Alfredo Romani

Postinfectious inflammatory disorders Subgroups based on prospective follow-up

Background: Acute disseminated encephalomyelitis (ADEM) refers to a monophasic acute multifocal inflammatory CNS disease. However, both relapsing and site-restricted variants, possibly associated with peripheral nervous system (PNS) involvement, are also observed, and a systematic classification is lacking. Objective: To describe a cohort of postinfectious ADEM patients, to propose a classification based on clinical and instrumental features, and to identify subgroups of patients with different prognostic factors. Methods: Inpatients of a Neurologic and Infectious Disease Clinic affected by postinfectious CNS syndrome consecutively admitted over 5 years were studied. Results: Of 75 patients enrolled, 60 fulfilled criteria for ADEM after follow-up lasting from 24 months to 7 years. Based on lesion distribution, patients were classified as encephalitis (20%), myelitis (23.3%), encephalomyelitis (13.3%), encephalomyeloradiculoneuritis (26.7%), and myeloradiculoneuritis (16.7%). Thirty patients (50%) had a favorable outcome. Fifteen patients (25%) showed a relapsing course. Poor outcome was related with older age at onset, female gender, elevated CSF proteins, and spinal cord and PNS involvement. All but two patients received high-dose steroids as first-line treatment, with a positive response in 39 (67%). Ten of 19 nonresponders (53%) benefited from high-dose IV immunoglobulin; 9 of 10 had PNS involvement. The data were not controlled. Conclusions: A high prevalence of “atypical variants” was found in this series, with site-restricted damage or additional peripheral nervous system (PNS) involvement. Prognosis and response to steroids were generally good, except for some patient subgroups. In patients with PNS involvement and steroid failure, a favorable effect of IV immunoglobulin was observed.

Vestibular evoked myogenic potentials in multiple sclerosis patients

OBJECTIVES Vestibular evoked myogenic potentials (VEMPs) are saccular responses to loud acoustic stimuli and are recordable from the sterno-cleido-mastoid muscle ipsilaterally to the stimulated ear. This study aimed to investigate VEMPs in patients suffering from multiple sclerosis (MS), and to compare these findings with both clinical and instrumental data. METHODS We recorded VEMPs from 70 MS patients, whose clinical data were retrospectively evaluated for the possible occurrence of: past and current (with respect to VEMP recording) brainstem and/or cerebellar symptoms; current brainstem and/or cerebellar signs. Sixty-five patients underwent brainstem auditory evoked potentials (BAEPs) recording; 63 of the same patients underwent saccadic eye movement recording and subjective visual vertical (SVV) evaluation. RESULTS VEMPs were abnormal in 31%, BAEPs in 38% and SVV in 21% of the patients. Saccadic eye movements showed a possible brainstem dysfunction in 44.4% of the patients. There was no correlation between the occurrence of abnormalities and the technical means of detection. The same held true for correlations with clinical data, with the exception of the BAEPs; these proved to be more frequently abnormal in patients presenting at neurological examination with brainstem and/or cerebellar signs that were possibly related to the complaint of dizziness. CONCLUSIONS VEMPs should be considered a useful complementary neurophysiological tool for the evaluation of brainstem dysfunction.

Effectiveness of intravenous immunoglobulin treatment in adult patients with steroid-resistant monophasic or recurrent acute disseminated encephalomyelitis

Abstract Randomized Controlled Trials have not jet established the best pharmacological management of Acute Disseminated Encephalomyelitis (ADEM). High dose steroids are usually employed with good results, but in a few cases the clinical outcome is poor. In other patients, particularly those affected by the site restricted ADEM variants (myelitis), the disease shows a recurrent course resembling that of Multiple Sclerosis. We present here five patients, 3 of them affected by classic disseminated encephalomyelitis and 2 by a post infectious myelitis, which showed a good response to intravenous immunoglobulin (IVIg) after steroid treatment failure. In our report high dose steroids administration was substantially uneffective in all but one case, who showed a good response only during the first episode. On the contrary IVIg injection (0,4 gr/kg/day) produced a marked functional improvement in all patients starting within the first five days of drug administration and reaching a maximum within three weeks. One patient experienced a good effect nothwithstanding a steady dysability. In all cases, clinical evidence was supported by MRI controls showing improving posttreatment changes.

Oligoclonal bands in Devic’s neuromyelitis optica and multiple sclerosis: differences in repeated cerebrospinal fluid examinations:

We studied repeated cerebrospinal fluids of patients with Devic’s neuromyelitis optica (NMO) and multiple sclerosis (MS). Variations of oligoclonal bands (OBs) had opposite trends in the two groups. In MS, O Bs were detected in 399 of 411 patients (97%) and never disappeared. In NMO, O Bs were detected in three of 11 patients (27%) and always disappeared. The hypothesis that NMO and MS follow distinct patho genetic pathways is supported by our findings, which can be useful for the differentiatio n of NMO from MS.

Predicting secondary progression in relapsing-remitting multiple sclerosis : a Bayesian analysis

With the aid of a Bayesian statistical model of the natural course of relapsing remitting Multiple Sclerosis (MS), we identify short-term clinical predictors of long-term evolution of the disease, with particular focus on predicting onset of secondary progressive course (failure event) on the basis of patient information available at an early stage of disease. The model specifies the full joint probability distribution for a set of variables including early indicator variables (observed during the early stage of disease), intermediate indicator variables (observed throughout the course of disease, prefailure) and the time to failure. Our model treats the intermediate indicators as a surrogate response event, so that in right-censored patients, these indicators provide supplementary information pointing towards the unobserved failure times. Moreover, the full probability modelling approach allows the considerable uncertainty which affects certain early indicators, such as the early relapse rates, to be incorporated in the analysis. With such a model, the ability of early indicators to predict failure can be assessed more accurately and reliably, and explained in terms of the relationship between early and intermediate indicators. Moreover, a model with the aforementioned features allows us to characterize the pattern of disease course in high-risk patients, and to identify short-term manifestations which are strongly related to long-term evolution of disease, as potential surrogate responses in clinical trials. Our analysis is based on longitudinal data from 186 MS patients with a relapsing-remitting initial course. The following important early predictors of the time to progression emerged: age; number of neurological functional systems (FSs) involved; sphincter, or motor, or motor-sensory symptoms; presence of sequelae after onset. During the first 3 years of follow up, to reach EDSS> or =4 outside relapse, to have sphincter or motor relapses and to reach moderate pyramidal involvement were also found to be unfavourable prognostic factors.

Fatigue in multiple sclerosis: multidimensional assessment and response to symptomatic treatment

Sixty relapsing-remitting multiple sclerosis (MS) patients were selected on the basis of their score on the Fatigue Severity Scale (FSS) and formed two groups: 40 patients (fatigued MS; MSf) scored above the 75th percentile of a previously assessed representative MS sample (100 patients), and 20 age- and sex-matched patients (nonfatigued MS patients; MSnf) scored below the 25th percentile. The patients underwent clinical evaluation (Expanded Disability Status Scale (EDSS)), further assessment of fatigue (Fatigue Impact Scale), scales evaluating depression (Hamilton Depression Rating Scale (HDRS) and Beck’s Depression Inventory (BDI)) and neuropsychological tests. All patients were evaluated for muscle fatigability and central activation by means of a biomechanical test of sustained contraction; they also underwent somatosensory evoked potentials (SSEPs) and transcranial magnetic stimulation (TMS). The patients of the MSf subgroup were then randomized to one of the following two treatments: 4-aminopyridine (4-AP) 24 mg/day and fluoxetine (FLX) 20 mg/day. After a one-week titration this treatment proceeded for 8 weeks. At the end of the treatment, EDSS, fatigue and depression scores were further evaluated. At baseline, fatigue test scores consistently correlated with depression and cognitive test scores, but not with the fatigability test. Fatigue scores decreased in both treatment groups in a similar way. Due to the design of the study, this cannot be disjoined from a placebo effect. The changes of fatigue scores could not be predicted in the FLX group, whereas in the 4-AP group higher basal fatigability test scores were associated with greater reduction in fatigue scores.

MRI and Brainstem Auditory Evoked Potential Evidence of Eighth Cranial Nerve Involvement in Multiple Sclerosis

An MS patient experienced sudden hearing loss.Brain-stem auditory evoked potentials, previously normal, showed substantial abnormalities that suggested the impairment of the distal part of the acoustic nerve. MRI detected a small hyperintense lesion along the acoustic nerve; the lesion decreased in size and then disappeared after steroid treatment. This demonstrates that a demyelinating lesion in the distal tract of the eighth cranial nerve may cause an acute hearing loss in MS. NEUROLOGY 1997;48: 270-272

Cytokines and chemokines in cerebrospinal fluid and serum of adult patients with acute disseminated encephalomyelitis.

Cytokines and chemokines contribute to the pathogenesis of acute disseminated encephalomyelitis (ADEM). Using a multiplex immunochemiluminescence ELISA, we measured 8 Th1/Th2 cytokines and 18 chemokines in the cerebrospinal fluid (CSF) and serum of 17 ADEM patients, 14 multiple sclerosis (MS) patients, and 7 healthy controls (HCs). Relative to HCs, ADEM patients had significantly high mean CSF concentrations of chemokines with attractant/activating properties towards neutrophils (CXCL1 and CXCL7), monocytes/T cells (CCL3 and CCL5), Th1 cells (CXCL10), and Th2 cells (CCL1, CCL22, and CCL17). Mean CSF concentrations of CXCL7, CCL1, CCL22, and CCL17 were higher in ADEM than in MS, whereas those of CCL11 were lower in MS than in ADEM and HCs. CSF pleocytosis correlated with CSF concentrations of CXCL1, CXCL10, CCL1, CCL17, and CCL22. Most of the functionally homologous chemokines correlated with each other. CSF Th1/Th2 cytokines were not detectable in most samples. Their mean concentrations did not differ in the three groups, and the same held for serum cytokines and chemokines. Our data suggest that the upregulation of chemokines active on neutrophils and Th2 cells differentiates ADEM from MS inflammation, and that both Th1 and Th2 chemokines might be produced in ADEM. Chemokines upregulated in ADEM could become CSF biomarkers after a posteriori evaluations in unselected case series.

Chronic cerebrospinal venous insufficiency in multiple sclerosis: clinical correlates from a multicentre study

BackgroundChronic cerebrospinal venous insufficiency (CCSVI) has recently been reported to be associated with multiple sclerosis (MS). However, its actual prevalence, possible association with specific MS phenotypes, and potential pathophysiological role are debated.MethodWe analysed the clinical data of 710 MS patients attending six centres (five Italian and one Canadian). All were submitted to venous Doppler sonography and diagnosed as having or not having CCSVI according to the criteria of Zamboni et al.ResultsOverall, CCSVI was diagnosed in 86% of the patients, but the frequency varied greatly between the centres. Even greater differences were found when considering singly the five diagnostic criteria proposed by Zamboni et al. Despite these differences, significant associations with clinical data were found, the most striking being age at disease onset (about five years greater in CCSVI-positive patients) and clinical severity (mean EDSS score about one point higher in CCSVI-positive patients). Patients with progressive MS were more likely to have CCSVI than those with relapsing-remitting MS.ConclusionThe methods for diagnosing CCSVI need to be refined, as the between-centre differences, particularly in single criteria, were excessively high. Despite these discrepancies, the strong associations between CCSVI and MS phenotype suggest that the presence of CCSVI may favour a later development of MS in patients with a lower susceptibility to autoimmune diseases and may increase its severity.

Early prediction of the long term evolution of multiple sclerosis: the Bayesian Risk Estimate for Multiple Sclerosis (BREMS) score

Aim: To propose a simple tool for early prediction of unfavourable long term evolution of multiple sclerosis (MS). Methods: A Bayesian model allowed us to calculate, within the first year of disease and for each patient, the Bayesian Risk Estimate for MS (BREMS) score that represents the risk of reaching secondary progression (SP). Results: The median BREMS scores were higher in 158 patients who reached SP within 10 years compared with 1087 progression free patients (0.69 vs 0.30; p<0.0001). The BREMS value was related to SP risk in the whole cohort (p<0.0001) and in the subgroup of 535 patients who had never been treated with immune therapies, thus reasonably representing the natural history of the disease (p<0.000001). Conclusions: The BREMS score may be useful both to identify patients who are candidates for early or for more aggressive therapies and to improve the design and analysis of clinical therapeutic trials and of observational studies.