Dominant perivenular enhancement of tumefactive demyelinating lesions in multiple sclerosis

Abstract Introduction Sleep-disordered breathing is common in persons with multiple sclerosis (PwMS), and may contribute to debilitating fatigue and other chronic MS symptoms. The majority of research to date on SDB in MS has focused on the prevalence and consequences of obstructive sleep apnea; however, PwMS may also be at increased risk for central sleep apnea (CSA), and the utility of methods to assess CSA in PwMS warrant further exploration. We present a patient with secondary progressive multiple sclerosis who was found to have severe central sleep apnea on WatchPAT testing. Report of case(s) A 61 year-old female with a past medical history of secondary progressive multiple sclerosis presented with complaints of fragmented sleep. MRI of the brain, cervical spine, and thoracic spine showed numerous demyelinating lesions in the brain, brainstem, cervical, and thoracic spinal cord. Upon presentation, the patient noted snoring, witnessed apneas, and daytime sleepiness. WatchPAT demonstrated severe sleep apnea, with a pAHI of 63.3, and a minimum oxygen saturation of 90%. The majority of the scored events were non-obstructive in nature (73.1% of all scored events), and occurred intermittently in a periodic fashion. Conclusion The differential diagnosis of fatigue in PwMS should include sleep-disordered breathing, including both obstructive and central forms of sleep apnea. Demyelinating lesions in the brainstem (which may contribute to impairment of motor and sensory networks that control airway patency and respiratory drive), and progressive forms of MS, have been linked to both OSA and CSA. The present data illustrate this relationship in a person with progressive MS, and offer support for the WatchPAT as a cost-effective means to evaluate for both OSA and CSA in PwMS, while reducing patient burden. PwMS may be at increased risk for CSA. Careful clinical consideration should be given to ordering appropriate sleep testing to differentiate central from obstructive sleep apnea in PwMS, particularly for patients with demyelinating lesions in the brainstem. Support (if any) 1. Braley TJ, Segal BM, Chervin RD. Obstructive sleep apnea and fatigue in patients with multiple sclerosis. J Clin Sleep Med. 2014 Feb 15;10(2):155–62. doi: 10.5664/jcsm.3442. PMID: 24532998; PMCID: PMC3899317.

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Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

Cells ◽

10.3390/cells10030686 ◽

2021 ◽

Vol 10 (3) ◽

pp. 686

Author(s):

Maria Concetta Geloso ◽

Nadia D’Ambrosi

Keyword(s):

Multiple Sclerosis ◽

Neuronal Death ◽

Environmental Changes ◽

Experimental Models ◽

Synaptic Dysfunction ◽

Synapse Elimination ◽

Neurodegenerative Process ◽

Immune Mediated ◽

Wide Range ◽

Demyelinating Lesions

Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients’ long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models.

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Remyelination of Demyelinated CNS Axons by Transplanted Human Schwann Cells: The Deleterious Effect of Contaminating Fibroblasts

Cell Transplantation ◽

10.3727/000000001783986774 ◽

2001 ◽

Vol 10 (3) ◽

pp. 305-315 ◽

Cited By ~ 27

Author(s):

C. M. H. Brierley ◽

A. J. Crang ◽

Y. Iwashita ◽

J. M. Gilson ◽

N. J. Scolding ◽

...

Keyword(s):

Multiple Sclerosis ◽

Schwann Cell ◽

Schwann Cells ◽

Axonal Degeneration ◽

Autologous Transplantation ◽

Growth Factor Receptor ◽

Adult Rats ◽

Demyelinating Lesions ◽

Cell Implantation

Areas of demyelination can be remyelinated by transplanting myelin-forming cells. Schwann cells are the naturally remyelinating cells of the peripheral nervous system and have a number of features that may make them attractive for cell implantation therapies in multiple sclerosis, in which spontaneous but limited Schwann cell remyelination has been well documented. Schwann cells can be expanded in vitro, potentially affording the opportunity of autologous transplantation; and they might also be spared the demyelinating process in multiple sclerosis. Although rat, cat, and monkey Schwann cells have been transplanted into rodent demyelinating lesions, the behavior of transplanted human Schwann cells has not been evaluated. In this study we examined the consequences of injecting human Schwann cells into areas of acute demyelination in the spinal cords of adult rats. We found that transplants containing significant fibroblast contamination resulted in deposition of large amounts of collagen and extensive axonal degeneration. However, Schwann cell preparations that had been purified by positive immunoselection using antibodies to human low-affinity nerve growth factor receptor containing less than 10% fibroblasts were associated with remyelination. This result indicates that fibroblast contamination of human Schwann cells represents a greater problem than would have been appreciated from previous studies.

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Recent advances on immunosuppressive drugs and remyelination enhancers for the treatment of multiple sclerosis

Current Pharmaceutical Design ◽

10.2174/1381612827666210127121829 ◽

2021 ◽

Vol 27 ◽

Author(s):

Jennifer Cadenas-Fernández ◽

Pablo Ahumada-Pascual ◽

Luis Sanz Andreu ◽

Ana Velasco

Keyword(s):

Multiple Sclerosis ◽

Intracellular Signaling ◽

Demyelinating Disease ◽

Lipid Synthesis ◽

Immunosuppressive Drugs ◽

Nerve Fibers ◽

Myelin Sheaths ◽

Demyelinating Lesions ◽

The Central Nervous System ◽

Lipid Structures

: Mammalian nervous systems depend crucially on myelin sheaths covering the axons. In the central nervous system, myelin sheaths consist of lipid structures which are generated from the membrane of oligodendrocytes (OL). These sheaths allow fast nerve transmission, protect axons and provide them metabolic support. In response to specific traumas or pathologies, these lipid structures can be destabilized and generate demyelinating lesions. Multiple sclerosis (MS) is an example of a demyelinating disease in which the myelin sheaths surrounding the nerve fibers of the brain and spinal cord are damaged. MS is the leading cause of neurological disability in young adults in many countries, and its incidence has been increasing in recent decades. Related to its etiology, it is known that MS is an autoimmune and inflammatory CNS disease. However, there are no effective treatments for this disease and the immunomodulatory therapies that currently exist have proven limited success since they only delay the progress of the disease. Nowadays, one of the main goals in the MS research is to find treatments which allows the recovery of neurological disabilities due to demyelination. To this end, different approaches, such as modulating intracellular signaling or regulating the lipid metabolism of OLs, are being considered. Here, in addition to immunosuppressive or immunomodulatory drugs that reduce the immune response against myelin sheaths, we review a diverse group of drugs that promotes endogenous remyelination in MS patients and whose use may be interesting as potential therapeutic agents in MS disease. To this end, we compile specific treatments against MS that are currently in the market with remyelination strategies which have entered into human clinical trials for future reparative MS therapies. The method used in this study is a systematic literature review on PubMed, Web of Science and Science Direct databases up to May 31, 2020. To narrow down the search results in databases, more specific keywords, such as, “myelin sheath”, “remyelination”, “demyelination”, “oligodendrocyte” and “lipid synthesis” were used to focus the search. We favoured papers published after January, 2015, but did not exclude earlier seminal papers.

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Overexpression of sphingosine-1-phosphate receptors on reactive astrocytes drives neuropathology of multiple sclerosis rebound after fingolimod discontinuation

Multiple Sclerosis Journal ◽

10.1177/1352458518763095 ◽

2018 ◽

Vol 24 (8) ◽

pp. 1133-1137 ◽

Cited By ~ 14

Author(s):

Maria Teresa Giordana ◽

Paola Cavalla ◽

Antonio Uccelli ◽

Alice Laroni ◽

Fabio Bandini ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Disease Activity ◽

Multiple Sclerosis Patient ◽

Fatal Outcome ◽

Reactive Astrocytes ◽

Normal Appearing White Matter ◽

Sphingosine 1 Phosphate ◽

Demyelinating Lesions

We present the neuropathological description of an autoptic case of fatal rebound of disease activity after fingolimod discontinuation in a multiple sclerosis patient. MRI prior to the fatal outcome showed several large tumefactive demyelinating lesions. These lesions were characterized by prominent astrocytic gliosis, with a remarkable preponderance of large hypertrophic reactive astrocytes showing intense expression of sphingosine-1-phosphate receptor 1. Prominent astrocytic gliosis was also diffusely observed in the normal-appearing white matter. Dysregulated sphingosine-1-phosphate signaling on astrocytes following fingolimod withdrawal might represent a possible contributing mechanism to disease rebound and might account for the unusual radiological and neuropathological features observed in the present case.

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Multiple Sclerosis and Cognitive Impairment

10.1093/med/9780197583425.003.0012 ◽

2021 ◽

pp. 39-41

Author(s):

Cristina Valencia-Sanchez ◽

Jonathan L. Carter

Keyword(s):

Magnetic Resonance Imaging ◽

Multiple Sclerosis ◽

Cognitive Impairment ◽

Information Processing ◽

Magnetic Resonance ◽

Processing Speed ◽

Rehabilitation Program ◽

Resonance Imaging ◽

The Past ◽

Demyelinating Lesions

A 60-year-old woman with a history of multiple sclerosis was evaluated for cognitive concerns. At age 30 years she had an episode of optic neuritis, followed by an episode of bilateral lower extremity numbness at age 35 years. In the following years, she had at least 6 further multiple sclerosis relapses, the last one approximately 3 years before the current presentation. She was initially treated with interferon, but she did not tolerate it. She had been taking glatiramer acetate for the past 3 years. She had noticed progressive deterioration of her gait for the past 3 years, having to use a cane on occasions. Magnetic resonance imaging of the brain showed multiple demyelinating lesions), and magnetic resonance imaging of the cervical spine showed 1 small demyelinating lesion at C6. Vitamin B12 level and thyroid function were normal. Comprehensive neuropsychological testing showed multidomain cognitive impairment, mainly impairment of speed of information processing, spatial discrimination skills, and attention/concentration. The patient’s multiple sclerosis phenotype was consistent with secondary progressive multiple sclerosis. Her cognitive impairment profile, mainly affecting information processing speed and disinhibition suggestive of frontal dysfunction, was consistent with multiple sclerosis. The patient began a cognitive rehabilitation program, and learning and memory aids were recommended. Lifestyle changes were also recommended, including weight loss and physical exercise. She was given recommendations for sleep hygiene and began taking gabapentin for neuropathic pain and restless legs. Cognitive impairment is common in patients with multiple sclerosis. Slowed cognitive processing speed and episodic memory decline are the most common cognitive deficits in MS, with additional difficulties in executive function, verbal fluency, and visuospatial analysis.

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Plasma Exchange in a Patient with Tumefactive, Corticosteroid-Resistant Multiple Sclerosis

International Journal of MS Care ◽

10.7224/1537-2073.2014-078 ◽

2015 ◽

Vol 17 (5) ◽

pp. 231-235 ◽

Cited By ~ 6

Author(s):

Kristin M. Ikeda ◽

Donald H. Lee ◽

J. Alexander Fraser ◽

Seyed Mirsattari ◽

Sarah A. Morrow

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Plasma Exchange ◽

Magnetic Resonance Images ◽

Periventricular White Matter ◽

Disease Modifying Therapy ◽

Natalizumab Treatment ◽

Demyelinating Lesions ◽

Recent Diagnosis ◽

Tumefactive Multiple Sclerosis

Tumefactive multiple sclerosis (MS) is an aggressive form of MS that can be difficult to treat with standard therapies. In severe MS relapses, plasma exchange (PLEX) has shown some benefit, but reports of its use in patients with tumefactive MS are limited. This article describes the successful use of PLEX in a patient with tumefactive MS. A 46-year-old right-handed woman with a recent diagnosis of MS presented with drowsiness, dysarthria, horizontal nystagmus, and quadriparesis. Her brain magnetic resonance images demonstrated multiple tumefactive demyelinating lesions in the medulla, bilateral periventricular white matter, and corona radiata white matter. She was initially treated with a 10-day course of intravenous methylprednisolone without benefit; therefore, PLEX was initiated. After the second exchange, the patient started to improve and was discharged initially to rehabilitation and then home. She was started on disease-modifying therapy with natalizumab and did not experience further relapses but had slow clinical decline during the next year, which led to discontinuation of natalizumab treatment. PLEX may be used as second-line treatment in corticosteroid-resistant MS relapses, but there are limited reports of its use in patients with tumefactive MS. This patient presented with aggressive disease with multiple tumefactive lesions and did not respond to standard treatment with corticosteroids. PLEX was successful in improving her symptoms, allowing her to return home, although the disease progressed during the next year.

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Bipolar disorder and multiple sclerosis

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2007000700016 ◽

2007 ◽

Vol 65 (4b) ◽

pp. 1177-1180 ◽

Cited By ~ 8

Author(s):

Mariana Inés Ybarra ◽

Marcos Aurélio Moreira ◽

Carolina Reis Araújo ◽

Marco Aurélio Lana-Peixoto ◽

Antonio Lucio Teixeira

Keyword(s):

Multiple Sclerosis ◽

Bipolar Disorder ◽

Adverse Reaction ◽

Mood Disorders ◽

Psychiatric Symptoms ◽

Biological Factors ◽

Demyelinating Lesions

Bipolar disorder may be overrepresented in multiple sclerosis (MS) patients. Although research in this area is limited, studies assessing the nature of this association have focused on genetic aspects, adverse reaction to drugs and brain demyelinating lesions. Herein we report three patients with MS that also presented bipolar disorder. The coexistence of neurological and psychiatric symptoms in most MS relapses highlights the relevance of biological factors in the emergence of mood disorders in these patients.

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Delayed-Onset multiphasic demyelinating lesions after high dose radiofrequency electromagnetic field exposure: A multiple sclerosis (MS) mimic

Multiple Sclerosis and Related Disorders ◽

10.1016/j.msard.2020.102318 ◽

2020 ◽

Vol 45 ◽

pp. 102318

Author(s):

Sophia M Raefsky ◽

Amit Chaudhari ◽

Michael Y. Sy

Keyword(s):

Multiple Sclerosis ◽

Electromagnetic Field ◽

High Dose ◽

Field Exposure ◽

Delayed Onset ◽

Demyelinating Lesions ◽

Radiofrequency Electromagnetic Field

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Multiple Sclerosis and HTLV-I associated myelopathy/tropical spastic paraparesis are two distinct clinical entities

Multiple Sclerosis Journal ◽

10.1177/135245859600200205 ◽

1996 ◽

Vol 2 (2) ◽

pp. 88-90 ◽

Cited By ~ 2

Author(s):

Fidias E Leon-S ◽

Kimiyoshi Arimura ◽

Mitsuhiro Osame

Keyword(s):

Multiple Sclerosis ◽

Clinical Features ◽

Spastic Paraparesis ◽

Early Response ◽

Blink Reflex ◽

Tropical Spastic Paraparesis ◽

Diagnosis And Therapy ◽

Neurophysiological Data ◽

Demyelinating Lesions ◽

Radiological Studies

Multiple sclerosis (MS) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) can overlap in their clinical features and thereby cause difficulties for clinicians in relation to diagnosis and therapy. However, epidemiological biochemical, immunological, virological and radiological studies point to a number of significant differences. Recent comparative neurophysiological data, induding blink reflex studies, obtained in these disorders, is briefly reviewed here and provides additional evidence of difference. The abnormal blink reflex in patients with MS consist of prolonged latencies and absences of R1 and R2 responses and are mainly due to demyelinating lesions around the pons. In contrast, in HAM/TSP the blink reflex abnormalities frequently include an unusual early response, R/k, which is probably a consequence of interneuronal hyperexcitability around the brainstem. Thus these findings provide further support for our contention that HAM/TSP and multiple sclerosis are distinctly different both as clinical entities and in their underlying pathomechanisms.

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