Document LK49ewgRp1L5XoO477Lj0Kzy5

U\ ^ v^ r ' >* " - -' "'' V.v "''\?v*r' i*`-' -'.- '..' "S`" -v ^.4 '*) -` ^ fcA,` ''*" Evidence for peripheral neurotoxic effect of trichloroethylene Robert G. Feldman, M.D., Richard M. Mayer, M.D., and Arthur Taub, M.D., Ph.D. The analgesic and anesthetic properties of the chlorinated hydrocarbon, trichloroethylene (TCE), are well recognized.1-3 Its value as a grease solvent and extracting agent has been appreciated by industry for many years.4 The possible neurological manifestations of trichoroethylene poisoning weie pointed out as early 1915 by Plesxner3 and more recently by rkers in the fields of industrial medicine4'-8 and anesthesiology.9"11 Case reports describing cranial neuropathies following inhalant anes thesia using this material have been numer ous.1--"1 The most common finding associated with trichloroethylene intoxication, trigeminal neuropathy, has been so well accepted that intentional exposure to TCE has been con sidered a useful treatment for tie douloureux.n'lS That irichloioethylene was selective in its ac tion on the trigeminal nerve was questioned by Glaser19 when he noted tliallbis substance was capable of producing sleep. He suggested that TCE was not specific for the trigeminal tract or its sensory mots but rather depressed the cortex, affecting peiceplion of painful stimuli. In agreement, Jackson10 believed that TCE acted directly on the central nervous system, producing a general analgesia in which the trigeminal nerve connections were affected ini tially. Experimental or quantitative measurements of peripheral nerve function under conditions of TCE intoxication have been reported. Hardy, Wolff, and Goodcll19 measured the praiin threshold on the forehead and on the k of the head in 3 human subjects after jn'lation of 1 ml. of TCE. In those areas, the pain threshold was increased nearly 45% after fifteen minutes but lasted for one hundred twenty minutes on the forehead as compared with forty minutes on the back of the head. This pointed to more efficient analgesia in the trigeminal territory and did not support the notion of a central nervous system mechanism for the analgesia. Rubinstein et al.90 observed blood pressure responses following stimulation of the afferent- sciatic nerve fibers or dura (trigeminal nerve supply) in the waking dog. These responses were eliminated in the pres ence of TCE anesthesia, suggesting that this substance produced its effects through an anes thetic action capable of depressing trigeminal and sciatic sensory pathways. Additional data from acute animal experimentation reported by Defalque91 showed little difference between the effects of TCE upon reflexes mediated by the trigeminal nerve or a spinal nerve. He found that the pulp-chewing reflex (trigemi nal) and the skin-twitch reflex (spinal nerve) were depressed equally in intensity and dura tion in the presence of trichloroethylene. In a critical review of the literature concerning TCE since its discovery by Fisher in 1864, Defalque9- emphasized that the toxicology of trichloroethylene is still controversial because of a lack of careful clinical observations and From the Department of Neurology, Boston University School of Medicine; Boston Veterans Administration Res pit'd; Neurological Unit, Boston City Hospital; Department of Neurology, Harvard Medical School; and Department of Psychology, Massachusetts Institute of Technology, Bos ton Submitted for publication July 3, *969; resubmitted Sept. 4, 1909; accepted Sept, 15, 1969, Dr. Feldman's address is Boston Univeisily School of Medi cine, SO Concord Street, Boston, Massachusetts 02118, ycurologij / Volume 20 / June 1970 599 /Aar/.*icSA . 600 NEUROLOGY experimental studies, especially regarding evi dence for selective or specific analgesic effect on the fifth nerve. This communication deals with the studies of the toxic effects of TCE on the peripheral and cranial nerve function in a young man following exposure to warm vapors produced by a degreasing machine utilizing trichloro ethylene. CASK SUMMAHY A 26-year-old man investigated a leak in an overheated degreasing machine which utilized tri chloroethylene. He had direct exposure to vapors for about five minutes and indirect exposure through a potassium tetroxide eannister gas mask without a fresh air supply for one and one-half hours. Although he felt somewhat giddy after the exposure, no symptoms appeared for the first ten to twelve hours. At that time, nausea and vomiting, blurred vision, and numbness of the faee, mouth, and oral pharynx were present. Articulation and chewing were difficult because of facial and jaw muscle weakness. Neurological examination sixty hours after the exposure repealed a voung man who was lethargic, passive, and easily confused. He was oriented in time and circumstance but had difficulty following simple commands. Aiomas of Fig. 2. Bilateral facial paresis was indicated by flattening of nasolabial folds, inability to furrow brow, and weakness in showing teeth. Left eyelid ptosis and miosis were also noted. Fig. 1. The visual fields of the patient, de termined three days after toxic exposure to trichloroethylene. Centra! (upper diagram) and periphtial visual fields (lower diagram) were constricted bilateralh. tobacco and vanilla were recognized. Peripheral visual fields appealed constricted upon confronta tion; when tested bv perimeter and tangent screen, a definite constriction of the visual field was found (Fig. 1). These constricted xisual fields were checked by appropriate changes in the size uf ob ject as well as distance in relation to the screen, and repeatability of the findings rul'd out nu emotional basis for visual field defects of a con stricted and a contracted type. Optic 'nerve heads were not elevated and good vascularization was present. The right pupil measuied 6 ml. and the left pupil measured 4.5 ml.; both icacted to light directly and conseiisuallv. rfhe left pupil did not react to accommodation as did the right One Anes thesia to all modalities, including pinprick, touch, cold, and two-point discrimination was present in the entire distribution of the trigeminal nei\r bilateially. Corneal anesthesia was pic.xcnt bi laterally. Moderate limitation of lat-oa! movement of both eyes was noted. Diplopia wax pn-sent upon red lens testing. The left uppei eyelid ensured onethird of the upper half uf the iris There was flat tening ol the nasolabial folds bilateralh' (Fig. 2). Perception of taste over the antePur two-thirds of the tongue was reduced. Hoarst-t .-is of voice was noted. Tests of eomdination weie uni'emaikable. Deep tendon ic/lexes weie present and ctpial throughout. Except for anesthesia of the face, sen sation oxer the trunk, neck, and extremities was' intact. Bahinxki signs were absent. SL 033881  7 ",, ,_' ' '( ' ' V' ' n ` ` * ~r' " ' '`"' 1 - '-- f a **.v2 `A'"*i ' l*,"'''i ,VJv z) \\ % ; ,W ' ' -t ' `r Vi-'V-.' ' -v,Vy.*,/,'( C' V^'-*,?4 rha/r/yy^AL A^u/iorox/c effect of trichloroethylene 3/24/65 4/21/65 5/20/65 601 t ' i. Xi; 7f ' ? -']rL*` /' V/V'1 fi'i' "'y v.- a4' \ ' t,\_ ; ' ,N3.- & s * t ;v i: * Ip * ', 8/9/65 i 1/8/65 9/28/66 ' r- Hypalgesia 53 Decreased temperature sensitivity Fig. 3. Serial .sensory maps showing complete anesthesia and subsequent recovery pattern. Note early letnni of sensation over tip of nose. Anisocoria and .left ptosis of eyelid are depicted, as well as the ictiiin of the nasolabial folds. Kxaminatinii one month later resealed that the edge of taeial anesthesia had receded from the periphery and the tip ol the nose was hypalgesic rather than anesthetic, as were most other areas of tin- three disisions of the trigeminal nerve dis- ilnition. .Subsequent examination revealed pro- # s.\ise recovers ot sensation. It can be seen from Figure 3 that perception of pinprick initially re turned irr the periphery of the face and progressed in a concentric fashion toward the nasal-buccal region. The tip of the raise regained sensation to pinprick at about the same rate as did the edge of this anesthetic mask. The recovery on the face seemed asv mnrctrieal in its exact distribution but SL 033882 '{v-'x 1 ,"VgL *:^T. l - * s'g'f'.V''" -=' ,.->"i; : , ,-V '*; .f .-^v ? .^f.;3i*^;.'V-'.:w.x :asiasfetes-ij 602 NEUROLOGY LEFT- RIGHT 78 weeks 79 weeks 122 weeks 500 mv [^ Fig. 4, Motor responses recorded with a bi polar needle electrode in the orbicularis oris following supramaximal percutaneous stimu lation of the facial nerve. A progressive de crease in latency is seen over the period of one hundred twenty-two weeks (from top to bottom). quite comparable in its rate in the three divisions of the trigeminal distribution. Motor function of the facial muscles, as well as strength in the masseter and pterygoid muscles, improved during this eighteen-month period. The vision recovered com pletely. Voice was normal and sensation had re turned except for a slight dulling to pinprick in a patchy distribution. Methods. Conduction velocities were determined in the fastest motor and sensory fibers in the ulnar nerve, using the equipment and techniques which we have previously reported .** The nerve was stimulated initiallv with threshold electric shocks in order to elicit the monosynaptic (H) reflex.*1*5 The stimulus intensity was then increased gradu ally to suprainaxiimtin to obtain the maximal direct motor response which was necessary to determine the motor conduction velocity. This stimulus ob literated the H reflex and evoked the antidromic motor (F wave) response."1 " The II reflex and the F response could be separated and were furthei evaluated by the following techniques: [1] rapid Stimulation, 10 to 30 shocks per second, [2] tetanic stimulation (300 to 450 shocks per second) of the nerve for thirty seconds, followed by single test shocks of the same intensity for 2 to 1,000 msec., and [3] pairs of like stimuli to study the excita bility cycles.**-** The velocities in afferent fibers in the ulnar nerve subserving the II reflex were de termined between xvrist anti elbow and compared with the rate in the fastest motor and sensory fibers in the same segment. Recordings ot at least 10 observations of each response were made with either surface electrodes (7-mrn. silver disks) or intramuscular bipolar needle electrodes (0.3-mrn. platinum wires with an interelcctrode distance of 0.5 mm.). The facial nerve was stimulated at the stylo mastoid foramen and the motor responses were recorded in the orbicularis oris and oculi muscles.*1" The normal conduction time ranged from 2.2 to 3 msec, for the age group of 20 to 29 years5*-"' and was used as a basis of comparison in our patient. Serial recordings of responses were made initially at weekly and then monthly intervals. Electrophysiologic results. The evoked motor responses in the orbicularis oris are shown in Figure 4. Polyphasic and complex motor unit po tentials occurred after a prolonged latency early in the illness. A more synchronous response of muscle fibers appeared with recovery over the eighteenmonth period. A similar prolongation of conduc tion time was observed in the facial nerve to the orbicularis oculi. The conduction times (latencies) in the facial nerve are plotted on the graph in Figure 5. Conduction velocity in the ulnar nerve" was reduced only in distal sensory fibers at two weeks, as shown in. the table. The velocities re turned toward normal nine weeks after exposure but remained abnormal at thirty-fou'- weeks, al though the patient had no signs or symptoms re ferable to the ulnar nerve. The slowing of velocityin the idnar nerve was sensory more than motor and distal more than proximal. H reflexes, which usually cannot be recorded in normal adult hand muscles,11-2* were present in the hypothenar muscles throughout the period of the testing (Fig. 6). The velocity in the afferent fibers was less than that in the fastest sensory and Slwks ^4- "O-Xhj^ a kt ! 6- XN /Lett X/ Right ^X70wks Facial Nerve i: o - .--Con!f ol ""-`,v:r <o S> Ronqe *-* * "i'\v v Ci % <3 Ls 01IJL1 -----------LI 20 40 60 GO 100 120 WEEKS AFTER TOXIC EXPOSURE TO TCE Fig. 5. The responses shown in Figure 5 are plotted on this graph to demonstrate the recovery curve of facial neuropaths- follow ing toxic exposure to trichloroethylene. r t,,.- .. _ rerjif ^ I'.-^i=u<n- T Vi*S VY... '^V-.^*-''1,*^ \ , .J. '1-.'. >; ,\i VERIFHERAL NEUROTONIC EFFECT OF TRICHLOROETHYLENE 603 CONDUCTION VELOCITY IN t'LNAK NERVE (motets per second) 7 tme '2 weeks 9 weeks 34 weeks Xoi m:il Nerve action potentials i'ingcr-tvrijrt Wrist-clhow Efboic-fl.-tMii 46 57 54 64.7 3.9 63 60 58 64.8 3.S 66 61 66 69.1 w 4.3 Ttm<* 2 9 weeks 34 weeks Normal Motor Wtisf-mm-efe Etfemo-tcrtst 2.8 msec. 2.5 msec. 2.8 msec. 2.7 .3 53 51 50 58.9 2.2 Axill<i-eibo\c 60 61 58 64.4 rt 2.6 Time H reflex \Vrist-elbo\o 2 weeks 9 weeks 34 weeks 48 47 48 composes, under the influence of light, into phosgene, hydrochloric acid, and carbon mon oxide, as well as dichloracetylene.30-31 Dichloracetylene may, itself, decompose into phosgene and carbon monoxide. In the presence of mois ture, dichloracetylene may hydrolyze to dichloraeetyl chloride and further hydrolysis may produce the corresponding acid. The condi tions in the poorly ventilated room in which our patient was working encouraged volntization of the material since the temperature was well over 100 F. Short exposure to the de composition products of trichloroethylene may be sufficient to produce cranial neuropa thies.'1--34 In our patient, as in the workers first de scribed by Plessner in 1915, survival after ex posure to TCE was accompanied by extensive anesthesia of the face, oral cavity, and tongue mucosa. Difficulty in chewing was present, partly because of anesthesia inside the mouth motor fibers in the same segment. Posttetanic polentiation of tire II response was observed but not Jpf the F wave. The latency of the F response (24 rinsec.. elbow to muscle) was tire same as that of the H ieflr-s. No abnormality of tire F ware was observed. DISCUSSION Enderby13 emphasized the rarity of cranial neuropathies associated with pure trichloro ethylene anesthesia, finding only one case in 2,000 anesthetized patients. In that patient, soda lime contaminated the vapors. There ap pears to be no report of injury to cranial nerves by undoubtedly pure trichloroethylene.29 In dustrial trichloroethylene- is said to impose in jury' in a frequency rate of 0.3 per million ex posure hours.s The patient described in this re port was the victim of acute poisoning by the trichloroethylene vapors and its probable breakdown products elaborated from a defec tive degreasing machine. Some authors believe that trichluroethanol is important in the patho genesis of trichloroethylene poisoning,30 while others31 believe that there is no danger of trichloroethylene intoxication under clinical anesthesia unless the substance is brought into contact with an alkaline, when it may break' down into hydrochloric acid and diehloracetylene. Industrial trichloroethylene contains alka line substances or cresol. It volatizcs and de Fig. 6. Recordings of the H reflex (II) in the hvpotheuar muscle with [A] threshold stimulation. With increasing stimulus inten sity [A through D], the (M) response was elicited and the H response was depressed. Calibration: 10 msfc. SL 033884 V ""2VC. >' * 'll - ,Vsf ' 1 .. rv- - \-.v"' -' 7. ' t t i* * s' ` * 4l A V1 ftft, f k. . lr-y`~5 . r ' ' , . .*, ''i 'Vri* TV ri, Aj IM vy.^^vr^1;y.,r-> } .1 "r. ', - /f '.-51* -*J*t .- V,f>!.-.J - "..' - .-w 'V.5T '.; -r. -;HBsi'`f'i^'*iV:'''4'>;' ' A. /& *? i~ ~v'frilflifr* Vv~^r^r k^ilf -'a iaUm'W *- ,-^jK' i , G04 NEUROLOGY and partly because of weakness in tbe mastica tory muscles. In must cases previously reportecl i.s.s-.'tT the trigeminal involvement was pres ent for at least one year after cessation of the toxic exposure. According to Stuber,1 tbe cra nial neuropathy was not clearly a result of central damage of the roots, as in tabetic tri geminal neuropathy, nor clearly a peiipheral neuritis because of tbe irreversible damage, tilepredilection for sensory fibers over motor fibers. Buxton and Hayward10 reported 4 cases of cranial neuropathy following toxic exposure to industrial trichloroethylene. One of these pa tients, age 39, died after aspiration pneumonia before any return of facial sensation bad oc curred. The most striking finding on autopsy included bilateral extensive myelin and axon degeneration of the trigeminal nerve and its proximal root. In luxol bine and silver prepara tion, scarcely any myelinated axons remained;myelin was aggregated into irregular globules and axons were reduced in number. Some of the reports in the literature care fully document the pattern of progression and recovery of sensory loss over tbe face. One patient (Case 4), described by Humphrey and McClelland,1:1 showed total anesthesia for ten days before the skin over tbe forehead and cheeks felt "swollen and stretched." She also had a tingling sensation around the nose. Hypalgesia was piesent over the face except for an exaggerated response to pinprick on the nose. A second patient (Case 11), reported by the same authors, experienced subjective numb ness in all divisions of the trigeminal nerve with paresthesia and initial recovery occurring over the nose. These two patients developed facial sensory loss after exposure to trichloro ethylene anesthesia delivered by a machine containing soda lime and employing a "to-andfro" method. One of the workers described by Buxton and Hayward"' spent four- hours in the warm vapors of trichloroethylene inside a tank and had initial circumoral numbness which de veloped into complete analgesia in the tri geminal distribution. In these cases, as well as the one presented in this communication, the onset of numbness occurred around the snout and spread centrifugally in the distribution of the fifth nerve. During recover), our patient showed return of sensation in a centripetal, concentric, "onion-peel" pattern. Sherrington'13 postulated that the skin field of the trigeminal nerve lepresented supply by peripheral nerve trunks rather than those of sensory nerve roots. Each division--ophthalmic, maxillary, and mandibular--was found to have a delineated area of supply leaching the mid line with varying degrees of overlapping. Later authors, including Dejeriiie,31' Kraus,"1 aud Bing,4* clearly defined the segmental sensory pattern of the face as well as peripheral nerve fields. Facial dermatomes have been depicted as having a concentric or "onion-peel'' arrange ment centering on the nose. The explanation of this sensation distribution is usually based on Dejerine's observation of progression of sen sory loss associated with expanding cervicomedullary lesions such as syringobulbia, that is, facial segmentation is a reflection of the lami nation of the nucleus of the spinal tract of the trigeminal nerve. The upper part of the nucleus innervates the field nearest the nose and the mouth, the intermediate part contains aflerenls from the semicircular area from the forehead to the chin, anterior to the ear, and the lower part receives input from the. caudal area of the face. There have been many attempts to cm relate the receptive field location of trigeminal cuta neous aiferents with the level of termination within the spinal tract. Van Valkenhurg13 re ported that maxillary and mandibular divisions extend most caodally. The revel so observation lias been made by others.4:4-45 Dejerine's opin ion that the termination of fibers within the spinal tract is related, not to the peripheral division in which they lie hut to the distance of their receptive field from the perioral region, received support iiom recent histological stud ies in rut,,! aud the cat and monkey.4" Single unit recordings' have shown that tactile sen sory fields terminate at all levels, extending caudalwarrl to CL. Other observations"1--'" re vealed that small myelinated fibei.x within the tract do not extend beyond the obex in the cat. Wall and Taub"' demonstrated that the largest peripheral trigeminal nerve fibers suc ceed in penetrating long distances from the root entrance zone, allowing for all sizes of peripheral nerve fibers to converge on the most rostral cells of the trigeminal nucleus, while the more caudal cells receive only the largest mye linated fibers. The rostral cells would corre spond to the snout region while the most can- Si 338seBtSS FILRIFUERAL NEUROTONIC EFFECT OF TRICHLOROETHYLENE 605 Lull colls would correspond to the peripheral areas. A concentric sensory pattern is thus formed, based on a rostral-caudal nuclear ar rangement of diflcrent fiber sizes. Fewer C-fibcis are found in the sensory blanches of the trigeminal nerve than in com parable spina] nerves. Gerard'' found only about 15" of unmyelinated fibers in the trigem inal sensory root. "Wall and Taub1" found no libers smaller than 3/.i. The smaller fibers are concentrated at the front of the face, around the tip of the nose and the snout, while the larger ones are in the back of the face, in the periphery of a concentric distribution. J11 this way. a condition w hich affects peripheral con duction, possihlv bv altering myelin, could pro duce a clinical picture of a concentric pattern of sensation loss. The clinical manifestations would first appear where the density of smaller fibers was highest and progress centrifugallv. The recovery would occur in reverse pattern. The smaller fibers concentrated in the snout jjgion m.iv be afiected more and sooner than |e larger ones, the. recovery may take place in the larger fibers moving from the back of ibc head foiward. The "onion-peel" appearance of sensation loss could, theiefore, be due to peripheral neuropathy by a decrease in the number of affeient impulses reaching the piiinaiv nuclei ol the trigeminal system, rather than damage to the nuclei themselves. In agreement with the suggestion of Simp son."-' reversible slow nerve conduction velocity in our patient most likely is secondary to demyelination and remyelination. Stuber' postu lated the action of TCJ?"Dn nervous tissues to be a manifestation ot its physical property as a lipid solvent and that this substance adsorbed to ueive membranes, resulting in anesthesia. When a toxic amount was present, there was an ineversible effect by extraction of lipid con tent rather than by adsorption. Although unpinved. this explanation seems quite plausible in the piedilection for peiipheral nerves, sensoiv moie than motor, ami the manifestations in altered conduction characteristics, as demoustiated in this report. The conduction studies of the motor fibers of the seventh nerve, as well as the sensoiv and motor potentials studied in the ulnar and tibia! nerves, provided inferential valence that conduction characteristics of the flh nerve mav he similailv involved. Mac Donald"'1 found reduction in thickness or abste. e of mv elin over variable lengths of nerve fibers in experimental diphtheritic neuropathy and considered this an important factor in re ducing individual fiber conduction velocity. The application of saponin (a fat solvent, as is TCE) resulted in damage to the myelin sheaths and a delay of excitation at nodes of lfanvier.TM If vve assume that demyelinization resulting from the lipid solvent effect of TCE would alter the large and small fibers in pro portion to the amount of myelin present, then there would be a possibility that the smaller fibers might be damaged proportionately and perhaps slowed even more than the larger ones. In the stage of complete anesthesia, all fibers would be affected, but as recovery en sued, the differences in sensation loss pattern of the face might coincide with the fiber spec tra of different parts of the head. Gradual re covery in function would coincide with an in crease in the number of fibers possessing re established conduction.n:'''i,! Sl'MM.AllY A young man with industrial trichloroethyl ene intoxication has been carefully studied. The interesting observations in this study in clude electrophysiologic evidence of a periph eral neuropathy and the clinical definition of the pattern of trigeminal sensory loss and re covery. The onion-peel distribution, usually in dicative of segmental or nuclear trigeminal le sions, is best explained in this ease by dis turbed nerve conduction, possibly due to the lipid solvent effect of trichloroethylene on pe ripheral myelin sheaths. REFERENCES 1. o4rLhHE, c.; TricMorethylene Anesthesia. Edinburgh: K. & S. 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SL 033886 - " , * C ^ J* i-}^, I) r - *. -.'f iTG0v-v0 - -v.c m 1 I rZ&f&ifc&Z:'.-. - Vi't-VAv; -j/. -va > ,'V `VT- s T'--.: :-T mm & W^SP P' ***v ~ v r^>v_ - ; `' *`J?],.."..-u:*.';-i ^-.`o->V'?;->" .; "^ '* t V-*> '' -...*',<' r v'.? i,v^^;'v^-:vy'.-v':-t^' s i ""V**"^' " ' ' *.",,* '^,1^ `J,' , s.,_ ^ ,. ~ ^ "v :v:^^ *;} >.'; 1 ' ;/W:S..~*,;:Vy:'M^-'i' 'V v M' ;; ,< S'*?*' -i-.../.v-?.'*-s.-ya^ <-y'v>'i'J>.; .'v- ' 606 XEUROLOGY 9. joachtmoglu, c,: Die* Pharmakok.jric dv* Trichlcracthyleiis. Berk klin. Wschr, .58:147, 192). 10. jackson, . ft.: Study of anahaMn and anesthesia with special reference to such substances ns trichlorethylene and vinethvlene. Ancsth. Analg. Curr, Re*. 13:198, 193*1. 11. atkinson, n. s.; Trichlorethylene anesthesia. Anes thesiology 21:67, 1960. 12. hewer, c. l.: Further observations on trichlorethylene. Froc. roy. Soc. Med. 36:403, 1913, 13. Humphrey, j. il, and McClelland, M-: Cranial nerve polsies with herpes following general anesthesia. 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