A STUDYOF THE NUTRITIONAL DEFECTIN WERNICKE'SSYNDROME

THE EFFECT OF A PURIFIED DIET, THIAMINE, ANDOTHERVITAMINSONTHE CLINICAL MANIFESTATIONS1

By GERALDB. PHILLIPS, MAURICEVICTOR, RAYMONDD. ADAMS, ANDCHARLESS. DAVIDSON

(From the Thorndike Memorial Laboratory, Second and Fourth Medical Services [Harvard],Boston City Hospital, the Department of Neurology, Massachusetts General Hospital

and Boston City Hospital, and the Departments of Medicine and Neurology,Harvard Medical School, Boston, Mass.)

(Submitted for publication December 15, 1951; accepted July 29, 1952)

The salient clinical features of Wernicke's syn-drome (1) are partial to complete paralysis of ex-tra-ocular muscles (most commonly the externalrecti), nystagmus, ataxia and mental disturbances.Postmortem examination reveals changes in thenervous structures adjacent to the third and fourthventricles and the aqueduct. The lesions are char-acterized by varying degrees of necrosis of bothnerve cells and nerve fibers with appropriate reac-tions of microglia and astrocytes, alteration of thesmall blood vessels, and in some cases, petechialhemorrhages (2-5).

The syndrome is usually associated with chronicalcoholism and for that reason has sometimes beenattributed to a neurotoxic effect of the alcohol;but the occurrence of the same clinical sequence innon-alcoholic patients with malnutrition (1, 2,4-8) has directed attention to nutritional deficiencyas the etiological basis. Moreover, similar patho-logical lesions have been produced in the rat (9,10), fox (11, 12), and pigeon (3, 9, 13, 14), bymaintaining these animals on thiamine-deficientdiets.

The first extensive clinical investigation of thenutritional disorder of Wernicke's syndrome wasconducted by Jolliffe, Wortis, and Fein (15), whofollowed twenty-seven patients on various dietswith specific vitamin supplements and concludedthat the ophthalmoplegia responded to thiaminebut that the whole syndrome was probably due toa "combination of several nutritional deficiencies."Other reports concur that thiamine deficiency

1 The expenses of this investigation were defrayed inpart by grants from Merck and Company, Inc., Rahway,New Jersey, and Sharpe and Dohme, Inc., Glenolden,Pennsylvania.

plays a definite role in the etiology of this syndrome(7, 8, 16).

The study reported in the present communica-tion was designed to define more clearly the effectof bed rest, withdrawal of alcohol, and adminis-tration of vitamins on the individual clinical signscomprising Wernicke's syndrome. Patients with,typical manifestations of this syndrome were main-tained for varying periods of time on a purifieddiet consisting solely of glucose and minerals.At appropriate times specific vitamins were added.The principal components of the clinical picture,i.e., the ophthalmoplegia, nystagmus, ataxia, andmental disturbances, were examined at frequentintervals.

MATERIALS ANDMETHODS

Nine patients with the typical signs of Wernicke's syn-drQme were observed on the wards of the Boston CityHospital. Only patients with a definite degree of ophthal-moplegia who had received no food after admission wereincluded. All patients were men, white, and over 40 yearsof age. Dietary histories could not be obtained fromeight because of mental disturbances, but it was learnedfrom their families and friends that they were confirmedchronic alcoholics and had been drinking heavily andeating little or no food in the weeks preceding entry tothe hospital. Objective evidence of undernutrition, suchas looseness of the skin and thinness of muscle, was ob-served in all cases. In addition, six (Cases Nos. 1through 6) had liver disease as indicated by abnormal"liver function" tests, and in three (Cases Nos. 1, 3, and4) this was confirmed by needle biopsy. No evidence ofberiberi was found in any patient except for a frankperipheral neuropathy in one (Case No. 6). Pellagrinousskin lesions were seen in only one patient (Case No.9), whereas two showed tender, red tongues (Cases Nos.2 and 3). One patient (Case No. 9) had perifollicularhemorrhages and another (Case No. 2) manifested hoarse-ness. No other signs suggesting deficiency disease were

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detected, and in no case was any other serious abnormalityfound, except for delirium tremens, which was evident inCase No. 1. Significant fever was not present in any pa-tient. All the patients survived their disease.

The subjects received no food from the time they en-tered the hospital and all, except Case No. 9, were startedimmediately on a regimen consisting of the oral adminis-tration of a solution which contained 200 gm. of glucoseand 1.3 gm. of sodium chloride per liter of water. CaseNo. 9 was given an infusion containing multiple vitamins 2including thiamine on admission and was started on aregular hospital diet twelve hours later. Cases Nos. 3,5, and 6 received potassium chloride in addition to glu-cose and saline in an attempt to eliminate potassium de-ficiency as an etiological component of the mental dis-turbance. Occasionally, prophylactic penicillin and smalldoses of paraldehyde were given. No other form of sus-tenance or medication was administered except for cer-tain vitamins as specified below. An exact measure ofthe amount of the solution consumed by each patient wasdifficult to obtain, but each ingested approximately 1 to2 liters a day. After 3 to 11 days of the purified diet, aregular hospital diet was instituted for the remainder of thehospitalization. The period of observation on the purifieddiet was not extended beyond 11 days because of the seri-ous nature of Wernicke's syndrome. Three subjectsvomited infrequently, but it was impossible to determinewhether this was due to an alcoholic gastritis, to Wer-nicke's syndrome, to the possible gastric irritation of glu-cose and saline, or to some other factor.

All the patients, except Case No. 4, were confined tobed until they were able to walk without assistance.Case No. 6 could not walk during his hospitalization butwas allowed to sit in a chair after the third week in thehospital.

The ophthalmoplegia, nystagmus, ataxia, and mentaldisturbances were observed closely and an attempt wasmade to quantitate them on a 1 + to 4 + scale. Since theprincipal ocular derangement in all the cases was a bi-lateral weakness of the external rectus muscles, thepower of abduction of the eyes was used as an index ofthe degree of ophthalmoplegia. A total inability to ab-duct the eye beyond the midline was considered as 4 +, aslight abductive movement as 3 +, moderate abduction as2 + and almost full lateral movement with only a small,amount of sclera showing between the limbus and outercanthus or an inability to sustain lateral gaze for morethan a few seconds, as 1 +. Coarse, well-sustainednystagmus demonstrated on lateral or vertical gaze wasdesignated as 4 +, lesser degrees of it as 3 + or 2 + anda barely perceptible nystagmus as 1 +. With respect toataxia, 4+ denoted an inability to walk even with someassistance; 3 + meant that the patient could walk if aided;

2 "Berocca C" (Hoffmann-LaRoche). Each 2 cc. con-tains thiamine hydrochloride, 10 mgm.; riboflavin, 6mgm.; niacinamide, 80 mgm.; pyridoxine hydrochloride,6 mgm.; panthenol (equivalent to 6 mgm. Ca panto-thenate), 6 mgm.; ascorbic acid, 100 mgm. with 3%gentisic acid ethanolamide as a preservative.

2 + indicated ability to walk alone but with staggering;and 1 + represented competent locomotion but with slightataxia. The degree of psychic derangement was mostdifficult to evaluate. In these patients several aspects ofthe mental disturbance were discernible, i.e. alertness andthe capacity for sustained mental activity, confusion, andmemory defect with confabulation. None of the patientsexhibited an appreciable variation in the degree of am-nesia during the period of observation. Rough quanti-tative data are given only on the confusional aspect.Four plus implied extreme confusion, often with suchtotal disorientation that the patient did not know whetherhe was standing or lying, dressed or undressed, indoors oroutdoors, or whether it was day or night. He failed torecognize and often misidentified obj ects and peoplearound him. He could not carry on a conversation oranswer questions adequately. Three plus represented thestate in which there was greater awareness of the im-mediate environment, but still gross disorientation as toplace and time. Two plus and one plus indicated lesserdegrees of confusion, particularly in regard to orientationin place and time. Often confabulation was more evi-dent as the patient improved. None of the patients weredisoriented as to person.

RESULTS

Since the regimen varied somewhat from patientto patient, the clinical data on each will be con-sidered separately.

Case 1 (Table I). This 67-year old man was ad-mitted to the hospital after collapsing in court.His son testified that he was accustomed to drink-ing in long sprees, the one preceding his admissionhaving lasted 2 months. During this time his dietwas said to have consisted of a sandwich at longand irregularly spaced intervals.

He was, on first examination, slightly tremulousand florid. There was considerable loss of muscle.The liver, which was tender and palpable 4 cm.below the right costal margin, showed a largeamount of fat and minimal, if any, fibrosis on bi-opsy; in addition, "liver function" tests were ab-normal.

Questions were answered in a normally alertand cooperative manner. He was disoriented inplace and time. In addition, he did not knowwhat clothing he had on; he spoke of lying on abench in the station waiting to be picked up by hisdaughter. He did not realize that he was ill andgave quite irrational answers, the responses vary-ing from one minute to the next.

Since he had a coarse tremor and transient hal-lucinations, he was thought to have delirium tre-mens in addition to his Wernicke's syndrome.

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TABLE I

Case No. 1-B. R., male, age 67

Hospital day 1 2 3 4 5* 6 7 8* 9* 10 11* 12 15 19 35

Externalrectusparalysis 3+ 3+ 3+ 3+ 4+ 1 + d 4 0 0 0 0 0 0 0

Horizontalnystagmus 3+ 3+ 3+ 3+ 3+ 3+ 3+ 2+ 2+ 1+ 1+ 1+ 1+ 1+ 1+

Ataxia 4+ 4+ 4+ 4+ 4+ 3+ 2+ 2+ 2+ 2+ 1 + 1+

Confusion 4+ 4+ 3+ 3+ 3+- 2+ 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3+

Glucose and salineThiamine

100 200 mgm.mgm. i.m.

i.m. daily RegularTherapy Niacin hospital

1000 mgm. dietP.O.

dailyMultiplevitaminst-*

* Measurements recorded on the day a therapy was started are pre-therapy.t "Berocca C" (see footnote 2) 4 cc. i.v. daily.

There was a bilateral internal strabismus due toan almost complete external rectus paralysis, aswell as a coarse horizontal nystagmus on attemptedlateral gaze. His actions betrayed a markeddiplopia. Ataxia was manifest on standing; hecould not walk even with assistance.

He was given only glucose and saline for fourdays, during which time his external rectusparalysis became even worse, the nystagmus andataxia remained the same, his hallucinations andtremor disappeared, and he seemed somewhat lessconfused. On the fifth day he was started on 100mgm. of thiamine intramuscularly twice a day inaddition to the glucose and saline. Within 5 hoursafter the first dose, his external rectus paralysiswas barely detectable. After three days of thia-mine (Day 8), external rectus weakness was onlyquestionably present, nystagmus was less, andwalking was accomplished with assistance, but hismental state, which seemed to have temporarilyimproved within 24 hours after thiamine was in-stituted, was no better than before thiamine. OnDay 8, 1000 mgm. of niacin orally per day wasadded. On Day 9, no external rectus weaknesscould be detected, and he walked without assist-ance for the first time; the mental status, however,showed no change. On this day, a multiple vita-

min preparation, given intravenously, was addedto the regimen. On Day 10, nystagmus wasslightly less and ataxia and mental status were thesame as on the previous day. Food was startedon Day 11. Thirty-five days after entry, the pa-tient had no ocular palsies, minimal horizontalnystagmus, and a somewhat wide-based gait. Hismental disorganization was as marked as prior tothe institution of thiamine. Confabulation wasmore spontaneous at this time than on entry.

Case 2 (Table II). This 57-year old single manwas discovered in his room in an irrational andneglected state. He had been there for an indeter-minate period of time and was quite unable to sup-ply a history of his illness.

He was very thin and unkempt. His liver wasenlarged to two finger-breadths below the rightcostal margin, and there was laboratory evidenceof abnormal function. He was alert, but inatten-tive and incapable of sustaining a conversation.His remarks and behavior were facetious and' in-appropriate. He had no idea of the place or dateand could give no rational answers to any questionsconcerning his past history or circumstances ofhis arrival to the hospital. There was diplopia inall directions, and he usually kept one eye closed.

3 "Berocca C"; 4 cc. were given daily.

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G. B. PHILLIPS, M. VICTOR, R. D. ADAMS, AND C. S. DAVIDSON

TABLE II

Case No. 2-E. H., male, age 57

Hospital day 1 2 3 4 5l 6 7 8* 9 10* 18

External rectusparalysis 3+ 3+ 4+ 4+ 4+ 1+ 1 + 0 0 0

Horizontalnystagmus 0 0 0 0 0 3+ 3+ 2+ 1 + 1 +

Ataxia 3+ 3+ 3+ 3+ 3+ 2+ 2+ 1 + 1 + 1+

Confusion 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3 + 3+ 3 + 3+

Glucose and saline-Thiamine

200 mgm. 200 mgm. RegularTherapy i.m. S.C. | hospitaldaily diet

Multiplevitaminst

* See footnote to Table I.t "Berocca C" (see footnote 2) 4 cc. i.m. daily.

Abduction of each eye was limited to a few mil-limeters, and nystagmus was not evident. Heneeded considerable coaxing and support to standor take a few steps, both of which acts were car-ried out in a markedly ataxic manner. Ankle jerkswere absent and knee jerks depressed, but therewere no other signs of neuropathy.

After four days of the glucose and saline regi-men, the paralysis of his external recti was com-plete. Nystagmus was absent and the ataxia re-mained unchanged. His responses were even lessadequate than on entry and he was more carelessof his speech and dress. One hundred mgm. ofthiamine were then injected intramuscularly andfour hours later, there having been no improve-ment, another 100 mgm. were given. Within a halfhour after the second dose, strabismus and diplopiahad disappeared, external rectus motion was al-most normal, and a coarse horizontal nystagmusbecame evident for the first time. After three daysof thiamine administration, external rectus paraly-sis was gone, nystagmus was less and ataxia wasmuch improved; his confusional state, however,remained unchanged. A multiple vitamin prepara-tion 3 was given intramuscularly for the next twodays without discernible improvement in themental state. On Day 10 food was started. Eight-een days after admission, his ocular disturbancewas limited to a fine horizontal nystagmus on farlateral gaze, and his gait was slightly wide-based

and unsteady. He was more alert, entered intosustained conversation more readily, and requiredno stimulation to confabulate. His confusion, how-ever, was as marked as prior to the administrationof thiamine and other vitamins.

Case 3 (Table III). This 46-year old man,who had been hospitalized nine months previouslyfor cirrhosis of the liver, was readmitted because ofirrational behavior and inability to walk for threeto four days.

Since youth he had, been consuming on the aver-age of 2 qts. of wine daily. His family stated thatfor at least three years he had eaten only one mealdaily, and then "only picked at his food."

There was general emaciation, roughness anddryness of the skin, and enlargement of the liverto 10 cm. below the right costal margin. "Liverfunction" tests were deranged, and a liver biopsyrevealed a large amount of fat with definitefibrosis.

The patient was alert and not tremulous or hal-lucinated. He realized he was in bed, but literallynothing more. His conversation showed a totallack of understanding of what was going on aroundhim and he misidentified the examiner and otherpatients. Disorientation in place and time wassevere. In addition, there was a pronounced mem-ory defect from the time of entry, and the tend-ency to confabulate became obvious within a fewdays.

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NUTRITIONAL DEFECT STUDY IN WERNICKE'S SYNDROME

TABLE III

Case No. 3-P. F., male, age 46

Hospital day 1 2 3* 4 5 6 7 8 9* 20

External rectusparalysis 2+ 2+ 4+t :1M _ | 0 0 0 0 0

Horizontal nystagmus 1+ + 0 1 + 1 + I 1+ 1 + 1 + 0 0

Vertical nystagmus 0 0 0 1 + 1+ 0 0 0 0 0

Ataxia 3+ 3+ 3+ 2+ 2+ 2+ 2+ 2+ 1+ 1+

Confusion 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3+

Glucose and salineTherapy Thiamine Regularngm. 15 mgm. hospital--'

L.v. P.O. dietdaily

* See footnote to Table I.t Paralysis of lateral gaze.

On entry there was a mild internal strabismus;abduction of both eyes was incomplete and a mildhorizontal nystagmus developed on attempting thismovement. The pupils were normal in size andreacted briskly to light. His gait was ataxic, andhe required support to walk. Knee and ankle jerkswere absent, but motor power and sensation wereadequate.

On the third day of the glucose and saline regi-men, there was an increase of the ocular defectmanifested by a paralysis of gaze; there was al-most a complete inability to perform lateral. con-jugate movements of the eyes although upward anddownward gaze was unimpaired. Moreover, thepupils became miotic and non-reacting. Fivemilligrams of thiamine were then administered in-travenously. Within six hours, lateral gaze wasalmost normal, and the pupils became dilated andreactive to light. After five subsequent days ofthiamine (15 mgm. orally per day) in addition tothe glucose and saline, external rectus paralysisand nystagmus were not detectable, and the ataxiawas only slight in degree. The mental disturbance,however, was unimproved. After 11 subsequentdays of food, ataxia was evident only on heel-to-toe walking, and there was still no change inmental status.

Case 4 (Table IV). This 43-year old manwas admitted because of advanced liver dis-ease and complaints of double vision. He gave ahistory of alcoholic excess (50 to 60 glasses of ale

daily) for 20 years. In the last three monthsanorexia was extreme, and he claimed to have lost25 pounds in weight in the month preceding entryinto the hospital. Diplopia was present for sevendays before admission. On physical examination,his liver was found to be enlarged to three to fourfinger-breadths below the right costal margin;"liver function" tests were markedly altered anda liver biopsy revealed a marked degree of fatand fibrosis.

When first examined, no mental defect wasdemonstrable. The abnormal eye signs consistedof an alternating internal strabismus, a moderatebilateral external rectus weakness, and a coarsehorizontal nystagmus on lateral gaze. Ataxia wasslight and difficult to assess because of an old rightperoneal palsy.

On the second day of the glucose and saline diethe developed a quiet confusion, which increasedover the subsequent two days to the point wherehe was wandering aimlessly around the ward, dis-oriented, irrational, and unaware of the meaningof all that was happening around him. The ocu-lar disorder and ataxia remained unchanged. OnDay 4 he was given 500 mgm. of niacin orally; 24hours later (Day 5) his condition was no dif-ferent except for an increase in the external rectusweakness and a decrease in horizontal nystagmus.On Day 5 he was given 50 mgm. of thiamine intra-venously and in one and a quarter hours there wasa definite decrease in external rectus palsy; in one

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G. B. PHILLIPS, M. VICTOR, R. D. ADAMS, AND C. S. DAVIDSON

TABLE IV

Case No. 4-P. S., Male, age 43

Hospital day 1 2 3 4* 5* 6* 7 8 9 10 11 14

External rectusparalysis 2+ 2+ 2+ 2+ 3+ 0 0 0 0 0 0 0

Horizontal nystagmus 3+ 3+ 3+ 3+ 2+ 2+ 2+ 1 + 1+ 14

Ataxia 1+ 1+ I1+ 1+ 1+ I1+ I1+ I1+ 0

Confusion 0 1 + 2 + 3 + 3 + 3 + 0 2 + 2 + 0 0

Glucose and salineNiacin Thiamine

500 mgm. 50 mgm.P.O. i.v. Regular

Therapy Niacin hospital1000 mgm. diet

P.O.Multiple

vitaminst

* See footnote to Table I.t See footnote to Table I.

and three-quarter hours he could abduct his eyes The regular hospital diet was begun that eveningalmost to their full extent, and in three hours he and when seen the next morning (12 hours later)had full range of movement, but still had difficulty he showed no mental abnormality, but still hadin sustaining lateral gaze. Several hours later he nystagmus and slight ataxia. One day later, how-was given 1000 mgm. of niacin orally and a mul- ever, he lapsed into a confused state, which re-tiple vitamin preparation3 intravenously. On Day versed completely within 36 hours. On the four-6, 48 hours after starting niacin and 24 hours af- teenth day after admission he had only a question-ter thiamine and multiple vitamins, he was still able nystagmus, but no abnormality of ocularthoroughly confused even though no external rec- movement, gait, or mental function.tus weakness was evident and nystagmus was less. Case 5 (Table V). This 58-year old man

TABLE V

Case No. 5-C. Z., male, age 58

Hospital day 1* 2* 3 4* 5 6 7 8 9 10 it 23

External rectusparalysis 3+ 4+ 1+ 1 4 AA+ 0 0

Horizontalnystagmus 2+ 1 + 3+ 3+ 3+ 3+ 3+ 3+ 2+ 2+ 1 + 0

Verticalnystagmus 4+ 4+ =1 0 0

Ataxia 4+ 4+ 3+ 3+ 3+ 2+ 2+ 2+ 2+ 2+ 2+ 1+

Confusion 3+ 3+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+

Glucose and saline-'Multiple vitaminsj-. Regular

Therapy Thiamine hospital50 mgm. i.v. diet

* See footnote to Table I.j The following vitamins were given orally daily: Ca pantothenate, 100 mgm.; pyridoxine, 100 mgm.; folic acid,

10 mgm.; ascorbic acid, 250 mgm.; riboflavin, 10 mgm.; niacin, 250 mgm. In addition, 10 pgm. of vitamin Bi, wereadministered intramuscularly on Day 1.

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NUTRITIONAL DEFECT STUDY IN WERNICKE'S SYNDROME

was brought to the hospital by the police becauseof the acute onset of confusion and abdominaldistress. He had been leading a derelict's exist-ence for many years, moving from one job andlodging house to another and drinking steadily.In the months preceding his admission, his familyhad noted an aversion to food and a severe weightloss of undetermined amount.

He was a wasted, untidy man with evidence ofmild liver disease. He was alert and cheerful andnot hallucinating. Orientation in place and time,recent and past memory, judgment and insightwere all impaired. His ocular defect consisted ofinternal strabismus, almost complete paralysis ofthe external recti, and a marked vertical and finehorizontal nystagmus. He exhibited severe ataxia,despite the presence of normal reflexes, motorpower and sensation.

He was given glucose and saline and multiplevitamins (see Table V). Twenty-four hours laterhis condition was the same except that his ex-ternal rectus paralysis had become complete andhorizontal nystagmus less. The vitamins of theprevious day were repeated, except for vitaminB12, with no further change. Later in the day hewas given 50 mgm. of thiamine intravenously andwithin four hours he could abduct his eyes almostcompletely. Associated with this improvementwas an increase in horizontal nystagmus. On Day3, only slight external rectus weakness was evidentand although the horizontal nystagmus was still

rather marked, the presence of any vertical nystag-mus was doubtful. Ataxia was somewhat less andhis mental status was improved to the extent thathe was now oriented in place; also, confabulationwas now becoming prominent.

On Day 4, food was started, and, 19 days laterno ocular abnormality of any kind was elicitable,and ataxia was slight in degree. He was orientedin place but grossly disoriented in time; no im-provement in retentive memory had occurred butconfabulation was more easily provoked than onadmission.

Case 6 (Table VI). This 50-year old man wasadmitted because of irrationality and inability towalk of two days duration. On physical examina-tion, his liver was found to be three finger-breadthsbelow the right costal margin. In addition, therewere slight abnormalities of the "liver function"tests.

On entry he was profoundly confused in placeand time as well as to his immediate bodily en-vironment. He had no idea what clothing he hadon or who the examiner was. His memory wasequally badly disordered, and confabulation wasdetectable at the first examination. He showeda moderate external rectus weakness, slight hori-zontal nystagmus and diplopia. Standing was im-possible because of a severe peripheral neuropathy,and thus ataxia could not be assessed.

During the first four days of glucose and salinehis nystagmus and confusion grew worse, and

TABLE VI

Case No. 611-J. M., male, age 50

Hospital day 1 2 3 4 5* 6 7* 8 9 to 23 35

External rectusparalysis 2+ 2+ 2+ 2+ 2+ 3+ 4+$ 1 + I1+ I1+ 0 0

Horizontalnystagmus 1+ 1+ 1+ 2+ 2+ 0 0 3+ 3+ 3+ 3+

Confusion 3+ 3+ 3+ 4+ 4+ 4+ 4+ 3+ 3+ 3+ 3+ 3+

Glucose and salineMultiple Thiamine Regular

Therapy vitamms§ 100 mgm. hospitali.v. diet

* See footnote to Table I.Paralysis of gaze.The following vitamins were given orally daily: Ca pantothenate, 100 mgm.; pyridoxine, 100 mgm.; folic acid,

10 mgm.; ascorbic acid, 500 mgm.; riboflavin, 10 mgm.; niacin, 500 mgm. In addition, 10 pgm. of vitamin BU wereadministered intramuscularly on Day 5.

11 No evaluation of ataxia was possible because of peripheral neuropathy.1 Started evening of Day 7.

865

G. B. PHILLIPS, M. VICTOR, R. D. ADAMS, AND C. S. DAVIDSON

TABLE VII

Case No. 7-F. L. malk, age 60

Hospital clay 1* 2 3 4 5 6 10 11* 12 15 18 29

External rectusparalysis 3+ 1+ I1+ 1+ 1+ 1 + 1 + 0 0 0 0 0

Horizontal nystagmus 0 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3+

Vertical nystagmus 2+ 2+ 2+ 2+ 2+ 0 0 0 0 0 0 0

Ataxia 4+ - - - 3+ 2+ 2+ 2+ 2+ 1+ 1+ 1+

Confueion 3+ 3+ 3+ 3+ | 3+ | 3+ 3+ 3+ | 3+ 3+ 3+ | 3+

Glucose and saline RegularTherapy Thiamine hospital

100 mgm. i.m. daily diet

* See footnote to Table I.

there was an increase in general weakness. OnDay 5, he was given several vitamins exclusive ofthiamine (see Table VI). On Day 6, there wasalmost complete external rectus paralysis with aconcomitant disappearance of nystagmus. He wasnoisy, irrational, uncooperative and generallyweaker. By Day 7, he had lost all movements ofhis eyes except for upward gaze, and a verticalnystagmus was noted for the first time. Onehundred milligrams of thiamine were then in-jected intravenously and within 2 hours lateralconjugate movements improved considerably andhorizontal nystagnus became prominent. A fewhours later food was started. On Day 8, his ex-ternal rectus weakness was slight and he was gen-erally more alert and cooperative and, perhaps,less confused. Thirty-five days after admission,examination disclosed absence of external rectusweakness, a fine vertical nystagmus, and a coarsehorizontal nystagmus. His mental status, exceptfor increased alertness and attentiveness, was un-changed. The neuropathy was still very severe.

Case 7 (Table VII). This 60-year old mancollapsed in court while answering charges ofdrunkenness. He showed, generalized wasting butno definite evidence of liver disease. He layquietly in bed and would reply only to persistentquestioning, being quite content to turn over andsuspend the conversation. He could give only hisname correctly. He thought he was in a school-house, mistook the examiner for a saleswoman,and had no idea of the date, his address, or themeaning of what he saw around him. His eyes

could be abducted only slightly from the mid-line,and no horizontal nystagmus was demonstrable.Upward gaze was limited, and a vertical nystagmusdeveloped on this movement. He was unable tostand without help and reeled when attempting towalk. Motor power was intact, but knee and anklejerks could not be obtained.

After the initial examination, the diet of glucoseand saline was instituted and continued for tendays. He was given, on entry and once dailythereafter, 100 mgm. of thiamine intramuscularlyas the only supplement.

Three hours after the first injection of thiamine,ocular movement was improved, and a coarsehorizontal nystagmus appeared'; 12 hours laterabduction was almost complete. Over the nextnine days there was gradual improvement in hisability to sustain lateral gaze. Vertical nystagmusdisappeared by the sixth day, but the!horizontalnystagmus remained unchanged' from the time itappeared. The ataxia showed slow but progres-sive improvement over the ten-day period; at theend of this time he was getting about freely, al-though his gait was still wide-based, and he stag-gered slightly on turning quickly. Mentally thepatient became more alert and cheerful. He en-tered into conversation readily and confabulatedfreely. Only in these respects was there a changein his mental status since admission. Food wasstarted on the eleventh day. Eighteen days laterataxia was further improved but no essentialchange could be detected in his horizontal nystag-mus or confusion.

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NUTRITIONAL DEFECT STUDY IN WERNICKE'S SYNDROME

Case 8 (Table VIII). This 74-year old manwas brought to the hospital by the police afterhaving collapsed in a doorway. He was poorlynourished and his skin was dry, loose, and coveredwith pediculous excoriations. No definite evi-dence of liver disease was detected. He spentmost of the day lying in bed with his eyes closed,a state from which he could be aroused easily.He then answered questions alertly, although hedid not enter into spontaneous conversation. Hewas consistently and grossly disoriented in time,being wrong as to the season, and giving the yearas 1970. His confusion in regard to his sur-roundings varied. At times he thought he was ina hospital, at others in a hotel. Memory spanwas impaired to the extent that he could not re-call two facts after a lapse of one minute. Con-fabulation could be elicited at the first examina-tion. There was marked bilateral external rectusweakness, and a coarse horizontal nystagmus de-veloped on lateral gaze. The patient walked veryslowly, with small uncertain steps, requiring sup-port occasionally, especially on turning. Therewere no signs of peripheral neuropathy.

After an observation period of 24 hours, the glu-cose and saline diet was instituted and continuedfor 11 days, with a daily supplement of 100 mgm.of thiamine intramuscularly for the first ten days.The patient was not seen again until 12 hours af-ter the first dose of thiamine, at which time therewas a marked improvement in the external rectuspalsy; complete abduction, however, was accom-plished only after five days of therapy. The ny-

stagmus also was reduced in degree within 12hours; after three days it was barely detectableon left lateral gaze only, a state which then per-sisted for as long as the patient was followed. Hisataxia improved progressively over the ten days,although it was still evident at the end of this time.

By the end of the ten-day period of the purifieddiet and thiamine administration, there was aslight but definite improvement in mental state.He was less confused in time, consistently givingthe correct month and approximating the year.When questioned on general information as wellas events in his own life, he gave many more cor-rect answers than on admission. His memoryspan was increased by several minutes; confabula-tion was unchanged.

A multiple vitamin preparation 8 was given in-tramuscularly on Day 12 with no further changein the patient's condition. One day later food wasstarted and after four days of the regular hospitaldiet, there was still no discernible change.

Case 9. This 68-year old man was admitted af-ter collapsing in the street. He showed signs ofgeneral neglect and marked wasting. There werenumerous petechiae over his thighs and kneessuggesting scurvy. No evidence of liver diseasewas found. He was disinclined to speak, but hisfew responses indicated profound disorientationand memory loss. His eyes showed an almost com-plete external rectus paralysis, coarse horizontalnystagmus, and fine vertical nystagmus. His gaitwas broad-based and his steps short and uncertain

TABLE VIII

Case No. 8-D. S., male, age 74

Hospital day 1 2* 3 4 5 6 7 8 9 10 11 12* 13* 17

External rectusparalysis 3+ 3 + 1+1 + 1+1I+ 0 0 0 0 0 0 0 0

Horizontalnystagmus 3+ 3+ 2+ 1+ 1+ 1+ 1+ 1+ 1+ 1+ 1+ 1+ 1+ 1+

Ataxia 3+ 3+ 3+ 2+ 1++1+ 1+ 1+ 1+ + 1+ 1+ +_

Confusion 3+ 3+ 3+ 3+ 3+ 3+ 3+ 2+ 2+ 2+ 2+ 2+ 2+ 2+

Glucose and saline Multiple RegularTherapy Thiamine vitaminst hospital-'-

100 mgm. dieti.m. daily

* See footnote to Table I.t See footnote to Table II.

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G. B. PHILLIPS, M. VICTOR, R. D. ADAMS, AND C. S. DAVIDSON

in the face of adequate motor power, normal re-flexes, and intact sensory function.

On the night of admission he was given 500mgm. of thiamine and a multiple vitamin prepara-tion4 intravenously. When he was next seentwelve hours later, his external rectus weaknesswas strikingly improved and consisted only of aninability to sustain lateral gaze. Otherwise, hiscondition was essentially unchanged. Food, wasstarted at this time. Four days later no externalrectus weakness was detectable, but nystagmusand ataxia were the same; the patient was muchmore alert and cheerful, and he could be inducedto confabulate. Re-evaluation 40 days after ad-mission disclosed no oculomotor weakness andonly slight horizontal and vertical nystagmus.Ataxia was present only on attempting to walk astraight line. Memory for recent events was vir-tually nil, and he confabulated freely. In otherrespects his mental derangement was much thesame as it had been four days after admission.

DISCUSSION

The patients included in this study were selectedon the basis of ophthalmoplegia, but it is note-worthy that all of them exhibited some degree ofnystagmus, ataxia and mental disturbance. Thiscombination of clinical findings, is so distinctivethat there can be little doubt as to the accuracyof the diagnosis.

The ophthalmoplegia was surprisingly uniform.In all the patients, it consisted on admission ofbilateral external rectus muscle weakness, whichwas usually asymmetrical in degree. Of the sixpatients who were sustained on glucose and salinebefore the institution of thiamine, the ocular paraly-sis became worse in all, progressing to an almostcomplete paralysis of gaze in two (Cases Nos. 3and 6). In another of these patients (Case No. 4)a definite increase in the degree of ocular paraly-sis occurred within 24 hours after niacin alone wasadded to the purified diet, and in two (Cases Nos.5 and 6) within 24 hours after the addition of mul-tiple vitamins exclusive of thiamine. The possi-bility of an accentuation of a thiamine depletionby the addition of other vitamins deserves con-sideration in these three patients, especially in viewof the experiments of Alexander, Pijoan, and

4 "Berocca C."

Myerson (13), who claimed that the characteristicchanges of Wernicke's encephalopathy could beproduced in pigeons more easily if large suppliesof other vitamins were added.

The most striking response to thiamine therapyin these patients was the rapid improvement in theocular palsies, which cleared considerably withinone and a quarter to six hours following parenteraladministration of thiamine (after as little as 5 mgm.of this vitamin given to one patient). Neverthe-less, it sometimes took several days for the residualweakness to disappear entirely. The miotic, non-reacting, pupils of one patient (Case No. 3), whichdeveloped while on glucose and saline only, re-turned to normal as the external ocular palsiescleared.

The rapid reversal of the ophthalmoplegia withthiamine makes it unlikely that these paralyses re-sulted from the structural lesion which is con-sidered to be so characteristic of Wernicke's syn-drome. Instead, it implies that this part of theclinical disorder was biochemical in nature. Thepathological study of Riggs and Boles (4) lendssupport to this interpretation, for in five caseswith oculomotor paralysis the ocular nuclei werenot significantly damaged. Furthermore, Prickett(9) in a study of thiamine deficient rats and pi-geons also noted a prompt reversal of the neuro-logical disturbances after the administration ofthiamine. Such dramatic response to thiamine,moreover, leaves little doubt as to the specificityof this vitamin for the ophthalmoplegia of Wer-nicke's syndrome. An important clinical lesson tobe obtained from this material is that the ophthai-moplegia, which is an essential diagnostic criterionof Wernicke's syndrome, may be eradicatedpromptly by the administration of thiamine, eitherparenterally or possibly in the diet. Many ofthese cases are not then recognized as havingWernicke's syndrome.

Some degree of horizontal nystagmus occurredin all of the patients. Only in recent years has thesignificance of nystagmus been fully appreciated.de Wardener and Lennox (7), who studied 52patients with Wernicke's syndrome, described nys-tagmus as the earliest ocular sign. In our pa-tients during the glucose and saline control period,the horizontal nystagmus decreased only in as-sociation with an increase in ocular palsy and re-turned in full force after the ocular palsy was re-

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NUTRITIONAL DEFECT STUDY IN WERNICKESSYNDROME

lieved by thiamine, indicating that it did not actu-ally improve in the pre-thiamine period but hadbecome less apparent because of increased paraly-sis of eye muscles. Improvement in nystagmusafter thiamine, unlike ocular weakness, tended tobe more gradual. Two patients (Cases Nos. 1 and2), whose horizontal nystagmus did not improveover a four-day control period, showed definitedecrease within three days after thiamine alonewas added; in another (Case No. 8) there wasmarked improvement within one day of addition ofthiamine alone. In one patient (Case No. 5) themarked vertical nystagmus present on admissionshowed no improvement after 24 hours on a groupof vitamins exclusive of thiamine but cleared al-most completely within 12 hours after thiamineonly was added. In another (Case No. 7) thevertical nystagmus disappeared within five daysafter the institution of thiamine alone. These re-sults suggest that the horizontal and vertical nys-tagmus also respond to thiamine. In four patients(Cases Nos. 1, 6, 7, and 9), however, nystagmuswas still present after a month in the hospital.Two of these (Cases Nos. 6 and 7) failed to showany decrease in nystagmus after 27 and 18 dayson-food, respectively. Indeed, nystagmus has beennoted to persist for months or years (17, 8) afteran attack of Wernicke's syndrome.

Seven patients in this group had a markedlyataxic gait on admission, one (Case No. 4) showedonly slight ataxia, and one (Case No. 6) couldnot be tested for character of gait because of thepresence of a polyneuropathy which was so severethat he could not stand. The ataxia was essentiallyone of stance and gait and could seldom be welldemonstrated in movements of the arms and legsindividually, such as by finger-to-nose and heel-to-shin testing. Like the nystagmus, the ataxia wasslow to improve, and of the seven patients who dem-onstrated it to a marked degree on admission, onlyone recovered from his ataxia completely, whilesix still showed it to a slight but definite degreewhen last examined. In no patient was there anyimprovement during the pre-thiamine control pe-riod, but in two (Cases Nos. 1 and 2), following afour-day control period, there was definite im-provement within three days and one day, respec-tively, after thiamine alone was added. Similarly,Case No. 3, following a two-day control period,showed decrease in ataxia one day after thiamine

was started and continued to improve on glucoseand saline and thiamine only. In Cases Nos. 7 and8, where glucose and saline and thiamine alone weregiven over a ten-day period, there was progres-sive improvement in the ataxic gait. It is note-worthy that in these five patients, the ataxia im-proved despite a low caloric intake. The ataxia,therefore, also seems to be related to a deficiencyof thiamine, but because of the slow responses con-clusions on this point are less certain than in thecase of the ophthalmoplegia.

The mental component of the Wernicke syn-drome presented the greatest difficulty in evalua-tion. Of the nine patients, only one (Case No. 4)was lucid on admission; however, he became in-creasingly confused during the period of glucoseand saline administration and showed no improve-ment 48 hours after niacin and 24 hours after thia-mine was started. Food was then given and in 12hours he was again mentally clear; a day later,however, he developed an episode of confusion,which lasted 36 hours. It was impossible in thisinstance to determine whether improvement wasdue to a delayed effect of niacin or thiamine, tosome other substance in food, to a spontaneous re-covery from an unrelated confusional psychosissuch as delirium tremens, or to some other factor.

The remaining eight patients all showed a pro-found degree of mental disorder on admission tothe hospital. With only minor variations, cer-tain features were common to all. When firstseen the patients were alert, although not hyper-active or hallucinating. Often, their attitude wasone of complete disinterest, rather than drowsi-ness. Spontaneous speech was minimal; theytended to answer questions in a perfunctory man-ner, with no desire to sustain a conversation. Theywere unable to focus their attention on any onetopic, and would often suspend a conversation.The questions that were answered betrayed disori-entation in time and place, misidentification of thepeople attending them, and complete inability tograsp the meaning of their illness or what was go-ing on around them. In addition, many of theirremarks were irrational, nor did these show anyconsistency from one moment to the next. If theexaminer was persistent in his questioning, it wasalso obvious that retentive memory, especially forrecent events, was already an important featureof the general mental disorganization.

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G. B. PHILLIPS, M. VICTOR, R. D. ADAMS, AND C. S. DAVIDSON

The eventual outcome of the mental disturbancevaried to some degree. One patient (Case No. 5)seemed to clear somewhat within 48 hours afterreceiving multiple vitamins and 12 hours afterthiamine, and another (Case No. 8) becameslightly less confused while maintained on glucoseand saline and thiamine only. The improvementin these two patients was mainly in their orienta-tion in place. In the other six patients, no changeof this sort could be detected. If one measuredthe difference in mental state in terms of increasedalertness, cheerfulness, ability to concentrate andsustain a conversation, and ready confabulation,then some degree of change occurred in most of thepatients. Since this change occurred only afterthiamine was added to the diet, it is possible thatthis aspect of the mental disorder was related tothiamine deficiency. With respect to memory de-fect and confabulation and to a lesser extent con-fusion, no significant improvement could be dis-cerned in these patients within the periods of ob-servation. Since these aspects of the mental dis-turbances characteristically resolve slowly, if atall (17), the periods of observation on the purifieddiet may have been too short to evaluate the effectof thiamine. This failure to improve after thia-mine administration, therefore, does not excludethiamine deficiency as a cause of the mental dis-turbances.

SUMMARYAND CONCLUSIONS

1. Nine patients with Wernicke's syndrome,characterized by ophthalmoplegia, nystagmus,ataxia, and mental disturbances were given a puri-fied diet composed solely of glucose and minerals.Specific vitamins were added after appropriate in-tervals of observation.

2. Prior to the administration of thiamine, therewas no improvement in any of the signs. Morespecifically, despite alcohol withdrawal, bed rest,and the addition of other vitamins (niacin, cal-cium pantothenate, pyridoxine, folic acid, ascorbicacid, riboflavin, B12), the ophthalmoplegia pro-gressed and the ataxia remained unchanged, whilethe nystagmus decreased only in association withan increase in ocular paralysis.

3. Whenthiamine only was added to the purifieddiet, the ophthalmoplegia cleared considerably infrom one and a quarter to six hours; diminution

in nystagmus and, ataxia also occurred in some ofthe patients, but the change was more gradual;there was improvement in mental disturbance, butit was minimal in degree and consisted of increasedattentiveness and capacity to maintain a conversa-tion and greater ease of confabulation.

4. In view of these observations, there seems tobe little doubt that the ophthalmoplegia of Wer-nicke's syndrome is related to a specific lack ofthiamine. The nystagmus and ataxia also appearto be related to thiamine deficiency, but the evi-dence is less conclusive. No definite conclusionscan be drawn regarding the relationship of themental disturbances to the deprivation of thiamineor other vitamins.

REFERENCES

1. Wernicke, C., Lehrbuch der Gehirnkrankheiten furAerzte und Studirende. Theodor Fischer, Kassel,1881, p. 229.

2. Spillane, J. D., Nutritional Disorders of the Nerv-ous System. Williams and Wilkins, Baltimore,1947, p. 82.

3. Alexander, L., Wernicke's disease. Identity of le-sions produced experimentally by B1 avitaminosisin pigeons with hemorrhagic polioencephalitis oc-curring in chronic alcoholism in man. Am. J.Path., 1940, 16, 61.

4. Riggs, H. E., and Boles, R. S., Wernicke's disease.A clinical and pathological study of 42 cases.Quart. J. Stud. Alcohol, 1944, 5, 361.

5. Campbell, A. C. P., and Biggart, J. H., Wernicke'sencephalopathy (polioencephalitis haemorrhagicasuperior): its alcoholic and non-alcoholic incidence.J. Path. & Bact., 1939, 48, 245.

6. Campbell, A. C. P., and Russell, W. R., Wernicke'sencephalopathy: the clinical features and theirprobable relationship to vitamin B deficiency.Quart. J. Med., 1941, N.S. 10, 34, 41.

7. de Wardener, H. E., and Lennox, B., Cerebral beri-beri (Wernicke's encephalopathy). Review of 52cases in a Singapore prisoner-of-war hospital.Lancet, 1947, 1, 11.

8. Cruickshank, E. K, Wernicke's encephalopathy.Quart. J. Med., 1950, N.S. 19, 43, 327.

9. Prickett, C. O., The effect of a deficiency of vitaminB1 upon the central and peripheral nervous systemsof the rat Am. J. Physiol., 1934, 107, 459.

10. Church, C. F., Functional studies of the nervous sys-tem in experimental beriberi. Am. J. Physiol.,1935, 111, 660.

11. Green, R. G., and Evans, C. A., A deficiency diseaseof foxes. Science, 1940, N.S. 92, 154.

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NUTRITIONAL DEFECT STUDY IN WERNICKES SYNDROME

12. Owen, P. S., and Ferrebee, J. W., The anti-thiaminefactor in fish. New England J. Med., 1943, 229,435.

13. Alexander, L., Pijoan, M., and Myerson, A., Beri-beri and scurvy; an experimental study. Tr. Am.Neurol. A., 1938, 64, 135.

14. Swank, R. L., and Prados, M., Avian thiamine de-ficiency. II. Pathologic changes in the brain andcranial nerves (especially the vestibular) and their

relation to the clinical behavior. Arch. Neurol. &Psychiat., 1942, 47, 97.

15. Jolliffe, N., Wortis, H., and Fein, H. D., The Wer-nicke syndrome. Arch. Neurol. & Psychiat., 1941,46, 569.

16. Wortis, H., Bueding, E., Stein, M. H., and Jolliffe, N.,Pyruvic acid studies in the Wernicke syndrome.Arch. Neurol. & Psychiat., 1942, 47, 215.

17. Victor, M., and Adams, R. D. (To be published.)

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