Genomics and proteomics: role in the management of multiple sclerosis

Epidemiological studies and neuro-imaging have provided important insights into the natural course and prognostic factors of multiple sclerosis (MS), but our ability to predict different courses of the disease, and especially its response to treatment, is still very limited. Pharmacogenetic, pharmacogenomic and proteomic studies aim to assess gene and protein function in disease and promise to help to fill this important gap in our knowledge. Such studies may increase our understanding of disease mechanisms and responses to therapeutic compounds. Large-scale transcriptional expression profiling can be performed using gene chip microarrays; this technology allows screening for differentially expressed genes without having well-defined underlying hypotheses ("discovery-driven research”). To complement the technique, real time reverse transcription and polymerase chain reaction (RT-PCR) can be used for more targeted profiling and provides quantitative data on pre-selected genes. However, to maximise their clinical utility, expression profiling results need to be combined with well-documented clinical and imaging data. Two forthcoming studies will investigate the long-term effects of early treatment with interferon beta-1b (IFNβ) on the course of MS. The BENEFIT (BEtaseron®/Betaferon® in Newly Emerging MS for Initial Treatment) study will incorporate pharmacogenetic and pharmacogenomic analyses to determine the genetic elements controlling treatment response. BEST-PGx (Betaferon®/Betaseron® in Early relapsing-remitting MS Surveillance Trial—Pharmacogenomics) is an exploratory 2-year study that will investigate the value of RNA expression profiling and pharmacogenetics in predicting treatment response to IFNβ in patients with early relapsing MS. The main goal of BEST-PGx is the identification of differences in gene expression profiles of patients showing differential treatment responses. In addition, this study may reveal new information relevant to the mechanism of action of interferon treatment in MS and also to differences in the underlying pathology of the immune system. These data may help us approach the goal of a really "individualised therapy” with increased efficacy, reduced adverse drug reactions and more efficient use of healthcare resource

Optical coherence tomography reflects clinically relevant gray matter damage in patients with multiple sclerosis

BACKGROUND: Retinal degeneration leading to optical coherence tomography (OCT) changes is frequent in patients with multiple sclerosis (PwMS). OBJECTIVE: To investigate associations among OCT changes, MRI measurements of global and regional brain volume loss, and physical and cognitive impairment in PwMS. METHODS: 95 PwMS and 52 healthy controls underwent OCT and MRI examinations. Mean peripapillary retinal nerve fiber layer (pRNFL) thickness and ganglion cell/inner plexiform layer (GCIPL) volume were measured. In PwMS disability was quantified with the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Associations between OCT, MRI, and clinical measures were investigated with multivariable regression models. RESULTS: In PwMS, pRNFL and GCIPL were associated with the volume of whole brain (p < 0.04), total gray matter (p < 0.002), thalamus (p ≤ 0.04), and cerebral cortex (p ≤ 0.003) -both globally and regionally-, but not white matter. pRNFL and GCIPL were also inversely associated with T2-lesion volume (T2LV), especially in the optic radiations (p < 0.0001). The brain volumes associated with EDSS and SDMT significantly overlapped with those correlating with pRNFL and GCIPL. CONCLUSIONS: In PwMS, pRNFL and GCIPL reflect the integrity of clinically-relevant gray matter structures, underling the value of OCT measures as markers of neurodegeneration and disability in multiple sclerosis

Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study

Background: Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies. Methods: For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry. Findings: We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1–2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0–8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35–4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08–6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry. Interpretation: The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials. Funding: Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche

["Numb chin syndrome": first presenting syndrome of multiple sclerosis?]

HISTORY AND CLINICAL FINDINGS: A 34-year-old previously healthy woman presented with a five-day history of subacute onset of a numb chin. Examination on admission revealed isolated hypesthesia on the left side of the chin and lower lip. INVESTIGATIONS: Brain magnetic resonance imaging (MRI) demonstrated a lesion involving the pontine trigeminal fibers and multiple periventricular T2-hyperintense white matter lesions suggestive of inflammatory /demyelinating disease. Cerebrospinal fluid analysis revealed oligoclonal IgG bands (only in cerebrospinal fluid) and an increased IgG index. A follow-up MRI after four months demonstrated new supratentorial brain lesions, confirming a syndrome, highly suggestive of multiple sclerosis as the likely underlying diagnosis. TREATMENT AND FOLLOW-UP: The facial sensory disturbance resolved spontaneously. Prophylactic treatment with interferon-beta was started. CONCLUSION: The numb chin syndrome may be the initial presentation of a clinically isolated syndrome suggestive of multiple sclerosis. Prophylactic immunomodulatory treatment may be started after the suspicion of inflammatory/demyelinating activity is confirmed

Utility of neuropsychological testing for guiding treatment decisions in paediatric multiple sclerosis

In the past years, there has been growing awareness about childhood onset multiple sclerosis (MS) and the relevance of psychosocial aspects such as cognitive disturbances, fatigue and depression in this population. We describe a case of a 16-year-old patient with relapsing-remitting multiple sclerosis (RRMS) who presented at our clinic with severe fatigue symptoms and who underwent repeated neuropsychological examinations. A sudden significant slowing indicated a new relapse while neurological examination did not. This case highlights the high sensitivity and clinical relevance of neuropsychological testing in patients with juvenile MS even in the context of treatment decisions

Intravenous levetiracetam : treatment experience with the first 50 critically ill patients

Levetiracetam (LEV) is a broad-spectrum antiepileptic drug with no known interactions and a favorable profile of adverse events. These properties make it a good candidate for use in critically ill patients. An intravenous formulation of LEV was recently approved. The present study retrospectively assesses the safety and efficacy of LEV in the first 50 critically ill patients treated with intravenous LEV. Indications for use were seizure prophylaxis, acute symptomatic seizures, and all forms of status epilepticus. There were no major adverse effects, although less prominent changes may have been masked by the already severely compromised condition of these patients. Two patients (4%) had transiently lowered platelet counts (55,000 and 82,000, respectively). Efficacy, defined as cessation of seizure activity or prevention of its recurrence, was observed in 41 of 50 patients (82%). Antiepileptic treatment of critically ill patients with LEV seems to be effective and safe according to the data for this small cohort, but this observation warrants further prospective investigation in a larger number of patients