Multiple Sclerosis Causes and Treatment

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Example 161 Natalizumab plus interferon beta1a for relapsing multiple sclerosis the Sentinel study

Figure 16.1 Patient disposition in the SENTINEL trial. (Rudick RA Stuart WH, Calabresi PA, Confavreux C et ai. for the SENTINEL Investigators (2006) 'Natalizumab plus interferon beta-1a for relapsing multiple sclerosis' New England Journal of Medicine, 354, 911-923. (2006) Massachusetts Medical Society.) Figure 16.1 Patient disposition in the SENTINEL trial. (Rudick RA Stuart WH, Calabresi PA, Confavreux C et ai. for the SENTINEL Investigators (2006) 'Natalizumab plus interferon beta-1a for relapsing multiple sclerosis' New England Journal of Medicine, 354, 911-923. (2006) Massachusetts Medical Society.)

Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, often progressive, inflammatory demyeli-nating disease of the CNS. Large numbers of immunocompetent cells are present in brain and spinal fluid and concentrations of immunoglobulins also are increased in these compartments. The target of the inflammatory response is presumed to be the oligodendrocyte-myelin complex. As a result, there is extensive, multifocal demyelination, little in the way of remyelination, and frequent astrocytic proliferation.

The Role Of Proteolytic Enzymes In Autoimmune Demyelinating Diseases An Update

Twenty-three years ago a review by this author (MES) summarized the evidence for the participation of proteolytic enzymes in myelin destruction in experimental allergic (autoimmune) encephalomyelitis (EAE)1. Because EAE was, as now, considered to be an animal model for multiple sclerosis (MS), the review described investigations up to that time, pointing to the involvement of proteolytic enzymes in EAE lesions and by analogy, in MS plaques. Since then, due to intensive investigations of proteolytic enzymes in these demyelinating conditions, it has become even more apparent that tissue destruction in EAE and MS, as well as in other degenerative diseases is dependent on proteolytic enzymes. These enzymes are contained in inflammatory cells such as macrophages, neutrophils, and lymphocytes that utilize proteases for their invasive mechanisms, as well as for tissue destruction. At the turn of a new century it is instructive to compare our former ideas with those of the present state of...

Evaluation Guidelines Table31

Electroencephalography (EEG) is helpful in the evaluation of seizure disorders and metabolic encephalopathy and, to a lesser extent, for documentation of regional physiological malfunctions. In patients with psychosis, the EEG should be normal, whereas metabolic disorders can cause disorganization and generalized slowing. The EEG can reveal physiological abnormalities that may not be reflected on structural imaging studies. Old trauma, a postictal state, or migraine headache may be associated with behavioral abnormalities and may cause focal EEG findings when the mRi is normal. Rarely, disorders of emotion, mood, or thought with subclinical seizures or complex partial status epilepticus may be diagnosed only with EEG. The use of evoked responses in neuropsychiatric disorders remains a research tool except when organic explanations such as multiple sclerosis are being actively considered.

Affective Disorder Syndromes

The differential diagnosis of depression includes primary psychiatric syndromes other than major depression such as behaviors associated with schizophrenia, generalized anxiety disorder, and obsessive-compulsive neuroses. Medical and neurological disorders either associated with or mimicking depression include malignancy, infections, medications (steroids, reserpine, levodopa, benzodiazepines, propranolol, anticholinesterases), endocrinological dysfunction (Cushing's disease, hypothyroidism, apathetic hyperthyroidism, diabetes), pernicious anemia, and electrolyte and nutritional disorders (inappropriate secretion of antidiuretic hormone, hyponatremia, hypokalemia, hypercalcemia). Depression is also associated with multiple sclerosis, Parkinson's disease, head trauma, stroke (particularly of the left frontal lobe), and Huntington's disease. Interictal changes in temporal lobe epilepsy may mimic depression, particularly with right-sided epileptic foci. Patients with diencephalic and...

Associated Neurological Findings

Attention to ataxia, apraxia for orolingual movements, oculomotor abnormalities, coordination problems, gait disturbances, tremor, bradykinesia, and rigidity is critical, since alterations in the ability to smell are present in some patients with Huntington's chorea and multiple sclerosis, and in approximately 90 percent of patients with early-stage Parkinson's disease. In Korsakoff's syndrome, ataxia of the trunk but not of the limbs is frequently present, as are signs of acute alcohol withdrawal (e.g., tremor, delirium, and tachycardia).

Diverse functions and dynamic expression of neuronal sodium channels

Nearly a dozen genes encode different Na+ channels, sharing a common overall motif but with subtly different amino acid sequences. Physiological signatures have now been established for some Na+ channels and it is clear that, from a functional point of view, Na+ channels are not all the same different channels can have different physiological characteristics, and they can play different roles in the physiology of excitable cells. Moreover, the expression of Na+ channels within neurons is not a static process. Plasticity of Na+ channel gene expression occurs in the normal nervous system, where it accompanies transitions between different physiological states (e.g. low-frequency versus high-frequency firing states) in some types of neurons. Maladaptive changes in Na+ channel gene expression also occur in some pathological neurons. For example, transection of the peripheral axons of spinal sensory neurons triggers down-regulation of some Na+ channel genes and up-regulation of...

Outcome measures for clinical care

Walking speed over 10 m or 50 ft, 2- or 6-min walking distance and heart rate change from rest, a timed stand up and walk task, and measures of impairment such as the Berg balance scale, Fugl-Meyer motor assessment, and ASIA motor score provide quick and reliable measures relevant to walking after stroke or SCI (Steffen et al., 2002 Duncan et al., 2003b). These measures may be more sensitive to changes during a subacute intervention compared to a treatment in chronically disabled subjects. The Multiple Sclerosis Functional Composite scale includes a 25-foot timed walk that, with its other two measures, has proven valuable for clinical trials (Kalkers et al., 2000). Serial monitoring of walking speed can serve as both

Ocular Flutter and Opsoclonus

Abnormal repetitive eye movements in which the fast phase or saccades are abnormal include ocular flutter and opsoclonus. Opsoclonus is a continuous succession of multidirectional conjugate saccadic eye movements with no intersaccadic interval. In the acute stage, it is usually associated with violent ataxia and high-amplitude tremor of all limbs. As recovery occurs, some patients go through a phase in which there are spontaneous bursts of horizontal back-to-back saccades, again without intersaccadic interval. In adults, opsoclonus usually results from brain stem encephalitis, either sporadic or as a remote effect of carcinoma. In infants and children, opsoclonus can be a remote manifestation of neuroblastoma. Ocular flutter comprises bursts of saccades in one plane, typically horizontal, during forward fixation. There are no intervals between saccades. Patients can manifest ocular flutter when developing or recovering from opsoclonus, and both disorders probably share...

Trigeminal Neuralgia Tic Douloureux

Painful neuralgia of the trigeminal nerve results in the clinical syndrome of tic douloureux or trigeminal neuralgia. y The paroxysmal disorder presents as excruciating, lancinating painful spasms affecting one or more divisions of CN V. Trigeminal neuralgia is unilateral and usually affects the second or third division of CN V (3rd 2nd 1st). In less than 5 percent of cases V1 is affected, whereas V3 is affected in more than 70 percent of cases. y Rarely, pain may occur bilaterally, although simultaneous bilateral spasms are quite atypical. The pain occurs spontaneously as brief lightning-like spasms lasting seconds to minutes, or pain may be precipitated by cutaneous or auditory stimuli. In many instances, there is a demonstrable trigger point that can reproduce pain, and some patients may be unable to chew, eat, drink, shave, or brush their teeth for fear of triggering a spasm. y Paroxysms recur throughout the day and night. Between attacks, there are no symptoms, but the patient is...

Evidence Supporting Disconnection

Circumscribed lesions of the arcuate fasiculus that spare overlying cortex also support disconnection (Aihara et al., 1995 Arnett, Rao, Hussian, Swanson, & Hammeke, 1996 Tanabe et al., 1987), but with white matter lesions (caused by multiple sclerosis, for example) it is not possible to differentiate between the relative importance of disruption of the arcuate fasiculus and disconnections of overlying neurons along its course.

Proteins And Proteolytic Enzymes Of Myelin

Myelin is largely composed of lipids (70 ) and proteins (30 ). The two major proteins of myelin are myelin basic protein (MBP) and proteolipid protein (PLP) which constitute 30 and 50 of all myelin proteins, respectively. PLP (24kD molecular weight) is tightly bound to lipids while MBP (18kD molecular weight) is also complexed with lipids, but with less affinity than PLP16. Minor myelin proteins with important roles include MAG (myelin-associated glycoprotein) MOG (myelin oligodendrocyte-specific glycoprotein), MOBP (myelin oligodendrocyte-specific basic protein), and DM-20 of the PLP family of proteins. Proteinases, lipases, kinases, and peptidases are also present 13 17-22. MBP is highly susceptible to proteolysis and is digested by cathepsin B and D, calpain, metalloproteinase, trypsin, and pepsin while PLP is resistant to trypsin. The latter however, is partially digested by elastase23, trypsin and calpain, if detergent is present23-26 . The intact MBP, PLP, and MOG proteins or...

The previously silent SNS Na channel gene is abnormally expressed in some demyelinated neurons

Multiple sclerosis (MS) has traditionally been viewed as a disorder in which myelin is the primary target. However, there is recent evidence for abnormal SNS expression in experimental models of demyelination and in MS. Black et al (1999b) studied Na+ channel expression in the taiep rat, a mutant model in which myelin is initially formed normally, but then lost as a result of an oligodendrocyte abnormality. They observed the abnormal expression of SNS Na+ channel mRNA and protein in Purkinje cells following loss of myelin. More recently, Black et al (2000) demonstrated that SNS mRNA and protein, which are not detectable in normal Purkinje cells, are expressed within Purkinje cells in a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis. Black et al (2000) have also demonstrated the expression of SNS mRNA (Fig. 7a, b) and protein (Fig. 7e, f) within cerebellar Purkinje cells from tissue obtained post-mortem from MS patients, but not in controls with no...

Diversity and dynamic expression challenges and opportunities

Research described in this chapter has been supported, in part, by grants from the National Multiple Sclerosis Society, and from the Rehabilitation Research Service and Medical Research Service, Department of Veterans Affairs. We also thank the Eastern Paralysed Veterans Association and the Paralysed Veterans of America for support, including a gift that supports the Yale London Collaboration.

Supranuclear Hemispherical Lesions Jable143

Hemorrhage, tumor, multiple sclerosis, brain abscess) may result in some weakness of neck and tongue musculature so that the chin deviates toward the lesion. Atrophy and fasciculations are not present in an upper motor neuron lesion. y , y An irritative unilateral supranuclear lesion (e.g., a seizure focus) may result in forced deviation of the head or tongue away from the lesion. y

Last observation carried forward LOCF

For example, if there is an underlying worsening trend in disease severity then patients who withdraw early will tend to provide better outcomes than those who withdraw later on in the treatment period. If one treatment has more early dropouts than the other, possibly because of side effects say, then there will be bias caused by the use of LOCF. Multiple sclerosis and Alzheimer's disease are settings where this could apply. The opposite will of course be true in cases where the underlying trend is one of improvement depression would be one such therapeutic area. These scenarios emphasise the earlier point that there is no universally valid way to deal with missing data.

Evaluation Guidelines j Table194

Somatosensory evoked potentials allow assessment of sensory impulse conduction along the entire sensory axis from peripheral nerve to sensory cortex. They have their greatest application in lesions proximal to the dorsal root ganglion. In the upper extremity the median nerve is the most frequent site of stimulation in the lower extremity it is the tibial nerve. This test is useful in patients with multiple sclerosis, brain stem structural lesions, Friedreich's ataxia, spinal cord injury, plexopathy, or radiculopathy. The brain stem auditory evoked response may be useful in identifying a subclinical focus of demyelination in multiple sclerosis, a brain stem structural lesion, or Friedreich's ataxia. Cerebrospinal Fluid. A lumbar puncture can be helpful when multiple sclerosis, myelitis, meningitis, acute inflammatory demyelinating polyneuropathy, and certain other peripheral neuropathies are suggested. Attention

Evaluation Guidelines Table211

MRI Magnetic resonance imaging EMG, electromyography NCv, nerve conduction velocity LEMS, Lambert-Eaton myasthenic syndrome ANNA, antineuronal nuclear antibody (anti-Hu) NE, norepinephnne tSt, thermoregulatory sweat test CSF, cerebrospinal fluid MS, multiple sclerosis MRI Magnetic resonance imaging EMG, electromyography NCv, nerve conduction velocity LEMS, Lambert-Eaton myasthenic syndrome ANNA, antineuronal nuclear antibody (anti-Hu) NE, norepinephnne tSt, thermoregulatory sweat test CSF, cerebrospinal fluid MS, multiple sclerosis

Structural Abnormalities

Lesion deficit correlation studies demonstrate that certain disorders are more likely to be associated with a major depression than others (a) discrete brain lesions, as seen with trauma, surgery, stroke, tumors, and certain types of epilepsy (b) neurodegenerative diseases with regionally confined pathologies such as Parkinson's, Huntington's, and Alzheimer's diseases (c) disorders affecting diffuse or multiple random locations such as multiple sclerosis and (d) system illness with known central nervous system effects such as thyroid disease, cancer, and acquired immunodeficiency syndrome (AIDS) (Table 7.1). Multiple sclerosis Studies of systemic disorders, such as lupus erythematosus, Sjogren's syndrome, thyroid and adrenal disease, AIDS, and cancer, describe mood symptoms in subsets of patients. As with the more diffuse neurodegenerative diseases, such as Alzheimer's disease (Cummings and Victoroff, 1990), a classic lesion-deficit approach is generally...

Functional Abnormalities

Positron emission tomography (PET) and single-photon emission tomography (SPECT) studies of both primary depression (unipolar, bipolar) and depression associated with specific neurological conditions (focal lesions, degenerative diseases, epilepsy, multiple sclerosis) identify many common regional abnormalities (reviewed in Mayberg, 1994 Ketter et al., 1996). For example, in depressed patients with one of three prototypical basal ganglia disorders Parkinson's disease, Huntington's disease, and left caudate stroke resting-state paralimbic hypometabolism (ventral prefrontal cortex, anterior cingulate, anterior temporal cortex) was found to differentiate depressed from nondepressed patients within each group, as well as depressed from nondepressed patients, independent of disease etiology (Mayberg, 1994). These regional findings, replicated in other neurological disorders (Bromfield et al., 1992 Hirono et al., 1998 Starkstein et al., 1990c), suggests involvement of...

Magnetic Resonance Imaging Of The Spine

MRI is uniquely sensitive in detecting the presence of intramedullary spinal cord diseases. Common primary intramedullary neoplasms that can be elucidated include astrocytoma, ependymoma, and spinal cord hemangioblastoma. Contrast medium-enhanced MRI can help differentiate tumoral cord edema, as seen in these entities from the primary tumoral masses. Other causes of abnormal signal within the spinal cord include inflammatory or demyelinating diseases such as acute disseminating encephalomyelitis, transverse myelitis, or multiple sclerosis. The evaluation of spinal cord edema, secondary to trauma, either from chronic discogenic disease or in situations of acute complex fracture injuries is becoming increasingly essential, particularly in national trauma centers.

Abnormal EMG Activity

Myokymic discharges consist of a spontaneously occurring grouped pattern of firing of motor units double, triple, or multiple discharges occur, followed by a period of silence and then by another grouped discharge. They may occur in patients with radiation-induced plexopathy or myelopathy and occasionally with chronic radiculopathies or entrapment neuropathies, Guillain-Barre syndrome, multiple sclerosis, or gold intoxication they may also be found in facial muscles in patients with brain stem gliomas.y , y

Male Orgasmic Disorder

Male Orgasmic Disorder, previously referred to as Inhibited Ejaculation, has received very little attention in the therapeutic literature. As initially reported by Masters and Johnson (1970), this remains a relatively rare dysfunction, and etiology remains unclear. Clinical case studies suggest a variety of psychological factors as causes, but there is virtually no empirical support for these theories (Dow, 1981 Schull & Sprenkle, 1980). Male Orgasmic Disorder can, however, result from a number of physiological conditions, such as multiple sclerosis and damage to the hypothalamus. Finally, the inability to reach orgasm may be a side effect of several medications, including anti-hypertensives sedatives and anti-anxiety, anti-depressive, and antipsychotic agents (Ban & Freyhan, 1980).

Control of tumor cell growth

In addition to infectious diseases, MCA holds promise for identifying drug targets for treatment of multi-factorial diseases such as cancer, multiple sclerosis, diabetes type 2 and atherosclerosis. These diseases are complex by nature, hence difficult to understand. For cancer, for instance, many genes have been causally implicated in oncogenic transformation 43 . Most of these genes function in signal transduction pathways governing cell proliferation, apoptosis, angiogenesis, metastasis or invasion 44, 45 . Complicated network organization (regulatory circuitry, crosstalk between pathways, etc.) and non-linear kinetics of biochemical reactions and the multitude of factors involved, complicate understanding of signaling. Furthermore, interactions between tumor cells and other cell types generate a complex supra-cellular communication network. Therefore, even though many molecular differences have been identified between cancer cells and their healthy counterparts, the emerging...

Plasticity ofNa channel expression in other CNS demyelinating conditions

It is worth noting that demyelinated axons studied in clinical cases of multiple sclerosis may also display continuous increases of 3H saxitoxin binding, as seen in shiverer (Moll et al 1991), indicating that similar plasticity of Na+ channel expression can occur in some types of this heterogeneous human disorder, where it may contribute to functional neurological recovery following intermittent demyelinating attacks. In addition, multiple sclerosis is often accompanied by tonic seizures that respond to Na + channel blockers such as lidocaine (Sakurai & Kanazawa 1999). Thus dynamic changes in Na+ channel biology may be part of the clinical problem, as well as part of the solution at various stages of these diseases, and excessive axonal hyperexcitability with seizures and spasms may represent the price that is paid to restore function to inexcitable fibres.

Other Potential Roles As A Neuropeptidase

Inflammation has been repeatedly proven to be a critical player in a number of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and many others. Strangely, this diverse metallopeptidase 24.15 has a number of potential connections to the role of inflammation as well.

Mechanisms of poststroke depression

Data obtained from several of our clinical studies have been consistent with this hypothesis. In one study, we examined a consecutive series of 20 patients admitted to the hospital with an acute stroke who underwent a lumbar puncture (Bryer et al. 1992). Samples were obtained after 12 h of overnight fast and bed rest (activity and diet can both affect the concentrations of cerebrospinal fluid (CSF) biogenic amine concentrations). Patients were also examined within 5 days following stroke and CSF specimens were taken from the same lumbar space and from the same aliquot (i.e., 3 ml CSF was taken after the first 20 ml had been removed). Control patients (n 7) were hospitalized at the same time, four with multiple sclerosis and three with seizure disorder. Although depressed and non-depressed stroke patients did not differ significantly in their background characteristics, and none of the patients was taking antidepressant medications, depressed patients (n 4, three major depression, one...

Olfaction in Neurological Disorders

Deficits in olfaction (acuity, memory, and identification) appear early in the course of a number of neurodegenera-tive disorders, including cortical Dementia of the Alzheimer's Type, and some of the subcortical dementias, namely Parkinson's disease, Huntington's disease, and HIV-related dementia. However, such deficits have not been reported in patients with atypical parkinsonian syndromes, including corticobasal degeneration and progressive supranuclear palsy (see Doty, 2001 Pantelis, Brewer, & Maruff, 2000). These findings are consistent with the nature of involvement of the relevant olfactory circuits in these various disorders, and suggest that smell ability may assist in differential diagnosis. Studies have also found deficits in olfactory memory in chronic alcohol abusers and of identification ability in patients with Korsakoff syndrome (Potter & Butters, 1980). Olfactory identification deficits have also been found in motor neuron disease (MND), multiple sclerosis (MS), and...

Common Pathologic States of the Optic Nerve

Optic neuritis typically occurs in women in their second or third decade. The visual loss is acute and accompanied by pain that is exacerbated with eye movement. The optic nerve head is often normal, but the visual field is abnormal. An afferent pupillary defect is present unless the contralateral side has been previously damaged. Most patients begin to improve in six weeks and regain near-normal visual function. Recurrent bouts of optic neuritis or magnetic resonance imaging evidence of multifocal periventricular demyelination make the diagnosis of multiple sclerosis likely. Acute visual loss should be treated with a 3-day course of intravenous Methylprednisolone followed by an oral Prednisone taper. Oral corticosteroids alone are con-traindicated because they increase the risk of subsequent episodes.

Mitochondrial Encephalopathy Lactic Acidosis and Strokelike Episodes

Conditions to exclude include any other causes of stroke in childhood, infancy, or adulthood other mitochondrial multisystem disorders, such as MERRF or KSS chronic progressive external ophthalmoplegia (CPEO), or other uncharacterized disorders and any neurological disease in adulthood with an overall progressive course but relapses that leave residuals, such as multiple sclerosis or other demyelinating diseases.

Lebers Hereditary Optic Neuropathy

LHON presents as loss of central visual acuity in adolescence or early adulthood, acutely or subacutely, although it rarely can occur in children. Fundoscopic examination shows telangiectatic microangiopathy and swelling of the nerve fiber layer around the optic disc in acute presentations and optic atrophy in subacute to chronic presentations. Up to almost one fourth of patients regain vision. In addition to blindness, complex neurological features include signs suggestive of multiple sclerosis, multisystem atrophy, or MELAS. Extrapyramidal features like dystonia may develop with bilateral striatal necrosis. Ihe differential diagnosis includes other causes of optic neuritis, multiple sclerosis, MELAS, Leigh's disease, subacute combined degeneration due to vitamin B 12 deficiency, Friedreich's-like ataxia, other causes of multisystem degeneration. Ihe general paradigm should be followed, but in leukocyte platelet analysis, for major manifestations, MINDI*LHON4160 and MTND4*LHON11778...

Familial Spastic Paraplegias

Differential Diagnosis and Evaluation. The FSPs are diagnoses of exclusion. Particular care is necessary if the family history is not revealing or if there are numerous complications or atypical features. Because FSP can mimic treatable disorders, such as vitamin B12 deficiency, doparesponsive dystonia, cervical spondylosis, or multiple sclerosis, exhaustive evaluation is justified. 17

In Neurology And Ophthalmology

The classical application of VEP measurements for clinical purposes is its contribution to the diagnosis of multiple sclerosis (MS). The main characteristic of this disease is the patchy demyelination of afferent and efferent nerve fibers distributed all over the nervous system, and the patients have neurological symptoms that cannot be explained by a single lesion. Myelin is an insulating sheath, found on most axons, that increases conduction velocity (cf. Kandel et al., 2000), thus, electrophysiologically, latency prolongations are expected when demyelination occurs. In many patients the visual system is affected at an early state of the disease, and one finds patients with pathological VEP results who, however, do not display any subjective visual symptoms (i.e., they have normal visual acuity and visual fields). An optic neuritis occurs frequently at a very early stage of the disease, which in general is followed by a recovery after several weeks, whereas other symptoms...

Human TCell Lymphotrophic Virus Type

The differential diagnosis includes myelopathy due to a compressive lesion of the cord from a disk, tumor, or infection, subacute combined degeneration resulting from vitamin B12 deficiency, HIV-1 myelopathy, multiple sclerosis, and syphilis. Serological testing should be performed to detect HTLV- 1 antibodies in serum. Magnetic resonance imaging (MRI) of the brain may demonstrate hyperintense lesions in the subcortical white matter on T2-weighted scans, resembling the lesions of multiple sclerosis. y Elevated antibody titers to HTLV-1 can be detected in blood and cerebrospinal fluid of patients with HAM-TSP.

Respiratory drive disorders

Any lesions in the medulla may disrupt respiratory control and lead to ventilatory failure during sleep. Tumours, haemorrhage, infarction, encephalitis, trauma, neurosurgery, irradiation, multiple sclerosis, syringobulbia and multiple system atrophy may all be responsible. These conditions usually cause a complex clinical picture because of the site of the lesion and this may make it difficult to assess the respiratory complications.

Astrid E Cardona and Richard M Ransohoff

Actions of chemokines and the interaction with specific receptors within the central nervous system (CNS) surpass their original defined role of leukocyte recruitment to inflamed tissues. Chemokine receptor expression by resident CNS cells is crucial for normal brain development and architectural organization, neuronal protection during inflammatory and neurotoxic challenges, and, among many others, protective mechanisms during inflammatory conditions such as multiple sclerosis. The chemo-kine chemokine receptor systems involved in such significant functions include CXCR4 CXCL12, CXCR2 CXCL1, and CX3CR1 CX3CL1. In this chapter, we discuss how these receptors might contribute to modulate communication within the CNS and with peripheral elements, and we also suggest potential mechanisms of action of fractalkine and the translation of these into the understanding of microglial function during neuro-inflammatory conditions. Key Words Chemokine receptors CNS multiple sclerosis microglia NK...

Expression of Chemokine Receptors in Cells Intrinsic to the Central Nervous System

Increasing evidence highlights the prominence of chemokines in a variety of physiologic and pathologic processes in the CNS. In particular, chemokines have been shown to be critical determinants in the positioning of cellular population in the development of CNS inflammation due to autoimmune reactions or infectious diseases (2,15). Several lines of evidence indicate that all resident cells of the CNS express functional chemokine receptors in the intact human brain and in the CNS of rodent and macaques as experimental models. Astrocytes and microglia express most of the chemokine receptors including CCR3 (16-18), CCR5 (17), CXCR3 (19-21), and CXCR4 (18,22,23). Functional expression of CCR2 by fetal human astrocytes (24) and by reactive microglia in multiple sclerosis (MS) lesions (25) has been documented. Confined exclusively to microglia in vivo is the expression of CX3CR1 (26,27). Neurons exhibit expression of CCR1 (28), CXCR1 (29), CXCR2 (29), and CXCR4. Neuronal CCR1 expression,...

Emotional Regulatory Network

Prefrontal and orbitofrontal cortex often bear the brunt of damage in traumatic brain injuries. Also, the system may degrade in patients with stroke, multiple sclerosis, the cortical and subcortical dementias, and other cerebral disorders. Behavioral and mood syndromes caused by frontal lobe injury are recapitulated by lesions in subcortical structures of the circuits.

White Spot In Spinal Cord

Intramedullary Spinal Cord Tumors

MRI scans of a 50-year-old woman with multiple sclerosis. a This contrast-enhanced, T1-weighted image shows an enhancing intramedullary spot at C4, which could be mistaken for an angioblastoma. b Sagittal T2-weighted image showing some perifocal edema and another hyperdense lesion at C2. c Axial T2-weighted image demonstrating a lesion in the posterior midline and a normally shaped cord. d Cranial T2-weighted scan displaying further lesions in the white matter, particularly on the left side. Fig. 3.25. MRI scans of a 50-year-old woman with multiple sclerosis. a This contrast-enhanced, T1-weighted image shows an enhancing intramedullary spot at C4, which could be mistaken for an angioblastoma. b Sagittal T2-weighted image showing some perifocal edema and another hyperdense lesion at C2. c Axial T2-weighted image demonstrating a lesion in the posterior midline and a normally shaped cord. d Cranial T2-weighted scan displaying further lesions in the white matter, particularly...

Autonomic Dysfunction Secondary to Focal Central Nervous System Disease

Inflammation (multiple sclerosis, poliomyelitis) Multiple sclerosis Other brain stem disorders associated with autonomic dysfunction include tumors, syringobulbia, Arnold-Chiari malformation type 1, multiple sclerosis, and poliomyelitis. Brain stem tumors may present with intractable vomiting, orthostatic hypotension, or paroxysmal hypertension. Syringobulbia may produce Horner's syndrome, orthostatic hypotension, cardiovagal dysfunction, lability of arterial pressure, and central hypoventilation. y Syncope, sleep apnea, and cardiorespiratory arrest have been reported in association with the Arnold-Chiari malformation type 1. Less common manifestation of brain stem dysfunction include hypertension due to involvement of the medullary reticular formation in poliomyelitis (see Chapter . ) autonomic hyperactivity, most likely due to disinhibition of preganglionic sympathetic and parasympathetic neurons in tetanus (see Chapterii39 ) and fulminant neurogenic pulmonary edema due to...

Peroxisomal Leukodystrophies Adrenoleukodystrophy

In the adolescent cerebral ALD syndrome, signs and symptoms of cerebral involvement are manifest, yet the onset of disease usually occurs between the ages of 10 and 21. The adult form usually presents with dementia, psychiatric disturbances, seizures, and spastic paraparesis with onset at some time after the age of 21. Such patients have presentations similar to those of other problems such as multiple sclerosis, schizophrenia, and brain tumor. They show a reasonably rapid regression.

Cortical Versus Subcortical Dementing Syndromes

A distinction has been noted between the cortical dementia typically seen in Alzheimer's or Pick's disease and the subcortical dementia typified by Huntington's and Parkinson's disease but noted also in progressive supranuclear palsy, multiple sclerosis, Wilson's disease, and human immunodeficiency virus (HIV) infection. y Dementia seen in diseases with primarily subcortical neuropathology feature slowed movement (bradykinesia) and thought (bradyphrenia), disproportionate problems in the efficient use of memory, poor planning, judgment, and reasoning, and often affective changes.

Nuclear Brain Stem Syndromes

Other pathological processes within the brain stem can produce trigeminal dysfunction. Tumors, hemorrhage (hypertensive, ruptured arteriovenous malformation), infarctions, demyelinating disease such as multiple sclerosis, infections such as brain stem abscesses and brain stem encephalitis, and inflammatory conditions such as tuberculosis or sarcoidosis affecting the lateral pons or midbrain may result in ipsilateral or contralateral facial sensory loss, respectively, as well as severe paroxysmal hemifacial pain. Facial weakness, muscle atrophy, difficulty chewing, and diminished jaw jerk reflex may be identified in amyotrophic lateral sclerosis as

Ian Wilmut and Lesley Ann Paterson phd

Human stem cells offer great potential for lifelong treatment of deteriorating and debilitating diseases such as Parkinson's disease, diabetes, multiple sclerosis, and heart disease. There are primarily two stem cell sources available those derived from embryos and those derived from adult tissues (including the umbilical vein).

Neuromuscular Disorders

Neuromuscular disorders may be most easily characterized in terms of level and degree of motor neuron involvement. Disorders involving the upper motor neuron tracts, such as progressive spastic bulbar paralysis, and demyeli-nating diseases, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), cause bulbar paralysis. Symptoms typically include difficulty speaking and swallowing, and respiratory failure.

Action or Non Rest Tremors TabieMB

Disease of cerebellar outflow (dentate nucleus and superior cerebellar peduncle) Multiple sclerosis, trauma, tumor, vascular disease, Wilson's acquired hepatocerebral degeneration, drugs, toxins (e.g., mercury), others Cerebellar kinetic tremor, sometimes referred to as an intention tremor, is most apparent during a goal-directed limb movement such as that used in the finger-to-nose or heel-to-shin test. In contrast to postural tremor, the patient's greatest disability occurs at the end point, when a sudden destabilization occurs with severe shaking. This tremor is usually caused by a lesion in the cerebellar outflow (dentatorubral) tracts, y and therefore it is seen most typically in patients with multiple sclerosis, cerebrovascular accidents, or primary cerebellar disorders. Likewise, rubral tremor, a tremor that mixes rest, postural, and kinetic tremors, is generally not an idiopathic tremor and is induced by structural disease in the midbrain or fiber pathways connecting this...

Network Emotional Regulatory Network Spatial Awareness Network Language Network Summary

Tem, from behavioral systems to interregional and local circuits, to neurons and their dendritic trees and spines, to microcircuits on axons and dendrites, and most importantly, to synapses and their molecules and ions. Experience and practice lead to adaptations at all levels. Knowledge of mechanisms of this activity-dependent plasticity may lead to the design of better sensorimotor, cognitive, phar-macologic, and biologic interventions to enhance gains after stroke, traumatic brain and spinal cord injury, multiple sclerosis, and other diseases.

Supranuclear Syndromes

Facial sensory loss may occur in the setting of lesions involving the trigeminothalamic pathways, corona radiata or internal capsule white matter projections from the VPM nucleus of the thalamus to primary sensory cortex, or within sensory cortex itself. Specific pathological processes affecting these pathways include ischemia, hemorrhage, neoplasm, and demyelinating diseases. All result in contralateral hemifacial and hemibody numbness. In seizures, facial tingling often occurs in association with hand numbness and suggests a lesion in the postcentral gyrus. In the cheiro-oral syndrome, ipsilateral numbness in the hand and at the corner of the mouth reflects an insult, typically vascular, at adjoining portions of the ventroposterolateral and VPM nuclei of the thalamus where the anatomical distributions of these regions are directly adjacent to one another. In contrast, a persistent deep, aching, poorly localized facial pain has been reported in patients with thalamic lesions...

Cranial Nerve Dysfunction

Oligoclonal bands (OCB) are present in the CSF when three to five bands are seen on gel electrophoresis. This finding implies that a single clonal population of plasma cells is responsible for each band. More than one oligoclonal band rarely occurs in normal CSF. A serum sample should also be obtained simultaneously with the acquisition of the CSF to determine whether the OCB are unique to the CSF. Oligoclonal bands are present in 83 to 94 percent of patients with multiple sclerosis, 100 percent of patients with subacute sclerosing panencephalitis, 25 to 50 percent of patients with other inflammatory CNS disorders (CNS lupus, neurosarcoidosis, cysticercosis, Behcet's and viral, fungal, and bacterial infections), as well as most with some brain tumors, and Guillain-Barre syndrome. Because OCBs are present in such varied conditions, their presence offers little to a specific diagnosis.

Triple Flexion Is A Spinal Reflex

Bethesda Category

When planning treatment the patient's underlying neurologic and medical conditions should always be considered. For example, spinal cord injured patients with autonomic dysreflexia, patients on antihypertensive medications, or elderly patients often do not tolerate antispasticity medications with hypotensive side effects. Patients with traumatic brain injury, stroke, or multiple sclerosis who have significant cognitive impairments may not tolerate drugs that are sedating. Furthermore, patients with marginal strength may lose functional abilities if treated with medications that cause muscle weakness. Therefore, the pros and cons of the various treatments must always be considered for each individual patient. An algorithm for the management of spasticity is presented in Fig. 17.1. This is by no means exhaustive. In all patients with spasticity, medical conditions or extrinsic factors that can worsen spasticity should always be sought. For example, fever can worsen spasticity. Certain...

Ocular Misalignment Syndromes

The clinical importance of diagnosing the MLF syndrome is its exquisite localizing value for lesions deep in the substance of the brain stem tegmentum. This general area in the brain stem contains the ascending reticular activating system, which is necessary for consciousness, along with several adjacent cranial nerve nuclei, and various ascending and descending sensory and cerebellar pathways. Therefore, the isolated occurrence of an MLF syndrome in an alert individual without other brain stem signs or symptoms suggests the presence of a highly discrete lesion. In the adult, this is caused by either small demyelinating plaques of multiple sclerosis, by small infarctions due to small vessel disease, and very occasionally can be encountered in the setting of head trauma. In children, the MLF syndrome can be the first sign of a brain stem glioma. Differentiating between multiple sclerosis (see C.ha.p.te,r 4.8 ) and small vessel infarctions (see Chapter , and Chapter45 ) can be...

Abnormal Findings and Clinical Uses of Polysomnography

Evoked potential recordings provide a means of detecting lesions in the afferent pathways under study. They assess the functional integrity of these pathways, whereas imaging techniques such as magnetic resonance imaging evaluate their anatomical basis. Thus, evoked potential studies sometimes reveal abnormalities missed by magnetic resonance imaging, and vice versa. The findings may be important for diagnostic purposes, in following the course of certain neurological disorders, or for determining the extent of pathological involvement. y In patients with known pathological processes involving the CNS, evoked potential studies help to detect and localize lesions. Subclinical abnormalities may be detected in a variety of disorders, and multifocal abnormalities occur not only in multiple sclerosis but also in a variety of different settings. The electrophysiological findings must therefore be interpreted in the clinical context in which they are obtained. Evoked potential studies are...

Arteriovenous Malformations

Clinical Features and Associated Disorders. As AVMs enlarge, symptoms are related to a number of mechanisms. They can cause bleeding, seizures, vascular headache, and chronic ischemia. Bleeding is most likely due to fragility of the abnormal vessels. The angiomas that most frequently rupture are of the AV type. Symptoms and signs depend on the location of hemorrhage. There are usually signs of meningeal irritation due to bleeding into the CSF. Not all ruptures are symptomatic but evidence of previous bleeding is often observed at necropsy. About one half of the patients present with epilepsy. Progressive neurological signs may develop secondary to a mechanism called intracerebral steal or compression of adjacent brain tissue by the pulsating blood vessels. Chronic migrainous headaches are also a frequent complaint in patients with vascular malformations. Patients with unruptured AVMs may present with increased ICP and papilledema. Angiomas in the brain stem may cause serious bleeding...

Assessment Of Immune Response With Antigen Arrays

Antigen microarrays have been employed to target other human diseases as well. Different sets of potential antigens and allergens (both peptides and proteins) were used to evaluate auto-antibodies in the sera of patients with systemic rheumatic diseases, autoimmune encephalomyelitis, or multiple sclerosis 69-71 . Recently, tumor-derived proteins have been arrayed and incubated with sera obtained from cancer patients and healthy controls 72-74 . Positive responses have been observed in prostate cancer and lung cancer patients, indicating the wider applicability of antigen microarrays to elicit specific antibodies in complex biological fluids.

Impulse Control Disorders

Sloan et al81 treated six individuals with acquired brain injury with fluoxetine (20 mg day) in an open trial. Five had suffered a cerebrovascular accident (CVA) and all had emotional lability. Within 1 week of commencing treatment marked improvement in emotional lability was seen in all 6 patients. Seliger et al82 treated 13 patients with emotional lability (post-stroke or due to multiple sclerosis) over 12 months using fluoxetine (20 mg day). Significant responses were seen within 3-14 days in all patients and were sustained for the period of treatment. On discontinuation, two patients had a relapse of emotional lability which resolved in one when fluoxetine was recommenced.

Evaluation Guidelines Table173

Compared with CT scanning, MRI offers an increased capacity for demonstrating cerebellar (and brain stem) lesions because of a lack of bone artifact. MRI demonstrates cerebellar atrophy as well as spinal and brain stem involvement in degenerative cerebellar disorders. In addition, MRI is much more sensitive to white matter lesions, particularly demyelination. Therefore, MRI should be performed when multiple sclerosis is suspected. Cerebrospinal Fluid. Lumbar puncture and examination of the cerebrospinal fluid are applied when inflammatory or infectious disorders are expected. Pleocytosis, increased total protein content, and oligoclonal bands are found in patients with multiple sclerosis, viral cerebellitis, and paraneoplastic cerebellar disorders. In addition, serum and cerebrospinal fluid anti-Purkinje cell antibodies (anti-Yo, anti-Hu, and anti-Ri) are useful in the diagnosis of paraneoplastic cerebellar degeneration.y

Evaluation Guidelines Table95

Cerebrospinal fluid (CSF) examination is often a critical part of investigation for dysfunction of cranial nerves III, IV, and VI because these nerves are often affected selectively in meningeal infections, as well as in inflammatory and neoplastic infiltrating disorders. In addition, patients with multiple sclerosis (see Chapter 48 ) may present a typical profile of CSF abnormalities, and patients with this disease often present with ocular motility disturbance from central lesions (gaze palsy, INO) and less frequently with ophthalmoplegia from plaques affecting the intramedullary portion of cranial nerves III, IV, or VI.

Evaluation Guidelines Table82

The major exceptions are typical optic neuritis (although magnetic resonance imaging MRI scan may be appropriate to determine the prognosis for developing subsequent multiple sclerosis) or classic anterior ischemic optic neuropathy. Transient visual loss in the setting of migraine does not require neuroimaging when the historical features are characteristic and results of the neurological examination are normal. All patients with chiasmal and retrochiasmal patterns of visual loss should undergo imaging examination. Electrophysiology. Other diagnostic tests used in combination with the clinical examination include electrophysiologic testing such as an electroretinogram (ERG) or visual evoked potential (VEP). ERGs measure rod and cone photoreceptor function and help to distinguish the retinal degenerations and dystrophies. VEPs measure the cortical activity in response to flashes of light or checkerboard stimuli and if abnormal suggest a lesion of the afferent...

Spinal Cord Myelopathy

Generally with transverse lesions of the spinal cord there is a demonstrable sensory level with bilateral loss of all modalities of sensation below a definite level. With involvement of the dorsal columns there is loss of proprioception, discriminative modalities, and vibration within a couple of levels caudad to the lesion site. With smaller lesions it is possible to selectively involve certain dorsal column modalities owing to the topographical distribution of the various modalities fibers carrying discriminative touch are most posterior, vibratory fibers are most anterior, and proprioceptive fibers are intermediate within the dorsal funiculi. There will be no significant loss of light touch however, pressure sensation may be impaired. Examples are a metastatic lesion to the spinal cord, cord infarction, and multiple sclerosis plaque.

Could Amyotrophic Lateral Sclerosis Be Caused By A Spirochete

It has been suggested that spirochetes may also be responsible for a number of other diseases other than those listed above, including multiple sclerosis and amyotrophic lateral sclerosis (ALS) (Mattman, 2001) however, this has not been conclusively proven. The thought that these mammalian diseases

Alexias And Agraphias Languagerelated Disorders

Scanning speech is part of Charcot's triad (ataxia, nystagmus, scanning speech), which is historically considered to be pathognomonic for multiple sclerosis, but it is more common with head injuries. Scanning speech is characterized as a slow, deliberate, segmented, and monotonous output, presented as individual words or major segments of words. The output retains both grammatical and semantic competence, and articulation remains relatively normal. It is the prosodic quality, particularly of the rhythm and inflection, that are disrupted. The major pathology underlying In clinical practice, a mixed dysarthria syndrome that has characteristics of several types of motor speech disorders is commonly seen. Several classic neurological disorders, such as multiple sclerosis, Wilson's disease, and advanced amyotrophic lateral sclerosis, produce several variations of dysarthria concurrently including spastic, flaccid, ataxic, and hypokinetic and hyperkinetic dysarthrias.

Disorders of the hypothalamus

These may be focal lesions, as in multiple sclerosis, tumours, or trauma, following surgery and the effects of radiotherapy. Excessive daytime sleepiness is associated with lesions of the posterior hypothalamus which increase the homeostatic sleep drive, but circa-dian rhythm disorders develop if the suprachiasmatic

Syndromes of Overactivation

This is a progressive, irregular fibrillation of individual facial muscle fibers. Usually, it begins in the frontalis and extends to involve all the ipsilateral facial muscles. Electromyographic findings include spontaneous activity of motor units at a rate of 30 to 70 per second. Common causes include pontine gliomas and multiple sclerosis. 4

Stress Proteins As Targets Of Immune Responses

Two characteristics of stress proteins greatly increase the likelihood that these proteins may become autoantigens involved either in initiating or perpetuating autoimmune diseases. First is their great phylogenetic conservation across major species barriers from prokaryotes to mammals. The second is their immuno-dominance that is, their ability to evoke strong immune responses during the course of infections with a large number of infectious agents (detailed elsewhere in this book). Thus, exposure to an infectious agent, in a genetically susceptible host, at the appropriate time during the host's development could result in an immune response to the infecting agent's stress proteins that either cross reacts with normal host stress proteins or cross reacts with organ-specific proteins, resulting in an autoimmune disease. Several laboratories tested the feasibility of this hypothesis in the human disease multiple sclerosis and in its animal model, experimental autoimmune...

Abnormal Findings and Clinical Uses of the SEP

Figure 24-14 Median-elicited somatosensory evoked potential elicited A, a normal subject by right-sided stimulation, anB, a patient with multiple sclerosis by left-sided stimulation. Two trials are superimposed to show the replicability of the findings. In the responses recorded in the patient, an Erb's point potential is present but responses over the cervical spine and scalp are absent. EP, Erb's point CV5, 5th cervical spine i, ipsilateral c, contralateral other abbreviations as in earlier illustrations. In patients with multiple sclerosis, SEP abnormalities may indicate the presence of subclinical lesions, thereby helping to establish the diagnosis. y The presence of such abnormalities may also suggest that vague sensory complaints have an organic basis when this is hard to determine clinically. The SEP is abnormal in about 80 percent of patients with multiple sclerosis (see Figs.,24 .1.4 and 2.4i15. ), but SEP abnormalities are found in only about 30 percent of patients when this...

Cognitive Impairments

Minor cognitive impairment not meeting the criteria for a diagnosis of dementia is detectable in 0.4 of patients in the asymptomatic period (70). Rarely, there may be an early-phase dementia, which occurs soon after infection with HIV and reflects an encephalopathy (70). There may also be an uncommonly reported middle-phase dementia, which presents similarly to multiple sclerosis after what appears to be an autoimmune reaction affecting the white matter of the brain (71).

Abnormal Findings and Clinical Uses of the Blink Reflex

The blink reflex may be abnormal with polyneuropathies, thereby indicating the extent of the disorder. Abnormalities may also occur with tumors in the cerebellopontine angle involving either or both nerves or the brain stem and with brain stem lesions involving the central pathways subserving the reflex, such as in multiple sclerosis, sometimes in the absence of clinical evidence of brain stem involvement.

Control Of Central Nervous System Iron

A large number of diseases are associated with excessive central nervous system (CNS) iron. In some diseases, such as neuroferritinopathy, aceruloplasmine-mia, Freiderich's ataxia, and Hallervordan-Spatz (aka, neuronodegeneration with brain iron accumulation 1), the iron accumulation is culpable, resulting in direct neurotoxicity. Other diseases, such as Parkinson's disease, Alzheimer's disease, tardive dyskinesia, and multiple sclerosis, demonstrate excessive iron deposits, but the exact relationship between this and the disease process is not known. Restless legs syndrome (discussed in detail in Chapter 7) demonstrates reduced CNS iron.

Pathological laughing and crying

Pathological laughing and crying is a phenomenon characterized by outbursts of emotion which are out of proportion to the underlying feelings of happiness and sadness (Wilson 1923). The clinical manifestations of pathological emotions may range from facial expressions of happiness or sadness to loud and uncontrolled outbursts of laughing or weeping. These uncontrolled outbursts of pseudoemotion are almost uniformly embarrassing to patients. Fears of developing uncontrollable emotional display can lead to social phobia and withdrawal. This phenomenon has been referred to by a variety of names including pathological emotions, emotional lability, emotional incontinence, and emotionalism as well as pseudobulbar affect (Lawson and Macleod 1969 Wolf et al. 1979 Ross and Stewart 1987 Hanger 1993). This condition has also been associated with a variety of neurological disorders including stroke, multiple sclerosis, traumatic brain injury, amyotrophic lateral sclerosis, central pontine,...

RLS Associated with Spinal Cord Lesions

There are numerous case reports describing the onset of RLS in close temporal association with spinal pathologies such as lumbosacral radiculopathy (73), borrelia-induced myelitis (74), transverse myelitis (75), vascular injury of the spinal cord (76), multiple sclerosis (77), traumatic lesions (77), cervical spondylotic myelopathy (77), or syringomyelia (77). After spinal anesthesia, 8.7 of 161 patients developed transient new onset RLS (78). Many subjects in these reports responded to dopaminergic treatment (74,75,77,79), while in one subject (76) relief was obtained by a combination of tilidin and zolpidem.

Comprehensive Metabolomic Profile Analysis Of Human Cerebrospinal Fluid

On the other hand, CSF may hold the key to understanding complex neurological disorders such as Alzheimer's, Creutzfeldt-Jacob, multiple sclerosis, and meningitis. Currently, there is a relatively standard set of CSF clinical parameters that is used for diagnostics. These parameters include supernatant color, cell counts, histological examination, total protein concentration, cell culture, latex agglutination, polymerase chain reaction (PCR), and measurements of certain metabolites.1819 For example, increased protein can be attributed to a decreased turnover of CSF (known as the CSF flow rate), which is often associated with disease onset. Decreased turnover can result in a nonspecific accumulation of molecules (both proteins and metabolites), and to date, total CSF protein is still claimed to be the most sensitive indicator of nonspecific CNS pathology.1920 However, the average adult CSF protein concentration can range anywhere between 18 and 58 mg dl, and the average concentrations...

Rehabilitation Psychology

Rehabilitation psychologists work in diverse settings including acute care hospitals and medical centers, inpatient and outpatient physical rehabilitation units centers, nursing homes and assisted living centers, community agencies specializing in services for a particular type of disability (e.g., cerebral palsy, multiple sclerosis, deafness), and other types of settings such as pain and sports injury centers and cardiac rehabilitation facilities. They may work for private facilities or for such government facilities as Veterans Administration hospitals and centers. Rehabilitation psychologists serve individuals throughout the life span, from early childhood through late adulthood. Many rehabilitation psychologists are full-time university or college faculty and focus primarily on teaching and research. Others may work in or consult industry, provide expert legal testimony, or conduct assessments and evaluations for insurance agencies. Rehabilitation psychologists advocate for...

Differential Diagnosis

The incidence of misdiagnosis may be declining. Watson and Buranen (1979) found after a 10-year follow-up period that 25 of diagnoses of conversion disorder were in fact false-positive diagnoses. In a more recent 4-year follow-up study, Kent et al. (1995) found that only 13 of patients were initially misdiag-nosed. Even though the rate of misdiagnosis has declined, these studies confirm that medical illness continues to be the cause of the original presenting complaint in a substantial number of patients initially diagnosed with conversion disorder. For this reason, it is imperative that patients thought to have conversion disorder receive a thorough neurological and medical evaluation. Conversion disorder should not be considered a diagnosis of exclusion. Rather, it is a well-defined entity that mimics neurological processes. On the other hand, the presence of a neurological condition does not preclude the diagnosis of conversion disorder. In fact, as previously noted, some studies...

Abnormal Findings and Clinical Uses of the VEP

Patients with suspected optic neuritis and may be delayed even when magnetic resonance imaging of the optic nerve is normal. y Abnormalities may relate to either recent or long-standing pathological processes. The VEP may be abnormal in patients without a past history of optic neuritis, thereby providing evidence of subclinical involvement of the optic nerve. For this reason, it is useful to record the VEP in such patients when multiple sclerosis is a diagnostic possibility. y

Abnormal Findings and Clinical Uses of the BAEP

BAEPs have been used to detect subclinical brain stem pathology in patients with suspected multiple sclerosis. y , y However, the yield in this circumstance is less than with the visual or somatosensory evoked potentials, possibly because the auditory pathway is relatively short or is more likely to be spared.

When walking fails

Difficulty walking is reported by 10 of Americans (Iezzoni, 2003). One-third report major difficulty. They are unable to walk or climb stairs or stand. The most rapid rates of increase occur after ages 54 and 74 years old. Musculoskeletal and joint diseases account for 24 of causes of major difficulty, back pain for 8 , stroke for 5 , and multiple sclerosis for 2 . Falls affect 41 of these people yearly. Eleven percent never leave their homes and only 32 get out of the home daily. By report, 25 receive some physical therapy during the year of major difficulty walking. At this level of difficulty, 48 with stroke use a cane, 28 use a walker, and 44 a wheelchair.

Brain Injuries

Some techniques use X rays to reveal images of abnormal blood flow through cerebral arteries (carotid angiogra-phy) or lesions produced by stroke or brain tumors (CT scans). MRI scans provide images of the brain without X rays, and because of the nature of the magnetic signals that produce MRI images, the scans can easily visualize small tumors, multiple sclerosis plaques, and infarctions. Another group of imaging techniques such as PET, SPECT, and fMRI provide images of regional cerebral blood flow, blood volume, or glucose metabolism, all of which are closely coupled and correlated with neuronal activity and are thus indirect measures of brain functioning. Normal

Brain Stem

Lesions that may affect the brain stem include vascular malformations such as angiomas, which may be a cause of spontaneous hemorrhage infectious diseases such as tuberculosis, although this is rare in developed countries de-myelinating diseases such as multiple sclerosis and tumors.

Clinical History

When interviewing a patient with complaints referable to the trigeminal system there are several key considerations to address. First is the nature of the patient's complaint (that is, pain, sensory changes, sensory loss, or motor difficulty) because the characteristic clinical features are critical components of an appropriate neurological diagnosis. For example, lancinating excruciating pain suggests trigeminal neuralgia and is distinguished from the more tolerable yet disturbing paresthesias of trigeminal sensory neuropathy. Determination of whether the symptoms are intermittent, paroxysmal, or chronic and the temporal profile of symptom development (i.e., whether symptoms began in an acute, subacute, or indolent fashion) also provides diagnostic clues. Thus, sudden complaints of sensory loss, paresthesias, or motor dysfunction in the face are consistent with vascular, traumatic, or demyelinating processes, whereas similar complaints developing over weeks more often reflect...

The Calpain Family

In autoimmune demyelinating diseases such as multiple sclerosis and EAE, the corresponding animal model, degradation of myelin proteins in CNS lesions suggested a role for calpain since all major myelin proteins are substrates of this enzyme. Calpain is a cytosolic cysteine endopeptidase (EC that retains characteristics of the thiol proteinase, papain and calcium binding protein, calmodulin. The proteinase has been localized in every mammalian cell type studied, and calpain homologues have been identified in lower order organisms including nematodes, insects, yeast, and fungi96. The calpain family consists of at least six homologous members divided into two classes according to tissue distribution, i.e., ubiquitous or tissue specific. Recently discovered tissue specific calpains, such as p94 and nCL-2 (localized in muscle), exist as monomers or oligomers of the 80 kD catalytic subunit. Ubiquitous calpain is distributed in every cell, most often as a heterodimeric complex...

Eventrelated Fields

The latency of appearance of both these components is much delayed in patients with multiple sclerosis. Furthermore, in such patients the responses recorded with a latency of about 50-80 msec for the area representing the hand, within the SI, are abnormally large (Karhu et al., 1982).


Cruveilhier (1791-1874) was a medical graduate of Montpellier, and was appointed Professor of Anatomy in Paris on the advice of the surgeon Guy Dupuytren in 1825, the world's first chair in this subject. His knowledge of morbid anatomy was encyclopaedic and was encapsulated in his beautifully illustrated Anatomie Pathologique du Corps Humain (1829-1842), followed by his 'Treatise on General Pathological Anatomy' (1849-1864). His studies revealed that gastric acid was the cause of ulcers he described a progressive muscular atrophy that is named in his honour (Cruveilhier's disease) and he recognised congenital liver cirrhosis. He gave the first account of multiple sclerosis. He was particularly famed for the 'doctrine of Cruveilhier', the proposition 'La phl bite domine toute la pathologie' (Warren 1980), and he believed that what we now term 'thrombosis' resulted from injury to the venous endothelium (Duckworth 1913 Talbot 1970).

Cerebellar Speech

Hemispherical disorders are associated with cerebellar dysarthria more frequently than are vermal lesions. The paramedian regions of the superior cerebellar hemispheres are most relevant for the development of cerebellar dysarthria. y , y Left hemispherical cerebellar lesions appear to be more frequently associated with cerebellar dysarthria than right hemispherical or vermal lesions. 3 Cerebellar dysarthria is frequently present in degenerative forms of cerebellar ataxias and multiple sclerosis. Cerebellar hemorrhage, infarcts (in particular of the SCA), tumors, and trauma may all cause cerebellar speech.

Muscle Relaxants

Skeletal muscle relaxants may be used for relief of spasticity in neuromuscular diseases, such as multiple sclerosis, as well as for spinal cord injury and stroke. They may also be used for pain relief in minor strain injuries and control of the muscle symptoms of tetanus. Dantrolene (Dantrium) has been used to prevent or treat malignant hyperther-mia in surgery.

Social effects

The impact of narcolepsy on the quality of life varies according to its severity, the combination of symptoms, age of onset and the patient's understanding and ability to cope with the symptoms, as well as the availability of support from those around the patient 35 . The impact is, in general, comparable to that of epilepsy or multiple sclerosis.


This medical orientation predominates in current professional practice and public policy. Its bias is inherent in most major classification systems currently available for categorizing disabilities and handicaps. For instance, the Federal Rehabilitation Act of 1973, Section 504, uses the term handicap to refer to a range of conditions including speech, hearing, visual, and orthopedic impairments and cerebral palsy, epilepsy, muscular dystrophy, multiple sclerosis, cancer, diabetes, heart disease, mental retardation, emotional or psychiatric disorders, drug or alcohol addiction, and specific learning disabilities. The particular do

Other Body Fluids

In normal conditions, it originates from the blood there is no antibody production within the central nervous system. Only up to 20 of CSF proteins are intrathecally synthesized, but the major fraction is blood derived.108 In case of inflammatory neurological diseases such as multiple sclerosis, additional oligoclonal Ig bands or spots appear that are present in CSF but not in serum. One-dimensional isoelectric focusing for detection of CSF-specific oligoclo-nal Ig bands is used for diagnosis of multiple sclerosis.108110 Basic research in this field has been performed with 2DE main differences in CSF patterns of healthy individuals and patients with various neurological diseases have been detected in the Ig light-chain pattern. Changes were of qualitative and quantitative nature additional light chains were oligoclonal. Especially for multiple sclerosis, the overall CSF pattern of patient samples suggested that Igs were produced from cells within the...

Specific Indications

Lesion abnormalities, and diffuse abnormalities. Mass lesions include most neoplasms and neoplastic or non-neoplastic cysts, some forms of infection (abscesses, cerebritis, tuberculomas, some encephalitides), specific vascular disorders (hemorrhages, early infarcts), malformations or developmental lesions (hamartomas, some migrational abnormalities), and a variety of miscellaneous conditions (sarcoidosis, acute multiple sclerosis, and adrenoleukodystrophy). Conditions that produce imaging study abnormalities that are not necessarily mass lesions include (1) forms of neoplasia (infiltrating gliomas, gliomatosis, lymphomas) (2) cerebrovascular disorders (vasculitides, vasculopathies) (3) infections (viral encephalitis, progressive multifocal leukoencephalopathy, CNS syphilis) (4) degenerative diseases (Creutzfeldt-Jakob disease, Huntington's disease) (5) inflammatory and immunologic disorders (acute disseminated encephalomyelitis, limbic encephalitis, Rasmussen's encephalitis) (6)...

Alexanders Syndrome

In the juvenile form, which is much less common than the infantile form, onset usually occurs between 7 and 14 years of age, and the duration is approximately 8 years. Bulbar and pseudobulbar dysfunction predominates, with dysphagia, dysarthria, nystagmus, ptosis, full facial palsy, and tongue atrophy. y , y Generalized spasticity and weakness may also occur, but unlike the severe mental retardation characteristic of the infantile form, mentation tends to remain intact. y The adult form of Alexander's syndrome resembles multiple sclerosis clinically and is characterized by blurred vision, spasticity, nystagmus, dysarthria, and dysphagia. Since the types of Alexander's disease are phenotypically distinct, the differential diagnosis varies by age. If one encounters an infant with chronically developing megencephaly or macrocephaly with mild regression in psychomotor milestones in the absence of any other obvious cause, Alexander's syndrome is a highly probable diagnosis. Juvenile...


Any condition that affects the cauda equina, roots S-2 through S-4, and the pudendal nerve can cause pelvic pain. Degenerative disease of the spine, primary or metastatic disease of the spine, primary or metastatic tumors, cysts, and local trauma must all be considered. Other neurologic disease, such as multiple sclerosis or spastic neuropathy, can produce pain. Laxity of the pelvic floor may cause traction on the pelvic nerves, creating this type of pain syndrome. Specific physiologic testing, such as electromyography (EMG), anorectal manometry, and dynamic proctography, may be useful in the assessment of these conditions. Last, psychiatric illness is frequently associated with the complaint of pelvic pain. When indicated, competent psychiatric evaluation may be illuminating.

Human Herpesvirus6

Clinical Features and Associated Findings. As previously stated, HHV-6 is the etiological agent of childhood exanthem subitum. The most common CNS complications of primary HHV-6 infection are seizures, meningoencephalitis, and encephalopathy. W1 HHV-6 has been reported as the etiological agent of focal encephalitis in a bone marrow transplant recipient and in immunocompetent adults with focal encephalitis in whom the clinical presentation suggested herpes simplex virus encephalitis. W , W1 CNS infection with HHV-6 has also been associated with diffuse or multifocal demyelination and a clinical picture of fulminant multiple sclerosis. 139 Disseminated HHV-6 infection has been reported in children and adults with AIDS. 140 , 141 Encephalitis and Focal Encephalitis. HHV-6 DNA has been recovered from the brain of a patient at autopsy who died of encephalitis 5 months after undergoing allogeneic bone marrow transplantation. 138 Three of 37 patients with a clinical presentation suggestive...

Antiviral Drugs

Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics, specific antivirals are used for specific viruses. Viruses cause more diseases than any other group of parasites. They can cause blindness, deafness, paralysis, mental retardation, various birth defects, and in at least a few plants and animals, cancer. Of all the most well-known viral diseases, the ones that should be stated are measles, mumps, smallpox, chicken pox, influenza, poliomyelitis, and yellow fever. There is suspicion that viruses are the cause of multiple sclerosis, Hodgkin's disease, Down's syndrome, and possibly even schizophrenia. However, along with the significant progress made in the area of treating bacterial infections, the development of chemotherapy of viral diseases has been relatively modest. There is only a small selection of attainable drugs for treating a very limited number of viral infections.

David A Gelber

Spasticity is commonly defined as excessive motor activity characterized by a velocity-dependent increase in tonic stretch reflexes. It is often associated with exaggerated tendon jerks, and is often accompanied by abnormal cutaneous and autonomic reflexes, muscle weakness, lack of dexterity, fatigability, and co-contraction of agonist and antagonist muscles (Young, 1987 Young, 2002 Sanger et al., 2003). It is a common complication of central nervous system disorders, including stroke, traumatic brain injury, cerebral palsy, multiple sclerosis, anoxic brain injury, spinal cord injury, primary lateral sclerosis, and hereditary spastic paraparesis (Young, 2002).

Other Hypotheses

Cells such as those that are infected or malignant (Young and Elliott, 1989) Although self-cpn60-related protein is constitutively expressed on the surface of human cells (Jarjour et al., 1990), interferon-- stimulates the expression of a surface-localized form of cpn60 on murine bone marrow macrophages (Kaufmann et al., 1990). In areas of inflammation, such as multiple sclerosis brain lesions, there is colocalization of y8 T cells and cpn60-expressing oligodendrocytes (Selmaj et al., 1991). In addition, heat shock proteins and heat shock can regulate the expression of the murine class lb molecules that may be the antigen-presenting molecules for yS T cells (Imani and Soloski, 1991). This evidence supports the idea that chaperonins are upregulated in stressful situations such as inflammation. The possibility that yS T cells eliminate cpn60-expressing cells is supported by the finding that cpn60-related surface protein is recognized by T cell clones that specifically lyse...


Shaving Someone With Hypertrichosis

Acquired hypertrichosis may be generalized or localized also. Acquired hypertrichosis lanuginosa ( malignant down ) is a rare but striking cutaneous manifestation of internal malignancy. Fairly generalized hypertrichosis may occur in patients with diverse diseases such as porphyrias, dermatomyositis, anorexia nervosa, mercury intoxication, insulin-resistant diabetes, Cushing's disease, hypothyroidism, postencephalitis, multiple sclerosis, head injuries, and POEMS syndrome polyneuropathy (sensorimotor), organomegaly (heart, spleen, kidneys), endocrinopathy, skin changes (hyperpigmentation, hypertrichosis, hyperhidrosis, thick skin, clubbed nails, leukorychia, angiomas) . Drugs can induce hypertrichosis (see T.a.bie 2Z-1). Localized acquired hypertrichosis may occur over areas of inflammatory dermatoses such as venous stasis or areas occluded by a plaster cast or may be a feature of a benign nevus. Acquired hypertrichosis of ears and eyebrows as well as long eyelashes may be seen in...

Neurologic diseases

ED can occur as a result of various neurologic diseases or lesions. The hippocampus and paraventricu-lar nucleus and medial preoptic area are considered as the main centers regulating sexual drive and behavior 37,38 . Lesions at these areas may result in ED, depending on their severity. Central neurologic disorders frequently associated with ED include disorders at the level of the brain (e.g. multiple sclerosis, temporal lobe epilepsy, Parkinson's disease, stroke or Alzheimer's disease), or at the level of spinal cord (e.g. spinal cord injury) 39,40,41 . Peripheral neurologic disorders related to ED include afferent (sensory) neuropathies, such as dorsal penile nerve affections (e.g. diabetic neuropathy), or efferent (au-tonomic) lesions, such as autonomic neuropathy or lesions of the cavernous nerves after radical pelvic surgery 42 .

Clinical Features

The differential diagnosis of hypochondriasis is important to keep in mind when evaluating the patient. First, a medical condition must be excluded. Given that some medical diseases may be hard to exclude completely because their early stages are less apparent or because adequate laboratory diagnostic tools are unavailable for them (e.g., multiple sclerosis, systemic lupus erythematosus, Lyme disease, occult malignancies), the physician working with a patient whose hypochondriasis does not improve with psychiatric treatment should reconsider the possibility that a diagnosis of medical illness has been missed. Similar to somatization disorder, hypochondriasis is characterized by the presence of unexplained symptoms or sensations. However, the patient with hypochondriasis takes these symptoms one step further by leaping to a catastrophic cognitive misinterpretation of the significance of these symptoms.


P., Klein, S. A. and Fender, D. H. (1981), Location of sources of evoked scalp potentials Corrections for skull and scalp thickness. IEEE Trans. Biomed. Eng. BME-28, 447-452. Bauer, H. J. , Poser, S., and Ritter, G. (eds.) (1980). Progress in Multiple Sclerosis Research. Springer, Berlin. Belliveau, J. W., Kennedy, D. D., Kinstry, R. C., Buchbinder, B. R., Weisskoff, R. M., Cohen, M. S., Venea, J. M., Brady, T. J., and Rosen, B. R. (1991). Functional mapping of the human visual cortex by magnetic resonance imaging. Science 245, 716-719. McKhann, G. M. (1982). Multiple sclerosis. Annu. Rev. Neurosci. 5, 219-239.


Although the process of myelination enables axons to propagate action potentials quickly and in a compact manner, the complexity of this neuron glia interaction results in an increased vulnerability of the nervous system to disease. Indeed, there are a large number of identified pathological conditions that primarily target myelin (Hopkins, 1993). These diseases, which can lead to the destruction of the myelin sheath, are categorized as either acquired (i.e., multiple sclerosis) or hereditary diseases (i.e., leukodystrophies). Multiple sclerosis, which is the most common human demyelinating disease, is characterized by the formation of plaques, or areas of demyelinated axons that can develop virtually anywhere in the central nervous system (Figure 3). Although axons can be spared in the plaque regions and remyelinate during periods of disease remission, cumulative axonal loss is thought to provide the pathologic substrate for the progressive disability that most long-term MS patients...

Pontine Lesions

A unilateral lesion in the brain stem (e.g., stroke, multiple sclerosis, abscess, tumor) may produce dissociated weakness, with ipsilateral weakness of the SCM and contralateral weakness of the trapezius. y In addition, the supranuclear fibers for the SCM muscle probably decussate twice. A lesion in the right side of the pons may result in left-sided weakness (i.e., involvement of the corticospinal tract fibers before their decussation in the medulla) and possible deviation of the head to the left (i.e., involvement of supranuclear input to the left SCM muscle after the first but before the second decussation). Involvement of the paramedian pontine reticular formation may also result in deviation of the eyes toward the weakness.

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