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An International Working Group for Treatment Optimization in MS met to recommend evidence-based therapeutic options for the management of suboptimal responses or intolerable side-effects in patients treated with disease-modifying drugs (DMDs) for multiple sclerosis (MS). Several DMDs are now available for the treatment of MS that have been shown to alter the clinical course of the disease by decreasing disease activity and delaying the progression of disability. Nevertheless, many patients continue to experience disease activity whilst on treatment, and recommendations have been made on how the success of therapy in an individual patient can be assessed. However, even after having identified criteria for a suboptimal response to current treatments, clinicians require guidance on how to improve the outcomes. This report summarizes the conclusions from a workshop at which this issue was addressed. We suggest treatment pathways for optimizing therapy for those patients with suboptimal responses to DMDs, and therapeutic options for patients with unacceptable side-effects on their current therapy.

The beneficial effects of interferon beta (IFN-beta) on disease activity in relapsing-remitting multiple sclerosis (RRMS) have been confirmed in several clinical trials. Three IFN-beta products are currently available and licensed for use in RRMS at different dosages and with different routes of administration. For the prescribing physician, therefore, questions remain about the effect these differences may have on the success of therapy. This paper reviews the four large placebo-controlled clinical trials that have been conducted with IFN-beta in patients with RRMS. The evidence available indicates that optimal results are likely to be achieved with the highest tolerable dosage of IFN-beta. Furthermore, as inflammatory brain lesions in MS have been shown to exhibit more extensive and early axonal damage than previously suspected, early treatment may be advisable in order to delay disease progression in RRMS.

Mulltiple sclerosis and pregnancy Multiple sclerosis (MS) is diagnosed between the second and fourth decade. More than 2/3 of patients are women and are often in childbearing age. We may ask two main questions: Which implication of pregnancy on the evolution of MS has to be considered ? Which influence of MS on the pregnancy is expected? In other words could the pregnancy worsen MS and could MS represent specific risks for the pregnancy?

The incidence of anti-GM1 antibodies in the serum of 104 patients with neurological diseases, 35 patients with non-neurological diseases (NND) and 41 normal controls was determined by enzyme-linked immunosorbent assay (ELISA). Anti-GM1 antibodies were found in 90% of patients presenting with a motor neuropathy (all except one had multifocal conduction blocks). A large proportion (60%) of these patients displayed high antibody titer ranging from 101 to 788. A low incidence of anti-GM1 antibodies was found in the other groups of patients, i.e. 21% of amyotrophic lateral sclerosis (ALS), 26% of other neurological diseases (OND) and 23% of NND. High antibody titers ranging from 106 to 260 were found in two (5%) ALS patients, one (2%) OND patient (myasthenia gravis), and one (3%) NND patient (Waldenström's disease). This study shows that high titers of anti-GM1 antibodies are found in a large proportion of patients with motor neuropathy with multifocal conduction blocks. This argues for a possible autoimmune origin of this neuropathy. We suggest that anti-GM1 antibody determination should be included systematically in the evaluation of all patients with motor neuron diseases and predominantly motor neuropathies.

Neuromyelitis optica (NMO) or Devic's syndrome is a severe demyelinating disease of the central nervous system involving preferentially the optic nerves and the spinal cord. Until recently, NMO was described as an atypical multiple sclerosis IMS), characterized by an unusual clinical presentation, a severe relapsing progression, and a poor response to usual MS treatments. The recent discovery of the so-called NMO-IgG, a highly NMO-specific antibody directed against the blood brain barrier and the aquaporine-4, allowed to refine diagnostic criteria and to classify this disease as an autoimmune channelopathy. According to this recent advance, early diagnostic and specific treatment targeting the humoral response should be considered.

We describe a patient with acute disseminated encephalomyelitis (ADEM) who was treated with high-dose intravenous methylprednisolone 2 days after onset of neurologic symptoms. Despite poor prognostic factors and extensive white matter lesions, the patient recovered dramatically with no need for maintenance steroid therapy. This case report of fulminant ADEM treated successfully with early high-dose intravenous methylprednisolone, although uncontrolled, suggests that this agent should be studied in other cases.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

We report the case of a woman suffering from progressive bulbopontine paralysis in whose the first symptom, bilateral hypoacousia, began in childhood. This clinical picture is that of the Brown-Vialetto-Van Laere (BVVL) syndrome. Anti-ganglioside GM1 antibodies were moderately elevated in this patient. Intravenous immunoglobulins produced little benefit. The main clinical characteristics of 29 BVVL patients reported in literature are reviewed, and the pathological significance of anti-GM1 antibodies is discussed in the context of this disorder.

The aim of this study was to develop a test allowing to monitor disease activity in patients with multiple sclerosis (MS). A simple, fast and reliable test was used to assess the cytokine production capacity of blood leucocytes. The whole blood test (WBT) involved in vitro stimulation of a whole blood sample with either the mitogen phytohaemagglutinin (PHA), or specific antigens. We focused our attention on the production of tumor necrosis factor alpha (TNF), because of the possible involvement of this cytokine in MS pathogenesis. Under in vitro stimulation with PHA or MBP, TNF production was found to be significantly higher in patients during the clinical relapses than during remissions. The increment of TNF production correlated with the severity of the relapses, as determined by the modification of Kurtzke EDSS scale. Moreover, each clinical relapse appeared to be preceded by a peak of TNF production. We then retrospectively analysed 21 patients with the relapsing-remitting form of the disease, in whom the WBT was performed every 2-4 weeks, for periods ranging from 16 to 52 months. Seventy-three peaks of TNF production (defined as the doubling or more of the individual baseline value, which was found to be stable for each patient during remissions), and 47 relapses, including 36 objective and 11 subjective, were observed. Forty-seven out of the 73 TNF peaks were followed by or concomitant with a clinical relapse. In 10 out of the 26 cases where no relapse followed the TNF peak, another cause (mainly infections) of increased TNF production was found. Thus, by excluding other causes, the specificity of the WBT, i.e., the probability to develop a relapse when a TNF peak was found to be 74.6% (47/63). The sensitivity of the WBT was 100%, since all the 47 relapses were preceded by a TNF peak. Assessment of TNF production capacity by the WBT may thus be useful in the follow-up of MS patients, particularly for the follow-up of various treatments. Information provided by the WBT may also be useful to orientate the therapeutic decision for an incipient relapse. Earlier treatment is likely to result in an improved prevention of neurological damage.

Human immunodeficiency virus infection frequently involves the peripheral or central nervous system. Seven cases of isolated peripheral facial palsy that occurred at various stages of the disease are reported. The palsy was the first manifestation of the disease in 5 patients, and revealed it in 3 of them. The palsy involved the right side in 6 cases (complete N = 2; incomplete N = 4); it was bilateral in one (complete on both sides). Abnormalities of the cerebrospinal fluid were present in all patients but differed depending on the stage of the retroviral infection. Electroneuromyography defined the type of the palsy, principally due to axonotmesis in 4 patients (including the bilateral one) and principally to neurapraxia in 3 patients. The outcome was good in most cases. The physiopathology remains undetermined.

In systemic lupus erythematosus (SLE), neurological involvement has been reported to occur with frequencies ranging from 14% (severe cases) to 83% (mild forms included). In spite of early diagnosis and aggressive treatment, neuropsychiatric SLE may represent a serious problem of management. We describe three cases, one with acute transverse myelitis, one with hemiparesis, and one with signs of focal and diffuse cerebral dysfunction, in whom improvement following intrathecal therapy with methotrexate and dexamethasone was observed.

No biological parameter is currently available as a specific marker of multiple sclerosis (MS) activity. The aim of this study was to determine whether an evolution of the neurological disability is associated with a modified profile of cytokine production. Clinical disease activity was quantitated by the Kurtzke's expanded disability status scale (EDSS). Whole blood was stimulated with phytohemagglutinin (PHA) for 2 hours at 37 degrees C and the activated plasma was assayed for Tumor necrosis factor alpha (TNF-alpha) and Interleukin-1 beta (IL-1 beta). Relapsing-remitting MS patients enduring a relapse (RRMS, in relapse) (721 +/- 58 pg/ml, n = 27) and chronic progressive MS (CPMS) patients (516 +/- 33 pg/ml, n = 17) had an higher TNF-alpha production capacity as compared to healthy subjects (143 +/- 25 pg/ml, n = 17), RRMS, stable patients, (123 +/- 11 pg/ml, n = 26) or other neurological diseases (OND) without immunological or inflammatory disease in the peripheral immune compartment (131 +/- 24 pg/ml, n = 14) (t test: p0.0001). IL-1 beta production was also significantly higher but to a lesser extent in the same conditions. Concentration of TNF-alpha was also found to be significantly higher in the cerebrospinal fluid (CSF) of CPMS patients (199 +/- 7.8 pg/ml, n = 7, p0.0001) but also in RRMS, in relapse (149 +/- 5.7 pg/ml, n = 11, p0.05) as compared to RRMS, stable (130 +/- 4.4 pg/ml, n = 7) or OND without inflammatory or immunological disease of the central nervous system (CNS) (142 +/- 6.2 pg/ml, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)

HTLV-I/II (human T-cell lymphotropic virus type I and II) infection is endemic in South Japan, Subsaharan Africa, the Caribbean and in regions of South America and of the United States. The infection almost always remains asymptomatic but is also associated with two distinct diseases: tropical spastic paraparesis (TSP), and adult T-cell leukemia (ATL). Although very rare in Europe, HTLV-I/II infection may occur in patients originating from endemic areas. We report the cases of four patients seropositive for HTLV-I/II, all of them living in Switzerland. Three of them originate from Zaire; the fourth is a Swiss female married to a Taiwanese. One patient has TSP; one has pyramidal signs along with systemic vasculitis-associated neuropathy; the third is HIV-position with stage III B infection, without symptoms of TSP or ATL; the last is entirely asymptomatic.

In this preliminary study we demonstrated that cytokine production by short whole blood PHA stimulated culture is correlated with clinical evolution of MS patients. The TNF alpha production could forewarn the physician of a new relapse.

1. The hypothesis that a transcortical loop can be activated by electrical stimulation of low-threshold muscle afferents was tested. The effect of these afferents on the excitability of motoneurones was measured with the monosynaptic spinal reflex (H-reflex). 2. Four monkeys were trained to maintain a constant tonic activity in the soleus muscle so that the amplitude of evoked H-reflexes was constant. The intensity of conditioning stimuli was just subthreshold for direct or reflex electromyographic responses. The intensity of the test stimuli was adjusted to evoke an H-reflex of maximal amplitude. The amplitude of the H-reflex was recorded for different intervals between conditioning and test stimuli (10-1000 msec). 3. The excitability curve obtained showed three components: (1) an early excitatory process, F1, at intervals of 10-20 msec, (2) a late excitatory process, F2, at intervals of 40-80 msec and (3) a short latency depression of about 400 msec duration, on which F1 and F2 were superimposed. 4. F2 was selectively abolished during cooling of the contralateral motor cortex, after an irreversible lesion of the motor cortex, and after pyramidotomy; however, F1 and the inhibition remained unchanged. 5. The conduction time from the tibial nerve to the somatosensory cortex (SI), the cortical delay between SI and motor cortex, and the conduction time from motor cortex to the soleus muscle were measured in an anaesthetized animal. The sum of these values as an estimate of the transcortical loop time was 5 msec shorter than the latency of F2. 6. It is concluded that a transcortical loop can be activated by electrical stimulation of low-threshold muscle afferents and, by analogy, also by mechanical perturbations applied during a motor task.

The Ta1 (CDw26) Ag distinguishes a subset of circulating T lymphocytes that is the major population proliferating to recall Ag challenge. Unlike receptors for growth factors such as IL-2 and transferrin, the Ta1 Ag is present on T cell lines and clones irrespective of cell cycle. The appearance of Ta1 on T cells that respond to recall Ag allowed us to investigate activation requirements that may be associated with T cell immune memory. Ta1+ peripheral blood T cells were induced to proliferate by mAb recognizing either the invariant chains of the TCR, or by pairs of mitogenic antibodies directed to the CD2 molecule. In contrast, Ta1- cells were not stimulated by these antibodies. In addition, Ta1-cells did not proliferate maximally after addition of the phorbol ester PMA in combination with the calcium ionophore Ionomycin, suggesting that the intracellular targets of these agents may not be fully active. Anti-CD3-induced elevation of intracellular calcium levels was equivalent in the two subpopulations, suggesting that calcium mobilization mechanisms were intact. In contrast, PMA-induced phosphorylation of TCR CD3 chains was significantly greater in Ta1+ cells as compared to Ta1- T cells. Taken together, our results indicate that Ta1 expression, which is associated with T cell activation and memory, may be causally related to TCR and CD2-mediated activation mechanisms. The PMA inducible TCR phosphorylation in Ta1+ memory cells associated with their increased ability to proliferate after CD3/TCR or CD2 stimulation suggests that intracellular phosphorylation events may be causally associated with T cell immune memory.

Peripheral and supraspinal loops activated by electrical stimulation of the tibial nerve were studied in alert monkeys. Weak conditioning stimuli below the threshold for muscle contraction and strong conditioning stimuli which elicited a direct motor response and an H-reflex were applied to the tibial nerve, while soleus EMG was recorded. The motoneuronal excitability was measured with a test H-reflex for different intervals between conditioning and test stimuli. A facilitation of the motoneuronal pool occurred with a latency of about 50 ms for weak, as well as strong, conditioning stimuli. The facilitation was superimposed on a long-lasting inhibition which was more pronounced when strong stimuli were used. The shape of the excitability curve of the motoneurons after strong conditioning stimuli was studied before and after various lesions. The shape of the curve did not change after an ipsilateral cerebellectomy except that the facilitation was more pronounced. A few days after pyramidotomy, the facilitation diminished in size but it recovered to its initial size after 3 months. Spinal hemisection did not abolish the facilitation. We concluded from these results that a peripheral loop was activated when conditioning stimuli above the threshold for a direct motor and reflex response were applied. The facilitation might be mediated by the muscle contraction and following activation of muscle afferents. Superimposed on thus loop is a previously demonstrated transcortical loop of similar latency.

Persistent generalized lymphadenopathy (PGL) is observed predominantly in subjects at risk of developing AIDS. Twenty-seven individuals belonging to such groups: twelve homosexual males and fifteen intravenous drug users, were investigated for immunological abnormalities with particular attention to monocyte functions. They were compared with five AIDS patients. Twenty out of twenty-two individuals had anti-LAV/HTLV-III antibodies and most had abnormalities characteristic of AIDS: polyclonal hypergammaglobulinemia, decreased cell-mediated immunity, inverted T-cell helper/suppressor ratio and histological alterations of lymph nodes. As for peripheral blood monocyte functions, phagocytic capacity and production of O2- were normal and bactericidal capacity was decreased. Monocytes cultured in the presence of concanavalin A produced less PGE2 and more IL-1/MCF than normal monocytes. Similar abnormalities were found using monocytes from AIDS patients. These data suggest that monocytes from patients with PGL have functional alterations that may be either intrinsic or secondary to lymphocyte dysfunction(s); these alterations do not account for the decreased capacity of lymphocytes to respond to mitogens but may explain the uncontrolled activation of B cells.

The Ta1 (CDw26) Ag distinguishes a subset of circulating T lymphocytes that is the major population proliferating to recall Ag challenge. Unlike receptors for growth factors such as IL-2 and transferrin, the Ta1 Ag is present on T cell lines and clones irrespective of cell cycle. The appearance of Ta1 on T cells that respond to recall Ag allowed us to investigate activation requirements that may be associated with T cell immune memory. Ta1+ peripheral blood T cells were induced to proliferate by mAb recognizing either the invariant chains of the TCR, or by pairs of mitogenic antibodies directed to the CD2 molecule. In contrast, Ta1- cells were not stimulated by these antibodies. In addition, Ta1-cells did not proliferate maximally after addition of the phorbol ester PMA in combination with the calcium ionophore Ionomycin, suggesting that the intracellular targets of these agents may not be fully active. Anti-CD3-induced elevation of intracellular calcium levels was equivalent in the two subpopulations, suggesting that calcium mobilization mechanisms were intact. In contrast, PMA-induced phosphorylation of TCR CD3 chains was significantly greater in Ta1+ cells as compared to Ta1- T cells. Taken together, our results indicate that Ta1 expression, which is associated with T cell activation and memory, may be causally related to TCR and CD2-mediated activation mechanisms. The PMA inducible TCR phosphorylation in Ta1+ memory cells associated with their increased ability to proliferate after CD3/TCR or CD2 stimulation suggests that intracellular phosphorylation events may be causally associated with T cell immune memory.

In two groups of subjects at risk for acquired immune deficiency syndrome (AIDS), homosexual males and intravenous drug users with persistent generalized lymphadenopathy, humoral and cell-mediated immunity were compared. A small group of patients with definite AIDS were also studied. It was found that levels of immunoglobulins, serological markers for virus and other infections, cell-mediated immunity and histology of lymph nodes were similar in homosexuals and drug users, whereas the lymphocyte sub-populations differed completely. The number of T4+ lymphocytes was markedly decreased in homosexuals but normal in drug users; the number of T8+ lymphocytes was much higher in drug users than in homosexuals. This discrepancy may explain the extremely low prevalence of AIDS cases observed among Swiss drug users as compared with the high frequency noted among homosexuals.