Background Interpretation of cognitive impairment (CI) in persons with multiple sclerosis (PwMS) is limited by discrepancies between objective and subjective evaluation. Objectives Evaluate relationships between subjective and objective cognitive measures, accounting for contributors. Methods Multiple Sclerosis Neuropsychological Questionnaire (MSNQ), patient-reported outcomes, Processing Speed Test (PST), Rey Auditory Verbal Learning (RAVLT), Visual Memory Test (VMT), Face Emotion Recognition (FER), Corsi, and Flanker test scores were collected. Spearman correlations, diagnostic metrics, and latent profile analysis assessed associations and cognitive phenotypes. Results In 83 PwMS, only 4.8–15.7% showed objective domain-specific CI, yet 42.2% reported significant CI. However, 51.8% had objective impairment in ≥1 domain. Compared with PwMS without objective or subjective CI, those with subjective but no objective CI had higher Hospital Anxiety Depression Scale-A (9.92 vs. 4.83) and D (8.23 vs. 2.88), and Fatigue Severity Scale (5.56 vs. 3.80) scores, p < 0.05. Latent profile analysis identified a performant cluster (C1, n = 36) and a less performant cluster (C2, n = 46) with higher mean z-scores on PST (0.46 vs. −0.70), VMT (0.32 vs. −0.54), RAVLT (0.99 vs. −0.06), and FER (0.57 vs. −0.80), p < 0.005, in C1. The MSNQ scores were similar between clusters. Conclusion A discrepancy between subjective and objective CI is observed. Subjective CI is associated with anxiety, depression, and fatigue. Multidomain testing and assessment of contributors may help reconcile this discrepancy.

BACKGROUND:Adult-onset genetic leukoencephalopathies are frequently misdiagnosed due to their overlap with more common acquired white matter diseases. The White Matter (WM) Rounds Network includes clinicians and scientists from more than 15 centers around the world who meet monthly to discuss undiagnosed white matter diseases. A key barrier to optimizing diagnosis that arose during these monthly discussions was the lack of MRI protocol standardization between institutions. We aimed to: 1) assess the state of practice of current MR protocols for investigating suspected genetic leukoencephalopathies and 2) propose a core standard protocol. METHODS:We used a Delphi method to facilitate group judgements. We submitted a survey for feedback to a panel of neuroimaging experts whose final version was circulated to the entire WM Rounds Network. The results were analyzed, and specific recommendations were put forward during Delphi rounds, for which the stop criterion was 75% agreement. KEY MESSAGE:The MR protocols had an average magnet time of 40 minutes (range 25-60) and included: 3-dimensional (3D) T1 MPRAGE and 3D FLAIR obtained in the sagittal plane, axial T2 and T2-FLAIR, axial DWI/ADC, and axial SWI. Cervical and thoracic spine imaging were also frequently performed. A standardized core imaging protocol inclusive of the above-listed sequences would help harmonize sequence acquisition across institutions and promote cost-effective optimization of the imaging work-up of adult-onset leukoencephalopathies. Four additional recommendations were proposed: 1) contrast-enhanced T1 sequences should be performed for patients with strong clinical and/or radiologic suspicion of adult genetic leukoencephalopathy; 2) cervical and thoracic spine MRI may provide diagnostic value; 3) head CT is of little added value and should not be included routinely; and 4) MR spectroscopy, diffusion tensor imaging, and other advanced imaging techniques are not yet ready to be implemented in the protocol but may be helpful in supporting a working diagnosis.

OBJECTIVE:Genetic white matter disorders may be difficult to distinguish from multiple sclerosis (MS). This article reviews the clinical and radiologic features of leukodystrophies in adults and how to differentiate them from MS. LATEST DEVELOPMENTS:The rapid implementation of next-generation sequencing techniques in clinical practice has led to an increasing number of adult patients diagnosed with leukodystrophies, often with expanded clinical and radiologic phenotypes that include features mimicking MS. Advances in neuroimaging tools allow for the identification of radiologic features that distinguish between genetic and acquired white matter disorders. ESSENTIAL POINTS:Although individually rare, adult-onset leukodystrophies represent a non-negligible diagnostic challenge to clinicians assessing patients for MS. Patients with adult-onset leukodystrophies often present with multifocal white matter involvement that may mimic MS lesions. Their variable clinical presentation, often characterized by progressive spasticity, ataxia, and cognitive decline, can overlap with that of primary progressive MS, further adding to the diagnostic challenge of correctly identifying these rare disorders. The impact on patients is considerable and extends from potential exposure to inappropriate immunomodulatory treatments to missing timely genetic counseling and targeted leukodystrophy-specific therapies. Thus, it is crucial to know clinical and radiologic red flags for adult-onset leukodystrophies that can assist the differential diagnosis.

Importance Cellular mechanisms underlying mitochondrial dysfunction, a hallmark feature of many neurodegenerative conditions, remain incompletely understood, and their true diversity is unknown. Objective To identify and functionally validate novel genetic variants causative of Leigh syndrome. Design We performed whole genome sequencing (WGS) and first-degree relative genotyping on two unrelated adult subjects with brain MRI abnormalities evoking Leigh syndrome. Blue native polyacrylamide gel electrophoresis (BN-PAGE) and respiratory chain enzymatic activity assays were performed to screen for respiratory complex assembly and/or oxidative phosphorylation impairments. Cells obtained from patient dermal and muscular biopsies were immortalized and later genetically corrected to evaluate cellular response to metabolic stress. Setting Subjects were recruited from The Neuro (McGill University), Rizk Hospital (Lebanese American University), and Centre Hospitalier Universitaire Sainte-Justine (University of Montreal). Research connections were established through the White Matter Rounds Network and GeneMatcher. Participants Four subjects representing three families with undiagnosed Leigh syndrome (age range 10-40 years) were ultimately recruited. Main outcome(s) and Measure(s) DNA sequencing uncovered a new autosomal recessive Leigh syndrome-associated gene that was functionally validated. Results Bi-allelic pathogenic variants in AMPD2 were detected in all subjects. BN-PAGE of patient skeletal muscle mitochondria captured an isolated complex V assembly defect in the context of mTOR activation, while the accompanying enzymological assays reported decreased activities of complexes I and IV. Opposite to controls, patient-derived cell lines lacked AMPD2 protein, attributing null status to the variants detected. During metabolic challenge, mutant cells suffered from mitochondrial hyperfusion and high-order cytosolic IMPDH2 oligomerization, implying simultaneous ATP accumulation and GTP deficiency. However, both complex V assembly and mTOR status were impervious to these conditions. All cellular phenotypes observed collectively reverted upon exogenous introduction of wild-type AMPD2. Conclusions and Relevance The recognition of AMPD2-related Leigh syndrome (AMPD2-LS) as a novel entity provides strong evidence for classifying AMPD2 deficiency as a mitochondrial disease. Our data suggest that respiratory capacity is significantly modulated by AMPD2, a cytosolic enzyme selectively regulating complex V assembly through an elusive process. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement JS has received scholarships from the Canadian Institutes of Health Research (CIHR) and the Fonds de Recherche du Quebec en Sante (FRQS). RLP has received a Research Scholar Junior 1 award from the FRQS, research funds for this study from the CIHR (grant 202309PJT-506913), the Canadian Radiological Foundation, and Hoffman-La Roche Limited. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of The Neuro (Montreal Neurological Institute-Hospital) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data in the present study are available upon reasonable request to the authors.

Several epidemiological and phenotypic differences in multiple sclerosis (MS) are observed across populations. The prevalence of MS is increasing in the Middle East and North Africa (MENA) region, in part due to better access to earlier diagnosis. Many MENA countries are now considered to fall in moderate to high MS risk zones. MS in MENA populations occurs at a younger age and is more severe, specifically in North African populations. Large disparities in MS care are observed among MENA countries. Access to care remains a significant obstacle in countries with low incomes, countries with active wars, and countries with a large number of refugees. The MENA MS population could serve as participants in the evaluation of several genetic, epigenetic, and environmental risk factors for MS. Indeed, low vitamin D levels due to reduced sun exposure in hijab-wearing women might explain the striking rising prevalence in Iran after the Islamic revolution, and the prevention of MS with vitamin D could be evaluated in this community. Moreover, because immigration is part of the history of MENA populations, it can serve as an archetype for the study of the impact of immigration on MS risk and severity. Unfortunately, MENA populations are underrepresented in clinical trials, limiting our understanding of this group. However, with the creation of the Middle East and North Africa Committee for Treatment and Research in Multiple Sclerosis and the emergence of highly specialized MS centers in several countries, better access to care and collaborative research efforts are expanding.

Cellular mechanisms underlying mitochondrial dysfunction, a hallmark feature of many neurodegenerative conditions, remain incompletely understood, and their true diversity is unknown. To identify and functionally validate novel genetic variants causative of Leigh syndrome. We performed whole genome sequencing (WGS) and first-degree relative genotyping on two unrelated adult subjects with brain MRI abnormalities evoking Leigh syndrome. Blue native polyacrylamide gel electrophoresis (BN-PAGE) and respiratory chain enzymatic activity assays were performed to screen for respiratory complex assembly and/or oxidative phosphorylation impairments. Cells obtained from patient dermal and muscular biopsies were immortalized and later genetically corrected to evaluate cellular response to metabolic stress. Subjects were recruited from The Neuro (McGill University), Rizk Hospital (Lebanese American University), and Centre Hospitalier Universitaire Sainte-Justine (University of Montreal). Research connections were established through the White Matter Rounds Network and GeneMatcher. Four subjects representing three families with undiagnosed Leigh syndrome (age range 10-40 years) were ultimately recruited. DNA sequencing uncovered a new autosomal recessive Leigh syndrome-associated gene that was functionally validated. Bi-allelic pathogenic variants in AMPD2 were detected in all subjects. BN-PAGE of patient skeletal muscle mitochondria captured an isolated complex V assembly defect in the context of heavy mTOR activation, while the accompanying enzymological assays reported decreased activities of complexes I and IV. Opposite to controls, patient-derived cell lines and muscle lacked AMPD2 protein, attributing null status to the variants detected. During metabolic challenge, only mutant cells suffered from mitochondrial hyperfusion and high-order cytosolic IMPDH2 oligomerization, implying simultaneous ATP accumulation and GTP deficiency. However, under these conditions, both complex V assembly and mTOR status in mutant cells and myotubes remained unchanged relative to the corrected lines. All mutant phenotypes observed collectively reverted upon exogenous introduction of wild-type AMPD2. The recognition of AMPD2 -related Leigh syndrome ( AMPD2 -LS) as a novel entity provides strong evidence for classifying AMPD2 deficiency as a mitochondrial disease. Our data suggest that respiratory capacity is significantly modulated by AMPD2, a cytosolic enzyme selectively regulating complex V assembly through an elusive process. Do AMPD2 mutations cause mitochondrial disease? In this case series, we found that four subjects from three families with molecularly unexplained Leigh syndrome carried bi-allelic, loss-of-function variants in AMPD2 , a gene not previously linked to mitochondrial disease. Biochemical analyses uncovered an isolated complex V assembly defect, providing diagnostic confirmation of a new entity: AMPD2 -related Leigh syndrome ( AMPD2 -LS). The cytosolic purine cycle is a primordial determinant of oxidative phosphorylation and mitochondrial health.

Background Immunosenescence is accelerated by chronic infectious and autoimmune diseases and could contribute to the pathobiology of multiple sclerosis (MS). How MS and disease-modifying therapies (DMTs) impact age-sensitive immune biomarkers is only partially understood. Methods We analyzed 771 serum samples from 147 healthy controls and 289 people with MS (PwMS) by multiplex immunoassays. We determined cytomegalovirus (CMV) serostatus and collected retrospective clinical information. We performed unsupervised and multivariable analyses. Findings Unsupervised analyses revealed that MS immune profile was characterized by low relative levels of antiinflammatory/neuroprotective factors IL-4, IL-10, TNF, and (3-NGF but high levels of growth factors EGF and bFGF. Serum levels of IL-4, (3-NGF, IL-27, BDNF, and leptin were significantly influenced by sex and/or CMV status. IL-4 and (3-NGF levels were lower in untreated PwMS compared to controls, while EGF and bFGF levels were influenced by age and markedly elevated in PwMS in multivariable analysis. Samples from treated PwMS, but not untreated PwMS, showed lower levels of BDNF and TNF than controls. Initiation of high efficacy DMTs, but not low efficacy DMTs, was associated with reduced levels of bFGF and EGF. Samples associated with distinct DMTs exhibited specific profiles for age-sensitive immune markers. Finally, lower levels of IL-6, TNF, IL-10, and (3-NGF were observed at baseline in PwMS who subsequently experienced clinical failure after DMTs initiation. Interpretation Age, sex, CMV status, and specific DMTs significantly influence levels of age-sensitive immune biomarkers associated with MS and must be considered when investigating inflammation-related biomarkers. Copyright (c) 2025 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).

Cognitive impairment (CI) is a common and disabling symptom in people with multiple sclerosis (PwMS), significantly affecting employment outcomes and quality of life. Despite its prevalence, routine assessment of CI is often hindered by limited access to comprehensive neuropsychological evaluations and challenges in interpreting subjective concerns. The relationship between objective and subjective measures of cognition is complex and often discordant. This review provides an overview focused on patient-reported CI, emphasizing on the association with objective measures of CI, the role of confounding factors, and the limitations of current screening approaches. Regardless of the underlying processes driving these concerns, patient-reported CI has a significant impact on day-to-day quality of life of PwMS and needs to be efficiently evaluated and addressed as several reversible causes can be managed efficiently when detected.

BACKGROUND:Adult-onset neurogenetic diseases (NGDs) with white matter abnormalities are rare and often misdiagnosed as Multiple Sclerosis (MS) due to overlapping clinical and radiological features. Misdiagnosis can lead to unnecessary immunosuppressive treatments and delayed genetic counseling. This study combines a retrospective multicenter analysis with a systematic review of the literature to assess the characteristics of patients with NGDs misdiagnosed as MS (Mis-MS) or with coexisting MS (NGD-MS), with the goal of improving diagnostic accuracy. METHODS:The retrospective study was conducted across seven tertiary MS centers in Europe and North America. Patients with confirmed NGDs initially misdiagnosed as MS or with coexisting MS were included. Clinical, radiological, and genetic data were analyzed. Brain MRIs were evaluated for MS-consistent and atypical features using standardized criteria. A systematic literature review of NGDs mimicking MS was also performed. RESULTS:The retrospective study included 46 patients (37 Mis-MS, 9 NGD-MS). Common NGDs in Mis-MS were Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) (22 %), Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (8 %), and Adult-onset Alexander Disease (AOAD) (5 %). NGD-MS cases were primarily mitochondrial disorders (67 %). The median diagnostic delay for NGDs was nine years. Despite 80 % of Mis-MS patients showing atypical MRI features, 41 % met MS dissemination in space and 20 % dissemination in time criteria. CSF oligoclonal bands were absent in 92 % of Mis-MS patients but present in 83 % of NGD-MS patients. Literature review identified 81 Mis- MS and 22 NGD-MS cases, with Fabry disease and CADASIL most frequently involved. DISCUSSION:Diagnosing NGDs that mimic MS is challenging. CADASIL, ALSP, and AOAD were the most commonly misdiagnosed neurogenetic diseases as MS. Vasculopathies like CADASIL are challenging to differentiate from MS due to similar clinical and imaging features, including remitting course and gadolinium enhancement. Recognizing atypical MRI patterns and integrating clinical and genetic evaluations can improve diagnostic accuracy and patient care by preventing unnecessary MS treatment and enabling timely genetic counseling.

Einleitung: Wir berichten über einen herausfordernden Fall von Autoimmunenzephalitis bei einem Patienten mit einem Thymom, das Titin- und Acetylcholinrezeptor-Antikörper enthielt. Trotz Thymektomie und aggressiver Erstlinien-Immuntherapie erlitt er mehrere Schübe. Letztendlich wurden GABAA-Rezeptor-Antikörper identifiziert. Falldarstellung: Dieser 40-jährige Mann wurde mit Kopfschmerzen, Schwäche, Diplopie, Hörverlust und Anfällen, die bis zum Status epilepticus reichten, vorstellig. Eine Magnetresonanztomografie (MRT) des Gehirns zeigte multifokale kortikale und subkortikale, in der T2/Fluid-Attenuated-Inversion-Recovery-Bildgebung hyperintensive Läsionen ohne Verbesserung. Bei anfänglichen neuronalen Antikörpertests wurden nur Acetylcholinrezeptor- und Titin-Antikörper identifiziert. Der Patient zeigte mehrere schwere Schübe trotz vollständiger Thymomresektion, intravenöser Gabe von Methylprednisolon mit Immunglobulinen oder Plasmapherese und Mycophenolat-Mofetil. Die Zweitlinien-Immuntherapie mit Rituximab linderte die Symptome und normalisierte die Elektroenzephalografie (EEG)- und MRT-Befunde nach der Identifizierung von Anti-GABAA-Rezeptor-Antikörpern durch die umfassenderen neuronalen Antikörpertests auf Autoimmunenzephalitis.

BACKGROUND: Cognitive impairment (CI) is common in multiple sclerosis (MS). Processing speed (PS) is often affected, making it an ideal target for monitoring CI. This study aims to evaluate the association between disease-modifying therapy (DMT) use and intensity and longitudinal changes in Processing Speed Test (PST) scores for individuals with MS. METHODS: A retrospective analysis of individual PST scores at a single MS center was conducted. Individuals with 2 or more PST assessments were included. Scores on the PST were compared longitudinally between those who had been on a DMT for 2 or more years and those who had been off a DMT for 2 or more years and between those on high-efficacy DMTs and those on low-/moderate-efficacy DMTs. A linear regression model was approximated to evaluate the rate of cognitive change over time. A propensity score adjustment was conducted using a multivariable logistic regression. RESULTS: The cohort was 642 individuals, 539 on DMT and 103 off DMT. Median age and disease duration was 49.7 (IQR 42.4-57.9) and 16.6 years (IQR 9.3-23.0) in the DMT group, and 58.9 (IQR 52.2-65.3) and 20.0 years (IQR 14.1-31.4) in the non-DMT group. Both cohorts were predominantly female (75% DMT, 79.6% non-DMT), with a mean of 4 assessments (IQR 3-5), and an average monitoring duration of 1.9 years (1.2-2.4) in the DMT group, and 1.8 years (1.4-2.4) in the non-DMT group. After adjusting for multiple factors, DMT status and intensity were not found to be significant predictors of longitudinal PST change. CONCLUSIONS: Neither DMT status nor intensity was a significant predictor of cognitive processing speed over a period of approximately 2 years. Future prospective studies are needed to further support these findings.

Introduction: We report a challenging case of autoimmune encephalitis in a patient with a thymoma harboring titin and acetylcholine receptor antibodies, who experienced multiple relapses despite thymectomy and aggressive first-line immunotherapy, and for whom GABAA receptor antibodies were ultimately identified. Case presentation: This 40-year-old man presented with headaches, weakness, diplopia, hearing loss and seizures progressing to status epilepticus. Brain MRI showed multifocal cortical and subcortical T2/fluid attenuated inversion recovery hyperintense lesions without enhancement. Initial neural antibody testing identified only acetylcholine receptor and titin antibodies. He presented multiple severe relapses despite complete thymoma resection, intravenous methylprednisolone with immunoglobulins or plasmapheresis, and mycophenolate mofetil. Second-line immunotherapy with rituximab was successful to alleviate symptoms and normalize the EEG and MRI after identification of anti-GABAA receptor antibodies on more comprehensive neural antibody testing for autoimmune encephalitis. Conclusion: This case demonstrates the complexity and importance of identifying pathogenic antibodies and selecting 2nd line treatment accordingly in patients with autoimmune encephalitis when multiple antibodies coexist. Despite tumor resection, aggressive immunotherapy may be needed to prevent further deterioration in anti-GABAA receptor encephalitis.

Background Effective communication between providers and people with multiple sclerosis (pwMS) is essential. Objectives To determine the level of concordance between provider- and pwMS-reported disease course. Methods Patient encounters from December 2015 through April 2020 were retrospectively reviewed for MS disease course self-reported by the patient and separately documented by the provider at each visit. The proportion of agreement was compared across disease course Cohen's kappa, and subsequently stratified by sex, race, and level education. Results Across 1335 encounters, the proportion of disease course agreement varied. Compared with RRMS, there was statistically significant difference across all other disease courses. Overall concordance between providers and pwMS was 64 % with a Cohen's kappa of 0.312. Concordance was higher amongst female patients, black patients, and patients with a higher level of education (>14 years). Conclusion Overall agreement on MS disease course amongst patients and providers was suboptimal. A concerted effort to understand these discrepancies is needed.

With a rapidly aging global population and improvement of outcomes with newer multiple sclerosis (MS)-specific disease-modifying therapies (DMTs), the epidemiology of MS has shifted to an older than previously described population, with a peak prevalence of the disease seen in the 55–65 years age group. Changes in the pathophysiology of MS appear to be age-dependent. Several studies have identified a consistent phase of disability worsening around the fifth decade of life. The latter appears to be independent of prior disease duration and inflammatory activity and concomitant to pathological changes from acute focal active demyelination to chronic smoldering plaques, slow-expanding lesions, and compartmentalized inflammation within the central nervous system (CNS). On the other hand, decreased CNS tissue reserve and poorer remyelinating capacity with aging lead to loss of relapse recovery potential. Aging with MS may imply longer exposure to DMTs, although treatment efficacy in patients >55 years has not been evaluated in pivotal randomized controlled trials and appears to decrease with age. Older individuals are more prone to adverse effects of DMTs, an important aspect of treatment individualization. Aging with MS also implies a higher global burden of comorbid illnesses that contribute to overall impairments and represent a crucial confounder in interpreting clinical worsening. Discontinuation of DMTs after age 55, when no evidence of clinical or radiological activity is detected, is currently under the spotlight. In this review, we will discuss the impact of aging on MS pathobiology, the effect of comorbidities and other confounders on clinical worsening, and focus on current therapeutic considerations in this age group.

Over the past decade, a considerable number of biomarkers have been evaluated in neurological disorders. In this review we provide a summary of various clinical, biological, genetic, and imaging biomarkers of multiple sclerosis with a focus on their clinical significance and utility.

La région du Moyen-Orient et de l'Afrique du Nord (MENA) est classiquement considérée comme une zone à prévalence faible à modérée de sclérose en plaques (SEP). Cependant, et en parallèle à l'augmentation mondiale de l'incidence et de la prévalence de la SEP, une augmentation similaire est observée dans la région MENA. Ceci est en partie secondaire à un diagnostic plus précoce, mais est aussi liée à une réelle augmentation de l'incidence de la SEP, pouvant être en lien avec l'urbanisation accrue des pays arabes (et par conséquent une diminution de l'exposition solaire, une exposition aux polluants, une augmentation du stress et du tabagisme, et une sédentarisation). Sur le plan phénotypique, les patients moyen-orientaux et d'Afrique du Nord atteints de SEP semblent avoir une présentation clinique plus agressive, atteignent des niveaux de handicap physique plus rapidement, et sont en moyenne plus jeunes au diagnostic que les patients Européens. D'autres particularités importantes sont à noter telle que la disponibilité des traitements et l'impact des conflits particulièrement violents qui impactent directement la prise en charge des personnes atteintes de maladies chroniques dans certains pays de la région. Le nombre massif de réfugiés déplacés dans des pays voisins déjà en difficulté économique entraîne un lourd impact sur les systèmes de santé des pays d'accueil. Un exemple illustratif est la crise des réfugiés syriens au Liban. Sur le plan de la recherche clinique, plusieurs obstacles limitent l'interprétation des données des essais cliniques et des études observationnelles ainsi que leur généralisation sur la population MENA, entre-autre, la sous-représentation des ces individus dans les essais contrôlés randomisés pivots et l'absence de « race arabe » dans les consensus américains de catégories raciales. Il pourrait en effet y avoir des différences génétiques et environnementales inhérentes à cette population qui pourraient altérer l'efficacité et le profil sécuritaire des traitements approuvés par les agences de santé occidentales.