The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL.

OBJECTIVE: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. METHODS: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon beta-1a [INF beta]1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as "transiently positive" if they had detectable antibodies (>or=0.5 microg/mL) at a single time point or "persistently positive" if they had antibodies at two or more time points >or=6 weeks apart. RESULTS: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p

MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS.

BACKGROUND: In a 2-year, placebo-controlled trial (the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] study), involving 942 patients with relapsing multiple sclerosis (MS), natalizumab significantly reduced the relapse rate by 68% and progression of sustained disability by 42% vs placebo. We report the effect of natalizumab on MRI measures from the AFFIRM study. METHODS: The number and volume of gadolinium (Gd)-enhancing, new or enlarging T2-hyperintense, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years. RESULTS: Compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (means 2.4 vs 0.2; p < 0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means 11.0 vs 1.9; p < 0.001), and a 76% decrease in new T1-hypointense lesions (means 4.6 vs 1.1; p < 0.001) over 2 years. Median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p < 0.001); median T1-hypointense lesion volume decreased by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p < 0.001). Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated patients. CONCLUSION: Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.

Natalizumab reduces visual loss in patients with relapsing multiple sclerosis.

OBJECTIVE: To examine the effects of natalizumab on low-contrast letter acuity as a prespecified tertiary endpoint in two randomized clinical trials and to evaluate the usefulness of low-contrast letter acuity testing as a candidate test of visual function in multiple sclerosis (MS). METHODS: AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of natalizumab in relapsing MS. Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to interferon beta-1a in SENTINEL. Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%). RESULTS: The risk of clinically significant visual loss (predefined as a two-line worsening of acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the natalizumab treatment arms by 35% in AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models). Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-natalizumab groups. CONCLUSIONS: Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of visual outcomes in future multiple sclerosis trials.

Blood levels of selected hormones in patients with multiple sclerosis.

BACKGROUND: Hormonal studies in patients with multiple sclerosis are rare and they often produce results which are difficult to interpret. These investigations, however, are becoming more and more important as they may cast some light on possible interrelationships between hormonal and immune systems. The aim of the present work was to investigate endocrine function in patients with multiple sclerosis on the basis of blood levels of selected pituitary (TSH, ACTH, GH) and thyroid hormones (T3, T4), and cortisol. MATERIAL AND METHODS: Forty-nine MS subjects, including 25 menstruating women, 6 post-menopausal women and 18 men were included in the analysis. The hormones were measured by radioimmunoassay and immunoradiometric assay kids. RESULTS: Pituitary function in respect of TSH, corticotropin and growth hormone secretion was normal. Both men and women suffering from multiple sclerosis manifested low serum T3 concentrations coexisting with normal T4 levels which may indicate changed peripheral conversion pathway of thyroid hormones. On the other hand, the disturbances in pituitary-adrenal cortex system in respect of glycocorticosteroid secretion were not observed. CONCLUSIONS: Normal function in respect to pituitary hormones (TSH, corticotropin, growth hormone) and normal T4 level versus low serum T3 concentration may indicate changes in peripheral conversion pathway of thyroid hormones in MS patients.

Effect of immunosuppressive cladribine treatment on serum leucocytes system in two-year clinical trial in patients with chronic progressive multiple sclerosis.

BACKGROUND: Multiple sclerosis is presumably cell-mediated autoimmune disorder with immune abnormalities as presence of activated T-cells and increase interleukin 2 (IL-2) and soluble IL-2 receptor (sIL-2R) levels in central nervous system and peripheral blood of patients. The aim of immunosuppressive treatment is to diminish such activation. The aim of this study was to evaluate the influence of immunosuppressive cladribine treatment with total dose of 2.1 mg/kg b.w. administered in 7 cycles for 12 months, on serum leucocytes in 34 chronic progressive multiple sclerosis (CPMS) patients observed for 2 years as well as IL-2 and sIL-2R serum levels assessed before and right after the treatment. MATERIAL AND METHODS: The study was designed as a randomised, placebo-controlled, double-blind trial. The patients were divided in two groups: group I, cladribine-treated, n = 34; group II, placebo-treated, n = 35. Group III were healthy controls, n = 20. Leucocyte levels were determined with flow-cytometry. IL-2 and sIL-2R levels were assessed with enzyme-linked immunosorbent assay. RESULTS: Statistically significant gradual decrease of lymphocyte level was observed from 7th week to 12th month after the beginning of treatment. During the following 12 months, lymphocyte levels remained decreased in comparison to baseline. Mean values of IL-2 and sIL-2R levels measured 12 months after the treatment were found to be lowered by 20% (p. = 0.01) and by 24% (p. = 0.0005), respectively. CONCLUSION: The results obtained indicate fast and long-lasting decrease of serum leucocyte level and suppressive influence of cladribine treatment on immune processes in multiple sclerosis patients.

[Spontaneous intracranial epidural accumulation of air in a patient with excessive skull pneumatization]. / Samoistna nadtwardówkowa odma wewnatrzczaszkowa u pacjenta z nadmierna pneumatyzacja czaszki.

We report a rare case of spontaneous epidural accumulation of air in the occipital region resulting from an unusual hyperpneumatization of the cranium in a 37-year-old miner. For suspected subarachnoid haemorrhage the patient was admitted to neurological department. Performed computed tomography (CT) revealed extensive hyperpneumatization of the cranium, involving also the upper part of the cervical vertebral column, and epidural pneumocephalus. To the authors knowledge, so much pneumatization of the cranium seems to be very rare and when present, however, can cause spontaneous pneumocephalus. Based on the two years follow-up of this patient, conservative therapy showed to be sufficient for him, despite this, we have suggested him periodically perform CT of the head.

[Comparative assessment of treatment efficacy with lamotrigine (Lamictal) together with valproate and/or carbamazepine in patients with refractory epilepsy]. / Ocena porównawcza skutecznosci leczenia skojarzonego lekoopornej padaczki lamotrygina (Lamictal) z leczeniem walproinianem i/lub karbamazepina.

For the study 17 patients aged 26-55 years were qualified after ineffective treatment with carbamazepine and/or valproate for simple partial, complex partial or secondary generalized seizures. The criterion of resistance to treatment was the occurrence of four or more seizures monthly. The treatment with lamotrigine was successful in 9 (52%) cases, with reduction of seizures by at least 50%. In 2 cases the seizure activity in EEG became normal. In 8 cases the addition of lamotrigine was ineffective and the drug was discontinued (in one case due to allergic rash and in one the cause was toxic hepatocellular damage).

[Cyclophosphamide changes oligoclonal immunoglobulin G spectrum in cerebrospinal fluid in slowly progressing multiple sclerosis]. / Cyklofosfofamid zmienia oligoklonalne spektrum immunoglobuliny G plynu mózgowo-rdzeniowego w przewlekle postepujacej postaci stwardnienia rozsianego.

The effects of treatment with cyclophosphamide (CY) and prednisone on the spectrum of oligoclonal IgG (olgG) of the cerebrospinal fluid were studied in 33 cases of slowly progressing multiple sclerosis. CY was administered intravenously in a total dose of 4 g during 10 days. This treatment was supplemented with prednisone 775 mg p.o. given during the following 25 days. The electrophoretic separation of proteins in non-concentrated CSF and in serum before and immediately after the treatment was done by Laemili's method with associated impregnation with silver salts. The analysis of these electrophorograms showed the presence of qualitative and quantitative changes of olgG spectrum. Quantitative changes found in 59% of the cases included more pronounced (8% of cases) appearance or attenuation (51% of cases) of individual bands. Qualitative changes in form of elimination of bands were noted in 29% of cases, and in 12% of cases new bands appeared. The authors conclude that, the results confirm a strong immunosupressive effect of CY on olgG in slowly progressing m.s.

[Importance of genetic factors in pathogenesis of subacute spongiform viral encephalitis]. / Znaczenie czynników genetycznych w patogenezie podostrych transmisyjnych encefalopatii gabczastych.

Recently there has been achieved a substantial progress in research concerning pathogenesis of subacute spongiform viral encephalopathies. For this group of disorders, there has been found a common unconventional virus - proteinaceous infectious particle (PrP). There has been recognised a molecular mass, biochemical composition and physicochemical properties of this infectious form. Mutations of scrapie amyloid precursor gene discovered in Gerstmann-Sträussler-Scheinker syndrome (GSS) and familial cases of Creutzfeldt-Jakob disease (CJD) have been revealed. Nowadays examinations in the field of relationships between prion protein and mutations of scrapie precursor gene are continued.

[Evaluation of treatment efficiency of acute hemispheric strokes using intravenous nimodipine infusions]. / Ocena skutecznosci leczenia ostrych udarów niedokrwiennych dozylnym wlewem nimodypiny.

The authors present the results of treating acute hemispheric stroke with intravenous nimodipine. 17 patients were additionally treated with nimodipine given intravenously in 1 mg-2 mg dose, and the control group consisted of 71 patients treated in standard way with Dextran 40,000. The selection of patients for the study was random, and the treatment was conducted by blind trial method. All patients were admitted within 24 hours since acute stroke onset. The diagnosis was based on clinical examination and CT. The analysis of treatment results was made twice before and after the treatment according to criteria recommended by WHO Karnofsky scale. Statistical analysis showed that in the group treated additionally with nimodipine neurological and social consequences of stroke were significantly lower in comparison with standard therapy (p < 0.001).

[Diabetes and multiple sclerosis]. / Cukrzyca a stwardnienie rozsiane.

We report four patients who had multiple sclerosis associated with diabetes mellitus. Multiple sclerosis and diabetes mellitus share clinical, epidemiological and immunological features. The association between these two putative autoimmune diseases may suggest a similar pathogenic mechanism.

[Changes in the cerebrospinal fluid levels of adenosine cyclic- 3',5'-monophosphate (c-AMP) in patients with generalized tonic-clonic epileptic seizures]. / Zmiany stezenia cyklicznego adenozyno 3'5' monofosforanu (c-AMP) w plynie mózgowo rdzeniowym (p.m.r.) u chorych z uogólnionymi toniczno-klonicznymi napadami padaczki.

Authors evaluated the activity of c-AMP in the CSF as the biochemical marker for evaluation of epileptic seizure activity in patients with epilepsy. The impact of monitored phenytoin treatment on c-AMP activity in CSF was investigated. It was shown that the general tonic-clonic seizures cause a significant concentration increase of c-AMP in CSF. Monitored phenytoin treatment had a stabilizing effect on c-AMP activity in CSF.

[Mortality in vascular diseases of the central nervous in the Katowice province in comparison with other provinces and all Poland (evaluation based on hospital statistical charts)]. / Czestosc zgonów z powodu chorób naczyniowych osrodkowego ukladu nerwowego w województwie katowickim w porównaniu z innymi województwami i cala Polska (ocena na podstawie szpitalnych kart statystycznych).

As part of the programme of investigations on the effect of environmental pollution, which is far advanced in the Upper Silesian Industrial Region, on the health of the population the authors analysed the death rate from vascular diseases of the central nervous system. Using the data of the Central Statistical Bureau this death rate in the years 1976-1986 in the Province of Katowice was compared with those in the neighbouring provinces of Bielsko, Czestochowa and Opole, and with those in the so called clean provinces--Chelm, Zamosc, Zielona Góra. The death rate from these diseases in the provinces of Katowice, Czestochowa and Opole (with particularly high pollution of air and soil) was higher than in the control provinces, and the authors consider the possibility of a harmful effect of this pollution on the incidence of and mortality from the vascular diseases of the central nervous system. The increase of the death rate in the Province of Katowice was due to a 49% rise in the mortality in the group of men aged 50-59 years. The rise of this death rate in Poland was caused by increased mortality in the age group 40-59 years, and not in the older age groups, as it had been prognosticated earlier. The authors suggest long-term prospective studies in this region.

Effect of immunosuppressive therapy on humoral immune response in multiple sclerosis.

The purpose of this study was to evaluate the effect of various therapeutic regimens on: 1) intrathecal IgG synthesis on the basis of IgG Index value, 2) oligoclonal IgG spectrum visualized by SDS-PAGE of unconcentrated CSF, 3) CSF antibody specific activity against MBP estimated by solid phase RIA and expressed in cpm/micrograms IgG, and 4) immune complex (CIC) level in the CSF estimated by C1q binding solid phase RIA. CSF antibody against Gal-C and ganglioside was also estimated. Patients with clinically definite MS were selected according to 4 therapeutic regimens: group 1, subjected to Mega-dose prednisone therapy (4000 mg over 54 days), group 2, subjected to moderate dose prednisone therapy, group 3 subjected to Mega-dose Solu-Medrol therapy (7500 mg over 10 days), and group 4, subjected to intravenous Cyclophosphamide therapy (4000 mg over 10 days). This last group was characterized by chronic progressive course of disease. Intrathecal IgG production was significantly reduced in all 4 groups as a result of therapy. More pronounced reduction was obtained in Mega-dose prednisone (p below 0.001) and CY (p below 0.001) treated group. Therapeutic regimens did not influence the IgG oligoclonal pattern. The moderate dose prednisone therapy and Mega-dose Solu-Medrol therapy on CSF IgG anti-MBP antibody specific activity were less effective than the Mega-dose prednisone medication. CY therapy did not influence anti-MBP antibody specific activity in MS group characterized by chronic progressive course of disease. The influence of therapeutic regimens on elevated CIC level in the CSF was insignificant. In our study CSF the anti-galactocerebroside antibody appeared to be of IgM class.

[Evaluation of the results of treating progressive multiple sclerosis with cyclophosphamide]. / Ocena wyników leczenia cyklofosfamidem przypadków stwardnienia rozsianego o przebiegu postepujacym.

Cyclophosphamide (4000 mg intravenously, in daily doses of 400 mg) in combination with moderate dose of prednisone (1075 mg during 30 days) was given to 39 patients with the chronically progressing form of multiple sclerosis. The results of this treatment were evaluated immediately after the treatment and one and two years later, using a numerical scale of neurological examination in the scales of motor efficiency A. I. (ambulation index) and the DDS (disability status scale of Kurtzke). In the first year after this treatment stabilization of the disease (60% of cases) or even clinical improvement (10-20%) were noted. However, in the second year after the treatment an evident progression of symptoms occurred in 50-60% of cases. In view of moderately positive results of this treatment it is necessary to carry out observations extended over many years, to repeat cyclophosphamide cycles, and to compare the results with those after other immunosuppressants.

[Value of polyacrylamide gel electrophoresis of non-concentrated cerebrospinal fluid in the diagnosis of multiple sclerosis]. / Wartosc elektroforezy poliakrylamidowej niezageszczonego plynu mózgowo-rdzeniowego w diagnostyce stwardnienia rozsianego.

Using SDS-PAGE for non-concentrated cerebrospinal fluid investigations connected with immunofixation and silver impregnation of gels the authors found oligoclonal IgG in 39 cases (95%) of clinically reliably diagnosed multiple sclerosis, and in 92.3% of probable multiple sclerosis cases. The number of IgG lines reached 13, while in the control group of neuroses it never exceeded 6-8. Comparative analysis of the IgG spectrum in cerebrospinal fluid and serum in the same multiple sclerosis cases demonstrated different IgG patterns which were only partly similar. Moreover, it was found that the electrophoretic pattern of cerebrospinal fluid proteins in each case of multiple sclerosis had an individual peculiar pattern of Ig spectrum. The use of SDS-PAGE in combination with silver impregnation made possible obtaining of qualitatively very good separation in 10-20 microliters samples of non-concentrated cerebrospinal fluid. The silver impregnation method is 50-100 times more sensitive than the traditional staining of gel with Coomasie Blue R-250. In multiple sclerosis SDS-PAGE of non-concentrated cerebrospinal fluid combined with silver impregnation of gel is a very god diagnostic method.

[Eales disease and multiple sclerosis. Case report]. / Choroba Ealesa a stwardniene rozsiane--opis przypadku.

The authors report a case of coexistence of Eales disease and multiple sclerosis in which signs of perivenous retinitis preceded by 25 years the appearance of neurological changes. Considering the similarity in the course of both disease and the histological character of perivascular changes the authors suggest presence of a common causative factor and pathological mechanism of the development of clinical changes.

[Prospective evaluation of the effectiveness of high doses of methylprednisolone in multiple sclerosis]. / Prospektywna ocena skutecznosci wysokich dawek metyloprednizolonu w stwardnieniu rozsianym.

The aim of the reported study was an assessment of the effectiveness of high doses of methylprednisolone in the treatment of active exacerbation and its effect on the natural course of multiple sclerosis. The study was carried out on 24 patients with clinically certain disease, who were divided, according to the treatment given to them, into two subgroups: treated with methylprednisolone and treated with prednisone. The treatment was conducted by the double blind method. The statistical analysis of the results obtained in this material showed that in patients with acute and severe exacerbation of the disease methylprednisolone administration in high doses caused a rapid regression of paralysis and paresis and improved motor efficiency. However, an evaluation of the results after a year from treatment termination showed in both subgroups a progression of clinical changes and increased motor deficiency. This suggests that treatment with corticosteroids has no significant effect on the course of multiple sclerosis.