Long-term results of stem cell transplantation for MS: a single-center experience.

OBJECTIVE: To report long-term results of a phase I/II study conducted in a single center in order to investigate the effect of hemopoietic stem cell transplantation (HSCT) in the treatment of multiple sclerosis (MS). METHODS: Clinical and MRI outcomes of 35 patients with aggressive MS treated with HSCT are reported after a median follow-up period of 11 (range 2-15) years. RESULTS: Disease progression-free survival (PFS) at 15 years is 44% for patients with active CNS disease and 10% for those without (p=0.01); median time to progression was 11 (95% confidence interval 0-22) and 2 (0-6) years. Improvements by 0.5-5.5 (median 1) Expanded Disability Status Scale (EDSS) points were observed in 16 cases lasting for a median of 2 years. In 9 of these patients, EDSS scores did not progress above baseline scores. Two patients died, at 2 months and 2.5 years, from transplant-related complications. Gadolinium-enhancing lesions were significantly reduced after mobilization but were maximally and persistently diminished post-HSCT. CONCLUSION: HSCT is not a therapy for the general population of patients with MS but should be reserved for aggressive cases, still in the inflammatory phase of the disease, and for the malignant form, in which it can be life-saving. HSCT has an impressive and sustained effect in suppressing disease activity on MRI. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that HSCT results in PFS rates of 25%. PFS rate was significantly better in patients with active MRI lesions; HSCT also resulted in a significant reduction in the number and volume of gadolinium-enhancing lesions on MRI.

Autologous stem cell transplantation in progressive multiple sclerosis--an interim analysis of efficacy.

Based on the good results of experimental transplantation in animal models of multiple sclerosis and of other autoimmune diseases, we have treated 24 patients suffering from chronic progressive multiple sclerosis with high-dose chemotherapy (BEAM regimen) followed by autologous blood stem cell rescue and antithymocyte globulin. Blood stem cells were mobilised with cyclophosphamide at 4g/m2 and G- (or GM-) CSF. In 9 cases, additional CD34+ cell-selection of the graft was performed. Here we update previously published results of this novel treatment, mainly with regard to clinical efficacy, as the median follow-up time has reached 40 months (range, 21-51). Infections were the principal toxicity early after the procedure, with death of a patient from aspergillosis 65 days post stem cell infusion. No serious late events occurred apart from a case of autoimmune thyroiditis that developed 11 months after transplant in a patient who had received a CD34+ cell-depleted graft. Mild and transient neurotoxicity was observed in 10 patients (42%), most probably associated with fever and infections. Eighteen patients (18/23; 78%) responded to the treatment, i.e., they were improved or stabilized, while five patients progressed, of which 4 had primary progressive disease. Of those improved or stabilised (18), 9 patients have maintained stable condition whereas 9 developed relapses or they slowly resumed progression, although their disability scores have not gotten worse than they were before transplantation. The probability of progression-free survival (compared to entry status) at 3 years is 92% for patients with secondary progressive disease and 39% for the primary progressive type. CD34+ cell-selection did not seem to yield better results except for a delay in progression or in relapse after transplantation. These results appear better than those achieved by any other treatment of progressive multiple sclerosis, including beta-interferon, but they need to be confirmed by other open or controlled studies in view of the well-known difficulty of judging objectively the effect of a treatment in patients with this disease.

Myasthenia gravis: correlation of age with clinical course and anti-AChr antibody levels.

We studied the significance of age as a factor affecting prognosis and anti-AChR antibody levels in myasthenia gravis, comparing patients with symptom onset before 50 (37 patients) and at or after 50 (33 patients). More of the older patients, compared to younger ones (69.9% versus 32.4%,p<0. 05) progressed to severe disease in the first three years of treatment. Five older patients died during myasthenic crises, whereas no deaths occured in the younger group. In addition; older patients did not respond as favorably as younger ones to anticholinesterase treatment and more of them required combination therapy. AntiAChR antibody levels were significantly lower in older patients (9.2 versus 34.9 nM, p<0.005). We conclude that symptom onset at or after the age of 50 predicts unfavorable outcome in myasthenia gravis and is associated with lower anti-AChR antibody levels. This group of patients requires earlier treatment with corticosteroids, immunosuppressive drugs or both.

Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study.

Several experimental autoimmune diseases (AID), including allergic encephalomyelitis, ie the multiple sclerosis (MS) model, respond to TBI and chemotherapy followed by BMT. Remissions of AID may also occur in patients with concomitant malignancies treated with allogeneic or autologous BMT. These observations have emphasized the possibility of treating AID with high-dose therapy and haematopoietic stem cell transplantation (HSCT). In a phase I/II pilot study, 15 patients with progressive MS were treated with BEAM followed by autologous blood SCT and antithymocyte globulin (ATG). Patients were severely disabled, with median EDSS and SNRS scores of 6 (5-7.5) and 42 (33-62), respectively. Cyclophosphamide (4 g/m2) and G/GM-CSF (5 microg/kg/day) were used for stem cell mobilization, which caused no neurotoxicity. On days +1 and +2, ATG (2.5-5 mg/kg) was given for in vivo T cell-depletion. Allergy (93%) and infections (87%) were the principal toxic complications. Mild, transient, neurotoxicity was observed in six patients in the immediate post-transplant period. The median follow-up time is 6 months (6-18). Durable neurologic improvements have been detected on both the EDSS (7/15) and SNRS (15/15) systems. One patient worsened at 3 months and two have relapsed. Autologous HSCT appears feasible in MS; it does not aggravate disability and seems to offer a clinical benefit. However, these observations need confirmation and long-term outcomes will show if benefits counterbalance toxicity and cost.

Cognitive event-related potentials and magnetic resonance imaging in myotonic dystrophy.

Fourteen patients with myotonic dystrophy (MyD) were studied with means of an auditory "oddball" event-related potential (ERP) paradigm. The results were compared with data from 53 controls. The early components (N1, P2) of the ERP were not affected, whereas later components (N2, P3), which are thought to reflect cognitive processes, were abnormal in eight patients who were the oldest in the sample. Magnetic resonance imaging (MRI) was performed in twelve patients and revealed, in five of them, multiple focal white matter lesions. These findings, however, could not be associated with neurophysiological abnormalities. It is concluded, that cognitive ERP, particularly N2 and P3 components, are abnormal in some patients suffering from MyD. Possible etiologies of the electrophysiological abnormalities are discussed.

Correlation of dementia, neuropsychological and MRI findings in multiple sclerosis.

Twenty patients diagnosed as having multiple sclerosis (MS) were examined by MRI and 9 neuropsychological scales: MMSE, BCRS, RMB, SDMT, BNT, VM, FAS, Benton and Hamilton. The number and distribution of the lesions, and cerebral and corpus callosum atrophy were evaluated by MRI. MR images were generated by a 0.5 Tesla instrument utilizing T1WI, PD and T2WI imaging techniques. The results reveal (1) that patients with MS are impaired in a broad range of cognitive functions but mainly memory is affected; (2) number of lesions in the corona radiata, insula and hippocampus is correlated with cognitive impairment, and (3) enlargement of the IIIrd ventricle is an indicator of memory impairment in MS patients.

[Psychopathometric double blind study with nicergoline versus placebo in geriatric patients with slight transit syndromes]. / Psychopathometrische Doppelblind-Verlaufsstudie mit Nicergolin versus Plazebo bei geriatrischen Patienten mit leichteren Durchgangs-Syndromen.

A double-blind study was carried out on 56 geronto-psychiatric in-patients who suffered from cerebral metabolic and nutritional disturbances to prove the effectiveness of 10-methoxy-1,6-dimethyl-ergoline-8 beta-methanol-(5-bromonicotinate (nicergoline, Sermion). After a washout-phase of eight days the patients in the verum group received 3 x 1 dragée at 10 mg for a period of 12 weeks. For methodical reasons only patients with slight transit syndromes and, of these, only the first four weeks of examination were included in the present analysis. Thus 8 verum and 9 placebo patients remain whose findings during the trial are recorded in three procedures of capacity and two procedures of self-assessment (syndrome short test, repeating figures and letters, reading letters; scale for general somatic discomfort, scale for vegetative functional disturbances). In the measuring procedures there is a tendency towards improvement under the treatment with nicergline compared with placebo during the first three weeks. But the present results are not sufficient to come to a clear decision on the effectiveness of nicergoline in patients with cerebrovascular insufficiency.