Multiple Sclerosis: Frohman EM

Goodin DS, Arnason BG, Coyle PK, Frohman EM, Paty DW, Anonymous00113. · Therapeutics and Technology Assessment Subcommittee, American Academy of Neurology, St. Paul, MN 55116, USA. · Neurology. · Pubmed #14638950 No free full text.

Abstract: Mitoxantrone is the first drug approved for the treatment of secondary progressive multiple sclerosis (SPMS) in the United States. This assessment considers use of mitoxantrone in the treatment of MS. Mitoxantrone probably reduces the clinical attack rate and reduces attack-related MRI outcomes in patients with relapsing MS (Type B recommendation). Also, mitoxantrone may have a beneficial effect on disease progression in patients with MS whose clinical condition is worsening (Type B recommendation). The potential for serious toxicity of mitoxantrone, however, must be taken into account when considering this therapy in individual patients. Moreover, because the potential clinical benefits on disease progression appear to be only modest, the results of the single phase III trial should be replicated in another (and hopefully much larger) clinical study before this agent is widely recommended for the treatment of patients with MS.

Frohman EM, Goodin DS, Calabresi PA, Corboy JR, Coyle PK, Filippi M, Frank JA, Galetta SL, Grossman RI, Hawker K, Kachuck NJ, Levin MC, Phillips JT, Racke MK, Rivera VM, Stuart WH, Anonymous00118. · University of Texas Southwestern Medical Center at Dallas, USA. · Neurology. · Pubmed #12963748 No free full text.

Abstract: Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.

Goodin DS, Frohman EM, Garmany GP, Halper J, Likosky WH, Lublin FD, Silberberg DH, Stuart WH, van den Noort S, Anonymous00242. · No affiliation provided · Neurology. · Pubmed #11805241 No free full text.

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Frohman EM, Zivadinov R. · No affiliation provided · Neurology. · Pubmed #18056576 No free full text.

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Stüve O, Eagar TN, Frohman EM, Cravens PD. · No affiliation provided · Arch Neurol. · Pubmed #17923622 No free full text.

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Frohman EM, Havrdova E, Lublin F, Barkhof F, Achiron A, Sharief MK, Stuve O, Racke MK, Steinman L, Weiner H, Olek M, Zivadinov R, Corboy J, Raine C, Cutter G, Richert J, Filippi M. · Departments of Neurology and Ophthalmology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA. · Arch Neurol. · Pubmed #16606781 No free full text.

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Racke MK, Hawker K, Frohman EM. · No affiliation provided · Arch Neurol. · Pubmed #14967763 links to  free full text

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Racke MK, Hawker K, Frohman EM. · No affiliation provided · Arch Neurol. · Pubmed #11176933 links to  free full text

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Frohman EM, Racke M, van Den Noort S. · No affiliation provided · Arch Neurol. · Pubmed #10891973 links to  free full text

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Frohman EM, Eagar T, Monson N, Stuve O, Karandikar N. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA. · Neuroimaging Clin N Am. · Pubmed #19068403 No free full text.

Abstract: Multiple sclerosis is widely recognized as the most commonly identified cause of progressive neurologic disability in young adults throughout the developed world. The disorder is clinically suspected when patients experience either acute attacks of neurologic compromise or instead are afflicted by a steadily progressive deterioration in functional capabilities. The pathophysiology of acute exacerbations is thought to be related to the development of inflammation and its consequences, within strategic and often discrete central nervous system tract systems. Although a myriad of hypotheses have been formulated to explain the underpinnings of the mechanisms that contribute to both the predilection and triggering of the multiphasic inflammatory events that personify multiple sclerosis, much remains to be done to understand fully the specific set and sequence of events that produce the disease and its cardinal features.

Frohman EM, Fujimoto JG, Frohman TC, Calabresi PA, Cutter G, Balcer LJ. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75235, USA. · Nat Clin Pract Neurol. · Pubmed #19043423 No free full text.

Abstract: The pathophysiology of multiple sclerosis (MS) is characterized by demyelination, which culminates in a reduction in axonal transmission. Axonal and neuronal degeneration seem to be concomitant features of MS and are probably the pathological processes responsible for permanent disability in this disease. The retina is unique within the CNS in that it contains axons and glia but no myelin, and it is, therefore, an ideal structure within which to visualize the processes of neurodegeneration, neuroprotection, and potentially even neurorestoration. In particular, the retina enables us to investigate a specific compartment of the CNS that is targeted by the disease process. Optical coherence tomography (OCT) can provide high-resolution reconstructions of retinal anatomy in a rapid and reproducible fashion and, we believe, is ideal for precisely modeling the disease process in MS. In this Review, we provide a broad overview of the physics of OCT, the unique properties of this method with respect to imaging retinal architecture, and the applications that are being developed for OCT to understand mechanisms of tissue injury within the brain.

Zivadinov R, Reder AT, Filippi M, Minagar A, Stüve O, Lassmann H, Racke MK, Dwyer MG, Frohman EM, Khan O. · Buffalo Neuroimaging Analysis Center, Jacobs Neurological Institute, 100 High Street, Buffalo, NY 14203, USA. · Neurology. · Pubmed #18606968 No free full text.

Abstract: Disease-modifying agents (DMAs), including interferon beta (IFNbeta) and glatiramer acetate (GA), are the mainstays of long-term treatment of multiple sclerosis (MS). Other potent anti-inflammatory agents like natalizumab and different types of chemotherapeutics are increasingly being used for treatment of MS, particularly in patients with breakthrough disease activity. Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy. Low-dose, low frequency IFNbeta administered once weekly and GA appear to partially reduce BV decline over the second and third years of treatment. High dose, high frequency IFNbeta demonstrated no clear effect on BV loss during this time period. Current evidence suggests that changes in BV after immunoablation may not be due entirely to the resolution of edema but may be related to potential chemotoxicity of high dose cyclophosphamide. Natalizumab reduces the development of BV decline in the second and third years of treatment. IV immunoglobulin showed a positive effect on decelerating BV reduction in relapsing and advanced stages of MS. These differences between DMAs may be explained by the extent of their therapeutic effects on inflammation and on the balance between inhibition or promotion of remyelination and neuronal repair in the CNS. We described the mechanisms of action by which DMAs induce accelerated, non-tissue-related BV loss (pseudoatrophy) in the short term but, in the long run, may still potentially lead to permanent BV decline. The effects of corticosteroid therapy on changes in BV in patients with MS help clarify the mechanisms through which potent anti-inflammatory treatments may prevent, stabilize, or induce BV loss.

Frohman EM, Costello F, Stüve O, Calabresi P, Miller DH, Hickman SJ, Sergott R, Conger A, Salter A, Krumwiede KH, Frohman TC, Balcer L, Zivadinov R. · Department of Ophthalmology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390, USA. · Arch Neurol. · Pubmed #18195137 links to  free full text

Abstract: A major objective in multiple sclerosis therapeutics is to develop strategic targeting of specific injury pathways to provide neuroprotection and potentially even restoration. Here we underscore the potential utility of the anterior visual system for the purpose of modeling neuroprotection in response to novel therapies.

Stüve O, Bennett JL, Hemmer B, Wiendl H, Racke MK, Bar-Or A, Hu W, Zivadinov R, Weber MS, Zamvil SS, Pacheco MF, Menge T, Hartung HP, Kieseier BC, Frohman EM. · Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, Texas 75216, USA. · Drugs. · Pubmed #18081373 No free full text.

Abstract: Currently, six medications are approved by the US FDA for the treatment of relapsing forms of multiple sclerosis (MS). In contrast, no pharmacological agent has proved to be effective in patients with secondary-progressive MS without relapses, or in patients with primary-progressive MS. One of the principal issues concerning an optimal pharmacotherapy for relapsing forms of MS is the optimal time of treatment initiation. There is now an almost universal consensus among MS experts that many patients will benefit from early therapy. However, several formidable challenges exist in identifying individuals who will benefit versus those who will do well without intervention. How do we define early MS and what clinical and paraclinical markers may be useful in defining the timing and nature of therapy? Do patients with a benign form of MS require therapy or are they exposed unnecessarily to adverse effects of our currently available medications? How do we identify disease progression and treatment failures? This review discusses these issues and outlines the evidence for application of 'early' treatment in patients with relapsing forms of MS.

Stuart R, Lovett-Racke AE, Frohman EM, Hawker K, Racke MK. · Department of Neurology, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390, United States. · J Neuroimmunol. · Pubmed #17920697 No free full text.

Abstract: Several studies have examined whether a dimorphism in the CD152 costimulatory molecule may influence the development of multiple sclerosis (MS). A sample of 108 patients with a diagnosis of relapsing remitting (RRMS), 28 with secondary progressive (SPMS), 23 with primary progressive (PPMS) and 63 people with no prior history of neurological conditions were selected from the MS clinic at the University of Texas Southwestern Medical Center at Dallas. Peripheral blood was separated with gradient extraction for leukocytes and genomic DNA extracted for CD152 A/G dimorphism analysis. A 163 bp PCR product in exon 1 including the position 49 A/G dimorphism was examined via single strand conformation polymophism (SSCP). Patient haplotype frequencies were compared between cases and controls and Pearson Chi-Square test performed to demonstrate statistical differences between MS groups and controls. Our results, similar to several recent studies, suggest that there is no statistical association with the risk of developing MS and no increased frequency in A or G at position 49 of exon 1 of CD152. Demonstration of prolonged proliferation in patient samples containing the GG genotypes and altered CD152 surface expression was also not demonstrated suggesting that the CD152 exon 1 position 49 A/G dimorphism does not contribute significantly to the development of MS in this patient population.

Shah A, Eggenberger E, Zivadinov R, Stüve O, Frohman EM. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235, USA. · Neurotherapeutics. · Pubmed #17920543 No free full text.

Abstract: Physicians who treat multiple sclerosis (MS) face the challenge of patients exhibiting ongoing disease activity, including exacerbations, loss of functional capabilities, intellectual decline, and radiologic progression, despite being on a disease-modifying agent (DMA). After searching for factors that might at least in part explain these changes--such as nonadherent drug-taking behavior, or the presence of interferon-neutralizing antibodies--some providers may ultimately decide to switch the patient to another DMA. In most circumstances, patients likely derive only partial effects from these agents, even in the absence of compromising factors. Thus, a number of factors must be considered in order to intensify the treatment regimen in response to disease progression. In the context of an inadequate treatment response to a DMA, some clinicians will convert the patient to an alternative therapy, and others will instead use a second agent in combination with the first (the so-called platform agent). In the first of this two-part series, we explored the use of anti-inflammatory CS and ACTH to treat MS exacerbations. Although we underscored the limited availability of evidence-based studies to support specific regimens for this purpose, there is an even greater paucity of data to support the routine use of these agents in order to achieve chronic disease-modifying effects in those who continue to deteriorate clinically, radiographically, or both. Without doubt, a number of factors influence the formulation of combination treatment plan for MS. Nevertheless, we will focus on the rationale and practical schemes that can be considered for using corticosteroids (CS) (and perhaps even ACTH) in an attempt to modify various domains of ongoing disease activity.

Frohman EM, Shah A, Eggenberger E, Metz L, Zivadinov R, Stüve O. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235, USA. · Neurotherapeutics. · Pubmed #17920542 No free full text.

Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disorder characterized by a multiphasic course of neurological exacerbations, periods of clinical remission, and, in most patients, ultimately progressive deterioration of functional capabilities. The relapsing-remitting phase of the disease involves acute interruption in neurological functioning relating to areas of inflammation in discrete central-tract systems. The treatment of MS exacerbations with anti-inflammatory agents such as corticosteroids and adrenocorticotropic hormone has represented an established practice throughout the neurology community. Although there is scientific rationale supporting application of these agents for this purpose, the broad diversity of approaches to using these drugs in clinical practice is a derivative of expert opinion and anecdotal experience. Ultimately, the treatment of MS-related exacerbations is part science, but mostly art. This review discusses the pharmacology of these agents, to better understand how they may act to mitigate attacks and to provide some practical formulations for how to use them in the clinic for the benefit of patients.

Frohman EM, Kerr D. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235, USA. · Arch Neurol. · Pubmed #17562944 No free full text.

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Stüve O, Marra CM, Cravens PD, Singh MP, Hu W, Lovett-Racke A, Monson NL, Phillips JT, Cohen Tervaert JW, Nash RA, Hartung HP, Kieseier BC, Racke MM, Frohman EM, Hemmer B. · Neurology Section, Medical Service, Veterans Affairs North Texas Health Care System, Dallas, TX, USA. · Arch Neurol. · Pubmed #17296831 links to  free full text

Abstract: Natalizumab (Tysabri) is an effective therapy for multiple sclerosis. Recently, 3 patients who were treated with natalizumab developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyomavirus JC. The pathogenesis of natalizumab-associated PML may be different from that of PML not associated with the drug. We reviewed biologically feasible interventions for patients diagnosed as having PML or other infections while receiving natalizumab therapy. Existing interventions include antiviral treatment, immunomodulatory therapies, hematopoietic growth factors, plasma exchange, intravenous immunoglobulins, and leukapheresis and autotransfusion of leukocytes. In addition, we examined the feasibility of experimental therapies, including small interfering RNA, the in vivo use of antiserum, and recombinant natalizumab-blocking molecules. There is only circumstantial evidence that any of the proposed treatments will benefit patients with multiple sclerosis treated with natalizumab who may develop PML. In addition, the expected incidence of PML in this patient population will likely be too low to test any of the proposed interventions in a controlled manner. Because it is currently impossible to identify patients at risk, and thus to prevent PML as a consequence of natalizumab therapy, it is important that neurologists be aware of possible therapeutic interventions.

Frohman EM, Racke MK, Raine CS. · Department of Neurology and Ophthalmology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. · N Engl J Med. · Pubmed #16510748 No free full text.

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Frohman EM, Stüve O, Havrdova E, Corboy J, Achiron A, Zivadinov R, Sorensen PS, Phillips JT, Weinshenker B, Hawker K, Hartung HP, Steinman L, Zamvil S, Cree BA, Hauser S, Weiner H, Racke MK, Filippi M. · Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Arch Neurol. · Pubmed #16216934 links to  free full text

Abstract: In the management of patients with multiple sclerosis (MS), providers are all faced with the highly formidable challenge of ascertaining whether, and to what degree, disease-modifying therapy is effective in the individual patient. While much has been learned in randomized, controlled clinical trials, we cannot simply extrapolate the outcomes of these initiatives and apply them to the care of a single patient. In the future, the application of pharmacogenetic techniques, proteomics, and microarray analysis will yield novel profiling information on individual patients that will substantially refine the specific therapeutic questions of relevance: (1) What is the best treatment for an individual patient? (2) Which patients require intensive therapeutic combination regimens to optimize control of the disease process? (3) What are the appropriate drug dosing targets for an individual patient? and (4) Which patients will be predisposed to the development of drug-related adverse events? Such data may provide a novel variable of drug responsiveness that will mandate its inclusion into the process of covariate analyses for clinical trials.

Frohman EM, Filippi M, Stuve O, Waxman SG, Corboy J, Phillips JT, Lucchinetti C, Wilken J, Karandikar N, Hemmer B, Monson N, De Keyser J, Hartung H, Steinman L, Oksenberg JR, Cree BA, Hauser S, Racke MK. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 75235, USA. · Arch Neurol. · Pubmed #16157741 links to  free full text

Abstract: Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.

Frohman EM, Frohman TC, Zee DS, McColl R, Galetta S. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, TX 75235, USA. <> · Lancet Neurol. · Pubmed #15664543 No free full text.

Abstract: Multiple sclerosis (MS) is the most common disabling neurological disease in young people. Most CNS lesions involve neuroanatomically non-eloquent zones that often do not result in symptomatic complaints. By contrast, tissue-injury mechanisms involving inflammatory demyelination can involve more eloquent sites, such as the optic nerve and brainstem, which can correspondingly produce the development of well recognised syndromes such as optic neuritis and internuclear ophthalmoplegia, respectively. In this review we discuss the broad landscape of abnormalities that affect the afferent visual system and the ocular motor apparatus, and emphasise relevant features, the recognition and treatment of which are of importance to general neurological practice. The commonness of visual sensory and eye movement abnormalities in MS highlights the importance of understanding the principles addressed in this review.

Frohman EM. · Department of Neurology , University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA. · Med Clin North Am. · Pubmed #12834152 No free full text.

Abstract: Multiple sclerosis (MS) is the most common disabling neurologic disease of young people affecting between 350 and 450,000 individuals in the United States. Substantial advances have been made in the diagnostic assessment and treatment interventions over the last 10 years such that we are now able effectively to treat both the disease process and the associated symptomatic complaints associated with MS. Most patients consult with their primary care physician at the time when the first clinical manifestations of MS emerge. These physicians play a central role in the early identification and treatment of patients with MS. This article emphasizes the expanding diagnostic and therapeutic capabilities evolving for the MS patient and the crucial role played by primary care physicians in collaboration with neurologists in the coordination of the initial diagnostic and treatment plan.

Frohman EM, Kramer PD, Dewey RB, Kramer L, Frohman TC. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235, USA. · Mult Scler. · Pubmed #12814171 No free full text.

Abstract: OBJECTIVE: To report on the most common causes of vertigo in patients with multiple sclerosis (MS) and emphasize appropriate diagnostic techniques and treatment interventions. BACKGROUND: True vertigo is estimated to occur in about 20% of MS patients. Lesions within the vestibular nuclei and in the root entry zone of cranial nerve VIII represent the most common locations where demyelinating activity can provoke vertigo in patients with MS. However, other causes of vertigo should be explored in MS patients in order to avoid unnecessary treatment with corticosteroids and vestibular suppressants. Recently, we reviewed our four-year experience with new onset vertigo in our university-based MS population and found that benign paroxysmal positioning vertigo (BPPV) to be the most common cause. All patients diagnosed with BPPV were treated successfully with particle repositioning maneuvers. The remaining patients were treated with conventional therapies appropriate for the specific diagnosis. CONCLUSIONS: Empiric treatments with corticosteroids and/or vestibular suppressants should not be employed until all MS patients undergo a careful bedside examination, which includes diagnostic positional and, if indicated, particle repositioning maneuvers. Here we emphasize the pathophysiology of BPPV and illustrate the proper techniques for the diagnostic and therapeutic maneuvers.