Multiple Sclerosis.

Many groundbreaking advances have occurred in the field of multiple sclerosis since this series last reviewed the disorder in 2014. The U.S. Food and Drug Administration has approved 7 new medications for relapsing-remitting multiple sclerosis and approved the first medication for primary progressive multiple sclerosis. The McDonald criteria for diagnosing multiple sclerosis were updated in 2017. New blood tests can now differentiate patients with multiple sclerosis from those with neuromyelitis optica spectrum disorder, and 3 new medications have been approved specifically for the latter disorder. Also, new medications for treating the symptoms of multiple sclerosis have been introduced.

Development of Neuromyelitis Optica Spectrum Disorder and Spinal Arachnoid Cysts in a Patient With Intractable Epilepsy.

Neuromyelitis optica is an inflammatory, demyelinating disease of the central nervous system that is characterized by severe relapsing attacks of optic neuritis and transverse myelitis. The current case describes a 29-year-old man with intractable epilepsy and diplegic spastic cerebral palsy who was given the diagnosis of neuromyelitis optica spectrum disorder after presenting with weakness, incontinence, and decreased visual acuity. His symptoms recurred 21 months after initial presentation. Magnetic resonance imaging of his spine revealed arachnoid cysts with regional mass effects. Differentiation of arachnoid cysts from a demyelinating process may be difficult in the early stages of the disease. Close monitoring of patients with neuromyelitis optica spectrum disorder is important, especially in patients with recurrent or refractory symptoms.

Triosephosphate isomerase- and glyceraldehyde-3-phosphate dehydrogenase-reactive autoantibodies in the cerebrospinal fluid of patients with multiple sclerosis.

Our previous results revealed that Igs in lesions and single chain variable fragment Abs (scFv-Abs) generated from clonal B cells in the cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) bind to axons in MS brains. To study the axonal Ags involved in MS, we identified the glycolytic enzymes, triosephosphate isomerase (TPI) and GAPDH, using Igs from the CSF and scFv-Abs generated from clonal B cells in the CSF and in lesions from MS patients. Elevated levels of CSF-Abs to TPI were observed in patients with MS (46%), clinically isolated syndrome (CIS) suggestive of MS (40%), other inflammatory neurological diseases (OIND; 29%), and other noninflammatory neurological diseases (ONIND; 31%). Levels of GAPDH-reactive Abs were elevated in MS patients (60%), in patients with CIS (10%), OIND (14%), and ONIND (8%). The coexistence of both autoantibodies was detected in 10 MS patients (29%), and 1 CIS patient (3%), but not in patients with OIND/ONIND. Two scFv-Abs generated from the CSF and from lesions of a MS brain showed immunoreactivity to TPI and GAPDH, respectively. The findings suggest that TPI and GAPDH may be candidate Ags for an autoimmune response to neurons and axons in MS.

Diagnosis and management of multiple sclerosis: case studies.

Although substantial capabilities have emerged in the ability to globally manage patients who have MS, clinicians continue to be confronted with formidable challenges. Reduction in disease activity and its impact on dis-ability progression remains the central objective of disease-modifying therapy and most current MS research initiatives. Nevertheless, the principal factors that determine the day-to-day limitations on functional capabilities(activities of daily living, work performance, quality of life, and so forth)are a derivative of the pathophysiology of the disease process itself. The substrate for these limitations is inherent in the pathology of demyelination and axonal dysfunction. Identifying measures that can optimize the performance and fidelity of axonal conduction mechanisms may translate into a reduction in MS-related symptoms. Chronic neurologic disease management (with MS representing a signature example) can be optimized when all members of the care team (including patients and their families) collaborate in the co-ordination of interdisciplinary care models that address all aspects of suffering.

Recent use of oral contraceptives and the risk of multiple sclerosis.

BACKGROUND: Exogenous estrogens affect the onset and clinical course of experimental allergic encephalomyelitis. Oral contraceptives, a frequent source of exogenous estrogens in humans, could have a role in the development of multiple sclerosis (MS). OBJECTIVE: To examine whether recent oral contraceptive use and pregnancy history are associated with the risk of MS. DESIGN AND SETTING: A case-control study nested in the General Practice Research Database. This database contains prospective health information (drug prescriptions and clinical diagnoses) on more than 3 million Britons who are enrolled with selected general practitioners. PARTICIPANTS: One hundred six female incident cases of MS, younger than 50 years, with at least 3 years of continuous recording in the General Practice Research Database before the date of first symptoms (index date), identified between January 1, 1993, and December 31, 2000, and 1001 controls matched on age, practice, and date of joining the practice. Main Outcome Measure Incidence of first symptoms of MS, confirmed through medical records. RESULTS: The incidence of MS was 40% lower (odds ratio, 0.6; 95% confidence interval, 0.4-1.0) in oral contraceptive users compared with nonusers during the previous 3 years. The risk of MS increased in the 6 months after pregnancy (odds ratio, 2.9, 95% confidence interval, 1.2-6.6), but it was not otherwise related to parity. CONCLUSIONS: The hormonal changes that occur during oral contraceptive use and pregnancy may be associated with a short-term reduction in the risk of MS, and the postpartum period may be associated with a short-term increase in the risk of MS.

Clonal expansion of IgA-positive plasma cells and axon-reactive antibodies in MS lesions.

Immunoglobulin A (IgA), the predominant immunoglobulin class in mucosal secretions, has been found in the cerebrospinal fluid of patients with multiple sclerosis (MS). In this study we examined the infiltration of clonally expanded IgA plasma cells in lesions of MS brains. Sequences of complementarity-determining region 3 of IgA variable heavy chain (V(H)) genes demonstrated the clonal expansion of IgA-bearing plasma cells in MS lesions. Somatic mutations and ongoing intra-clonal mutations occurred in their V(H) genes. Immunohistochemical study demonstrated infiltration of dimer and polymer IgA1- and A2-positive plasma cells in perivascular spaces, in the parenchyma of MS lesions, and in the adjacent white matter. Double immunofluorescence staining showed binding of IgA antibody on axons and walls of microvessels in the areas of chronic active and inactive demyelination. Bielshowsky's silver impregnation revealed axonal damage in these areas. These findings suggest that IgA in the CNS are localized on axons in lesions and may contribute to axonal damage in MS.

Axon reactive B cells clonally expanded in the cerebrospinal fluid of patients with multiple sclerosis.

Demyelination and axonal loss have been described as the histological hallmarks of inflammatory lesions of multiple sclerosis (MS) and are the pathological correlates of persistent disability. However, the immune mechanisms underlying axonal damage in MS remain unknown. Here, we report the use of single chain-variable domain fragments (scFv) from clonally expanded cerebrospinal fluid (CSF) B cells to show the role of an anti-axon immune response in the central nervous system (CNS) in MS. The cellular and subcellular distribution of the antigen(s) recognized by these CSF-derived clonal scFv antibodies (CSFC-scFv Abs) was studied by immunochemical staining of brain tissues obtained at autopsy from patients with MS. Immunochemistry showed specific binding of CSFC-scFv Abs to axons in acute MS lesions. The stained axons showed three major types of axonal pathological changes: 1) linear axons, axonal ovoid formation, and axonal transection were seen in the myelinated white matter adjacent to the lesion; 2) accumulation of axonal ovoid formations and Wallerian degeneration were seen at the border between demyelinated lesions and the adjacent white matter; and 3) Wallerian degeneration occurred at the center and edge of acute demyelinated lesions. These findings suggest a B cell axonal specific immune response in the CNS in MS.

Cigarette smoking and the progression of multiple sclerosis.

An increased risk of multiple sclerosis among smokers has been found in several prospective epidemiological studies. The association between smoking and progression of multiple sclerosis has not been examined. We identified patients who had a first multiple sclerosis diagnosis recorded in the General Practice Research Database (GPRD) between January 1993 and December 2000. Their diagnosis and date of first symptoms were confirmed through examination of medical records. Smoking status was obtained from the computer records. To assess the association between smoking and risk of multiple sclerosis, we conducted a case-control study nested in the GPRD. Up to 10 controls per case were randomly selected, matched on age, sex, practice, date of joining the practice and availability of smoking data. To assess the association between smoking and progression of multiple sclerosis, we conducted a cohort study of multiple sclerosis cases with a relapsing-remitting onset. Our nested case-control study included 201 cases of multiple sclerosis and 1913 controls. The odds ratio [95% confidence interval (CI)] of multiple sclerosis was 1.3 (1.0-1.7) for ever smokers compared with never smokers. Our cohort study included 179 cases with a mean (median) length of follow-up of 5.3 (5.3) years. The hazard ratio of secondary progression was 3.6 (95% CI 1.3-9.9) for ever smokers compared with never smokers. These results support the hypothesis that cigarette smoking is associated with an increased risk of multiple sclerosis, and suggest that smoking may be a risk factor for transforming a relapsing-remitting clinical course into a secondary progressive course.

Polyclonal B-cell expansion in the cerebrospinal fluid of patients with pseudotumor cerebri.

To investigate the hypothesis that pseudotumor cerebri (PTC) is associated with humoral immunity, we analyzed immunoglobulin heavy chain variable region (Ig-VH) genes of B cells in the cerebrospinal fluid (CSF) of 10 patients with PTC. Using RT-PCR and sequencing techniques, intrathecal B-cell Ig-VH genes were amplified in 6 of 10 PTC samples. Sequence analysis of complementarity-determining region 3 (CDR 3) and VH genes revealed a polyclonal intrathecal B-cell expansion in these patients. The nucleotide sequences showed that one-third of analyzed sequences had a high replacement to silent nucleotide substitution ratio, indicating an antigen-driven T-cell-dependent intrathecal B-cell proliferation. Moreover, other one-third had germline VH genes without or with a few nucleotide mutations, suggesting a T-cell-independent natural B-cell-mediated humoral immunity in the CNS of these patients. Our results suggest that both T-cell-dependent and T-cell-independent humoral immunity are present in the CSF of PTC.

Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study.

BACKGROUND: A potential link between the recombinant hepatitis B vaccine and an increased risk of multiple sclerosis (MS) has been evaluated in several studies, but some of them have substantial methodologic limitations. METHODS: The authors conducted a nested case-control study within the General Practice Research Database (GPRD) in the United Kingdom. The authors identified patients who had a first MS diagnosis recorded in the GPRD between January 1993 and December 2000. Cases were patients with a diagnosis of MS confirmed through examination of medical records, and with at least 3 years of continuous recording in the GPRD before their date of first symptoms (index date). Up to 10 controls per case were randomly selected, matched on age, sex, practice, and date of joining the practice. Information on receipt of immunizations was obtained from the computer records. RESULTS: The analyses include 163 cases of MS and 1,604 controls. The OR of MS for vaccination within 3 years before the index date compared to no vaccination was 3.1 (95% CI 1.5, 6.3). No increased risk of MS was associated with tetanus and influenza vaccinations. CONCLUSIONS: These findings are consistent with the hypothesis that immunization with the recombinant hepatitis B vaccine is associated with an increased risk of MS, and challenge the idea that the relation between hepatitis B vaccination and risk of MS is well understood.

Intrathecal B-cell clonal expansion, an early sign of humoral immunity, in the cerebrospinal fluid of patients with clinically isolated syndrome suggestive of multiple sclerosis.

The development of somatically mutated memory and plasma B cells is a consequence of T cell-dependent antigen-challenged humoral immunity. To investigate the role of B cell-mediated humoral immunity in the initiation and evolution of multiple sclerosis (MS), we analyzed Ig variable heavy chain genes of intrathecal B cells derived from patients with a first clinical manifestation suggestive of MS. Sequences of Ig variable regions showed that B cells in the cerebrospinal fluid from most of these patients were clonally expanded and carried somatic hypermutated variable heavy chain genes. The mutations showed a high replacement-to-silent ratio and were distributed in a way suggesting that these clonally expanded B cells had been positively selected through their antigen receptor. In comparison, intrathecal B-cell clonal expansion often precedes both oligoclonal IgG bands and multiple magnetic resonance imaging lesions. Clinical follow-up study showed that patients with clonally expanded intrathecal B cells had a high rate of conversion to clinically definite MS. The findings provide direct evidence of recruitment of germinal center differentiated B lymphocytes into the central nervous system during the initiation of MS. These results indicate B cell-mediated immune response in the cerebrospinal fluid is an early event of inflammatory reaction in the central nervous system of MS. This procedure also provides a more sensitive method to evaluate the association of humoral immunity in the evolution of MS.

Infection with Chlamydia pneumoniae and risk of multiple sclerosis.

BACKGROUND: Chlamydia pneumoniae (Cpn) has been proposed as a possible etiologic agent for multiple sclerosis (MS), but results of previous studies are conflicting. METHODS: Using a nested case-control design, we examined the association between Cpn infection and MS in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II) cohorts. Among 32,826 women in the NHS and 29,722 women in the NHS II with blood samples, 141 incident cases of definite or probable MS were documented. Each case was matched to two healthy controls on year of birth and NHS cohort. Serum samples were tested for the presence of Cpn-specific immunoglobin G antibodies using microimmunofluorescence. RESULTS: Cpn immunoglobin G seropositivity was positively associated with risk of MS (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.1-2.7). This association did not change after adjusting for age at blood collection, ancestry, latitude of residence at birth, and smoking (OR = 1.9; CI = 1.1-3.1). Seropositivity for Cpn was only moderately associated with risk of relapsing-remitting MS (OR = 1.7; CI = 0.9-3.2), but it was strongly associated with risk of progressive MS (OR = 7.3; CI = 1.4-37.2). Geometric mean titers of Cpn-specific immunoglobin G antibody were similar in women with relapsing-remitting MS as compared with matched controls (44 vs 39), but they were elevated in women with progressive MS (99 vs 40). CONCLUSIONS: These results support a positive association between Cpn infection and progressive MS.