Medical records and multiple sclerosis: A population-based case–control study

doi:10.21203/rs.3.rs-2213817/v1

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Research Article

Medical records and multiple sclerosis: A population-based case–control study

https://doi.org/10.21203/rs.3.rs-2213817/v1

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Background

Medical records on multiple sclerosis progression is not complete. This study aimed to review the medical records and sociodemographic findings of the multiple sclerosis population in Mazandaran province.

Method

This case-control study included cases and two groups of patient control and healthy control groups (n=200 per group). Multivariable analysis was used to calculate odds ratios and 95% confidence intervals (CI).

Result

The participants’ mean age was 36.5 ± 11.9 years, and there were 381 (63.5%) female cases in this study. According to adjusted odds ratios, the highest and the lowest roles for the multiple sclerosis progression included measles (4.40; 95% CI: 1.73 to 11.1), psoriasis (4.63; 95% CI: 0.35 to 60.6), myasthenia gravis (7.15; 95% CI: 1.87 to 27.2) and amoxicillin (4.75; 95% CI: 2.05 to 11), seizure (0.14; 95% CI: 0.03 to 0.69), and epilepsy (0.17; 95% CI: 0.02 to1.49).

Conclusion

Myasthenia gravis and seizure had the highest and lowest association with multiple sclerosis, respectively. Hence, this study implied that autoimmune diseases were more frequently correlated with the multiple sclerosis progression.

Multiple sclerosis

Population-based study

Medical history

Mazandaran Province

Multiple sclerosis (MS) is a debilitating disease caused by inflammation and the degenerative process leading to demyelination and subsequent progressive axonal and gliosis damage (1). Its exact mechanism is unknown; however, it is attributed to the interactions of genetic, environmental, and immunological factors [(2). The progressive rate of MS incidence among the Iranian population may be associated with the improvement of health care. According to some health hypotheses, the rate of autoimmune diseases increased spontaneously following a decrease in antigens exposure (3).

Moreover, the inflammatory process and the alteration of cytokine cascades associated with the high activity of the immune system increased the incidence of diseases such as inflammatory bowel disease (IBD), celiac disease, irritable bowel syndrome (IBS), uveitis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), myasthenia gravis (MG), type 1 diabetes mellitus (T1DM), and psoriasis(4).

According to our previous findings, the incidence of MS in Mazandaran province has increased in recent years, and the increase is observed in both genders and individuals with positive family history. Although the interaction between genetic and environmental factors has played a role in enhancing its incidence rate, environmental factors seem to play a more potent role (5-7). The present study aimed to determine the role of each factor and their effect size on the MS development in a case-control study.

This case-control study encompassed three groups of participants, including MS and non-MS (individuals with neurological problems other than MS), patients referred to the neurology clinic of Abu-Ali Sina Hospital, and the normal population (healthy control). The participants were selected regarding the following inclusion and exclusion criteria.

Inclusion criteria

1. Aged above18 years;

2. Patients with a definite diagnosis of MS based on the McDonald Criteria 2017 (8) and diagnostic tests performed by a neurologist (case group); and

3. Residing in Mazandaran province.

Exclusion criteria

1. Unwillingness to participate in the study, and

2. Problems in recorded patient information.

Regarding the research objectives, the study participants were divided into two case and control groups.

Case group:

This group included patients with known MS referred to the clinic for a routine checkup. Our clinic covers above 1000 MS patients coming from different cities of Mazandaran province and its neighborhoods. Two hundred persons were randomly selected (n = 200), and their information was collected during interviews using a pre-prepared questionnaire and reviewing patient records.

Control group:

Two control groups were included in this study:

Population-based control: Information was collected from the normal population by an electronic questionnaire (n = 200). First, a list of all cities in Mazandaran province was prepared, then ten cities were randomly selected. The questionnaires were equally distributed among the cities. For this purpose, an electronic questionnaire was prepared, which could be accessed via the following link: https://forms.gle/KWh7heebmUFA5aXt5
The link was sent to the residents of the ten cities, and the completed questionnaires were re-sent to the Author's email.
Clinic-based control: The group encompassed patients referred to the neurology clinic with no history of MS, i.e., non-MS Patients (n = 200). The information was collected by interviewing the participants and reviewing their records.

Data collection:

A pre-prepared questionnaire was completed for each patient by interviewing, reviewing patient records and their electronic questionnaire. Patients' information was collected by two doctors using a questionnaire addressing the participants’ demographic characteristics (age, gender, marital status, number of children, and level of education), psychosocial conditions (death of first-degree relatives, family breakdown, duration of homelessness, history of imprisonment, severe illness of first-degree family members, injury and illness, suicide of first-degree family members, divorce, death of spouse, indebtedness, dismissal, unemployment and being a burden on family), immigration to another city or country, retirement, taking an entrance exam (any period during the last six months). Moreover, the participants’ medical history of depression, measles, rubella, mumps, chicken pox, hepatitis B, influenza, SLE, RA, hypothyroidism and hyperthyroidism, Crohn's disease, ulcerative colitis, IBS, leukemia, T1DM, celiac disease, psoriasis, MG, Hodgkin’s and non-Hodgkin's lymphoma, melanoma, skin cancer (non-melanoma), migraine, seizure, epilepsy, vertigo, headache, Amnesia, Parkinson, hypertension, T2DM, and kidney diseases was also recorded, and the duration of the disease, if any, was recorded. Moreover, the family history of T1DM, MS, leukemia, head trauma and its frequency, antibiotic consumption from 13 to 19 years old, consumption of antibiotics for two weeks or more during the last three years and the name of the antibiotics and the duration of consumption was also recorded.

Statistical analysis:

The collected data were analyzed with STATA software version 13 (StataCorp, College Station, TX, USA). Data were displayed as frequencies (percent) or mean (standard deviation). Chi-square or Fisher's exact test was used to compare the three groups’ variables, including qualitative variables, and the analysis of variance (ANOVA) or Kruskal-Wallis H test was also used for the quantitative variables. To study the relationship between MS and medical records, an MS risk assessment was performed by calculating the odds ratios (ORs, with a 95% confidence interval [CI]) using a logistic regression model. Multiple protentional confounders entered the final model to estimate an adjusted OR for each medical history, encompassing age, gender, level of education, death of relatives, family breakdown, duration of homelessness, severe illness of family members, injury and illness, indebtedness, separation from spouse, and entrance exam. The model's goodness of fit was assessed using the Hosmer and Lemeshow test. Multicollinearity between the independent variables was ultimately checked in the final model using the LMCOL command and calculating the VIF index (variance inflation factor). In this study, p<0.05 was set as the significance level.

The 600 persons participating in this study were divided into three groups (n=200). The participants’ mean age was 36.5 ± 11.9 years, and 63.5 %( n=381) of these individuals were females, with 36.5 %(n=219)males. Table 1 presents a summary of the participants’ demographic, basic, and clinical characteristics.

Table1.

Basic and clinical characteristics of participants

Demographic findings	Groups			P-Value
Demographic findings	MS (N=200)	Patients Control (N=200)	Normal Population (N=200)	P-Value
Age, year	33.8±9.10	40.2±13.8	35.3±11.2	<0.001
Sex, Female	147(73.5%)	133(66.5%)	101(50.5%)	<0.001
Married	147(73.5%)	157(78.5%)	129(64.5%)	0.007
Having children	123(61.5%)	152(76%)	99(49.5%)	<0.001
Illiterate	2(1%)	13(6.50%)	0(0%)	<0.001
Elementary literacy	10(5%)	18(9%)	4(2%)	0.008
Middle literacy	22(11%)	22(11%)	9(4.5%)	0.030
High school	9(4.5%)	12(6%)	9(4.5%)	0.729
Diploma literacy	56(28%)	55(27.5%)	33(16.5%)	0.010
Postgraduate Literacy	15(7.5%)	19(9.5%)	38(19%)	0.003
Bachelor of Literature	67(33.5%)	44(22%)	78(39%)	0.001
Relatives death	51(25.5%)	47(23.5%)	25(12.5%)	0.019
Mother Father Sister Brother Child	21(10.5%) 24(12%) 2(1%) 2(1%) 2(1%)	23(11.5%) 15(7.5%) 4(2%) 4(2%) 1(0.5%)	10(5%) 10(5%) 5(2.5%) 0(0%) 0(0%)	0.019
Family breakdown	10(5%)	17(8.5%)	3(1.5%)	0.015
Homelessness periods	3(1.5%)	0(0%)	0(0%)	0.049
imprisonment history	1(0.5%)	0(0%)	0(0%)	0.367
Severe illness of 1st degree family members	21(10.5%)	38(19%)	17(8.5%)	0.004
Injury and illness	20(10%)	40(20%)	25(12.5%)	0.012
Suicide of first-degree family members	2(1%)	3(1.5%)	0(0%)	0.244
Spouse separation	17(8.5%)	4(2%)	3(1.5%)	<0.001
Spouse death	3(1.5%)	1(0.5%)	1(0.5%)	0.446
Being in debt's money	30(15%)	38(19%)	20(10%)	0.039
Dismissal from employment	3(1.5%)	0(0%)	2(1%)	0.244
Unemployment and being a burden on the family	11(5.5%)	4(2%)	6(3%)	0.146
immigration to another city or country	9(4.5%)	8(4%)	4(2%)	0.355
Retirement	4(2%)	2(1%)	0(0%)	0.133
Entrance Exam	21(10.5%)	8(4%)	26(13%)	0.006
Psychosocial conditions during the last 6 months
Marriage	1(0.5%)	1(0.5%)	7(3.5%)	0.133
Relatives death	8(4%)	7(3.5%)	3(1.5%)
Family breakdown	1(0.5%)	1(0.5%)	0(0%)
Homelessness periods	0(0%)	0(0%)	0(0%)
Imprisonment history	0(0%)	0(0%)	0(0%)
Severe illness of 1st degree family members	1(0.5%)	6(3%)	5(2.5%)
Injury and illness	1(0.5%)	2(1%)	3(1.5%)
Suicide of first-degree family members	0(0%)	0(0%)	0(0%)
Spouse separation	1(0.5%)	0(0%)	0(0%)
Spouse death	1(0.5%)	0(0%)	0(0%)
Being in debt's money	8(4%)	6(3%)	2(1%)
Dismissal from employment	2(1%)	0(0%)	0(0%)
Unemployment and being a burden on the family	2(1%)	1(0.5%)	2(1%)
immigration to another city or country	1(0.5%)	0(0%)	2(1%)
Retirement	0(0%)	0(0%)	0(0%)
Entrance Exam	0(0%)	1(0.5%)	0(0%)

Data are shown as standard deviation ± mean or (percentage) number.

P-value was obtained by Fisher's exact test.

Among their medical history, depression and migraine were the most common, reported for 106 and 103 participants, respectively. Chickenpox, mumps, and measles were more prevalent than other viral diseases. Reviewing the antibiotic consumption history demonstrated that amoxicillin was consumed most frequently. Moreover, MG was recognized as a significant medical history for the MS progression. Among the neurological diseases, migraine headaches were more common than others. SLE, Crohn's disease, ulcerative colitis, celiac, leukemia, Hodgkin's and non-Hodgkin's lymphoma, melanoma, and IBS were reported in none of the participants. Table 2 presents the findings concerning the participants’ medical history and the duration of the aforementioned diseases.

Table 2

The distribution and duration of the medical histories in the 3 groups.

Variables/Medical history	Groups{number (percentage), Mean.±St.Dev}			P-Value
Variables/Medical history	MS (N=200)	Patients Control (N=200)	Normal Population (N=200)	P-Value
Depression	41(20.5%)	50(25%)	15(7.5%)	<0.001ᵃ
Duration of depression(weeks ago)	75.4 ± 260.2	56 ±153.3	12.8 ± 59.9	0.001ᵇ
Measles	29(14.5%)	25(12.5%)	7(3.5%)	0.001ᵃ
Duration of measles (weeks ago)	208.9 ± 543.2	190.7 ± 569.5	62.8 ± 336.3	0.005ᵇ
Rubella	12(6%)	11(5.5%)	0(0%)	0.002ᵃ
Duration of Rubella(weeks ago)	78.2 ± 330.9	102.3 ± 462	0	0.005ᵇ
Mumps	24(12%)	33(16.5%)	5(2.5%)	<0.001ᵃ
Duration of Mumps(weeks ago)	156 ± 442.5	215.9 ± 541.3	27.3 ± 178.5	<0.001ᵇ
Hepatitis-B	0(0%)	0(0%)	1(0.5%)	0.406ᵃ
Duration of Hepatitis-B(weeks ago)	0	0	4.32 ± 61.04	0.368ᵇ
Chickenpox	83(41.5%)	76(38%)	28(14%)	<0.001ᵃ
Duration of Chickenpox(weeks ago)	452.4 ± 690.7	394.8 ± 586.6	145.3 ± 436.5	<0.001ᵇ
Influenza	4(2%)	3(1.5%)	3(1.5%)	0.903ᵃ
Migraine	35(17.5%)	65(32.5%)	3(1.5%)	<0.001ᵃ
Duration of Migraine(weeks ago)	106.4 ± 222.9	80.2 ± 248.9	4.32 ± 38.8	<0.001ᵇ
Seizure	2(1%)	21(10.5%)	0(0%)	<0.001ᵃ
Duration of seizure(weeks ago)	8.68 ± 88.5	13 ± 80.1	0	0.156ᵇ
Parkinson	6(3%)	8(4%)	1(0.5%)	0.069ᵃ
Duration of Parkinson(weeks ago)	25.9 ± 159.6	6.72 ± 43.5	0.02 ± 0.35	0.019ᵇ
Headache	9(4.5%)	36(18%)	1(0.5%)	<0.001ᵃ
Duration of Headache(weeks ago)	0.03 ± 0.17	14.7 ± 84.9	0	0.002ᵇ
Epilepsy	1(0.5%)	9(4.5%)	0(0%)	0.001
Duration of Epilepsy(weeks ago)	3.6 ± 50.9	29.4 ± 173.5	0	<0.001
Amnesia	7(3.5%)	10(5%)	0(0%)	0.008
Duration of Amnesia(weeks ago)	0.15 ± 0.73	9.3 ± 50.5	0	0.001ᵇ
Rheumatoid arthritis	0(0%)	4(2%)	2(1%)	0.133ᵃ
Duration of Rheumatoid arthritis(weeks ago)	0	13.2 ± 140.3	8.16 ± 102.6	0.415ᵇ
Hypothyroidism	11(5.5%)	21(10.5%)	10(5%)	0.058ᵃ
Duration of Hypothyroidism(weeks ago)	25.2 ± 133.1	54 ± 237	14.4 ± 72.6	0.042ᵇ
Hyperthyroidism	1(0.5%)	6(3%)	0(0%)	0.027ᵃ
Duration of Hyperthyroidism(weeks ago)	3.36 ± 47.5	6.98 ± 59.9	0	0.287ᵇ
Type 1 diabetes mellitus	1(0.5%)	1(0.5%)	2(1%)	0.777ᵃ
Duration of Type 1 diabetes mellitus(weeks ago)	2.4 ±33.9	5.76 ± 81.4	6.24 ± 75.8	0.823ᵇ
Psoriasis	2(1%)	0(0%)	1(0.5%)	0.366ᵃ
Duration of Psoriasis(weeks ago)	3.6 ± 37.8	0	±33.9	0.459ᵇ
Myasthenia gravis	11(5.5%)	3(1.5%)	0	0.001ᵃ
Duration of Myasthenia gravis(weeks ago)	0	3.6 ± 31.8	0	0.079ᵇ
Kidney disease	5(2.5%)	6(3%)	6(3%)	0.941
Duration of Kidney disease(weeks ago)	5.06 ± 41	4.09 ± 32.9	8.22 ± 56.9	0.628ᵇ
Hypertension	2(1%)	11(5.5%)	1(0.5%)	0.001
Duration of Hypertension(weeks ago)	9.12 ± 100.7	32.4 ± 164.3	0.48 ± 6.78	0.012ᵇ
Type 2 diabetes mellitus	3(1.5%)	14(7%)	3(1.5%)	0.002ᵃ
Duration of type 2 diabetes mellitus(weeks ago)	9.6 ± 92.1	45.06 ± 224.2	2.88 ± 27.4	0.005ᵇ
Skin cancer, non-melanoma	1(0.5%)	0)0%)	0(0%)	0.367
Family history of type 1 diabetes mellitus	3(1.5%)	0	11(5.5%)	0.001ᵃ
Family history of Leukemia	1(0.5%)	5(2.5%)	5(2.5%)	0.227ᵃ
Family history of MS	18(9%)	13(6.5%)	2(1%)	0.002ᵃ
Head trauma	38(19%)	21(10.5%)	11(5.5%)	<0.001ᵃ
Frequency of Head trauma	0.22 ± 0.55	0.11 ± 0.34	0.06 ±0.30	0.000ᵇ
Antibiotic consumption for two weeks or more during the last three years	37(18.5%)	29(14.5%)	28(14%)	0.398ᵃ
Antibiotic consumption between 13-19 years old	12(6%)	5(2.5%)	4(3.5%)	0.060ᵃ
Duration of Antibiotic consumption between 13-19 years old(week)	0.08 ± 0.44	0.10 ± 0.61	0.13 ± 0.56	0.654ᵇ
Co-Amoxiclav	8(4%)	5(2.5%)	9(4.5%)	0.542ᵃ
Duration of Co-Amoxiclav(week)	0.07 ± 0.35	0.07 ± 0.45	0.11 ± 0.50	0.582ᵇ
Gentamycin	2(1%)	1(0.5%)	0	0.406ᵃ
Duration of Gentamycin(week)	0.03 ± 0.35	0.005 ± 0.07	0	0.190ᵇ
Cefexim	7(3.5%)	6(3%)	2(1%)	0.238ᵃ
Duration of Cefexim(week)	0.11 ±0.71	0.06 ± 0.40	0.01 ± 0.15	0.118ᵇ
Cefalexin	7(3.5%)	3(1.5%)	1(0.5%)	0.075ᵃ
Duration of Cefalexin(week)	0.08 ± 0.44	0.03 ± 0.29	0.01 ± 0.14	0.080ᵇ
Penicillin	4(2%)	0	0	0.018ᵃ
Duration of Penicillin(week)	0.05 ± 0.57	0	0	0.164ᵇ
Azithromycin	7(3.5%)	4(2%)	4(2%)	0.540ᵃ
Duration of Azithromycin(week)	0.08 ± 0.44	0.04 ± 0.32	0.03 ± 0.25	0.397ᵇ
Amoxicillin	18(9%)	7(3.5%)	4(2%)	0.003ᵃ
Duration of Amoxicillin(week)	0.18 ± 0.60	0.10 ± 0.65	0.03 ± 0.25	0.026ᵇ
Metronidazole	5(2.5%)	4(2%)	0	0.094ᵃ
Duration of Metronidazole(week)	0.10 ± 0.71	0.07 ± 0.63	0	0.169ᵇ

MS: multiple sclerosis

Data are shown as standard deviation ± mean or (percentage) number

ᵃ P-value was obtained by Fisher's exact test

ᵇ P-value was calculated by Mann-Whitney U test

The risk assessment of the medical records indicated that MG had the largest OR compared to other medical history for MS. On the other hand, a history of seizures was also associated with a decrease in the rate of MS progression (OR 0.18, 95%CI 0.04-0.78). Among the viral diseases, Rubella was a more affective medical history in increasing the likelihood of MS(OR 2.25, 95%CI 0.97-5.21). On the other hand, Chickenpox had the smallest OR (OR 0.99, 95%CI 0.96-1.01). Among the antibiotic profiles, amoxicillin and cefalexin had the largest OR (OR 3.49, 1.61-7.55, and OR 3.5, 1.03-12.4, respectively). MG and psoriasis played the most prominent role in MS, (OR 7.70, 95%CI 2.12-27.9 and OR 4.03, 95%CI 0.36-44.7, respectively). Among the neurological diseases, Amnesia had the largest OR for increasing the likelihood of developing MS (OR 1.41, 95%CI 0.53-3.77). The estimated ORs of the medical history associated with the MS risk are listed in Table 3.

Table 3

MS risk assessment (Crude OR) of medical histories

Variables/Medical history	Groups (Crude OR (95%CI))
Variables/Medical history	Patients Control	Normal Population	All controls
Depression	(0.77, 0.48 to 1.23)	(3.1, 1.69 to 5.96)	(1.32, 0.86 to 2.05)
Measles	(1.18, 0.66 to 2.10)	(4.67, 1.99 to 10.94)	(1.95, 1.14 to 3.32)
Rubella	(1.09, 0.47 to 2.54)	-----------	(2.25, 0.97 to 5.21)
Mumps	(1, 0.98 to 1.02)	(5.34, 1.99 to 14.3)	(1.30, 0.75 to 2.24)
Chickenpox	(0.98, 0.92 to 1.04)	(4.35, 2.67 to 7.10)	(0.99, 0.96 to 1.01)
Influenza	(1.34, 0.29 to 6.06)	(1.34, 0.29 to 6.06)	(1.34, 0.37 to 4.80)
Migraine	(0.44, 0.27 to 0.70)	(13.9, 4.20 to 46.1)	(1.03, 0.66 to 1.62)
Seizure	(0.08, 0.01 to 0.37)	-----------	(0.18, 0.04 to 0.78)
Parkinson	(0.74, 0.25 to 2.17)	(6.15, 0.73 to 51.5)	(1.3, 0.47 to 3.82)
Headache	(0.21, 0.10 to 0.45)	(9.37, 1.17 to 74.7)	(0.46, 0.21 to 0.97)
Epilepsy	(0.10, 0.01 to 0.84)	-----------	(0.21, 0.02 to 1.7)
Amnesia	(0.68, 0.25 to 1.84)	-----------	(1.41, 0.53 to 3.77)
Hypothyroidism	(0.49, 0.23 to 1.05)	(1.1, 0.45 to 2.66)	(0.69, 0.34 to 1.40)
Hyperthyroidism	(1.06, 0.87 to 1.30)	-----------	(1.1, 0.85 to 1.42)
Type 1 diabetes mellitus	(1, 0.06 to 16)	(0.49, 0.04 to 5.53)	(0.66, 0.06 to 6.43)
Psoriasis	-----------	(2.01, 0.18 to 22.3)	(4.03, 0.36 to 44.7)
Myasthenia gravis	(3.82, 1.04 to 13.9)	-----------	(7.70, 2.12 to 27.9)
Hypertension	(0.17, 0.03 to 0.79)	(2.01, 0.18 to 22.3)	(0.32, 0.07 to 1.47)
Type 2 diabetes mellitus	(0.20, 0.05 to 0.71)	(1, 0.19 to 5.01)	(0.34, 0.09 to 1.18)
Kidney disease	(0.82, 0.24 to 2.76)	(0.82, 0.24 to 2.76)	(0.82, 0.28 to 2.38)
Family history of type 1 diabetes mellitus	-----------	(0.26, 0.07 to 0.95)	(0.53, 0.14 to 1.95)
Family history of Leukemia	(0.19, 0.02 to 1.69)	(0.19, 0.02 to 1.69)	(0.19, 0.02 to 1.54)
Family history of MS	(1.42, 0.67 to 2.98)	(9.79, 2.24 to 42.7)	(2.53, 1.25 to 5.15)
Head trauma	(1.99, 1.12 to 3.54)	(4.03, 1.99 to 8.14)	(2.69, 1.62 to 4.47)
Antibiotic consumption for two weeks or more during the last three years	(1.33, 0.78 to 2.27)	(1.39, 0.81 to 2.38)	(1.36, 0.86 to 2.15)
Antibiotic consumption between 13-19 years old	(2.48, 0.86 to 7.20)	(3.12, 0.99 to 9.86)	(2.77, 1.14 to 6.69)
Co-Amoxicillin	(1.62, 0.52 to 5.05)	(0.88, 0.33 to 2.34)	(1.14, 0.47 to 2.78)
Cefixime	(1.17, 0.38 to 3.55)	(3.5, 0.73 to 17.5)	(1.77, 0.63 to 4.97)
Cefalexin	(2.38, 0.60 to 9.34)	(7.21, 0.87 to 59.2)	(3.5, 1.03 to 12.4)
Azithromycin	(1.77, 0.51 to 6.16)	(1.77, 0.51 to 6.16)	(1.77, 0.63 to 4.97)
Amoxicillin	(2.72, 1.11 to 6.68)	(4.84, 1.60 to 14.5)	(3.49, 1.61 to 7.55)
Metronidazole	(1.25, 0.33 to 4.74)	-----------	(2.5, 0.67 to 9.55)

OR: odds ratio; CI: confidence interval; MS: multiple sclerosis

After adjusting the ORs for medical history, the calculated value was still largest for MG (OR 7.15, 95% CI 1.87-27.2) and smallest for seizure (OR 0.14, 95% CI 0.03-0.69), while the effect of potential confounders was controlled. However, among the viral diseases, measles played the most critical role in increasing the likelihood of developing MS (OR 4.40, 95% CI 1.73-11.1) and chickenpox had the least role(OR 0.99, 95%CI 0.96-1.02). As previously discussed, the evaluation of antibiotic history revealed the more powerful role of amoxicillin (OR 4.75, 95% CI 2.05 to 11) than cefalexin (OR 3.32, 95% CI 0.85-12.9) in increasing the likelihood of MS. Moreover, psoriasis (OR 4.63, 95%CI 0.35-60.6) still played the most prominent role in increasing the likelihood of MS, following MG. Among the neurological diseases, Amnesia still played the most effective role (OR 2.82, 95% CI 0.94 to 8.43). Table 4 presents the calculated adjusted ORs of medical history.

Table 4

MS risk assessment (Adjusted OR) of medical histories

Variables/Medical history	Groups (Adjusted ORᵈ (95%CI))
Variables/Medical history	Patients Control	Normal Population	All controls
Depression	(0.88, 0.52 to 1.50)	(2.86, 1.41 to 5.78)	(2.85, 1.41 to 5.76)
Measles	(1.38, 0.73 to 2.60)	(4.33, 1.70 to 11)	(4.40, 1.73 to 11.1)
Rubella	(1.51, 0.60 to 3.77)	-----------	(1.31, 0.81 to 2.11)
Mumps	(1, 0.98 to 1.01)	(5.84, 2.01 to 16.9)	(1.25, 0.70 to 2.22)
Chickenpox	(0.87, 0.54 to 1.39)	(4.51, 2.61 to 7.81)	(0.99, 0.96 to 1.02)
Influenza	(1, 0.20 to 4.95)	(0.69, 0.13 to 3.61)	(1.20, 0.31 to 4.65)
Migraine	(0.41, 0.24 to 0.70)	(12.42, 3.57 to 43.2)	(0.91, 0.56 to 1.49)
Seizure	(0.05, 0.01 to 0.27)	-----------	(0.14, 0.03 to 0.69)
Parkinson	(1.43, 0.40 to 5.05)	(10.3, 1.04 to 101.8)	(2.54, 0.78 to 8.27)
Headache	(0.16, 0.07 to 0.39)	(13.6, 1.53 to 122.3)	(0.42, 0.19 to 0.94)
Epilepsy	(0.09, 0.01 to 0.81)	-----------	(0.17, 0.02 to 1.49)
Amnesia	(1.42, 0.45 to 4.49)	-----------	(2.82, 0.94 to 8.43)
Hypothyroidism	(0.54, 0.23 to 1.28)	(0.68, 0.25 to 1.80)	(0.56, 0.26 to 1.21)
Hyperthyroidism	(1.08, 0.85 to 1.36)	-----------	(1.12, 0.82 to 1.53)
Type 1 diabetes mellitus	(1.10, 0.06 to 20.1)	(0.29, 0.01 to 4.63)	(0.62, 0.05 to 6.71)
Psoriasis	-----------	(2.12, 0.14 to 30.2)	(4.63, 0.35 to 60.6)
Myasthenia gravis	(3.22, 0.82 to 12.5)	-----------	(7.15, 1.87 to 27.2)
Hypertension	(0.83, 0.14 to 4.71)	(2.37, 0.09 to 60.1)	(0.87, 0.16 to 4.73)
Type 2 diabetes mellitus	(0.59, 0.14 to 2.52)	(1.7, 0.28 to 10.7)	(0.72, 0.18 to 2.87)
Kidney disease	(1.12, 0.28 to 4.41)	(0.45, 0.11 to 1.83)	(0.93, 0.30 to 2.91)
Family history of type 1 diabetes mellitus	-----------	(0.05, 0.01 to 0.26)	(0.27, 0.06 to 1.09)
Family history of Leukemia	(0.22, 0.02 to 2.05)	(0.22, 0.02 to 2.11)	(0.21, 0.02 to 1.76)
Family history of MS	(1.43, 0.63 to 3.24)	(9.99, 2.14 to 46.4)	(2.62, 1.23 to 5.57)
Head trauma	(1.98, 1.02 to 3.82)	(4.85, 2.13 to 11.06)	(3.14, 1.77 to 5.58)
Antibiotic consumption for two weeks or more during the last three years	(1.57, 0.84 to 2.91)	(1.06, 0.57 to 1.98)	(1.31, 0.79 to 2.19)
Antibiotic consumption between 13-19 years old	(2.13, 0.67 to 6.72)	(2.61, 0.71 to 9.53)	(2.52, 0.95 to 6.65)
Co-Amoxicillin	(1.94, 0.56 to 6.66)	(0.61, 0.18 to 2.03)	(1.12, 0.43 to 2.91)
Cefixime	(0.54, 0.14 to 2.09)	(3.82, 0.65 to 22.2)	(1.43, 0.44 to 4.61)
Cefalexin	(1.60, 0.34 to 7.42)	(11.6, 1.16 to 115.8)	(3.32, 0.85 to 12.9)
Azithromycin	(2.13, 0.54 to 8.40)	(1.35, 0.30 to 6.14)	(2.14, 0.66 to 6.86)
Amoxicillin	(3.90, 1.43 to 10.6)	(6.91, 2.07 to 23)	(4.75, 2.05 to 11)
Metronidazole	(1.70, 0.36 to 7.94)	-----------	(2.40, 0.54 to 10.6)

OR: odds ratio, CI: confidence interval; MS: multiple sclerosis

ᵈ Odds ratio were adjusted according to age, sex, education, death of relatives, family breakdown, period of homelessness, severe illness of family members, injury and illness, being in debt's money, separation from spouse, and entrance exam

In this large population-based study, designed as a case-control research in the north of Iran, above two-thirds of the MS patients were female. MG, psoriasis, measles, head trauma, amoxicillin, and cefalexin significantly increased the likelihood of the MS progression. On the other hand, a history of seizures and epilepsy had the smallest value for the MS development.

The prevalence of depression in the MS and control groups was 20.5% and 16%, respectively. Depression increased MS odds about 32% to 1.85 folds. Consistent with our findings, the high prevalence of depression for the MS progression was reported in the Canadian community health study, in which the MS odds were 1.3 times larger than the control group (9) . Maroufi et al. reported that depression increased the rate of primary progressive MS by 2.12-2.2 times compared to the control group (10). Abdollahpour et al. pointed to the high prevalence of depression; however, the meaningfulness of this correlation was not examined (11). It should be noted that the high prevalence of depression in both groups is due to social and economic problems; hence, it is necessary to consider that the calculated MS odds for depression cannot accurately reflect the MS likelihood.

The rates of head trauma were 19% and 8% for the MS and control groups, respectively. Head trauma raised MS chance by 1.69 to 2.14 folds. A systematic review and meta-analysis by Warren et al. (included 13 case-controls and three cohorts) did not support the correlation between the history of traumatic injury and the MS progression (12). In a case-control study, Ibrahim Abdollahpour et al. reported a 2 - 27% increase in the likelihood of MS for a history of head injury compared to the control group; however, the increase was not meaningful .(11) The suggested mechanism for plaque formation contributed to the alteration of the blood-brain barrier function and access of the reactive agents to the central nervous system (CNS)(13). Inconsistent likelihood rates of the MS progression can be justified by factors such as severity and age of injury as well as various immune responses to trauma (14).

The prevalence of measles was higher in the MS group than in the control one (14.5% vs. 8%). Measles increased the likelihood of the MS progression by 95% -3.4 times. Also, rubella and mumps raised the MS odds about 31% -1.25 times and 25% -30%, respectively. Abdollahpour et al. did not support the role of viral diseases in the MS progression, and contradictory findings were reported; measles and rubella decreased the MS odds by 17-19% and 2-11%, but mumps increased it only 3% (15). In a study on 660 MS patients and 421 controls, Abbasi et al. reached findings in line with the present findings; mumps, measles, and rubella were associated with an increase in the likelihood of the MS progression by 85, 60, and 47%, respectively (16). Maroufi et al. discussed conflicting findings for the association between viral diseases and the MS progression. They stated that measles increased the likelihood by 19-23%, while mumps and rubella decreased it by 2-23% and 55-73%, respectively (17). The antibodies of viral diseases such as measles and mumps have been reported in the MS patients. Moreover, previous studies have claimed the role of high levels of serum and cerebral spinal fluid antibodies against measles in the MS progression(16, 18). Furthermore, vaccination against viral diseases such as measles, mumps, and rubella has been reported to reduce the infection rate; however, the MS rate has not changed (19). The correlation between viral diseases and the MS progression is attributed to the following mechanisms: (1) Molecular antigenic similarity between pathogens and host antigens , (2) Destruction of host CNS tissue by antibodies produced by stimulated B lymphocytes , (3) innocent bystander: Damage to myelin sheaths by cytokines produced by stimulated T lymphocytes (19).

Regarding the participants’ medical history, the highest likelihood of MS was associated with MG followed by psoriasis. The prevalence of MG was 5.5% in the MS group vs. 0.75% in the control groups. MG and psoriasis increased the MS probability by 6.15-6.7 and 3.03-3.63 folds. To investigate the role of autoimmune diseases in the MS progression, Langer-Gould et al. reported MG and psoriasis increased MS risk approximately 1.5-folds and 10% , respectively (20). Neuromyelitis optica spectrum disease (NMOSD) and MG are two immune-mediated diseases underpinned by similar mechanisms. Antibodies against proteins such as acetylcholine receptors and aquaporin 4 are involved in these diseases (21). However, MS is not caused by peculiar antibodies similar to NMOSD and MG. MS has a mechanism more similar to NMOSD than MG which is caused to be accompanied with NMOSD more (22). Another finding in MG and MS patients is antinuclear antibodies (ANAs (40% and 30%, respectively), which have an impact on the dysregulation of the immune system (23). There are insufficient studies on the risk of MS and MG, and the most strong association has been reported between NMOSD and MS (24, 25). Makhani N et al. discussed evidences in favor of the MS prodrome phase, which help us better understand factors leading to the MS progression. Although the mechanisms and duration of prodrome are not apparent, they highlighted prodromal findings, including signs and symptoms before the MS onset and the early management of the disease(26). For example, the evaluation of mental health status in the prodromal stage of immune-mediated disorders was proportional to the increased likelihood of depression caused by the high inflammation(27).

The evaluation of antibiotic profile has revealed an increased MS likelihood of 31-36% compared to the control group. The prevalence of amoxicillin consumption was 9% vs. 2% among MS and control groups, respectively. Amoxicillin and cefalexin increased the MS risk about 2.49-3.75 and 2.3-2.5 folds, respectively. Abdollahpour et al. discussed the role of antibiotics in the MS progression. They reported that antibiotic administration for more than 14 days in the last three years was associated with a 31-35% decrease in the MS progression. The MS odds for penicillin and cephalosporin were associated with decreases by 50-41% and 75-59%, respectively (15). Alonso assessed the likelihood of the MS progression regarding antibiotic consumption over the past three years. The overall MS odds of antibiotic use for less than a week and less than two weeks during the last three years were associated with an increase by 40 and 30%, respectively. Moreover, using cephalosporin for less than a week and more during the last three years was associated with an increase of the MS probability about 20% and 40%, respectively (28). The alteration of normal gut flora is the proposed mechanism for the interaction between the use of antibiotics and the MS progression. Since gut microbiota is closely related to the T-cell population and T-cell regulatory function, it changes in normal flora by antibiotics play an important role in developing autoimmune diseases (29). According to another hypothesis, the hygiene hypothesis, the consumption of fewer antibiotics is associated with fewer infectious diseases. It points to the role of antibiotics against the MS progression; however, it needs to be examined in different populations (30).

Study limitations

One of the limitations of the present study was inevitably associated with the recall bias caused by the retrospective study design. Given that the relationship between the factor and the outcome is investigated, a cohort study can better show this correlation. Another limitation, called protopathic bias, is for the calculated ORs of antibiotics, which was associated with the onset of first symptoms and the time of MS diagnosis.

This study aimed to review different categories of medical histories and introduce the power of each factor in the MS progression. Among different factors, MG and psoriasis, followed by a history of antibiotic use, had the highest odds. Moreover, seizure and epilepsy played the least critical role in the MS progression regarding the sample size of the study.

MS: multiple sclerosis

OR: odds ratio

CI: confidence intervals

AOR: adjusted OR

MG: myasthenia gravis

IBD: inflammatory bowel disease

IBS: irritable bowel syndrome

RA: rheumatoid arthritis

SLE: systemic lupus erythematous

T1DM: type 1 diabetes mellitus

CNS: central nervous system

NMOSD: neuromyelitis optica spectrum disease

ANAs: antinuclear antibodies

Ethics approval and consent to participate

The study was approved by ethics committee of Mazandaran University of Medical sciences and certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Ethics committee of Mazandaran University of Medical sciences approved the study (approval ID: IR. MAZUMS.REC.1400.8335). Informed consent was obtained from all subjects and/or their legal guardian(s) as minor/illiterate participants are involved.

Consent for publication

Written informed consent to write the article has been obtained from the patients.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Competing interests

The authors report there are no competing interests to declare.

Funding

None. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There was no source of extra-institutional commercial funding as well.

Authors' contributions

Conceptualization: S.M.B and M.G. and F.e.; data curation and interpretation: S.M.B and F.e. and M.G. and H.D.K; methodology: S.M.B. and M.G.; data analysis: H.D.K; data validation: S.M.B and H.D.K. and M.G. and F.e.; article writing: M.G. and S.M.B. and F.e. and H.D.K.; final review and revision: S.M.B. and M.G. and F.e. and H.D.K.

Acknowledgment

Hereby, we sincerely thank all the collaborators who helped us advance this project, especially Seyed Mohammad Baghbanian in designing and conducting the study. We would like to thank all the participants who contributed to the publication of this article.

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No competing interests reported.

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Medical records and multiple sclerosis: A population-based case–control study

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