Consensus statement of the Spanish Society of Neurology on the treatment of multiple sclerosis and holistic patient management in 2023.

The last consensus statement of the Spanish Society of Neurology's Demyelinating Diseases Study Group on the treatment of multiple sclerosis (MS) was issued in 2016. Although many of the positions taken remain valid, there have been significant changes in the management and treatment of MS, both due to the approval of new drugs with different action mechanisms and due to the evolution of previously fixed concepts. This has enabled new approaches to specific situations such as pregnancy and vaccination, and the inclusion of new variables in clinical decision-making, such as the early use of high-efficacy disease-modifying therapies (DMT), consideration of the patient's perspective, and the use of such novel technologies as remote monitoring. In the light of these changes, this updated consensus statement, developed according to the Delphi method, seeks to reflect the new paradigm in the management of patients with MS, based on the available scientific evidence and the clinical expertise of the participants. The most significant recommendations are that immunomodulatory DMT be started in patients with radiologically isolated syndrome with persistent radiological activity, that patient perspectives be considered, and that the term "lines of therapy" no longer be used in the classification of DMTs (> 90% consensus). Following diagnosis of MS, the first DMT should be selected according to the presence/absence of factors of poor prognosis (whether epidemiological, clinical, radiological, or biomarkers) for the occurrence of new relapses or progression of disability; high-efficacy DMTs may be considered from disease onset.

Specific Cutaneous Lesions in Patients With Neurosarcoidosis. / Lesiones cutáneas específicas en pacientes con neurosarcoidosis.

Neurosarcoidosis is an uncommon but potentially serious disease of the central nervous system that can cause major sequelae. We analyzed the presence and diagnostic usefulness of specific cutaneous lesions in 58 patients with neurosarcoidosis. Sixteen patients (27.6%) had specific cutaneous lesions (14 men and 2 women; mean age, 50 years [range, 20-84 years]). Twenty-four types of neurological lesions were observed: cranial neuropathy (n=7), parenchymal lesions (n=4), meningeal lesions (n=3), myelopathy (n=3), pituitary lesions (n=1), hydrocephalus (n=2), and peripheral neuropathy (n=4). Twenty types of specific cutaneous lesions were observed: maculopapular lesions (n=6), plaques (n=9), lupus pernio (n=1), and scar sarcoidosis (n=4). These last lesions coexisted with maculopapular lesions in 2 patients and plaques in another 2. Specific cutaneous lesions were present at diagnosis of neurosarcoidosis in 13 patients. Recognition of specific cutaneous lesions in a patient with suspected neurosarcoidosis is important as biopsy can accelerate diagnosis.

A guide to treating gait impairment with prolonged-release fampridine (Fampyra®) in patients with multiple sclerosis. / Guía de tratamiento del deterioro de la marcha con fampridina de liberación prolongada (Fampyra®) en pacientes con esclerosis múltiple.

INTRODUCTION: Gait impairment, a frequent sign in multiple sclerosis (MS), places a major burden on patients since it results in progressive loss of personal and social autonomy, along with work productivity. This guide aims to provide recommendations on how to evaluate gait impairment and use prolonged-release fampridine (PR-fampridine) as treatment for MS patients with gait impairment in Spain. DEVELOPMENT: PR-fampridine dosed at 10mg every 12hours is currently the only drug approved to treat gait impairment in adults with MS. Additionally, PR-fampridine has been shown in clinical practice to significantly improve quality of life (QoL) in patients who respond to treatment. Treatment response can be assessed with the Timed 25-Foot Walk (T25FW) or the 12-item MS Walking Scale (MSWS-12); tests should be completed before and after starting treatment. The minimum time recommended for evaluating treatment response is 2 weeks after treatment onset. Patients are considered responders and permitted to continue the treatment when they demonstrate a decrease in their T25FW time or an increase in MSWS-12 scores. A re-evaluation is recommended at least every 6 months. The SF-36 (Short Form-36) and the MSIS-29 (MS Impact Scale-29) tests are recommended for clinicians interested in performing a detailed QoL assessment. This drug is generally well-tolerated and has a good safety profile. It should be taken on an empty stomach and renal function must be monitored regularly. CONCLUSIONS: These recommendations will help ensure safer and more efficient prescription practices and easier management of PR-fampridine as treatment for gait impairment in Spanish adults with MS.

Long-Term Adherence to IFN Beta-1a Treatment when Using RebiSmart® Device in Patients with Relapsing-Remitting Multiple Sclerosis.

The effectiveness of disease-modifying drugs in the treatment of multiple sclerosis is associated with adherence. RebiSmart® electronic device provides useful information about adherence to the treatment with subcutaneous (sc) interferon (IFN) ß-1a (Rebif®). The aim of the study was to determine long-term adherence to this treatment in patients with relapsing-remitting multiple sclerosis (RRMS). This retrospective multicentre observational study analysed 258 patients with RRMS who were receiving sc IFN ß-1a (Rebif®) treatment by using RebiSmart® until replacement (36 months maximum lifetime) or treatment discontinuation. Adherence was calculated with data (injection dosage, time, and date) automatically recorded by RebiSmart®. Patients in the study had a mean age of 41 years with a female proportion of 68%. Mean EDSS score at start of treatment was 1.8 (95% CI, 1.6-1.9). Overall adherence was 92.6% (95% CI, 90.6-94.5%). A total of 30.2% of patients achieved an adherence rate of 100%, 80.6% at least 90%, and only 13.2% of patients showed a suboptimal adherence (<80%). A total of 59.9% of subjects were relapse-free after treatment initiation. Among 106 subjects (41.1%) who experienced, on average, 1.4 relapses, the majority were mild (40.6%) or moderate (47.2%). Having experienced relapses from the beginning of the treatment was the only variable significantly related to achieving an adherence of at least 80% (OR = 3.06, 1.28-7.31). Results of this study indicate that sc IFN ß-1a administration facilitated by RebiSmart® could lead to high rates of adherence to a prescribed dose regimen over 36 months.

Listeria monocytogenes meningoencephalitis in adults: analysis of factors related to unfavourable outcome.

PURPOSE: To analyse the short-term outcome in patients with Listeria monocytogenes meningoencephalitis (LMME) to improve management and outcome. METHODS: Observational study with adult patients with LMME between 1977 and 2009 at a tertiary hospital in Barcelona, Spain. Parameters that predicted outcome were assessed with univariate and logistic regression analysis. RESULTS: Of 59 cases of LMME, 28 occurred in the last decade. Since 1987, a new protocol has been used and 29/45 patients (64%) treated since then received adjuvant dexamethasone. In patients who received this treatment there was a trend towards fewer neurological sequelae (5 vs 33%; p = 0.052). Antiseizure prophylaxis with phenytoin was administered in 13/45 (28%) patients. Seizures occurred in 7/45 (16%) patients, all in the group who did not receive phenytoin. Hydrocephalus presented in 8/59 (14%). It was never present at admission and five patients needed neurosurgical procedures. Sequelae after 3 months were present in 8/45 (18%), mostly cranial nerve palsy. Rhombencephalitis (RE) was related to the presence of neurologic sequelae (OR: 20.4, 95% CI: 1.76-236). Overall mortality was 14/59 (24%), 9/59 (15%) due to neurological causes related to hydrocephalus or seizures. Mortality was defined as early in 36% and late in 64%. In the multivariate analysis, independent risk factors for mortality were presence of hydrocephalus (OR: 17.8, 95% CI: 2.753-114) and inappropriate empirical antibiotic therapy (OR: 6.5, 95% CI: 1.201-35). CONCLUSIONS: Outcome of LMME may be improved by appropriate empirical antibiotic therapy, suspicion and careful management of hydrocephalus. Use of adjuvant dexamethasone or phenytoin in a subgroup of these patients might have a benefit.

Neurosarcoidosis: report of 30 cases and a literature survey.

INTRODUCTION: Neurosarcoidosis accounts for approximately 5% of cases of sarcoidosis. OBJECTIVE: To determine the frequency of Neurosarcoidosis in our setting and analyze the clinical-radiological findings and evolution of 30 patients consecutively diagnosed. METHODS: The medical records of patients with a diagnosis of Neurosarcoidosis were reviewed, and data regarding the clinical features, ancillary tests performed, treatment, and outcome were recorded. We revised the literature to summarize and discuss the previous clinical series of Neurosarcoidosis. RESULTS: It accounted for 6.7% of all cases of sarcoidosis. Seven patients had definite diagnosis and 23 had probable diagnosis. The mean age at onset of Neurosarcoidosis was 48.3 years and 66.7% of patients were women. Neurologic clinical features were the first manifestation of Neurosarcoidosis in 70% of cases. Cranial neuropathy was present in 17 patients and 14 of them had facial palsy. The central nervous system was affected in 10 patients and the peripheral nervous system in 5. Chest disease, the most common extraneurologic manifestation, was present in 20 patients. All patients were treated with corticosteroids, and all those with central nervous system involvement had poor outcome. CONCLUSION: Neurosarcoidosis requires a high degree of suspicion to establish the diagnosis. Central nervous system involvement is associated with a poor prognosis.

[Wernicke's encephalopathy in non-alcoholic patients: a series of 8 cases]. / Encefalopatía de Wernicke en pacientes no alcohólicos: una serie de 8 casos.

INTRODUCTION: Wernicke's encephalopathy (WE) is an underdiagnosed condition, usually associated with alcoholism, and has a worse prognosis if there is a delay in diagnosis. A series of 8 non-alcoholic patients with WE is presented and an assessment is made on whether a delay in diagnosis leads to a worse prognosis. PATIENTS AND METHODS: The clinical records of patients admitted to 2 university hospitals between 2004 and 2009 with the diagnosis of WE, excluding those with a history of alcoholism, were retrospectively reviewed. RESULTS: The study included 4 men and 4 women aged 35-82 of whom 7 had a history of gastrointestinal pathology, and persistent vomiting was the precipitating factor in 7. Encephalopathy was the most frequent onset symptom (4). The classical triad was present in seven patients. Thiamine levels were low in 3/6 and normal in 3/6 cases. MRI was abnormal in seven patients, with high signal intensity in the diencephalon and mammillary bodies (7), periaqueductal grey matter (6), cortex (3) and cerebellum (1). Seven improved with thiamine. Sequelae were mild in 6, and severe in 2 after 6-12 months of follow-up. All patients with a diagnostic delay less than 18 days had mild sequelae. CONCLUSIONS: Non-alcoholic WE frequently occurs after gastrointestinal disturbances that could result in lower thiamine absorption. Whereas thiamine levels can be normal in many cases, in almost all cases the MRI shows signal alterations in typical locations. A delay in the diagnosis, and therefore, in treatment leads to a worse prognosis.

Association of HLA-DRB1*15 allele and CSF oligoclonal bands in a Spanish multiple sclerosis cohort.

BACKGROUND AND OBJECTIVE: The HLA-DRB1*15 allele is consistently associated with multiple sclerosis (MS) susceptibility in most studied populations. This study investigated the association between HLA-DRB1 alleles and the presence of oligoclonal immunoglobulin G bands (OCB) in the cerebrospinal fluid (CSF) in a Spanish population with MS. METHODS: The HLA-DRB1 typing was performed in 268 patients with sporadic MS and the detection of OCB in CSF. HLA-DRB1 allelic frequencies were compared between OCB-positive and OCB-negative patients, and both groups were also compared with 1088 unrelated healthy controls. Moreover, we correlated the various HLA-DRB1 genotypes, considering all the combinations of both parental alleles found with the presence or absence of OCB. RESULTS: We found 206 OCB-positive and 62 OCB-negative patients. The HLA-DRB1*15 allele in OCB-positive patients had a higher frequency when compared with OCB-negative patients (39.3% in OCB-positive vs. 16.1% in OCB-negative, OR = 1.38 95% CI = 1.18-1.61, P < 0.001). The other alleles did not show differences. When we compared with controls, the HLA-DRB1*15 allele was associated with the disease only in the OCB-positive patients group. None of the 55 genotypes found showed any association with the presence or absence of OCB. CONCLUSIONS: HLA-DRB1*15 allele is associated with OCB-positive patients with MS when studying a Spanish MS population.

HLA-DRB1: genetic susceptibility and disability progression in a Spanish multiple sclerosis population.

BACKGROUND AND OBJECTIVE: The association of HLA-DRB1*15 with susceptibility to multiple sclerosis (MS) has been consistently reported although its effect on the clinical phenotype is still controversial. The objectives of this study are to investigate the influence of the HLA-DRB1 alleles on the genetic susceptibility to MS and to study their impact on disability progression in a Spanish population. METHODS: HLA-DRB1 typing was performed by PCR-SSP in 380 patients with sporadic MS and 1088 unrelated healthy controls. Allelic frequencies were compared between groups. We studied the correlation between the different alleles and the progression of MS. RESULTS: The HLA-DRB1*15 allele in patients with MS had a statistically significant higher frequency when compared with controls (18.9% in patients vs. 10.1% in controls, Odds ratio (OR)=2.07, 95% CI=1.64-2.60, P<0.001). In the univariate analysis, the DRB1*01 and DRB1*04 alleles were associated with a worse prognosis when considering the time to reach an EDSS of 6, whereas the DRB1*03 was correlated with a better outcome. In the multivariate analysis, the alleles*01 and *04 were demonstrated to be independent factors to have a worse prognosis. CONCLUSIONS: HLA-DRB1*15 is associated with MS when comparing patients with unrelated healthy controls in a Spanish population. The HLA-DRB1*01 and HLA-DRB1*04 alleles are related to a worse prognosis when considering the time taken to reach severe disability.

Clinicopathologic features and outcomes of neuro-Behçet disease in Spain: a study of 20 patients.

BACKGROUND: To describe the clinical characteristics and evolution of a series of adult patients hospitalized for neuro-Behçet disease (NBD). METHODS: Consecutive patients admitted for NBD in a teaching hospital were retrospectively selected. Disability at discharge and during follow-up was graded with the modified Rankin Scale, and outcome classified as good or poor (grades 3-6). RESULTS: Twenty patients were included (M/F, 13/7). Mean age at NBD diagnosis was 36.3 years. Nineteen patients had other manifestations of Behçet disease (BD) before NBD developed, but only 7 met the complete diagnostic criteria for BD. Fever, headache, motor weakness, and cranial nerve palsy were each present in approximately 60% of patients. There was a low prevalence of behavioral changes (5%), seizures (5%), and sphincter incontinence (0%), and a relatively high prevalence of meningism (25%). Non-neurologic manifestations of BD were concurrently detected in 15 patients (75%). 80% had parenchymal involvement. Brain biopsies during 5 attacks showed perivascular lymphocytic infiltration with reactive astrocytosis, but no frank vasculitis. During a mean follow-up of 6.3 years per patient, 12 had at least one relapse. In total, there were 22 relapses; all but two were in the same location and were symptomatically similar in each patient. At the end of follow-up, 7 patients (35%) had a poor outcome, including 4 who died. CONCLUSION: Recording of previous manifestations of BD and a physical examination to detect concomitant systemic manifestations of BD may help establish an early diagnosis of NBD. Relapses frequently occurred in the same location. No frank vasculitis was present in brain biopsies.

Anticipation of age at onset in multiple sclerosis: methodologic pitfalls.

BACKGROUND/AIM: There are several reports that claim anticipation in complex or polygenic diseases such as multiple sclerosis (MS), Crohn disease or schizophrenia. The aim of the present study was to assess age at onset of MS during the last 60 years in the region of Costa de Ponent (Barcelona, Spain) showing how apparent changes in age at onset between generations can be an artefact of analysis based on cohorts that have not been followed enough time. METHODS: The study comprised 1100 patients diagnosed of MS. The method used to correct for follow-up time bias involves constructing comparison cohorts that had been observed for the same amount of time. To ensure equal follow-up times, we restricted our analysis to patients whose onset was by 37 years of age (percentile 75) and were at least 37 years old. We analysed differences in age at onset using log-rank test to compare survival curves estimated by Kaplan-Meier method. RESULTS: Age at onset decreases progressively from older to younger generations. However, when adjustment to equal follow-up time was done, anticipation in age at onset was not found. CONCLUSION: Anticipation of age at onset is undetectable when adjusted for follow-up time.

Anticipation of age at onset in familial multiple sclerosis.

BACKGROUND AND OBJECTIVE: Anticipation of age at onset in the younger generations is a widely known characteristic of many diseases with genetic inheritance. This study was performed to assess whether there is anticipation of age at onset in younger generations of familial multiple sclerosis (MS) in a Spanish population and to compare clinical characteristics of familial and sporadic MS. METHODS: We studied a cohort of 1110 patients diagnosed with MS and followed-up in our MS Unit. Patients were considered as familial MS if they had in their family at least one relative of first or second degree diagnosed with MS. Otherwise, patients were considered to have sporadic MS. We compared the age at onset between relatives from different generations, and we also compared the age at onset of familial and sporadic MS. RESULTS: A lower age at onset in the younger generations was found (median 22 years vs. 30 years, P < 0.001) and a significant lower age at onset of the disease in familial MS comparing to sporadic MS (median 25 years vs. 29 years, P = 0.042). CONCLUSIONS: There is an anticipation of the age at onset of MS in the younger generations of patients with familial MS. There is also a lower age at onset in familial versus sporadic MS.

18F-FDG PET/CT in the evaluation of POEMS syndrome.

In POEMS syndrome the identification and biopsy of an osteosclerotic lesion or a lymph node typical of Castleman's disease (CD) is essential to establish the diagnosis and plan appropriate treatment. We report four patients in whom the localisation and identification of diagnostic bone lesions or lymphadenopathies were guided by fluorodeoxyglucose positron emission tomography integrated with computerised tomography (FDG PET/CT). FDG PET/CT identified bone lesions not detected with other techniques in one patient, and revealed hypermetabolic characteristics in bone lesions or adenopathies in the others, thus guiding the diagnostic biopsy in those with hypermetabolism. In conclusion, FDG PET/CT may be useful in detecting and selecting bone lesions and lymph nodes for biopsy in patients with suspected POEMS syndrome.

Reversible acute leukoencephalopathy as a form of presentation in cerebral amyloid angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) may present as cerebral haemorrhage, cerebral infarction and periventricular white matter lesions. Reversible leukoencephalopathy is a rare manifestation of CAA. AIMS OF THE STUDY: To describe two patients with reversible acute leukoencephalopathy as the first manifestation of CAA. PATIENTS: Two consecutive patients were admitted to our neurology department with transient focal neurological symptoms. They showed reversible focal leukoencephalopathy on magnetic resonance imaging (MRI). CAA was finally diagnosed in both, and pathologically confirmed in one. The latter patient showed multiple foci of petechial bleeding in the cortex and subcortex in T2-weighted GRE sequences, suggestive of CAA. CONCLUSION: Reversible acute focal leukoencephalopathy may be an infrequent clinical and radiological pattern of CAA.

[Cerebral vasoreactivity in high-altitude cerebral edema]. / Vasorreactividad cerebral en el edema cerebral asociado a la altura.

INTRODUCTION: High-altitude cerebral edema is a potentially fatal neurologic syndrome that develops in subjects exposed to high-altitude. It may appear associated to other forms of altitude illnesses as acute mountain sickness or high-altitude pulmonary edema. The exact pathophysiology of high-altitude cerebral edema is still unknown and there is not consensus about the primarily type of edema: vasogenic or cytotoxic. We present a patient who suffered high-altitude cerebral edema and the clinical, neuroimaging and ultrasonographic findings at first and during the follow up. CLINICAL CASE: A 49 year old man, mountain climber, at altitude of 5,400 m presented altered mental status and ataxia with progressive neurologic deterioration, associated to pulmonary edema. After being introduced at hyperbaric chamber, patient was descended to hospital. The magnetic resonance imaging (MRI) revealed increased T2 signal in the white matter, especially in the splenium of the corpus callosum. Corticosteroids and acetazolamide were administered and patient was transferred to our hospital. Transcranial Doppler sonography (TCD-A) using acetazolamide showed an impaired cerebral vasoreactivity. Clinical improvement of the patient was fast. MRI performed 14 days after clinical onset showed partial resolution of corpus callosum lesion. MRI and TCD-A performed six months after were normal. CONCLUSIONS: TCD-A in our patient show a diminished cerebral vasoreactivity related to high-altitude cerebral edema. These findings suggest that impairment of cerebral autoregulation might play a role in high-altitude cerebral edema pathogenesis. Reversible clinical and neuroimaging changes indicate a predominant vasogenic edema.

An approach to estimating the intangible costs of multiple sclerosis according to disability in Catalonia, Spain.

Multiple sclerosis (MS) is a chronic demyelinating disease, which represents a great economic burden to society. Cost-of-illness studies of MS tend to underestimate the intangible costs related to pain, anxiety and helplessness. The purpose of this study was to estimate the intangible costs of MS, and determine whether these costs increase as disability progresses. We studied 211 consecutive patients with MS who attended our MS unit. Patients mean age was 41.6 (SD: 10.7) years, 69% were female, and their mean Expanded Disability Status Scale (EDSS) score was 2.47 (SD: 2.05). Quality-of-life was measured with the EuroQoL visual analogue scale. Quality-adjusted life year (QALY) was calculated for each patient. Patients were grouped into five disability stages according to their EDSS, and QALY was compared between patients and a group of healthy controls matched by age and sex. A benchmark value was ascribed to each QALY lost, and the intangible costs per patient-year were calculated as Euros 0 (EDSS =0), Euros 1100 (EDSS =1-3), Euros 8250 (EDSS =3.5-5.5), Euros 9900 (EDSS =6-7) and Euros 11,000 (EDSS >7.5). Sensitivity analysis showed a similar progression of costs. We conclude that intangible costs are relevant in MS, especially when disability increases. Although the method to calculate the costs remains controversial, we consider that they should be included in cost analysis of MS.