In recent years, both the general public and health-care professionals have become increasingly aware of the potential hazards of exposure to certain chemicals. At the same time, the introduction of more chemical agents into the work and social environments has led to an increased risk of exposure to potential neurotoxins. Similarly, many pharmacologic agents have adverse effects that include neurotoxicity. The neurologic consequences of toxin exposure vary, depending on the agents to which exposure has occurred, but either the central or peripheral nervous systems, or both, may be affected. Central disturbances are manifested most commonly as neurobehavioral changes, but sometimes more specific deficits affect cognition, motor or sensory function of the limbs, cerebellar function, or the autonomic nervous system.
The published literature concerning the consequences of exposure to neurotoxic agents is extensive, but many publications fail to permit valid conclusions to be reached concerning the risks or consequences of exposure to particular chemical agents. Clinical reports are often of anecdotal material, and interpretation is confounded by the multiplicity of factors that may have led to the occurrence of symptoms or neurologic signs. Formal studies in humans to evaluate the neurotoxicity of particular agents are often confounded, in turn, by inadequacies of study design, concomitant use of alcohol or psychoactive medication, exposure to multiple chemical agents, and the nonspecific nature of many of the complaints attributed to toxic exposure. Careful matching of subjects for age, sex, and educational and cultural background is important in epidemiologic studies but is often neglected.
In this setting, electrodiagnostic studies should have an important role in helping to:
Confirm the organic basis of symptoms
Define the nature of clinical disturbances and their anatomic sites of origin
Determine the severity of any dysfunction
Monitor progression of the disorder
Recognize early neurologic involvement after known exposure to a neurotoxic agent so that further exposure can be limited.
Electrophysiologic approaches have been especially helpful in evaluating the peripheral rather than the central nervous system. Both will be considered briefly in this chapter.
Neurotoxic disorders of the central nervous system
A number of medications are neurotoxic and lead to behavioral or other neurologic disturbances when taken either in excessive amounts or at recommended doses for therapeutic purposes. Drugs taken for recreational purposes also have well-recognized neurotoxicity. Concern has increased, however, about the potential neurotoxicity of chemicals encountered in other contexts such as the work environment. Many of the symptoms that are alleged to reflect a toxin-related neurobehavioral disorder are common in the general population, and their relationship to chemical exposure is therefore hard to ascertain. In consequence, claims for the occurrence of certain cognitive or neurobehavioral disorders as a result of toxin exposure are difficult to validate scientifically. Many published clinical and epidemiologic studies provide limited information about the degree of exposure; vary in the manner in which exposed individuals are identified; or involve exposure to a variety of different chemicals, which complicates interpretation of the findings.
Some published studies involve self-reports by one or more individuals of subjective neurologic complaints without adequate control populations. The nonspecific nature of such complaints and the failure to control other variables confound interpretation of these studies. Studies in animals are sometimes helpful in confirming a relationship between clinical disorders and toxin exposure, but animal models of neurobehavioral disorders are difficult to find. Again, when the occurrence of a neurobehavioral disorder in exposed workers is compared, for example, with the incidence of this same disorder in a suitable control group, the toxic basis for the disorder may not be evident. Reports of single or small series of subjects with symptoms attributed to toxin exposure are common, but their significance is uncertain, especially when the clinical disorder develops after an interval rather than in close temporal relationship to the exposure. Indeed, it may not be possible to accept a causal relationship between toxin exposure and the later development of a neurobehavioral disorder when several years elapse between exposure and the clinical disorder. It is especially difficult to recognize such an association when symptoms are nonspecific ones that could relate to a variety of different causes, rather than unusual ones that are difficult to explain by other means. Some studies involve information derived from death certificates, but major methodologic concerns detract from such reports. For example, toxin exposure often is not indicated in the report and has to be inferred from the patient’s occupation. Exposure to certain toxins may indeed occur in relation to various occupations, but the one occupation listed on a death certificate is typically the final or usual one and therefore may be misleading.
The importance of adequate control subjects cannot be overemphasized. For example, if intellectually less capable persons are hired to work in less desirable occupational settings, it will not be surprising if behavioral testing shows differences between them and normal college students. This concern is more than theoretical. For example, Errebo-Knudsen and Olsen, in their review of the so-called painters’ syndrome, noted that approximately 28 percent of boys who later became painters were from the lowest IQ group and none was from the highest; 77 percent of those who became painters had IQs below the median of a group of 11,352 boys who were studied. Careful examination of the methodologies of the Scandinavian studies that established the existence of a painters’ encephalopathy in the 1970s reveals them to be so methodologically flawed that they are invalid.
Electrophysiologic studies have been used to evaluate patients with presumed dysfunction of the central nervous system as a result of neurotoxic exposure. In general, the findings have been of limited utility and uncertain clinical relevance.
The electroencephalogram (EEG) has been used widely to evaluate patients with neurobehavioral disturbances related to possible neurotoxic exposure. The marked variability of the EEG in normal subjects, however, has limited its utility. As indicated in Chapter 3 , the EEG generally is evaluated subjectively, and such evaluation may lead to interpretive differences between different observers. Moreover, a number of variables (e.g., age, level of arousal, and certain medications) are known to affect the EEG, and these variables render comparison between individuals difficult, especially when only nonspecific abnormalities that have a high incidence in the general (unexposed) population are encountered.
In many patients with encephalopathies related to medication (including chemotherapy), recreational drugs, or chemical exposure in other contexts, the EEG shows nonspecific slowing. In some instances, paroxysmal epileptiform activity is also found, as with mercury or lead poisoning; exposure to chlorinated hydrocarbons (as in the manufacture of DDT); organophosphate poisoning; or patients receiving aminophylline, isoniazid, lithium, high-dose penicillin therapy, or neuroleptic drugs. The EEG changes with clozapine have been particularly well described and relate to serum levels. Patients with a history of alcohol abuse may have focal epileptiform or slow-wave abnormalities, but the EEG is often normal; during acute intoxication, however, the EEG is slowed. The findings during acute alcohol-withdrawal states are varied; mild generalized slowing is often found, and photoparoxysmal responses and generalized epileptiform discharges may also be present. Stimulant drugs (e.g., amphetamines and cocaine) are associated with an increase in frequency of background rhythms. Benzodiazepines and barbiturates lead to an increase in beta activity and then, with increasing doses, to some slowing of the EEG. The effects of antiepileptic drugs are considered in Chapter 3 .
Attempts have been made to objectify EEG interpretation by using quantitative techniques, as discussed in Chapter 8 . The use of such techniques to evaluate workers with possible exposure to neurotoxic agents generally has been unrewarding. This is because most studies have involved multiple comparisons of different aspects of the EEG, and false-positive results are therefore likely to occur on the basis of chance alone. Quantitative approaches require comparison of a test group to a reference sample and also require that the same approach be used to collect and analyze EEG data. The two groups must be matched for factors such as age, sex, social class, educational and occupational backgrounds, alcohol and substance abuse, medication use, and level of arousal and cognitive function. All too often, comparisons are made to groups that are not matched in this way, so any departure from normality is of uncertain relevance. Alterations in the level of arousal may lead to marked changes in the EEG that may be attributed mistakenly to toxin exposure if the true basis of the altered EEG is not recognized. Furthermore, other artifacts must be excluded before computerized analysis of the EEG if misinterpretation is to be avoided. Any computerized EEG analysis must also be interpreted cautiously because many thousands of separate statistical results may be generated by the analysis, and chance alone therefore may result in apparent deviations from normality in a number of instances. This problem, discussed further in Chapter 8 , is pertinent when studies involving quantitative EEG are interpreted to determine the presence or nature of neurotoxic disorders. The sensitivity and specificity of EEG abnormalities are poor when the EEG is used to screen for the development of subclinical encephalopathies, and more studies are necessary to clarify the role, if any, of quantitative EEG analysis in this context. , Certainly, at the present time, it is hard to justify the use of quantitative EEG for medicolegal purposes to establish the presence of an encephalopathy that might have an occupational or toxic basis, and this accords with the position adopted by the American Academy of Neurology. The EEG findings, whether analyzed subjectively or quantitatively, are not a reliable means of distinguishing between different types of encephalopathic disorder. Even when changes have been noted by individual observers, their relevance for clinical diagnosis or screening purposes is uncertain.
These various issues have limited the utility of the EEG and continue to confound its application as a means of monitoring for neurotoxic exposure. The EEG certainly may be abnormal when acute encephalopathy is caused by neurotoxicity, but in such circumstances additional ancillary investigations are usually unnecessary to confirm the presence of an organic disorder, and the EEG findings in themselves do not reveal the underlying cause of cerebral dysfunction. In patients referred for EEG evaluation after any acute encephalopathic process has resolved, the presence of a normal EEG is not helpful in excluding the possibility of a prior encephalopathic process.
Evoked Potential Studies
Evoked potential studies have been used for a number of years to evaluate the functional status of certain afferent systems. Because they provide quantitative data, they permit objective evaluation and facilitate comparisons between subjects or comparisons of the same subject at different times. As indicated in chapter 22 , chapter 23 , chapter 24 , chapter 25 , chapter 26 , chapter 27 , a standardized protocol is used to record the response of the central nervous system following visual, auditory, or somatosensory stimuli. Depending on the sensory modality being tested, the latency, amplitude, and intercomponent latency of the response is determined and compared with values obtained in normal age- and sex-matched subjects. Alterations in the configuration or duration of a response are more difficult to quantify, and criteria for abnormality have not been agreed. Because the range of normal values is affected by numerous technical factors, a control population of normal subjects should be studied under the same conditions as individual subjects or any test populations are studied. Technical details are provided in earlier chapters. Evoked potential studies are important in determining the organic basis of complaints involving various afferent systems and in helping to indicate the likely site of the responsible pathology. In occasional instances, they may be helpful in detecting toxin-related changes at a subclinical stage so that further damage is avoided by preventing further exposure to the offending agent. For example, evoked potentials are particularly sensitive to the toxic effects of ethambutol on the visual system. In general, however, the findings are not specific to any individual disorder but provide information about the pathophysiologic basis of symptoms. Furthermore, certain evoked potentials (e.g., brainstem auditory evoked potentials) are generally resistant to changes related to metabolic or toxic disorders.
Endogenous potentials are considered in detail in Chapter 29 . They are recorded over the vertex of the scalp in response to a stimulus to which the subject directs attention to distinguish it from other, more frequently occurring stimuli. Endogenous potentials depend on the setting in which the target stimulus is delivered rather than on the physical characteristics of that stimulus. In patients with cognitive changes, endogenous potentials may be delayed in comparison with age-matched control subjects. The size of the response is of little clinical consequence because it varies between subjects and depends on the level of attention of the subject. Endogenous potentials are recorded mainly to evaluate patients with suspected cognitive deficits and, in particular, to distinguish between dementia and depression. They have been used only on limited occasions to evaluate patients with neurobehavioral disturbances related to neurotoxic exposure, and their utility in this context is uncertain.
Evaluation of Central Neurotoxic Disorders
General comment was made earlier on the EEG findings in certain toxic encephalopathies. The use of electrophysiologic techniques to evaluate the central nervous system following exposure to selected chemical agents, particularly in an industrial or occupational setting, is discussed in this section. It is not intended to provide a comprehensive account, however, but only to exemplify the utility and limitations of these approaches.
n -Hexane is an organic solvent that has been used in paints, lacquers, and glues, and in the printing and rubber industries. Exposure to it has occurred in various occupational settings and following inhalation of certain glues for recreational purposes. Oxidative metabolism of n -hexane occurs in the liver, forming 2,5-hexanedione, the purported neurotoxic component. The most conspicuous feature is a peripheral neuropathy, discussed on page 822, but evoked potential studies have also revealed central effects of exposure to it. Chang performed multimodality evoked potential studies in 22 patients with polyneuropathy, 5 with subclinical polyneuropathy, and 7 unaffected workers. Pattern-evoked visual evoked potentials (VEPs) were prolonged in the patients with clinical or subclinical polyneuropathy when compared with normal control subjects, and the VEPs were somewhat attenuated in amplitude in the group with clinically evident neuropathy. Others have also noted reversible changes in the latency of VEPs. Their occurrence supports an organic basis for the visual symptoms that may follow n -hexane exposure, but whether they relate to cerebral involvement or pathology of the optic nerve or macula is unclear. Brainstem auditory evoked potentials (BAEPs) showed a prolongation in the I–V interpeak latency that corresponded to the severity of the polyneuropathy, whereas somatosensory evoked potentials (SEPs) showed prolonged absolute latencies and central conduction time in patients with clinical or subclinical polyneuropathy. The BAEP abnormalities support a central (brainstem) effect of the toxin exposure, but in the presence of peripheral pathology it is hard to determine the significance of the SEP findings reported by Chang. SEP abnormalities have not always been found in patients with toxic polyneuropathy who were exposed to a variety of industrial toxins, including n -hexane. Nevertheless, evoked potential studies have revealed clearly that the neurologic disorder following n -hexane exposure may involve the central as well as the peripheral nervous system.
Toluene is used widely for industrial purposes both as a solvent in paints and glues and to synthesize certain compounds (e.g., benzene). Exposure occurs especially among painters and linoleum layers and in the printing industry. Toluene inhalation for recreational purposes is also problematic.
Hormes and colleagues reported residual damage in 20 chronic solvent vapor abusers when evaluated at least 4 weeks after total abstinence from intoxicants. Exposure had been primarily to toluene for 2 or more years. In 13 of the 20 patients, neurologic abnormalities included cognitive, pyramidal, cerebellar, and cranial nerve findings. The pattern of cognitive dysfunction suggested a subcortical dementia, with apathy, poor concentration, impaired memory, visuospatial dysfunction, and impaired complex cognition. The EEG was recorded in 7 neurologically impaired patients, and 3 had an excess of slow activity that was diffuse and continuous in one instance and intermittent in two. BAEPs were abnormal in 3 of 4 patients, with prolongation of the I–III interpeak latencies or abnormalities of waves III, IV, and V bilaterally. In one patient no other evidence of brainstem involvement was noted. In a subsequent study, Rosenberg and co-workers defined the BAEP findings in 11 chronic toluene abusers. In 5, the BAEPs were abnormal, and analysis of the group showed a prolongation of the absolute latency of wave V and the I–V and III–V interpeak latencies when compared with control subjects. Two of the 5 patients with abnormal BAEPs had normal findings on neurologic examination and magnetic resonance imaging (MRI). These findings and other reports of BAEP abnormalities in toluene abusers suggest a possible role for the BAEP in the early detection of central nervous system injury from toluene inhalation when clinical MRI findings are normal.
Carbon disulfide has been used as a soil fumigant in various industrial and manufacturing processes, as a constituent of certain insecticides and varnishes, and as a solvent for various chemicals. Acute exposure to high concentrations may lead to an encephalopathy with marked behavioral disturbances, whereas lower levels of exposure may lead to a mild encephalopathic disturbance that is revealed only by neurologic testing. The EEG has been used to evaluate exposed workers and reportedly has shown abnormalities more commonly in such workers than in healthy control subjects, but the findings are not consistent and their nonspecific nature suggests that the EEG has little practical utility as a screening technique. Thus, a study of 10 patients showed that none had abnormal EEGs, another study revealed that the EEG findings were inconsistent but mostly normal, and a third study showed frequency changes of dubious relevance. Carbon disulfide may also lead to optic neuropathy as well as a clinical or subclinical polyneuropathy that is similar to that produced by n -hexane (see p. 822 ). Whether VEP studies have any role in monitoring for the development of optic neuropathy is uncertain.
Exposure to carbon monoxide may lead to cerebral hypoxia with neurologic sequelae. Such cases may result from industrial exposure, especially in miners or gas workers. The effect of acute exposure depends on the severity of intoxication, but cognitive or behavioral disturbances may occur, and focal neurologic deficits may also be evident. Generalized or lateralized EEG abnormalities have been described. After hyperbaric oxygen therapy, improvement of occipital alpha activity on quantitative EEG analysis (increased peak alpha frequency and relative alpha power) has suggested that monitoring of peak alpha frequency may be a useful indicator of therapeutic efficacy, but this requires substantiation. Whether chronic low-level exposure to carbon monoxide leads to an encephalopathy is uncertain, and electrophysiologic techniques have not been helpful as a means of detecting such an encephalopathy at a subclinical stage.
Organophosphate compounds are used as pesticides and herbicides. Acute toxicity relates to anticholinesterase activity and is characterized by both central and peripheral manifestations. The central effects include behavioral disturbances, seizures, and eventually coma or death. Visual inspection of the EEG does not permit central neurotoxicity to be recognized in individual subjects. Quantitative analysis of the EEG recorded 1 year or more after exposure has revealed statistically significant group differences when compared with normal subjects, and similar changes are seen after acute exposure; however, their significance is uncertain. Cognitive processing may be delayed and abnormalities of endogenous potentials have been described after chronic exposure to organophosphate pesticides, but the significance of such findings is uncertain. Organophosphates may affect neuromuscular transmission (p. 827). Certain organophosphates also lead to the development of a delayed polyneuropathy about 2 to 3 weeks after acute exposure (see page 821 ).
A well-recognized syndrome follows poisoning with organic mercury compounds. Numbness and paresthesias occur initially, followed by constriction of the visual fields, blindness, hearing loss, pyramidal deficits, and dyskinesias. Electrophysiologic studies have shown VEP abnormalities in monkeys and dogs, which is in keeping with a central origin of the visual disturbance and with reports of pathologic changes in the visual cortex. The VEP changes may involve morphology, which is difficult to quantify, and amplitude, which is variable even in normal subjects. Median-derived SEPs show loss of the cortically generated N20 response that presumably relates to pathology in the somatosensory cortex. Thus, electrophysiologic findings indicate that neurologic disturbances have a central rather than peripheral origin in patients with methylmercury poisoning. Studies of preschool Inuit children suggest that VEPs can be used to assess the developmental neurotoxicity of methylmercury and other contaminants in fish-eating populations. However, subtle changes, possibly due to low-level methylmercury exposure, are of uncertain clinical relevance and must be interpreted cautiously.
Styrene is a colorless, volatile organic solvent that has been associated with behavioral effects, as well as with a possible peripheral neuropathy. , It has widespread application in the plastics industry, particularly in the polyester resin boat industry. Styrene is absorbed readily following inhalation. Numerous studies published over the years have suggested that an encephalopathy may result from styrene exposure. A critical review of the literature by Rebert and Hall provided no indication of persisting neurologic damage following styrene exposure. Much of the literature was flawed methodologically, and conclusions from it therefore were invalid.
Electrophysiologic studies have not been used widely in the evaluation of patients with suspected neurobehavioral disorders attributed to styrene exposure. Even when the EEG has been used, the changes have varied markedly between subjects and have not been consistent. Problems referred to earlier with regard to the EEG as a means of evaluating behavioral disorders are particularly apparent in the literature concerning the potential neurotoxicity of styrene. Matikainen and associates did undertake a quantitative evaluation of the EEG in patients from several plastics factories. They attempted to minimize the effects of drowsiness by recording the EEG in the morning and discarding EEG epochs obtained during periods of obvious drowsiness, but it is not clear how drowsiness was assessed. Various quantitative abnormalities were identified but, as pointed out by Rebert and Hall, these authors made some 798 comparisons, so by chance alone about 40 significant results would be expected with a significance criterion of 0.05. When several redundant parameters were eliminated and the channel count was restricted, the number of comparisons was reduced to 192, from which 10 significant findings would still be expected by chance alone. In fact, the number of significant comparisons was markedly less than expected by chance, and the biologic meaning of the finding is unclear because of the absence of an adequate control group. Neurometric discriminant analysis was used for classifying subjects in terms of EEG abnormalities, but the reference normative data were not an appropriate standard. Finally, even if abnormalities had been detected in this study of apparently healthy workers, there is no justification in concluding that the EEG changes reflect subclinical dysfunction related to neurotoxic exposure.
Chronic Painters’ Encephalopathy
Gade and colleagues reanalyzed the psychologic test data in a group of subjects who were reported to have chronic painters’ syndrome and compared the findings with those of matched controls. They could not confirm previous impressions of significant intellectual impairment in the solvent-exposed subjects when the influence of age, education, and intelligence was taken into account. This study is of particular note because it was performed in the same department as the original studies that identified this syndrome. The use of electrophysiologic tests (often subjected to sophisticated quantitative analysis) to validate the existence of a syndrome that, on clinical grounds, is now questionable , seems difficult to justify. The relevance and validity of any electrophysiologic abnormalities detected are uncertain.
Neurotoxic disorders of the peripheral nervous system
Patients with suspected neurotoxic disorders are often referred for neurophysiologic examination, which plays an important role in their evaluation. This role includes documenting the organic nature of a suspected disorder; classifying the abnormalities in a way that reduces the number of possible diagnoses in the differential diagnosis; and, occasionally, identifying the underlying pathophysiology. More recently, electrophysiologic studies have had application as screening instruments in clinical pharmaceutical and occupational or environmental studies. These applications include use as endpoint measures (as in a pharmaceutical trial) and to identify unsuspected adverse neurotoxicity. Because iatrogenic toxic neuropathies are common, this latter role is increasingly important.
Electrophysiologic tests have limitations, and their indiscriminate use in the evaluation of occupational or environmental disorders is inconsistent with their intended application. Few, if any, neurotoxic disorders are associated with electrophysiologic features that are so characteristic as to be diagnostic. In most instances, electrophysiologic abnormalities are nonspecific and of limited use in establishing the cause of neurologic impairment. Although toxic neuropathies are common, they probably are overdiagnosed, so that idiopathic neuropathies sometimes are attributed erroneously to toxic-metabolic causes. Toxic neuropathies are important to recognize, however, because improvement may occur once exposure is reduced or eliminated. With regard to cross-sectional group evaluations of persons with suspected neurotoxic disorders, electrophysiologic measures purporting to identify subclinical abnormalities must be interpreted cautiously because of numerous potential confounders that influence such data.
The role of electrophysiologic studies relates to their sensitivity in identifying abnormalities, sometimes in the absence of clinical symptoms or signs, and the ability to localize abnormalities to a specific level of the nervous system. The application and limitations of conventional electrophysiologic studies in the evaluation of suspected neurotoxic disorders are relatively well established, especially with regard to individual patient evaluations. Because the most common peripheral nervous system toxins produce neuropathy, this discussion will emphasize those disorders.
The electrodiagnostic examination is never performed in isolation but is designed in the context of the patient’s complaints and clinical abnormalities. The nature of peripheral abnormalities simplifies the physician’s task in terms of establishing the presence of neuropathy. Unfortunately, most neurotoxic disorders have no specific features to distinguish them from neurologic disorders arising from other causes. Importantly, the neuroanatomic diagnoses of neuropathy, myopathy, or defective neuromuscular transmission are established independently from an etiologic diagnosis. Most peripheral neurotoxic disorders are symmetric, however, and only rare exceptions to this rule exist. Occasionally, identification of some cardinal abnormality will be the first clue in identifying a specific toxic disorder, although recognition usually stems from a high level of suspicion. More commonly, a systematic neurologic examination focuses the subsequent electrodiagnostic and other laboratory evaluations. Clinical symptoms and signs are used to identify the presence of a peripheral disorder and to formulate a differential diagnosis. The differential diagnosis is used to select among the variety of clinical and laboratory tests available to confirm the presence of peripheral dysfunction and refine the diagnosis, as discussed in the following sections.
Most electromyographers consider nerve conduction studies and needle electromyography (EMG) as extensions of the neurologic examination. These studies can be repeated at intervals to confirm previous findings and to document progression or improvement. The most important role of electrodiagnostic testing is to localize abnormality to specific levels of the peripheral nervous system. A secondary role includes identification of the most likely pathophysiology to produce a more manageable differential diagnosis that may include a toxic etiology after competing causes have been eliminated.
Standardized techniques should be used when performing nerve conduction studies to evaluate the nervous system, as discussed in Chapter 13 . Normal values depend on numerous factors including technique, patient age and size, temperature, and even occupation. A major source of variability is limb temperature; cooling decreases the rate at which ionic channels open, thereby producing an increased response amplitude and decreased conduction velocity. To reduce the effect of temperature, standard practice requires monitoring of limb temperatures and warming to approximately 32° to 36°C, if necessary.
Sensory nerve action potentials and compound muscle action potentials are recorded in response to percutaneous electrical stimulation of peripheral nerves with surface electrodes. Measurement of response amplitude is very important because it reflects in part the number and size of functioning nerve or muscle fibers. Any disorder causing a substantial loss of axons or muscle fibers (e.g., a toxic neuropathy or myopathy) produces a response of reduced amplitude. Conventional recordings of nerve conduction velocity measure conduction in the fastest conducting fibers. Distal latency reflects conduction along the terminal portion of the nerve. In contrast, F-wave latency (see Chapter 18 ) reflects transmission time from the stimulation site to the spinal cord and then back along the entire nerve to the recording site. The long distance along the entire nerve accentuates minor conduction abnormalities. Blink reflex studies (see Chapter 19 ) record involuntary reflexes that occur in response to stimulation of the trigeminal nerve. These reflexes involve peripheral and brainstem connections, and they have occasional application in the evaluation of neurotoxic disorders.
Sensory conduction studies primarily evaluate the large myelinated sensory axons. One means of assessing smaller axons involves evaluation of the autonomic nervous system (see Chapter 21 ). Skin potential or sympathetic skin responses are mediated by small nerve fibers and represent a measure of autonomic function. They are recorded from the skin, between areas of high and low sweat gland density. They occur spontaneously or in response to a variety of stimuli, including electrical stimulation or startle. They have limited sensitivity and specificity, but intact responses argue against a significant abnormality of autonomic sudomotor function.
The method most commonly used to evaluate neuromuscular transmission is repetitive motor nerve stimulation (see Chapter 17 ). Impaired neuromuscular transmission is identified by a decrement in the amplitude of compound muscle action potentials with repeated percutaneous nerve stimulation. Low-rate stimulation of motor nerves challenges neuromuscular transmission by taking advantage of the normal decrease in the availability of acetylcholine immediately after discharge, before replenishment by mobilization. The primary role of these studies in neurotoxic disorders is to identify impaired neuromuscular transmission in acute organophosphorus poisoning, botulinum intoxication, and penicillamine-induced myasthenia gravis. Single-fiber EMG (see Chapter 17 ) is the most sensitive measure of neuromuscular transmission, but it has limited application in the evaluation of neurotoxic disorders.
The conventional needle examination (see Chapter 11 ) is a sensitive indicator of partial denervation or muscle fiber necrosis. It is an important component of the electrodiagnostic examination but has a secondary role in the evaluation of neurotoxic disorders when compared with nerve conduction studies. An exception is in the evaluation of toxic myopathy, although the abnormalities are nonspecific. Separation of a muscle fiber from its nerve supply, regardless of cause, results within weeks in the appearance of abnormal insertion activity characterized by positive waves and fibrillation potentials. These spontaneous discharges represent involuntary muscle fiber action potentials associated with denervation hypersensitivity caused by proliferation of acetylcholine receptors on the muscle fiber surface. They are recognized easily, are not confused easily with other EMG signals, and are not present in normal muscle.
Application of Electrodiagnostic Studies in Peripheral Neurotoxic Disorders
Electrodiagnostic examination is important in the following:
Identifying polyneuropathy, mononeuropathy multiplex, or polyradiculopathy
Recognizing selective involvement of sensory or motor fibers
Revealing substantial conduction slowing (suggesting a disturbance of myelin or membrane) or amplitude loss (axon degeneration)
Detecting impaired neuromuscular transmission
Indicating isolated muscle fiber involvement.
The findings do not address whether a specific toxin is responsible for the findings, but instead begin by localizing any abnormality to a focal, multifocal, or diffuse distribution. In the case of a diffuse polyneuropathy, the presence of predominant sensory or motor involvement is established, followed by determination of whether the abnormalities are characterized by substantial conduction slowing or simply by loss of response amplitude. Electrodiagnostic test results are used to classify peripheral disorders. This classification is easy to apply and reduces, to an extent not clinically possible, the number of disorders that must be considered in the differential diagnosis. Neurotoxic disorders may present with very different electrophysiologic features, however, depending on their severity and the time of testing in relation to the clinical course.
An important part of the classification system involves a determination of whether motor nerve conduction velocity is decreased to an extent greater than can be caused by axonal loss alone. This determination is often difficult, and existing criteria for conduction slowing are relatively insensitive. Most criteria represent attempts to identify a surrogate electrophysiologic measure for segmental demyelination. Unfortunately, other pathologies (e.g., axonal inclusions, axonal stenosis, channelopathies, and selective loss of large myelinated motor fibers) produce substantial slowing. In the classification scheme, conduction slowing is used in a general sense to include any slowing unlikely to result from axon-loss lesions alone, regardless of cause. In this context, conduction velocities less than 80 percent of the lower limit of normal or distal and F-wave latencies exceeding 125 percent of the upper limit of normal usually fulfill this requirement. Before any problem can be attributed to a toxic neuropathy, hereditary disorders causing conduction slowing must be excluded. Partial conduction block and abnormally increased temporal dispersion are important features of acquired neuropathies. Their absence suggests uniform involvement of all fibers and supports a hereditary etiology.
Establishing the cause of any disorder is difficult, and many common diseases of the peripheral nervous system are of unknown etiology. Nevertheless, diagnosing a toxic neuropathy implies that the etiology has been established. Clinical medicine is based on the scientific method of hypothesis generation and testing, and most clinicians apply general scientific principles in the formulation of a differential diagnosis without giving thought to the process. Formal criteria exist, however, for establishing the cause of a problem. In the appropriate clinical setting, laboratory tests are useful in establishing an increased body burden of a potential neurotoxin or in identifying characteristic pathologic features of toxic exposure. However, in general, the electrodiagnostic examination represents the most important clinical measure in identifying a toxic neuropathy. Among the criteria useful in establishing a toxic etiology, electrodiagnostic studies have their most important role in establishing the presence of abnormality and in identifying competing explanations.
Certain pathophysiologic changes are relevant to the clinical electrodiagnosis of neuropathy. The most important changes include axonal degeneration, axonal atrophy, demyelination, and metabolic changes that alter nerve conduction. Examples follow with disorders separated into broad categories based on electrodiagnostic evidence of sensory or motor involvement combined with evidence of axonal loss or definite conduction slowing.
Predominantly Motor Axonal Neuropathies
Predominantly motor neuropathies are uncommon, and identification of such disorders suggests a relatively limited differential diagnosis. Many neuropathies in this category have toxic causes, often involving medications.
Dapsone produces a neuropathy characterized by weakness and muscle wasting that often involves the arms more than the legs. It is one of several toxins associated with motor or predominantly motor involvement and is characterized by axonal loss without conduction slowing. Mild sensory abnormalities may also be present. The neuropathy usually develops after prolonged (years-long) use. Dapsone is metabolized by acetylation in the liver, and neuropathy may be related to abnormal metabolism in slow acetylators. Dapsone motor neuropathy occasionally resembles multifocal motor neuropathy or mononeuropathy multiplex. Electrodiagnostic testing demonstrates normal sensory nerve conduction studies; motor responses may be asymmetric and characterized by borderline-low or reduced amplitudes in multiple locations but without conduction block. On needle EMG examination, fibrillation potentials and large-amplitude, long-duration, polyphasic motor unit potentials are present in the upper and lower extremities in an asymmetric distribution involving the distal muscles of different peripheral nerve and root innervation. This asymmetry is not characteristic of most toxic neuropathies and may suggest a diagnosis of motor neuron disease. A slow but progressive improvement in motor function occurs after discontinuing dapsone use. Most patients recover in 1 to 3 years.
The primary toxicity of nitrofurantoin is neuropathy, but this sequela is rare. Initial sensory involvement with paresthesias and sometimes pain is followed by the rapid onset of severe weakness, especially in elderly women with impaired renal function and presumably high nitrofurantoin blood levels. The neuropathy is a mixed sensorimotor polyneuropathy. The disorder may progress to respiratory failure and superficially resembles acute Guillain–Barré syndrome. When nitrofurantoin use is discontinued, most patients improve or recover, although recovery may be incomplete. In its most severe form, the neuropathy involves motor more than sensory fibers; it is characterized by a markedly reduced response amplitude but no conduction slowing, a finding that cannot be explained by isolated loss of myelinated nerve fibers.
Organophosphates (see p. 817 ) produce a slowly reversible inactivation of acetylcholinesterase and accumulation of acetylcholine in cholinergic neurons. , Muscarinic overactivity results in miosis, increased secretions, profuse sweating, gastric hyperactivity, and bradycardia. Nicotinic overactivity results in fasciculations and weakness. If not fatal, the acute effects resolve, but some organophosphates produce a rapidly progressive neuropathy 2 to 4 weeks after acute exposure. Organophosphate-induced delayed neuropathy is manifested by dysesthesias and progressive weakness, especially distally. Reflexes are reduced at the ankles, but they may be normal or brisk elsewhere. Recovery is often incomplete, and spasticity later becomes a prominent feature. Clinically evident or subclinical neuropathy does not appear to result from exposures to organophosphate insecticides at levels that do not produce cholinergic toxicity. , During acute organophosphate intoxication, repetitive compound muscle action potentials occur after a single stimulus, presumably from recurrent postsynaptic depolarization by persistent acetylcholine. Other electrodiagnostic findings are consistent with axonal degeneration of motor and, to a lesser extent, sensory fibers. Conduction velocity remains essentially normal, but amplitudes of compound muscle and sensory nerve action potentials are reduced and there is needle EMG evidence of severe denervation characterized by diffuse fibrillation potentials.
Vincristine usually produces an axonal sensorimotor neuropathy with sensory involvement exceeding motor involvement. However, a form of rapidly progressive weakness is associated with vincristine and can result in functional quadriplegia with little associated increase in sensory involvement. In some patients, the arms initially may be involved more than the legs, and the disorder resembles a pure motor neuropathy or neuronopathy. The electrodiagnostic findings then are those of an axonal neuropathy in which motor nerve abnormalities predominate, with evidence of severe neurogenic changes on needle EMG.
Predominantly Motor Neuropathies with Conduction Slowing
Amiodarone is associated with a slowly progressive motor neuropathy with prominent conduction slowing, often in the range of 20 to 30 m/sec. Abnormal temporal dispersion and partial conduction block are not features of this neuropathy, and the conduction slowing is related to preferential loss of the largest myelinated fibers. The motor abnormalities are associated with low-amplitude sensory responses when the neuropathy is severe.
Acute arsenical neuropathy is one component of a systemic illness characterized by nausea, vomiting, diarrhea, pancytopenia with basophilic stippling, and abnormal liver function tests reflecting hepatic damage. Features of chronic toxicity include dermatitis (hyperkeratosis, pigmented dermatitis), cardiomyopathy, portal hypertension with esophageal varices, and splenomegaly. Nerve conduction studies performed shortly after acute exposure may be suggestive of Guillain–Barré syndrome with reduced conduction velocity, increased temporal dispersion, partial conduction block, and low-amplitude or absent sensory responses. , Serial studies suggest a dying-back neuropathy with progressive axonal degeneration. The initial findings are probably secondary and appear before generalized axonal failure. Mees lines appear on the nails about 1 month after exposure. (See page 824 for additional findings of chronic arsenic intoxication.)
Disulfiram (Antabuse) is metabolized to acetaldehyde when combined with alcohol, which forms the rationale for promoting alcohol abstinence. Disulfiram is associated with a progressive, predominantly motor neuropathy. The onset of weakness is sometimes abrupt and mimics Guillain–Barré syndrome. The electrodiagnostic findings may be indistinguishable from those of the axonal form of Guillain–Barré syndrome or may show substantial motor conduction slowing in association with axonal degeneration with paranodal and internodal swellings due to accumulation of neurofilaments, similar to the abnormalities attributed to n -hexane neuropathy (see below). ,
Excessive exposure to n -hexane produces a dying-back neuropathy characterized by distal weakness, stocking-glove sensory loss, and absent ankle reflexes. In most reports, motor signs predominate, but this feature is not invariable. Clinical progression for several weeks after cessation of exposure is typical of many toxic neuropathies and is called “coasting.” Nerve conduction studies reveal reduced sensory and motor response amplitudes and conduction velocities, sometimes to 35 or 40 percent of the lower limit of normal. The conduction slowing is often associated with partial conduction block and is typically sufficient to suggest acquired demyelination. These findings are atypical of toxic neuropathy but are consistent with acute Guillain–Barré syndrome. Laboratory support for a diagnosis of Guillain–Barré syndrome also includes a slightly elevated cerebrospinal fluid protein concentration early in the course of illness. It is now established that the reduced conduction velocity and partial conduction block are explained by secondary myelin changes caused in part by axonal swelling in peripheral and central nerve fibers. Sural nerve biopsy demonstrates multifocal axonal distension with paranodal swelling and neurofilamentous masses. The axonal swellings consist of neurofilament aggregates, which may accumulate because of abnormalities in fast and slow axonal transport mechanisms. Improvement follows removal from exposure, although conduction slowing may persist in severely involved patients.
Tetrodotoxin and Saxitoxin
Neurotoxins that block sodium channels include tetrodotoxin derived from the puffer fish and saxitoxin derived from contaminated shellfish (red tide). These natural toxins are of interest because they produce a neuropathy characterized by conduction slowing, a finding typically associated with demyelinating neuropathies. The sodium channel blockade produced by these neurotoxins decreases the local currents associated with action potential propagation, thereby slowing conduction velocity, an effect similar to that seen with reduced temperature. Amplitudes of compound muscle action potentials are reduced, but no abnormal temporal dispersion or partial conduction block is present.
Sensory Axonal Neuropathies
Sensory involvement is common in mixed sensorimotor polyneuropathy, but exclusive and severe sensory involvement is unusual. Axonal sensory neuropathies or neuronopathies include those associated with pyridoxine, cisplatin, small-cell lung cancer, Sjögren’s syndrome, the Miller Fisher variant of Guillain–Barré syndrome, and Friedreich ataxia. All present subacutely with unpleasant paresthesias and evidence of reduced vibration and joint position sensation, areflexia, and minimally decreased pain sensation; weakness is not observed. Electrodiagnostic findings include markedly reduced or absent sensory nerve action potentials with normal motor conduction studies. Sequential studies demonstrate a progressive decline in the amplitude of sensory nerve action potentials. There is no needle EMG evidence of denervation. It is difficult, if not impossible, to distinguish a sensory neuropathy from a neuronopathy, although a length-dependent process suggests the former.
Cisplatin is an antineoplastic agent. Its major dose-limiting toxicity relates to the central and peripheral nervous systems, with preferential uptake in the posterior root ganglia producing a profound sensory neuropathy or neuronopathy. Toxicity is dose-related, but most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Sensory symptoms and signs usually develop several weeks to months after administration. Absent reflexes are an early finding. Occasional patients report distal weakness, but this “weakness” probably reflects impaired proprioception, not true weakness. Cisplatin neuronopathy is indistinguishable from the paraneoplastic sensory neuronopathy associated with small-cell lung cancer and anti-Hu antibodies. Sequential studies of patients receiving cisplatin chemotherapy demonstrate a progressive reduction in the amplitude of sensory nerve action potentials with no clear abnormality in motor nerve conduction studies and no needle EMG evidence of denervation. Neuroprotective therapies have been sought to limit the neurotoxicity of cisplatin and related antineoplastic agents, and nerve conduction studies have been used to evaluate their efficacy. ,
Pyridoxine is a vitamin (vitamin B 6 ) that occasionally is taken in “megadoses” by health faddists to treat a variety of nonspecific syndromes. It also is used to treat poisoning or exposure to several toxins, including the false morel Gyromitra esculenta . Like cisplatin, it has been associated with a profound sensory neuropathy. , Neurologic toxicity either is related to long-term cumulative exposure or occurs after short-term administration of large doses. With particularly large exposures, sensory loss may be virtually complete, including facial and mucous membrane areas, and produces ataxia and choreoathetoid movements. Such profound loss is consistent with a sensory neuronopathy. Apparent weakness may relate to impaired proprioception. Pyridoxine-induced sensory neuronopathy is indistinguishable from paraneoplastic sensory neuronopathy. Sequential electrophysiologic studies demonstrate progressive attenuation of sensory nerve action potentials with no clear abnormality in motor conduction and no needle EMG evidence of partial denervation.
Workers with chronic styrene exposure may develop paresthesias in the fingers and toes without clear neurologic abnormalities, but electrodiagnostic evaluation reveals mild findings consistent with a sensory neuropathy. Mild sensory nerve conduction deficits were reported in 23 percent of workers exposed to less than 50 ppm styrene and in 71 percent of workers exposed to more than 100 ppm, but no conduction slowing was found in a small group of 5 men exposed to more than 100 ppm for less than 4 weeks. These results of styrene-induced neurotoxicity have not been confirmed in animal models, and failure to identify a clear dose–response relationship in human subjects reduces the clinical significance of the reported work, although a possible peripheral neurotoxic effect cannot be excluded.
Thalidomide is associated with a predominantly sensory, axonal, length-dependent neuropathy that presents typically with painful paresthesias or numbness. Electrodiagnostic studies may show reduced sensory nerve action potentials ; sural nerve biopsies may show evidence of Wallerian degeneration and loss of myelinated fibers. Reports of proximal weakness being greater than distal weakness suggest anterior horn cell degeneration.
Thallium intoxication is associated with a small-fiber neuropathy and alopecia. Clinical symptoms include a severe, painful, distal sensory neuropathy associated with evidence of dysautonomia including abdominal pain, constipation, and nausea. Distal weakness may be present, but weakness is a minor complaint in comparison to the severe painful distal dysesthesias. Pin-pain sensation is the most markedly impaired, and muscle stretch reflexes may remain normal.
Sensorimotor Axonal Polyneuropathy
Distal axonopathy is the most common finding in a variety of toxic or metabolic disorders. Presumably, failure of axonal transport of some nutrient required for maintenance of the distal axon occurs in response to the metabolic abnormality. Axonal atrophy may precede axonal degeneration. Conduction velocity is proportional to axonal diameter and is reduced along the atrophic axon. Most toxic or metabolic neuropathies demonstrate axonal degeneration (dying back) of sensory and motor axons. Unfortunately, they are difficult to distinguish from each other electrodiagnostically. Sensory symptoms and signs initially predominate and include dysesthesias, paresthesias, distal sensory loss, and loss of Achilles’ reflexes. Weakness and atrophy of the distal muscles develop, followed by more proximal involvement as a late finding. Amplitudes of sensory nerve action potentials are typically abnormal, even early in the course of disease. Compound muscle action potentials subsequently become attenuated, particularly in the legs. Conduction velocity, distal latency, and F-wave latency remain normal until the loss of large myelinated fibers is substantial. Distal latency may be abnormal with normal proximal conduction, a reflection of axonal atrophy. Fibrillation potentials and positive waves appear in distal extremity muscles before clinical evidence of weakness. Motor unit recruitment is reduced, and motor unit action potentials are increased in amplitude and duration.
Axonal sensorimotor neuropathies are the most common forms of toxic neuropathy. A description of all potential neurotoxicants producing this type of neuropathy is beyond the scope of this section. However, in addition to the chemicals described in the following sections, other substances that may produce a neuropathy characterized by sensory or sensorimotor involvement without conduction slowing include acrylamide, amitriptyline, carbon monoxide, ethambutol, ethylene oxide, elemental mercury, gold, hydralazine, isoniazid, lithium, metronidazole, nitrous oxide (myeloneuropathy), perhexiline, phenytoin, thallium, and zinc (myeloneuropathy).
Acute arsenical neuropathy was discussed on page 822 . Once developed, chronic arsenical neuropathy is characterized by sensorimotor neuropathy of the axonal type.
Colchicine is associated with mild axonal neuropathy among patients who are receiving it for gout prophylaxis. Associated weakness has been attributed to an underlying myopathy, and the combined abnormality has been referred to as a myopathy–neuropathy syndrome. ,
Ethyl alcohol is associated with several neurologic disorders related to the direct neurotoxic effects of alcohol or its metabolites, to nutritional deficiency, to genetic factors, or to some combinations of these factors. Clinically similar neuropathies occur in vitamin-deficient states, including thiamine and other B vitamins. However, a typical alcohol neuropathy may occur with normal nutrition, perhaps in association with impaired axonal transport. The incidence of neuropathy in alcoholic patients is high, usually consisting of a nonspecific sensorimotor neuropathy, although some patients present with subacute-onset sensory neuropathy. Paresthesias and painful distal dysesthesias are early symptoms and are followed by distal sensory loss; distal weakness; and gait ataxia, often accompanied by dysautonomia. Tendon reflexes are absent or hypoactive. Nerve conduction studies and needle EMG are characteristic of an axonal neuropathy.
The major dose-limiting toxicity of vincristine, an antineoplastic alkaloid, is neuropathy, the onset and severity of which are dose-dependent. Initial symptoms appear within weeks of a single dose and include distal paresthesias, absent ankle reflexes, superficial sensory loss, and diminished vibration sensation. Minimal distal weakness, particularly of toe extensor and hand intrinsic muscles, may be apparent. With increasing severity, dysautonomia characterized by constipation, abdominal pain, ileus, impotence, and orthostatic hypotension may become evident. Treatment with vincristine and other potentially neurotoxic medications at dosages considered “nontoxic” can produce significant worsening of a pre-existing neuropathy. Electrophysiologic findings in mild neuropathy are consistent with a predominantly sensory axonal polyneuropathy. Amplitudes of sensory nerve action potentials and compound muscle action potentials are reduced, but conduction velocities are essentially normal or reduced only slightly, consistent with the loss of large myelinated fibers. An early finding is persistent H waves when ankle reflexes are absent. This paradox relates to early involvement of muscle spindles that interrupt the muscle stretch reflex arc. H-reflex studies depolarize large myelinated fibers directly, independent of muscle spindles. Partial denervation can be seen on needle EMG examination, particularly in distal limb muscles.
Polyradiculoneuropathy with Conduction Slowing
Aerosolized Porcine Neural Tissue
Exposure to aerosolized porcine brain tissue among slaughterhouse workers has been associated recently with a sensory-predominant polyradiculoneuropathy, sometimes with additional features of a transverse myelitis, meningoencephalitis, or aseptic meningitis. The polyradiculopathy is characterized by painful paresthesias, distal sensory loss and weakness, impaired tendon reflexes, and autonomic dysfunction developing at least 1 month after initial exposure. Cerebrospinal fluid protein concentrations are generally high. Electrophysiologic findings include a reduction in amplitude of sensory responses. The combination of normal motor conduction velocities without conduction block or abnormal temporal dispersion and prolonged F-wave, blink reflex, and motor latencies localizes abnormalities to the most proximal and distal nerve segments where the blood–nerve barrier is most permeable. Prominent MRI abnormalities have confirmed proximal involvement at nerve roots or ganglia, showing ganglia enlargement, T2 hyperintensity, or enhancement in posterior roots and enlarged (mostly anterior) roots in the cauda equina. Sural nerve biopsies reveal mild inflammatory demyelination, axonal degeneration, and perivascular foci of inflammation. No systemic disorder or infectious agent has been identified that could trigger a similar neurologic disease. However, sera from affected and many unaffected workers but not from community controls have a distinctive neural-reactive immunoglobulin (Ig)G that correlates with exposure risk. Among cases, 75 percent had sera showing an IgG specific to myelin basic protein. Although not typical of most neurotoxic conditions, the evidence suggests that this polyradiculoneuropathy has an autoimmune origin and likely is related to occupational exposure to multiple aerosolized porcine brain-tissue antigens. Similar immune-based mechanisms are associated with penicillamine-induced myasthenia gravis and Guillain–Barré syndrome attributed to some vaccinations.
Multifocal Sensorimotor Neuropathy (Mononeuropathy Multiplex)
As indicated on page 821 , dapsone-associated neuropathy can mimic multiple entrapment neuropathies, although the paucity of sensory abnormality is atypical of a nerve entrapment syndrome. Electrodiagnostic evaluation demonstrates evidence of neurogenic atrophy with chronic denervation and reinnervation. Compound muscle action potentials are reduced in amplitude, but sensory studies are usually normal. Conduction slowing, when present, presumably relates to loss of the largest motor fibers.
Few neurotoxicants produce a clinical picture of mononeuritis multiplex. In fact, it is difficult to propose how a systemic exposure could cause a multifocal, asymmetric mononeuropathy. Nevertheless, the eosinophilia–myalgia syndrome is a multifocal disorder of the peripheral nervous system associated with the ingestion of l -tryptophan. Eosinophilia, skin changes (peau d’orange), arthralgia, myalgia, fatigue, painful paresthesias, sensory loss, and weakness occur. Sensory loss may predominate and is typically asymmetric, but most patients have distal sensory loss and weakness. Reflexes are sometimes absent distally, but they may be preserved depending on the distribution of abnormality. Electrodiagnostic evaluation confirms multifocal involvement (axonal loss) of sensory more than motor fibers and suggests a mononeuropathy multiplex. Sensory responses for some nerves may be markedly abnormal with little accompanying motor response abnormality and no needle EMG evidence of denervation in appropriate muscles. This sensory-motor dissociation is reminiscent of the abnormalities seen in lepromatous neuropathy, in which individual sensory nerves occasionally are involved in the subcutaneous tissue, whereas deeper motor branches are spared. Sural nerve biopsies demonstrate axonal degeneration with epineural and perivascular mononuclear inflammation.
A dose–response relationship exists, although the greatest neurologic impairment occasionally develops months after discontinuing l -tryptophan use. Epidemiologic investigations have linked the syndrome to l -tryptophan produced by using a strain of Bacillus amyloliquefaciens that possibly contained impurities consisting of a novel form of tryptophan that contributed to the toxicity. , Discontinuation of the process and decreased use of l -tryptophan have resulted in disappearance of the syndrome. The combined evidence suggests that an immune response to the novel amino acid contaminant resulted in an inflammatory vasculopathy, with mononeuritis multiplex being one component of a systemic response, as opposed to a direct neurotoxic effect.
In children, toxic exposure to lead produces encephalopathy; in adults, exposure produces peripheral abnormalities, although lead neuropathy is among the rarest of neurologic disorders. The neuropathy is described as involving the upper before the lower limbs, with preferential extensor involvement resulting in weakness of wrist and finger extensors that later extends to other muscles. Associated systemic features include a microcytic, hypochromic anemia and basophilic stippling. The distribution may be asymmetric and involves motor more than sensory fibers. These peripheral findings are similar to those of porphyric neuropathy, with multifocal motor involvement suggestive of a neuronopathy with variable amounts of sensory loss. Like porphyria, lead toxicity demonstrates abnormal excretion of heme precursors, delta-aminolevulinic acid, and coproporphyrin, perhaps related to aminolevulinic acid dehydratase inhibition. Lead lines may be apparent on gums or on bone radiographs. Few patients have been studied with modern techniques. Existing studies describe mild slowing of motor and sensory velocity, but in severe cases there is evidence of severe axonal loss. , Needle EMG shows findings consistent with axonal involvement. Sural nerve biopsy has shown similar axonal loss. The multifocal, asymmetric involvement on EMG is consistent with mononeuropathy multiplex or a diffuse neuronopathy, although sensory studies could be interpreted as consistent with a sensory neuronopathy.
Impaired Neuromuscular Transmission
Many drugs are known to exert effects at the neuromuscular junction, aggravating weakness among patients with myasthenia gravis or inducing myasthenic syndromes among “normal” individuals. Nevertheless, the neuromuscular junction is an uncommon target for neurotoxic medications compared with the peripheral nerves or muscles. Botulinum toxin, perhaps the most potent natural neurotoxin, does, however, directly assault the neuromuscular junction. Fortunately, electrophysiologic measures are sensitive indicators of defective neuromuscular transmission.
Botulinum toxin is a presynaptic neuromuscular junction poison that inhibits acetylcholine release. Food-borne and infantile botulism are the most common forms of botulinum toxicity. , Of the seven types of botulinum toxin, three (types A, B, and E) produce human disease. Signs of botulinum poisoning include internal and external ophthalmoplegia with skeletal muscle weakness or paralysis involving bulbar, respiratory, and extremity muscles. The irreversible neuromuscular blockade produced by botulinum toxin results in a flaccid paralysis that typically appears about 12 to 72 hours after exposure. Because involved muscle fibers are functionally denervated, recovery is prolonged. Electrophysiologic evaluation is important in identifying evidence of impaired neuromuscular transmission, localizing the impairment to the presynaptic neuromuscular junction, and establishing the magnitude of denervation. Cherington described the most consistent electrophysiologic abnormality as a low-amplitude motor response in a clinically affected muscle. Less consistently, abnormal post-tetanic facilitation is identified in affected muscles. These abnormalities are similar to those of the Lambert–Eaton myasthenic syndrome, but they tend to be more variable in magnitude and distribution than the relatively severe and uniform involvement typically observed in that disorder. Single-fiber EMG shows markedly increased jitter and prominent muscle-fiber action potential blocking, which become less marked following activation. Shortly after onset of weakness, conventional needle EMG shows only decreased recruitment, but serial examinations confirm the presence of severe denervation characterized by profuse fibrillation potentials.
Penicillamine is associated with a disorder of neuromuscular transmission that is distinguishable from idiopathic myasthenia gravis only by the complete and permanent resolution of all symptoms, signs, and laboratory abnormalities after removal from additional penicillamine exposure. Although many medications interfere with neuromuscular transmission by a pharmacologic effect, penicillamine does so by means of an immunologic assault that involves the production of acetylcholine receptor antibodies. The resultant immune-mediated damage to the neuromuscular junction results in abnormal fatigability of skeletal muscle, involving primarily ocular, bulbar, and proximal limb muscles. Patients with penicillamine-induced myasthenia gravis display varying degrees of diplopia, ptosis, and generalized weakness. Electrophysiologic tests are valuable in documenting defective neuromuscular transmission in the form of a decremental response on repetitive motor nerve stimulation or increased jitter on single-fiber EMG, but the findings are identical to those in idiopathic myasthenia gravis.
Gutmann and Besser reported that electrophysiologic studies performed during acute organophosphate intoxication demonstrated repetitive discharges to a single depolarizing stimulus, presumably related to recurrent depolarization of the postsynaptic endplate by persistent acetylcholine. Others showed that increasing neuromuscular blockade was associated with a decline in motor response amplitudes among patients with organophosphate poisoning from attempted suicide. The decremental response associated with acute organophosphate intoxication differs from the abnormalities observed in postsynaptic or presynaptic disorders such as myasthenia gravis or the myasthenic syndrome, showing a decremental response at high rates of stimulation (30 Hz and occasionally at 10 Hz) but not at lower rates of stimulation (3 Hz). During the 24 to 96 hours after acute organophosphate poisoning, occasional patients develop an intermediate syndrome that is characterized by weakness of cranial, respiratory, and proximal limb muscles, a distribution resembling that of myasthenia gravis. Electrodiagnostic studies performed in these patients reportedly have shown evidence of a presynaptic defect, although repetitive motor nerve stimulation at low rates did not produce a decremental response. Many of the observations involving the results of repetitive motor nerve stimulation in organophosphate poisoning are difficult to reconcile with our current understanding of neuromuscular physiology.
The muscle fiber is the target of numerous myotoxicants, mainly in the form of medications, as is reviewed in detail elsewhere.
The cholesterol-lowering medications in general and the statin medications (HMG-CoA reductase inhibitors) in particular are among the medications associated most commonly with myopathy. Cholesterol-lowering agent myopathy is a syndrome characterized by muscle pain, weakness, elevated serum creatine kinase levels, and EMG evidence of muscle fiber necrosis confirmed by muscle biopsy. The myopathy may be severe enough to produce fulminant disintegration of skeletal muscle cells, with resultant rhabdomyolysis, myoglobinuria, and acute renal failure. Most patients who develop a statin-induced myopathy have complicated medical problems or are receiving combined therapies with other cholesterol-lowering agents or medications that share common metabolic pathways. The precise underlying mechanisms are unknown, but a relationship between mitochondrial dysfunction and muscle cell degeneration is speculated.
Electrophysiologic abnormalities associated with the disorder are those of any myopathy producing muscle fiber necrosis. The results of the EMG evaluation are important in confirming the presence of myopathy and in identifying the underlying pathophysiology, but they are nonspecific as to the cause of the myopathy. Muscle fiber necrosis of any cause produces a profound abnormality of spontaneous activity, with profuse fibrillation potentials and positive waves. Fibrillation potential and positive waves are most apparent in proximal muscles, reflecting the distribution of clinical involvement. Other features of myopathy (e.g., increased motor unit recruitment and abnormal motor unit potential configuration) may also be encountered but are not specific.
Colchicine is a potential cause of a myopathy–neuropathy syndrome. Colchicine myopathy is associated with an elevated serum creatine kinase level. Rhabdomyolysis may occur with sufficient myoglobinuria to produce acute renal failure, typically in association with multiple risk factors in addition to colchicine. The needle EMG examination in colchicine myopathy is reported to show proximal muscle abnormalities characterized by profuse fibrillation potentials and positive waves, complex repetitive discharges, and “myopathic” motor unit potentials. In muscle biopsies, the presence of a vacuolar myopathy with acid phosphatase-positive vacuoles, myofibrillar disarray foci, and degenerating and regenerating muscle fibers, without evidence of inflammation, vasculitis, or connective tissue disease, has been documented. The mechanism by which colchicine produces myopathy is thought to involve membrane disruption and segmental necrosis of muscle fibers. The myopathy improves, sometimes dramatically, shortly after discontinuation of the colchicine.
Nondepolarizing Neuromuscular Blockade and Corticosteroids
Critical illness myopathy is characterized by a rapidly evolving quadriparesis with normal sensation. It typically emerges in a critically ill patient in the setting of a systemic inflammatory response syndrome with sepsis; most (but not all) patients who develop critical illness myopathy have received nondepolarizing neuromuscular blocking agents during respiratory support and corticosteroids. , Serum creatine kinase levels may be elevated or normal. Electrophysiologic studies show low-amplitude motor responses but normal sensory potentials, unless there is a coexisting critical illness neuropathy. Normal neuromuscular transmission studies exclude the possibility of a prolonged neuromuscular blockade caused by nondepolarizing neuromuscular blocking agents. Needle EMG typically demonstrates a full interference pattern with minimal muscle contraction, often in the presence of complete paralysis (electromechanical dissociation). Some patients develop myonecrosis and show profuse fibrillation potentials, whereas others show only loss of muscle excitability, perhaps because of muscle membrane depolarization or alteration in sodium channels. Light microscopy may show few abnormalities, but electron microscopy evidence of myosin-deficient muscle fibers confirms the presence of a critical illness myopathy. The biopsy results differ from the marked atrophy of type 2 muscle fibers associated with a chronic corticosteroid myopathy. The combined electrophysiologic and biopsy abnormalities suggest that critical illness myopathy results from several different pathophysiologic mechanisms. The prognosis for recovery is excellent. The combination of sepsis and concomitant use of high-dose corticosteroids, often with nondepolarizing neuromuscular blocking agents, suggests the myotoxic potential of these events.