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Article: Targeting Neuroinflammation to Alleviate Chronic Olfactory Dysfunction in Long COVID: A Role for Investigating Disease-Modifying Therapy (DMT)?

Di Stadio, Arianna / Bernitsas, Evanthia / La Mantia, Ignazio / Brenner, Michael J / Ralli, Massimo / Vaira, Luigi Angelo / Colizza, Andrea / Cavaliere, Carlo / Laudani, Matteo / Frohman, Teresa C / De Vincentiis, Marco / Frohman, Elliot M / Altieri, Marta

Life (Basel, Switzerland)

2023 Volume 13, Issue 1

Abstract: Chronic olfactory dysfunction after SARS-CoV-2 infection occurs in approximately 10% of patients with COVID-19-induced anosmia, and it is a growing public health concern. A regimen of olfactory training and anti-neuroinflammatory therapy with co- ... ...

Abstract	Chronic olfactory dysfunction after SARS-CoV-2 infection occurs in approximately 10% of patients with COVID-19-induced anosmia, and it is a growing public health concern. A regimen of olfactory training and anti-neuroinflammatory therapy with co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT) has shown promising results in clinical trials; however, approximately 15% of treated patients do not achieve full recovery of a normal olfactory threshold, and almost 5% have no recovery. Disease-modifying therapies (DMTs), which are used to treat autoimmune neuroinflammation in multiple sclerosis (MS), have not been studied for treating persistent inflammation in refractory post-COVID-19 smell disorder. This study evaluated COVID-19-related smell loss and MS-related smell loss, comparing the responses to different therapies. Forty patients with MS and 45 reporting post-COVID-19 olfactory disorders were included in the study. All patients underwent nasal endoscopy and were evaluated by using validated Sniffin' Sticks testing. The patients with long COVID were treated for three months with um-PEA-LUT plus olfactory training. The patients with MS were treated with DMTs. Olfactory functions before and after treatment were analyzed in both groups. At the experimental endpoint, 13 patients in the COVID-19 group treated with um-PEA-LUT had residual olfactory impairment versus 10 patients in the MS group treated with DMTs. The severity of the persistent olfactory loss was lower in the MS group, and the patients with MS treated with IFN-beta and glatiramer acetate had the preservation of olfactory function. These data provide a rationale for considering prospective trials investigating the efficacy of DMTs for post-COVID-19 olfactory disorders that are refractory to um-PEA-LUT with olfactory training. This study is the first to consider the role of DMT in treating refractory post-viral olfactory loss in patients with long COVID.
Language	English
Publishing date	2023-01-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life13010226
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Article ; Online: New Ways of "Seeing" the Mechanistic Heterogeneity of Multiple Sclerosis Plaque Pathogenesis.

Meltzer, Ethan I / Costello, Fiona E / Frohman, Elliot M / Frohman, Teresa C

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society

2018 Volume 38, Issue 1, Page(s) 91–100

Abstract: Background: Over the past few decades, we have witnessed a transformation with respect to the principles and pathobiological underpinnings of multiple sclerosis (MS). From the traditional rubric of MS as an inflammatory and demyelinating disorder ... ...

Abstract	Background: Over the past few decades, we have witnessed a transformation with respect to the principles and pathobiological underpinnings of multiple sclerosis (MS). From the traditional rubric of MS as an inflammatory and demyelinating disorder restricted to central nervous system (CNS) white matter, our contemporary view has evolved to encompass a broader understanding of the variable mechanisms that contribute to tissue injury, in a disorder now recognized to affect white and grey matter compartments. Evidence acquisition: A constellation of inflammation, ion channel derangements, bioenergetic supply: demand mismatches within the intra-axonal compartment, and alterations in the dynamics and oximetry of blood flow in CNS tissue compartments are observed in MS. These findings have raised questions regarding how histopathologic heterogeneity may influence the diverse clinical spectrum of MS; and, accordingly, how individual treatment needs vary from 1 patient to the next. Results: We are now on new scaffolding in MS; one that promises to translate key clinical and laboratory observations to the application of emerging patient-centered therapies. Conclusions: This review highlights our current knowledge of the underlying disease mechanisms in MS, explores the inflammatory and neurodegenerative consequences of tissue damage, and examines physiologic factors that contribute to bioenergetic homeostasis within the CNS of affected patients.
MeSH term(s)	Central Nervous System/pathology ; Humans ; Multiple Sclerosis/diagnosis ; Multiple Sclerosis/etiology ; Multiple Sclerosis/physiopathology
Language	English
Publishing date	2018-03-12
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1189901-3
ISSN	1536-5166 ; 1070-8022
ISSN (online)	1536-5166
ISSN	1070-8022
DOI	10.1097/WNO.0000000000000633
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Article ; Online: Cerebellar Control of Eye Movements.

Beh, Shin C / Frohman, Teresa C / Frohman, Elliot M

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society

2017 Volume 37, Issue 1, Page(s) 87–98

Abstract: ... in all classes of eye movements both in real-time control and in long-term calibration and learning (i.e ...

Abstract	Background: The cerebellum plays a central role in the online, real-time control, and long-term modulation of eye movements. Evidence acquisition: We reviewed the latest (fifth) edition of Leigh and Zee's textbook, The Neurology of Eye Movements, and literature in PUBMED using the following terms: cerebellum, flocculus, paraflocculus, vermis, oculomotor vermis, dorsal vermis, caudal fastigial nucleus, fastigial oculomotor region, uvula, nodulus, ansiform lobule, eye movements, saccades, ipsipulsion, contrapulsion, smooth pursuit, vergence, convergence, divergence, gaze-holding, down beat nystagmus, vestibulo-ocular reflex (VOR), angular VOR, translational VOR, skew deviation, velocity storage. Results: The cerebellum is vital in optimizing the performance of all classes of gaze-shifting and gaze-stabilizing reflexes. The flocculus-paraflocculus are crucial to VOR gain and direction, pulse-step matching for saccades, pursuit gain, and gaze-holding. The ocular motor vermis and caudal fastigial nuclei are essential in saccadic adaptation and accuracy, and pursuit gain. The nodulus and ventral uvula are involved in processing otolothic signals and VOR responses, including velocity storage. Conclusions: The cerebellum guarantees the precision of ocular movements to optimize visual performance and occupies a central role in all classes of eye movements both in real-time control and in long-term calibration and learning (i.e., adaptation).
MeSH term(s)	Animals ; Cerebellum/physiology ; Eye Movements/physiology ; Humans ; Reflex, Vestibulo-Ocular/physiology
Language	English
Publishing date	2017-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1189901-3
ISSN	1536-5166 ; 1070-8022
ISSN (online)	1536-5166
ISSN	1070-8022
DOI	10.1097/WNO.0000000000000456
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Article ; Online: Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Meltzer, Ethan / Frohman, Elliot M / Costello, Fiona E / Burton, Jodie M / Frohman, Teresa C

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society

2018 Volume 38, Issue 4, Page(s) 502–510

MeSH term(s)	Humans ; Magnetic Resonance Imaging/methods ; Multiple Sclerosis/complications ; Multiple Sclerosis/diagnosis ; Optic Neuritis/diagnosis ; Optic Neuritis/etiology ; Spine/diagnostic imaging
Language	English
Publishing date	2018-08-24
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1189901-3
ISSN	1536-5166 ; 1070-8022
ISSN (online)	1536-5166
ISSN	1070-8022
DOI	10.1097/WNO.0000000000000685
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Article ; Online: Precision Terminology: Why to Avoid the Term "Atypical Optic Neuritis".

Eggenberger, Eric R / Costello, Fiona / Frohman, Elliot / Pless, Misha / Van Stavern, Greg

Neurology

2022 Volume 99, Issue 24, Page(s) 1108–1109

MeSH term(s)	Humans ; Optic Neuritis/diagnosis ; Multiple Sclerosis
Language	English
Publishing date	2022-12-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000201474
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Article ; Online: Papilledema in a Patient Being Treated for Multiple Sclerosis.

Frohman, Larry / Turbin, Roger E / Wawrzusin, Peter J / Srivastava, Gaurav / Sakla, Nicole M

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society

2021 Volume 41, Issue 4, Page(s) e816

MeSH term(s)	Humans ; Multiple Sclerosis/complications ; Multiple Sclerosis/diagnosis ; Multiple Sclerosis/drug therapy ; Papilledema/diagnosis ; Papilledema/etiology
Language	English
Publishing date	2021-10-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1189901-3
ISSN	1536-5166 ; 1070-8022
ISSN (online)	1536-5166
ISSN	1070-8022
DOI	10.1097/WNO.0000000000001346
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Article ; Online: Multiple Sclerosis Followed by Neuromyelitis Optica Spectrum Disorder: From the National Multiple Sclerosis Society Case Conference Proceedings.

Goldschmidt, Carolyn / Galetta, Steven L / Lisak, Robert P / Balcer, Laura J / Hellman, Andrew / Racke, Michael K / Lovett-Racke, Amy E / Cruz, Roberto / Parsons, Matthew S / Sattarnezhad, Neda / Steinman, Lawrence / Zamvil, Scott S / Frohman, Elliot M / Frohman, Teresa C

Neurology(R) neuroimmunology & neuroinflammation

2022 Volume 10, Issue 1

Abstract: A woman presented at age 18 years with partial myelitis and diplopia and experienced multiple subsequent relapses. Her MRI demonstrated T2 abnormalities characteristic of multiple sclerosis (MS) (white matter ovoid lesions and Dawson fingers), and CSF ... ...

Abstract	A woman presented at age 18 years with partial myelitis and diplopia and experienced multiple subsequent relapses. Her MRI demonstrated T2 abnormalities characteristic of multiple sclerosis (MS) (white matter ovoid lesions and Dawson fingers), and CSF demonstrated an elevated IgG index and oligoclonal bands restricted to the CSF. Diagnosed with clinically definite relapsing-remitting MS, she was treated with various MS disease-modifying therapies and eventually began experiencing secondary progression. At age 57 years, she developed an acute longitudinally extensive transverse myelitis and was found to have AQP4 antibodies by cell-based assay. Our analysis of the clinical course, radiographic findings, molecular diagnostic methods, and treatment response characteristics support the hypothesis that our patient most likely had 2 CNS inflammatory disorders: MS, which manifested as a teenager, and neuromyelitis optica spectrum disorder, which evolved in her sixth decade of life. This case emphasizes a key principle in neurology practice, which is to reconsider whether the original working diagnosis remains tenable, especially when confronted with evidence (clinical and/or paraclinical) that raises the possibility of a distinctively different disorder.
MeSH term(s)	Humans ; Adolescent ; Female ; Middle Aged ; Neuromyelitis Optica ; Aquaporin 4 ; Multiple Sclerosis/diagnosis ; Multiple Sclerosis/complications ; Oligoclonal Bands ; Myelitis, Transverse/diagnosis ; Myelitis, Transverse/complications ; Immunoglobulin G
Chemical Substances	Aquaporin 4 ; Oligoclonal Bands ; Immunoglobulin G
Language	English
Publishing date	2022-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2767740-0
ISSN	2332-7812 ; 2332-7812
ISSN (online)	2332-7812
ISSN	2332-7812
DOI	10.1212/NXI.0000000000200037
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Article ; Online: Identification and treatment of the visual processing asymmetry in MS patients with optic neuritis: The Pulfrich phenomenon.

Sobhanian, Millad J / Agarwal, Rohit / Meltzer, Ethan / Kildebeck, Eric / Frohman, Benjamin S / Frohman, Ashley N / Galetta, Steven L / Saidha, Shiv / White, Owen / Villoslada, Pablo / Paul, Friedemann / Petzold, Axel / Rennaker, Robert L / Martinez-Lapiscina, Elena H / Balcer, Laura J / Kardon, Randy / Frohman, Elliot M / Frohman, Teresa C

Journal of the neurological sciences

2018 Volume 387, Page(s) 60–69

Abstract: ... a history of optic neuropathy (e.g. related to acute optic neuritis or subclinical optic neuropathy ...

Abstract	Background: The Pulfrich phenomenon (PF) is the illusory perception that an object moving linearly along a 2-D plane appears to instead follow an elliptical 3-D trajectory, a consequence of inter-eye asymmetry in the timing of visual object identification in the visual cortex; with optic neuritis as a common etiology. Objective: We have designed an objective method to identify the presence and magnitude of the PF, in conjunction with a cooresponding strategy by which to abolish the effect; with monocular application of neutral density filters to the less affected fellow eye, in patients with MS and a history of optic neuropathy (e.g. related to acute optic neuritis or subclinical optic neuropathy). Methods: Twenty-three MS patients with a history of acute unilateral or bilateral optic neuritis, and ten healthy control subjects (HC) were recruited to participate in a pilot study to assess our strategy. Subjects were asked to indicate whether a linearly moving pendulum ball followed a linear 2-D path versus an illusory 3-D elliptical object-motion trajectory, by reporting the ball's approximation to one of nine horizontally-oriented colored wires that were positioned parallel to one another and horizontal to the linear pendulum path. Perceived motion of the bob that moved along wires behind or in front (along the 'Z' plane) of the middle reference wire indicated an illusory elliptical trajectory of ball motion consistent with the PF. Results: When the neutral density filter titration was applied to the fellow eye the severity of the PF decreased, eventually being fully abolished in all but one patient. The magnitude of neutral density filtering required correlated to the severity of the patient's initial PF magnitude (p < 0.001). Conclusions: We ascertained the magnitude of the visual illusion associated with the PF, and the corresponding magnitude of neutral density filtering necessary to abolish it.
MeSH term(s)	Adult ; Female ; Flicker Fusion/physiology ; Humans ; Illusions/physiology ; Male ; Middle Aged ; Motion Perception/physiology ; Multiple Sclerosis/complications ; Optic Neuritis/complications ; Optic Neuritis/diagnosis ; Optic Neuritis/therapy ; Photic Stimulation ; Tomography, Optical Coherence ; Visual Acuity/physiology ; Young Adult
Language	English
Publishing date	2018-02-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80160-4
ISSN	1878-5883 ; 0022-510X ; 0374-8642
ISSN (online)	1878-5883
ISSN	0022-510X ; 0374-8642
DOI	10.1016/j.jns.2018.01.029
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Article ; Online: Interferon beta and long-term disability in multiple sclerosis--reply.

Greenberg, Benjamin M / Frohman, Elliot

JAMA neurology

2013 Volume 70, Issue 5, Page(s) 652–653

Language	English
Publishing date	2013-05
Publishing country	United States
Document type	Comment ; Letter
ZDB-ID	2702023-X
ISSN	2168-6157 ; 2168-6149
ISSN (online)	2168-6157
ISSN	2168-6149
DOI	10.1001/jamaneurol.2013.1
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Article ; Online: Mitigating alemtuzumab-associated autoimmunity in MS: A "whack-a-mole" B-cell depletion strategy.

Meltzer, Ethan / Campbell, Sarah / Ehrenfeld, Benjamin / Cruz, Roberto A / Steinman, Lawrence / Parsons, Matthew S / Zamvil, Scott S / Frohman, Elliot M / Frohman, Teresa C

Neurology(R) neuroimmunology & neuroinflammation

2020 Volume 7, Issue 6

Abstract: ... driven pilot study, 10 patients received low-dose rituximab (50-150 mg/m: Results: Five patients ...

Abstract	Objective: To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19 Methods: In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50-150 mg/m Results: Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed. Conclusions: An anti-CD20 "whack-a-mole" B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation. Classification of evidence: This study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases.
MeSH term(s)	Adult ; Alemtuzumab/administration & dosage ; Alemtuzumab/adverse effects ; Alemtuzumab/pharmacology ; Autoimmune Diseases/chemically induced ; Autoimmune Diseases/prevention & control ; B-Lymphocytes/drug effects ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Humans ; Immunologic Factors/administration & dosage ; Immunologic Factors/adverse effects ; Immunologic Factors/pharmacology ; Male ; Middle Aged ; Multiple Sclerosis/drug therapy ; Outcome Assessment, Health Care ; Pilot Projects ; Rituximab/administration & dosage ; Rituximab/adverse effects ; Rituximab/pharmacology
Chemical Substances	Immunologic Factors ; Alemtuzumab (3A189DH42V) ; Rituximab (4F4X42SYQ6)
Language	English
Publishing date	2020-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2767740-0
ISSN	2332-7812 ; 2332-7812
ISSN (online)	2332-7812
ISSN	2332-7812
DOI	10.1212/NXI.0000000000000868
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