PONE-D-20-29759

The association of fibromyalgia and fibromyalgia-related symptoms with self-reported seizures

PLOS ONE

Dear Dr. Klooster:

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Hyunmi Choi, MD, MS

Academic Editor

PLOS ONE

Additional Editor Comments:

Dear Dr. Klooster:

Your paper has been reviewed by our reviewers. Enclosed are the reviewers' comments, which I urge you to address in revising your manuscript. Please consider Reviewer 1's comments about the use of self-reported seizures, and further expand your limitation section in Discussion. Also, please include a sentence in the Abstract to balance your conclusion, with a statement about the limitations of using self-reported seizure, specifically about possible inclusion of those with psychogenic nonepileptic seizures. Please make the recommended changes as per Reviewer 2.

Sincerely,

Hyunmi Choi, MD, MS

Academic Editor

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Reviewers' comments:

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Reviewer #1: Partly

Reviewer #2: Partly

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: Summary:

This studies intends to describe the association of fibromyalgia with self reported seizures. Overall study is well written

Major comments:

- This paper has a very fundamental issue, which is that the definition of seizures used out of patient self report is not a rigorous one. Patients often use the term seizures very informally for any type of episodes of loss of awareness or focal neurological deficit. That may include stroke, epilepsy, syncope and other diagnosis. So using patient self report without verification by a physician can just answer the question does fibromyalgia has association with any neurological symptom. Second there is the problem that typically neurologists refer to seizures as repetitive neurological disturbance caused by electrical brain disturbance. So psychogenic events (PNES) is not typically considered a seizure. So no sure that this paper will provide any useful information for clinical practice.

- Perhaps the medication criteria is a better surrogate of possible diagnosis of seizures/epilepsy even though not perfect. However, why where these list of Antiepileptic medications were chosen ? our of convinience or what it was available in the database. There is more anticonvulsants in existence not in the list and very common like valproic acid (depakote), levetiracetam etc.

- I dont know about the value of the Seizure drug analysis. Furthermore, the division of the drugs into Pure drugs, mixed and mixed plus makes the study overly complicated and provide very little or limited clinical value. I do understand that authors are trying to compensate for the seizure self reporting nature of the study. Why not rather use the drugs as a way to assess accuracy of possible epilepsy diagnosis if possible.

- The point made in line 290 further confirm the concern about the use of self reporting seizure. Some of the patient using "pure" seizure drug have more likelyhood of FM even when they report no seizures. Now why would that be the case. Normally people who take those drugs should report seizures. Not sure the dataset is robust enough to be confident on the seizures. THe FM diagnosis seems fairly robust but not sure seizure are

Minor comments:

- It would be useful to the unfamiliar reader with the dataset if the author describe the response rate by patients for this questionnaire and how rigorous is the questionnaire administration process.

- Results Line 214: I will add % of seizures as it is not intuitive that 89 FM+ report sz an 97 FM- but 89 represented higher rate of seizures within that group.

Reviewer #2: The authors examine the association between fibromyalgia (assessed using validated self-reported symptom-based diagnostic criteria) and self-reported seizures, among patients with rheumatoid arthritis, using the National Databank for Rheumatic Diseases. This study follows multiple clinical and epidemiological studies that have previously examined this association, with similar findings. They conclude that there is a significant association between fibromyalgia (as well as multi-symptom comorbidities more generally) and self-reported seizures.

The study is overall clinically valuable in that it confirms, strengthens, and somewhat elucidates prior findings of an association between fibromyalgia and seizures. The methodology is generally sound, and the writing is generally clear and precise.

This study does make an important improvement in that it assesses fibromyalgia based on validated criteria rather than self-reported diagnosis or unstandardized clinical diagnosis. There is substantial reason to think that clinical fibromyalgia diagnoses are often inaccurate, so this is a notable improvement. However, unlike some prior clinical studies, the current study assesses seizures based solely on self-report, and does not differentiate between epileptic or psychogenic seizures. Epileptic and psychogenic seizures are thought to have entirely different etiologies, so an association with self-reported undifferentiated “seizures” is of unclear clinical or biological significance. As the authors note, multiple prior clinical studies have demonstrated a strong association between self-reported fibromyalgia and psychogenic seizures specifically, so readers might well wonder what fraction of the self-reported seizures in this study are psychogenic.

The authors appropriately note both the reliance on self-report of seizures and the failure to differentiate between epileptic and psychogenic seizures in the limitations. I think they might go further and suggest that future studies might use both validated assessments of fibromyalgia and, at the very least, clinical diagnoses of epileptic and psychogenic seizures.

This study is also importantly limited in that it is conducted entirely in a population with rheumatoid arthritis. The authors present this solely as a strength of the study, noting that patients with rheumatoid arthritis have higher rates of fibromyalgia, and also higher rates of seizures. But this is also a significant limitation in that the associations demonstrated in this study may not hold in the general population. The authors speculate that the association may be even stronger in the general population, but the study offers no actual data regarding the association between fibromyalgia and seizures in the general population. This fact is not reflected in the study’s conclusions which state “we found a significant association of FM diagnostic and FM-related variables including the number of somatic symptoms and comorbidities, with self-reported seizures” (lines 436-437). The conclusions as currently written are not supported by the evidence in the study. The concluding sentence should end with a caveat such as “among people with RA.” Similar caveats should be added in the abstract.

The authors also evaluate seizure medications among patients with and without seizures, demonstrating that seizure patients treated with anti-seizure medications had worse outcomes than those not so treated. As the authors note, the presence or absence of anti-seizure medications is not a good marker for epileptic vs. psychogenic seizures. The authors appropriately break these medications down into those that are usually used to treat seizures and those that are commonly used for other purposes. Surprisingly they do not include levetiracetam at all, which is today among the most commonly prescribed seizure medications. Also surprisingly, primidone is listed as a pure seizure drug when in adults it is more commonly prescribed for tremor. Acetazolamide, which is listed as being used for glaucoma and diuresis, is also commonly used for idiopathic intracranial hypertension. I would suggest including levetiracetam if at all possible and switching primidone from the pure to the mixed seizure drug category.

The manuscript includes a number of typos and grammatical errors, and would benefit from close line editing. For example:

Lines 153-154: “The continues PSD score has been shown to…”

Lines 162-163: “A total symptom count was calculated for this study based on a checklist of 60 specific symptom, dived over 8 categories…”

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Reviewer #1: No

Reviewer #2: Yes: Benjamin Tolchin, MD, MS

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The relation of fibromyalgia and fibromyalgia symptoms to self-reported seizures

PONE-D-20-29759R1

Dear Dr. Klooster,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Hyunmi Choi, MD, MS

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I appreciate the authors' responses to reviewers' comments.