Ram Narayan

Neurotherapeutic Strategies for Multiple Sclerosis

Multiple sclerosis (MS) is the most common disabling neurologic disease of young adults. There are now 16 US Food and Drug Administration (FDA)-approved disease-modifying therapies for MS as well as a cohort of other agents commonly used in practice when conventional therapies prove inadequate. This article discusses approved FDA therapies as well as commonly used practice-based therapies for MS, as well as those therapies that can be used in patients attempting to become pregnant, or in patients with an established pregnancy, who require concomitant treatment secondary to recalcitrant disease activity.

The Role of EGFR-Met Interactions in the Pathogenesis of Glioblastoma and Resistance to Treatment

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is a devastating and intractable disease with a poor outcome. Aberrant receptor tyrosine kinase signaling is a key driver in gliomagenesis and resistance to treatment. EGFR gene amplification and mutations are an important genetic alteration in GBM resulting in increased expression of EGFR wild type (EGFRwt) as well as mutant oncogenic forms of the EGFR. EGFRvIII is the most common oncogenic mutant in GBM and is usually co-expressed with EGFRwt. EGFRvIII does not bind ligand and is constitutively active. Recent studies have also highlighted a key role for Met in gliomagenesis and the EGFR and Met may act in concert to promote the malignant phenotype. Met is transactivated by EGFRvIII and plays a key role in EGFRvIII-mediated resistance to targeted treatment. HGF, a Met ligand, is highly expressed in GBM. HGF and Met create an important autocrine signaling loop that promotes GBM invasion. In addition, HGF/Met is able to induce EGFR activation, leading to enhanced activation of oncogenic signaling in GBM. In this review, we discuss the evidence for EGFR and Met interaction in GBM and discuss the mechanisms and biological consequences of transactivation between the two kinases. Additionally, we discuss the therapeutic potential of targeting both EGFR and Met signaling for the treatment of GBM.

Atypical Anti-MOG syndrome with aseptic meningoencephalitis and pseudotumor cerebri-like presentations

OBJECTIVE To describe 2 atypical cases with Anti-MOG antibody related demyelinating syndrome. METHODOLOGY Case series. RESULTS We present two cases. Case 1 is an 18-year-old woman who presented with headache, blurred vision, and papilledema and was initially diagnosed with pseudotumor cerebri syndrome. CSF showed mildly elevated opening pressure and lymphocytic pleocytosis and a diagnosis of aseptic meningitis was considered. MRI brain and spinal cord revealed longitudinally extensive bilateral simultaneous optic neuritis and multiple spinal cord lesions. Case 2 is a 28-year old man who presented initially with unilateral optic neuritis followed by aseptic meningitis three weeks later and subsequently acute disseminated encephalomyelitis (ADEM). Serology was positive for Anti-MOG antibody on a cell-based assay in both these cases. DISCUSSION Although bilateral optic neuritis has been well described in MOG related disorders, aseptic meningitis and pseudotumor cerebri-like syndromes are notable alternate presentations. The presence of eosinophils in the CSF (in the first patient) is a unique finding in our case series. CONCLUSION In a patient with an aseptic meningitis like presentation, the presence of optic neuritis, brain and/or spinal cord lesions should raise suspicion for an MOG-Ab related syndrome.

Anti-Myelin Oligodendrocyte Glycoprotein Antibody Associated With Gray Matter Predominant Transverse Myelitis Mimicking Acute Flaccid Myelitis: A Presentation of Two Cases

BACKGROUND Anti-myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders frequently manifest as optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis. While their clinical phenotypes overlap with relapsing inflammatory Central nervous system (CNS) conditions such as multiple sclerosis and neuromyelitis optica spectrum disorder, MOG-related syndromes frequently occur in a younger age group. In children, longitudinally extensive transverse myelitis (LETM) is less specific for anti-aquaporin-4 associated neuromyelitis optica spectrum disorder, and has also been reported in pediatric multiple sclerosis, idiopathic transverse myelitis, and acute flaccid myelitis. METHODS We summarize two patients with positive MOG antibodies and myelitis. RESULTS We identified two individuals with anti-MOG associated LETM that demonstrate primarily gray matter involvement. Clinically these patients exhibited hyperreflexia and had rapid improvement with immunotherapies. CONCLUSIONS Anti-MOG diseases can cause LETM with gray matter predominance mimicking acute flaccid myelitis, but clinically these patients can have retained reflexes and respond favorably to immunotherapies.

Emerging drugs for primary progressive multiple sclerosis

ABSTRACT Introduction: The identification of effective therapies for progressive forms of multiple sclerosis (MS) has remains a priority and challenge for the global MS community. Despite a few proposed mechanisms, a more complete understanding of the mechanisms involved in the pathogenesis of these MS phenotypes, animal models that incorporate these pathogenic characteristics, novel trial designs, drug repurposing strategies, and new models of collaboration between clinical and basic science personnel may be required in identifying effective therapies. Areas covered: Here, we review the current knowledge on putative pathogenic mechanisms in primary progressive MS (PPMS). Also, the rationale and outcomes of key phase II or III trial initiatives in PPMS are summarized. Future perspectives are outlined. Expert opinion: The recent approval of ocrelizumab is a major milestone forward in the therapy of PPMS. One reason for success of this drug is appropriate patient selection. The ultimate goal in PPMS therapy should be the reversal of disability, and the arrest of disease progression. Our current understanding of PPMS suggests that a combination of immune-modulatory, myelin-restorative, and neuro-regenerative therapies particularly early in the disease course would be a reasonable strategy. Finally, selection of appropriate patients, selection of appropriate outcomes and monitoring therapy is again crucial for success of therapeutic strategies.

The emergence of neuroepidemiology, neurovirology and neuroimmunology: the legacies of John F. Kurtzke and Richard ‘Dick’ T. Johnson

As the 1950s approached, the enigma known as multiple sclerosis (MS) presented more questions to the inquisitive mind than answers. Since Charcot’s illustration of the distinct pathology and description of a disease with a highly complex semiology and widely heterogeneous clinical course, which he initially named ‘la sclérose en plaques’ in 1868 [1], early observations germane to the putative pathoetiological rudiments of the disorder were influenced by Charcot’s French contemporary, Louis Pasteur. In particular, it was Pasteur’s work on ‘germ theory’ and his corresponding proscription that the development of vaccines would ultimately represent a fundamental shift in medicine from descriptive pathology and its pathophysiologic consequences, to the formulation of specifically targeted medical therapeutics for those disorders where infection was the causative factor. Knowledge of this fundamental, rapidly emerging tenet of medical diagnosis and treatment led Pierre Marie, a protégé of Charcot’s, to first postulate an infectious root for the disease we today know as MS [2]. Ranvier’s discovery of myelin in 1878 [3], and Uhthoff’s peculiar and reproducible case descriptions of fully reversible, and typically stereotypic symptom attacks in those who were previously afflicted by acute events of what were most likely events of acute optic neuritis [4] laid part of the groundwork, that would be considerably advanced by Ian McDonald, for our understanding of the pathophysiologic mechanisms related to inflammatory demyelination upon the intact, albeit compromised axon [5, 6]; an advance that was directly germane to the translation of laboratory observations concerning the consequences of demyelination, into the development of the first non-invasive and specific test for demonstrating demyelination [7]. In particular, following McDonald’s move from Otago, New Zealand to London, UK, together with Martin Halliday and Joan Mushin, they developed visual evoked potentials, a powerful and objective method by which we could document the effects of demyelination (e.g., conduction slowing or even conduction block), and loss of axons in the anterior visual system (e.g., by persistent attenuation of the P100 amplitude response, not due to conduction block) [7]. After the formation of the National MS Society by Sylvia Lawry in 1946, one of the society’s earliest grants funded Elvin Kabat’s historic investigations that ultimately E. J. Kildebeck and R. Narayan contributed equally to the development and authorship of this paper.

Teaching NeuroImages: Spherules in spine Vertebral coccidioidomycosis

A 39-year-old African American immunocompetent man with frequent travels to Mexico presented with progressive descending weakness over 2 weeks. Physical examination revealed chest ulcers, cervical lymphadenopathy, spastic quadriparesis, decreased sensation to touch and pain up to C7 dermatome, hyperreflexia, and bilateral positive Hoffman and Babinski sign. MRI of the spine showed multilevel osteomyelitis and paraspinal abscesses involving the cervical and thoracic regions (figure, A). He underwent surgical debridement. Vertebral biopsy showed necrotizing, granulomatous inflammation and numerous thick-walled spherules (figure, B). Culture confirmed coccidioidomycosis. The patient was initiated on amphotericin B for 6 weeks, followed by fluconazole, and showed gradual clinical improvement.1