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R. Raid, M.A., M.D., Ph.D.

Clinical Director, University of Colorado School of Medicine

However, the investigators stressed that H2S appears to be a weaker toxicant to the respiratory epithelium than other pneumotoxicants. The authors stated that the olfactory epithelium appears to be more sensitive to the toxic effects of H2S than the respiratory epithelium. Histologic and ultrastructural alterations in the lungs of rats were reported in a similar study in which male Fischer 344 rats were exposed for 4 hours to either 82 or 440 ppm (116 or 613 mg/m3; n = 12 rats per dose level) H2S followed by sacrifice at 1, 18, or 42 hours postexposure (Lopez et al. Histologic changes were transient and mainly present in rats exposed to 440 ppm (613 mg/m3) H2S. While some histologic changes were noted at 82 ppm (116 mg/m3), no pathologic changes were reported at this exposure level. In rats exposed to 440 ppm (613 mg/m3) H2S, bronchiolar ciliated cells developed necrosis, but necrotic damage was rapidly repaired through mitosis. Examination of the lung demonstrated the notable edematogenic effect following exposure to 440 ppm (613 mg/m3) H2S. Based on findings from the postexposure groups, the investigators suggested a chronology to the edematogenic effect in which fluid first accumulates around the blood vessels, then the interstitium, and finally in the alveoli. Perivascular edema without involvement of the alveoli in animals exposed to 82 ppm (116 mg/m3) H2S suggested that fluid that accumulated in the interstitium was reabsorbed before it entered the bronchoalveolar spaces. The investigators also found a lack of structural changes in the -3333 alveolar endothelium, basement membrane, or type I pneumocytes, suggesting that H2S exposure to concentrations as high as 440 ppm (613 mg/m3) does not compromise the air-blood barrier. If damage to the air-blood barrier and mast cell degranulation is not responsible for the observed pulmonary edema following H2S exposure, then the investigators suggested that the edema may be due to an outflow of liquid from the peribronchovascular connective tissue into the lumen of small airways via high conductance pathways that fill the alveolar spaces in a retrograde manner. Male Fischer 344 rats were exposed to 0, 14, 280, or 560 mg/m3 (0, 10, 200, or 400 ppm) H2S for 4 hours. No animals died, but clinical signs of lethargy and epiphora were present in animals exposed to 560 mg/m3 H2S. Nasal lesions were present only in the high-dose group and manifested as necrosis and exfoliation of the respiratory and olfactory epithelium. Of the four different sections of the nasal cavity, sections two and three (mid-nasal cavity) were the most severely affected. The rostral section (section 1) was not affected, and section 4 was only slightly affected. At 44 hours postexposure, the respiratory mucosa was essentially repaired, but the olfactory mucosa continued to exfoliate. Marked abnormalities in surfactant activity were demonstrated in the lavagates from rats exposed to the highest concentration only 300 ppm (417 mg/m3) and not in the lavagate from the lower dose 200 ppm (278 mg/m3) or the controls. The lungs of high-dose animals showed areas of red atelectasis, patchy alveolar edema, and perivascular edema. These results are suggestive of a threshold for this surfactant response and subsequent histopathological progression. Rogers and Ferin (1981) exposed male Long-Evans rats to 45 ppm (636 mg/m3) H2S for 2, 4, or 6 hr followed by bacterial challenge to Staphylococcus epidermidis. In control animals, most of the bacteria was inactivated by the 6-hour postchallenge sacrifice time. The investigators suggest that an H2S-induced absence of bacterial inactivation may explain secondary pneumonias in humans subsequent to acute or subacute H2S exposure. The effect of bacterial -3434 inactivation was hypothesized by the investigators to be due to alveolar macrophage inactivation. The hypothesis is supported by Robinson (1982) who demonstrated that rabbit alveolar macrophages lost the phagocytic ability in vitro when exposed to 54 ppm (75 mg/m3) H2S for 24 hours. The nose was histologically examined 24 hours after exposure, and lesion recovery was assessed at 2 and 6 weeks following the 5-day exposure. The single 3-hour exposure to $ 80 ppm H2S resulted in regeneration of the respiratory mucosa and full thickness necrosis of the olfactory mucosa localized to the ventral and dorsal meatus, respectively. Repeated exposure to the same concentrations caused necrosis of the olfactory mucosa with early mucosal regeneration that extended from the dorsal medial meatus to the caudal regions of the ethmoid recess. Acute exposure to 400 ppm H2S induced severe mitochondrial swelling in sustentacular cells and olfactory neurons, which progressed to olfactory epithelial necrosis and sloughing.

Given the complexity of the exposure environment - in terms of the numbers of chemicals monitored, the few numbers of individuals studied and the very limited exposure measurements it is premature to attribute the deficits cited with H2S exposure. Neurobehavioral effects of H2S were studied in 16 individuals (male and female, ages 21 to 68 years) 2 to 22 years after exposure (Kilburn, 1997). Five individuals had been unconscious after exposure and four had downwind exposures. Five of the 16 individuals were categorized in the "chronic" exposure group, exposed for 11-22 years. Five were in the "acute" exposure category having been exposed for minutes and the remaining six were in the "hours" category. Results from a battery of tests were compared to those from 353 national referents, matched by age, sex, and years of education. Neurophysiologic and neuropsychologic tests, the latter adjusted for educational level, were employed. Brief high doses were "devastating," whereas protracted low doses of individuals in the chronic category showed effects (p<0. There was no indication of bias from the lawsuit and it was considered unlikely that the symptoms could be attributed to other causes. Kilburn (1997) concluded that moderate occupational exposure and downwind environmental exposure can cause permanent impairment. Neurobehavioral deficits attributed to low-level environmental exposure of 103 individuals to H2S were reported by Kilburn (1999). One group of 24 homeowners was exposed to H2S that had collected in crawlspaces and under concrete foundations. They exhibited abnormal balance, color discrimination, grip strength and delayed verbal recall. It was not stated if the exposure was ongoing at the time of the neurobehavioral assessment. In another group, 48 adults were exposed to measured peak levels ranging from 1 to 20 ppm at street level during a refinery explosion and fire in 1992. A third group consisted of 16 patients with a wide range of exposure who were assessed after latent periods of 1. A fourth group consisted of 13 workers and 22 residents living at or near stack gas emissions from a refinery and desulfurization plant. Referents (357) were selected from four towns (in four states) free of known chemical contamination. Analysis of variance and covariance adjusted for differences in age, education, gender, and height. Kilburn (1997) concluded that peak dose rather than duration of exposure is predictive of effects, and those exposed to nonlethal levels do not recover completely from H2S. Given the small number (24) of homeowners in the first group exposed to low levels and the type of deficits observed, it is premature to ascribe cause and effect to H2S. Of the clinical findings, neurologic, respiratory and opthalmologic ailments predominated. While some of these deficits can occur when the exposed individual remains conscious, it is less clearly established if intermittent or continuous exposure to "low levels" of H2S cause similar persistent symptoms. The fodder had been dried by sulfur-containing brown coal or other fuels containing H2S. The fodder was analyzed for H2S content by acidification with hydrochloric acid and iodometric determination prior to animal administration. In chickens (50 per group), no adverse effects were observed in feed intake, body weight, or survival in animals fed H2S-treated alfalfa (2-12% of total feed) and H2S-treated wheat bran (1-12% of total feed) daily for up to 70 days. Adult pigs (numbers not given) were fed diets containing 100, 200, or 400 grams of H2S-treated dried alfalfa (4, 8, and 24% of the diet, respectively) daily for 105 days. Pigs fed 200 or 400 grams of H2S-treated dried alfalfa had decreased weight gains of 4 and 22%, respectively, compared with the control group. Food intake decreased -1818 by 33% in animals fed 400 grams of H2S-treated dried feed per day. Diarrhea was reported in adult animals that consumed diets containing no treated dried feed that was suddenly changed to diets containing 24% treated dried feed.

These chronic forms of inflammatory neuropathy are described in a later section of this chapter. This type of neuropathy causes difficulty in weaning a patient from the ventilator, even as the underlying critical illness comes under control. The neuropathic process, predominantly of motor type, varies in severity from an electrophysiologic abnormality without obvious clinical signs to a pronounced quadriparesis with respiratory failure. Usually the cranial nerves are spared and there are no overt dysautonomic manifestations. Autopsy material has usually disclosed no inflammatory changes in the peripheral nerves. The toxic effects of drugs and antibiotics and nutritional deficiency must be considered in causation, but rarely can they be established. Perhaps some of the many systemic mediators of sepsis are toxic to the peripheral nervous system; tumor necrosis factor has been proposed as one such endogeneous toxin. This form of polyneuropathy must also be distinguished from a poorly understood acute quadriplegic myopathy that sometimes complicates critical illness (page 1237). High doses of corticosteroids, particularly in combination with neuromuscular blocking agents, have been implicated. Acute Sensory Neuronopathy (Sensory Ganglionopathy) Attention was drawn to this entity by Sterman and colleagues in a report of three adult patients with rapidly evolving sensory ataxia, areflexia, numbness, and pain, beginning in the face and spreading to involve the entire body. In each instance, the symptoms began within 4 to 12 days following the institution of penicillin therapy for a febrile illness (antibiotics were subsequently shown not to be the cause). Proprioception was profoundly reduced, but there was no weakness or muscle atrophy, despite generalized areflexia. The sensory deficit attained its maximum severity within a week, after which it stabilized and improved very little. Electrophysiologic studies showed absent or slowed sensory conduction but there were no abnormalities of motor nerve conduction or signs of denervation. Follow-up observations (for up to 5 years) disclosed no neoplastic or immunologic disorder, the usual causes of such a sensory neuronopathy. Lacking pathology, it was assumed, from the permanence of the condition, that sensory neurons were destroyed (sensory neuronopathy). A subsequent series of 42 patients reported by Windebank and colleagues emphasized an asymmetrical and brachial pattern of symptoms in some patients and an initial affection of the face in others. At present, this clinical pattern should be viewed as a syndrome rather than as a disease. Certain drugs and other agents, especially cisplatin and excessive intake of pyridoxine, are also causes of a sensory neuronopathy. In the latter, there is usually some degree of proximal weakness, and the sensory changes do not normally extend to the face and trunk. Acute Uremic Polyneuropathy In addition to the well-known chronic sensory neuropathy associated with chronic renal failure that is discussed later in the chapter, there is a more rapid ("accelerated") process that has not been widely appreciated as a cause of acute and subacute weakness. Most patients in our series were diabetics with stable end-stage renal failure who had been treated by peritoneal dialysis for their long-standing kidney disease (Ropper, 1993). In contrast to the better characterized and less severe chronic uremic neuropathy (page 1149), generalized weakness and distal paresthesias progress in over one or more weeks until a bedbound state is reached. More aggressive dialysis or a change to hemodialysis has little immediate effect, although kidney transplantation is curative. Electrophysiologic studies show some demyelinating features but usually not a conduction block. A few reported cases have been clinically almost indistinguishable from inflammatory demyelinating polyneuropathy, including, in some, a response to plasma exchange or gamma globulin. As with the more Diphtheritic Polyneuropathy (See page 1031) Some of the neurotoxic effects of Corynebacterium diphtheriae and the mode of action of the exotoxin elaborated by the bacillus are described in Chap. Local action of the exotoxin may paralyze pharyngeal and laryngeal muscles (dysphagia, nasal voice) within 1 or 2 weeks after the onset of the infection and shortly thereafter may cause blurring of vision due to paralysis of accommodation, but these and other cranial nerve symptoms may be overlooked. The weakness characteristically involves all extremities at the same time or may descend from arms to legs. After a few days to a week or more, the patient may be unable to stand or walk and occasionally the paralysis is so extensive as to impair respiration. Diphtheritic deaths that occur after the pharyngeal infection has subsided are due to cardiomyopathy or, less often, to severe polyneuropathy with respiratory paralysis. This type of polyneuropathy, now quite rare, should be suspected in the midst of an outbreak of diphtheritic infection, as occurred recently in Russia (Logina and Donaghy).

When cavernous sinus meningiomas compress the venous structures within that region or extend into the orbit, mild proptosis may occur (207,208,223). When angiography is performed, cavernous sinus meningiomas characteristically demonstrate abnormal vessels arising from both the internal and the external carotid arteries supplying the tumor. An enlarged meningohypophyseal trunk and an enlarged inferior cavernous sinus artery, both of which arise from the intracavernous portion of the internal carotid artery, are the abnormalities most commonly encountered. Tumor vessels originating from the external carotid artery via the middle meningeal artery, accessory meningeal artery, and artery of the foramen rotundum may also be seen, particularly when the meningioma is large. Most meningiomas produce a classic, homogeneous tumor ``blush' that may be seen during the capillary and venous phases of the angiogram (208,209). Angiography is particularly important when hyperostosis is extensive and surgical excision is planned. Total removal of the mass without damaging cranial nerves or the internal carotid is often difficult, but with microsurgical techniques, it is possible to operate within the cavernous sinus with a relative degree of safety (232). A variety of approaches are used, including subtemporal, pterional, orbito-zygomatico-malar, and transsphenoidal. Rare meningiomas, such as those attached to the outer wall of the cavernous sinus, may be completely removed. Those within the cavernous sinus can be significantly reduced in size, but there is significant risk to the oculomotor, trochlear, and abducens nerves if total removal is attempted. If the artery is encased with tumor, cerebral revascularization (with a saphenous vein graft or external carotid anastomosis) may be necessary (238,239). If neuroimaging is suggestive of encasement, a preoperative balloon occlusion test of the internal carotid artery is performed to evaluate the effect on cerebral blood flow. Cranial nerves have been successfully resutured directly or with an interposition graft. The oculomotor nerve had the most variable results because of the potential for aberrant regeneration. A good alternative to aggressive surgical resection is external beam radiation to the region of the tumor. Alternatively, with stereotactic radiosurgery, high-energy radiation may arrest the growth of some tumors (245). Many centers routinely use external beam radiation, or fractionated stereotactic radiation therapy, for cavernous sinus meningiomas either primarily or after confirmation of diagnosis and subtotal resection of tumor (188,232,246,247). Some investigators recommend that meningiomas that cannot be totally removed, such as those within the cavernous sinus, should be biopsied and the specimens assayed for the presence of estrogen and progesterone receptors. The role of a nonsteroidal anti-estrogen, such as tamoxifen citrate, is controversial (127,248,249). Other agents have also been tried, such as the antiprogesterone agent mifepristone, with mixed success (126). When the signs and symptoms are minimal, meningiomas in this location may be followed, because tumor growth is often slow (210,250). Indeed, some patients with these tumors experience spontaneous regression of symptoms and signs (210,251). The prognosis for binocular single vision in patients with meningiomas of the cavernous sinus is not particularly good, but prognosis for life is excellent, regardless of treatment (237). This should be kept in mind when considering the form of treatment to be used, particularly in older patients. Convexity Meningiomas the most frequent site of meningiomas is the cerebral convexity (178). Convexity meningiomas originate from the meninges of the cranial vault in locations other than the base of the skull, falx, or sagittal sinus. In most cases, convexity meningiomas are located in the frontal and parietal regions, rather than in the temporal or occipital regions. Seizures are a common early symptom of frontal, parietal, and temporal meningiomas. In rare instances, a seizure may be produced by hemorrhage into the meningioma (253). Additionally, frontal tumors may be associated with mental changes, tumors in the parietal region may produce contralateral motor or sensory abnormalities, and tumors in the occipital region may produce visual field defects (254).