A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis.

The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNß)-1a (Avonex(®) reference arm). RRMS patients age 18-55 years with Expanded Disability Status Scale (EDSS) scores of 0-5.5 and documented pre-study relapse (≥ 1 in previous year, 2 in previous 2 years, or 1 in previous 1-2 years and ≥ 1 GdE lesion in the previous year) were randomized (1:1:1) to laquinimod 0.6 mg once-daily, matching oral placebo, or IFNß-1a IM 30 µg once-weekly (rater-blinded design), for 24 months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod (n = 434), placebo (n = 450), and IFNß-1a (n = 447). ARR was not significantly reduced with laquinimod [-18 %, risk ratio (RR) = 0.82, 95 % CI 0.66-1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p < 0.001). Confirmed disability worsening was infrequent (10 % laquinimod, 13 % placebo). The change in confirmed disability worsening with laquinimod measured using EDSS was -31 % [hazard ratio (HR) 0.69, p = 0.063], and using Multiple Sclerosis Functional Composite (MSFC) z-score was -77 % (p = 0.150), vs. placebo. IFNß-1a reduced ARR 26 % (RR = 0.74, 95 % CI 0.60-0.92, p = 0.007), showed no effect on PBVC loss (+11 %, p = 0.14), and changes in disability worsening were -26 and -66 % as measured using the EDSS (HR 0.742, p = 0.13) and MSFC (p = 0.208), respectively. Adverse events occurred in 75, 82, and 70 % of laquinimod, IFNß-1a, and placebo patients, respectively. Once-daily oral laquinimod 0.6 mg resulted in statistically nonsignificant reductions in ARR and disability progression, but significant reductions in brain atrophy vs. placebo. Laquinimod was well-tolerated.

Glatiramer acetate-specific antibody titres in patients with relapsing / remitting multiple sclerosis and in experimental autoimmune encephalomyelitis.

Glatiramer acetate (GA) is an immunomodulatory drug approved for the treatment of clinically isolated syndrome (CIS) and relapsing/remitting multiple sclerosis (RRMS). As an antigen-based therapy, GA induces GA-specific antibodies in treated patients and animals. GA-specific antibodies do not neutralize therapeutic effects on relapses and disability. Rather, it has been suggested that GA-specific antibodies may be associated with improved clinical outcomes. We evaluated antibody responses in eight patients with RRMS treated with GA for 15 months and antibody responses in GA-treated C57BL/6 mice before and after induction of experimental autoimmune encephalomyelitis (EAE). There were no significant differences from pretreatment levels of total IgE or GA-specific IgE in patients with RRMS. Total IgG1, IgG3 and GA-specific IgG4 were significantly increased at 15 months of GA treatment. Antibody type and titre were not associated with clinical outcomes, i.e. expanded disability status scale (EDSS) score, disease burden on magnetic resonance images (MRI) or clinical relapses. In contrast, mice with EAE showed a marked increase in GA-specific IgE and GA-specific IgG1 antibody responses. GA-treated mice demonstrated improved clinical symptoms and lower mortality than untreated controls. Our results suggest that antibody responses to GA are heterogeneous among patients with RRMS, with no apparent association between antibody response and clinical outcomes. Clinical improvements in EAE-induced GA-treated mice suggest that GA-specific IgE and IgG1 may contribute to GA treatment effects in EAE.

A new EAE model of brain demyelination induced by intracerebroventricular pertussis toxin.

Experimental autoimmune encephalomyelitis (EAE) is a primary animal model of multiple sclerosis (MS). MS predominantly presents with evidence of lesions in the subcortical periventricular white matter regions of the brain. Research into the pathogenesis of the demyelinating lesions in the brain has been hampered by the fact that conventional models of EAE present with progressive ascending paralysis which recapitulates mainly the spinal cord lesions of multiple sclerosis. There is little evidence of brain involvement. Systemic administration of pertussis toxin (PTx) has been shown to induce the proinflammatory cascade of TGF-beta, IL-6, and Th17 in the central nervous system, which recently has been identified as essential in the development of EAE. To determine whether intracerebroventricular (icv) administration of PTx would result in subcortical periventricular demyelinating lesions in the brain, we examined the effect in a MOG induced EAE model. We found that icv PTx induced subcortical periventricular brain lesions that resemble the pathologic demyelinating lesions of MS. Moreover, icv PTx induced Th17 infiltration and increased expression of cytokines IL-6 and TGF-beta. We thus generated a highly reproducible model with remarkable histological similarities to the predominant demyelinating brain lesions seen in MS.

APOE epsilon 4 allele is associated with cognitive impairment in patients with multiple sclerosis.

BACKGROUND: The role of apolipoprotein E (APOE) polymorphism has been well recognized in other cognitive neurodegenerative disorders, such as Alzheimer disease. Its role in multiple sclerosis (MS) is less clear, though studies indicate that 40% to 60% of patients with MS have evidence of cognitive impairment. OBJECTIVE: To determine whether there is an association between APOE epsilon 4 and cognitive deficits in MS. METHODS: We performed a standardized battery of neuropsychological tests investigating the four cognitive domains commonly impaired in MS and assessed the association of the presence of APOE epsilon 4 with cognition in MS. RESULTS: A strong association was found between the presence of APOE epsilon 4 and cognitive deficits in patients with MS, particularly in the domains of learning and memory. This association was strongest in our youngest cohort (age 31 to 40) of patients with MS. CONCLUSIONS: APOE epsilon 4 is significantly associated with cognitive impairment in patients with multiple sclerosis (MS). However, the modest effects do not justify APOE genotyping of patients with MS in clinical practice.

IL-21 modulates CD4+ CD25+ regulatory T-cell homeostasis in experimental autoimmune encephalomyelitis.

The homeostasis of CD4+ CD25+ regulatory T cells (Tregs) depends on the cytokine interleukin (IL)-2. As IL-21 shares sequence homology with IL-2 and the IL-21 receptors contain a gamma-chain common to IL-2, we hypothesized that IL-21 could also affect the homeostasis of Tregs. We tested this hypothesis in experimental autoimmune encephalomyelitis (EAE), an animal model of relapsing-remitting human multiple sclerosis. We show that blockade of IL-21 in SJL/J mice before and after the induction of EAE enhances the influx of inflammatory cells into the central nervous system (CNS). The blockade of IL-21 leads to proliferation of proteolipid peptide (PLP(139-151))-autoreactive CD4+ T cells, which are capable to cause severe EAE in adoptively transferred recipient mice. Conversely, Tregs from mice where IL-21 was blocked, lose their capacity to prevent EAE induced PLP(139-151)-reactive T cells. Notably, direct effects of IL-21 on Tregs are confirmed by studies of blockade of IL-21 in mice expressing a green fluorescent protein 'knocked' into a Foxp3 allele, in which a reduction of the number of Tregs and a downregulation of their frequency and expression of Foxp3 are observed. These data suggest a role of the IL-21/IL-21R axis in the homeostasis of Tregs in CNS autoimmunity.

CD4(+)CD25(+) regulatory T cells contribute to the therapeutic effects of glatiramer acetate in experimental autoimmune encephalomyelitis.

CD4(+)CD25(+) regulatory T cells (Tregs) are potent immunosuppressors that are pivotal in the maintenance of self-tolerance. The involvement of Tregs in therapies for immune-mediated diseases has been proposed, but direct supporting evidence is still lacking. While investigating mechanisms underlying the clinical benefits of glatiramer acetate (GA) in an animal model of multiple sclerosis (MS), i.e., experimental autoimmune encephalomyelitis (EAE), we recently demonstrated that GA can protect mice deficient in the Th(2) cytokines IL-4, IL-10 and IL-4/IL-10 from acquiring EAE, suggesting that mechanisms other than Th(2) cells may be responsible for the therapeutic effects of GA. Here we demonstrate that GA treatment boosts the expression of Foxp3 on Tregs during EAE. Furthermore, adoptive transfer of purified Tregs from GA-treated EAE mice is more effective in preventing EAE development than Tregs from untreated EAE controls. Thus, our current data provide evidence that Tregs may be the major contributor to GA's therapeutic action in EAE and, possibly, MS. Further mechanistic studies to reveal the molecular events linking GA with Tregs may optimize GA treatment and lead to the development of new, even more effective therapies that utilize this mechanism of action.

An open-label safety and drug interaction study of natalizumab (Antegren) in combination with interferon-beta (Avonex) in patients with multiple sclerosis.

In this open-label drug-interaction trial, we studied 38 patients with relapsing-remitting multiple sclerosis (MS) who received 3.0 or 6.0 mg/kg of natalizumab as a single intravenous (i.v.) infusion during stable treatment with intramuscular (i.m.) interferon beta-1a 30 microg (IFNbeta-1a; Avonex). To assess the pharmacokinetic (PK) interaction of natalizumab and IFNbeta-1a, serum concentration-time data for both agents were collected and analysed. Biologic response markers of IFNbeta-1a activity, beta2-microglobulin and neopterin, were also assessed to determine effects of natalizumab on IFNbeta-1a pharmacodynamics (PD). Further, safety and immunogenicity were evaluated. The combination of drug therapies was well tolerated. Although natalizumab serum concentrations (and corresponding PK exposure measures) appeared to be somewhat elevated in the presence of IFNbeta-1a, when compared to the same dose (6.0 mg/kg) administered alone in a concurrent comparator study, the differences were generally small and unlikely to be clinically relevant. In general, natalizumab had no apparent clinically relevant effects on the PK or PD properties of IFNbeta-1a. The presence of antibodies to IFNbeta-1a and natalizumab was relatively low. Overall, the study provided safety, immunogenicity, PK and PD data to support a combination strategy for the use of natalizumab and IFNbeta-1a in the treatment of patients with relapsing-remitting MS. A large clinical study is currently in progress to evaluate the efficacy and long-term safety of this combination drug therapy.

Prevalence and treatment of spasticity reported by multiple sclerosis patients.

The objective of this study was to characterize the population of multiple sclerosis (MS) patients suffering from spasticity and to evaluate treatment patterns, including intrathecal baclofen (ITB) delivery, related to patient quality of life (QOL). We conducted a cross-sectional, two-level study using data from the Patient Registry of the North American Research Committee on MS (NARCOMS). In addition, we surveyed a subgroup of 198 preselected patients who are using ITB (ITBG) and a random sample of 315 oral drug users (ORALG). Among the registrants, 16% reported no spasticity, 31% minimal, 19% mild, 17% moderate (frequently affects activities), 13% severe (daily forced to modify activities) and 4% total (prevents daily activities). Patients experiencing greater severity included by proportion males, and those older and with longer duration of MS. QOL scores decreased inversely with severity. In the focused survey, ITBG reported lower levels of spasticity than ORALG, less stiffness in the legs, less pain and fewer spasms at any time. They scored significantly lower in the SF-36 physical component, yet reported less fatigue on the MFIS scale. Prevalence data reveal that one third of MS patients modify or eliminate daily activities as a result of spasticity. Treatment of spasticity can significantly impact QOL parameters by reducing spasms, pain and fatigue.

Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects.

BACKGROUND: Relapses in multiple sclerosis (MS) can cause significant neurologic disability. Natalizumab (Antegren) is a humanized anti-alpha4-integrin antibody that inhibits the trafficking of leukocytes across endothelium by blocking binding of alpha4beta1-integrin to vascular cell adhesion molecule-1. OBJECTIVE: To assess the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses. METHODS: In this randomized, double-blind, multicenter trial, the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses were assessed. MS patients (n = 180) in acute relapse were randomly assigned to receive a single dose of natalizumab 1 or 3 mg/kg or placebo and were followed for 14 weeks. RESULTS: There was no difference in Expanded Disability Status Scale (EDSS) score change over time between treatment and placebo groups. In all three groups, approximately half of patients showed EDSS improvement after 2 weeks, rising to 67% by 8 weeks. EDSS improved by a mean value of 0.8 point at week 1, 1.2 points at week 4, and 1.6 points at week 8 in the natalizumab group compared with EDSS improvement of 1.0 point at week 1, 1.6 points at week 4, and 1.6 points at week 8 in the placebo group. A significant decrease in Gd-enhancing lesion volume was seen in both active treatment groups at weeks 1 and 3 compared with placebo. CONCLUSIONS: A single dose of IV natalizumab did not hasten clinical recovery after relapse, although a significant decrease in Gd-enhancing lesion volume was observed at 1 and 3 weeks after treatment. These MRI findings are consistent with prior studies of natalizumab and support its further investigation as an agent for the treatment of MS.

Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord.

Schwann cells derived from human sural nerve may provide a valuable source of tissue for a cell-based therapy in multiple sclerosis. However, it is essential to show that transplanted human Schwann cells can remyelinate axons in adult CNS and improve axonal conduction. Sections of sural nerve were removed from amputated legs of patients with vascular disease or diabetes, and Schwann cells were isolated and cryopreserved. Suspensions of reconstituted cells were transplanted into the X-irradiation/ethidium bromide lesioned dorsal columns of immunosuppressed Wistar rat. After 3-5 weeks of extensive remyelination, a typical Schwann cell pattern was observed in the lesion zone. Many cells in the lesion were immunopositive for an anti-human nuclei monoclonal antibody. The dorsal columns were removed and maintained in an in vitro recording chamber; the conduction properties were studied using field potential and intra-axonal recording techniques. The transplanted dorsal columns displayed improved conduction velocity and frequency-response properties, and action potentials conducted over a greater distance into the lesion, suggesting that conduction block was overcome. These data support the conclusion that transplantation of human Schwann cells results in functional remyelination of a dorsal column lesion.

The dynamic link between the integrity of the immune system and zinc status.

The results of more than three decades of work indicate that zinc deficiency rapidly diminishes antibody- and cell-mediated responses in both humans and animals. The moderate deficiencies in zinc noted in sickle cell anemia, renal disease, chronic gastrointestinal disorders and acrodermatitis enteropathica; subjects with human immunodeficiency virus; children with diarrhea; and elderly persons can greatly alter host defense systems, leading to increases in opportunistic infections and mortality rates. Conversely, short periods of zinc supplementation substantially improve immune defense in individuals with these diseases. Mouse models demonstrate that 30 d of suboptimal intake of zinc can lead to 30-80% losses in defense capacity. Collectively, the data clearly demonstrate that immune integrity is tightly linked to zinc status. Lymphopenia and thymic atrophy, which were the early hallmarks of zinc deficiency, are now known to be due to high losses of precursor T and B cells in the bone marrow. This ultimately leads to lymphopenia or a failure to replenish the lymphocytic system. Glucocorticoid-mediated apoptosis induced by zinc deficiency causes down-regulation of lymphopoiesis. Indeed, zinc itself can modulate death processes in precursor lymphocytes. Finally, there is substantial evidence that zinc supplementation may well reduce the impact of many of the aforementioned diseases by preventing the dismantling of the immune system. The latter represents an important area for research.

A safety and pharmacokinetic study of intravenous natalizumab in patients with MS.

A phase 1, randomized, placebo-controlled, five-level dose escalation safety and tolerability and pharmacokinetic study of a single IV dose of natalizumab was performed. Doses of 0.03 to 3.0 mg/kg natalizumab or placebo were studied in 28 stable relapsing-remitting or secondary-progressive MS. All doses were safe and well tolerated in MS. Serum concentrations of natalizumab are detectable for 3 to 8 weeks after a single 1- or 3-mg/kg IV dose and justify controlled efficacy studies.

General cognitive ability following unilateral and bilateral fetal ventral mesencephalic tissue transplantation for treatment of Parkinson's disease.

OBJECTIVE: To contrast the neuropsychological profiles of Parkinsonian patients, before and after fetal ventral mesencephalic tissue transplantation. DESIGN: Case series of personally examined patients. SETTING: Patients were evaluated by neurologists, neurosurgeons, and neuropsychologists as outpatients at a university hospital. PATIENTS: Fetal mesencephalic tissue was implanted in the right caudate nucleus of three patients and both nuclei of one patient. These patients were evaluated prior to surgery and at 12, 24, and 26 months postoperatively. RESULTS: Factor analysis of the test battery identified four statistically orthogonal test clusters. No statistically significant changes were identified postoperatively for clusters assessing verbal cognitive ability, nonverbal cognitive ability, and information-processing speed. An improvement of verbal memory cluster index was observed 12 months after surgery, and the improvement reached the level of statistical significance at 24 months after surgery. However, the verbal memory of all patients declined between 24 and 36 months after surgery. CONCLUSIONS: Fetal tissue transplantation to one or both caudate nuclei did not permanently arrest cognitive dysfunction. Although there is some evidence of improved cognitive ability after transplantation, it is improbable that normal cognitive function can be restored by this procedure because the impairments of cognitive ability associated with Parkinson's disease do not appear to originate solely from dopamine deficiency.

Coccidioidal antigen reactive CD4+ T-lymphocytes in the cerebrospinal fluid in coccidioides immitis meningitis.

CSF lymphocytes from patients with Coccidioides immitis meningitis exhibited a significant antigen-specific response to in vitro stimulation with C. immitis antigens. In some patients, lesser responses to control antigens (Candida and PPD) were also detected. Antigen-specific responses by CSF lymphocytes were seen early in the course of this disease as well as several years after patients had entered remission. When compared to CSF cells, the response of autologous peripheral blood mononuclear cells was similar but of a much smaller magnitude and at times undetectable. Fluorescence activated cell sorting revealed an increased percentage of CD3+ (T-cells), CD4+ (helper/inducer) and CD3+/HLA-DR+ (activated T-cell) cells in the CSF of C. immitis meningitis patients compared to their blood. Most of the antigen-specific proliferative response resided in the CD4+ lymphocyte subset. CSF T-cell proliferation assays may have a role in the diagnosis of C. immitis meningitis.

Ocular myasthenia: a protean disorder.

Ocular myasthenia is a localized form of myasthenia clinically involving only the extraocular, levator palpebrae superioris, and/or orbicularis oculi muscles. Ocular manifestations can masquerade as a variety of ocular motility disorders, including cranial nerve and gaze palsies. A history of variable and fatiguable muscle weakness suggests this diagnosis, which may be confirmed by the edrophonium (Tensilon) test and acetylcholine receptor antibody titer. Anticholinesterases, corticosteroids and other immunosuppressive agents, and other therapeutic modalities, including thymectomy and plasmapheresis, are used in treatment. As the pathophysiology of myasthenia has been elucidated in recent years, newer treatment strategies have evolved, resulting in a much more favorable prognosis than several decades ago. This review provides historical background, pathophysiology, immuno-genetics, diagnostic testing, and treatment options for ocular myasthenia, as well as a discussion of drug-induced myasthenic syndromes.

Human immunodeficiency virus-associated motor axonal polyradiculoneuropathy.

OBJECTIVE: To report two cases of an axonal motor polyradiculoneuropathy associated with human immunodeficiency virus infection in otherwise asymptomatic subjects. DESIGN: Case series. SETTING: Tertiary care hospital neurology inpatient service. RESULTS: Electrophysiologic testing showed acute denervation with almost normal sensory potentials and no evidence of demyelination. CONCLUSIONS: These cases present an example of an acute axonal polyradiculoneuropathy in persons infected with human immunodeficiency virus without acquired immunodeficiency syndrome.

Idiopathic granulomatous angiitis of the central nervous system. Diagnostic challenges.

OBJECTIVE: Granulomatous angiitis of the central nervous system (CNS) is a rare cause of vasculitis involving the brain and spinal cord and is included in lists of disorders causing strokes. To determine the frequency of strokes (eg, sudden onset of focal symptoms) as a presenting complication and to determine the sensitivity of angiography and other technologies in detecting vasculitis in histologically proved cases of idiopathic granulomatous angiitis of the CNS (IGANS), we reviewed the published literature. DATA SOURCES: A biopsy-proved case of IGANS in a patient presenting without strokes and with a normal angiogram is reported. Additional cases of pathologically proved IGANS where results of angiography or other neuroimaging procedures were available were found by search of MEDLINE and bibliographies of pertinent articles and books. DATA EXTRACTION: We compared our case with 39 reported cases of histologically proved granulomatous angiitis of the CNS not associated with Hodgkin's disease, herpes zoster, sarcoidosis, or other proximate cause. We included only those cases that had been evaluated with angiography or other neuroimaging techniques before death or biopsy. DATA SYNTHESIS: Analysis of these cases shows that strokes as presenting complications are rare in IGANS. Most patients present with a diffuse encephalopathy and, when focal symptoms develop, they tend to develop gradually. Including our case, 56% of 41 angiograms performed in 31 reported patients with histologically proved IGANS were abnormal, but only 27% were diagnostic for vasculitis. CONCLUSIONS: We conclude that stroke is uncommon as a presenting complaint in IGANS and angiography is insensitive as a screening test for these patients.

Neuromuscular responses of patients with multiple sclerosis.

Muscle weakness, studied in 4 patients with multiple sclerosis (MS), was compared with values from normal subjects. Twitch occlusion showed that normal subjects could activate their muscles maximally, but patients rarely achieved greater than 60% activation. In both groups, motoneuron firing rates increased linearly with force. Consistent with the reduced level of activation, MCV firing rates in MS muscles rarely exceeded 17 Hz (compared with approximately 24 Hz for normals). However, for right and left muscles of one patient, mean maximum firing rates were 14.2 +/- 2 Hz and 8.0 +/- 2 Hz, but her muscles, could be activated to levels greater than 92% and 60%, respectively. This patient's ability to achieve higher than expected forces at low firing rates was probably due to her slow muscle contractile speeds, especially 1/2-relaxation time (75 to 115 ms, cf. approximately 60 ms for normals), and high twitch/tetanus ratio (0.4, cf. 0.2).