Hearing abnormalities in multiple sclerosis: clinical semiology and pathophysiologic mechanisms.

Auditory manifestations from multiple sclerosis (MS) are not as common as the well-recognized sentinel exacerbations of optic neuritis, partial myelitis, motor weakness, vertiginous episodes, heat intolerance, and eye movement abnormalities. This paper discusses four cases of auditory changes, secondary to MS, and describes the first case, to our knowledge, of palinacousis, the perseveration of hearing, despite cessation of the sound stimulus. For each we characterize the initial complaint, the diagnostic work up, and ultimately, underscore the individualized treatment interventions, that allowed us to achieve a remission in all four cases. Individually codifying the treatment regimens served to mitigate, if not to abolish, the clinical derangements in hearing. Special attention is focused upon examination of the clinical manifestations and the pathophysiologic mechanisms which are responsible for them. We further emphasize the differential diagnostic considerations, and physical exam findings, along with the results of laboratory testing, neuro-imaging sequences, and lesion localization. Taken together, such information is germane to organizing cogently coherent strategic treatment plan(s). We believe that this small case series represents a clinically pragmatic example of 'precision medicine'; a principal theme and goal throughout this paper, the achievement of such in MS, but also as an illustration for the assessment and management schema for neuroimmunologic disorders in general.

Part II. high-dose methotrexate with leucovorin rescue for severe COVID-19: An immune stabilization strategy for SARS-CoV-2 induced 'PANIC' attack.

Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial that high-dose methotrexate with leucovorin (HDMTX-LR) rescue can abolish 'PANIC', thereby 'left-shifting' severe COVID-19 patients to the group majority of those infected with SARS-CoV-2, who are designated as having mild, even asymptomatic, disease. HDMTX-LR is endowed with broadly pleiotropic properties and is a repurposed, generic, inexpensive, and widely available agent which can be administered early in the course of severe COVID-19 thus rescuing the critical and irreplaceable gas-exchange alveoli. Further, we describe a preventative treatment intervention regimen for those designated as having mild to moderate COVID-19 disease, but who exhibit features which herald the transition to the severe variant of this disease. Both of our proposed hypothesis-driven questions should be urgently subjected to rigorous assessment in the context of randomized controlled trials, in order to confirm or refute the contention that the approaches characterized herein, are in fact capable of exerting mitigating, if not abolishing, effects upon SARS-CoV-2 triggered 'PANIC Attack'. Confirmation of our immunotherapy hypothesis would have far-reaching ramifications for the current pandemic, along with yielding invaluable lessons which could be leveraged to more effectively prepare for the next challenge to global health.

Retinal Architecture and Melanopsin-Mediated Pupillary Response Characteristics: A Putative Pathophysiologic Signature for the Retino-Hypothalamic Tract in Multiple Sclerosis.

Importance: A neurophysiologic signature of the melanopsin-mediated persistent constriction phase of the pupillary light reflex may represent a surrogate biomarker for the integrity of the retinohypothalamic tract, with potential utility for investigating alterations in homeostatic mechanisms associated with brain disorders and implications for identifying new treatments. Objective: To characterize abnormalities of retinal architecture in patients with multiple sclerosis (MS) and corresponding alterations in the melanopsin-mediated sustained pupillary constriction response. Design, Setting, and Participants: The case-control study was an experimental assessment of various stimulus-induced pupillary response characteristics and was conducted at a university clinical center for MS from September 6, 2012, to February 2015. Twenty-four patients with MS (48 eyes) and 15 individuals serving as controls (30 eyes) participated. The melanopsin-mediated, sustained pupillary constriction phase response following cessation of a blue light stimulus was compared with the photoreceptor-mediated pupillary constriction phase response following cessation of a red light stimulus. Optical coherence tomography was used to characterize the association between pupillary response characteristics and alterations in retinal architecture, specifically, the thickness of the retinal ganglion cell layer and inner plexiform layer (GCL + IPL). Main Outcomes and Measures: Association of pupillary response characteristics with alterations in retinal architecture. Results: Of 24 patients with MS included in the analysis, 17 were women (71%); mean (SD) age was 47 (11) years. Compared with eyes from individuals with MS who had normal optical coherence tomography-derived measures of retinal GCL + IPL thickness, eyes of patients who had GCL + IPL thickness reductions to less than the first percentile exhibited a correspondingly significant attenuation of the melanopsin-mediated sustained pupillary response (mean [SD] pupillary diameter ratios at a point in time, 0.18 [0.1] vs 0.33 [0.09]; P < .001, generalized estimating equation models accounting for age and within-patient intereye correlations). Conclusions and Relevance: In this case-control study, attenuation of the melanopsin-mediated sustained pupillary constriction response was significantly associated with thinning of the GCL + IPL sector of the retina in the eyes of patients with MS, particularly those with a history of acute optic neuritis. Melanopsin-containing ganglion cells in the retina represent, at least in part, the composition of the retinohypothalamic tract. As such, our findings may signify the ability to elucidate a putative surrogate neurophysiologic signature that correlates with a constellation of homeostatic mechanisms in both health and illness.

High-dose methotrexate with leucovorin rescue: For monumentally severe CNS inflammatory syndromes.

BACKGROUND: At sufficiently high doses, methotrexate (HDMTX) achieves substantial CNS penetration, whereas other tissues can be rescued from the effects of HDMTX by leucovorin rescue (LR), which does not penetrate the blood-brain barrier. OBJECTIVES: To report on the efficacy and safety of HDMTX with LR (HDMTX-LR), in the treatment of acute demyelinating inflammatory CNS syndromes refractory to conventional immunotherapy. METHODS: We performed a retrospective chart review of 12 patients treated (6 multiple sclerosis [MS], 4 neuromyelitis optica [NMO], and 2 Sjogren's syndrome myelopathy [SSM]) with HDMTX-LR after failing to improve, or exhibiting worsening following conventional immunotherapy. 11 patients were followed for a total of 6months following HDMTX-LR (one was lost to follow up after 1month); and clinical findings were documented at 1month, 3months, and 6months following HDMTX-LR therapy. RESULTS: Ten patients demonstrated both clinical and radiologic evidence of near, if not complete, abolishment of disease activity, in conjunction with impressive reconstitution of neurologic function in the 6-month period following HDMTX-LR. Mean Kurtzke Expanded Disability Status Scale (EDSS) prior to HDMTX-LR was 8.1 (±1.4). Following HDMTX-LR, mean EDSS was 6.6 (±2.4) at 1month, 5.8 (±2.3) at 3months, and 5.7 (±2.3) at 6months. CONCLUSIONS: In this retrospective assessment of treatment-recalcitrant fulminant inflammatory CNS syndromes, HDMTX-LR was observed to be a safe and highly effective treatment, producing the rapid and near complete cessation of disease activity, in conjunction with an important corresponding and 'durable remission' in the majority of our small treatment cohort.

Optical coherence tomography reflects brain atrophy in multiple sclerosis: A four-year study.

OBJECTIVE: The aim of this work was to determine whether atrophy of specific retinal layers and brain substructures are associated over time, in order to further validate the utility of optical coherence tomography (OCT) as an indicator of neuronal tissue damage in patients with multiple sclerosis (MS). METHODS: Cirrus high-definition OCT (including automated macular segmentation) was performed in 107 MS patients biannually (median follow-up: 46 months). Three-Tesla magnetic resonance imaging brain scans (including brain-substructure volumetrics) were performed annually. Individual-specific rates of change in retinal and brain measures (estimated with linear regression) were correlated, adjusting for age, sex, disease duration, and optic neuritis (ON) history. RESULTS: Rates of ganglion cell + inner plexiform layer (GCIP) and whole-brain (r = 0.45; p < 0.001), gray matter (GM; r = 0.37; p < 0.001), white matter (WM; r = 0.28; p = 0.007), and thalamic (r = 0.38; p < 0.001) atrophy were associated. GCIP and whole-brain (as well as GM and WM) atrophy rates were more strongly associated in progressive MS (r = 0.67; p < 0.001) than relapsing-remitting MS (RRMS; r = 0.33; p = 0.007). However, correlation between rates of GCIP and whole-brain (and additionally GM and WM) atrophy in RRMS increased incrementally with step-wise refinement to exclude ON effects; excluding eyes and then patients (to account for a phenotype effect), the correlation increased to 0.45 and 0.60, respectively, consistent with effect modification. In RRMS, lesion accumulation rate was associated with GCIP (r = -0.30; p = 0.02) and inner nuclear layer (r = -0.25; p = 0.04) atrophy rates. INTERPRETATION: Over time GCIP atrophy appears to mirror whole-brain, and particularly GM, atrophy, especially in progressive MS, thereby reflecting underlying disease progression. Our findings support OCT for clinical monitoring and as an outcome in investigative trials.

Functional treatments in multiple sclerosis.

PURPOSE OF REVIEW: This review focuses on recent advances in the understanding and management of symptoms and dysfunctions associated with multiple sclerosis (MS). RECENT FINDINGS: A broad spectrum of dysfunctions associated with MS are under investigation. Research published in the past year and a half addresses gait dysfunction, exercise training, fatigue, bowel/bladder and sexual dysfunction, and sleep disruption. Functional electrical stimulation and strength training have been validated for improvement in gait and motor function. Exercise training has been shown to benefit mood and quality of life scores and to reduce circulating inflammatory cytokine levels. Fatigue remains a challenging problem with incremental improvements in understanding of underlying causes and effective drug therapies offered by recent work. Treatment of bowel, bladder and sexual dysfunction utilizing a variety of modalities has been investigated with some progress. SUMMARY: In the absence of treatments to reverse neurologic injury due to MS, effective symptom management and functional improvement remain essential to mitigate disability and maintain quality of life. Basic research, as well as controlled clinical trials, in this realm offers promising insights and solutions.

Sexual dysfunction in patients with multiple sclerosis: a multidisciplinary approach to evaluation and management.

Multiple sclerosis (MS) is the most common cause of progressive neurological disability in young adults. In addition to spasticity, tremors, weakness, sensory disturbances, depression, cognitive problems, and bladder or bowel dysfunction, sexual dysfunction (SD) is also a prevalent and destructive manifestation of the disease that severely affects quality of life. Evaluation of this disorder requires insight into the primary (changes that directly affect libido, sexual response and orgasm due to direct damage to the nervous system), secondary (complaints which are related to the physical disability of MS, such as fatigue, muscle rigidity, weakness and spasms), and tertiary (emotional, social and cultural aspects of MS) components of MS-associated SD. Given the complexity and multifactorial nature of SD, a multidisciplinary approach is necessary when treating patients with MS. The aim of this Review is to provide a holistic approach to the evaluation and management of SD in patients with MS, incorporating the latest data from the fields of urology, neurology, nursing, social work, and psychology. What is currently known regarding the evaluation and management of SD in patients with MS will be presented from the perspective of these specialties.

Acquired sexual paraphilia in patients with multiple sclerosis.

BACKGROUND: Sexual dysfunction in patients with multiple sclerosis is typically characterized by diminished libido, erectile and ejaculatory dysfunction in men, and poor lubrication and anorgasmy in women. In contrast, hypersexual behavior and paraphilias are distinctly uncommon in this population of patients, but have been associated with various focal brain lesions. PATIENT AND METHODS: We describe a man with clinically definite multiple sclerosis who developed profound and abrupt disinhibition and paraphilic behavior during an exacerbation. RESULTS: Neuroimaging revealed a marked increase in the number of enhancing lesions in the right sides of the hypothalamus and mesencephalon and extending into the right sides of the red nucleus, substantia nigra, and internal capsule. The altered sexual behavior was characterized by an obsessive and insatiable desire to touch women's breasts. CONCLUSIONS: Acquired sexual paraphilic behavior is uncommon in patients with multiple sclerosis but may occur when inflammatory demyelination involves the hypothalamic and septal regions of the basal prosencephalon. Our experience with this man illustrates the great difficulty involved in treating such patients when the paraphilic behavior becomes persistent.