Infection-associated encephalopathies: their investigation, diagnosis, and treatment.

Reduced level of consciousness is a common clinical finding in acutely sick patients. In the majority of cases a cause for the encephalopathy is readily identifiable,whilst in a minority the aetiology is more difficult to ascertain. Frequently the onset of encephalopathy is associated with, or follows, infection. The mechanisms through which infection leads to encephalopathy are diverse. They range from direct microbial invasion of the brain or its supporting structures, to remote, infection-triggered mechanisms such as acute disseminated encephalomyelitis. Most common however, is the encephalopathy caused through a remote effect of systemic sepsis-septic encephalopathy. This article discusses the clinical presentation and underlying pathogeneses of the acute encephalopathies associated with infection, aiming to aid both their recognition and treatment.

A double blind, randomised study of sildenafil citrate for erectile dysfunction in men with multiple sclerosis.

OBJECTIVE: Identifying and effectively treating erectile dysfunction (ED) can result in an improvement of the quality of life (QoL) in men with multiple sclerosis (MS). METHODS: This randomised, double blind (DB), placebo controlled, flexible dose study with an open label extension (OLE) assessed efficacy, QoL, and safety of sildenafil citrate in men with MS and ED. Overall, 217 men received sildenafil (25-100 mg; n = 104) or placebo (n = 113) for 12 weeks. Efficacy was assessed by the International Index of Erectile Function (IIEF) questionnaire that includes questions on achieving (Q3) and maintaining (Q4) an erection as well as a global efficacy question (GEQ). QoL was also assessed. RESULTS: After 12 weeks, patients receiving sildenafil had higher mean scores for IIEF Q3 and Q4 compared with those receiving placebo (p<0.0001), and 89% (92/103) reported improved erections compared with 24% (27/112) of patients receiving placebo (p<0.0001). At the end of the OLE phase, 95% of men reported improved erections. Patients receiving placebo during the DB phase showed a nearly fourfold increase in improved erections (97% v 26%). Men receiving sildenafil also showed improvements in five of the eight general QoL questions compared with men receiving placebo (p<0.05). The total mean score for the QoL questionnaire improved by 43% for the sildenafil group versus 13% for the placebo group (p<0.0001). Treatment related AEs were predominantly mild in nature, and no patient discontinued due to an AE. CONCLUSION: Sildenafil treatment for ED in men with MS was effective and well tolerated, and resulted in significant improvements in both general and disease specific QoL variables.

Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections.

BACKGROUND: Polymerase chain reaction (PCR) is used to detect viruses in the cerebrospinal fluid (CSF) of patients with neurological disease. However, data to assist its use or interpretation are limited. OBJECTIVE: We investigated factors possibly influencing viral detection in CSF by PCR, which will also help clinicians interpret positive and negative results. METHODS: CSF from patients with was tested for human herpesviruses types 1-6, JC virus, enteroviruses, and Toxoplasma gondii. The likelihood of central nervous system (CNS) infection was classified as likely, possible, or unlikely. PCR findings in these categories were compared using single variable and logistic regression analysis. RESULTS: Of 787 samples tested, 97 (12%) were PCR positive for one or more viruses. Of episodes likely to be CNS viral infections, 30% were PCR positive compared to 5% categorised as unlikely. The most frequent positive findings were Epstein Barr virus (EBV), enteroviruses, and herpes simplex virus (HSV). Enteroviruses and HSV were found predominantly in the likely CNS viral infection group, whereas EBV was found mainly in the unlikely group. Positive PCR results were more likely when there were 3-14 days between symptom onset and lumbar puncture, and when CSF white cell count was abnormal, although a normal CSF did not exclude a viral infection. CONCLUSIONS: The diagnostic yield of PCR can be maximised by using sensitive assays to detect a range of pathogens in appropriately timed CSF samples. PCR results, in particular EBV, should be interpreted cautiously when symptoms cannot readily be attributed to the virus detected.

Evaluation of neuromuscular symptoms in UK Gulf War veterans: a controlled study.

OBJECTIVES: To determine whether Gulf War veterans with neuromuscular symptoms that included weakness and fatigue had either 1) objective correlates for muscle weakness or fatigue; or 2) any etiologic explanation for such symptoms; and if so, 3) whether such objective measures or etiologic mechanisms were specific to Gulf War service. METHODS: Forty-nine ill Gulf War veterans with more than four neuromuscular symptoms (Gulf-ill) were compared with 26 Gulf-well veterans, 13 symptomatic Bosnian veterans (Bosnia-ill), and 22 symptomatic troops who were not deployed to the Gulf (Era-ill). Quantitative myometry was used to objectively measure weakness and fatigue. Subjects had an ischemic forearm exercise test, a subanaerobic bicycle exercise test, and a muscle biopsy. RESULTS: Quantitative strength and fatigue measures did not correlate with self-perception of weakness or fatigue for any of our groups. No specific muscle biopsy abnormalities were found. There was no defect of adenylate deaminase or glycogenolysis found. Gulf-ill subjects did find the subanaerobic bicycle exercise more effortful and generated significantly higher plasma lactate concentrations compared with Gulf-well subjects. CONCLUSION: Because complaints of weakness and fatigue in unwell servicemen do not correlate with actual weakness or fatigue, explanations for these symptoms must lie outside of the neuromuscular system. Increased lactate production during subanaerobic bicycle exercise reflects mitochondrial inefficiency, but it is unclear whether this reflects mitochondrial damage sustained during Gulf War service or inactivity secondary to ill health.

Expression ratios of the Bcl-2 family proteins and disease activity in multiple sclerosis.

There is emerging evidence that failure of apoptosis (programmed cell death) of potentially pathogenic T lymphocytes may be involved in the pathogenesis of multiple sclerosis (MS). The commitment of T lymphocytes to die is partly regulated by the Bcl-2 family proteins, which act as a checkpoint upstream of mitochondrial dysfunction. These proteins include the death antagonists Bcl-2 and Bcl-X(L), and death agonists Bax and Bad. Recent studies suggest that altered expression of Bcl-2 family proteins in T lymphocytes is involved in promoting cellular resistance to apoptosis in patients with MS. However, the relationship between these alterations in Bcl-2 proteins expression and clinical disease activity has not yet been evaluated. In this study, we analyzed the expression ratios of pro- to anti-apoptosis Bcl-2 family proteins in patients with clinically active MS and compared results to corresponding ratios in patients with stable MS and relevant control groups. We observed a significant reduction in the expression ratios of pro- to anti-apoptosis Bcl-2 members in peripheral lymphocytes from patients with active MS when compared to corresponding ratios in patients with stable MS or other controls. This imbalance in the expression ratios of pro- and anti-apoptosis proteins was functionally active in reducing cellular susceptibility to apoptosis in active MS. It also correlated with clinical features of disease activity, such as the number of gadolinium-enhancing MRI lesions and clinical relapses. Our findings indicate that dysregulated expression of Bcl-2 family proteins in peripheral lymphocytes is a feature of clinically active multiple sclerosis.

Hypocretin (orexin) deficiency in narcolepsy and primary hypersomnia.

The discovery that hypocretins are involved in narcolepsy, a disorder associated with excessive daytime sleepiness, cataplexy, and unusually rapid transitions to rapid eye movement sleep, opens a new field of investigation in the area of disorders of sleep and activation. Hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2) (also called orexin-A and orexin-B) are newly discovered neuropeptides processed from a common precursor. Hypocretin containing cells are located exclusively in the lateral hypothalamus, with widespread projections within the central nervous system. The role of the hypocretin system in other disorders causing excessive daytime sleepiness is more uncertain. This study reports the findings of a prospective study measuring cerebrospinal fluid concentrations of hypocretin-1 and hypocretin-2 in HLA DQB1*0602 positive narcolepsy with cataplexy, monosymptomatic narcolepsy, and primary hypersomnia. The results confirmed the previous observations, that hcrt-1 is deficient in narcolepsy and for the first time report very low levels of hcrt-1 in primary hypersomnia. It is also reported for the first time that there is a generalised defect in hcrt-2 transmission in all three of these clinical entities compared with controls.

Neurophysiologic analysis of neuromuscular symptoms in UK Gulf War veterans: a controlled study.

BACKGROUND: UK veterans who were deployed to the Gulf in 1990 to 1991 reported higher prevalence of neuromuscular symptoms. OBJECTIVE: To investigate whether these Gulf War-related symptoms were associated with objective evidence of neuromuscular dysfunction. METHODS: Forty-nine Gulf War veterans with more than four neuromuscular symptoms (Gulf-ill), 26 Gulf-well veterans, 13 symptomatic Bosnian veterans (Bosnia-ill), and 22 symptomatic veterans who were not deployed to the Gulf (Era-ill) underwent detailed neurophysiologic assessment: nerve conduction studies, quantitative sensory and autonomic testing, and concentric needle and single-fiber electromyography (EMG). RESULTS: Nerve conduction studies detected carpal tunnel syndrome in two Gulf-ill, two Gulf-well, one Bosnia-ill, and three Era-ill veterans. Ulnar neuropathy was detected in one Gulf-ill and two Era-ill veterans. However, results of detailed nerve conduction studies of the Gulf-ill veterans were comparable with results observed in the other three groups. Quantitative sensory and autonomic assessments also failed to show any specific abnormalities in the Gulf-ill group. Similarly, quantitative assessment of concentric needle and single-fiber EMG detected no chronic denervation or myopathic changes or any abnormalities of neuromuscular transmission in the Gulf-ill veterans. CONCLUSION: Gulf War-related neuromuscular symptoms are not associated with specific impairments of peripheral nerves, neuromuscular junctions, or skeletal muscles.

Expression of CD5 on B lymphocytes correlates with disease activity in patients with multiple sclerosis.

There is growing evidence that implicates B lymphocytes and their products in the pathogenesis of multiple sclerosis (MS). A subpopulation of B lymphocytes expressing the CD5 antigen are involved in several autoimmune disorders through the release of autoantibodies. In this study, we used three-color flow cytometry to examine the expression of CD5 antigen on B lymphocytes from patients with relapsing-remitting MS, and correlated this expression with features of disease activity and circulating levels of autoantibodies against myelin basic protein. CD5 expression on B lymphocytes was significantly higher in patients with active MS when compared to patients with clinically stable MS or those with inflammatory or noninflammatory neurologic disorders. CD5(+) B lymphocytes from patients with active MS correlated significantly with the number of gadolinium-enhancing MRI lesions, and inversely with disease duration. The expression of CD5 on B lymphocytes in MS patients also correlated with circulating levels antibodies against myelin basic protein. Results presented here indicate that clinically active MS is associated with an expanded population of peripheral CD5(+) B lymphocytes.

The expression of apoptosis-regulatory proteins in B lymphocytes from patients with multiple sclerosis.

The pathogenesis of multiple sclerosis (MS) is thought to involve T- and B-lymphocyte-mediated autoimmunity. However, the mechanisms that regulate lymphocyte activity in MS are poorly understood. In normal circumstances, programmed cell death (apoptosis) contributes to the maintenance of lymphocytes homeostasis and the deletion of autoreactive cells. Cellular commitment to apoptosis is partly regulated by the cell death receptor Fas, and the anti-apoptosis proteins Bcl-2 and FLIP. Although there is emerging evidence that dysregulations of apoptotic pathways play a role in T-cell autoimmunity in MS, the expression of apoptosis-regulatory proteins in B cells from MS patients is largely unknown. In this study, we analyzed the expression profiles of Fas, Bcl-2, and FLIP proteins in peripheral B lymphocytes from patients with relapsing-remitting and progressive MS, and from appropriate controls. We observed a significant up-regulation of Bcl-2 and FLIP proteins in B cells from relapsing-remitting MS when compared to corresponding expression in progressive MS, or in noninflammatory neurologic controls and healthy individuals. This cellular overexpression of Bcl-2 and FLIP proteins was not affected by treatment with interferon-beta, but was also observed in B cells from patients with systemic inflammatory diseases. Our findings suggest that cellular overexpression of the apoptosis-inhibitory proteins in patients with relapsing MS may promote apoptotic resistance of potentially pathogenic, autoreactive B lymphocytes and consequently, may allow for continuing autoimmune tissue destruction.

Upregulated survivin expression in activated T lymphocytes correlates with disease activity in multiple sclerosis.

Programmed cell death (apoptosis) is critical for the normal development and homeostasis of the immune system. There is emerging evidence that failure of apoptosis to eliminate potentially pathogenic, autoreactive T lymphocytes may be involved in the pathogenesis of multiple sclerosis (MS). This failure is related to multiple abnormalities of apoptosis-regulatory molecules that involve survivin, a recently described cell cycle-regulated anti-apoptosis protein. In this study, we investigated the relationship between survivin expression in peripheral T lymphocytes and clinical features of MS. We detected a significant over-expression of survivin in mitogen stimulated T lymphocytes from patients with active MS when compared with corresponding expression in patients with stable MS or those with inflammatory and non-inflammatory neurologic disorders. This over-expression of survivin in patients with active MS correlated with cellular resistance to apoptosis and with features of disease activity, such as disease duration and the number of enhanced lesions on cranial magnetic resonance imaging. There was no correlation between cellular survivin levels and the expression of other apoptosis-inhibitory proteins, such as Bcl-2 and Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (FLIP). Our findings indicate that cellular over-expression of the novel anti-apoptosis protein survivin is a feature of clinically active MS.

Reduced expression of the inhibitor of apoptosis proteins in T cells from patients with multiple sclerosis following interferon-beta therapy.

Treatment with interferon-beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that involve the augmentation of programmed cell death (apoptosis) of peripheral T lymphocytes. The recently identified family of inhibitor of apoptosis (IAP) proteins is a potent regulator of cell death. The expression of IAP-1, IAP-2, and X-linked IAP (XIAP) is upregulated in mitogen stimulated T lymphocytes from MS patients, and this expression correlates with MS disease activity. In this study, we sought to evaluate the effect of interferon-beta on cellular expression of IAP proteins and other apoptosis regulatory molecules. In a prospective study, we evaluated the expression of IAP proteins, the anti-apoptosis Bcl-2 protein, and the death receptor Fas in in vitro stimulated T lymphocytes from MS patients, before and serially after treatment with interferon-beta. We also investigated the long-term effects of interferon-beta on cellular expression of these proteins and T lymphocyte apoptosis in a cross-sectional study of MS patients receiving drug therapy for a mean of 4.8 years. Treatment with interferon-beta reduced the expression of IAP-1, IAP-2 and XIAP in stimulated T lymphocytes. This reduced expression correlated with increased T cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon-beta therapy did not alter cellular expression of Bcl-2 protein or the death receptor Fas. This downregulatory effect of interferon-beta on cellular expression of IAP proteins was maintained following long-term therapy. Our findings suggest that interferon-beta therapy exerts a regulatory effect on peripheral T lymphocytes through an anti-apoptosis mechanism that involves the downregulation of cellular IAP proteins expression.

Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit.

OBJECTIVE: The cause of axonal loss, an important contributor to disability in MS, is poorly understood. This study investigated whether progression in MS is associated with CSF antibodies to the 68-kd light neurofilament subunit (NF-L), an axonal cytoskeletal protein, and compared this with antibodies against tubulin and the heavy neurofilament subunit (NF-H). METHODS: IgG to NF-L, tubulin, and NF-H was measured by immunoassay in matched CSF and serum samples from patients with relapsing-remitting MS (RRMS; n = 39), primary progressive MS (PPMS; n = 10), and secondary progressive MS (SPMS; n = 18); patients with other inflammatory (n = 21) and noninflammatory (n = 40) neurologic diseases; and healthy controls (n = 12). Immunocytochemistry was performed to assess antibody binding to human brain sections, and isoelectric focusing with immunoblotting was performed to assess oligoclonal anti-NF-L production. RESULTS: Intrathecal production of anti-NF-L antibodies was significantly elevated in PPMS and SPMS. In contrast, there were no significant differences in CSF levels of antibodies to tubulin or NF-H between the groups. Anti-NF-L, antitubulin, and anti-NF-H levels correlated with the duration of disease before lumbar puncture and Expanded Disability Status Scale levels. Immunocytochemistry demonstrated binding of CSF or serum antibodies to axonal or neuronal components in six of seven RRMS patients, seven of seven PPMS patients, and eight of 10 SPMS patients tested. Isoelectric focusing demonstrated independent CSF oligoclonal bands reactive with NF-L in six of 13 specimens tested. CONCLUSIONS: Anti-NF-L antibodies seem to be raised in progressive MS and may serve as a marker for axonal loss and disease progression. They may contribute to axonal loss and the accumulation of disability.

The expression of pro- and anti-apoptosis Bcl-2 family proteins in lymphocytes from patients with multiple sclerosis.

Programmed cell death (apoptosis) is critical for the normal development and homeostasis of the immune system. There is increasing evidence that dysregulations of apoptotic pathways are associated with autoimmune disease, including multiple sclerosis (MS). Cellular commitment to apoptosis is partly regulated by the Bcl-2 family proteins, which includes the death antagonists Bcl-2 and Bcl-X(L), and death agonists Bax and Bad. Since the role of these proteins in the pathogenesis of MS is currently unknown, we analyzed their expression profile in peripheral and intrathecal lymphocytes from MS patients and appropriate controls. We observed a significant reduction in the expression ratios of pro-apoptotic to anti-apoptotic Bcl-2 members in both peripheral and intrathecal lymphocytes from MS patients when compared to corresponding ratios in patients with inflammatory or noninflammatory neurologic controls, or healthy individuals. The relative coexpression ratios of these pro- and anti-apoptotic Bcl-2 family proteins in MS were more significant than the expression of individual members. The low cellular expression ratios of pro-apoptotic proteins in MS were confirmed in vitro activated T lymphocytes. Cellular expression of Bcl-2, Bcl-X(L), Bax or Bad in MS patients was independent of the expression of other apoptotic regulatory molecules, such as Fas receptor protein or FLIP. Our findings suggest that the abnormal expression patterns of Bcl-2 family proteins in MS may promote apoptotic resistance of potentially pathogenic, autoreactive lymphocytes, and may allow for continuing cellular proliferation and tissue destruction within the central nervous system.

Heightened intrathecal release of axonal cytoskeletal proteins in multiple sclerosis is associated with progressive disease and clinical disability.

The pathologic basis of disease progression in multiple sclerosis (MS) is thought to involve axonal degeneration, which contributes to the accumulation of neurological disability. Recent reports suggest that intrathecal concentrations of the neurofilament protein in relapsing remitting MS correlate with disease activity and the degree of disability. We sought to investigate the intrathecal levels of other cytoskeletal components of axons, primarily actin, tubulin and the light subunit of neurofilament (NFL) in patients with progressive MS and relevant controls and correlate results with clinical parameters of disease severity. Cerebrospinal fluid (CSF) concentrations of actin, tubulin and NFL were significantly increased in MS patients when compared to corresponding levels in patients with other inflammatory or non-inflammatory neurological diseases. Moreover, the intrathecal release of actin and tubulin, and to a lesser extent NFL, was significantly more marked in patients with primary and secondary progressive MS when compared to patients with relapsing remitting disease and was correlated with clinical disability. Our findings suggest that progressive MS is associated with the heightened intrathecal release of axonal cytoskeletal proteins, and that CSF actin, tubulin and NFL are reliable markers of axonal damage.

Disease activity in multiple sclerosis correlates with T lymphocyte expression of the inhibitor of apoptosis proteins.

The pathogenesis of multiple sclerosis (MS) is thought to involve failure of programmed cell death (apoptosis) to eliminate potentially pathogenic, autoreactive T lymphocytes. This failure may be caused by multiple abnormalities of the cell death machinery. The inhibitors of apoptosis (IAP) proteins are central regulators of cell death that inhibit apoptosis induced by a variety of stimuli. In this study, we investigated the dynamics of cellular IAP-1, IAP-2, and X-linked IAP, in resting and mitogen stimulated T lymphocytes from MS patients and relevant controls. The expression of IAP proteins was significantly higher in mitogen stimulated T lymphocytes from patients with clinically active MS when compared to corresponding expressions from patients with stable MS or from other controls. Heightened expression of IAP proteins in patients with active MS correlated with clinical features of disease activity, and with T lymphocyte resistance to apoptosis. In contrast, cellular expression of the anti-apoptosis protein Bcl-2 did not differ between active and stable MS, and was relatively similar between MS patients and controls. These findings suggest that overexpression of IAP proteins in stimulated T lymphocytes is a feature of clinically active multiple sclerosis.

Heightened intrathecal release of soluble CD137 in patients with multiple sclerosis.

Human CD137 (ILA/4-1BB), a member of the tumour necrosis factor (TNF) receptor family, regulates the activation and proliferation of immune cells, and may induce apoptosis (programmed cell death) of activated lymphocytes. A soluble form of CD137 (sCD137) released by activated lymphocytes may interfere with the activities of the membrane-bound CD137. This study reports the detection of significantly high intrathecal and systemic levels of sCD137 in patients with clinically active multiple sclerosis (MS) when compared with corresponding levels from patients with clinically stable MS or those with inflammatory and non-inflammatory neurological disorders, or from healthy individuals. Intrathecal concentrations of sCD137 in patients with active MS correlate with the intrathecal release of the soluble death receptor protein Fas, but not with the release of interleukin-2, TNF or the synthesis of immunoglobulins G and M. Results presented here suggest that heightened release of sCD137 is a feature of clinically active MS.