Intense immunosuppression followed by autologous stem cell transplantation in severe multiple sclerosis.

Aggressive forms of multiple sclerosis (MS) represent a limited group of demyelinating diseases that rapidly progress to severe disability. Currently available therapies are poorly effective against these clinical entities. Recently, it has been demonstrated that intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT) can affect the clinical course of individuals with severe MS and completely abrogate the inflammatory activity detected by MRI. We report the result of the Italian phase 2 GITMO study, a multicentre study in which 21 MS patients, who were rapidly deteriorating and not responding to the usual therapeutic strategies, were treated with this procedure. The clinical effect of the treatment is long lasting, with a striking abrogation of inflammation detected by MRI findings. These results support a role for intense immunosuppression followed by ASCT as treatment in rapidly evolving MS cases unresponsive to conventional therapies.

Brain tissue loss occurs after suppression of enhancement in patients with multiple sclerosis treated with autologous haematopoietic stem cell transplantation.

To assess whether brain tissue loss occurs after profound and sustained suppression of magnetic resonance imaging (MRI) enhancement, we measured brain volume changes from 10 patients with rapidly evolving secondary progressive multiple sclerosis (MS) treated with autologous haematopoietic stem cell transplantation and followed up for 24 months. An average yearly decrease of brain volume of about 1.9% was observed despite only five enhancing lesions seen on triple dose follow up scans of two patients. This indicates that, in MS, progressive loss of tissue can occur independently of concomitant MRI-visible inflammation.

A post-marketing study on interferon beta 1b and 1a treatment in relapsing-remitting multiple sclerosis: different response in drop-outs and treated patients.

BACKGROUND: Interferon beta 1b (Betaferon) and 1a (Avonex) were licensed in Italy for treating relapsing-remitting multiple sclerosis in February 1996 and August 1997, respectively. OBJECTIVES: To evaluate the effectiveness of these agents on the basis of clinical experience in northern Italian multiple sclerosis centres. DESIGN: Clinical data on patients with relapsing-remitting multiple sclerosis were collected on an appropriate form from 65 centres in northern Italy. Intention to treat analysis was not possible, so patients who discontinued treatment (drop-outs) and who continued treatment (treated) were analysed separately. The main outcome measures were annual relapse frequency, number of relapse-free patients, mean change in extended disability status scale score (EDSS), and number of patients who worsened. RESULTS: 1481 patients were included; 834 were treated with Betaferon and 647 with Avonex for mean periods of 21.4 and 12.0 months, respectively. Basal EDSS was 2.37 and 2.17, respectively, and relapse frequency was 1.62 and 1.45. The annual relapse rate decreased by more than 60% with Betaferon and 55% with Avonex. The proportions of relapse-free, improved, and worsened patients were similar in the two groups. More patients interrupted treatment with Betaferon (41.1%) than with Avonex (15.3%); such patients showed more active disease at baseline and during treatment. The incidence of side effects was higher in Betaferon treated patients. CONCLUSIONS: The effectiveness of Betaferon and Avonex is confirmed. There was a more marked effect than expected from the experimental trial results. This might reflect differences in inclusion criteria, or, more likely, loss of drop-outs, favouring selective retention of responders.

Evaluation of Gd-enhancement in brain MR of multiple sclerosis: image subtraction with and without magnetization transfer.

The aim of our study was to test the possibility of using image subtraction in detecting enhancing lesions in brain MR scans with and without magnetization transfer (MT) in multiple sclerosis (MS). Ten MS patients underwent 1.5-T MR imaging of the brain with spin-echo T1-weighted sequences with and without MT, repeated after 0.1 mmol/kg of an usual two-compartment paramagnetic contrast agent (Gadoteridol, Gd-HP-DO3A). Precontrast images were subtracted from postcontrast. Enhancing lesions were counted on the postcontrast images only (post-Gd), comparing pre- and postcontrast images by direct visual control (pre/post-Gd), and on the subtracted images (SI) only. Without MT, 36 enhancing lesions were counted on post-Gd, 36 on pre/post-Gd, and 59 on SI; using MT, 69, 52, and 50, respectively. Significant differences were found for pre/post-Gd without MT vs SI without MT ( p=0.028) and vs pre/post-Gd with MT ( p=0.012) as well as for pre/post-Gd with MT vs post-Gd with MT ( p=0.028). With pre/post-Gd, MT allowed the detection of 1.6 enhancing lesions per patient more than without MT. Whereas the SI without MT allow the detection of an increased number of enhancing lesions, SI with MT do not. An off-site final assessment allowed calculation of sensitivity and positive predictive value as follows: without MT were 63 and 94% (post-Gd), 67 and 100% (pre/post-Gd), 96 and 88% (SI); and with MT were 93 and 73% (post-Gd), 96 and 100% (pre/post-Gd), 91 and 98% (SI), respectively. Thus, SI seem to increase the sensitivity without MT; moreover, they could be used to correct the pseudoenhancement that impair post-Gd images with MT.

Central and peripheral nervous system complications following allogeneic bone marrow transplantation.

Although graft vs. host disease (GvHD) is a frequent complication of allogeneic bone marrow transplantation (BMT), involvement of the central and peripheral nervous systems (CNS and PNS, respectively) has not been demonstrated conclusively. Here, we report of a patient who, following allogeneic BMT for lymphoblastic T-cell lymphoma, suffered a syndrome characterized by self-remitting cerebellar and pyramidal signs associated with a progressive involvement of the peripheral nervous system (PNS). Clinical course and laboratory findings correlated with relapses of systemic GvDH, thus suggesting the possibility that involvement of CNS and PNS may be sustained by a similar pathogenic mechanism.

Autologous hematopoietic stem cell transplantation suppresses Gd-enhanced MRI activity in MS.

BACKGROUND: Autologous hematopoietic stem cell transplantation (ASCT) has been recently utilized with encouraging results in patients with poorly controlled MS. OBJECTIVE: To determine in severe cases of MS the effect of ASCT on gadolinium (Gd)-enhanced MRI and to obtain information on clinical course and safety. METHODS: In a cooperative study, 10 patients with rapidly evolving secondary progressive MS were transplanted, after BEAM conditioning regimen (carmustine, etoposide, cytosine-arabinoside, and melphalan), with unmanipulated autologous peripheral blood SC mobilized with high-dose cyclophosphamide (CY; 4 g/m2) and granulocyte-colony-stimulating factor. Triple-dose Gd-enhanced scans were performed monthly for a pretreatment period of 3 months and compared with serial monthly Gd-enhanced MRI for the following 6 months and then once every 3 months. RESULTS: The median follow-up is now 15 months (range 4 to 30 months). The number of Gd-enhancing lesions decreased immediately after mobilization with CY and finally dropped to zero in all cases after the conditioning regimen. The number of new T2-weighted positive lesions paralleled data obtained for Gd-enhanced MRI. Clinically, patients improved slightly or remained stable. CONCLUSION: These results demonstrate that the therapeutic sequence CY-BEAM-ASCT has the capacity to completely suppress MR-enhancing activity, an effect that is sustained with time. The final impact of this procedure on disease course remains to be established.

Dynamics of the reactivity to MBP in multiple sclerosis.

Though many lines of evidence support the importance of myelin basic protein (MBP) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), its role in multiple sclerosis (MS) is still debated as well as the significance of epitope spreading in disease progression. We characterised the response to MBP in eight MS subjects and three of these were followed over time. In one case, the follow up lasted over a 6-year period. Clonal expansion, clonal persistence and epitope spreading against other MBP determinants was detected irrespective of disease course. In one patient we identified a novel T-cell receptor variable gene (BV28S2) which may be involved in the selection of MBP determinants, as suggested by experiments performed in the presence of mismatched antigen presenting cells (APC) between two subjects compatible for HLA-DR2 subtype but differing for the epitope recognised. Our findings do not sustain a role for the response to MBP effecting on clinical course and suggest that a novel TCR gene may be involved in the recognition of unusual self antigens.