Successful Autologous Hematopoietic Stem Cell Transplant in Glycine Receptor Antibody-Positive Stiff Person Syndrome: A Case Report

BACKGROUND AND OBJECTIVES: To describe a case of glycine receptor (GlyR) antibody-positive stiff person syndrome (SPS) treated with autologous hematopoietic stem cell transplant (aHSCT). METHODS: This was a multicenter collaboration for the treatment of a single patient who underwent aHSCT as part of a clinical trial (NCT00716066). To objectively assess the response to transplantation, several clinical outcome measures were evaluated pretransplant and up to 18 months post-transplant, including modified Rankin Score (mRS), stiffness index, Hauser Ambulation Score (HAS), hypersensitivity index, timed 25-foot walk, and Montreal Cognitive Assessment. RESULTS: After transplant, the patient achieved sustained clinical improvement evidenced across various clinical scales, including mRS, stiffness index, HAS, and 25-foot walk time. DISCUSSION: aHSCT represents a promising treatment option for SPS, including for GlyR-positive patients. In addition, this case represents the need to validate and standardize best clinical outcome measures for patients with SPS. CLASSIFICATION OF EVIDENCE: Class IV; this is a single observational study without controls.

A comparison of anxiety symptoms and correlates of anxiety in people with progressive and relapsing-remitting multiple sclerosis.

BACKGROUND: Anxiety appears to be more prevalent in people with multiple sclerosis (MS) than in the general population, though it is unclear if anxiety varies by MS disease course. There are experiences unique to each disease course that might increase the likelihood of anxiety. Additionally, the majority of research in MS has focused on people with relapsing-remitting MS (RRMS), while the experiences of people with progressive forms of MS are understudied. This study examined anxiety in people with progressive MS (PMS) and examined group differences in anxiety compared to people with RRMS, and assessed unique and common correlates of anxiety in people with PMS and RRMS. METHODS: Secondary analysis of data from the fourth survey in a longitudinal study of quality of life in people with physical disabilities. The current study included a subset of participants with MS. Anxiety level was measured by the 4-item Patient-Reported Outcomes Measurement Information System - Anxiety Short Form T-score. T-test and chi-square analyses were used to compare groups. Correlates of anxiety were tested by examining the interaction of MS subtype (PMS and RRMS) and each potential correlate in multiple regression models with bootstrapping. RESULTS: Participants were 464 adults with MS (PMS n = 183; RRMS n = 281) who were predominately female, non-Hispanic white, and not employed with a mean age of 56.9 ± 10.3 years and disease duration of 17.5 ± 9.3 years. On average, participants with PMS reported anxiety symptoms (50.6 ± 8.6) that were comparable to those in the United States general population and statistically lower than participants with RRMS (52.8 ± 9.5; p = .01). Across MS courses, common factors associated with greater anxiety symptoms were shorter disease duration, lower household income, greater speech and/or swallowing problems, and current smoking (tobacco), adjusted R2 = .19, F(4, 391) = 22.68, p < .001. There was no evidence of unique correlates of anxiety symptoms in participants with either MS course. CONCLUSIONS: In this community sample, people with MS, regardless of disease course, reported similar levels of anxiety to the United States general population. This is inconsistent with prior literature that largely involves clinical samples, suggesting a need for further research with community samples of individuals with MS. This discrepancy may also be due to measurement differences between studies (e.g., screen versus symptom measures). Participants with RRMS reported greater average anxiety compared to those with PMS. This statistically significant difference was small and not clinically significant, indicating the need for further examination and replication. Overall, the findings highlight the wide heterogeneity of anxiety presentation within people with MS and identify potential factors to improve conceptualization and treatment of anxiety in this population. Further research is needed with community and clinical samples to understand anxiety in MS as well as risk and protective factors to improve conceptualization and treatment of anxiety in this population.

Brain pathology of a patient 7years after autologous hematopoietic stem cell transplantation for multiple sclerosis.

Aggressive immunosuppression followed by autologous hematopoietic stem cell transplantation (aHSCT) can be an effective treatment for severe multiple sclerosis (MS), but not all stages of disease may benefit equally. The case of a 49-year-old woman with advanced secondary-progressive MS whose clinical course was not improved by aHSCT and who seven years after transplantation succumbed to complications of severe MS disease-related disability is presented. Autopsy findings of ongoing neurodegeneration despite only rare infiltrating T-lymphocytes illustrate that late MS disease may not represent a suitable disease stage for aHSCT.

Dietary Interventions in Multiple Sclerosis: Development and Pilot-Testing of an Evidence Based Patient Education Program.

BACKGROUND: Dietary factors have been discussed to influence risk or disease course of multiple sclerosis (MS). Specific diets are widely used among patients with MS. OBJECTIVE: To design and pilot-test an evidence based patient education program on dietary factors in MS. METHODS: We performed a systematic literature search on the effectiveness of dietary interventions in MS. A web-based survey among 337 patients with MS and 136 healthy controls assessed knowledge, dietary habits and information needs. An interactive group education program was developed and pilot-tested. RESULTS: Fifteen randomised-controlled trials (RCTs) were included in the systematic review. Quality of evidence was low and no clear benefit could be seen. Patients with MS significantly more often adhered to a `Mediterranean Diet`(29.7% versus 14.0%, p<0.001) compared to controls. 143 (42%) of the patients with MS had tried special MS diets. Important information needs addressed effectiveness of MS diets (44%) and relation between nutrition and MS (43%). A pilot test of our newly developed patient education program with 13 participants showed excellent comprehensibility and the MS-specific content was judged as very important. However, the poor evidence base for dietary approaches in MS was perceived disappointing. CONCLUSIONS: Development and pilot-testing of an evidence-based patient education program on nutrition and MS is feasible. Patient satisfaction with the program suffers from the lack of evidence. Further research should focus on generating evidence for the potential influence of lifestyle habits (diet, physical activity) on MS disease course thus meeting the needs of patients with MS.

Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project.

BACKGROUND: Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate that was approved in 2011 for the treatment of patients with anaplastic large cell and Hodgkin lymphomas. The product label indicates that 3 patients who were treated with BV developed progressive multifocal leukoencephalopathy (PML), a frequently fatal JC virus-induced central nervous system infection. Prior immunosuppressive therapy and compromised immune systems were postulated risk factors. In the current study, the authors reported 5 patients who developed BV-associated PML, including 2 immunocompetent patients. METHODS: Case information was obtained from clinicians (4 patients) or a US Food and Drug Administration database (1 patient). RESULTS: All 5 patients had lymphoid malignancies. Two patients with cutaneous T-cell lymphomas had not previously received chemotherapy. PML developed after a median of 3 BV doses (range, 2 doses-6 doses) and within a median of 7 weeks after BV initiation (range, 3 weeks-34 weeks). Presenting findings included aphasia, dysarthria, confusion, hemiparesis, and gait dysfunction; JC virus in the cerebrospinal fluid (2 patients) or central nervous system biopsy (3 patients); and brain magnetic resonance imaging scans with white matter abnormalities (5 patients). Four patients died at a median of 8 weeks (range, 6 weeks-16 weeks) after PML diagnosis. The sole survivor developed immune reconstitution inflammatory syndrome. CONCLUSIONS: PML can develop after a few BV doses and within weeks of BV initiation. Clinicians should be aware of this syndrome, particularly when neurologic changes develop after the initiation of BV treatment. The decision to administer BV to patients with indolent cutaneous lymphomas should be based on consideration of risk-benefit profiles and of alternative options.

Cerebrospinal fluid JC virus antibody index for diagnosis of natalizumab-associated progressive multifocal leukoencephalopathy.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), can occur in patients receiving natalizumab for multiple sclerosis (MS). JCV detection by quantitative polymerase chain reaction (qPCR) in cerebrospinal fluid (CSF), or brain biopsy, is required for probable or definite diagnosis of PML. However, in some patients only low levels of JCV DNA (<100 copies/ml) are present in CSF, making the diagnosis challenging. Our objective was to assess the complementary value of a CSF JCV antibody index (AIJCV ) in the diagnosis of natalizumab-associated PML. METHODS: AIJCV was assessed in 37 cases of natalizumab-associated PML and 89 MS-patients treated with natalizumab without PML. Sera and CSF were tested in a capture enzyme-linked immunosorbent assay, using JCV-VP1 fused to glutathione S-transferase as antigen. Albumin levels and total immunoglobulin G concentration were determined by immunonephelometry, and the AIJCV was calculated as published. RESULTS: Twenty-six of 37 (70%) patients with natalizumab-associated PML exhibited an AIJCV > 1.5, whereas this was seen in none of the controls (p < 0.0001). At time of the first positive qPCR for JCV DNA, 11 of 20 (55%) patients with natalizumab-associated PML had an AIJCV > 1.5. JCV DNA levels of <100 copies/ml were seen in 14 (70%) of these 20 patients, of whom 8 (57%) demonstrated an AIJCV > 1.5. INTERPRETATION: Determination of the AIJCV could be an added tool in the diagnostic workup for PML and should be included in the case definition of natalizumab-associated PML.

PML-IRIS in a patient treated with brentuximab.

A 38-year-old woman was diagnosed with cutaneous anaplastic T-cell lymphoma that proved refractory to methotrexate, bexarotene, denileukin diftitox, interferon γ-1b, interferon α-2b, vorinostat, and pralatrexate. She was therefore started on the newly approved monoclonal anti-CD30 antibody brentuximab vedotin. Treatment with brentuximab 1.8 mg/kg IV every 3 weeks quickly led to disappearance of her cutaneous tumors. The day after her second brentuximab infusion she developed word-finding difficulties and unsteady gait. Due to further neurologic deterioration, she was admitted to an outside hospital. Brain MRI revealed multifocal enhancing white matter lesions throughout bilateral cerebral hemispheres and posterior fossa (figure, A-C). Brain biopsy was performed 15 days after her last brentuximab dose to rule out metastases and she was diagnosed with progressive multifocal leukoencephalopathy (PML) (figure, J). The patient was discharged home with hospice care. Upon discharge, she was started on prednisone 50 mg daily to help treat her eczema. Her family brought her to our clinic for a second opinion.

The influence of nutritional factors on the prognosis of multiple sclerosis.

The effect of nutrition and dietary supplements on the course of multiple sclerosis (MS) is a topic of great interest to both patients and clinicians. In particular, vitamin D status has been shown to influence both the incidence and the course of MS. High vitamin D levels are probably protective against the development of MS, although the efficacy of vitamin D supplementation in slowing progression of MS remains to be established. The influence of polyunsaturated fatty acids (PUFAs) on the development and course of MS has also long been under investigation. Small clinical trials suggest a modest reduction in the severity and duration of relapses in patients with MS receiving PUFA supplements. Other nutritional factors have been evaluated for their effect on MS disease progression, including milk proteins, gluten, probiotics, antioxidants (uric acid, vitamins A, C and E, lipoic acid), polyphenols, Ginkgo biloba extracts and curcumin. However, further studies are needed to evaluate the effects of these dietary components on the relapse rate and progression of MS. This Review gives an overview of the literature on the nutritional factors most commonly implicated as having an effect on MS and discusses the biological rationale that is thought to underlie their influence.

Viral load determines the B-cell response in the cerebrospinal fluid during human immunodeficiency virus infection.

OBJECTIVE: Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is frequently associated with intrathecal immunoglobulin synthesis and cerebrospinal fluid (CSF) pleocytosis, but little is known about the B-cell response in the CSF of these patients. In this study, we investigated the relation between virus load and the frequency and phenotype of B cells in the CSF of HIV-infected patients. METHODS: The distribution of T cells, B cells, short-lived plasmablasts, and long-lived plasma cells was analyzed by flow cytometry in CSF and peripheral blood of 33 patients with HIV infection compared with 12 patients with noninfectious CNS diseases. HIV RNA copy number in CSF and serum was quantified by kinetic polymerase chain reaction. RESULTS: B-cell and plasmablast levels were increased in the CSF of HIV-infected patients compared with patients with noninfectious CNS diseases. Whereas CSF B cells were found at similar frequency during early and late stages of HIV infection, plasmablasts were more prevalent in the CSF during early infection. Plasmablasts in the CSF correlated with intrathecal IgG synthesis and even stronger with HIV RNA copy numbers in CSF, in particular, in untreated, early HIV-infected individuals. Initiation of antiviral treatment in therapy-naive patients strongly decreased HIV copy numbers and plasmablasts in CSF. INTERPRETATION: Our findings demonstrate that HIV infection of the CNS triggers an early profound B-cell response, with plasmablasts serving as the main virus-related B-cell subset in the CSF.

Accumulation of class switched IgD-IgM- memory B cells in the cerebrospinal fluid during neuroinflammation.

Inflammatory diseases of the central nervous system (CNS) are characterized by cerebrospinal fluid (CSF) pleocytosis often involving the recruitment of B cells. Little is still known about B cells that are found in the CSF during neuroinflammation. To address the phenotype of these B cells, we studied the distribution of the major B cell subsets in peripheral blood (PB) and CSF of 25 patients with inflammatory diseases of the nervous system by flow cytometry. Six different B cell subsets were identified in PB and CSF according to the surface expression of IgM, IgD, CD27 and CD19. In all patients analysed, memory B cells outnumbered naïve B cells in the CSF, whereas naïve B cells were more prevalent in PB. The accumulation of memory B cells in the CSF was largely due to the recruitment of IgM-IgD- class switched memory B cells. The distribution of IgM+IgD+, IgM-IgD+, IgM+IgD- memory cells and immature cells did not differ significantly between CSF and PB. These findings demonstrate a selective recruitment of IgM-IgD- memory B cells to the CSF suggesting a specific role of these cells during neuroinflammation.