Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

The clinical and radiologic impact of developing neutralizing antibodies (NAbs) to interferon beta (IFNbeta) while on this therapy for multiple sclerosis (MS) is assessed. On the basis of Class II and III evidence, it is concluded that treatment of patients with MS with IFNbeta (Avonex, Betaseron, or Rebif) is associated with the production of NAbs (Level A). NAbs in the serum are probably associated with a reduction in the radiographic and clinical effectiveness of IFNbeta treatment (Level B). In addition, the rate of NAb production is probably less with IFNbeta-1a treatment than with IFNbeta-1b treatment, although the magnitude and persistence of this difference is difficult to determine (Level B). Finally, it is probable that there is a difference in seroprevalence due to variability in the dose of IFNbeta injected or in the frequency or route of its administration (Level B). Regardless of the explanation, it seems clear that IFNbeta-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFNbeta preparations (either IFNbeta-1a or IFNbeta-1b) given multiple times per week subcutaneously (Level A). However, because NAbs disappear in some patients even with continued IFNbeta treatment (especially in patients with low titers), the persistence of this difference is difficult to determine (Level B). Although the finding of sustained high-titer NAbs (>100 to 200 NU/mL) is associated with a reduction in the therapeutic effects of IFNbeta on radiographic and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, or which cutoff titer to apply (Level U).

Baló's concentric sclerosis: surviving normal myelin in a patient with a relapsing-remitting dinical course.

Baló's concentric sclerosis is a demyelinating disorder in which bands of demyelination alternate with concentric bands of myelin preservation. The pathogenesis of the lesion is unknown. Previous reports using modern histopathologic techniques have shown the bands of myelin preservation to be comprised of remyelinated or partially demyelinated myelin. Here we report a case of Baló's concentric sclerosis in a 24-year-old East Indian patient with a previous history of relapsing-remitting multiple sclerosis (MS). Pathologically, the bands of myelin preservation showed myelin sheaths of normal thickness, with focal areas of demyelination. The findings, taken together with those of previously reported cases, suggest that Baló's concentric sclerosis is a variant of MS, and the concentric lesion may be an intermediary form in evolution of a chronic active MS plaque. The pathogenesis of this concentric lesion may be explained by periodic suppression of demyelination in the rapidly expanding border, allowing remyelination or only transient incomplete demyelination to occur.

HTLV type I/II in British Columbia Amerindians: a seroprevalence study and sequence characterization of an HTLV type IIa isolate.

It has been established that the human T cell lymphotropic viruses type I and II (HTLV-I and HTLV-II) are both present in some indigenous peoples of the Americas. While HTLV-I has been identified in coastal British Columbia Indians (BCIs), HTLV-II has not been previously reported in the BCIs or other Canadian Amerindians. The prevalence of HTLV-I and HTLV-II in these populations has not been extensively studied. In this article, we examine a group of BCIs from Vancouver Island who belong to the Nuu-Chah-Nulth and are known to have an increased incidence of rheumatic disease. In 494 serum samples from this tribe, the levels of prevalence of HTLV-I and HTLV-II were 2.8 and 1.6%, respectively. No association could be made between arthropathy and HTLV-I infection. In addition, we characterized an HTLV-II isolate of a BCI from the coastal mainland of British Columbia and with a history of intravenous drug abuse. This case represents the first molecular characterization of a Canadian Amerindian HTLV-II isolate: a subtype IIa virus with phylogenetic affinity for intravenous drug user isolates and containing an extended form of the Tax protein. These results are consistent either with this strain having been sampled from a polymorphic ancestral pool of HTLV-II that gave rise to the current epidemic spread of this virus by intravenous drug use and sexual transmission, or with its being "back-transmitted" into the BC Amerindian population in association with intravenous drug use.

An apparent case of human T-cell lymphotropic virus type II (HTLV-II)-associated neurological disease: a clinical, molecular, and phylogenetic characterisation.

Several studies have reported an association between HTLV-II and a neurological condition which has come to be called HTLV-II-associated myelopathy and is similar, in some cases, to HTLV-I-associated myelopathy. To further explore the establishment of an etiological link between this virus and neurological disease, we determined the HTLV status of three individuals, one of which presented with symptoms of progressive ataxia. Since the patient with neurological disease and her husband were HTLV-II positive, we had the potential to study one of few cases of an HTLV-II-associated neurological disorder, and the first case in Canada. However, although the individual with the neurological disease was HTLV-II positive, we discovered that her brother, who displays the same clinical symptoms, was not positive for either HTLV-II or HTLV-I. Thus, disease association with HTLV-II became unsupportable. We present here, nevertheless, the first sequence and phylogenetic analysis of an HTLV-II isolate in Canada. This study suggests that cases of HTLV-II and neurological disease must be carefully investigated before any etiological conclusions can be made.

Crusted scabies in association with human T-cell lymphotropic virus 1.

BACKGROUND: Human T-cell lymphotropic virus I (HTLV- 1) infection can lead to myelopathy/tropical spastic paresis and adult T-cell leukemia/lymphoma (ATLL). Infection with HTLV-1 has also been associated with clinically significant immunosuppression. Crusted scabies, also known as Norwegian scabies, is an uncommon presentation of scabies that may occur in conjunction with immunosuppression. Although crusted scabies has been reported in association with HTLV-1 infection, to our knowledge it has never been described in association with HTLV-1 associated myelopathy. OBJECTIVE: The aim is to describe a case of HTLV-1 associated myelopathy and concomitant crusted scabies. METHODS: This article includes a case report and a literature review. CONCLUSIONS: Crusted scabies is reported in association with HTLV-1 infection with or without concomitant ATLL. Crusted scabies should be considered in the differential diagnosis of a generalized cutaneous eruption in an HTLV-1 positive patient. Patients with crusted scabies from an HTLV-1 endemic population should be rested for a possible HTLV-1 infection. These patients may be at increased risk of progressing to ATLL.

Thymus in myasthenia gravis: comparison of CT and pathologic findings and clinical outcome after thymectomy.

PURPOSE: To correlate computed tomographic (CT) appearance of the thymus with results from histologic examination of thymic tissue and clinical outcome in patients with generalized myasthenia gravis who underwent thymectomy. MATERIALS AND METHODS: Forty-five patients with myasthenia gravis underwent CT of the thorax and thymectomy. Findings at clinical follow-up were available in all patients. RESULTS: Twenty-six patients had normal CT findings, seven had a diffusely enlarged thymus, and 12 had a focal mass. The results of histologic examination showed that 16 of 26 patients with normal CT findings had normal thymic tissue and 10 had lymphoid follicular hyperplasia; all seven patients with an enlarged thymus had lymphoid hyperplasia. Five of 12 patients with a focal mass at CT had lymphoid hyperplasia, and seven had thymoma. Clinical improvement following thymectomy was observed in 27 (93%) of 29 patients with lymphoid hyperplasia or thymoma and 11 (69%) of 16 patients with normal histologic examination (P < .03, chi(2) test). CONCLUSION: The presence of an enlarged thymus or a focal mass in patients with myasthenia gravis indicates lymphoid hyperplasia or thymoma. However, CT is of limited value in distinguishing lymphoid follicular hyperplasia from a normal thymus or thymoma and in predicting clinical outcome.

HTLV-I associated adult T cell leukemia/lymphoma: report of two cases from an Amerindian population in coastal northwest British Columbia.

Epidemiological studies of HTLV-I infection have demonstrated the presence of this virus in certain Amerindian populations in Central and South America. We have recently reported the first evidence of endemic HTLV-I infection in North American Amerindians from the coastal regions of British Columbia, Canada. While the predominant HTLV-I-associated disease observed in British Columbia Amerindians is the HTLV-I associated neurological disease (HTLV-I-associated myelopathy/tropical spastic paraparesis), we report here the first two cases of HTLV-I-associated adult T cell leukemia/lymphoma (ATL). Clinical and PCR evidence to support the diagnosis of HTLV-I-associated ATL in these two Amerindians is presented. Both cases of ATL were found in the same tribe although neither patient was directly related to each other. While reports of HTLV-I-associated ATL have been reported in Circumartic native peoples, reports of ATL in North American single ancestry Amerindians have not been previously made to our knowledge.

Pregnancy and multiple sclerosis. A prospective study.

OBJECTIVE: To conduct a prospective assessment of pregnancy on women with multiple sclerosis (MS), focusing on pregnancy outcome and relapses during gestation and up to 6 months after delivery. DESIGN: Expected numbers of relapses were based on data for (1) "self-controls": the mothers ("cases") themselves prior to becoming pregnant and (2) "matched controls": female patients with MS "matched" to the mothers for year of birth, age of MS onset, MS type, MS course, and initial MS symptom(s). SETTING: Cases and controls were identified from an ambulatory care MS clinic that serves the province of British Columbia, Canada. PATIENTS OR OTHER PARTICIPANTS: Women with a diagnosis of MS who attended the MS clinic during 1982 through 1986 and subsequently became pregnant during 1982 through 1989 inclusive were included in this study as cases. Matched controls were women with MS who attended the MS clinic during the same period but did not become pregnant. RESULTS: No significant increase in relapse rate was found for cases during the first two trimesters of gestation. The number of relapses was significantly less than expected during the third trimester compared with matched controls (chi 2 = 6.80, df = 1, P < .02), but not compared with self-controls (chi 2 = 3.39, df = 1, P > .05). The observed number of relapses for the 6 months after delivery did not differ significantly from expected (self-controls: chi 2 = 2.84, df = 2, P > .05; matched controls: chi 2 = 1.76, df = 2, P > .05). CONCLUSION: These data suggest that neither pregnancy nor the 6-month period after delivery is a risk factor for relapse in MS. They are consistent with previous observations that, in the long term, pregnancy does not influence subsequent MS disability.

HTLV-I infection associated with disease in aboriginal Indians from British Columbia: a serological and PCR analysis.

BACKGROUND: Recent epidemiology studies have demonstrated the presence of HTLV-I and its close relative, HTLV-II in several aboriginal populations in North, Central and South America but not in Canadian Indian populations. HTLV-II appears to be more prevalent than HTLV-I in aboriginal populations of the Americas. Recently several clinical cases of HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a case of adult T-cell leukemia (ATL) have been identified in British Columbian Indians. This data suggests that a new endemic area of HTLV-I infection may be present within British Columbian Indian population. However, it has recently been shown that HTLV-II may also be associated with a neurological disease similar to HAM/TSP. OBJECTIVES: The purpose of the work reported here was to demonstrate whether HTLV-I, HTLV-II or both were responsible for the diseases seen in the British Columbian Indians. STUDY DESIGN: In this study serological and gene amplification techniques were used to determine whether HTLV-I or HTLV-II was present in four families and three unrelated individuals all from different bands of aboriginal Native Indians in British Columbia. In each family, one member had an HTLV-associated disease, three cases of HAM/TSP and one case of ATL. Of the three individual aboriginal natives unrelated to the four families, two had HAM/TSP while the third was asymptomatic for HTLV-associated diseases. RESULTS: This study demonstrated the presence of HTLV-I in the aboriginal Indians with disease and in some of their family members. HTLV-II was not detected in any of the British Columbian Indians tested in this study. CONCLUSIONS: These British Columbian Indians represent the first Canadian aboriginal Indians with HTLV-I infection and associated diseases. Furthermore, the British Columbian Indian population may represent a previously unrecognized endemic population of HTLV-I infection.

Magnetic resonance imaging in the evaluation of clinical trials in multiple sclerosis.

Magnetic resonance imaging (MRI) provides an objective method of evaluating multiple sclerosis clinical trials and is at least five times more sensitive to disease activity. In a recent clinical trial, MRI was also approximately twice as sensitive as clinical measurements to the treatment effect of a drug.

HTLV-I associated myelopathy: an endemic disease of Canadian aboriginals of the Northwest Pacific coast?

Human T-cell lymphotropic virus type 1 (HTLV-I) is responsible for HTLV-I associated myelopathy or tropical spastic paraparesis (HAM/TSP) and for adult T-cell leukemia/lymphoma (ATLL). Both diseases have been well described in individuals living in Japan, West Indies, Seychelles Islands and Columbia where infection with HTLV-I is considered endemic and in persons whose descendants originated from these endemic areas. We report here 4 cases of HAM/TSP in 4 natives from 4 different tribal groups from British Columbia (B.C.). These are the first case reports of HTLV-I linked diseases found among North American Aboriginals. Possible routes of infection for HTLV-I infection included sexual transmission, breast feeding, blood transfusions and IV drug use. The seroprevalence of HTLV-I in North American Native population is unknown and we suggest that it is endemic in this ethnic group.

Seronegative generalized myasthenia gravis: low frequency of thymic pathology.

We have reviewed thymus histology, preoperative serum acetylcholine receptor antibody status, and clinical features of all 50 patients who underwent thymectomy for generalized myasthenia gravis in the University of British Columbia-affiliated hospitals over the last 8 years. Seven patients had thymoma, 25 had hyperplasia, and 18 had a normal thymus. The seven thymoma patients all had severe limb involvement and all had circulating antibodies against the acetylcholine receptor. Patients without circulating antibodies had only minimal limb involvement and half of them had a normal thymus. Only two of the 32 (6%) patients with abnormal thymus were antibody-negative; this contrasts with six of the 18 patients (33%) with normal thymus. We conclude that seronegative patients with generalized myasthenia gravis constitute a distinct subgroup which may not be immunologically homogeneous and could be subgrouped with normal or abnormal thymic histology.

Systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. II. Immunologic evaluation.

Immunologic functions are studied in conjunction with a placebo-controlled trial of lymphoblastoid interferon (IFN) in patients with chronic progressive (CP) multiple sclerosis. Prior to treatment, CD4+ cells are significantly increased and CD8+ cells decreased in the blood of MS patients. Both CD5+ and CD4+ cells increase significantly with IFN therapy early during the treatment phase of the trial, while the number of CD8+ cells decreases steadily, becoming significant at 6 months. CNS IgG synthesis rates increase with IFN treatment and maximize at 3 months. Serum antiviral activity also increases with IFN treatment. In the IFN-treated group, a trend toward improvement, determined clinically and by MRI, likely reflects the influence of a subpopulation of 10 patients. This subpopulation is now further characterized by an early increase in CNS IgG synthesis and numbers of CD5+ cells in the blood. Although these immune functions may identify a number of CP MS patients who might benefit from IFN, it is unlikely that these mechanisms actually mediate the potentially beneficial effects of this cytokine.

Magnetic resonance imaging of the head in the diagnosis of multiple sclerosis: a prospective 2-year follow-up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT.

We previously compared the diagnostic capabilities of MRI of the head with CT, evoked potentials, and CSF oligoclonal banding (OB) analysis in a prospective evaluation of 200 patients with suspected multiple sclerosis (MS). To examine the ability of MRI and other paraclinical tests to predict the diagnosis of clinically definite MS (CDMS), we did a systematic clinical follow-up of 200 patients who were previously reported. In that study, 85 of 200 could be diagnosed as having laboratory-supported definite MS (LSDMS). In follow-up, we excluded one patient diagnosed as LSDMS who in retrospect was considered to have had CDMS at entry and 15 patients who were eventually diagnosed as having other diseases. After a mean follow-up of 2.1 years, 55 of the remaining 184 patients (30%) had developed CDMS. Thirty-eight of 84 patients with an original diagnosis of LSDMS (45%) and 17 of the remaining 100 patients with suspected MS (17%) had become CDMS. Forty-six of the 55 patients who developed CDMS in follow-up (84%) had an initial MRI that was strongly suggestive of MS. Fifty-two of those 55 CDMS patients (95%) had at least one MS-like abnormality on MRI when originally studied. In contrast, 38 of 55 (69%) had CSF OB, 38 of 55 (69%) had an abnormal VEP, 35 of 55 (64%) had an abnormal SEP, and 21 of 55 (38%) had an abnormal CT when first studied. MRI was the most sensitive single paraclinical test for predicting CDMS. CDMS developed during follow-up in 46 of the 94 patients (49%) whose initial MRI was strongly suggestive of MS.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. I. Clinical and MRI evaluation.

A randomized, double-blind, placebo-controlled, noncrossover trial determined the efficacy of lymphoblastoid interferon (IFN) in chronic progressive multiple sclerosis (CP MS). Fifty patients received 5 X 10(6) IU IFN subcutaneously daily for 6 months while 50 received placebo. After 2 years, there were no significant differences between the 2 groups based on clinical evaluations and quantitative MRI analysis of the brain, although a trend was observed in the IFN group. Clinically, the IFN group was worse at 1 and 3 months and improved at 6 to 18 months, when compared with the placebo group. Results of MRI evaluations of the brain at 6 months support this trend. This trend likely resulted from a subpopulation of 10 IFN-treated patients, characterized by a higher women:men ratio and a lower EDSS score at entry into the trial. We cannot recommend lymphoblastoid IFN as treatment for CP MS at this time.

Chronic progressive multiple sclerosis: serial magnetic resonance brain imaging over six months.

Eight patients in the chronic progressive stage of multiple sclerosis were studied prospectively with magnetic resonance imaging of the head and neurological examination every 2 weeks for 6 months. There were no clinical relapses and disability ratings did not change between the start and completion of the study. Despite the clinical inactivity, a total of 86 active events (new, reappearing, or enlarging lesions) were identified by magnetic resonance imaging over the 6 months, with 50 (51%) of 98 follow-up scans showing evidence of one or more active lesions. New and changing lesions were indistinguishable in appearance, distribution, and temporal pattern from those previously seen in patients who had relapsing and remitting multiple sclerosis. However, as noted previously, the patients in the chronic progressive stage had many more confluent lesions than did the group in relapse. These results strongly suggest that the frequently observed clinical evolution of multiple sclerosis into a chronic progressive course is not accompanied by a fundamental change in the disease process. In fact the chronic progressive stage seems associated with more active changes demonstrated by scans than does relapsing and remitting multiple sclerosis. This study also confirms our previous experience that serial magnetic resonance imaging is much more sensitive than clinical examination in detecting disease activity in multiple sclerosis.

The lesion of multiple sclerosis: imaging of acute and chronic stages.

Increased blood-brain barrier (BBB) permeability, important in the pathogenesis of MS, may be demonstrated as lesion enhancement with high-volume delayed CT (HVDCT). We studied 40 MS patients with history, neurologic examination, HVDCT, and MRI. In addition, 7 of the patients with enhancing CT lesions were followed with serial MRI for up to 3 years and 7 months. In 3 of these patients we repeated the HVDCT. Patients with enhancing lesions on CT were younger, had shorter duration of disease, and had more frequent clinical relapses than did patients without enhancement. More than half (56%) of the enhancing CT lesions were in the deep white matter, 23% were periventricular, and 21% were at the gray/white matter junction. Half the CT enhancing lesions, when followed by serial MRI, showed significant changes in lesion size. Although the majority (59%) of these lesions faded, some remained actively changing (25%) or became confluent with adjacent lesions (16%). In 48% of the MRI examinations that showed activity, some lesions were increasing in size while others were simultaneously decreasing in size. This study confirms that MS is a dynamic process in which recurrent episodes of BBB disruption and inflammation play a major role. Recurrent episodes of inflammation may well be a prelude to the largely irreversible changes of demyelination and gliosis.