V. Cosi

Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies.

The two chemokines, monocyte chemoattractant protein (MCP)-1 and gamma-interferon inducible protein (IP)-10, are thought to be involved in the pathogenesis of multiple sclerosis (MS). We measured MCP-1 and IP-10 levels in serum and CSF samples from 38 acute and 25 stable MS patients and from 40 controls. The latter consisted in patients with other inflammatory neurological diseases (OIND) or with non-inflammatory neurological diseases, and healthy controls. CSF MCP-1 levels exceeded those found in serum in all the patients studied as well as in healthy controls. CSF MCP-1 levels were significantly lower in acute MS [468+/-(S.E.M.) 18 pg/ml] than in stable MS (857+/-104 pg/ml). When detectable, serum and CSF IP-10 levels were significantly higher in acute MS (serum 331+/-66 pg/ml; CSF 118+/-16 pg/ml) than in stable MS (serum 69+/-7 pg/ml; CSF 25+/-2 pg/ml). Among OIND patients, those with HIV-1-associated dementia showed high serum and CSF levels of both MCP-1 and IP-10. Those with encephalitis showed high serum and CSF levels of IP-10 and CSF mononuclear pleiocytosis. We also evaluated the effects of 6-methylprednisolone or IFN-beta1a therapy on circulating MCP-1 and IP-10 levels. Neither MCP-1 nor IP-10 post-therapy levels varied significantly from baseline values. Our findings suggest that (a) MCP-1 could be constitutively produced within the brain; (b) MCP-1 and IP-10 CSF levels in acute MS vary significantly from those in stable MS, and these variations are inverse; and (c) current MS therapies do not modify circulating levels of MCP-1 and IP-10.

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.

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.

ICHD‐II diagnostic criteria for Tolosa–Hunt syndrome in idiopathic inflammatory syndromes of the orbit and/or the cavernous sinus

A bibliographical search was conducted for papers published between 1999 and 2007 to verify the validity of International Classification of Headache Disorders (ICHD)-II criteria for the Tolosa-Hunt syndrome (THS) in terms of (i) the role of magnetic resonance imaging (MRI); (ii) which steroid treatment should be considered as adequate; and (iii) the response to treatment. Of 536 articles, 48, reporting on 62 patients, met the inclusion criteria. MRI was positive in 92.1% of the cases and it normalized after clinical resolution. There was no evidence of which steroid schedule should be considered as adequate; high-dose steroids are likely to be more effective both to induce resolution and to avoid recurrences. Pain subsided within the time limit required by the ICHD-II criteria, but signs did not. We conclude that THS diagnostic criteria can be improved on the basis of currently available data. MRI should play a pivotal role both to diagnose and to follow-up THS.

A multicentre follow-up study of 1152 patients with myasthenia gravis in Italy

SummaryA multicentre retrospective study was carried out on the characteristics and course of myasthenia gravis (MG) in Italy. Data from 1152 patients, fairly representative of the myasthenic population seeking medical advice, were analysed for diagnostic criteria, clinical aspects and therapeutic approaches. Mean follow-up was 4.9 years. The disease was correctly diagnosed within 2 years of the onset in 80% of cases. Onset of symptoms peaked in the second and third decade in females and fell between 20 and 59 years in males. At first observation 87% of the patients had generalized MG. Maximal worsening was observed within 3 years in 77% of patients. At the last follow-up, 35% of cases were symptom-free (pharmacological remission 24%, remission without treatment 11%). The more severe the disease at the first observation and at the maximal worsening of symptoms, the lower was the proportion of remissions. Steroids were given in 54% and immunosuppressants in 18%. Thymectomy was performed in 72%, mostly in women, younger than age 40, and with generalized MG. Thymectomy seemed to improve the course of the disease, mostly in patients operated on shortly after diagnosis and those with generalized mild-to-moderate disease and with a normally involuted thymus. MG was lethal in 4% of patients, principally men, older than 40, in grade 3 or worse at first observation, with a short history of disease, and with thymona.

Treatment of myasthenia gravis with high‐dose intravenous immunoglobulin

ABSTRACT We treated 37 patients affected by autoimmune generalized myasthenia gravis (MG) with high‐dose intravenous gammaglobulin (HDIVIg), 400 mg/kg per day on 5 consecutive days. A one‐degree improvement of Oosterhuis global clinical classification of myasthenic severity (OGCCMS), the disappearance of bulbar involvement or both were recorded 12 days after the beginning of the treatment in 70.3% of the patients and persisted up to 60 days in 58.7%. A two‐degree improvement of OGCCMS was recorded in 54.1% of the patients and it was maintained up to 60 days in 37.8%. The percentage of improvement did not significantly differ between patients entering the treatment in a long‐standing, drug‐refractory stationary phase of the illness (n = 26) and patients who received HDIVIg in an acute phase of MG (n = 11). None of the patients experienced side effects. Our data indicates that HDIVIg is an interesting, virtually riskless therapeutic choice for MG patients, and allows the planning of a controlled trial versus plasma‐exchange.

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.

Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an autoimmune acute peripheral neuropathy. Frequently a flu-like episode or a gastroenteritis precede GBS, and the cross-reactivity between microbial and neural antigens partly explains the pathophysiology of the disease and the possible detection of antiganglioside antibodies. The weakness reaches its nadir in 2–4 weeks: the patients may be chair- or bed-bound, may need artificial ventilation and frequently experience dysautonomic dysfunction; 5–15% of the patients die and more patients are left with a disabling motor deficit and/or fatigue. Electrophysiology and cerebrospinal fluid evaluation support the diagnosis. The treatment of GBS is multidisciplinary, and both plasma exchange and high dose immunoglobulin (IVIg) are effective in reducing both the severity of the disease and the residual deficits. Finally, steroids are not effective in GBS.

Sensitivities and predictive values of paraclinical tests for diagnosing multiple sclerosis.

The sensitivities and predictive values of visual, somatosensory, and brain auditory evoked potentials (EPs), cerebrospinal fluid oligoclonal banding (CSF-OB) and magnetic resonance imaging (MRI) were evaluated for the early diagnosis of clinically definite multiple sclerosis (CDMS). Paraclinical evidence of asymptomatic lesions allows a diagnosis of CDMS. Eighty-two patients in whom MS was suspected but diagnosis of CDMS was not possible entered the study prospectively. Paraclinical examinations were performed at entry. Patients were examined and underwent EPs every 6 months, and MRI yearly. After a mean follow-up of 2.9 years, 28 patients (34%) had developed CDMS (McDonald-Halliday criteria). The initial MRI was strongly suggestive of MS in 19 of these (68%), while 27 (96%) had at least one MS-like abnormality in the initial MRI. CSF-OB and EPs had lower sensitivities. CDMS developed during follow-up in 19 of the 36 patients (53%) who had an initial MRI strongly suggestive of MS but in only 1 of the 25 who had normal MRI when first studied. These results support previous conclusions that MRI is the most sensitive test for detecting white matter asymptomatic lesions, and the most predictive for the diagnosis of CDMS.