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Demyelinating diseases 1071 Multiple sclerosis

Multiple sclerosis (MS) was recognized by the mid 19th century, and already in 1871 Hammond referred to it as a cerebrospinal sclerosis it was Charcot who, in 1877, realized the role of disrupted myelin in the pathogenesis of this disease. MS is an inflammatory demyelinating disease of the CNS, which culminates in progressive neurological deterioration. The aetiology of MS remains elusive, as both genetic predisposition and environmental factors are indicated. The importance of genetic predisposition is evident from very high concordance of the disease occurrence between monozygotic twins, whereas the environmental factors are implicated by the existence of geographical areas with remarkable differences in MS prevalence (generally, MS is significantly more frequent in northern than in southern parts of the world). The general theory regards MS aetiology as an infection which presents the immune system with an antigen similar to CNS myelin the resulting antibodies eventually attack CNS...

Multiple sclerosis

Multiple Sclerosis (MS) is a chronic T-cell mediated demyelinating autoimmune disease of the central nervous system. Disease onset usually occurs between 20 and 40 years of age, after which progression is variable, but generally slow. The geographic distribution of the disease has led to much debate over the relative importance of racial susceptibility (presumably genetic) and environment. On the one hand, there is a strong gradient towards higher prevalence at higher latitudes, both north and south of the equator on the other, there are marked deviations from this pattern, including a high prevalence among Sardinians and Palestinians, and low prevalence among Chinese and Japanese, black Africans, Maoris and Amerindians (Rosati, 2001).

Neurological Disease And Therapy

Handbook of Multiple Sclerosis, edited by Stuart D. Cook 43. Handbook of Multiple Sclerosis Second Edition, Revised and Expanded, edited by Stuart D. Cook 53. Handbook of Multiple Sclerosis Third Edition, edited by Stuart D. Cook 80. Handbook of Multiple Sclerosis, Fourth Edition, edited by Stuart D. Cook Handbook of Multiple Sclerosis Fourth Edition

Susceptibility Linkage

It has long been recognized that, despite living at geographical latitudes where multiple sclerosis (MS) is common, genetically isolated ethnic groups including Gypsies in Hungary (1) Indians and Orientals in North America (2) Aborigines in Australia (3) and Maoris in New Zealand (4) remain resistant to the disease. Systematic analysis of familial aggregation of MS in particular, studies of twins (5-8), adoptees (9), and half-siblings (10) has also confirmed Eichhorst's description from the 1890s of MS as a heritable disorder (11). The degree to which a disease is heritable can be estimated by dividing the lifetime risk of siblings to affected individuals by the population prevalence of the disease, to yield the so-called ks statistic. For MS, in high-risk populations, ks is between 20 (0.02 0.001) and 40 (0.04 0.001) a value similar to that seen in insulin-dependent diabetes mellitus (12). Data from twin studies which show that the concordance rate of approximately 30 in monozygotic...

What Is The Pathogenic Role Of Inflammation In Ms

Figure 5 (See color insert.) Inflammation in multiple sclerosis lesions. The inflammatory infiltrate within an active multiple sclerosis lesion contains variable numbers of perivascular and parenchymal CD3+ T-lymphocytes (A), cytotoxic CD8+ T-lymphocytes (B), macrophages (C KiMIP), CD20+ B-lymphocytes (D), and plasma cells (H& E). Figure 5 (See color insert.) Inflammation in multiple sclerosis lesions. The inflammatory infiltrate within an active multiple sclerosis lesion contains variable numbers of perivascular and parenchymal CD3+ T-lymphocytes (A), cytotoxic CD8+ T-lymphocytes (B), macrophages (C KiMIP), CD20+ B-lymphocytes (D), and plasma cells (H& E).

Oligodendrocyte Pathology and Early Remyelination

Figure 6 Electron microscopy of an early multiple sclerosis lesion reveals active demyelina-tion occurring simultaneously with remyelination. A macrophage containing myelin debris is in proximity of both completely demyelinated axons (Ax), as well as thinly remyelinated axons (*). Source Photo courtesy of Dr. Moses Rodriguez, Mayo Clinic, Rochester, Minnesota, U.S.A. Figure 6 Electron microscopy of an early multiple sclerosis lesion reveals active demyelina-tion occurring simultaneously with remyelination. A macrophage containing myelin debris is in proximity of both completely demyelinated axons (Ax), as well as thinly remyelinated axons (*). Source Photo courtesy of Dr. Moses Rodriguez, Mayo Clinic, Rochester, Minnesota, U.S.A.

Balo Concentric Sclerosis BCS

Figure 12 (See color insert.) Spectrum of inflammatory demyelinating diseases. Marburg type multiple sclerosis Macroscopically, confluent lesions lead to mass effect and herniation (A and B). Microscopically, there is extensive demyelination and axonal loss (C, LFB PAS D, Bielschowsky). Balo concentric sclerosis Note the characteristic alternating bands of demyelination and preserved myelin (E). ADEM The lesions are characterized by perivascular inflammation and only minimal, mainly perivenular demyelination (circles, F). Tumefactive lesion Note with severe edema and mass effect (G). Creutzfeld-Peters cell The presence of these cells should prompt consideration of an active demyelinating lesion (H). Abbreviations LFB PAS, luxol fast blue periodic acid schif ADEM, acute disseminated encephalomyelitis. Source From Ref. 163. Figure 12 (See color insert.) Spectrum of inflammatory demyelinating diseases. Marburg type multiple sclerosis Macroscopically, confluent lesions lead to mass effect...

Mechanisms of Recovery

Figure 15 Sagittal diffusion tensor magnetic resonance image of the cervical cord from a patient with relapsing-remitting multiple sclerosis mean diffusivity map (A), fractional aniso-tropy map (B), and color-encoded map of directionality (dark gray color means a preferential fiber direction along the z-axis, gray color along the x-axis, light gray color along the y-axis). The loss of normal fiber directionality is visible (C). Figure 15 Sagittal diffusion tensor magnetic resonance image of the cervical cord from a patient with relapsing-remitting multiple sclerosis mean diffusivity map (A), fractional aniso-tropy map (B), and color-encoded map of directionality (dark gray color means a preferential fiber direction along the z-axis, gray color along the x-axis, light gray color along the y-axis). The loss of normal fiber directionality is visible (C). Table 3 Main Damaging Recovery Aspects of Multiple Sclerosis and Magnetic Resonance Imaging Techniques with the Potential to Provide...

Mri In Monitoring Treatment Efficacy In Ms Trials

Figure 17 (A) Scatterplot of the correlation between the relative activation of the contralateral primary sensorimotor cortex and average lesion mean diffusivity in nondisabled relap-sing-remitting multiple sclerosis patients during a simple motor task. (B) Scatterplot of the correlation between the relative activation of the contralateral infraparietal sulcus and normal appearing brain tissue average mean diffusivity in nondisabled relapsing-remitting multiple sclerosis patients during a simple motor task. Figure 17 (A) Scatterplot of the correlation between the relative activation of the contralateral primary sensorimotor cortex and average lesion mean diffusivity in nondisabled relap-sing-remitting multiple sclerosis patients during a simple motor task. (B) Scatterplot of the correlation between the relative activation of the contralateral infraparietal sulcus and normal appearing brain tissue average mean diffusivity in nondisabled relapsing-remitting multiple sclerosis patients...

The Chronic Inactive MS Lesion

Multiple Sclerosis Lesions

Figure 1 (See color insert.) Chronic multiple sclerosis. Grossly, plaques appear as well-circumscribed, slightly depressed gray areas of increased tissue texture. The chronic inactive plaque microscopically appears as a sharply circumscribed area of myelin pallor (A, LFB PAS) with variable reduction in axonal density (B, neurofilament protein). The lesions are hypocel-lular and lack macrophages containing myelin debris (C, KiMlP for macrophages). Abbreviation LFB PAS, luxol fast blue periodic acid schif. Figure 1 (See color insert.) Chronic multiple sclerosis. Grossly, plaques appear as well-circumscribed, slightly depressed gray areas of increased tissue texture. The chronic inactive plaque microscopically appears as a sharply circumscribed area of myelin pallor (A, LFB PAS) with variable reduction in axonal density (B, neurofilament protein). The lesions are hypocel-lular and lack macrophages containing myelin debris (C, KiMlP for macrophages). Abbreviation LFB PAS, luxol fast blue...

Brief Review Of Basic Aspects Of Nonconventional Mr Techniques

Magnetisation Transfer Weighted Images

Figure 3 Axial magnetic resonance images from a patient with multiple sclerosis. The proton density weighted scan (A) shows multiple lesions. On the scalp-stripped magnetization transfer ratio map (B), lesions appear as hypointense areas. The degree of hypointensity is related to decrease in magnetization transfer ratio and indicates damage to myelin and to axonal membranes. Figure 3 Axial magnetic resonance images from a patient with multiple sclerosis. The proton density weighted scan (A) shows multiple lesions. On the scalp-stripped magnetization transfer ratio map (B), lesions appear as hypointense areas. The degree of hypointensity is related to decrease in magnetization transfer ratio and indicates damage to myelin and to axonal membranes. Figure 4 Axial magnetic resonance images from a patient with multiple sclerosis. (A) Proton density-weighted image. On the scalp-stripped mean diffusivity map (B), some of the lesions appear as hyperintense areas. The degree of hyperintensity...

The Role Of Mri In Understanding Ms Pathophysiology

Tcuadro Clinico Tumores Cerebrales

Figure 12 Relative cortical activations on a rendered brain during the performance of a simple motor task with the dominant, functionally unaffected right hand in patients with clinically isolated syndromes suggestive of multiple sclerosis who evolved to definite multiple sclerosis over a short-term follow-up period (A and B) compared with those who did not (C and D). When compared with (C and D), in (A and B), a more extensive and widespread activation of the sensorimotor network is visible. Figure 12 Relative cortical activations on a rendered brain during the performance of a simple motor task with the dominant, functionally unaffected right hand in patients with clinically isolated syndromes suggestive of multiple sclerosis who evolved to definite multiple sclerosis over a short-term follow-up period (A and B) compared with those who did not (C and D). When compared with (C and D), in (A and B), a more extensive and widespread activation of the sensorimotor network is visible....

The Role Of Mri In The Diagnosis And Prognosis Of Ms

Meningitis Mri Images

Figure 6 Axial fast-fluid-attenuated inversion recovery images (A and B) from a patient with multiple sclerosis. In (A) and (B), multiple sclerosis lesions appear as areas of increased signal. The suppression of the signal of the cerebrospinal fluid allows a better identification of the lesions located in the periventricular and juxtacortical regions. Figure 6 Axial fast-fluid-attenuated inversion recovery images (A and B) from a patient with multiple sclerosis. In (A) and (B), multiple sclerosis lesions appear as areas of increased signal. The suppression of the signal of the cerebrospinal fluid allows a better identification of the lesions located in the periventricular and juxtacortical regions. Figure 7 Axial proton density-weighted (A) and postcontrast (Gd DTPA, 0.1mmol kg) T1-weighted (B) magnetic resonance images of the brain from a patient with multiple sclerosis. In (B), two patterns of enhancement are visible a homogeneous one (indicating newly formed lesions) (continuous...

Late Remyelination

Figure 7 (See color insert.) Remyelination in chronic multiple sclerosis is characterized by the reduced staining intensity of myelin and may be restricted to the lesion edge (A MBP) or present throughout the lesion (B, shadow-plaque LFB PAS). Abbreviation LFB PAS, luxol fast blue periodic acid schif. Source From Ref. 163. Figure 7 (See color insert.) Remyelination in chronic multiple sclerosis is characterized by the reduced staining intensity of myelin and may be restricted to the lesion edge (A MBP) or present throughout the lesion (B, shadow-plaque LFB PAS). Abbreviation LFB PAS, luxol fast blue periodic acid schif. Source From Ref. 163.

Pathological Studies

Figure 10 (See color insert.) Axon loss in multiple sclerosis. Axonal density is reduced at the plaque edge and the plaque center, relative to the PPWM (A neurofilament protein). Some of the reduced neurofilament staining at the active plaque edge can be attributed to macrophage infiltration. Consistent with acute axonal injury are numerous enlarged axonal profiles, axonal spheroids, and fragmented axons within the lesion (B, amyloid precursor protein C, Bielschowsky silver). Abbreviation PPWM, periplaque white matter. Figure 10 (See color insert.) Axon loss in multiple sclerosis. Axonal density is reduced at the plaque edge and the plaque center, relative to the PPWM (A neurofilament protein). Some of the reduced neurofilament staining at the active plaque edge can be attributed to macrophage infiltration. Consistent with acute axonal injury are numerous enlarged axonal profiles, axonal spheroids, and fragmented axons within the lesion (B, amyloid precursor protein C, Bielschowsky...

Types of MS Lesions

Lesion Medicale

Figure 4 (See color insert.) Types of multiple sclerosis plaques (KiMlP, macrophage marker). (A) Acute active multiple sclerosis plaques are characterized by extensive macrophage infiltration throughout the extent of the lesion with macrophages containing both early and late myelin degradation products. (B) The radially expanding active rims consist of macrophages containing early and late myelin degradation products clustered at the advancing edge of the plaque, and diminishing in number towards the inactive plaque center. (C) Smoldering plaques are characterized by a low grade of demyelinating activity at the plaque edge, with very few macrophages containing myelin degradation products. (D) The inactive plaque is hypocellular and contains no early or late myelin degradation products within the macrophages. Figure 4 (See color insert.) Types of multiple sclerosis plaques (KiMlP, macrophage marker). (A) Acute active multiple sclerosis plaques are characterized by extensive macrophage...

Marburg MS

The Marburg variant of MS, recognized as a fulminant and lethal subtype of multiple sclerosis by Otto Marburg in 1906 (138), is characterized by rapid progression and an exceptional severity. The course is generally monophasic and relentlessly progressive, with death consequent to brainstem involvement or mass effect with herniation. Peripheral nervous system involvement may also occur in this variant of MS. Pathologically, the lesions are more destructive than typical MS and characterized by a large confluent area of white matter destruction with massive macrophage infiltration, pronounced acute axonal injury, and frank tissue necrosis (Figure 12). Uncommonly, multiple small lesions may be disseminated throughout the brain and spinal cord, or may coalesce to form large confluent areas of destruction. In some cases, areas of remyelination are observed. An autopsied case of Marburg disease documented pronounced post-translational changes, in which MBP was converted to an extensively...

The Active MS Lesion

Figure 2 (See color insert.) Active multiple sclerosis lesion. Active lesions are hypercellular demarcated regions of myelin loss characterized by an admixture of macrophages and reactive astrocytes (A, LFB PAS). Creutzfeld-Peters cells are astrocytes containing fragmented nuclei that resemble astrocytic mitoses (arrows A and B, H& E). Abbreviation LFB PAS, luxol fast blue periodic acid schif. Figure 2 (See color insert.) Active multiple sclerosis lesion. Active lesions are hypercellular demarcated regions of myelin loss characterized by an admixture of macrophages and reactive astrocytes (A, LFB PAS). Creutzfeld-Peters cells are astrocytes containing fragmented nuclei that resemble astrocytic mitoses (arrows A and B, H& E). Abbreviation LFB PAS, luxol fast blue periodic acid schif.

HHV6 Genome Similar and Different

Roseoloviruses, human herpesviruses 6 and 7 (HHV-6, HHV-7) are widespread T lymphotropic and neurotropic viruses causing mostly benign infections. However, particularly for HHV-6, during some primary as well as secondary reactivated infections, which can follow immune aberrations or deficiencies, there can be severe complications which can lead to fatalities. Thus, this is of relevance for immuno-suppressed HIV AIDS or transplantation patients, as well as increasingly, for those with neurological disease, including encephalitis and a link with multiple sclerosis (primarily HHV-6A). Understanding when and how this virus does or does not cause disease is key to developing effective treatments plus evaluating the impact of HHV-6 infections on worldwide populations. Studies on the virus genome provide a foundation for this exploration and can guide the way towards development of new anti-virals as well as possible novel treatments for immune-related pathologies using this well-adapted...

Application to Medical Image Segmentation

Although such a threefold classification of brain tissue may be sufficient for numerous clinical applications, it should be emphasized that the concept presented in this chapter can be extended to an arbitrary number of tissue classes. Especially one may think of introducing additional classes for the identification of pathological tissue, e.g., multiple sclerosis plaques or malignant brain tumor structures.

Jeanmartin Charcot And The Salpetriere School

Belladonna Parkinson

FIGURE 16 Charcot's early tremor recordings. Charcot adapted the sphygmograph, an instrument originally used for recording arterial pulsation, to record tremors and movements of the wrist. His resultant tremor recordings (lower right), conducted at rest (A-B) and during activity (B-C), differentiated multiple sclerosis (top recording) from the pure rest tremor (lower recording) or mixed tremor (middle recording) of Parkinson's disease (19). FIGURE 16 Charcot's early tremor recordings. Charcot adapted the sphygmograph, an instrument originally used for recording arterial pulsation, to record tremors and movements of the wrist. His resultant tremor recordings (lower right), conducted at rest (A-B) and during activity (B-C), differentiated multiple sclerosis (top recording) from the pure rest tremor (lower recording) or mixed tremor (middle recording) of Parkinson's disease (19).

Biological aspects of variants A and B

HHV-6 infects a wide variety of cell types including diploid lung fibroblasts, neural cells, megakaryocytes and NK cells. In most of these cell lines there is a low level of viral replication. It has been shown that HHV-6A induces CD4+ receptor on CD8+ cells, making them infectable with HIV. It has also been shown that B-lymphocytes are not infectable with HHV-6A, but Epstein-Barr virus (EBV)-pos-itive B-lymphocytes can be infected with HHV-6A. It was reported that HHV-6A, not HHV-6B, activates EBV and similarly HHV-6A also activates HHV-8 (Flamand et al., 1993 Cuomo et al., 1995 Zeng et al., 2005). It was also shown that HHV-6A induces cell membrane receptor expression that predisposes them to superinfection by other viruses, such as EBV and HIV (Krueger et al., 1990 Schonnebeck et al., 1991). HHV-6B (Z-29) grew best in HTLV-1 transformed cell line MOLT-4, which is not infectable with HHV-6A. The propagation and replication of HHV-6A and B isolates have been studied. HHV-6A (GS...

Disease associations of HHV6A and 6B variants

It was previously thought that primary infection of HHV-6 in infants and young children lead to roseola and febrile illnesses. This infection was attributed to HHV-6B (Yamanishi et al., 1988). Some of the symptoms identified include diarrhea, vomiting, seizure, nasal congestion, rash and high fever. Similar symptoms were noted in Africa in children and the DNA analysis from the peripheral blood from these children revealed HHV-6A infections (Hidaka et al., 1997 Kasolo et al., 1997 Randhawa et al., 1997). It is, therefore, obvious that both variants A and B participate in infecting growing children with identical pathologies. Hall et al. (1994) also observed that one third of congenital infection was due to HHV-6A. Later on these children still retained HHV-6A DNA. There have not been longitudinal follow-up studies to assess whether these children with congenital HHV-6A infection could be at risk of developing a central nervous system (CNS) illness such as multiple sclerosis.

Serologic assays Techniques

A current trend is the identification of target proteins by means of immunoblot or immunoprecipitation assays combined with the use of monoclonal antibodies (Balachandran et al., 1989). Such approach has permitted to recognize the protein p100 (U11 gene product) as a major determinant of immune response (Yamamoto et al., 1990 Neipel et al., 1992). Similarly, a 101 kDa protein (101K) has been identified as an immunodominant virion protein for both IgG and IgM reactivity (LaCroix et al., 2000). The early antigen p41 38 (U27 gene product) had been chosen to develop a specific ELISA (Iyengar et al., 1991 Patnaik et al., 1995a). This early protein has been found to contain a divergent epitope which permits to differentiate HHV-6A from HHV-6B (Xu et al., 2001). However, further results obtained with recombinant p41 as the ELISA antigen have been rather disappointing both in terms of overall serum reactivity and variant specificity (Xu et al., 2002). The residues 4-10 of U24 gene product...

Contraindications And Precautions

Commission E warns against using echinacea in cases of autoimmune disorders, such as multiple sclerosis, SLE and RA, as well as tuberculosis or leukocytosis (Blumenthal et al 2000). This is based on theoretical considerations and has not been tested in controlled trials. In practice, echinacea has been successfully used by herbalists in autoimmune disease without mishap (Mills & Bone 2005). Duration of use Based on evidence that parenterally administered echinacea reversibly depresses immune parameters, Commission E has recommended that echinacea should not be used for more than 8 weeks. However, in a study in which it was taken orally for up to 6 months, no changes in immune parameters were detected (Vonau et al 2001). As such, no conclusive evidence demonstrates that long-term use is detrimental.

Noninsulindependent Type II diabetes mellitus

A full account of the natural selection pressures in relation to NIDDM remains elusive. However, it is near certain that critical variations in dietary circumstances, over time, have evolution-arily shaped the pattern of differences in metabolic handling of dietary substrates. Viewed within this frame, environment is a formative influence on the human genotype. The complex dependence of immune system development and functioning on vitamin D synthesis and action may be another such example. This is illustrated by the epidemiology of multiple sclerosis, with its evidence of both environmental and genetic influences on aetiology.

Lymphatic and hematopoietic system see also chapters 14 and

HHV-6 replicates with low efficiency in neuroglial cells (Luppi et al., 1995). Viral DNA and antigen have been successfully demonstrated in human brain tissue, both in healthy organs and in diseased tissues, with subtype A being about three times more frequent than subtype B (Fig. 2 Luppi et al., 1995 Hall et al., 1998 Cuomo et al., 2001). There are increasing reports of HHV-6-associated meningitis, encephalitis in children with febrile seizures (Caserta et al., 1994 Wilborn et al., 1994 Knox and Carrigan, 1995 Bonthius and Karacay, 2002 Eeg-Olofsson, 2003), acute necrotizing or hemorrhagic encephalitis and demyelinating brain diseases in immune-deficient patients and in persons suffering from multiple sclerosis (Challoner et al., 1995 Wagner et al., 1997 Solldan et al., 2000 An et al., 2002 Cirone et al., 2002 Chapenko et al., 2003 Tejada-Simon et al., 2003). CNS infections with HHV-6 appear more frequent in patients with T-cell immune deficiency (Pruitt, 2003).

Clinical Applications

In neurophysiology, electrophysiological data - indirect indicators of fibre integrity - could be better interpreted using tractography, which is capable of displaying fibre tracts directly. For instance, corticospinal fibres can be identified and reconstructed with tracto-graphy from their origin through the centrum semiovale, corona radiata, internal capsule and cerebral peduncle. Identification of this bundle is important in neurological diseases like multiple sclerosis, where de-myelination and the consequent axon damage even at a distance from the lesion site can be documented and quantified using these techniques 59-74 .

Psychiatric Diagnosis and Management of Psychosis in Dementia

Psychotic and behavioral disturbances are associated with all dementing disorders, including frontal lobe dementia, basal ganglia diseases with dementia, vascular dementias, traumatic brain injury, multiple sclerosis, central nervous system (CNS) infections, and Huntington's disease (Ballard, Gray, & Ayre, 1999 Binetti et al., 1993 Sultzer, Levin, Mahler, High, & Cummings, 1993). However, this review focuses predominantly on clinical treatment trials of psychosis in AD patients. The safety and efficacy in the treatment of psychosis of AD is presumed to be similar to that in other dementia diagnoses. These diseases and their associated risks from antipsy-chotic treatments are discussed only briefly. Controlled treatment trials in other specific dementia diagnostic groups are still needed thus, recommendations in their management are limited.

Nonneoplastic Conditions

Neurogenic bladder a wide range of neuromuscular conditions (e.g., cerebrovascular accident, multiple sclerosis, spinal cord trauma, diabetes mellitus) can cause voiding dysfunction by interfering with bladder wall compliance, detrusor muscle activity or sphincter function, resulting eventually in either a tightly contracted or flaccid bladder. These are usually treated by behavioural, pharmacological or electrophysiological means but occasionally surgical intervention may be indicated, e.g., augmentation cystoplasty to increase capacity in a contracted bladder, where a segment of stomach or intestine is isolated and anastomosed to the native bladder. Rarely, adenocarcinoma may supervene later in the augmented bladder.

Systemic Associations

Similar to dorsal midbrain syndrome, INO is an anatomic rather than etiological diagnosis. A host of structural, metabolic, immunological, inflammatory, degenerative, and other processes can interfere with the function of the MLF and nearby structures. In young adults, multiple sclerosis is by far the most common cause of INO.342 Multiple sclerosis also underlies most cases of bilateral INO. Although patients with bilateral INO generally remain orthotropic in primary position, they sometimes exhibit an exotropia in the wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome.311 Additional causes of INO include Arnold-Chiari malformation,23,99,118,533 hydrocephalus,352 meningoencephalitis,64,226 brainstem or fourth ventricular tumors,99,439,482,496 head trauma,49,84,254 metabolic disorders, drug intoxications, paraneoplastic effect, carcinomatous meningitis, and others. Peripheral processes, particularly myasthenia gravis and Miller Fisher syndrome, may closely mimic INO and...

Treatment and Prognosis

The first goal is to treat the underlying etiology. For example, steroid therapy is necessary in multiple sclerosis, and blood pressure management is required for a hypertensive stroke. After this initial consideration, if the disorder persists and remains stable for at least 6 months, the accompanying exotropia may be corrected by surgery. In a series of three patients treated surgically for diplopia caused by bilateral INO (from brainstem vascular disease) with exotropia of 55 to 70 prism diopters, favorable results were achieved by bilateral medial rectus resections and bilateral lateral rectus recessions (with one lateral rectus on an adjustable suture in each of the three).74 After a minimum of 6 months postoperative follow-up, all three patients achieved excellent cosmesis. In one of the three patients, binocularity was restored in the primary position, in the second diplopia was eliminated in primary and downgaze, and in the third diplopia was completely eliminated.

Discussion and conclusions

Twenty years after its discovery, HHV-6 is an emerging pathogen with an increasing body of data to support disease associations spanning the self-limiting rash of childhood to the ravages of multiple sclerosis. Applying scientific rigor to assessing these associations will be necessary to verify the etiology of these diseases particularly those like fibromyalgia, which remains very difficult to diagnose. The development of additional immunological research tools (both cellular and humoral) as well as molecular, which can also distinguish variants A and B will be synergistic to scientific discovery while providing future tools for monitoring the efficacy of therapy, whatever is the eventual target of treatment. By virtue of its dual tropisms for lymphocytes and nervous tissue, HHV-6 is one of a growing list of viruses, which present both the research challenge and excitement of bridging two important disciplines immunology and neurobiology. This critical connection has enormous...

HHV6 infection of the central nervous system

(AIDS) patients with areas of demyelination (Knox and Carrigan, 1995) and associated with multiple sclerosis (MS) (Akhyani et al., 2000 Kim et al., 2000 Soldan et al., 2000 Rotola et al., 2004). This chapter will focus on evidence suggesting an association of HHV-6 with four major disorders of the CNS childhood febrile seizures, mesial temporal-lobe epilepsy (MTLE), MS, and progressive mul-tifocal leukoencephalopathy (PML).

Complications and Recurrence

As long as the surgical endpoint selected is mild to moderate hypes-thesia, there will be a recurrence rate of 20 to 25 , depending on the time elapsed after surgery, with recurrence rates being twice as high for trigeminal neuralgia associated with multiple sclerosis. Recurrent pain occurs either because of regeneration of injured myelin or from progression of the disease to include untreated trigeminal sensory divisions.

The association of HHV6 with MS

To extend the observation of cell-free serum HHV-6 DNA in MS patients, a longitudinal study consisting of 215 samples obtained from 59 MS patients followed prospectively for a 5-month period of time was conducted (Berti et al., 2002). Serum HHV-6 DNA was detected from significantly fewer sera obtained during periods of clinical remission. These data suggest a statistically greater likelihood of detecting HHV-6 DNA in the serum of an MS patient during an exacerbation (Berti et al., 2002). This report supports a role for HHV-6 in the pathogenesis of MS by suggesting that the presence of serum HHV-6 DNA, similar to the presence of gadolinium-enhancing lesions, coincides with clinical worsening in a subset of patients (Berti et al., 2002). Additional studies have demonstrated that HHV-6A active replication is associated with a subset of relapsing-remitting multiple sclerosis (RRMS) patients and that HHV-6A active infection increases the risk of exacerbations in these patients...

Neurological dilemmas

The most common pitfall that occurs with neurological disorders is misdiagnosis, and the most common reason for misdiagnosis is an inadequate history. Failure to appreciate the neurological meaning of points elicited during the history is another reason for misdiagnosis. Some very important neurological disorders are presented in this section Parkinson's disease, which is common and can be easily misdiagnosed especially when the classic 'pill rolling' tremor is absent or mild multiple sclerosis (MS), because it is difficult to diagnose initially and acute idiopathic demyelinating polyneuropathy (Guillain-Barre syndrome), because it can be rapidly fatal if misdiagnosed. MS can masquerade as almost anything 'If you don't know what it is, think of MS.' Another brain teaser for the family doctor is to diagnose accurately the various types of epilepsy. The most commonly misdiagnosed seizure disorders are complex partial seizures or atypical generalised tonic clonic seizures (see Chapter...

Upper Motor Neuron Disease

The apt expression jiggling describes a mixed spasticity and cerebellar ataxia and is most frequently seen in patients with multiple sclerosis. The intention tremor of the lower limbs as each foot comes down to the floor plus the stiffness results in a whole body movement that is a fine tremble or jiggle, mostly in the vertical dimension.

Relationship to Behavioural and Neural Functioning

As for FA, MTR is a non-specific marker of neural damage, such as demyelina-tion. Many of the published MT studies have focused on patients with multiple sclerosis, who show decreased MT in both ROI and whole-brain histogram analyses. In other diseases, results are similar, indicating MTR is a viable marker for affected white and gray matter. MTR has been shown to increase with brain development during the first several years of life (Rademacher et al. 1999 van Buchem et al. 2001) and regional decreases with aging have been found (Armstrong et al. 2004). Differences in MTR were sufficiently large to distinguish patients with mild cognitive impairment from patients with Alzheimer's disease and controls (Kabani et al. 2002a Kabani et al. 2002b). A number of published studies have also used magnetization transfer methods to compare the brains in patients with schizophrenia against healthy control subjects (Foong et al. 2001 Bagary et al. 2003 Kiefer et al. 2004 Kubicki et al. 2005)....

Causes and symptoms

An example of shared psychotic disorder involving the delusion of persecution, is that of a 52-year-old married female and her 48-year-old husband with multiple sclerosis, who believed that they were being harassed and watched by the Irish Republican Army (IRA). They were hospitalized and both became stable after two weeks on an antipsychotic medication. However, an interesting point in this case is that they were separated for that two-week period. The general consensus has been that, once separated, the submissive partner will let go of the delusion, that it would resolve itself simply due to separation. That did not happen in this case. Both partners had to be treated with proper medications before the delusion resolved.

Acquired Delayed Ejaculation

The onset of ejaculation delay may be sudden or gradual and deteriorates progressively to global unremitting ejaculatory inhibition. A rather normal delay of ejaculation occurs during aging. Androgen deficiency or hypogonadism may be accompanied by loss of sexual desire and delay of ejaculation. Any neurological disease, injury, or surgical procedure that traumatizes the lumbar sympathetic ganglia and the connecting nerves (multiple sclerosis, diabetic neuropathy, abdo-minoperineal resection, lumbar sympathectomy) may lead to a delay or failure of ejaculation. A wide range of drugs (SSRIs, tricyclic antidepressants, antipsychotics, alpha-sympathicolytics) can impair the ejaculatory process through central and peripheral mechanisms. Alcohol can delay or abolish ejaculation by a direct effect after acute abuse and indirectly by neurological or hormonal disturbances during chronic abuse.

Disorders of the Urogenital Tract

Disorders of the urogenital tract can occur for a wide variety of reasons (see Refs. 236, 237). Those involving the autonomic nervous system range from trauma and diseases such as multiple sclerosis that affect the preganglionic autonomic neurons in the spinal cord to iatrogenic causes such as radical surgery or x-irradiation, which can result in local nerve damage, and, finally, metabolic disorders such as diabetes, which affect autonomic neuromuscular transmission. In some cases the precise nature of the changes that occur in human beings has proved difficult to determine and, where possible, much information has been derived from animal models.

Neuroprotectant Properties

Collectively, these results indicate that TDZDs can be very effective neuroprotective and anti-inflammatory compounds in neuronal cells through, at least in part, activation of the nuclear receptor PPARy. This study suggests possible therapeutic uses for TDZDs in certain brain disorders, such as multiple sclerosis, as well as Parkinson's and Alzheimer's diseases, where inflammatory responses play a major role.

Surgical Complications

Surgical complications are those that occur within 30 days of surgery. These complications are typical of those seen with other intracranial stereotactic procedures and generally occur in less than 5 of the patients. These complications include hemorrhage, ischemic lesions, seizures, infections, and misplaced leads. Several studies have focused on the examination of surgical complications related to DBS. Beric et al. (46) reported 86 patients who received 149 DBS implants in the VIM nucleus of the thalamus, GPi or STN for PD, essential tremor, multiple sclerosis, or dystonia. In this cohort, 2.3 (n 2) of the patients had a hemorrhage, 2.3 (n 2) had seizures, 1.2 (n 1) had a delayed hematoma two months after surgery, and 4.7 (n 4) had postsurgical confusion. Umemura et al. (47) reported surgical complications in 109 patients receiving DBS of the VIM nucleus of the thalamus, GPi, STN, or anterior nucleus of the thalamus for PD, essential tremor, epilepsy, or dystonia. They reported two...

Hardware Related Complications

Several reports have also focused on hardware complications related to DBS. Beric et al. (46) examined complications for 86 DBS patients and found electrode failure in 3.5 (n 3), extension wire failure in 4.7 (n 4), IPG malfunction in 1.2 (n 1), and pain at the IPG in 1.2 (n 1). Kondziolka et al. (49) examined hardware complications in 66 patients undergoing unilateral thalamic DBS for either essential tremor, parkinsonian tremor, multiple sclerosis, or other forms of tremor. There were a total of 23 hardware-related complications affecting 27 of the patients. Lead breakage occurred in 10 patients (15.2 ), system infection in seven patients (10.6 ), connector erosion in two patients (3.0 ), and cranial lead migration, chronic subdural hematoma, defective IPG, and a defective connector each in one patient (1.5 , each). Oh et al. (50) reported hardware complications for 79 patients who received 124 DBS implants. DBS was done for PD, essential tremor, pain, epilepsy, dystonia, multiple...

Diseases Of The Motor Neurons And Corticospinal Tracts Figures 81 and

Tabes Dorsal

Classic lesions of the spinal cord. (A) Poliomyelitis and progressive infantile muscular atrophy (We rd nig-Hoffmann disease). (B) Multiple sclerosis. (C) Dorsal column disease (tabes dorsalis). (D) Amyotrophic lateral sclerosis. (E) 1 lemisecrion of the spinal cord (Brown-S6quard syndrome). (F) Complete ventral spinal artery occlusion of the spinal cord. (G) Subacute combined degeneration (vitamin B,2 neuropathy). (H) Syringomyelia. Figure 8-2. Classic lesions of the spinal cord. (A) Poliomyelitis and progressive infantile muscular atrophy (We rd nig-Hoffmann disease). (B) Multiple sclerosis. (C) Dorsal column disease (tabes dorsalis). (D) Amyotrophic lateral sclerosis. (E) 1 lemisecrion of the spinal cord (Brown-S6quard syndrome). (F) Complete ventral spinal artery occlusion of the spinal cord. (G) Subacute combined degeneration (vitamin B,2 neuropathy). (H) Syringomyelia.

Lieve Naesens Leen De Bolle Erik De Clercq

In contrast to other human herpesviruses such as herpes simplex virus (HSV) or cytomegalovirus (CMV), HHV-6 has not been the subject of extensive antiviral screening, the main reason being the uncertainty about the large need for specific anti-HHV-6 therapies. Transplant recipients commonly show laboratory signs of HHV-6 reactivation, but the frequency by which this is associated with serious disease is still ill defined (Yoshikawa, 2004). Even more controversial is the role of HHV-6 in chronic neurological disorders, such as multiple sclerosis (MS) or chronic fatigue syndrome (CFS). In the absence of HHV-6-specific therapies, treatment of HHV-6 infections currently relies on the relatively broad-spectrum antiherpetic agents (val)ganciclovir and foscarnet. Although these drugs offer an indisputable benefit in the therapy or prophylaxis of CMV, their clinical efficacy against HHV-6 can only be estimated from a number of heterogeneous case reports. Long-term administration of these...

Indications For Thalamic Surgery

Thalamotomy Mri

The indications for thalamotomy or thalamic stimulation are similar. Patients should have tremor that is refractory to medical therapy and represents the predominant form of disability. The best candidates for thalamic surgery are patients with incapacitating benign essential tremor and those with tremor-predominant PD that is unilateral or asymmetric. Patients with PD who have other motor signs should be considered for surgery aimed at other targets, such as the globus pallidus internus (Gpi) or the subthalamic nucleus (STN). Thalamic surgery may also be useful in patients with tremor secondary to multiple sclerosis or trauma, although the results are less predictable because of the associated injury to other brain structures inherent in these afflictions.

Practical Issues of Peptide Immunization Assessed in Early Human Clinical Trials

Two studies with peptide administered intramuscularly, however, found transient immune responses at even the lowest doses of 10 g used (50,70). Several studies showed little difference in immune responses to peptide doses > 100 g (50, 56,57). Clinical vaccine trials in multiple sclerosis have shown that immunization with T-cell receptor (TCR) peptides in doses > 1000 g could produce a tolerizing Th2 peptide-specific response with clinical response (71,72). These results suggest that peptide doses of 100-1000 g may be appropriate for human peptide vaccines targeting cancer-associated antigens. In addition, because peptides themselves have not to date demonstrated considerable toxicity and are unlikely to exert a biologic effect in the same way as pharmacological agents, the paradigm of dose-escalation studies in phase I trials should perhaps be different. Rather than determining the maximal tolerated dose, a better goal may be to establish the...

Proton MRS in Neuroradiology

Proton magnetic resonance spectroscopy of the brain reveals specific biochemical information about cerebral metabolites, which may support clinical diagnosis and enhance the understanding of neurological disorders. Analysis of the resonance signals of low-molecular weight brain metabolites (concentrations in mmol) provides information on metabolite concentrations and makes it possible to correlate their modifications with various pathological conditions. The high diagnostic specificity of MRS enables the biochemical changes that accompany various diseases to be detected, as well as disease characterization, sometimes diagnosis, and monitoring. At 1.5 T the main metabolites detected vary according to the acquisition parameters (TR, TE) and type of pulse sequence adopted (STEAM, PRESS). 1.5 T brain MRS currently has a number of clinical applications, including the characterization of cerebral tumours and the monitoring of their treatment (e.g., radiation necrosis versus recurrence...

Current immunological tools

Disease associations between HHV-6 infection and multiple sclerosis, fibromyalgia, and chronic fatigue syndrome Ablashi et al. (2005) have performed a meta-analysis of over 85 published papers in which the relationship between HHV-6 and patients with multiple sclerosis or fibromyalgia, or chronic fatigue syndrome (CFS) was examined. Although a clear causal relationship has not been established between HHV-6 and these chronic illnesses, his study discerned that there is evidence of correlation in more than 75 of those papers that distinguish between active and latent virus. Since both in vitro studies and in vivo clinical experience provide evidence that HHV-6 is immuno-suppressive, patients with a history of CFS (data provided through the courtesy of Daniel Peterson, MD) were tested for the functionality of their global T-cell response using an FDA-cleared test for cell-mediated immunity assessment (Cylex Immune Function Assay, ImmuKnowTM) and these cellular immune responses were...

Validation with Real Data

Ring Enhancing Lesion

The images are part of an extensive study of the evolution of the multiple sclerosis (MS) disease performed at the Brigham and Woman's Hospital (Harvard Medical School, Boston) by Dr. Guttmann and Prof. Kikinis. Each patient underwent a complete head MR examination several times during one year (typically 24 different 3D acquisitions). The aim is to register precisely all the images acquired at multiple time points in order to segment the lesions and evaluate very accurately their evolution (Fig. 12).

Some Diseases Of The Visual System Retina and Optic Nerve Lesions

There may be a past history of episodes of multiple sclerosis or this illness may be the first manifestation of it. The fundus is usually normal. Afferent pupillary defect is commonly present. Be careful and persistent with patients with visual loss. Lesions in the chi-asmal region can be deceptive and extremely chronic. The chronicity and slow progression seem to make the symptoms more acceptable and less demanding. Every neurologist and neurosurgeon has had some bad experience with patients thought to have multiple sclerosis, amblyopia from childhood, low-tension glaucoma, retinitis pigmentosa sine pigmento, or atypical macular degeneration as an explanation for their blindness who eventually turn out to have a chiasmal lesion as the true cause. It does not help the patient to

The Icelandic Health Sector Database

Although the conflict over the Icelandic database broke in 1998, its origins go back to the summer of 1994. Then two Harvard-based clinical neurologists, the Icelander Kari Stefansson and his U.S. colleague Jeff Gulcher, were visiting Iceland to collaborate in a study of multiple sclerosis (MS) with an Icelandic neurologist, John Benedikz. The research project was to look for a possible genetic predisposition to the disease. In helicopter science mode, the researchers flew in during the summer, secured as many samples as possible from patients and their families, and then returned to the Medical School at Harvard to do the lab work.4

Mark Tuszynski MD PhD

Handbook of Multiple Sclerosis, edited by Stuart D. Cook Handbook of Multiple Sclerosis Second Edition, Revised and Expanded, edited Handbook of Multiple Sclerosis Third Edition, edited by Stuart D. Cook Long-Term Effects of Stroke, edited by Julien Bogousslavsky Handbook of the Autonomic Nervous System in Health and Disease, edited by C. Liana Bolis, Julio Licinio, and Stefano Govoni

Is Absent or Impaired Genital Responsiveness a Valid Diagnostic Criterion

Medical conditions that have been associated with sexual arousal disorder, other than SCI and diabetes, are pelvic and breast cancer, multiple sclerosis, brain injury, and cardiac disease (50). Mental disorders such as depression may also interfere with sexual function. It is important to consider the direct biological

Frontotemporal Dementia

Consensus criteria have made them more general, but they are similar to previous criteria (McKhann et al., 2001). These criteria, shown in Table 4.2, are supplemented by core features of the three common presentations of FTD outlined by Neary et al. All presentations of FTD have an insidious onset and gradual progression. Onset is frequently before age 65, and a family history of FTD is common. Features of motor neuron disease or parkinsonism can been seen during the course of FTD, but hyperkinetic movement disorders (e.g., myoclonus, chorea) are not seen. Clinical features that would suggest an alternative cause of dementia are used to exclude FTD, including evidence of vascular dementia, HIV-associated dementia, multiple sclerosis, chronic alcoholism, herpes simplex encephalitis, or dementia due to closed head injury.

Statistical Methods for Brain Segmentation

Fuzzy-connectedness methods developed by Udupa and Samarasekera 31 are based on knowledge of tissue intensities, followed by statistical region-growing methods. This method has been successfully used to segment the brain in 1000 multiple sclerosis patients 32 , but is rather computationally intensive. Again, user interaction is required to seed the regions.

Immunomodula Tion

According to in vitro data quercetin induces Th1 -derived cytokines (promoting cellular immunity) and inhibits Th2-derived cytokines, which exert negative effects on cellular immunity (Nair et al 2002). An excess of Th2 cytokines has also been implicated in allergic tendencies, which provides a theoretical basis for the use of quercetin as an anti-allergic substance. Conversely animal studies have demonstrated that quercetin is able to inhibit Th1 differentiation and signalling of IL-12 (Muthian & Bright 2004). As this occurred in the presence of a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis suggestive of Th1 excess, a possibility exists that quercetin actually exerts an immunomodulatory effect on these cells. Further trials are required to elucidate the exact effects of quercetin under different conditions.

Quadruple Contrast Enhancement with MRA and MR Spectroscopic Imaging

Figure 3.33 An approach is represented to improve the multiple sclerosis lesion-to-tissue contrast using MRA images by a fast imaging pulse sequence incorporating both cerebrospinal fluid signal and flow attenuation with magnetization transfer contrast. The technique suppressed gray matter or white matter and highlighted the lesion-to-tissue contrast. Figure 3.33 An approach is represented to improve the multiple sclerosis lesion-to-tissue contrast using MRA images by a fast imaging pulse sequence incorporating both cerebrospinal fluid signal and flow attenuation with magnetization transfer contrast. The technique suppressed gray matter or white matter and highlighted the lesion-to-tissue contrast. proton magnetic resonance spectroscopic imaging (MRSI) estimated individual tissue contributions to the spectroscopic voxels in multiple sclerosis (MS).

Anticancer

In vitro experiments have demonstrated the possible benefits of andrographolide on various cancer cells. The compound has been shown to increase apoptosis of prostate cancer cells (Kim et al 2005), inhibit proliferation of human cancer cells and increase IL-2 induction in human peripheral blood lymphocytes in vitro (Kumar et al 2004, Rajagopal et al 2003). However, contradictory results have been described from a murine model. Andrographolide was found to decrease IFN-gamma and IL-2 production and therefore shown to have an immunosuppressive effect. Burgos et al (2005) concluded that andrographis may be useful for autoimmune disease, especially where high levels of IFN-gamma are present, for example, in multiple sclerosis and RA. In vitro and in vivo data has recently shown that andrographolide has the ability to interfere with T-cell proliferation, cytokine release and maturation of dendritic cells, as well as drastically decreasing the antibody response in delayed-type...

Cellular homologues

U83 encodes a functional chemokine (Zou et al., 1999). Although the gene has relatively little sequence similarity to human chemokine genes, the protein expressed has the typical cysteine residues of a chemokine, transduces signals that involve calcium fluxes and induces chemotactic activation. The recombinant U83 protein is capable of inducing transient calcium mobilization in THP-1 cells and of chemotactically activating THP-1 cells (Zou et al., 1999). Furthermore, the U83 has been found to cause calcium mobilization as efficiently through the CCR2 receptor (Luttichau et al., 2003), suggesting that the U83 protein might play an important role in HHV-6 propagation in vivo by activating and trafficking mononuclear cells to sites of viral replication, or U83 during reactivation of the virus in for example monocyte-derived microglia could perhaps be involved in the pathogenesis of the CCR2-dependent disease, multiple sclerosis.

Summary

This chapter presented a fully automated hybrid intracranial boundary detection algorithm that has proven effective on clinical and research MR data sets acquired from several different scanners using PD-T2 spin-echo sequences. The algorithm has three sequential steps that provide first background removal, then an initial brain mask, and then a final brain mask. In the first step, the head is localized using histogram analysis, and a region that completely surrounds the brain is generated. The second step applies a nonlinear anisotropic diffusion filter and sets an automated threshold to produce a mask that isolates the brain within the head region of the first step. The third step uses this mask as an initial position for an active contour algorithm to determine the final intracranial boundary. This algorithm was robust in the presence of RF inhomogeneities and partial volume effects. It is in regular use for studies of multiple sclerosis lesions and MRI-PET registration studies. The...

Medical conditions

Depression can be an integral part of the symptomatology of some medical conditions, including neurological disorders such as Parkinson's disease, dementia, multiple sclerosis, and anaemia endocrine disorders such as hypothyroidism virus infections such as influenza and deficiencies of vitamins such as B12 and folate.

MRI Segmentation

MRI is one of the most common diagnostic tools in neuroradiology. In brain pathology study, brain and brain tissues have often regions of interest from which abnormality such as the Alzheimer disease or multiple sclerosis (MS) lesions are diagnosed. Numerous techniques in computer-aided extraction of the brain, brain tissues, such as the gray matter, white matter, and cerebrospinal 6.4.1.2 Segmentation of Lesions in Multiple Sclerosis from MRI

Neuroimaging

Neuroimaging has provided insight into the pathophysiology and natural history of Parkinson's disease (PD) and has emerged as a tool to monitor disease progression and to assess new potentially neuroprotective or neurorestorative therapies for PD. Diverse imaging methods have been successfully applied to neurological disorders. Although technology such as functional magnetic resonance imaging or magnetic resonance spectroscopy has been especially useful in assessing stroke, multiple sclerosis, and epilepsy (1-3), in vivo neuroreceptor imaging using single photon emission tomography (SPECT) and positron emission tomogrpahy (PET) have so far been most valuable in assessing PD. SPECT and PET use specific radioactively labeled lig-ands to neurochemically tag or mark normal or abnormal brain chemistry. Recent advances in radiopharmaceutical development, imaging detector technologies, and image analysis software have expanded and accelerated the role of imaging in clinical research in PD,...

Fatigue

The neurologic disorder in which fatigue has been best evaluated is multiple sclerosis in which at least 78 of these patients suffer from fatigue and is often the most disabling symptom of this disease (55). Similarly, in a study of over 1300 cancer patients, 58 of patients described problems with fatigue, yet less than 52 of those ever reported symptoms to their caregivers, and only 14 had received some type of treatment (56). Perhaps the greatest obstacle to recognizing fatigue is in terms of definition as various health care professionals define fatigue differently based on their area of expertise. The most common complaint heard in our outpatient brain tumor clinic on a daily basis from patients, regardless of stage of treatment, is that they feel fatigue. This may be further defined as tiredness, exhaustion, muscle weakness, lethargy, or depression. Because fatigue can mean different things to physicians and patients it is imperative that the physician obtain a comprehensive...

Organic Disorders

Organic brain disorders are either acute or chronic. Acute brain dysfunctions can result from myriad conditions alcohol intoxication, anemia, brain tumors, cardiovascular disorders, emphysema, fever, infections, infectious diseases, lead poisoning, liver disease, medication, mercury poisoning, multiple sclerosis, stroke, thyroid disorders, and vitamin deficiencies. The two most common chronic brain disorders Alzheimer's disease and multi-

Clinical Aspects

Phospholipids & Sphingolipids Are Involved in Multiple Sclerosis and Lipidoses In multiple sclerosis, which is a demyelinating disease, there is loss of both phospholipids (particularly ethanolamine plasmalogen) and of sphingolipids from white matter. Thus, the lipid composition of white matter resembles that of gray matter. The cerebrospinal fluid shows raised phospholipid levels.

Clinical Studies

Magnetic resonance imaging (MRI) is frequently used to document in vivo neuropathology in humans, such as stroke, multiple sclerosis and Alzheimer's disease. However, this imaging technology has also been applied to human aging studies, in both cross-sectional and longitudinal designs. The utility of repeated imaging is that each individual serves as his or her own baseline, avoiding many of the pitfalls of cross-sectional studies (secular trends). In general, these studies have concentrated on the evaluation of dual-echo or 3-dimensional scans generated by MRI sequences (SPGR, MPRAGE), which yield high-resolution images that can be used to measure total brain volume or segmented into various tissue compartments (gray, white, cerebrospinal fluid) or specific anatomical regions.

Physical effects

Cannabis has many physiological effects, including cardiovascular ones, which may be dangerous in people with heart disease. Cannabis taken in pregnancy is thought to be teratogenic. Chronic effects include those of the associated tobacco smoking. Cannabis has analgesic and other properties, which have been the subject of randomised trials. For example, it has been tried in multiple sclerosis, but so far has not been considered to be an improvement on existing treatments (Robson, 2001).

Demyelinating

Multiple sclerosis (MS), like head trauma, is more frequently encountered as a cause of dementia when younger populations are studied. MS has its peak onset in the third and fourth decades of life and is more common in women than men by 2 1. The risk of MS is significantly higher among those raised in latitudes farther from the equator, particularly for the Northern Hemisphere (Kurtzke, 1985). As with alcoholism, neuropsychological impairment may be detected in 50 of persons with MS, but fewer than 10 have frank dementia (Halligan, Reznikoff, Friedman, & LaRocca, 1988).

Immunity

However, there is also preliminary evidence that iron may be implicated in the pathogenesis of auto-immune disorders, including SLE, scleroderma, type 1 diabetes, Goodpasture syndrome, multiple sclerosis and RA (Bowlus 2003). Current evidence suggests that moderately elevated iron stores may be associated with an overall increased risk for cancer, especially colorectal cancer (McCarty 2003). Additionally, it has been proposed that iron may increase HIV replication and the rate of progression of HIV infection, although doses of 60 mg of elemental iron twice weekly for 4 months did not appear to affect HIV-1 viral load in clinical studies (Olsen et al

Other GPCRs

It is now becoming clear that effective analgesia can be separated from psychotropic effects by selective modulation of CB receptors. Data from animal models demonstrated high efficacy analgesia in response to all types of nociception (acute and inflammatory states) tested with a number of agents currently under investigation.169170 Clinical trials using synthetic cannabinoids and extracts of whole plant cannabis (including delta-9-tetrahydocannabinol and cannabidiol) have shown mixed results for efficacy in treating pain and muscle spasticity associated with multiple sclerosis and various neuropathic pain conditions.170174 The results of future trials using more selective agents with properties that allow oral dosing are eagerly awaited.

Future Developments

Effect of interferon-beta-lb on cognitive functions in multiple sclerosis. European Neurology, 47, 11-14. Comi, G., Rovaris, M., Falautano, M., Santuccio, G., Martinelli, V., Rocca, M. A., et al. (1999). A multiparametric MRI study of frontal lobe dementia in multiple sclerosis. Journal of the Neurological Sciences, 171, 135-144. Franklin, G. M., Heaton, R. K., Nelson, L. M., Filley, C. M., & Seibert, C. (1988). Correlation of neuropsychological and MRI findings in chronic progressive multiple sclerosis. Neurology, 38, 1826-1829. Geisler, M. W., Sliwinski, M., Coyle, P. K., Masur, D. M., Doscher, C., & Krupp, L. B. (1996). The effects of amantadine and pemoline on cognitive functioning in multiple sclerosis. Archives of Neurology, 53, 185-188. Halligan, F. R., Reznikoff, M., Friedman, H. P., & LaRocca, N. G. (1988). Cognitive dysfunction and change in multiple sclerosis. Journal of Clinical Psychology, 44, 540-548. Kurtzke, J. F. (1985)....

Abstract

Fibromyalgia, chronic fatigue syndrome (CFS), and potentially multiple sclerosis. As molecular, serological, and cellular methodologies for HHV-6's detection improve, insight into causality will provide avenues for developing prophylactic and treatment strategies for this ubiquitous virus that affects millions of individuals.

Neuropathic Pain

''Central pain'' generically includes a large number of deafferentation pain syndromes that can occur after injury to the central nervous system. These include thalamic pain, post-stroke pain, pain caused by multiple sclerosis, parkinsonism, and syringomyelia. Phantom pain is the neuropathic pain that may occur after the amputation of any body part (limb, breast, tooth).

New Prospects 1131

Recent advances in functional imaging have allowed fMRI to be applied to a broad range of clinical disease processes. The combination of conventional BOLD Imaging with Diffusion Tensor Imaging and other physiologic techniques such as drug challenges holds great promise for understanding neuronal processes and the development of clinically meaningful diagnostic tests. Clinical applications of fMRI have largely relied on block style BOLD fMRI techniques to answer relatively simple questions regarding motor and language mapping in patients. These techniques have been applied most broadly in preoperative evaluations in the setting of brain tumours and epilepsy. More recent techniques such as event related paradigms and combinations of event and block style paradigms have allowed for better study of more sophisticated cognitive processes. These paradigms not only produce more complete assessments of cognitive processes presurgically, but they also open up the potential for non-invasive...

Treatment

The surgical treatment of patients with trigeminal neuralgia can be either nondestructive or destructive. The nondestructive procedure most frequently used is microvascular decompression of the trigeminal nerve root entry zone. The modern procedure, developed by Peter Jannetta, is based on observations made by Walter Dandy that in patients with trigeminal neuralgia, vascular compression of the trigeminal root at the pons is the etiology of the pain. By elevating the vessel off the nerve root entry zone, the procedure aims to produce pain relief without causing dysfunction of the tri-geminal nerve. Microvascular decompression is a very effective treatment giving long-term pain relief in more than 90 of patients who undergo the procedure. It may not be appropriate, however, for patients in poor health or in elderly patients who would not tolerate a craniotomy. It is also not appropriate in patients whose symptoms are caused by multiple sclerosis.

Fcabapentin

Gabapentin is used in combination with other antiseizure (anticonvulsant) drugs to manage partial seizures with or without generalization in individuals over the age of 12. Gabapentin can also be used to treat partial seizures in children between the ages of three and 12. Off-label uses (legal uses not specifically approved by the United States Food and Drug Administration FDA ) include treatment of severe, chronic pain caused by nerve damage (such as occurs in shingles, diabetic neuropathy, multiple sclerosis, or post-herpetic neuralgia). Studies are also looking at using gabapentin to treat bipolar disorder (also known as manic-depressive disorder).

Acknowledgements

The authors would like to thank Mariana Lazar, Yu-Chien Wu, Alexey Samsonov, Yijing Wu, and Aaron Field at the University of Wisconsin for providing figures, as well as Steve Smith from Oxford and Greg Stanisz from Sunnybrook Health Sciences Centre, and thanks also to Ana Solodkin at the University of Chicago for lively discussions. Some of the diffusion MRI work presented here was supported by NIH grant RO1 MH 62015 and the MT and MWF data was generated from a grant from the National Multiple Sclerosis Society (University of Wisconsin).

Chelation

Chelation is typically used as an intravenous therapy (sometimes oral) to remove a particular substance that is found to occur at a toxic level in the body such as lead, copper, mercury, or arsenic. The amino acid complex, ethylene-diamine-tetra-acetic acid, is the most commonly used chelating agent, though herbs and supplements may sometimes be used. Though there is a higher incidence of PD occurring in persons with chronic exposure to heavy metals such as manganese and copper and also with exposure to pesticides and herbicides, no specific toxic agent directly linked to the cause of PD has ever been identified and it is unclear what one would attempt to chelate out of the body of someone with PD. There is no scientific evidence to support the use of chelation therapy for the treatment of PD. In fact, chela-tion therapy has come under investigation and criticism for making false statements about its curative powers for a number of diseases such as multiple sclerosis, Alzheimer's...

A5021 297

CNS demyelination 312-6 febrile seizures 214-5 HHV-6 infection 213-4, 215, 257f mesial temporal-lobe epilepsy (MTLE) 215 multiple sclerosis (MS) 215-8 progressive multifocal leukoencephalopathy (PML) 219-20 cerebral lymphomas 194 characteristic tissue reaction 140f chronic allograft nephropathy 205, 286 chronic fatigue syndrome (CFS) 86-7, 207-9, 251-2, 309

Longterm Results

Bullard and Nashold have reported their results in 25 patients undergoing nucleus caudalis DREZ lesions for refractory trigeminal neuralgia, atypical headaches or facial pain, multiple sclerosis, brainstem infarction, postherpetic neuralgia, posttraumatic closed head injuries, cancer-related pain Rossitch, 1989 and postsurgical anesthesia dolorosa. Initial postsur-gery results were impressive for such usually refractory indications, with 24 of 25 patients having good to excellent pain relief at the time of discharge. Good to excellent results were maintained in 19 of 25 patients (76 ) patients at 1 month and 17 of 25 patients (60 ) at 3 months. Follow-up at 1 year included only 18 patients, but 12 of 18 (67 ) maintained good to excellent pain relief, two reporting fair and four reporting poor pain relief. Because of disruption of the spinocerebellar pathway directly overlying the nucleus caudalis in the brainstem, 15 of 25 (60 ) of patients had significant transient

Joseph H Brewer

The potential therapeutic approaches for human herpesvirus-6 (HHV-6) infections include antiviral therapy and immune therapies. Several experimental therapy approaches have possible benefits for such infection based on theoretical grounds as well as clinical studies. These therapies may alter viral infection via immune-mediated mechanisms, which relate to either humoral immunity or cell-mediated immune function. There may also be direct or indirect antiviral effects. Herein, these therapy alternatives are reviewed in terms of experimental and clinical data. Most of the clinical studies regarding these therapies that have implications for patients with HHV-6 infection have generally been done in groups of patients with disease states or syndromes that are possibly associated with HHV-6 infection. The main examples of such clinical syndromes that are addressed in this section are chronic fatigue syndrome (CFS) and multiple sclerosis (MS). Hong J, Tejada-Simon MV, Rivera VM, Zang YC,...

Drosophlia Immunity

Toll Pathway Human Versus Drosophila

The existence of autoimmune diseases, however, perhaps weakens this idea to some extent. Human examples of autoimmunity include many life-threatening diseases type 1 (juvenile) diabetes mellitus in which the host destroys its own pancreas, the nerve demyelination disease multiple sclerosis, systemic lupus erythe-matosus, which attacks a variety of organs, and many others. However, these may not simply reflect aberrant anti-self attack, because there is some evidence that they occur with various epidemic patterns in populations, including after the host has experienced an infection. An idea has been that some infections can closely mimic self antigens and the similarity triggers an autoimmune reaction as a consequence of an attack on the infectious agent. In any case, the mechanism by which purging of self-recognition molecules is controlled, once thought to be known, seems now not to be so well understood.

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