Lilyana Amezcua

Blood-brain barrier breakdown in the aging human hippocampus.

UNLABELLED The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimers disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment. VIDEO ABSTRACT

Pregnancy and fetal outcomes following natalizumab exposure in pregnancy. A prospective, controlled observational study

Background: Safety data on first-trimester natalizumab exposure are scarce, as natalizumab is usually withdrawn three months before pregnancy. Objective: The objective of this paper is to investigate the fetal safety of exposure to natalizumab (Tysabri®) during the first trimester of pregnancy using disease-matched (DM) and healthy control (HC) comparison groups. Methods: A total of 101 German women with RRMS exposed to natalizumab during the first trimester of pregnancy were identified. Birth outcomes in the exposed group were compared to a DM group (N = 78) with or without exposure to other disease-modifying drugs, and an HC group (N = 97). Results: A total of 77, 69 and 92 live births occurred in the Exposed, DM and HC groups, respectively. The rates of major malformations (p = 0.67), low birth weight (<2500 grams) (p = 1.0) and premature birth (p = 0.37) did not differ among groups. Higher miscarriage rates (p = 0.002) and lower birth weights (p = 0.001) occurred among the Exposed and DM groups, as compared to the HC; however, there was no significant difference between the Exposed and DM groups. Conclusion: Exposure to natalizumab in early pregnancy does not appear to increase the risk of adverse pregnancy outcomes in comparison to a DM group not exposed to natalizumab.

Prevalence of Neurobehavioral, Social, and Emotional Dysfunction in Patients Treated for Childhood Craniopharyngioma: A Systematic Literature Review

Background Craniopharyngiomas (CP) are locally invasive and frequently recurring neoplasms often resulting in neurological and endocrinological dysfunction in children. In addition, social-behavioral impairment is commonly reported following treatment for childhood CP, yet remains to be fully understood. The authors aimed to further characterize the prevalence of neurobehavioral, social, and emotional dysfunction in survivors of childhood craniopharyngiomas. Materials and Methods A systematic literature review was conducted in PubMed to identify studies formally assessing neurobehavioral, social, and emotional outcomes in patients treated for CP prior to 18 years of age. Studies published between the years 1990-2012 that reported the primary outcome (prevalence of neurobehavioral, social, emotional/affective dysfunction, and/or impaired quality of life (QoL)) in ≥10 patients were included. Results Of the 471 studies screened, 11 met inclusion criteria. Overall neurobehavioral dysfunction was reported in 51 of 90 patients (57%) with available data. Social impairment (i.e. withdrawal, internalizing behavior) was reported in 91 of 222 cases (41%). School dysfunction was reported in 48 of 136 patients (35%). Emotional/affective dysfunction was reported in 58 of 146 patients (40%), primarily consisting of depressive symptoms. Health related quality of life was affected in 49 of 95 patients (52%). Common descriptors of behavior in affected children included irritability, impulsivity, aggressiveness, and emotional outbursts. Conclusions Neurobehavioral, social, and emotional impairment is highly prevalent in survivors of childhood craniopharyngioma, and often affects quality of life. Thorough neurobehavioral/emotional screening and appropriate counseling is recommended in this population. Additional research is warranted to identify risk factors and treatment strategies for these disorders.

Multiple sclerosis in Hispanics: a study of clinical disease expression

Background: Hispanics living with multiple sclerosis (MS) in the United States are not well defined. Objective: To describe the clinical characteristics of MS among Hispanic Whites (HW) in Southern California with those of non-Hispanic Whites (NHW). Methods: We performed a medical chart review to identify all cases of HW with MS (n = 125) who were treated at our institution during a 1-year period. We also identified cases of NHW with MS (100 NHW) treated at those clinics. All HW patients were interviewed to ascertain ancestry including detailed migration history. Disease progression was assessed by ambulatory disability and defined as Expanded Disability Status Scale (EDSS) score ≥6. Results: Compared with NHW, HW were more likely to have a relapsing–remitting form of MS and a younger age of onset (28.4 ± 0.97 years) with presenting symptoms of optic neuritis and transverse myelitis. However, overall ambulatory disability did not differ between HW and NHW. Migration to the US at age >15 years was associated with increased risk of disability in HW. Conclusions: HW living in the USA may be at risk of developing MS at an earlier age compared with NHW. Migration history can play an important role in the management of HW with MS.

Multiple sclerosis in US minority populations: Clinical practice insights

The heterogeneity of multiple sclerosis (MS) characteristics among various ethnic minority populations is a topic of recent interest. However, these populations are consistently underrepresented in clinical trials, leading to limited data on the effectiveness of treatments in these groups of patients and lack of an evidence-based approach to treatment. In order to achieve optimal disease management in the ethnic minority MS populations, a better understanding of the regional, socioeconomic, and cultural influences that result in underrepresentation of these groups in clinical trials is needed. Furthermore, it would be beneficial to identify the genetic factors that influence disease disparity in these minority populations. Suggestions for the identification and implementation of best practices for fostering the trust of ethnic minority patients with MS and enhancing their participation in clinical trials are offered.

Clinical Characteristics of Pediatric-Onset and Adult-Onset Multiple Sclerosis in Hispanic Americans

Multiple sclerosis can affect pediatric patients. Our aim was to compare characteristics between pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanic Americans. This was a cross-sectional analysis of 363 Hispanic American multiple scleroses cases; demographic and clinical characteristics were analyzed. A total of 110 Hispanic patients presented with multiple sclerosis before age 18 and 253 as adult multiple sclerosis. The most common presenting symptoms for both was optic neuritis. Polyfocal symptoms, seizures, and cognitive symptoms at presentation were more prevalent in pediatric-onset multiple sclerosis (P ≤ .001). Transverse myelitis was more frequent in adult-onset multiple sclerosis (P ≤ .001). Using multivariable analysis, pediatric-onset multiple sclerosis (adjusted odds ratio, 0.3OR 95% confidence interval 0.16-0.71, P = .004) and being US born (adjusted odds ratio, 0.553, 95% confidence interval 0.3-1.03, P = .006) were less likely to have severe ambulatory disability. Results suggest that pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanics have differences that could be important for treatment and prognosis.

Adrenocorticotropic hormone versus methylprednisolone added to interferon β in patients with multiple sclerosis experiencing breakthrough disease: a randomized, rater-blinded trial

Background: The objective of this study was to evaluate monthly intramuscular adrenocorticotropic hormone (ACTH) gel versus intravenous methylprednisolone (IVMP) add-on therapy to interferon β for breakthrough disease in patients with relapsing forms of multiple sclerosis. Methods: This was a prospective, open-label, examiner-blinded, 15-month pilot study evaluating patients with Expanded Disability Status Scale (EDSS) score 3.0–6.5 and at least one clinical relapse or new T2 or gadolinium-enhanced lesion in the previous year. Twenty-three patients were randomized to ACTH (n = 12) or IVMP (n = 11) and completed the study. The primary outcome measure was the cumulative number of relapses. Secondary outcomes included EDSS, Mental Health Inventory (MHI), plasma cytokines, MS Functional Composite (MSFC), Quality-of-Life (MS-QOL) score, bone mineral density (BMD), and new or worsened psychiatric symptoms per month. Brain magnetic resonance imaging was analyzed post hoc. This was a preliminary and small-scale study. Results: Relapse rates differed significantly [ACTH 0.08, 95% confidence interval (CI) 0.01–0.54 versus IVMP 0.80, 95% CI 0.36–1.75; rate ratio, IVMP versus ACTH: 9.56, 95% CI 1.23–74.6; p = 0.03]. ACTH improved (p = 0.03) MHI (slope 0.95 ± 0.38 points/month; p = 0.02 versus slope −0.38 ± 0.43 points/month; p = 0.39). On-study decreases (all p < 0.05) in eight cytokine levels occurred only in the ACTH group. However, on-study EDSS, MSFC, MS-QOL, BMD, and MRI lesion changes were not significant between groups. Psychiatric symptoms per patient were greater with IVMP than ACTH (0.55, 95% CI 0.12–2.6 versus 0; p < 0.0001). Other common adverse events were insomnia and urinary tract infections (IVMP, seven events each) and fatigue or flu symptoms (ACTH, five events each). Conclusions: This study provided class II evidence that ACTH produced better examiner-assessed cumulative rates of relapses per patient than IVMP in the adjunctive treatment of breakthrough disease in multiple sclerosis.

Headaches in multiple sclerosis: Cross-sectional study of a multiethnic population

OBJECTIVES Headaches in MS are common, but there is little data on the influence of race, comorbidities, MS disability and socioeconomic issues on headaches, especially migraine. We aimed at looking at prevalence and type of headache across a multiethnic MS population, and relationship between MS related clinical factors and migraine. PATIENTS AND METHODS This is a cross-sectional study of 233 MS patients at two clinical sites, one at a county hospital, and the other a private academic center clinic. We collected demographic data, MS characteristics, and headache histories using validated survey instruments including Headache Impact Test (HIT-6) and Patient Health Questionnaire-9 (PHQ-9). The relationship between MS and migraine was examined using logistic regression. RESULTS Majority of our patients were female (N=156, 67%), average age 44 years, with relapsing remitting MS (N=214, 92%). Our cohort was multi-ethnic predominantly Whites (N=106, 46%) and Hispanics (N=87, 37%). Public sector patients were significantly disadvantaged in socioeconomic measures (p<0.0001) and younger (40 vs 47 yrs, p<0.0001), compared to the private sector patients who had a higher MS burden. Headaches were common, regardless of sector (N=115, 49.4%), the most common type being migraine (N=83, 36%). Chronic migraine was more common among Hispanics (82%) than Whites (18.2%) (p=0.012). Headache impact on daily life, measured by HIT-6 score (p=0.006) and PHQ-9 score (p=0.004) were significantly higher in the public sector. After controlling for income and education, female gender (OR 2.59, 95% CIs 1.312-5.127) and ambulatory disability were found to be more likely to suffer from migraines. CONCLUSION Headache, especially migraine is common among MS patients regardless of socio-economic status and treatment setting. Female MS patients with walking disability and longer disease duration tend to get migraines. Hispanic MS patients have a higher likelihood of suffering from chronic migraines. Thorough headache evaluation and headache treatment are essential to comprehensive MS care.

Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility: A multiethnic study

Objective: To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis. Methods: Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for HLA-DRB1*1501 status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth. Results: Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups (p < 0.001 for blacks and whites, p = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics (p = 0.004) but not in blacks (p = 0.95) or whites (p = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics (p = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics. Conclusions: The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations.

Ethnic Considerations and Multiple Sclerosis Disease Variability in the United States

Minorities in the United States such as African Americans and Hispanics may have more severe disease than non-Hispanic whites. Factors contributing to these disparities are reviewed. The variations in disability from non-Hispanic whites may be the result of differences in clinical presentation, genetic underpinnings, and sociocultural factors. Creating awareness and increasing participation in research studies may improve our understanding.