Multiple Sclerosis: Hawker K

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.

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

This publication has no abstract.

Hawker K. · Ohio State University, Columbus, Ohio 43210, USA. · Curr Opin Neurol. · Pubmed #18388796 No free full text.

Abstract: Strategies for treating autoimmune disorders are increasingly employing targeted therapies rather than non-specific, multitargeted treatments. Accumulating evidence on the involvement of B lymphocytes in the pathophysiology of autoimmune demyelinating disease has led to a renewed interest in B cells as potential therapeutic targets. In particular, antigen presentation between B cells and T cells, increased trafficking of B cells across the blood-brain barrier, and autoantibodies produced by plasma cells may contribute to the pathophysiology of autoimmune disorders such as multiple sclerosis. Several B-cell-targeted, depletion therapies are currently in development, including rituximab, epratuzumab, diphtheria toxin-single chain Fv (DC2219), belimumab, atacicept, abatacept, and abetimus sodium. Of these agents, only rituximab and abatacept have been evaluated in multiple sclerosis patients. Preliminary results of a phase II trial of rituximab in multiple sclerosis suggest that rituximab is well tolerated and significantly reduces the number of gadolinium enhancing lesions over 24 weeks of treatment. Results of an exploratory analysis suggest the potential promise of abatacept 10 mg/kg for multiple sclerosis. It is expected that future clinical trials will establish a role for B-cell-targeted therapies in the treatment of multiple sclerosis and other autoimmune neurological diseases. This article describes the mechanism of action behind B-cell-targeted depletion therapies in development and reviews available clinical data.

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.

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.

Hawker K, Frohman E. · Multiple Sclerosis Program, Department of Neurology, University of Texas, Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Room J3.134, Dallas, TX 75390-9036, USA. · Prim Care. · Pubmed #15110166 No free full text.

This publication has no abstract.

Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK. · Department of Neurology and Center for Immunology, The University of Texas Southwestern Medical Center, Dallas 75390, USA. · Arch Neurol. · Pubmed #15710854 links to  free full text

Abstract: BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody that depletes CD20(+) B cells, has demonstrated efficacy in peripheral neurological diseases. Whether this efficacy can be translated to neurological diseases of the central nervous system with possible autoimmune B-cell involvement remains unknown. OBJECTIVE: To determine the effect of rituximab on cerebrospinal fluid B cells in patients with multiple sclerosis. DESIGN: Four patients with primary progressive multiple sclerosis were treated with rituximab. Cerebrospinal fluid and peripheral blood B-cell subsets were identified by flow cytometry from each patient before and after rituximab treatment. RESULTS: The B cells in cerebrospinal fluid were not as effectively depleted as their peripheral blood counterparts. Rituximab treatment temporarily suppressed the activation state of B cells in cerebrospinal fluid. The residual B cells underwent expansion after rituximab treatment. CONCLUSION: The effect(s) of rituximab on the cerebrospinal fluid B-cell compartment is limited in comparison with the effect(s) on the B cells in the periphery, but this finding will need to be confirmed in a larger group of MS patients.

Lemack GE, Frohman EM, Zimmern PE, Hawker K, Ramnarayan P. · Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, USA. · Urology. · Pubmed #16635509 No free full text.

Abstract: OBJECTIVES: To evaluate the urodynamic characteristics of neurogenic detrusor overactivity (NDO) secondary to multiple sclerosis (MS) compared with idiopathic DO (IDO) to determine whether urodynamic distinctions could differentiate the different etiologies of DO. METHODS: The urodynamic characteristics of DO in women with MS (n = 54) were compared with the overactive contractions found in women with lower urinary tract symptoms and IDO (n = 42). Among other parameters, the amplitude of the first overactive contraction, maximal detrusor contraction, and threshold volume for the first overactive contraction were evaluated to assess the DO severity. A sensitivity analysis using cutoff values determined from those urodynamic parameters that differed between the patient groups is presented. RESULTS: The amplitude of the first overactive contraction was statistically greater in the patients with MS and NDO compared with patients with IDO (28.3 cm H2O versus 20.5 cm H2O, P = 0.003), as was the maximal detrusor contraction (46.4 cm H2O versus 30.8 cm H2O, P = 0.002). The threshold volume for DO was greater among patients with NDO (186.8 mL versus 150.5 mL, P = 0.037), likely secondary to the elevated postvoid residual urine volume noted among patients with MS (P = 0.049). Using a cutoff value of 30 cm H2O for amplitude of the first overactive contraction achieved a positive predictive value of 88% for identifying MS in our data set. CONCLUSIONS: The urodynamic characteristics of NDO differed significantly from those of IDO. Additional investigation is required to determine whether these differences are due to neurogenic influences directly on the detrusor muscle through aberrant innervation or by other mechanisms, such as enhanced outlet resistance during voiding.

Lemack GE, Hawker K, Frohman E. · Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, USA. · Urology. · Pubmed #15882710 No free full text.

Abstract: OBJECTIVES: To determine the incidence of upper tract abnormalities on renal ultrasonography in patients with multiple sclerosis (MS) referred for urologic evaluation, as well as to identify any risk factors present on the basis of the historical information and urodynamic findings. METHODS: Data were derived from all patients with MS referred to the neurourology clinic during a 4-year period. The database was specifically queried for patients found to have upper tract abnormalities on screening renal ultrasonography. Demographic parameters, as well as laboratory values (creatinine) and urodynamic results, were evaluated for risk factors associated with abnormal upper tract findings. RESULTS: Of the 113 patients referred and evaluated, 66 completed both urodynamic testing and renal ultrasonography. Eleven (16.7%) had abnormal ultrasound findings, with focal caliectasis the most common finding. No demographic parameter (age, sex, time since MS diagnosis, MS pattern) was associated with a greater likelihood of abnormal renal ultrasonography on univariate analysis. Neither serum creatinine nor any urodynamic finding (including the presence of dyssynergia or the threshold and amplitude of detrusor overactivity) was associated with abnormal renal ultrasound findings. CONCLUSIONS: No patients in our series had any indication of obstructive uropathy more severe than mild hydronephrosis. Of the 16.7% of patients with any abnormal findings, most were noted to have minor caliectasis, likely to be of little clinical significance. Although no factors identifying patients at risk of renal abnormalities at presentation were found, ongoing evaluation of patients with baseline findings will serve to identify those at risk of progression.

Frohman EM, Brannon K, Racke MK, Hawker K. · Department of Neurology, University of Texas, Southwestern Medical Center at Dallas, USA. · Clin Neuropharmacol. · Pubmed #15252268 No free full text.

Abstract: OBJECTIVE: To describe experience with the use of mycophenolate mofetil (MMF) in the treatment of multiple sclerosis (MS). BACKGROUND: MMF is a potent immunosuppressant that is a selective inhibitor of inosine 5'-monophosphate dehydrogenase type II, the enzyme responsible for the de novo synthesis of the purine nucleotide guanine within activated T and B lymphocytes and macrophages. METHODS: A retrospective review of experience in treating 79 MS patients with MMF (61 with secondary progressive, 14 with relapsing-remitting, and 4 with primary progressive MS) in the authors' MS center. RESULTS: In most cases, MMF was added as adjunctive therapy in patients already being treated with either interferon-beta (n = 44) or glatiramer acetate (n = 20). Fifteen patients not able to use interferon or glatiramer acetate were treated with MMF monotherapy. Seventy percent of the patients continued MMF therapy. Eight patients discontinued therapy because of side effects, 7 patients continued to exhibit evidence of disease progression, 4 were denied insurance coverage, 2 were lost to follow-up, and 1 patient had an elevation of hepatic transaminases that resolved on discontinuation of MMF. One patient discontinued MMF therapy secondary to cytomegalovirus diarrhea. CONCLUSION: MMF was well tolerated by the majority of patients treated. While these clinical observations were uncontrolled, the clinical course of MS was either unchanged or subjectively improved in many of the treated patients. A randomized controlled trial of MMF in MS, either as monotherapy or in conjunction with interferon or glatiramer acetate, appears warranted.

Frohman EM, Brannon K, Alexander S, Sims D, Phillips JT, O'Leary S, Hawker K, Racke MK. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75235, USA. · Mult Scler. · Pubmed #15222696 No free full text.

Abstract: BACKGROUND: The objective for this article is to highlight some of the adverse skin manifestations associated with injectable disease modifying therapy for multiple sclerosis (MS). Early identification and intervention can often lead to minimal consequences and prolonged patient tolerance and compliance with these agents. At the University of Texas Southwestern Medical Center at Dallas and Texas Neurology in Dallas we actively follow approximately 5000 MS patients. The majority of our patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) are treated with one of the currently available disease modifying agents (DMAs). Our experience with these patients, and the challenges they face in continuing long-term treatment, constitutes the basis of our proposed treatment strategies. CONCLUSION: Skin reactions in response to injectable DMA therapy in MS are generally mild. However, some reactions can evolve into potentially serious lesions culminating in infection, necrosis, and in some circumstances requiring surgical repair.

Hawker K, Frohman E, Racke M. · University of Texas Southwestern Medical Center at Dallas, TX 75390-9036, USA. · Arch Neurol. · Pubmed #14676055 links to  free full text

Abstract: BACKGROUND: Spasticity is a common and debilitating symptom of multiple sclerosis (MS). Current treatments are effective, but may be difficult to tolerate for many patients. OBJECTIVE: To determine if levetiracetam, a second-generation antiepileptic drug, may be useful for the treatment of spasticity in MS. METHODS: A retrospective medical record review of patients attending the Multiple Sclerosis Program at the University of Texas, Southwestern Medical Center at Dallas was performed. A series of 12 patients who had been treated with levetiracetam for spasticity was identified. Most of the patients were female (10/11), and the mean age was 41.0 years. The main outcome measure was a change in Penn spasm score or modified Ashworth score. Both scores are measured on a scale of 0 to 4. RESULTS: The Penn Spasm score (a measure of phasic spasticity) was decreased for all patients following treatment with levetiracetam. The mean +/- SD Penn Spasm score was 2.7 +/- 0.65 at baseline and decreased to 0.9 +/- 0.29 at follow-up. There was no change in modified Ashworth scores (a measure of tonic spasticity). Five patients reported adverse events; 1 patient discontinued treatment owing to an adverse event (edema). Three patients incidentally reported improvements in neuropathic pain. CONCLUSIONS: Levetiracetam was effective for reducing phasic spasticity but not tonic spasticity in this 12-patient case series. The drug was well tolerated and therefore shows promise as a treatment for phasic spasticity. Large, well-controlled trials are needed to confirm these findings.

Frohman E, Phillips T, Kokel K, Van Pelt J, O'Leary S, Gross S, Hawker K, Racke M. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 75235, USA. · Neurologist. · Pubmed #12803682 No free full text.

Abstract: BACKGROUND: The objective for this article is to highlight several challenges faced by patients and providers in the utilization of disease-modifying agent (DMA) therapy in multiple sclerosis (MS) and to offer practical management strategies that can effectively mitigate or even prevent limiting adverse reactions and enhance treatment compliance. REVIEW SUMMARY: Our discussion will be limited to the use of interferon beta1a (Avonex, Rebif), interferon beta1b (Betaseron), and glatiramer acetate (Copoxane) as these are the primary agents used in the United States for primary disease-modifying therapy in relapsing forms of MS. Some of the recommendations contained herein are derived from evidence-based studies, while others are contingent upon our collective clinical experiences. At the University of Texas Southwestern Medical Center at Dallas and Texas Neurology in Dallas we actively follow approximately 5000 MS patients. The majority of our patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) are treated with one of the currently available DMAs. Our experience with these patients, and the challenges they face in continuing long-term treatment, constitutes the basis of our proposed treatment strategies. As part of this effort we formulated an assessment and intervention instrument that can be used in the clinic and by telephone to enhance compliance and minimize adverse events. CONCLUSION: A comprehensive treatment approach to the utilization of disease-modifying therapy in MS can serve to optimize the management of our patients and effectively meet the challenges that arise during the course of treatment.

Frohman EM, Frohman TC, O'Suilleabhain P, Zhang H, Hawker K, Racke MK, Frawley W, Phillips JT, Kramer PD. · Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #12082045 links to  free full text

Abstract: BACKGROUND: There is a poor correlation between multiple sclerosis disease activity, as measured by magnetic resonance imaging, and clinical disability. OBJECTIVE: To establish oculographic criteria for the diagnosis and severity of internuclear ophthalmoparesis (INO), so that future studies can link the severity of ocular dysconjugacy with neuroradiological abnormalities within the dorsomedial brain stem tegmentum. METHODS: The study involved 58 patients with multiple sclerosis and chronic INO and 40 normal subjects. Two dimensional infrared oculography was used to derive the versional dysconjugacy index (VDI)-the ratio of abducting to adducting eye movements for peak velocity and acceleration. Diagnostic criteria for the diagnosis and severity of INO were derived using a Z score and histogram analysis, which allowed comparisons of the VDI from multiple sclerosis patients and from a control population. RESULTS: For a given saccade, the VDI was typically higher for acceleration v velocity, whereas the Z scores for velocity measures were always higher than values derived from comparable acceleration VDI measures; this was related to the greater variability of acceleration measures. Thus velocity was a more reliable measure from which to determine Z scores and thereby the criteria for INO and its level of severity. The mean (SD) value of the VDI velocity derived from 40 control subjects was 0.922 (0.072). The highest VDI for velocity from a normal control subject was 1.09, which was 2.33 SD above the normal control mean VDI. We therefore chose 2 SD beyond this value (that is, a Z score of 4.33) as the minimum criterion for the oculographic confirmation of INO. Of patients thought to have unilateral INO on clinical grounds, 70% (16/23) were found to have bilateral INO on oculographic assessment. CONCLUSIONS: INO can be confirmed and characterised by level of severity using Z score analysis of quantitative oculography. Such assessments may be useful for linking the level of severity of a specific clinical disability with neuroradiological measures of brain tissue pathology in multiple sclerosis.

Frohman EM, Zhang H, Kramer PD, Fleckenstein J, Hawker K, Racke MK, Frohman TC. · Department of Neurology, University of Texas Southwestern Medical Center, Dallas 02115, USA. · Neurology. · Pubmed #11552000 No free full text.

Abstract: OBJECTIVE: The authors imaged the medial longitudinal fasciculus (MLF) in 58 patients with MS and chronic internuclear ophthalmoparesis (INO) to determine which MRI technique best shows the characteristic lesion associated with this ocular motor syndrome. METHODS: Using quantitative infrared oculography, the authors determined the ratios of abduction to adduction for velocity and acceleration, to confirm the presence of INO and to determine the severity of MLF dysfunction in 58 patients with MS and INO. Conventional MRI techniques, including proton density imaging (PDI), T2-weighted imaging, and fluid-attenuated inversion recovery (FLAIR) imaging, were used to ascertain which technique best shows MLF lesions within the brainstem tegmentum. T1-weighted imaging was performed to determine the frequency of brainstem tegmentum hypointensities. RESULTS: All patients studied had evidence of an MLF lesion hyperintensity on PDI, whereas T2-weighted imaging and FLAIR imaging showed these lesions in 88% and 48% of patients, respectively. With PDI, dorsomedial tegmentum lesions were seen in the pons in 93% of patients and in the midbrain of 66% of patients. Lesions were observed at both locations in 59% of patients. One patient had an MLF lesion with a corresponding T1 hypointensity. CONCLUSIONS: PDI best shows the MLF lesion in patients with MS and INO.

Frohman EM, Frohman TC, Fleckenstein J, Racke MK, Hawker K, Kramer PD. · Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #11309470 links to  free full text

Abstract: The objective was to describe in multiple sclerosis, a cerebellar eye movement syndrome that resulted from an acute episode of inflammatory demyelination. Contrapulsion is an ocular motor disturbance characterised by a triad of (1) hypermetric saccadic eye movements in a direction opposite from a precisely localised lesion within a specific white matter pathway, the uncinate fasciculus, at the level of the superior cerebellar peduncle (SCP); (2) hypometric saccades towards the side of the lesion; (3) oblique saccades directed away from the side of the lesion on attempted vertical saccades. Infrared oculography was used to demonstrate the characteristic features of contrapulsion in two patients with multiple sclerosis. Brain MRI showed lesions within the region of the uncinate fasciculus and superior cerebellar peduncle in both patients. Eye movement recordings showed saccadic hypermetria away from the side of the lesion and saccadic hypometria towards the side of the lesion. The hypometria decomposed into a series of stepwise movements as the eye approached the target. Oblique saccades directed away from the side of the lesion were seen on attempted vertical saccades.In conclusion, ocular contrapulsion can be seen in patients with multiple sclerosis and results from a lesion in the region of the SCP, involving the uncinate fasciculus.