F
NEUROLOGIC EXAMINATION

The neurologic examination includes a complete patient history and assessment by a clinician of a patient’s mental status, cranial nerve function, motor control, strength, posture, gait, and the functioning of sensory and reflex pathways. The history is important for determining potential sources of occupational or environmental exposures that might be associated with symptoms and clinical findings. Specific symptoms and signs—such as motor weakness, incoordination, sensory loss and altered mental status—arise from abnormalities in the functioning of the specialized cells of the brain, spinal cord, and peripheral nerves.

This appendix covers the neurologic examination and, more specifically, testing for three of the neurologic outcomes discussed in Chapter 7: peripheral neuropathy, neurobehavioral effects, and sensory effects. The tests described are not limited to neurotoxicology; they also apply to the study of neurologic diseases and psychiatric disorders.

TESTING FOR AND DIAGNOSIS OF PERIPHERAL NEUROPATHY

Peripheral neuropathy is a general term referring to any abnormality, inflammation, or disease of a peripheral nerve. Diabetes and alcoholism are the most common causes of peripheral neuropathy (Poncelet, 1998). Exposure to neurotoxins, including heavy metals, also can cause peripheral neuropathy. Most peripheral neuropathies from neurotoxins present as a pattern of distal symmetric signs and symptoms, that is, a dying-back process starting in the tips of the toes and progressing proximally in a stocking-glove distribution. The two types of underlying pathophysiologies are axon loss and demyelination.

The diagnosis of peripheral neuropathy relies on findings of a clinical neurologic examination, including patterns and time course of signs and symptoms and the exposure history. The findings should be confirmed with quantitative laboratory testing through nerve conduction studies and electromyography.

The most common symptoms and signs of exposure to neurotoxins appear first in sensory and later in motor nerves (Poncelet, 1998). Symptoms of peripheral neuropathy include fatigability, weakness, paresthesia, numbness, spontaneous sensation of burning heat and cold, and pain. Signs include loss of power (e.g., reduced grip strength), and abnormalities in reflexes and sensations (e.g., of vibration, touch, and position). The time course is important, inasmuch as most neurotoxic, nutritional, and systemic causes of



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Gulf War and Health: Insecticides and Solvents, Volume 2 F NEUROLOGIC EXAMINATION The neurologic examination includes a complete patient history and assessment by a clinician of a patient’s mental status, cranial nerve function, motor control, strength, posture, gait, and the functioning of sensory and reflex pathways. The history is important for determining potential sources of occupational or environmental exposures that might be associated with symptoms and clinical findings. Specific symptoms and signs—such as motor weakness, incoordination, sensory loss and altered mental status—arise from abnormalities in the functioning of the specialized cells of the brain, spinal cord, and peripheral nerves. This appendix covers the neurologic examination and, more specifically, testing for three of the neurologic outcomes discussed in Chapter 7: peripheral neuropathy, neurobehavioral effects, and sensory effects. The tests described are not limited to neurotoxicology; they also apply to the study of neurologic diseases and psychiatric disorders. TESTING FOR AND DIAGNOSIS OF PERIPHERAL NEUROPATHY Peripheral neuropathy is a general term referring to any abnormality, inflammation, or disease of a peripheral nerve. Diabetes and alcoholism are the most common causes of peripheral neuropathy (Poncelet, 1998). Exposure to neurotoxins, including heavy metals, also can cause peripheral neuropathy. Most peripheral neuropathies from neurotoxins present as a pattern of distal symmetric signs and symptoms, that is, a dying-back process starting in the tips of the toes and progressing proximally in a stocking-glove distribution. The two types of underlying pathophysiologies are axon loss and demyelination. The diagnosis of peripheral neuropathy relies on findings of a clinical neurologic examination, including patterns and time course of signs and symptoms and the exposure history. The findings should be confirmed with quantitative laboratory testing through nerve conduction studies and electromyography. The most common symptoms and signs of exposure to neurotoxins appear first in sensory and later in motor nerves (Poncelet, 1998). Symptoms of peripheral neuropathy include fatigability, weakness, paresthesia, numbness, spontaneous sensation of burning heat and cold, and pain. Signs include loss of power (e.g., reduced grip strength), and abnormalities in reflexes and sensations (e.g., of vibration, touch, and position). The time course is important, inasmuch as most neurotoxic, nutritional, and systemic causes of

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Gulf War and Health: Insecticides and Solvents, Volume 2 peripheral neuropathy develop over weeks or months. A slowly progressive course suggests a hereditary or metabolic cause. Nerve conduction and electromyography are used to confirm the diagnosis and to determine the type of pathophysiologic effect, especially whether the neuropathy is demyelinating or axonal. Measuring nerve conduction is a key method for testing the functioning of a peripheral nerve. Its purpose is to localize where the pathology is along the length of the nerve. It also aids in characterizing the pathology—namely, whether it affects axons, cell bodies, or the myelin sheath (Aminoff, 1987). Testing often involves stimulating a nerve at one point along its path and recording the electrical impulse from the nerve at another point. Nerve-conduction testing typically measures conduction velocity, expressed as meters/second. Conduction velocity is calculated by dividing the distance between the stimulating and recording points by the time from stimulation to onset of recorded impulse (the latency). Nerve conduction testing also measures the amplitude of the compound action potential of a sensory nerve or the muscular wave (M wave) for a motor nerve. Compound action potential is the sum of individual impulses from axons within the nerve. It is recorded at the surface of a sensory nerve after the nerve has been electrically stimulated. The M wave is the compound action potential recorded from the surface of a muscle after stimulation of a motor nerve. The M wave refers to the sum of individual impulses from axons that control muscular contraction. If the axon is affected, the amplitude (maximal voltage, in microvolts) of the compound action potential or M wave is generally smaller than normal. Nerve impulses can be conducted only by the remaining undamaged axons and this reduces the magnitude of the compound action potential. If the myelin sheath is affected, the conduction velocity is slower than normal, and other electrophysiological parameters can be affected too. Nerve conduction studies examine functioning of the peripheral nervous system, and a similar type of testing—known as evoked potentials—is used to examine the functioning of both the peripheral and the central nervous systems. Studies using evoked potentials examine the characteristics of electrical waveforms generated by a stimulus delivered to a sensory receptor or nerve or applied directly to a particular area of the brain, spinal cord, or muscle. There are many types of evoked potentials—including auditory evoked potentials, brainstem auditory evoked potentials, and visual evoked potentials—and each is designed to uncover and localize pathology in distinct parts of the nervous system. Electromyograms (EMG) Electromyography (EMG) is used to test motor unit function; a motor unit consists of the motor neuron, its axon, and the muscle cell it innervates. The EMG helps to define the type of neurotoxic insult or neuromuscular disorder. A typical test uses a recording electrode inserted through the skin into the muscle to measure electrical activity. Thousands of motor units are in the legs. Fewer units are in the head and neck. A reduced number of motor units is evidence of denervation (the loss of connection between the motor neuron, its axon, and the muscle fiber it supplies). Denervation of motor units is necessary before muscle cells begin to develop abnormal, spontaneously discharging potentials. Therefore, the timing of an abnormal electromyogram in relation to a toxic exposure is very important in the interpretation of the results. As toxic neuropathy develops and clinical signs appear, greater EMG changes are recordable. Denervated muscle fibers manifest spontaneous electrical discharges, called fibrillations,

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Gulf War and Health: Insecticides and Solvents, Volume 2 which can be recorded from a needle electrode inserted into the muscle when it is at rest. Polyphasic potentials are other electrical discharges that can be recorded from a previously denervated muscle that has become reinnervated by adjacent axons. Vibrotactile Threshold The vibrotactile threshold, a measure of sensory nerve function, is tested to evaluate the ability to perceive a vibrating stimulus. The test can be performed during a clinical examination with a tuning fork (128 Hz) placed over a toe or finger pad or joint of the foot, ankle, tibia, finger, or wrist. Subjects indicate to the examiner when they feel the vibration or when it diminishes and disappears. Testing can be performed with quantitative standardized methods; this is sometimes referred to as quantitative sensory testing (QST). One commonly used device, known as a Vibratron, assesses the function of large axons (fibers) of a peripheral nerve carrying the sensations of position and vibration. It has a stimulator that delivers vibrations of various amplitudes through two probes applied to the skin over a finger pad or an extremity joint with a constant frequency of vibration (100 Hz). With the so-called forced-choice method (choosing between two alternatives), subjects indicate when they perceive or do not perceive one or both probes vibrating. Testing of an exposed person soon after exposure and later, after removal from exposure, yields evidence of possible impairment and then recovery of vibrotactile sensation perception. Because height and age are known covariates of vibration threshold, epidemiologic studies control for height and age in the analysis and interpretation of results. NEUROBEHAVIORAL EFFECTS Neurobehavioral Tests Neurobehavioral tests (also called neuropsychologic tests) are standardized tests designed to identify functional deficits associated with exposure to neurotoxicants. The tests also help to develop hypotheses about mechanisms of toxicity or localization of affected brain areas. There are at least 250 distinct neurobehavioral tests, but they can be grouped under distinct domains of mental functioning. No test can be used alone to identify dysfunction as a result of a toxic exposure; rather, many tests are grouped into batteries to provide a broad characterization of a dysfunction (Fiedler et al., 1996). Some standardized test batteries have been developed (such as the WHO Neurobehavioral Core Test Battery and the Halstead-Reitan Battery). The batteries can be administered manually or by computer. Computer-administered tests consume less time and are less expensive to administer. The individual tests in a given battery are known as subtests. Summary scores for subtests in a battery can be used to determine the nature and degree of functional impairment. One of the most important features of neurobehavioral testing is comprehensiveness of test selection. Given the wide array of tests available, batteries generally should include at least one test from each of the functional domains (Table F.1): overall cognitive ability; attention and concentration; motor skills; visuomotor coordination; visuospatial relations; memory; affect and personality. The functional domains to some extent overlap.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Testing for overall cognitive ability is important for obtaining a measure of pre-exposure ability. Because standardized indicators of pre-exposure cognitive function are not generally available in study subjects, researchers measuring post-exposure effects often depend on the vocabulary test from the Wechsler Adult Intelligence Scale-Revised to indicate pre-exposure functioning. That approach relies on the assumption that neurotoxicants do not impair performance on well-learned information, such as vocabulary or reading ability. Other important criteria in test selection and interpretation are a test’s psychometric properties (such as standardization and reliability) and its sensitivity to the effects of the neurotoxicant in question. The test should be able to evaluate more than one output performance modality, for example, pushing buttons on a computer and giving verbal responses. A test of a single modality restricts the range of responses available to the subject. For example, spoken tests rely disproportionately on language aptitude and retrieval of information from semantic memory (White and Proctor, 1992; White et al., 1994). Electroencephalography Electroencephalography (EEG) provides real-time monitoring of electrophysiological activity of the brain. Electrical activity arising from neurons of the cerebral cortex is recorded from the scalp with electrodes placed on the surface of the skull. Sensitive electronic equipment, which is used to amplify electrical signals, displays patterns of mixed frequencies, amplitudes, and their topographical distributions. The EEG yields predictable patterns in normal waking, drowsing, and sleeping states. Mixtures of high (beta and alpha) and low (theta and delta) frequencies from the frontal, temporal, and occipital lobes are detected. Impairment in brain function, known as encephalopathy, is diagnosed when the EEG symmetry, amplitude, frequencies, and patterns diverge from normal. Spiked discharges indicate sites of epileptic activity. Increased slow-wave activity occurs during exposure to neurotoxicants that depress central nervous system function. The EEG tracing typically returns to a normal pattern after removal from the agent, although behavioral manifestations may persist clinically, or be detectable on further neuropsychologic testing. As with all laboratory tests, the significance of an EEG result depends on its integration with other clinical information and examinations. Electroencephalography is most helpful when an abnormality is chronologically related to exposure to the neurotoxicant. Posturography Posturography is used to assess ability to maintain balance. It is more objective than the clinician-administered Romberg test. Maintaining balance is a dynamic process that requires interaction of the peripheral and central nervous systems. Therefore, abnormalities on posturography can suggest central or peripheral dysfunction or both. Quantitative assessment of body sway is accomplished by placing a subject on a multiaxis force platform consisting of two parallel plates with strain gauges that measure and record the changes in pressure associated with the subject’s attempt to maintain balance in response to tilting of the platform. Body sway is measured along the lateral and anterior-posterior axis. The test is performed with the subject’s eyes open and eyes closed.

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Gulf War and Health: Insecticides and Solvents, Volume 2 SENSORY EFFECTS Color Vision Testing In the Lanthony D-15 test, a subject is shown is a color arrangement consisting of 15 color caps that form a color circle covering the visual spectrum. The subject is asked to select the cap that is closest in hue to a reference cap. The patient places caps in the tray in an orderly transition of hue. The caps are designed so that a person with normal color vision or a mild color-vision deficit will arrange the caps in a perfect color circle. The test does not indicate the degree of color deficiency other than to separate those with normal color vision and mild congenital color blindness from patients with moderate to severe color deficits. It can distinguish significant defects, particularly if a person is screened prior to exposure to a toxicant. Audiometry Audiometry measures the ability to discriminate pure tones (500, 1000, 2000, 4000, 6000, and 8000 Hz) presented at 5-dB intervals through a headset. The test takes about 10 minutes to complete and requires concentration on the part of the subjects to distinguish between tones just above and just below the threshold of detection. In the early stages, exposure selectively affects the ability to detect high-frequency sounds (4000, 6000, and 8000 Hz). After continuing exposure, speech frequency sounds (500–2000 Hz) may also be affected. Audiometry can distinguish between sensorineural hearing loss and hearing loss due to middle ear infections or central nervous system lesions by incorporating additional tests, including measurement of bone conduction, audio evoked potentials, and immittance. Testing of the latter includes acoustic-reflex testing (based on reflex tightening of the tympanic membrane by the stapedius muscle after presentation of an auditory signal and measured by changes in tympanic membrane impedance) and evaluation of decay in the acoustic reflex (associated with central nervous system lesions). The acoustic reflex threshold is established by using an ascending and descending 5-dB increment-bracketing procedure to determine the minimal intensity required for person to note a change in middle ear compliance. An abnormal reflex decay occurs when a stimulus is present at 10 dB above the reflex threshold, and the amplitude of the reflex decreases to less than half its original value in 10 seconds or less. The main objective in performing immittance measurements is to obtain information on the site of lesions by investigating acoustic reflex findings.

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Gulf War and Health: Insecticides and Solvents, Volume 2 TABLE F.1 Neurobehavioral Tests Domain of Function Test Examples Overall cognitive ability Wechsler Adult Intelligence Scale-Revised (WAIS-R); Raven Progressive Matrices; syntactic reasoning Attention and concentration Digit-span test from WAIS-R; Bourdon-Wiersma Vigilance Test; Continuous Performance Test Motor skills Grooved pegboard; finger-tapping; Santa Ana dexterity test; simple reaction time Visuomotor coordination Digit-symbol from WAIS-R; Trails A and B; Aiming (Pursuit Aiming II) Visuospatial relations Block design from WAIS-R Memory Wechsler Memory Scale-Revised, including paired associates; Benton Visual Retention; serial digit learning Affect and personality Profile of Mood States (POMS); Minnesota Multiphasic Personality Inventory (MMPI); MMPI-2   SOURCE: Adapted from Fiedler et al., 1996; Proctor and White, 1990. REFERENCES Aminoff MJ. 1987. Electromyography in Clinical Practice: Electrodiagnostic Aspects of Neuromuscular Disease. 2nd ed. New York: Churchill Livingstone. Fiedler N, Feldman R, Jacobson J, Rahill A, Wetherell A. 1996. The assessment of neurobehavioral toxicity: SGOMSEC (Scientific Group on Methodologies for the Safety Evaluation of Chemicals) joint report. Environmental Health Perspectives 104(Suppl 2):179–191. Poncelet AN. 1998. An Algorithm for the Evaluation of Peripheral Neuropathy. Available: http://www.aafp.org/afp/980215ap/poncelet.html [accessed February 1998]. Proctor S, White R. 1990. Psychoneurological criteria for the development of neurobehavioral test batteries (Chapter 26). In: Johnson BL, ed. Advances in Neurobehavioral Toxicology. Chelsea, MI: Lewis Publishers. White RF, Proctor SP. 1992. Research and clinical criteria for development of neurobehavioral test batteries. Journal of Occupational Medicine 34(2):140–148. White RF, Gerr F, Cohen RF, Green R, Lezak MD, Lybarger J, Mack J, Silbergeld E, Valciukas J, Chappell W, Hutchinson L. 1994. Criteria for progressive modification of neurobehavioral batteries. Neurotoxicology and Teratology 16(5):511–524.