Vesna V. Brinar

Diagnostic criteria for multiple sclerosis

Over a hundred years ago, Charcot set down what he considered to be some of the clinical characteristics of multiple sclerosis (MS). His triad was not specific but it was the first attempt to separate this disease from the many others affecting the nervous system. The history of clinical diagnostic criteria demonstrates the evolution from rather tentative classifications of restricted value to the more elaborate 1983 scheme which incorporates some laboratory procedures under the rubric paraclinical tests, considered to be extensions of the neurological examination, as well as a new category based on the presence of specific abnormalities of the cerebrospinal fluid (CSF). It is curious that until then the term definite MS had been avoided except for autopsy-proven cases, perhaps a wise move, since exact diagnosis may require long term observation. All the proposed schemes have been based on the twin principles of dissemination in both time and space. The diagnosis of MS must remain a clinical one, supported but not supplanted by the increasingly popular magnetic resonance imaging, which is non-specific and is frequently overinterpreted by radiologists lacking appropriate clinical information. Reliance on the MRI as the principal if not exclusive basis for the diagnosis leads to error in as many as one third of cases. This assumes a great deal of importance considering that such non-MS patients may be counted in epidemiological surveys and included in therapeutic trials for disease-modifying drugs, or eventually treated with these very expensive drugs with still controversial long term efficacy. Not surprisingly, attempts to develop reliable criteria for the MRI diagnosis of MS have been unsuccessful in view of the lack of specificity of that procedure. Great care should be taken to exclude the presence of extrinsic cervical spine lesions which might impinge on the cord, leading to the formation of plaques, or mimic the course of MS. An MRI of the cervical spine is recommended in all patients suspected of having MS who have symptoms suggestive of spinal cord involvement. The diagnosis of MS is, and will remain, based on clinical criteria which codify the characteristic dissemination in time and space of MS.

Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial

BACKGROUND The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. METHODS In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348. FINDINGS 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. INTERPRETATION Alemtuzumabs consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. FUNDING Genzyme (Sanofi) and Bayer Schering Pharma.

Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 Clinical Trial

Objective: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon β-1a (IFNβ-1a) through extended follow-up (up to 60 months from baseline). Methods: Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNβ-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months. Results: Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNβ-1a (both p < 0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNβ-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNβ-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNβ-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNβ-1a patients. Immune thrombocytopenia occurred in 3% of alemtuzumab patients and 0.9% of IFNβ-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab patient developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab. Conclusions: Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNβ-1a, with a safety profile consistent with previous reports. Classification of Evidence: This study provides Class III evidence that alemtuzumab is more effective than interferon β-1a in reducing relapses and disability in patients with RRMS in a long-term follow-up of a rater-blinded, randomized clinical trial with 59.5% of patients participating in the extended follow-up period.

Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes

BACKGROUND Alemtuzumab is a humanised monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation. In a 3-year, rater-blinded phase 2 study (the CAMMS223 study) in patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab reduced relapse rate and the risk of sustained accumulation of disability compared with subcutaneous interferon beta-1a, and the mean expanded disability status scale (EDSS) score of the alemtuzumab cohort improved compared with baseline. Adverse events included infusion-associated reactions, predominantly mild to moderate infections, thyroid disorders, and immune thrombocytopenia. In this study, we further analysed the CAMMS223 data with the aim of determining whether demographic and baseline disease-related characteristics affect the beneficial effects of alemtuzumab. Additionally, we aimed to describe a new outcome measure in multiple sclerosis research: sustained reduction in disability. METHODS 334 treatment-naive patients with active, early RRMS were randomly assigned in a 1:1:1 ratio to receive interferon beta-1a (44 μg subcutaneously three times per week), or 24 mg per day or 12 mg per day alemtuzumab intravenously for 2 or 3 annual cycles. We analysed freedom from clinical disease activity (CDA; defined as no relapses and no sustained accumulation of disability) and occurrence of sustained reduction in disability (SRD; a ≥1 point decrease on the EDSS sustained for 6 consecutive months for patients with a baseline EDSS ≥2), and analysed efficacy outcomes for subgroups based on age, sex, geographic region, MRI-T1 brain volume, MRI-T2 lesion volume, disease duration, number of previous relapses within 2 years, and EDSS. FINDINGS 322 patients were analysed. 161 of 215 patients treated with alemtuzumab were free of CDA at 36 months (Kaplan-Meier estimate 71·8%, 95% CI 63·1-78·8%) compared with 52 of 107 patients treated with interferon beta-1a (42·6%, 32·4-52·4%; hazard ratio [HR]=0·31, 0·20-0·46; p<0·0001). For the 199 patients with a baseline EDSS score greater than or equal to 2, SRD was more likely (HR=2·61, 1·54-4·43; p=0·0004) among patients treated with alemtuzumab (66 of 133 patients, Kaplan-Meier estimate 51·6%, 95% CI 43·2-60·7%) than patients treated with interferon beta-1a (15 of 66 patients, 27·2%, 17·2-41·4%). All disability and relapse outcomes showed evidence of beneficial effects of alemtuzumab compared with interferon beta-1a across all analysed patient subsets, and no subgroup of patients consistently responded better than others to alemtuzumab. INTERPRETATION Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis. FUNDING Genzyme and Bayer Schering Pharma.

Epilepsy and multiple sclerosis

A review of 29 published clinical series of adult patients who had epileptic seizures and multiple sclerosis (MS) yielded a prevalence of 2.3%, about three to six times that in the general adult population. The probable anatomic basis for the seizures is areas of inflammation, edema, and/or demyelination in the cerebral cortex and the juxtacortical white matter generated by a mechanism that is not completely understood; the fact that these plaques are very common suggests that other factors must operate in view of the rarity of seizures in MS. Seizures have been observed before and presumably marking the clinical onset of the disease, and during acute bouts. In some instances convulsions appear to be the only manifestations of an attack of MS, but there is no general acceptance of seizures as the first and only symptoms of the disease. The coincidental occurrence of both diseases, the nonspecific triggering effect of MS on latent epilepsy, and actual causation by MS are all possible explanations, but the last named is, in our opinion, extremely unusual.

Multiple sclerosis 2001

The last several years have seen an enormous outpouring of research papers in multiple sclerosis (MS). This explosion of what has often rather exuberantly been called new knowledge, has sparked some existing controversies and engendered new ones. The First Dubrovnik International Conference on MS was organized for the purpose of reviewing and assessing some of this new information in a congenial and collegial atmosphere in a unusually picturesque setting, the magnificent medieval city of Dubrovnik on the Dalmatian coast of Croatia. We believe that the Conference was a success and wish to thank the speakers, the participants, the sponsors and all those students and residents who worked so hard behind the scenes, for their contributions. Many aspects of MS remain shrouded in mystery and many of the controversies continue unabated. The following discussion is designed to comment on some of the recent developments and on the important questions that still need to be resolved.

Non-MS recurrent demyelinating diseases

The introduction of MRI has shown that the acute, recurrent (R), and multiphasic (M) forms of disseminated encephalomyelitis (DEM) are more common than suspected in adults, and that their MR images are sufficiently characteristic in most instances to make differentiation from multiple sclerosis (MS) possible. In addition, a number of clinical features of DEM are rarely seen in MS: fever, malaise, nausea, vomiting, positional vertigo, convulsions, aphasia, meningism, bilateral optic neuritis, and CSF leukocytosis and elevated protein. CSF oligoclonal bands are usually absent. It is remarkable that confusion between R- and MDEM and MS persists despite the numerous published reports on recurrent DEM dating back 70 years, many illustrating the characteristic MRIs. There are many case reports of DEM erroneously diagnosed as MS, Schilders, Marburgs, Devics, and Balós disease, and, in particular brain tumors. It is probable that acute DEM is occasionally mistaken for a clinically isolated symptom of MS. Possible mechanisms for recurrence include localization at the site of a previous injury to the nervous system, or by the phenomenon of molecular mimicry. The importance of differentiating R- and MDEM from MS is greater today due to the recommendation that immunodulatory treatment be initiated in patients with a clinically isolated syndrome, or when the occurrence of a second clinical episode establishes the diagnosis of MS.

Changes of attention and memory in a group of patients with multiple sclerosis

Cognitive impairment was observed in patients with multiple sclerosis (MS), not only in the later phase of the disease, but also early in the disease [1 /3]. There is no evidence that its occurrence has been a consequence of depression, mood changes, or fatigue after physical exercise. Furthermore, a certain degree of cognitive impairment may occur without any major physical disability symptoms in these patients [4]. The most frequently observed disturbances of cognitive functions in patients with MS were those of shortterm memory and sustaining of attention, followed by conceptual thinking problems and verbal fluency disorder [5]. The nature of attention-related problems in MS has not been definitely explained by previous investigations [5 /9]. Several methods were used to assess different aspects of attention in those patients (paced auditory serial addition test (PASAT), the Stroop test, Sternberg memory scanning test, vigilance tasks auditory As and auditory trails A tests). Working memory, which is a part of short-term memory processes, is closely associated with visual and auditory attention systems [10]. Disturbances of explicit memory in patients in the early and middle phases of MS were observed both on verbal and non-verbal tasks [11]. According to Litvan et al. [12] the short-term memory performance in patients with MS is generally intact, except for the retrieval of data, measured through digit-retention capacity. On the other hand, deficit of digit retention capacity has been reported to exist in patients with less than 2 years’ duration of illness [13]. Few studies on implicit memory [14,15] suggested that patients with MS would perform normally on a motor skill task and priming. The aim of this investigation was to assess the cognitive performance of patients with MS on attentionand memory-related tasks. The contributions of patients’ clinical and demographic characteristics to their cognitive performance were also analyzed in the present study.

Isolated cranial nerve palsies in multiple sclerosis.

Data on patients with multiple sclerosis and cranial nerve involvement as a presenting sign or a sign of disease exacerbation were retrospectively analyzed. Isolated cranial nerve involvement was present in 10.4% out of 483 patients, either as a presenting symptom (7.3%) or a symptom of disease relapse (3.1%). Trigeminal nerve was most frequently involved, followed by facial, abducens, oculomotor and cochlear nerves. Only 54% of patients had brainstem MRI lesion that could explain the symptoms. As multiple sclerosis is a disease characterized by multiple neurological symptoms, while early diagnosis and therapy are critical for the prognosis and course of the disease, the diagnosis of multiple sclerosis should be considered in young adults with cranial nerve involvement.

Nutrition in multiple sclerosis

Multiple sclerosis (MS) is a chronic idiopathic inflammatory demyelinating disease that causes neurological disability in young adults. Etiology of the disease is still unknown, but it has an immune-mediated basis and occurs in genetically susceptible individuals. Nutritional status and dietary habits in MS patients have not been extensively studied or reported, however individual findings suggest that many patients suffer from various forms of malnutrition. In patients with MS, malnutrition has been associated with impairment of the immune system; it affects mental function, respiratory muscle strength and increases a risk of specific nutrient deficiencies. These findings emphasize the need for nutritional support in MS patients. On the other hand, several nutritional compounds have been investigated as a possible treatment in MS, mostly polyunsaturated fatty acids and vitamin D, however their role in the treatment is yet to be confirmed. The aim of this review is to present data on the role of nutritional assessment and treatment in patients with MS.