Elena Grebenciucova

Anti- N -methyl-D-aspartate-receptor encephalitis: diagnosis, optimal management, and challenges

Objective Anti-N-methyl-D-aspartate-receptor (NMDA-R) encephalitis is a new autoimmune disorder, often paraneoplastic in nature, presenting with complex neuropsychiatric symptoms. Diagnosed serologically, this disorder is often responsive to immunosuppressant treatment. The objective of this review is to educate clinicians on the challenges of diagnosis and management of this disorder. Materials and methods A review of the relevant literature on clinical presentation, pathophysiology, and recommended management was conducted using a PubMed search. Examination of the results identified articles published between 2007 and 2014. Results The literature highlights the importance of recognizing early common signs and symptoms, which include hallucinations, seizures, altered mental status, and movement disorders, often in the absence of fever. Although the presence of blood and/or cerebrospinal fluid autoantibodies confirms diagnosis, approximately 15% of patients have only positive cerebrospinal fluid titers. Antibody detection should prompt a search for an underlying teratoma or other underlying neoplasm and the initiation of first-line immunosuppressant therapy: intravenous methylprednisolone, intravenous immunoglobulin, or plasmapheresis, or a combination thereof. Second-line treatment with rituximab or cyclophosphamide should be implemented if no improvement is noted after 10 days. Complications can include behavioral problems (eg, aggression and insomnia), hypoventilation, catatonia, and autonomic instability. Those patients who can be managed outside an intensive care unit and whose tumors are identified and removed typically have better rates of remission and functional outcomes. Conclusion There is an increasing need for clinicians of different specialties, including psychiatrists, neurologists, oncologists, neurooncologists, immunologists, and intensivists to become familiar with this disorder and its potential complications. Remission can be optimized with prompt detection and aggressive, collaborative treatment within a multidisciplinary team.

Immunologic mechanisms of fingolimod and the role of immunosenescence in the risk of cryptococcal infection: A case report and review of literature

BACKGROUND Fingolimod is a disease-modifying agent used in the treatment of relapsing/remitting multiple sclerosis. In MS clinical studies, the overall rate of infections in fingolimod group was overall similar to placebo, except for slightly more common lower respiratory tract infections and to a lesser extent HSV. Recently, an increasing number of cryptococcal infections associated with a long-term use of this medication have been reported. METHODS We reviewed literature for cases of cryptococcal infection associated with the use of fingolimod and reported a case at our institution, as well as carefully evaluated the established immune mechanisms of the medication and discussed new insights into its short-term and long-term immunologic effects that may become important in the context of risk of infection. RESULTS Unique characteristics of cryptococcal pathogen, its immune escape mechanisms, its ability to establish a latent infection with a potential for later reactivation, fingolimods effects on many lines of immune system, both quantitatively and qualitatively, duration of therapy, and long-term effects of fingolimod, not previously described, in conjunction with effects of natural immunosenescence of the patient population, that appears to be most at risk, may be meaningful in further understanding the risk of infection with long-term use of fingolimod in people of older age.

Immunosenescence: the Role of Aging in the Predisposition to Neuro-Infectious Complications Arising from the Treatment of Multiple Sclerosis

Purpose of ReviewThis review highlights some of the important changes in the immune system that occur in the process of normal aging. Immunosenescence as a concept is directly relevant to the world of neuro-inflammation, as it may be a contributing factor to the risks associated with some of the current immunosuppressive and immunomodulatory therapies used in treating multiple sclerosis (MS) and other inflammatory disorders.Recent FindingsProfound qualitative and quantitative changes occur in the adaptive and innate immunity compartments during aging. These changes may explain why patients of older age are at an increased risk of infections and infection-associated mortality.SummaryImmunosenescence-associated changes may be additive or synergistic with the effects produced by immunomodulatory and immunosuppressive medications. Clinicians should exercise a high level of vigilance in monitoring the risk of infections in older patients on these treatments.

Infections in Patients Receiving Multiple Sclerosis Disease-Modifying Therapies

Purpose of ReviewThis paper will systemically review the risk of infections associated with current disease-modifying treatments and will discuss pre-treatment testing recommendations, infection monitoring strategies, and patient education.Recent FindingsAside from glatiramer acetate and interferon-beta therapies, all other multiple sclerosis treatments to various degrees impair immune surveillance and may predispose patients to the development of both community-acquired and opportunistic infections. Some of these infections are rarely seen in neurologic practice, and neurologists should be aware of how to monitor for these infections and how to educate patients about medication-specific risks. Of particular interest in this discussion is the risk of PML in association with the recently approved B cell depleting therapy, ocrelizumab, particularly when switching from natalizumab.SummaryThe risk of infection in association with MS treatments has become one of the most important factors in the choice of therapy. Balance of the overall risk versus benefit should be continuously re-evaluated during treatment.

The extracellular domain of myelin oligodendrocyte glycoprotein elicits atypical experimental autoimmune encephalomyelitis in rat and Macaque species

Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund’s adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund’s adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6–7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection that occurs in patients whose immune system is compromised either because of an underlying illness or an immunosuppressive medication. John Cunningham virus, prevalent in 60% or more of the adult population as a latent or persistent infection, is responsible for the syndrome of PML. This article reviews PML in association with the most common immunotherapies and discusses risk mitigation and monitoring strategies.

Immunopathogenesis and Treatment of Guillain-Barre Syndrome and Chronic Inflammatory Demyelinating Polyneuropathy

This chapter discusses the clinical manifestations, pathogenesis, and treatment of Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), including recent advances in immunopathogenesis as well as the treatments in pipeline. GBS and CIDP are part of the spectrum of autoimmune-mediated neuropathy. The target antigen remains elusive in CIDP and acute inflammatory demyelinating polyneuropathy, the most common variant of GBS in North America. Autoimmunity against different gangliosides is involved in the pathogenesis of GBS variants, i.e., acute motor axonal neuropathy, Miller Fisher syndrome, and acute motor and sensory axonal neuropathy, as well as their sub-variants. As GBS is a monophasic disease, immunomodulatory treatment, currently consisting of intravenous immunoglobulin infusions or plasma exchange, is required only during the acute phase, unless there are relapses. On the other hand, maintenance treatment with the aforementioned treatment modalities, as well as corticosteroids or other immunosuppressants, is frequently needed in CIDP patients. Further advances in the understanding of immunopathogenesis of these diseases will likely result in development of new treatments involving targeted immunotherapy.

Miller-Fischer syndrome after etanercept

The authors describe a case of Miller-Fisher syndrome, a rare demyelinating syndrome, preceded by a viral prodrome and three doses of etanercept, an anti-tumor necrosis factor α (anti-TNFα) agent. Anti-TNFα agents are associated with an induction of episodes of demyelination and may unmask multiple sclerosis in those who are immunogenetically predisposed.

Central nervous system blastomycosis presenting as a year-long chronic headache

Elena Grebenciucova1, Maciej S. Lesniak2, Peter Pytel3, Rimas V. Lukas1 1Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, USA. 2Department of Neurosurgery, Northwestern University, Chicago, IL 60637, USA. 3Department of Pathology, University of Chicago Medical Center, Chicago, IL 60637, USA. This case describes a posterior fossa mass due to blastomycotic infection in a non-immunocompromised 41-year-old male presenting with a chronic headache for over one year. Given the risk of herniation, no lumbar puncture could be performed. A full work-up found no evidence of systemic infection. Surgical resection helped identify the mass as a blastomycotic abscess. Magnetic resonance imaging characteristics of the mass were helpful in the identification of the mass as a fungal abscess.

Corrigendum to ‘Immunologic mechanisms of fingolimod and the role of immunosenescence in the risk of cryptococcal infection: A case report and review of literature’ [Mult. Scler. Relat. Disord. 9 (2016) 158–162]

The authors regret that there was an error on p. 159, first paragraph of the above article. The words ‘cryptococcal antigen/antigenemia’ should be ‘cryptococcal antibody’ and should be read as following: ‘Different geographic populations may exhibit different levels of antibody positivity (Goldman et al., 2001), A study on pre-solid organ transplant patients showed that cryptococcal antibody positivity prior to the transplant was evident in 52% of patients who later developed active infection and correlated with the risk and timing of development of cryptoccal meningitis post-transplant. Patients who were antibodypositive prior to the transplantation developed cryptococcocal infection significantly earlier after transplant than patients without preexistent antibody positivity (5.6 +/3.4 months compared to 40.6 +/63.8 months) (Saha et al., 2007)’. The authors would like to apologize for any inconvenience caused.