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Multiple Sclerosis Reviews: 2007
Wingerchuk, D. M. (2007). "Diagnosis and treatment of neuromyelitis optica." Neurologist 13(1): 2-11.
BACKGROUND: Neuromyelitis optica (NMO) is an uncommon CNS demyelinating syndrome often mistaken for severe multiple sclerosis (MS). Several clinical, laboratory, and neuroimaging characteristics may accurately distinguish NMO from MS early in the disease course. REVIEW SUMMARY: NMO is usually a relapsing disorder associated with early, severe, attack-related residual disability. It is associated with a highly specific antibody marker, NMO-IgG, which targets the water channel aquaporin-4. Revised NMO diagnostic criteria require optic neuritis, acute myelitis, and 2 of the following 3 characteristics: disease-onset brain magnetic resonance imaging (MRI) that is nondiagnostic for MS, contiguous spinal cord MRI lesion extending over 3 or more vertebral segments, and NMO-IgG seropositive status. Symptoms referable to central nervous system regions other than the optic nerve and spinal cord do not necessarily exclude the diagnosis of NMO, nor does the presence of brain MRI lesions. NMO-IgG has facilitated an appreciation that the spectrum of NMO is wider than previously recognized, and includes a proportion of patients with each of recurrent longitudinally extensive myelitis, recurrent isolated optic neuritis, and Japanese opticospinal MS. In contrast to typical MS, clinical experience and case series suggest that NMO requires long-term immunosuppressive therapy. CONCLUSIONS: NMO can be reliably differentiated from MS at an early stage using validated diagnostic criteria. The spectrum of NMO is wider than previously appreciated. Accurate, early diagnosis is critical to facilitate initiation of immunosuppressive therapy for attack prevention.
Wilson, A. S., B. E. Power, et al. (2007). "DNA hypomethylation and human diseases." Biochim Biophys Acta 1775(1): 138-62.
Changes in human DNA methylation patterns are an important feature of cancer development and progression and a potential role in other conditions such as atherosclerosis and autoimmune diseases (e.g., multiple sclerosis and lupus) is being recognised. The cancer genome is frequently characterised by hypermethylation of specific genes concurrently with an overall decrease in the level of 5 methyl cytosine. This hypomethylation of the genome largely affects the intergenic and intronic regions of the DNA, particularly repeat sequences and transposable elements, and is believed to result in chromosomal instability and increased mutation events. This review examines our understanding of the patterns of cancer-associated hypomethylation, and how recent advances in understanding of chromatin biology may help elucidate the mechanisms underlying repeat sequence demethylation. It also considers how global demethylation of repeat sequences including transposable elements and the site-specific hypomethylation of certain genes might contribute to the deleterious effects that ultimately result in the initiation and progression of cancer and other diseases. The use of hypomethylation of interspersed repeat sequences and genes as potential biomarkers in the early detection of tumors and their prognostic use in monitoring disease progression are also examined.
Waziri, A., J. P. Vonsattel, et al. (2007). "Expansile, enhancing cervical cord lesion with an associated syrinx secondary to demyelination. Case report and review of the literature." J Neurosurg Spine 6(1): 52-6.
The authors describe the case of a patient with an enhancing, intramedullary cervical spinal cord lesion and associated syrinx. Biopsy sampling of the cervical lesion was performed, and the histological findings were consistent with a demyelinating process supporting the diagnosis of multiple sclerosis (MS). Syrinx formation associated with demyelinating disease has only been described in isolated cases, almost exclusively in Japanese patients with MS. A 22-year-old woman of Caribbean descent presented with a subacute, progressive myelopathy including symptoms of pain and weakness in all extremities, bladder incontinence, and the inability to ambulate. Magnetic resonance imaging of the brain and spinal cord demonstrated an enlarged cervical cord with enhancement and central cavitation consistent with a syrinx. The patient underwent a C3-7 laminoplasty and placement of a dural graft for cord decompression as well as fenestration of the central syrinx. Biopsy sampling of the lesion was performed, and the histopathological analysis, in conjunction with subsequent laboratory and diagnostic testing, supported the diagnosis of demyelinating disease. After treatment with a course of high-dose dexamethasone and inpatient rehabilitation therapy, the patient demonstrated significant clinical improvement. Spinal cord involvement is not uncommon in patients with demyelinating disease; however, enhancing lesions associated with extensive tissue loss and syrinx formation have rarely been reported. For the consulting neurological surgeon, demyelinating disease should be included in the differential diagnosis of such lesions given the level of complexity and risk to the patient associated with open biopsy of the spinal cord.
Vrenken, H. and J. J. Geurts (2007). "Gray and normal-appearing white matter in multiple sclerosis: an MRI perspective." Expert Rev Neurother 7(3): 271-9.
Besides focal white matter lesions, multiple sclerosis brain tissue also displays abnormalities in the gray matter and the normal-appearing white matter. Recent advances in magnetic resonance imaging studies of both types of tissue are discussed. Herein, normal-appearing white matter abnormalities are being found in quantitative magnetic resonance investigations, consistent with a limited degree of axonal damage and/or demyelination, and an increase of glial cells, but the specific nature of the histopathological changes underlying the quantitative magnetic resonance abnormalities remains unclear. Gray matter studies have demonstrated that much of the disease process remains undetected by conventional magnetic resonance imaging. Although newly developed techniques, such as 3D double-inversion recovery, may greatly improve detection of cortical pathology, it remains important to investigate the resultant effects on the cortical tissue alongside this, by studying integrity of normal-appearing cortical tissue through quantitative magnetic resonance studies, as well as the net neurodegenerative effect through measurements of cortical thickness and cortical atrophy (rates). To improve our understanding of normal-appearing white and gray matter changes, their mutual relations, and their relations to clinical changes, further in vivo magnetic resonance imaging studies are required. Specifically, it is proposed that more spatially specific investigations, ideally utilizing subject-specific anatomical information from, for example, diffusion fiber-tracking techniques, could be used to gain more insight into the relations between normal-appearing white matter changes, cortical changes, magnetic resonance visible focal-lesions, and physical and cognitive deficits.
van der Rhee, H. J., E. de Vries, et al. (2007). "[Favourable and unfavourable effects of exposure to sunlight]." Ned Tijdschr Geneeskd 151(2): 118-22.
The negative effects of sunlight include the more frequent or earlier development of skin cancer and degenerative changes in the skin, and the occurrence ofphotodermatoses. - However, sunlight also has a favourable effects; specifically, it may inhibit the development and progression of diseases of the bones, muscles and skin, ofvarious malignancies (carcinoma of the prostate, breast, colon and ovary, non-Hodgkin lymphoma), and may prevent certain autoimmune diseases, particularly multiple sclerosis. - This protective effect is ascribed to an increased synthesis of vitamin D, which is important for bone metabolism and is also able to regulate cell proliferation and differentiation, apoptosis, tumour invasion and angiogenesis. - The possible consequence of this new information is that public information regarding exposure to sunlight must continue to include a warning against excessive exposure to the sun, while at the same time stimulating regular although limited sunbathing.
Stuve, O., C. M. Marra, et al. (2007). "Potential risk of progressive multifocal leukoencephalopathy with natalizumab therapy: possible interventions." Arch Neurol 64(2): 169-76.
Natalizumab (Tysabri) is an effective therapy for multiple sclerosis. Recently, 3 patients who were treated with natalizumab developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyomavirus JC. The pathogenesis of natalizumab-associated PML may be different from that of PML not associated with the drug. We reviewed biologically feasible interventions for patients diagnosed as having PML or other infections while receiving natalizumab therapy. Existing interventions include antiviral treatment, immunomodulatory therapies, hematopoietic growth factors, plasma exchange, intravenous immunoglobulins, and leukapheresis and autotransfusion of leukocytes. In addition, we examined the feasibility of experimental therapies, including small interfering RNA, the in vivo use of antiserum, and recombinant natalizumab-blocking molecules. There is only circumstantial evidence that any of the proposed treatments will benefit patients with multiple sclerosis treated with natalizumab who may develop PML. In addition, the expected incidence of PML in this patient population will likely be too low to test any of the proposed interventions in a controlled manner. Because it is currently impossible to identify patients at risk, and thus to prevent PML as a consequence of natalizumab therapy, it is important that neurologists be aware of possible therapeutic interventions.
Samuels, M. A. (2007). "Update in neurology." Ann Intern Med 146(2): 128-32.
Ryu, H. and R. J. Ferrante (2007). "Translational therapeutic strategies in amyotrophic lateral sclerosis." Mini Rev Med Chem 7(2): 141-50.
Amyotrophic lateral sclerosis (ALS) is a clinically severe and fatal neurodegenerative disease characterized by a loss of both upper and lower motor neurons, resulting in progressive muscle loss and paralysis. While the exact cause of neuronal death in ALS remains unknown, it is proposed that multiple molecular defects trigger motor neuron cell death. These pathophysiological mechanisms include oxidative stress, mitochondrial impairment, protein aggregation, glutamate cytotoxicity, transcription dysfunction, inflammation, and apoptotic cell death. An understanding of how these potential therapeutic targets interrelate will provide direction both in the development of a pharmacotherapy and in the design of clinical trials in ALS. Important issues related to therapeutic development are the principals that should be followed in designing and conducting experiments using genetic animal models and what body of evidence is desirable to fully inform clinical decision making. In the context of ALS, we review some of the salient issues related to the use of genetic models in providing a guide to assessing studies in translating therapeutic strategies to patients with ALS and discuss therapeutic targets and pharmacological approaches to slowing disease progression. As in other neurodegenerative diseases, the most effective neuroprotection may result from combined treatment strategies.
Rees, P. M., C. J. Fowler, et al. (2007). "Sexual function in men and women with neurological disorders." Lancet 369(9560): 512-25.
The advent of non-invasive functional brain imaging has clarified which regions of the brain are recruited during sexual arousal. Injuries to those regions, and to the spinal cord and peripheral nerves that link genitalia to limbic and cognitive centres, can profoundly influence sexual wellbeing. In epilepsy, expressions of hypersexuality and hyposexuality interact with the location of epileptogenic foci in the temporolimbic circuitry, and are tempered by the sexual effects of drug treatments. We outline the sexual consequences of epilepsy, stroke, multiple sclerosis, Parkinson's disease, and other common neurological disorders. Management of sexual dysfunction from both disease and treatment is discussed. Nerve-sparing techniques could mitigate the substantial sexual dysfunction in both men and women through surgical disruption of the autonomic nerves during radical pelvic surgery.
Rajanikant, G. K., D. Zemke, et al. (2007). "The therapeutic potential of statins in neurological disorders." Curr Med Chem 14(1): 103-12.
Statins are currently among the most commonly prescribed agents for the prevention of cardiovascular disease. Statins reduce serum cholesterol levels by reversibly inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, in the nanomolar range. Mounting evidence suggests that in addition to their vascular effects such as stabilization of atherosclerotic plaques and decreased carotid intimal-medial thickness, statins have additional properties such as endothelial protection via actions on the nitric oxide synthase system as well as antioxidant, anti-inflammatory and anti-platelet effects. These effects of statins might have potential therapeutic implications in various neurological disorders such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis and primary brain tumors. In this review, the major protective mechanisms of statins and their applicability to the treatment of neurological disease are summarized. Although further experiments are required, currently available data would seem to indicate that clinical trials to determine the safety and efficacy of statins in a number of disorders are warranted.
Pirko, I., C. F. Lucchinetti, et al. (2007). "Gray matter involvement in multiple sclerosis." Neurology 68(9): 634-42.
Gray matter (GM) involvement is detected even in the earliest stages of multiple sclerosis (MS), and GM atrophy occurs at a faster rate than white matter (WM) atrophy early in the disease course. Studies published to date establish that 1) GM involvement and in particular cortical demyelination can be extensive in MS; 2) GM pathology may occur in part independently of WM lesion formation; 3) a primarily GM-related process may be the earliest manifestation of MS; 4) GM involvement is associated with physical disability, fatigue, and cognitive impairment in MS; and 5) GM disease might help explain the observed dissociation between markers of inflammatory demyelination (relapses, WM gadolinium enhancement, WM lesion burden) and disease progression. It remains likely that GM damage is related to WM damage. However, continued studies of GM pathology as well as neuronal and axonal involvement in MS and related experimental models are necessary to better understand the etiology and pathogenesis of the degenerative components.
Perry, V. H., C. Cunningham, et al. (2007). "Systemic infections and inflammation affect chronic neurodegeneration." Nat Rev Immunol 7(2): 161-7.
It is well known that systemic infections cause flare-ups of disease in individuals with asthma and rheumatoid arthritis, and that relapses in multiple sclerosis can often be associated with upper respiratory-tract infections. Here we review evidence to support our hypothesis that in chronic neurodegenerative diseases such as Alzheimer's disease, with an ongoing innate immune response in the brain, systemic infections and inflammation can cause acute exacerbations of symptoms and drive the progression of neurodegeneration.
O'Connor, P. (2007). "Natalizumab and the role of alpha 4-integrin antagonism in the treatment of multiple sclerosis." Expert Opin Biol Ther 7(1): 123-36.
Natalizumab is a powerful new therapy with a novel mechanism of action for the treatment of multiple sclerosis. In a randomized, double-blind, Phase III study (the AFFIRM [Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis] study), natalizumab monotherapy 300 mg intravenous every 4 weeks reduced the risk of sustained disability progression by 42% and annualized relapse rate by 68% over 2 years (both p < 0.001 versus placebo). Natalizumab was approved in the US in November 2004 for the treatment of relapsing multiple sclerosis, but was voluntarily withdrawn in February 2005 due to three cases of progressive multifocal leukoencephalopathy. Following a safety evaluation and regulatory review, the US FDA approved natalizumab as monotherapy for the treatment of relapsing multiple sclerosis in June 2006 generally for patients who have had an inadequate response to, or are unable to tolerate, alternative treatments.
Moscarello, M. A., F. G. Mastronardi, et al. (2007). "The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis." Neurochem Res 32(2): 251-6.
The pathogenesis of MS is unknown. In our studies, we have demonstrated an important role for citrullinated myelin basic protein (MBP). The accompanying loss of positive charge compromises the ability of MBP to interact with the lipid bilayer. The conversion of arginine to citrulline in brain is carried out by an enzyme peptidyl arginine deiminase (PAD) 2. The amount of PAD 2 in brain was increased in MS normal-appearing white matter. The mechanism responsible for this increase involved hypomethylation of the promoter region in the PAD 2 gene in MS, but no change (compared to normal) was found in thymus tissue DNA from the same MS patients. In addition, no change was observed in other neurological diseases, including Alzheimer's, Parkinson's, and Huntington's. We propose that citrullinated MBP, resulting from elevated levels of PAD 2 represents an important biochemical pathway in the pathogenesis of MS.
McQualter, J. L. and C. C. Bernard (2007). "Multiple sclerosis: a battle between destruction and repair." J Neurochem 100(2): 295-306.
Multiple sclerosis (MS) is a chronic neurodegenerative disease of the CNS in which an unrelenting attack from the innate and adaptive arms of the immune system results in extensive demyelination, loss of oligodendrocytes and axonal degeneration. This review summarizes advances in the understanding of the cellular and molecular pathways involved in neurodegeneration following autoimmune-mediated inflammation in the CNS. The mechanisms underlying myelin and axonal destruction and the equally important interaction between degenerative and repair mechanisms are discussed. Recent studies have revealed that the failure of CNS regeneration may be in part a result of the presence of myelin-associated growth inhibitory molecules in MS lesions. Successful therapeutic intervention in MS is likely to require suppression of the inflammatory response, in concert with blockade of growth inhibitory molecules and possibly the mobilization or transplantation of stem cells for regeneration.
Mazza, M., M. Pomponi, et al. (2007). "Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: an overview." Prog Neuropsychopharmacol Biol Psychiatry 31(1): 12-26.
RATIONALE: Omega-3 fatty acids are known to play a role in nervous system activity, cognitive development, memory-related learning, neuroplasticity of nerve membranes, synaptogenesis and synaptic transmission. The brain is considered abnormally sensitive to oxidative damage, and aging is considered one of the most significant risk factors for degenerative neurological disorders. Recently, clinical trials of several neurodegenerative diseases have increasingly targeted the evaluation of the effectiveness of various antioxidants. OBJECTIVES: The effects of omega-3 fatty acids and antioxidants on the anatomic and functional central nervous system development and their possible therapeutical use in some neurological and psychiatric pathologies are evaluated. RESULTS: A number of critical trials have confirmed the benefits of dietary supplementation with omega-3 fatty acids not only in several psychiatric conditions, but also in inflammatory and autoimmune and neurodegenerative diseases. Many evidences indicate that antioxidants are also essential in maintaining a correct neurophysiology. CONCLUSIONS: Omega-3 fatty acids could be useful in the prevention of different pathologies, such as cardiovascular, psychiatric, neurological, dermatological and rheumatological disorders. A number of studies suggest that antioxidants can prevent the oxidation of various macromolecules such as DNA, proteins, and lipids. The ideal use of antioxidants should be a prophylactic and continue treatment before aging.
Kuba, M., Z. Kubova, et al. (2007). "Motion-onset VEPs: characteristics, methods, and diagnostic use." Vision Res 47(2): 189-202.
This review article summarises the research on the motion-onset visual evoked potentials (VEPs) and important motion stimulus parameters which have been clarified. For activation of the visual motion processing system and evocation of the motion-onset specific N2 peak (with latency of 160-200ms) from the extra-striate temporo-occipital and/or parietal cortex, the following stimulus parameters can be recently recommended: low luminance (<ca. 20cd/m(2)) and low contrast (<ca. 10%-sinusoidally modulated) of a moving structure with low velocity and temporal frequency (<ca. 6Hz). A short (up to 200ms) duration of motion and a long (at least 1s) inter-stimulus interval reduce adaptation to motion and predominance of a pattern-related P1 peak. Radial motion (with increasing velocity and decreasing spatial frequency towards the periphery) produces larger reactions as compared to a unidirectional translation. In view of the slow maturation (up to the age of 18 years) and early ageing of the visual motion processing system, the use of age-dependent latency norms may be necessary. Since early or selective involvement of the motion processing system is suspected in some CNS disorders, we suggest an evaluation of the utility of motion-onset VEPs as part of the electrophysiological CNS examination since this method may recognise motion processing involvement better than other methods. Motion-onset VEPs might increase the sensitivity of this examination for diagnosing CNS diseases including Multiple Sclerosis, Neuroborreliosis, Glaucoma, Dyslexia and Encephalopathies.
Konsman, J. P., B. Drukarch, et al. (2007). "(Peri)vascular production and action of pro-inflammatory cytokines in brain pathology." Clin Sci (Lond) 112(1): 1-25.
In response to tissue injury or infection, the peripheral tissue macrophage induces an inflammatory response through the release of IL-1beta (interleukin-1beta) and TNFalpha (tumour necrosis factor alpha). These cytokines stimulate macrophages and endothelial cells to express chemokines and adhesion molecules that attract leucocytes into the peripheral site of injury or infection. The aims of the present review are to (i) discuss the relevance of brain (peri)vascular cells and compartments to bacterial meningitis, HIV-1-associated dementia, multiple sclerosis, ischaemic and traumatic brain injury, and Alzheimer's disease, and (ii) to provide an overview of the production and action of pro-inflammatory cytokines by (peri)vascular cells in these pathologies of the CNS (central nervous system). The brain (peri)vascular compartments are highly relevant to pathologies affecting the CNS, as infections are almost exclusively blood-borne. Insults disrupt blood and energy flow to neurons, and active brain-to-blood transport mechanisms, which are the bottleneck in the clearance of unwanted molecules from the brain. Perivascular macrophages are the most reactive cell type and produce IL-1beta and TNFalpha after infection or injury to the CNS. The main cellular target for IL-1beta and TNFalpha produced in the brain (peri)vascular compartment is the endothelium, where these cytokines induce the expression of adhesion molecules and promote leucocyte infiltration. Whether this and other effects of IL-1 and TNF in the brain (peri)vascular compartments are detrimental or beneficial in neuropathology remains to be shown and requires a clear understanding of the role of these cytokines in both damaging and repair processes in the CNS.
Kling, A. and R. Dahlqvist (2007). "[Promising results with methylprednisolone in multiple sclerosis. Lack of patent rights makes drug industry less interested]." Lakartidningen 104(3): 128-30.
Kieseier, B. C. and H. P. Hartung (2007). "Interferon-beta and neuroprotection in multiple sclerosis--facts, hopes and phantasies." Exp Neurol 203(1): 1-4.
Harguindey, S., S. J. Reshkin, et al. (2007). "Growth and trophic factors, pH and the Na+/H+ exchanger in Alzheimer's disease, other neurodegenerative diseases and cancer: new therapeutic possibilities and potential dangers." Curr Alzheimer Res 4(1): 53-65.
Abnormalities in the intricate intracellular signalling pathways play a key role in the deregulation of either spontaneous (normal or pathological) or induced (therapeutic) cell death mechanisms. Some of these pathways are increasingly becoming molecular therapeutic targets in different processes, ranging from neurodegenerative diseases to cancer. Recent discoveries in research and treatment have shown that failure to induce selective cell apoptosis in hyperproliferative processes, like neoplastic diseases, and the failure to prevent spontaneous cell death in neurodegenerative diseases (HNDDs) such as Alzheimer's disease (AD), multiple sclerosis (MS), amyothrophic lateral sclerosis (ALS), Huntington's disease (HD), and retinitis pigmentosa (RP), can be interpreted as problems stemming from the same basic mechanisms but moving in diametrically opposed directions. The integrated approach advanced here represents an interdisciplinary attempt to stimulate an integrated vision of two otherwise widely separated areas of research, experimental neurology and oncology. This kind of approach to the prevention of apoptosis (therapeutic antiapoptosis) and/or other forms of cell death in HNNDs, as well as to resistance to therapeutic apoptosis in cancer (pathological antiapoptosis), has the scope to improve the understanding of the dualistic nature of the basic abnormalities underlying the pathological deregulation of cell death. In this context, an intracellular pH (pH(i))-related approach to these opposed situations is advanced to provide a unified theory of the apoptosis-antiapoptosis machinery. Some potential therapeutic possibilities opened by these lines of research, regarding the utilization of human growth factors and/or cellular anti-acidification measures directed to sustain cellular acid-base homeostasis in different HNNDs are considered because of their potential therapeutic benefit. Finally, we advance some possible dangers and side-effects raised by these very same treatment efforts.
Harauz, G. and A. A. Musse (2007). "A tale of two citrullines--structural and functional aspects of myelin basic protein deimination in health and disease." Neurochem Res 32(2): 137-58.
Myelin basic protein (MBP) binds to negatively charged lipids on the cytosolic surface of oligodendrocyte membranes and is responsible for adhesion of these surfaces in the multilayered myelin sheath. The pattern of extensive post-translational modifications of MBP is dynamic during normal central nervous system (CNS) development and during myelin degeneration in multiple sclerosis (MS), affecting its interactions with the myelin membranes and with other molecules. In particular, the degree of deimination (or citrullination) of MBP is correlated with the severity of MS, and may represent a primary defect that precedes neurodegeneration due to autoimmune attack. That the degree of MBP deimination is also high in early CNS development indicates that this modification plays major physiological roles in myelin assembly. In this review, we describe the structural and functional consequences of MBP deimination in healthy and diseased myelin.
Han, L. and Y. Z. Niu (2007). "[Toll-like receptors and nervous system disease]." Zhongguo Dang Dai Er Ke Za Zhi 9(1): 90-2.
Halder, R. C., A. Jahng, et al. (2007). "Mini review: immune response to myelin-derived sulfatide and CNS-demyelination." Neurochem Res 32(2): 257-62.
Here we briefly review our understanding of the immune response to myelin-derived glycolipids during an inflammatory autoimmune response in the central nervous system (CNS). We focus primarily on the recognition of the self-glycolipid sulfatide by a distinct population of non-invariant NK T cells. The results of studies we have obtained so far in investigating the presentation of sulfatide by CNS-resident cells including microglia and their interactions with T cells indicate that this pathway might be successfully targeted for the treatment of autoimmune demyelination in multiple sclerosis.
Gold, R., M. Stangel, et al. (2007). "Drug Insight: the use of intravenous immunoglobulin in neurology--therapeutic considerations and practical issues." Nat Clin Pract Neurol 3(1): 36-44.
Over the past few years, we have achieved increasing success in the treatment of a number of autoimmune-mediated disorders affecting nerves and muscles. This success is partly attributable to the use of high-dose polyclonal intravenous immunoglobulin (IVIg), which has dramatically changed our treatment options. On the basis of results from controlled, but non-FDA-approved, clinical trials, IVIg is now the treatment of choice for Guillain-Barre syndrome, chronic idiopathic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy; IVIg offers rescue therapy for patients with rapidly worsening myasthenia gravis, and is a second-line therapy for dermatomyositis, stiff-person syndrome, and pregnancy-associated or postpartum multiple sclerosis attacks. The ability of IVIg to treat such immunologically diverse disorders effectively, coupled with its excellent safety profile, has led clinicians to use the drug more liberally, even in diseases for which the data are weak and not evidence-based and in patients with coexisting conditions. Use of IVIg for such indications can increase the risk of complications while raising the cost of the drug. Practical issues regarding dosing and frequency of infusions generate dilemmas in clinical practice. In this article, we review the current indications for IVIg treatment, address practical issues related to the use and costs of the drug, and summarize its mechanisms of action.
Giovanetti, F. (2007). "Travel medicine interventions and neurological disease." Travel Med Infect Dis 5(1): 7-17.
As a consequence of increased mobility worldwide, persons with underlying medical conditions set out on a journey more often than in the past. Among pre-existing medical conditions, some neurological diseases, including multiple sclerosis and other demyelinating diseases, Guillain-Barre syndrome and myasthenia gravis often create management problems to travel medicine practitioners. There is some concern that these conditions could be worsened either by naturally acquired infections or by some travel medicine interventions. The aim of this review is to suggest a practical approach to each of these conditions and to examine the feasibility and the impact of travel medicine interventions on the underlying disease.
Buttmann, M. and P. Rieckmann (2007). "Interferon-beta1b in multiple sclerosis." Expert Rev Neurother 7(3): 227-39.
In 1993, interferon (IFN)-beta(1b) for subcutaneous injection became the first US FDA-approved immunomodulatory treatment for multiple sclerosis, a chronic inflammatory disease of the CNS. In this review of IFN-beta(1b), we first present a short introduction to multiple sclerosis and currently available therapeutics. We then summarize current knowledge about the biochemical structure of IFN-beta(1b), as well as pharmacokinetics and pharmacodynamics, including data on putative mechanisms underlying therapeutic as well as adverse effects. Furthermore, a critical review of ongoing and recently published clinical trials investigating IFN-beta(1b) in multiple sclerosis will be provided. Main topics are: trials investigating IFN-beta(1b) after a first clinical event, at higher dosages or in comparison to once-weekly subcutaneous IFN-beta(1a) injections, 16 years of long-term follow-up, IFN-beta(1b) in Japanese patients, the role of neutralizing antibodies, biomarkers for the prediction of therapy response, IFN-beta(1b) and pregnancy, and IFN-beta(1b) treatment of children with multiple sclerosis. Finally, we discuss how novel drugs, especially monoclonal antibodies and orally administered immunosuppressants, might soon challenge the position of this well-established agent on the multiple sclerosis therapeutics market.
Bos, J. D. (2007). "Psoriasis, innate immunity, and gene pools." J Am Acad Dermatol 56(3): 468-71.
Recently, emphasis has shifted from T cells to innate (natural) immunity as the possible major culprit in psoriasis. All known elements of innate immune responses are up-regulated in psoriasis lesions, which must have a polygenetic origin. We hypothesize that urbanized populations have been under evolutionary pressure that selects for increased innate immunity responses because those offer relative but immediate protection from epidemic infections. That would have resulted in a changing gene pool, in which alleles of polymorphisms associated with increased innate immunity responses have amplified in these populations. Having too many of these genes together in one individual would result in a relatively low number of infections. On the other hand, it would also result in a higher prevalence of diseases related to increased innate immunity, such as psoriasis, and perhaps also multiple sclerosis and rheumatoid arthritis. Indeed, in indigenous people (Inuit, Aborigines, Ami) who have not been under this selection pressure, morbidity due to infections is high and the prevalence of psoriasis is low or even absent.
Bespalov, M. M. and M. Saarma (2007). "GDNF family receptor complexes are emerging drug targets." Trends Pharmacol Sci 28(2): 68-74.
Glial-cell-line-derived neurotrophic factor (GDNF) family ligands (GFLs), which consist of GDNF, neurturin, artemin and persephin, regulate the development and maintenance of the nervous system. GDNF protects and repairs dopamine-containing neurons, which degenerate in Parkinson's disease, and motoneurons, which die in amyotrophic lateral sclerosis. GDNF and neurturin have shown promise in clinical trials of Parkinson's disease, and artemin is currently undergoing clinical trials for chronic pain treatment. However, the delivery of GFLs into the brain through invasive approaches such as neurosurgery, viral vectors or by the use of encapsulated cells is associated with multiple obstacles. The development of small molecules that specifically activate GFL receptors and that can be applied systemically would overcome most of these problems. The unique nature of the GFL receptors, recent progress in elucidation of the 3D structures of GFLs and GFL-receptor complexes and the use of high-throughput screening have resulted in the development of the first small molecules that mimic the effects of the different GFLs.
Aktas, O., O. Ullrich, et al. (2007). "Neuronal damage in brain inflammation." Arch Neurol 64(2): 185-9.
In contrast to traditional textbook paradigms, recent studies indicate neuronal damage in classic neuroinflammatory diseases of the brain, such as multiple sclerosis or meningitis. In these cases, immune cells invade the central nervous system compartments, accompanied by a massive breakdown of the blood-brain barrier and typical changes of the cerebrospinal fluid. On the other hand, inflammation within the central nervous system is a common phenomenon even in classic noninflammatory brain diseases that are characterized by degeneration or trauma of neuronal structures, such as Alzheimer disease, Parkinson disease, or stroke. In these cases, inflammation is a frequent occurrence but displays different, more subtle, patterns compared with, for example, multiple sclerosis. Concepts for directly protecting neurons and axons in neuroinflammatory diseases may improve the outcome of the patients. In parallel, epidemiological and animal experimental evidences, as well as first clinical trials indicate the benefit of immunomodulatory therapies for classic noninflammatory brain diseases. We review the evidence for inflammatory neuronal damage and its clinical impact in the context of these diseases.