Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis.

BACKGROUND: Certain stem cell transplantation procedures might slow down inflammatory pathology in multiple sclerosis (MS). AIMS: To halt disease progression in aggressive MS by a bone marrow transplantation (BMT) protocol aimed at maximum T cell suppression. METHODS: Autologous BMT was performed in 14 patients with rapid secondary progressive MS (median EDSS score at baseline, 6; median disease duration, five years). To accomplish rigorous T cell ablation, a strong conditioning protocol was chosen--cyclophosphamide, total body irradiation, and antithymocyte globulin. To minimise the possibility of reinfusing mature T cells in the graft, bone marrow, not peripheral blood, was used as the CD34+ stem cell source. RESULTS: Median follow up was 36 months (range, 7-36). Post-transplant haemopoietic recovery was successful in all patients. Early toxicity included Epstein-Barr virus related post-transplantation lymphoproliferative disorder. Longterm effects were development of antithyroid antibodies (three) and myelodysplastic syndrome (one). One patient died of progressive disease five years after transplantation. Treatment failure, defined by EDSS increase sustained for six months or more, was seen in nine patients and stabilisation or improvement in five. Other clinical parameters generally showed the same outcome. No gadolinium enhanced lesions were seen on post-treatment magnetic resonance imaging, in either cerebral or spinal cord scans. However, cerebrospinal fluid oligoclonal bands remained positive in most cases. CONCLUSIONS: This strong immunosuppressive regimen did not prevent clinical progression in patients with aggressive secondary MS. The lack of efficacy, together with some serious side effects, does not favour the use of similar rigorous T cell depleting protocols in the future.

Epstein-Barr virus and disease activity in multiple sclerosis.

OBJECTIVES: To study in relapsing-remitting (RR) multiple sclerosis (MS) whether exacerbations and brain activity as measured by magnetic resonance imaging (MRI) are associated with plasma levels of anti-Epstein Barr (EBV) antibodies and EBV DNA. METHODS: This was a prospective study with 73 RR MS patients followed for an average of 1.7 years with frequent neurological examination and blood sampling. Antibodies to various EBV proteins were measured by ELISA and plasma EBV DNA was measured by PCR. RESULTS: All MS patients had IgG antibodies to EBV (viral capsid antigen (VCA) and/or EBV nuclear antigen (EBNA)), irrespective whether samples were taken at stable disease or exacerbation. A significantly elevated percentage of the patients (48%) had antibodies against EBV antigens (early antigen, EA) that indicate active viral replication, compared with the age matched healthy controls (25%). Antibodies against a control herpesvirus, cytomegalovirus, were similar between the two groups. The percentage of EA positive individuals and EA titres did not differ between stable disease or exacerbation. Anti-VCA IgM was positive in three cases, unrelated to disease activity. Using a highly sensitive PCR on 51 samples taken at exacerbation visits, only three patients were found to have one timepoint with viraemia, and this viraemia was unrelated to disease activity. Of special note was the fact that anti-EA seropositive patients remained seropositive during follow up, with stable titres over time. We hypothesised that these patients may constitute a subgroup with higher disease activity, due to the triggering effect of a chronic attempt of the virus to reactivate. The EA positive group did not differ from the EA negative with respect to clinical disease activity or other characteristics. However, in the EA positive group, analysis with gadolinium enhanced MRI indicated more MRI disease activity. CONCLUSIONS: There was no evidence for increased clinical disease activity in the subgroup of MS patients with serological signs of EBV reactivation. However, the observation that chronic EBV reactivation may be associated with increased inflammatory activity as assessed by gadolinium enhanced MRI lesions should be reproduced in a larger and independent dataset.

Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation. BMT-MS Study Group.

Recent reports suggest the possible beneficial effects of haemopoietic stem cell transplantation (HSCT) in autoimmune diseases such as multiple sclerosis (MS). The definition of the risk/benefit ratio for such a treatment is perceived as a major issue for the neurological community worldwide. The First Consensus Conference on Bone Marrow Transplantation in Patients with Multiple Sclerosis was held in Milan, Italy on 21 February 1998. Participants from 16 European, North American, and South American countries discussed the guidelines for performing HSCT in MS. This conference was organized in order to: (a) define criteria for patient selection; (b) define transplantation procedures to maximize efficacy of the treatment and minimize its toxicity; (c) standardize patient outcome evaluation; and (d) establish an international working group to evaluate the efficacy and safety of HSCT in MS and to study the immunological changes related to HSCT in MS patients. During the meeting in Milan agreement was reached on: (a) the preparation and distribution of a consensus report on HSCT in MS and (b) the design of an open trial for an initial assessment of the safety and efficacy of HSCT in MS. The consensus reached during the meeting and the design of the clinical trial are summarized in this contribution.

Critical illness polyneuropathy and myopathy (CIPNM): evidence for local immune activation by cytokine-expression in the muscle tissue.

In a longitudinal prospective study a muscle biopsy was taken from 30/32 (33%) of the 98 patients who developed critical illness polyneuropathy and myopathy (CIPNM). Neuropathic changes were found in 37%, myopathic in 40%, and a combination in 23% of the biopsies. The immunohistopathology showed macrophages and Th-cells in 40% and 60% of the muscle biopsies respectively. Small mainly perivascular infiltrates contained macrophages and Th-cells. ICAM-1, VCAM and MAC were found on the vascular endothelium in 58%, 53% and 79% respectively. In all biopsies there was an upregulation of both HLA-I and HLA-DR. Proinflammatory cytokines and TNFalphaR75 were also produced locally (IL-1beta in 71%, IFN-gamma in 40%, IL-12 in 73%, TNFalphaR75 in 90%). The anti-inflammatory cytokine IL-10 was simultaneously expressed in 96% of the biopsies. HLA-DR, TNFalphaR75 and IL-10 differed significantly when compared with control muscle biopsies. Our data provide evidence that small numbers of activated leukocytes producing both pro- and anti-inflammatory cytokines infiltrate skeletal muscle of CIPNM patients. We propose that the local balance of leukocyte activities is of importance in the pathophysiology of muscle weakness in CIPNM.

Long-term results of uvulopalatopharyngoplasty for obstructive sleep apnea syndrome.

OBJECTIVES: Assessment of the long-term effect of uvulopalatopharyngoplasty (UPPP) on snoring, excessive daytime sleepiness, and nocturnal oxygen desaturation index (ODI) in patients with obstructive sleep apnea syndrome. STUDY DESIGN: Evaluation of snoring, excessive daytime sleepiness, and ODI in patients treated by UPPP earlier. MATERIALS AND METHODS: Patients (n = 58) with a follow-up period of 11 to 74 months (median, 34 mo) were included in this study. Snoring and excessive daytime sleepiness were scored on specially designed semiquantitative scales. In all patients ODI was calculated from pulse-oximetry combined with polysomnography at base line and by polygraphy (MESAM 4) during follow-up in 38 patients. Long-term response was compared with 6-month response in the same cohort. RESULTS: There was a long-term improvement of snoring in 63% of patients, no change in 23%, and a deterioration in 14% (P < .00001). Overall snoring increased slightly between 6 months and long-term follow-up. There was an improvement of excessive daytime sleepiness in 38%, no change in 27%, and a deterioration in 35% (P = .80). Excessive daytime sleepiness showed a relapse to preoperative levels between 6 months and long-term follow-up. The median improvement of ODI was -1 (95% interpercentile range, 73-51) and was not significant (P = .35). In 5 of 13 patients in whom ODI at baseline exceeded 20, ODI was reduced to less than 20. In 4 of the 38 patients ODI was reduced to less than 5. The improvement of ODI decreased significantly between 6 months and long-term follow-up (P = .03). No relation was found between body mass index, Mueller maneuver, X-cephalometry, and long-term outcome. An additional finding was that the ODI decreased after UPPP in combination with tonsillectomy, compared with a slight increase after UPPP alone; the difference was significant (P = .008). CONCLUSION: The response to UPPP for obstructive sleep apnea syndrome decreases progressively over the years after surgery. UPPP in combination with tonsillectomy was more effective than UPPP alone.

The spectrum of antecedent infections in Guillain-Barré syndrome: a case-control study.

OBJECTIVE: To determine which antecedent infections are specifically associated with the Guillain-Barré syndrome (GBS). BACKGROUND: Infections with many agents have been reported preceding GBS. Some infections are related to specific clinical and immunologic subgroups in GBS. Most agents were reported in case reports and uncontrolled small series of GBS patients only, and their relation to GBS and its subgroups remains unclear. METHOD: A serologic study for 16 infectious agents in 154 GBS patients and 154 sex- and age-matched controls with other neurologic diseases. Acute phase, pretreatment samples were used from clinically well-defined GBS patients. The seasonal distribution of serum sampling in the GBS and control group was the same. RESULTS: Multivariate analysis showed that in GBS patients, infections with Campylobacter jejuni (32%), cytomegalovirus (13%), and Epstein-Barr virus (10%) were significantly more frequent than in controls. Mycoplasma pneumoniae infections occurred more often in GBS patients (5%) than in controls in univariate analysis. Infections with Haemophilus influenzae (1%), parainfluenza 1 virus (1%), influenza A virus (1%), influenza B virus (1%), adenovirus (1%), herpes simplex virus (1%), and varicella zoster virus (1%) were also demonstrated in GBS patients, but not more frequently than in controls. C. jejuni infections were associated with antibodies to the gangliosides GM1 and GD1b and with a severe pure motor form of GBS. Cytomegalovirus infections were associated with antibodies to the ganglioside GM2 and with severe motor sensory deficits. Other infections were not related to specific antiganglioside antibodies and neurologic patterns. CONCLUSIONS: Recent infections with C. jejuni, cytomegalovirus, Epstein-Barr virus, and M. pneumoniae are specifically related to GBS. The variety of infections may contribute to the clinical and immunologic heterogeneity of GBS.

High-dose intravenous immunoglobulin therapy for myasthenia gravis.

The objective of this open, retrospective study was to investigate whether intravenous immunoglobulin (IVIg) could induce a clinically obvious improvement in patients with generalized myasthenia gravis (MG), as judged by MG functional status. Fourteen patients with generalized MG were treated during at least one episode with 0.4 g IVIg per kilogram body weight per day for 5 consecutive days. Patients with confounding variables were excluded; this left 11 patients (16 episodes) to be further analysed. We defined improvement as at least a one-step improvement in MG functional status (according to the University of Virginia's Modification of Osserman's classification). Of the treatment episodes, 56% were classified as positive responses. If improvement occurred, onset of improvement started after 3 (1-12) days and peak effect was reached after 7 (4-30) days (median and range). All four patients who required artificial ventilation could be weaned from it 8.5 (6-11) days after the start of IVIg (median and range). Of the patients treated on two occasions, only one patient had a positive response during both. In MG functional status 5, improvement was observed during five of seven episodes. None of the patients with MG functional status 3 responded. Patients with an acute relapse of MG seemed to respond equally well to IVIg compared with patients with subacute deterioration/ chronic-static state (50% versus 60%). The MG functional status at the start of IVIg and on the day of maximal improvement was compared for all episodes together, and significant improvement was noted (P = 0.0052). We did not see any serious side-effects after IVIg treatment. This retrospective analysis suggests that high-dose IVIg is an effective therapy in some patients with deterioration of generalized MG. If improvement occurs, it starts within a few days of the onset of IVIg and the effect seems to peak within 2 weeks.

Dietary antioxidants and Parkinson disease. The Rotterdam Study.

OBJECTIVE: To investigate whether high dietary intake of antioxidants decreases the risk of Parkinson disease (PD). SETTING: The community-based Rotterdam Study, the Netherlands. DESIGN: The cross-sectional study formed part of a large community-based study in which all participants were individually screened for parkinsonism and were administered a semiquantitative food frequency questionnaire. The study population consisted of 5342 independently living individuals without dementia between 55 and 95 years of age, including 31 participants with PD (Hoehn-Yahr stages 1-3). RESULTS: The odds ratio for PD was 0.5 (95% confidence interval [CI], 0.2-0.9) per 10-mg daily dietary vitamin E intake, 0.6 (95% CI, 0.3-1.3) per 1-mg beta carotene intake, 0.9 (95% CI, 0.4-1.9) per 100-mg vitamin C intake, and 0.9 (95% CI, 0.7-1.2) per 10-mg flavonoids intake, all adjusted for age, sex, smoking habits, and energy intake. The association with vitamin E intake was dose dependent (P for trend = .03). To assess whether the association was different in participants with more advanced disease, we excluded those with PD who had a Hoehn-Yahr stage of 2.5 or 3. This did not fundamentally alter the results. CONCLUSION: Our data suggest that a high intake of dietary vitamin E may protect against the occurrence of PD.

Liver function disturbances in Guillain-Barré syndrome: a prospective longitudinal study in 100 patients. Dutch Guillain-Barré Study Group.

In 100 consecutive patients with Guillain-Barré syndrome, we assessed liver function on admission and at fixed intervals after either intravenous immunoglobulin (IgIV) or plasma-exchange (PE) treatment. On admission, 38% showed a plasma alanine aminotransferase elevation, gamma glutamyl transferase elevation, or both or more than 1.5 times the upper limit of normal. Ten of these patients had serologic evidence of recent cytomegalovirus infection. The remaining 28 patients were negative for other known causes of liver damage, including infection with Epstein-Barr virus or hepatitis A, B, and C; alcohol abuse; hepatotoxic drugs; recent surgery; and concurrent liver disease. In a hospital control group of 100 consecutive patients with subarachnoid hemorrhage, only 5 had unexplained liver function disturbances on admission (p < 0.0001). In the IgIV-treated group, the percentage of patients with elevated liver function tests increased from 35% before to 69% shortly after treatment at 2 weeks postadmission (p < 0.005). In the PE-treated group, this percentage decreased somewhat from 41% to 36% (not significant). There was also a significant rise in median plasma activity of the various liver enzymes in the IgIV group. At 1 month, however, significant difference had disappeared. At 3 and 6 months, the percentage of patients with liver function disturbances reached a significantly lower level in both treatment groups compared with the time of admission. We concluded that many patients with Guillain-Barré syndrome had mild liver function disturbances without obvious cause. In addition, IgIV treatment was associated with mild transient liver function disturbances through an unknown mechanism.

In vivo effects of sera from Guillain-Barré subgroups: an electrophysiological and histological study on rat nerves.

Serum from 20 patients with Guillain-Barré syndrome (GBS), 10 healthy controls and 10 patients with recent cytomegalovirus, Epstein-Barr virus, or Campylobacter jejuni/coli infections was injected into rat sciatic nerve. The 20 GBS patients consisted of 2 groups of 10 patients with different electrophysiological and clinical disease patterns. The main aim of the study was to investigate possible differences in humoral (auto)-immunity between these subgroups. We found no statistically significant differences in electrophysiological or histological parameters between nerves injected with sera from the 2 GBS groups. The sera of the GBS groups caused significantly more compound muscle action potential reduction at 3 to 5 days postinjection than the healthy control sera. No significant difference in nerve conduction was found between nerves injected with GBS serum and serum of patients with proven infections without GBS. Histological analysis of the same nerves that were studied electrophysiologically showed no significant differences in demyelination or other histological parameters between patients and controls at 5 days postinjection. Based on the findings in this study that sera of GBS groups with important differences in disease pattern and sera of patients with proven infection but without GBS show similar in vivo effects on rat nerves, we suggest it may be more likely that these effects are caused by aspecific serum factors associated with immune-system activation, especially by precedent infections, than by specific disease-related factors such as anti-myelin antibodies.

Arachnoid cysts in the middle cranial fossa: cause and treatment of progressive and non-progressive symptoms.

Ten consecutive patients with arachnoid cysts in the middle cranial fossa, diagnosed by CT, were studied. They were divided into three clinical groups: (1) four patients with progressive symptoms caused by secondary bleeding, (2) five patients with non-progressive symptoms of headache or epilepsy, and (3) one asymptomatic patient. The nine symptomatic patients were operated upon and eight showed clinical improvement. Measurements of the CT scans revealed equal brain volumes on the affected and normal sides, refuting the hypothesis that the cyst is caused by agenesis of the temporal lobe. The hemicranium on the affected side was larger, accommodating both the cyst and a normal brain volume. The progressive symptoms after bleeding were caused by brain shift and increased CSF pressure. The cause of the non-progressive symptoms has not yet been established: two mechanisms are suggested: (1) expansion of the cyst accompanied by compression of surrounding structures, and (2) disturbed CSF dynamics without increased intracystic pressure. Removal of the membranes of the cyst with an opening to the basal cisterns should resolve both problems. After surgery a residual cyst may remain.