Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives, Volume II

Peripheral Nervous System

James W. Albers, Stanley Berent

• Publisher: Taylor & Francis
• Year: 2005
• ISBN:
  9781135421069
• Edition: 1
• Topic: Psychology
• Subtopic: History & Theory in Psychology
• Index: Psychology

This book, the second of three volumes, concentrates on peripheral nervous system disorders. Examining the effects of neurotoxicants on nerve, muscle and the neuromuscular junction, it builds on the scientific principles outlined in volume 1 by looking at the application of the methods discussed, particularly in terms of the evaluation and diagnosis of individual patients and the related process of establishing causation.

Neurobehavorial Toxicology, Volume 2 will be of interest to practicing neurologists and neuropsychologists, as well as to occupational medicine physicians and medical toxicologists.

10 Industrial and
environmental agents

Much of our understanding about and our need for clinical neurobehavioral toxicology derives from industrial and environmental exposures. These exposures occur in one or more of several circumstances, including chronic, ongoing contact with the neurotoxic substance during some manufacturing process, acute exposure during an industrial mishap, or inadvertent exposure as a bystander without any known contact with the substance. On occasion, information about the magnitude of exposure is available through industrial hygiene air monitoring or biological sampling programs. More often, exposure is inferred from other information that sometimes includes potential exposure to many purported neurotoxicants. This chapter addresses issues related to peripheral nervous system disorders resulting from industrial and environmental exposures. The material that follows includes case presentations representative of several well-established neurotoxic syndromes. As stated earlier, our rationale for selecting specific neurotoxic agents was based on several considerations, including our personal familiarity with the syndromes in our clinical practice and the frequency with which these syndromes appear in the differential diagnosis of neuromuscular disorder. We selected certain agents over others to present a variety of neurotoxic disorders involving the different forms of neuropathy (sensory, motor, and sensorimotor), as well as disorders of the neuromuscular junction and muscle fibers. We have avoided presenting an encyclopedic list of known or suspected neurotoxicants because our primary intent is to emphasize the process of establishing a clinical diagnosis and, separately, the process of establishing the cause of the identified disorder. To the extent that animal toxicology is available and relevant to establishing causation, it is introduced. There is an emphasis on peripheral neuropathy in this chapter because neuropathy is said to be the most common neurotoxic syndrome produced by industrial and agricultural chemicals (He, 1985; Albers & Wald, 2002). A discussion of myotoxicants is included in the following chapter. Two neurotoxicants discussed in this chapter, botulinum toxin and the organophosphorus compounds, are of particular interest and importance, given the current concern about potential agents of bioterrorism. As in other chapters, the discussion emphasizes the importance of developing a complete differential diagnosis, and therefore the tables used for several of the case presentations reflect important diagnostic considerations, not limited to those related to neurotoxicants.

Selected presentations

Acrylamide

The neurotoxicity of the vinyl monomer acrylamide is well established, and acrylamide is commonly used in animal models of toxic neuropathy. Acrylamide has commercial application in soil grouting for stabilization, water proofing, and as a flocculator. The polymer, polyacrylamide, is non-toxic, but it can be contaminated with acrylamide monomer (Mulloy, 1996). Acrylamide is water-soluble, and it is absorbed via oral, dermal, and respiratory exposures. Following sufficient exposure, acrylamide produces dermal irritation, stocking–glove sensory loss and weakness, unsteady gait, and loss of reflexes (Garland & Patterson, 1967). The first descriptions of acrylamide intoxication appeared shortly after it was commercially manufactured (Gold & Schaumburg, 2000). Initial descriptions of occupationally exposed workers emphasized sensory and motor signs of neuropathy plus a degree of ataxia that was thought to be disproportionate to the magnitude of sensory loss, perhaps representing cerebellar involvement (Garland & Patterson, 1967). In spite of the known neurotoxic potential, clinical examples of acrylamide neuropathy are not particularly common. As of 1992, there had been only 67 documented cases of acrylamide poisoning worldwide, excluding China, although mild or subclinical cases may go unrecognized (Gold & Schaumburg, 2000). The following case presentation, taken from the literature, is representative of other reports of acrylamide intoxication and consistent with information derived from animal models.

Case presentation (Davenport, Farrell, & Sumi, 1976)¹

This 25-year-old man was admitted to the University of Washington Hospital because of loss of sensation and unsteady gait. He was the only worker in his factory who handled acrylamide and had been working with this chemical for 6 months. His work involved the mixing of raw acrylamide powder with other dry and liquid reagents in a sealed reactor vessel. He followed the company’s safety directions, wearing coveralls, clear plastic gloves and a filtering face mask. Shortly after beginning his job, intense irritation of his palms and soles developed, with moist, red, raised ulcerations. Over the next 3 months, he noted increasing fatigue, became anorectic, and lost 40 pounds. Two weeks before admission, he awoke one morning with an unsteady gait, the day before having been able to stand easily on a narrow ledge to paint a wall. He stopped work but had progressively worsening ataxia. A week later, he began to have tingling in his hands and found them clumsy for fine manipulations. Two days before consultation, he first noted slurred speech and vague dysphagia.

His medical history was unremarkable. He was taking no medication and had no allergies. He drank socially and had a 10 pack-year smoking history. No other toxins were identified in his environment.

On examination, his vital signs were normal. There was hyperhydrosis of the palms and soles with irregular areas of blistering. He had mild weakness of the extensor muscles of the wrists and ankles; muscle tone was decreased. Terminal dysmetria and intention tremor of the upper extremities and a moderate truncal and gait ataxia with wide base were observed, and he was unable to walk in tandem. Appreciation of pinprick and temperature was impaired below the midcalf and midforearm, with raised threshold for light touch in the same areas. Position and vibration senses were absent below the knees and the Romberg test was positive. No deep tendon or plantar reflexes could be elicited. Eye movements were conjugate and full with fine sustained nystagmus on lateral gaze. There was a mild lingual dysarthria, with normal palatal and pharyngeal function.

DIFFERENTIAL DIAGNOSIS

This patient was thought to have clinical conditions of the skin and the nervous system typical of acrylamide toxicity. The nervous system localization of the patient’s neurologic disorder and other possible considerations that could have been included in the differential diagnosis are examined in the following paragraphs.

Discussion

NERVOUS SYSTEM LOCALIZATION

This patient’s neurologic problem appeared localized primarily, but not entirely, to the peripheral nervous system. The symptoms included ‘tingling’ in the hands, problems with fine hand coordination, progressive ataxia, and slurred speech. No symptoms specific for decreased sensation were reported, but interpretation of any neurologic symptoms involving the hands was complicated by the intense dermatitis involving the palms. Symmetry is an important feature of most peripheral neuropathies, but predominant involvement of the hands as opposed to a stocking–glove distribution pattern is atypical. Ignoring for a moment the intense palmar dermatitis, additional neurologic considerations include cervical syringomyelia, multiple mononeuropathies, Tangier disease, or other uncommon disorders that show a predilection for the upper extremities. None of these possibilities explains all of the presenting symptoms. Based on the history, symptoms reflecting incoordination and slurred speech could have had a central origin, possibly involving the cerebellum. Central demyelinating disorders, such as multiple sclerosis, could be considered to explain the apparent multifocal involvement, assuming that the sensory symptoms involved central, not peripheral, pathways.

The neurologic examination results helped establish the primary localization to the peripheral nervous system. Neurologic signs supporting a diagnosis of peripheral neuropathy included distal weakness, profound stocking–glove sensory loss, and areflexia. Absent joint position and vibration sensations below the knees could reflect a peripheral or spinal cord localization, and such severe sensory loss could produce unsteadiness sufficient to be confused with cerebellar ataxia. The positive Romberg sign indicates that sensory loss, not cerebellar incoordination, explains the abnormal station. Taken together, the neurological findings are most consistent with, and fulfill, standard criteria for a severe sensorimotor polyneuropathy. The symptoms and signs that are not entirely explained by this diagnosis are those reflecting possible cerebellar involvement, particularly slurred speech. Only rarely is sensory involvement so severe as to produce an ataxic dysarthria.

The clinical examination, while confirming a primary peripheral localization, does not identify the principal pathophysiology producing the neuropathy. The next step in the neurological evaluation usually would include an electrodiagnostic examination. Unfortunately, only limited nerve conduction results were reported, although the information available was considered state-of-the-art at the time of the evaluation. The report described motor nerve conduction velocities that were unremarkable in the arms, but of borderline–reduced velocity (80–90% of the lower limit of normal) in the legs. A needle EMG examination revealed definite evidence of denervation (fibrillation potentials) in the muscle examined in the legs. The most important tests capable of localizing the neurologic signs to the peripheral nervous system are sensory nerve conduction studies and sensory nerve biopsy. Evidence of axonal loss in either of these studies localizes the problem to the peripheral nervous system, at or distal to the dorsal root ganglia. Sensory responses were not reported. A sural nerve biopsy, however, confirmed loss of sensory axons.

VERIFICATION OF THE CLINICAL DIAGNOSIS

The clinical diagnosis of sensorimotor peripheral neuropathy satisfies all explicit questions required to verify the diagnosis (Richardson, Wilson, Williams, Moyer, & Naylor, 2000). This impression included neuropathology confirmation. Secondary or superimposed central nervous system involvement remains possible, but the clinical evidence supporting a central nervous system localization is inconclusive.

CAUSE/ETIOLOGY

What evidence establishes acrylamide monomer as a peripheral neurotoxicant? The evidence includes case reports and cross-sectional studies supportive of the hypothesis, plus a robust animal model and a molecular understanding that establishes the biologic basis of acrylamide as a peripheral neurotoxicant.

The determination of an acrylamide neuropathy for this patient was based on several considerations. First, there was a definite opportunity for exposure. Second, the dermatological features were consistent with the dermal irritant nature of acrylamide. In addition, increased sweating of the palms has been attributed to acrylamide exposure, although this finding by itself is non-specific. Third, peripheral signs of acrylamide intoxication include weakness, distal sensory loss, areflexia, and perhaps autonomic dysfunction with excessive sweating (LeQuesne, 1985). Vibration sensation loss is thought to be an early marker of neuropathy, correlating with the early involvement of fibers to Paccinian corpuscles. Fourth, signs suggestive of cerebellar involvement commonly are attributed to acrylamide. Fifth, the EMG evaluation, although limited, produced findings consistent with acrylamide intoxication (Table 10.1). Sixth and most importantly, the sural nerve biopsy showed evidence of focal axonal swellings containing masses of neurofilaments. This pathologic evidence, while not specific for acrylamide, is associated with a relatively small number of conditions, thereby greatly reducing the number of considerations in the differential diagnosis. The few conditions that produce a ‘giant axonal neuropathy’ include acrylamide intoxication. Although the case presentation did not provide sufficient follow-up information to establish the clinical outcome, removal from acrylamide exposure in the early stages of neuropathy results in the eventual complete recovery of the neuropathy (Gold & Schaumburg, 2000). Progression in the absence of ongoing exposure would not be consistent with acrylamide intoxication.

Almost all reported cases of acrylamide toxicity have been attributed to handling the monomer. Polyacrylamide is not toxic (Smith & Oehme, 1991). The initial description of acrylamide neurotoxicity involved six workers who developed a sensorimotor neuropathy and ataxia. All six were recognized to have a common occupational exposure to acrylamide (Garland & Patterson, 1967). Subsequent evaluations of a subset of these workers, all of whom were recovering at the time of evaluation, attributed electrophysiological abnormalities to loss of large myelinated nerve fibers (Fullerton, 1969a; Aminoff, 1985). A cross-sectional evaluation of 210 tunnel workers exposed for about 2 months to a chemical grouting agent containing acrylamide and N-methylolacrylamide reported 23 workers thought to have peripheral nervous system impairments due to acrylamide; all but two had recovered 18 months after the cessation of exposure (Hagmar et al., 2001). In addition to peripheral neuropathy, a few case reports exist that associate other forms of neurotoxicity with acrylamide exposure. These associations are likely coincidental, but they include parkinsonism and, in the case of severe intoxication, encephalopathy (LeQuesne, 1985; He et al., 1989; Mulloy, 1996).

In addition to the case reports associating peripheral neuropathy with occupational exposure to acrylamide monomer, some cross-sectional evaluations have identified mild or subclinical adverse effects, usually in the form of neuropathy detected by quantitative electrodiagnostic and sensory measures (Deng, He, Zhang, Calleman, & Costa, 1993; Myers & Macun, 1991...

Table of contents

• Cover Page
• Title Page
• Copyright Page
• From the Series Editor
• Acknowledgments
• Disclosures
• 9. Clinical and Electrodiagnostic Evaluations of the Peripheral Nervous System
• 10. Industrial and Environmental Agents
• 11. Medications and Substances of Abuse
• 12. Conditions That Sometimes Mimic Peripheral Nervous System Disease
• 13. Consequences of an Incomplete Differential Diagnosis
• 14. Issues and Controversies Involving the Peripheral Nervous System Evaluation
• Postscript
• Appendix