Adil Javed

Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician

Several lines of evidence link immunosuppression to inflammation in patients with multiple sclerosis (MS) and provide a rationale for the increasing use of immunosuppressive drugs in the treatment of MS. Treatment-refractory, clinically active MS can quickly lead to devastating and irreversible neurological disability and treating these patients can be a formidable challenge to the clinician. Patients with refractory MS have been treated with intense immunosuppression, such as cyclophosphamide or mitoxantrone, or with autologous haematopoeitic stem cell transplants. Evidence shows that intense immunosuppression might be effective in patients who are unresponsive to immunomodulating therapy, such as interferon beta and glatiramer acetate. Natalizumab, a new addition to the armamentarium for treating MS, might also have a role in the treatment of this MS phenotype. This Review describes the use of intense immunosuppressant drugs and natalizumab in patients with rapidly worsening MS and provides clinicians with guidelines for the use of these drugs in this patient group.

Type I interferon signature is high in lupus and neuromyelitis optica but low in multiple sclerosis

OBJECTIVE Neuromyelitis optica (NMO) is characterized by selective inflammation of the spinal cord and optic nerves but is distinct from multiple sclerosis (MS). Interferon (IFN)-β mitigates disease activity in MS, but is controversial in NMO, with a few reports of disease worsening after IFN-β therapy in this highly active disease. In systemic lupus erythematosus (SLE), IFNs adversely affect disease activity. This study examines for the first time whether serum IFN-α/β activity and IFN-β-induced responses in peripheral blood mononuclear cells (MNC) are abnormally elevated in NMO, as they are in SLE, but contrast to low levels in MS. METHODS Serum type I IFN-α/β activity was measured by a previously validated bioassay of 3 IFN-stimulated genes (RT-PCR sensitivity, 0.1 U/ml) rather than ELISA, which has lower sensitivity and specificity for measuring serum IFNs. IFN responses in PBMNC were assessed by in vitro IFN-β-induced activation of phospho-tyrosine-STAT1 and phospho-serine-STAT1 transcription factors, and MxA proteins using Western blots. RESULTS Serum IFN-α/β activity was highest in SLE patients, followed by healthy subjects and NMO, but was surprisingly low in therapy-naïve MS. In functional assays in vitro, IFN-β-induced high levels of P-S-STAT1 in NMO and SLE, but not in MS and controls. IFN-β-induced MxA protein levels were elevated in NMO and SLE compared to MS. CONCLUSIONS Serum IFN activity and IFN-β-induced responses in PBMNC are elevated in SLE and NMO patients versus MS. This argues for similarities in pathophysiology between NMO and SLE and provides an explanation for IFN-induced disease worsening in NMO.

Minor salivary gland inflammation in Devic’s disease and longitudinally extensive myelitis:

Devic’s disease is often considered as a variant of multiple sclerosis (MS). However, evidence suggests that Devic’s disease may be distinct from MS. Devic’s disease can coexist with connective tissue diseases, particularly Sjögren’s disease, but this association is rare with MS. Diagnosis of Sjögren’s disease in patients with neurological symptoms is often difficult. During early stages of Sjögren’s disease, patients may not fulfill all criteria for Sjögren’s disease. A high percentage of patients with Sjögren’s disease have inflammatory infiltrates in minor salivary glands, and this may be a reliable indicator of early or subclinical disease. We show high prevalence (80%) of salivary gland inflammation in Devic’s disease and longitudinally extensive transverse myelitis (LETM). We diagnosed 16 patients with Devic’s disease, and 2 of these satisfied criteria for Sjögren’s disease as did 2 of 9 patients with LETM. Anti-SSA/B titers were infrequently elevated. Although most did not satisfy criteria for Sjögren’s disease. 9 of 12 Devic’s disease patients and 7 of 8 LETM patients had severe salivary gland inflammation. Thus: (1) patients with Devic’s disease or with LETM who have positive labial biopsies but do not satisfy criteria for Sjögren’s disease could have subclinical Sjögren’s diseases. Alternatively, (2) as patients with Devic’s disease have elevated titers of several autoantibodies, so there may exist a set of antibodies that react with antigens in minor salivary glands and cause inflammation. Minor salivary gland biopsy is more sensitive than anti-SSA/B serology in providing histological evidence for possible Sjögren’s disease with CNS lesions.

Efficacy and safety of rituximab in pediatric neuromyelitis optica.

Neuromyelitis optica is a central nervous system disease characterized by optic neuritis and transverse myelitis. It is a devastating illness, and early treatment may prevent future relapses and severe disability. However, there is much variability in protocols used for treatment. In limited studies, rituximab has shown efficacy in adult neuromyelitis optica patients. There is a paucity of literature on the efficacy and tolerability of rituximab in the pediatric population. The authors report the use of rituximab in 2 pediatric patients with neuromyelitis optica, demonstrating its efficacy, dosing, and tolerability. This report may be a useful guide for administering rituximab safely in pediatric neuromyelitis optica patients.

Cross-Immunoreactivity between Bacterial Aquaporin-Z and Human Aquaporin-4: Potential Relevance to Neuromyelitis Optica

Neuromyelitis optica (NMO) is a chronic inflammatory disease of the CNS that is mediated, in part, by a self-reactive Ab against the astrocyte aquaporin-4 protein. In the current study, we examined the possibility and the biological significance of cross-immunoreactivity between bacterial aquaporin-Z and human aquaporin-4 proteins. Sequence-alignment analysis of these proteins revealed several regions of significant structural homology. Some of the homologous regions were also found to overlap with important immune and disease-relevant epitopes. Cross-immunoreactivity between aquaporin-Z and aquaporin-4 was investigated and ascertained in multiple immune-based assays using sera from patients with neuromyelitis optica, immune mouse serum, and Abs raised against aquaporin-Z. The biological significance of this phenomenon was established in series of experiments demonstrating that induction of an immune response against aquaporin-Z or its homologous regions can also trigger an autoimmune reaction against aquaporin-4 and inflammation of the CNS. Our study indicates that the autoimmune response against aquaporin-4 in neuromyelitis optica may be triggered by infection-induced cross-immunoreactivity and presents a new perspective on the pathogenesis of this disease.

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.

Chapter 35 – Acute disseminated encephalomyelitis

Abstract Acute disseminated encephalomyelitis (ADEM) is an acute multifocal demyelinating disease of the central nervous system that typically follows an infectious illness. Its clinical course in most cases is monophasic; however, relapsing ADEM is rarely seen, which poses a diagnostic challenge for distinguishing this disease from multiple sclerosis (MS). Although typically encountered in children, it also occurs in adults with disease characteristics slightly different from the pediatric cases. Formerly, ADEM occurred particularly often in children with measles. However, the illness most often follows a non-descript viral or even bacterial infectious illness. ADEM occurs throughout the world, and may even be more common in less-developed countries, where MS is rare, than in developed ones, where MS is common. Children seldom get MS as opposed to adults, indicating that ADEM constitutes a distinct entity from MS. The prognosis of ADEM is generally good, but severe neurologic sequelae after ADEM are occasionally seen. In this chapter, the etiology, clinical/laboratory/radiologic characteristics, treatment options, and prognosis of ADEM are discussed.

Homonymous hemimacular thinning: A unique presentation of optic tract injury in neuromyelitis optica

A 42-year-old African American woman with a 5-year history of neuromyelitis optica was found to have an incongruous homonymous hemianopia. Optical coherence tomography (OCT) showed corresponding left homonymous hemimacular thinning. Magnetic resonance imaging of the brain demonstrated a demyelinating lesion in the left optic tract (OT) just anterior to the lateral geniculate nucleus and diffusion tensor magnetic resonance tractography confirmed axonal fiber loss in the left OT. This case illustrates the complementary and confirmatory roles of visual field testing, macular OCT, and neuroimaging in an OT lesion, which caused selective hemimacular thinning through retrograde degeneration.

Rising JCV-Ab index during natalizumab therapy for MS Inauspicious for a highly efficacious drug

Infection with JC virus (JCV) is not noticeable and is usually inconsequential. Natalizumab therapy, however, blocks the very late antigen-4 adhesion molecule on immune cells, preventing them from attaching to vascular cell adhesion molecule-1 on brain endothelial cells and then penetrating into the CNS. The dearth of T cells, and perhaps other factors, allows JCV to infect oligodendroglia and cause progressive multifocal leukoencephalopathy (PML), at a risk of 1/1,000 per year. In this issue of Neurology® Neuroimmunology & Neuroinflammation, Schwab et al.1 find that natalizumab markedly increases levels of the JCV antibodies that may foretell the risk of PML.

Effective treatment of CLIPPERS with long-term use of rituximab

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare CNS inflammatory syndrome first described in 2010 by Pittock et al.1 Taieb et al.2 reported about 60 known cases throughout the world. The underlying pathogenesis of CLIPPERS has not been fully elucidated, and a neural autoantibody target has not been discovered. Steroid treatment is effective in treating the inflammatory component of the disease, but long-term treatment of CLIPPERS with steroids is limited by side effects. Steroid withdrawal is associated with recrudescence of the disease, and each relapse is associated with additional disability. Moderately efficacious steroid-sparing treatments include methotrexate, hydroxychloroquine, and cyclophosphamide.2 However, the long-term efficacy and safety of these agents in CLIPPERS remain to be determined. Anti-CD20 molecules benefit several antibody-mediated CNS inflammatory diseases. Herein, we describe a case of CLIPPERS successfully treated with rituximab (mouse chimeric anti-CD20 monoclonal antibody) over the course of 4 years. We describe imaging and histological features of this disease, as they are relevant to disease pathology and treatment (figure).