John R. Horn PharmD, FCCP

• Professor of Pharmacy, School of Pharmacy, University of Washington
• Associate Director of Pharmacy Services, Department of Medicine, University of Washington Medicine, Seattle

https://sop.washington.edu/people/john-horn/

The occurrence of hyperthermia demands the use of a cooling mattress or evaporative cooling in addition to specific treatment for any infec tion that may be present allergy shots not effective buy nasonex nasal spray 18 gm on line. An additional important element in treatment is the correction of fluid and electrolyte imbalance allergy treatment naturopathic order generic nasonex nasal spray canada, particularly hypokalemia and severe hypomagnesemia allergy medicine congestion buy nasonex nasal spray with visa. Severe degrees of agitation and perspiration may require the administration of up to 5 L of fluid daily allergy shots lexington ky discount nasonex nasal spray 18gm visa, of which at least 1 allergy medicine without decongestant cheap nasonex nasal spray 18 gm on line,500 to 2 allergy testing boulder purchase cheap nasonex nasal spray on line,000 mL should be normal saline. The specific electrolytes and the amounts that must be administered are governed by the laboratory values for these electrolytes. If the serum sodium is extremely low, one must be cautious in raising the level lest a central pontine myelinolysis be induced (see Chap. In the rare case of hypoglycemia, the administration of glucose is an urgent matter. Corticosteroids have no place in the treatment of the withdrawal syndrome and more potent agents such as propofol are usually not necessary. The administration of intravenous glucose may serve to consume the last available reserves of thiamine and precipitate Wernicke disease. Typically, these patients have subsisted on a diet disproportionately high in carbohydrate (in addition to alcohol, which is metabolized entirely as carbohydrate) and low in thiamine, and their body stores of B vitamins may have been further reduced by gastroenteritis and diarrhea. For this reason it is good practice to add B vitamins, specifically thiamine (which may also be supplemented by intramuscular injection), in all cases requiring parenterally administered glucose even though the alcoholic disorder under treatment. With respect to the use of medications to treat the withdrawal syndromes, it is important to distinguish between mild symptoms, which are essentially benign and responsive to practically any sedative drug, and full blown delirium tremens. There is no certain way to predict whether a patient with the early signs of withdrawal will progress to delirium tremens. In the latter state, the object of therapy is to blunt the psychomotor and autonomic overactivity, prevent exhaustion, and facilitate the administration of parenteral fluid and nursing care; one should not attempt to suppress agitation "at all costs," as doing so requires an amount of drug that might depress respiration. The more popular ones have been chlordiazepoxide (Librium), diazepam (Valium), and the ancillary medications, clonidine and beta adrenergic blockers, and a number of both older and newer anticonvulsant drugs such as gabapentin, which may reduce the requirement for sedative drugs. There is little to choose among the primary sedative drugs in respect to their therapeutic efficacy. More importantly, there are few data to indicate that any one of them can prevent hallucinosis or delirium tremens, or shorten the duration, or alter the mortality rate of the latter disorder (Kaim et al). In general, phenothiazine drugs should be avoided because they may reduce the threshold to seizures. Probably, the use of any of the diazepine medications is as effective as a single dose of lorazepam in prophylactically suppressing seizures (see earlier discussion). If p arenteral medication is necessary, we still prefer 10 mg of diazepam or chlordiazepoxide given intravenously and repeated once or twice at 20- to Wem icke-Korsa koff Syndrome and Alcohol ic-N utritional Diseases (See Chap. Although only a small proportion of alcoholics develop nutritional diseases, the overall number of these dis eases is substantial because of the frequency of alcohol ism. The importance of the alcohol-induced deficiency diseases relates to the fact that they are preventable and, if neglected, may lead to permanent disability. These ill nesses, particularly the Wernicke-Korsakoff syndrome, are discussed fully in Chap. Contrary to popular opinion with regard to the prevention of Wernicke dis ease, the content of B vitamins in American beer and other liquors is so low as to have little nutritional value (Davidson). The former is almost certainly of nutritional origin; in the latter a nutritional metabolic etiology seems likely but has not been estab lished. Central pontine myelinolysis, although frequently observed in alcoholics, is more appropriately considered with the acquired metabolic disorders, usually the too rapid correction of hyponatremia (see Chap. Certain disorders of skeletal and cardiac muscle associated with alcoholism (acute alcoholic myopathy and cardiomyopathy) are described in Chap. There remain to be discussed sev eral diverse disorders that have been attributed to alco holism but whose causal relationship to alcohol abuse, nutritional deficiency, or some other relevant factor is not clear. Unfortunately, a syndrome sub sumed under the title of alcoholic dementia and its many synonyms that appear in the older literature (alcoholic dete 30-min intervals until the patient is calm but awake; we also favor midazolam in closely controlled circumstances when hyperactivity and hallucinosis are extreme. Beta-adrenergic-blocking agents, such as propranolol, labetalol, and atenolol, are helpful in reducing heart rate, blood pressure, and the tremor to some extent. Lofexidine, an alpha2-agonist that blocks autonomic riorated state, chronic alcoholic psychosis, chronic or organic brain S! Jndrome due to alcohol) has never been delineated satisfactorily, either clinically or pathologically. In the Comprehensive Textbook of Psychiatry, it has been defined as "a gradual disintegration of personality structure, with emotional lability, loss of control, and dementia" (Sadock and Sadock). Cutting, as well as Lishman, expressed the view that the term Korsakoff psychosis should be limited to patients with a fairly pure disorder of memory of acute onset and that patients with more global symptoms of intellectual deterioration, of gradual evolution, be considered to have alcoholic dementia. More importantly, in none of the patients designated by these authors as having alcoholic dementia was there a neuropathologic examination, without which the clinical assessment must remain arbitrary and imprecise. The pathologic changes that purportedly underlie primary alcoholic dementia are even less precisely defined than the clinical syndrome. Courville, whose writings have been quoted most frequently in this respect, described a series of cerebral cortical changes that he attributed to the toxic effects of alcohol. Some of them turn out on close inspection to be quite nonspecific, reflecting nothing more than the effects of aging or the insignificant artifacts of tissue fixation and staining. The majority of cases that come to autopsy with the label of alcoholic dementia prove simply to have the lesions of the Wernicke-Korsakoff syndrome. Other cases show the lesions of Marchiafava-Bignarni disease, hepatic encephalopathy, subdural hematomas, or an unrelated communicating hydrocephalus, Alzheimer disease, ischemic necrosis, or some other disease quite unrelated to alcoholism. Practically always in our material, the clinical state can be accounted for by one or a combination of these disease processes and there has been no need to invoke a hypothetical toxic effect of alcohol on the brain. This has also been the experience of Torvik and associates; with a few exceptions, such as coincidental Alzheimer disease, all their cases that had been diagnosed as having alcoholic dementia turned out, on neuropathologic examination, to have the chronic lesions of Wernicke-Korsakoff disease. In brief, the most serious flaw in the concept of a primary alcoholic dementia is that it lacks a distinctive, well-defined pathology. Until such time as the morphologic basis is established, its status must remain ambiguous. A more detailed discussion of this subject and of so-called alcoholic cerebral atrophy (see later) can be found in the review by Victor (1994). Relatively young alcoholics, some with and some without symptoms of cerebral disease were often found to have enlarged cerebral ventricles and widened sulci, mainly of the frontal lobes (see. However, from the studies by Harper and colleagues (1982 and 1985) it may indeed be the case that chronic exposure to alcohol induces cerebral atrophy, but this requires confirmation. The idea of alcoholic atrophy is open to criticism mainly on the grounds that dilated ventricles have in fact been reversible to a considerable extent when abstinence is maintained (Carlen et al; Lishman; Zipursky et al; Schroth et al). Fetal Alcohol Syndrome That parental alcoholism may have an adverse effect on the offspring has been a recurrent theme in medical writ ings. Probably the first allusion to such a relationship was that of Sullivan in 1899, who reported that the mortality among the children of drunken mothers was more than two times greater than that among children of nondrink ing women of "similar stock. The idea that maternal alcoholism could damage the fetus was generally rejected and rel egated to the category of superstitions about alcoholism or the claims of temperance ideologues. In the late 1960s, the effects of alcohol abuse on the fetus were rediscovered, so to speak. Lemoine and associates in France, and then Ulleland and Jones and Smith in the United States, described a distinctive pattern of abnormalities in infants born of severely alcoholic mothers. They stated that the affected infants are small in length in comparison to weight, and most of them fall below the third percentile for head circumference. They are distinguished also by the presence of short palpebral fissures (shortened distance between inner and outer canthi) and epicanthal folds; maxillary hypoplasia, micrognathia, indistinct philtrum, and thin upper lip; and longitudinally oriented palmar creases, flexion deformities of the fingers, and a limited range of motion of other joints. Minor anomalies (usually spontaneously closing cardiac septal defects), anomalous external genitalia, and cleft lip and palate are much more frequent than in the general population. The degree of maternal alcoholism that is necessary to produce the syndrome and the critical stage in gestation during which it occurs are still vague. The various teratogenic effects described earlier are estimated to occur in the embryonic period, i. Other nonteratogenic effects appear to be related to periods during gestation when the fetus is exposed to particularly high alcohol levels. A comprehensive and not outdated account of alcohol-related birth defects and the controversial issues surrounding this subject is contained in a special issue of Alcohol Health and Research World, published by the National Institutes of Health (Vol. The newborn infants suck and sleep poorly, and many of them are irritable, restless, hyperactive, and tremulous; these last symptoms resemble those of alcohol withdrawal except that they persist. Among 23 infants born to alcoholic mothers, there was a neonatal mortality of 17 percent; among the infants who survived the neonatal period, almost half failed to achieve normal weight, length, and head circumference or remained backward mentally to a varying degree, even under optimal environmental conditions. Several large groups of severely affected children have now been observed for 20 years or longer (see Streissguth). Distractibility, inattentiveness, hyperactivity, and impairment of fine motor coordination are prominent features in early childhood. Most such children fall into the category of attention-deficit hyperactivity disorder. Slow growth of head circumference is a consistent finding throughout infancy and childhood. The physical stigmata of the syndrome become less distinctive after puberty, but practically all adolescents are left with some degree of mental retardation and behavioral abnormalities. The pathologic changes that underlie the syndrome have been studied in a small number of cases and no uniform change has emerged. Of some interest are observations such as those of Ikonomidu and coworkers that demonstrate a profound effect of alcohol exposure on the deletion of millions of neurons in the developing rat brain by a mechanism of apoptosis. The main vulnerability occurs during periods of synaptogenesis, which in humans extends from the sixth month of gestation onward. It is noteworthy that infants born to nonalcoholic mothers who had been subjected to severe dietary deprivation during pregnancy (during World War 18, 1994). To treat only the medical complications and leave the man agement of the drinking problem to the patient alone is shortsighted. Almost always, drinking is resumed, with a predictable recurrence of medical illness. For this reason the medical profession must be prepared to deal with the addiction or at least to initiate treatment. A common misconception among physicians is that specialized training in psychiatry and an inordinately large amount of time are required to deal with the addictive drinker. Actually, a successful program of treatment can be initiated by any interested physician, using the standard techniques of history taking, establishing rapport with the patient, and setting up a schedule of frequent visits, although not necessarily for prolonged periods. Our position on this matter was reinforced by a controlled study of problem drinkers in whom treatment was equally successful whether carried out by general practitioners or by specialists (Drummond et al). They favor brief and focused interventions that point out the problem in unambiguous terms and offer empathetic advice; the physician is often the central person in this interaction. It appears that the requisite for successful treatment is total abstinence from alcohol; for all practical purposes, this represents the only permanent solution. Alcohol readily crosses the placenta in humans and animals; in the mouse, rat, chick, miniature swine, and beagle dog, alcohol has been shown to have both embryotoxic and teratogenic effects. Thus, the evidence to date favors a toxic effect of alcohol, although a possible toxic effect of acetaldehyde and smoking and a possible contributory role for nutritional deficiency have not been totally excluded. It is important to state that a relationship to lesser degrees of alcohol intake is far less secure. Alcoholic patients must be made fully aware of the medical and social consequences of continued drinking. They must also be made to understand that because of some constitutional peculiarity (like that of the diabetic, who cannot handle sugar) they are incapable of drinking in moderation. These facts should be presented in much the same way as one would explain the essential features of any other disease; there is nothing to be gained from adopting a punitive or moralizing attitude. Yet patients should not be given the idea that they are in no way to blame for their illness; there appears to be an advantage in making them feel that they are responsible for doing something about their drinking. Anumberofmethodshaveproved valuable in the short and long-term management of alcoholic patients. The more important of these are admission to a detoxification or special hospital unit, rehabilitative therapy; aversion treatment, the use of disulfiram (Antabuse), and the participation in self-help organizations for recovery from alcoholism. Detoxification clinics and special hospital units for the treatment of alcoholism are now widely available. The physician should be aware of all the community resources available for the management of this problem and should be prepared to take advantage of them in appropriate cases. Most inpatient programs include individual and group counseling, didactics about the illness and recovery, and family intervention. Outpatient treatment (of individuals or groups) is widely available, either from specialized facilities or from specialized therapists in general mental health facilities; family counseling is usually offered as well and is often beneficial. Disulfiram, less used in recent years, interferes with the metabolism of alcohol, so that a patient who takes both alcohol and disulfiram accumulates an inordinate amount of acetaldehyde in the tissues, resulting in nausea, vomiting, and hypotension, sometimes pronounced in degree. It is no longer considered necessary to demonstrate these effects to patients; it is sufficient to warn them of the severe reactions that may result if they drink while they have the drug in their bodies. The opioid antagonist naltrexone (50 mg / d orally) or a long-acting injectable formulation has also been used for this purpose, with overall favorable results in numerous trials. The depot injectable form has the advantage of improving compliance in this population that is difficult to treat and to retain in clinical trials. The relevant trials and clinical implementation of naltrexone for alcohol dependence are summarized by Anton (2008). Putatively, a novel approach has been to block the addicting effects of alcohol on the mesolimbic doparninergic system by the use of anticonvulsants such as topiramate. Johnson and colleagues were able to demonstrate a reduction in alcoholic intake in patients taking this drug, in comparison to placebo, albeit over only a 12-week period. The use of these medications and the possible reasons for conflicting results between studies are given in a review by Swift. A complex randomized trial conducted by Anton and colleagues (2006) compared naltrexone, cognitive-behavioral therapy, and both, and found that abstinence was most likely, in the short period of 4 months, with the drug alone or when combined with the psychologic therapy; those who received the cognitive therapy but neither naltrexone or a placebo pill did somewhat worse. Treatment with disulfiram is instituted only after the patient has been sober for several days, preferably longer. Should the patient drink while taking disulfiram, the ensuing reaction is usually severe enough to require medical attention, and a protracted spree can thus be prevented.

Diseases

• Pitt Hopkins syndrome
• Acute anxiety
• Long QT syndrome type 2
• Waardenburg anophthalmia syndrome
• Cocaine antenatal infection
• Cranioectodermal dysplasia

The structure of the axonal membrane in the gaps between segments of the myelin sheaths (nodes of Ranvier) is specialized allergy shots causing joint swelling purchase genuine nasonex nasal spray on-line, containing a high concentration of sodium channels and permitting the saltatory electrical conduction of nerve impulses as described in Chap allergy forecast rapid city sd discount 18gm nasonex nasal spray otc. Unmyelinated fibers allergy testing lincoln ne order nasonex nasal spray overnight delivery, more numerous in peripheral nerves than myelinated ones allergy nose sprays buy genuine nasonex nasal spray online, also arise from cells in dorsal root and autonomic ganglia allergy forecast durham nc discount nasonex nasal spray 18gm mastercard. Small bundles of these naked (unmyelinated) axons are enveloped by a single Schwann cell; delicate tongues of Schwann cell cytoplasm partition these bundles and separate individual axons allergy medicine nighttime discount nasonex nasal spray 18gm fast delivery. A subset of these is characterized by the binding of circulating antibodies to the specialized regions at the nodes of Ranvier, causing a block of electrical conduction. A complement-dependent humoral immune reaction against the radicular or peripheral axon is also known. Toxic or immunologic agents that selectively damage the Schwarm cells or their membranes cause demyelination of peripheral nerves, leaving axons relatively intact, or a toxin may specifically affect axons and dendrites by poisoning their cell bodies, the axolemma, or the lengthy and complex axonal trans port apparatus. Finally, one might correctly suppose that axons of the motor or sensory nerves, sympathetic fibers of vary ing diameter and length, or the end organs to which they are attached would each have its own particular liability to disease. At present we can cite only a few examples of diseases that cause disease through these mechanisms exclusively. Analogous anatomic pathways are probably impli cated in other diseases by mechanisms that remain to be discovered. Among the genetically determined neuropathies, the altered gene products are now known in some cases to lead to defective myelination, which greatly slows conduction along nerves. In other genetic diseases it is known that structural components of the axon are dis rupted, leading to axonal degeneration and impaired electrical conduction. Pathologic Reactions of Periphera l Nerve Several distinct histopathologic changes are recognized in the peripheral nerve, although they are not disease specific and they may be present in varying combina tions in any given case. The myelin sheath is the most susceptible element of the nerve fiber, for it may break down as part of a pri mary process involving the Schwarm cells or of the myelin itself, or it may be damaged secondarily as a consequence of disease affecting its axon. Focal degeneration of the myelin sheath with sparing of the axon is called segmen tal demyelination. In wallerian degeneration, there is degeneration of the axis cylinder and myelin distal to the site of axonal interruption (arrow) and central chromatolysis. In axonal degeneration, there is a distal degeneration of myelin and the axis cylinder as a result of neuronal disease. Myelin may also degenerate from axonal disease in a general process that may occur either proximal or distal to the site of axonal interruption. By means of retro grade axonal transport, the cell bodies receive signals to increase their metabolic activity and to produce growth factors and other materials needed for axonal regenera tion. In an incompletely defined way, the axon also cre ates a local environment that allows the Schwarm cell to maintain the integrity of the adjacent myelin sheath. Loss of this trophic influence leads to dissolution of the myelin sheath, but not of the Schwarm cell itself. There are also highly characteristic histopathologic changes in the nerve cell body termed wallerian degeneration, a reaction of both the axon and myelin distal to the site of disruption of an axon. Wallerian is degeneration might be described as "dying forward," a process in which the nerve degenerates from the point of erates as part of a "dying-back" phenomenon in a more generalized metabolically determined polyneuropathy, it is termed axonal damage outward. These retrograde changes consist of swelling of the cell cyto plasm and marginalization and dissolution of the Nissl substance. The important point again is that despite the destructive changes in the nerve fibers, the nerve cells, while altered in histologic appearance, are left intact with preservation of the apparatus required for recovery. In segmental demyelination, recovery of function may be rapid because the intact but denuded axon needs only become remyelinated. The newly formed internodal segments are initially thinner than normal and of vari able length. By contrast, recovery is much slower with wallerian or axonal degeneration, often requiring months to a year or more because the axon must first regener ate and then reinnervate the muscle, sensory organ, or blood vessel before function returns. When the regen erating axon first becomes myelinated, the internodal myelin segments are short, the length of one normal internode being replaced by three or four shorter new ones. Recurrent demyelination and remyelination lead to "onion bulb" formations and enlargement of nerves, the result of proliferating Schwarm cells and fibroblasts that encircle the axon and its progressively from the distal-most site to the proximal, with dissolution of myelin that occurs roughly in parallel with the axonal change. One possible explanation for this process is that the primary damage is to the neuronal cell body, which fails in its function of synthesizing proteins and delivering them to the distal parts of the axon. Certain toxic and metabolic processes affect axons uniformly along their length or impair anterograde axonal transport to the periphery; the functional impairment is then proportional to the size and length of the blocked axons. Destruction of a proximal spinal motor root results in a gradual dissolution of the distal motor nerve and its myelin sheath (a form of wallerian degeneration). The neuronal motor cell body that gives rise to the motor fiber undergoes characteristic retrograde morphologic changes described below but does not die. Similar destruction of the dorsal spinal root produces secondary wallerian degeneration of the posterior columns of the spinal cord, but not of the peripheral sensory nerve because the dor sal root ganglion cell maintains the integrity of the distal axon. In other words, destruction of axons results within several days in wallerian degeneration of the myelin distal to the point of injury but not transgressing the neuronal cell body. The myelin breaks down into blocks or ovoids in which lie fragments of axons (digestion chambers of Cajal). The myelin fragments are then converted, through the action of macrophages, into neutral fats and choles terol esters and carried by these cells to the bloodstream. Certain diseases affect the neuron primarily rather than the axon and cause either a motor or sensory neu the former case, the anterior horn cell is cells are destroyed, no recovery of function is possible except by collateral regeneration of axons from intact nerve cells. Interruption of a nerve fiber by severing or by crude destruction usually prevents continuity from being reestablished. Regenerating axon filaments take aberrant courses and, with fibroblastic scar formation, they may form a disorganized clump of tissue termed pseudoneuroma. These relatively few pathologic reactions do not, in themselves, differentiate the many dozens of diseases of the peripheral nerves, but when they are considered in relation to the selective effects on various types and sizes of fibers, the topography of the lesions, and the time course of the process, they furnish criteria for fairly accu rate diagnosis. Moreover, the identification of these basic reactions is of great value in the inspection of pathologic material obtained from biopsy or autopsy. There are additional special pathologic changes, not specifically neural in nature that characterize certain diseases of the peripheral nervous system. These involve inflammatory or vascular changes or deposition of mate rial in the interstitium of the nerve. For example, acute demyelinative polyneuritis of the Guillain-Barre type is characterized by endoneuria! In affected by a disease process (motor neuron disease, or motor neuronopathy) and in the latter, the sensory gan glion cell (ganglionopathy) is destroyed. Some of these pathologic reactions are more easily understood if one considers certain features of cytoskel etal structure and function of nerve cells and their axons. The axon contains longitudinally oriented neurofila ments and microtubules, which are separated but inter connected by cross-bridges. Their main function involves the transport of substances from nerve cell body to axon terminal (anterograde transport) and from the distal axon back to the cell body (retrograde transport). Diphtheritic polyneuropathy is typified by the demyelin ative character of the nerve fiber change, the location of this change in and around the roots and sensory ganglia, the subacute course, and the lack of inflammatory reac tion. A number of neuropathies are characterized by the deposition of antibodies and complement on the myelin sheath or on elements of the axon. Many other polyneuropathies (paraneoplastic, nutritional, porphyric, arsenical, and uremic) are topo graphically symmetrical and represent forms of axonal degeneration but cannot be easily distinguished from one another on histopathologic grounds. Concerning the pathology of the the far distal parts of the largest and longest nerves and advance along the affected fibers toward their nerve cell bodies (dying-back neuropathy; or "distal axonopathy"). The muscles of the feet and legs are typically affected earlier and more severely than those of the hands and forearms. Truncal and cranial muscles are usually the last to yield, and then only in severe cases. This represents the "length-dependent" pattern that is typical of axonal degeneration. The nutritional, metabolic, and toxic neuropathies assume this predominantly distal "axonal" pattern. An exception is porphyria, an axonal process in which there may be mainly proximal weakness. By contrast, in demyelinating polyneuropathies, the multifo cal nature of lesions and blockage of electrical conduction often leads to weakness of proximal limb and facial mus cles before or at the same time as distal parts are affected. Another pattern of neuropathic weakness is one in which all the muscles of the limbs, and neck are involved almost simultaneously, often including respira tory paralysis, therefore making it impossible to deter mine if the axons or myelin, or both, have been damaged. Less common causes of generalized mononeuropathies, our knowledge is somewhat more complete. Compression of nerve or nerve roots, local or segmental ischemia, stretch, and laceration of nerves are understandable mechanisms and their pathologic changes can be reproduced experi mentally. Tumor infiltration and importantly, vasculitis with ischemic infarction of nerve account for a propor tion of cases. Of infections and granulomas localized to single nerves, leprosy; sarcoid, and herpes zoster represent identifiable disease states. For most of the acute mononeu ropathies that are a result of transient compression, the pathologic changes have yet to be fully defined, as they are usually reversible states that provide no opportunity for complete pathologic examination. Experimental models of nerve compression indicate disruption of tubular transport and local demyelination. The common symptoms of com pression such as paresthesias are explained, as discussed further on, by exposure of sodium channels along denuded axons and spontaneous and ectopic electrical discharges. A predominantly bibrachial paralysis is an unusual presentation of neuropathic disease but may occur in the inflammatory-demyelinating polyneuropathies, as well as in Sjogren syndrome, chronic immune or paraneoplas tic neuropathies, lead neuropathy, Tangier disease, and in a familial type of brachial neuritis. Grouping them into syndromes based on their temporal and topographic features has proved to be of great value in clinical diagnosis. Although motor, sensory, reflex, and trophic changes are taken together to determine specific diagnosis, each element of the neuropathic diseases is first given in detail further on. Atrophy of weak or paralyzed muscles is characteris tic of chronic disease of the motor neuron or motor axon and conversely, demyelinating neuropathies relatively spare muscle bulk because of the absence of denervation. Atrophy proceeds slowly over several weeks and months, the degree being proportional to the number of damaged motor nerve fibers. The degree of weakness is proportional to the number of axons or motor neurons affected. Polyneuropathies that are the result of axonal damage are characterized foremost by a relatively symmetric distribution of weakness that is, moreover, distal because the pathologic changes begin in 120 days and reduces muscle volume by 75 to 80 percent. In chronic axonal neuropathies, the degrees of paralysis and atrophy tend to correspond. As mentioned previously; atrophy does not coincide with weakness in acute paralysis caused by the demyelinative neuropathies in which the nerve fiber is rela tively less affected than is the myelin. Ultimately in muscle atrophy, there is degeneration and loss of the denervated muscle fibers. This process begins in 6 to position senses) are impaired or eventually lost, although one modality is affected disproportionately to the others, or pain and temperature sensation (small afferent fibers) may be impaired more than joint position and vibration (larger fibers). As an axonal neuropathy worsens, there is spread of sensory loss from the distal to more proximal parts of the limbs and eventually, to the anterior abdomen, thorax, and the face. An "escutcheon" pattern of sensory loss over the abdomen and thorax in severe axonal neu ropathy may be mistaken for the sensory level of a spinal cord lesion. Another characteristic form of sensory loss affects the 12 months; in 3 to 4 years, most of the denervated fibers will have degener function and muscle volume may be restored. If reinnervation takes place within a year or so, motor Tendon Reflexes As a rule, neuropathies are associated with a reduction or loss of tendon reflexes. Most often, this is the result of an interruption of the afferent (sensory) portion of the monosynaptic reflex arc. The reflexes may be diminished if muscular function is impaired, but this occurs mainly in the case of extreme atrophy, in which there are too few muscle fibers to manifest a contraction. There are, of course, many other processes that reduce the tendon reflexes, but it is the neuropathies with which loss of reflexes is most closely associated. An exception is the group of small-fiber neuropathies, in which tendon reflexes may be retained, even with marked loss of perception of painful stimuli. This discrepancy is attributable to the dependence of the afferent component of the tendon reflex arc on the large, heavily myelinated fibers that originate in muscle spindles. Conversely; in neuropathies that affect the largest diameter, heavily myelinated fibers, the tendon reflexes are diminished early and disproportionately to weakness. Slowing of conduction in sensory fibers may also abolish the reflex by dispersing the afferent volley of impulses initiated by the tendon tap. There is generally a concordance between areflexia and a loss of propriocep tive and joint-position senses; i. Furthermore, loss of sensory functions that are dependent on these large fibers in the presence of preserved reflexes implicates the central projections of the sensory ganglion cells i. Most often, trunk, scalp, and face; this is the pattern of a universal sensory loss is attributable to an acquired disease affecting the sensory ganglia (sensory neuronopathy); a paraneoplastic process, certain toxic or immune diseases are usually responsible. In some neuropathies, paresthesias and numbness are the only symptoms and objective sensory loss is lacking or minimal. Certain neu ropathies characteristically cause pain, which is described as burning, aching, sharp and cutting, or crushing and at times may resemble the lightning pains of tabes dorsalis. Perversion of sensation (allodynia) is also commonplace in some polyneuropathies-e. Under these conditions a stimulus induces not only an aberrant sensation but also one that radiates to adjacent areas and persists after the stimulus is with drawn. Painful paresthesias and dysesthesias are particu larly common in diabetic, alcoholic-nutritional, and amy loid neuropathies. These differences are emphasized in the descriptions of individual peripheral nerve diseases in later parts of the chapter. It has been theorized that a loss of large touch-pressure fibers disinhibits the pain-receiving nerve cells in the posterior horns of the spinal cord. An argument against this explanation is the lack of pain in Friedreich ataxia, in which the larger neurons degener ate, and also in certain purely sensory polyneuropathies, where only the perception of tactile stimuli (large fibers) In the axonal polyneuropathies, sensation is affected symmetrically in the distal segments of the limbs and more in the legs than in the arms, owing to the length dependent nature of most diseases t hat affect peripheral nerves. A more likely explanation, supported by micro neurographic recordings, is that dysesthetic pain results from ectopic discharges arising at many sites along sur viving intact or regenerating nerve fibers or their terminal receptors.

Treatment with plasma exchange allergy shots with a cold buy nasonex nasal spray without prescription, gamma globulin allergy forecast montgomery al buy nasonex nasal spray with amex, or immunosuppres sion has had only a minimal effect allergy medicine home remedies buy 18gm nasonex nasal spray visa, but there are anecdotal reports of success with each of these treatments applied early in the course allergy medicine zyrtec d buy genuine nasonex nasal spray on line. In the report by Uchuya and colleagues allergy testing hair generic nasonex nasal spray 18 gm on-line, only 1 of 18 patients with a subacute sensory neuropathy improved and another became dependent for sustained improvement on immune globulin; most of the others sta bilized or worsened and the authors concluded that treat ment was of doubtful value allergy weight gain buy nasonex nasal spray uk. Corticosteroids have not been tested in a systematic way for paraneoplastic neuropathy and there is little clinical evidence to support their use. Here it is emphasized that the ingestion of fish in many areas of the industrialized world gives high levels of blood and urine arsenic, but the metal is in the form of arsenobetaine, which has low toxicity and does not cause neuropathy. In adults, i t occurs follow ing chronic exposure to lead paint or fumes (from smelting industries or burning batteries) or from ingestion of liquor distilled in lead pipes. Its most characteristic presentation is a motor mononeuropathy in the distribution of the radial nerves (wrist and finger drop). In a few person ally observed patients this was the main abnormality, but there was also a sensory loss in the radial territory of the hand. Less commonly, there is foot-drop occurring alone or in combination with weakness of the proximal arm and shoulder girdle muscles. Although the neuropathy has been known since ancient times, details of the pathobiology are still obscure. Axonal degeneration with secondary myelin change and swelling and chro matolysis of anterior horn cells has been described. Lead accumulates in the nerve and may be toxic to Schwann cells or to endothelial capillary cells, causing edema. The diagnosis is established by the history of lead exposure, the predominant and restricted motor involve ment, associated medical findings (anemia, basophilic stippling of red blood cell precursors in the bone marrow, a "lead line" along the gingival margins, colicky abdomi nal pain, and constipation), and the urinary excretion of lead and coproporphyrins. Coproporphyrin in the urine is abnormal in any amount, but it may also be found in porphyria, alcoholism, iron deficiency, and other disor ders as well as in lead intoxication. Treatment consists of terminating the exposure to lead and eliminating lead from the bloodstream and the bones by chelation as discussed in Chap. Su bacute Toxic Neuropath ies Arse n ica l Po lyneu ropathy Of the neuropathies caused by metallic poisoning, that caused by arsenic is particularly well characterized. In cases of chronic poisoning, the neuropathic symptoms develop rather slowly, over a period of several weeks or months and have the same sensory and motor distribution as the nutritional polyneuropathies. Gastrointestinal symptoms, the result of ingestion of arsenic compounds, may precede the polyneuropathy, which is nearly always associated with anemia, jaundice, brownish cutaneous pigmentation, hyperkeratosis of palms and soles, and later with white transverse banding of the nails (Mees lines). Pathologically, this form of arsenical neuropathy is catego rized as of the dying-back (axonal degeneration) type. In patients who survive the ingestion of a single massive dose of arsenic, a more rapidly evolving poly neuropathy may appear after a period of 8 to 21 days as discussed earlier. A predominantly motor neuropathy is induced by occupational exposure to metallic mercury and mercury vapor but any connection to the mercury content in dental amalgam has little cred ibility. The devastating encepha lopathy of organic mercury toxicity does not, to our knowledge, cause neuropathy. Most often the cumu lative dose of gold had exceeded 1 g but in a few instances the neuropathy occurred with 0. Painful distal burning is the initial complaint with weakness and wasting follow ing. A distal, symmetrical sensorimotor (predominantly sensory) neuronopathy may follow exposure to certain hexacarbon industrial solvents. Operating room nurses may be affected by the latter when the agent is absorbed through the skin, leaving a characteristic rash at exposed sites (usually the wrists, where a surgical gown ends). Nurses are also subject to a risk of nitrous oxide neurotoxicity and this usually takes the form of a myelopathy similar to that seen with cobalamin deficiency. As with vitamin B-12 deficiency, the syndrome may be mistaken for a neu ropathy but nerve conduction studies fail to demonstrate one. The associated macrocytic anemia is reversed by the administration of B12, but the neurologic illness may be less responsive as discussed in Chap. Both of these drugs cause a dying-back polyneuropathy with axonal degeneration and have been used experimentally to produce this effect. Vacor, a phenylnitrosourea rodenticide, taken as a suicidal agent, gives rise to a profound sensory and autonomic neuropathy with abdominal pain and hyperglycemia caused by acute pancreatitis. Detailed accounts of the clinical and experimental neurotoxicology of these agents can be found in the monograph by Spencer and colleagues. Most are dose-dependent and are therefore more or less predict able after large cumulative doses of the drug have been given. A more complete list than can be compiled here can be found in the review by England and Asbury. Some patients develop acrodynia and episodic color changes in the fingertips and toes suggesting that autonomic nerves are also involved; in severe cases there is sensory ataxia and pseudoathetosis. The severity of histopathologic changes in the peripheral nervous system corresponds to the concentration of platinum in these tissues, the highest being found in dorsal root ganglia. Secondary degenera tion in the posterior columns is the basis for a Lherrnitte symptom reported by some patients. The taxanes paclitaxel and the more potent docetaxel, both cited as inhibitors of the depolymerization of neu rotubules, are used mainly in the treatment of ovarian cancer. Pathologic studies have shown a neuronopathy and distal axonopathy affecting mainly large fibers. For decades it has been known that peripheral neu ropathy commonly complicates the use of vincristine, an antineoplastic agent most widely used in treatment of the lymphomas and leukemia. Paresthesias are the most common early symptom, and loss of ankle jerks is an early sign. Some degree of weakness usually precedes objective sensory loss; the extensor muscles of the fingers and wrists are affected; later the dorsiflexors of the toes and feet causing foot-drop or, more often in our experi ence, foot-drop may appear first. With the dose regimens currently used, the weakness is usually mild, but in the past, some patients became quadriparetic and bedbound. Adults are more severely affected than are children, as are persons with preexisting polyneuropathies. The neu ropathy is strictly dose-related and reduction in dosage is followed by improvement of neuropathic symptoms although this may take several months. Many patients are then able to tolerate vincristine in low dosage, such as 1 mg every 2 weeks, for many months. Symptoms of neuropathy appeared between 3 and 35 weeks after treatment was begun and affected approximately 10 percent of patients receiving therapeutic doses in the upper range (10 mg/kg daily). The initial symptoms are symmetrical numbness and tingling of the toes and feet spreading, if the drug is continued, to the knees and occasionally to the hands. Isoniazid produces its effects on the peripheral nerves by interfering with pyridoxine metabolism, per haps by inhibiting the phosphorylation of pyridoxine (the collective name for the B6 group of vitamins) and decreasing the tissue levels of its active form, pyridoxal phosphate. The administration of 150 to 450 mg of pyri doxine daily in conjunction with the isoniazid completely prevents the neuropathy. The same mechanism is prob ably operative in the neuropathies that occasionally complicate the administration of the isoniazid-related substances such as ethionamide, used sometimes in the treatment of tuberculosis and the now little-used antihy pertensive agent use of disulfiram in the treatment of alcoholism. Pathologic data, although scant, tend to discredit this notion, insofar as disulfiram evokes a wallerian type of axonal degeneration, whereas carbon disulfide neuropathy is characterized by swollen (giant) axons that are filled with neurofilaments (Bouldin et al). Some patients who have taken phenytoin for decades may lose ankle and patellar reflexes and acquire mild distal sy. Paradoxically, the taking of extremely high doses of pyridoxine over a prolonged period 1983). A relatively mild sensory neuropathy (acral paresthe may actually cause a disabling, predominantly sensory ganglionopathy (Schaumburg et al, statin drugs have been tentatively sia) associated with optic neuropathy occasionally compli cates chloramphenicol therapy. The chronic administration of metronidazole may have the same effect (and can produce lesions in the deep cerebellum). The newer antimicrobial, linezolid, has been associated with a fairly severe sensory neuropathy in a few cases after prolonged use. A pre dominantly motor neuropathy has been reported with the chronic administration of implicated in a painful, paresthetic distal axonal polyneu ropathy with retained reflexes (Gaist et al). The frequency of polyneuropathy is low but, if no other expla nation is identified, it may be advisable to discontinue the drug. Colchicine has long been known to cause a myopathy, but a few cases of predominantly axonal sensory neuropa thy have also been reported dapsone, a sulfone used to treat (neuromyopathy). Stilbamidine, used in the treatment of kala azar, may also induce a purely sensory neuropathy with a propensity to affect the the introduction, in 1952, of nitrofurantoin for the treat ment of bladder infections was soon followed by reports of trigeminal nerves. Among various other agents that cause neuropathy are hydroxychloroquine and colchicine are known to cause a toxic neuropathy. The anesthetic agent ethylene, predilection for cranial nerves, particularly the fifth. The neurotoxicity is apparently caused by dichloroacetylene, as with the aforementioned stilbamidine, has a If the drug is not discontinued, the disorder progresses to a toms are pain and tingling paresthesias of the toes and feet, followed shortly by similar sensations in the fingers. Patients with chronic renal failure are particularly prone to neuro toxicity from nitrofurantoin because of diminished drug excretion resulting in high tissue levels. To make matters more complex, the uremic state itself may be responsible for a polyneuropathy so that the distinction between ure mic and nitrofurantoin neuropathy may be impossible. The neuropathologic studies of Lherrnitte and colleagues disclosed an axonal degeneration in peripheral nerves and sensory roots. There may be an eosinophilic infiltrate in nerves, but the neuropathy is probably the result of a direct toxic mechanism. A sensory neuropathy, resulting from excessive Cardiac Drugs Amiodarone, a drug used for treat ing recalcitrant ventricular tachyarrhythmias, induces a motor-sensory neuropathy in about 5 percent of patients pyridoxine ingestion after several months of treatment. Perhexiline maleate for the treatment of angina pectoris may also cause a generalized, predomi nantly sensory polyneuropathy in a small proportion of patients. Patients taking alluded to earlier, is still seen among individuals who take huge doses of vitamin supplements. Amitriptyline is capable of producing paresthesias, but the effect seems to be idiosyncratic and infrequent. We are referring mainly cholesterol levels may experience distal and truncal paresthesias, but an associated neuropathy has been identified. In recent years, attention has also been directed to a possible association between a nondescript sensory polyneuropathy and impaired glucose tolerance, even without manifest diabetes, per sistent hyperglycemia, or an elevation of hemoglobin A1 c. The survey by Sumner and colleagues makes a case for such an association, but we remain uncertain about the relationship between glucose intolerance alone and polyneuropathy. By statistically adjusting for relevant factors such as glycemic control and glycosylated hemo globin, Tesfaye and colleagues have suggested that some cardiovascular risk factors subsumed under the term "metabolic syndrome" (triglyceride levels, body mass, hypertension) are themselves risk factors for diabetic polyneuropathy. Approximately Most of the syndromes listed here are likely to be a result of ischemia or infarction of nerves or nerve fas cicles, because of a diabetic microvasculopathy. In recent years, an inflammatory process has been postu lated as yet another mechanism of peripheral nerve dam age. The main complaints are persistent and often distressing numbness and tingling, usually confined to the feet and lower legs and worse at night. As a rule, sensory loss is confined to the distal parts of the lower extremities, but in severe cases the hands are involved and the sensory loss may even spread to the anterior trunk, simulating a sensory level of spinal cord disease (Said et al, 15 percent of patients with diabetes have symptoms and signs of polyneuropathy, but nearly 50 percent of cross-sectional population samples have evidence of peripheral nerve damage as judged by nerve conduction abnormalities. Fewer than 10 percent of patients have clinically evident polyneuropathy at the time of discovery of diabetes, but this figure rises to 1983). Trophic changes in the form of deep ulcerations and neuropathic degeneration of the joints (Charcot joints) are encountered in the most severe and long-standing cases, presumably as a result of sensory analgesia, trophic changes, and repetitive injury. In another group of patients with diabetic polyneu ropathy the clinical picture may be dominated instead by loss of deep sensation, ataxia, and atony of the bladder, with only slight weakness of the limbs, in which case it resembles tabes dorsalis (hence the term 50 percent after 25 years. The presence of diabetic retinopathy is associated with higher incidences of neu ropathy. It is not surprising, therefore, that neuropathy is most common in diabetics older than 50 years; it is 30 years and is rare in childhood. Dyck and colleagues (1993) studied diabet infrequent in those younger than age ics in Rochester, Minnesota, and found that 54 percent with type 1 (insulin-deficient) and 45 percent with type 2 (insulin-resistant) had polyneuropathy. The percent ages were lower when patients were selected on the basis of clinical symptoms alone rather than on the presence of changes in nerve conduction; close to 15 percent at the time of diagnosis in both groups. In the syndromes described further on, both type 1 and type 2 diabetic patients are susceptible, the duration of diabetes being a major factor. Several fairly distinct clinical syndromes of diabetic neuropathy have been delineated: diabetic pseudota if lan bes). The similarity to tabes dorsalis is even closer (1) the most common (2) acute ophthal cinating pains in the legs, unreactive pupils, abdominal pains, and neuropathic arthropathy are present. It commonly presents as isolated, painful third nerve palsy with sparing of pupillary function. In the first autopsied patient reported by Dreyfus and colleagues, there was an ischemic lesion in the center of the retroor bital portion of the third nerve. Isolated involvement of practically all the major peripheral nerves has been described in diabetes, but the ones most frequently affected are the femoral, sci trunk including a painful thoracolumbar radicu lopathy; (4) an acute or subacute painful, asymmetrical, predominantly motor, multiple neuropathy affecting the upper lumbar roots and the proximal leg muscles ("diabetic amyotrophy"); (5) a more symmetrical, proxi mal motor weakness and wasting, usually without pain and with variable sensory loss, pursuing a subacute or chronic course; and (6) an autonomic neuropathy involv ing bowel, bladder, sweating and circulatory reflexes. These forms of neuropathy often coexist or overlap, par ticularly the autonomic and distal symmetrical types and the subacute proximal neuropathies. A syndrome of painful unilateral or asymmetrical mul tiple neuropathies tends to occur in older patients with relatively mild or even unrecognized diabetes. Multiple nerves are affected in a random distribution (mononeu ropathy multiplex). The mononeuropathies often emerge during periods of transition in the diabetic illness, for example, after an episode of hyper- or hypoglycemia, when insulin treatment is initiated or adjusted, or when there has been rapid weight loss. Pain, which can be severe, begins in the low back or hip and spreads to the thigh and knee on one side; the dis comfort has a deep, aching character with superimposed lancinating jabs and there is a propensity for pain to be most severe at night. Weakness and later atrophy are evi dent in the pelvic girdle and thigh muscles, although the distal muscles of the leg may also be affected. Curiously, we have found the opposite patellar reflex to be absent in some patients without explanation.

However allergy medicine cat dander discount nasonex nasal spray online mastercard, even serum levels of 200 to 300 pg/mL may still be associated (in 5 to 10 percent of cases) with cobalamin deficiency allergy medicine 013 buy nasonex nasal spray 18gm on line. High serum concentrations of cobalamin metabolites allergy kit for dogs order line nasonex nasal spray, methyl malonic acid (normal range allergy shots at home generic 18 gm nasonex nasal spray free shipping, 73 to 271 nmol/L) allergy quiz diagnosis nasonex nasal spray 18gm overnight delivery, and homo cysteine (normal range 5 allergy symptoms 3 days buy generic nasonex nasal spray on-line. It must be emphasized that the serum cobalamin level is not a measure of total-body cobalamin. In a patient who stops absorbing ingested cobalamin, the serum levels may remain in the normal range for months or years despite decreasing tissue reserves. In patients who have received vitamin B12 parenterally, the 2-stage Schilling test is a more reliable indicator of cobalamin deficiency because it uncovers a defect in absorption of the vitamin; however, the Schilling test has been largely supplanted for routine diagnosis by the measurement of antibodies to intrinsic factor and parietal cells. Achlorhydria is almost invariably present in patients with pernicious anemia; its presence can be inferred by measuring the serum gastrin level. Antibodies to gastric parietal cells are also present in as many as 90 percent of patients with cobalamin deficiency, specifically in those with pernicious anemia as opposed to those with dimin ished B12 intake, but this test, although diagnostically specific, is positive in only 60 percent of cases. A relation ship between helicobacter gastritis and autoimmunity against gastric parietal cells is being explored. Low cobalamin levels with or without the clinical signs of deficiency may occur in patients with atrophic gastritis or after subtotal gastrectomy as mentioned. The malab sorption in such cases is thought to be because of a failure to extract cobalamin from food rather than a failure of the intrinsic factor mechanism ("food-cobalamin malabsorp tion"). Because the absorption of free cobalamin is normal, the Schilling test is unimpaired (Carmel, 1990). Infection of the gastric mucosa with Helicobacter pylori has been impli cated in some cases. There are also rare inherited defects in the gene for intrinsic factor that render it ineffective. The results of nerve conduction tests have varied in vitamin B1 2-deficient patients. This again raises the controversy regarding the presence of a peripheral nerve disorder in uncomplicated B12 deficiency. Authoritative texts indicate that a neuropathy is present but certainly, such involvement is not integral to the disease as many patients with prominent neurological marlifestations, particularly early in the course, have normal nerve con duction studies. In patients with normal peripheral nerve studies, the somatosensory evoked potentials usually show abnormalities attributable to central conduction delays, implicating the posterior columns as the cause of the sensory symptoms (Fine and Hallett). In advanced cases, motor conduction and late responses may be affected to a slight degree. These ambiguities reflect the inconsistent and poorly understood role of the peripheral neuropathic component of this disease. The frequency of these findings, however, is not known, and their absence cannot be considered evidence against the diagnosis. In cases of pernicious anemia, the patient is given 1,000 ftg of cyanocobalamin or hydroxo cobalamin intramuscularly each day for several days. The usual approach is to repeat the injection weekly for a month and then monthly for an indefinite period. Although most of the injected cobalamin is excreted, these patients must be flooded with the vitamin because the repletion of cobala min tissue stores is a direct function of the dose. In recent years, the notion that all forms of B 1 2 defi ciency must be circumvented by parenteral administra tion of the vitamin has been questioned and the use of oral cobalamin 500 to 1,000 Jg daily has been used as an alternative, particularly for maintenance treatment. Several studies have indicated the effectiveness of this approach in elderly patients with poor B 1 2 absorption and in persons with restricted diets, such as vegans, but we would express reservation regarding the use of oral replacement in the treatment of manifest subacute combined degeneration with neurologic manifestations until further studies have been published. The most important factor influencing the response to treatment is the duration of symptoms; age, sex, and the degree of anemia are of lesser importance. The great est improvements occur in patients whose disturbance of gait has been present for less than 3 months and recov ery is usually complete if therapy is irlstituted within a few weeks after the onset of symptoms. All neurologic symptoms and signs may improve, mostly during the first 3 to 6 months of therapy, and then at a slower tempo during the ensuing year or even longer. In practically all irlstances, there is some degree of improvement after treatment, although in cases of longest duration, the best that can be accomplished is an arrest of progression. The same mechanism has been proposed to explain the neurologic disorders that sometimes complicate abet alipoproteinernia (see Chap. Vitamin E deficiency has also been observed in young children with chronic cholestatic hepatobiliary disease (Rosenblum et al). Ataxia, loss of tendon reflexes, ophthalmoparesis, proximal muscle weakness with elevated serum creatine kinase, and decreased sensation are the usual manifesta tions of vitamin E deficiency. These symptoms are refer able to parts of the nervous system and musculature that are found to be diseased in animals deprived of vitamin E: degeneration of Clark columns, spinocerebel lar tracts, posterior columns, nuclei of Coil and Burdach, and sensory roots (Nelson et al). Local differences in the natural concentration of vitamin E in various parts of the nervous system and musculature are believed to account for the distribution of the lesions. In affected children, neurologic function improves after long-term daily sup plementation with high doses of vitamin E. In recent years there have been reports of a form of spinocerebellar degeneration attributable to an inherited but conditioned deficiency of vitamin E that may closely mimic the phenotype of Friedreich ataxia ("familial iso lated vitamin E deficiency" as discussed in Chap. The onset is usually in early adolescence, but there is variability, particularly among different families. In these patients, absorption and transport of vitamin E to the liver is normal, but hepatic incorporation of tocopherol (the active form of vitamin E) into very-low-density lipo proteins is defective (Traber et al). An important feature of these cases is that chronic oral administration of large doses of vitamin E can halt and even reverse progression of the ataxia (Gabsi et al). Here we refer especially to a syndrome of spastic ataxia, blindness, and a severe painful neuropathy with glossitis but there are other derivative syndromes that we discuss in this section. The main clinical signs are spastic weakness of the legs, with absent abdominal and increased tendon reflexes, clonus, extensor plantar responses, and a loss of position and vibratory senses. In our experience, this syndrome has usually been associ ated with other nutritional disorders such as Wernicke disease and peripheral and optic neuropathy. In prisoner of-war camps, the "spastic syndrome" was observed in association with mental and emotional changes and dim ness of vision, and at times with widespread muscular rigidity, confusion, coma, and death. The latter syndrome has never been studied pathologically, so that it is impos sible to state whether the lesions are the same as or dif ferent from those of pellagra or from Strachan syndrome, described further on. The syndromes of tropical spastic paraparesis and of lathyrism, another form of spastic paraplegia common in India and certain parts of Africa, were for many years sus pected of being nutritional in origin but are now known to be caused by a virus and a toxin, respectively. These and other types of tropical spastic paraplegia are discussed in greater detail with the spinal cord diseases (see Chap. A chronic tropical disease of the peripheral nerves, called "ataxic neuropathy of Nigeria," has been attributed to the ingestion of inadequately detoxified cassava (Osuntokun). Another form of spastic ataxia, called "konzo," has been attributed to the production of cyanide by an ingested toxic glycoside in individuals who are protein deficient. The differential diagnosis of progressive spastic ataxia is quite broad and includes multiple sclerosis. Vitamin A deficiency sometimes occurs with mal absorption syndromes, causing impairment of vision. Excess of vitamin A in children or adults may result in the syndrome of pseudotumor cerebri (see Chap. Vitamin D deficiency is associated with hypoparathyroidism or a malabsorption state that leads to hypocalcemia, proximal muscle weakness, and rickets. The defect in vision is the result of a lesion of the optic nerves, more or less confined to the region of the pap illomacular bundle. Typically, the patient complains of dimness or blurring of vision for near and distant objects, evolving gradually over a period of several days or weeks. Examination discloses a reduction in visual acuity because of the presence of central or centrocecal scotomata, which are larger for colored than for white test objects. These abnormalities are bilateral and roughly symmetrical and, if untreated, may progress to blindness and irreversible optic atrophy. Although the precise deficiency responsible for this disease cannot be determined, its nutritional basis was established beyond doubt during World War ll and the Korean War, when innumerable instances were observed in prisoners of war who had been confined for prolonged periods under conditions of severe dietary deprivation. Fisher described the optic nerve lesions in 4 such patients who had died of unrelated causes between 8 and 10 years after the onset of amblyopia. In each case, there was a loss of myelin and axis cylinders restricted to the region of the pap illomacular fibers. Of the 4 cases, 3 also showed demyelin ation of the posterior columns of the spinal cord, no doubt an expression of the associated sensory polyradiculopathy. In the Western world, a visual disorder indis tinguishable clinically and pathologically from that observed in prisoners of war is observed infrequently, mainly among undernourished alcoholics. For many years this had been referred to as tobacco-alcohol amblyo pia, with the implication that the visual loss is a result of the toxic effects of alcohol, tobacco, or both. Actually, the evidence is overwhelming that so-called tobacco-alcohol amblyopia is caused by nutritional deficiency and not by toxic exposure. There are data in humans and animals that under certain conditions a deficiency of one or more of the B vitamins: thiamine, vitamin B12, and perhaps riboflavin, may cause degenerative changes in the optic nerves, a situation that pertains in the peripheral nerves as well. Part of the confusion in delineating a specific cause has been sporadic outbreaks of optic neuropathy in underdeveloped countries that may have been caused by a disseminated ingested toxin as described further on. In the 1960s, a popular theory held that the com bined effects of vitamin B12 deficiency and chronic poi soning by cyanide (generated in tobacco smoke) were responsible for "tobacco amblyopia. Recent outbreaks of an apparently nutritional or perhaps toxic optic neuropathy occurred in Cuba during the period 1991 to 1993 and in Tanzania. In both instances the optic neuropathy was frequently associated with peripheral neuropathy. The association of this epidemic with widespread dietary deprivation and the salutary response of both optic and peripheral nerve symptoms to treatment with B vitamins suggests a nutritional causa tion (see Centers for Disease Control and Prevention and the report of the Cuba Neuropathy Field Investigation Team), but a toxic cause could not be excluded. Shortly thereafter, Plant and colleagues reported on a similar out break of optic and peripheral neuropathy from Tanzania. There remains to be considered a neuropathic syn drome that almost certainly is nutritional in origin but does not conform clinically to beriberi or pellagra, the classic deficiency diseases. This syndrome was origi nally observed by Strachan in 1897 among Jamaican sugarcane workers. The main symptoms in his patients were pain, numbness, and paresthesias of the extremi ties; objectively there was ataxia of gait, weakness, wasting, and loss of deep tendon reflexes and sensa tion in the limbs. Dimness of vision and impairment of hearing were common findings, as were soreness and excoriation of the mucocutaneous junctions of the mouth. This disorder, originally known as "Jamaican neuritis," was quickly recognized in other parts of the world, particularly in the undernourished populations of tropical countries. The clinical descriptions from these varied sources are not entirely uniform, but certain features are com mon to all of them and occur with sufficient frequency to allow the delineation of the neurologic syndrome; it appears to be almost identical to the one described by Strachan. The latter consists mainly of sensory symptoms and signs, and the former of the subacute evolution of failing vision, which, if untreated, progresses to complete blindness and pallor of the optic discs. Deafuess and vertigo are uncommon, but in some outbreaks among prisoners of war, these symptoms were frequent enough to earn the epithet "camp dizzi ness. Along with the neurologic signs there may be varying degrees of stomatoglossitis, corneal degenera tion, and genital dermatitis (the orogenital syndrome). Aside from the changes in the papillomacular bundle of the optic nerve, which are similar to the deficiency amblyopia discussed previ ously, the most consistent abnormality has been a loss of myelinated fibers in each column of Goll adjacent to the midline. Fisher interpreted this change to indicate a degeneration of the central processes of the bipolar sensory neurons of the dorsal root ganglia. The fact that the primary sensory neuron is the main site of the neuropathic disorder is consistent with the predominantly sensory symptomatology. The present authors find it difficult to draw a sharp divid ing line between the nutritional peripheral (and optic) neuropathy described previously and the Strachan syndrome. It is characterized clinically by a wide-based stance and gait, varying degrees of instability of the trunk, and ataxia of the legs, the arms being affected to a lesser extent and often not at all. In addition to an ataxic (intention) tremor, there may be a tremor of the fingers or hands resembling 1 of the 2 types of parkinsonian tremor, but appearing only when the limbs are placed in certain sustained postures. Mauritz and coworkers demonstrated that the instability of the trunk in these cases consists of a specific 3-Hz rhythmic swaying in the anteroposterior direction; by contrast, patients with lesions of the cerebellar hemispheres show only slight postural instability without directional pre ponderance. In most cases, the cerebellar syndrome evolves over a period of several weeks or months, after which it remains unchanged for many years. In others, it develops more rapidly or more slowly, but in these cases also the dis ease eventually stabilizes. Occasionally, the cerebellar disorder progresses in a saltatory manner, the symptoms worsening in relation to a severe infectious illness or an attack of delirium tremens. The pathologic changes consist of a degeneration of all the neurocellular elements of the cerebellar cortex but particularly of the Purkinje cells in the anterior and superior aspects of the vermis. In one, the clinical abnor malities are limited to an instability of station and gait, individual movements of the limbs b eing unaffected. The pathologic changes in such cases are restricted to the anterosuperior portions of the vermis. Here, except for their reversibility, the cerebellar symptoms are identi cal to those that characterize the chronic, fixed form of the disease. In this transient type, the derangement is only one of function ("biochemical lesion") and has probably not progressed to the point of fixed structural changes. These forms of cerebellar disease, and par ticularly the restricted and reversible varieties, cannot be distinguished from the cerebellar manifestations of Wernicke disease either on p athologic or on clinical grounds. In each case, coronal sectioning of the former term being applicable when the cerebellar abnormalities are associated with ocular and mental signs and the latter when the cerebellar syndrome stands alone and becomes persistent. Alcoholic cerebel lar degeneration is in all likelihood a result of nutri tional deficiency and not of the toxic effects of alcohol, for reasons already indicated. Insofar as the cerebellar ataxia usually improves to some extent under the influ ence of thiamine alone (see earlier, under "Wernicke Korsakoff Syndrome [Thiamine (B 1) Deficiency] "), it is likely that a deficiency of this vitamin is in whole or part responsible for the cerebellar lesion, but this has not been proven. Microscopically, the lesion proved to be confined to the middle lamina (which makes up about two-thirds of the thickness of the corpus callosum), in which there was a loss of myelin and, to some degree, of the axis cylinders; macrophages were abundant in the altered zone, and astrocytic proliferation had followed. In 1907, Bignami described a case in which the corpus callosum lesion was accom panied by a similar lesion in the central portion of the anterior commissure. We believe the cortical lesions are best explained as secondary to the callosal degeneration.

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