Volume 9, Issue 7 p. 967-971
BRIEF REPORT
Free Access

Patient-Reported Symptoms in the Global Multiple System Atrophy Registry

Jose-Alberto Palma MD, PhD

Jose-Alberto Palma MD, PhD

Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, New York, USA

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Florian Krismer MD, PhD

Florian Krismer MD, PhD

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria

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Wassilios G. Meissner MD, PhD

Wassilios G. Meissner MD, PhD

Centre Hospitalier Universitaire, Bordeaux, Service de Neurologie des Maladies Neurodégénératives, Bordeaux, France

Department of Neurology, University of Bordeaux, Bordeaux, France

Department of Medicine, University of Otago, Christchurch, New Zealand

New Zealand Brain Research Institute, Christchurch, New Zealand

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Mechteld Kuijpers

Mechteld Kuijpers

Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, New York, USA

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Patricio Millar-Vernetti MD

Patricio Millar-Vernetti MD

Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, New York, USA

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Miguel A. Perez

Miguel A. Perez

Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, New York, USA

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Alessandra Fanciulli MD, PhD

Alessandra Fanciulli MD, PhD

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria

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Lucy Norcliffe-Kaufmann PhD

Lucy Norcliffe-Kaufmann PhD

Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, New York, USA

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Pam Bower

Pam Bower

Multiple System Atrophy Coalition, McLean, Virginia, USA

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Gregor K. Wenning MD, PhD

Gregor K. Wenning MD, PhD

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria

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Horacio Kaufmann MD

Corresponding Author

Horacio Kaufmann MD

Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, New York, USA

Correspondence to: Dr. Horacio Kaufmann, Department of Neurology, Dysautonomia Center, New York University Grossman School of Medicine, 530 First Ave, Suite 9Q, New York, NY, 10016 USA; E-mail: [email protected]

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First published: 10 August 2022

Relevant disclosures and conflicts of interest are listed at the end of this article.

ABSTRACT

Background

The Global Multiple System Atrophy Registry (GLOMSAR) was established in 2013. It is an online patient-reported contact registry open and free that relies on self-reported diagnosis by the patient or caregiver.

Objectives

To report the demographics of patients enrolled in GLOMSAR and the results of an ancillary online symptom questionnaire.

Methods

Patients enrolled in GLOMSAR were invited to complete a custom-designed online questionnaire about disease onset and symptom prevalence.

Results

At the time of writing, there were 1083 participants in GLOMSAR, of which 33% (365) completed the questionnaire. The onset and frequency of most symptoms was similar to those reported in the literature in physician-reported studies. Some were understudied or not typically associated with multiple system atrophy (MSA), including reduced female sexual sensation (55%), forgetfulness (60%), pseudobulbar affect (37%), olfactory changes (36%), and visual hallucinations (21%).

Conclusions

Patient-reported studies and ancillary online questionnaires are valid, underused research tools useful to advance our knowledge on understudied MSA features and highlight the patients' voice.

Multiple system atrophy (MSA) is a rapidly progressive and rare neurodegenerative synucleinopathy with an estimated prevalence of 3.4 to 4.9 cases per 100,000 people.1 Recognizing the value of patient registries in rare diseases,2 in 2013 the US Autonomic Rare Disorders Clinical Research Network (ARDCN) and the European MSA Study Group jointly established an online contact registry for patients with MSA (Global Multiple System Atrophy Registry [GLOMSAR]).3

Here we report the basic demographics of patients registered in GLOMSAR to date. Because the only inclusion criterion was a self-reported MSA diagnosis, there was a concern that some enrollees may be misdiagnosed, which would question the validity of the registry. To test the hypothesis that the participants in GLOMSAR had similar demographics and symptoms to patients with probable and possible MSA enrolled in previous physician-reported studies, we designed and conducted an online questionnaire to understand the frequency of specific MSA symptoms. We electronically sent this questionnaire to all GLOMSAR registrants and discuss its results in light of those obtained in past natural history, and cross-sectional physician-reported MSA studies.

Methods

Global Multiple System Atrophy Registry

GLOMSAR was established as an online contact registry for patients with MSA and their caregivers by the US ARDCN and the European MSA Study Group in 2013, supported by the National Institutes of Health (National Institutes of Neurological Diseases and Stroke U54-NS065736) and the MSA Coalition. Registration in GLOMSAR occurred through a dedicated website hosted by the US ARDCN Data Management and Coordinating Center at the University of South Florida (Tampa, FL). Registration in GLOMSAR could be completed by the patient or a caregiver. Enrollment in GLOMSAR typically occurred after a physician encouraged a potential participant to participate, after the patient/caregiver found the link to GLOMSAR when browsing the internet for MSA-related research activities, or because the patient was informed of GLOSMAR by the MSA Coalition, a patient advocacy group. Data collected by GLOMSAR includes name, e-mail, phone number, address, sex, ethnicity, and date and country of birth. Because GLOMSAR is intended as a contact registry, it does not have data fields on clinical or disease features except for date of diagnosis. GLOMSAR is accessible at https://redcap.link/nyuglomsar, and registration remains open and free to date.

Patient-Reported Symptoms Questionnaire

We (J.-A.P., F.K., W.G.M., G.K.W., L.N.K., A.F., H.K.) designed a web-based questionnaire focusing on the patient's journey, including symptom onset and disease progression (File S1), which are data not included in GLOMSAR. All patients registered in GLOMSAR received a link to the symptom questionnaire on July 24, 2017, and were invited to participate by creating a single login to access the questionnaire. After the questionnaire was completed and closed, the data could not be edited. The symptom questionnaire remained open until October 3, 2017.

We used descriptive statistics, and the results are expressed as frequency in percentage (number of patients) or as median ± standard deviation. We used χ2 for comparisons of qualitative (eg, yes/no) variables, and analysis of variance (ANOVA) for comparisons of 3 or more quantitative (eg, age at onset) variables.

Results

Global Multiple System Atrophy Registry

At the time of writing, 1100 participants had enrolled in GLOMSAR. Of these, 17 (1.5%) were 39 years old or younger at the time of registration. After an individual scrutiny, given the extremely low likelihood that these participants had MSA, they were excluded from further analysis. Information on 1083 participants remained, of which 64.3% (696) records were entered by a patient, a 35.7% (387) entered by a caregiver. Participants were on average 62 ± 8.7 years old (range, 40–88 years), and 58% (628) were men.

The mean age at diagnosis of MSA was 59.8 ± 8.5 years (range, 33–86 years), and the mean disease duration was 2 ± 2.4 years (range, 0–17 years).

The majority (88.6% [960]) self-identified as Caucasian, 7.4% (80) as Black or African American, 2.0% (22) as Native Hawaiian/Other Pacific Islander, 1.4% (15) as Asian, and 1.3% (14) as other. Fifteen reported having 2 or more races. Only 52 (4.8%) self-identified as Hispanic.

The countries with the most participants were the United States (830 participants, 76.6%), Canada (59 participants, 5.4%), Australia (34 participants, 3.1%), and the United Kingdom (19 participants, 1.7%). Participants in Europe (54 participants, 4.8%), Asia (40 participants, 3.6%), South America (16 participants, 1.4%), Africa (8 participants, 0.9%), and the Middle East (1 participant, 0.1%) comprised a small minority.

Among the 830 US participants, most were in California (114 participants, 14%), followed by New York state (60 participants, 7%), Florida (59 participants, 7%), Texas (51 participants, 6%), Washington state (43 participants, 5%), and Ohio (32 participants, 4%).

Patient-Reported Symptoms Online Questionnaire

Of the 1083 registered GLOMSAR participants, 33% (365) completed the online symptom questionnaire entirely or partially. The online questionnaire responders were, on average, 65 ± 8 years (range, 40–92 years), and 55% (202) were men. The majority were from the United States (174 participants, 48%), followed by Canada (18 participants, 5%), Australia (12 participants, 3.3%), and South Africa (4 participants, 1.1%).

The most common first symptom was trouble moving in 29% (107), trouble with blood pressure or urination in 21% (79), acting out dreams in 21% (78), and falls in 14% (53); 9% (32) were unsure.

Overall, the mean age at symptom onset was 59 ± 8.7 years (range, 31–87 years). When considering the first symptom, the age at onset was numerically younger in those reporting acting out dreams and trouble moving (aged 59 ± 8 years in both) followed by problems with blood pressure or urination (aged 59 ± 10 years) and falls (aged 61 ± 9 years). The differences were, however, not statistically significant (ANOVA P value = 0.245).

The mean age at MSA diagnosis was 62 ± 9 years (range, 33–87 years). Disease duration at the time of the questionnaire completion was 3.2 ± 3 years (range, 0–18 years).

The mean diagnostic delay (time elapsed between symptom onset and diagnosis) was 3.3 ± 3 years (range, 0–5 years).

Most patients (83% [307]) reported a significant disease worsening within the 3 months before completing the online questionnaire.

Movement Symptoms

Of the respondents, 94% (344) reported problems with balance, 91% (333) problems walking, 79% (289) muscle stiffness, 58% (212) tremor in hands or feet, 93% (338) changes in handwriting, and 47% (170) reported their neck bending forward and having difficulty lifting their head. A total of 63% (229) received levodopa, with only 20% (72) reporting some improvement. Twenty-seven percent (97) reported using a cane, and of these, 34 patients had been using it for <1 year, 38 patients for 1 to 3 years, and 23 patients for >3 years. A total of 45% (166) reported using a walker, and of these patients, 70 had been using it for <1 year, 68 patients for 1 to 3 years, and 27 patients for >3 years. Of the respondents, 53% (195) reported using a wheelchair, and of these patients, 88 had been using it for <1 year, 63 patients for 1 to 3 years, and 40 patients for >3 years.

Sleep Symptoms

Seventy-seven percent (283) reported acting out their dreams, with 33% (124) reporting a formal diagnosis of rapid eye movement sleep behavior disorder; 71% (260) reported snoring.

Autonomic Symptoms

Ninety-five percent (348) reported 2 or more autonomic symptoms. Among men, 88% (193) reported erectile dysfunction with 5% (11) answering “does not apply” or not answering the question, and 55% (79) of women reported reduced genital sensation with 19% (27) answering “does not apply” or not answering the question.

A total of 58% (214) reported frequent urination within 3 months prior to completing the questionnaire, and 64% (234) reported urinary incontinence; 30% (109) were using a catheter, and of these, 32 patients had been using it for <1 year, 58 patients for 1 to 3 years, and 19 patients for >3 years. Forty percent (145) reported shoulder/neck discomfort when standing up (suggesting symptomatic orthostatic hypotension). Fifty-six percent (203) reported reduced sweating; 74% (271) reported cold hands or feet.

Forty-seven percent (172) reported drooling, 62% (226) reported dysphagia, 80% (291) reported constipation, and 21% (75) reported diarrhea.

Other Symptoms

Eighty-four percen (307) reported a softer voice, 87% (318) reported slurred speech, 36% (130) reported noisy breathing while awake, 37% (136) had crying or laughter for no reason, 61% (222) reported forgetfulness, 57% (207) reported feeling depressed, and 22% (79) reported seeing things that are not there (ie, visual hallucinations). The presence of visual hallucinations was not associated with a history of levodopa intake (χ2 = 0.39; P = 0.53). Of the respondents, 36% (133) reported changes in olfaction within 5 years prior to completing the questionnaire; 21% (80) had a history of head trauma or concussion.

Figure 1 shows a summary of the percentage of questionnaire participants reporting each symptom.

Details are in the caption following the image
Cross-sectional prevalence of symptoms in patients with multiple system atrophy (MSA) participating in the Global Multiple System Atrophy Registry who completed the online questionnaire.

Discussion

We report the largest cross-sectional sample of patients with MSA ever assembled (1083 patients), a subset of whom (365 patients) completed an online questionnaire on disease timelines and symptoms. Although acknowledging the potential limitations of a self-reported MSA diagnosis, the questionnaire results are consistent with the prevalence of symptoms reported in natural history, cross-sectional studies, and meta-analyses of patients with probable and possible MSA. Age at onset (59 years); slight prevalence of male sex (55%); response to levodopa in a minority (20%); wheelchair use (53%); slurred speech (87%); dysphagia (62%); prevalence of urinary (up to 64%), genital (88% of men reported erectile dysfunction), or gastrointestinal dysfunction (80% reported constipation); cold hands/feet (74%); depression (57%); and dream enactment behavior (77%) had all been previously reported with similar frequencies.1, 4-10 This suggests that the self-reported diagnosis of MSA and its associated symptoms are accurate.

A novel finding of the online questionnaire is the presence of symptoms not traditionally associated with MSA. Specifically, 61% of patients reported forgetfulness even though cognitive impairment is not among the commonly presenting features of MSA; 36% reported olfactory changes despite olfactory function being typically preserved in MSA; and 22% reported visual hallucinations, although this is usually considered a red flag against the diagnosis of MSA (supporting, instead, a diagnosis of dementia with Lewy bodies). In our sample, the presence of visual hallucinations was not associated with a history of levodopa intake. Although we have no information on comorbidities that could explain these atypical features (eg, smoking could explain the hyposmia, treatment with dopaminergic agonists could explain the hallucinations), these features may either suggest that some of these patients may have been misdiagnosed or that these features are not as infrequent in MSA as previously thought. The latter is supported by research highlighting the fact that cognitive deficits, including memory complains, are prevalent in patients with MSA,11, 12 that some patients with MSA may develop psychosis unrelated to dopaminergic therapies,13 and that some patients with MSA have mild or moderate hyposmia.14-16 Additional studies in these MSA populations is warranted as the identification of these patients with atypical features may have clinical, therapeutic, and research implications. Importantly, the questionnaire shed light on MSA aspects that remain understudied, such as female sexual dysfunction (55% of women had reduced sexual sensation, similar to a previously reported percentage17) or pseudobulbar affect (37%). Finally, the questionnaire found a long diagnostic delay of MSA, with an average 3.3 years from first symptom to diagnosis, with the caveat that this question did not take into account if the first symptom was motor or nonmotor.

Most of the online questionnaire responders answered from English-speaking countries, which was expected as the questionnaire was in English. Future online questionnaires should consider translation into other languages. Another limitation is the lack of ascertainment on the severity of symptoms or the impact of the symptoms on the patients' function/quality of life. Finally, neither GLOMSAR nor the questionnaire included questions on the participants' predominant MSA phenotype (parkinsonian vs. cerebellar), which may have impacted the frequency of symptoms.

Our results confirm that patient registries are useful research instruments in rare diseases, such as MSA, with the potential to reach thousands of patients including those from underserved geographical locations (eg, Africa). Data obtained from GLOMSAR and its online ancillary questionnaire appear reliable, consistent with previous reports, and useful to advance the knowledge on understudied MSA features, underlining the patients' voice to inform the development of novel clinical outcome assessment tools or the selection of assessments and end points for clinical trials. Using similar questionnaires at multiple prospective time points may be useful to obtain data to inform disease progression. GLOMSAR is active, free, and open to participation to patients with MSA (https://redcap.link/nyuglomsar).

Acknowledgments

We thank all the patients with multiple system atrophy (MSA) and their caregivers who participated in the Global Multiple System Atrophy Registry and the questionnaire as well as the MSA Coalition for logistical support.

    Author Roles

    (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

    J.-A.P.: 1A, 1B, 1C, 2A, 2C, 3AF.K.: 1A, 1B, 1C, 2A, 2C, 3B

    W.G.M.: 1A, 1B, 1C, 2A, 2C, 3B

    M.K.: 1C, 2B, 3B

    P.M.V.: 1C, 2B, 3B

    M.A.P.: 1C, 2B, 3B

    A.F.: 1A, 1B, 1C, 2A, 2C, 3B

    L.N.K.: 1A, 1B, 1C, 2A, 2C, 3B

    P.B.: 1C, 3B

    G.K.W.: 1A, 1B, 1C, 2A, 2C, 3B

    H.K.: 1A, 1B, 1C, 2A, 2C, 3B

    Disclosures

    Ethical Compliance Statement: The New York University Institutional Review Board approved Global Multiple System Atrophy Registry and the ancillary web-based symptom questionnaire. All participants signed an online informed consent. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

    Funding Sources and Conflicts of Interest: Funding was received from the Multiple System Atrophy (MSA) Coalition and the National Institutes of Neurological Diseases and Stroke (R01NS107596 and U54NS065736). Financial disclosures and conflicts related to this article included the following: J.-A.P. received research funding from the National Institutes of Health (NIH) and MSA Coalition and is an employee of Novartis. F.K. received personal fees from Institut de Recherches Internationales Servier, Clarion Healthcare, Takeda Pharmaceuticals, and the Austrian Society of Neurology and grant support from the MSA Coalition outside of the submitted work. P.M.V. received research funding from the Familial Dysautonomia Foundation and Theravance Biopharma and is principal investigator in studies funded by Biohaven Pharmaceuticals and Theravance Biopharma. M.A.P. received research funding from the Familial Dysautonomia Foundation. L.N.K. received research funding from the NIH, The Michael J. Fox Foundation, MSA Coalition, Familial Dysautonomia Foundation FDA and a salary from 23andme. H.K. received research funding from the NIH, The Michael J. Fox Foundation, MSA Coalition, Familial Dysautonomia Foundation, US Food and Drug Administration, and Biogen; is an advisory board member for Lundbeck, Biogen, Biohaven, Theravance, PTC Therapeutics, ONO, Takeda, Vaxxinity, and Lilly; and is Editor-in-Chief of Clinical Autonomic Research. W.G.M., M.K., A.F., P.M., G.K.W., and H.K. have no disclosures related to this article to report.

    Financial Disclosures for the Previous 12 Months: J.-A.P. received research funding from the National Institutes of Health (NIH) and the Multiple System Atrophy (MSA) Coalition and is an employee of Novartis. F.K. received personal fees from Institut de Recherches Internationales Servier, Clarion Healthcare, Takeda Pharmaceuticals and the Austrian Society of Neurology and grant support from the MSA Coalition outside of the submitted work. W.G.M. reports fees for editorial activities with Elsevier; consultancy for Lundbeck, Biohaven, Roche, Alterity, Servier, Inhibikase, Takeda, and Teva; and teaching honoraria from UCB. P.M.V. received research funding from the Familial Dysautonomia Foundation and Theravance Biopharma and is principal investigator in studies funded by Biohaven Pharmaceuticals and Theravance Biopharma. M.A.P. received research funding from the Familial Dysautonomia Foundation. A.F. received royalties from Springer Verlag; personal fees from Impact Medicom, Theravance Biopharma, AbbVie, Healthware, the International Parkinson Disease and Movement Disorders Society, the Austrian Neurology Society, and the Austrian Autonomic Society; and research grants from the Parkinson Fond, the US MSA Coalition, the Dr Johannes and Hertha Tuba Foundation, and the Austrian Exchange Program outside of the present work. L.N.K. received research funding from the NIH, The Michael J. Fox Foundation, MSA Coalition, Familial Dysautonomia Foundation, and US Food and Drug Administration (FDA) and is an employee of 23andme. H.K. received research funding from the NIH, The Michael J. Fox Foundation, MSA Coalition, Familial Dysautonomia Foundation, FDA, and Biogen; is an advisory board member for Lundbeck, Biogen, Biohaven, Theravance, PTC Therapeutics, ONO, Takeda, Vaxxinity, and Lilly; and is Editor-in-Chief of Clinical Autonomic Research. M.K., P.M., and G.K.W. have no other disclosures to report.