Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon ß-1a in MS.

OBJECTIVE: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon ß-1a (SC IFN-ß-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS). METHODS: The impact of alemtuzumab 12 mg vs SC IFN-ß-1a 44 µg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II). RESULTS: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-ß-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-ß-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-ß-1a. CONCLUSIONS: Alemtuzumab demonstrated greater efficacy than SC IFN-ß-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-ß-1a in RRMS. CLINICALTRIALSGOV IDENTIFIER: NCT00530348 and NCT00548405. CLASSIFICATION OF EVIDENCE: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-ß-1a on multiple MRI endpoints.

Should MS be treated by escalation or induction therapy?

MS is a chronic, increasingly disabling disease whose long-term outcomes determine the key social, medical and economic impact of this disease. Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are prescribed to delay disease progression and to protect a patient's functional capability. The concepts of escalation and induction immunotherapy in MS represent different therapeutic strategies for the treatment of MS. Both strategies may be valuable options for patients starting on DMT, however, induction therapy mainly focuses on patients with very aggressive course of MS from the onset. Using a patient unique approach to selection of treatment, MS can be effectively control disease and may delay or even prevent the development of secondary progressive 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: Alemtuzumab's 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.

Early-onset ataxia with progressive external ophthalmoplegia associated with POLG mutation: autosomal recessive mitochondrial ataxic syndrome or SANDO?

Autosomal recessive ataxias caused by mutations of the polymerase γ (POLG) gene make an important group of progressive ataxias accompanied by a diverse spectrum of neurological disorders. Because the clinical picture can be quite miscellaneous, it is challenging to assort patients to any of the currently described syndromes; therefore, to provide such a patient with a conclusive diagnosis can be challenging for the neurologist. A typical magnetic resonance imaging finding is probably the most useful landmark in the diagnostic process, which will steer the clinician toward POLG gene testing. To illustrate this, we present a case of progressive ataxia caused by A467T and W748S mutations of POLG gene, who presented with overlapping symptoms of autosomal recessive mitochondrial ataxic syndrome and SANDO, as well as choreoathetotic movements and dysphonia. After lengthy investigations, magnetic resonance imaging showed T2 and FLAIR hyperintensities in the thalamus, inferior olives, and cerebellum, which led us to the analysis of POLG mutations.

Diagnostic approach of patients with longitudinally extensive transverse myelitis.

The aim of this study is to present a diagnostic and therapeutic approach in patients with LETM. In a period between June 2008 and June 2010, all patients who fulfilled criteria for LETM were included in the study. All patients underwent a standardized protocol of investigations presented in this paper. Ten patients were included (5 male, 5 female, with the age distribution from 24 to 70 years). Four patients were diagnosed with NMO/spatially limited NMO spectrum disorder, three patients were diagnosed with spinal cord ADEM, two multiple sclerosis (MS) and one patient with copper deficiency myelopathy. Laboratory support for the diagnosis of NMO was positive NMO-IgG antibody; for the diagnosis of ADEM signs of peripheral nervous system involvement on electromyoneurography; and for the diagnosis of MS brain MRI lesions typical for MS, as well as positive oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). All cases with inflammatory myelopathy were treated either with steroids or plasma exchange and copper replacement was started in the case of copper deficiency. The mean time from the first symptom until the final diagnosis was 16.3 months (range 1 month to 7 years). As each of idiopathic inflammatory demyelinating diseases that can present with LETM have specific therapy, the postponement in making the correct diagnosis can lead to a poor recovery. In patients with LETM, a standardized diagnostic approach can result in a correct diagnosis and appropriate treatment.

Psychotic reaction as a manifestation of multiple sclerosis relapse treated with plasma exchange.

We present a patient with a clinically isolated syndrome suggestive of multiple sclerosis, who developed a full-blown picture of paranoid psychosis with suicidal attempt. Four new lesions were observed on brain MRI, one in the left and one in the right temporal lobe, one subcortically in the cingulate gyrus and one centrally in the tegmentum of the midbrain. The patient was treated with plasma exchange and recovered completely. Psychosis is not so rare symptom of multiple sclerosis as previously reported, and poses a major treatment challenge. A combination of lesions at strategic locations was a presumed mechanism of psychosis in this patient.

Sporadic CJD in a patient with relaplsing-remitting multiple sclerosis on an immunomodulatory treatment.

Creutzfeld-Jacob disease (CJD) is a degenerative, invariably fatal brain disorder. Multiple sclerosis (MS) is a chronic, potentially disabling, immune-mediated inflammatory demyelinating disease of the central nervous system. Here, we report a 50-year-old woman who, two years after the diagnosis of relapsing remitting MS, developed altered consciousness, dystonic posture of the left hand and myoclonic jerks. Repeated brain MRI showed hyperintensities on T2 sequences in basal ganglia bilaterally and diffusion restriction in these areas, and, since typical EEG and CSF features were present, the diagnosis of CJD was made. To the best of our knowledge, this is the first report of a glatiramer acetate-treated MS patient who developed sporadic CJD. This combination is interesting in the light of recent data suggesting that CJD and MS may share similar mechanisms of "molecular mimicry" and autoimmunity. This case also emphasizes the importance of critically assessing every new symptom even in a patient with an established diagnosis of MS.

Spinal cord tumor versus transverse myelitis.

BACKGROUND CONTEXT: Longitudinally extensive transverse myelitis (LETM) is one of the defining features of neuromyelitis optica (NMO). Despite the well-established criteria, clinical and paraclinical features, the disease is often misdiagnosed and erroneously treated. PURPOSE: We report on a case of LETM in a patient with spatially limited NMO spectrum disorder that was misdiagnosed as spinal cord tumor and underwent spinal cord biopsy. STUDY DESIGN: A 43-year-old female patient is described. METHODS: The patient developed spastic tetraparesis over 1 week. Spinal cord magnetic resonance imaging (MRI) revealed LETM, and she was treated with steroids and recovered. Nine months later, her condition worsened and repeat spinal cord MRI was interpreted as a large intramedullary tumor in the cervical region with irregular postcontrast enhancement. Biopsy revealed demyelination. Cerebrospinal fluid (CSF) analysis revealed positive oligoclonal IgG bands, and serum was positive for NMO-IgG antibody. RESULTS: The patient was diagnosed with spatially limited NMO spectrum disorder, treated with plasma exchange, high-dose corticosteroids, and cyclophosphamide, and with good recovery. CONCLUSIONS: The factors favoring inflammatory LETM are acute or subacute onset of clinical symptoms, positive oligoclonal bands in the CSF, positive NMO-IgG or other antibodies, and brain MRI showing demyelinating lesions. Postcontrast axial MRI sequences of the spinal cord can also be helpful. In doubtful situations, a trial of therapy and follow-up MRI a month later might be a more prudent approach if the patient is not rapidly deteriorating.

Central positioning upbeat nystagmus and vertigo due to pontine stroke.

We present a female patient with central positioning nystagmus and vertigo (c-PPV) due to a pontine stroke. To our knowledge this is the first report of central upbeat positioning nystagmus caused by pontine lacunar stroke. This report, together with those published previously, supports the existence of a crossing ventral tegmental tract in humans.

Downbeat nystagmus, ataxia and spastic tetraparesis due to coeliac disease.

A 25-year-old female presented to a university neurology clinic with a 1-month history of progressive ataxia, downbeat nystagmus and spastic tetraparesis. Personal history revealed polyarthralgias and weight loss. Family history was negative. Following thorough history, laboratory, neurophysiological and MRI investigations, a diagnosis of cerebellar ataxia due to coeliac disease was done. The patient was treated with strict gluten-free diet and intravenous administration of immunoglobulins. Although there are many controversies about neurological manifestations of coeliac disease, this case pointed to strong association between these two disorders. The findings of elevated protein content in the cerebrospinal fluid with positive oligoclonal bands suggested an immune-mediated process, further supported by positive anti-endomysium antibodies and anti-transglutaminase antibodies in the cerebrospinal fluid.

Genes associated with multiple sclerosis: 15 and counting.

Evaluation of: The International Multiple Sclerosis Genetics Consortium (IMSGC). IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes Immun. 11(5), 397-405 (2010). Multiple sclerosis (MS) develops in genetically susceptible populations as a result of environmental exposures, and discovering these genetic and/or environmental factors will provide fundamental new insights into the pathogenesis, diagnosis and treatment of this disabling disease. With the introduction of genome-wide association studies, the number of genes found to be associated with MS has increased rapidly. In all of these genes, in a study by the International Multiple Sclerosis Genetics Consortium, the classic MS risk locus, HLA-DRB1, stood out with remarkably strong statistical significance, but they also identified 12 other loci and/or genes associated with MS. However, all of these alleles have a very modest odds ratio and they explain approximately 3% of the variance in MS risk. Recently, the International Multiple Sclerosis Genetics Consortium provided evidence for three new loci that show significant association at a genome-wide level: RGS1, IL12A and MPHOSPH9/CDK2AP1. In this article, we will review the three newly discovered susceptibility loci and the implications of genome-wide association studies in MS on clinical practice.

Treatment of steroid unresponsive relapse with plasma exchange in aggressive multiple sclerosis.

The options for treating steroid unresponsive relapses in relapsing remitting multiple sclerosis (RRMS) are modest. We present a small series of patients with an aggressive course of RRMS whose steroid unresponsive relapses were treated with plasma exchange. In the period from January 2007 until February 2009 we identified four patients with steroid unresponsive relapses. All recorded relapses were treated with methylprednisolone, either with 500 mg for 5 days or 1000 mg for 3 days. If there was no improvement, patients were given five cycles of plasma exchange. If there was no recovery after the initial five cycles, five more were administered. Each patient's clinical status was monitored using the extended disability status scale. The median time from symptom onset until starting plasma exchange was 30 days (23-45 days). For four relapses, five cycles of plasma exchange were given with marked recovery in one, moderate in two, and mild in one case. In one patient, after five cycles there was no recovery, so five more cycles were administered, after which a moderate recovery ensued. This study further supports the efficacy of plasma exchange in the treatment of steroid unresponsive relapses in aggressive RRMS.

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.

Rare infections mimicking MS.

The diagnosis of multiple sclerosis (MS), despite well defined clinical criteria is not always simple. On many occasions it is difficult to differentiate MS from various non-MS idiopathic demyelinating disorders, specific and infectious inflammatory diseases or non-inflammatory demyelinating diseases. Clinicians should be aware of various clinical and MRI "red flags" that may point to the other diagnosis and demand further diagnostic evaluation. It is generally accepted that atypical clinical symptoms or atypical neuroimaging signs determine necessity for broad differential diagnostic work up. Of the infectious diseases that are most commonly mistaken for MS the clinician should take into account Whipple's disease, Lyme disease, Syphilis, HIV/AIDS, Brucellosis, HHV-6 infection, Hepatitis C, Mycoplasma and Creutzfeld-Jacob disease, among others. Cat scratch disease caused by Bartonella hensellae, Mediterranean spotted fever caused by Riketssia connore and Leptospirosis caused by different Leptospira serovars rarely cause focal neurological deficit and demyelinating MRI changes similar to MS. When atypical clinical and neuroimaging presentations are present, serology on rare infectious diseases that may mimic MS may be warranted. This review will focus on the infectious diseases mimicking MS with presentation of rare illustrative cases.

Genomics in multiple sclerosis.

Multiple sclerosis (MS) is chronic, inflammatory disease of the central nervous system that mainly affects young adults and is characterized with dissemination of demyelinating lesions in time and space. It is well known that MS is very heterogeneous disease, so biomarkers that would reliably determine disease course, outcome or treatment response in early stages of the disease (preferentially clinically isolated syndrome) are desperately needed. Genome-wide expression analysis represents the profile of all genes in a certain tissue or cell population in a certain time point. Therefore, as the sequence of the human genome is entirely known, it is possible to analyze any given human gene in any given context. This review will discuss results and possible applications of genome-wide expression studies in brain tissue and blood samples of MS patients.

Diagnostic imaging in acute disseminated encephalomyelitis.

Acute disseminated encephalomyelitis is an idiopathic inflammatory demyelinating disease of the CNS that is particularly difficult to differentiate from the first episode of multiple sclerosis, so called clinically isolated syndrome. Currently, no diagnostic criteria exist that could reliably differentiate these two diseases. More importantly no single clinical, neuroimaging or cerebrospinal fluid feature defines a disorder with absolute certainty. This review will summarize clinical and paraclinical characteristics of acute disseminated encephalomyelitis in adults, with special emphasis on diagnostic imaging.

Primary diffuse meningeal melanomatosis.

Primary diffuse meningeal melanomatosis can clinically mimic a wide variety of other conditions, including lymphoma, leukemia, neurosarcoidosis, metastatic carcinoma, acute disseminated encephalomyelitis, subacute meningitis, viral encephalitis, and idiopathic hypertrophic cranial pachymeningitis. We report on a young patient with primary diffuse meningeal melanomatosis who presented with papilledema, flaccid paraparesis, and cognitive impairment. The importance of imaging of the whole central nervous system, cerebrospinal fluid analysis, and pathohistological examination is emphasized in making the appropriate diagnosis.