Chapter 33 Toxic neuropathies

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 33

Toxic neuropathies James W. Albers* and James W. Teener Department of Neurology, University of Michigan Health System, MI, USA

33.1. Introduction1 Most clinicians at some time in their career have attributed a peripheral neuropathy to an as of yet unidentified “toxic/metabolic” cause. The rationale for the relatively indiscriminate use of such a diagnosis is not entirely without merit, as toxic neuropathies (as in association with alcohol abuse) and metabolic neuropathies (as in association with diabetes mellitus) constitute the most common forms of neuropathies diagnosed in the US today. There may also be the implicit assumption by some clinicians that many neuropathies of unknown cause probably reflect the influence of some neurotoxicant on the peripheral nervous system. Yet, a thorough evaluation of patients who present with a previously unclassified, idiopathic neuropathy frequently identifies a specific cause for the neuropathy. The most common causes identified include genetic, inflammatory, or systemic etiologies, and only occasionally is an unsuspected toxic cause identified (Dyck et al., 1981). Nevertheless, toxic neuropathies are not rare, and their importance exceeds their number in terms of recovery once the cause is identified and further exposure is reduced or eliminated (Sahenk, 1987; Schaumburg and Spencer, 1987). What is special about toxic neuropathies? In general, nothing, as there are no neurological or electrodiagnostic features that reliably distinguish toxic neuropathies from the numerous other types of neuropathy discussed in this volume. As is the case for most neurological disorders, it is not necessary to know the cause of the problem in order to establish the

*Correspondence to: Dr. James W. Albers, MD, PhD. Department of Neurology, 1C325/0032 University Hospital, University of Michigan Health System, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-0032, USA. E-mail address: [email protected] Tel.: +1-734-936-8586; fax: +1-734-936-5185.

general neuroanatomic and neurophysiologic diagnosis of peripheral neuropathy. Classification schemes based on specific neurotoxicants and resultant clinical and laboratory findings have limited utility, other than in the Gestalt approach to establishing a diagnosis. Conversely, assuming, rather than suspecting, the cause of the neuropathy at the onset introduces an assumption into the diagnostic process that may obscure the correct diagnosis. For example, concluding at the beginning of an evaluation that a specific neurotoxicant caused neuropathy just because the patient had the opportunity for exposure may preclude additional evaluations that could identify an alternative explanation for the patient’s neuropathy. The investigation of any patient with a suspected neuropathy begins with establishing the presence of neuropathy. Of course, many peripheral neurotoxicants are also systemic poisons, and the general clinical and laboratory examinations may suggest important clues in identifying a possible toxic cause for a patient’s neuropathy. Unfortunately, most patients found to have a toxic neuropathy have no cardinal features of toxicity. Even those features highly supportive of a toxic cause (e.g., Mees’ lines or a characteristic skin rash) often do not appear until well after the neuropathy is established, limiting their initial diagnostic importance. For these reasons, the emphasis of this chapter is on the use of clinical and electrodiagnostic information to categorize the different forms of neuropathy. As will be seen, some forms of neuropathy are associated with certain neurotoxicants, and these substances should be included in the resultant differential diagnosis. This increased specificity reduces the number of disorders listed in the differential diagnosis, thereby focusing the subsequent investigations. Some consideration will be given to the laboratory investigation of specific toxins, but, in

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Portions of this chapter rely on materials modified from Albers (1999, 2003).

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general, such investigations are beyond the scope of this chapter. The methodologies used to establish causation will be discussed, as these concepts are fundamental to the investigation of any toxic neuropathy. Finally, some forms of toxic neuropathy are first suspected only when two or more patients with similar types of neuropathy are found to share a common potential exposure. Recognition of such a “cluster” suggests a possible toxic etiology. Regardless of the presentation, however, identification of a toxic neuropathy usually stems from a high level of suspicion and an understanding that numerous substances are capable of producing neuropathy. 33.2. The clinical evaluation of suspected toxic neuropathy The evaluation of a suspected toxic neuropathy requires suspicion that some neurotoxicant explains the patient’s symptoms and signs. When should a toxic etiology be suspected as the cause of a patient’s neuropathy? The simple answer is “always,” because most patients who develop a toxic neuropathy have no distinguishing features. Some guidelines exist, however, to indicate when a toxic etiology should be seriously considered. Foremost is the presence of co-existing systemic signs of toxicity, in addition to the signs of neuropathy. Systemic signs may represent some cardinal feature, relatively specific to a group of toxicants, such as alopecia, Mees’ lines, photosensitivity or laboratory evidence of basophilic stippling. Other features are nonspecific, yet suggest more than the coincidental association of neuropathy and a systemic abnormality such as abdominal pain and psychosis, evidence of a postural tremor, or coexisting hepatic or cardiac failure. The opportunity for exposure, or, in the case of some medications, a known dose of exposure, to an established neurotoxicant clearly raises suspicion for a relationship between exposure and development of neuropathy. Similarly, information that a cluster of individuals with a similar exposure opportunity have developed objective evidence of neuropathy requires investigation. Regardless, the most important guideline is that there is nothing special about the evaluation of a suspected toxic neuropathy. The diagnosis of neuropathy is established independent of knowing the cause of the neuropathy. It is only after the diagnosis of neuropathy is secure that the cause of the neuropathy is established, following the standard differential diagnosis approach.

JAMES W. ALBERS AND JAMES W. TEENER

In the context of a potential toxic neuropathy, a thorough history is used to identify potential environmental or occupational exposures. Such information, including data about exposure dose, is ultimately important in establishing the cause of an identified neuropathy. However, the exposure history is derived independent of establishing the neuroanatomical diagnosis, and the history format should be identical to that used for any neurological evaluation. In fact, the process of establishing the diagnosis of neuropathy proceeds independently from the process of identifying the cause of neuropathy. Information about the onset and time course (temporal profile) of motor, sensory, and autonomic complaints is reviewed, as is a description of the magnitude, type, and distribution of those complaints. Complaints of sensory loss or weakness should not be taken at face value. All complaints require a description of what the patient is experiencing. Sensory symptoms may reflect altered function (e.g., clumsiness), negative features (e.g., numbness), or positive features (e.g., paresthesias, hyperesthesia, hyperpathia, painful dysesthesias, or distorted sensations). Sometimes, the only complaint reflecting altered sensation involves decreased balance or incoordination. Even the complaint of weakness occasionally is described in confusing ways, such as fingers and toes feeling “stiff” or “numb” as opposed to weak. The history of potential toxic exposures should include a description of frequently used medications, as well as over-the-counter preparations, including vitamins. Social habits, use of alcohol or recreational drugs, or use of chemicals in hobbies should be investigated. The family history should include a description of any neuromuscular problems, pes cavus, or hammertoe deformities. The review of symptoms is important, as positive responses occasionally provide the only indication of an underlying systemic disease. As there is nothing specific about most toxic neuropathies, the resultant clinical signs resemble those produced by neuropathies of other causes. Examination of the peripheral nervous system has been described elsewhere and will not be repeated in detail here. The peripheral nervous system examination is relatively straightforward, but it comprises only one part of the clinical neurological and general physical examinations. Some toxic neuropathies are associated with signs of systemic poisoning. These signs most often involve the skin or nails, in the form of Mees’ line, dermatitis, or abnormal pigmentation (as in a gum lead line). Other features of system toxicity reflect the organ system involved, such as

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hematopoietic, cardiovascular, gastrointestinal, or renal systems. The peripheral nervous system also may be injured in association with the central nervous system, emphasizing the importance of a complete neurological examination. The clinical examination of suspected neuropathy usually emphasizes the most distal portions of the nervous system, as most forms of toxic neuropathy involve the longest and the largest axons in a “dying-back” stocking or stocking-glove distribution (Schaumburg and Spencer, 1987). This distribution reflects involvement of the neuron as the target of many toxins, an involvement that ultimately interferes with the neuron’s ability to maintain its distal axon. Most clinicians find the peripheral nervous system examination less complicated than examination of the central nervous system or behavior. This impression reflects the relative simplicity of peripheral nervous system function in contrast to the complexity of the central nervous system. In the context of suspected neuropathy, the examiner looks for signs of impairment, placing greatest emphasis on the most objective signs. For example, muscle stretch reflexes are sensitive to mild levels of abnormality, yet independent of patient motivation, education, level of concentration, or effort. Subjective signs of peripheral dysfunction include most of the clinical sensory tests, making these tests more difficult to interpret. The sensory examination includes evaluation of large sensory fibers subserving vibration, joint position, and touchpressure (“fine-touch”) sensations, and evaluation of small sensory fibers subserving pin-pain and temperature sensations. Light touch is difficult to quantify but, nevertheless frequently abnormal in large fiber neuropathies. Joint position is a relatively insensitive measure of sensory function relative to vibration sensation. Joint position abnormalities do not appear until a neuropathy becomes moderately severe. In contrast, Romberg testing accentuates the abnormalities of joint position sensation. Maintaining balance with the eyes closed is a functional sensory test when other problems, such as disorders of the vestibular system, are excluded. Normal balance with the eyes closed is inconsistent with other than a mild large fiber sensory neuropathy. Pin-pain sensation is a sensitive indicator of small fiber dysfunction. However, few predominant or exclusive small fiber neuropathies are caused by neurotoxicants. Most neuropathies that involve motor fibers are most severe in the distal lower extremities. Therefore, the feet are examined for atrophy and weakness, look-

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ing for high arches and hammer toe deformities. Experienced clinicians can reliably detect mild motor impairments and distinguish “apparent” weakness, due to pain inhibition or poor effort, from “true” weakness, due to loss of motor axons. Whereas a grip dynamometer is unable to distinguish between poor effort and a neurologic impairment, most clinicians can readily make this distinction (Albers, 2003). Reflex abnormalities are found in most clinically significant neuropathies, typically in the form of absent ankle reflexes. The afferent reflex arc is mediated by large sensory axons, the axons most often involved in all forms of neuropathy, including toxic neuropathies. The reflex examination results are reproducible, and absent ankle reflexes are an important sign of neuropathy. Reflexes that are easily elicited with facilitation should not be considered abnormal. The neurological examination includes substantial redundancy, increasing the overall reliability of combined findings. For example, fine touch, vibration, ankle reflexes, and balance (Romberg) are all mediated by the same large sensory axons. Therefore, a neuropathy producing loss of vibration sensation usually results in a positive Romberg sign and abnormal ankle reflexes. 33.3. The electromyography examination of suspected toxic neuropathy Electromyography (EMG), as used throughout this volume, consists primarily of motor and sensory conduction studies, evaluation of late responses, and the needle EMG examination. Few clinicians would debate the importance of the electrodiagnostic examination in the evaluation of neuropathy. The EMG examination is the foundation of Electrodiagnostic Medicine, and EMG results are used to confirm clinical signs, localize lesions to a degree not clinically possible, and identify pathophysiologic mechanisms (Albers, 1993). With few exceptions, electrodiagnosis is considered the “gold standard” for identifying and defining peripheral nerve abnormalities. Exceptions to this general axiom are primarily related to disorders involving small nerve fibers or sensory receptors, disorders that are usually not attributable to neurotoxic exposure. Nerve conduction studies have a prominent role in the evaluation of suspected neuropathy. The results are important in defining the type, distribution, and degree of peripheral involvement. Importantly, sensory conduction studies are the only noninvasive measures available able to localize sensory loss to the periphery.

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The role of the needle EMG examination in the evaluation of neuropathy is less important than that of nerve conduction studies. The needle EMG examination is used to document the distribution of axonal lesions and identify disorders such as polyradiculopathy that may be clinically indistinguishable from neuropathy. 33.3.1. Background Only a finite number of major pathophysiologic changes are relevant to the EMG classification of neuropathy. These changes include lesions associated with axonal degeneration, axonal stenosis, demyelination, and ionic channel abnormalities (channelopathies) (Aminoff and Albers, 1999). Axonal degeneration produces EMG changes similar to those associated with nerve transection, varying only in degree. Following transection, the distal axon degenerates (Wallerian degeneration). Several of the electrophysiologic changes are not immediately apparent, but they develop as Wallerian degeneration progresses. Landau (1953) showed that nerve stimulation distal to the site of nerve transection continued to evoke muscle contraction (and sensory and motorevoked responses) for several days, in spite of absent voluntary activity. Sensory and motor amplitudes subsequently diminish and ultimately disappear within about one week. The most objective EMG confirmation of “denervation” appears in the form of fibrillation potentials, which appear one to four weeks after the axonal degeneration (Gilliatt and Taylor, 1959). Spontaneous fibrillation potentials reflect muscle fiber hypersensitivity to acetylcholine (ACh). Over time, fibrillation potentials disappear as muscle fibers are reinnervated. When reinnervation is incomplete, as is often the case, the amplitude of persisting fibrillation potentials diminishes in association with muscle fiber atrophy (Albers, 1993). This information is relevant to the evaluation of patients with suspected toxic neuropathy because the most common response to a variety of neurotoxins is a distal “axonopathy” reflecting a metabolic failure of axonal transport of some nutrient essential for maintaining the distal axon (Schaumburg et al., 1983b). The timing of physiological changes after axonal degeneration is important, as many toxic neuropathies present in response to acute exposures. EMG evaluations performed in the first few days after clinical onset of the resultant neuropathy sometimes provide confusing information, which can be reconciled only by repeat evaluation in the context of evolving EMG changes.

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Axonal stenosis refers to reduced caliper or atrophy of the distal axon. In some forms of chronic toxic neuropathy, axonal stenosis develops before complete axonal degeneration. Alternately, small caliper axons may reflect regenerating axons. Regardless, conduction along an axon is proportional to axonal diameter, so conduction is reduced along distal axons. Because the axon continues to conduct a nerve impulse, the evoked amplitude remains essentially normal, membrane excitability remains intact, and volitional motor unit recruitment is unaffected (Albers, 1993). Disorders of the myelin sheath (demyelination or dysmyelination) or axonal membrane interfere with nerve conduction (Albers, 1993). Several models of demyelination are relevant to the evaluation of patients with suspected toxic neuropathy, because the metabolic lesions attributable to some peripheral neurotoxins also produce evidence of conduction slowing or conduction block. For many disorders, including several toxic neuropathies, the underlying pathophysiology at a given site along the axon resembles the findings associated with focal nerve compression (Ochoa, 1980). In models of focal compression, structural changes reduces or block local ionic current flow at the site of compression, thereby slowing or blocking propagation of the action potential (Ochoa et al., 1972; Fowler and Ochoa, 1975; Ochoa, 1980). Similar findings are associated with some toxic neuropathies, and decreased conduction velocity is not always diagnostic of primary demyelination. For example, conduction slowing is associated with decreased temperature, but this slowing is unrelated to any abnormality of the myelin sheath. With cooling, the slowing reflects prolonged opening and closing times of ionic channels. Troni et al. (1984) showed that transient hyperglycemia also produces conduction slowing that resolves within hours after glucose levels are normalized. Similarly, prolonged hyperglycemia is associated with decreased nerve myo-inositol and increased polyol pathway activity related to the increased conversion of glucose to sorbitol by aldose reductase (Greene et al., 1990). Reduced myo-inositol levels lead to reduced Na+/K+-ATPase activity and an increase in intracellular Na+. These metabolic changes produce a slight depolarization of the resting membrane potential, decreasing conduction along the axon independent of any structural alteration. A variety of neurotoxins potentially produce similar changes by inactivating or blocking the ionic channels (Sima et al., 1986).

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33.3.2. EMG protocol The most fundamental question addressed by the EMG evaluation involves localization of an abnormality to the peripheral nervous system. Additional questions addressed by the EMG evaluation include: (1) Do abnormalities involve primarily or exclusively sensory axons, motor axons, or a combination of both? (2) Are the abnormalities best explained by a polyneuropathy (diffuse involvement of nerves), a mononeuropathy multiplex (multifocal involvement of individual nerves), or a polyradiculopathy (diffuse involvement of nerve roots)? (3) Is there substantial slowing of nerve conduction to an extent greater than can be explained by loss of large caliber axons? The EMG protocol is designed to answer these questions and thereby characterize the patient’s neuropathy, using anatomical and physiological information to define the patient’s problem. The EMG results do not identify the cause of the patient’s diagnosis. In fact, the EMG results never “diagnose” a toxic neuropathy in isolation, as few EMG findings are specific for any one particular disorder. However, certain results suggest a specific class of disorders, and classification schemes based on combined clinical and EMG results allow the clinician to develop a differential diagnosis that is more focused than the one derived from the clinical evaluation alone. In the evaluation of a suspected neuropathy, the nerve conduction studies are particularly important in the classification scheme described above. The needle EMG examination plays a secondary role, and will usually be abnormal because most peripheral neurotoxins produce some degree of axonal degeneration, independent of an abnormality of the myelin sheath or the axonal membrane. The needle examination also permits evaluation of otherwise inaccessible muscles, such as paraspinal muscles. In this context, the EMG evaluation plays an important role in excluding or identifying disorders that mimic neuropathy, such as a polyradiculopathy, a distinction that cannot always be made clinically. In addition, information derived from the needle examination also addresses questions related to the time and extent of axonal injury more readily than do the nerve conduction study results (Albers, 1993). The use of additional electrodiagnostic tests, such as use of blink reflex studies, nerve excitability, or autonomic testing, should be based on the clinical presence (symptoms or signs) of dysfunction involving the particular areas being tested (e.g., brain stem dysfunction or dysautonomia). The sympa-

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thetic skin response (SSR) is a measure of small nerve fiber function that involves a differential recording from skin between areas of high and low sweat gland density. SSRs can be used to document autonomic impairment involving the sweat glands, but they have limited application in neurotoxic disorders. In general, neither their sensitivity nor specificity is known. Other tests of autonomic nervous function exist (e.g., R-R interval, Q-SART), but none has had extensive application or evaluation in the neurotoxic disorders (Albers, 2002). None of the neurotoxicants described in this chapter exhibits isolated autonomic nervous system toxicity. A few, such as the organophosphate compounds, exhibit transient cholinergic effects in response to acute intoxication, but there is no evidence that autonomic testing facilitates the diagnosis of toxic neuropathy. Indiscriminate use of any electrodiagnostic measures rarely, if ever, results in identification of diagnostically useful information in suspected toxic neuropathies. EMG protocols used to evaluate suspected neuropathy are straightforward. When clinical signs are mild, the evaluation is directed toward the most sensitive or susceptible sites, usually the distal lower extremities. When severe, evaluation of less involved sites is performed because absent responses provide no information about conduction slowing. Bilateral studies of some nerves are used to evaluate symmetry or to identify focal abnormalities at common sites of compression or cumulative trauma. The needle EMG examination supplements the nerve conduction studies, by documenting the presence of a suspected distal to proximal severity gradient, a finding characteristic of most forms of neuropathy. Information derived from motor unit configuration and insertional activity measures (amplitude and distribution) can distinguish acute, subacute, and chronic denervation. 33.3.3. Special considerations In the evaluation of any suspected neuropathy, several features of the EMG study deserve special attention. Amplitude measures reflect the number of activated nerve or muscle fibers, and these measures are particularly sensitive to axonal loss lesions. Therefore, careful electrode placement and use of supramaximal percutaneous stimulation are important in obtaining reliable results. Errors in either produce false-positive information, resulting from low amplitude responses or decreased conduction velocity due to failure to stimulate the largest axons. The distance between the

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stimulation site and the recording electrode also influences sensory and motor amplitudes. When the distance is short, amplitudes are larger than those recorded over longer distances. Similarly, improper surface measurements can result in inaccurate calculation of conduction velocity along the segment being studied. Temperature is perhaps the most important factor known to influence nerve conduction results that can be controlled. Near-nerve temperature has a profound effect on nerve conduction measures of amplitude, conduction velocity, and distal latency. Limb temperature should be monitored, and cool limbs warmed to maintain minimally acceptable temperatures. It is not sufficient to monitor room temperature, as room temperature has little relationship to limb temperature. 33.4. Additional measures There are additional tests used to supplement the clinical examination of sensory function. For example, quantitative sensory testing (QST) is a noninvasive and reproducible quantitative measure of sensation. However, the sensitivity and specificity of QST is known for only a few selected measures, and QST requires good subject cooperation and motivation, as it is sensitive to subtle motivational factors, as well as learning and age-effects. In general, QST has limited specificity, being unable to distinguish central from peripheral sensory disorders. Comparisons of QST with nerve conduction study results obtained from a population of patients with diabetic neuropathy found QST complimentary, but ancillary, to nerve conduction study results, with the sural recording being the best single predictor of mild neuropathy (Redmond et al., 1992). At present, routine clinical application of QST is limited, as is general application of QST in the investigation of toxic neuropathy (Bleecker, 1985, 1986; Beckett et al., 1986; Moody et al., 1986; Maurissen, 1988). Tissue biopsy is occasionally used in neurotoxicology evaluations. For example, among patients with solvent-induced neuropathy associated with n-hexane intoxication, peripheral nerve biopsy shows characteristic focal axonal swellings due to neurofilament aggregates. Biopsy of skin, fascia, muscle, and nerve obtained from patients with eosinophilia-myalgia syndrome associated with l-tryptophan intoxication typically demonstrates perivascular inflammation with lymphocytes and eosinophils. There are few neurotoxic disorders, however, in which tissue biopsy is

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indicated, other than to document the presence of problems unrelated to toxic exposure. For example, nerve biopsy can identify the evidence of vasculitis, sarcoidosis, amyloid deposits, and other distinctive pathological changes. Biopsy of most tissues, particularly nerve, is rarely useful in screening in the context of toxic neuropathy. The diagnosis of small fiber neuropathy is made on the basis of the clinical examination, normal or near normal nerve conduction study results, and documented abnormalities using specialized tests of smallfiber function (Lacomis, 2002). Recently, in addition to quantitative sensory testing and conventional nerve biopsy, skin biopsy has been used to evaluate the terminal portions of small nerve fibers, measuring the intraepidermal nerve fiber (IENF) density (Kennedy and Wendelschafer-Crabb, 1996; Holland et al., 1997; Mendell et al., 2001). Skin biopsies obtained from patients with suspected small fiber neuropathy may show a length-related reduction (most severe distally) in the IENF density, even in the presence of normal reflexes and normal sural responses (Holland et al., 1997). A study by the same group evaluated patients with idiopathic “burning feet” for which no cause had been established (Holland et al., 1998). All exhibited neuropathic pain but normal clinical and EMG evaluation. These patients also showed a reduced IENF density. Among patients with sural nerve biopsy, a few had normal results despite the abnormal skin biopsies, suggesting that skin biopsy was more sensitive than sural nerve biopsy for detecting small fiber abnormalities. Although skin biopsy shows potential for evaluating patients with painful small-fiber neuropathies, the sensitivity, specificity, and reproducibility of this technique remains to be determined. This technique appears to have limited application in the evaluation of toxic neuropathy, as few neurotoxicants are known to produce an exclusive small fiber neuropathy. 33.5. Documenting the dose of a substance to which a patient has been exposed A description of the methodologies used to establish the dosage of a specific neurotoxicant to which an individual is exposed is beyond the scope of this chapter. Recent reviews exist that address exposure assessment issues relevant to clinical neurotoxicology (Ford, 1999). Exposure may have little to do with the absorbed dose, and once absorbed, many factors influence development of neurological disease. Many biological monitors are important in estimating the dose

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to which an individual is exposed, including breath, blood, plasma, urine, red blood cells, adipose tissue, hair, nails, and bone. Suffice it to say, numerous factors, including the half-life in different compartments, influence the interpretation of the results vis-à-vis dose. Some techniques that measure substances directly or indirectly in the serum are particularly applicable to ongoing or recent exposures. For example, the effects of organophosphate pesticides on serum butyrylcholinesterase or red blood cell acetylcholinesterase can be measured, as can the metabolites of some organophosphate compounds. For example, 3,5,6 trichloro-2-pyridinol (TCP) is the main metabolite of chlorpyrifos, an organophosphate insecticide, and measurement of TCP in the urine provides a direct indication of recent dose. Occasionally, urinary excretion of the specific substance (e.g., arsenic) can be measured, providing another indication of recent dose to which an individual was exposed. However, laboratory results can be misleading. For example, total arsenic levels in urine contain nontoxic organic arsenic from ingestion of certain seafoods, thereby providing a “false positive” indication of high arsenic exposure. Some substances are stored in specific tissues, including arsenic in hair or nails, lead in bone, and some chlorinated compounds in fat. Measurement of arsenic in hair or nails gives an indication of the magnitude of arsenic dose over a relatively long time (months). Similarly, because absorbed lead is stored in bone, where it has a half-life of more than 25 years, blood lead levels reflect a combination of ongoing exposures from the environment and bone lead stores (Ford, 1999). Based on a patient’s age and residence (e.g., urban or rural), current blood lead levels can be used to determine if greater than anticipated background lead exposures have been experienced by the individual. For many substances, a specific biological measure of the dose to which an individual was exposed is unavailable. The duration and dose of exposure is, however, associated with development of neurotoxicity, and this information is important in establishing the cause of a suspected toxic neuropathy. For example, a toxic neuropathy may result from exposures to some substances that are acute and of relative massive dosage, recurrent and of moderate dosage, or chronic and low dosage. Certain neurotoxicants, such as arsenic, produce neuropathies that differ in their appearance depending on whether the exposure was acute or chronic. Other substances, such as Dapsone, produce neuropathy only after many years of cumula-

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tive exposure. Yet other substances, such as nitrofurantoin, produce different forms of neuropathy as exposure is continued after the first signs of neurotoxicity development (e.g., initially sensory followed by a motor-predominant neuropathy). The reason for these differences is not always clear, but it undoubtedly involves many additional factors including half-life, renal clearance, metabolism, genetic difference, target sensitivity, coexisting illnesses, competition with other neurotoxicants, and the ability and rate of the peripheral nervous system to repair ongoing damage. Fortunately, just as the clinician can establish the diagnosis of neuropathy independent of knowing that the patient was exposed to a particular neurotoxicant, information regarding the exposure profile is relevant only in establishing the cause of a particular neuropathy. It is in this context that the diagnostic scheme used in this chapter that limits the differential diagnosis to a manageable number of conditions for further evaluation has its greatest utility. 33.6. Classification of neuropathies based on EMG results There are many approaches to the classification of neuropathy. Most use clinical or neuropathological information to focus the investigation by reducing the number of disorders that must be considered in the differential diagnosis. The classification that follows relies heavily on EMG results (Donofrio and Albers, 1990), and this scheme is preferred for identifying toxic neuropathies because it incorporates a combination of information involving the modality of abnormality and the suggested pathophysiology. The physician first determines whether the presumed neuropathy is symmetrical and, therefore, consistent with a polyneuropathy, or whether signs are asymmetrical or multifocal, suggesting a mononeuritis multiplex or some atypical form of neuropathy. The information needed to make this determination is derived predominantly from the history and neurological examination results. On occasion, nerve conduction studies show substantial side-to-side amplitude differences, sufficient to suggest asymmetry. The needle EMG results also can sometimes identify subclinical asymmetry, thereby distinguishing, for example, neuropathy from a confluent mononeuritis multiplex. Conversely, asymmetries explainable by some factor unrelated to the neuropathy, such as a preexisting traumatic mononeuropathy, should not detract from a diagnosis of “polyneuropathy.” It is next determined whether

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motor or sensory fibers are involved exclusively. When both fiber types are involved, one involved more than the other (e.g., motor predominant neuropathy), or is the neuropathy best characterized as a combined sensorimotor polyneuropathy? In this classification scheme, the evaluation of motor conduction velocity is important and requires additional explanation. Criteria exist that can be used to identify conduction slowing that likely results from an abnormality of the myelin sheath (Albers and Kelly, 1989). However, conduction slowing, as applied to this classification of neuropathy, is used in a more general sense to include any slowing that cannot be attributed to a typical axonal loss neuropathy. This clarification is important, because several other pathophysiologic conditions produce substantial conduction slowing. These additional conditions include axonal inclusions, axonal stenosis, channelopathies, and selective loss of large axons. Information about conduction slowing comes from several sources, including segmental conduction velocity, F-wave latency, and distal latency. How much slowing is required to be considered abnormal? In this classification scheme, the emphasis is not on fulfilling strict conduction slowing criteria in a simple “yes” or “no” manner. In general, normal or near normal conduction velocities are associated with most axonal neuropathies, whereas abnormal conduction velocities are associated with disorders of the nerve membrane, caliber, or myelin sheath. In general, evidence of reduced motor conduction velocities in the vicinity of 80% of the lower limit of normal or distal latencies and F-wave latencies near or exceeding 125% of the upper limit of normal usually fulfill this requirement (Cornblath et al., 1991). As a general rule, however, conduction velocities less than 70% of the lower limit of normal cannot be attributed to axonal loss alone (Kelly, 1989). Abnormalities of this type should be found in more than one motor nerve. Criteria used to identify acquired demyelination usually rely on information about abnormal temporal dispersion or partial conduction block. Although this information is important, it is not used directly in the classification that follows. This is because several of the exceptions to the general rules about acquired demyelination involve atypical findings that are associated with some forms of toxic neuropathy. At least two explanations exist for the atypical types of conduction slowing associated with some toxic neuropathies. The first explanation involves conduction studies performed very early in the course of a severe, acute

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axonal neuropathy. Days before total axonal loss, nerve conduction findings may fulfill the criteria for acquired demyelination, analogous to the findings associated with severe vasculitic neuropathy (Donofrio et al., 1987). The second explanation involves neuropathies with a predilection for the largest motor fibers. These neuropathies also show substantial conduction slowing that resembles hereditary demyelination, differing only in their temporal profile. For these reasons, the classification scheme that follows relies primarily on the presence or absence of conduction slowing, deemphasizing the reliance on abnormal temporal dispersion and partial conduction block. In making the distinction about the presence or absence of substantial conduction slowing, there are three important considerations. The first consideration involves technique, as it is assumed that factors related to limb temperature, use of supramaximal stimulation, and distance measurements have been addressed appropriately. The second consideration involves attention to potential co-existing findings. It is important that conduction slowing from a pre-existing mononeuropathy is not attributed to a generalized neuropathy. The third consideration involves the converse of the second consideration. Namely, generalized conduction slowing that just fails to fulfill criteria of definite slowing should not be ignored. It may be relatively unlikely that the slowing represents a primary axonal neuropathy, particularly if motor response amplitudes are preserved and the findings are widespread. These latter two considerations directly involve overlapping issues involving EMG sensitivity and specificity. As the criteria become more specific, sensitivity is sacrificed, whereas more lenient criteria reduce specificity. Although different types of toxic neuropathy can be classified into broad categories based on EMG findings (e.g., Table 33.1), the categories are not exclusive, and several neuropathies appear in more than one of the categories. This lack of specificity reflects the limited number of responses to nerve injury from any cause, yet the physiological appearances may differ depending on the temporal proximity to injury. Numerous neurotoxicants are capable of producing identical physiologic findings, as are numerous other disorders including inflammatory diseases, hereditary neuropathies, and neuropathies associated with systemic illnesses. At times, any one of a large number of disorders provides an equally plausible explanation for the EMG findings. Further identification of the different forms of neuropathy often

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Table 33.1

Table 33.2

General Classification of neuropathy based on electrodiagnostic findings, modified from Albers (2003)

Toxic neuropathies presenting as a motor or motor greater than sensory neuropathy with conduction slowing, modified from Donofrio et al. (1990), Albers and Berent (1999), and Albers (2003)

1. Motor or motor greater than sensory Conduction slowing No conduction slowing 2. Sensory 3. Mixed sensorimotor Conduction slowing No conduction slowing 4. Mononeuritis multiplex or asymmetric neuropathy

requires recognition of systemic features or identification of a causative risk factor or agent (occupational, social, or pharmacologic). Conversely, symptomatic neuropathy often precedes recognition of a systemic disorder, identification of which may suggest the cause of a patient’s neuropathy. Although the emphasis of this chapter is on toxic neuropathies, the sections that follow include a brief description of the differential diagnosis that best reflects the particular EMG classification. The more general information is included to emphasize the numerous disorders that produce similar forms of neuropathy. More complete discussions exist in the referenced material. Discussion of every known toxic neuropathy is beyond the scope of this chapter. However, the most common or the most characteristic of a particular category are described. 33.6.1. Motor or motor greater than sensory neuropathy, with conduction slowing Conditions associated with a pure motor or a motor predominant neuropathy characterized by conduction slowing are listed in Table 33.2. The list is separated into general subcategories based on the known or suspected pathophysiology or cause, beginning with toxic causes, but followed by other neuropathies with similar patterns, including hereditary, inflammatory/infectious, metabolic, nutritional, or paraneoplastic disorders. At first glance, it might appear that most of the neuropathies would be easily distinguishable by their clinical features. This assumption is incorrect, however, as several of the disorders are virtually indistinguishable from one another. Conversely, the clinical features and temporal profile of a patient with a toxic neuropathy are unlikely to be confused with a slowly progressive hereditary neuropathy. The exception to this generalization is the patient whose neuropathy develops insid-

Amiodarone Arsenic (shortly after exposure) Carbon disulfide Cytosine arabinoside (ara-C) n-Hexane Methyl n-butyl ketone Perhexiline Saxitoxin (sodium channel blocker) Suramin Swine flu vaccine Other neuropathies with similar patterns Hereditary Hereditary motor sensory (demyelinating form CMT [HMSN I]) Hereditary tomaculous (liability to pressure palsy) Inflammatory/infectious Acute inflammatory demyelinating polyneuropathy (AIDP) Chronic inflammatory demyelinating polyneuropathy (CIDP) Diphtheria Dysimmune neuropathies HIV-associated Lyme disease Sjögren’s syndrome Systemic lupus erythematosus Vasculitis (confluent mononeuritis)

iously and is first “discovered” in the setting of a suspected exposure to a known neurotoxicant. For most forms of hereditary neuropathy, a careful family history, examination of close relatives, or genetic testing reduces the confusion. Examination of relatives in suspected disorders like hereditary motor sensory neuropathy type I (HMSN I), the demyelinating form of Charcot–Marie–Tooth disease, is particularly important because asymptomatic individuals with HMSN I may have clinically evident impairments or dramatic EMG abnormalities. Of course, an increasing number of hereditary neuropathies are amenable to genetic testing. Disorders producing these EMG findings are the inflammatory neuropathies, acquired immune diseases that produce demyelinating neuropathy. Included are acute and chronic inflammatory demyelinating polyneuropathy (AIDP and CIDP), as well as other types of dysimmune neuropathies (monoclonal gammopathy, osteosclerotic myeloma, multiple myeloma,

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Waldenström’s macroglobulinemia, gamma heavy chain disease, cryoglobulinemia, lymphoma, systemic lupus erythematosus, Castleman’s disease, occult malignancy, or human immunodeficiency virus infection). Many of these neuropathies are treatable, so their recognition is important. Among these conditions on the list, AIDP and CIDP are the most common, and the two disorders most likely to be confused with several forms of toxic neuropathy listed. Consider, for example, arsenic neuropathy. Neuropathy is a common and feared complication of arsenic intoxication (Poklis and Saady, 1990). Symptoms and signs of neuropathy appear 5 to 10 days after acute exposure and progress over weeks to a flaccid, areflexic quadriparesis with bifacial weakness, often requiring respiratory support. The EMG features of arsenic neuropathy produce substantial diagnostic confusion, based in part on the results obtained at different intervals after an acute exposure. Initial EMG findings are those of a motor greater than sensory neuropathy characterized by reduced amplitudes, borderline-low conduction velocities, absent F-waves, and partial conduction block in several motor nerves suggesting the possibility of acquired demyelination (Donofrio et al., 1987). The magnitude and nonuniform nature of conduction slowing usually suggests the presence of multifocal or segmental demyelination, and the findings are often thought to reflect a diagnosis of AIDP. The descriptions of arsenic neuropathy that identify it as a severe axonal neuropathy, are more characteristic of chronic arsenic intoxication or of findings remote from an acute arsenic poisoning. Follow-up EMG studies of an acute arsenical neuropathy that initially suggest the presence of acquired demyelination, typically show only absent sensory and motor response and severe denervation on the needle examination. There is only a brief time during which the conduction abnormalities are apparent, and all subsequent findings are more consistent with a dying-back axonal neuropathy. Findings suggestive of acquired demyelination probably reflected a generalized axonal failure before complete axonal degeneration. Unfortunately, the time interval during which those findings are present coincides with the period when the clinical diagnosis is unclear. Initial EMG studies may show absent sural responses when median sensory responses are still recordable. This finding is atypical of a “normal sural-absent median” sensory pattern frequently attribute to early AIDP, but it certainly does not exclude the diagnosis (Bromberg and Albers, 1993).

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Arsenic is a general protoplasmic poison, and the systemic features of arsenic poisoning suggest that something other than idiopathic AIDP explains the neuropathy. The initial symptoms of acute arsenic intoxication, nausea and vomiting, are symptoms indistinguishable from a gastrointestinal “flu.” Laboratory abnormalities include evidence of impaired liver function and bone marrow depression producing pancytopenia and basophilic stippling, a nonspecific abnormality of the red blood cell that occurs in response to several toxins. Abnormal liver function frequently accompanies acute AIDP, perhaps reflecting the preceding viral infection. Pancytopenia, however, is atypical of AIDP, although it also may reflect a postviral syndrome. Nevertheless, pancytopenia may provide the first indication of a toxic exposure or result in additional evaluation. An elevated CSF protein often is considered a prominent component of AIDP. In the appropriate clinical setting, it may be used to secure the diagnosis. However, an elevated CSF protein reflects damage to the blood-CSF barrier. The CSF protein is elevated in most patients with severe arsenic neuropathy, particularly when the onset is acute or subacute, as is common. In suspected arsenic neuropathy, additional investigations include a 24-hour urine evaluation for “heavy metals.” Additional clues suggesting a diagnosis of arsenic intoxication as the cause for a patient’s acute neuropathy develop over weeks and include a brownish desquamation of the hands and feet (arsenical dermatitis). About the same time, Mees’ lines appear on the fingernails and toenails. Unfortunately, none of these textbook features of arsenic intoxication typically appears until the diagnosis is no longer in question. Such systemic features are, nonetheless, important findings among patients with recurrent or chronic arsenic exposure. Several hexacarbon solvents and glues are implicated in neuropathy characterized by conduction slowing. Most exposures result from occupational or recreational use. The neuropathy associated with n-hexane is characterized by distal sensory loss, reduced or absent reflexes, weakness, muscle atrophy, and autonomic dysfunction. Among “huffers” who volitionally inhale n-hexane, the most common presentation is a motor greater than sensory neuropathy characterized by reduced evoked amplitudes and conduction velocities into a range suggestive of primary demyelination (Smith and Albers, 1997). Conduction slowing in this neurotoxic neuropathy is thought to reflect secondary myelin damage associated with giant axonal swellings. The axonal swellings reflect accumulation of neurofilaments.

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Inclusion of the swine flu vaccination among the “toxic” causes of neuropathy requires explanation. Epidemiological studies associated an excess number of cases of AIDP among those receiving the A/New Jersey/8/76 (swine flu) vaccination compared to a referent group (Safranek et al., 1991). However, the mechanism was thought to be immune-mediated, in the form of molecular mimicry, not a direct neurotoxic effect. 33.6.2. Motor or motor greater than sensory neuropathy, without conduction slowing Conditions producing a motor or motor greater than sensory neuropathy without conduction slowing are listed in Table 33.3. The list includes several neurotoxicants. However, by far the most prevalent condition listed involves the hereditary disorders, as many “idiopathic” neuropathies are eventually determined to be hereditary or familial. Among adults, the axonal form of Charcot–Marie–Tooth disease (HMSN II) is a common axonal motor greater than sensory neuropathy (Dyck, 1984). This autosomal dominant neuropathy is important because it is not always recognized among family members, and neuropathic symptoms and signs are attributed to “age.” It also is important because the findings are representative of several other conditions in this category. HMSN II begins insidiously after the third decade of life, with symptoms of distal weakness and sensory loss. Signs Table 33.3 Toxic neuropathies presenting as a motor or motor greater than sensory neuropathy without conduction slowing, modified from Albers (2003) and Albers and Berent (1999) Toxic Cimetidine Dapsone Disulfiram (carbon disulfide?) Lead? Nitrofurantoin Organophosphates (organophosphate-induced delayed neurotoxicity; OPIDN) Vincristine and related agents Other neuropathies with similar patterns Hereditary (axonal form of CMT [HMSN II]) Inflammatory/infectious (acute motor axonal neuropathy [AMAN], acute motor sensory axonal neuropathy [AMSAN]) Metabolic (hyperinsulin/hypoglycemia and porphyria) Paraneoplastic (lymphoma)

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include distal muscle atrophy producing an inverted champagne bottle appearance to the legs, pes cavus, hammer toes, hyporeflexia, and mild stocking or stocking-glove distribution sensory loss. The EMG examination shows low amplitude motor responses with normal, or only mildly slowed, conduction velocities. Patients may have normal sensory responses, making it difficult to differentiate the condition from progressive muscular atrophy. The needle EMG examination demonstrates a distal predilection of fibrillation potentials and chronic neurogenic motor unit changes. When the diagnosis is in question, patients with HMSN II and their physicians frequently question whether the neuropathy can be explained by a toxic exposure. Several inflammatory disorders produce a motor greater than sensory axonal neuropathy. This include axonal forms of AIDP, sometimes referred to as acute motor axonal neuropathy (AMAN) (Feasby et al., 1986) and acute motor sensory axonal neuropathy (AMSAN). There also are remote-effect (paraneoplastic) motor neuropathies associated with lymphoma (Schold et al., 1979) or carcinoma (Yamada et al., 1988). An important disorder in the list is “porphyria.” The hepatic porphyrias include acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, a group of metabolic diseases associated with the overproduction of porphyrin precursors and porphyrins. Acute attacks of porphyrias are characterized by the triad of abdominal pain, psychosis, and neuropathy (Bloomer and Bonkovsky, 1989; Sack, 1990; Albers, 2001). The importance of the porphyrias vis-`a-vis toxic neuropathy is related to the large number of substances, particularly medications, capable of inducing a porphyric attack. In this context, patients who share the genetic abnormality associated with the hepatic porphyrias, therefore, represent a particularly susceptible group. Porphyria neuropathy resembles acute AIDP, presenting with weakness, areflexia, dysautonomia, and elevated CSF protein. Mental status changes, an initial proximal predilection, photosensitivity, and biochemical evidence of abnormal porphyrin metabolism are important features of porphyria. Patients with porphyric neuropathy often present with asymmetric weakness, a finding atypical of most forms of neuropathy. For this reason, porphyria also is listed among the conditions producing an asymmetric neuropathy. EMG features of porphyric neuropathy are those of an axonal neuropathy or polyradiculoneuropathy. Motor amplitudes are reduced and conduction is

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normal or minimally reduced, consistent with the loss of large myelinated axons. Abnormal temporal dispersion and abnormal conduction block are not typical features. Motor unit recruitment is decreased consistent with the degree of clinical weakness, and profuse fibrillation potentials appear after the fourth week of weakness, confirming the extent of axonal loss (Albers et al., 1978). Sensory responses may be normal or show diminished amplitude. Rare studies fulfill criteria for primary demyelination, but this may reflect a generalized axonal failure prior to complete axonal degeneration, similar to the findings in acute arsenic neuropathy. Many of the neurotoxicants that produce a motor or motor greater than sensory axonal neuropathy are medications. Vincristine, vinblastine, vinorelbine, and related chemotherapy medications produce an axonal sensorimotor neuropathy. On occasion, however, treatment results in rapidly progressive weakness with little sensory loss resembling a “pure motor” neuropathy or neuronopathy. EMG studies confirm the axonal pathophysiology, with low-amplitude motor responses, mild conduction slowing consistent with loss of large myelinated axons, and profuse fibrillation potentials and neurogenic motor unit changes. The motor “neuropathy” may localize to the motor neuron, not the distal axon, per se, making motor neuronopathy a more accurate descriptor. Dapsone is another medication that produces a motor neuropathy (Gutmann et al., 1976). However, Dapsone neuropathy is an “atypical” neuropathy, which may present with marked asymmetry. Dapsone is metabolized by N-acetyl transferase, the same enzyme the acetylates isoniazid, and susceptible patients may be slow acetylators (Ahrens et al., 1986). Other medications associated with this category of neuropathy include disulfiram and nitrofurantoin (Holmberg et al., 1980; Penn and Griffin, 1982; Davey, 1986). Disulfiram is used to promote alcohol abstinence. Disulfiram blocks the metabolism of alcohol at the acetaldehyde stage, resulting in high levels of acetaldehyde and unpleasant symptoms, forming the rationale for promoting abstinence. Disulfiram produces a dose-related neuropathy characterized by weakness, few or no sensory symptoms or signs, and areflexia (Davey, 1986). Weakness usually develops gradually, but, on occasionally, it may be sufficiently rapid as to mimic AIDP (Palliyath et al., 1990). Nitrofurantoin may produce a motor neuropathy, although it more typically produces a mild neuropathy characterized by paresthesias, pain, and stocking or

JAMES W. ALBERS AND JAMES W. TEENER

stocking-glove sensory loss and distal areflexia. This form of neuropathy is said to occur in about 0.2% of patients receiving nitrofurantoin (Davey, 1986), usually after long-term use for chronic urinary tract infection among elderly females who have impaired renal function and presumably abnormally elevated blood levels (Holmberg et al., 1980; Penn and Griffin, 1982). In contrast, nitrofurantoin-induced motor neuropathy produces a rapid onset of severe weakness. This motor neuropathy is superimposed on the sensory neuropathy but does not produce additional sensory symptoms or signs. Organophosphate esters have application in pesticides and some “nerve gases” (Lotti et al., 1984; Davis et al., 1985; Senanayake and Karalliedde, 1987). These compounds inactivate acetylcholinesterase, and acetylcholine accumulates in muscarinic and nicotinic cholinergic neurons (Moretto and Lotti, 1998). In the setting of an acute intoxication, muscarinic overactivity produces miosis, increased secretions, sweating, gastric hyperactivity, and bradycardia, whereas nicotinic overactivity results in fasciculations and skeletal muscle weakness. Exposure to some organophosphate compounds, in amounts sufficient to produce substantial inhibition of plasma butyrylcholinesterase and red blood cell cholinesterase, may be followed within a few weeks by onset of a rapidly progressive neuropathy. This motor predominant neuropathy develops after recovery from the effects of an acute poisoning, thus the name organophosphate-induced delay neurotoxicity (OPIDN) (Lotti et al., 1984; Senanayake and Karalliedde, 1987). OPIDN is characterized as a distal axonopathy affecting the peripheral nerves and the spinal cord (Moretto and Lotti, 1998). Spinal cord involvement is inferred from late development of the corticospinal tract signs as the neuropathy resolves (Aring, 1942; Abou-Donia and Lapadula, 1990). This combination of neuropathy with pyramidal tract signs has been associated with Jamaica ginger (“jake”) palsy, a syndrome observed commonly during the late 1920s when many Americans purchased adulterated Jamaica ginger to circumvent existing Prohibition laws (Morgan and Penovich, 1978). The adulterant was triorthocresyl phosphate (TOCP), a neurotoxic organophosphate. Like OPIDN, the earliest manifestation of jake palsy was peripheral neuropathy. In time, as the peripheral signs resolved, a pyramidal tract syndrome emerged. Currently, only a few cases of OPIDN are reported world wide per year, typically after a massive suicidal ingestion of an organophosphate insecticide producing life-threatening cholinergic effects

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and requiring intensive medical treatment (Lotti et al., 1986; Moretto and Lotti, 1998). 33.6.3. Sensory neuropathy or neuronopathy, without conduction slowing Neuropathies or neuronopathies characterized by exclusive, severe sensory loss are atypical of most neuropathies. Sensory neuronopathies present with unpleasant paresthesias and numbness in association with signs of choreoathetoid movements (pseudoathetosis), gait ataxia, diminished vibration and joint position sensations, minimally decreased pain sensation, a positive Romberg, and areflexia. The EMG examination shows substantially reduced or absent sensory responses, normal motor responses, and a normal needle evaluation. The differential diagnosis includes a manageable number of disorders (Table 33.4). Among the conditions unrelated to toxic exposures, Sjögren’s syndrome is probably the most common systemic disorder producing a severe sensory neuronopathy. The diagnosis of Sjögren’s syndrome in the presence of a sensory neuronopathy is suggested by accompanying complaints of dry eyes and mouth. The diagnosis is supported by elevated autoantibodies SSA (Ro) and SSB (la) and a salivary gland biopsy showing inflammatory infiltrates (Laloux et al., 1988). A paraneoplastic sensory neuronopathy frequently accompanies a small cell malignancy and anti-neuronal nuclear antibodies (Kiers et al., 1991). Carcinomatous sensory neuronopathy is proba-

Table 33.4 Toxic neuropathies presenting as a sensory neuropathy or neuronopathy, without conduction slowing, modified from Albers (2003) and Albers and Berent (1999) Toxic Cisplatin Ethyl alcohol Metronidazole Nitrofurantoin Pyridoxine Thalidomide Thallium (small fiber) Other neuropathies with similar patterns Hereditary (Friedreich’s ataxia, hereditary sensory) Inflammatory/infectious (Fisher variant of AIDP, human immunodeficiency virus, idiopathic sensory ganglionitis, Lyme disease, Sjogren’s syndrome) Nutritional (gastric resection, isoniazid, vitamin deficiency) Paraneoplastic

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bly the most distinctive remote-effect neuropathy (Donofrio et al., 1989). Chronic Lyme disease has been associated with a sensory neuropathy, as part of acrodermatitis chronica atrophicans (Kindstrand et al., 2000); cranial neuritis remains the most common neurological manifestation of Borrelia infection. Asymmetric or multifocal presentations of dense sensory loss suggest the diagnosis of inflammatory ganglionitis. On occasion, patients who are human immunodeficiency virus (HIV) positive develop a sensory neuronopathy. Vitamin deficiency syndromes, including those associated with thiamine (vitamin B1), pyridoxine (vitamin B6), cobalamin (vitamin B12), and alpha-tocopherol (vitamin E) deficiency show prominent sensory loss. However, only the syndromes associated with pyridoxine and tocopherol show exclusive sensory loss when severe (Nolan and Albers, 2003). Isoniazid anti-tuberculous therapy produces a neuropathy characterized by isolated sensory symptoms and signs during its early stages. With continued treatment, distal weakness may develop. Isoniazid produces neuropathy by depleting pyridoxine, as it combines with pyridoxine, and the combined derivative is excreted, resulting in pyridoxine deficiency (Ross, 1958). The Fisher syndrome is a variant of AIDP, and a presumed immune-mediated disorder that presents with subacute onset sensory loss, gait ataxia, impaired eye movements, and abnormal sensory responses (Fross and Daube, 1987). In addition, numerous forms of hereditary sensory neuropathy exist. The most common neurotoxicants producing a sensory neuropathy or neuronopathy are medications (e.g., cisplatin, isoniazid, metronidazole, nitrofurantoin, and thalidomide) (Lagueny et al., 1986). The best studied of these are cisplatin and related antineoplastic chemotherapy medications. Cisplatin produces a sensory neuronopathy as its main dose-limiting effect. Most patients treated with cisplatin develop symptomatic large fiber sensory loss and diminished reflexes. Sensory response amplitudes are used to monitor the onset of neuropathy during chemotherapy. A close relationship has been demonstrated between the decline in the sensory amplitude and onset of clinical symptoms and loss of reflexes (Molloy et al., 2001). Cisplatin neuronopathy is indistinguishable from the paraneoplastic sensory neuronopathy associated with small cell lung carcinoma. The presence of anti-neuronal nuclear antibodies supports an paraneoplastic cause (Kiers et al., 1991), but does not exclude the possibility of a superimposed toxic neuropathy.

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Pyridoxine (vitamin B6) is an essential vitamin. However, it is also a potent sensory neurotoxicant. Pyridoxine is occasionally taken in “megadoses” to treat a variety of nonspecific syndromes. Schaumburg and associates (1983a) associated dose-related neurotoxicity with excessive (long-term, low level cumulative or short-term, high level) pyridoxine exposure. With large doses, sensory loss may have abrupt onset, be complete and irreversible, and involve all cutaneous and facial and mucous membrane areas (Albin et al., 1987). Like all severe sensory neurotoxicants, sensory responses disappear as sensory loss increases. Alcohol-associated neuropathy is considered among the most common neuropathies. It is, therefore, ironic that a causal relationship between ethyl alcohol exclusive of nutritional deficiency has not been established. Although neuropathy frequently accompanies chronic alcoholism, the cause of the neuropathy is surrounded in controversy (Nolan and Albers, 2003). It is unclear whether alcohol-related neurological manifestations reflect the direct neurotoxicity of alcohol or its metabolites, poor nutrition, genetics, or combinations of these factors (Charness et al., 1989). The pathogenesis of alcohol-related neuropathy remains controversial because most individuals who consume large amounts of alcohol are also nutritionally compromised (Victor et al., 1989). Nevertheless, ethyl alcohol, alone or in combination with vitamin deficiency states, exerts adverse effects at multiple levels of the nervous system (Albers and Bromberg, 1995). The most common form of alcohol-related neuropathy is a slowly progressive sensorimotor axonal neuropathy (Charness et al., 1989). Another classic form of alcohol-nutritional deficiency neuropathy presents with distal burning paresthesias, lancinating leg pain, distal sensory loss, poor balance, and distal areflexia, findings suggestive of a pure sensory neuropathy. EMG evaluation shows only low amplitude sensory responses with slightly prolonged distal latencies in the hands and absent sensory responses in the legs. Motor conduction studies and the needle EMG are unremarkable. On occasion, other neurological manifestations, such as thiamine-responsive Wernicke syndrome (dementia, ophthalmoplegia, and ataxia) may first suggest the possibility of an alcohol-nutritional deficiency syndrome. Systemic evidence of alcohol toxicity includes hepatic cirrhosis. Unfortunately, there is nothing unique to distinguish the sensory neuropathies of excessive alcohol consumption or vitamin deficient states. Support for a nutritional cause of alcohol-related neuropathy includes evidence that neuropathy is not

JAMES W. ALBERS AND JAMES W. TEENER

induced by excessive alcohol among individuals who receive nutritional supplementation (Victor et al., 1989). Further, a typical Wernicke–Korsakoff encephalopathy and neuropathy occasionally develop after gastroplasty for morbid obesity in the absence of alcohol exposure (Cirignotta et al., 2000). Yet, alcohol is known to impair axonal transport (McLane, 1987), and Behse and Buchthal (1977) reported the occasional development of a typical alcohol neuropathy despite of normal nutrition. A unique neuropathy is associated with thallium intoxication. Thallium, like several other metals and metalloids including arsenic, lead, mercury, and lithium, is a neurotoxicant. Thallium neuropathy, however, is atypical of most other toxic neuropathies in its degree of small nerve fiber involvement. Most reports of acute thallium toxicity emphasize painful dysesthesias in the feet and legs, symptoms reminiscent of arsenic poisoning (Bank, 1980; Wilbourn, 1984; Windebank, 1993; Kubis et al., 1997). Dysautonomia with abdominal colic, nausea, vomiting, diarrhea, and anhidrosis frequently accompany thallium intoxication, often preceding onset of the neuropathy (Kalantri and Kurtz, 1988; Herrero et al., 1995). Findings of markedly diminished pin-pain sensation but preserved reflexes support the impression that thallium produces a small fiber neuropathy. In severe thallium neuropathy, distal weakness develops, so this is not an exclusive sensory neuropathy. In fact, thallium neuropathy may produce quadriparesis and respiratory failure, similar to that seen in AIDP (Andersen, 1984; Cavanagh, 1984). Like many neurotoxicants, thallium induces neuropathy in the setting of systemic poisoning, producing skin rash, Mees’ lines, and, the cardinal clinical feature of thallium neuropathy, alopecia. 33.6.4. Sensory greater than motor (sensorimotor) neuropathy, with conduction slowing Few disorders fulfill the description for this form of neuropathy (Table 33.5). Ironically, the most common neuropathy in the US, diabetic neuropathy, falls in this category. In the context of toxic neuropathy, diabetes is important because a clinically evident or subclinical diabetic neuropathy can present before the diagnosis of diabetes mellitus has been established. Therefore, a patient exposed to a potential neurotoxicant and found to have neuropathy may inadvertently be diagnosed with a toxic neuropathy based on opportunity for exposure. Failure to develop an appropriate differential diagnosis often occurs when the diagnosis appears

TOXIC NEUROPATHIES Table 33.5 Toxic neuropathies presenting as a sensorimotor neuropathy with conduction slowing, modified from Donofrio et al. (1990) Toxic Saxitoxin (red tide) Tetrodotoxin (puffer fish) Other neuropathies with similar patterns Inflammatory/infectious (chronic inflammatory demyelinating [CIDP]) Metabolic (diabetes mellitus, uremic [end stage renal disease])

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out any evidence of abnormal temporal dispersion or partial conduction block (Albers, 1997). Conditions that commonly produce neuropathy, such as diabetes mellitus, are occasionally implicated in the controversy of whether or not an underlying neuropathy of any cause predisposes that individual to a toxic neuropathy. This concept may have its origin in association with the apparent predisposition to compression neuropathy among patients with a known diabetic neuropathy. However, the hypothesis that patients with neuropathy of any cause show increased susceptibility to known neurotoxicants remains unproven. 33.6.5. Sensory greater than motor (sensorimotor) neuropathy, without conduction slowing

obvious. Fortunately, diabetes mellitus is one of only a few sensorimotor neuropathies that produce findings of axonal loss and substantial conduction slowing. Patients who have renal failure independent of diabetes mellitus develop a sensorimotor neuropathy characterized by low amplitude motor and sensory responses, sometimes in association with pronounced conduction slowing (Dyck et al., 1975). This is most apparent among patients with end-stage renal disease, where the degree of conduction slowing is greater than expected if it was due only to loss of large myelinated fibers (Said et al., 1983). Setting aside the discussion of whether or not the conduction slowing in diabetes or uremia represents primary demyelination or a membranopathy, there are few situations or neurotoxicants that produce diagnostic confusion. Arguably, the most common situation to produce diagnostic confusion involves poor technique, because reduced limb temperature produces conduction slowing that resembles the slowing associated with diabetic neuropathy. Of course, conduction slowing due to cool limb temperature also produces increased (not decreased) sensory amplitudes, making the distinction from a toxic-metabolic lesion relatively apparent. Neurotoxicants that block sodium channels reduce conduction velocity, but they are uncommon. Two that do, however, are tetrodotoxin derived from the puffer fish and saxitoxin derived from contaminated shell fish (red tide) (Jacques et al., 1980; Lombet et al., 1988; Long et al., 1990). Blockade of sodium channels decreases the local currents associated with action potential propagation, an effect similar to that seen with reduced temperature that slows conduction velocity. Motor response amplitudes are reduced with-

Sensorimotor neuropathies of the axonal type are the most common neuropathies encountered by the neurologist. Typically, they present with symmetrical sensory signs or with sensory more than motor signs in a stocking or stocking-glove distribution. Signs include diminished touch-pressure, vibration, and pin-pain sensations; distal weakness and muscle atrophy concordant with the degree of weakness; and hypoactive or absent reflexes. Most neuropathies in this category show EMG evidence of low amplitude or absent sensory responses early in the clinical course, followed later by low amplitude motor responses. Criteria for substantial conduction slowing are not fulfilled. The needle examination shows evidence of denervation (fibrillation potentials and positive waves) and reinnervation (chronic motor unit changes). Numerous conditions produce findings of the type described in the preceding paragraph, including many toxic or metabolic neuropathies. The differential diagnosis for an axonal sensorimotor neuropathy includes hereditary, degenerative, metabolic, systemic, nutritional, granulomatous, and toxic disorders. Unfortunately, the numerous disorders are often difficult to distinguish from one another, either clinically or based on EMG results. Further, of all the categories of neuropathy described, this form is likely to include the largest number of idiopathic neuropathies that remain undiagnosed even after extensive evaluation. Some of the neurotoxicants capable of producing an axonal sensorimotor neuropathy are listed in Table 33.6. This table also does not include the other numerous causes that must be included in the differential diagnosis of any sensorimotor neuropathy (see, for example, Donofrio and Albers, 1990). Surprisingly,

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many of the toxic neuropathies in this category are slowly progressive and relatively mild, a generalization that may simply reflect the magnitude of exposure, as many of the items are included among the other categories when exposure is greater. Consider arsenic exposure, for example. Chronic, low-level arsenic exposure in sufficient amounts produces a mild sensorimotor axonal neuropathy. Exposure to higher levels is associated with a severe, acute neuropathy resembling AIDP. For many of the neurotoxicants listed in Table 33.6, the only evidence linking them to a patient’s neuropathy is evidence of an abnormally elevated blood, urine or tissue level. Such a finding, in isolation, is insufficient to establish causation. However, assuming the elevated level reflects ongoing exposure, removal from exposure with a resultant resolution of the neuropathy is strong evidence supporting a causal relationship, as most toxic neuropathies are reversible once ongoing exposure is terminated. Following removal from exposure, there may be progression for a few weeks before stabilization and improvement of the neuropathy (coasting). For a few items listed in the table, there may be additional clues in the form of combined findings suggesting a toxic etiology. Examples include the association of postural tremor and neuropathy produced by lithium or mercury intoxication (Pamphlett and Mackenzie, 1982; Albers et al., 1988), neuropathy with preserved reflexes with abnormal corticospinal tract signs and anemia produced by vitamin B12 deficiency (McCombe and McLeod, 1984), and neuropathy and myopathy produced by colchicine (Kuncl et al., 1987). The role of clinical and EMG follow-up is relevant to the evaluation of slowly progressive sensorimotor neuropathies. On occasion, the cause of a neuropathy is only apparent after a period of continued observation. This is frequently the case in some of the hereditary axonal neuropathies, as additional involved relatives are subsequently identified. The controversy involving ethyl alcohol-related neuropathy was discussed in association with the sensory neuropathies. Regardless of whether or not the alcohol-related neurologic disorders reflect a direct neurotoxic effects of alcohol, its metabolites, nutritional disorders, genetic factors, or combinations of these factors (Behse and Buchthal, 1977; Charness et al., 1989; Victor, 1989), alcohol abuse frequently is associated with an axonal sensorimotor neuropathy characterized by slowly progressive sensory loss, distal weakness, unsteady gait, and areflexia.

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Chronic exposure to some medications, among which phenytoin is a good example, produces a neuropathy. Phenytoin neuropathy is characterized by large fiber sensory abnormalities, imbalance, and hypo- or areflexia. EMG results show low amplitude sensory responses, normal motor responses, and borderline-low motor conduction velocities. The needle examination shows chronic neurogenic changes, with reduced recruitment and large amplitude motor units, but little evidence of abnormal insertional activity, findings indicating very slow denervation so that re-innervation keeps pace with ongoing denervation. The diagnosis of a phenytoin neuropathy often is serendipitous, and abnormalities identified only when an EMG evaluation is performed for a reason unrelated to the question of neuropathy (e.g., radicular pain). 33.6.6. Mononeuritis multiplex, with or without conduction slowing Most neuropathies are characterized by symmetric motor or sensory signs. Generalized neuropathies that defy that axiom are listed in Table 33.7. Hereditary neu-

Table 33.6 Toxic neuropathies presenting as a sensorimotor neuropathy with no conduction slowing, modified from Albers (2003) and Albers and Berent (1999) Acrylamide Amitriptyline Arsenic (chronic) Carbon monoxide Cobalamin (Vitamin B12) deficiency Colchicine (neuromyopathy) Ethambutol Ethyl alcohol Ethylene oxide Gold Hydralazine Isoniazid Lithium Mercury (elemental) Metronidazole Nitrofurantoin Nitrous oxide (myeloneuropathy) Paclitaxel Perhexiline Phenytoin Thallium Vincristine

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ropathy with liability to pressure palsies (HNLPP) may mimic a diffuse sensorimotor neuropathy (Felice et al., 1994). “Inflammatory” disorders of presumed autoimmune etiology constitute the most common cause of asymmetric neuropathies. They include acute motor axonal neuropathy (AMAN), multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, and multifocal motor neuropathy (MMN). AMAN represents an axonal form of AIDP, which shows a strong association with anti-ganglioside antibodies against GM1, GD1a, GalNAc-GD1a, or GD1 (Ogawara et al., 2000). MADSAM neuropathy, or Lewis-Sumner syndrome, presents with multifocal motor and sensory loss and nerve conduction evidence of conduction block and other features of demyelination (Saperstein et al., 1999). MMN produces asymmetrical weakness and muscle wasting in association with prominent conduction slowing in motor nerves, but normal sensory responses in the same nerves. Anti-GM1 ganglioside antibodies may be present (Chaudhry et al., 1993). Lyme disease frequently presents as a cranial neuritis involving the facial nerves (Eggenberger, 1993). Finally, this category of “neuropathy” includes disorders caused by structural abnormalities, such as syringomyelia, cervical spondylosis, and

Table 33.7 Toxic neuropathies presenting as a mononeuritis multiplex or asymmetric neuropathy Toxic-metabolic Dapsone Lead Porphyria Trichloroethylene (cranial neuritis) Toxic oil syndrome l-Tryptophan Other neuropathies with similar patterns Hereditary (distal myopathy, hereditary neuropathy with liability to pressure palsies [HNLPP], Kennedy syndrome, progressive muscular atrophy) Idiopathic (atypical motor neuron disease [e.g., Aran–Duchenne], inclusion body myositis) Inflammatory/infectious (acute motor axonal neuropathy [AMAN], diabetic amyotrophy, idiopathic brachial neuritis [Parsonage Turner], Lyme disease, multifocal acquired demyelinating sensory and motor [MADSAM], multifocal motor neuropathy [MMN], poliomyelitis, vasculitis, West Nile virus) Structural (cervical spondylosis, polyradiculopathy, without neuropathy, syringomyelia)

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polyradiculopathy without neuropathy (McGonagle et al., 1990). There are many syndromes producing a mononeuritis multiplex or a markedly asymmetrical motor or motor greater than sensory neuropathy. However, more than 100 years ago, lead was the only neurotoxicant associated with this form of neuropathy. It is curious, therefore, that most descriptions of lead neuropathy were reported at a time when lead also would have been one of the few items appearing in a differential diagnosis of an asymmetric neuropathy. Therefore, a painter, who had an opportunity for exposure to leadbased paints in the early 1990s and who developed an asymmetric motor neuropathy, likely would have been diagnosed with lead neuropathy. The differential diagnosis would not have included the numerous other conditions listed in Table 33.7, as most were not described until the mid- to late-twentieth century. Porphyria was discussed among the forms of motor neuropathy without conduction slowing, and it was noted that asymmetric weakness is a characteristic feature of porphyric neuropathy. The metabolic defects associated the hepatic porphyrias interfere with heme syntheses at sites along the synthesis pathway. All of these sites are close to the site at which lead interferes with heme synthesis. This similar site of action may explain, indirectly, the similarities between the historical descriptions of lead neuropathy and porphyric neuropathy, namely asymmetric, pure motor weakness. It also is conceivable that lead is simply one of the numerous substances capable of inducing porphyric neuropathy among patients with porphyria, not a peripheral neurotoxicant in and of itself. Dapsone neuropathy is included among the motor or motor greater than sensory neuropathies, without conduction slowing. Dapsone (4,4-diamminodiphenyl sulphone) was widely used to treat leprosy without reports of neuropathy. It also is prescribed for a variety of skin conditions, including dermatitis herpetiformis. Initial descriptions of Dapsone-induced neuropathy appeared about 30 years ago in association with chronic, long-term exposures at relatively high dosage (Gutmann et al., 1976; Koller et al., 1977). Most reports include descriptions of asymmetrical weakness in a distribution suggesting a diagnosis of mononeuritis multiplex. However, the paucity of sensory signs is inconsistent with that diagnosis. Trichloroethylene (TCE) exposure is associated with a cranial neuritis with a predilection of trigeminal nerve involvement (Feldman, 1970). This cranial mononeuropathy multiplex is so characteristic of TCE

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over-exposure, that it is thought unwise to incriminate TCE as the cause of a neuropathy unless cranial nerves were involved (Fullerton, 1969). This cranial neuritis is said to follow TCE exposure via inhalation anesthesia (perhaps in combination with soda lime) or occupation exposures (Buxton and Hayward, 1967; Feldman et al., 1970). Eosinophilic myalgia syndrome (EMS) was associated with l-Tryptophan, or perhaps with a novel amino acid contaminant associated with its production (Belongia and et al., 1990; Selwa et al., 1990). EMS consists of eosinophilia, characteristic peau d’ orange skin changes, myalgia, and an atypical mononeuritis multiplex showing patchy sensory loss with sparing of motor fibers in the same nerves. EMS has essentially disappeared after the initial case reports, perhaps because of decreased use of l-tryptophan or because of correction of the defective manufacturing process. Sensory axons may have selectively injured as they transverse the subcutaneous tissues, the primary site of inflammation and perhaps the autoimmune target. As such, sensory involvement may represent a bystander effect, not direct neurotoxicity. A reactive fibrosis of subcutaneous tissue could explain neurologic progression after removal from exposure, another feature atypical of other forms of toxic neuropathy. The 1981 Spanish “toxic-oil syndrome” (TOS) epidemic resembles EMS. Patients diagnosed with TOS showed eosinophilia, myalgia, weakness, and they ultimately developed contractures of the jaw and extremities resembling scleroderma. TOS was linked to consumption of aniline-denatured and refined rapeseed oil that had been illegally marketed as cooking oil (Kaufman, 1991; Verity et al., 1991; Bolster and Silver, 1994; Kaufman and Krupp, 1995). Although many aniline-derived oil components were identified, no causative agent was ever identified for

TOS (Schurz et al., 1996). The similarities between EMS and TOS, including the distribution of prominent sensory involvement, could reflect an underlying vasculitis or fasciitis. 33.6. Establishing the cause of neuropathy The first step in identifying the cause of a neuropathy is to consider the numerous possibilities. In the context of potential toxic neuropathies, pharmaceutical, industrial, recreational, and environmental exposures are all possible considerations. However, the opportunity for exposure does not prove that the exposure caused the neuropathy, even when the exposure is to a known neurotoxicant. Simply identifying the presence of a potential neurotoxicant does not ensure that it produced the neuropathy. Simply put, association does not establish causation. How then does the clinician establish the cause of neuropathy? Fortunately, the methodology use to establish causation is well developed and intuitive to most clinicians, as it resembles the methodology used to establish a clinical diagnosis. Clinicians use the scientific method of hypothesis generation and testing to establish a diagnosis of neuropathy and to formulate a differential diagnosis. However, arriving at the correct neurological diagnosis does not ensure that the cause of the underlying neurological problem has been identified. A separate process is used to establish the cause of neuropathy. The methodology used to establish causation in the context of a suspected toxic neuropathy is sometimes referred to as the Bradford–Hill criteria (1965). These criteria consist of a list of questions that must be considered (Table 33.8). The questions address issues of temporal association, dose, biologic plausibility, and identification and elimination of competing causes to establish a

Table 33.8 Questions useful in establishing a toxic etiology, modified from Hill (1965) 1. 2. 3. 4. 5. 6. 7. 8.

Temporality: appropriate timing of exposure and signs? Plausibility: is the effect biologically plausible? Biological gradient: expected dose-response relationship? Coherence: removal from exposure modifies effect? Existence of animal model? Specificity: cause-effect relationship limited to exposed individuals? Strength of association: high relative risk based on sound epidemiology studies? Consistency: repeated observations among different studies and different investigators? Differential diagnosis: other causes eliminated?

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neurotoxic etiology. The answers to the questions help distinguish association from causation. The fundamental concept involving a temporal association between exposure to a potential neurotoxicant and the subsequent development of neuropathy is important. Yet, temporal association is only one of several important considerations. While it is obvious that the effect (neuropathy) cannot proceed the cause (exposure), general pharmacologic and toxicologic principles of doseresponse are often not considered in establishing causation. A neurotoxicant cannot produce neuropathy without being present in sufficient amount. Unfortunately, the ability to establish a neurotoxic cause frequently is limited by the absence of a definite measure of exposure. The Bradford–Hill criteria also address issues related to epidemiological studies. All scientific studies are not equal. Case reports are useful in generating hypotheses about possible cause-effect issues, but only cohort studies and case-control studies are capable of establishing causation. Conversely, a well-designed but negative cross-sectional study provides no support for a toxic association. To most clinicians, the most difficult question listed among the Bradford–Hill criteria, and the one that requires the greatest clinical experience, is the one related to competing causes. The expression “consistent with” frequently links some clinical symptom, sign, or EMG finding to a particular cause, without acknowledging that the finding likely is consistent with numerous other causes. All causes must be identified before they can be evaluated and possibly eliminated from consideration. The fact that many neuropathies are idiopathic or without known cause complicates this process. The example given earlier involving lead neuropathy highlights the problem of an incomplete differential diagnosis. In the earlier twentieth century, a patient with lead exposure and asymmetrical weakness, a finding consistent with lead neuropathy, could not have been diagnosed with any of the numerous other disorders consistent with asymmetrical weakness because the conditions had not as of then been described. Similarly, development of severe sensory loss and areflexia in the setting of excessive alcohol consumption is consistent with an alcohol-related sensory neuronopathy. If, in fact, this is the only cause of sensory neuropathy known to the clinician, the explanation seems obvious. However, suggesting a toxic etiology just because no other etiology is apparent rarely results in the correct diagnosis, as there is no guarantee that the only cause considered is the correct explanation. In the case of acute sensory loss, an alco-

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hol-related sensory neuronopathy is indistinguishable from the neuronopathy attributable to Sjogren’s syndrome, neoplasm, human immunodeficiency virus, idiopathic sensory ganglionitis, vitamin E deficiency, the Fisher variant of AIDP, and several other neurotoxicants including Vacor, cisplatin, metronidazole, pyridoxine, and thalidomide. Eliminating competing explanations is the most difficult task addressed by the Bradford–Hill criteria. Although it is often difficult to identify a toxic etiology based on some particular findings, there are clues suggesting a possible toxic etiology. These “clues” usually represent some specific cardinal feature of a certain toxin. Recognizing such clues stems from a high level of suspicion, but even casual recognition of some clues raises suspicion for a possible toxic etiology, which then can be explored. A list of clinical or laboratory findings associated with certain neurotoxicants is listed in Table 33.9. These associations, while important, do not establish causation, as few produce features sufficiently characteristic to be considered pathognomonic. In the context of a neuropathy attributable to an occupational or environmental exposure, identifying an “outbreak” or cluster of individuals who share a common exposure should raise clinical suspicion for a common cause. The concept refers to wellestablished, homogeneous forms of neuropathy, not to individuals sharing diverse, nonspecific symptoms such as intermittent paresthesias. The concept also refers to groups of individuals who develop neuropathy within a relatively uniform interval following exposure. In this context, establishing evidence of subclinical neuropathy, based on cross-sectional comparison of unexposed and exposure individuals, should always be viewed cautiously. Such studies, including those using nerve conduction studies or quantitative sensory testing, are incapable of establishing the cause of any identified group differences. When small yet statistically significant group differences are identified within the normal range of any given measure, they usually reflect inadvertent (and unidentified) confounding, not a neurotoxic effect. 33.7. Group evaluations of suspected toxic neuropathy Consider the situation in which a group of individuals has a common exposure to a potential peripheral nervous system neurotoxicant. If there are few or no overt signs of neuropathy among individuals in the group,

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Table 33.9 Selected systemic clues associated with specific peripheral neurotoxicants, modified from Ford (1999) Neurotoxicant

Systemic feature

Acrylamide Arsenic

Irritant dermatitis, palmar erythema, desquamation, hyperhidrosis, axonal swellings Gastrointestinal symptoms, hyper-pigmentation, hyperkeratosis, Mees’ lines, cardiomyopathy, hepatomegaly, renal failure, anemia, basophilic stippling of red blood cells, elevated levels in blood, urine, hair, or nails Dysosmia, glossitis, pigmented skin and nails, atrophic gastritis, achlorhydria, pernicious anemia, megaloblastic anemia, corticospinal tract signs, anemia, low serum B12, elevated serum methylmalonic acid and homocysteine Myopathy (neuromyopathy) After years or decades of use, ?slow acetylators Nutritional factors, Wernicke syndrome (dementia, ophthalmoplegia, and ataxia), midline cerebellar degeneration, abnormal liver function, cirrhosis Irritant dermatitis, axonal swellings Gastrointestinal symptoms, musculoskeletal complaints, weight loss, gum lead line, Mees’ lines, renal failure, anemia, basophilic stippling, bone lead line, elevated levels in blood and bone Postural tremor Anorexia, gingivitis, hypersalivation, papular rash, hyperkeratosis, lens opacities, postural tremor, nephrotic syndrome, respiratory tract irritation, metal fume fever, elevated levels in urine Elderly with impaired renal function Myelopathy Irritant dermatitis, acute cholinergic effects, corticospinal tract residua, ?impaired glucose tolerance, non-cardiogenic pulmonary edema, biological effect on serum and red blood cell cholinesterase activity, urine metabolites of specific organophosphate compounds Gingival hyperplasia, cerebellar ataxia Abdominal pain, encephalopathy (psychosis), neuropathy, photosensitivity, abnormal excretion of porphyrin precursors, genetic predilection Gastrointestinal symptoms, irritant dermatitis, alopecia, non-cardiogenic pulmonary edema Vasodilation with ethanol ingestion, irritant dermatitis, elevated liver function test, cirrhosis Respiratory tract irritation, irritant dermatitis Peau d’ orange skin changes, eosinophilia

Cobalamin (B12) deficiency Colchicine Dapsone Ethyl alcohol n-Hexane Lead Lithium Mercury, elemental Nitrofurantoin Nitrous oxide Organophosphate pesticides Phenytoin Porphyria Thallium Trichloroethylene Toluene l-Tryptophan

how might they be investigated for evidence of a subclinical toxic neuropathy? The question is more than theoretical, and it is a question that is addressed frequently in the context of epidemiological studies. Although the question is straightforward, the answer is complicated by several factors, some of which are beyond the scope of this chapter. The obvious answer to the question is that some measure of peripheral nervous sytem function could be compared to a group of referent individuals with no exposure to the neurotoxicant in question. Yet, only certain types of tests are amenable for quantitative evaluation of the peripheral nervous system function. Nerve conduction studies are the measures most frequently used. They are not particularly uncomfortable, and they are quantitative, reproducible, and independent of subject motivation. In contrast, the needle EMG examination is relatively

uncomfortable and includes subjective determinations and qualitative measures that limit its application to epidemiological investigations. Other neurological measures, such as quantitative sensory testing, while quantitative, are influenced by many factors, including subject motivation, limiting their usefulness in certain types of investigations (e.g., those involving litigation or possible secondary gain). Unfortunately, regardless of the outcome measures used, only certain types of group comparisons among exposed individuals and referent subjects are capable of establishing the cause of any identified differences. This is because most studies, including cross-sectional investigations of exposed and unexposed individuals, cannot be certain that the groups were similar before exposure to the suspected neurotoxicant. Therefore, there is no way of determining that the differences

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reflect exposure to the substance in question or the effect of some unrecognized factor(s). Numerous factors, including age, height, weight, body mass index, hand size, and perhaps even smoking history, educational level or intelligence measures (reflecting socioeconomic factors), and anxiety level potentially influence nerve conduction study results. These influences, referred to as confounding, occur because the factor is associated with the exposure group in some way (e.g., manual labor and large body size and low amplitude sensory responses) but is independent of the cause of the effect under study. In addition, numerous forms of bias (e.g., selection bias, healthy worker effect, low participation rate, misclassification) may introduce systematic errors that influence the results in a positive or negative way, yet defy identification. The results of prospective cohort studies, such as used to evaluate pharmaceutical agents, measure performance before and after exposure, randomly assign subjects to exposure categories, mask subjects and investigators to exposure information, and use objective measures of peripheral nerve function. Cohort studies can establish the cause of identified effects. Such studies are difficult to perform, and certain aspects of these studies, such as randomly assigning subjects to exposure categories, are unrealistic for epidemiological investigations. Prospective cohort studies measure performance at the beginning of a study to establish that the exposure groups are comparable at baseline and then remeasure performance after an interval of additional exposure among the exposed subjects. These studies also can establish whether or not the additional exposure causes a measurable interval deterioration in function. These studies have application in occupational evaluations, but they have limited application to situations involving inadvertent exposure to some suspected neurotoxicant. The investigations most frequently used to evaluate toxic neuropathy involve cross-sectional comparisons of exposed and referent groups. Any results suggesting subclinical group differences within the normal range of the electrophysiological measure must always be interpreted cautiously because of the numerous factors that influence the results, independent of peripheral nervous system pathology. 33.8. Summary There is nothing special about the evaluation of a patient with a suspected “toxic” neuropathy. The initial evaluation of a suspected neuropathy is identical to

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the evaluation of any nervous system problem, regardless of localization. It is neither necessary nor helpful to know the “cause” of the patient’s problem before beginning the investigation. In fact, such information, if incorrect, may hinder an appropriate evaluation if important diagnostic steps are neglected. The clinical and EMG examinations are the most important components of the evaluation of suspected peripheral neuropathy. They are complementary in establishing a diagnosis. Unfortunately, there is no characteristic presentation of a toxic neuropathy, as the most classic form of toxic neuropathy is a sensorimotor, dyingback neuropathy of the axonal type, the form of neuropathy most frequently encountered by the practicing neurologist. However, once a diagnosis of neuropathy has been established, the EMG evaluation can be used to categorize the neuropathy based on sensory or motor involvement and the presence or absence of conduction slowing. The resultant classification serves the important purpose of limiting the number of items that must be considered in the differential diagnosis, thereby directing the subsequent evaluation. In this context, the EMG examination is the most important and useful “test” in recognizing the cause of any given neuropathy. In the context of toxic neuropathy, it is important to understand the methodology used to establish causation. The methodology for establishing a toxic cause of neuropathy is an uncomplicated yet difficult task. It is sometimes approached in the form of questions (Bradford-Hill criteria) that address appropriate timing of exposure and signs, dose-response information, available epidemiological studies, and appropriate animal models of toxicity to demonstrate the feasibility of any potential association. In seeking an explanation for a patient’s neuropathy, systemic or laboratory clues sometimes suggest a possible toxic explanation. For some neurotoxicants, an abnormal body burden is established by direct or indirect laboratory measurement, whereas, for others, characteristic systemic or pathologic clues help ascertain the identity. Most toxic neuropathies improve following removal from exposure. Many of the toxic neuropathies encountered in clinical practice result from exposure to prescribed medications, sometimes after years of use. A familiarity with the numerous neurotoxicants and a high index of suspicion are important clinical attributes for the practicing neurologist. The most important attribute, however, is an ability to formulate an accurate and complete differential diagnosis, before attributing a neuropathy to a toxic etiology.

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