Raghav Govindarajan

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Parkinson’s disease (PD) is a progressive movement disorder characterized by neuroinflammation and dopaminergic neurodegeneration in the brain. 1-methyl-4-phenylpyridinium (MPP+), a metabolite of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces the release of inflammatory mediators from glial cells and neurons. Glia maturation factor (GMF), a brain proinflammatory protein, MPP+, and mast cell-derived inflammatory mediators induce neurodegeneration which eventually leads to PD. However, the precise mechanisms underlying interaction between glial cells, neurons and mast cells in PD still remain elusive. In the present study, mouse bone marrow-derived mast cells (BMMCs) and mouse fetal brain-derived mixed glia/neurons, astrocytes and neurons were incubated with MPP+, GMF and mast cell-derived inflammatory mediators mouse mast cell protease-6 (MMCP-6), MMCP-7 or tryptase/brain-specific serine protease-4 (tryptase/BSSP-4). Inflammatory mediators released from these cells in the culture medium were quantitated by enzyme-linked immunosorbent assay. Neurodegeneration was quantified by measuring total neurite outgrowth following microtubule-associated protein-2 immunocytochemistry. MPP+-induced significant neurodegeneration with reduced total neurite outgrowth. MPP+induced the release of tryptase/BSSP-4 from the mouse mast cells, and tryptase/BSSP-4 induced chemokine (C-C motif) ligand 2 (CCL2) release from astrocytes and glia/neurons. Overall our results suggest that MPP+, GMF, MMCP-6 or MMCP-7 stimulate glia/neurons, astrocytes or neurons to release CCL2 and matrix metalloproteinase-3. Additionally, CD40L expression is increased in BMMCs after incubation with MPP+ in a co-culture system consisting of BMMCs and glia/neurons. We propose that mast cell interaction with glial cells and neurons during neuroinflammation can be explored as a new therapeutic target for PD.

Shortcomings in the Current Amyotrophic Lateral Sclerosis Trials and Potential Solutions for Improvement

Amyotrophic lateral sclerosis (ALS) is a clinically progressive neurodegenerative syndrome predominantly affecting motor neurons and their associated tracts. Riluzole and edaravone are the only FDA certified drugs for treating ALS. Over the past two decades, almost all clinical trials aiming to develop a successful therapeutic strategy for this disease have failed. Genetic complexity, inadequate animal models, poor clinical trial design, lack of sensitive biomarkers, and diagnostic delays are some of the potential reasons limiting any significant development in ALS clinical trials. In this review, we have outlined the possible reasons for failure of ALS clinical trials, addressed the factors limiting timely diagnosis, and suggested possible solutions for future considerations for each of the shortcomings.

Response to immunotherapy in a patient with adult onset Leigh syndrome and T9176C mtDNA mutation

Leigh syndrome is a mitochondrial disease caused by mutations in different genes, including ATP6A for which no known therapy is available. We report a case of adult-onset Leigh syndrome with response to immunotherapy. A twenty year-old woman with baseline learning difficulties was admitted with progressive behavioral changes, diplopia, headaches, bladder incontinence, and incoordination. Brain MRI and PET scan showed T2 hyperintensity and increased uptake in bilateral basal ganglia, respectively. Autoimmune encephalitis was suspected and she received plasmapheresis with clinical improvement. She was readmitted 4 weeks later with dysphagia and aspiration pneumonia. Plasmapheresis was repeated with resolution of her symptoms. Given the multisystem involvement and suggestive MRI changes, genetic testing was done, revealing a homoplasmic T9176C ATPase 6 gene mtDNA mutation. Monthly IVIG provided clinical improvement with worsening when infusions were delayed. Leigh syndrome secondary to mtDNA T9176C mutations could have an autoimmune mechanism that responds to immunotherapy.

Developing an outline for teleneurology curriculum: AAN Telemedicine Work Group recommendations

The emerging field of teleneurology is delivering quality care to neurologic patients in increasingly numerous technologies and configurations. Teleneurology is well-positioned to address many of the logistical issues neurologists and their patients encounter today. However, formalized medical training has not caught up with this developing field, and there is a lack of formal education concentrating on the specific opportunities and challenges of teleneurology. Considering this, the American Academy of Neurology Telemedicine Work Group identified equivalencies with which any practitioner of teleneurology should be familiar. The purpose of this curriculum is not to define teleneurology or mandate where its use is appropriate, but rather to provide guidance on basic equivalencies that students, residents, and practitioners should know while practicing teleneurology. Comprehensive training in clinical bedside neurology is necessary to safely practice teleneurology and the components of this curriculum are an extension of that training. In this article, we offer a detailed discussion on the rationale for the contents of this curriculum and conclude by providing a model curriculum and an outline for evaluating residents in teleneurology.

Co-Expression of Glia Maturation Factor and Apolipoprotein E4 in Alzheimer’s Disease Brain

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimers disease (AD). The E4 allele of ApoE plays a crucial role in the inflammatory and neurodegenerative processes associated with AD. This is evident from the multiple effects of the ApoE isoforms in amyloid-β (Aβ) aggregation. Glia maturation factor (GMF) is a brain-specific neuroinflammatory protein that we have previously demonstrated to be significantly upregulated in various regions of AD brains compared to non-AD control brains and that it induces neurodegeneration. We have previously reported that GMF is predominantly expressed in the reactive astrocytes surrounding amyloid plaques (APs) in AD brain. In the present study, using immunohistochemical and dual immunofluorescence staining, we show the expression and colocalization of GMF and ApoE4 in AD brains. Our results show that ApoE4 is present within the APs of AD brain. Further, we found that GMF and ApoE4 were strongly expressed and co-associated in APs and in the reactive astrocytes surrounding APs in AD. An increased expression of GMF in APs and neurofibrillary tangles in the AD brain, and the co-localization of GMF and ApoE4 in APs suggest that GMF and ApoE4 together should be contributing to the neuropathological changes associated with AD.

Electrodiagnostic and Advanced Neuroimaging Characterization for Successful Treatment of Spinal Extradural Arachnoid Cyst

BACKGROUND Spinal extradural arachnoid cysts are relatively uncommon. Rarely, large cysts presented with spinal cord compression requiring surgical intervention. CASE DESCRIPTION We report a patient with a progressively enlarging spinal extradural arachnoid cyst causing worsening right S1 radiculopathy and gastrocnemius muscle atrophy. Electromyography and nerve conduction studies revealed an S1 motor radiculopathy. Serial magnetic resonance imaging findings confirmed enlargement of the small cyst originating from the sacral thecal sac on the right while 2 smaller cysts on the left remained stable. Dynamic computed tomography myelogram revealed connection to the thecal sac behind the right S1 nerve root. We performed a right hemilaminectomy from L5 to S2, exposed the cyst pedicle ligated it, and marsupialized the cyst. After surgery, the patient showed clinical and electrodiagnostic improvement. CONCLUSION This case illustrates the principles of timely surgical intervention after advanced diagnostic imaging and electrodiagnostic testing to improve neurologic function and minimize complications.

Sleep Disorders in Peripheral Neuropathy

The relationship between sleep apnea and peripheral neuropathy is complex. Neuropathy can cause or worsen sleep apnea while sleep apnea can be an independent risk factor for neuropathy. Both central and peripheral mechanisms operate in neuropathic conditions and can result in both central and obstructive sleep apnea syndromes. Along with sleep apnea, neuropathies can also be associated with hypoventilation, restless legs syndrome, and insomnia. In this chapter, we attempt to go over the sleep issues seen in common neuropathies.

Sleep Issues in Pediatric Neuromuscular Disorders

The clinical effects surfacing with either hereditary or nonhereditary neuromuscular disorders (NMD) in children have significant impact in terms of morbidity and mortality. Furthermore, the resulting neuromuscular weaknesses of these disorders predispose to sleep-related breathing disorders (SRBD) such as obstructive sleep apnea syndrome (OSAS), hypoventilation, and central sleep apnea. SRBD are very common in neuromuscular disorders and are often overlooked and misdiagnosed. Besides, NMD and OSAS are both prevalent disorders that overlap, thereby making it more challenging in delineating one from the other in deriving its etiology. SRBD become more prominent, severe, and persistent with the progression of underlying NMD. The effects of SRBD on cognition, learning, behavior, and respiratory status demonstrably influence their neurological functioning and quality of life. The strategies in creating awareness and early recognition of these patients benefit in identification of sleep problems and associated SRBD, respiratory complications. Besides, it aids in initiation of early treatment and thereby optimizing quality of life. We review SRBD in children with various NMD, along with assessment tools for early recognition and appropriate cost-effective therapies for treatment.

Sleep Issues in Neuromuscular Junction Disorders

Disorders of the neuromuscular junction (NMJ) typically cause weakness. However, as a part of their full clinical presentation, patients with disorders of NMJ have a variety of sleep problems. Of them, Sleep-Related Breathing Disorders (SRBD) like sleep apnea and hypoventilation are the most common ones. Sometimes, the associated sleep disorder may be the presenting symptoms of the NMJ disorder. The associated sleep disorder can contribute to the fatigue that already exists due to the NMJ disorder. Identification of the associated sleep disorder and selection of appropriate treatment is critical to better patient outcomes. In this chapter, we go over the neuromuscular junction, the most common NMJ disorders, the associated sleep issues and discuss the therapeutic options.

Evidence-based medicine for every day, everyone, and every therapeutic study: Bedside EBM

The rapid growth in published medical literature makes it difficult for clinicians to keep up with advances in their fields. This may result in a cursory scan of the abstract and conclusion of a study without critically evaluating study quality. The application of evidence‐based medicine (EBM) is the process of converting the abstract task of reading the literature into a practical method of using the literature to inform care in a specific clinical context while simultaneously expanding ones knowledge. EBM involves 4 steps: (1) stating the clinical problem in a defined question; (2) searching the literature for the evidence; (3) critically appraising the evidence for its validity; and (4) applying the evidence in the context of the patients situation, preferences, and values. In this review, we use the recently published trial of thymectomy in myasthenia gravis as an example and systematically go through the steps of assessing internal validity, precision, and external validity. Muscle Nerve 58: 486–496, 2018