Multiple Sclerosis Treatment

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Loosing Control Inflammatory Escalation during Multiple Sclerosis

During multiple sclerosis (MS), circulating myelin-specific T cells from the lymphatic tissue cross the blood-brain barrier and enter the brain parenchyma, where they engage in close contact with microglial cells, the antigen-presenting immunoeffector cell of the CNS. As a consequence of this contact, microglial cells become activated, stimulate B cells to produce myelin-specific antibodies, and release oxygen and nitrogen free radicals and toxic cytokins, which then attack neurons and the myelin sheath. Together with inflammation, neuronal pathology involving axonal transection plays a pivotal role in MS, and the corresponding animal model disease EAE, even during the early phase of inflammation (Ferguson et al. 1997, Meyer et al. 2001, Trapp et al. 1998, Diestel et al. 2003, Aktas et al. 2005). It has become evident that long-term disability in MS correlates better with ax-onal damage than with the degree of demyelination (Bjartmar et al. 2003). Moreover, cortical thinning has been...

Evaluation of Autoimmunity to Transaldolase in Multiple Sclerosis

Transaldolase is a target of autoimmunity mediated by T cells and antibody (Ab) in patients with multiple sclerosis. Functional T-cell assays, T- and B-cell epitope mapping, and detection of transaldolase-specific antibodies in patients with multiple sclerosis are described. Recombinant transaldolase was produced in a prokaryotic expression vector for use in Western blot analysis of sera of these patients. Overlapping transaldolase peptides 15 amino acids (aa) long were synthesized onto cellulose membranes to map immunodominant B-cell epitopes. Amino acid sequence homologies between viral peptides and immunodominant B-cell epitopes of transaldolase were identified using a computer-based algorithm. Direct assessment of molecular mimicry between transaldolase B-cell epitopes and related viral peptides is also shown. T-cell epitopes are mapped in a T-cell proliferation assay using multiple sclerosis patient and control donor cells. Autoantigen-specific T cells are identified by...

Multiple Sclerosis

Low bone density has been reported in multiple sclerosis (MS). Seventy-one women with MS underwent total body BMD measurements with DXA (Norland XR-26) (70). Seventy-one healthy women served as controls. Total body BMC was reduced in the women with MS by approximately 8 . When the women with MS were evaluated based on their ambulatory status, only nonambulatory women with MS were found to have lower total body BMC when compared to controls. The authors concluded that physical disuse is the major contributing factor in reduced bone mass in MS although corticosteroid use also contributes.

Examples of Neuron Glia Interactions

One potential complication that arises from the Shiverer mice is that these animals have developmental hypomyelination, making it difficult to conclude that myelin actively regulates the kinds of channels expressed in axons. To address this more directly, two models of adult-onset demyelination have been used experimental autoimmune encephalitis (or EAE), and a transgenic mouse with two extra copies of the proteolipid protein (Plp) gene (Kagawa et al. 1994). In both models, subsequent to central demyelination, there is a dramatic increase in the amounts of Nav1.2 channels found in the axon (Craner et al. 2003 Rasband et al. 2003). In the case of the Plp over-expressor, the amount of Nav1.2 channels in demyelinated optic nerve axons increases by more than 6-fold. The results described here do not appear to be a phenomenon unique to mice. In fact, post-mortem brain tissue from multiple sclerosis patients shows a dramatic increase in Nav1.2 channels in demyelinated lesions (Craner et al....

Clinical Picture of HIV Infection

Although most of the attention given to the HIV virus has gone to suppression of the immune system or AIDS, the virus is associated also with brain diseases and several types of cancer. The brain and spinal cord disease caused by HIV was first detected in brain and spinal cord tissues from AIDS patients in 1984. The chief pathologies observed in the brain, which appears to be independent of the immune deficiency, are an abnormal proliferation of the glial cells that surround the neurons and lesions resulting from loss of white matter (which is, along with gray matter, one of the two main types of brain tissue). This can ultimately give rise to a wide range of neurological symptoms such as dementia and multiple sclerosis.

Scientific Foundations

Man undergoing plasmapheresis treatment for multiple sclerosis. In this treatment, blood is removed from the patient and the harmful agents that attack the nerve cells are filtered out before returning the blood to the body. Annie Griffiths Belt Corbis. Since that time, the National Multiple Sclerosis Society has divided MS into four types for the purposes of identification and treatment relapsing-remitting, secondary-progressive, primary-progressive, and progressive relapsing. Relapsing-remitting involves unpredictable relapses and attacks followed by remission (periods of no attacks). When symptoms go away between remission periods, it is called benign MS. It is the second most common type of MS. Secondary-progressive patients first go through a relapsing-remitting phase, which is followed by less severe attacks (but total remission does not occur). It is the most common type of MS.

Guide To Further Reading

Journal of Medicine 344 1145-1151 Cook T M, Protheroe R T, Handel J M 2001 Tetanus a review of the literature. British Journal of Anaesthesia 87 477-487 Compston A, Coles A 2002 Multiple sclerosis. Lancet Polman C H, Uitdehaag B M J 2000 Drug treatment of multiple sclerosis. British Medical Journal 2000 490 94

The Visual System

Parietal Lobe Lesion Quadrantanopia

Fig. 34 The visual pathways as seen from above the brain. Letters A-F refer to visual field defects following lesions in the corresponding brain areas. Circles indicate what the left and right eyes see (the left and right visual fields). Black areas represent visual field defects. A. Constricted field left eye (e.g end-stage glaucoma). When constricted fields are bilateral, it sometimes signifies hysteria. B. Central scotoma (e.g., optic neuritis in multiple sclerosis), C. Total blindness of the left eye. D. Bitemporal hemianopia (e.g., pituitary gland tumor). H. Right homonymous hemianopia (e.g stroke). F. Right superior quadrantanopia.

Traditional Views Of The Cp

How infected leukocytes or activated T lymphocytes cross the CP is unknown, but it is intuitively obvious that their crossing can have disastrous consequences. The CP might be involved in the CNS entry of activated, myelin-directed autoreactive T lymphocytes during multiple sclerosis (MS). Activated T-lymphocyte infiltration into the brain results in the formation of demyelination plaques that underlie the clinical symptoms of MS. Because these plaques are frequently located in the periventricular area, the CP may constitute a preferential way for T lymphocytes to reach these structures. T lymphocytes and T-lymphocyte chemo-attractants are found in the CSF from MS patients.

TNFa and Semimature DCs

In this regard, TNFa may play a role, since it has been shown that injection of DCs cultivated in presence of TNFa acted in a tolerogenic fashion 14 . In these experiments, DCs were able to block autoimmunity in a murine model of multiple sclerosis (EAE). This suppressive effect was mediated by the induction of IL-10-producing regulatory T cells. The subsequent phenotypic analysis revealed that the DCs expressed regular amounts of MHC class II and T cell co-stimulatory molecules, i.e., according to the authors these DCs displayed a mature phenotype as judged by their surface-marker expression. In contrast, these DCs failed to secrete IL-1 , IL-6, TNFa and in particular IL-12. The importance of IL-12 production for full maturation of DCs and acquisition of an immunostimulatory phenotype is further substantiated by results showing that IL-10 as well as cAMP are potent agonists of IL-12p70 secretion. In fact, DCs treated with these agents are resistant to terminal maturation and induce T...

Implication for the medical use of marijuana

The use of cannabis for both recreational and medicinal purposes dates back to thousands of years. In recent times, there has been an increase in calls for marijuana to be legalized for medicinal use in AIDS, cancer, multiple sclerosis and other medical conditions where patients might benefit from the biological effects of cannabis. Synthetic cannabinoids such as dronabinol, marinol and nabilone already have an established use as antiemetics in nausea and vomiting associated with cancer chemotherapy. The reported beneficial effects in cancer and AIDS patients might reflect improved weight gain, owing to the well-documented anti-emetic and appetite stimulating effects of cannabinoids. This might be a major advantage for cancer patients undergoing rigorous chemotherapy, or advanced AIDS patients. Interestingly, although cannabis is widely used as a recreational drug in humans, only a few studies revealed an appetitive potential of cannabinoids in animals. However, evidence for the...

The Effect Of Thymectomy On Autoimmune Diseases

Involvement in the pathogenesis of MG affects the response to thymectomy whereas 80 of the patients with thymic hyperplasia are expected to have significant clinical improvement or even complete remission after thymectomy, the response to thymectomy is disappointing in the presence of thymoma 30 . Similarly, thymectomy results in a good clinical response in patients with relapsing-remitting multiple sclerosis rather than patients with chronic-progressive disease 31 . Another condition in which thymectomy was found beneficial is ulcerative colitis in a series of ulcerative colitis patients, thymectomy induced high percentage of remission, and decreased the anticolon antibody activity 32 ,

Proinflammatory Cytokines

Solid tumours 15 , this cytokine has been implicated as the initiating signal for a variety of cellular and metabolic events seen in critically ill patients. TNF-a may circulate predominantly as a complex with its soluble receptors, making detection of the bioactive ligand more difficult. Increased levels of these soluble TNF-a receptors are seen in response to diverse inflammatory stimuli including sepsis, cancer and AIDS 16 . Nevertheless, elevated TNF-a levels are detected in many disease states including bacterial infections, cancer, sepsis and AIDS 17 . TNF-a is a metabolic hormone acting both in a paracrine fashion, and, in some istances, as an endocrine hormone 18 . Systemically, TNF-a has been suggested to act in the brain to cause anorexia and subsequent body weight loss 19 . The metabolic effects of TNF-a seem to promote redistribution of body protein and lipid stores. The result is a net loss of peripheral tissue protein with a concomitant increase in hepatic uptake 20 ....

Remyelination and Aging

Ibanez et al. 66 have reviewed the affects of aging on the remyelination of nerve fibers and the regenerative capacity of myelin sheaths to be restored in conditions such as multiple sclerosis. They cite data to show that as animals grow older, their capacity for remyelination declines. They suggest that the capacity for remy-elination can be partially reversed by steroid hormones and their derivatives.

Calpains In Myelodegenerative Diseases

Banik et al. (1994) have shown that component I of human MBP is more susceptible to proteolysis by calpain than components II and III. They have identified two major and several minor cleavage sites in MBP. Because MBP is degraded in demyelinating diseases such as multiple sclerosis (MS), the potential role of calpains in the pathogenesis of MS has been studied in several laboratories.

Caloric Restriction

Increases in several inflammatory responses are well documented during the aging process, and involve neuronal and nonneuronal (e.g., astrocytes, microglia, vascular elements, and epithelial cells) cells within the CNS 123-125 . For example, SPs, the extracellular amyloid deposits composed of Abeta peptides and other proteins that are prevalent throughout aged brain as well as in neurodegenerative disorders such as AD and Down's syndrome, are surrounded by astrocytes and infiltrated by microglial cells 17, 126, 127 . Inflammatory responses have been documented in virtually all age-related paradigms, ranging from normal senescence to neurodegen-erative disorders such as AD, PD, ischemia, motor neuron disease, and multiple sclerosis 25, 117, 123, 128-130 . The prevalence of the inflammatory changes, however, is tempered by the question as to whether the inflammatory response is a primary event or a secondary response based upon primary neurodegenerative cell death, or injury-based...

Regulation of Immune Cell Entry into the Central Nervous System

Abstract The central nervous system (CNS) has long been regarded as an immune privileged organ implying that the immune system avoids the CNS to not disturb its homeostasis, which is critical for proper function of neurons. Meanwhile, it is accepted that immune cells do in fact gain access to the CNS and that immune responses can be mounted within this tissue. However, the unique CNS microenvironment strictly controls these immune reactions starting with tightly controlling immune cell entry into the tissue. The endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid (CSF) barrier, which protect the CNS from the constantly changing milieu within the bloodstream, also strictly control immune cell entry into the CNS. Under physiological conditions, immune cell migration into the CNS is kept at a very low level. In contrast, during a variety of pathological conditions of the CNS such as viral or bacterial infections, or during inflammatory diseases such as...

The Immune Privilege of the CNS Reconsidered

Protection of the neurons from the constantly changing milieu in the periphery is achieved by the presence of highly specialized endothelial cells lining the walls of CNS microvessels that form the blood-brain barrier (BBB) (Engelhardt 2003) and additionally by the existence of the epithelial cells of the choroid plexus, which establish a blood-cerebrospinal fluid (CSF) barrier (Engelhardt et al. 2001). Both barriers inhibit the free diffusion of molecules from the blood into the CNS and were originally thought to also block immune cell entry into the CNS. The view of the immune privilege of the CNS, where no immune cell entry takes place has, however, been in conflict with observations already made by Medawar and colleagues (Medawar 1948), who demonstrated that an allogeneic tissue graft into the CNS, which would be tolerated in a naive host, is readily rejected in a recipient, who was specifically sensitized to the allo-antigens prior to transplantation. Additional observations of...

Human clinical studies

Recently, Mikuriya (1999) reported on interviews of 1800 patients who used marijuana for various medical conditions. Of these patients, he reported that 41 experienced analgesia following traumatic inflammation induced pain, autoimmune disorder-induced pain and ideopathic pain. Similarly, Consroe et al. (1997) found self-reported reductions in pain in patients with multiple sclerosis. Consroe et al. (1998) found similar self-reported pain reduction in patients with spinal cord injury. Schnelle et al. (1999) used an anonymous standardized survey of the medical use of cannabis and cannabis products of patients in Germany, Austria and Switzerland. Data from 128 170 patients were usable. Of these, 5.4 used cannabis for back pain and 3.6 for headache. Table 2.2 lists human studies of cannabinoid effects on pain.

Alphaglucosidase inhibitor blocks hydrolysis of an

Multiple endocrine neoplasia - one of several inherited endocrine gland syndromes caused by a defect in tumor suppressor genes multiple myeloma - a malignant disease characterized by the infiltration of bone and bone marrow by neoplastic plasma cells multiple sclerosis - a progressive neurodegenerative disease affecting the axons of nerves in the area surrounding the ventricles of the brain but not the peripheral nerves

Peptide Vaccine Induced Anaphylaxis in the NOD Mouse

The identification of autoantigens in autoimmune diseases such as type 1 diabetes or multiple sclerosis has made peptide immunotherapy possible. In fact, peptide vaccine trials are currently underway in type 1 diabetes for an altered peptide ligand of insulin peptide B 9-23 (20), for GAD peptides, and for heat shock protein 60 (HSP60) (p277) (21). However, in mouse studies of peptide vaccination, anaphylaxis has been reported in diabetes experiments using the B 9-23 peptide (22) and GAD peptides (23) and in multiple sclerosis studies (experimental autoimmune encephalitis) using proteolipid protein (PLP) (139-151) and myelin oligodendrocyte glycoprotein (MOG) (35-55) peptides (24). Even more concerning is the report of systemic hypersensitivity reactions in humans during phase II trials with an altered peptide ligand for myelin basic protein (MBP) (83-99) (25,26), which led to the premature discontinuation of therapy in some patients. More research into peptide-induced anaphylaxis,...

P2X Glial Signalling and Plasticity Responses

Taken together these data indicate the strict links between purinergic signalling and glial mediated CNS inflammatory responses. The purinergic mediated release of inflammatory cytokines from microglial cells is of particular relevance taking into account the suggested role of cytokines in different CNS pathologies. Cytokine mediated inflammation mechanisms were suggested as pathogenic mechanisms in multiple sclerosis, Alzheimer's and Parkinson's disease.103 The availability of specific purinergic agonists antagonists and the definition of the P2X receptors role in controlling the inflammatory cascade is providing important data for planning new therapeutic strategies for neurodegenerative diseases.

CSF Proteomic Applications in Central Nervous System Diseases

Only a few comparative proteomic analyses of CSF proteins have been employed for studies of pathophysiological mechanisms in neurodegenerative diseases. Using 2-DE gel and the silver staining technique, large differences in protein patterns in CSF between patients with brain disorders such as AD, schizophrenia, Parkinson's disease, and multiple sclerosis were shown 24, 25, 28, 73 , however many of these proteins have not yet been identified. Fonteh and Harrington reported at the 2002 meeting in Siena an increase of specific isoforms of apo-lipoproteins A1, J, K and prostaglandin D synthase (PGDS) in the CSF of AD study participants 74 . Moreover, Harrington and colleagues have described significant changes in the abundance of 10 CSF proteins during the headache phase of migraine and more subtle changes in isoforms of two other proteins in the wellstate of a migraineur population compared with controls who were not susceptible to headaches 75, 76 . In a proteomic study of CSF proteins...

Isolation of Retroviruses by Self Generated Gradients18

Human cells from patients suffering from multiple sclerosis were cultivated, and the supernatants were separated from cells and debris after centrifugation at 1000 g at 4 C for 30 min. The supernatant was transferred to a 60-mL centrifuge tube, and underlaid with 4 mL of a concentrated solution of iodixanol, an iodinated, nonionic density gradient medium, in HEPES-NaOH (60 mM, pH 7.4, 0.8 NaCl). This dense underlay medium is called a cushion , and prevents the pelleting of particles less dense. Particles then concentrate at the interface between the supernatant and the cushion. The tubes were centrifuged in a fixed angle rotor (22.5 ) at 45,000 g (4 C, 2 h) and the supernatant removed from the tubes by aspiration, leaving only of 4-5 mL in the proximity of the cushion. The cushion and the overlying supernatant were combined, and the volume measured for final regulation of the concentration of the gradient medium.

The epidemiology and impact of chronic fatigue syndrome

CFS has a marked impact on people's lives. Studies have shown that they report greater levels of dysfunction in almost all domains of life when compared to patients who have multiple sclerosis (MS), hypertension, congestive heart failure, type II diabetes mellitus, and acute myocardial infarction (Komaroff et al. 1996 Schweitzer et al. 1995). In fact, only terminally ill cancer and stroke patients are known to report equivalent levels of disability to CFS patients (Schweitzer et al. 1995). Approximately a quarter of all CFS patients describe themselves as regularly bedridden (Komaroff and Buchwald 1991), with around 40 per cent unemployed because of their illness and a further 20 to 30 per cent having to reduce their work commitments to part-time (Bombardier and Buchwald 1995 Lloyd et al. 1990).

Biological Activity and Side Effects

Mitoxantrone is used in first-line therapy for acute myelocytic leukemia (AML) (198), and along with cytosine arabinoside, is suggested as salvage therapy in AML and chronic myelocytic leukemia (CML) (199). I n combination with a steroid, it is the drug of choice for palliative treatment of hormone-resistant prostate cancer (200). It is also an effective treatment for secondary progressive multiple sclerosis, but the duration of treatment is lim

Mechanisms of Incontinence

Tension Free Vaginal Tape

This patient has long-standing diabetes mellitus, which is a risk factor for a neurogenic bladder leading to overflow incontinence. Other causes include spinal cord injury or multiple sclerosis. These patients generally do not feel the urge to void and accumulate large amounts of urine in their bladders. The best therapy for overflow incontinence (neurogenic bladder) is intermittent self-catheterization.

Surrogate Endpoints

A third reason for using surrogate endpoints is that they are often more objective measures than are the true clinical endpoints. For example, measurements on x-rays of arthritic joints may be more objective than assessments of inflammation or pain, and changes on magnetic resonance imaging (MRI) scan in a patient with multiple sclerosis may be less subjective than reports of disability. Use of objective endpoints can offer substantial benefits in protection against bias, particularly in unblinded trials and trials partially unblinded by drug effects.

Annexin 1 And Inflammation

Annexin 1 is up-regulated in multiple sclerosis and in an experimental model of the disease (experimental autoimmune encephalomyelitis-EAE) intracerebroven-tricular administration of annexin 1 proved to be neuroprotective. Annexin 1 is present in both macrophages and astrocytes localised in the lesions (Bolton et al., 1990 Huntinga et al, 1998). In experimental autoimmune neuritis (EAN), a model for human Guillain-Barre syndrome, increased annexin 1 expression was also observed in macrophages and T-cells in the inflamed sciatic nerve (Gold et al.,1999).

Lim mwal orthopaedic examination

Disc prolapses in the thoracic spine are rare and have a variety of presentations, often with a confusing clinical picture. There may be bandlike chest pain, scoliosis, bizarre neurological disturbances with peripheral temperature changes, altered reflexes, and weakness of the limbs. A number are misdiagnosed as multiple sclerosis or amyotrophic lateral sclerosis. They may be diagnosed by MRI scan, and treated by transthoracic excision.

Lymphoid Malignancies

Full-blown autoimmune diseases, such as multiple sclerosis, Grave's disease, RA, SLE and pernicious anemia have also been recorded in the family members of these patients, again suggesting that a common genetic factors predispose to B-cell proliferation and antiself reactivity. Conversely, levels of serum IgG, IgM and IgA have been reported to be abnormally high in 25,17 and 50 of RA patients and 10, 23 and 8 of their relatives

Medical Examination Under Section 4 of the RTA

Whether the examination is carried out by a forensic physician in London or an emergency room physician in San Francisco, the aim of the examination is to exclude any medical condition other than alcohol or drugs as the cause of the driver's behavior. The differential diagnosis is wide and includes head injury, neurological problems (e.g., epilepsy, stroke, cerebral tumour, and multiple sclerosis), metabolic problems (e.g., hypoglycemia), hepatic or renal failure, and mental illness. The procedure should include introductory details, full medical history, and clinical examination. In Scotland, forensic physicians use form F97. Appendix 6 contains a form that has been found useful. Similar forms are not available in the United States, but there is nothing to prevent any emergency department in the United States from drafting and providing a similar document. Even if no special form is provided, most of the relevant material will have been (or at least should be) recorded in the...

Spasm Of Striated Muscle

Tion of the spasm in a variety of ways, including psychotherapy, sedation and the use of a centrally-acting muscle relaxant as well as non-narcotic analgesics, e.g. baclofen, diazepam clinical efficacy is variable (see Other muscle relaxants, p. 357). Local infiltration with lignocaine (lidocaine) is sometimes appropriate. Hzanidine is an a2-adrenoreceptor agonist that may be used to relieve muscle spasticity in multiple sclerosis, spinal cord injury or disease.

Immunosurveillance of the CNS Immune Cell Entry into the Healthy CNS

Direct evidence for immune cell entry into the healthy CNS was established by studying experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, reviewed by (Lassmann 1983 Martin and Mc-Farland 1995 Sospedra and Martin 2005). In contrast to multiple sclerosis, the etiology of which remains unknown to date, EAE is a T cell mediated autoimmune disease of the CNS that can be induced in susceptible animals including different rat and mouse strains by immunization with selected myelin components, reviewed in (Wekerle et al. 1994) or by intravenous injection of freshly activated neuroantigen-specific, i.e., encephalitogenic, CD4+ T cell blasts into syngeneic naive recipients (Ben-Nun et al. 1981). In both types of EAE, activation of the CD4+ auto-aggressive T cells takes place outside of the CNS. Tracing intravenously injected radioactively labelled encephalitogenic T cell blasts revealed that they are able to penetrate the non-inflamed BBB in healthy Lewis...

Experimental Autoimmune Encephalomyelitis EAE

EAE is a primarily CD4+ T cell-mediated demyelinating disease of the CNS, and it is widely used as an animal model for human multiple sclerosis (MS). EAE can be induced in susceptible animal strains by immunization with various myelin proteins or immunodominant peptide epitopes derived from myelin basic protein (MBP), proteolipoprotein (PLP), or myelin oligodendrocyte glycoprotein (MOG) peptide emulsified in complete Freund's adjuvant (CFA) together with pertussis toxin treatment (Gonatas etal., 1986 Wekerle, 1991). THl-type responses appear to be responsible for EAE pathogenesis, while TH2 responses seem to be protective (Adorini and Sinigaglia, 1997 Liblau et al., 1995). The adjuvant and pertussis might be necessary to skew the systemic cytokine profile to TH1 phenotype, affect the blood-brain barrier, and support prolonged inflammation.

Modulators Of Bloodbrain Barrier Functions And Their Interrelationships

The passage of immunomodulators across the BBB has been the subject of much research activity, especially because of the known impairment in BBB functioning in autoimmune diseases such as multiple sclerosis (MS).74 It is generally considered that basic mechanisms of brain inflammation involve massive, yet transient, disruption of BBB functioning that plays an important role in the acute episodes of several autoim-

Inflammation In Alzheimer Dementia

It should be emphasized that the theory of inflammation as a primary disease-aggravating hallmark, opposed to a secondary or even a disease-ameliorating factor, remains a hypothesis. One should be aware that our current knowledge of microglia is still incomplete, speculative, and mainly based upon in vitro observations rather than in vivo studies (33). Indeed, B or T cells and immunoglobulins (Igs) are not readily detectable in the Alzheimer's dementia brain and are found only in very small amounts in relation to amyloid plaques (without IgM IgA) (34). Likewise, although the presence of leukocytes has been demonstrated, their role in Alzheimer's dementia has not been established (35). As such, the evidence for an antigen-driven acquired immune response in Alzheimer's dementia, with T cells eliminating amyloid and B cells producing Ap-specific antibodies, is not as overt as in well-established neuro-inlfammatory diseases (e.g., multiple sclerosis 36).

Future Strategies And Developments In Mrbased In Vivo Metabolic Imaging

Modification of spectra with metabolite-nulling sequences allow for improved evaluation of lipids and other macromol-ecules, with improved resolution of peaks at 0.9 ppm, and 1.3 ppm, and 2.1 ppm. These correlated to spectra of methyl groups, methylene, and terminal methylene groups, respectively. Findings have been evaluated in the setting of acute stroke and multiple sclerosis. Mader et al. (165) found significant evaluation in macromolecular peaks in the setting of acute MS plaques in contrast to normal-appearing white matter and chronic MS lesions, perhaps representing the residues from cytosolic protein that may become elevated during the course of disruption.

Peroxisomal Disorders

The first manifestations of ALD may be psychiatric or behavioral hence, diagnosis may be delayed. In the classic forms, progressive dementia ensues with disturbances of gait manifest by spastic paraplegia. Other features include cerebellar signs of clumsiness and incoordination, dysarthria, dysphagia, and neurosensory loss. Visual loss occurs because of optic atrophy or bilateral occipital white matter lesions. Seizures, when present, are multifocal in origin. Features may appear asymmetric in onset. Pace of deterioration is variable. Adrenomyeloneuropathy or AMN is a phenotypic variant and may occur in families with boys with classic adrenoleukodys-trophy. This variant involves additionally, distal polyneuropa-thy. Females, because of their allelic heterogeneity and variant X-inactivation, may appear unaffected or display variable symptoms from mild to more significant. Features may mimic multiple sclerosis.

Charles W Stratton and Subramaniam Sriram 1 Introduction

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS).(1'2)It commonly affects adults between the ages of 18 and 50 years, with the mean onset of initial symptoms being 29 years of age. In the general population, the prevalence of MS is approximately 1 1000. Women are generally affected more commonly than men. Most MS patients initially present with a relapsing remitting course. This relapsing remitting course slowly evolves into a progressive disease. The exact pathogenesis of MS remains unknown, which adversely affects attempts at medical intervention. The following discussion reevaluates the current hypothesis concerning autoimmunity in MS and describes how an infectious process may influence the development of MS and proposes that C. pneumoniae is a likely candidate pathogen in the development of MS.(3-6)

Conditions inducing bloodbrain barrier disruption

Several diseases are known which are associated with BBB disruption. These include brain tumor metastases epilepsy and the more severe condition of status epilepticus cerebrovascular disorders autoimmune diseases such as multiple sclerosis acute cerebral infarcts meningeal carcinomatosis and ischemic white matter lesions.77 84 Several genetic polymorphisms are known which increase the susceptibility to BBB disruption. These include polymorphisms in glutathione transferase, important for protection against oxidative stress,85 and malfunctioning variants of serum BChE (e.g., atypical BCHE)86 In particular, such mutations increase the risk of BBB disruption that is involved with exposure to anticholinesterases or to lead sulfate batteries, with subsequent increased risk for Parkinson's disease.87,88

Generation of altered oxidized bases in DNA such as 8oxoguanine or 5hydroxyuracil and thymine

The role of peroxynitrite in the nerve degeneration causing multiple sclerosis (MS) has been brought into focus with the observation that patients with gout hardly ever develop MS, suggesting that the chronic uric acid elevation causing gout also prevents the development of MS.

Clinical Approach

Less common causes of dementia include medical conditions such as Wernicke encephalopathy resulting from thiamine (vitamin B,) deficiency, vitamin B , deficiency resulting from pernicious anemia, untreated hypothyroidism. or chronic infections such as HIV dementia or neurosyphilis. A variety of primary central nervous system (CNS) diseases can lead to dementia, including Huntington disease, multiple sclerosis, neoplastic diseases such as primary or metastatic brain tumors (although they are much more likely to produce seizures or focal deficits rather than dementia), or leptomeningeal spread of various cancers. Normal pressure hydrocephalus is a potentially reversible form of dementia in which the cerebral ventricles slowly enlarge as a result of disturbances to cerebral spinal fluid resorption. The classic triad is dementia, gait disturbance, and urinary or bowel incontinence. Relief of hydrocephalus through placement of a ventriculoperitoneal shunt may reverse the cognitive decline....

Interpreting symptoms

Any situational factor that raises the awareness of symptoms or illness promotes their recognition by individuals. So when a friend you have just had lunch with suddenly feels ill, this is likely to set up a search for similar symptoms consistent with your friend's illness. Studies have shown that individuals are very susceptible to noticing symptoms in this way. There are a number of real life examples of this. A common one in the environment we work in is 'medical students' disease'. Here, students studying the symptoms of an illness focus on their own internal states, and symptoms consistent with the illness they are studying tend to emerge. In a medical school class, typically about a third of students will by their third year admit to this phenomenon, with a number commonly self-diagnosing (incorrectly) a brain tumour, heart attack or multiple sclerosis.

The Relationship Between Sun Exposure and Other Diseases

There is in Australia unanimous agreement by the ACOD, OA, ANZBMS, and CCA that there is high-level evidence for the harmful effects of sun exposure in terms of skin cancer and for the beneficial effects of sun exposure in maintaining adequate vitamin D levels to protect against bone fracture (Trivedi et al. 2003). However, all parties agree that substantially more evidence is required before conclusions can be drawn between sun exposure and a possible beneficial effect with other cancers such as breast, prostate, bowel, or non-Hodgkin lymphoma and autoimmune diseases such as multiple sclerosis. The biological pathways underlying these empirically observed observations are still not clear and in some instances the epidemiological evidence is equivocal. It was agreed by all parties that it is not appropriate to make statements about a protective effect of UV radiation exposure for these diseases because substantially more studies with good individual exposure measures by season is...

Viral Persistence and Immune Mediated Demyelination

Viral persistence in white matter tracts results in a chronic demyelinating disease in which foci of demyelination are associated with areas of viral RNA antigen 51 . Clinically, mice develop loss of tail tone and a partial to complete hind-limb paralysis. As a result of the clinical and histologic similarities between MHV-induced demyelination and the human demyeli-nating disease multiple sclerosis (MS), the MHV system is considered a relevant model for studying the underlying immunopathologic mechanisms contributing to immune-mediated demyelinating diseases 51 . A variety of different mechanisms have been postulated to contribute to MHV-induced demyelination. Several studies suggest that MHV-induced demyelination involves immunopathologic responses against viral antigens expressed in infected tissues 30, 31, 37,47 . Although virus-specific antibody is considered important in suppressing viral recrudescence 84, 85 , it may also have a role in promoting demyelination 48 . MHV...


Acknowledgements The authors wish to thank Craig Walsh for helpful discussion. This work was supported by National Institutes of Health grants NS41249, NS18146, and National Multiple Sclerosis Society Grant 3278 to T.E.L. J.L.H. is supported by postdoctoral fellowship 1652 from the National Multiple Sclerosis Society.


Ca2+ to covalently bound EF-hand motifs, to a separate EF-hand subunit, but also to two Ca2+-binding sites of novel type located close to the catalytic center. The two dimeric calpains designated as m and m are ubiquitous. Other tissue-specific calpains, by contrast, are monomeric and may not contain the endogenous EF-hand motifs. However, as they still contain the non-EF-hand Ca2+-binding sites, they are still likely to be controlled by Ca2+. Calpains are regulatory proteases that do not demolish protein substrates completely rather, they remove from them limited peripheral portions, frequently leading to their activation. The two ubiquitous dimeric calpains have been involved in a long list of cell dysfunction states related to disturbances of Ca2+ homeostasis which could have lead to abnormal calpain activation. Alzheimer's disease, cataract, and multiple sclerosis have frequently been mentioned a particularly interesting and well documented case is that of excitotoxic neuronal...

Central Cytokines

Glia cells and neurons in various brain areas express proinflammatory cytokines and cytokine receptors 9, 10 . Acute and chronic CNS diseases (e.g., meningitis, encephalitis, multiple sclerosis, Alzheimer's disease, stroke and brain tumours) stimulate CNS cytokine production 11, 12 . Cytokines produced within the blood-brain barrier (BBB) can act directly on neural circuitries controlling energy balance, and intracerebroven-tricular (ICV) administration of proinflammatory cytokines presumably models the clinical features of such diseases, e.g. anorexia. Peripheral immune stimulation may increase de novo proinflammato-ry cytokine synthesis in the brain, and this may contribute to anorexia in some of these conditions 3, 13-15 . Often, however, centrally produced cytokines may not be essential in the anorexia of systemic immune challenges because a crucial cytokine is not expressed in the brain 16 , the cytokine expression pattern does not fit a role in the anorexia 17 , and only...

Spastic Conditions

A discussion of the efficacy of cannabis in the relief of spasticity associated with multiple sclerosis appears in Section 2.3. This should not be viewed in isolation, as it is possible that the underlying neuropharmacology and thus approach to treatment of a range of disorders, may be similar.

Functional Coimaging

Attempts have been made to visualize inflammation by means of cobalt radioisotopes. Both in vivo and in vitro experiments have shown that Ca2 accumulates in the damaged nerve cell body and degenerating axons by two mechanisms (1) a passive influx caused by a shortage of ATP following ischemia, resulting in the disappearance of the membrane potential, and (2) neuronal and glial uptake by divalent cation-permeable kainate-activated non-N-methyl-D-aspartate glutamate receptor-operated channels in the membrane (5257). 57Co (SPECT) and 55Co (PET), both as Ca2+-analogs, can reflect Ca2+-influx in ischemically or neurotoxically damaged cerebral tissue. In this way, both 57Co SPECT and 55Co PET have been shown capable of visualizing focal neurode-generative changes, reactive gliosis, endangered brain tissue, and or ongoing neuronal tissue decay, including inflammatory lesions in various brain diseases, for example, multiple sclerosis, trauma, tumors, and stroke (58-64). Moreover, the time...

Brain Stem

Brain Stem Motor Nuclei Images

In evaluating a patient, the neurologist asks a sequence of questions. First, where is the lesion (spinal cord, brain stem, cerebrum, etc.) Second, what is the lesion (tumor, infection, hemorrhage, etc.) third, what can be done to help the patient (medication, surgery, etc.) The neurologist tries to determine if a single lesion can account for the patient's symptoms and signs. If multiple lesions must be postulated, this generally implies either metastatic disease, multiple sclerosis, the presence of two different diseases, or the presence of malingering or hysteria.


The first 4 years of childhood (De Bolle et al. 2005). The time of HHV-6A infection is still unknown, but is thought to occur following infection with HHV-6B. As a consequence, roseoloviruses are ubiquitously spread in the general adult population, usually reaching a seroprevalence of greater than 95 . Primary infection with HHV-6b or HHV-7 results in an acute febrile illness that is in some cases followed by the appearance of a mild skin rash on the face and trunk (i.e., exanthem subitum or roseola infantum Yamanishi et al. 1988 Tanaka et al. 1994). Interestingly, infection with HHV-6A is usually asymptomatic (Dewhurst et al. 1993 Stodberg et al. 2002 Freitas et al. 2003). Clinical complications of (primary) HHV-6 and -7 infections include febrile seizure, but also meningoencephalitis, encephalopathy, and multiple sclerosis (for a review see De Bolle et al. 2005). Importantly, primary HHV-7 infection can reactivate HHV-6 (Frenkel and Wyatt 1992 Katsafanas et al. 1996 Tanaka-Taya et...

Human studies

Consroe et al. (1997) found that anxiety was reduced in 85 of patients, using cannabis, with multiple sclerosis in a self-report questionnaire. In another self-report study (Consroe et al., 1998) patients with spinal cord injuries, who used cannabis, reported similar reductions in anxiety.


In a study of normal subjects, Musty (1988) found a positive correlation on the depression scale of the MMPI with feelings of euphoria after smoking marijuana, while there was no correlation between anxiety (Hysteria Scale) and somatic concerns (Hypochondriasis Scale) with feeling euphoric, suggesting an antidepressive effect from marijuana use. Schnelle, Grotenhermen, Reif et al. (1999), in a survey of 128 patients in Germany, 12 reported marijuana use for relief of depression. Consroe et al. (1997) found that depression was reduced in patients with multiple sclerosis (who smoked cannabis) using a self-report questionnaire. In another self-report study (Consroe et al., 1998) of patients with spinal cord injuries similar reductions in depression were reported. In cancer patients, Regelson (1976) found THC relieved depression in advanced cancer patients. Finally, Warner and colleagues (1994) found reported relief from depression, in a survey of 79 mental patients. At present, there are...


That can be improved through new genomic methods are suffering because of the diversion of research resources from their disease. This diversion phenomenon was seen in patients suffering from cancer, multiple sclerosis, and other diseases when federal funding focused on the elimination of AIDS. As more research laboratories focus on the leading edge genomic issues in medicine, research focused on patients with less exciting diseases are likely to be ignored to a degree.


1997), analysis of subcortical structure volumes in schizophrenia (Iosifescu et al., 1997), estimation of structural variation in normal and diseased populations (Collins et al., 1994b Thompson et al., 1997), and segmentation and classification of multiple sclerosis lesions (Warfield et al., 1995). Projection of digital anatomic models into PET data can also serve to define regions of interest for quantitative calculations of regional cerebral blood flow (Ingvar et al., 1994). These template-driven segmentations require extensive validation relative to more labor-intensive manual delineation of structures but show considerable promise in medical imaging applications.

Future Prospects

Therapeutic research with cannabis in the fields of depression, anxiety and insomnia has ceased. There is objective evidence that in several disorders, such as nausea and vomiting associated with cancer chemotherapy, glaucoma, pain relief and relief of muscle spasm, adjunctive use will provide benefit in some patients at certain stages of their disease. In some cases, e.g. cancer, multiple sclerosis, AIDS, the nature of the illness is such that to deny access to this potentially valuable drug without first obtaining the necessary proof of efficacy from conventional clinical trials, seems unreasonably pedantic. There is considerable evidence that selected patients would and should obtain relief from the symptoms of their disease using cannabis or derivatives thereof, when no other substance will suffice. Reasons for this may be that conventional therapy is contraindicated in terms of route, dose, side effect profile or hypersensitivity or that the cannabinoid in question has a...

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