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Pregnancy Outcomes from the Branded Glatiramer Acetate Pregnancy Database

Until the World Health Organization declared an end to COVID-19 as a global health emergency worldwide in 2023, people with multiple sclerosis (MS) were hesitant to get the COVID-19 vaccine. This study aimed to assess the final vaccination status, attitude, and adverse events related to the COVID-19 vaccine among people with MS in Egypt.

A self-administered survey was offered to people with MS who came to the Alexandria University MS Clinic in Egypt between June 2023 and November 2023.

Of 150 surveys completed, 77% of participants were women. Their median age was 35.5 years (range, 19-59 years); their median disease duration was 4 years. Only 81 (54%) participants received a COVID-19 vaccine. Of that 81, 81.5% received 2 doses. The median fear of COVID-19 score (FCV-19S) was 11, and 15.3% had high levels of fear. Worrying about the worsening effect of the vaccine on MS (69.3%) and about the long-term adverse events (AEs) of the vaccines (63.3%) were the most common causes of fear. The only factor that was significantly related to receiving the vaccine was the FCV-19S score (

 = .049). Among those who received the vaccine, fatigue was the most common AE reported in 48%; 5% had a neurological relapse. No other serious AEs occurred.

In this study, almost half of study participants with MS did not receive a COVID-19 vaccination, mainly due to fear. AEs attributed to the vaccine were mild. Implementing educational programs during future pandemics will be necessary to improve the vaccination rates of people with MS.

From the Department of Neurology (EH, SE-B) and the Department of Community Medicine (EHD), School of Medicine (AD [student]), Alexandria University, Alexandria, Egypt. 

Eman Hamdy, MD, PhD, 17 Champollion Street, Al-Azarrita, Al-Massalah Bab Sharq, Alexandria Governorate, Alexandria, Egypt; 

Even following the US Food and Drug Administration (FDA) approval of the SARS coronavirus 2 (COVID-19) vaccination in 2021,

 acceptance among global citizens varied.

 According to several studies, more than one-third of the population studied did not receive a COVID-19 vaccination despite the critical situation of the pandemic.

 Hesitancy about taking the vaccine was more prevalent among people with chronic illnesses, including those with multiple sclerosis (MS).

Clear guidance about the necessity and urgency of offering COVID-19 vaccines to people with MS was soon released,

 but some members of the MS community continued to have concerns about it.

 People with MS in Egypt had a high rate of vaccine hesitancy—26% at the peak of the pandemic.

 In May 2023, the World Health Organization (WHO) declared an end to COVID-19 as a global health emergency,

 but data about the final vaccination rate in Egypt are scarce. This study aims to uncover the 2023 COVID-19 vaccination status among a cohort of people with MS, their feelings and fears during and then following the pandemic, and any reported adverse events (AEs) from vaccination.

This was a cross-sectional, self-administered survey given to adults with MS seen at the Alexandria University MS Clinic between June 2023 and November 2023. People with relapsing MS (RMS) and progressive MS (PMS) were eligible.

The survey had 6 sections: (1) sociodemographic characteristics; (2) clinical data about the disease (eg, disease duration, phenotype, Patient-Determined Disease Steps [PDDS] score,

 number of relapses in the past year, and disease-modifying therapies [DMTs]); (3) fear of COVID-19 scale (FCV-19S) score

; (4) questions about prior exposure to COVID-19 and commitment to preventive measures; (5) previous vaccinations, DMTs, steroids, and attitudes toward the vaccine; (6) vaccine-related AEs and postvaccination relapses.

All data were analyzed using the IBM SPSS software package, version 20.0. For comparison based on data type, χ

, Monte Carlo, and Fisher exact tests were used.

Ethical approval was obtained from the ethics committee of Alexandria University School of Medicine (IRB no 0012098 [expires October 6, 2025]), which operates according to the International Conference on Harmonization Good Clinical Practice Guideline and applicable local and institutional regulations and guidelines. The ethics committee has a federal-wide assurance from 2010 (FWA no. 00018699 [expires January 21, 2026]).

Of 200 patients invited, 150 (75%) responded to the survey during the study period. The median age of the participants was 35.5 years (range, 19-59). Approximately 77% were women; 47% were highly educated (

). The median disease duration was 4 years (range, 0.019-22), and the median PDSS was 2 (range, 0-7). Approximately 54% (n = 81) received a COVID-19 vaccination (

). Sinopharm, Pfizer, and AstraZeneca vaccines were the most common brands given to 39.2%, 24.1%, and 19%, respectively (Table 1).

The median FCV-19S score was 11 (range, 7-35). Approximately 42.7% of the patients experienced COVID-19 symptoms, and 14.7% had positive COVID-19 tests. Two participants (1.3%) were hospitalized due to COVID-19 infection. The exposure data and commitment to infection control precautions are detailed in Table S2. Of 150 participants, 66 (44%) received 2 doses of COVID-19 and 69 (46%) did not receive any vaccines (Table S3).

Of those who did not receive the vaccine, 65.2% did not want to receive the vaccine at all. The main 2 causes were worries about making their MS worse (69.3%) and being worried about long-term AEs (63.3%) (Table S3).

Of the 81 people with MS who received the vaccine, 20 (24.7%) had a clinical relapse 1 month before vaccination; 16 (19.8%) received corticosteroids during the month before vaccination; and 3 (3.7%) postponed their DMT because of vaccination. They were on dimethyl fumarate, fingolimod, and rituximab. Of note, the only factor significantly related to vaccination state was FCV-19S scores. Two-thirds (65.2%) of patients with a high level of fear did not receive the vaccine vs 67.6% of those with moderate fear and 46.2% of those with low fear (

Fatigue was the most common AE, occurring in 48% of participants in general and in 32% after the second dose (

). Five (≈ 6.2%) people with MS who received the COVID-19 vaccination had a relapse following vaccination. The relapses were confirmed clinically but not radiologically. The details of those who had a relapse are compared with those who did not have a relapse in 

. Of note, relapse occurrence was higher for patients receiving immunosuppressants than for those receiving immunomodulatory DMTs. (All DMTs used were considered immunosuppressants except interferons.) Relapse symptoms are depicted in 

. Imbalance was the most common neurological symptom reported (18%). This was followed by weakness (15%), gait problems (15%), visual disturbances (14%), urinary or bowel symptoms (14%), and sensory symptoms (9%) (Figure 1B).

Although the COVID-19 pandemic is no longer a health emergency, it was essential to investigate vaccine hesitancy among the Egyptian people with MS to help develop regulations and educational programs for the future. We found that approximately only half of the Egyptian people with MS surveyed received the COVID-19 vaccine, mainly due to fear of potential AEs or a negative impact on their MS. In this cohort, 5% had an MS relapse, but no other serious AEs were reported.

Compared to the WHO's 70% vaccination target,

 the vaccination status among Egyptian people with MS is inadequate, especially taking into consideration that 27.3% of those who received the vaccine were forced to do so for work- or travel-related reasons. These numbers are similar to those reported by Ghanem et al,

 who studied 289 people with MS from Cairo and found a hesitancy rate of 26.3%. However, in their study of 160 Egyptian people with MS, Gad et al

 reported a vaccination rate of 40.6%. Although the vaccination rate was low among people with MS in Egypt (either in our study or in previous Egyptian studies

), the rate is slightly higher than that noted among the general Egyptian population, where about 49% (of 18,107 individuals interviewed) were vaccinated.

 This higher rate among people with MS may be due to better education from their neurologists or their perception that they are more vulnerable than people who do not have MS. Vaccination rates among people with other neurological disorders were similar, including immune-mediated diseases (59.2%)

 and other diseases such as cerebrovascular disorders (41.6%),

 People with MS in Egypt were more likely to receive a COVID-19 vaccination than those with stroke or epilepsy, but less likely to receive it compared to those with headache. Regardless, the vaccination rate in Egypt, whether among the general population or among patients with various neurological disorders, is low compared to the WHO target.

The vaccination numbers from Egypt are significantly lower than what has been reported in the literature. For instance, in a 2022 systematic review and meta-analysis of 5983 people with MS mainly from the United States, the United Kingdom, Ireland, Iran, and China, only 2% of people with MS were unwilling to receive COVID-19 vaccines.

 In a study of 4955 people with MS from the North American Research Committee on Multiple Sclerosis (NARCOMS), 84.1% received a COVID-19 vaccine.

 Similarly, of 193 people with MS in Germany, 84.5% and 78.2% received first and second COVID-19 vaccine doses, respectively.

 Data from 2 Australian health care services in 2021 showed a vaccination rate of 82.9% among 281 people with MS.

 The differences noted are likely due to fear and poor knowledge about the vaccine safety, efficacy, and potential AEs.

The case is different in other countries in the Middle East and North Africa (MENA) region. A cross-sectional study of 3041 people with MS from MENA reported a 60.2% willingness rate to receive a COVID-19 vaccine booster.

 Alroughani et al, in a study from Kuwait of 647 people with MS, reported a 59.28% vaccination rate.

 Felemban et al reported that 89.02% of 173 people with MS in Saudi Arabia received the vaccine.

 The only region where the vaccination rate was lower than our study was South Africa, with 17.5% of 394 people with MS receiving the COVID-19 vaccine.

 Although the rate was low, approximately 60.2% had a positive attitude toward vaccination. Here again it seems that the Egyptian population might need specific education as well as detailed studies to investigate what is engendering such a negative attitude toward vaccination.

Fear of vaccination was similar in our study to what has been reported in the literature. In the NARCOMS cohort, the reasons for not getting the COVID-19 vaccine were fear of potential AEs (47.7%), possible lack of efficacy (13.7%), and uncertainty about need for the vaccine (17.1%).

 And, unlike with our cohort, many factors were significantly correlated to receiving the vaccine, including older age, higher socioeconomic status, physical activity level, and DMT.

 Similarly, age, level of education, Expanded Disability Status Scale score, disease duration, depression, psychological status, and DMT use affected reception of COVID-19 vaccination.

 In a German study, concern about potential AEs was the most common reason to not get the vaccine (82.1%) followed by believing the vaccine was not adequately tested (64.3%).

 In an Australian study in 2021, young age and short disease duration (ie, 5 years or less) were the main factors determining the vaccination status.

 In Saudi Arabia, the main determinant for getting the COVID-19 vaccine was education level (

 In a Malawi study, the lack of knowledge about COVID-19 vaccination benefits and importance was the main factor in people choosing to not get the vaccine.

Vaccine AEs in our cohort were mild, with fatigue being the most commonly reported symptom by approximately half of the sample. The relapse rate following vaccination was 6.2%. Patients who had a relapse following vaccination were similar to those who did not experience a relapse except that they were on immunosuppressants. This might be attributed to the vulnerability of the host immune system increasing the risk of vaccine-induced inflammatory response and promoting a relapse. In an Egyptian cohort, the relapse rate following vaccination was 7.7%, and the prevalence of vaccine-related AEs was 33%, mainly in the form of injection-related reactions and general constitutional symptoms.

 In Western countries, the prevalence of AEs related to COVID-19 was 52.8%

 In the Kuwait cohort, 1.31% had relapses following vaccination.

Taken together, it is clear that the COVID-19 vaccination rate among people in Egypt with MS is poor. This is similar to the population in Egypt in general, but inadequate compared with international standards. Although the reported reason for poor vaccination is worry about the potential negative impact of the vaccine on their MS and their general health, in this study, the vaccine did not have any major negative impact on the MS disease or the general condition of the Egyptian cohort. Local educational programs about the importance and safety of vaccination should be provided for this vulnerable population. Further studies are also needed to investigate other potential causes of fear of vaccination among this population.

The main strength of this study is that it concerns people with MS in Egypt, a country with a large population but limited publications on this topic, and it is the first (to the best of our knowledge) to assess final vaccination status. The main limitation of the study is that it was performed after the peak of the COVID-19 pandemic. Still, the study's aim was to present the final vaccination state of a vulnerable group of the population and to demonstrate how excessive concerns over vaccine risks affect COVID-19 vaccine uptake.

More than half of the study cohort of people in Egypt with MS did not receive a COVID-19 vaccine mainly due to fear about its potential negative consequences on their MS disease progression; however, all vaccine-related AEs were mild. These findings emphasize the importance of implementing awareness and education programs for patients with chronic diseases in future pandemics.

Final COVID-19 Vaccination Status, Attitude, and Adverse Events Among People With Multiple Sclerosis: A Cross-Sectional Study From Egypt

 People with multiple sclerosis (MS) often experience psychiatric symptoms, such as anxiety and depression, that impact disease progression and quality of life. Cognitive impairment, particularly in processing speed and episodic memory, is common in MS. There are several studies studying the relationship between anxiety and cognition in the population with MS. This study reviews that literature.

This bibliographic review covers publications in Spanish and English from January 2006 to June 2022. It focuses on quantitative investigations of the relationship between anxiety symptoms and cognitive variables in people with MS.

A majority of studies found an association between anxiety and cognition in people with MS. Anxiety significantly affects information processing speed, learning, memory, attention, working memory, and verbal fluency in people with MS. However, some studies find no association. The impact of depressive symptoms and the bidirectional relationship between anxiety and cognition are highlighted.

Anxiety in people with MS is associated with cognitive impairment. Further research is needed to understand the mechanisms and establish causal relationships between anxiety and cognition in this population.

From the Demyelinating Diseases Working Group (CUEM), Neurology Division, Ramos Mejía Hospital, Buenos Aires, Argentina (RMS, NC, ALM, RA, MBE); and the Research Institute in Psychology, School of Psychology, Buenos Aires University, Buenos Aires, Argentina (NC, MBE). 

 María Bárbara Eizaguirre, JD, Perón 3051, La Matanza, Buenos Aires, Argentina. ZC: 1754; 

We extend our gratitude to the authors of the studies included in this review, whose work has greatly enriched our understanding of the subject.

Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. It is the most common cause of neurologic disability in young adults.

 Psychiatric manifestations, such as symptoms of anxiety and depression, are prevalent in people with MS and are associated with disease progression and a poorer quality of life.

 Although these manifestations are present in up to 60% of people with MS, they are often not adequately treated.

 In contrast, the prevalence of cognitive impairment in adults with MS ranges from 34% to 65% and symptoms vary according to the course of the disease.

 Cognitive impairment is also a neglected but common symptom with a profound effect on essential activities of daily living. Neuropsychological research suggests that cognitive processing speed and episodic memory are the most frequently affected cognitive domains.

MS can be described as a pathology with an uncertain outcome: a chronic, unpredictable neurological disorder with recurrent relapses (the most common form of MS, the relapsing-remitting MS phenotype) that seem to occur at random; it carries the risk of eventual progression to a chronic progressive disease after years or decades of stability. Therefore, it is quite possible that the unpredictable nature of this disease, particularly with regard to relapses and the potential for future progression and disability, causes anxiety.

Clinical anxiety is defined as an intermittent or persistent feeling of apprehension or fear that can be associated with physical symptoms, including tachycardia, sweating, palpitations, dizziness, and autonomic gastrointestinal symptoms.

 The severity of anxiety symptoms can be assessed in 2 ways: (1) via self-report scales or questionnaires that measure the patient's current self-perceive1d mood, such as the Hospital Anxiety and Depression Scale (HADS),

 or (2) through clinical reporting, such as the Structured Clinical Interview for the 

Diagnostic and Statistical Manual of Mental Disorders

 (SCID), which uses more formal diagnostic criteria to establish the presence of a possible or proven anxiety disorder.

 Studies indicate that between 30% and 50% of people with MS present with clinically significant anxiety

 and it is associated with negative health-related outcomes, such as lower adherence to treatment

; increased fatigue; physical, psychiatric, and social dysfunction

Depression is known to be a common comorbid symptom with anxiety in people with MS, and anxiety was found to be a strong predictor of depression through both direct and indirect pathways, suggesting a possible causal relationship.

 Although the role of each variable has been studied separately, recently, the presence of multiple comorbidities in people with MS has drawn the attention of clinicians and researchers, which has led to mediation studies

 that seek to understand the interaction of both variables and their relationship with cognition.

There is evidence of prefrontal cortical atrophy in people with MS who have anxiety, involving structures that resemble known neurobiological circuits of anxiety. MRI studies found an association between atrophy in the superior and middle gyri of the right frontal lobe and anxiety scores in people with MS.

 These findings clarify the appearance of anxiety as part of the pathology of the disease.

It is known that the influence of emotional stimuli—especially stimuli of a threatening or anxiogenic nature—interferes with performance in attention tasks, working memory, and cognitive inhibition.

 This is important for understanding the relationship between anxiety and cognition in MS; some authors have proposed that it is bidirectional or synergistic, which would imply that anxiety can negatively affect domains such as complex attention and processing speed, thus interrupting cognition. In addition, anxiety contributes to slower processing speed, which creates anxiety symptoms and, therefore, negatively affects cognition.

 The neuropsychological findings regarding the relationship between anxiety and cognition are not consistent, both those that refer to people without MS

 Is it possible to identify a neuropsychological profile and establish a characteristic pattern of functioning across the different cognitive domains in people with anxiety and MS? We conducted a narrative review of the bibliography available to date on the relationship between anxiety and cognition in people with MS to investigate.

We searched for the following terms in PubMed and the Scientific Electronic Library online (SciELO): 

anxiety symptoms, neuropsychiatric disorders

. We selected articles published from January 2006 to June 2022 that quantitatively investigated the relationship between anxiety symptoms and 1 or more cognitive variables in people with MS. The search yielded 53 articles. After discarding 10 papers that addressed anxiety and cognition outside the scope of MS and 8 that addressed anxiety and MS but did not include cognitive variables, 35 studies remained (

Anxiety is a complex construct that implies a multidimensional conceptualization. It includes physiological, behavioral, cognitive, and affective variables; thus, its evaluation requires the assessment of multiple dimensions.

 Indeed, in the MS clinic, anxiety symptoms can be measured in many ways, for example, indirectly by taking standardized interviews that complement psychopathology and mental health manuals, such as the Schedules for Clinical Assessment in Neuropsychiatry

 Another possibility is using scales, questionnaires, and inventories, including subjective measures such as the patient's self-report, to complete what is referenced in the medical records and in the direct objective measures of the physiological and behavioral dimension of the anxiety spectrum.

 Some of these scales and questionnaires are used as early detection or screening tools and may require additional evaluation to confirm a diagnosis.

 Several of these instruments have been validated to measure anxiety in people with MS: the Hamilton Anxiety Rating Scale,

 the State-Trait Anxiety Inventory (STAI),

 Because some common symptoms of MS, eg, tingling, dizziness, or muscle tension, can overlap with the somatic symptoms of anxiety and lead to misclassification or overestimation of anxiety presentations or criterion contamination, investigators of the Canadian Institutes of Health Research

 evaluated the validity and reliability of dimensional measures of anxiety in people with MS and concluded that the HADS anxiety subscale (HADS-A) is a reliable assessment with greater sensitivity and specificity for people with MS than other tools, such as the BAI or the Generalized Anxiety Disorder 7-Item scale.

 We found that the HADS-A cutoff points used for other medical populations were also appropriate for those with MS. Scores greater than or equal to 8 indicate clinically significant anxiety, while scores greater than or equal to 11 indicate an anxiety disorder with a sensitivity of 88.5% and a specificity of 80.7%.

 Of the 35 articles reviewed, 21 used the HADS-A to measure clinically significant anxiety,

 1 used the Mental Health Inventory with the Neuroticism scale from the NEO Five-Factor Inventory,

 1 used the Depression Anxiety Stress Scales,

 and 1 used the Zung Self-Rating Anxiety Scale.

 Only 5 of the studies supplemented the anxiety measures with evaluations from standardized neuropsychiatric interviews for anxiety disorders (SCID)

 and only 2 added a second tool to measure anxiety, the Symptom Checklist-90-Revised with the HADS

 and the Penn State Worry Questionnaire with the STAI.

Prevalence of Anxiety Disorders and Anxiety Symptoms in MS: Associated Factors

According to previous studies, the prevalence of anxiety is 3 times higher in people with MS than in the general population.

 A prevalence rate close to 30% was replicated in a cross-sectional study from 2018 in a sample of 244 people with MS in Canada. That study found that higher odds of anxiety were associated with depression, low levels of education, and impaired quality of life.

 The RELACCEM study, a multicenter investigation that evaluated neuropsychiatric symptoms among participants from Argentina, Chile, Colombia, Mexico, Uruguay, and Venezuela, found that anxiety symptoms were present in up to 33% of people with MS.

 An Argentinian cross-sectional study that evaluated 88 people with MS found that 45% of their sample presented with anxiety and anxiety was significantly associated with younger age, shorter time from diagnosis, history of other psychiatric disorders, depression, and poor quality of life.

 A recent systematic review with a meta-analysis found that the overall prevalence of anxiety in people with MS is 35.19%, which is higher than the prevalence reported in previous studies.

 This review also found that anxiety is more prevalent in different clinical forms of MS—21.40% in relapsingremitting MS (RRMS) and 24.07% in progressive MS (PMS)—than depression (15.78% in RRMS and 19.13% in PMS).

Relationship Between Anxiety and Cognition in MS

In the field of MS, neuropsychological batteries are used to assess cognition, including the classic Brief Repeatable Battery for Neuropsychological evaluation (BRB-N) by Rao,

 or the Minimal Assessment of Cognitive Function in MS (MACFIMS),

 which assess attention, working memory, learning, and verbal and visual episodic memory, as well as verbal fluency. MACFIMS can also be used to assess executive functions and visuospatial processing. In 2012, a committee of experts proposed the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) as a brief, practical, and universal cognitive assessment instrument.

 Some of the studies included in this review used one of these cognitive assessment batteries: 8 used the BRB-N,

 Other studies used different neuropsychological batteries or combinations of tests to measure 1 or more domains in particular: Three used tests from the Behavioural Assessment of the Dysexecutive Syndrome (BADS),

 3 evaluated using portions of the Test of Everyday Attention (TEA),

 2 used the Montreal Cognitive Assessment,

 2 used the Neuropsychological Screening Battery for MS,

 1 used the Luria–Nebraska Neuropsychological Battery,

 11 used a set of tests selected ad hoc or as a screening method,

 2 evaluated only 1 area or cognitive domain,

 and lastly, 2 used computerized batteries.

Studies investigating the association between anxiety and cognition in MS trend toward 3 different conclusions: confirming that anxiety is a predictor of cognitive functioning (12 cross-sectional studies

); finding that anxiety predicts subjective cognitive functioning, ie, the perception of cognitive impairment or cognitive difficulties (12 cross-sectional studies

); and finding no association between anxiety and cognition (5 cross-sectional studies

Studies confirming the association between anxiety and cognition in MS

. Several studies found that cognitive dysfunction correlates significantly with an increase in anxiety,

 or that anxiety independently predicts objective cognitive performance.

 One longitudinal study even suggests that anxiety is a significant predictor of cognitive changes over time.

 A recent article, with a 2-year follow-up, found that correlations between scores on anxiety and cognitive measures (HADS and BICAMS) were not significant at baseline, but weak to moderate negative correlations were found at follow-ups after 1 and 2 years.

 A subsequent article, with a 3-year follow-up, found that at any point in time, individuals with high anxiety symptoms exhibited lower performance in processing speed, verbal learning, and working memory.

 Other current cross-sectional studies also confirm that anxiety correlates with certain measures of cognitive functioning.

Information processing speed appears in several investigations as the function most affected by anxiety.

 Cross-sectional studies that included the Symbol Digit Modalities Test,

 to measure information processing speed, reported that people with MS who had anxiety were less efficient on executive tasks, particularly tasks that included a processing speed component.

 Another study that controlled for associated demographic and clinical factors, such as depression and fatigue, reported that anxiety in people with MS was independently related to lower information processing speed.

 Similarly, a significant difference was found in measures of processing speed in people with MS who had anxiety compared with people with MS who did not have anxiety.

 Another study found that lower disability, shorter disease duration, and lower levels of anxiety predicted performance in processing speed.

 This relationship was also found in a longitudinal study that followed the evolution of cognitive measures and values of associated clinical factors for 3 years in 4 cohorts of people with inflammatory diseases, including MS.

 These authors concluded that, at any point in time, individuals with high symptoms of anxiety exhibited lower processing speed. Vissicchio et al

 conducted 2 mediation analyses to explore the relationships between anxiety, processing speed, and verbal learning. The first analysis revealed that anxiety affects verbal learning through processing speed. The second analysis established that processing speed influences verbal learning while being mediated by anxiety. The results suggest a bidirectional relationship between anxiety and processing speed, with both factors influencing performance in verbal learning.

Different findings confirm that verbal episodic memory and visual episodic memory are 2 of the cognitive domains affected or interfered with by anxiety.

 A longitudinal study exploring cognitive changes in people with MS, who were assessed at baseline and after 1 year of followup, found that baseline measures of negative affect, including depressed mood and anxiety, tended to more strongly predict changes (25% of variability) in verbal and visuospatial episodic memory measures; however, the relationship between negative affect and cognition was not reciprocal.

 Another cross-sectional study showed that, in combination with gender, age, and disability, anxiety explained 24% of the variance in the memory domain in people with MS.

 A study that investigated the established relationship between anxiety and verbal learning and memory in people with MS found that anxiety was a significant predictor of deficits in verbal learning.

 Likewise, other studies found that high anxiety present in people with RRMS or in the early stages of the disease was associated with cognitive memory impairment and language disorders.

 A recent paper that studied the relationship between cognitive impairment, sleep disorders, and the role of anxiety and depression among people with MS established that memory scores were negatively correlated with state anxiety, whereas a high level of trait anxiety moderated the relationship between waking up at night and worse memory performance.

 Recent studies also report that a current diagnosis of anxiety disorder or elevated anxiety symptoms, even in the absence of a diagnosed anxiety disorder, were associated with reduced information processing speed, lower working memory performance, and lower learning and verbal memory performance.

 A 2016 study agreed that there was a relationship between anxiety and visual episodic memory and concluded that levels of impairment measured by the HADS-A were significantly related to measures of visual episodic memory, as well as visual episodic memory processing speed and working memory.

 Other articles identify strong relationships between cognition and mood and suggest that both anxiety and depression correlate with cognition in MS, even though they both have dissociable cognitive patterns: A lower level of anxiety is associated with better visual memory while a lower level of depression is related to better attention and information processing speed.

Several studies concluded that complex attention—either sustained or divided attention—and working memory are also affected by anxiety.

 Previous research examining the impact of anxiety on the cognitive performance of people with MS found that anxiety as a state, measured by the STAI, predicted performance on the executive functioning index.

 Likewise, anxiety has been independently related to lower performance in complex attention tasks and information speed processing

 as well as alterations in inhibition processes, verbal fluency, and practical-constructive problem solving.

 Other studies also found a significant difference between loading measures for working memory in anxious and nonanxious people with MS.

 A recent study showed that disease duration, physical disability, and high levels of state anxiety significantly and negatively predict performance on the Paced Auditory Serial Addition Test (PASAT), a test validated among the population with MS that requires complex attention and working memory.

 Similarly, 2 of the papers cited above found that self-reported anxiety symptoms were associated with lower working memory performance and processing speed.

Most of the aforementioned studies included language tests, but only 2

 found that anxiety measures were associated with language measures, and more specifically, with verbal fluency tasks. One concluded that high levels of anxiety and depression can be predictors of alterations in phonological and semantic verbal fluency.

 The other, seeking to establish cognitive phenotypes in people with MS, indicated that elevated anxiety are present in people with RRMS, people in the early stages of the disease, and people with memory and language disorders.

Studies that find association between anxiety and subjective cognitive impairment in MS. 

Twelve articles indicate that anxiety, along with other clinical variables (depression, fatigue, etc), in people with MS makes them more likely to report cognitive difficulties.

 In 10 of these studies, depression was present, suggesting that this variable could be involved in subjective rather than objective measures of cognition. Cross-sectional and longitudinal research studies have investigated the relationship between anxiety and subjective measures of cognitive impairment in MS using, for the most part, self-report questionnaires such as the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ),

 the Cognitive Failures Questionnaire (CFQ),

 the Prospective and Retrospective Memory Questionnaire (PRMQ),

Magnhild Sandberg-Wollheim, MD, PhD

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