Chronic toxic encephalopathy investigated using dynamic posturography

Am J

0101aryng01

12:96-100,1991

Chronic Toxic Encephalopathy Investigated Using Dynamic Posturography TORBJ~RNLEDIN, MD, PHD, ELISABETHJANSSON,MD, CLAES MILLER, MD, PHD, and LARS M. ~)DKVIST,MD, PHD Seven male patients previously exposed to industrial solvents and diagnosed with chronic toxic encephalopathy (aged 38 to 89 years; mean age, 58 years) were investigated by dynamic posturography and compared with healthy, age-matched male control patients. Dynamic posturography comprises two phases: a sensory organization (SO) phase, in which the support surface and visual surround are either stable or referenced to the patient’s sway, with eyes open or closed, and a movement coordination (MC) phase, in which the platform makes active movements. In SO testing, the patient group showed significantly impaired equilibrium performance compared with the control group in most test conditions. The MC test revealed no differences between groups. A relationship was found between the equilibrium score resulting from SO testing with stable support and visual surround and the sway area of the confidence ellipse elicited 3 years previously by static posturography with eyes open. We conclude that patients with chronic toxic encephalopathy have impaired equilibrium, as demonstrated by dynamic posturography testing. AM J OTOLARYNGOL12:98-100. Copyright 0 1991 by W.B. Saunders Company Key words: psycho-organic syndrome, chronic toxic encephalopathy, dynamic posturography, cerebellum, solvents.

Romberg test and computerized static posturography, were significantly impaired in the CTE group. In addition, central auditory test results, ocular smooth pursuit data, and visual suppression of the vestibulo-ocular reflex (VOR) were significantly abnormal in the CTE group. The researchers concluded that solvents cause disturbances of cerebellar and brain stem functions as well as of central nervous system (CNS) auditory mechanisms. Static balance testing has proven valuable in assessing equilibrium performance in workers exposed to styrene” and in CTE-impaired workers.5 The present study is a 3-year follow-up of these CTE patients, using a questionnaire, a physical examination, and a reinvestigation of equilibrium performance. As the demands on stability in real life are seldom restricted to static conditions, dynamic posturography testing was performed in this study. The hypothesis was that impairment of equilibrium functions would be found, especially in conditions in which sensory inputs are disturbed, diminished, or absent.

Solvents are known to cause central as well as peripheral nervous system damage.l-* One possible outcome of long-term exposure to solvents is a chronic toxic encephalopathy (CTE) characterized by neurasthenia, personality changes, reduction of intellectual capacity, vertigo, dizziness, and This condition has been unsteadiness.l*“‘l termed psycho-organic syndrome in the literature. It poses serious problems in an age in which the use of solvents in industry is growing and safe limits for exposure are not always well established.” In a previous study, Miiller et al5 evaluated audiologic and otoneurologic functions in a group of nine men with CTE compared with nine healthy age-matched control patients not exposed to solvents at work. The results demonstrated that balance functions, clinically tested with both the

Received September 14,1990, from the Department of ENT, University Hospital, Linkiiping, Sweden. Accepted for publication November 27, 1990. Supported by grants from the Swedish Work Environmental Fund. Address correspondence and reprint requests to Torbjiirn Ledin, MD, PhD, Department of ENT, University Hospital, S581 65 LinkBping, Sweden. Copy&ht 0 1991 by W.B. Saunders Company 0196~0709/91/1202-0001$5.00/O

MATERIALS

AND METHODS

Of the nine male workers investigated in 1988,5 seven agreed to participate in this study; one refused and one 96

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LEDIN ET AL could not be contacted. The patients (aged 38 to 69 years; mean age, 56 years) had been exposed to mixtures of alcohol and aromatic and aliphatic industrial solvents for between 8 and 30 years (mean, 21 years). No subject had a history of metabolic, neurologic, or psychiatric disease. None was considered an abuser of alcohol, although all but one used alcohol occasionally. Each had been previously diagnosed with CTE in the Department of Occupational Medicine based on his case history and on neurophysiologic and psychologic testing.’ None of the subjects had worked with solvents since 1985. Their alcohol use had not changed; none was considered abusive. Six of the seven workers had disability pensions; one was professionally active. As a control group, the nine age-matched (range, 39 to 66 years; mean, 56 years) healthy male controls used by Miiller et al5 were investigated. They had not been exposed to solvents at work. Their drinking habits did not differ from those of the GTE-affected workers. All patients underwent a physical examination, including ear, nose, and throat status, cranial nerves, past pointing, diadochokinesis, Romberg test, walking, and turning around. In addition, dynamic posturography was performed in patients and controls. All subjects also answered a questionnaire regarding subjective symptoms of disturbances of balance, memory, emotional life, and other mental functions. Dynamic posturography (Equitest, Neurocom International Inc, Clackamas, Oregon) was performed as described by Nashner13 and Cyr et a1.14 In this test, the subject stands on a dual forceplate enclosed by a visual surround. Both the forceplate and the surround can be made to move with, or independent of, the person’s anteroposterior (AP) sway, thus allowing programmed disturbance of the equilibrium. The dual forceplate records vertical forces between the feet and ground as well as horizontal shear forces, thereby allowing estimation of both the position of the swaying body and the pattern of sway in terms of hip or ankle strategy for maintaining balance. The investigation is divided into two main sections: sensory organization (SO) and movement coordination (MC) testing. The fundamentals of the SO part have been thoroughly described by Black et alI5 and those of the MC part have been described by Diener et alI6 The SO part is divided into six separate tests [Fig l), each lasting 29 seconds. Test SO 1 is a quantified version of the Romberg test. The subject stands with eyes open; the surroundings as well as the ground are stable.

VISUAL

CONDITION

Test SO 2 is identical, except that the subject’s eyes are closed. Tests SO 3 through 6 are repeated to get more stable values. In SO 3, performed with the eyes open, the visual surround moves in response to body sway, thereby giving incorrect visual information. In test SO 4, the platform is sway referenced and the surrounding is stable. In test SO 5, the eyes are closed and the platform is sway referenced. In test SO 6, both the platform and the surrounding are sway referenced. Note that in SO 3 and SO 6, the tested subject might derive some orientation information from the visual surround, as it moves only in the AP direction and not in the lateral direction. From each test an equilibrium score is computed. The score, 100 for absolutely no sway, decreases with increasing sway range during the 26-second measurement time, falling to zero in cases of 12.5 degrees sway range or more or in case of falling. A strategy score related to the amount of horizontal shear force exerted is computed, expressing the degree of ankle or hip movements; an increase of shear force indicates increased hip movements. A strategy score of 100 means solely ankle and no hip movement. A zero score corresponds to a horizontal shear force of approximately 110 N. The MC evaluation is divided into eight separate tests: small, medium, and large backward and forward translation perturbations of the platform, to simulate falling forward and backward, are each repeated three times. Additionally, the platform is tilted toes-down and toes-up five times each. From the translation perturbations, the force response of each foot is evaluated to yield force symmetry scores comparing right and left feet. The latency of force recruitment is also assessed to give estimations of the reaction of each foot separately. The average value of both feet is used in the analysis. Finally, the toes-up and toes-down tiltings are evaluated to estimate adaptation in terms of the decreasing “energy” (however, not in exact physical units) required to correct the disturbance. Energy estimations are compared both between groups (average of fourth and fifth trial for both types of tilting) and also to the limit of normality specified by the system (Neurocom, unpublished data). The results of static posturography performed in the patient group 3 years earlier were correlated to the results of dynamic posturography. Static posturography requires the subject to stand upright in a darkened room for 60 seconds on a stable force platform with eyes closed as well as open. The center of pressure is measured in the AP and lateral directions, and a confidence ellipse area for the location is computed as a measurement of postural sway.17 The results of dynamic posturography in the patient group were compared with those of the control group using Student’s t-test. The number of pathologic subjects in both groups was compared using Fisher’s exact test. Correlation analysis was used to assess relationships between static and dynamic posturography results in the patient group. The probability of the correlation coefficient equalling zero was statistically evaluated. In all tests, a probability level of 5% was considered significant.

RESULTS

Figure 1. The six different sensory conditions of dynamic posturography.

The yielded ported

subjective assessment of health status inconclusive results. Two subjects reexperiencing fewer disequilibrium prob-

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DYNAMIC POSTUROGRAPHY IN CHRONIC TOXIC ENCEPHALOPATHY

lems than at the time of testing 3 years earlier, while two reported increased instability and three remained unchanged. In the physical examination, two patients displayed pathologic tandem Romberg test results. All other subjects were normal on physical examination. In the SO phase of dynamic posturography, the CTE group had lower equilibrium scores than the control group in all test conditions (Table l), but two were not significant. In test condition SO 1 (stable platform and visual surround) with eyes open, the difference did not reach the level of significance (P < .064); however, with eyes closed (SO 2), the equilibrium score was significantly lower (P < 609). In the third test condition (SO 3, sway referenced visual surround and stable platform), no significant difference could be found between the groups (P < .19). In all three conditions with a sway-referenced platform, significant differences were found. The probability values were P < .019 when the visual surround was stable (SO 4), P < .05O when vision was absent (SO 5), and P < .003 when both visual surround and platform were sway referenced (SO 6). Strategy scores were lower in conditions SO 2 (absent vision, stable platform; P < 627) and SO 6 (both platform and visual surround sway referenced; P < 604). Regarding adaptations, four of seven CTE subjects were pathologic in one or both tilting directions, toes up or toes down, compared with one of nine controls (P < .lO). For variables not mentioned above, no signifiTABLE 1.

Results of Dynamic Posturographyin the Patient and Control Groups CTE (N = 7) Mean

Equilibrium scores 90.1 so 1 77.1 so2 80.1 so3 67.4 so4 43.1 so5 46.7 SO6 Strategy scores 93.0 STR 1 86.0 STR 2 81.1 sTR3 71.7 STR 4 65.9 STR 5 55.8 STR 6 Latencies in movement Backwards 201 Small Medium 166 150 Large Forwards 196 Small 217 Medium 173 Large * P < .Ol. t P < .05.

CONTROLS

(N = 9)

SD

Mean

SD

P

6.1 13.4 12.6 23.7 30.4 19.4

94.3 90.7 86.7 90.8 65.8 72.4

1.3 1.3 5.9 2.7 8.7 9.3

d.064 (NS) <.oos* 4.19 (NS) <.010* <.050t <.003*

0.8 2.7 2.9 1.4 5.4 4.4

<.21 (NS) <.027t <.18 (NS) c.076 (NS) <.24 (NS) <.004*

14.2 99.1 97.4 13.7 29.6 94.9 91.6 31.4 78.8 31.0 81.0 21.7 coordination (ms) 23 18 9

194 167 146

17 13 13

<.59 (NS) <.98 (NS) <.51 (NS)

23 98 45

205 161 151

33 13 10

<.65 (NS) <.ll (NS) <.17 (NS)

cant differences were found in the SO or MC phases of dynamic posturography. Correlation analysis between static and dynamic posturography results for the seven CTE patients revealed a significant correlation between the confidence ellipse area with eyes open in static posturography and the equilibrium score when both platform and visual surround were stable (SO 1) in dynamic posturography (r = -.79, P < .05). However, no correlation was found between the eyes-closed condition in static posturography and the corresponding dynamic posturography condition (SO 2, stable platform and absent vision). Correlation coefficients are displayed in Table 2. DISCUSSION Experiments in animals and humans have demonstrated that acute intoxication with hydrocarbon solvents influences the VOR system.3’7 Findings indicate primarily cerebella-brain stem disturbance, diminishing the inhibition of the VOR, and perturbing the ocular smooth pursuit function and multisynaptic auditory mechanisms. The underlying biochemical mechanism might involve incorporating solvent molecules into the nerve cell membrane, thus affecting ionic transfer?**” Another hypothesis has solvents affecting the gamma-amino-butyric acid (GABA) inhibitory system. This model is supported by rabbit studies in which it was found that GABA inhibitors picrotoxin and bicuculline produced positional nystagmus similar to that elicited by solvents, whereas the administration of the GABA agonist baclofen before exposure to styrene prevented its occurrence.1g’20 The long-term effects of solvent exposure are probably related to nerve cell destruction in the CNS.5 The cerebella-brain stem seems to be an early and vulnerable target for the solvents. Thus, the signals to be integrated are probably unaffected, but the integration is likely to be defective; eg, if vision is disturbed, it could be difficult to use the proprioceptive and vestibular signals properly. TABLE 2. Correlations Between Static and Dynamic Posturography in the Patient Group [N = 7) DYNAMIC POSTUROGRAPHY so1 so2 so3 so4 so5 SO6

STATICPOSTUROGRAPHY EyesOpen (P) -

0.79 0.17 0.42 0.32 0.06 0.07

1.05) (NS) (NS) (NS) (NS) (NS)

NOTE.Probability values refer to probability coefficient equalling zero.

Eyes Closed (P) -

0.75 0.08 0.36 0.27 0.01 0.04

(NS) (NS) (NS) (NS) (NS) (NS)

of correlation

LEDINETAL Tests in human volunteers have indicated that oculomotor functions are more sensitive to solvent intoxication than is the peripheral vestibular system.’ In a recent study involving workers with CTE, Moller et al5 documented disturbances in the vestibulo-oculomotor system, auditory functions, and equilibrium performance due to industrial solvent exposure. The present study is a follow-up of these workers using a new equilibrium estimation method, dynamic posturography. It is the first to quantify permanent damage to the CNS in terms of visual, proprioceptive, and vestibular integration. Seven of the nine patients investigated by Moller et al in 19865 participated in the follow-up. The statistical analysis was hampered by the loss of two of the nine subjects. Accordingly, only one significant correlation between static and dynamic posturography could be demonstrated, that of SO 1 (stable support and surrounding) compared with the eyes-open condition in static posturography. It is of course also difficult to compare data derived from static posturography, which takes both AP and lateral directional sway into account, with that derived from dynamic posturography, which measures sway in the AP direction only. Furthermore, the investigations were performed several years apart. In a previous follow-up study in CTE, Juntunen et alzl studied 80 patients 3 to 9 years (mean, 6 years) after diagnosis. Although subjective symptoms had decreased, many objective measures of neurologic function had worsened, including gait and stance. It must be noted, however, that many of these subjects had continued to work with organic solvents during the follow-up period. Our patients had not been exposed to solvents for at least 5 years, so increased CNS lesions due to solvents were not a factor. These subjects were also considerably younger (mean age, approximately 45 years) than those participating in our investigation. In dynamic posturography testing, the CTE workers exhibited worse equilibrium scores than controls in all SO conditions and, in four of six tests, the differences were significant. In the SO 1 condition (stable support and surrounding), the difference was close to significance. In 1986, static posturography yielded abnormal results whether vision was present or absent. Although the values in 1986 were not compared with controls, but instead to a standard of the laboratory, the discrepancy between SO 1 and static posturography with vision present deserves comment. As discussed above, dynamic posturography measures sway in the AP direction only, while static posturography also takes the lateral direction into account. The measurement time in static postur-

99

ography is 60 seconds, compared with 20 seconds in dynamic posturography. Minor disturbances of balance could perhaps remain undetected in dynamic posturography due to this shorter measurement time. Furthermore, static posturography uses the average of three clinical trials, whereas SO 1 is usually conducted only once. On the other hand, the longer measurement time could cause a suspicion that static posturography measures mental alertness and endurance more than balance. In SO 2 (absent vision on stable platform), the difference between groups was significant, consistent with the results of static posturography with absent vision; patients with CTE clearly seem to show a greater dependence on vision than controls. In SO 3 (sway referenced surrounding and stable platform], the difference was not significant, but in all conditions with swayreferenced platform (SO 4 through 6), significant differences were found. Patients with CTE clearly have pronounced difficulties when the proprioceptive information is distorted, but seem to be able to handle situations on a stable platform, at least when visual cues are available. In this study, patients with CTE showed deteriorated balance performance even 5 years or more from the time of last exposure. Discontinued exposure to hazardous chemicals might have prevented a further decline in equilibrium function. However, the poor capacity of cell regeneration and repair in the CNS is well known; therefore, it is unlikely that any improvement in CNS or cerebellar function occurred during the 3-year follow-up period or, for that matter, since exposure ended, in 1985 or earlier. However, recovery and plasticity mechanisms must be taken into account. The increased age of these patients is statistically a source of decreased balance performance,” although this also applies to controls. Current posture pathology findings thus indicate a similar or even worse status at the time of exposure and diagnosis. Strategy scores were lower for all SO conditions expressed as ankle/hip correction patterns; these scores were significantly lower in SO 2 (absent vision and stable platform) and SO 6 (both surround and platform sway-referenced). In most cases, strategy scores are related to the equilibrium scores, ie, a lower equilibrium score is correlated to a lower strategy score. Therefore, great caution should be taken when evaluating strategy scores. It is important to account for the underlying distribution of equilibrium scores when inferring conclusions from data for groups of patients. The increased use of hip movements in SO 2 and SO 6 emphasizes the importance of the equilibrium score findings. Regarding the latencies in the MC test, no clear

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DYNAMIC POSTUROGRAPHY IN CHRONIC TOXIC ENCEPHALOPATHY

pattern of differences was seen, and in no test was the difference significant. This was expected, as the latencies mainly reflect peripheral nervous systemz3 and muscular function. Solvents present industrialized society with both benefits and disadvantages. While the standard of living in a world without solvents would presumably be greatly reduced, the use of solvents often poses environmental hazards. To the individual exposed, problems range from initial symptoms of nausea after instances of heavy exposure to a fully developed CTE, with intellectual reduction and personality changes. The process is very slow and perhaps not recognized until irreversible damage has occurred. Even after exposure cessation, subjective and objective impairment is likely to persist, and an increased intolerance to even minimal exposure to solvent vapor may arise. ” Therefore, as long as we continue to use hazardous chemicals, knowledge of these problems must be propagated and efficient investigatory procedures developed. In addition to a careful case history, exposure calculation, physical examination, psychometry, and auditory and vestibulo-oculomotor tests, dynamic posturography should prove valuable in the investigation and early detection of lesions that can evolve into CTE. The investigation of suspected as well as asymptomatic workers exposed to these materials is essential to the conduct of preventive occupational medicine. Dynamic posturography is easily performed in 20 minutes, involves no electrode attachment, and is a fully computerized procedure, making it convenient for screening purposes. Acknowledgment The technical assistance of Johan Deblen is gratefully acknowledged. References 1. Hoastedt C, Hane M, Axelsson 0: Diagnostic and health care aspects on workers exposed to solvents. In Zenz C (ed]: Developments in Occupational Medicine. Chicago, IL, Medical Year Book Publishers, 1980 2. Hyden D, Larsby B, Andersson H, et al: Impairment of visuo-vestibular interaction in humans exposed to toluene. ORL 1933; 45:262-269 3. Larsby B, C)dkvist LM, Hyden D, et al: Disturbances vestibular system by toxic agents . Acta Physiol Stand 440:157(suppl)

of the 1976;

4. Larsby B, Tham R, Odkvist LM, et al: Exposure of rabbits to metylchloroform: Vestibular disturbances correlated to

blood and cerebrospinal fluid levels. Int Arch Occup Environ Health 1978; 41:7-15 5. Mijller C, Odkvist LM, The11 J, et al: Otoneurological findings in psycho-organic syndrome caused by industrial solvent exposure. Acta Oiolaryngol (Stockh) 1989;- 107:5-12 6. Mdller C. Odkvist LM. Larsbv B. et al: Otoneuroloaical findings in workers exposed to styrkne. Stand J Work En&on Health 1990; 16:189-194 7. C)dkvist LM, Larsby B, Fredrickson JM, et al: Vestibular and oculo-motor disturbances caused bv industrial solvents. J Otolaryngol 1980; 9:53-59 8. Odkvist LM. Larsbv B. Tham R. et al: Vestibulooculomotor disturdances iaused by industrial solvents. Otolaryngol Head Neck Surg 1983; 91:537-539 9. Arlien-Soborg P, Zilstorff K, Grandjean B, et al: Vestibular dysfunction in occupational chronic solvent intoxication. Clin Otolaryngol 1981; 6:285-290 10. Axelsson 0, Hane M, Hogstedt C: A case-referent study on neuro-psychiatric disorders among workers exposed to solvents. &and J Work Environ Health 1976; 2:14-20 11. World Health Organization: Chronic effects of solvents on the central nervous system and diagnostic criteria. WHO Regional Office, Copenhagen, Denmark, and the Nordic Council of Ministers, Oslo, Norway, 1985 12. Flodin U, Ekberg K, Andersson L: StyreneNeuropsychiatric effects of exposure below the Swedish TLW. Br J Ind Med 1989; 46:805-808 13. Nashner LM: A systems approach to understanding and assessing orientation and balance disorders. Advances in Diagnosis and Management of Balance Disorders Conference, Boston, MA, October 1987 (can be obtained from Neurocom International Inc) 14. Cyr DG, Moore GF, Miiller CG: Clinical application of computerized dynamic posturography. Ear Nose Throat J 1988; 9:36-47 (suppl) 15. Black FO, Wall C III, Nashner LM: Effects of visual and support surface orientation references upon postural control in vestibular deficient subjects. Acta Otolaryngol (Stockh) 1983; 95:199-210 16. Diener HC, Horak FB, Nashner LM: Influence of stimulus parameters on human postural responses. J Neurophys 1978; 59:1888-1905 17. Sahlstrand T, C)rtengren R, Nachemsson A: Postural equilibrium in adolescent idiopathic scoliosis. Acta Orthop Stand 1978; 49:354-365 18. Baker R: Pharmacological profit of inhibition in the vestibular and ocular nuclei. In Bradley PB, Dhawan BN (eds): Drugs and Central Synaptic Transmission. London, UK, Macmillan, 1976 19. Odkvist LM, Larsby B, Tham R, et al: On the mechanism of vestibular disturbances caused by industrial solvents. Adv Otorhinolaryngol 1979: 25:167-172 20. Odkvist LM, Larsby B, Tham R, et al: Positional nystagmus elicited by industrial solvents. In Hood JD (ed): Vestibular Mechanism in Health and Disease. London, UK, Academic, 1978, pp 188-194 21. Juntunen J, Antti-Poika M, Tola S, et al: Clinical prognosis of patients with diagnosed chronic solvent intoxication. Acta Neurol Stand 1982; 65:488-503 22. Overstall PW, Exton-Smith AN, Imms FJ, et al: Falls in the elderly related to postural imbalance. Br Med J 1977: 1:261264 23. Ledin T, Odkvist LM, Vrethem M, et al: Dynamic posturography in assessment of polyneuropathic disease. J Vest Res 1991; 1:123-128 24. Gyntelberg F, Vesterhauge S, Fog P, et al: Acquired intolerance to organic solvents and results of vestibular testing. Am J Ind Med 1986; 9:363-370