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HEPATIC COMA: THE ELECTROENCEPHALOGRAPHICPATTERN

By REGINALDG. BICKFORDANDHUGHR. BUTT

(From the Section of Physiology and the Section of Medicine, Mayo Clinic and Mayo Founda-tion,' Rochester, Minn.)

(Submitted for publication June 28, 1954; accepted February 23, 1955)

Recent advances in our knowledge of the neuro-physiologic mechanisms underlying sleep and ex-perimental states of coma (1) suggest the need fora neurophysiologic approach to the many complexclinical syndromes associated with disturbance ofconsciousness. The coma syndrome associatedwith hepatic disease and usually known as he-patic coma was chosen for investigation sinceit presents a good example of toxic coma withoutgross structural change in the brain. The rapidchanges in level of consciousness which frequentlyoccur in this syndrome make it particularly sus-ceptible to experimental study.

The observations described below represent aneffort to analyze such electroencephalographic(EEG) patterns as may be observed in patientswith various forms of hepatic disease before, dur-ing, and after the clinical state known as hepaticcoma.

MATERIAL AND METHODS

The patients to be described fall into two categories.The first is a series of 8 patients in whom there wasclear evidence of hepatic disease (cirrhosis) which, ona clinical estimate, might be expected to culminate inhepatic coma. At the time of recording, these patientswere in a normal mental state. This series of patientsformed a control group to evaluate the EEG effect ofhepatic disease without coma. The second category con-sists of a group of 13 patients in whoma state of hepaticcoma developed.

Owing to the grave clinical condition of the patientsin coma it was felt advisable to make recordings in thepatient's room. Conventional solder disc electrodeswere used, the placement being that shown in Figure 1,and in the early cases the recordings were made on aspecially constructed 4-channel, portable inkwriting elec-troencephalograph. More recently, recordings have beenmade on a standard 8-channel, Grass, inkwriting oscillo-graph. The state of consciousness of the patient wasevaluated throughout the recording. The effect ofarousal stimuli, such as a loud clap, squeezing of the

1 Mayo Foundation, Rochester, Minnesota, is apart of the Graduate School of the University of Min-nesota.

toes and pinprick, were investigated. In most instances,photic stimulation by means of strobatron light (250,000foot candles) was carried out, the light being held 1 footfrom the patient's eyes. The patients in the control groupunderwent a standard EEG recording using a Grass8-channel instrument. In all instances the mental stateof the patient was classified on the basis of the followingterms: 1) alert, 2) confused, 3) semicoma, and 4) coma.The semicomatose patients were out of contact withtheir environment and spoke only a few, usually inap-propriate, monosyllables. Comatose patients were thosewho showed little spontaneous movement and no re-sponse to noxious stimuli.

RESULTS

Control group

The EEGfindings in the group of patients withhepatic disease in the absence of mental changesare shown in Table I. An alpha rhythm wasrecognizable in all cases and in no instance werethe EEGchanges considered to be beyond normallimits. A comparison of Tables I and II indi-cates that the kind of hepatic involvement in thecirrhotic group without mental changes was es-sentially similar to that found in the group exhibit-ing coma (Table III). It can be concluded thatthe existence of hepatic disease per se in the ab-sence of mental change is not associated with anydetectable EEGabnormality.

Hepatic coma

The EEGchanges seen in patients showing vari-ous grades of hepatic coma are summarized inTable II. In the early phases of this investiga-tion it became apparent that at certain stages ofhepatic coma, the occurrence of an unusual kindof discharge became evident in the EEG. Thisdischarge, which we have called the "triphasicwave," was at first mistaken for an eyeblink arti-fact, which it resembles very closely. However,it is not difficult to eliminate eyeblink artifact asa cause of these waves since blinking is relatively

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FIG. 1. EEG CHANGESIN HEPATIC COMACase 12, above, and case 13, below, illustrate typical groups of triphasic

waves with periods of relative quiescence.

TABLE I

Patients who had cirrhosis without mental change

EEGfindings*Age Tn-

Case years Clinical diagnosis Alpha Theta phasic Delta

1 41 Cirrhosis of liver, hemorrhage fromesophageal varices. Alcoholic + - - -

2 47 Portal cirrhosis of liver, ascites.Alcoholic ++ - - -

3 41 Portal cirrhosis of liver.Alcoholic + - - -

4 57 Portal cirrhosis of liver, ascites.Alcoholic + - - -

5 49 Cirrhosis of liver, ascites.Alcoholic +++ - -

6 55 Cirrhosis, ascites. Lefthydrothorax + +

7 35 Obstructive jaundice, biliarycirrhosis + + +

8 48 Postnecrotic cirrhosis +

* - indicates absence.+, ++, + ++ indicate presence on a scale of 1 to 3, depending on persistence of discharges.

791

7REGINALDG. BICKFORD AND HUGHR. BUTT

TABLE II

Parexts with hepatic coma

EEGfindings*Survival

Age Tr- afterCase years Clinical diagnosis Mental status Alpha Theta phasic Delta test

9 66 Cirrhosis of liver, ascites. Coma - - ++ - 2 daysAlcoholic

10 51 Cirrhosis of liver, eso- Alert-foretfulphageal varices (7-1-52) - ++ - - 6 days

Confused (7-25-52) - + + + -

11 43 Cirrhosis of liver. G.I. Alert (7-6-8) + + - - Few hoursbleeding. Alcoholic Semicoma (7-19 48) - ++ +

Coma (7-22-48) - + ++12 52 Cirrhosis of liver, ascites. Coma - - ++ + 2 days

Alcoholic13 72 Cirrhosis of liver, ascites Semicoma (6-27-52) - - ++ - 2j months

Semicoma (6-28-52) - - + +Coma (6-30-S52) - - + +Confused (7-2-52) + + + -

14 64 Cirrhosis of liver. Cere- Semicoma (101348) - + + - 6 weeksbral degeneration Semicoma (10-19-48) - + + +(Wilson's disease?). Coma (10-2148) - + + +Alcoholic Confused (10-2248) - + +

Alert (10-2548) + + - +Alert (10-2648) - + + +Semicoma (1 1-948) - - - +Confused (3-4-49) - + ++

15 76 Biliary cirrhosis. Carci- Coma - - + ++ Ij hoursnoma of pancreas caus-ing obstruction of bileduct

16 33 Biliary cirrhosis second- Semicoma (11-29-52) - + +++ - 1 dayary to common-duct Alert (12-2-52) +++stricture Coma (12-9-52) - - - +

17 46 Biliary cirrhosis second- Coma - - +++ - S daysary to common-ductstricture. Ascites

18 42 Homologous serum hepa- Coma (4-2049) - + + + 2 days. Notitis Coma (4-2549) - + +++ - EEGchange

Semicoma (4-2649) - + + + + + with 2 cc.Confused (4-22949) + + - - campolon

I.V.19 63 Infectious hepatitis Alert (2-2748) + - - + 2 days

Alert (3-148) + - - +Alert (7-12-48) + - - +Coma (8-1748) - - ++

20 17 Postnecrotic cirrhosis. Coma - - - +++ 12 hoursChronic ulcerativecolitis

21 55 Metastatic carcinoma of Coma - - ++ + 5 daysliver from breast

* - indicates absence.+, ++, +++ indicate presence on

rare in comatose patients and the detailed prop-erties of the waves, such as the fronto-occipitaldelay, could not be explained on the basis of eyemovement. The properties of these waves willnow be considered.

a scale of 1 to 3, depending on persistence of discharges.

Triphasic waves

Two recordings illustrating the form and dis-tribution of the triphasic waves are shown inFigure 1. In both instances triphasic waves aremost clearly defined in the frontal and sylvian

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fRONTO-OCCIPITAL

DELAY HNILLISEC 90

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FIG. 2. VRIABILrY IN DELAYANDDISTRIBUTION OF THE TRIPHASIC WAVESA, patient, 12; patient, case 13; J, synthetic waves from a model. In all

cases the delays have beeii corrected for pen alignment and arc distortion

of the trace.

areas, the amplitude falling to a relatively lowvalue in the occipital region. The main deflectionis downward, indicating a surface positive change.The main deflection is usually preceded and fol-lowed by low-amplitude negative deflections givingthe whole complex a triphasic contour. The shapeof the complex varies owing to changes in therelative prominence of the three waves.

There is a tendency for the occipital dischargesto lag slightly in time in relation to the frontal dis-charges. This is well shown in Figure 2, in whichthe fronto-occipital delay has been measured fora series of waves belonging to various patients(A to I). The occipital regions show a delayvarying from 25 to 140 milliseconds, following thepeak of the main positive frontal discharge. Thesedelays were not so- clearly distinguishable in mono-

polar recordings. There is some variation in thecontour of the discharge in different areas of thecortex and in a few instances (I) the amplitude ismaximal in the occipital area. At other times thewave almost disappears before reaching the occi-

pital area (G). Another variant is the wave

which appears to arise in the sylvian regions andsweep posteriorly without involving the frontalregions appreciably. A tendency for the dischargeto broaden as it migrates toward the occipitalarea is also frequently observed (F). The varia-bility described above-is usually bilateral so thata high degree of symmetry between recordingsfrom the two hemispheres is maintained. In ad-dition to this there is usually bilateral synchronyof the triphasic waves within a few milliseconds.

The mechanism by which the triphasic waves

are generated by the cortex is obscure, but evi-dence of delay in the peak of the discharge in theoccipital areas, as compared with the frontal,naturally raises the question of a traveling wave

of positivity sweeping the cortex from the frontalto the occipital regions. That such a moving elec-trical field will produce a deflection roughly com-

parable to the triphasic waves of the human beingis shown in J (Figure 2), which is a recordingfrom a model consisting of a saline bath in which

TABLE IV

EEC stages in hepaic coma

EEGpattern

Theta (4-7 c/o) Triphasic Delta (0.5-3 c/9)

Alpha Present but may be partly Usually absent Absentdisorganized

Mental Range from normal to mild Range from disorientation Semicoma to deepstatus confusion with forgetful- and confusion to semicoma

ness and irrational behavior comaPrognosis May recover May recover Usually terminal

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a positive pole is swept past a series of electrodesrepresentative of their position on the scalp. Aconduction rate for this wave of about 1.5.metersper second would be required to give the observeddelays, a value which is well within the observedconduction rates for the central tracts in anmals.

A further possibility is that the primary disturb-

ance is traveling at a subcortical (thalamic ?) leveland that the changes in potential field observed onthe cortical surface are merely the reflection of theprimary disturbance (via thalamocortical relays)on to the cortical surface. The evidence at -baddoes not allow us to distinguish between these twohypotheses.

SEMICOMA 1-29-52

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Triphasic waves are closely clustered in the recording on November 29,1952, though their presence is clearly evident in tracings from electrodes 1-3and 2-4.

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POST COTIC RRHOMS ED 12 HOUtS LATERFIG. 5. CASE20: SLOWIRREGULARWAVESOF THE DELTA STAGE IN A CASE OF

POSTNECROTICCIRRHOSISThe patient died 12 hours'after lthe recording was made.

1. Occurrence of triphasic waves. While refer-ence to Table II shows that triphasic waves wereobserved in all but one of the patients with dis-turbed consciousness, -multiple recordings werefrequently necessary to demonstrate their pres-ence. A review of the findings indicates that theyoccur at a certain phase in the developmient ofhepatic coma. The first change indicated in therecords of these patients at the time that earlymental changes become detectable appears to beslowing and disorganization of the alpha rhythm,a finding which is contrary to the observations ofAdams and Foley (2) who reported preservationof the alpha rhythm to a late stage of hepaticcoma. Associated with this change is the appear-

ance of waves 6f a frequency of 4 to 7 per secondtrox all areas of the cortex: This may be calledthe "theta phase"'- (Table IV' and Figure 3), andat this stage the patient is usually slightly dis-oilented withu respect to time and place. Withfurther deterioration in the clinical condition, tri-phasic waves make their appearance so that theycan be recognized occasionally among the slowwaves in the background. The appearance oftriphasic waves (triphasic stage) is usually as-sociated with the onset of a deeper coma fromwhich the patient can be only partially aroused bya painful stimulus. At this time the triphasicwaves may come to dominate the record to the ex-clusion of other frequencies. In some instances

CASE NO. BIPOLAR FRONTAL ELECTROENCEPHALOGRAM At

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FIG. 6. SOMETYPICAL TRACINGS SHOWINGTRIPHASIC WAVESIN HEPATIC COMA,WITH WRORDINGSFROMA PATIENT UNDERGOINGETHER ANESTHESIA AND FROMA

PATIENT WITH A CONVULSIVEDISORDERFOR COMAISONThese are bipolar recordings from frontomotor regions.

79d6


the patient may make a rapid recovery from thisstage with a return to normal pattern within a fewhours (Figure 4). It should be noted how com-plete the EEGrecovery can be without a vestige ofabnormal activity remaining in the tracing. Inthe event of no recovery, the deepening coma isaccompanied by the appearance of slower arrhyth-mic delta waves (Figure 5) followed by general-ized suppression of activity (Figure 4). In ourlimited experience patients have not regained con-sciousness once the delta phase has been estab-lished for several days, which may, therefore, beregarded as having a grave prognosis.

2. Tiphasic waves in other clinical conditions.The triphasic wave cannot be regarded as beingentirely characteristic of the EEGin hepatic comasince its presence is confined to certain phases ofthe illness. In addition, somewhat similar dis-charges may be seen in such diverse conditionsas ether anesthesia (Figure 6) and in rare in-stances in convulsive disorders. It.has not beenour experience that the discharge resembles thespike and wave of petit mal as suggested by Foley,Watson, and Adams (3) though there may be afairly close resemblance to certain atypical bilater-ally synchronous discharges which may be seenin the electroencephalogram of epileptic children.Cobb, Martin, and Pampiglione (4) have reportedtriphasic waves in cases of cerebral lipidosis butcareful inspection of their tracings indicates thatthe polarity, duration, and distribution are differ-ent from those described here. A recent reviewof the EEGrecords of 345 patients with disturb-

TABLE V

Diagnostic categoris of 345 patens with a mena state ofconfusion, semicma or coma but witout

triphasic waves(chronxoogic unseected group)

Diagnosis Patients

Cerebral tumor 129Degenerative disease of brain 50Cerebrovascular disease 43Cerebral trauma 27Encephalitis, meningitis 20Subdural hematoma 18Cerebral infarct 18Psychosis 12Organic psychosis 9Convulsive disorder, postictal 8Drug intoxication 5Diabetes 4Anoxic encephalopathy 1Uremia 1

ances of consciousness (confusion, semicoma,coma) from varied causes, as shown in Table V,did not. reveal the presence of any discharges thatcould be confused with the- well-developed tri-phasic patterns seen in the patients with hepaticcoma. Workers investigating the EEG in comaof nonhepatic origin have not reported the pres-ence of triphasic waves (5). It may be concludedthat the presence of triphasic waves in the recordof a patient in coma may be taken as very sug-gestive evidence that the coma is hepatic in origin.

Effect of sensory stimulationThe effect of a painful arousal stimulus was de-

termined in many patients in the various stages ofhepatic coma. In the triphasic stage, the patientusually showed some response such as the with-drawal of a limb, but no consistent change in theEEG pattern during stimulation was observed.Likewise, photic stimulation was usually ineffec-tive in producing a change in the triphasic pat-tern, and no response at the flash frequency usedwas seen in any case. The lack of response ofthe triphasic pattern to afferent stimulation is cer-tainly in contrast to the responsiveness of abnor-mal patterns seen in some other varieties of coma,for example, postictal coma.

Effect of liver extract on electroencephalogram

In view of the possibility that these patientswere suffering from some kind of deficiency ofliver secretion, the effect of liver extract (cam-polon) on the electroencephalogram was observedin one patient (case 18). After a control tracinghad been made, 2 cc. of campolon was given in-travenously and the recording was continued fora further 90 minutes. No clinical or EEGchangewas noted.

COMMENT

While the EEG changes described cannot beregarded as indicating a specific pathologic state,they did give some clues to the likely mechanismsof the mental and neurologic symptoms of he-patic coma. The strict bilateral synchrony of theelectrical discharges in the triphasic stage wouldsuggest the participation of a diffuse synchroniz-ing network, such as the thalamocortical reticu-lar system. The rapid and complete reversibility

797


of the EEGchanges, at least in the triphasic stage,argues in favor of a chemical rather than a struc-tural change in the region of the brain primarilyinvolved. Furthermore, some chemical sub-stances, such as ether, can produce electricalchanges resembling those of hepatic coma.

The existence of some metabolic relationshipbetween the liver and the brain has been suspectedfor more than a century.. The demonstrationby Geiger and Magnes (6) that a substance con-

tained in the liver (or liver extract) is necessary

for the persistence of electrical activity in the ar-

tificially perfused brain provided a physiologicbasis for this relationship. More recently, Taylor(7) has attributed this survival-prolonging ef-fect of liver extract upon EEG activity in theisolated brain preparation to its property of re-

ducing permeability of the brain cell to glucose.The data reported here seem to indicate that

the particular kind of hepatic involvement (portalor biliary cirrhosis, or metastasis to the liver as incase 21) is unimportant so far as the tendency toproduce characteristic EEGchanges is. concerned.This would suggest that the EEGchanges resultfrom some factor common to various types ofhepatic pathology.

Independent evidence has recently been pre-

sented which suggests that various chemical sub-stances are the responsible agents in the produc-tion of hepatic coma. Walshe (8) has reportedan increased glutamine concentration in the cere-

brospinal fluid of three patients who were in he-patic coma. More recently a number of workershave suggested that hepatic coma is related tometabolism of ammonia. Gabuzda, Phillips, andDavidson (9) described a syndrome indistinguish-able, from hepatic coma occurring in patients withcirrhosis given certain ammonia-containing cation

exchange resins. The cause of the reaction was

not apparent, but it was suggested that the effectswere due to ammonia intoxication. The EEGal-teration seen in one of their patients was said tosimulate those described in hepatic coma. Later,Phillips, Schwartz, Gabuzda, and Davidson (10)demonstrated that apparently identical untowardeffects can be provoked in patients with cirrhosisof the liver by administration of ammonium chlo-ride, diammonium citrate, urea or dietary pro-

tein. The published illustration of the EEGtrac-ings taken at the peak of the clinical reaction to

these substances showed the nonspecific slowwave which may be seen in coma due to a numberof different causes. No triphasic waves wererecognizable in these tracings. Although increasein blood ammonia was suspected as being the causeof the reaction, the correlation between the con-centration of blood ammonia and the abnormalsigns observed was not consistent enough to estab-lish a relation.

More recently, McDermott and Adams (11)have described a patient with an Eck fistula whosemental condition seemed to be related to the levelof blood ammonia, and who presented episodes ofstupor when the intake of substances related toammonia metabolism was changed artificially.The described changes in the EEGagain appearto be nonspecific, and in the absence of publishedtracings it is impossible to be certain whether ornot triphasic waves were present at any stage.

It is evident that an increasing difficulty in thesecases is that of relating induced "hepatic-comalike"syndromes now encountered in both clinical andanimal work with the genuine clinical hepatic-coma syndrome. Electroencephalographic datashould contribute useful evidence in establishingthese relationships in addition to their diagnosticand perhaps prognostic value in individual pa-tients.

SUMMARY

In the electroencephalograms of 12 patients invarious stages of hepatic coma the followingstages have been recognized as the depth of comaincreased: 1) theta stage, with diffuse waves ofa frequency of 4 to 7 per second, 2) triphasicstage characterized by diffuse bilaterally syn-chronous triphasic waves whose maximal deflec-tion is surface positive, and 3) delta stage inwhich random arrhythmic waves with little bi-lateral synchrony dominate the record. A con-trol group of 8 patients who had hepatic cirrhosisand impairment of hepatic function, as measuredby laboratory means, that were essentially as greatas that of the 13 patients, but who had no mentalchange, showed EEGrecordings that were withinnormal limits.

Patients in the theta stage are usually moder-ately confused, while those in the triphasic anddelta stages are usually semicomatose or com-pletely unresponsive.

798


Some evidence from latency muremeits wg- Li. C.-L., Jasper, H., and Henderson, L., Jr., Thegests that the triphasic wave is a conducted dis- effect of arousal mechanisms on various forms of

turbance. Waes. somewhat similar. to the ~abnormality in the electroencephalogram. Electro-turbance. waves somewhat similar to the tri-hav.beenseenin other ..di encephalcg. & Clin. NeurophysioL, 1952, 4, 513.phasic discharges have- 'been seen mn offer`co'ndi-phasidiscrge Geiger, A., and Magnes, J., The isolation of the cere-

tions such as ether anesthesia and convulsive dis- bral circulation and the perfusion of the brain inorders but not in patients in coma- from other the living cat. Am. J. Physiol., 1947, 149, 517.causes. -- ;. Taylor, R. M, Technic for perfusion of the com-

It is suggested that in addition to being clini- pletely isolated brain in the living cat in Milbankcally useful from the diagnostic and perhaps prog- Memorial Fund, 27th Annual Conference: The

Biology of Mental Health and Disease, New York,nostic points of view, the EEGmay assist in re- Pai B. Hoebr,.Inc, 1952, pp.-48-53.lating experimenta1 coma syndromes to genuine 8. Walshe, J. M-., Observations on the symptoznatologyhepatic coma. ' and patlhogenesis of, hepatic coma. Quart. 3. Med.,

REF AENCES 1951, n.s. 20 421.-'':-''.. 9. G d, G. ., Jr., Phillips, G. B., and Avidso,

1. Magoun, H. W., The ascending reticular activating C S. Reversible toxic manifestations in patientssystem. A. Research Nerm. & Ment. Dis., Proc., w195230,0 ~~~~~~~~~~~~withcirrhosis of the liver. gien -cation-tchanje1952,30,480. ~~~~~~~~resins. New. England J. Med., 1952, 246, :124,,2. Adams, R. D., and Foley, J. M., The neurological e NG

disorder associated with liver disease. A. Re- . B. Schwartz R., Gabuza G J. Jsearch Nerv. & Ment. Dis., Proc., 1953, 32, 9. and Davidson, C S., The syndrome of impending

3. Foley, J.;M., Watson, C. W., and Adams, R. D., hepatic coma in patients with cirrhosis of the liverSignificance of the electroencephalographic changes given certain nitrogenous substances. New Eng-in hepatic coma. Tr. Am. Neurol. A., 1950, 75, land J. Med., 1952, 247, 239.161. 11. McDermott, W. V., Jr., and Adams, R. D., Epi-

4. Cobb, W., Martin, F., and Pampiglione, G., Cerebral sodic stupor associated with an Eck fistula in thelipidosis: An electroencephalographic study. Brain, human with particular reference to the metabolism1952, 7S, 343. of ammonia J. Clin. Invest, 1954, 33, 1.

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minn.)€¦ · a neurophysiologic approach to the manycomplex clinical syndromes associated with...

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