New acute and chronic black holes in patients with multiple sclerosis randomised to interferon beta-1b or glatiramer acetate.

BACKGROUND: Hypointense lesions on T1 weighted MRI, referred to as black holes (BH), are a marker of demyelination/axonal loss in multiple sclerosis (MS). There is some evidence that glatiramer acetate (GA) may decrease the conversion of new brain lesions to BH. METHODS: Monthly 3-Tesla brain MRI scans were used for up to 2 years to study the development and evolution of new BH in 75 patients with MS randomised to GA or Interferon beta-1b (IFNbeta1b) in the BECOME study. FINDINGS: Of 1224 newly enhancing lesions (NEL) appearing at baseline through 24 months in 61 patients, 767 (62.7%) showed an acute BH (ABH). The majority of ABH were transient and of similar duration by treatment group. Of 571 ABH in which MRI follow-up scans were available for >or=1 year, 103 (18.8%) were still visible >or=12 months after onset and were considered chronic BH (CBH). Only 12.1% of the 849 NEL with MRI follow-up >or=1 year converted to CBH, 9.8% with IFNbeta1b and 15.2% with GA (p = 0.02). The conversion from ABH to CBH was also lower with IFNbeta1b (15.2%) than with GA (21.4%), of borderline significance (p = 0.06). The majority of patients who developed NEL did not develop CBH; however, about a quarter had conversion rates from ABH to CBH greater than 20%. INTERPRETATION: Only a minority of new brain lesions in patients with MS treated with GA or IFNbeta1b convert to CBH.

Keratoconus: matrix metalloproteinase-2 activation and TIMP modulation.

Keratoconus is an ocular condition that causes corneal thinning, cone formation and scarring. In view of a hypothesis that activated MMP-2 may initiate or facilitate disease progression, the MMP-2/TIMP systems of stromal cells derived from normal and keratoconic corneas have been compared. To achieve this, stromal cell cultures were established from normal, clear keratoconic (KCS-1) and scarred keratoconic (KCS-2) corneas. The secreted MMP-2 was assayed using [(3)H]Type IV collagen and analysed by zymography. Optimally maintained and nutrient deprived cells were subsequently incubated with [(3)H]lysine. The secreted radiolabelled macromolecules were separated and quantified. The results obtained indicated that optimally maintained KCS-1 stromal cells produced more MMP-2 than normal stromal cells but not TIMP. Nutrient deprivation induced MMP-2 activation and cell death. Surviving cells upregulated TIMP-1 synthesis and in this respect became similar to the KCS-2 stromal cells that did not excessively generate activated MMP-2 or die as a consequence of nutrient deprivation. From these results, it was concluded that KCS-1 stromal cells over-expressed MMP-2 without increasing TIMP production. This may facilitate MMP-2 activation in vivo and hence advance the keratoconic condition. KCS-2 cultures over-expressed both MMP-2 and TIMP-1. Because TIMP-1 inhibits MMP-2 activity and protects against cell death it may be of significance in initiating repair processes and curtailing keratoconus.

Cladribine in aggressive forms of multiple sclerosis.

Cladribine (2-chlorodeoxyadenosine) is an immunosuppressant drug previously evaluated in multiple sclerosis (MS) with variable results. We report six patients with aggressive relapsing MS who despite a poor response to other therapies had a favourable clinical evolution after cladribine. Four women and two men with a rapid increase in the number and severity of relapses leading to increasing disability [mean Expanded Disability Status Scale (EDSS) 6.42, standard deviation +/- 0.58, mean relapse rate per year in the 2 years prior to study entry 2.67 +/- 0.75] were retrospectively evaluated. Brain magnetic resonance imaging (MRI) performed in five patients showed active disease with gadolinium-enhancing lesions. Cladribine was given at 0.07 mg/kg/day for five consecutive days once monthly with a total of 2- to 4-monthly courses. After 6 months, mean EDSS decreased to 3.75 +/- 1.64 and MRIs showed a decrease or suppression in the number of gadolinium-enhancing lesions. After 1 year from first dose, cladribine dosage was repeated in four patients because of recurrence of relapses with subsequent similar positive clinical results. In the follow-up period (49.33 +/- 39.66 months), the mean relapse rate decreased to 0.71 +/- 0.55 and no unexpected or serious adverse events were observed.

Rheumatoid keratolysis: a series of 40 eyes.

PURPOSE: Rheumatoid keratolysis (RK) is a rare but a serious cause of ocular morbidity in rheumatoid patients. The aim of this study was to analyze the presenting features, the subsequent treatment, and the outcome of patients with RK in the authors' department. METHODS: A retrospective study was undertaken of all patients with a diagnosis of RK at Bristol Eye Hospital between January 1987 and June 2002. RESULTS: Forty eyes of 38 patients were identified in total. The mean age at presentation was 70 years. The mean duration of rheumatoid arthritis at presentation was 15 years. Most (22, 55%) ulcers were peripheral. Three patients (8%) developed RK within a month of cataract surgery. Out of the 19 patients who did not have a further RK, 11 were immunosuppressed. A total of 37 grafts were performed on 26 eyes. Twenty-two grafts (59%) failed. Immunosuppression increased the chance of anatomical success following penetrating keratoplasty. Infection was identified as a cause of graft failure for immunosuppressed patients in the postoperative period. Nine patients had reversible side effects from immunosuppressant treatment. Four eyes (10%) had to be surgically removed and a further 10 (25%) had severe visual loss (visual acuity less than 6/60). Eleven of the 38 patients subsequently died (29% mortality). CONCLUSIONS: Although the visual prognosis is often poor, surgical preservation of the eye can be achieved by penetrating keratoplasty and systemic immunosuppression. With careful observation and regular monitoring, immunosuppressive medication appears to be safely tolerated in this group of patients.

Evidence for multiple sclerosis as an infectious disease.

Evidence for a viral cause of multiple sclerosis (MS) is indirect since no infectious agent has been reproducibly isolated from MS tissues nor has viral genome or antigen been consistently identified. The occurrence of spontaneous human and animal models of demyelination, serologic studies, and epidemiologic data provide persuasive circumstantial evidence for an infectious trigger in this disease. Potential mechanisms for viral induced demyelination include persistent infection of host tissues or immune mediated organ damage either in the presence or absence of the infectious agent. Any proposed viral candidate should cause demyelination in animals or man and the pattern of infection should be consistent with the unique geographic features of MS epidemiology. In addition, serologic studies should support an infection by the agent and/or viral genome should be detected in MS tissues. At this time no virus can be unequivocally linked to MS but cumulative evidence is more supportive of canine distemper virus than other viruses.

Disease markers in acute multiple sclerosis.

Three serum components that are known to become elevated during inflammation and tissue destruction, C-reactive protein, C3 proactivator, and orosomucoid, which are acute phase reactants, and serum lgM were measured in patients with multiple sclerosis (MS) hospitalized with acute exacerbations. Significantly elevated levels of one or more of these serum components were found in 12 of 13 patients with clinically active MS. Serial studies in two patients revealed that clinical improvement was accompanied by a decline in the serum levels of these factors. These findings suggest that measurement of these serum proteins may be of value in assessing progress of disease activity in MS patients.

Steroid therapy in multiple sclerosis. Point of view.

A number of studies have demonstrated that high-dose corticosteroid treatment improves the rate of recovery from acute exacerbations of multiple sclerosis. The beneficial effect is more rapidly and consistently produced by high-dose corticosteroid administration than with adrenocorticotropic hormone. The most rapid improvement in clinical condition and cerebrospinal fluid parameters of patients has been observed with short courses of very high-dose intravenous therapy. This form of treatment would be most advantageous for patients with severe and rapidly progressive exacerbations. Ultimately, the duration of treatment will depend on the patient's response to treatment, tolerance of corticosteroid withdrawal, and the occurrence of significant complications of therapy. However, in our experience, a three- to four-month slowly tapered course of oral therapy is often needed, and is usually well tolerated, with few serious side effects when given once daily in the morning.

Household pets among veterans with multiple sclerosis and age-matched controls. Pilot survey.

A pilot study was carried out among 22 Vietnam-era male US veterans with multiple sclerosis (MS) and 55 age- and sex-matched controls for prior exposure to dogs, cats, and animals with a distemperlike illness. No difference in dog ownership, or sick animals, and subsequent human illness was found in the group with MS or the control group. However, the distribution of dogs by indoor-outdoor status, as reported by patients with MS or controls, showed significant variation by tier of residence. Indoor dogs were more common in northern than southern latitudes, and this may be an important finding in light of the variation in the risk of MS with latitude.

Elevated neopterin levels in Guillain-Barré syndrome. Further evidence of immune activation.

Neopterin is a by-product of guanosine triphosphate metabolism and is produced by macrophages in response to lymphocytic activation. We have studied serum neopterin levels in patients with Guillain-Barré syndrome to obtain further evidence of immune activation in this disease. Serum neopterin levels were significantly elevated in patients with Guillain-Barré syndrome compared with patients with other peripheral neuropathies and multiple sclerosis and with healthy control subjects. Serial analysis demonstrated that as neopterin levels fell, the clinical status of the patients with Guillain-Barré syndrome improved and soluble interleukin 2 receptor levels dropped. Thus, lymphocytic and macrophage activation may play a role in the pathogenesis of Guillain-Barré syndrome.

Multiple sclerosis and viruses: an overview.

The evidence for a viral etiology of MS has been reviewed. The strongest evidence favoring a virus is based primarily on epidemiologic considerations. Less convincing evidence comes from pathologic studies, serology, lymphocyte reactivity to viral antigens, and reports of identification of virus in MS tissues. Animal models of viral demyelination exist, which may provide insight into possible etiologic agents and pathogenetic mechanisms. Considering all the data, it is clear that no agent can be convincingly linked to MS at the present time. If a single virus causes the majority of cases of MS, then a morbilliform virus--canine distemper--is a leading contender, because this agent is consistent with the epidemiologic and serologic findings and is highly neurovirulent for animals ranging from mice to primates. Since no virus fulfills the usual criteria for linking an infectious agent to a disease, other possibilities must be considered. If MS is caused by a single virus, it may be a common virus not presently considered as being associated with MS, or an agent as yet unidentified. It is also conceivable that multiple agents, acting alone or in concert, initiate the MS process, perhaps through a common immune-mediated pathway. In this regard, another human demyelinating disease--the Guillain-Barré syndrome--which may in some instances become a chronic remitting and relapsing disorder, is thought to be initiated by multiple infectious agents but to have an immunologic pathogenesis.

Serum IFN neutralizing antibodies and neopterin levels in a cross-section of MS patients.

OBJECTIVE: To determine levels of serum interferon beta (IFNbeta) neutralizing antibody (NAb) and neopterin-an IFN biologic response marker-in patients with MS treated with Betaseron or Avonex. BACKGROUND: Controversy exists over the relative immunogenicity of IFNbeta-1a and IFNbeta-1b and the reasons for any such difference. To determine the role of patient profile and test methodology in IFNbeta, NAb levels need to be measured blindly and simultaneously in a predefined closely matched MS patient cohort. METHODS: Serum NAb and neopterin levels were measured in closely matched patients on Avonex (n = 98) or Betaseron (n = 64). NAb were determined by Athena Diagnostics and serum neopterin levels by Covance Laboratories using a competitive binding radioimmunoassay. RESULTS: More patients taking Betaseron (22%) than Avonex (7%) had elevated titers of NAb (p = 0.008). Mean serum neopterin levels were lower in patients with high as compared to low NAb titers (p = 0.0002). No difference in mean neopterin levels was found comparing the total Betaseron group to the Avonex group; however, in the subset of patients with low NAb titers, mean neopterin levels were higher in the Betaseron than in the Avonex group (p = 0.027). A random cross-sectional sampling of patients on Avonex showed a decrease in neopterin levels over time between weekly doses. CONCLUSION: NAb are more commonly found with Betaseron than Avonex. More studies are needed to determine the correlation among serum neopterin levels, other biologic response markers, NAb, and disease activity in patients with MS being treated with IFNbeta.

Canine distemper virus-specific antibodies in multiple sclerosis.

Current postulates support the idea that MS is triggered by an infectious agent or agents through an autoimmune reaction directed against brain antigens in genetically susceptible individuals. Evidence for an infectious etiology of MS is indirect. We have proposed that MS may, in some instances, be due to a zoonotic infection and that canine distemper virus, a measles-like virus in dogs, is a likely candidate in the causation of this disorder. The high homology between canine distemper and measles virus proteins has made it extremely difficult to distinguish distemper from measles antibodies serologically. We now provide evidence that humans can be infected with this neurotropic dog virus. Furthermore, a high titer of canine distemper virus antibodies is significantly associated with MS. Identification of the etiologic agent in MS may lead to the elucidation of disease pathogenesis and to disease prevention through appropriate public health and vaccination programs.

Possible beneficial effect of high-dose intravenous steroid therapy in acute demyelinating disease and transverse myelitis.

Intravenous steroid followed by oral prednisone was administered to patients with Guillain-Barré syndrome (five), acute transverse myelitis (three), and multiple sclerosis in acute relapse (seven). Preliminary experience with each of these disorders revealed prompt clinical improvement in some patients. The approach used in this uncontrolled study deserves further investigation.

Rate and types of fractures in corticosteroid-treated multiple sclerosis patients.

In a retrospective study of 103 corticosteroid-treated MS patients, the average rate of fracture events was 3.2% of the patients per year over 7.1 (+/- 5.7 SD) years at risk. Fractures of the ribs, pelvis, hip, or vertebrae occurred in 11 patients and became most common 5 years after starting steroids. Relatively high or low cumulative doses of steroids did not correlate predictably with the occurrence of fractures.

Clinical correlation with serum-soluble interleukin-2 receptor levels in Guillain-Barré syndrome.

In patients with Guillain-Barré syndrome (GBS) soluble interleukin-2 receptor (sIL-2R) levels were elevated compared with those of patients with other neurologic diseases (OND), and of healthy controls. Smaller increases in sIL-2R levels occurred in OND patients compared to healthy subjects. Monitoring of GBS patients clearly demonstrated that decreases in sIL-2R levels correlated with clinical recovery. Thus, T-cell activation may be relevant in the pathogenesis of GBS.

Increased free light chains in the urine from patients with multiple sclerosis.

We quantitated free kappa (kappa) and lambda light (L) chains in coded urine specimens from subjects with clinically definite multiple sclerosis (MS) (N = 56), other neurologic diseases (OND) (N = 30), and age-matched normal controls (N = 28). Urine from MS patients showed statistically significant increases in free L chains compared with the other groups, although there was overlap between MS patients and OND patients. The ratio of kappa/creatinine was significantly greater in the relapsing-remitting MS group than in patients with clinically stable MS, OND, and normal controls. Elevated free L chains were usually independent of urinary albumin and beta 2-microglobulin levels. Serial studies showed that urinary free kappa/creatinine ratios were elevated during periods of clinical worsening in seven of eight MS patients and subsequently decreased during clinical recovery. The measurement of free L chains in urine obtained at intervals from MS patients may be useful as a marker to monitor disease activity.

Declining incidence of multiple sclerosis in the Orkney Islands.

The incidence of MS in the Orkney Islands has been updated from 1941 to September 21, 1983. Since 1965, MS incidence rates have fallen significantly when compared with those for 1941 to 1964. Alterations in age-specific prevalence, mean duration of illness, and mean age of the MS population are consistent with the decline in incidence of MS in recent years. Although the reason for the decreasing incidence is uncertain, it is consistent with the hypothesis that MS may be caused by canine distemper virus.

Quantitative functional measures in MS: what is a reliable change?

As a first step toward understanding which changes should be considered as meaningful, the authors assessed the reliability of quantitative functional tests on 5 consecutive days in 63 patients with MS, determining the range of measurement variability present when patients are clinically stable. Time to walk 25 feet (T25FW) and the 9-hole peg test (9HPT) varied by <20% of individual mean scores on repeated testing. Therefore, a 20% change on these tests can be considered to be the threshold that reliably indicates a true change in function for an individual.

Comparison between multiple sclerosis in India and the United States: a case-control study.

The prevalence of MS in India is low, and it is unclear whether the manifestations of the disease in India are similar to the United States. We carried out a case-control study to compare the disease in the two populations and used clinical, evoked potential, and MRI criteria to assess similarities and differences. Our results indicate that the rate of disease progression and frequency of involvement of the cerebral hemispheres, cerebellum, spinal cord, and brainstem were similar in the two populations. The visual system was more frequently involved in Indian patients. No Indian patient had a family history of MS; this suggests an environmental disease-triggering agent.