Thomas F. Scott

Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial

To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis.

Neurosarcoidosis: progress and clinical aspects.

Neurosarcoidosis (NS) is a relatively rare disorder, affecting only 5% of all cases of sarcoidosis.l,z About one half of all patients with NS will present with neurologic symptoms. Our understanding of this illness has rapidly expanded; progress in neuroimaging has been especially rapid. This article is a brief review of important clinical aspects of NS, highlighting new discoveries that should prove helpful to clinicians.

Evidence-based guideline: clinical evaluation and treatment of transverse myelitis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

Objective: To assess the evidence for diagnostic tests and therapies for transverse myelitis (TM) and make evidence-based recommendations. Methods: A review of the published literature from 1966 to March 2009 was performed, with evidence-based classification of relevant articles. Recommendations: Level B recommendations: neuromyelitis optica (NMO)–immunoglobulin G (IgG) antibodies should be considered useful to determine TM cause in patients presenting with clinical acute complete transverse myelitis (ACTM) features. The presence of NMO-IgG antibodies (aquaporin-4–specific antibodies) should be considered useful in determining increased TM recurrence risk. Level C recommendations: in suspected TM, distinction between ACTM or acute partial transverse myelitis may be considered useful to determine TM etiology and risk for relapse (more common with APTM). Age and gender may be considered useful to determine etiology in patients presenting with TM syndrome, with spinal infarcts seen more often in older patients and more female than male patients having TM due to multiple sclerosis (MS). Brain MRI characteristics consistent with those of MS may be considered useful to predict conversion to MS after a first partial TM episode. Longer spinal lesions extending over >3 vertebral segments may be considered useful in determining NMO vs MS. CSF examination for cells and oligoclonal bands may be considered useful to determine the cause of the TM syndrome. Plasma exchange may be considered in patients with TM who fail to improve after corticosteroid treatment. Rituximab may be considered in patients with TM due to NMO to decrease the number of relapses. Level U recommendations: there is insufficient evidence to support or refute the efficacy of other TM therapies or the usefulness of ethnicity to determine the cause of a subacute myelopathy. GLOSSARY: ACTM: acute complete transverse myelitis APTM: acute partial transverse myelitis CI: confidence interval IgG: immunoglobulin G MS: multiple sclerosis NMO: neuromyelitis optica OCB: oligoclonal band TM: transverse myelitisObjective: To assess the evidence for diagnostic tests and therapies for transverse myelitis (TM) and make evidence-based recommendations. Methods: A review of the published literature from 1966 to March 2009 was performed, with evidence-based classification of relevant articles. Recommendations: Level B recommendations: neuromyelitis optica (NMO)–immunoglobulin G (IgG) antibodies should be considered useful to determine TM cause in patients presenting with clinical acute complete transverse myelitis (ACTM) features. The presence of NMO-IgG antibodies (aquaporin-4–specific antibodies) should be considered useful in determining increased TM recurrence risk. Level C recommendations: in suspected TM, distinction between ACTM or acute partial transverse myelitis may be considered useful to determine TM etiology and risk for relapse (more common with APTM). Age and gender may be considered useful to determine etiology in patients presenting with TM syndrome, with spinal infarcts seen more often in older patients and more female than male patients having TM due to multiple sclerosis (MS). Brain MRI characteristics consistent with those of MS may be considered useful to predict conversion to MS after a first partial TM episode. Longer spinal lesions extending over 3 vertebral segments may be considered useful in determining NMO vs MS. CSF examination for cells and oligoclonal bands may be considered useful to determine the cause of the TM syndrome. Plasma exchange may be considered in patients with TM who fail to improve after corticosteroid treatment. Rituximab may be considered in patients with TM due to NMO to decrease the number of relapses. Level U recommendations: there is insufficient evidence to support or refute the efficacy of other TM therapies or the usefulness of ethnicity to determine the cause of a subacute myelopathy. Neurology 2011;77:2128–2134

Transverse myelitis: Comparison with spinal cord presentations of multiple sclerosis

We delineated the clinical and laboratory features that help distinguish acute myelopathic MS (MMS) from acute transverse myelitis (ATM), specifically testing the hypothesis that the symmetry of motor and sensory impairments at presentation can reliably distinguish between ATM and MMS. We reviewed 20 consecutive patients with ATM and 16 patients with MMS. Clinical criteria were used to assign patients to the ATM group. Patients assigned to the MMS group had onset of MS symptoms referable to the spinal cord and eventually fulfilled Posers criteria for MS. The relative contribution of the symmetry of both motor and sensory symptoms for the accurate identification of ATM versus MMS was evaluated using a discriminant function analysis. Fifteen of 16 MMS patients and all 20 ATM patients presented with symptoms of motor dysfunction. Additionally, all patients in both groups presented with sensory complaints. MMS patients had asymmetric motor or sensory symptoms in all but one patient, whereas ATM patients exhibited symmetric weakness uniformly and symmetric sensory loss in all but one patient (statistically significant). None of the MS patients met criteria for ATM at presentation. None of the ATM patients developed MS over an average follow-up period of 4.5 years. In conclusion, MMS was easily distinguished from ATM in this study.

Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS

Objective: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNβ-1a) combined with methotrexate (MTX), IV methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNβ-1a monotherapy. Methods: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0–5.5, and ≥1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNβ-1a monotherapy. Participants continued weekly IFNβ-1a 30 μg IM and were randomized in a 2 × 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. Results: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNβ-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNβ neutralizing antibody titers. Conclusions: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis. ACT = Avonex Combination Trial; BPF = brain parenchymal fraction; DEXA= dual energy X-ray absorptiometry; EDSS = Expanded Disability Status Scale; GdE = gadolinium-enhancing; IFNβ-1a = interferon beta-1a; IVMP = IV methylprednisolone; MSFC = MS Functional Composite; MTX = methotrexate; N/E = new or enlarged; NAb = neutralizing antibody; OR = odds ratio; RRMS = relapsing-remitting multiple sclerosis; SENTINEL = Safety and Efficacy of Natalizumab in Combination with Interferon β-1a in Patients with Relapsing-Remitting MS.

Measurement of treatment response to sertraline in depressed multiple sclerosis patients using the Carroll scale.

We studied 11 patients with stable multiple sclerosis (MS) with major depression in terms of response to Sertraline at 100 mg q.d. in an open label trial. Patients were evaluated with self assessment measurements (Carroll scale) prior to and during treatment. Only one patient discontinued the drug during the three month treatment trial, and this was due to perceived lack of efficacy by the patient. The remainder of the patients completed at least three months of treatment and had significant improvement in depressive symptoms by self assessment measurements. No patients experienced side effects. Sertraline appears to be well tolerated and effective in treatment of major depression in MS. The Carroll scale is an easily administered means of assessing treatment response, and correlated highly with our clinical impressions.

Short-term prognosis in early relapsing-remitting multiple sclerosis

Objective: To characterize a group of patients with early MS using prognostic factors and to determine whether these prognostic factors impact on short-term prognosis. Methods: Data were collected prospectively on 98 patients newly diagnosed with MS in our MS clinic between 1990 and 1998 (average follow-up, 37 months from the time of onset of clinically definite MS [CDMS]). Six prognostic factors were recorded: age at onset, symptoms at onset, MRI status at onset and at diagnosis of CDMS, interval between the first and second attack, attack frequency in the first 2 years, and completeness of recovery from initial attacks. Completeness of recovery was determined using Expanded Disability Status Scale scores (EDSS). Progression was determined by final EDSS and changes in EDSS between initial presentation and final follow-up. Results: Patients predicted to have low risk of progression of MS based on the prognostic factors represented 17% of our patient population (0 to 1 risk factor for progression). The patients with high risk of progression (4 to 6 risk factors) represented 24% of patients. Patients with a high number of risk factors did significantly worse than those with a small or medium number of risk factors in terms of final EDSS and progression to higher EDSS. At the time of diagnosis of CDMS, MRI findings suggestive of MS were seen in 84% of patients (suspicious in 13%, negative in 3%). Conclusion: Short-term prognosis was influenced by the presence or absence of a high number of these six risk factors.

Acute partial transverse myelitis with normal cerebral magnetic resonance imaging: transition rate to clinically definite multiple sclerosis.

Objective: To determine the long-term risk of developing clinically definite multiple sclerosis (CDMS) in patients with acute partial transverse myelitis (APTM) and normal cerebral magnetic resonance imaging (MRI) scans. Methods: We retrospectively studied 30 consecutive patients with clinical evidence of APTM. Patients with symmetric severe acute transverse myelitis were considered to have complete transverse myelitis and were excluded. All patients underwent spinal and cerebral MRIs, 13 underwent cerebrospinal fluid analysis and 11 patients underwent evoked potential studies. Various other studies were performed to assess for connective tissue disease and causes of APTM other than demyelinating disease. Results: After an average follow-up of 61 months, all laboratory and clinical evidence, including relapse history, indicated that three patients developed lesions on cerebral MRI and could be classified as CDMS by either Poser criteria (two patients) or MacDonald criteria (one patient). Relapses limited to the spinal cord seen clinically were seen in 14/30 (46.6%) patients. Oligoclonal bands were seen in 8/13 (62%) patients; one patient transitioned to CDMS. Unifocal lesions of the cord were seen in 19/30 (63%) patients, multifocal lesions were seen in 8/30 (27%) and 3/30 (10%) had negative MRIs. The three patients who converted to CDMS did so within five years of the onset of myelitis. Conclusion: APTM with normal cerebral MRI had a low rate of conversion to CDMS in this long-term study. To date, there have been only a few follow-up studies that have addressed this issue.

Nosology of idiopathic transverse myelitis syndromes

Several terms are now commonly used to describe various presentations of idiopathic myelitis, including acute transverse myelitis, acute partial transverse myelitis, and secondary myelitis. Ideally, a classification system would be able to encompass various presentations in a manner that not only assists in prognosis, but also in treatment decisions. Unfortunately, we are limited in our ability to accurately identify those patients who will progress to develop multiple sclerosis, Devic’s syndrome, relapsing myelitis, or will remain monophasic. However, general principles are emerging that assist in prognosis based on the particular presenting features of any patient. We review the most recent criteria proposed for various forms of transverse myelitis and highlight the limitations of these classification schemes.

The PROMiSe trial: baseline data review and progress report

The PRO MiSe trial is a multinational, multicentre, double-blind, placebo -controlled trial evaluating the effects of glatiramer acetate treatment over 3 years in patients with primary progressive multiple sclerosis (PPMS). A total of 943 patients were enrolled, and all those remaining on-study had completed at least 24 months as of O ctober 2002. Baseline clinical and MRI character istics and select correlations are reported here. A total of 3.9% of patients exhibited confirmed relapse over 1904 patient-years of exposure, indicating success of efforts to exclude relapsing MS types. O f the 26.3% of patients who have prematurely withdrawn from the study, only 36% discontinued after meeting the study primary endpoint of disease progression. The progression rate in patients in the low Expanded Disability Status Scale (EDSS) stratum (3.0-5.0) observed thus far is markedly lower than the 50% annual progression rate estimate used for determining size and statistical power of the trial; progression was observed in 16.1% of patients with 12 months of study exposure. These early findings raise some concern about the ability of the trial to demonstrate a significant treatment effect, and suggest that the short-term natural history of PPMS may not be as aggressive as previously assumed.