Katelyn Kavak

Higher weight in adolescence and young adulthood is associated with an earlier age at multiple sclerosis onset

Background: Growing evidence suggests an association between adolescent obesity and increased risk of multiple sclerosis (MS). Objective: The objective of this paper is to investigate whether weight or body mass index (BMI) in adolescence and young adulthood was associated with age at MS symptom onset. Methods: Our cohort is comprised of a sub-group of 184 women enrolled in the New York State MS Consortium registry. Individuals were asked to recall their weight at the time of first menstruation and at age 25. BMI was calculated accordingly for age 25. Regression analyses were carried out to investigate the association between weight or BMI and age at onset. Results: Weight at menarche was significantly related to younger age at symptom onset (β = −0.073, p = 0.001). These results were also found at age 25 for weight (β = −0.080, p < 0.001) and BMI (β = −0.448, p = 0.001). Significantly earlier disease onset (26.9 years ±9.9) was observed in individuals who were overweight at 25 compared to those who were not overweight (32.1 years ±9.2, p = 0.006). Conclusions: Women who reported higher weight in adolescence and BMI in early adulthood were younger at MS onset. Future research should investigate whether there is a causal link between body weight and MS, as prevention lifestyle and dietary interventions could be implemented.

Randomised natalizumab discontinuation study: taper protocol may prevent disease reactivation

Objectives To compare two modes of natalizumab cessation interventions: immediate versus tapered down, as measured by serial MRI and the occurrence of relapses during a 12-month period. Background Weighing progressive multifocal encephalopathy risk associated with ≥24 months of natalizumab therapy against the benefits of disease control, we initiated a natalizumab discontinuation study. Methods A phase IV, 12-month, single-blinded randomised (MRI) study. Fifty relapsing patients with multiple sclerosis (MS) who had been on natalizumab therapy ≥24 months and were contemplating natalizumab discontinuation were enrolled. Participants were randomised to either the immediate discontinuation group (IDG) or the tapered group (TG). IDG discontinued natalizumab at once and initiated another disease modifying therapy (DMT) following the last natalizumab infusion, while the TG received two more natalizumab infusions, at 6 and 8 weeks (14 weeks from study entry) before initiating another DMT. Standardised MRI was performed at baseline, 6 and 12 months from the last natalizumab infusion. Results A higher rate of relapses in the IDG (n=28) compared to the TG (n=8) over 12 months from the last infusion (p=0.007) was observed, most relapses occurred within 3 months of discontinuation (20 vs 7 relapses, p=0.012). The IDG showed a higher number of new T2 lesions within 6–12 months of discontinuation (p=0.025), a higher mean absolute T2-LV change from 0 to 12 months (1.1 vs 0.1 mL, p=0.024) and a higher number of new T1-hypointense lesions over 0–12 months (p=0.005) as well as from baseline to 6 months (p=0.026) compared to the TG. Conclusions Natalizumab discontinuation therapy was associated with development of new disease activity. Our tapered protocol showed benefits, as patients in the TG experienced less relapses and lower accumulation of MRI lesions compared to those in the IDG.

Parity Associated with Long-Term Disease Progression in Women with Multiple Sclerosis

Background: Pregnancy in multiple sclerosis (MS) is marked by a decrease in relapse activity with a corresponding rebound in the first months postpartum. Because MS typically occurs during childbearing years, it is important to determine the long term effect of pregnancy. Design/Methods: Subjects were part of the New York State Multiple Sclerosis Consortium registry. 1,195 parous and 328 nulliparous women with clinically definite MS age 45 or older were analyzed to determine time to a disability milestone, Expanded Disability Status Scale (EDSS) 6.0. A Cox proportional hazards model was used to examine the effect of parity on time from MS disease onset to EDSS 6.0, adjusted for confounding factors. Results: The average disease duration for 1,523 women was 18.1 years. During a mean follow-up period of 5.6 years 23.1% of the parous group reached EDSS 6.0, compared to 26.5% of the nulliparous women. Cox survival curves between parous and nulliparous women were significantly different (HR=.68, CI=.53-.87, p=.002), with parous women showing a longer time to reach the disability outcome. Follow-up analyses stratified by MS type showed that parity remained a significant predictor of disease progression in relapsing remitting (RRMS) patients, whereas this effect was not observed within progressive subtypes. Conclusions: Our results demonstrate that parous women with RRMS take a longer time to reach a well-defined disability milestone (i.e. use of cane) compared to nulliparous women, suggesting that pregnancy may convey a long term benefit. Further research is needed to determine why pregnancy might be protective against long term MS disability progression.

Decreased risk of cancer in multiple sclerosis patients and analysis of the effect of disease modifying therapies on cancer risk

BACKGROUND Although dysimmunity is considered an important link between multiple sclerosis (MS), family history and cancer risk, their relationship to the use of disease modifying therapies (DMT) is not fully understood. OBJECTIVE To assess the observed versus expected number of cancers in MS patients, and family history of cancer, among DMT users and DMT naïve patients. METHODS Cancer, DMT use, and family history of cancer were assessed using the New York State Multiple Sclerosis Consortium (NYSMSC) registry. Self-reported cancers in MS patients were tested for associations with DMT use, family history of cancer and other factors. Expected number of cancer cases was estimated using age- and gender-specific prevalence and incidence rates from the general population. RESULTS The prevalence of cancer in males and females in the NYSMSC cohort was lower than expected (p<0.001). Patients with cancer were older at MS diagnosis and more likely to be female (p<0.001). MS patients with a personal history of cancer were more likely to report DMT use (p<0.001) and family history of cancer (p<0.001). Multivariable analysis did not support a higher risk of cancer after DMT initiation. CONCLUSIONS We report a lower than expected number of cancer cases in MS patients compared to the general population. MS patients with a personal history of cancer were more likely to report DMT use suggesting that DMTs may abrogate the lower incidence of cancer in MS.

Disease modifying therapies use associated with comorbid autoimmune diseases in multiple sclerosis patients

BACKGROUND The relation between the use of disease modifying therapies (DMT׳s) and the occurrence of comorbid autoimmune diseases (AID׳s) in multiple sclerosis (MS) patients is still unclear. OBJECTIVE To investigate the difference in duration from MS symptom onset to first reported AID in subjects using DMT׳s vs. DMT naïve. Type and prevalence of comorbid AID׳s was also investigated. METHODS Data was extracted from the New York State MS Consortium (NYSMSC) registry and comprised of MS patients with a minimum of 5 years follow-up. After exclusion, 1792 patients were enrolled in the study, 1478 had no AID, and 314 patients had comorbid AID׳s that developed after the initial enrollment. Patients who had an AID were divided into two groups: those with an AID after DMT initiation (n=281) and patients with an AID who were DMT naïve (n=33). Logistic regression analysis was used to test differences in duration between MS symptom onset and the development of AID between the two groups while adjusting for confounders RESULTS DMT use did not change the frequency of self-reported AID (17.2 vs. 20.4%). However, the duration between first MS symptom onset and the initial reported occurrence of a comorbid AID was significantly shorter in the DMT user group (192 months±115) compared to the DMT naïve group (262 months±107, p=.002). CONCLUSION There were no group differences between DMT users vs. DMT naïve subjects with regards to AID frequency. The DMT user group reported the development of an AID earlier than the DMT naïve group. Further studies that can identify patients with higher risk for developing AID׳s is warranted.

Characteristics influencing therapy switch behavior after suboptimal response to first-line treatment in patients with multiple sclerosis

Background: Factors driving disease-modifying therapy (DMT) switch behavior are not well understood. Objective: The objective of this paper is to identify patient characteristics and clinical events predictive of therapy switching in patients with suboptimal response to DMT. Methods: This retrospective study analyzed patients with relapsing–remitting multiple sclerosis (MS) and a suboptimal response to initial therapy with either interferon β or glatiramer acetate. Suboptimal responders were defined as patients with ≥1 MS event (clinical relapse, worsening disability, or MRI worsening) while on DMT. Switchers were defined as those who changed DMT within six to 12 months after the MS event. Results: Of 606 suboptimal responders, 214 (35.3%) switched therapy. Switchers were younger at symptom onset (p = 0.012), MS diagnosis (p = 0.004), DMT initiation (p < 0.001), and first MS event (p = 0.011) compared with nonswitchers. Compared with one relapse alone, MRI worsening alone most strongly predicted switch behavior (odds ratio 6.3; 95% CI, 3.1–12.9; p < 0.001), followed by ≥2 relapses (2.8; 95% CI, 1.1–7.3; p = 0.040), EDSS plus MRI worsening (2.5; 95% CI, 1.1–5.9; p = 0.031) and EDSS worsening alone (2.2; 95% CI, 1.2–4.1; p = 0.009). Conclusions: Younger patients with disease activity, especially MRI changes, are more likely to have their therapy switched sooner than patients who are older at the time of MS diagnosis and DMT initiation.

Ketogenic diet: Predictors of seizure control:

Background: The ketogenic diet is an effective non-pharmacologic treatment for medically resistant epilepsy. The aim of this study was to identify any predictors that may influence the response of ketogenic diet. Methods: A retrospective chart review for all patients with medically resistant epilepsy was performed at a tertiary care epilepsy center from 1996 to 2012. Patient- and diet-related variables were evaluated with respect to seizure reduction at 1, 3, 6, 9 and 12-month intervals and divided into four possible outcome classes. Results: Sixty-three patients met inclusion. Thirty-seven (59%) reported >50% seizure reduction at 3 months with 44% and 37% patients benefiting at 6-month and 12-month follow up, respectively. A trend toward significant seizure improvement was noted in 48% patients with seizure onset >1 year at 12-month (p = 0.09) interval and in 62% patients with >10 seizure/day at 6-month interval (p = 0.054). An ordinal logistic regression showed later age of seizure to have higher odds of favorable response at 1-month (p = 0.005) and 3-month (p = 0.013) follow up. Patients with non-fasting diet induction were more likely to have a favorable outcome at 6 months (p = 0.008) as do females (p = 0.037) and those treated with higher fat ratio diet (p = 0.034). Conclusion: Our study reports the effectiveness of ketogenic diet in children with medically resistant epilepsy. Later age of seizure onset, female gender, higher ketogenic diet ratio and non-fasting induction were associated with better odds of improved seizure outcome. A larger cohort is required to confirm these findings.

Low-Dose Medication and Long-Term Outcome in Myasthenia Gravis.

Objectives: Many advances have been made in the diagnosis, treatment, and management of myasthenia gravis (MG) and most patients will eventually progress to experience minimal manifestations (MM) of the disease or remission. However, there is a paucity of literature on medication dosing needed to achieve such a favorable clinical status in the long term. The objective of this article was to (1) study the course of MG and identify clinical predictors of maintenance of eventual disease remission or minimal manifestations and (2) determine if patients on low-dose medications have comparable MG Foundation of America (MGFA) scores and postintervention statuses (PIS) with those on conventional therapeutic dosing. Methods: This is a retrospective longitudinal chart review of 74 patients with MG. A subset of 28 of 74 patients diagnosed with MG after 2000 who were followed for at least 3 consecutive years from the year of diagnosis were also analyzed. An annual MGFA score, PIS, medication doses, and thymectomy status were obtained. Remission or MM of disease was defined as MGFA clinical classification <2 that persisted over the past 2 follow-up visits. Results: Thirty-four of 74 patients were on low-dose medications at last follow-up. There was no statistical difference between medication dosages and MGFA scores. In a subset of 28 patients, 23 (88.5%) with eventual disease remission or MM at last follow-up had an MGFA class <2 at their third year of diagnosis. In contrast, only 3 of 9 subjects with more symptomatic disease had similar results (P = 0.005). In terms of PIS at last follow-up, most patients were either in complete stable remission, pharmacologic remission, or MM status. Most patients (78.3%) had an MGFA class of 0 or 1 at last follow-up; 45% were on low-dose medications. Conclusions: Most patients with MG will realize disease stability characterized by either remission or MM status. A significant number of such patients were able to be maintained on low doses of medications to treat MG. The MGFA class at year 3 of diagnosis is a clinical predictor of long-term disease prognosis. There was no statistical difference between medication doses and MGFA scores at last follow-up.

Walking disability measures in multiple sclerosis patients: Correlations with MRI-derived global and microstructural damage

BACKGROUND The relationship between walking disability in multiple sclerosis (MS) patients and their macro- and microstructural MRI-derived measures still remains unclear. OBJECTIVE To assess the correlations between walking disability and MRI-derived lesion, atrophy, and microstructural/axonal integrity outcomes. METHODS Seventy-one (71) MS patients were clinically examined, the expanded timed get-up and go (ETGUG), and timed 25-foot walk (T25FW) tests were assessed. Additionally, the Symbol Digit Modalities Test (SDMT) was obtained. Normalized brain (NBV), gray matter (GMV), white matter (WMV), cortex (CV), and deep GM (DGM) volumes, as well as lesion volumes (LV) and diffusion tensor imaging (DTI) scalar maps of fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity were calculated. Spearman correlation, partial correlation and stepwise regression analyses were performed. RESULTS T25FW and ETGUG were associated with T2-LV (p < .001), global (NBV, p < .001), tissue-specific (GMV and CV, p < .001) and regional (DGM p < .001; and thalamus p < .001) volumes. The ETGUG remained correlated with T1-LV, GMV, CV and total DGM volume (all p < .001) after age, sex, and disease duration adjustment. The WMV was not associated with walking disability. Similarly, DTI measures did not show significant association with the walking tests. The regression analysis outlined DMG volume as best predictor of T25FW (Adj R2 = 0.231, standardized β = -0.435, and p = .001), and CV for ETGUG (Adj R2 = 0.176, standardized β = -0.417, and p = .004). SDMT was associated with both T25FW (p = .004) and ETGUG (p = .013). CONCLUSION Despite the low disability levels, walking as measured by T25FW and ETGUG, is largely explained by the loss of cortical and nuclei specific GM volumes.

Treatment Considerations in Female MS Patients of Reproductive Age

Women of childbearing age are the most prevalent group of multiple sclerosis (MS) patients. Clear management guidelines for this population of patients regarding contraception, conception, pregnancy, and postpartum period are not available. This chapter reviews the current state of knowledge and offers some guidance on family planning matters as they relate to disease state and available MS therapeutics.