MSA: orthostatic hypotension A retired scientist developed orthostatic intolerance with frequent presyncopal symptoms, severe constipation, erectile dysfunction, and rapid eye movement sleep behavior disorder at the age of 65 years. He had been affected by arterial hypertension for the previous 6 years. He was first seen by a cardiologist, who ordered a tilt-table test (Figure 1). This examination disclosed severe, symptomatic orthostatic hypotension (–60 mmHg for systolic blood pressure) owing to primary autonomic failure. The cardiologist tapered the patient’s antihypertensive treatment and prescribed fludrocortisone 0.2 mg/day, together with various nonpharmacological measures, such as the use of elastic stockings and a high-salt diet. This regimen led only to partial resolution of the autonomic disorder. At the age of 71 years, the patient was found to be bradykinetic by his cardiologist and was consequently referred for a neurological consultation. During this consultation, a parkinsonian disorder associated with autonomic failure was diagnosed; this finding was subsequently confirmed by cerebral dopamine transporter single-photon emission CT, which showed asymmetric reduced uptake of the tracer in the striatum. An MRI scan of the brain was unremarkable. As the patient did not respond significantly to dopaminergic therapy, he was diagnosed as having probable MSA with parkinsonian features (MSA-P). Abbreviation: MSA, multiple system atrophy.
Mean 138.6 mmHg (SD 6.8 mmHg, range 116.5–152.6 mmHg)
Mean 110.8 mmHg (SD 16.1 mmHg, range 73.9–156.4 mmHg)
Tilt
Figure 1 | Cardiovascular autonomic testing in a patient presenting with orthostatic intolerance. A tilt-table test demonstrates a significant blood pressure drop on tilting. In this test, blood pressure and heart rate are recorded using a photoplethysmographic technique. These values are recorded at baseline (during a 15 min rest) and at various time points (2, 5, 10 and 15 min) after sympathetic activation by head-up tilt with an angle of inclination of 70° (lasting 15 min in total).
Box 4 | Nonmotor presentations of MSA: laryngeal stridor A 57 year-old accountant attended an ear, nose and throat clinic with a 12 month history of increasing nocturnal stridor and exertional dyspnea. His past medical history was unremarkable. Laryngoscopy revealed bilateral abductor vocal cord paralysis (Gerhardt syndrome), for which no clear cause was found despite a full investigation, including imaging of the neck and skull base. After noninvasive treatment of the symptoms, the patient’s condition remained stable, with no recovery in vocal cord function. Following subsequent onset of progressive slowness, gait unsteadiness and dysarthria, associated with increased urinary frequency, the patient’s general practitioner referred him to our movement disorder clinic, where a diagnosis of the parkinsonian variant of MSA (MSA-P) was made. Abbreviation: MSA, multiple system atrophy.
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that allows them to understand the disease prognosis, avoid unnecessary tests and useless procedures, and benefit from symptomatic therapies and disease-specific support services. The prospect of an early diagnosis is becom ing increasingly important in view of the novel therapeutic approaches to MSA, characterized by different compounds with potential diseasemodifying properties, that have recently been reported24,25 or are currently being evaluated. Although the initial results from these trials have been negative, the situation could change in the near future, and recruitment of patients in the initial disease stages will be mandatory for upcoming trials. Department of Neurology and Psychiatry, “Sapienza” University of Rome, Viale dell’Università 30, 00185 Rome, Italy
[email protected] 1.
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PERSPECTIVES 13. Kirchhof, K., Apostolidis, A. N., Mathias, C. J. & Fowler, C. J. Erectile and urinary dysfunction may be the presenting features in patients with multiple system atrophy: a retrospective study. Int. J. Impot. Res. 15, 293–298 (2003). 14. Bannister, R. & Mathias, C. J. Clinical features and investigations of the primary autonomic failure syndromes. in Autonomic Failure: a Textbook of Clinical Disorders of the Autonomic Nervous System (eds Bannister, R & Mathias, C. J.) 531–547 (Oxford University Press, Oxford, 1992). 15. Plazzi, G., Corsini, R. & Provini, F. REM sleep behavior disorders in multiple system atrophy. Neurology 48, 1094–1097 (1997). 16. Kew, J., Gross, M. & Chapman, P. Shy–Drager syndrome presenting as isolated paralysis of vocal cord abductors. BMJ 300, 1441 (1990). 17. Glass, G. A., Josephs, K. A. & Ahlskog, J. E. Respiratory insufficiency as the primary presenting symptom of multiple-system atrophy. Arch. Neurol. 63, 978–981 (2006).
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18. Bardoux, N., Leroi, A. M., Touchais, J. Y., Weber, J. & Denis, P. Difficult defecation and/ or faecal incontinence as a presenting feature of neurologic disorders in four patients. Neurogastroenterol. Motil. 9, 13–18 (1997). 19. Donadio, V. et al. Anhidrosis in multiple system atrophy: a preganglionic sudomotor dysfunction? Mov. Disord. 23, 885–888 (2008). 20. Apostolova, L. G., Klement, I., Bronstein, Y., Vinters, H. V. & Cummings, J. L. Multiple system atrophy presenting with language impairment. Neurology 67, 726–727 (2006). 21. Quinn N. Multiple system atrophy in Movement Disorders III (eds Marsden, C. D. & Fahn, S.) 262–281 (Butterworth-Heinemann, London, 1994). 22. Gilman, S. et al. Consensus statement on the diagnosis of multiple system atrophy. J. Neurol. Sci. 163, 94–98 (1999). 23. Gilman, S. et al. Second consensus statement on the diagnosis of multiple
system atrophy. Neurology 71, 670–676 (2008). 24. Bensimon G. et al. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study. Brain 132, 156–171 (2009). 25. Dodel, R. et al. Minocycline 1‑year therapy in multiple‑system‑atrophy: effect on clinical symptoms and [11C] (R)-PK11195 PET (MEMSA-trial). Mov. Disord. 25, 97–107 (2010).
Acknowledgments The author wishes to thank A. Berardelli, G. Fabbrini and C. Fieschi for allowing him to present data from patients under their care, S. Strano for providing the figure on tilt-table testing, and G. Wenning and T. Bak for useful suggestions about the clinicopathological correlations in this disease. Written consent was obtained from the patients whose cases are featured in Boxes 2–4.
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