walter h. fink, m.d. the ocular pathology of methyl ... · toxicity of methyl alcohol the cause of...

THE OCULAR PATHOLOGY OF METHYL-ALCOHOL POISONING.

WALTER H. FINK, M.D.Minneapolis, Dfi,uresota

INTRODUCTION many of the conclusions reached tAQ

Methyl-alcohol poisoning in relation tocerni thegn ofeffecteff memethyl alcohol

the eye is of interest not only because it isthe human are based upon the results

clinically important, but also because the H.of experimental work on animals by H

resulting pathologic processes in theHoldenl in 1890 and Birch-Hirschfeld*

knownare not fully nown. in 1900, We must be skeptical of such

studies s t

tu

theWhoever u literature on theconclusions, for Holden's work cannot be

suhject must be impressed with the lackconsidered scientifically accurate. Like-

of uniformity of opinion as to the effectswise, Birch-Hirschfeld' work in 1900

of meth} l alcohol upon the ocular struc-should not be considered too seriously; he

lures. Opinions concerning the toxicologic toasmust have had some serious doubts

process are also at variance. Most of theits accuracy since he repeated it in 1926.'

opinions are based upon conclusionsDoubt of the accuracy of the positive find-

drawn from clinical observation, autopsyings in this animal experimentation is also

reports, and the results of experimentalstrengthened bby the critical work of de

work in animals,Schweinitz,

,

who was unable to reproduce

literature is devoidThe ofllypracticatheir results. Jonas Friedenwald5 likewise

reports of studies upon pathologic speci-o andresultsvenegatiobtainedibta concconcluded,

mens from the human eye. In most in-like de Schweinitz, that the previous

stances the reports were incomplete, andwork was probably in error. That such an

the material was not immediately fixed,error is possible is evident when we con--'

thus allowing post-mortem degenerationssider how very rapidly post-mortem

to ensue. It is well known that the retina,changes occur in the retina. Also we must

even though refrigerated, immediatelyconsider artifact and defective staining

disintegrates, causing an appearance thattechnique. It is entirely possible that thenegative findings of de Schweinitz and

may be interpreted as a pathologic changeFriedenwald are correct, and that animal

resulting from methyl alcohol. Anotherexperimentation is of no value in solving'

criticism of the early autopsy findings isthe problem. It is well known that animal

that the fixing and staining process usedtissues do not always exhibit the toxic

was not adequate to show minute changeseffects of drugs that are manifested in the

accurately. It seems, therefore, that what-tissues of the human body.

ever evidence may have been adduced asThe pathologic effect of methyl alcohol.the result of human autopsy should he

on the human being should be consideredheld in question.

not only as to its effect upon the eye butConsidering the ocular findings as the

also on the whole body, since its effect isresult of animal experimentations, doubt

d specificwidesprea and not confined to aagain arises. The fact impresses us__that_. ._..action on the retina, as some authors* Candidate's Thesis (condensed) for mem- would have us believe.

bership in the American Ophthalmological So- Because of the uncertainty which ap-ciety, 1942. Details of the original animal ex-perimentation appear in the Transactions of patently exists concerning these ques-that Society, 1942. tions, further study of the subject seems

694

OCULAR PATHOLOGY OF METHYL-ALCOHOL POISONING 695

vindicated. The following investigation was,undert

aken to obtain more concrete in-formation and thus establish a more defi-nite conception of the ocular changes thatare present in these cases.

TOXICITY OF METHYL ALCOHOL

The cause of the peculiarities ofmethyl-alcohol poisoning has not been sat-isfactorily explained. There is a paucityof facts regarding the actual behavior ofmethyl alcohol in the animal organism, sothat the underlying causes of its extremetoxicity are by no means clearly under-stood. Certain facts, however, have beendetermined by animal experimentationand clinical observations which aid ma-terially in drawing conclusions. Theseare:

Methyl alcohol may develop its lethalaction through three different avenues ofentrance into the system; namely, inges-tion, inhalation, and cutaneous absorption.

The presence of various impurities doesnot influence the toxic action, and it isgenerally believed that the effect is dueto a property incident in the methyl alco-hol itself.

Methyl alcohol is a poison in whichidiosyncrasy plays an important part,some persons being greatly affected bydoses that would not harm the majorityof people.

There is no evidence to show 'that ato

lerance to methyl alcohol can be devel-oped.

Man appears to be relatively more sus-ce

ptible to a poison like methyl alcoholthan is the dog or the rabbit, for it seemsthat poisons which powerfully affect the1iighly differentiated nerve structures arePro

portionately more dangerous the morehighly developed the nervous system.The fate of methyl alcohol in the hu-

man body is not definitely known. Thereis evidence suggesting that it is not the'nethyl alcohol itself but some of the

chemical by-products of incomplete oxi-dation that originate these poisonous ef-fects. It appears that formaldehyde andformic acid are the chief toxic agents,although there may be others. The toxiceffect is thought to be due to the cir-culation of these toxic combinations in.the blood and their coming in direct con-tact with the tissues.

It has been demonstrated that the dif-ference in the character of intoxicationbetween ethyl and methyl alcohol is dueto the fate of these substances followingtheir administration. Whereas ethyl al-cohol is oxidized into easily excretedproducts, carbon dioxide and water,methyl alcohol is only partially oxidizedand the products of this incomplete oxi-dation are formaldeh yde and formic acid.Some explain this difference in the fateof the two alcohols by the difference intheir rate of oxidation. Methyl alcoholin slow oxidation makes formic acid,while in rapid oxidation it forms carbondioxide and water; hence, when it rapidlyoxidizes it is comparatively harmless,while in slow oxidation, which usuallyoccurs in some people, it is exceedinglytoxic. The variation in effect on individ-uals therefore may be partly explained bythe rate of oxidation which takes place inthe person.

If this transformation of methyl alco-hol into formaldehyde and formic acidtakes place, we have an example of apoisonous compound forming two inter-mediate compounds which are much moretoxic than the original. It has been esti-mated that formaldehyde is about 30 timesand formic acid 6 times more toxic thanmethyl alcohol.

In considering formaldehyde as the in-termediate product of oxidation it must beconceded that from a chemical standpointsuch formation is possible; but upon'sur-veying the experimental evidence, verylittle is found to substantiate the claim.

696 WALTER H. FINK

Most evidence points against its presencein the tissues and the only positive evi-dence found was given by Poh16 whofailed to find support for the view thatany "considerable quantities" of for-maldehyde are formed, but "it may be thatformaldehyde is formed and that it isquickly converted into formic acid."

It must therefore be concluded that ifformaldehyde is present it is present buta short time, which may, however, besufficient to produce a toxic action.

In considering the presence of formicacid in the body there is indisputable evi-dence that it is present, for it is excretedin the urine, but when it is formed andhow much is formed is not known. Ininane instances it is apparently the finaloxidation product, although some individ-uals may have the power to decomposethe meth yl alcohol further to carbon di-oxide and water. That formic acid is notpresent in the tissues to any degree isevident if tissue analysis can be dependedupon as a criterion. Pohl thought it prob-able that all the methyl alcohol adminis-tered is converted into formic acid, thatpart of the latter is then oxidized to car-bon dioxide. As he did not find it in thetissues to any degree he concluded thatvery probably either methyl alcohol it-self or one of its derivatives is retainedin the body and is then slowly convertedinto formic acid. Bongers r on the otherhand, asserts that after the administrationof methyl alcohol considerable quantitiesof methyl alcohol are excreted in theurine. It would seem from this that notall the methyl alcohol is converted intoformic acid.

Varied tests made upon the distillatesfrom tissues appear to establish the factthat methyl alcohol and not formaldehydeand formic acid is the principal recover-able toxic substance. Very rarely haveeven traces of formaldehyde and formicacid been detected. It therefore seems evi-

dent that methyl alcohol itself is retainedin the body for some time and is a ppar-ently excreted unaltered or as formic acidwhich apparently is slowly formed.

It seems that the human body in manyinstances has great difficulty in oxidizingmethyl alcohol. It has been stated thatbut 3 percent of the body metabolism canbe attributed to the methyl alcohol, whichseems to be conclusive evidence of theinability of the body to cope with it.

In the opinion of certain investigators,there is a more profound disturbance ofthe metabolism than is indicated by thesimple failure of the body properly tooxidize methyl alcohol. Observations sup-port the view that acidosis plays an eti-ologic role in the production of the symp-toms following methyl-alcohol poisoning.As in a variety of other pathologic stateswhere there is a reduction of the reservealkali of the blood, the exact significanceof this reduction is not clearly understood.There is evidence strongly suggesting thatthe disturbance of the acid-base balancemay, in itself, cause definite anatomicchanges. It must be conceded that acidosismight be an important factor in produc-ing the poisonous action of methyl alco-hol. Harrop and Benedict' were the firstto treat a patient on this assumption.In the case reported by these authorsthere was a definite reduction in thereserve alkali and there was also thecharacteristic air hunger.

A highly significant feature of thisphase of the problem is the slow elimina-tion of the methyl alcohol or its conver-sion products from the organism, whichleads to a subtle danger in the form ofaccumulated toxic products. Investigatorshave indicated that the probable explan

a

-tion of the unduly pronounced poisonouscharacter of methyl alcohol is not onlythe failure of combustion but also thedelay in elimination. According to H en

-derson and Haggard," more than a week


is required to eliminate the methyl alco-hol acquired by a single large absorption.If the exposure is repeated before the elim-ination is completed, a cumulative effectresults; the amount absorbed at each ex-posure is added to that which remains un-eliminated. A toxic concentration is thusgradually built up in the blood as a resultof repeated exposure to concentrationsthat do not cause an appreciable effect ona single exposure. Placet 1° has shownthat the complete elimination of woodalcohol requires a period of time fivetimes as long as that of ethyl alcohol.

It therefore appears evident that thetoxicity of methyl alcohol may to somedegree be attributed to the fact that it re-mains for a long period of time in theanimal organism where it has time toproduce varied and grave changes of achemical and chemicophysical nature.

Most evidence points to the fact thatthe methyl alcohol is distributed very rap-idly to all tissues and fluids of the body.There is practically no lag in themethanol-water concentration of theblood behind that found in any tissue ata particular instant regardless of whetherthe animal was accumulating methanol,was in a steady state, or was eliminatingmethanol following exposure. Conse-quently, all kinds of tissue or body cellsare exposed to practically the sameme

thanol-water concentration, there beingno selective accumulation, retention, orpr

edilection. The results also show thatthe amount of methyl alcohol in the bodyor in a particular tissue can be estimatedfrom a determination of the methyl alco-hol in any tissue or fluid.

It seems, therefore, that once consumedor inhaled, methyl alcohol quickly dis-perses to all tissues of the body, havingno selective affinity but apparently in-juring by direct action the more highlyspe

cialized tissues of the retina, brain,kidneys, and liver and to a lesser extent

the other tissues. Experimental data con-firm this fact as regards the eye becauseit has been demonstrated that the sub-stances produced in the body by poisoningwith methyl alcohol penetrate the eyereadily.

On the other hand, there is some .evi-dence to prove that methyl alcohol has amarked selective affinity for the mosthighly differentiated nerve elements ofman. According to this evidence, the vari-ous organs do not show identical findingsin the fixation of methyl alcohol; thebrain and other nerve tissues exhibit adecided electivity for this substance, andcontain the largest quantities of it. Liver,kidney, and muscles then show decreasingproportions of it. The specific affinity isin accord with that which might be ex-pected from its lipoid make-up. This isexplained by the fact that the alcohols,like ether, chloroform, and other volatilenarcotics, are notably soluble in lipoidssuch as those characterizing the nervoussystem. With equal concentration of ethyland methyl alcohol, methyl alcohol hasthe greater effect of modifying the lipoidcontent of organs. It should also be notedin this connection that there is a consid-erable increase in the fatty-acid and cho-lesterol content of the blood serum, result-ing from acute experimental poisoningwith methyl alcohol.

Furthermore, experimental evidence in-dicates that there is a greater absorptionof methyl alcohol in the retina than thereis of ethyl alcohol.

It is of importance to trace the ulti-mate fate of methyl alcohol in the body.Whereas ethyl alcohol is eliminated fromthe body chiefly through the lungs and, toa far greater extent, through oxidation inthe tissues, methyl alcohol is also elim-inated through the lungs, but is only to asmall extent oxidized in the tissues. It isstated that only about 10 percent of thetotal amount of ethyl alcohol which dis-

698 WALTER H. FINK

appears from the body is eliminated inthe expired air. Of methyl alcohol, onthe contrary, more than 70 percent ofthe amount that disappears from thebody appears in the expired air.

Voltz and Dietrich" found that afteradministration of 2 c.c. of methyl alcoholper kilogram of the body weight of a dog,24.3 percent was excreted in 48 hours,of which 21.5 percent was in the expiredair, and 2.18 percent in the urine. As36.7 percent was found in the body, itfollows that only 39.0 percent was oxi-dized in the body. If the caloric value ofthe methyl alcohol oxidized is calculated,it will be found that this represents onlyabout 3 percent of the total metabolism ofthe body. These results are in markedcontrast to those obtained in studies ofethyl alcohol under analogous conditions.It seems evident therefore that the bulkof poison is eliminated through the lungs,skin, and kidneys.

Comment. To draw conclusions fromthe data available is difficult. We mustkeep in mind that most of the positiveevidence is the result of animal experi-mentation and may not hold true forman. It is to be regretted that so littleeffort has been made to obtain toxicologicdata from the bodies of people who die asthe result of methyl-alcohol poisoning. Ina few instances the tissues were analyzedfor methyl alcohol only, but nothing hasbeen done that can be called conclusive.Considering the number of fatalities,from this form of poisoning the thorough-ness of our scientific work leaves much tobe desired. It is therefore evident that weare obliged to a great extent to draw con-clusions on suppositions based mainly ontheory and animal experimentation.

It seems evident that methyl alcoholcannot be oxidized readily by some indi-viduals and consequently acts as a poison.It is most probable that the toxic sub-stances remain in the system as such and

are distributed to all of the tissues. Becauseof their prolonged contact with the tissuesthey cause pathologic changes, but to agreater degree in the highly specializedtissues such as the central nervous sys.tern, kidney, liver, and other organs. It ypossible that the more highly develop,tissues of the central nervous system aremost affected because of their chemicalstructure and the resulting disturbancein their nutrition.

In review of the evidence at hand itdoes not seem logical to conclude thatone specific substance causes the change.It would appear instead to be due toseveral factors. A profound change inthe chemistry of the body caused by alack of chemical balance such as is seenin instances of acidosis might be a factor.In addition to this, there could be a directchemical action of methyl alcohol itselfor in combination with the products ofoxidation.

. The degree of these reactions wouldnaturally vary with the individual toler-ance or the ability to cope with the drug.

It is significant that the patient in mostof these cases does not experience animmediate toxic effect. It seems logicalthat if methyl alcohol were the only toxicagent, the patient would evince the pro-found toxic effect immediately upon tak-ing the alcohol, for it is known that thelatter is absorbed and circulates in theblood, almost immediately coming in con-tact with sensitive tissues. Instead, toxicsymptoms in most cases are manifestedmany hours later. This would point tothe fact that the pathologic changes occut.after some drastic chemical upheaval hastaken place in the chemistry of the bodY,such as is seen in acidosis or as the resultof oxidation.

Just what action is responsible for thepathologic change it is difficult to state.The presence of methyl alcohol has beendemonstrated in the tissues, but there is


o definite evidence to prove the presenceof formaldehyde or formic acid in thetissues. That formic acid is formed inthe body is proved by its excretion fromthe kidneys. The fact that it is excreted

,, for such a long period suggests that thetransformation into formic acid is a verygradual process. The exact period oftime during which the formic acid re-mains in the body is probably of littlesignificance, for a chemical of this degreeof toxicity need act but for a moment toproduce pathologic changes.

Admitting that methyl alcohol has aneffect, the presence of its by-products isstrong presumptive evidence that theseare additional toxic elements which eitheralone or in combination with the alcoholcause a profound alteration in the chem-istry of the body cells. This change inthe body chemistry could produce anacidosis which in combination with theother factors causes pathologic Inanifes-tations in all tissues and especially in thetissues of lipoidal structure such as theretina and brain. We know that thesehighly specialized tissues are always moresensitive and will show degenerativechanges even in a temporary upset thatinterferes with the normal metabolismof its cells.

From the data available, it may bestated that some chemical combinationsare not tolerated by the body so readilyas are others. Perhaps one of those mostpoorly tolerated by a large percentageOf people is methyl alcohol. Althoughsome individuals have the metabolic abil-ity to cope with this drug, the greaternumber do not, and when it is taken into

the body the abnormal metabolic proc-esses that do occur produce chemical com-pounds that tend to act as poisons andalter the normal chemical balance so nec-essary to physical well being. It is gen-eral ly known, and confirmed by the au-thor's experiments on animals, that one

of the oxidation products—namely, for-mic acid—can cause changes similar tothose produced by methyl alcohol alone.It would be incorrect to state that be-cause formic acid is known to be presentin the body during the time of the toxiceffect, it alone is the causative agent;but rather that formic acid is a factor andvery probably acts in conjunction withmethyl alcohol and other oxidation prod-ucts to produce the pathologic changes.There is no conclusive proof that methylalcohol alone is responsible, and untilfurther proof is available the aforemen-tioned statement may stand as a possiblededuction.

SUBJECTIVE OCUL:.R SYMPTOMS

VISUAL ACUITY

Fairly characteristic changes in thevisual acuity are found in cases ofmethyl-alcohol poisoning.

In acute cases, the changes are suffi-ciently constant to be diagnostic. Thecharacteristic visual change is first of alla sudden diminution of vision which maybe of marked degree. This is followedby a gradual improvement in a few weeks,but is followed later by a gradual loss ofvision which may progress to total blind-ness.

Comment. It is fairly accurate to as-sume that the initial loss of vision maybe caused by the action of the chemicalon either the ganglion cells, the nervefibers, or both. Its sudden onset, followedin a few weeks by a return of vision, sug-gests that there is at first an edema of thetissues. Not necessarily all the tissue cellsare involved. Microscopic study showsthat the cells may be destroyed in patches,with some fairly normal cells between theareas of destruction. It is conceivable thatthe edema which undoubtedly resultswould for the time being inhibit the actionof these undestroyed nerve cells, tempo-rarily causing the total or almost total loss

700 WALTER H. FINK

of vision. The edema may be localizedin the nerve, the retina, or both, but,judging from the ophthalmoscopic pic-tures, it is most frequentl y seen in theregion of the papilla. When the ophthal-moscope does not show changes referableto edema, the latter may be retrobulbar.It is also possible that a retinal andchoroidal edema may be present but notevident under the ophthalmoscope.

After a few weeks, the edema subsidesand the ganglion cells that were not previ-ously destroyed again function so that acertain degree of vision returns. Becauseof the disturbed nutrition resulting fromthe toxic effect on the cell and the edemaduring the acute process, many of thesepartially affected cells may die; this wouldaccount for the gradual second reductionin vision. The final vision depends uponthe number of cells that survive. In thefinal stage, only a few cells may remainsufficiently normal to function, and thevision may be practically gone. In othercases, in which there is but a slight per-manent loss of vision, only a few cellshave been destroyed.

In order to appreciate these statementsrecourse must be had to a study of micro-scopic slides. In the retina may be seen atotal destruction of ganglion cells, and ad-jacent to these cells ranging from normalto complete destruction. The edema is alsodefinitely present and must inhibit themetabolism of the still undestroyed cells.

In the chronic cases, the gradual loss ofvision follows the same processI to a lessdegree. There is no sudden death of theganglion cells and very little edema, butrather a gradual loss of vitality due to thealtered metabolism of these highly sensi-tized cells.

PERIMETRY DATA

The perimetry findings are not charac-teristic. Scotoma are the most frequentfinding and may be single or multiple.A central scotoma is the most con-

stant finding. There is frequently a pe.ripheral contraction of the field whichvaries greatl y in degree and position.

Comment. From this observation, it isevident that the toxic effect is diffuse andvariable. The constant occurrence o fiscotomata suggests that the effect variesin intensity, some areas being profoundlyaffected. The frequency of the centralscotoma suggests the papillomacular bun-dle as an important point of involvement.

Because the ophthalmoscopic picture sofrequently indicates a retrobulbar involve-ment or an in volvement of the optic discwith little or no visible change in theretina, it would seem logical to concludethat the scotomata are the result of anoptic-nerve edema. It is not certain, how-ever, that they are not the result of local-ized involvement of the retina also. Thevariability of the perimetry findings overa period of time is in keeping with thevisual acuity, and can be attributed to thesame process.

It seems evident that with regard tothe perimetry findings, a rule as to the ex-act structure affected cannot be estab-lished. Undoubtedly, both the retina andthe nerve are involved in all cases; insome, however, one or the other may showthe predominating change. From the peri-metric evidence alone, one is inclined toconsider the optic nerve as the portionchiefly affected, because the perimetricchanges are more characteristic of thistype of involvement.

OBJECTIVE OCULAR FINDINGS

EXTERNAL

The objective findings give evidence ofa disturbance in the pupillary and accom-modation reflex arcs. That the involve-ment is variable is shown by the variablepupillary and accommodative reactions.

The symptom of ocular tenderness,both on pressure and on movement of theglobe, is evidence of an ocular or retrO-bulbar congestion or edema. The picture


can be described as comprising phenom-ena which accompany an acute edema.

Comment. As to the localizing value,the objective findings suggest an involve-ment of the entire nerve and vascularelements of the eyeball, together with cer-tain suggestions of retrobulbar involve-ment. There are also findings which provethat the reflex arcs of the pupil and ac-commodative mechanism are affected,pointing to a central involvement. Thepresence of ptosis and the involvement ofcertain extraocular muscles suggest a dif-fuse affection of nerves other than theoptic and in all probability located in thehigher centers.

OPUTHALMOSCOPIC DATA

From a study of the various ophthal-moscopic reports, it is evident that in theacute stage, the optic nerve is the mostfrequently involved part of the eye.

The process may at first involve theretrobulbar portion of the optic nerveonly, or it may spread forward to includethe papilla. It may involve the papillafrom the onset. Most reports make littleor no mention of the retina except theportion surrounding the papilla.

There are indications of circulatory dis-turbance with edema. The picture variesfrom a congestion of the nerve head to anintense edema. Mention is made of thedilated retinal vessels.

The optic atrophy that follows is pro-portional to the primary nerve involve-ment.

Comment. It seems evident from thesedata that the optic nerve is the portion ofthe visual apparatus primarily affected,and the process suggests an edema thatmay vary in degree. At least this wouldbe one explanation for the ophthalmo-scopic description given in the variouscases reported. In the greatest number of

these it is noted that the optic papillashows signs of congestion or edema atvarious stages of severity; retinal edema

is present but gradually diminishes in de-gree away from the disc. The retina notadjacent to the disc may show no signs ofpathologic change except for hyperemia.

It is difficult to understand this picturewhen the microscopic descriptions empha-size so strongly the retinal phase of thechange and show so little evidence ofoptic-nerve disturbance. It is, of course,possible that the retinal edema by com-parison appears insignificant and givesthe impression of a mere congestionwhen, in reality, it is quite severe. In otherwords, the marked optic-nerve involve-ment as seen with the ophthalmoscopedoes not preclude edema or destructionof the retinal elements. The absence ofdefinite choroidal changes would tend tominimize the retinal ophthalmoscopic pic-ture.

One may venture the opinion that incases where the optic-nerve change is thepredominating factor, a similar involve-ment occurs in the retina and choroid thatis not shown ophthalmoscopically exceptfor what appears to be hyperemia. Thedirect action of the toxemia in the retinamay cause necrosis, but with little reac-tion visible ophthahnoscopically.

Undoubtedly, some cases are moredefinitely retrobulbar than others, where-as others show more intraocular changes.It seems that all of them on examinationwill exhibit some signs of involvement ofboth elements.

Another factor which indicates a moregeneral involvement than merely the op-tic nerve is the postneuritic atrophy thatdevelops. In these cases, reports show thepresence of retinal atrophy as well.

It therefore seems plausible to con-clude that the ophthalmoscopic evidencebears out the contention that the entirenerve structure of the eye is involved, in-cluding the retina and optic nerve. In ad-dition to this there is a choroidal dis-turbance. The process is not always uni-formly the same; instead, one part may

702- WALTER H. FINKz

show the predominating picture of patho-logic change.

It seems evident that the initial tissueinjury is manifested ophthalmoscopicallyas an edema or hyperemia only, and thatundoubtedly many retinal changes, notvisible with the ophthalmoscope but nonethe less important, may not be observable.

MICROSCOPIC EVIDENCE FOUND IN THEIIUMAST EYE

The following summary describes thesignificant changes observed in the casesreported in the literature:

In the autopsies reported by Pick andBielschowsky," the most interesting his-tologic findings appeared in the ganglion-cell layer of the retina, in comparison withwhich the other layers of the retina wereonly slightly altered. The tangible changeswere demonstrable onl y in the innergranular layer where an agglomeration ofthe chromatin substance into coarsemasses had taken place.

In the retrobulbar section of the opticnerve, changes were found which, how-ever, in comparison with those in theretina, seemed trivial. In occasional med-ullary sheaths, a fine-grained fatty de-generation was found. There were to benoted, at some points, swellings and in-flations in the axis cylinders. If all thesefindings in the optic nerve are taken to-gether, we may say with certainty that anacute destruction of the nerve substancemust have taken place.

In the central nervous system, thergwere both chronic and recent changes ihall three cases. The chronic changes wereno doubt due to a chronic alcoholism ineach case. The acute changes were ex-clusively in the ganglion cells. Comparedwith the changes in the retina, these wereonly trivial, from a quantitative as wellas a qualitative point of view.

Comment. These findings are signifi-cant because they describe in considerabledetail the results as found in the retina,optic nerve, and the higher centers in

three patients who died of acute methyl.alcohol poisoning. It is the most completedescription of this situation in the litera-ture and offers most significant data fromwhich conclusions can be drawn. How.ever, the question of post-mortem changesarises, and there is no way of determining'its validity. It may be said that the de-scribed changes are very suggestive ofpost-mortem changes. This point is em-phasized by study of the author's cases inwhich post-mortem changes occurred.These showed a striking similarity tothose described by Pick and Bielschow-sky.

The latter's statement that the most im-portant changes occurred in the ganglioncells bears out the findings in animal ex-perimentation. They also stress the ob-servation that the changes in the opticnerves were slight by comparison. In spiteof the fact that they minimize the optic-nerve changes, there is evidence of patho-logic processes which should not be mini-mized. The degenerative changes in themedullary sheaths and the swelling of thenerve fibers are definite signs of optic-nerve injury.

In the central nervous system the find-ing of ganglion-cell destruction is sig-nificant and shows that the process is notconfined to the eye.

The case reported by Rymowitsch"was that of a man who died of chronicmethyl-alcohol poisoning. He noted hy-dropic and fatty degeneration of theretinal ganglion cells, varicose hyper-trophy of the nerve fibers, and edematous,saturation of the granular layers. Nodetailed account was recorded.

Comment. The report is much too briefto be of scientific value. It does, however,indicate changes in the retina that seemto be characteristic.

In Schwarti s" two cases in whichdeath occurred from methyl-alcoholpoisoning, the following facts were noted:There were no changes in the opticnerves; there were alterations, however,


in the vagus and phrenic nerves. Changesfound in the retina accounted for the

blindness.

Comment. The report is much too brief

to be of scientific value. It is significant

that no changes were found in the optic

nerves. Unfortunately, the changes in theretina, vagus, and phrenic nerves were

not described.In MacDonald's' s three patients who

died as a result of imbibing methyl alco-

hol, the following changes were noted.

Case 1. The retina showed marked de-

generation in the ganglion-cell layer. The

vessels of the choroid were considerably

congested.Case 2. The ganglion cells were de-

creased in number and degenerated, andcystic spaces were seen throughout this

laver. The vessels of the choroid were

markedly congested.

Case 3. The retina showed marked

changes. The ganglion cells were de-

creased in number, and cystic spaces were

seen throughout this and the nerve-fiber

layer.In view of the well-known early post-

mortem degenerative changes that take

place in the delicate ganglion-cell struc-ture, MacDowell could not say that his

findings were of value; they suggest that

the central scotoma and loss of vision

were due to toxic degenerative changes

that take place in the ganglion cells. He

believed that the subsequent changeswhich result in optic atrophy are due to

ascending degeneration of the nerve fiberfollowing the damage to the ganglion cell.

The optic-nerve changes, he believed, to

be late, for no pathologic alteration could

be observed in the optic nerves of any ofhis cases.

Comment. Without doubt, post-mortemchanges account for some of these tissuech

anges, and it is difficult to evaluate thefindings. The cases were so acute that the

Pathologic changes had not progressed

very far. It is important to note the ab-sence of signs of edema in the retina and

the absence of signs of pathologic involve-

ment in the optic nerves.

In Menne's'" two patients who died ofmethyl-alcohol poisoning, the following

points were noted.

Microscopically, there was little change

in the optic nerves except edema and

hyperemia and some patchy proliferation

of glial cells. The most pronounced al-

terations were observed in the ganglion

cells of the retinas, most marked nearestthe disc. There were no noteworthy

changes in the glial cells except for

marked edema.

Comment. It is important to note the

presence of edema of the optic nerve and

the fact that the ganglion-cell Iayers againshowed the greater change. Edema of theretina was also noted. It is unfortunate

that more detail was not given so that a

proper evaluation could be made.

The author's two cases were the result

of methyl-alcohol poisoning with fatal

outcome. The interpretation of the find-

ings is as follows.

CASE 1, A. There appeared to be a small

amount of papilledema. Disintegration of

the elements was observed in the rods andcones, forming an albuminouslike pre-

cipitate. There was a wealth of ganglion

cells and this layer showed no evidences

of increased gliosis. However, practically

all of the ganglion-cell nuclei were pushed

to the extreme periphery of the cell. Inmany of the cells the Nissl substance was

arranged in a peripheral ring, while in

still other cells there was more advanced

dissolution of the Nissl substance indi-cating chromatolytic changes. All the

ganglion cells were distinctly swollen, in-

cluding those in the , macular region. Thisperhaps represents an early stage in a

destructive process.CASE 1, B. This eye was similar to the

preceding one.

CASE 2, A. There was a definite edema of

the nerve head, more marked than in thepreceding eye. There seemed also to be

704 WALTER H. FINK

an increase in the glial elements in thenerve-fiber layer of the retina surround-ing the disc and passing into the opticnerve. The rod-and-cone layer had under-gone dissolution. The ganglion cells werequite plentiful, but there was an increasednumber of glial cells in this layer. Theganglion cells themselves were swollen.The nuclei tended to bulge peripherallyfrom the cell body. The Nissl substancehad disintegrated, and in some cells wasplaced peripherally; in others it had takenon a finely granular appearance; and instill others the cell had only a shadowyappearance. It seemed that many of theganglion cells in the macular region werebetter preserved than those in the pe-riphery.

CASE 2, B. This was similar to A. Therewas an occasional normal ganglion cell,however, and in places the retina was de-tached because of the great accumulationof debris from the disintegrated rod-and-cone layer.

The optic nerves in 58 A and B appearedto be normal; that of 59 B showed somepink-staining areas which had the char-acteristics of edema, but no change wasapparent in that of 59 A.

Comment. In these cases there shouldhave been obvious post-mortem changesin the retina because the specimens werenot fixed in formalin until 12 hours afterdeath. However, the material was re-frigerated. Evidently some of the changesare post mortem. It is significant that theycorrespond very closely to the retinalchanges reported as occurring in the othercases, and the question naturally arises asto how many of these are due to post-mortem changes.

In the author's cases the engorged cho-roidal vessels and some edema of theretina are worthy of note. Also of im-portance is the presence of optic-nervechanges in one case.

To draw conclusions from the pre-ceding autopsy reports is difficult be-

cause : (1) there are not sufficient cases;(2) the reports are not complete; (3)there is a possibility that the tissues werenot fixed immediately and that many ofthe findings are the result of post-mortemchanges.

The findings that are most significantemphasize the retinal changes, which arechiefly in the ganglion layer. It shouldbe borne in mind that post-mortem proc-esses would cause alterations similar tothese. Undoubtedly, some of the changesare the result of the toxic process, but, tobe scientifically accurate, it is difficult toascertain how many are actually due tothis cause.

It is rather significant that there werefew changes in the optic nerves. Althoughthere were some changes that suggest atoxic process, many were undoubtedlypost mortem.

If we can assume that the reported find-ings are not post mortem, we have indeedvaluable data. We can then say with as-surance that the retina suffers most fromthe toxic exposure and especially theganglion cells. This would be expectedbecause of their greater sensitivity tochange. The presence of injury in theganglion cells of the brain is proof thatsimilar changes are found elsewhere inthe body.

The presence of degenerative changesin the optic nerves in some of the casesshows that the process is not confined tothe retina. Likewise, edema was presentin both the retina and the optic nerve.The absence of pathologic changes in theoptic nerve in many instances may be dueto the acute process, the type of tissue ar-rangement where early changes may notshow so readily, and the possibility of im-proper staining to show these earlychanges.

The presence of choroidal congestionappears.to indicate that the vascular por-tion of the eye is involved. Some investi-gators claim that the entire, process is avascular one, but this does not appear to

OCULAR PATHOLOGY . OF METHYL-ALCOHOL POISONING 705

be the case, judging from the descriptiongiven. It must be admitted that the evi-dence of changes in the human eye is themost forcible argument that can be pre-sented as to the pathologic process result-igg from methyl-alcohol poisoning.

ANIMAL EXPERIMENTATION CARRIED OUT

PY OTHER INVESTIGATORS TO DETERMINE

TIIE EFFECT OF METHYL ALCOHOL

0\ THE OCULAR STRUCTURES

The essential facts concerning these ex-periments are as follows:

In one dog HoIden lT found degenera-tive changes in the ganglion-cell and thenerve-fiber layers of the retina, and themedullary sheaths of the fibers of theoptic nerve. The author concluded thatthe retina is affected primarily, and thechange in the optic nerve represents asecondary stage of the process.

Comment. It is rather impractical tocome to any conclusion after an investi-gation on one dog. Suspicion arises thatpost-mortem changes may have given riseto errors in evaluating the findings.

Birch-Hirschfeld= experimented withrabbits and chickens and made the fol-lowing observations: The toxic effect firstappeared in the ganglion cells of theretina. After this the inner granules de-generated, later the outer granules.

In only one case could distinct signsof degeneration of the nerve fibers befound, and these appeared in the animalwhich showed the greatest changes in theretinal lacers—in a temporal wedge-shaped region of the cross-section begin-ning immediately behind the bulbus.There was distinct disintegration offibers, extending posteriorly for about 5mm., the remainder of the cross-sectionsshowing fairly normal conditions. In the

Preparations no sign was found of round-

cell infiltration even in the degeneratedregion, nor a noteworthy 'connective-tis-

sue proliferation.Birch-Hirschfeld further stated that

vithout doubt the degenerative changes

in the optic nerve were of a secondarynature. This is indicated by their ab-sence in the other cases, where the toxiceffect on the retinal cells was less pro-nounced.

Comment. This research is undoubted-ly significant; that it has been recognizedas such is evident from the repeatedreferences to it in the literature. Criti-cally considered, however, it should beborne in mind that these findings ap-ply to rabbits and chickens and arenot necessarily indicative of what maybe found in the human eve. There isalso the possibility that other factorsenter into the situation which may pro-duce some of the changes: (1) post-mortem changes which appear so rapidlyin the retina; (2) trauma as the resultof killing the animal; (3) imperfect stain-ing and fixing.

If his work is scientifically accurate, hisdata do bear out his contention thatmethyl alcohol, even in small doses inthe experimental animal (rabbit andchicken), in the first place appreciably in-jures the cells of the retina; and that onlyin secondary fashion can the degenerativeprocesses occur in the optic nerve. Theremust have been some doubt in his mindas to the accuracy of this work becausein 1920 he repeated it.

Friedenwald, working on a rabbit,noted the toxic effect on the ganglioncells of the retina. The retinal ganglioncells showed marked degeneration, andthe inner and outer nuclear layers wereless affected.

Comment. The same criticism may beapplied to this work that applied to Hol-den's. Insufficient data were presentedto substantiate the conclusions.

Tyson and Schoenberg, 1e working withguinea pigs, rabbits, dogs, and a monkey,concluded that microscopic findings indi-cated an edema of the tissues with veryearly signs of beginning degeneration ofthe ganglion layer of the retina.

They found that the choroid gave the

706 WALTER H. FINK

impression of hyperemia. As to the retina,the rods and cones and the external nu-clear laver were normal. The outer reticu-lar layer was slightly edematous, the innernuclear layer normal, the inner reticularlayer also slightly edematous. The gang-lion cells were swollen and surroundedby clear areas, the nuclei being displacedfar toward the periphery. The innerlavers of the retina showed some edema.The medullary sheath of the optic nervetook Weigert's stain rather weakly.

Comnaent. This work is especially sig-nificant because it confirms the findings ofretinal degeneration with ophthalmo-scopic evidence to support it.

The change in H-ion concentration ofthe aqueous and evidence of acidosis aresuggestive of chemical changes in theeyeball that substantiate to a measuretheir theory as to the process leading tothe retinal degeneration.

The evidence they obtained of the in-creased susceptibility of higher animals isvaluable; of special significance is theircontention that methyl alcohol is a truehematoxin and produces a degenerativechange in all tissues.

Kazas; ° in his work on the effect ofmethyl alcohol on rabbits, found that thegeneral picture of changes in the retina,except the degenerative process, pre-sented the phenomena of dropsical satu-ration. The degeneration was not alwaysconnected with dropsy. Changes in theretina were markedly expressed in all itslayers including the layer of rods andcones. An adipose degenerationof highgrade was noted, not only in the layer ofnerve fibers but also in the ganglion-celllayer, in the cells proper, and in the in-ner molecular and nuclear layers.

Adipose degeneration was expressed inall optic nerves. A considerable increaseof connective tissue was found. Adiposedegeneration was markedly expressed inthe N. oculomotorius and the chiasma.

He therefore succeeded in obtain i ng -.changes as follows: in the vascular mem-brane; in the membranes of the opticnerve; in the retina, beginning with drop-sy and degeneration up to albuminuricretinitis; and in the optic nerve, beginningwith parenchymatous degenerated neuri-tis up to axial atrophy.

Comment. The results of this investiga-tion appear to confirm the previous re-search on this subject. The microscopicpicture reported is in agreement with thatobserved by others, although this writerlays special stress on the independence ofthe degenerative changes and the dropsychanges. The finding of adipose degen-eration in the optic nerve and the ocu-lomotor nerve is especially important.The increase of connective tissue is sig-nificant. Important also is his contentionthat the affection of the nerves was inde-pendent of the retinal changes. His expla-nation of the pathologic process is worthyof thought.

Igersheimer and Verzar20 attempted todetermine whether the sense of light mightbe used as a clinical criterion of the toxiceffect upon the retina. As experimentalanimals they chose chickens.

They concluded that the light percep-tion was temporarily impaired threeweeks after the beginning of the poison- 'ing. There was then complete restora-tion; after four additional weeks ofpoisoning, the perception of light wasagain reduced. The retina showed nochanges of note.

Comment. The significapce of this re-search is that no pathologic changes werenoted in the chickens' eyes. The techniqueof applying the drug was apparently cor-rect, and the method of sectioning theeyes was apparently not at fault. Thewriters emphasize the point that acuteintoxication was avoided, and it is pos-sible that this avoidance may account forthe absence of retinal pathology. The


fact remains that under careful experi-mental conditions the retina showed noevidence of pathology.

Schanz' t believed that between the tak-ing of the poison and the onset of blind-ness there is an interval in which lighthas a sensitizing effect which must benecessary before the poison can have itseffect. As an experimental confirmationof this theory, he gave methyl alcoholto three rabbits, protected one eye fromlight, and exposed the other to the sunfor a number of hours, five or six timesin the course of several weeks. He con-sidered the toxic amblyopia to be the re-sult of a sensitization injury to the retina,which absorbed more light, especiallyshort-wave rays, under the influence ofsensitizers. In one of these experimentalrabbits, killed on the nineteenth day afterthe last exposure, he found '`rather largeexudates in the lower half of the retinaof the exposed eye, while the protectedeye was free from every change."

In the eye exposed to methyl alcohol,he found a distinct diffuse degenerationof the entire cross-section of the opticnerve behind the point where the vesselsenter the eyeball. The optic nerves of theeye kept in darkness were found to benormal.

Comment. This experiment provesnothing of note. The insufficient datado not allow conclusions to be drawn.The theory that light is a factor, actingin conjunction with the methyl alcohol toproduce retinal changes, is a new ap-proach but does not appeaq to have muchbasis for acceptance.

In 1920 Birch-Hirschfeld s repeatedhis experiments, using dogs and monkeys.He found that distinct signs of degenera-tion (analogous to those previously foundin rabbits and -chickens following thesame form of intoxication) were presentin the ganglion cells.

Extensive degenerative changes could

be observed even in the beginning por-tion of the medullary optic nerve, im-mediately behind the lamina cribrosa.These changes did not appear in the en-tire cross-section. There were all stagesof change ranging from beginning partialdegeneration of individual fibers to prac-tically complete disintegration of the en-tire bundle; but in the degenerated areasit showed distinct changes.

The primary change in the glial tissuerests upon a degenerative process; thisdegenerative process the author assumedto be due to edematous saturation lead-ing to loosening and disintegration of thefibers.

He concluded that the degeneration ofthe nerve fibers in the optic nerve wasnot the result of pressure necrosis due tothe proliferated septal tissue or similartissue showing inflammatory infiltration.

In view of this, and of the normalmacroscopic condition of the optic nervewith reference to size of the cross-sectionand consistency, the author assumed thatthe exudative processes in the nerve trunkhad not yet fully developed.

Comment. This research confirmedBirch-Hirschfeld's earlier findings and inaddition demonstrated their presence inhigher forms of animals, such as the mon-key. His conclusions concerning the optic-nerve findings seem to be more definitein this investigation, especially thechanges in the nerve fibers.

He stresses the absence of inflamma-tory reaction and edema, although thenerve tissue showed extensive degenera-tion in areas. The degeneration also in-volved the glial tissue and suggests thatit is the result of the direct action of thepoison.

De Schweinitz' examined dogs whichhad been acutely and chronically poisonedby methyl alcohol and in no case didmicroscopic study reveal pathologicchanges in the retina.

708 WALTER H. FINK

Comment. These findings are of spec-ial significance. Although the r_search isbrief, it is, as is characterist:: of thisauthor's work, most reliable. The ab-sence of positive findings is in •ide vari-ance with other similar work :nd leavesit all open to question.

Friedenwald and Felty 22 pe-:ormed asimilar set of experiments usin ; rabbits,guinea pigs, and dogs.

They were unable to product any reti-nal or optic-nerve lesions iv : :n methylalcohol and concluded that tht originalreports of Birch-Hirschfeld :n regardto alleged changes in ganglion. cells wereartifacts, since they could proc_ce similarchanges in material from non::al animalsby variations in fixation and trnbedding.

Comment. For scientific a:curacy ofcomparison, it is of value to c: , mpare themethods used with those used by otherswho did find retinal change:. Frieden-wald is an accurate observer and this addsweight to the importance of i..is findings.

Schwarzkopf23 experiment d with rab-bits and dogs, and studied t.e effect oflight in relation to ocular c_.anges.

In the retina he found pronounced de-generation, chiefly in the ganglion cells.Inflation of the cell body and nucleus,to the point of obliteration of the cellboundaries, alternated witL shrinkageprocesses and clumping of tl:_ chromatin.There was no edema. The vessels werenormal. The inner granules -resented in-distinct chromatin structu-,, inflation,and chromatolysis.

In the optic nerve a biIkteral diffusedegeneration was observed immediatelybehind the bulbus, almost to the point ofentrance of the vessels. Er.:argement ofthe septa and multiplication of nuclei oc-curred only in the anteor sections.There was inflammatory infiltration.

Comment. Schwarzkopf's anatomic in-vestigations are a complete confirmationof the Birch-Hirschfeld results. In the

retina, the ganglion-cell layer offered thefirst and most conspicuous changes. It isespecially significant that he found de-generative changes in the optic nervesimmediately behind the eyeball.

Scott, Helz and McCord'* performedexperiments on 31 monkeys, 58 rabbits,and 176 white mice.

Upon studying the eyes and opticnerves of these animals these investiga-tors found constant changes both in retinaand nerve. However the changes in theretina predominated and were uniformlyof the nature of an acute toxic lesion. Thevessels of the choroid were markedly con-gested. The entire retina was edematous,but especially the fiber and ganglionic-cell layers. The ganglion cells were de-generated. This degeneration was patchyin occurrence, normal areas being im-mediately adjacent to markedly de-generated ones. These degenerated areaswere not confined to any one portion ofthe retina but were scattered throughout.These retinal changes were quite similarto those found by MacDonald in humancases, and by Holden, Friedenwald, Ty-son and Schoenberg, and Birch-Hirsch-feld in experimental animals. It seemednot uncommon to find degenerations inthe retina in the absence of any degen-erative changes in the optic nerve.

Comment. As in other works on ani-mals the retinal changes seemed to pre-dominate. The findings in this work werein accord with the changes found byother investigators.

To summarize the results of this ex-perimental work: It is interesting to notethat nine papers reported definite patho-logic changes in the retina and opticnerve. The authors of three reports failedto find evidence of change.

In all nine instances the findings werein fair agreement. In describing theretina, it was common to find the changes


consisted of definite degenerative altera-tions in the ganglion cells and a changeof less degree in the other layers. A typi-cal statement reads as follows:

"The changes in the retina predomi-nated and were uniformly of the natureof an acute toxic lesion. The vessels ofthe choroid were markedly congested.The entire retina was edematous, butespecially the fiber and ganglionic celllavers. The retinal ganglion cells _ .owedmarked degeneration; the inner and outernuclear layers were less affected. Thisdegeneration was patchy in occurrence,normal areas being immediately ad:acentto markedly degenerated ones. Thesedegenerated areas were not confined toany one area of the retina but were scat-tered throughout."

As regards the optic-nerve changes, allnine authors found evidence of patho-logic involvement, and it seemed commonto find degenerations in the retina asso-ciated with the degenerative changes inthe optic nerve. The retinal changes seemto predominate.

It is especially significant that degen-erative changes in the optic nerves werefound immediately behind the eyeball.Most of the writers agreed that the de-generative changes in the optic nerve wereless conspicuous. The following quota-tions are characteristic:

"In cross-sections,. extensive degenera-tive changes could be observed even inthe beginning portion of the medullaryoptic nerve, immediately behind thelamina cribosa. Thee changes did notappear in the entire cross-section. There

• were all stages of change ranging frombeginning partial degeneration of indi-vidual fibers to practically complete dis-integration of the entire bundle; but inthe degenerated areas there were distinctchanges.

"In the preparations was found no sign

of round-cell infiltration even in the de-generated region, nor a noteworthy con-nective-tissue proliferation.

"The primary change of the glial tissuerests upon a degenerative process; thisdegenerative process was assumed to bedue to edematous saturation which leadsto loosening and disintegration of thefibers. The degeneration of the nervefibers in the optic nerve was not the , resultof pressure necrosis due to the prolifer-ated septum tissue or similar tissue show-ing inflammatory infiltration."

It seems that the predominant finding inboth the retina and the optic nerve wasedema. This was associated with signs ofnecrosis or degeneration of all parts butespecially the higher differentiated cells ofthe retina. There was no evidence of in-flammatory infiltration nor of vascularengorgement except for a slight amount inthe choriod.

Contrary to these findings are thenegative results found in the work of deSchweinitz and Friedenwald. It is difficultto explain the difference in result. As thedetails of their experimental work werenot published, it is impossible to make afair analysis. It might be of value to men-tion that de Schweinitz must have beenstill in doubt, in spite of his experimentalwork, because he personally suggested tothe author that this problem should besolved. The findings of two such reliableobservers should be considered significant.The following statement by Friedenwaldshould be borne in mind in making a finaldecision:

"The original findings of Birch-Hirsch-feld in regard to alleged changes in theNissi bodies of the ganglion cells wereartifacts, since he could produce similarchanges in material from normal animalsby variations in fixation and embedding."

(To be concluded)

walter h. fink, m.d. the ocular pathology of methyl ... · toxicity of methyl alcohol the cause of...

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