Paramagnetic rim lesions and the central vein sign: Characterizing multiple sclerosis imaging markers.

BACKGROUND AND PURPOSE: Paramagnetic rims and the central vein sign (CVS) are proposed imaging markers of multiple sclerosis (MS) lesions. Using 7 tesla magnetic resonance imaging, we aimed to: (1) characterize the appearance of paramagnetic rim lesions (PRLs); (2) assess whether PRLs and the CVS are associated with higher levels of MS pathology; and (3) compare the characteristics between subjects with and without PRLs in early MS. METHODS: Prospective study of 32 treatment-naïve subjects around the time of diagnosis who were assessed for the presence of PRLs and the CVS. Comparisons of lesion volume and macromolecular pool size ratio (PSR) index, a proxy of myelin integrity, between PRLs and non-PRLs, and CVS-positive and CVS-negative lesions were carried out. Differences in clinical/demographic characteristics between patients with PRLs and those without were tested. RESULTS: Fifteen subjects had ≥1 PRL for a total of 36 PRLs, of which two-thirds had a full rim. PRLs predicted a larger lesion size and decreased PSR signal. Lesion volume and presence of cervical spine lesions were significantly different between subjects with PRLs and those without, although neither remained significant after adjusting for multiple comparisons. One hundred and eighty-one lesions with CVS were identified with no differences between CVS-positive and CVS-negative lesions in volume (p = .27) and PSR values (p = .62). CONCLUSIONS: PRLs, but not CVS-positive lesions, are larger and have lower myelin integrity. Our findings indicate that PRLs are associated with higher levels of lesion-specific pathology prior to the start of disease-modifying therapy.

Pregnancy outcomes and postpartum relapse rates in women with RRMS treated with alemtuzumab in the phase 2 and 3 clinical development program over 16 years.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) is frequently diagnosed in women of reproductive age. Because the use of disease-modifying therapies (DMTs) early in the disease course is increasing, it is important to evaluate the safety of DMTs in pregnant women and their developing fetuses. Alemtuzumab, approved for the treatment of relapsing forms of MS, is administered as 2 courses of 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Alemtuzumab is eliminated from the body within approximately 30 days after administration; it is recommended that women of childbearing potential use effective contraception during and for 4 months after treatment. Here, we report pregnancy outcomes in alemtuzumab-treated women from the phase 2 and 3 clinical development program over 16 years. METHODS: We followed 972 women who had alemtuzumab in phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies, and/or in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). In the extension studies, patients could receive additional alemtuzumab (12 mg/day on 3 days; ≥12 months apart) as needed for disease activity. All women who received alemtuzumab in the clinical development program were included. Pregnant or lactating patients were followed up for safety. RESULTS: As of November 26, 2018, 264 pregnancies occurred in 160 alemtuzumab-treated women, with a mean age at conception of 32.6 years, and mean time from last alemtuzumab dose to conception of 35.9 months. Of the 264 pregnancies, 233 (88%) were completed, 11 (4%) were ongoing, and 20 (8%) had unknown outcomes; 16 (6%) conceptions occurred within 4 months, and 5 conceptions within 1 month of the last alemtuzumab dose. Of the 233 completed pregnancies with known outcomes, there were 155 (67%) live births with no congenital abnormalities or birth defects, 52 (22%) spontaneous abortions, 25 (11%) elective abortions, and 1 (0.4%) stillbirth. Maternal age was associated with an increased risk of spontaneous abortion in alemtuzumab-treated patients (<35 years: 15%; ≥35 years: 37%; relative risk [RR], 2.46 [95% CI: 1.53-3.95], p=0.0002). Risk of spontaneous abortion was not increased in patients becoming pregnant ≤4 months versus >4 months since alemtuzumab exposure (19% vs 23%; RR, 1.08 [95% CI: 0.41-2.85], p=0.88). Autoimmune thyroid adverse events did not increase risk for spontaneous abortion (patients with vs without thyroid adverse events, 23.7% vs 21.3%; RR, 1.11 [95% CI: 0.69-1.80], p=0.75). Annualized relapse rate was 0.10 and 0.12 in the 2 years prior to pregnancy (post alemtuzumab), and was 0.22, 0.12, and 0.12 in each of the first 3 years postpartum, respectively. CONCLUSION: Normal live births were the most common outcome in women exposed to alemtuzumab 12 mg or 24 mg in clinical studies. Spontaneous abortion rate in alemtuzumab-treated patients was comparable with rates in the general population and treatment-naive MS patients, and was not increased in women with pregnancy onset within 4 months of alemtuzumab exposure. There was a minimal increase in postpartum relapses.

Future treatment approaches to multiple sclerosis.

The modern treatment era for multiple sclerosis (MS) began in 1993 with the approval of the first disease-modifying agent. Since then the field has greatly expanded, with 10 therapies currently approved to treat MS. These treatments are effective to reduce relapses and changes on MRI, and slow disability. However, despite these medications some patients continue to have exacerbations, accumulate disability, and develop progressive disease due to partial effectiveness. New molecules with novel mechanisms of action and targets are being explored. Hopefully these agents will yield even greater efficacy without significant safety concerns. As more aggressive therapies are available to treat MS, the goals and expectations of treatment are also likely to change. Some of the emerging therapies, including alemtuzumab, daclizumab, rituximab, ocrelizumab, laquinimod, estriol, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), vitamin D, and stem cell transplantation, will be discussed in this chapter. In the future, therapies with different mechanisms may be combined, but this will need to be evaluated in clinical trials. Neuroprotection and repair definitely warrant further study. The future of MS treatment is very exciting, especially as our armamentarium expands.

Presentation of neuromyelitis optica spectrum disorder after more than twenty years of systemic sclerosis.

Neuromyelitis optica is an autoimmune disorder characterized by optic neuritis, transverse myelitis, and aquaporin-4 autoantibodies. The term "neuromyelitis optica spectrum disorder" refers neuromyelitis optica features occurring in association with other systemic rheumatologic conditions. We present a case of a 51-year-old woman with long-standing systemic sclerosis who developed transverse myelitis in association with the presence aquaporin-4 autoantibodies. This is the first report case of neuromyelitis optica spectrum disorder associated with systemic sclerosis. Given that patients with neuromyelitis optica spectrum disorder with aquaporin-4 autoantibodies have a high risk for clinical relapse, this report underscores the need for recognition of this disorder in patients with systemic sclerosis and neurological dysfunction.

Current disease-modifying treatment of multiple sclerosis.

The treatment era for multiple sclerosis began in 1993 with the approval of the first disease-modifying therapy. This changed the management of multiple sclerosis from treating acute exacerbations to focusing on preventive therapeutic options that lessen the risk for exacerbations, changes on magnetic resonance imaging, and disability as measured by the Expanded Disability Status Scale. Currently, there are 8 therapies approved to treat multiple sclerosis: beta-interferons (Avonex, Betaseron, Extavia, and Rebif), fingolimod (Gilenya), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), and natalizumab (Tysabri). These agents will be reviewed including the pivotal trial data, mechanisms of action, and side effects. The timing of beginning therapy and selection of these agents must be individualized for each patient depending upon patient preference, tolerability, clinical and magnetic resonance imaging disease activity, and disease course. All of the current treatments are approved for relapsing disease. To date only the injectable agents, including interferons and glatiramer acetate, have been shown to be of benefit when started after an initial demyelinating event referred to as clinically isolated syndrome. Mitoxantrone was approved for progressive relapsing and secondary progressive multiple sclerosis, although its use is limited by potential risks such as cardiotoxicity and leukemia. Although these agents have made a significant impact on the treatment of multiple sclerosis, they are often only partially effective, so patients may continue to have disease activity. Multiple new agents are currently being tested in clinical trials and it is likely our treatment paradigms will change as more effective therapies become available.

Abnormal eye movements predict disability in MS: two-year follow-up.

We conducted a two-year follow-up study of 40 patients with MS in whom we had reported that abnormal eye movements (AEM) were associated with greater general disability. AEM patients (17/40) remained significantly (p < .001) more disabled (median EDSS of 7.0) than those with normal eye movements (median EDSS of 5.0). AEM and great disability were associated with abnormal MRI signals in brainstem or cerebellum, where disease may involve control circuits for eye movements as well as descending motor pathways.

Role of eye movement examination and subjective visual vertical in clinical evaluation of multiple sclerosis.

BACKGROUND AND PURPOSE: Modern neuroimaging has demonstrated progression of disease in multiple sclerosis (MS) that may not be detected by standard clinical protocols, prompting a search for new, sensitive tests. METHODS: In fifty patients with MS, we examined eye movements, with particular attention to the speed and accuracy of saccades, and the vestibulo-ocular reflex during small, high-speed head rotations. We also measured the subjective visual vertical (SVV), using a modified laser-pointer. Visual function was measured, and patients were graded using the Kurtzke Functional Neurological Status (FSS), and Expanded Disability Status Scale (EDSS). RESULTS: Our main finding was that patients showing abnormalities of eye movements (20/50) were more disabled than those with a normal examination (EDSS scores significantly different, p < 0.01), although the ages and duration of disease were similar in both groups. Saccadic dysmetria and internuclear ophthalmoparesis were common. SVV was abnormally large in 36 % of patients; these showed abnormal eye movements and poorer visual acuity more commonly than those with normal SVV. In patients with the largest deviations of SVV, Kurtzke FSS cerebellar functions were significantly worse (p = 0.021). CONCLUSIONS: Clinical examination of eye movements, with attention to dynamic properties of saccades and the vestibulo-ocular reflex, takes only a few minutes to perform, but may provide better information concerning the presence of brainstem and cerebellar involvement than Kurtzke protocols. Measurement of SVV is possible in the clinic and is a sensitive sign of brainstem dysfunction; our present study suggests that SVV is also affected when cerebellar circuits are involved in MS. Prospective studies are required to determine whether the development of abnormalities with ocular motor and SVV testing are predictive of disease activity and progressive disability in MS.