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Response of lingual manifestations of pernicious anemia to pteroylglutamic acid and vitamin B12
RESPONSE ANEMIA
OF LINGUAL MANIFESTATIONS OF PERNICIOUS TO PTEROYLGLUTAMIC ACID AND VITAMIN B,,
the therapeutic effectiveness of s~rrthetic pteroylglutaniic A LTEJVOUGII acid in the rnajority Of paticnt.s with pernicious anemia has been satisfactor)+, short-comings have been observed. At the heginning Of therapy, The rise in rwl reticulocytosis although prompt is often snl~optimal. ~~11 (?Ourrt is usdly slower thnrr with liver est I*il(‘t. Mncrocytosis may the blood values may prsist for months, and during maintenance thr>u1)y evpll (leclirle.“s IO.11,I2318,17,21,30 While some patients with the neurologic r~l;lrlifestil~tiorrS of pernicious anemia may show i~lrprovement early in the cout~e Of pteroylglutamic acid therapy,‘~ 5. R,!’ the f;lilure of this con~~~ountl irl dOSeS Of 2.5 to 20 mg. per tlay to l)rwtcct p;ltiClltS ;igainst neurologic rcln.psc has beeI of great collcer~r1~2.11,1%11.17,“1, ?i, 27,23.30,31 The effect of pteroylglntanlic acid on the t,hirtl inlportant clinicill manifestation Of pernicious anemia, that of atrophy and inflammation of the liugtttll mucosn, has received less study, hut in SOIIIP cases at, least it ;lp])eat~S IO he nrisatisfactor.y.“, ?‘a2i, 28 The purpose Of t,his paper is to repod additiorlal patients with the lingual manifestations of lwrnic+Ous anemia w-ho were treated with ptcr~oylglutnmic acid. In some the response was gootl. in othem p00l’. TWO tle~clolwtl severe lingual rel;rl,stJs while taking Xl to 50 mg. per ilily Of the COlll~~Ol~llCl. The lingu;~l nl)nol.m:ilitics in the latter casts responded to injections Of vitamin C12’” as promptly as (lit1 the lilignill IllirrlifcStat.i(~TIS in patients with pernicious aucmin. who had had no llwvious tl*eiltrrletlt. Each Of the following pnticrrts cshil)itctl OIIC or’ 11101~: of the clinical manifestations of pcrrticious anen&. All Of tllCl~1 h;ltl hislamine I’~!fl’il.CtOT’~ g;lStric arhlorhydria. Other coin~~licatinp tliseasw \v(lre not pwsent. IMails of the neurologic clisense in some c:ises will he wportcd later. The following patient was One of two in wlronl ~~te~oyl~lut;rtr~ic acid therapy protluced a rapid restoration of nortlrnl lingunl rnucOsa~ The tonglre remained normal and there was ncurologic imprO\-cmcnt in spitca of an incomplete
hemnt,ologic
rrnlission.
W. P., 68799. This 55-year-old mulatto, admittell to 1)&e IIospit,zl 011 Aug. 16, l$l#j, first dOvc?lopd the lingunl and anemic m:mifcstations of pernicious nnelnia in 1936. lie rc:spondcd wvcll to injections of liver extract, hut, being indifferent :~l)out m:lintennnc~e ther:lpy, suffered at least, three rel:rprm, one with mnsi~ler:~l~lc neurologic tlamlge. For at least. six
Pteroylglutamic acid was gi\-csll ill a dose of $5 mg. daily by mouth. “‘\ftrr Six tl:cyS of therapy, the tongue had becornr~ pale pink in color and faintly coated. Filiform Impillae The pteroylglutmnic acid WRS n1aint:lillf~cl during had grown to ncarl~- normal height,. The rrwrologic~ the nest five montlls, a(; first 30 mg. pvr II:I~ ant1 t hrw 1 .T milligrams. The appearance ol returned to work. symptoms of recent onset subsidwl ax111the patknt The rc11 blootl count ditl not rise to over 3,560,000, llr)n~~~VOr,a1111 his tongue remained normal. \\‘:,s rwom Hecausc 0 f‘ the persisf-ent niacro~~ptosia, lircr cxtrwt macrocytosis persistetl. mended as permanent maintennnw 1thwa py.
The following patient W;IS one of four with pclxicious pteroylglutamic acid fniletl to produce an adequate lingual extract was more effective finally in correcting the lingual festations of the disease.
anemi:l in whon~ response. Iriver ant1 other mani-
E. IV., R-87399. This 6%year~old white woman ? admitted to Duke IIospital on Aug. 2X, 1946, had enjoyed good general health with t,hc exception of a mild convulsive disorder of six Three or four years hefortl her hospital admission her tongw became years? cluration. intermittently red and sore. Numlmrss anal l.ingling developed in her hands and feet. These although she was a hearty eater, her selection symptoms led to the diagnosis of pellagra, of food was reasonably good, and no other member of her family had symptoms of nutritional
deficiency. Dietary treatment xv-as attempted without notable success. Six months before admission she became markedly forgetful. At that time her tongue again became red and S”lX Kumbness and tingling in her extremities became worse. Two months before admission, confusion, weakness, au11 gross unstentlincss iu walking Iw:true severe enough to confine her to bed. E:s:tmination showed a confused, poorly orientell, inai tentive woman barely able to move her legs in bed and just able to sit up alone. The tongue was beefy ret1 and entirely smooth except along the margins where remnants of filiform papillae were just visible. Keurologic rxamination sho~~2d evidence of severe peripheral neuropnthy, posterior and latfral column (iisease. The hemoglobin was 13.5 grams per 100 cc.; R.R.C., 4,O”O.OOO; \V.l%.(‘., 191000; hemntocrit, 40.8 per ceut; and avcragc cell volunic, 101 cul)is micra. Ptcroylglutamic acid was given by mouth for four weeks in a daily dose of 100 niilligrams. After seven days the color of the tongue was nwrly normal and regenerating filiforni papillae were CilSily visible. During the second \veclt the patiwt IVY:U~P stronger and clcarcr mentally lmt then she appeared to get worse. Tllc tiliforru papillae which had renlainccl stubby I~~:trnc shorter and the color of the tongue became a llceper red. The red cell count fell to 3,ti30,000 ant1 the hmn~tocrit to 38.0 J)cr cent. Thcrc: was no change in her conditirm after fire days of vi tnmin R therapy, 30 mg. of thiamin, 1.5 Gm. par:t-nrllinol,ellzoic~ acitl, 10 mg. riboflavin, 300 mg. niacin, 50 nrg. calcium p:intothen:i te, and 5 mg. pyritlosinr: hcing given daily. It was then considered advisable to begin intensive liver extract thornJ)y. There was little apparent improvcmcnt tluring the first month cswpt for regrowth of lingm~l p:~pill:w and rise in blood values. After tn-o months of liver therapy the patient’s strength and motor The hematologic values and the appearance of the tongue ability began to improve steadily. became normal ant1 remained so. At the end of twelve montlis of liver therapy she was able TTer mental con~lition im to do all ordinary activities at home with little motor handicap. Ncurologic examination co11tinuctl proved until she was about as I\-ell as bcfnrc her illnrss. to show 111~expected resi~lunls of posterior and lntcral column rliscnsr.~”
The Collowing two patients frrated with l’ter(Jplglllt~lllli~ distinct lillg~~;~l rcla.pses du&g the third mollth OF therapy factory ht~inatologic and ncnrologic rrsponses.
acid tlt~vclopl in sl)itc of sntis-
Y. D., U-33368. This 30.year-old, married, postal clerk was admitted to ~)ukc: JJospital on hpril ?ti, I%#. I’ive years previously she had (levelopecl :L “red and slick’ 7 tongue that despite vitamin H therapy became sore from time to time. She became chronically weak and nervous and worried intensely about minor incidents. She was afraid of “ losing her mind. ’ ’ Nine weeks before admission to the hospital her tongue became particularly sore. d few days later she found it difficult to control the movements of her feet. IIer legs began to feel stiff ami tight. IIer memory deteriorated and she bc~~une confused. F’or several days before her hospital admission, she was confined to bed by cxt.reme weakness. E:x:tmination showed a confused and apprehensiro young ~vonmn. She m:~de many mistakes in doing mental arithmetic. The tongue was scarlet in color, had no coat, and in the middorsum there were no visible papillae. She was unable to gc,t out of bed without as sistance and could not walk without suppport from both sides. The tendon reflexes in upper and low7 extremities were hypersrtive. The cutaneous senses were severely blunted below the knees. Thrrc \\a~ lmt little ataxia with the heel to shin test. The vibratory sense was absent l~low the wsl a1 margins. The plant nr reslmus~‘s wcrc flexor. ‘I’hrre was 7rlstairkml ankle rclonus more pronounce~l on the left sille. 7’110 hemoglobin was l2.0 grams Jwr 100 cc.; 1LFJ.C:. 3,300,000; \V.B.C., 8,730 ; l~emnto~ crit, 34 per cent; ant1 the average cell volume, 101 cul)ic micra. l~Zs:rminntiou of fhe bonc~ marrow shon-ed early evidence of megalol~lastic ccl1 dcvelopmen~ . acid was Starte(l under close 01,servntion. I:xpcriment~al therapy Ivith pterylglutamic During the first month the patient WBS given 100 mg. of the acid daily by mouth and for the next two months 50 mg. daily. The red cell count row to 4,100,OOO during the first month
Early in the third month of pteroylglutamic acid therapy she complained of soreness and redness of the tongue lasting two or three days. Two weeks later these symptoms became persistent and she felt generally worse. I’:saminnt,ion showc~l a beefy red tongue without coai, completely devoid of papillae except in one sm:~ll patch near the tip (ll’ig. 2, J). There xv:ls no evidence of neurolopic relapse and the l~lou~l values rcimained normal. The pteroylglutamic acill therapy \\:is tl iscontinucd and 0.050 nlg. of vitamin 13,? was gjven intramuswl:lrlv “. The redness ant1 soreness of the tongue subsided within a week. On a checkup esaminat~ion twwty clays after the injection the tongue KM pink in color, lightly caoatetl, an11 covwed with filiform papillae of normal height (Fig. 3. I: 1. The neurolopic starus sllowed no olldcctive rahangcs. M. J., 33597. This 55.year-old farmer’s widow V:IS :~dmittetl to I)ukc Hospital on April 11, 19-M. Two years previously she had develop4 a periodically sore tongue, lost her desire to eat,, and had begun to lose weight. Tier hands and feet became numb. She was cow tined to bell for several wvtcks by extreme weakness, but improved after injections were given by her family physician. Home months later she began to have progressive ditticulty in walking, with gross unsteadiness. Two months before her hospital admission, she became rapidly worse and was confined to bed, unable to stand or !vulk. Her family physician g:L\e her oral medications and injections for pellxgr:~ without. Iwnefit. On c%~mination the patient was a thin, Veak, apathetic womau appearing chronically ill. The tongue was pale and completely devoid of papillae. She WLS able to sit up in bed without assistance but was too weak to get out of bed, stand, or \wlk. The superficial sensations DXI’C impaired below the elbows and knees. The scnsc UC motion and position was poor in the lower extremities. The vibratory sense was impaired over the lowr ribs and absent at the pelvis and below. The plantar reflexes were extensor. On admission to the hospital the hemoglobin was 6.X gmms par 160 IX:.; R.B.C., 1,750,000; W.B.C., 2,360; hematocrit, 19.5 per cent; average ccl1 volume, 112 cubic micra; and ret,iculocytcs, 5.1) per cent. During the first ten days in the hospital an imxmplete, apparently spontaneous remission in the anemia occurred. There was no improvement, however, in the appearance of the tongue. dftcr ten days of observation, the administration of pteroylglutamic acid was begun in a dose of 50 mg. per day by month. 21 secondary reticulocytosis occurred. One week after the start of pteroylglut:~mic acitl t,hcrapy, beginning regeneration of lingual papillae was evident. After eighteeu days of therapy the papillae were of normal height. I3y this time the pat.ient had gained strength ant1 \vas able to sit up three to four hours a day as ~11 as walk about the ward holding to furniture. After four weeks of anti3-ftw six w&s the dose of pteroylanemic thc7apy t,he blood values were entirely normal. glutamic: :wi,t was retluce~l lo 30 mg. daily and she returned honw. Grneral improvement contillued. On :t ~llecli-up examiuntion two months afwr the beginning of pteroylglutamic w-id therapy, howrvcr, the tongue was observed to be reddened at the tip. The papillae remained tall. Five weeks late- she complained of a sore, ’ ‘scalded ” tongue. Examination showetl it to be scarlet red in color xnd entirely smooth (Fig. 2, C). Tier di(lt:wy habits were reinvestigat,etl and it appeared that her food hat1 betw well selected The l)lno(l wluw remainetl nurm:~l and average in nutritional atlcquacy. ill1 ii :rhrc n~~urologi(* examination showed continued improvement, certainly no relapse. Al this time the pteroylglutamic acid administration was stopped aod 0.025 rug. of The lingual sorcn~~ss promptly sul)sidedt and after vilamin l(,, ~1s injected intramuscularly. one wxk the color of the tongue KM grayish-pink ant1 the dorsum ~vas covered Isith a uniShe lwliered that her strength and (Fig. 2, D). form crop of budding filiform papillae motor ability had improved.
The following patient was one of five showin g the lingual nlanifestxtions of untreated pernicious anemia in whom the injection of vitamin BlzzO in a close of 0.001 mg. daily to 0.010 mg. in a single close led to regeneration of lingual papi1la.e in 5-7 days.
b’ig. 3.--d 11’. S., C-6035. Dusky 1~x1 tongue lacking papillae in a patient with untrPatcd pernicious anen&. B Repeat photograph five days after tlic injection of 0.010 R~C. of vitxmin of papillae. BU showing regeneration On examination the tongue W:LY deeply furrowed~ completely lacking in c’ua~. flusky wd devoid uf papillae (Fig. 3, A). His grip IV:LS estremc~ly \vcak. in color, and completely Tendon reflexes in the upper extremities were absent. The superficial sensations I\ ere I,luntcd about the hands auci forearms an11 the vibratory sense \V:LS imp:tirctl below the wrists and at the ankles. The hemoglobin was 12.X grwns per 100 C.C.; R.B.C., 3,400,OOO; \V.H.(!.J li,ziOO; I’&xmiit:tticm cut’ the hematocrit, 35 per cent; and avcragc cell volume, 103 cubic micra. boue marrow showed early megalubl:~st ic Jcvelopmcnt. lie was given 0.010 mg. of vitamin I& intramuscularly. 1~~s uurm:tl in color and its dorsum \\:ts c~orrrctrl with medium I$) in spite of his continuing to V~PU lob:~c~
Five clays latw the tongue* tall filiform papillae (Fig. 3,
Discussion Periodic atrophy and inflammation of the lingual mucosa, so vividly deas often the first sy11pt0111 oi scribed nearly fifty years ago by 1lunteP pernicious anemia, has become a well-recognized clinical manifestation of the disease. Significant abnormalities of the lingual mucosa arc seen, with or wit,hout hematologic or neurologic manit’estations, in about one-third of present-day patients with pernicious anemia in relapse. Mucosal changes of similar appearance may result, of course, from the lack of common vitamin B components in
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diet,‘G from iron deficiency,” in association with serious hepatic discaw or abdominal ncoplasms, from use of oral pcnicilliir,~‘~ ‘:) etc. Among the benefits of a diet rich in liver ill the trcatmtnt OF lwrnicious anemia! Minot and M~rphy’~ obscrvctd a gradual return of Ilorma.1 lingual mucosa in a matter of a few weeks or nionths. 1Yith potent liwr cxlrntl or hog stomach therapy a niore rapid lingual response occu13. F‘ilifo~m papilliw sprout from smooth tongues in fire to seven da)-s ant1 attain a norn~al height iTi two to three weeks. Relapses do not occur with adecluate maintenance therap!-. The lingual abnormalities of pernicious anemia are liot affected l)\- ~wtrqwcific therapy, the administration of the coJJmJon vitamin I3 components.” rxf~. ‘l’hc lingual response may serve accordingly as a useful and relii~ble thcrapt~utic twt for pernicious anemia in patients who have little or ii0 anemia or iti whoIll tllr cause of lingual or neurolopic disease is in doubt. the
In the therapeutic evaluation of lIteroSlglutamic acid in pcrnicions anctnia most attention has been given to the hcmatologic an{1 neurologic aspcct,s. 11 few investigators have noted lwor lingual responses at ihe IJegiJJJJing of tlJcr:~p?; and relapses later during maintenancc.‘l, I312il 2S The frequency of this ocww rcnce is uncertain. It appears to be especially common in the patients rc~lwrtcd who developed neurologic relapses. 111 0111’ six p:JtiPllk whose ~iIl~ll~l~ tWpoJJsc~S were poor or who later relapsed, the blood levels remaint4 below normal :lJrtl neurologic disease progressed in one, and the reel cell count fell signific%ntly iI1 alJotllcr. Had the ptero>-lglntamic acid therapy beet] continued lotlger in these paCents. a higher incidence of hcnratologic :1~1(111olwologic failures ttrizht \v(lll have been observctl. The regeneration of lingual mucosa followin g the injection of vitaniiu El3 after relapse has occurred during pteroplglntamic acid therapy shows that the former substance has a nutritional value lacking ill the latter. The l~romptness of the response, equal to that obserred in patients with untwatrd pernicious anemia. suggests that the pteroylglutamic~ acid failed to corrwt an existing dcficiencp rather than having exerted a positively harmful effect.‘, ‘I. ?I The effect, of vitamin IS,, in correcting this type of lingual relapse appears lo IV equal to that expected from liver extract, as preliminary rrporis intliwte it, to he in other respects.‘, 2:x23.?6 2g Whether or not the different, manifestations of pernicious anemia-arrest in hemopoiesis, atrophy and inflammation of the lingual mucosa, ant1 disease of the peripheral and central nervous system-represent one or more closcl,v related nutritional deficiencies has been a perennial question.1, *, 21 ~I;:aclt of these manifestations is dissociated from the others and may occur singly or in rombination as the disease first appears or relapses. Potent liver extracts. however refined or fractionated, and hog stomach preparations affect all aspects The impression has arisen that ptcroylof pernicious anemia in parallel. glutamic acid corrects one portion of the basic deficiency, having nn entirely satisfactory hematologic effect but being entirely ineffective regnr(linp the hemniologie Jwnissions, neurologic nianifestntions.14~ “9 24,3” The incomplete
1. The lingual manifesl,at,ions of pernicious anemia. in relapse may respon(i well or poorly to synthetic pteroylglutamic acid. 2. Two patients taking 20 and 50 mg. of pteroylglutamic avid daily tlevelopetl in the third month of thcral))- achutely sore tongues will1 m~~cos:~l atrophy. The lingual abnorninlities tlis;rpptwrccl within five to seven days after the injection of vitamin 1:,2. 3. The lingual mucosal atrophy of five 1)atient.s with urrtrtatrtl pfxrtlicions anemia responded in five to seven days lo injections of vitamin I:,,. 4. The therapeutic limitations of pteroylglutxmic a&l in pernicious anemia relate to all manifestnt,ions of the clisens+ -anemic.. neurologic, and lingual-rather than to merely ihc neurolo~ic~. References 1. Berk,
Lionel, Denny-Brown, I)erek, Finland, Maxwell, and Castle, William B.: Efl’ectiveness of Vitamin B,? in i’ornhined System J)isease: New England ,J. Med. 239: 328, 1948. of Therapy in Perniciou!: Anemia to 2. Bethell, F. H, and Sturgis, C. C.: The Relation Changes In the Nervous System, Blood 3: 57, 194s. Glossodvnia and ISxfolistion of Pauillae Filaments After Oral Adminix3. Brown. R. L.: tiation of Penicillh, Arch. Otolaryng. 45: 355;1947. A Survey of the Treatment of Pernicious Anemia in Relapse: (a) -1. Clark, Guy W.: A Comparison of the Hematopoietic Response to Liver Extract and Folic Acid I,-Casei Factor). (1~) Limitations of the Reticulocyte Response as a Measure of Anti-Pernicious iinemia Potency, Am. J. M. SC. 216: 71, 1948. Folic Arid, Pernicious Anemia and Pend~~lums, Blood Editorial: ,5 Dameshek, William: 3: 699, 1948. of Iron Deficiency, 5. A. &I. .4. 130: 830, J.: The Oral Manifestations 6. Darby, William 1946.
L. S. P., and Gird\\oo(l, 11. H.: ‘1’1~ Tmbnlancc of XTitmnins, 1,:tnc’et 1: 360, 7. Davidson, 1948. an I
anemic Prouerties
1: $27,
104%
of Vitamin
Ii,,. South. 1\I. .i. 41: 532. 1948.
OF LINGUAL MANIFESTATIONS OF PERNICIOUS TO PTEROYLGLUTAMIC ACID AND VITAMIN B,,
the therapeutic effectiveness of s~rrthetic pteroylglutaniic A LTEJVOUGII acid in the rnajority Of paticnt.s with pernicious anemia has been satisfactor)+, short-comings have been observed. At the heginning Of therapy, The rise in rwl reticulocytosis although prompt is often snl~optimal. ~~11 (?Ourrt is usdly slower thnrr with liver est I*il(‘t. Mncrocytosis may the blood values may prsist for months, and during maintenance thr>u1)y evpll (leclirle.“s IO.11,I2318,17,21,30 While some patients with the neurologic r~l;lrlifestil~tiorrS of pernicious anemia may show i~lrprovement early in the cout~e Of pteroylglutamic acid therapy,‘~ 5. R,!’ the f;lilure of this con~~~ountl irl dOSeS Of 2.5 to 20 mg. per tlay to l)rwtcct p;ltiClltS ;igainst neurologic rcln.psc has beeI of great collcer~r1~2.11,1%11.17,“1, ?i, 27,23.30,31 The effect of pteroylglntanlic acid on the t,hirtl inlportant clinicill manifestation Of pernicious anemia, that of atrophy and inflammation of the liugtttll mucosn, has received less study, hut in SOIIIP cases at, least it ;lp])eat~S IO he nrisatisfactor.y.“, ?‘a2i, 28 The purpose Of t,his paper is to repod additiorlal patients with the lingual manifestations of lwrnic+Ous anemia w-ho were treated with ptcr~oylglutnmic acid. In some the response was gootl. in othem p00l’. TWO tle~clolwtl severe lingual rel;rl,stJs while taking Xl to 50 mg. per ilily Of the COlll~~Ol~llCl. The lingu;~l nl)nol.m:ilitics in the latter casts responded to injections Of vitamin C12’” as promptly as (lit1 the lilignill IllirrlifcStat.i(~TIS in patients with pernicious aucmin. who had had no llwvious tl*eiltrrletlt. Each Of the following pnticrrts cshil)itctl OIIC or’ 11101~: of the clinical manifestations of pcrrticious anen&. All Of tllCl~1 h;ltl hislamine I’~!fl’il.CtOT’~ g;lStric arhlorhydria. Other coin~~licatinp tliseasw \v(lre not pwsent. IMails of the neurologic clisense in some c:ises will he wportcd later. The following patient was One of two in wlronl ~~te~oyl~lut;rtr~ic acid therapy protluced a rapid restoration of nortlrnl lingunl rnucOsa~ The tonglre remained normal and there was ncurologic imprO\-cmcnt in spitca of an incomplete
hemnt,ologic
rrnlission.
W. P., 68799. This 55-year-old mulatto, admittell to 1)&e IIospit,zl 011 Aug. 16, l$l#j, first dOvc?lopd the lingunl and anemic m:mifcstations of pernicious nnelnia in 1936. lie rc:spondcd wvcll to injections of liver extract, hut, being indifferent :~l)out m:lintennnc~e ther:lpy, suffered at least, three rel:rprm, one with mnsi~ler:~l~lc neurologic tlamlge. For at least. six
Pteroylglutamic acid was gi\-csll ill a dose of $5 mg. daily by mouth. “‘\ftrr Six tl:cyS of therapy, the tongue had becornr~ pale pink in color and faintly coated. Filiform Impillae The pteroylglutmnic acid WRS n1aint:lillf~cl during had grown to ncarl~- normal height,. The rrwrologic~ the nest five montlls, a(; first 30 mg. pvr II:I~ ant1 t hrw 1 .T milligrams. The appearance ol returned to work. symptoms of recent onset subsidwl ax111the patknt The rc11 blootl count ditl not rise to over 3,560,000, llr)n~~~VOr,a1111 his tongue remained normal. \\‘:,s rwom Hecausc 0 f‘ the persisf-ent niacro~~ptosia, lircr cxtrwt macrocytosis persistetl. mended as permanent maintennnw 1thwa py.
The following patient W;IS one of four with pclxicious pteroylglutamic acid fniletl to produce an adequate lingual extract was more effective finally in correcting the lingual festations of the disease.
anemi:l in whon~ response. Iriver ant1 other mani-
E. IV., R-87399. This 6%year~old white woman ? admitted to Duke IIospital on Aug. 2X, 1946, had enjoyed good general health with t,hc exception of a mild convulsive disorder of six Three or four years hefortl her hospital admission her tongw became years? cluration. intermittently red and sore. Numlmrss anal l.ingling developed in her hands and feet. These although she was a hearty eater, her selection symptoms led to the diagnosis of pellagra, of food was reasonably good, and no other member of her family had symptoms of nutritional
deficiency. Dietary treatment xv-as attempted without notable success. Six months before admission she became markedly forgetful. At that time her tongue again became red and S”lX Kumbness and tingling in her extremities became worse. Two months before admission, confusion, weakness, au11 gross unstentlincss iu walking Iw:true severe enough to confine her to bed. E:s:tmination showed a confused, poorly orientell, inai tentive woman barely able to move her legs in bed and just able to sit up alone. The tongue was beefy ret1 and entirely smooth except along the margins where remnants of filiform papillae were just visible. Keurologic rxamination sho~~2d evidence of severe peripheral neuropnthy, posterior and latfral column (iisease. The hemoglobin was 13.5 grams per 100 cc.; R.R.C., 4,O”O.OOO; \V.l%.(‘., 191000; hemntocrit, 40.8 per ceut; and avcragc cell volunic, 101 cul)is micra. Ptcroylglutamic acid was given by mouth for four weeks in a daily dose of 100 niilligrams. After seven days the color of the tongue was nwrly normal and regenerating filiforni papillae were CilSily visible. During the second \veclt the patiwt IVY:U~P stronger and clcarcr mentally lmt then she appeared to get worse. Tllc tiliforru papillae which had renlainccl stubby I~~:trnc shorter and the color of the tongue became a llceper red. The red cell count fell to 3,ti30,000 ant1 the hmn~tocrit to 38.0 J)cr cent. Thcrc: was no change in her conditirm after fire days of vi tnmin R therapy, 30 mg. of thiamin, 1.5 Gm. par:t-nrllinol,ellzoic~ acitl, 10 mg. riboflavin, 300 mg. niacin, 50 nrg. calcium p:intothen:i te, and 5 mg. pyritlosinr: hcing given daily. It was then considered advisable to begin intensive liver extract thornJ)y. There was little apparent improvcmcnt tluring the first month cswpt for regrowth of lingm~l p:~pill:w and rise in blood values. After tn-o months of liver therapy the patient’s strength and motor The hematologic values and the appearance of the tongue ability began to improve steadily. became normal ant1 remained so. At the end of twelve montlis of liver therapy she was able TTer mental con~lition im to do all ordinary activities at home with little motor handicap. Ncurologic examination co11tinuctl proved until she was about as I\-ell as bcfnrc her illnrss. to show 111~expected resi~lunls of posterior and lntcral column rliscnsr.~”
The Collowing two patients frrated with l’ter(Jplglllt~lllli~ distinct lillg~~;~l rcla.pses du&g the third mollth OF therapy factory ht~inatologic and ncnrologic rrsponses.
acid tlt~vclopl in sl)itc of sntis-
Y. D., U-33368. This 30.year-old, married, postal clerk was admitted to ~)ukc: JJospital on hpril ?ti, I%#. I’ive years previously she had (levelopecl :L “red and slick’ 7 tongue that despite vitamin H therapy became sore from time to time. She became chronically weak and nervous and worried intensely about minor incidents. She was afraid of “ losing her mind. ’ ’ Nine weeks before admission to the hospital her tongue became particularly sore. d few days later she found it difficult to control the movements of her feet. IIer legs began to feel stiff ami tight. IIer memory deteriorated and she bc~~une confused. F’or several days before her hospital admission, she was confined to bed by cxt.reme weakness. E:x:tmination showed a confused and apprehensiro young ~vonmn. She m:~de many mistakes in doing mental arithmetic. The tongue was scarlet in color, had no coat, and in the middorsum there were no visible papillae. She was unable to gc,t out of bed without as sistance and could not walk without suppport from both sides. The tendon reflexes in upper and low7 extremities were hypersrtive. The cutaneous senses were severely blunted below the knees. Thrrc \\a~ lmt little ataxia with the heel to shin test. The vibratory sense was absent l~low the wsl a1 margins. The plant nr reslmus~‘s wcrc flexor. ‘I’hrre was 7rlstairkml ankle rclonus more pronounce~l on the left sille. 7’110 hemoglobin was l2.0 grams Jwr 100 cc.; 1LFJ.C:. 3,300,000; \V.B.C., 8,730 ; l~emnto~ crit, 34 per cent; ant1 the average cell volume, 101 cul)ic micra. l~Zs:rminntiou of fhe bonc~ marrow shon-ed early evidence of megalol~lastic ccl1 dcvelopmen~ . acid was Starte(l under close 01,servntion. I:xpcriment~al therapy Ivith pterylglutamic During the first month the patient WBS given 100 mg. of the acid daily by mouth and for the next two months 50 mg. daily. The red cell count row to 4,100,OOO during the first month
Early in the third month of pteroylglutamic acid therapy she complained of soreness and redness of the tongue lasting two or three days. Two weeks later these symptoms became persistent and she felt generally worse. I’:saminnt,ion showc~l a beefy red tongue without coai, completely devoid of papillae except in one sm:~ll patch near the tip (ll’ig. 2, J). There xv:ls no evidence of neurolopic relapse and the l~lou~l values rcimained normal. The pteroylglutamic acill therapy \\:is tl iscontinucd and 0.050 nlg. of vitamin 13,? was gjven intramuswl:lrlv “. The redness ant1 soreness of the tongue subsided within a week. On a checkup esaminat~ion twwty clays after the injection the tongue KM pink in color, lightly caoatetl, an11 covwed with filiform papillae of normal height (Fig. 3. I: 1. The neurolopic starus sllowed no olldcctive rahangcs. M. J., 33597. This 55.year-old farmer’s widow V:IS :~dmittetl to I)ukc Hospital on April 11, 19-M. Two years previously she had develop4 a periodically sore tongue, lost her desire to eat,, and had begun to lose weight. Tier hands and feet became numb. She was cow tined to bell for several wvtcks by extreme weakness, but improved after injections were given by her family physician. Home months later she began to have progressive ditticulty in walking, with gross unsteadiness. Two months before her hospital admission, she became rapidly worse and was confined to bed, unable to stand or !vulk. Her family physician g:L\e her oral medications and injections for pellxgr:~ without. Iwnefit. On c%~mination the patient was a thin, Veak, apathetic womau appearing chronically ill. The tongue was pale and completely devoid of papillae. She WLS able to sit up in bed without assistance but was too weak to get out of bed, stand, or \wlk. The superficial sensations DXI’C impaired below the elbows and knees. The scnsc UC motion and position was poor in the lower extremities. The vibratory sense was impaired over the lowr ribs and absent at the pelvis and below. The plantar reflexes were extensor. On admission to the hospital the hemoglobin was 6.X gmms par 160 IX:.; R.B.C., 1,750,000; W.B.C., 2,360; hematocrit, 19.5 per cent; average ccl1 volume, 112 cubic micra; and ret,iculocytcs, 5.1) per cent. During the first ten days in the hospital an imxmplete, apparently spontaneous remission in the anemia occurred. There was no improvement, however, in the appearance of the tongue. dftcr ten days of observation, the administration of pteroylglutamic acid was begun in a dose of 50 mg. per day by month. 21 secondary reticulocytosis occurred. One week after the start of pteroylglut:~mic acitl t,hcrapy, beginning regeneration of lingual papillae was evident. After eighteeu days of therapy the papillae were of normal height. I3y this time the pat.ient had gained strength ant1 \vas able to sit up three to four hours a day as ~11 as walk about the ward holding to furniture. After four weeks of anti3-ftw six w&s the dose of pteroylanemic thc7apy t,he blood values were entirely normal. glutamic: :wi,t was retluce~l lo 30 mg. daily and she returned honw. Grneral improvement contillued. On :t ~llecli-up examiuntion two months afwr the beginning of pteroylglutamic w-id therapy, howrvcr, the tongue was observed to be reddened at the tip. The papillae remained tall. Five weeks late- she complained of a sore, ’ ‘scalded ” tongue. Examination showetl it to be scarlet red in color xnd entirely smooth (Fig. 2, C). Tier di(lt:wy habits were reinvestigat,etl and it appeared that her food hat1 betw well selected The l)lno(l wluw remainetl nurm:~l and average in nutritional atlcquacy. ill1 ii :rhrc n~~urologi(* examination showed continued improvement, certainly no relapse. Al this time the pteroylglutamic acid administration was stopped aod 0.025 rug. of The lingual sorcn~~ss promptly sul)sidedt and after vilamin l(,, ~1s injected intramuscularly. one wxk the color of the tongue KM grayish-pink ant1 the dorsum ~vas covered Isith a uniShe lwliered that her strength and (Fig. 2, D). form crop of budding filiform papillae motor ability had improved.
The following patient was one of five showin g the lingual nlanifestxtions of untreated pernicious anemia in whom the injection of vitamin BlzzO in a close of 0.001 mg. daily to 0.010 mg. in a single close led to regeneration of lingual papi1la.e in 5-7 days.
b’ig. 3.--d 11’. S., C-6035. Dusky 1~x1 tongue lacking papillae in a patient with untrPatcd pernicious anen&. B Repeat photograph five days after tlic injection of 0.010 R~C. of vitxmin of papillae. BU showing regeneration On examination the tongue W:LY deeply furrowed~ completely lacking in c’ua~. flusky wd devoid uf papillae (Fig. 3, A). His grip IV:LS estremc~ly \vcak. in color, and completely Tendon reflexes in the upper extremities were absent. The superficial sensations I\ ere I,luntcd about the hands auci forearms an11 the vibratory sense \V:LS imp:tirctl below the wrists and at the ankles. The hemoglobin was 12.X grwns per 100 C.C.; R.B.C., 3,400,OOO; \V.H.(!.J li,ziOO; I’&xmiit:tticm cut’ the hematocrit, 35 per cent; and avcragc cell volume, 103 cubic micra. boue marrow showed early megalubl:~st ic Jcvelopmcnt. lie was given 0.010 mg. of vitamin I& intramuscularly. 1~~s uurm:tl in color and its dorsum \\:ts c~orrrctrl with medium I$) in spite of his continuing to V~PU lob:~c~
Five clays latw the tongue* tall filiform papillae (Fig. 3,
Discussion Periodic atrophy and inflammation of the lingual mucosa, so vividly deas often the first sy11pt0111 oi scribed nearly fifty years ago by 1lunteP pernicious anemia, has become a well-recognized clinical manifestation of the disease. Significant abnormalities of the lingual mucosa arc seen, with or wit,hout hematologic or neurologic manit’estations, in about one-third of present-day patients with pernicious anemia in relapse. Mucosal changes of similar appearance may result, of course, from the lack of common vitamin B components in
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diet,‘G from iron deficiency,” in association with serious hepatic discaw or abdominal ncoplasms, from use of oral pcnicilliir,~‘~ ‘:) etc. Among the benefits of a diet rich in liver ill the trcatmtnt OF lwrnicious anemia! Minot and M~rphy’~ obscrvctd a gradual return of Ilorma.1 lingual mucosa in a matter of a few weeks or nionths. 1Yith potent liwr cxlrntl or hog stomach therapy a niore rapid lingual response occu13. F‘ilifo~m papilliw sprout from smooth tongues in fire to seven da)-s ant1 attain a norn~al height iTi two to three weeks. Relapses do not occur with adecluate maintenance therap!-. The lingual abnormalities of pernicious anemia are liot affected l)\- ~wtrqwcific therapy, the administration of the coJJmJon vitamin I3 components.” rxf~. ‘l’hc lingual response may serve accordingly as a useful and relii~ble thcrapt~utic twt for pernicious anemia in patients who have little or ii0 anemia or iti whoIll tllr cause of lingual or neurolopic disease is in doubt. the
In the therapeutic evaluation of lIteroSlglutamic acid in pcrnicions anctnia most attention has been given to the hcmatologic an{1 neurologic aspcct,s. 11 few investigators have noted lwor lingual responses at ihe IJegiJJJJing of tlJcr:~p?; and relapses later during maintenancc.‘l, I312il 2S The frequency of this ocww rcnce is uncertain. It appears to be especially common in the patients rc~lwrtcd who developed neurologic relapses. 111 0111’ six p:JtiPllk whose ~iIl~ll~l~ tWpoJJsc~S were poor or who later relapsed, the blood levels remaint4 below normal :lJrtl neurologic disease progressed in one, and the reel cell count fell signific%ntly iI1 alJotllcr. Had the ptero>-lglntamic acid therapy beet] continued lotlger in these paCents. a higher incidence of hcnratologic :1~1(111olwologic failures ttrizht \v(lll have been observctl. The regeneration of lingual mucosa followin g the injection of vitaniiu El3 after relapse has occurred during pteroplglntamic acid therapy shows that the former substance has a nutritional value lacking ill the latter. The l~romptness of the response, equal to that obserred in patients with untwatrd pernicious anemia. suggests that the pteroylglutamic~ acid failed to corrwt an existing dcficiencp rather than having exerted a positively harmful effect.‘, ‘I. ?I The effect, of vitamin IS,, in correcting this type of lingual relapse appears lo IV equal to that expected from liver extract, as preliminary rrporis intliwte it, to he in other respects.‘, 2:x23.?6 2g Whether or not the different, manifestations of pernicious anemia-arrest in hemopoiesis, atrophy and inflammation of the lingual mucosa, ant1 disease of the peripheral and central nervous system-represent one or more closcl,v related nutritional deficiencies has been a perennial question.1, *, 21 ~I;:aclt of these manifestations is dissociated from the others and may occur singly or in rombination as the disease first appears or relapses. Potent liver extracts. however refined or fractionated, and hog stomach preparations affect all aspects The impression has arisen that ptcroylof pernicious anemia in parallel. glutamic acid corrects one portion of the basic deficiency, having nn entirely satisfactory hematologic effect but being entirely ineffective regnr(linp the hemniologie Jwnissions, neurologic nianifestntions.14~ “9 24,3” The incomplete
1. The lingual manifesl,at,ions of pernicious anemia. in relapse may respon(i well or poorly to synthetic pteroylglutamic acid. 2. Two patients taking 20 and 50 mg. of pteroylglutamic avid daily tlevelopetl in the third month of thcral))- achutely sore tongues will1 m~~cos:~l atrophy. The lingual abnorninlities tlis;rpptwrccl within five to seven days after the injection of vitamin 1:,2. 3. The lingual mucosal atrophy of five 1)atient.s with urrtrtatrtl pfxrtlicions anemia responded in five to seven days lo injections of vitamin I:,,. 4. The therapeutic limitations of pteroylglutxmic a&l in pernicious anemia relate to all manifestnt,ions of the clisens+ -anemic.. neurologic, and lingual-rather than to merely ihc neurolo~ic~. References 1. Berk,
Lionel, Denny-Brown, I)erek, Finland, Maxwell, and Castle, William B.: Efl’ectiveness of Vitamin B,? in i’ornhined System J)isease: New England ,J. Med. 239: 328, 1948. of Therapy in Perniciou!: Anemia to 2. Bethell, F. H, and Sturgis, C. C.: The Relation Changes In the Nervous System, Blood 3: 57, 194s. Glossodvnia and ISxfolistion of Pauillae Filaments After Oral Adminix3. Brown. R. L.: tiation of Penicillh, Arch. Otolaryng. 45: 355;1947. A Survey of the Treatment of Pernicious Anemia in Relapse: (a) -1. Clark, Guy W.: A Comparison of the Hematopoietic Response to Liver Extract and Folic Acid I,-Casei Factor). (1~) Limitations of the Reticulocyte Response as a Measure of Anti-Pernicious iinemia Potency, Am. J. M. SC. 216: 71, 1948. Folic Arid, Pernicious Anemia and Pend~~lums, Blood Editorial: ,5 Dameshek, William: 3: 699, 1948. of Iron Deficiency, 5. A. &I. .4. 130: 830, J.: The Oral Manifestations 6. Darby, William 1946.
L. S. P., and Gird\\oo(l, 11. H.: ‘1’1~ Tmbnlancc of XTitmnins, 1,:tnc’et 1: 360, 7. Davidson, 1948. an I
anemic Prouerties
1: $27,
104%
of Vitamin
Ii,,. South. 1\I. .i. 41: 532. 1948.