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The characteristic angiokeratomas tend to be most prominent periumbilically and resemble small angiomas that obliterate slightly with pressure. Desnick and colleagues have reviewed the neurologic, neuropathologic, and biochemical findings in this disease, and Cable, Kolodny, and Adams have written informatively on the autonomic aspects. The two main trials of this treatment, summarized in an editorial by Pastores and Thadhani, were each conducted quite differently. Both showed an improvement in kidney and other organ function but only one demonstrated a reduction in neuropathic pain, and neither studied the risk of stroke. Like enzyme replacement therapy for Gaucher disease, prolonged treatment is expensive; but some evidence from the trials cited above indicates that certain aspects of the disease are reversible. The painful neuropathic features that have brought several cases to our attention are discussed with the polyneuropathies, on page 1159. Sulfite Oxidase Deficiency this disorder was discussed briefly with the neonatal metabolic disorders (page 804). The occurrence of stroke as a complication of this disorder was placed on record by our colleagues Shih et al. Another unrelated child, supposedly normal until 2 years of age, entered the hospital with fever, confusion, generalized seizures, right hemiplegia, and aphasia (infantile hemiplegia); subluxation of the lenses (upward) was discovered later. There was an increased level of sulfite and thiosulfite and an abnormal amino acid, S-sulfocysteine, in the blood. The diagnosis and management of these metabolic diseases are so unusual that some special remarks are appropriate. All the metabolic diseases of late childhood and adolescence may share to some degree the property of deranging behavior, thinking, feeling, and emotional reactions. Usually, they present later in adolescence and adult life and evolve more slowly than childhood forms. The most obvious and easily detectable of these derangements are in the cognitive sphere, i. Impulsivity, loss of self-control, and antisocial behavior are the most troubling behavioral abnormalities. Certain forms of these impairments are attributable to integrated systems of modules of cerebral neurons and are recognized as special neurologic deficits, such as disinhibition or muting of behavior and affect, the amnesic state, aphasia, dyscalculia, and visualperceptual disorientation. Intellectual functions are little developed in early childhood; it is therefore difficult to judge the normal qualities of the mind for this age group. Slowness in learning and in acquiring language functions become manifest in school, and may then be interpreted loosely as mental retardation. Up until school age, these intellectual functions have not developed sufficiently to allow recognition of their regressive course. Only in late childhood do mental retardation and dementia become clearly distinguishable and measurable by standardized tests. Far less tangible are subtle changes in personality and behavior that must always be judged against the standards of the cultural group of which the patient is a member. The principle that most neuropsychiatrists follow in selecting from the large mass of maladjusted adolescents those with a metabolic brain disease is that such a condition will sooner or later cause a regression in cognitive and intellectual functions. Schizophrenia and manic-depressive psychosis and the sociopathies and character disorders do so little or not at all. This is not to say that personality changes and emotional disturbances do not occur in the metabolic encephalopathies; they certainly do. However, their recognition depends more on the demonstration of failing memory, impaired thinking, inability to learn, and loss of verbal and arithmetic abilities, many of which are measured quantitatively by intelligence tests. The appearance of pyramidal signs, aphasia, apraxia, ataxia, or areflexia always sets them apart. Nonwilsonian copper disorder (hereditary ceruloplasmin deficiency) In each of these diseases, dementia and personality disorder may gradually develop and persist for many months, even a year or two, before other neurologic signs appear. One must look carefully for the earliest signs of movement disorders and other neurologic abnormalities, which greatly clarify the diagnostic problem.

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• You feel dizzy or lightheaded
• The goal is to keep blood pressure at or below 130/80 mmHg
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Neuritic plaques and neurofibrillary changes are found in all the association areas of the cerebral cortex, but it is the neurofibrillary tangles and neuronal alterations and loss, not the plaques, that correlate best with the severity of the dementia (Arriagada et al). Only a few tangles and plaques are found in the hypothalamus, thalamus, periaqueductal region, pontine tegmentum, and granule-cell layer of the cerebellum. Experienced neuropathologists recognize a form of Alzheimer disease, particularly in older patients (75 years), in which there are senile plaques but few or no neuronal tangles (over 20 percent of 150 cases reported by Joachim et al). Another problem for the neuropathologist is to distinguish between the normal aged brain and that of Alzheimer disease. It is not unusual to find a scattering of senile plaques in individuals who were thought to be mentally normal during life. Henderson and Hubbard studied 27 demented individuals aged 64 to 92 years and 20 age-matched, nondemented controls. In the former, 3 to 38 percent of the hippocampal neurons contained neurofibrillary tangles; in all but 2 of the controls, the number of hippocampal neurons with tangles fell below 2. Hence, the difference between plaques and tangles in the aging brain and in Alzheimer disease is largely quantitative. Also of interest is the observation of Joachim and associates that 18 percent of Alzheimer cases had sufficient neuronal loss and Lewy bodies in the substantia nigra to justify a diagnosis on histopathologic grounds of Parkinson disease. Leverenz and Sumi found that 25 percent of their Alzheimer patients showed the pathologic (and clinical) changes of Parkinson disease- a much higher incidence than can be attributed to chance. Similarly, of 11 patients with progressive supranuclear palsy (discussed further on) reported by Gearing and coworkers, 10 were demented and 5 had the neuropathologic features of Alzheimer disease. It is of historical interest that Alzheimer was not the first to describe plaques, one of the hallmarks of this pathologic state. These miliary lesions ("Herdchen") had been observed in senile brains by Blocq and Marinesco in 1892 and were named senile plaques by Simchowicz in 1910. In 1907, Alzheimer described the case of a 51-year-old woman who died after a 5-year illness characterized by progressive dementia. Pathogenesis Careful analyses of the "senile" plaques and neuronal fibrillary changes have been made in the last few decades in an attempt to elucidate the mechanism of Alzheimer disease. Several histologic techniques assist in this endeavor, including refined methods for silver impregnation that stain both amyloid and its main constituent (amyloid protein, or A); immunostaining using antibodies specific to such proteins as ubiquitin, neuronal tau protein, and amyloid protein; and visualization of beta-pleated protein sheets using thioflavine S and Congo red with ultraviolet and polarized light. Tau is a discrete cytoskeletal protein that promotes the assembly of microtubules, stabilizes their structure, and participates in synaptic plasticity in a yet to be defined manner. In the pathologic circumstances of Alzheimer disease, progressive supranuclear palsy, and frontotemporal dementia (see further on), tau is hyperphosphorylated and aggregates, resulting in an overloading of the perikarya and neurites with paired helical filaments comprising neurofibrillary tangles. Electrophoretically, tau moves with the 2-globulins and is thought to function as a transferrin, i. The sequential cleavage by and then produces tiny fragments that are not toxic to neurons. The latter A 42 form is toxic in several models of Alzheimer disease, and it is proposed that the ratio of A 42 to A 40 is critical to the neuronal toxicity of amyloid. Several pieces of evidence favor the view that elevation of the levels of A 42 leads to aggregation of amyloid and then to neuronal toxicity. It appears that the diffuse deposition of A 42 precedes the formation of better-defined neurofibrils and plaques. The fibrillary form of amyloid is neurotoxic, a mechanism favored as the cause of cell damage in Alzheimer disease. The ApoE4 allele is associated with inadequate clearance of A 42 and is another mechanism that promotes fibrillogenesis. The presenilins interact with or may be a component of secretase, the enzyme that produces the A 42 fragment. There is also a provocative relationship between certain circulating proteins, particularly -amyloid and selected isoforms of the ApoE lipoproteins, as discussed further on. The current notions of amyloid metabolism and the role of A 42 are summarized in.

A nasal pattern of speech with air escaping from the nose is a usual accompaniment. In the latter cases a decreased frequency of swallowing also causes saliva to pool in the mouth (leading to drooling) and adds to the risk of aspiration. Although the case has been made above that swallowing is a brainstem reflex, aspiration and swallowing difficulty after severe stroke occur in a surprisingly large number of cases of cerebral infarction and hemiparesis without brainstem damage. The problem is most evident during the first few days after a hemispheral stroke on either side of the brain (Meadows). These effects last for weeks and render the patient subject to pneumonia and fever. In the clinical and fluoroscopic study by Mann and colleagues, half of patients still had manifest abnormalities of swallowing 6 months after their strokes. Some insight into the nature of swallowing dysfunction after stroke is provided by Hamdy and colleagues, who correlated the presence of dysphagia with a lesser degree of motor representation of pharyngeal muscles in the unaffected hemisphere, as assessed by magnetic stimulation of the cortex. Pain on swallowing occurs under a different set of circumstances, the one of most neurologic interest being glossopharyngeal neuralgia (pages 163 and 1185). Videofluoroscopy has become a useful tool in determining the presence of aspiration during swallowing and in differentiating the several types of dysphagia. The movement of the bolus by the tongue, the timing of reflex swallowing, and the closure of the pharyngeal and palatal openings are judged directly by observation of a bolus of food mixed with barium or of liquid barium alone. However, authorities in the field, such as Wiles, whose reviews are recommended (see also Hughes and Wiles), warn that unqualified dependence on videofluoroscopy is unwise. They remark that observation of the patient swallowing water and repeated observation of the patient while eating can be equally informative. Having the patient swallow water is a particularly effective test of laryngeal closure; the presence of coughing, wet hoarseness or breathlessness, and/or the need to swallow small volumes slowly are indicative of a high risk of aspiration. Based on bedside observations and on videofluoroscopy studies, an experienced therapist can make recommendations regarding the safety of oral feeding, changes in the consistency and texture of the diet, postural adjustments, and the need to insert a tracheostomy or feeding tube. The first, as the "head ganglion" of the autonomic nervous system, was described in the preceding chapter; the second, as the circadian and seasonal clock for behavioral and sleep-wake functions, was considered in Chap. In the hypothalamus, these systems are integrated with one another as well as with neocortical, limbic, and spinal influences. Together, they maintain homeostasis and participate in the substructure of emotion and affective behavior. The expansion of knowledge of neuroendocrinology during the past few decades stands as one of the significant achievements in neurobiology. It has been learned that neurons, in addition to transmitting electrical impulses, can synthesize and discharge complex molecules locally and into the systemic circulation, and that these molecules are capable of activating or inhibiting endocrine, renal, and vascular cells at distant sites. The concept of neurosecretion probably had its origins in the observations of Speidel, in 1919 (and later those of the Scharrers in 1929), who noted that some of the hypothalamic neurons had the morphologic characteristics of glandular cells. Their suggestion that such cells might secrete hormones into the bloodstream was so novel, however, that it was rejected by most biologists at the time. This seems surprising now that neurosecretion is viewed as a fundamental part of the science of endocrinology. Following these early observations, it was found that certain peptides secreted by neurons in the central and peripheral nervous systems were also contained in glandular cells of the pancreas, intestines, and heart. This seminal observation was made in 1931 by Euler and Gaddum, who isolated a substance from the intestines that was capable of acting on smooth muscle. But it was not until some 35 years later that Leeman and her associates purified the substance and identified it as substance P (see Aronin et al). Then followed the discovery of somatostatin by Brazeau and colleagues in 1973 and the endogenous opioids (enkephalin) by Hughes and coworkers in 1975; since then a series of hypothalamic releasing factors that act on the pituitary gland have been isolated. It is bounded posteriorly by the mammillary bodies, anteriorly by the optic chiasm and lamina terminalis, superiorly by the hypothalamic sulci, laterally by the optic tracts, and inferiorly by the hypophysis. It comprises three main nuclear groups, the standard nomenclature for which was proposed in 1939 by Rioch and colleagues: (1) the anterior group, which includes the preoptic, supraoptic, and paraventricular nuclei; (2) the middle group, which includes the tuberal, arcuate, ventromedial, and dorsomedial nuclei; and (3) the posterior group, comprising the mammillary and posterior hypothalamic nuclei. The lateral part lies lateral to the fornix; it is sparsely cellular and its cell groups are traversed by the medial forebrain bundle- which carries finely myelinated and unmyelinated ascending and descending fibers to and from the rostrally placed septal nuclei, substantia innominata, nucleus accumbens, amygdala, and piriform cortex- and the caudally placed tegmental reticular formation. The medial hypothalamus is rich in cells, some of which are the neurosecretory cells for pituitary regulation and visceral control.

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