Clinical Features of Patients With Familiar Multiple Sclerosis in Lithuania

Background. Most multiple sclerosis (MS) cases are sporadic, however about 20 percent are hereditary 2. It is still unclear whether heredity affects the progression and severity of the disease. The aim of this study is to assess the effect of heredity on the development of multiple sclerosis and on the course of disease by analyzing the results of disability, severity scales and clinical studies, and comparing them with sporadic cases. Methods. Our study included 104 patients with MS. The study group was comprised of 38 patients with family history of MS; the control group consisted of 66 patients with no family history. The survey included questions about demographic and clinical characteristics. Diagnostic results were evaluated retrospectively from medical records. Disability assessment was made according to EDSS. MSSS score was calculated using conversion table. Results. Patients with a family history tend to have slower onset of the disease, while control group is more likely to have an acute onset (p <0.001). Study group more often complained of symptoms related to pyramidal (74 % vs. 50 %) and brainstem (68 % vs. 20 %), cognitive dysfunction (47 % vs. 20 %), headache (37 % vs. 9 %), back pain (32 % vs. 9 %) than those in control group, p <0.05. EDSS and MSSS scores were higher in familiar cases (p <0.05). The number of exacerbations per year was also higher in study group (1.4 vs. 0.8; p <0.05). Patients with a family history have a higher incidence of MRI changes in brainstem (74% vs. 30%) and cerebellum (58% vs. 30%) than the control group (p <0.01). Conclusions. Patients with a family history tend to have slower onset of the disease, while control group is more likely to have an acute onset. Patients with a family history of MS more often complained of brainstem and cortical dysfunction, and pain in head or back. Both EDSS and MSSS scores were higher in familiar cases. They also have a higher number of exacerbations per year. Patients with a family history have a higher incidence of MRI changes in brainstem and cerebellum.


Background
Multiple sclerosis (MS) is a chronic demyelinating CNS disease. Abnormalities caused by this disorder disrupt the spread of the nerve impulse and manifest in a variety of neurological symptoms [1,3], such as double vision, blindness of one eye, muscle weakness, sensory or coordination disorders [2]. Due to uncontrolled deterioration of the nervous system, patients become disabled and incapacitated. Their mobility is impaired and leads to a need for constant care [1].
Most MS cases are sporadic, however about 20 percent are hereditary [2]. Although the etiology of the disease is not entirely clear, genetic factors are undoubtedly important. An association between MS and HLA-DR2 allele belonging to the main human cohesive compatibility complex (MHC) has been identified [4,5]. However, according to preliminary estimates, the MHC can be only considered a cause in 17-62 percent of genetically determined MS cases. Studies with familiar disease cases have shown that HLA-DR2 is only found in some patients. Thus, there are other genetic factors that determine heterogeneity of inheritance [4]. HLA-DRB 15 is most commonly detected among Lithuanian patients with MS and plays an important role in susceptibility of disease [6].
Incidence of familiar MS is greater in regions with the highest prevalence of this disease (in North America, Europe) [2], and lower where the prevalence is low (in Asia) [7][8][9].
Familiar cases are more common between first and second degree relatives. The relative risk of developing MS has been found to be 9.2 if the first-degree relative has MS, and 3.2 or 2.9 if the second-or third-degree relative suffers from MS, respectively [10]. Hereditary MS cases are more common among twins, especially between sisters. The smallest number of such cases is found between father and son or mother and son. According to studies, the risk of getting a second twin with MS is up to 4.7 percent, and this is a 31 times higher risk compared to the general population [11]. A higher incidence of familiar cases among 4 sisters can be attributed to a higher incidence of MS in women.
It is still unclear whether heredity affects the progression and severity of the disease. It has been established that age of onset between sporadic and familiar cases is similar, and that the course of the disease between twins is similar. However, there is insufficient data to determine whether the course of hereditary disease is different from sporadic. Several studies have noted that heredity increases the likelihood of disease progression, but does not affect the severity of the disease itself.  The results of the study group were compared with the results of the control group which had the same inclusion criteria except for the family history. were considered abnormal if the P100 latency was longer than 114 ms (i.e., 2 SD above the mean).

Multiple Sclerosis Severity Score (MSSS)
MSSS (Multiple Sclerosis Severity Score) is a supplemental scale to EDSS, adding a factor of disease duration to an EDSS score. This gives a derived score that better reflects the severity of the disease itself and has a better prognostic value. Thus, the severity of the disease in patients with the same EDSS score will depend on how long they are sick.
Higher MSSS score will accordingly reflect a shorter duration of the disease and, at the same time, a more severe course and faster progression. The MSSS score is derived from the conversion table (Figure 1) with the EDSS score and disease duration in the year. This scale has not been applied in Lithuania yet. Figure 1. Source [12]: Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology. 2005 Apr 12;64 (7):1144-51.

Evaluation of MRI findings
All imaging studies were conducted with a 1.5-T MR scanner (MAGNETOM Avanto, Siemens, Erlangen, Germany) with a standard head coil. The locations of MS lesions in MRI were analyzed in two different scans: the very first scan (usually at time of diagnosis) and the last scan (during study period). Descriptions of two MRI images were reviewed and compared retrospectively from the medical records of the patients, and the conclusion about the dynamics of lesions in MRI was made. There were three categories of MRI dynamics: positive (decreasing activity of lesions), negative (increasing activity of lesions), or no dynamics (activity and localization of lesions were similar in both images).

Statistical Analysis of Data
Analysis of the collected data was performed using the statistical package SPSS version 25.0. Comparisons of mean age at onset of MS across groups were carried out using the Student t test. Parametric statistical criteria were used for the normally distributed quantitative variables (estimated with Kolmogorov-Smirnov and Shapiro-Wilk tests) and the mean and standard deviations (SD) were calculated. For the control of type I error, the level of significance was selected to be a = 0.05. Values of p lower than 0.05 (p < a) were considered to indicate statistical significance.

Results
The study consisted of 104 patients with MS. The study group consisted of MS with family history of MS: 13 men and 25 women. The control group consisted of MS without a family history: 17 men and 49 women. Both groups did not differ by gender or age (p> 0.05). The 7 duration of disease in the study group was 14.34 ± 3.76 years, while in the control group -15.14 ± 8.46 years (p> 0.05). The age at the onset of the disease was similar in both groups (p>0.05). Patients with a family history tend to have slower onset of the disease, while control group is more likely to have an acute onset (p <0.001). The majority of MS with family history considered that their disease is caused by certain factors: childbirth (24%), mental trauma or stress (21%), infectious diseases (11%), head or spinal trauma (8%), meanwhile, 71% of patients in the control group considered that the disease started without any identifiable cause (p <0.05). MS patients with family history tend to have relapsing -remitting (42%) or secondary progressive (42%) types of disease; meanwhile most frequent type in control group is relapsing-remitting (79%), p = 0.001). Mother was the most frequent family member with MS in familiar cases (84%), although no significant relationship between the gender of the subject and his/her family member was found (p> 0.05). (Table 1     VEP-visual evoked potential, MRI -magnetic resonance imaging, OGBs -oligoclonal bands

Discussion
Our study revealed that majority of MS patients with family history considered their disease to be caused by certain factors. 21% of patients indicated stress as a potential trigger for disease onset. According to literature, stress is considered to be one of the risk factors for the development of MS because it leads to changes in the hypothalamicpituitary-adrenal axis [15]. 24% of women with MS in first degree relative thought that the birth of child could trigger the onset of the disease. According to the authors, hormonal changes occurring during pregnancy can affect the onset and remission of MS in already ill women [16]. In addition, one of the predisposing factors for MS may be infectious disease 12 [17]. When considering the types of disease, the prevalence of relapsing-remitting (RR) and secondary progressive types were equally common in MS with family history, while RR was the most common type in the control group. According to literature, the most frequent type of MS is RR (85%) [18]. Our study confirms it, because the majority of patients with MS were diagnosed with RR type overall. However, it is obvious that patients with a family history are also characterized by frequent secondary progression (SP). These are mostly the patients who progressed from RR type to SP. As our study focused on the role of inheritance, each participant revealed if they have a first-degree relative with MS. We found that the most frequent family member of MS participant, who is also affected by MS, was a mother. Metanalysis found that the risk of having a child with MS depends on the sex of the diseased parent [8][9][10][11][12][13][14]. Many studies have found that the risk increases with an affected mother [8,13,14].
Our study revealed that the number of exacerbations per year in familiar cases was higher than in the control group (1.4 vs. 0.8). Rate of exacerbations is higher in the first year of disease and gradually decreases [18]. Some studies suggest that the higher frequency of exacerbations in the first five years of the disease is associated with an increased risk of developing SP type and disability [19]. Exacerbations are more common after stressful experiences [20]. Availability of data and materials The dataset generated and analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
The study was supported by the grant from the Research Foundation, Lithuanian University of Health Sciences.
Authors' contributions DA collected and analyzed data, drafted the manuscript and carried out the literature search. RB, IK participated in the acquisition and interpretation of data. RB, AV made contributions to supervision in data collection and management and revising the manuscript. All authors read and approved the final manuscript, and agreed to be accountable for all aspects of the work.