Spontaneous Relapse Research Articles

Inhibition of nitric oxide synthase initiates relapsing remitting experimental autoimmune encephalomyelitis in rats, yet nitric oxide appears to be essential for clinical expression of disease.

Myelin basic protein-CFA-induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats is an acute monophasic disease from which animals recover. In this model, spontaneous relapses do not occur and rats develop a resistance to further active reinduction of disease. Previously, we reported that oral administration of the NO synthase inhibitor N-methyl-L-arginine acetate (L-NMA) to recovered rats precipitated a second episode of disease in 100% of animals. Further studies now show that this second clinical episode is actually a chronic relapsing disease that persists for months. This occurs only in rats that have recovered from actively induced EAE and not in rats recovered from passively induced EAE, suggesting the need for a peripheral Ag depot to induce secondary disease. We have also determined that clinical signs of EAE in L-NMA-treated recovered rats do not appear until L-NMA treatment has stopped. This is despite the fact that, at the same time point, CNS inflammatory lesions in symptomless animals receiving L-NMA are qualitatively and quantitatively similar to those with severe disease symptoms from whom L-NMA treatment has been withdrawn. The latter animals have significantly higher levels of reactive nitrogen intermediates in the cerebrospinal fluid than the former group. This study examines the mechanism of reinduction of disease by L-NMA treatment, and the findings suggest a dual role for NO in regulation of pathology in EAE that is dependent on site and timing of NO production.

Nitric Oxide Plays a Critical Role in the Recovery of Lewis Rats from Experimental Autoimmune Encephalomyelitis and the Maintenance of Resistance to Reinduction

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS and an animal model for the human demyelinating disease, multiple sclerosis. In the Lewis rat, myelin basic protein (MBP)-CFA-induced EAE is an acute monophasic disease from which animals recover fully, do not relapse, and develop a robust long-term resistance to further active reinduction of disease. In this paper, we report that rats recovering from MBP-CFA-induced EAE have significantly increased serum levels of reactive nitrogen intermediates indicative of increased NO production. These levels remain elevated after the recovery period and increase even further early after a rechallenge with MBP-CFA, and all animals are totally refractory to a second episode of disease. Oral treatment of rats with N-methyl-l -arginine acetate (l -NMA), beginning at peak disease on day 11 postimmunization, results in significant prolongation of disease and an alteration in the presentation of clinical symptoms from that of solely hind limb paresis/paralysis to severe fore limb involvement as well. Treatment of fully recovered rats with l -NMA 24 h before a rechallenge with MBP-CFA leads to decreased serum reactive nitrogen intermediate levels and results in a second episode of EAE in 100% of animals. Furthermore, l -NMA treatment of fully recovered rats in the absence of a rechallenge immunization leads to spontaneous relapse of disease.

Antibodies Against IL-12 Prevent Superantigen-Induced and Spontaneous Relapses of Experimental Autoimmune Encephalomyelitis

Immunization of (PL/J x SJL/J)F1 mice with myelin basic protein (MBP) induces relapsing experimental autoimmune encephalomyelitis (EAE). Relapses occur 7 to 10 days after recovery from the initial paralysis. Staphylococcal enterotoxins (SE) A or B, administered after recovery from the initial paralysis, induce immediate relapses. IL-12 is involved in the induction of EAE. Here, we show that SEA and SEB induce IL-12 in splenocytes from (PL/J x SJL/J)F1 mice in vitro and increase the level of IL-12 in the sera of mice treated with these superantigens. IL-12 administration mimics SE in inducing spontaneous relapses and in enhancing the severity and frequency of spontaneous relapses. IL-12 neutralization blocks SE-induced and subsequent relapses of EAE, and, when instituted after recovery from the initial attack, prevents spontaneous relapse. This is the first report of prevention of relapses of EAE with anti-IL-12 Ab, an approach which may prove useful in the prevention of exacerbations in multiple sclerosis.

Spontaneous spinal epidural haematomas with repeated remission and relapse.

We present a case of spontaneous spinal epidural haematoma (SSEH) with a rare clinical course of repeated spontaneous recovery and relapse. The patient suffered three episodes of upper-back pain of sudden onset followed by sensory and motor dysfunction after weight lifting. In the first two episodes, the neurological deficits recovered spontaneously and completely. In the last episode, paraplegia persisted even after emergency surgery. Serial studies with computed tomographic (CT) myelography and magnetic resonance imaging (MRI) demonstrated the remitting and relapsing course of the SSEHs. The possible causes of the SSEHs and the mechanisms of spontaneous recovery are discussed.

Ophthalmologic manifestation of Behçet's disease.

Loss of vision in Behçet's disease is one of the most common, as well as one of the most serious, of its varied manifestations. Total blindness may often be the eventual outcome. The underlying problem in the eye, as well as in other organ systems, is an occlusive vasculitis. Although the most common ocular symptom is that of iridocyclitis, the presence of retinovascular lesions, especially necrotizing retinitis, is well known but often obscured by the severity of the anterior reaction, which precludes a good view of the retina. While Behçet's disease is characterized by spontaneous remissions and relapses, no external factors have been found to explain the length of remissions. Blindness, which occurs in up to 25% of patients, is one of the major causes of permanent disability.

The effect of glucosaminylmuramyl dipeptide injection to mice on the course of tuberculous infection and in vitro superoxide anion production.

Immunotherapy as an adjunct to chemotherapy is of interest for optimizing therapeutic regimens for tuberculosis. In this context, we investigated the influence and mode of action ofglucosaminylmuramyl dipeptide (GMDP) in mouse experimental models. Intermittent injections of GMDP to Mycobacterium tuberculosis-infected mice reduced the viable bacilli in the lungs, but increased the counts in the spleens at 16 weeks, but not at earlier harvests after infection. Injections of GMDP selectively ameliorated also in the lungs the spontaneous relapse of infection following chemotherapy. The mode of GMDP action was examined in respect of superoxide anion production. The O2 production by phorbol myristate-induced peritoneal macrophages in vitro was reduced by preinjection of mice with 100 microg of GMDP. Notably, this outcome contrasts and can also override the previously known enhancing effect of MDP on O2- production. The inhibitory activity of GMDP became even more pronounced when testing macrophages from Mycobacterium bovis BCG-infected mice. However, these results do not explain readily the grounds for the contrasting effects of GMDP on the growth patterns of tubercle bacilli in the lungs and spleens. Although the observed effects on bacillary counts have been modest, such action of GMDP could represent a beneficial adjunct to suitably formulated chemotherapeutic regimens.

Chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice: enhancement by monoclonal antibodies against interferon-gamma.

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory and demyelinating disorder of the central nervous system. Depending on the experimental conditions, it takes an acute monophasic or a chronic relapsing-remitting course. We have previously reported that the incidence and severity of acute EAE in mice are reduced by administration of interferon (IFN)-gamma and augmented by treatment with neutralizing antibodies against IFN-gamma. Here, we investigated the role of IFN-gamma in chronic relapsing models of EAE (CREAE) in SJL/J and Biozzi ABH mice. Spontaneous relapses in Biozzi mice as well as induced relapses in SJL/J mice were facilitated by administration of neutralizing monoclonal antibody (mAb) against IFN-gamma in the disease-free interval. The enhancing effect of anti-IFN-gamma mAb given before and during the primary attack did not carry over to the relapses. However, early administration of IFN-gamma in Biozzi mice, which developed spontaneous relapses in a high proportion, provided partial protection not only against the first attack, but also against subsequent relapses. Administration of exogenous IFN-gamma during the remission phase provided some protection against subsequent relapses. These results indicate that in both types of relapses, IFN-gamma is produced and does provide a certain degree of protection against disease progression.

Characteristics of initial and reinduced experimental autoimmune encephalomyelitis.

The factors which influence expression of autoimmune disease in the central nervous system are still poorly understood. We determined the characteristics of experimental autoimmune encephalomyelitis (EAE) in twelve different inbred strains of mice using either mouse spinal cord homogenate or synthetic peptides as the encephalitogen. We also determined whether these strains were susceptible to reinduction of EAE at six weeks after the initial injection. The incidence, time of onset, severity, duration, and number of spontaneous relapses varied widely among the different strains. Duration of initial EAE correlated significantly with incidence of spontaneous relapses, and was greatest in C57L mice and in mice with a C57BL/10 background. Most strains of mice recovered from initial EAE, but recovery was unusual in A.SW and PERA mice. Incidence of reinduced EAE differed from incidence of initial EAE in some strains and did not correlate with incidence of spontaneous relapse. We conclude that the same factors control disease duration and incidence of spontaneous relapse, and that these factors are independent of the factors which control initial incidence. The factors controlling incidence of reinduced EAE are distinct from those controlling spontaneous relapse, and may also differ from those controlling initial incidence. Further investigation of the mechanisms effecting recovery from EAE and the genetic background underlying those mechanisms may help us understand human diseases such as multiple sclerosis.

Active and passively induced experimental autoimmune encephalomyelitis in common marmosets: a new model for multiple sclerosis.

A chronic relapsing-remitting form of experimental autoimmune encephalomyelitis was induced in the common marmoset Callithrix jacchus following a single immunization with human white matter. Individual animals in this species are born as natural bone marrow chimeras, allowing transfer of functional T-cell populations between genetically distinct siblings. The acute disease was characterized clinically by mild neurological signs. Pathologically, the disease was characterized by perivascular mononuclear cell infiltrates, large foci of primary demyelination, and reactive astrogliosis. No animal displayed hemorrhagic-necrotic lesions or polymorphonuclear cell infiltrates characteristic of other acute forms of primate experimental autoimmune encephalomyelitis. A late spontaneous relapse occurred in each of 2 animals followed for 3 to 12 months subsequent to recovery from the acute attack. In these animals, chronic lesions consisted of mononuclear cell infiltrates within large sharply defined areas of demyelination and astrogliosis, and resembled active plaques of chronic multiple sclerosis. Proliferative responses to myelin basic protein but not to myelin proteolipid protein were present in peripheral blood lymphocytes of immunized animals. Furthermore, myelin basic protein-reactive T-cell lines derived from immunized donors induced clinical signs of experimental autoimmune encephalomyelitis when adoptively transferred into a sibling, indicating that myelin basic protein-reactive T cells can induce disease in this species. Because of its clinical and pathological similarity to human multiple sclerosis and the ability to adoptively transfer experimental autoimmune encephalomyelitis, this model system should prove useful in the analysis of the immunological mechanisms responsible for autoimmune demyelination in outbred primates.

Lymphoma with Recurrent Cycles of Spontaneous Remission and Relapse — Possible Role of Apoptosis

We describe a patient with a unique mantle-cell lymphoma, with cycles of acute illness alternating with spontaneous remissions. During the acute phase the patient had fever, generalized lymphadenopathy, hepatosplenomegaly, increased liver-enzyme concentrations, leukocytosis, and thrombocytopenia. These bouts remitted after two to three weeks without treatment. Fifteen such cycles were documented over a period of 50 months. During the acute phase blast-like B lymphocytes in the blood expressed surface IgM, IgD, and CD5, whereas during clinical remission a small population of IgM and CD5+ lymphocytes persisted. Two B-cell clones with differently rearranged heavy-chain genes consistently appeared in the blood during the . . .

Oral 4-aminosalicylic acid versus 5-aminosalicylic acid slow release tablets. Double blind, controlled pilot study in the maintenance treatment of Crohn's ileocolitis.

4-Aminosalicylic acid (4-ASA) has been suggested as an effective treatment for both active and quiescent ulcerative colitis. 5-Aminosalicylic acid (5-ASA) is well accepted for the maintenance treatment of inactive ulcerative colitis. Moreover, recent studies suggest that 5-ASA may also be effective in maintaining remission in Crohn's colitis. As treatment with 4-ASA may result in less side effects, the efficacy of a one year's maintenance treatment with oral 4-ASA (1.5 g/d, slow release tablets, n = 19) and oral 5-ASA (1.5 g/d, slow release tablets, n = 21) was compared in a double blind, randomised trial in patients with quiescent Crohn's ileocolitis. Patients with ileocolonic or colonic involvement were enrolled if in stable remission for more than two months but less than one year. Baseline demography and clinical severity were similar in both groups. Total colonoscopy and ileoscopy were performed at enrollment and at the end of the study. After one year seven of 19 patients receiving 4-ASA (36%) and 8 of 21 receiving 5-ASA (38%) had developed a clinical relapse, as defined by a rise in the Crohn's disease activity index (CDAI) of more than 100 points to values higher than 150. The relapse rates between the 4-ASA and the 5-ASA groups were not statistically different although no comparison with the spontaneous relapse rate in a placebo group could be made. Clinical relapse was accompanied by a statistically significant rise in serum concentrations of soluble interleukin 2 receptor and by an increased percentage of activated peripheral blood T cells. There were no statistical differences between the 4-ASA and the 5-ASA groups regarding the height of rise in CDAI or of soluble interleukin 2 receptor concentrations during relapse, thus showing a similar severity relapsed disease activity. In conclusion, 4-ASA maybe as effective as 5-ASA in the maintenance treatment of quiescent Crohn's disease and there were no differences in the severity of relapse between both treatment groups.

Collagenous colitis and lymphocytic colitis.

Collagenous and lymphocytic colitis are newly recognized causes of chronic watery diarrhea that typically affect middle-aged patients. Although endoscopic studies are normal, inflammatory changes and (in the case of collagenous colitis) collagen deposition occur histologically in the colonic mucosa. The pathogenesis of these disorders remains a mystery, but the possible causes are intriguing. Patients may experience spontaneous remissions and relapses, but treatment with sulfasalazine or prednisone is usually effective for patients with distressing symptoms.

Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation.

A chronic relapsing form of experimental autoimmune encephalomyelitis (CR-EAE) was induced in SJL/J mice by adoptive transfer of lymph node cells (LNC) sensitized to guinea pig myelin basic protein (GMBP). We examined the efficacy of high dose immunosuppressive regimens (cyclophosphamide [CY] 300 mg/kg or total body irradiation [TBI] 900 cGy) followed by syngeneic bone marrow transplantation (SBMT) in prevention and treatment of already established CR-EAE. Treatment with TBI and SBMT on day 5 after the induction of CR-EAE, just before the onset of clinical signs, completely inhibited the appearance of the paralytic signs. The same treatment, applied 4 d after the clinical onset of the disease, led to a significant regression of the paralytic signs and to a total inhibition of spontaneous relapses during a follow-up period of 2 mo. Challenge of mice with GMBP+CFA 78 d after the passive induction of CR-EAE induced a relapse of the disease 7 d later in almost all of the untreated mice; in contrast, the same challenge given to TBI+SBMT-treated mice caused a delayed relapse (30 d later) in only a minority (3/7) of the challenged mice. In vitro lymphocytic proliferative responses to GMBP and purified protein derivative were significantly lower in TBI/SBMT-treated mice before and after the GMBP challenge, although these mice were fully immunocompetent, as evidenced by their normal lymphocytic proliferation to concanavalin A (ConA) and the FACS analysis of their lymphocytic subpopulations. A similar beneficial therapeutic effect was observed in mice treated with CY followed by SBMT, after the onset of CR-EAE. Our results could support possible clinical applications of similar therapeutic strategies, involving acute immunosuppression followed by stem cell transplantation and retolerization of the reconstituting immune cells in life-threatening neurological and multisystemic autoimmune diseases.

Clinical features of intradural neurinomas in the cauda equina and around the conus medullaris.

In this contribution the clinical features of eleven patients suffering from a neurinoma in the cauda equina and around the conus medullaris are analysed. Because of the relative mobility of the roots and the wide space in the spinal canal, tumours arising in the cauda equina or around the conus medullaris can become larger than any other spinal tumours. Lumbago was the predominant symptom as the initial complaint. Nocturnal pain relieved by walking was noticed in one patient. Two cases showed spontaneous remission and relapse. Multiple tumours were found in 6 cases (55%). Macroscopic cyst formation was found in 5 cases (45%). Among the eleven patients, total removal of the tumour, including the involved root, was performed in ten. The numbers of the resected nerve roots were one root in 6 cases, two roots in 2, and three roots in 2. Only one patient showed postoperative slight weakness of the leg.

Prednisolone‐responsive neuropathy in a cat

ABSTRACTChronic relapsing polyneuropathy was diagnosed in a 15‐month‐old cat with a 12‐week history of limb weakness. The clinical course was punctuated by spontaneous remissions and relapse. There were two striking physical findings, weak withdrawal reflexes and atrophy of the proximal and distal limb muscles. Electrophysiological findings typical of a demyelinating motor neuropathy were present, namely small, dispersed compound muscle action potentials, markedly slow motor conduction and denervation potentials that were more prominent dis‐tally. Muscle biopsies showed changes consistent with denervation and a paucity of myelinated axons in intramuscular nerve bundles. The neuropathy responded rapidly and completely to prednisolone administration, which was slowly tapered over several months.

The use of associated propafenone in patients with amiodarone-resistant ventricular tachycardia

To clarify the risk-benefit ratio involved in association of antiarrhythmic drugs, a combined therapy of amiodarone and propafenone was tested by means of continuous electrocardiographic monitoring, analysis of levels of the drug in the plasma and programmed electrical stimulation in a selected group of 10 patients who had left ventricular dysfunction and spontaneous relapses of sustained ventricular tachycardia despite treatment with amiodarone. Induction of sustained ventricular tachycardia, possible in each case during treatment with amiodarone, was suppressed after addition of propafenone in 2 patients (responders), who had the best ejection fractions of the entire group (> 45%). Worsening of spontaneous tachycardias developed in 4 cases during the combined therapy. These ventricular arrhythmias, although generally at a low rate, sometimes had the potential to degenerate into ventricular fibrillation and disappeared after both discontinuation of propafenone or increase of its dosage (1 patient). Of the six cases undergoing chronic combined treatment, only the responders to premature electrical stimulation were completely protected from recurrences of arrhythmia. Three cases, on the other hand, needed permanent endocardial pacing for symptomatic bradyarrhythmias. The combination of treatment with amiodarone and propafenone, although potentially useful in limiting dosages of and toxicity from amiodarone, is frequently associated with undersirable, and occasionally has severe, side-effects. The best candidates for this pharmacological association seem to be patients without severely depressed left ventricular function who have a greater probability of not presenting the inducibility of ventricular tachycardia after the addition of propafenone to the regimen for treatment.

Long‐term Reproducibility of Response to Noninvasive Programmed Cardiac Stimulation in Spontaneous, Sustained Ventricular Tachycardia Treated with Amiodarone Therapy

A total of 73 noninvasive serial electrophysiological studies were carried out in 12 patients with spontaneous sustained ventricular tachycardia, inducible in spite of chronic treatment with amiodarone, in order to verify the effect of this drug on the long‐term reproducibility of the test. A ventricular tachycardia was induced in 72 of 73 times; in 59% of cases, the clinical form was induced. In 8 of 12 patients, two or more types or morphologies of ventricular tachycardia could be induced. The induction modes (driving rate and number of extrastimuli) changed considerably in different studies. During a follow‐up of 12 ± 6 months, 5 out of 12 patients had spontaneous relapses. We observed no differences between these patients and the others regarding inducibility, types and morphologies of the induced tachycardias, or induction modes. Therefore, when ventricular tachycardia is inducible in spite of chronic amiodarone therapy, it is always inducible during follow‐up, even if a great intrapatient change of type and the morphology of induced tachycardias and induction modes is observed. However, since similar electrophysiological features are present in patients with and without spontaneous recurrence of ventricular tachycardia, serial electrophysiological studies are of little value in predicting the clinical outcome.

Enhancing Effects of Sound on Methamphetamine‐Induced Behavioral Aberrations in the Rat: A Model of Relapse of Schizophrenia‐Like Symptoms

Conditioning of methamphetamine (MAP)-induced behavioral aberrations, hyperactivity (HA), stereotyped (SB) and bizarre behavior (BB) in rats were examined using Pavlovian conditioning methods. A speaker-sound (SS) was used as the conditioning stimulus (CS) and MAP-induced behavior as the unconditioned stimulus (UCS). The rats belonging to the Sound Group were repeatedly administered with MAP or saline paired with SS in an observation room and those in the Soundless Group with MAP only in the housing room. After chronic administration with MAP, conditioned behavioral responses (CBR) such as HA, SB, and BB were observed more intensely in the Sound Group than in the Soundless Group while being subjected to SS. CBR were greatest on the 30th day after the last MAP administration and they did not disappear for 120 days. CBR were considered as analogous to the spontaneous relapse of schizophrenia-like symptoms. Furthermore, as a certain behavior which had been conditioned could easily be observed as CBR with both specific (SS) and nonspecific environmental cues (handling), it is difficult to distinguish the withdrawal behavioral effects of MAP that lacks those of CBR.

The personality pattern of duodenal ulcer patients in relation to spontaneous ulcer healing and relapse

One hundred consecutive out-patients with duodenal ulceration from a hospital and a gastroenterological clinic were tested with the Minnesota Multiphasic Personality Inventory (MMPI). This was carried out in order to investigate whether neuroticism or other personality disorders were characteristics of duodenal ulcer patients, and whether the presence of such possible personality disorders might influence the prognosis of the disease. Neuroticism occurred in 53% of the patients, but only in 5% of controls (P less than 0.0001). Overall, personality disorders were present in 69% of the patients compared with 30% of the controls (P less than 0.0001). Neuroticism was connected with a high frequency of relapse (P less than 0.05) whereas failure of spontaneous ulcer healing had no certain relation to personality disorders. Patients with non-neurotic personality disorders had more frequently suffered stressful life events before entrance to the study (P less than 0.05) and, like the neurotic patients, they had lower ego-strength to cope with such events (P less than 0.05). The results indicate that personality assessments make it possible to distinguish between subgroups of duodenal ulcer patients with different course of the disease.

DUODENAL BULB ACIDITY AND THE NATURAL HISTORY OF DUODENAL ULCERATION

Fasting and post-prandial duodenal bulb pH was recorded in 10 subjects with untreated duodenal ulcers (DU), 10 subjects with healed DU, and 15 healthy volunteers. During fasting, pH was less than 4 for a greater percentage of time in healed than in active DU. Ingestion of a solid test meal accentuated this difference: subjects with active DU and controls both showed less bulb acidification than subjects with healed ulcers. Bulb pH was similar in patients with active ulceration and controls. The finding of neutral bulb pH with active ulceration and low bulb pH with healing may explain the typical cycle of spontaneous healing and relapse in duodenal ulcer disease.