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 Abiodun Emmanuel Akinwuntan, PhD, MPH, Department of Physical Therapy, Georgia Health Sciences University, 987 St. Sebastian Way, Augusta GA 30912; e-mail: 

Prediction of Driving Ability in People with Relapsing-Remitting Multiple Sclerosis Using the Stroke Driver Screening Assessment

In the absence of gait automaticity, the need to allocate cognitive resources to walking has implications for everyday mobility and community participation. The purpose of this study was to examine the effects of different attentionally demanding conditions on gait metrics in people with multiple sclerosis (MS).

Twenty-one individuals (11 with MS, 10 without MS) wore wireless inertial sensors and completed 1-minute walking trials under 4 different attentional conditions: no-attentional-instruction, focus on gait quality, attention to a narrative discourse task, and attentional switching. Walking trials were performed at a self-selected and fast-paced walking speed. A 3-way linear mixed model including conditions, groups, speeds, and interactions was used to evaluate the effects on gait speed and stride length variability.

Participants with MS demonstrated slower gait speed and greater gait variability in all attentional conditions than participants without MS. During self-paced walking, participants with MS showed the greatest decline in mobility metrics during the attentional switch condition. When walking fast, significant differences were observed for both the divided attention and attentional switching conditions, with divided attention having the greatest effect on gait speed and attentional switching resulting in the greatest decrease in gait variability.

Difficult walking conditions, such as attentional switching, elicit greater gait deficits in people with MS. Evaluating attentional switching may be useful for mobility assessment in people with MS, and incorporating this attentional technique in future mobility training may improve stability and prevent falls.

The authors declare no conflicts of interest for
this study.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

This work, in part, was presented previously as 2 posters at the North American Federation of Adapted Physical Activity Conference; October 11-13, 2022; St. Catharines, Ontario, Canada.

Well-controlled and coordinated walking is essential for safe and successful community mobility, with automaticity—defined as the ability to walk with minimal reliance on attention-demanding cognitive resources—serving as a critical component of efficient gait.

 Automaticity allows individuals to walk without the need for continuous attentional monitoring, preserving cognitive capacity for navigating complex and dynamic environments.

When automaticity is compromised, walking becomes increasingly dependent on cognitive control, resulting in competition for attentional resources and contributing to gait difficulties and impaired performance of concurrent tasks.

 This is particularly relevant for individuals with multiple sclerosis (MS), who often exhibit reduced walking automaticity

 and report needing to consciously direct attention to their walking in order to maintain stability.

 Such compensatory strategies are concerning, as attentional difficulties have been shown to negatively impact walking

 and are associated with increased fall risk in this population.

 Accordingly, understanding how attentional deficits influence gait has important real-world implications.

While research has reported that between 20% and 50% of adults with MS have specific attentional difficulties,

much of the attentional research regarding gait has focused on walking while dividing attention (ie, dual tasking).

 Yet, to walk safely and successfully, individuals not only have to divide attention but must also be able to flexibly prioritize and switch attention in accordance with the demands of everyday conditions and circumstances.

 Attentional switching denotes the ability to flexibly shift back and forth between multiple tasks or mental sets.

 Recent research has sought to examine outcomes associated with flexible and adaptive attentional control in individuals with MS through task-switching paradigms. Migliore et al

 found that participants with MS demonstrated greater deficits in attentional switching compared with the control group when completing a computer-based cued-switching task while seated. However, research by Shiri and colleagues

 found no relationship between cognitive flexibility and static balance in study participants when attentional switching was assessed via common neuropsychological measures. Notwithstanding the methodological differences and inconsistencies across these 2 studies, no study to date has specifically investigated whether impaired attentional switching influences walking in people with MS.

During walking, competition for attentional resources is influenced not only by the timing of concurrent tasks but also by their complexity—that is, tasks that demand greater cognitive load or involve more advanced mental processes.

 Individuals with MS tend to have a reduced capacity to recruit additional cognitive resources in response to increasing task complexity.

 Moreover, gait impairments can often be exacerbated at faster walking speeds,

 highlighting the importance of understanding how individuals with MS manage attentional switching across varying gait speeds. This is particularly important given the demands of real-world ambulation, where navigating busy or unpredictable environments often requires rapid shifts in attention and adaptive motor responses.

Given the importance of cognitive resources for optimal gait performance, isolating the effects of cognitive flexibility from other cognitive processes and under differential cognitive loads may further the development of novel therapeutic interventions designed to enhance attentional switching and facilitate gait automaticity in people with MS. As such, the purposes of this study were to compare the effects of divided attention and attentional switching on gait in adults with and without MS and to explore the differential effects of these attentional conditions when walking at self-selected or fast-paced speeds.

A convenience sample of 11 individuals with MS and 10 without MS (NoMS) was recruited. An email invitation was sent to individuals with MS listed in the authors’ research database who had participated in previous research. Additionally, a flyer was posted in the multiple sclerosis center of the local medical center. Those with MS had to self-report (1) physician-diagnosed MS and (2) minimal to moderate disability (a score of 1-4 on the Patient-Determined Disease Steps [PDDS] scale).

 Individuals with MS were excluded if they had (1) a severe exacerbation of symptoms requiring medical intervention in the previous month or (2) any health condition or diagnosis besides MS that could influence balance or ambulation. Participants without MS were matched by age (±3 years) and sex, and also had to report no health condition or diagnoses affecting balance or ambulation. This study was approved by the Institutional Review Board of the University of Vermont, and all participants provided written consent prior to data collection.

Demographic data included age, sex, years post diagnosis, and MS phenotype. For additional insight into the sample, cognitive functioning was assessed using the Symbol Digit Modalities Test (SDMT) and the Montreal Cognitive Assessment (MoCA). The SDMT, a reliable and valid measure of cognitive impairment in MS,

 evaluates constructs of attention, perceptual processing, working memory, and psychomotor speed through a timed task of matching abstract symbols to numbers. The MoCA is a sensitive and useful cognitive screening tool used to detect early and mild cognitive impairment in people with MS.

 It assesses function across the cognitive domains of attention, executive functions, memory, language, visuo-constructional skills, conceptual thinking, calculations, and orientation.

Mobility impairment was measured with the 12-item Multiple Sclerosis Walking Scale, a reliable and valid instrument,

 whereby participants self-report how much their MS impacts their ability to walk under various circumstances. The Falls Efficacy Scale–International

 was used to assess participant concerns about falling during 16 activities of daily living.

Measurements of continuous walking were derived using APDM Opals, small wireless inertial motion sensors, and its related Mobility Lab software (Clario). Sensors were placed on a participant’s lumbar spine, sternum, and both feet. Data from the Opal sensors were collected wirelessly at 128 Hz. Measurements included gait speed (m/s) and stride length variability, which was expressed as the coefficient of variation (CV [%]) and calculated by stride length SD/stride length mean to represent relative gait variability.

 These metrics have been identified as sensitive measures of dual-task mobility impairment in individuals with MS.

Participants completed eight 1-minute trials walking between 2 lines 25 feet apart. The 8 walking bouts consisted of 4 different attentional conditions at both a self-paced (SP) and a fast-paced (FP) walking speed. For the no-attentional-instruction (NI) condition, participants were simply asked to walk back and forth. For the internal-focus (IF) condition, participants were instructed to focus their attention on their gait throughout the walking bout, a task selected based on research highlighting the impact of internally focused attention on daily walking in individuals with MS.

 In the divided-attention (DA) condition, participants were asked to walk while simultaneously completing a narrative discourse task, which required them to verbally produce a detailed and coherent story in response to an open-ended prompt (eg, “trip to New York City”) while walking, or a similarly structured alternate form (eg, “moving to a new city”).

 This task has been shown to be a cognitively demanding task of natural language formulation, planning skills, and discourse production requiring substantial attentional resources.

 In the attentional-switching (AS) condition, participants were instructed to switch their attention every 15 seconds between the IF and DA tasks throughout the 1-minute bout, allowing for an assessment of their ability to flexibly shift attention between internally and externally oriented tasks—an ability that mirrors the dynamic attentional demands of real-world environments (

). All walking trials and discourse topics were randomized across participants to minimize order effects. Participants were instructed to rest, as needed, between trials to minimize the impact of fatigue from both the mobility and cognitive components of the testing paradigm.

Descriptive statistics were performed to examine group differences with independent 

 test, Wilcoxon rank-sum test, or Fisher exact test after inspection of normality. To evaluate the effects of attentional conditions and walking speeds on gait metrics (gait speed and stride length variability), we employed a 3-way linear mixed model including attentional conditions (NI, IF, DA, AS), groups (MS, NoMS), speeds (SP, FP), and interaction terms (group × condition, group × speed, condition × speed, group × condition × speed) as fixed effects with participants as random effects to allow for the entry point to vary across participants. A linear mixed model was selected, as it accounts for the heterogeneity and correlation of repeated measures under different conditions and retains participants with partially missing data. Effect sizes and 95% CIs of the linear mixed model were calculated using fixed-effects regression coefficients. All analyses were performed using Stata 17 (StataCorp), and statistical significance was set at 

There were no significant differences in age (

 = .99) between participants with and without MS. Participants with MS had greater concerns about falling (

 < .001) than those without MS and lower cognitive functioning than the NoMS group, as indicated by SDMT (

 < .001) scores. The MS group reported a median PDDS score of 3 (ie, gait disability) and average years post diagnosis of 24.1 ± 12.8 (

The 3-way linear mixed model found significant group effects (

 < .05) in both gait metrics. Participants with MS showed significantly lower gait speed and greater stride length variability than participants without MS in all attentional conditions, regardless of speed instructions, except for stride length variability in the fast-paced internal-focus condition (

We also observed significant speed main effects (

 < .05) in both groups. Multiple post hoc contrast comparisons indicated that participants significantly increased their gait speed when instructed to walk at a faster speed. However, no significant differences in gait speed were found between self-paced and fast-paced walking in the divided-attention condition for participants with MS. Unlike gait speed, stride length variability did not differ among walking speeds across attentional conditions (Table 2).

Results revealed different patterns of attentional condition main effects based on speed instruction and group. In self-paced walking, there were significant attentional condition main effects on gait speed in the NoMS group, but not in participants with MS (

). No significant gait speed differences were observed across any of the attentional conditions in participants with MS. The NoMS group, on the other hand, showed the greatest decline in gait speed in the attentional-switching condition compared to the no-attentional-instruction condition (B = –0.13 m/s; 95% CI, –0.20 to –0.06; 

 < .001) and the divided-attention condition (B = –0.09 m/s; 95% CI, –0.17 to –0.01; 

 = .024). Compared to gait speed, however, we observed that the attentional-switching condition resulted in the greatest stride length variability in both groups at the self-selected pace. Participants with MS demonstrated significantly greater gait variability in the attentional-switching condition than in the no-attentional-instruction condition (B = 1.28%; 95% CI, 0.18-2.37; 

 = .022) and the internal-focus conditions (B = 1.67%; 95% CI, 0.03-3.31; 

 = .043), whereas the NoMS group had greater variability in the attentional-switching condition compared to the divided-attention condition (B = 1.23%; 95% CI, 0.08-2.38; 

In fast-paced walking, both groups demonstrated the slowest gait speed in the divided-attention condition (

). For the MS group, the divided-attention condition (B = –0.20 m/s; 95% CI, –0.28 to –0.12; 

 < .001) resulted in slower walking speed than in the attentional-switching condition (B = –0.16 m/s; 95% CI, –0.23 to –0.08; 

 < .001) when compared to the no-attentional-instruction condition. For the NoMS group, both the divided-attention and attentional-switching conditions significantly differed from the other conditions and one another (B = –0.08 m/s; 95% CI, –0.16 to –0.001; 

 = .047), although the divided-attention condition had the greatest effect on speed. For the MS group, while the divided-attention condition elicited greater stride length variability than the no-attentional-instruction (B = 1.47%; 95% CI, 0.30-2.63; 

 = .013) and the internal-focus conditions (B = 1.41%; 95% CI, 0.23-2.59; 

 = .019) during fast-paced walking, attentional switching had the greater impact on this outcome than did the divided-attention condition. Consistent with the MS group, the attentional-switching condition also revealed the greatest stride length variability across the attentional tasks for the NoMS group, with significant differences observed between the attentional switching and the no-attentional-instruction conditions (B = 1.69%; 95% CI, 0.50-2.87; 

 = .004) as well as the attentional-switching and divided-attention conditions (B = 1.61%; 95% CI, 0.46-2.75; 

Despite significant group and condition main effects, there were no significant group × condition interaction effects (

 .05) in either gait metric, as both groups showed similar patterns across attentional conditions. This insignificant finding indicated that the participants who did and did not have MS responded similarly to the varying attentional contexts.

Multiple contrasts analyses for the significant condition × speed interaction effect on gait speed (MS: 

 = .005) revealed significant differences between the no-attentional-instruction and the divided-attention conditions in both groups (

). Specifically, participants with and without MS maintained gait speed in the divided-attention condition compared to the no-attentional-instruction condition while self-paced walking. However, participants in both groups had decreased gait speed while fast-paced walking in the divided-attention condition compared to the no-attentional-instruction condition, contributing to the significant interaction effects. There was no significant condition × speed interaction effect for stride length variability.

Significant group × speed interactions and multiple contrast comparisons in gait speed (NI: 

 < .001) showed that the magnitude of gait speed differences between groups increased when walking at a fast pace compared to the self-selected pace under all attentional conditions (

). There were no significant group × speed interaction effects for stride length variability. Additionally, no significant group × condition × speed interaction effects were seen in either gait metric.

Moving through daily life requires the ability to flexibly switch attention between walking and other cognitive tasks or across varied environmental situations. For individuals with MS, walking requires greater attentional resources,

 and this can present a considerable challenge and an increased fall risk. The results of this study indicate that alterations in gait speed and gait variability are sensitive to varying attentional demands; the greatest decrements in gait quality occurred when participants walked faster and engaged in attentional switching. These findings extend prior research highlighting the critical role of attention in mobility among individuals with MS.

 Importantly, our results offer novel insights into mobility decline specifically related to attentional switching—an ecologically valid cognitive demand that reflects real-world challenges in everyday ambulation.

 participants with MS had slower gait speed and greater stride length variability compared to their counterparts without MS. As has been observed previously,

 participants with MS demonstrated twice as much variability in their gait as the participants without MS. Our MS sample also had slower cognitive processing speed, known to correlate with greater gait variability.

 Gait speed differences between groups were greater at a fast pace than at a self-selected pace, aligning with prior findings that fast walking reveals more pronounced deficits in individuals with MS.

 Collectively, participants with MS showed worse gait deficits than those without MS, regardless of attentional condition, and greater gait decrements were elicited in their fast-paced walking in this population.

When examining between-group differences, results were significant for all conditions except for internal focus while walking fast. While both groups showed variability, the underlying cause may differ. Whereas the gait variability observed in the MS group could be attributable to neuromotor and cognitive deficits, the variability seen in the NoMS group may have been a function of redirecting unnecessary attentional resources inward to their walking. Research findings show that internal focus on one’s movement pattern, thus bringing it under more conscious control, can interfere with already automatized movement control processes.

 Given that motor function was not directly assessed in the adults without MS, it is unclear if the observed variability in gait was indeed a function of attentional focus or of preexisting motor deficits. Future research is needed to more clearly elucidate these differences.

Although participants with MS exhibited worse gait speed and stride length variability than participants without MS, both groups showed relatively similar patterns of reductions in gait in response to attentional condition, resulting in insignificant group x condition interactions. Our finding is supported by recent evidence that suggests that there is only a minimal difference in cognitive-motor interference between individuals with and without MS.

 This further indicates that attentional conditions, particularly DA and AS, required effort from both groups and led to similar levels of cognitive-motor interference on gait. However, this should be interpreted with caution, given that this study did not assess cognitive performance during the DA and AS tasks to determine if there was a greater cost to the cognitive task in individuals with MS.

When examining within-group differences across the attentional conditions at a self-selected pace, the MS group exhibited no significant differences in gait speed. While speculative, previous research supports the idea that these participants may have employed increased cortical activity needed to maintain gait speed under the various attentional conditions or that the cost of dividing or switching attention may have negatively impacted the unmeasured cognitive task rather than the observed motor task.

 However, for participants without MS, when walking at a self-selected speed, the slowest gait speed occurred when engaging in attentional switching. It has been shown that as individuals age and mobility becomes more dependent on executive control, attentional switching produces high cognitive-motor interference and is a detriment to gait speed.

 These observed gait speed patterns, however, differed for both groups when walking faster, with the slowest gait speed occurring when participants divided their attention. For those with MS, this may have been due to the constant attention, and thus higher cognitive-motor demand, necessitated by both the concurrent cognitive task and the more challenging task of walking fast. Although there was also a significant difference in speed during the AS condition, attentional switching likely allowed at least some attention to be intermittently redirected back to an internal focus on walking with less cost to speed. For the NoMS group, the divided-attention condition also had the greatest impact on gait speed compared to all other attentional conditions, further supporting the increased need for executive control of gait when walking in more challenging situations, such as at a faster pace.

The differences regarding gait variability were greater when participants walked at either their self-selected or fast pace. Most noteworthy was the fact that the greatest variability for both groups was observed with attention switching rather than dividing attention. For those with MS, only attentional switching resulted in a significantly more variable gait when walking at a self-chosen pace. Whereas both divided attention and attention switching significantly impacted gait variability at the faster pace, the greatest decrease in gait variability occurred during the attention switching condition. Gait variability was also impacted by attentional switching in the NoMS group and was also the most pronounced in the fast-pace condition. This is in contrast to current research involving healthy older adults,

 which found that pace-related parameters, such as gait speed, were more closely associated with attention switching than variability-related parameters. The difference could be due to how and when attention switching was assessed. Our study observed the effects of attentional switching during gait and may reveal more ecological and important insights, as an inconsistent and unstable gait pattern has been shown to be a more sensitive indicator of fall risk than other gait metrics.

 Nevertheless, our results offer insight into the underpinnings of this previous research and advance support for the increasing challenge of attentional switching while walking, especially at a fast pace and in terms of gait variability.

The effects of different attentional conditions at varying walking speeds have important ecological and practical implications. The gait parameters examined, especially stride length variability, offer insight into the differential consequences underpinning gait deficits during attentionally demanding tasks in people with MS. Additionally, employing ecologically valid cognitive tasks may contribute to the generalizability of our findings beyond those traditionally obtained from laboratory-based cognitive assessments.

Nonetheless, some limitations exist. The relatively small sample with a narrow range of disability may not be representative of the larger MS population. Our study did not assess performance on a discourse task, leaving the cognitive cost of multitasking unknown. It was difficult to accurately assess where participants actually directed their attention when given no instruction or asked to internally focus. Finally, although this study aimed to enhance ecological validity within lab-based assessments, prior research has highlighted the constraints of laboratory walking tasks in capturing the complexity of real-world ambulation

 that is influenced by multiple interacting factors.

 While our attentional conditions were designed to reflect common cognitive demands, they may not fully replicate the dynamic and unpredictable nature of attentional challenges encountered during everyday walking.

Our data show that participants with MS had slower gait speed and greater gait variability than those without MS in all attentional conditions. Notably, we found that difficult walking conditions, such as attentional switching, elicited greater gait deficits, especially related to gait variability in persons with MS, and these deficits became profound in fast-paced walking. Thus, this study demonstrates the value of evaluating attentional switching for mobility assessment in people with MS and the need to incorporate this attentional technique in future mobility training to improve stability and prevent falls.

Walking while directing attention to other cognitively demanding tasks can negatively impact gait stability in people with multiple sclerosis.

The Impact of Attentional Focus on Gait in Adults With Multiple Sclerosis: A Preliminary Investigation

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects the central nervous system. Familial MS is arbitrarily defined as a type of MS that runs in families with 1 or more first- to third-degree relatives in addition to the index case affected by MS. The aim of this article is to report a unique case of familial MS from Saudi Arabia with 2 novel variants in the 

 gene that may contribute to the pathogenesis. We observed an unfavorable response to interferon therapy and successful treatment using fingolimod therapy. This observation needs further study, including whether this lack of response is specific to interferon treatment or possibly a chance occurrence. This family work-up illustrates the importance of genetic testing in identifying variants associated with familial MS, especially if more than 2 members of the same family are affected. Although this genetic tool is used mainly for research purposes, it had clinical implications for our patient, including the appropriate selection of disease-modifying therapy and prognostic counseling. Further large-scale studies are needed to expand the genetic spectrum of familial MS with clinical and pharmacologic correlation.

 The authors declare no conflicts of interest.

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects the central nervous system. It is a progressive disorder that may result in disability and impaired quality of life.

 The global prevalence of MS is 33 in 100,000 population. Using the Saudi Arabian National MS Registry, the prevalence of MS in Saudi Arabia was estimated to be 40.4 in 100,000 population.

 Familial MS is arbitrarily defined as a type of MS that runs in families with 1 or more first- to third-degree relatives in addition to the index case affected by MS. In the MS population, the prevalence of familial MS worldwide was calculated to be 12.6%.

 Among identical twins, the chances of MS are approximately 200 to 300 times greater than in the general population if 1 is affected.

MS is a complex disorder with a multifactorial etiology, including genetic, immunity-related, and environmental factors. With advancements in the field of molecular genetics, common genetic variants related to the immune system have been described in certain individuals. Therefore, the contribution of autoimmunity and the autoimmune nature of the disease disturbing the regulatory rather than the coding regions have been implicated.

 Among the major genetic factors now widely recognized as risks for developing MS are certain allelic variations of the human leukocyte antigen (HLA) class II on chromosome 6p21. The 

 of HLA class II is now verified as the strongest independent factor for MS in various populations.

Familial MS was the topic of study and research material by several neurologists in Saudi Arabia, with few papers available in the literature. Only a single study has been published in Saudi Arabia investigating the association of different HLAs with MS. The study depicted that several 

 alleles were associated with the disease.

 The aim of this article is to report 2 previously unreported novel variants in the 

 gene from a Saudi patient with familial MS. The patient had interesting clinical observations, including early onset of the disease, resistance to interferon therapy, and successful response to treatment with fingolimod.

The proband is a 25-year-old woman who received a diagnosis of relapsing-remitting MS at age 13. The diagnosis was based on dissemination in time and space and fulfillment of the McDonald criteria for the diagnosis of pediatric MS. She had multiple attacks involving the sensory, motor, cerebellar, and spinal cord regions. Magnetic resonance imaging (MRI) of the brain and spinal cord demonstrated multiple classical periventricular white matter demyelinating plaques with Dawson fingers and spinal cord involvement (

). She was started on weekly interferon beta (IFNβ)-1a at a dose of 30 μg per intramuscular injection. Unfortunately, her disease progressed both clinically and radiologically for 7 years, despite her adherence with interferon therapy (

). She had 1 to 4 relapses per year, which necessitated treatment escalation for which she was switched to fingolimod 0.5 mg once daily, with good control of her disease during the past 2 years. She has a positive family history of MS in her sister, who is 31 years old and was diagnosed at age 28, as well as her brother, who is 21 years old and was diagnosed at age 17 (

, which is published in the online version of this article at ijmsc.org). Her sister and brother used interferon therapy for 1 and 2 years, respectively, with multiple relapses and deterioration of Expanded Disability Status Scale scores and gait. They were shifted to fingolimod 0.5 mg once daily, with excellent response and improvement in Expanded Disability Status Scale scores. Their brain MRIs showed classical multiple periventricular demyelinating lesions, and they did not have cerebellar atrophy. The parents were not consanguineous, and none of the siblings had genetic diseases that run in the family, including cystic fibrosis, glucose-6-phosphate dehydrogenase deficiency, familial Mediterranean fever, or any other genetic diseases.

Whole-genome sequencing using next-generation sequencing was performed and identified 2 heterozygous novel variants in the 

 gene (RefSeq NM_002124.3). The first was a stop variant in exon 2 c.115C>T; (p.Gln39Ter). This variant is predicted to cause loss of normal protein function through protein truncation. The second was a missense variant in exon 5 c.785C>G; (p.Thr262Arg). There is a moderate physicochemical difference between threonine and arginine. Both variants are novel (not in any individuals) in the 1000 Genomes Project. Mutations in this gene are known to cause susceptibility to MS-1 (OMIM #126200). These variants are likely pathogenic, because the detailed clinical information in the patient and family histories also supports this report.

MS is an autoimmune disorder with an environmental predisposition that occurs in patients who are genetically susceptible. Susceptibility to MS has been linked to changes in certain 

 gene is responsible for encoding polymorphic glycoproteins. These cell-surface glycoproteins are crucial in immune regulation because of their role in recognizing either intracellular nonself (class I) or extracellular (class II) proteins. Specifically, the HLA class II gene has a stronger role in the genetic contribution of developing MS. The HLA class II gene encodes molecules that participate in antigen recognition and presentation to T cells.

In Saudi Arabia, the mean age at onset of MS is 27.8 years.

 However, there are no data regarding age at onset in familial cases. The present 3 siblings were diagnosed at young ages, which could be the true ages of onset, or the onsets could be even years before the clinical presentations or diagnoses. Patients with familial MS, specifically affected second- and third-degree family members, have a significantly shorter time from disease onset to MS diagnosis compared with patients with sporadic MS. This short duration was not found in published articles describing both first affected family members and sporadic cases.

 In the family described herein, this short duration was clearly demonstrated. Generally, relapsing-remitting MS is the most prevalent type of MS. In patients with familial MS, this form of the disease has the same prevalence as secondary progressive MS.

 This was not the case in the present report, because all 3 individuals had the relapsing-remitting form of the disease.

Although the cause of MS is still unknown, neurologic symptoms are thought to be immune-mediated tissue damage directed against myelin antigens. This will result in demyelination with the loss of axons and cell bodies that lead to progressive neurologic symptoms. Patients with MS typically experience symptoms such as focal weakness, monocular blindness, diplopia, sensory and coordination dysfunction, and muscle fatigue.

 pyramidal and brainstem lesion symptoms were more predominant early in the disease course in patients with MS with a first-degree family member than in the control group with no family history. In addition, cognitive dysfunction, headaches, and back pain were more common in familial MS. Furthermore, patients with familial MS present with more exacerbations annually, especially in the first year of disease activity, with a subsequent decline in the number of these attacks in the following years. Lesions in the brainstem and cerebellum are more commonly observed on MRIs of patients with familial MS. For all the previously mentioned reasons, and because of changes that occur in the hypothalamic-pituitary–adrenal axis, the degree of disability was higher in patients with familial MS.

 In the present patient, striking cerebellar atrophy was obvious on neuroimaging, which is a subject of research that needs explanation. The present patient was scanned using the same MRI machine and identical protocols at all visits. The MRI was performed regularly every 6 to 12 months during patient follow-up. Unfortunately, the quantification of cerebellar atrophy is not routinely performed in the neuroradiology department at our institution.

IFNβ has been used as a treatment for MS since the mid-1990s to decrease exacerbations and reduce disease burden. Although the exact mechanism of action of this drug is unknown, several immunomodulatory effects lead to its success in treating the disease.

 Patients with familial MS are less responsive to IFNβ.

 In fact, the present patient’s symptoms worsened while taking this medication. Although the efficacy in reducing relapses in MS is only 30%, the failure of this medication in all 3 siblings may indicate a lack of response to this therapy. In addition, high-resolution HLA typing identified 2 HLA class II alleles, which predisposed the patient to develop antibodies targeting IFNβ during treatment. Hoffmann et al

 defined the genetic factors that determined the immunogenicity of protein-based IFNβ, explaining the resistance to therapy. Further studies evaluating and comparing the percentage of patients with familial and sporadic MS with high neutralizing antibodies should be conducted. A limitation of this observation in the present patient is the lack of testing neutralizing antibodies.

Fingolimod is an oral medication used as first-line treatment for relapsing-remitting MS in the United States, whereas it is reserved for highly active cases in the European Union.

 Fingolimod decreases the annualized relapse rate by 65% to 70%, decreases disability progression, and decreases accumulation of T2 lesions on MRI, in addition to reducing new or enlarging T2-weighted lesions.

 The mechanism of action of fingolimod is sphingosine 1-phosphate receptor agonist (functional antagonist), which results in altering lymphocyte migration, thereby sequestering them in the lymph node and decreasing their number in the periphery.

 The favorable response to fingolimod is due to the modulation of NR4A2 expression, which is not observed in other disease-modifying therapies, including IFNβ. Fingolimod positively modulates this gene expression level in peripheral blood, which contributes to the final clinical response to this treatment.

 We believe this could be one factor, and further research should be conducted to explore other possible mechanisms. To our knowledge, the present cases are the first familial MS cases reported to be treated successfully with fingolimod.

Genetic testing, including whole-genome sequencing, is a useful tool in investigating patients presenting with familial MS. However, the results of these studies are not easily translated into daily clinical practice, because MS is a disease in which several common variants contribute to the genetic risk of developing this disease. Therefore, this tool of genetic testing is currently applied only for research purposes, with a possible promising role in the future.

In conclusion, we report a unique case of familial MS from Saudi Arabia with novel variants in the 

 gene that may contribute to the pathogenesis. We observed an unfavorable response to interferon therapy and successful treatment with fingolimod. This observation needs further study, including whether this lack of response is specific to interferon treatment or possibly a chance occurrence. The present family work-up illustrates the importance of genetic testing in identifying variants associated with familial MS, especially if more than 2 members of the same family are affected. Although this genetic tool is used mainly for research purposes, it had clinical implications for our patient, including the appropriate selection of disease-modifying therapy and prognostic counseling. Further large-scale studies are needed to expand the genetic spectrum of familial MS with clinical and pharmacologic correlation.

The aim of this article is to report a unique case of familial multiple sclerosis from Saudi Arabia with 2 novel variants in the HLA-DRB1 gene that may contribute to the pathogenesis. 

Novel Heterozygous Variants in the HLA-DRB1 Gene in a Saudi Family With Early-Onset Familial Multiple Sclerosis: Therapeutic Failure and Success

To improve the quality and standard of care, considerable resources are invested to produce clinical guidelines for multiple sclerosis (MS) management. We aimed to investigate MS clinicians’ use of guidelines and factors that influence use.

Interview guides were developed using Fisher’s framework to assess factors that influence guideline application (categorized as personal, guideline related, and external). Nurses and neurologists experienced in MS health care were recruited through convenience sampling. Semistructured online interviews were conducted from June 2023 to October 2023, and data were analyzed using inductive and deductive methods.

We interviewed 16 MS clinicians (10 nurses, 6 neurologists). Despite most clinicians believing that guidelines can improve consistency, safety, and quality of care, the application of guidelines was highly variable. Participants reported that clinical decision-making in MS management involves integrating guideline recommendations with clinical reasoning while considering patients’ circumstances and preferences, the complex nature of MS, and resource constraints. Personal barriers to guideline application included low awareness and familiarity. Guideline-related barriers included evidence, plausibility, accessibility, layout, and complexity. External barriers included a lack of resources. Facilitators were mostly guideline related, including relevance to local protocols, covering complex treatment or unfamiliar topics, and when guidelines were up to date and credible. Participants suggested various strategies to overcome barriers to guideline use.

Australian MS clinicians reported low awareness and high variability in the application of national and/or international MS guidelines. Clinical practice guidelines should be adaptable to local contexts, accessible, and regularly updated. Multifaceted strategies to better distribute and champion guidelines should be employed.

Yasmine Probst and Darshini Ayton declare that they are people living with multiple sclerosis (MS). Claudia H. Marck, PhD, was funded by a University of Melbourne Momentum fellowship and an MS Australia fellowship (20-216). Yvonne C. Learmonth was funded by an MS Australia fellowship (21-3-053) and the Western Australia Department of Health (WANMA EL 2022). Darshini Ayton is funded by a National Health and Medical Research Council Emerging Leader 1 fellowship (2021-2025; APP1195357). Yasmine Probst was funded by an MS Australia Senior fellowship (21-3-014). All other authors declare no competing interests.

Management of multiple sclerosis (MS) is complex and requires multidisciplinary care. Over 33,000 people live with MS in Australia, and the prevalence is increasing faster than population growth.

 However, although the standard of medical care is generally high in Australia, recent reports conclude that the standard of MS care is variable and impacts health outcomes. For example, 31.5% of people living with MS in Australia lack access to a specialist MS nurse, which is associated with worse health outcomes.

 Further, MS care provision in the Australian Capital Territory was reported to be fragmented, below the standard of recommended care, and lacking multidisciplinary integrated care.

 Other reports of inconsistencies or gaps in MS care include family planning,

 and referral to allied health for symptom and comorbidity management.

 These findings are in line with those of a large study that found that Australian adults received appropriate evidence-based health care in only 57% of health care encounters.

Opportunities to improve the standard and quality of care should be identified to ensure optimal outcomes and health equity for all Australians living with MS. Clinical practice guidelines (hereafter, 

) are designed to improve and maintain standards, effectiveness, and consistency of care; reduce inappropriate care; and reduce geographic variations and other inequities.

 High-quality guidelines are based on rigorous syntheses of best available evidence and expert consensus to support clinical decision-making. The application of guidelines should be viewed through the lens of comprehensive clinical decision-making, considering elements such as professional expertise, patient preferences, and practical feasibility.

The acceptability and uptake of guidelines among MS clinicians remain unclear in Australia, and only limited data exist globally. One Australian study assessed compliance among radiologists with the 2003 Consortium of Multiple Sclerosis Centers MRI diagnostic protocol and found incomplete compliance, potentially leading to incorrect or delayed diagnosis.

 Results from 2 German studies found that although there was an overall high level of agreement among 327 neurologists with the German MS treatment guidelines, many considered them too prescriptive and conservative.

 Findings from a 2024 study identified a large gap between the international MS Brain Health quality standard and its real-world adaptations among 71 German neurologists, many of whom reported that the standard was too ambitious, mostly due to a lack of resources.

Although barriers to MS guideline application are largely unknown, from other clinical areas, we know that barriers are commonly clinician related (such as lack of awareness, agreement, self-efficacy, outcome expectancy) or related to organizational factors such as lack of time and resources.

 Guideline-related barriers are also commonly reported, including shortcomings in validity, format, accessibility (eg, paywall, language barrier), credibility, and usability or specificity.

 Our review of 31 guidelines regarding complementary therapies in MS showed variable methodological quality,

 which may lead to suboptimal implementation. In addition, our systematic review of 19 physical activity guidelines for application by MS clinicians showed that these guidelines rarely specify the actions that clinicians should take, likely hindering application.

 Understanding barriers and facilitators to guideline application is the first step to creating strategies to improve guideline implementation and, ultimately, health outcomes.

Therefore, this study aimed to investigate the extent to which MS clinicians apply treatment guidelines and the barriers and facilitators to application. The study is underpinned by Fisher’s framework, designed to assess factors influencing guideline application, which includes 3 domains: personal/clinician factors, guideline-related factors, and external factors.

This study was a cross-sectional qualitative exploration using online semistructured interviews. The interview guide (See 

which is included as a PDF at the end of this article.) was informed by Fischer et al’s framework,

 tested for content and construct, and refined iteratively by the research team that included clinicians, researchers, and people with lived experience of MS (n=9). Ethics approval was obtained through the University of Melbourne Human Research Ethics Committee (Ethics ID 2023-26508-41004-3). We report our findings using the Consolidated Criteria for Reporting Qualitative Research checklist.

Interviews were conducted by 1 of 3 researchers (I.W-B., junior medical doctor and researcher, female; C.H.M, researcher, female; and Y.C.L, researcher and physiotherapist, female) with relevant training and experience in interviewing for clinical practice and/or qualitative research. There was no established relationship between the interviewer and any participants, and participants did not have knowledge about the interviewer that may have impacted the interview. Although several authors have previously been involved in developing guidelines for MS management, none have any competing interests or biases relevant to this work.

MS clinicians were eligible to participate if they were neurologists or MS nurses currently delivering or overseeing health care for people with MS in Australia in a public and/or private capacity. The sample represents the main clinician groups who deliver MS care in Australia and are the primary target audience of most MS guidelines. Participants were recruited through convenience sampling, including direct emails to clinicians and MS clinics, newsletters and websites of professional bodies and MS societies, online social media, professional contacts of our research team (via email or verbal invitation), and snowballing recruitment.

Researchers conducted one-to-one, semistructured 20- to 40-minute interviews online between June 2023 and October 2023. Interviews were conducted and recorded using an online platform (ie, Zoom or Microsoft Teams, depending on participant preference). Verbal informed consent was obtained at the start of each interview. Transcripts were not returned to participants for comment, but participants were asked to email the interviewer if they had any additional thoughts.

Data were analyzed using an iterative deductive-inductive thematic approach.

 An initial coding tree was created a priori based on the framework by Fischer et al,

 with theme descriptions clarified by Cabana et al.

 Data were first coded deductively according to Fischer et al’s framework and further coded as barriers, facilitators, or preferences and needs. Inductive coding was then performed to create new codes for emerging themes and delete irrelevant codes. Two researchers (I.W-B., C.H.M.) independently coded 3 transcripts, discussed discrepancies to reach consensus and ensure reliability, and then consulted with a third researcher (Y.C.L.) to reach agreement on the draft coding structure. One researcher (I.W.B.) coded the remaining transcripts. We integrated the deductive and inductive coding to identify final themes (

). Exemplar quotes are provided with the participant’s profession and years in specialist practice. Data were managed using NVivo 14 (QSR 14.24.0, 2023).

We interviewed 10 MS nurses and 6 neurologists from public and private settings (11 women and 5 men); 10 had 10 or more years of neurology specialty experience (

Multiple sclerosis clinicians in Australia report that guideline application can improve standards of care but report varying practices in applying treatment guidelines.

Abiodun Emmanuel Akinwuntan, PhD, MPH

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