Prevalence and correlates of diagnosed and undiagnosed epilepsy and migraine headache among people with severe psychiatric disorders in Ethiopia.

BACKGROUND: There is a paucity of research on the prevalence of diagnosed as well as undiagnosed neurological disorders with episodic manifestations such as epilepsy and migraine headaches in people with severe psychiatric disorders (SPD). To the best of our knowledge, this is the first study analyzing and comparing the prevalence of diagnosed and undiagnosed chronic neurological disorders with episodic manifestations including epilepsy and migraine headache in people with SPD.
METHOD: This quantitative cross-sectional survey was undertaken among 309 patients with SPD selected by a systematic random sampling technique. The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) was used to confirm SPD among the participants. The International Classification of Headache Disorders (ICHD-3) and International League Against Epilepsy (ILAE) were used to define migraine headache and epilepsy, respectively]. Risk factors for chronic neurologic disorders were explored by using logistic regression models. RESULT: In this study, the prevalence of overall neurological disorders, epilepsy, and migraine headache among people with SPD were found to be 5.2% (95%CI 3.2-8.3), 1.6% (95%CI 0.7-3.9), and 3.9% (95%CI 2.2-6.7), respectively. We found that a considerably higher proportion of people with SPD had undiagnosed overall neurological disorder (87.5%; 14/16), epilepsy (60%; 3/5), as well as migraine headaches (100%; 12/12). On the other hand, in this study, 12.5%, 40%, and 0% of patients with overall neurologic disorder, epilepsy, and migraine headaches respectively were diagnosed by the professionals. Higher disability score (WHODAS score) was associated with increased odds of having neurological disorders compared with the lower WHODAS score [OR = 1.30 (95% CI 1.02-1.66)].
CONCLUSION: Whilst the prevalence estimates of neurological disorders with episodic manifestations including epilepsy and migraine headache was high among people with SPD, the vast majority of them remained undiagnosed. The diagnosis rates of those disorders were significantly low, perhaps surprisingly zero for migraine headache. High WHODAS score was associated with increased odds of having neurological disorders. Routine screening and management of epilepsy and migraine headache are imperative among people with SPD.

Background

Severe psychiatric disorders (SPD) most commonly referring to the diagnosis of mental disorders with a substantial impairment over multiple domains [1]. These include schizophrenia, bipolar, schizoaffective, and depressive disorder [1]. According to the global burden of disease (GBD), SPDs are key contributors to the global burden of disease and they are among the major causes of morbidity and mortality worldwide [2, 3]. The prevalence estimates of SPD in adult ranges from 4 to 6%, which shows that a notably higher proportion of adults have SPD [4, 5].

Research evidence shows that a considerable percentage of people with SPD have comorbid medical conditions including neurologic disorders such as epilepsy and migraine headaches [6-9]. For example, a recent meta-analysis that assessed the prevalence of migraine headaches among patients with bipolar disorder involving seven studies on the subject found that roughly one-third of patients with bipolar disorder had comorbid migraine headaches (30.36%) [8]. However, the existing literature indicates that: (1) the vast majority of co-occurring medical conditions were untreated and undertreated; (2) most of them remain undiagnosed [10]; (3) even among those patients receiving treatment, the quality of service/care for both the comorbid medical condition and psychiatric disorders has been inadequate [11, 12]. Scientific evidence shows that early identification and treatment of comorbid medication conditions in patients with severe psychiatric disorders are associated with improvement in outcomes, increased quality of life, reduced burden and cost associated with medical services, and improved in functionality/productivity [13, 14].

Even though there are no previous studies that reported the rates of undiagnosed neurologic disorders with episodic manifestation (such as epilepsy and migraine headaches) among patients with SPD, evidence from the general population shows that the vast majority of patients with epilepsy and migraine headache remained undiagnosed in the general community. For example, in a recent study that assessed the prevalence of undiagnosed migraine headaches using 15000 US households selected by a door-to-door survey, the prevalence of undiagnosed migraine was 70% for males and 60% for females [15].

While there is a paucity of supportive epidemiologic data on the prevalence estimate of undiagnosed neurologic disorder (epilepsy and migraine headache) among people with SPD, it is assumed that the prevalence rates of epilepsy and migraine headache believed to be significantly higher in patients with SPD as compared to reported prevalence rates from the general population due to: (1) both SPD and neurologic disorders have common clinical manifestations which might increase the rates of undiagnosed disorders; (2) the nature of psychiatric disorders (SPD) which remarkably impairs the understanding and insight of the patients [16, 17]; (3) the reported higher prevalence rates of undiagnosed physical illness including epilepsy and headaches (up to 80%) in people with mental illness [7, 18], suggesting the high probability of those neurologic disorders to be undiagnosed.

To the best of our knowledge, this is the first study analyzing and comparing the prevalence of diagnosed and undiagnosed chronic neurologic disorders with episodic manifestations including epilepsy and migraine headache in people with SPD. The results will help to understand the approximate pictures of undiagnosed disorders (epilepsy and migraine headache) among patients with SPD and to suggest potential clinical and research recommendations.

Methods

Study design and period

This quantitative cross-sectional study was conducted among 309 patients with severe psychiatric disorders from May 1, 2017, to July 30, 2017. All participants were recruited from Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia, which is the only specialized psychiatry hospital in the country.

Inclusion and exclusion criteria

Participants satisfying the following criteria were included in this study: (1) adult (aged 18 years and above); (2) those patients who had a diagnosis SPD (including schizophrenia, bipolar, schizoaffective, and depressive disorders). Those patients who had a severe illness at the time of data collection (affecting communications) were excluded.

Sampling procedure

This survey is part of a comorbidity study among patients with severe psychiatric disorders in a specialized mental health setting in central Ethiopia. Hence, the sample size has been calculated considering the prevalence of comorbid physical conditions among people with SPD nearly 80% [7, 19]. The following assumptions were considered to calculate the sample size: (a) 95% confidence interval; (b) 80% proportion of comorbid medical conditions; (c) 30% non-response rate. The final sample size was 320.

Participants were selected using a systematic random sampling technique. The sampling interval (K = 11) was identified by dividing the total participants with SPD who had the follow-up and treatment during the study period by total sample size. A lottery method was used to select the first study participant, and a regular interval was used to select the remaining participants.

Measures

Diagnosis of severe psychiatric disorders

The structured clinical interview for DSM- ΙѴ-TR axis Ι disorders (SCID) was used to ascertain the presence of severe psychiatric disorders [20]. SCID is a validated instrument designed to assess the diagnosis of the Diagnostic Manual of Mental Disorders Axis I disorders (DSM-IV) (major psychiatric disorders), which is extensively used to assess those disorders in previous studies conducted in Ethiopia [21, 22].

Diagnosis of epilepsy

The current diagnosis of Epilepsy was identified according to the International League Against Epilepsy (ILAE) classification of seizure criteria, a neurological condition characterized by two or more unprovoked seizures that occurred at least 24 hours apart [23]. According to the ILAE guideline, an epilepsy case is defined as someone with an active, recurrent (two or more) condition of an epileptic seizure, which was unprovoked by an immediate cause. The same classification and definition of epilepsy have been used in previous studies in Ethiopia [24, 25]. The previous diagnosis of epilepsy was taken from the chart of the patients (yes/no).

Migraine headache case definition

The present case of migraine headache was defined based on the International Classification of Headache Disorders (ICHD-3) criteria of migraine headaches with or without aura [26].

The previous diagnosis of migraine was taken from the chart of the patients (yes/no).

Screening for disability

In this study, disability was assessed using the World Health Organization Disability Assessment Schedule (WHODAS-2), an instrument designed to measure functional impairment [27]. This tool covers six domains of functioning including cognition, mobility, self-care, getting along (interacting with other people), life activities, and community participation (25) and has been validated in Ethiopia on patients with severe psychiatric disorders [28].

Sociodemographic and other factors

We used structured questionnaires to collect data on sociodemographic and clinical characteristics such as age, marital status, educational status, ethnicity, religion sex, residence, suicide, duration of the illness, history of hospitalizations, and relapse. Trained psychiatry professionals, who have adequate knowledge and experience on SCID criteria, collected data.

Definitions of terms

In the present study, overall neurological disorders represent the presence of either epilepsy and migraine headaches in patients with SPD. Research studies suggest that epilepsy and migraine headaches are the two commonest chronic neurological disorders with episodic manifestations [29].

Data quality control

In this study, structured and interviewer-administered questionnaires that have been developed in English were translated into the local language (Amharic), and then to check the consistency the Amharic version of the questionnaires was translated back into English. Assessors with adequate knowledge and experience about the diagnostic statistical Manual of Mental Disorders (DSM), ICHD-3, and ILAE were recruited (MSc psychiatry professionals) to assure the quality of the data. Moreover, adequate training has been given regarding sampling procedure or protocol, on how to complete the questionnaire, eligibility criteria, ethical issues, data collection procedure, and the components of the questionnaire (sociodemographic and other variables), as well as the details of the two main data collection instruments (ICHD-3 and ILAE) for the supervisors and data collectors. The questionnaires have been pretested before the actual data collection and the essential modification was undertaken. Two Supervisors followed the data collection process and the necessary correction was made when needed. The supervisor and principal investigator reviewed the collected data and checked for completeness and relevance each day.

Statistical analysis

Stata (version 16) was used to conduct all the statistical analysis. Descriptive statistics for the participants were provided. Frequency/percentage was used to express categorical variables and mean (standards deviations) were used for continuous variables. The dependent variables (diagnosed and undiagnosed cases of neurologic disorders i.e. epilepsy and migraine headache) were measured using percentage. We conducted bivariate and multivariate logistic regression analysis to look at the association between dependent and independent variables. OR with 95% CI was used to measure the strength of the association and a P-value less than 0.05 was considered as statistically significant.

Ethical consideration

The study protocol was approved by Amanuel Mental Specialized Hospital (Research and training department) ─the human research and ethics committee (HREC). Informed written consent has been obtained from every participant after a clear and detailed explanation of the purpose, significance, objectives, harms, and benefits of participation.

Results

Sociodemographic characteristics of the participants

In this study, a total of 320 patients has been assessed for eligibility, out of which 309 (96.6%) patients with SPD including schizophrenia (n = = 135), bipolar (n = 54), schizoaffective (n = 28), and depressive (n = 92) disorders were included in the final analysis. The mean (±SD) age of the participants was 36.19 (± 10.45) years. Most of the participants were male (65.4%) and single by marital status (65.4%). More than one-third of the participants had attended secondary school, approximately half of the participants were Orthodox Christians (51.47%), and more than three-fourth were from urban areas (76.05%) (Table 1).

Table 1

Sociodemographic characteristics of the participants with severe psychiatric disorders in Addis Ababa, Ethiopia (n = 309).

Characteristics	Frequency	Percentage
Sex
Male	202	65.37
Female	107	34.63
Age
30 or less	110	35.6
30 to 40	106	34.3
41 and more	93	30.1
Educational status
Uneducated	30	9.71
Primary	103	33.33
Secondary	118	38.19
Higher	58	18.77
Religion
Muslim	87	28.16
Orthodox	157	51.46
Protestant	57	18.54
Others	6	1.94
Marital status
Single	202	65.37
Married	74	23.95
Divorcee/widowed	33	10.68
Ethnicity
Amhara	95	30.74
Oromo	91	29.45
Gurage	82	26.54
Others	41	13.27
Residence
Urban	235	76.05
Rural	74	29.95
SPD type
Schizophrenia	135	43.69
Bipolar disorder	92	29.77
Depressive disorder	54	17.48
Schizoaffective disorders	28	9.06
Catatonia
No catatonia	248	80.26
Catatonia	61	19.74
Psychosis
No psychosis	44	14.24
psychosis	265	85.76
History of relapse
Relapsed	226	73.14
No relapse	83	26.86
History of admission
Admission	196	63.42
No admission	113	36.57

The prevalence of neurologic disorders in patients with SPD

The overall prevalence of neurologic disorders (including epilepsy and migraine headache combined) in our study was 5.2% (95%CI 3.2–8.3). Specifically, the prevalence was 1.6% (95%CI 0.7–3.9)) for epilepsy and 3.9% (95%CI 2.2–6.7) for migraine headaches.

Additionally, the prevalence of comorbid migraine headache among epileptic patients was 20%, whereas the prevalence of comorbid epilepsy among migraine headache patients was 8.3%. We also found that 0.3% of patients with SPD had both epilepsy and migraine headache.

The prevalence of diagnosed and undiagnosed neurological disorders in patients with SPD

The prevalence of undiagnosed neurological disorders was 4.5% among the total participants and 87.5% of those participants with neurological disorders. Likewise, the prevalence of undiagnosed epilepsy was 1% among the total patients and 60% in patients with epilepsy.

Regarding migraine headache, the prevalence of undiagnosed migraine headache was 3.9% of the total participants and 100% in patients with migraine headaches (Table 2).

Table 2

The prevalence of undiagnosed neurologic disorders among patients with severe mental disorders in central Ethiopia, n = 309.

Disorder	Chart diagnosis, n (%)	Real diagnosis, n (%)	Undiagnosed disorder from the total, n (%)	Undiagnosed disorder from the cases, n (%)
Overall neurologic disorders	2 (0.65)	16 (5.18)	14 (4.53)	14 (87.50)
Epilepsy	2 (0.65)	5 (1.62)	3 (0.97%)	3 (60.00)
Migraine headache	0 (0.00)	12 (3.88)	12 (3.88)	12 (100)

Key: Chart diagnosis indicates the diagnosis of the patient taken from the chart, while real diagnosis indicates the current diagnosis of the patient according to the assessors (tools used).

On the other hand, in this study, 12.5%, 40%, and 0% of patients with overall neurologic disorder, epilepsy, and migraine headaches respectively were diagnosed by the professionals.

Factors associated with undiagnosed neurological disorders in patients with SPD

Multivariable logistic regression analysis revealed that none of the socio-demographic and clinical characteristics of participants included in the model were found to be associated with undiagnosed neurological disorders in patients with SPD. Higher WHODAS score, however, was associated with increased odds of having neurological disorders when compared with the lower WHODAS score [OR = 1.30 (95% CI 1.02–1.66)] (Table 3).

Table 3

Factors associated with neurologic disorders in people with severe mental disorders, Addis Ababa, Ethiopia.

Characteristics	Neurologic disorders		Crude odds ratio (95%CI)	Adjusted odds ratio (95%CI)
	Yes	No
Gender
Female	6	101	1.14 (0.40–3.23)	1.01 (0.33–3.08)
Male	10	192	1	1
Age
<35	6	135	1	1
≥ 35	10	158	1.42 (0.50–4.02)	1.34(0.34–3.35)
Residence
Urban	15	220	1	1
Rural	1	73	0.20 (0.26–1.55)	0.19 (0.02–1.60)
Marital status
Single	10	192	1	1
Married	3	71	0.81 (0.21–3.03)	1.07 (0.27–4.28)
Divorce/widowed	3	30	1.92 (0.50–7.34)	2.37(0.53–10.59)
Catatonia
No catatonia	11	237	1	1
Catatonia	5	56	2.56 (0.64–5.76)	1.85 (0.59–5.87)
Psychosis
No psychosis	2	14	1	1
Psychosis	14	251	1.17 (0.26–5.34)	1.07 (0.21–5.53)
Misdiagnosed severe psychiatric disorder
Correct diagnosis	13	175	1	1
Misdiagnosis	3	118	0.34 (0.09–1.23)	0.31 (0.08–1.15)
Relapse
Relapsed	13	23	1.63 (0.45–5.86)	1.38 (0.35–5.47)
No relapse	3	80	1	1
Admission
Admission	11	185	1.28 (0.43–3.79)	1.03(0.31–3.42)
No admission	5	108	1	1
WHODAS score			1.21 (1.00–1.51)	1.30 (1.02–1.66)*

* Significant association (p-value < 0.05).

Discussion

Main findings

To the best of our knowledge, this is the first study that examined the epidemiology of diagnosed and undiagnosed neurological disorders, including epilepsy and migraine headache in patients with severe psychiatric disorders in a specialized psychiatric setting. Our results indicated that a considerable proportion of people with severe psychiatric disorders had diagnosed and undiagnosed neurological disorders. The highest prevalence estimate of undiagnosed disorder was observed for migraine headache (100%) followed by overall neurological disorders (87.5%) and epilepsy (60%). Our findings suggest that routine screening and intervention for neurological disorders should be considered in people with SPD.

The prevalence and associated factors of neurological disorders in people with SPD

The prevalence of neurological disorders including epilepsy and migraine headache in this study were found to be much higher than the reported global prevalence of those disorders in the general population [24, 30–35]. For instance, a recent meta-analysis including 197 prevalence studies conducted across the globe revealed that the lifetime prevalence of epilepsy in the general community was 7.6 per 1000 population [36], which is considerably lower than the reported prevalence epilepsy among patients with severe psychiatric disorders(16.2 per 1000 population) in the current study. A recent meta-analysis conducted in Ethiopia reported that the prevalence of epilepsy in the general community was 5.2 per 1000 population) [35]. Our result was 3.12 times higher than this reported prevalence. There are wide ranges of explanations for higher prevalence rates of epilepsy among people with severe psychiatric disorders. One of the possible explanations is that these disorders might have shared genetic factors. For example, a recent genetic study by Lopez et.al found that epilepsy and bipolar disorders have a common genetic abnormality [37]. The above study revealed that abnormalities in ANK3-coded proteins in the brain (lower amount of ANK3 type proteins) in these disorders, which is responsible for increasing output (excitation) and holding back out (inhibitions) [37]. Additionally, epidemiologic evidence demonstrates that these two disorders have been treated by the same drugs including sodium valproate (VPA) and carbamazepine (CBZ), which are effective drugs for both disorders, indicating some underlying common pathways across these disorders [38]. Similarly, a genetic-based study conducted in the USA revealed that epilepsy and schizophrenia have a shared genetic abnormality including abnormal development of the brain and nervous system [39, 40]. Likewise, the existing scientific evidence indicates that depression and epilepsy have a shared genetic abnormity responsible for causing these disorders [41]. The other possible explanation for the higher prevalence rates of epilepsy among people with severe psychiatric disorders is having underlying common neurotransmitter abnormalities (neurochemical underpinnings) [42].

Regarding the prevalence of migraine headache, although we did not found previous studies concerning migraine headache among patients with overall severe psychiatric disorders (including schizophrenia, bipolar, schizoaffective, and depressive disorders combined), there are several studies conducted in specific categories of disorders. For example, a recent meta-analysis of seven studies on the subject showed that the prevalence of migraine headache among patients with bipolar disorders was 30.36% [8], which was significantly higher than the reported prevalence in the current study on severe mental disorders (3.88%). Another study that assessed the prevalence of migraine headache among schizophrenia patients found a remarkably lower prevalence (2%) [43] when compared with the prevalence in this study. The prevalence of migraine headache in the current study was more than 2 times higher than the reported prevalence in the general population, according to the global burden of disease study in 2016 (1.8%) [44]. The highest prevalence of migraine headache among patients with severe psychiatric disorders could be due to common genetic as well as environmental factors responsible for both migraine headache and severe psychiatric disorders [45, 46].

As for the associated factors, in this study, disability was associated with the diagnosis of neurological disorders. After adjusting all the potential confounders, greater disability (the highest WHODAS score) was associated with increased odds of having neurological disorders when compared with lower disability (the lower WHODAS score) [OR = 1.30 (95% CI 1.02–1.66)]. Consistent with our finding a recent study found a significant and positive association between greater disability and increased risks of depression [47].

The prevalence of undiagnosed neurological disorders diseases in people with SPD

In the current study, approximately nine out of ten (87.5%) participants with neurologic disorders were undiagnosed among people with SPD. For specific disorders, the rate of undiagnosed disorder was relatively higher for migraine headaches (100%) followed by epilepsy (60%), which were remarkably higher than the reported prevalence rates in the general population. For example, in a recent study that assessed the prevalence of undiagnosed migraine headache in the US revealed that the prevalence of undiagnosed migraine was 70% for males and 60% for females [15], which is remarkably lower than the reported magnitude in the current study (100%).

The possible reason for higher rates of undiagnosed neurological disorders (migraine headache and epilepsy) might be due to a significant overlap between symptoms of severe psychiatric disorder and neurological disorders. For instance, a study conducted by Moeno et.al found that more than one fourth (25.4%) of patients with major depressive disorders visited a primary care setting with a chief complaint of headache [48]. Similarly, a case-control study conducted by Marlow et.al reported that 32% of patients who reported headaches as the main symptoms were diagnosed with major depressive disorders [49]. More recently, a cross-sectional study that evaluated headache and schizophrenia revealed that 57% of patients with schizophrenia had an overlapping headache as a clinical presentation [50]. More recently, a cross-sectional study that evaluated headache and schizophrenia revealed that 57% of patients with schizophrenia had overlapping headaches as a clinical presentation [51, 52].

Likewise, a significant proportion of patients with epilepsy have overlapping psychiatric symptoms [53, 54], which might partly explain the higher levels of undiagnosed epileptic cases in patients with severe psychiatric disorders. The other possible reason for the observed higher rates of undiagnosed neurological cases could be due to the severity of the psychiatric disorders, which impairs the insight of the patients to adequately understand and report their complaints. Complementing this, a cross-sectional study that has assessed insight in patients with schizophrenia found that 50–60% of patients lack insight (either partially or completely) into their mental disorders [55]. Similarly, epidemiologic data shows that a significant proportion of patients with depressive and bipolar disorders have a lack of insight into their disorder [56, 57]. The skills, training as well as knowledge of the psychiatry professionals about those neurological disorders might be the other possible reasons for higher prevalence rates of undiagnosed disorders.

Recommendations for future research and clinical practice

This study has some implications for future clinical practice and research: (1) we found that rates of undiagnosed neurological disorders are significantly high but the estimates for the distinct categories SPD are not explored because of a small number of study participants for the specific disorder, indicating the need for future studies addressing these gaps. (2) This study found a higher prevalence of undiagnosed neurological disorders when compared with the reported prevalence in the general population, which needs future robust studies regarding the potential reasons for the discrepancies. (3) Training and strategies (including continuous medical education (CME)) to increase awareness of the neurological disorders, as well as the misdiagnosis rates for the psychiatric professionals, is warranted. (4) Routine screening and intervention for neurological disorders should be considered in people with SPD. (5) Future studies on the underlying factors for the higher rates of misdiagnosis are needed.

Strengths and limitations

This study has several strengths to note: (1) It is the first study analyzing and comparing the prevalence estimates of undiagnosed neurological disorders among people with SPD; (2) severe psychiatric disorders were confirmed by a standard and diagnostic instrument (SCID). (3) We have used a standard instrument to ascertain severe psychiatric disorders. (4) Epilepsy and migraine headache were defined based on standard measuring tools. However, this study has some potential shortcomings that should be noted: First, factors associated with neurological disorders may not imply causality as the study design was cross-sectional. Secondly, the use of chart records for diagnosis of neurological disorders might underestimate the diagnosed cases since some previous diagnoses may not be documented. Thirdly, the small number of participants (sample) should be considered in interpreting the results especially for the estimates of the specific disorders such as epilepsy and migraine headache. Also, future studies addressing this limitation are warranted.

Conclusion

In summary, this study showed that a significant proportion of people with SPD had neurological disorders including epilepsy and migraine headache. The highest prevalence estimate of undiagnosed disorder was observed for migraine headache followed by overall neurological disorders and epilepsy. Our findings suggest that routine screening and intervention for neurological disorders should be considered in people with SPD. Training and strategies to increase awareness of neurological disorders, as well as the misdiagnosis rates for psychiatric professionals, are warranted. Future longitudinal studies with adequate sample size are needed to identify the factors associated with undiagnosed neurological disorders particularly focusing on the specific disorders.

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18 Aug 2020

PONE-D-20-11101

The epidemiology of diagnosed and undiagnosed chronic neurological disorders with episodic manifestations in People with Severe Psychiatric Disorders in Ethiopia

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Reviewer #1: Also attached.

I find this to a very interesting paper and see no major concern. But, I would like the following points revised.

This paper mainly focussed on co-morbid epilepsy and migraine headache. But, the way it is presented in the title, described in the texts and discussed makes it look like, the focus is many, if not all neurological disorders. Taking this as “Epidemiology of…” also takes this work out of its context. I would suggest this is revisited. “Diagnosed and undiagnosed epilepsy and migraine headache co-morbidity in people with Severe Psychiatric Disorders in Ethiopia” or so.

This is a cross-sectional study where researchers assessed patients or interviewed. My understanding is that all patients were interviewed and I did not see why they looked into past diagnoses. Is this a life time prevalence data? They may need to comment on why the did that.

Readers may like to know more about how they used the instruments. Was it translated, validated? This includes ILAE and ICHD-3. Was this self reported on interview based. Please give some comments.

There were only 3/309 SPD patients who had undiagnosed epilepsy and 12/309 SPD patients with undiagnosed migraine headache. The way it looks in the abstract and texts is a bit exaggerated as 60% and 100%. I suggest that is made clear: 2/3 (60 percent) of co-morbid epilepsy and 12/12 (100 per cent) of co-morbid migraine headache were undiagnosed.

Reviewer #2: Comments for the manuscript titled “The epidemiology of diagnosed and undiagnosed chronic neurological disorders with episodic manifestations in People with Severe Psychiatric Disorders in Ethiopia”.

General comments

Over all, study was done in an important and un addressed area and authors also reported good findings. But major concern what authors should consider is that, most of the patients with severe mental illness have manifestations which are really similar symptoms of neurologic disorders, so how could authors really overcome with his issue and in my suggestion most of the reports you found might be primary symptoms of SPD not neurologic disorders/what are the contents of the tool you used to measure Neurologic disorders like epilepsy in terms commonly reported neurologic like symptoms of SPD?

Section comments

Abstract: your back ground statement and finding are not consistent, I think your focus of study is Epilepsy and migraine headache, but you reported the prevalence of overall neurologic disorder. What was the tool you used to assess over all neurologic disorder, since neurologic disorder includes plenty of disorders? Please clarify what is meaning of overall neurologic disorder?

Your conclusion is not also consistent with your title, what is importance of saying epidemiology of diagnosed and undiagnosed neurologic disorders? Since you only reported the finding of un diagnosed neurologic disorders in your result section of abstract.

You also reported that “Higher disability score (WHODAS score) was associated with increased odds of having neurological disorders” what kind of disability is it? We expect all most all of patients with severe mental disorders have disability, so how can you compare patients with SPD as disable and able? If so in terms of which domain of disability functioning?

Background:

Some modification in grammar, punctuation and English language should be done, for example line number 13 of background section; “Scientific evidence shows that early identification and treatment of comorbid medication conditions in patients with severe psychiatric disorders…….” Should be modified.

Line number 15 “improved” in should be modified as improvement in……

Even though, you reported scarcity of reports regarding prevalence of neurologic disorders among patients with severe mental illness it is better to include different magnitudes and burdens of neurologic disorders particularly epilepsy among patients with mental illness since there are literatures too.

Method:

Study was conducted on 309……. it is better to be modified as study was conducted among 309…..

Inclusion criteria were…… modify also

Exclusion criteria: Your exclusion criteria was patients having severe illness at time of data collection affecting communication, we expect most of patients are with severe illness as name indicates SPD and communication problem is also one of the hallmark symptom of severe mental illness, of so how could you managed this issue.

Sampling procedure: It is good to using systematic random sampling, but my concern is how you managed or calculated k value for more than one treatment units? Since it is expected that more than one OPDs might be available in hospital?

Measures: What was importance of using structured clinical interview for DSM- ΙѴ-TR axis Ι disorders (SCID) since you included already diagnosed patients?

Result: More than one-third of the participants had attended secondary school approximately half of the participants were Orthodox Christians…it needs coma in between school and approximately.

What was prevalence of diagnosed neurologic disorders, since I cannot accesses within your manuscript?

Factors associated with undiagnosed neurological disorders in patients with SPD

You found only higher WHODAS score was only variable associated with prevalence of neurologic disorders, would you explain your variable selection method and what was reason behind for this?

Why don’t authors perform regression separately for epilepsy and migraine headache?

Discussion: Our prevalence was more than 2 times higher than reported prevalence of migraine headache in the general population as reported by the global burden of disease (GBD) study in 2016 (1.8%)……. Modify this sentence

Even though you did not compare with similar studies, your discussion is well written.

Conclusion: Future longitudinal studies are needed to identify the factors associated with undiagnosed neurological disorders (what was difficulty you faced to do this study design)?

Table 3: I strongly recommend you to write cross tabulation results for each variable.

Reviewer #3: Sample size calculation

On sample size calculation, it is not clear that there are many comorbidities with severe psychiatric disorder. Therefore, better to deal with the prevalence of epilepsy and migraine headache. Report that you have considered the maximum sample size.

On statistical analysis

The researcher mentioned the independent variables; just remove from the statistical analysis.

Result

Sociodemographic characteristics of the participants

Rather than mentioning as the following “Sociodemographic and clinical data for our participants were summarized in Table 1” it is better to write (table 1) at the end of the paragraph.

The prevalence of undiagnosed neurological disorders in patients with SPD

Don’t put table 2 in each paragraph. Just put it at the end of last paragraph.

The prevalence and associated factors of neurological disorders in people with SPD

Discussion

The researchers should at least search for additional literature that has been done from different data bases. If no they can compare their finding which is cross-sectional study with the meta-analysis.

Some of the justification for the difference in the finding are not scientifically sound according to the context that they are studying. Which the stating as follows

“There are wide ranges of explanations for higher prevalence rates of epilepsy among people with severe psychiatric disorders as compared with the reported prevalence in the general population. One of the possible explanations is that these disorders might have shared genetic factors”

Therefore, better to explain in more acceptable and in details so that the reader will be convinced from the finding.

References

Outdates references should be corrected by the recently published works. I encourage the researchers even to look into additional references from Ethiopia.

General comment

The manuscript is scientifically sound and well written

**********

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Reviewer #1: No

Reviewer #2: Yes: Alemayehu Molla

Reviewer #3: Yes: Abraham Tamirat Gizaw

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Submitted filename: PLOS ONE_Reviewers Comments_1.doc

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10 Sep 2020

Point by point responses for reviewers comments

Dear Kyoung-Sae Na, M.D, Academic Editor, PLOS ONE

Thank you very much for giving us the opportunity to rerevise our manuscript “The epidemiology of diagnosed and undiagnosed chronic neurological disorders with episodic manifestations in People with Severe Psychiatric Disorders in Ethiopia”.

We would also like to thank the reviewers for detailed reviews and providing us with helpful suggestions that will strengthen our manuscript and knowledge. We have gone through the comments and tried to include the responses to all the comments and suggestions.

Comments by editor and reviewers

Reviewer #1

Q1. I find this to a very interesting paper and see no major concern. But, I would like the following points revised.

This paper mainly focussed on co-morbid epilepsy and migraine headache. But, the way it is presented in the title, described in the texts, and discussed makes it look like, the focus is many, if not all neurological disorders. Taking this as “Epidemiology of…” also takes this work out of its context. I would suggest this is revisited. “Diagnosed and undiagnosed epilepsy and migraine headache co-morbidity in people with Severe Psychiatric Disorders in Ethiopia” or so.

We addressed this comment accordingly. As the reviewer mentioned the current study did not include all the neurologic disorders. However, as we mentioned in the title as well as throughout the documents the paper addresses the epidemiology (prevalence, detection rates, as well as associated factors) of the two most common neurologic disorders with episodic manifestations such as epilepsy and migraine headache.

We now revised the title as “Prevalence and correlates of diagnosed and undiagnosed epilepsy and migraine headache among people with Severe Psychiatric Disorders in Ethiopia”

Q2. This is a cross-sectional study where researchers assessed patients or interviewed. My understanding is that all patients were interviewed and I did not see why they looked into past diagnoses. Is this a life time prevalence data? They may need to comment on why the did that.

The existing diagnoses have been taken from the chart in order to determine the detection rates or the rates of undiagnosed disorders, which require the prevalence of both the current and the existing diagnoses.

Q3.Readers may like to know more about how they used the instruments. Was it translated, validated? This includes ILAE and ICHD-3. Was this self reported on interview-based. Please give some comments.

We addressed this concern accordingly. We have included the following paragraph in the method sections”

Data quality control

In this study, structured and interviewer-administered questionnaires that have been developed in English were translated into the local language (Amharic), and then to check the consistency the Amharic version of the questionnaires was translated back into English. Assessors with adequate knowledge and experience about the diagnostic statistical Manual of Mental Disorders (DSM), ICHD-3, and ILAE were recruited (MSc psychiatry professionals) to assure the quality of the data. Moreover, adequate training has been given regarding sampling procedure or protocol, on how to complete the questionnaire, eligibility criteria, ethical issues, data collection procedure, and the components of the questionnaire (sociodemographic and other variables), as well as the details of the two main data collection instruments (ICHD-3 and ILAE) for the supervisors and data collectors. The questionnaires have been pretested before the actual data collection and the essential modification was undertaken. Two Supervisors followed the data collection process and the necessary correction was made when needed. The supervisor and principal investigator reviewed the collected data and checked for completeness and relevance each day”. (See method section page 6-7 line 175-190).

Q4. There were only 3/309 SPD patients who had undiagnosed epilepsy and 12/309 SPD patients with undiagnosed migraine headaches. The way it looks in the abstract and texts is a bit exaggerated as 60% and 100%. I suggest that is made clear: 2/3 (60 percent) of co-morbid epilepsy and 12/12 (100 percent) of co-morbid migraine headache were undiagnosed.

We addressed these concerns accordingly. we revised as “We found that a considerably higher proportion of people with SPD had undiagnosed overall neurological disorder (87.5%; 14/16), epilepsy (60%; 3/5), as well as migraine headaches (100%; 12/12). (See abstract section page 2 line 50-51).

Reviewer #2

General comments

Over all, study was done in an important and un addressed area and authors also reported good findings. But major concern what authors should consider is that, most of the patients with severe mental illness have manifestations which are really similar symptoms of neurologic disorders, so how could authors really overcome with his issue and in my suggestion most of the reports you found might be primary symptoms of SPD not neurologic disorders/what are the contents of the tool you used to measure Neurologic disorders like epilepsy in terms commonly reported neurologic like symptoms of SPD?

Section comments.

Thank you for your kind words. We appreciate that.

Regarding the identification of the symptoms of epilepsy and migraine headache, we have used diagnostic criteria, which requires trained professionals who correctly differentiate the symptoms of those conditions from other psychiatric disorders (SPD). We have recruited trained data collectors who have adequate knowledge and experience in both the above neurologic disorders and SPDs (MSC psychiatry professionals).

We have also clarified this issue in the revised version. We included the following statement in the method section “According to the ILAE guideline, an epilepsy case is defined as someone with an active, recurrent (two or more) condition of an epileptic seizure, which was unprovoked by an immediate cause. The same classification and definition of epilepsy have been used in previous studies in Ethiopia. (See method section page 5-6 line 146-149).

Q2. Abstract: your back ground statement and finding are not consistent, I think your focus of study is Epilepsy and migraine headache, but you reported the prevalence of overall neurologic disorder. What was the tool you used to assess over all neurologic disorder, since neurologic disorder includes plenty of disorders? Please clarify what is meaning of overall neurologic disorder? Your conclusion is not also consistent with your title, what is importance of saying epidemiology of diagnosed and undiagnosed neurologic disorders? Since you only reported the finding of un diagnosed neurologic disorders in your result section of abstract.

You also reported that “Higher disability score (WHODAS score) was associated with increased odds of having neurological disorders” what kind of disability is it? We expect all most all of patients with severe mental disorders have disability, so how can you compare patients with SPD as disable and able? If so in terms of which domain of disability functioning?

We addressed these comments accordingly. We have included the following sentence in the result or conclusion section “The diagnoses rates of those disorders were significantly low, perhaps surprisingly zero for migraine headaches.” ). (See abstract section page 2 -3 line 59-60).

We also included the following statement in method sections:

Definitions of terms

In the present study, overall neurological disorders represent the presence of either epilepsy and migraine headaches in patients with SPD. Research studies suggest that epilepsy and migraine headache are the two commonest chronic neurological disorders with episodic manifestations. (See method section page 6 line 170-174).

Regarding disability, as the reviewer mentioned, epidemiological evidence suggests that a considerable proportion of people with SPD including schizophrenia, bipolar, and major depression have disabilities. For example, a study by Chaudhury and colleagues revealed that roughly one-third of patients with major depression (30%) and bipolar disorder (33.3%) and nearly two-thirds of patients with schizophrenia had a disability (64.3%. In the present study, we have included disability score (WHODAS score) as only as one of the factors contributing to the higher rates of neurologic disorders among patients with SPD as suggested by previous studies. WHODAS is not prepared to classify patients into disable or not disable. However, it is a continuous scale whereby higher scores indicating higher disabilities and lower scores indicating less disability. Therefore, we have used the total scores and we found higher scores suggesting increased risks of neurological conditions. Also, as the reviewer suggested further studies might be needed to test the mechanisms and the particular type of disabilities that are more linked with the increased risks.

Q3,.Background:

A. Some modification in grammar, punctuation and English language should be done, for example line number 13 of background section; “Scientific evidence shows that early identification and treatment of comorbid medication conditions in patients with severe psychiatric disorders…….” Should be modified.

Line number 15 “improved” in should be modified as improvement in……

Done.

B. Even though, you reported scarcity of reports regarding prevalence of neurologic disorders among patients with severe mental illness it is better to include different magnitudes and burdens of neurologic disorders particularly epilepsy among patients with mental illness since there are literatures too.

We have addressed this issue accordingly. We included the following statement regarding the prevalence of migraine headache among patients with mental disorders (bipolar disorders) ‘” For example, a recent meta-analysis that assessed the prevalence of migraine headaches among patients with bipolar disorder involving seven studies on the subject found that roughly one-third of patients with bipolar disorder had comorbid migraine headaches (30.36%). (See introduction section page 3 line 76-79).

Surprisingly, we did not find previous studies that determined the prevalence of epilepsy among patients with any mental illness.

Q4,Method:

a. Study was conducted on 309……. it is better to be modified as study was conducted among 309…..

Inclusion criteria were…… modify

Done.

b. also Exclusion criteria: Your exclusion criteria was patients having severe illness at time of data collection affecting communication, we expect most of patients are with severe illness as name indicates SPD and communication problem is also one of the hallmark symptom of severe mental illness, of so how could you managed this issue.

Revised accordingly. See below revisions made concerning the eligibility criteria in the method section:

Inclusion and exclusion criteria

Participants satisfying the following criteria were included in this study: (1) adult (aged 18 years and above); (2) those patients who had a diagnosis SPD (including schizophrenia, bipolar, schizoaffective, and depressive disorders). Those patients who had a severe illness at the time of data collection (affecting communications) were excluded. (See method section page 5 line 118-122).

c. Sampling procedure: It is good to using systematic random sampling, but my concern is how you managed or calculated k value for more than one treatment units? Since it is expected that more than one OPDs might be available in hospital?

As the reviewer mentioned there are around eight OPDs particularly allocated for the diagnoses and treatment of mood and psychotic disorders (severe mental disorders). However, there is one central area to collect and distribute charts of patients with the above diagnoses for those allocated OPDs whereby we selected our participants based on the calculated intervals.

d. Measures: What was the importance of using structured clinical interviews for DSM- ΙѴ-TR axis Ι disorders (SCID) since you included already diagnosed patients.

We have used SCID for two main reasons: First, to confirm the diagnoses because studies have suggested that a significant proportion of patients with mental disorders are misdiagnosed (>50%) especially in low and middle-income countries where non-psychiatry professionals are involved in diagnoses and treatment of mental disorders. Second, this paper is part of the project, and the other section of the projects deals with rates of misdiagnoses of severe mental disorders in specialized psychiatric centers in Ethiopia which requires application of SCID.

Q5. Result:

A. More than one-third of the participants had attended secondary school approximately half of the participants were Orthodox Christians…it needs coma in between school and approximately.

Done.

B. What was the prevalence of diagnosed neurologic disorders, since I cannot accesses within your manuscript?

We addressed this comment accordingly. We have included the following sentence in the result section “On the other hand, in this study, 12.5%, 40% and 0% of patients with overall neurologic disorder, epilepsy, and migraine headache respectively were diagnosed by the professionals.” (See result section page 8 line 230-233).

C. Factors associated with undiagnosed neurological disorders in patients with SPD

You found only higher WHODAS score was only variable associated with prevalence of neurologic disorders, would you explain your variable selection method and what was reason behind for this?

We have selected a variable base on (1): P-value; those variables with P-value <0.2 in the bivariate logistic regression model were included in multivariable analysis modeL; (2) we also considered Bradford Hill’s causality and association criteria in addition to the P-value.

D. Why don’t authors perform regression separately for epilepsy and migraine headache?

We did not perform regression analysis specifically for epilepsy and migraine headche due to small samples for the specific conditions.

Q6. Discussion:

A. Our prevalence was more than 2 times higher than reported prevalence of migraine headache in the general population as reported by the global burden of disease (GBD) study in 2016 (1.8%)……. Modify this sentence

Revised as “The prevalence of migraine headache in the current study was more than 2 times higher than the reported prevalence in the general population, according to the global burden of disease study in 2016 (1.8%). (See discussion section page 10 line 286-288).

B. Even though you did not compare with similar studies, your discussion is well written.

Many thanks.

C. Conclusion:

D. Future longitudinal studies are needed to identify the factors associated with undiagnosed neurological disorders (what was the difficulty you faced to do this study design)?

Two main limitations if the current study: (1) the nature of the study prevented us to draw causal inference (cross-sectional study); (2) the small sample size particularly for the specific diagnosis. In fact, we did not analyze the factors associated with specific disorders because of the small sample size.

We clarified as “Future longitudinal studies with adequate sample size are needed to identify the factors associated with undiagnosed neurological disorders particularly focusing on the specific disorders. (See conclusion section page 13 line 364-366).

E. Table 3: I strongly recommend you to write cross tabulation results for each variable.

Done

Reviewer #3

Q1. On sample size calculation, it is not clear that there are many comorbidities with severe psychiatric disorders. Therefore, better to deal with the prevalence of epilepsy and migraine headache. Report that you have considered the maximum sample size.

As the reviewer said, it is advisable to calculate the sample size for the specific disorders and then take the larger samples for the final analysis. However, as mentioned in the method section this study is part of a comorbidity survey among patients with severe psychiatric disorders in a specialized mental health setting in central Ethiopia which is aimed in determining the detection rates of the severe mental disorders, the prevalence of undiagnosed and diagnosed medical comorbidities, as well as the outcomes of treatments. For the project, the sample size has been calculated considering the prevalence of overall comorbid physical conditions among people with SPD.

We included the following sentence in the limitation sections” Thirdly, the small number of participants (sample) should be considered in interpreting the results especially for the estimates of the specific disorders such as epilepsy and migraine headache. Also, future studies addressing this limitation are warranted.” (See discussion section page 12 line 354-356).

Q2. On statistical analysis

The researcher mentioned the independent variables; just remove from the statistical analysis.

Removed.

Q3. Result

a. Sociodemographic characteristics of the participants

Rather than mentioning as the following “Sociodemographic and clinical data for our participants were summarized in Table 1” it is better to write (table 1) at the end of the paragraph.

Done.

b. The prevalence of undiagnosed neurological disorders in patients with SPD

Don’t put table 2 in each paragraph. Just put it at the end of last paragraph.

Done.

Q4. Discussion

a. the researchers should at least search for additional literature that has been done from different data bases. If no they can compare their finding which is cross-sectional study with the meta-analysis.

Some of the justification for the difference in the finding are not scientifically sound according to the context that they are studying. Which the stating as follows

“There are wide ranges of explanations for higher prevalence rates of epilepsy among people with severe psychiatric disorders as compared with the reported prevalence in the general population. One of the possible explanations is that these disorders might have shared genetic factors”

Therefore, better to explain in more acceptable and in details so that the reader will be convinced from the finding.

As the reviewer mentioned, there are no studies on the prevalence as well as rates of undiagnosed and diagnosed chronic neurologic disorders with episodic manifestations such as epilepsy and migraine headache among patients with SPD. Hence, the vast majority of the comparisons of the findings of the current studies are with the findings from the general community. Now we have more elaborated or revised the discussions.

Our explanations regarding the higher rates of epilepsy and migraine headache are just to highlight or suggest the readers look into the details of those issues via various mechanisms. We also removed sentences regarding the prevalence in the community as they are not our objectives and not investigated in our study, as suggested by the reviewer.

Submitted filename: Point by point to ND PLOS ONE (revised Sep 11 2020).docx

Click here for additional data file.

19 Oct 2020

Prevalence and correlates of diagnosed and undiagnosed epilepsy and migraine headache among people with Severe Psychiatric Disorders in Ethiopia

PONE-D-20-11101R1

Dear Dr. Ayano,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Kyoung-Sae Na, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: These minor editorial comments attached.

Dear Editor,

Thank you for forwarding the revised document. Authors have accommodated my comments and I have no big concern in terms of the content. But, I have a couple of points that can still need revision.

Ref # 18 is incomplete.

The article will benefit some English language editorial before it Is published. There are too many unnecessary parentheses and punctuation errors.

Thanks

Reviewer #2: Title: Prevalence and correlates of diagnosed and undiagnosed epilepsy and migraine headache among people with Severe Psychiatric Disorders in Ethiopia

Dear editor, thank you for giving chance of reading this manuscript again, I appreciate authors since they were highly responsive in their reaction to the review and significantly improved the quality of the manuscript. I suggest accepting this study for publication.

Good lack authors!!!

Reviewer #3: I have no significant concern for the time.I am happy that the authors addressed all the comments provided by me. I appreciate their effort.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Alemayehu Molla

Reviewer #3: Yes: Abraham Tamirat Gizaw

26 Oct 2020

PONE-D-20-11101R1

Prevalence and correlates of diagnosed and undiagnosed epilepsy and migraine headache among people with Severe Psychiatric Disorders in Ethiopia

Dear Dr. Ayano:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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