Neurology_Adams

Neurology_Adams. the gag reflex to be retained. Tendon reflexes are lost in cases of severe generalized weakness. These symptoms and signs evolve rapidly, over 2 to 4 days as a rule, and may be mistaken for those of the Guillain-Barré syndrome. Sensation remains intact, however, and the spinal fluid shows no abnormalities. Severe constipation is characteristic of botulism, perhaps as a result of paresis of smooth muscle of the intestine. Consciousness is retained throughout the illness unless severe degrees of anoxia develop as a result of respiratory failure. In the past, the mortality was greater than 60 percent, but it has declined greatly in recent decades, with improvements in the intensive care of acute respiratory failure and the effectiveness of C. botulinum antitoxins.


Neurology_Adams

Neurology_Adams. The clinical diagnosis can be confirmed by electrophysiologic studies. Specifically, there is reduced amplitude of evoked muscle potentials and an increase in amplitude with rapid repetitive nerve stimulation (the opposite of what is found in myasthenia gravis). In patients who recover, improvement begins within a few weeks, first in ocular movement, then in other cranial nerve functions. Complete recovery of paralyzed limb and trunk musculature may take many months.


Neurology_Adams

Neurology_Adams. The three types of botulinum toxins—A, B, and E—cannot be distinguished by their clinical effects alone, so that the patient should receive the trivalent antiserum as soon as the clinical diagnosis is made. This antitoxin can be obtained from the Centers for Disease Control and Prevention in Atlanta, Georgia. An initial dose of 10,000 U is given intravenously after intradermal testing for sensitivity to horse serum, followed by daily doses of 50,000 U intramuscularly until improvement begins. Penicillin or metronidazole are given to eradicate the organism in a wound (but are not as useful if the exogenous preformed toxin has been ingested). Guanidine hydrochloride (50 mg/kg) has been somewhat useful in reversing the weakness of limb and extraocular muscles. Antitoxin and guanidine probably change the course of the illness relatively little and recovery depends on the effectiveness of respiratory care, maintenance of fluid and electrolyte balance, prevention of infection, and so on.


Neurology_Adams

Neurology_Adams. The therapeutic injection of small quantities of botulinum toxin into a muscle affected by dystonia or spasticity will weaken it for weeks to months (see Chap. 4). Mild symptoms of botulism can occur with relatively large therapeutic doses, mainly affecting the oropharyngeal and ciliary muscles, and was more common a few decades ago when experience was limited. Cases are seen after “botox parties” or illicit non-physician use. PLANT POISONS, VENOMS, BITES, Ergotism is the name applied to poisoning with ergot, a drug derived from the rye fungus Claviceps purpurea. Ergot is used therapeutically to control postpartum hemorrhage caused by uterine atony; one of its alkaloids, ergotamine, is used in the treatment of migraine (see Chap. 9), and a class of dopamine agonists, now less used in the treatment of Parkinson disease, has ergot activity (see Chap. 38). Chronic and repeated use of the drug is the usual cause.


Neurology_Adams

Neurology_Adams. Two types of ergotism are recognized: gangrenous, which is caused by a vasospastic, occlusive process in the small arteries of the extremities, and convulsive, or neurogenic, ergotism. The latter is characterized by fasciculations, myoclonus, and spasms of muscles, followed by seizures. In nonfatal cases, a tabes-like neurologic syndrome may develop, with loss of knee and ankle jerks, ataxia, and impairment of deep and superficial sensation. The pathologic changes consist of degeneration of the posterior columns, dorsal roots, and peripheral nerves, but they have been poorly described. The relation of these changes to ergot poisoning is not clear, because most of the cases occurred in areas where malnutrition was endemic.


Neurology_Adams

Neurology_Adams. Lathyrism is a neurologic syndrome characterized by the relatively acute onset of pain, paresthesia, and weakness in the lower extremities, progressing to a permanent spastic paraplegia. It is a serious medical problem in India and in some North African countries and is probably caused by a toxin contained in the chickling vetch pea, Lathyrus, a legume that is consumed in excess quantities during periods of famine. This disorder is discussed further with the spinal cord diseases (see Chap. 42). Konzo (Environmental Cyanide Poisoning. See Also Chap. 44)


Neurology_Adams

Neurology_Adams. Konzo (Environmental Cyanide Poisoning. See Also Chap. 44) This is caused by ingestion of cyanide, usually from insufficiently processed roots of the bitter cassava. The illness is a rapid upper motor syndrome (paraplegia, tetrapelgia) and usually irreversible. It is most common in rural Africa and peaks in incidence during times of food shortage and drought, when cassava is utilized as a food substitute and there is insufficient water to allow for adequate processing of the roots. Efforts are directed towards education and providing resources for processing.


Neurology_Adams

Neurology_Adams. The gathering of wild mushrooms, a popular pastime in late summer and early fall, always carries with it the danger of poisoning. As many as 100 species of mushrooms are poisonous. Most of them cause only transient gastrointestinal symptoms but some elaborate toxins that can be fatal. The most important of these toxins are the cyclopeptides, which are contained in several species of Amanita phalloides and muscaria and account for more than 90 percent of fatal mushroom poisonings. These toxins disrupt RNA metabolism, causing hepatic and renal necrosis. Symptoms of poisoning with Amanita usually appear between 10 and 14 h after ingestion and consist of nausea, vomiting, colicky pain, and diarrhea, followed by irritability, restlessness, ataxia, hallucinations, convulsions, and coma. The important clinical features have been reviewed by Koppel.


Neurology_Adams

Neurology_Adams. There may be added evidence of a neuromyopathy presenting as flaccid areflexic paralysis, high serum CK, diminished EMG potentials, and fiber necrosis. Other important mushroom toxins are methylhydrazine (contained in the Gyromitra species) and muscarine (Inocybe and Clitocybe species). The former gives rise to a clinical picture much like that caused by the cyclopeptides. The symptoms of muscarine poisoning, which appear within 30 to 60 min of ingestion, are essentially those of parasympathetic stimulation—miosis, lacrimation, salivation, nausea, vomiting, diarrhea, perspiration, bradycardia, and hypotension. Tremor, seizures, and delirium occur in cases of severe poisoning.


Neurology_Adams

Neurology_Adams. The mushroom toxins have no effective antidotes. If vomiting has not occurred, it should be induced with ipecac, following which activated charcoal should be administered orally in order to bind what toxin remains in the gastrointestinal tract. A local poison control center may help identify the poisonous mushroom and its toxin. Even more important, the gathering and ingestion of field varieties of mushrooms should be left to those absolutely certain of their identity.


Neurology_Adams

Neurology_Adams. A rapidly progressive and sometimes fatal paralysis follows the ingestion of the small fruit of the buckthorn shrub that is indigenous to northern Mexico and the neighboring southwestern parts of the United States. The responsible toxin causes a predominantly motor polyneuropathy, probably of axonal type. Except for a normal CSF protein concentration, the disorder closely resembles Guillain-Barré syndrome and tick paralysis (see later), and its recognition depends on awareness of ingestion of the fruit in endemic areas. Ingestion of marine toxins that block neural sodium channels is a common form of poisoning throughout coastal areas and islands of the world. It results from eating fish that have fed on toxin-containing microscopic dinoflagellates. Reef fish and shellfish ingest high concentrations of these organisms during periodic upswings in the population of the dinoflagellates. They may be so profuse as to color the surrounding water (red tide).


Neurology_Adams

Neurology_Adams. Although the toxins differ (tetrodotoxin—fugu, puffer fish; ciguatoxin—snails; saxitoxin and brevetoxin—shellfish), the neurologic and gastrointestinal symptoms that follow the ingestion of poisoned fish are similar. The initial symptoms are diarrhea, vomiting, or abdominal cramps coming on minutes to hours after the ingestion. These are followed by paresthesias that begin periorally and then involve the limbs distally. Hot and cold sensory stimuli (e.g., ice cream) are characteristically associated with electrical-like or burning paresthesias in the mouth. Muscle aches and shooting pains are also mentioned by most patients. In puffer fish poisoning, and in advanced stages of poisoning from other fish, weakness occurs, and there have been a few reports of coma and of respiratory failure.


Neurology_Adams

Neurology_Adams. The recognition of this type of fish poisoning is straightforward in endemic areas, in some of which there is a seasonal clustering of cases. In tourists returning home from endemic areas, and in persons consuming imported fish, the illness may be mistaken for Guillain-Barré syndrome. Prominent perioral paresthesias should suggest the correct diagnosis. Supportive treatment is all that is required but treatment with intravenous mannitol is said to hasten recovery. Pearn has reviewed the biochemistry and physiologic and clinical effects of the various marine toxins and points out a form of chronic intoxication that is apparently endemic in certain island communities. The main chronic effects are severe fatigue and asthenic weakness. The problem of distinguishing this syndrome from depression is acknowledged by the author and the cases on which we have consulted locally almost always fall into the psychiatric category. One of our patients developed chronic paresthesias.


Neurology_Adams

Venoms, Bites, and Stings

Neurology_Adams. Venoms, Bites, and Stings


Neurology_Adams

Neurology_Adams. Although relatively rare, they are nonetheless important causes of mortality. The venoms of certain species of snakes, lizards, spiders (especially the black widow spider, see Chap. 50), and scorpions contain neurotoxins that may cause a fatal depression of respiration and curare-like paralysis of neuromuscular transmission. In the United States, there are approximately 8,000 poisonous snake bites per year. Some, such as the coral snake envenomation, are neurotoxic, producing pupillary dilatation, ptosis, ocular palsies, ataxia, and respiratory paralysis. Others (rattlesnakes, water moccasin snakes) cause tissue necrosis and circulatory collapse. These are reviewed by Gold and colleagues. The serious effects of Hymenoptera stings (bees, wasps, hornets, and fire ants) are mainly the result of hypersensitivity and anaphylaxis. Several instances of cerebral and myocardial infarction have been reported after bee and wasp stings (Crawley et al). A substantial inception has been the


Neurology_Adams

Neurology_Adams. result of hypersensitivity and anaphylaxis. Several instances of cerebral and myocardial infarction have been reported after bee and wasp stings (Crawley et al). A substantial inception has been the development of an antivenom for scorpion stings that can be administered in parallel with diazepines to children and results in more rapid resolution of paralysis and respiratory failure (Boyer and colleagues). All of these disorders are discussed in detail in Harrison’s Principles of Internal Medicine.


Neurology_Adams

Neurology_Adams. This rare condition is the result of a toxin secreted by the gravid tick. In Canada and the northwestern United States, the wood tick Dermacentor andersoni is mainly responsible; in the southeastern United States it is Dermacentor variabilis, a dog tick (the tick in Australia is the Ixodes holocyclus), but various other ticks occasionally may have the same effect. Most cases occur in children because their small body mass renders them susceptible to the effects of relatively small amounts of the toxin. The illness arises almost exclusively in the spring when the mature gravid ticks are most plentiful. The illness is more common and is generally more severe in cases on the Australian continent than it is in North America. Clinical manifestations require that the tick be attached to the skin for several days.


Neurology_Adams

Neurology_Adams. The neurotoxin causes a generalized, flaccid, areflexic paralysis, appearing over 1 or 2 days and thereby mimicking the Guillain-Barré syndrome. In a few cases, several days of ataxia and areflexia precede the paralysis but sensory loss tends to be minimal. External ophthalmoplegia, which occurred in 5 of the 6 children described by Grattan-Smith and colleagues, is exceptional, judging by other reports; internal ophthalmoplegia and pharyngeal weakness are also known to occur, and while not typical, raise the possibility of botulism or diphtheria. The CSF is normal and electrophysiologic studies show reduction in the amplitude of the muscle action potentials but normal or only slightly slowed nerve conduction. Prominent ptosis and neck weakness may also raise the question of a neuromuscular process, but repetitive stimulation testing is normal or evokes only a slight decrement or increment in some cases.


Neurology_Adams

Neurology_Adams. The ticks tend to attach to the hairlines or in the matted hair of the scalp, neck, and pubis, where a careful search will reveal them (for which reason nurses and electroencephalography technicians often are most likely to find them; see Felz et al). The diagnosis is much in the awareness of clinicians in endemic areas during the tick season, for they are gratified with rapid and dramatic improvement when the tick is removed. The paralysis has been reported to become transiently worse after tick removal in some of the Australian cases. From a neurologic point of view, Lyme disease is a far more common tick-borne disorder. The causative agent is Borrelia burgdorferi, a spirochetal organism. The disorder is discussed fully with other infectious diseases in Chap. 31 and in Chap. 43, with the neuropathies. The causes and clinical manifestations of lead poisoning are quite different in children and adults.


Neurology_Adams

Neurology_Adams. The causes and clinical manifestations of lead poisoning are quite different in children and adults. In the United States, this disease has been identified most often in 1to 3-year-old children who inhabit urban slum areas where old, deteriorated housing prevails. (Lead paint was used in most houses built before 1940 and in many built before 1960.) The chewing of leaded paint is promoted by compulsive ingestion (pica) from windowsills and painted plaster walls. The development of an acute encephalopathy is the most serious complication, resulting in death in 5 to 20 percent of cases and in permanent neurologic and mental deficits in more than 25 percent of survivors.


Neurology_Adams

Neurology_Adams. Clinical manifestations These develop over a period of 3 to 6 weeks. The child becomes anorectic, less playful and less alert, and more irritable. These symptoms may be misinterpreted as a behavior disorder or a manifestation of mental retardation. Intermittent vomiting, vague abdominal pain, clumsiness, and ataxia may be added. If these early signs of intoxication are not recognized and the child continues to ingest lead, more flagrant signs of acute encephalopathy may develop—most frequently in the summer months, for reasons that are not understood. Vomiting becomes more persistent, apathy progresses to drowsiness and stupor interspersed with periods of hyperirritability, and, finally, seizures and coma supervene. This syndrome may evolve in a period of a week or less, most rapidly in children younger than 2 years of age; in older children, it is more likely to develop in recurrent and less severe episodes. This clinical syndrome must be distinguished from tuberculous meningitis,


Neurology_Adams

Neurology_Adams. children younger than 2 years of age; in older children, it is more likely to develop in recurrent and less severe episodes. This clinical syndrome must be distinguished from tuberculous meningitis, viral meningoencephalitis, and the various conditions causing acute increased intracranial pressure. Usually, in lead encephalopathy, the CSF is under increased pressure with manifest papilledema, and there may be a slight lymphocytic pleocytosis and elevated protein but normal glucose values. It follows that lumbar puncture should be done with caution and only if it is essential for diagnosis.


Neurology_Adams

Neurology_Adams. Diagnosis Because the symptoms of plumbism are nonspecific, the diagnosis depends on an appreciation of the potential causative factors and the results of certain laboratory tests. Lead lines at the metaphyses of long bones and basophilic stippling of red cells are seen but are too inconstant to be relied on, but basophilic stippling of bone marrow erythroblasts is uniformly increased. Impairment of hemoglobin synthesis, which is exquisitely sensitive to the toxic effects of lead, results in the increased excretion of urinary coproporphyrin (UCP) and of Δ-aminolevulinic acid (ALA). These urinary indices and the lead concentrations in the serum bear an imperfect relationship to the clinical manifestations. In the test for UCP, which is readily performed in the clinic and emergency department, a few milliliters of urine are acidified with acetic acid and shaken with an equal volume of ether; if coproporphyrin is present, the ether layer will reveal a reddish fluorescence under a Wood


Neurology_Adams

Neurology_Adams. a few milliliters of urine are acidified with acetic acid and shaken with an equal volume of ether; if coproporphyrin is present, the ether layer will reveal a reddish fluorescence under a Wood lamp. This test is strongly positive when the whole blood concentration of lead exceeds 80 mcg/dL. The diagnosis can be confirmed by promoting lead excretion with calcium disodium edetate (CaNa2 ethylenediaminetetraacetic acid [EDTA]), given in three doses (25 mg/kg) at 8-h intervals. Excretion of over 500 mg in 24 h is indicative of plumbism. The measurement of zinc protoporphyrin (ZPP) in the blood is another reliable means of determining the presence and degree of lead exposure. The binding of erythrocyte protoporphyrin to zinc occurs when lead impairs the normal binding of erythrocyte protoporphyrin to iron. Elevated ZPP can also be induced when access to iron is limited by other conditions, such as iron deficiency anemia.


Neurology_Adams

Neurology_Adams. At blood lead concentrations of 70 mcg/dL symptoms may be minimal, but acute encephalopathy may occur abruptly and unpredictably, for which reason the child should be hospitalized for chelation therapy (see below). Some children with a blood lead level of 50 mcg/dL may have symptoms of severe encephalopathy, whereas others may be asymptomatic. In the latter case, an attempt should be made to discover and remove the source of lead intoxication and the child should be reexamined at frequent intervals. The seriousness of lead encephalopathy is indicated by the fact that most of the children who become stuporous or comatose remain mentally retarded despite treatment. The physician’s aim, therefore, is to institute treatment before the severe symptoms of encephalopathy have become manifest.


Neurology_Adams

Neurology_Adams. Pathology In children who die of acute lead encephalopathy, the brain is massively swollen, with herniation of the temporal lobes and cerebellum, multiple microscopic ischemic foci in the cerebrum and cerebellum, and endothelial damage and deposition of proteinaceous material and mononuclear inflammatory cells around many of the small blood vessels. There are also hyperplastic changes in arteries and arterioles and in some places, perivascular infiltrates of lymphocytes and mononuclear cells. In the territories of some of these vessels there are foci of ischemic necrosis with surrounding glial reaction appropriate for the age of the lesion. Similar changes are present in the kidneys.


Neurology_Adams

Neurology_Adams. Treatment The plan of therapy includes the establishment of urinary flow, following which intravenous fluid therapy is restricted to basal water and electrolyte requirements. In cases of acute encephalopathy, combined chelation therapy with 2,3-dimercaprol (British anti-Lewisite [BAL]; 12 to 24 mg/kg) and CaNa2 EDTA (0.5 to 1.5 g/m2 body surface area) for 5 to 7 days. This is followed by a course of oral penicillamine (40 mg/kg, not exceeding 1 g/d). In acute cases the goal is to reduce the serum lead levels below 40 mcg/dL. Once the absorption of lead has ceased, chelating agents remove lead only from soft tissues and not from bone, where most of the lead is stored. Any intercurrent illness may result in a further mobilization of lead from bones and soft tissues and an exacerbation of symptoms of lead intoxication.


Neurology_Adams

Neurology_Adams. Repeated doses of mannitol may be used for relief of cerebral edema. Microcytic hypochromic anemia is treated with iron once the chelating agents have been discontinued. Seizures are best controlled with intravenous diazepam or midazolam. Prevention The prevention of reintoxication (or initial intoxication) demands that the child be removed from the source of lead. Although this is axiomatic, it is often difficult to accomplish, despite the best efforts of local health departments and hospital and city social workers. Nevertheless, an attempt to eliminate the environmental factor must be made in each case. Such attempts, among other things, have resulted in a marked decrease in the incidence of acute lead encephalopathy in the past two decades. Although florid examples of this encephalopathy are now uncommon, undue exposure to lead (blood levels greater than 30 mcg/dL) remains inordinately prevalent and a continuing source of concern to public health authorities.


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Neurology_Adams. As to the levels that pose a danger to the child, there is still some uncertainty. Rutter, who reviewed all of the evidence up to 1980, concluded that persistent blood levels above 40 mcg/dL may cause slight cognitive impairment and, less certainly, an increased risk of behavioral difficulties. More recently, Canfield and colleagues reported, from a prospective study of 172 children, that even lower levels may induce a decline in IQ at 3 and 5 years of age. These data require confirmation before general acceptance. Further compounding the problem of interpreting low-level lead exposure in children with blood lead concentrations below 45 mcg/dL is the observation by Rogan and colleagues that treatment with succimer, while successful in reducing lead levels, did not improve cognitive or behavioral function.


Neurology_Adams

Neurology_Adams. The oral lead chelator succimer is approved for outpatient treatment of asymptomatic children with blood lead levels higher than 45 mcg/dL. A 3-week course of treatment is given, with weekly monitoring of blood lead levels to identify lead mobilization from bones and soft tissues (Jorgensen).


Neurology_Adams

Neurology_Adams. In 1988, on the basis of epidemiologic and experimental studies in the United States, Europe, and Australia, the Agency for Toxic Substances and Disease Registry set a much lower threshold for neurobehavioral toxicity (10 to 15 mcg/dL). It estimated that 3 to 4 million American children have blood levels in excess of this amount. Needleman and colleagues studied the long-term effects of low doses of lead in asymptomatic children, 132 of whom had had demonstrable levels of lead in the dentin of shed teeth (average 24 mg/dL). Eleven years later, the children were found to have behavioral abnormalities proportionate to their early lead levels. In comparison to a normal population, more had dropped out of school and more had lower vocabulary and grammatical reasoning scores, more reading difficulty, poorer hand-eye coordination performance, slower finger-tapping rates, and longer reaction times. The authors claimed to have eliminated other confounding variables such as lower social class


Neurology_Adams

Neurology_Adams. poorer hand-eye coordination performance, slower finger-tapping rates, and longer reaction times. The authors claimed to have eliminated other confounding variables such as lower social class and genetic factors. These findings are similar to those of the long-term studies of Baghurst and colleagues (see also Mahaffey). There are no adequate pathologic or MRI studies of such cases.


Neurology_Adams

Neurology_Adams. Lead intoxication in adults is much less common than in children. The hazards to adults are the result of inhaling the dust of inorganic lead salts and the fumes from the burning of objects containing lead or involvement in processes that require the remelting of lead. Painting, printing, pottery glazing, lead smelting, welding, and storage battery manufacturing are the industries in which these hazards are likeliest to occur. In the past, miners and brass foundry and garage workers (during automobile radiator repair, when soldered joints are being heated; see Goldman et al) were the ones most at risk. Currently, other, sometimes idiosyncratic, sources are more common. For example, the authors have encountered a striking case of lead encephalopathy in a man of Indian origin who was taking large amounts of an Ayurvedic herbal remedy for arthritis. The first manifestation was a series of generalized seizures followed by a fluctuating encephalopathy. His serum lead level was 70 mcg/dL,


Neurology_Adams

Neurology_Adams. large amounts of an Ayurvedic herbal remedy for arthritis. The first manifestation was a series of generalized seizures followed by a fluctuating encephalopathy. His serum lead level was 70 mcg/dL, and 24-h urine collection contained 1,550 mg of lead (normal being less than 400 mg). There was a T2-weighted hyperintensity in the cerebral cortex. Whitfield and colleagues reviewed 23 instances of lead encephalopathy in adults. At the time of their report most cases were caused by moonshine (homemade whiskey from lead-lined stills). More recently, most cases have been from various herbal medications, as already mentioned. Combined lead and arsenic poisoning from herbal compounds is also known.


Neurology_Adams

Neurology_Adams. The usual manifestations of lead poisoning in adults are colic, anemia, and peripheral neuropathy. Encephalopathy of the type described above is decidedly rare. Lead colic, frequently precipitated by an intercurrent infection or by alcohol intoxication, is characterized by severe, poorly localized abdominal pain, often with rigidity of abdominal muscles but without fever or leukocytosis. The pain responds to the intravenous injection of calcium salts, at least temporarily, but responds poorly to morphine. Mild anemia is common. A black line of lead sulfide may develop along the gingival margins. Peripheral neuropathy, usually a bilateral wrist drop, is a rare manifestation and is discussed in Chap. 46. The diagnostic tests for plumbism in children are generally applicable to adults, with the exception of bone films, which are of no value in the latter. Also, the treatment of adults with chelating agents follows the same principles as in children.


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Neurology_Adams. Intoxication with tetraethyl and tetramethyl (organic) lead, used as additives in gasoline, is caused by inhalation of gasoline fumes. It occurs most often in workers who clean gasoline storage tanks. Insomnia, irritability, delusions, and hallucinations are the usual clinical manifestations, and a maniacal state may develop. The hematologic abnormalities of inorganic lead poisoning are not found, and chelating agents are of no value in treatment. Organic lead poisoning is usually reversible, but fatalities have been reported. The pathologic changes have not been well described.


Neurology_Adams

Neurology_Adams. In the past, medications such as Fowler solution (potassium arsenite) and the arsphenamines, used in the treatment of syphilis, were frequent causes of intoxication, but now the most common cause is the suicidal or accidental ingestion of herbicides, insecticides, or rodenticides containing copper acetoarsenite (Paris green) or calcium or lead arsenate. In rural areas, arsenic-containing insecticide sprays are a common source of poisoning. Arsenic is used also in the manufacture of paints, enamels, and metals; as a disinfectant for skins and furs; and also in galvanizing, soldering, etching, and lead plating. Occasional cases of poisoning are reported in relation to these occupations. Arsenic is still contained in some topical creams and oral solutions that are used in the treatment of psoriasis and other skin disorders and in some herbal remedies.


Neurology_Adams

Neurology_Adams. Arsenic exerts its toxic effects by reacting with the sulfhydryl radicals of certain enzymes necessary for cellular metabolism. The effects on the nervous system are those of an encephalopathy or peripheral neuropathy. The latter may be the product of chronic poisoning or may become manifest between 1 and 2 weeks after recovery from the effects of acute poisoning. It takes the form of a distal axonopathy that is described in Chap. 43 (see also Heyman et al). In cases of arsenical polyneuropathy we have cared for, a distal sensorimotor areflexic syndrome developed subacutely. At autopsy there was a dying back pattern of myelin and axons with macrophage and Schwann cell reactions and chromatolysis of motor neurons and sensory ganglion cells. The CNS appeared normal.


Neurology_Adams

Neurology_Adams. The symptoms of encephalopathy (headache, drowsiness, mental confusion, delirium, and convulsive seizures) may also occur as part of acute or chronic intoxication. In the latter case, they are accompanied by weakness and muscular aching, hemolysis, chills and fever, mucosal irritation (in patients exposed to arsine gas), diffuse scaly desquamation, and transverse white lines, 1 to 2 mm in width, above the lunula of each fingernail (Mees lines). Acute poisoning by the oral route is associated with severe gastrointestinal symptoms, shock and death in a large proportion of patients. The CSF is normal. Examination of the brain in such cases discloses myriads of punctate hemorrhages in the white matter. Microscopically, the lesions consist of capillary necrosis and of pericapillary zones of degeneration, which, in turn, are ringed by red cells (brain purpura). These neuropathologic changes are not specific for arsenical poisoning, but have been observed in such diverse conditions as


Neurology_Adams

Neurology_Adams. of degeneration, which, in turn, are ringed by red cells (brain purpura). These neuropathologic changes are not specific for arsenical poisoning, but have been observed in such diverse conditions as pneumonia, gram-negative bacillary septicemia from urinary tract infections, sulfonamide and phosgene poisoning, dysentery, disseminated intravascular coagulation, and others.


Neurology_Adams

Neurology_Adams. The diagnosis of arsenical poisoning depends on the demonstration of increased levels of arsenic in the hair and urine. Several of the aspects of testing have been reviewed by Moyer. Arsenic is deposited in the hair within 2 weeks of exposure and may remain fixed there for long periods. Concentrations of more than 0.1 mg arsenic per 100 mg hair are indicative of poisoning. Arsenic also remains within bones for long periods and is slowly excreted in the urine and feces. Excretion of more than 0.1 mg arsenic per liter of urine is considered abnormal; levels greater than 1 mg/L may occur soon after acute exposure. We would caution, however, that individuals who consume fish on a regular basis, as occurs in coastal regions, may have slightly or moderately elevated levels of arsenic and that various conditions such as neuropathy and amyotrophic lateral sclerosis (ALS) may be mistakenly attributed to this innocuous finding. The levels return to normal within a few months of abstaining from


Neurology_Adams

Neurology_Adams. conditions such as neuropathy and amyotrophic lateral sclerosis (ALS) may be mistakenly attributed to this innocuous finding. The levels return to normal within a few months of abstaining from fish.


Neurology_Adams

Neurology_Adams. The CSF protein level may be raised (50 to 100 mg/dL). Treatment Acute poisoning is treated by gastric lavage, vasopressor agents, dimercaprol (BAL), maintenance of renal perfusion, and exchange transfusions if massive hemoglobinuria occurs. Once polyneuropathy has occurred, it is little affected by treatment with BAL, but other manifestations of chronic arsenical poisoning respond favorably. There has been a gradual recovery from the polyneuropathy under our care.


Neurology_Adams

Neurology_Adams. Manganese poisoning results from the chronic inhalation and ingestion of manganese particles and occurs in miners of manganese ore and in workers who separate manganese from other ore. Several clinical syndromes have been observed. The initial stages of intoxication may be marked by a prolonged confusional-hallucinatory state. Later, the symptoms are predominantly extrapyramidal. They are often described as parkinsonian in type, but in the patients seen by the authors, the resemblance was not close: an odd gait (“cock” walk), dystonia and rigidity of the trunk, postural instability, and falling backward were features seen in two South American miners. Others, however, have reported stiffness and awkwardness of the limbs, often with tremor of the hands, “cogwheel” phenomenon, gross rhythmic movements of the trunk and head, and retropulsive and propulsive gait. Corticospinal and corticobulbar signs may be added. Progressive weakness, fatigability, and sleepiness as well as psychiatric


Neurology_Adams

Neurology_Adams. movements of the trunk and head, and retropulsive and propulsive gait. Corticospinal and corticobulbar signs may be added. Progressive weakness, fatigability, and sleepiness as well as psychiatric symptoms (manganese madness) are other clinical features. Rarely, severe axial rigidity and dystonia, like those of Wilson disease, are said to have been the outstanding manifestations. The emergence of an extrapyramidal syndrome from the use of illicit drugs that are synthesized with potassium permanganate has already been mentioned in relation to the cathionine stimulants. The differences between manganism and conventional parkinsonism have been reviewed by Calne et al.


Neurology_Adams

Neurology_Adams. Neuronal loss and gliosis, affecting mainly the pallidum and striatum but also the frontoparietal and cerebellar cortex and hypothalamus, have been described, but the pathologic changes have not been carefully studied. The neurologic abnormalities have not responded to treatment with chelating agents. In the chronic dystonic form of manganese intoxication, dramatic and sustained improvement has been reported with the administration of l-dopa; patients with the more common parkinsonian type of manganese intoxication have shown only slight, if any, improvement with l-dopa.


Neurology_Adams

Neurology_Adams. Mercury poisoning arises in two forms, one caused by inorganic compounds (elemental or mercury salt) and the other, more dangerous, caused by organic mercury. The sources of potential exposure are reviewed by Clarkson. Among the organic compounds, methylmercury gives rise to a wide array of serious neurologic symptoms that may be delayed for days or weeks after exposure, including tremor of the extremities, tongue, and lips; mental confusion; and a progressive cerebellar syndrome, with ataxia of gait and arms, intention tremor, and dysarthria. Choreoathetosis and parkinsonian facies have also been described. Changes in mood and behavior are prominent, consisting at first of subjective weakness and fatigability and later of extreme depression and lethargy alternating with irritability. This delayed form of subacute mercury poisoning has been reported in chemical laboratory workers after exposure to methyl mercury compounds. These agents, particularly dimethylmercury, are extremely


Neurology_Adams

Neurology_Adams. This delayed form of subacute mercury poisoning has been reported in chemical laboratory workers after exposure to methyl mercury compounds. These agents, particularly dimethylmercury, are extremely hazardous because they are absorbed transdermally and by inhalation, allowing severe toxicity to occur with even brief contact. In a fatal case of a chemist reported by


Neurology_Adams

Neurology_Adams. Nierenberg and colleagues, a rapidly progressive ataxia and stupor progressing to coma developed 154 days after exposure. Cerebellar function was most severely impaired, and visual function was affected. The pathologic changes are characterized by a striking degeneration of the granular layer of the cerebellar cortex, with relative sparing of the Purkinje cells and neuronal loss and gliosis of the calcarine cortex and to a lesser extent of other parts of the cerebral cortex, similar to the Minamata disease cases described later.


Neurology_Adams

Neurology_Adams. The chronic form of inorganic mercury poisoning occurs in persons exposed to large amounts of the metal used in the manufacture of thermometers, mirrors, incandescent lights, x-ray machines, and vacuum pumps. Because mercury volatilizes at room temperature, it readily contaminates the air and then condenses on the skin and respiratory mucous membranes. Nitrate of mercury, used formerly in the manufacture of felt hats (“mad hatters”), and phenyl mercury, used in the paper, pulp, and electrochemical industries, are other sources of intoxication. Paresthesias, lassitude, confusion, incoordination, and intention tremor are characteristic, and, with continued exposure, a delirious state occurs. Headache, various bodily pains, visual and hearing disorders, and corticospinal signs may be added, but their pathologic basis is unknown. The term erethism was coined to describe the timidity, memory loss, and insomnia that were said to be characteristic of chronic intoxication. If the exposure is


Neurology_Adams

Neurology_Adams. but their pathologic basis is unknown. The term erethism was coined to describe the timidity, memory loss, and insomnia that were said to be characteristic of chronic intoxication. If the exposure is more than a minimal degree over a long period, gastrointestinal disturbances are prone to occur (anorexia, weight loss), as well as stomatitis and gingivitis with loosening of the teeth.


Neurology_Adams

Neurology_Adams. Acute exposure to inorganic mercury in larger amounts is even more corrosive to the gastrointestinal system and produces nausea, vomiting, hematemesis, abdominal pain, and bloody diarrhea, as well as renal tubular necrosis. Isolated instances of polyneuropathy associated with exposure to mercury have also been reported (Albers et al; Agocs et al) and may be responsible for the paresthesias that accompany most cases, as well as the acrodynic syndrome described below. The polyneuropathy associated with mercury poisoning is discussed in Chap. 43.


Neurology_Adams

Neurology_Adams. The presence of mercury in industrial waste has contaminated many sources of water supply and fish, which are ingested by humans and cause mercurial poisoning. So-called Minamata disease is a case in point. Between 1953 and 1956, a large number of villagers living near Minamata Bay in Kyushu Island, Japan, were afflicted with a syndrome of chronic mercurialism, traced to the ingestion of fish that had been contaminated with industrial wastes containing methylmercury (Harada et al). Concentric constriction of the visual fields, hearing loss, cerebellar ataxia, postural and action tremors, and sensory impairment of the legs and arms and sometimes of the tongue and lips were the usual clinical manifestations. The syndrome evolved over a few weeks. Pathologically there was diffuse neuronal loss in both cerebral and cerebellar cortices, most marked in the anterior parts of the calcarine cortex and granule cell layer of the cerebellum. CT scans in survivors, years after the mass poisoning,


Neurology_Adams

Neurology_Adams. in both cerebral and cerebellar cortices, most marked in the anterior parts of the calcarine cortex and granule cell layer of the cerebellum. CT scans in survivors, years after the mass poisoning, disclosed bilaterally symmetrical areas of decreased attenuation in the visual cortex and diffuse atrophy of the cerebellar hemispheres and vermis, especially the inferior vermis (Tokuomi et al).


Neurology_Adams

Neurology_Adams. A painful neuropathy of children (acrodynia) has been traced to mercury exposure from interior latex paint, to calomel (mercurous chloride), to teething powders, and to a mercuric fungicide used in washing diapers (Agocs et al; Clarkson). Albers and colleagues observed the appearance of symptoms (mild decrease in strength, tremor, and incoordination) 20 to 35 years after exposure to elemental mercury. These authors believed that the natural neuronal attrition with aging had unmasked the neurologic disorder, a theory that we cannot validate.


Neurology_Adams

Neurology_Adams. The authors believe it worth mentioning that there is no convincing evidence linking typical dietary ingestion of fish containing metallic compounds such as mercury and any neurologic or developmental disease. The inhalation of vaporized mercury as a result of extensive dental work, or simply the presence of a large number of fillings (“amalgam illness”), is alleged to affect the peripheral nerves or to cause fatigue, but the connection is also highly doubtful as is the alleged relationship between vaccines containing mercury preservatives (thiomersal) and autism.


Neurology_Adams

Neurology_Adams. Treatment Treatment consists of removal from the source of mercury exposure, and for acute inorganic mercury poisoning, chelation therapy with penicillamine or dimercaprol (BAL). No chelator for methylmercury or ethylmercury is approved by the FDA. In the treatment of chronic mercury poisoning, penicillamine has been the drug of choice, because it can be administered orally and appears to chelate mercury selectively, with less effect on copper, which is an essential element in many metabolic processes. Nervous system function may be deranged as part of acute and frequently fatal poisoning with inorganic phosphorus compounds (found in rat poisons, roach powders, and match heads). More important clinically is poisoning with organophosphorus compounds, the best known of which is triorthocresyl phosphate (TOCP).


Neurology_Adams

Neurology_Adams. Organophosphates are widely used as insecticides. Since 1945, approximately 15,000 individual compounds in this category have come into use. Certain ones, such as tetraethylpyrophosphate, have been the cause of major outbreaks of neurologic disorder, especially in children. These substances have an acute anticholinesterase effect but no delayed neurotoxic action. Chlorophos, which is a 1-hydroxy-2,2,2-trichlorethylphosphonate, is an exception; it has both an acute and delayed action, as does TOCP.


Neurology_Adams

Neurology_Adams. The immediate anticholinesterase effect manifests itself by headache, vomiting, sweating, abdominal cramps, salivation, wheezing (secondary to bronchial spasm), miosis, and muscular weakness and twitching. Most of these symptoms can be reversed by administration of atropine and pralidoxime. The delayed effect manifests 2 to 5 weeks following acute organophosphorus insecticide poisoning. This takes the form of a distal symmetrical sensorimotor (predominantly motor) polyneuropathy, progressing to muscle atrophy (see Chap. 43). Recovery occurs to a variable degree and then, in patients poisoned with TOCP, signs of corticospinal damage become detectable. The severity of paralysis and its permanence vary with the dosage of TOCP. Whether a polyneuropathy can arise without the preceding symptoms of cholinergic toxicity is debated; however, based on a review of the subject and a study of 11 patients exposed to these agents, 3 of whom later acquired sensory neuropathy, Moretto and Lotti


Neurology_Adams

Neurology_Adams. of cholinergic toxicity is debated; however, based on a review of the subject and a study of 11 patients exposed to these agents, 3 of whom later acquired sensory neuropathy, Moretto and Lotti express the view that such an occurrence must be rare.


Neurology_Adams

Neurology_Adams. In addition to the acute and delayed neurotoxic effects of organophosphorus, an intermediate syndrome has been described (Senanayake and Karalliedde). Symptoms appear 24 to 96 h after the acute cholinergic phase and consist of weakness or paralysis of proximal limb muscles, neck flexors, motor cranial nerves, and respiratory muscles. Respiratory paralysis may prove fatal. In patients who survive, the paralytic symptoms last for 2 to 3 weeks and then subside. The intermediate and delayed symptoms do not respond to atropine or other drugs.


Neurology_Adams

Neurology_Adams. Several striking outbreaks of TOCP poisoning have been reported. During the latter part of the prohibition era and to a lesser extent thereafter, outbreaks of so-called jake paralysis were traced to drinking an extract of Jamaica ginger that had been contaminated with TOCP. Adams had examined several “ginger jake” patients many years later and related to us that he found only signs of corticospinal disease. Presumably in the early stage of this disease they were obscured by the neuropathy. Another outbreak occurred in Morocco in 1959, when lubricating oil containing TOCP was used deliberately to dilute olive oil. Several other outbreaks have been caused by the ingestion of grain and cooking oil that had been stored in inadequately cleaned containers previously used for storing TOCP.


Neurology_Adams

Neurology_Adams. The effect of TOCP on the peripheral nervous system has been studied extensively in experimental animals. In cats, there occurs a dying back from the terminal ends of the largest and longest medullated motor nerve fibers, including those from the annulospiral endings of the muscle spindles (Cavanagh and Patangia). The long fiber tracts of the spinal cord show a similar dying-back phenomenon. Abnormal membrane-bound vesicles and tubules were observed by Prineas to accumulate in axoplasm before degeneration. These effects have been traced to the inhibitory action of TOCP on esterases. There is still uncertainty as to the details of these reactions, and no treatment for the prevention or control of the neurotoxic effects has been devised.


Neurology_Adams

Neurology_Adams. In the late nineteenth century, thallium was used medicinally in the treatment of venereal disease, ringworm, and tuberculosis, and later in rodenticides and insecticides. Poisoning was fairly common. Sporadic instances of poisoning still occur, usually as a result of accidental or suicidal ingestion of thallium-containing rodenticides and rarely from overuse of thallium-containing depilatory agents. Patients who survive the effects of acute poisoning develop a rapidly progressive and painful sensory polyneuropathy, optic atrophy, and occasionally ophthalmoplegia—followed, 15 to 30 days after ingestion, by diffuse alopecia (see Chap. 43). The latter feature should always suggest the diagnosis of thallium poisoning, which can be confirmed by finding this metallic element in the urine. The main clinical features have been reviewed by Bank et al. Two of our patients with thallium poisoning had a severe sensory and mild motor polyneuropathy and alopecia, from which they were recovering


Neurology_Adams

Neurology_Adams. main clinical features have been reviewed by Bank et al. Two of our patients with thallium poisoning had a severe sensory and mild motor polyneuropathy and alopecia, from which they were recovering months later. It is not uncommon for the neuropathy to have a painful component involving acral regions. The condition can end fatally. The use of potassium chloride by mouth may hasten thallium excretion.


Neurology_Adams

Neurology_Adams. Iron, antimony, tin, aluminum, zinc, barium, bismuth, copper, silver, gold, platinum, and lithium may all produce serious degrees of intoxication. The major manifestations in each case are gastrointestinal or renal, but certain neurologic symptoms—notably headache, irritability, confusional psychosis, stupor, coma, and convulsions—may be observed in any of these if the poisoning is severe, often as a terminal event. Gold preparations, which are still used occasionally in the treatment of arthritis, may, after several months of treatment, give rise to focal or generalized myokymia and a rapidly progressive, symmetrical polyneuropathy (Katrak et al). The adverse effects of platinum are discussed later, with the antineoplastic agents. Lithium was discussed earlier.


Neurology_Adams

Neurology_Adams. Mentioned here is a novel but quite rare cobalt-chromium metallosis due to the leaching of metals from prosthetic hips into surrounding tissues. A painful sensorimotor polyneuropathy has been reported, in some patients accompanied by hearing loss. Although only a few cases have been documented, the process has attracted considerable attention and our only encounter with it has been the ill-advised revision of hip implants for nondescript sensory symptoms, similar to the peculiar obsession with removing dental fillings for erroneously diagnosed mercury poisoning.


Neurology_Adams

Neurology_Adams. Attention already has been drawn to the possible causative role of aluminum intoxication in so-called dialysis dementia or encephalopathy (see Chap. 39). Removal of aluminum from the water used in renal dialysis has practically eliminated this disorder. It should be noted that the neuropathologic changes in experimental aluminum intoxication (see later) are not those observed in dialysis dementia. Perl and colleagues have reported the accumulation of aluminum in tangle-bearing neurons of patients with Alzheimer disease and in the Guamanian Parkinson–dementia–ALS complex. However, analysis of neuritic plaques by nuclear microscopy, without using chemical stains, failed to demonstrate the presence of aluminum (Landsberg et al). The significance of these findings remains to be determined. Longstreth and colleagues described a progressive neurologic disorder consisting of intention tremor, incoordination, and spastic paraparesis in 3 patients who had worked for more than 12 years in the


Neurology_Adams

Neurology_Adams. and colleagues described a progressive neurologic disorder consisting of intention tremor, incoordination, and spastic paraparesis in 3 patients who had worked for more than 12 years in the same pot room of an aluminum smelting plant. Similar cases clearly attributable to aluminum intoxication have not been reported, however.


Neurology_Adams

Neurology_Adams. Organic compounds of tin may seriously damage the nervous system. Diffuse edema of the white matter of the brain and spinal cord has been produced experimentally with triethyltin. Presumably, this was the basis of the mass poisoning produced by a triethyltin-contaminated drug called Stalinon. The illness was characterized by greatly elevated intracranial pressure and by a spinal cord lesion in some cases (Alajouanine et al). Trimethyltin intoxication is much rarer; seizures are the main manifestation. Experimental studies in rats have shown neuronal loss in the hippocampus, largely sparing the Sommer sector, with later involvement of neurons in the pyriform cortex and amygdala (see review by LeQuesne).


Neurology_Adams

Neurology_Adams. A stereotyped episodic encephalopathy has been associated with bismuth intoxication, usually arising from the ingestion of bismuth subgallate. Large outbreaks have been reported in Australia and France (Burns et al; Buge et al). The onset of the neurologic disturbance is usually subacute, with a mild and fluctuating confusion, somnolence, difficulty in concentration, tremulousness, and sometimes hallucinations and delusions. With continued ingestion of bismuth, there occurs a rapid (24 to 48 h) worsening of the confusion and tremulousness, along with diffuse myoclonic jerks, seizures, ataxia, and inability to stand or walk. These symptoms regress over a few days to weeks when the bismuth is withdrawn, but some patients have died of acute intoxication. High concentrations of bismuth were found in the cerebral and cerebellar cortices and in the nuclear masses throughout the brain. These concentrations can be recognized as hyperdensities on a CT scan (Buge et al).


Neurology_Adams

Neurology_Adams. Some of these, the heavy metals, already have been considered. In addition, a large number of synthetic organic compounds are widely used in industry and are frequent sources of toxicity, and the list is constantly being expanded. The reader is referred to the references at the end of the chapter, particularly to the text edited by Spencer and Schaumburg, for details concerning these compounds. Here we can do little more than enumerate the most important ones: chlorinated diphenyls (e.g., dichlorodiphenyltrichloroethane [DDT]) or chlorinated polycyclic compounds (Kepone), used as insecticides; diethylene dioxide (Dioxane); carbon disulfide; the halogenated hydrocarbons (methyl chloride, tetrachloroethane, carbon tetrachloride, trichloroethylene, and methyl bromide); naphthalene (used in moth repellants); benzine (gasoline); benzene and its derivatives (toluene, xylene, nitrobenzene, phenol, and amyl acetate [banana oil]); and the hexacarbon solvents (n-hexane and methyl-n-butyl


Neurology_Adams

Neurology_Adams. in moth repellants); benzine (gasoline); benzene and its derivatives (toluene, xylene, nitrobenzene, phenol, and amyl acetate [banana oil]); and the hexacarbon solvents (n-hexane and methyl-n-butyl ketone).


Neurology_Adams

Neurology_Adams. With a few exceptions, the acute toxic effects of these substances are much the same from one compound to another. In general, the primary effect is on nonneurologic structures. Neural symptoms consist of varying combinations of headache, restlessness, drowsiness, confusion, delirium, coma, and convulsions, which, as a rule, occur late in the illness or preterminally. Some of these industrial toxins (carbon disulfide, carbon tetrachloride and tetrachloroethane, acrylamide, n-hexane, and diethylene glycol [Sterno; see Rollins et al]) may cause polyneuropathy, which becomes evident with recovery from acute toxicity.


Neurology_Adams

Neurology_Adams. Extrapyramidal symptoms may result from chronic exposure to carbon disulfide. A syndrome of persistent fatigue, lack of stamina, inability to concentrate, poor memory, and irritability has also been attributed to chronic exposure to solvents, but these symptoms are quite nonspecific, and evidence for such a syndrome is unsupported by convincing experimental or epidemiologic studies.


Neurology_Adams

Neurology_Adams. Of the aforementioned industrial toxins, the ones most likely to cause neurologic disease are toluene (methyl benzene) and the hexacarbons (see editorial on this subject in references). The chronic inhalation of fumes containing toluene (usually in glue, contact cement, or certain brands of spray paint) may lead to severe and irreversible tremor and cerebellar ataxia, affecting movements of the eyes (opsoclonus, ocular dysmetria) and limbs, as well as stance and gait. Cognitive impairment is usually associated; corticospinal tract signs, progressive optic neuropathy, sensorineural hearing loss, and hyposmia occur in some patients. Generalized cerebral atrophy and particularly cerebellar atrophy are evident on imaging studies (Fornazzari et al; Hormes et al). Also, it has become apparent that acute toluene intoxication is an important cause of seizures, hallucinations, and coma in children (King et al).


Neurology_Adams

Neurology_Adams. The prolonged exposure to high concentrations of n-hexane or methyl-n-butyl ketone may cause a sensorimotor neuropathy, so-called glue-sniffer’s neuropathy (see Chap. 43). These solvents are metabolized to 2,5- hexanedione, which is the agent that damages the peripheral nerves. The neuropathy may result from exposure in certain industrial settings (mainly the manufacture of vinyl products) or, more often, from the deliberate inhalation of vapors from solvents, lacquers, glue, or glue thinners containing n-hexane (see also Chap. 43). Impure trichloroethylene, through its breakdown product dichloroacetylene, has a predilection for the trigeminal nerve, which can be damaged selectively.


Neurology_Adams

Neurology_Adams. Hydrogen peroxide poisoning, usually by accidental ingestion, causes multiple small cerebral infarcts through a mechanism of gas embolus (Ijichi et al). Most cases have been reversible. According to Humberson and colleagues (cited by Ijichi et al) 120 mL of 35 percent hydrogen peroxide releases 14 L of oxygen on contact with organic tissue. The lung is involved, and the unmistakable brain lesions consist of tiny gas bubbles concentrated in parasagittal watershed areas.


Neurology_Adams

Neurology_Adams. The increasing use of potent antineoplastic agents has given rise to a diverse group of neurologic complications, the most important of which are summarized here. A more detailed account of these agents—as well as the neurologic complications of corticosteroid therapy, immunosuppression, and radiation—can be found in the monograph edited by Rottenberg and in the review of Tuxen and Hansen and in appropriate chapters of the book. The neurotoxic effects of certain agents used in the treatment of brain tumors are specifically considered in Chap. 30.


Neurology_Adams

Neurology_Adams. This drug is used in the treatment of acute lymphoblastic leukemia, lymphomas, and some solid tumors. Its most important toxic side effect, and the one that limits its use as a chemotherapeutic agent, is a peripheral neuropathy. Paresthesias of the feet, hands, or both may occur within a few weeks of the beginning of treatment; with continued use of the drug, a progressive symmetrical neuropathy evolves (mainly sensory with reflex loss). Cranial nerves are affected less frequently, but ptosis and lateral rectus, facial, and vocal cord palsies have been observed. Autonomic nervous system function may also be affected: constipation and impotence are frequent complications; orthostatic hypotension, atonicity of the bladder, and adynamic ileus are less frequent. The polyneuropathy caused by vincristine is described more fully in Chap. 43. Inappropriate antidiuretic hormone secretion and seizures have been reported but are uncommon.


Neurology_Adams

Neurology_Adams. Although rarely noted in the literature, the authors have seen an instance of reversible posterior leukoencephalopathy with cortical blindness and headache after a single dose of vincristine, identical to the syndrome reported with the use of calcineurin inhibitors (see further on). The neural complications of vinblastine are similar to those of vincristine but are usually avoided because bone marrow suppression limits the dose of the drug that can safely be employed. Vinorelbine is a more recently introduced semisynthetic vinca alkaloid. It has much the same antitumor activity as vincristine but is supposedly less toxic. Cisplatin, a heavy metal that inhibits DNA synthesis, is effective in the treatment of gonadal and head and neck tumors, as well as carcinoma of the bladder, prostate, and breast. The dose-limiting factors in its use are nephrotoxicity and vomiting and a peripheral neuropathy (see


Neurology_Adams

Neurology_Adams. Chap. 43). The latter manifests itself by numbness and tingling in fingers and toes, sometimes painful—symptoms that are being observed with increasing frequency. This toxic manifestation appears to be related to the total amount of drug administered, and it usually improves slowly after it has been discontinued. Biopsies of peripheral nerve have shown a primary axonal degeneration. Approximately one-third of patients receiving this drug also experience tinnitus or high-frequency hearing loss or both. Ototoxicity is also dose related, cumulative, and only occasionally reversible. Retrobulbar neuritis occurs rarely. Seizures associated with drug-induced hyponatremia and hypomagnesemia have been reported.


Neurology_Adams

Neurology_Adams. Taxol (paclitaxel) and Taxotere (docetaxel) are anticancer drugs derived from the bark of the western yew. Both are particularly useful in the treatment of ovarian and breast cancer, but they have a wide range of antineoplastic activities. A purely or predominantly sensory neuropathy is a common complication. These drugs are thought to cause neuropathy by their action as inhibitors of the depolymerization of tubulin, thereby promoting excessive microtubule assembly within the axon. The neuropathy is dose-dependent, occurring with doses greater than 200 mg/m2 of paclitaxel and at a wide range of dose levels for docetaxel (generally greater than 600 mg/m2). Symptoms may begin 1 to 3 days following the first dose and affect the feet and hands simultaneously. Autonomic neuropathy (orthostatic hypotension) may occur as well. The neuropathy is axonal in type, with secondary demyelination, and is at least partially reversible after discontinuation of the drug.


Neurology_Adams

Neurology_Adams. This drug, originally synthesized as a MAO inhibitor, is now an important oral agent in the treatment of Hodgkin disease and other tumors. It has also proved to be especially effective in the treatment of oligodendrogliomas. Neural complications are infrequent and usually take the form of somnolence, confusion, agitation, and depression. Diffuse aching pain in proximal muscles of the limbs and mild symptoms and signs of polyneuropathy occur in 10 to 15 percent of patients treated with relatively high doses. A reversible ataxia has also been described. Procarbazine, taken in conjunction with phenothiazines, barbiturates, narcotics, or alcohol, may produce serious degrees of oversedation. Other toxic reactions, such as orthostatic hypotension, are related to its inhibition of MAO.


Neurology_Adams

Neurology_Adams. This enzymatic inhibitor of protein synthesis is used in the treatment of acute lymphoblastic leukemia. Drowsiness, confusion, delirium, stupor, coma, and diffuse EEG slowing are the common neurologic effects and are dose related and cumulative. They may occur within a day of onset of treatment and clear quickly when the drug is withdrawn, or they may be delayed in onset, in which case they persist for several weeks. These abnormalities are at least in part attributable to the systemic metabolic derangements induced by l-asparaginase, including liver dysfunction. In recent years, increasing attention has been drawn to cerebrovascular complications of l-asparaginase therapy, including ischemic and hemorrhagic infarction and cerebral venous and dural sinus thrombosis. Fineberg and Swenson analyzed the clinical features of 38 such cases. These cerebrovascular complications are attributable to transient deficiencies in plasma proteins that are important in coagulation and fibrinolysis.


Neurology_Adams

Neurology_Adams. This is a pyrimidine analogue, used mainly as a secondary treatment of cancer of the breast, ovary, and gastrointestinal tract. A small proportion of patients receiving this drug develop dizziness, cerebellar ataxia of the trunk and the extremities, dysarthria, and nystagmus—symptoms that are much the same as those produced by cytarabine (ara-C; see below). These abnormalities must be distinguished from metastatic involvement of the cerebellum and paraneoplastic cerebellar degeneration. The drug effects are usually mild and subside within 1 to 6 weeks after discontinuation of therapy. The basis of this cerebellar syndrome is unknown. Methotrexate (See Also Chap. 30)


Neurology_Adams

Neurology_Adams. Methotrexate (See Also Chap. 30) Administered in conventional oral or intravenous doses, methotrexate (MTX) is not usually neurotoxic. However, given intrathecally to treat meningeal leukemia or carcinomatosis, MTX commonly causes aseptic meningitis, with headache, nausea and vomiting, stiff neck, fever, and cells in the spinal fluid. Very rarely, probably as an idiosyncratic response to the drug, intrathecal administration results in an acute paraplegia that may be permanent. The pathology of this condition has not been studied.


Neurology_Adams

Neurology_Adams. The most serious and more common of the neurologic problems associated with systemic MTX chemotherapy is leukoencephalopathy or leukomyelopathy, especially when it is given in combination with cranial or neuraxis radiation therapy. This develops several months after repeated intrathecal or high systemic doses of the drug, and a few milder cases are known to have occurred without radiation treatments, that is, with oral or intravenous MTX alone, such as the case reported by Worthley and McNeil. We have seen one such instance in a woman receiving oral MTX for a systemic vasculitis; no alternative explanation for widespread white matter changes and mild dementia could be discerned. Nonetheless, this must be quite uncommon. The full-blown syndrome consists of the insidious evolution of dementia, pseudobulbar palsy, ataxia, focal cerebral cortical deficits, or paraplegia. Milder cases show only radiographic evidence of a change in signal intensity in the posterior cerebral white matter


Neurology_Adams

Neurology_Adams. pseudobulbar palsy, ataxia, focal cerebral cortical deficits, or paraplegia. Milder cases show only radiographic evidence of a change in signal intensity in the posterior cerebral white matter (“posterior leukoencephalopathy”) that is similar to the imaging findings that follow cyclosporine use (see further on) and hypertensive encephalopathy (Fig. 41-2). In severe cases, the brain shows disseminated foci of coagulation necrosis of white matter, usually periventricular, which can be detected with CT and MRI.


Neurology_Adams

Neurology_Adams. Mineralizing microangiopathy (fibrosis and calcification of small vessels, mainly in the basal ganglia) is yet another complication of MTX therapy. It may occur with MTX treatment or with cranial irradiation but is particularly common when both forms of treatment are combined. The present authors have the impression that the severe necrotic lesions possess features comparable to (and therefore may be the result of) the coagulative necrosis of radiation encephalopathy. The Nitrosoureas


Neurology_Adams

Neurology_Adams. The Nitrosoureas Carmustine (BCNU) and lomustine (CCNU) are nitrosoureas used to treat malignant cerebral gliomas. They are not neurotoxic when given in conventional intravenous doses, but intracarotid injection of the drugs may cause orbital, eye, and neck pain, focal seizures, confusion, and possibly focal neurologic deficits. Postmortem examinations of patients who had been treated with intravascular BCNU have disclosed a diffuse vasculopathy characterized by fibrinoid necrosis and microthrombi and diffuse foci of swollen axis cylinders and myelin vacuolization (Burger et al; Kleinschmidt-de Masters).


Neurology_Adams

Neurology_Adams. This drug, long used in the treatment of acute nonlymphocytic leukemia, is not neurotoxic when given in the usual systemic daily doses of 100 to 200 mg/m2. The administration of very high doses (up to 30 times the usual dose) induces remissions in patients’ refractory to conventional treatments. It also may produce, however, a severe degree of cerebellar degeneration in a considerable proportion of cases (4 of 24 reported by Winkelman and Hines). Ataxia of gait and limbs, dysarthria, and nystagmus develop as early as 5 to 7 days after the beginning of high-dose treatment and worsen rapidly. Postmortem examination has disclosed a diffuse degeneration of Purkinje cells, most marked in the depths of the folia, as well as a patchy degeneration of other elements of the cerebellar cortex. Other patients receiving high-dose ara-C have developed a mild, reversible cerebellar syndrome with the same clinical features. Because patients older than 50 years of age are said to be far more likely to


Neurology_Adams

Neurology_Adams. patients receiving high-dose ara-C have developed a mild, reversible cerebellar syndrome with the same clinical features. Because patients older than 50 years of age are said to be far more likely to develop cerebellar degeneration than those younger than 50 years of age, the former should be treated with a lower dosage (Herzig et al).


Neurology_Adams

Neurology_Adams. Calcineurin Inhibitors (Cyclosporine, Tacrolimus, Sirolimus) These immunosuppressive drugs are used to prevent transplant rejection and to treat aplastic anemia and certain intrinsic immune diseases. Tremor is perhaps the most frequent side effect and myoclonus may be added. Sometimes these impart a stuttering character to speech. Headache and insomnia are common. Seizures may be a manifestation of toxicity, but the cause may lie with the other complications of organ transplantation and immunosuppression. Wijdicks has reviewed the neurologic effects of these drugs.


Neurology_Adams

Neurology_Adams. A posterior leukoencephalopathy syndrome (PRES, see Chap. 33) resembling hypertensive encephalopathy—headache, vomiting, confusion, seizures, and visual loss (cortical blindness)—may follow the use of either drug and with an expanding list of other agents including some of the new monoclonal antibodies used in the treatment of cancer and autoimmune diseases (Table 41-1). There does not seem to be a consistent dose-response effect, drug levels often being in the therapeutic range.


Neurology_Adams

Neurology_Adams. The appearance on CT and MRI of nearly symmetrical changes mainly in the posterior white matter conform to the pattern that is seen in hypertensive encephalopathy (reversible posterior leukoencephalopathy [RPLE] or PRES). Lesions may also appear subcortically in the frontal and parietal lobes as well as in deep structures and the brainstem. Interferon treatment for malignant melanoma and a number of other chemotherapeutic agents have been associated with the same condition. Hinchey and colleagues have described several such cases and suggested that cyclosporine alters the blood–brain barrier and that the fluid overload and hypertension which accompanies the use of cyclosporine underlies the radiologic changes. A variety of psychotic syndromes with delusions, paranoia, and visual hallucinations also have been ascribed to the use of these drugs (see Wijdicks).


Neurology_Adams

Neurology_Adams. Despite the catastrophic effects of thalidomide on the developing fetus (following its introduction as a soporific in 1957), this drug has now found several specific uses in the treatment of immunologic, neoplastic, and infectious diseases. It is effective in the treatment of leprosy, erythema nodosum, and the oral ulcerations of AIDS and Behçet disease. Experimental uses include suppression of graft-versus-host reactions and inhibition of blood vessel proliferation in vascular tumors such as renal cell cancer. A dose-dependent sensory neuropathy is the limiting factor in its use, and serial electrophysiologic testing is recommended if the medication is to be prescribed for protracted periods. Of course, it must not be given to a woman who is or might be pregnant.


Neurology_Adams

Neurology_Adams. A relatively new strategy for treating certain cancers involves increasing the activity of host antitumor immunity through inhibition of intrinsic down-regulators of T-cell immunity. Several drugs have been approved for the treatment of melanoma, non-small-cell lung cancer, and other malignancies; these include pembrolizumab, ipilimumab, nivolumab, and others. These drugs are monoclonal antibodies that target immune down-regulators such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). As reviewed by Postow and colleagues, the inhibition of intrinsic immune downregulation results in an increase in immune activity that is accompanied by inflammation. This inflammation can adversely affect any organ; from a neurological perspective, the main problems encountered are encephalitis, aseptic meningitis, hypophysitis, uveitis, and a Guillain-Barré type of generalized neuropathy. We have encountered cases of the last of these with widely varying severity but


Neurology_Adams

Neurology_Adams. are encephalitis, aseptic meningitis, hypophysitis, uveitis, and a Guillain-Barré type of generalized neuropathy. We have encountered cases of the last of these with widely varying severity but most have slowly, if incompletely, improved. These problems typically occur a few weeks to months after therapy is initiated. The susceptibility to these complications is variable and it is unclear whether the presence of complications correlates with improved treatment efficacy. The excessive inflammation can be treated with glucocorticoids or, if needed, additional immunosuppressive agents.


Neurology_Adams

Neurology_Adams. Another strategy for treating certain malignancies, mostly hematologic, involves the use of host T-cells that have been genetically engineered to express an antigen receptor that binds specifically to tumor cells. This binding facilitates cytotoxic destruction of tumor cells by the modified T-cells, and several trials have demonstrated not only a favorable response rate in patients with otherwise refractory malignancies but also occasional durable remissions. The most common toxicity associated with CAR-T-cell therapy is a cytokine-release syndrome that can manifest on a spectrum from mild constitutional symptoms to severe multi-organ dysfunction including, rarely, hemophagocytic lymphohistiocytosis. An encephalopathy termed CAR-T-cell-related encephalopathy syndrome (CRES) is the second most common toxicity and is associated with a confusional state and seizures that result from cerebral edema and elevated intracranial pressure. The disorder most often occurs about 5 days after


Neurology_Adams

Neurology_Adams. most common toxicity and is associated with a confusional state and seizures that result from cerebral edema and elevated intracranial pressure. The disorder most often occurs about 5 days after initiation of therapy, coincident with other cytokine-release symptoms, but may occur later as well. Efforts aimed at identifying and grading the symptoms have been established, as reviewed by Neelapu and colleagues. Current recommendations include obtaining a baseline brain MRI and initiating seizure prophylaxis before initiation of CAR-T-cell therapy, and frequent neurological assessments thereafter. Symptoms of cytokine-release syndrome and CRES can be managed with glucocorticoids, though at the expense of suppressing T-cell function. Interestingly, a high serum level of interleukin-6 (IL-6), one of the many cytokines released by activated T-cells, has been associated with more severe neurotoxicity. Antibody drugs that bind to and inhibit the IL-6 receptor, such as tocilizumab, have been


Neurology_Adams

Neurology_Adams. one of the many cytokines released by activated T-cells, has been associated with more severe neurotoxicity. Antibody drugs that bind to and inhibit the IL-6 receptor, such as tocilizumab, have been shown to reduce CRES, particularly in the early period following initiation of CAR-T-cell therapy.


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Neurology_Adams. Numerous antibiotics, cardioactive medications, and other drugs may have adverse effects on the central or peripheral nervous system. Some of the latter are addressed in Chap. 43. Here we mention mainly that penicillin and its derivatives such as imipenem, and to a lesser degree, the cephalosporins, are capable of causing seizures when high serum concentrations are attained. Cefepime, for example, has often been presumptively implicated in otherwise unexplained encephalopathies in patients we see as consultants on the wards and ICU. This complication is favored in most instances by concomitant renal failure.


Neurology_Adams

Neurology_Adams. Other important examples of antibiotic toxicity are optic neuropathy caused by ethambutol toxicity; ototoxicity and neuromuscular blockade from aminoglycoside and fluoroquinolone antibiotics; peripheral neuropathy, encephalopathy, and an Antabuse-like reaction to alcohol in patients taking metronidazole; a metronidazole-induced polyneuropathy, isoniazid (INH) neuropathy and optic neuropathy, and possibly a peripheral neuropathy caused by chloramphenicol. Woodruff and colleagues, as well as others, reported a curious and reversible cerebellar syndrome caused by metronidazole with MRI signal changes in the dentate nuclei, or more widespread signal changes in other parts of the brainstem and cerebral white matter as noted by Kim and coworkers, who carried out a MRI study of 7 patients. Dysarthria, confusion, and gait ataxia seem to form the core of the clinical syndrome but imaging changes may be found coincidentally as well.


Neurology_Adams

Neurology_Adams. The most notorious toxic consequences with this group of drugs were seen with clioquinol, which was sold as Entero-Vioform and was used in many parts of the world to prevent traveler’s diarrhea and as a treatment for chronic gastroenteritis. In 1971, clinical observations began to appear in medical journals of a subacute myelo-opticoneuropathy (SMON). During the 1960s, more than 10,000 cases of this disease were collected in Japan by Tsubaki and colleagues. Usually the illness began with ascending numbness and weakness of the legs, paralysis of sphincters, and autonomic disorder. Later, vision was affected. The onset was acute in about two-thirds of the cases and subacute in the remainder. The occurrence of these neurologic complications was found to be related to the prolonged use of clioquinol. In Japan, the drug was withdrawn from the market, and the incidence of SMON immediately fell, supporting the theory that it was caused by the drug. Recovery was usually incomplete.


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