Headache in multiple sclerosis and autoimmune disorders.

The headache may be considered among the neuropathic pain syndromes of multiple sclerosis (MS). Several studies have showed that it is more frequent in MS patients than in controls or general population. Headache may occur at the pre-symptomatic phase, at clinical onset and during the course of the disease. Tension-type headache and migraine without aura are the most common primary headaches reported in MS patients. The disease-modifying therapies, such as interferons, may cause or exacerbate headache, although the new available treatments do not seem to increase the risk of pain. Pharmacological and not pharmacological approach may be considered in selected patients to prevent the risk of headache, ameliorate quality of life and increase the adherence to treatment.

Responsiveness of patient reported outcome measures in multiple sclerosis relapses: the REMS study.

OBJECTIVES: To assess the responsiveness of the three most used patient reported multiple sclerosis (MS) specific questionnaires: the Functional Assessment of MS (FAMS), the MS Impact Scale (MSIS-29) and the 54 item MS Quality of Life (MSQOL-54). DESIGN: Prospective multicentre longitudinal study on 104 MS patients treated with intravenous steroids for clinical exacerbation. METHODS: Patient reported data, Expanded Disability Status Scale (EDSS) score and clinical information were collected at admission and 8 weeks later. "Internal" (distribution based) responsiveness was assessed by standardised response means (SRM). "External" (anchor based) responsiveness was assessed by receiver operating characteristic (ROC) curves in relation to corresponding changes in a pre-specified reference measure (anchor). The pre-specified anchor was patients' self-reported recovery assessed on a 5 point Likert scale. RESULTS: SRM was 0.39 for FAMS, 0.58 for MSIS-29 physical scale, 0.45 for MSIS-29 psychological scale, 0.71 for MSQOL-54 physical health composite and 0.57 for MSQOL-54 mental health composite. Seventy-three patients (70%) reported they had improved; physicians agreed substantially with patient assessments (kappa statistic 0.70, 95% CI 0.54 to 0.85). Areas under ROC curves differed significantly from 0.50 only for the MSIS-29 and MSQOL-54 scales where areas ranged from 0.65 (95% CI 0.53 to 0.76) for the MSIS-29 psychological scale to 0.70 (95% CI 0.58 to 0.81) for the MSQOL-54 mental health composite. Areas under ROC curves assessed using a physician based anchor were similar to the patient based areas. CONCLUSIONS: The responsiveness of the MS specific instruments was less than ideal. The MSIS-29 and MSQOL-54 were significantly more responsive, using both distribution based and anchor based approaches, than FAMS, and should be preferred in longitudinal studies.

Hypothalamic stimulation for trigeminal neuralgia in multiple sclerosis patients: efficacy on the paroxysmal ophthalmic pain.

Trigeminal neuralgia is a disorder characterized by paroxysmal pain arising in one or more trigeminal branches; it is commonly reported in multiple sclerosis. In multiple sclerosis patients the ophthalmic branch may be frequently involved and the risks carried by neurosurgical ablative procedures are higher including major adverse effects such as corneal reflex impairment and keratitis. The objective of this works is to assess the role of posterior hypothalamus neuromodulation in the treatment of trigeminal neuralgia in multiple sclerosis patients. Five multiple sclerosis patients suffering from refractory recurrent trigeminal neuralgia involving all three trigeminal branches underwent deep brain stimulation of the posterior hypothalamus. The rationale of this intervention emerges from our earlier success in treating pain patients suffering from trigeminal autonomic cephalalgias. After follow-up periods that ranged from 1 to 4 years after treatment, the paroxysmal pain arising from the first trigeminal branch was controlled, whereas the recurrence of pain in the second and third trigeminal branches necessitated repeated thermorhizotomies to control in pain in two patients after 2 years of follow-up. In conclusion, deep brain stimulation may be considered as an adjunctive procedure for treating refractory paroxysmal pain within the first trigeminal division so as to avoid the complication of corneal reflex impairment that is known to follow ablative procedures.

Confocal laser endomicroscopy in celiac disease: description of findings in two cases.

Duodenal confocal laser endomicroscopy (CLE) was carried out in six patients to compare the findings with histology. The visibility and quality of the endomicroscopy images were quantified using the following score: 0 = none; 1 = poor; 2 = fair; 3 = good. Four patients had a normal duodenal mucosa, whereas two patients in whom CLE indicated villous atrophy showed histologic features typical of celiac disease. Histology and CLE images were similar in both normal and celiac disease patients; patients with celiac disease had an average score of 3 for epithelial architecture, 3 for goblet cells, 3 for vessels, 1 for inflammatory infiltrate, and 2 for crypt visibility.

Cyclophosphamide for multiple sclerosis.

BACKGROUND: Multiple sclerosis is a presumed cell-mediated autoimmune disease of the central nervous system. Cyclophosphamide (CFX) is a cytotoxic and immunosuppressive agent, used in systemic autoimmune diseases. Controversial results have been reported on its efficacy in MS. We conducted a systematic review of all relevant trials, evaluating the efficacy of CFX in patients with progressive MS. OBJECTIVES: The main objective was to determine whether CFX slows the progression of MS. SEARCH STRATEGY: We searched the Cochrane MS Group Trials Register (searched June 2006), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3 2006), MEDLINE (January 1966 to June 2006), EMBASE (January 1988 to June 2006) and reference lists of articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the clinical effect of CFX treatment in patients affected by clinically definite progressive MS.CFX had to be administered alone or in combination with adrenocorticotropic hormone (ACTH) or steroids. The comparison group had to be placebo or no treatment or the same co-intervention (ACTH or steroids) DATA COLLECTION AND ANALYSIS: Two reviewers independently decided the eligibility of the study, assessed the trial quality and extracted data. We also contacted study authors for original data. MAIN RESULTS: Of the 461 identified references, we initially selected 70: only four RCTs were included for the final analysis. Intensive immunosuppression with CFX (alone or associated with ACTH or prednisone) in patients with progressive MS compared to placebo or no treatment (152 participants) did not prevent the long-term (12, 18, 24 months) clinical disability progression as defined as evolution to a next step of Expanded Disability Status Scale (EDSS) score. However, the mean change in disability (final disability subtracted from the baseline) significantly favoured the treated group at 12 (effect size - 0.21, 95% confidence interval - 0.25 to -0.17) and 18 months (- 0.19, 95% confidence interval - 0.24 to - 0.14) but favoured the control group at 24 months (0.14, CI 0.07 to 0.21). We were unable to verify the efficacy of other schedules. Five patients died; sepsis and amenorrhea frequently occurred in treated patients (descriptive analysis). AUTHORS' CONCLUSIONS: We were unable to achieve all of the objectives specified for the review. This review shows that the overall effect of CFX (administered as intensive schedule) in the treatment of progressive MS does not support its use in clinical practice.

HLA-DRB1*15 association with multiple sclerosis is confirmed in a multigenerational Italian family.

Environmental and genetic factors seem to play a pathogenetic role in multiple sclerosis (MS). The genetic component is partly suggested by familial aggregation of cases; however, MS families with affected subjects over different generations have rarely been described. The aim of this study was to report clinical and genetic features of a multigenerational MS family and to perform a review of the literature on this topic. We describe a multigenerational Italian family with six individuals affected by MS, showing different clinical and neuroradiological findings. HLA-DRB1* typing revealed the presence of the DRB1*15:01 allele in all the MS cases and in 4/5 non-affected subjects. Reports on six multigenerational MS families have previously been published, giving similar results. The HLA-DRB1*15:01 allele was confirmed to be linked to MS disease in this family; moreover, its presence in non-affected subjects suggests the involvement of other susceptibility factors in the development and expression of the disease, in accordance with the complex disease model now attributed to MS.

Divry-Van Bogaert syndrome. Clinical and ultrastructural findings.

A case of a progressive disease with epilepsy, marble skin, and roentgenographic evidence of tapering of the distal carotid branches with corticomeningeal angiomatosis was studied. The clinical course, angiographic findings, and skin biopsy results justified the diagnosis of noncalcifying venous capillary angiomatosis, or Divry-Van Bogaert syndrome.

Physical rehabilitation has a positive effect on disability in multiple sclerosis patients.

BACKGROUND: Although physical rehabilitation is commonly administered to MS patients, its efficacy has not been established. OBJECTIVE: We assessed the efficacy of an inpatient physical rehabilitation program on impairment, disability, and quality of life of MS patients with a randomized, single-blind, controlled trial. METHODS: Fifty ambulatory MS patients were assigned to 3 weeks of inpatient physical rehabilitation (study treatment) or exercises performed at home (control treatment). Patients were evaluated at baseline and at 3, 9, and 15 weeks by a blinded examining physician. RESULTS: No changes in impairment occurred in either group, as measured by the Expanded Disability Status Scale. At the end of the intervention the study group improved significantly in disability, as assessed by the Functional Independence Measure (FIM) motor domain, compared with controls (p = 0.004), and the improvement persisted at 9 weeks (p = 0.001). The effect size statistic was usually large or moderate in all scale scores of the FIM motor domain at 3 weeks and moderate to fair thereafter. The study group also improved in overall health-related quality of life profile compared with controls; however, the difference was significant only for the mental composite score at 3 (p = 0.008) and 9 weeks (p = 0.001). CONCLUSIONS: Despite unchanging impairment, physical rehabilitation resulted in an improvement in disability and had a positive impact on mental components of health-related quality of life perception at 3 and 9 weeks.

Cerebrospinal fluid thrombomodulin and sVCAM-1 in different clinical stages of multiple sclerosis patients.

In order to investigate whether brain endothelial cells activation and/or damage could be selectively monitorized, soluble vascular cell adhesion molecule 1 (sVCAM-1) and thrombomodulin (TM) levels were studied in serum and cerebrospinal fluid (CSF) of 39 multiple sclerosis (MS) patients in various phases of the disease, 19 patients with other non-inflammatory neurological diseases (OND) and 15 patients with inflammatory neurological diseases (IND). No differences in sVCAM-1 CSF levels were detected, except for lower levels in IND compared to OND. Serum TM levels were lower in IND compared to progressive MS patients. Moreover, a significant decrease both in VCAM index and in TM index was detected in IND compared to all other groups. TM index was higher in MS patients in progression as compared to OND. The combined analysis of sVCAM-1 and TM might be a useful tool in monitoring brain endothelium activation or damage in different phases of MS.

Effects of beta-IFN-1b treatment in MS patients on adhesion between PBMNCs, HUVECs and MS-HBECs: an in vivo and in vitro study.

The in vivo effects on the expression of adhesion molecules and on the adhesion between mononuclear cells and multiple sclerosis human brain endothelial cells (MS-HBECs) were investigated at the beginning of beta-IFN-1b treatment of MS patients. MS-HBECs were isolated from a surgical specimen obtained from an MS patient undergoing brain surgery for vascular aneurysm. 48 h after the first single administration of beta-IFN-1b, PBMNCs of 10 MS patients were analyzed for HLA-DR, CD11a, CD18 and VLA-4 expression and the adhesion between PBMNCs and both stimulated and unstimulated MS-HBECs evaluated. sICAM-1 and sVCAM-1 dosage in the serum of the patients was checked as well. The experiments were repeated using HUVECs in order to detect possible endothelial organ-specific differences. The experiments were also performed after six months of beta-INF-1b treatment on HUVECs. No significant effects on mononuclear cells/endothelium adhesion were detected at 48 h, but adhesion of PBMNCs to HUVECs decreased at six months. An increase in HLA-DR and VLA-4 and a decrease of CD18 was detected in monocytes. The serum level of sVCAM-1 increased at T2 and was still higher than at T0 at six months. The effect of the beta-IFN-1b treatment on both MS-HBECs and HUVECs, was selectively studied in vitro by testing the expression of cytokine-induced adhesion molecules HLA-DR, ICAM-1 and VCAM-1. The in vitro experiments confirmed that beta-IFN-1b is able to antagonize gamma-IFN-induced HLA-DR expression on MS human brain endothelial cells without relevant effects on VCAM-1 and ICAM-1.

Transmigration of PBMNCs from beta-IFN-1b-treated MS patients: a one-year longitudinal study.

To evaluate the effects of in vivo beta-IFN-1b treatment on transmigration of mononuclear cells, we monitored for one year in vitro mononuclear cells trafficking through HUVECs monolayers stratified over a collagen gel during beta-IFN-1b treatment of 7 RR MS patients. The number of transmigrated cells was analysed before treatment (T0) and after 3 (T3), 6 (T6) and 12 months (T12); at the same time, levels of serum MMP-9 were quantified. The number of transmigrated cells decreased during treatment compared to pre-treatment values: the lowest number of transmigrated cells was detected at T3, and, although transmigration was still lower at T12, there was a trend to a return to pre-treatment levels over time. The amount of MMP-9 also decreased during therapy, although we could not find an absolute correlation between transmigration and levels of MMP-9, nor between either parameter and the clinical course of patients.

A double blind study on azathioprine efficacy in multiple sclerosis: final report.

Forty patients, affected by multiple sclerosis with remitting-relapsing or progressive course, were included in a double blind study of treatment with azathioprine (2 mg/kg/day) lasting 3 years. The mean changes on the Expanded Disability Status Scale and in the survival analysis show a trend in favour of azathioprine both in slowing disease progression and reducing relapse frequency. These findings, repeatedly observed in similar trials, indicate that azathioprine should be used in the treatment of multiple sclerosis.

Cryptococcal meningoencephalitis: intrathecal immunological response.

The intrathecal immune response is reported in a patient with cryptococcal meningoencephalitis. CSF IgM and IgG levels were significantly related to the favourable clinical evolution. IgM response was specifically directed against the pathological agent, while IgG were mostly non-specific. The data are discussed and compared with the other chronic infections of the central nervous system.

Diffuse arachnoiditis following epidural analgesia.

Four cases of spinal arachnoiditis are reported, which occurred as a delayed complication of epidural anaesthesia. Different causes are considered: the most convincing hypothesis is that there was a subarachnoid hyperergic reaction to the drugs injected during epidural anaesthesia.

HLA and multiple sclerosis in Italy: a review of the literature.

HLA antigens of locus A, C, B, DR and DQ were typed in 104 Italian multiple sclerosis patients and in 905 healthy controls; the results have been compared with those published in the Italian literature. The Italian studies have been reviewed regarding the ethnic origin of the typed population and the corresponding prevalence of the disease. The data suggest a lack of association between A3 and B7 antigens and Italian multiple sclerosis and a relevance of other DR locus antigens (mainly DR4 and DR5), in addition to DR2, in the susceptibility to the disease.

Immunological monitoring of azathioprine treatment in multiple sclerosis patients.

Despite the longstanding clinical use of azathioprine as an immunosuppressive agent in multiple sclerosis, little is known about the action of this drug on a number of parameters of putative pathogenic relevance in the disease. Eleven patients with multiple sclerosis, treated with azathioprine 2.5-3 mg/kg per day, and six untreated patients were studied with serial blood sampling for 1 year. The following immunological parameters were investigated: peripheral blood lymphocyte subsets, natural killer activity, serum IgG, IgM, ICAM-1 and tumour necrosis factor alpha (TNF-alpha). The most relevant changes included a decrease in CD3- CD56+ cells, an increase in CD4+ CD45RA+ cells and a decrease in TNF-alpha levels only in treated patients, while no changes occurred in untreated patients over a 1-year period. The decrease in TNF-alpha levels and the increase in "suppressor-inducer" lymphocytes could reduce chronic inflammation in multiple sclerosis, and paralleled an overall favourable clinical response to azathioprine treatment in our patients.

Low serum interleukin-10 levels in multiple sclerosis: further evidence for decreased systemic immunosuppression?

Serum interleukin 10 (IL10) levels were assessed in patients with multiple sclerosis who were either in a stable or active clinical condition. The levels were compared with values in healthy controls. Lower IL10 levels than in controls were seen in multiple sclerosis patients, regardless of clinical disease activity. Low IL10 levels were also seen in patients with systemic lupus erythematosus. No clear-cut relationships emerged between IL10 levels and those of tumour necrosis factor alpha and transforming growth factor beta, or between IL10 and lymphocyte subsets in peripheral blood.

Immunological effects of in vivo interferon-beta1b treatment in ten patients with multiple sclerosis: a 1-year follow-up.

Ten patients with multiple sclerosis and treated with interferon-beta1b (IFN-beta1b) were followed-up for 1 year with quantitation of serum VCAM-1 and ICAM-1 levels, mean fluorescence intensity of HLA-DR, VLA-4, CD11a, and CD18 on peripheral blood monocytes and lymphocytes, and adhesion of peripheral blood monocytes and CD45+ cells on endothelial cell monolayers. Adhesion molecule expression and adhesion of peripheral blood monocytes to endothelium were also monitored in healthy controls. No differences in adhesion were detected between MS patients before treatment and healthy controls, while after 1 year a marked decrease in the number of monocytes and mononuclear cells adhering to human umbilical vein endothelial cell monolayers was observed in patients treated with IFN-beta1b. After 1 year of treatment a significant increase in HLA-DR on peripheral blood monocytes was also detected. Our findings regarding lowered adhesion add information to available evidence of the mechanisms of action of IFN-beta1b in MS.

Spinal cord involvement and systemic lupus erythematosus: clinical and magnetic resonance findings in 5 patients.

We report the clinical, magnetic resonance imaging (MRI) and laboratory findings in 5 patients with clinical spinal cord involvement with an acute or subacute course; in two of the patients the myelitic episode preceded, in one it was concomitant to, and in two it followed the diagnosis of systemic lupus erythematosus (SLE). The marked clinical and MRI heterogeneity detected in our patients suggests that various factors may be implied in the pathogenesis of spinal cord involvement in SLE. The possibility of a future evolution to SLE should be kept in mind in women presenting spinal cord involvement with no other explanation, and should be assessed by means of extensive and repeated clinical and laboratory evaluations.

Cyclophosphamide for multiple sclerosis.

BACKGROUND: Multiple sclerosis is a presumed cell-mediated autoimmune disease of the central nervous system. Cyclophosphamide (CFX) is a cytotoxic and immunosuppressive agent, used in systemic autoimmune diseases. Controversial results have been reported on its efficacy in MS. We conducted a systematic review of all relevant trials, evaluating the CFX efficacy in patients with progressive MS. OBJECTIVES: The main objectives were to determine whether CFX slows the disease progression. SEARCH STRATEGY: Electronic databases (including MEDLINE, EMBASE, Cochrane Controlled Trials Register) were systematically searched. References list of retrieved studies and conference abstracts on the main meetings on Multiple Sclerosis were handsearched. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the clinical effect of CFX treatment in patients affected by clinically definite progressive MS. CFX had to be administered alone or in combination with ACTH or steroids. The comparison group had to be placebo or no treatment or the same co intervention (ACTH or steroids) The main outcome criteria were : progression of disability (defined as an increase of 0.5 point in Kurtzke Extended Disability Status Scale (EDSS) for patients with baseline EDSS > or = 6 and 1 for EDSS < or = 5.5), differences of disability between treatment-control groups and the number of patients with side effects. DATA COLLECTION AND ANALYSIS: The identified references were reviewed by two reviewers who independently decided the eligibility of the study, extracted and summarized data and assessed the trial's quality. The statistical analysis was performed using the Cochrane RevMan software and analyzed using Cochrane MetaView. MAIN RESULTS: Of the 326 identified references, 80 were selected for full review, only four RCTs were selected for the final analysis. Intensive immunosuppression with CFX (alone or associated with ACTH or prednisone) in patients with progressive MS compared to placebo or no-treatment (152 participants) did not prevent the long -term (12-18-24 months) risk to evolution to a next step of EDSS. However, the mean change in disability (final disability subtracted from the baseline) significantly favoured the treated group at 12 (effect size - 0.21; C. I. - 0.24, - 0.17) and 18 months (- 0.19; C. I. - 0.24, - 0.14). We were not able to verify the efficacy of other schedules. Five patients died; sepsis and amenorrhea frequently occurred in treated patients (descriptive analysis). REVIEWER'S CONCLUSIONS: Only limited objectives were reached. This review shows a role of CFX in the treatment of progressive MS, but less toxic schedules must be considered, before its use in the clinical practice.