Gloria Dalla Costa

Vitamin D levels and risk of multiple sclerosis in patients with clinically isolated syndromes

Background: Growing evidence suggests that vitamin D deficiency may be one of the most important environmental factors for the development of multiple sclerosis (MS). Objectives: The objectives of this paper are to evaluate serum 25-hydroxyvitamin D (25(OH)D) levels in patients with clinically isolated syndromes (CIS) and to examine whether they are related to MS risk. Methods: This is a retrospective study of 100 CIS patients hospitalized from 2000 to 2009 at San Raffaele Hospital, Milan, Italy. We evaluated baseline 25(OH)D level as well as clinical, brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) data. Results: A total of 52% of CIS patients had vitamin D deficiency (25(OH)D < 50 nmol/l). During follow-up (median: 7.17 years), 55 patients developed clinically definite MS (CDMS). Patients with very low (< 10th percentile) and low (< 25th percentile) 25(OH)D levels were particularly at risk of CDMS (HRs (95% CIs): 2.12 (0.91–4.96) and 1.61 (0.85–3.03), respectively), while no further reduction in the HRs of disease was observed at high levels of 25(OH)D. This association was even stronger after adjustment for additional risk factors for CDMS development (HRs (95% CIs) for 25(OH)D levels < 10th and 25th percentiles: 3.34 (1.32–8.45) and 2.04 (0.96–4.36), respectively). Conclusion: Low serum vitamin D is associated with increased MS risk in patients with CIS.

Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome

Background Neurofilament light chain (NfL) represents a promising biomarker for axonal injury. We present the first exploratory study on serum NfL in patients with a clinically isolated syndrome (CIS) and healthy controls. Methods We investigated serum NfL levels in 100 patients with CIS with a short conversion interval to clinically definite multiple sclerosis (MS) (fast converters (FC), median (IQR) conversion time: 110 days (79–139)); 98 patients with non-converting CIS (non-converters (NC), follow-up: 6.5 years (5.3–7.9)); and 92 healthy controls. Results NfL levels were higher in FC (24.1 pg/mL (13.5–51.8)) and NC (19.3 pg/mL (13.6–35.2)) than in healthy controls (7.9 pg/mL (5.6–17.2)) (OR=5.85; 95% CI 2.63 to 13.02; p=1.5×10−5 and OR=7.03; 95% CI 2.85 to 17.34; p=2.3×10−5, respectively). When grouping FC and NC, increased serum NfL concentration was also associated with increasing numbers of T2 hyperintense MRI lesions (OR=2.36; 95% CI 1.21 to 4.59; p=0.011), gadolinium-enhancing lesions (OR=2.69; 95% CI 1.13 to 6.41; p=0.026) and higher disability scores (OR=2.54; 95% CI 1.21 to 5.31; p=0.013) at CIS diagnosis. Conclusions If replicated in future studies, serum NfL may represent a reliable and easily accessible biomarker of early axonal damage in CIS and MS.

Recurrent disease-activity rebound in a patient with multiple sclerosis after natalizumab discontinuations for pregnancy planning

Natalizumab discontinuation is a frequent clinical practice, mainly as part of the progressive multifocal leukoencephalopathy (PML) risk management strategy, but this approach has raised concerns about the possible consequences related to subsequent multiple sclerosis (MS) reactivation. Preliminary results of a randomized prospective trial1 and observational studies yielded conflicting results (Table 1).2-9 We report the case of 16-year-old woman who in December 1996 developed relapsing–remitting MS with acute-onset lower limb paraesthesia followed by four relapses in the subsequent 10 months. Interferonbeta 1a therapy was initiated, but in the following years she had six new relapses and in July 2002 was enrolled in the SENTINEL study (natalizumab plus interferon beta 1a).2 At that time, she had mild disability (Expanded Disability Status Scale (EDSS) 2.0) and the pre-treatment brain MRI performed in June 2002 showed six gadolinium (Gd)-enhanced lesions. During natalizumab treatment, no clinical or radiological relapses occurred but in February 2005, after 31 Letter 492246 MSJ0010.1177/1352458513492246Multiple Sclerosis JournalMartinelli et al. 2013

Dysregulation of MS risk genes and pathways at distinct stages of disease

Objective: To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions. Methods: We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining. Results: Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage–specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS. Conclusions: Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways.

Clinical significance of the number of oligoclonal bands in patients with clinically isolated syndromes

CSF oligoclonal bands (OCBs) in patients with clinically isolated syndromes (CIS) are a risk factor for clinically definite multiple sclerosis (CDMS). We aimed to address the relevance of the number of OCBs in the prognosis of CIS patients. 219 CIS patients were included in the study, and 42% of them developed the disease during follow-up (median: 5.04 years). Patients with a high number of CSF OCBs (third quartile, 8-12 OCBs) had 2.5-fold increase in CDMS risk, while no further increase in the HR of disease was observed for patients with more than 12 OCBs. The results did not change after adjustment for additional correlates of CDMS development. This association may be due to the epitope-spreading phenomenon and may reflect the stage of the disease at the time of the examination.

Parry Romberg Syndrome associated with chronic facial pain

Parry Romberg Syndrome (PRS) is a rare condition of unknown cause and pathophysiology. It is characterized by progressive facial hemiatrophy, and neurological abnormalities are found in 20% of cases. We describe a 50-year-old woman with PRS and severe neurological involvement (lateralised epileptic seizure activity and facial pain refractory to medication). Pain intensity and frequency was reduced and control of epileptic crises was improved using levetiracetam as an additional therapy. In previous published cases associated with facial pain, the most frequent diagnoses were migraine and trigeminal neuralgia. Our findings suggest that in this patient PRS-related persistent pain has peculiar features possibly attributed to the underlying musculoskeletal abnormalities.

MiR-125a-3p timely inhibits oligodendroglial maturation and is pathologically up-regulated in human multiple sclerosis.

In the mature central nervous system (CNS), oligodendrocytes provide support and insulation to axons thanks to the production of a myelin sheath. During their maturation to myelinating cells, oligodendroglial precursors (OPCs) follow a very precise differentiation program, which is finely orchestrated by transcription factors, epigenetic factors and microRNAs (miRNAs), a class of small non-coding RNAs involved in post-transcriptional regulation. Any alterations in this program can potentially contribute to dysregulated myelination, impaired remyelination and neurodegenerative conditions, as it happens in multiple sclerosis (MS). Here, we identify miR-125a-3p, a developmentally regulated miRNA, as a new actor of oligodendroglial maturation, that, in the mammalian CNS regulates the expression of myelin genes by simultaneously acting on several of its already validated targets. In cultured OPCs, over-expression of miR-125a-3p by mimic treatment impairs while its inhibition with an antago-miR stimulates oligodendroglial maturation. Moreover, we show that miR-125a-3p levels are abnormally high in the cerebrospinal fluid of MS patients bearing active demyelinating lesions, suggesting that its pathological upregulation may contribute to MS development, at least in part by blockade of OPC differentiation leading to impaired repair of demyelinated lesions.

Migralepsy: a new case confirming the existence of this migraine complication and proposing therapy

We describe the case of a 43-years-old, right handed woman, who suffered from migraine with aura and epilepsy. Co-morbidity of migraine and epilepsy is a well known condition since more than 100 years ago [1]. Although it is a rare phenomenon, migraine attack may trigger an epileptic seizure. ICHD II (International Classification of Headache Disorders) [2] classified migralepsy (migraine triggered seizures) as a complication of migraine (coded 1.5.5) if two diagnostic criteria are fulfilled: (1) migraine fulfilling diagnostic criteria for coded 1.2 migraine with aura and (2) a seizure fulfilling diagnostic criteria for one type of epileptic attack developing during or within 1 hour of a migraine aura. Despite the fact that the term migralepsy (attributed to Lennox and Lennox) [3] was coined in 1960 both to define an ‘‘ophtalmic migraine with perhaps nausea and vomiting followed by symptoms characteristics of epilepsy’’ and to describe three specific cases, the migraine-epilepsy sequence (migralepsy) seems to be less common than epilepsymigraine (hemicrania epileptica coded 7.6.1) and post-ictal headache (coded 7.6.2). A review of the literature suggested that migralepsy as coded by ICHD II is quite infrequent but not indeed inexistent [4]. A 43-years-old woman referred to the ER Department of San Raffaele Hospital, Milano, because of a generalized tonic seizure. She was born full term with a normal delivery and had normal developmental milestones. She has a family history positive for migraine with aura (mother) but no family member suffered from epilepsy. At age 9 years she developed migraine with visual and sensitive aura. Aura consisted of flickering flashing lights, developing gradually in 15 min with a global duration of 45 min, followed by sensitive symptoms (paresthesia of hand and face) and finally by headache with migraine features (frequency of 1 attack/month in the past; in the last months they rapidly increased to 8 attacks/month). In 21 September 2011, at 10:30 a.m. she experienced her typical visual aura (photopsia) for 15 minutes. After few minutes she noted the appearance of clonic palpebral movements in her right eye. She eventually lost consciousness, felt to the ground and had a generalized seizure (lasting 5 min). She was rapidly admitted at the Hospital, being unresponsive and confused during the transport. At Neurological examination (11:30 a.m.), patient was responsive to pain stimulus with no other signs. At general examination, blood pressure was 140/80, Heart rate 98 and O2 saturation 96 %. A slight metabolic acidosis was detected at blood gas analysis. Brain CT scan (12:00) was normal. She was treated with Diazepam i.v. (10 mg). A second neurological examination (1:30 p.m.) was normal, but patient reported the onset of a severe migraine attack (9/10 VAS) localized on the left parietal and temporal side with nausea, vomiting and photo-phonophobia. EEG (2:30 p.m.) revealed epileptiform discharges in right temporal hemisphere. Brain MRI was normal and when she performed EEG again, a normalization of the previously described epileptiform features was noted, with only residual theta slowing over the left hemisphere. A therapy with topiramate was started at the initial dose of 50 mg (after one week the dose was increased to 100 mg). At follow-up (3 and 6 months), she reported only three migraine attacks without aura in the first month of therapy (VAS 5/10) and no more migraine with aura attacks or epileptic seizures. EEG was normal. B. Colombo D. Dalla Libera (&) M. A. Volontè F. Spagnolo G. Dalla Costa V. Martinelli G. Comi Department of Neurology, San Raffaele Hospital, Vita-Salute University, Via Olgettina 48, Milan, Italy e-mail: dallalibera.dacia@hsr.it

Free Light Chains and Intrathecal B Cells Activity in Multiple Sclerosis: A Prospective Study and Meta-Analysis.

Background. The presence of CSF oligoclonal bands (OBs) is an independent prognostic factor for multiple sclerosis (MS), but the difficulties in the standardization of the test and the interlaboratory variation in reporting have contributed to its limited use in the diagnosis of the disease. Standard nephelometric assays to measure free light chains (FLC) levels have been recently developed and the test may improve the detection of intrathecal B cells activity. Methods. The presence of OBs, kappa and lambda FLC levels, and standard indices of intrathecal inflammation were assessed in 100 consecutive patients, including patients with MS, clinically isolated syndromes (CIS), other inflammatory diseases of the CNS, and other noninflammatory diseases. Results. Both KFLC and LFLC correlated strongly with the presence of OCBs and with all common tests for intrathecal inflammation (p < 0.001 for all comparisons). KFLC and LFLC were significantly different in patients with MS and CIS compared to the other groups (p < 0.001 and p < 0.001, resp.) and had a better diagnostic accuracy than all the other tests (area under the curve 82.3 % for KFLC index and 79.3 % for LFLC index). Conclusion. Nephelometric assays for KFLC in CSF reliably detect intrathecal immunoglobulin synthesis and discriminate MS patients.

Opinion & Special Articles: Professionalism in neurology Maintaining patient rapport in a world of EMR

Health information technology is playing a critical role in fostering more efficient and effective health care systems by improving how information is recorded, organized, and exchanged through the use of electronic medical records (EMR). EMR are defined, according to the International Organization for Standardization, as “repositories of patient data in digital form, stored and exchanged securely, and accessible by multiple authorized users. They contain retrospective, concurrent, and prospective information, and their primary purpose is to support continuing, efficient, and quality integrated healthcare.”1