Myasthenia Gravis with a Myeloma-Type,Gamma-G (IgG)

Immunoglobulin Abnormality*LEWIS P. ROWLAND, M .D .,t ELLIOTT F. OSSERMAN, M .D .,t WILLIAM B . SCHARFMAN, M.D . .

RICHARD F. BALSAM, M.D . and STANLEY BALL, M .D .

New York, New York

A patient with myasthenia gravis improved after thymectomy but subsequentlysuffered a severe relapse . A serum globulin of the myeloma type was present andbecause of this evidence of a plasma cell dyscrasia the patient was treated withmelphalan when the myasthenia became life-threatening. An essentially com-plete remission of myasthenia followed, but this was not associated with a signifi-cant change in the serum concentration of the M-protein . Depression of the bonemarrow developed and persisted after administration of melphalan was discon-tinued. Numerous blood transfusions were required, and the patient ultimatelydied of hepatitis and lung abscess. Whether therapy with melphalan was actuallyresponsible for the remission of myasthenia is uncertain, but the association withan M-protein adds to the growing list of immunologic abnormalities in patientswith myasthenia gravis .

S ERUM PROTEIN abnormalities are rare in un-

CASE REPORTcomplicated myasthenia [1,2], although by- In January 1964 a fifty-four year old college pro-

pergammaglobulinemia [3] and hypogamma- fessor was making a radio broadcast when lie be-globulinemia [4] are occasionally found. The came aware of dysarthria. A few days later he hadpresent report concerns a patient with myas- ptosis of the right eyelid and diplopia . Subse-thenia and an M-type (myeloma) gamma-G quently lie had difficulty chewing, and there was(IgG) protein in the serum, an association suf- weakness of the arms and neck. Symptoms tendedficiently rare to warrant documentation . Be- to be more severe late in the day and varied from

cause the protein abnormality was considered day to day. In April his condition improved after

to be possibly related to the ntyasthenie syn- starting a regimen consisting of intramuscularly

drome, therapy with melphalan (L-phenyl- administered neostigmine and pyridostigmine, 120

alanine mustard) was instituted and was fol-

mg. orally every three hours. Despite this medica-tion, however, his symptoms persisted, and he was

lowed by a remission of myasthenic symptoms ; admitted to the Neuroiogical Institute on May 24,whether this treatment was responsible for the

1964.symptomatic improvement is problematic for

General examination revealed no abnormalities;reasons which will be explained .

there were no signs of thyrotoxicosis, no ade-

From the Neurological Research Center, Neurological Institute ; the Francis Delafield Hospital, Columbia-Presbyterian Medical Center ; the Departments of Neurology and Medicine, College of Physicians and Surgeons,Columbia University, New York, New York ; and the Departments of Medicine and Neurology, Albany Medical Col-lege of Union University, Albany, New York . This study was supported by Grants B-3359 and B-4613 from the Na-tional Institute of Neurological Diseases and Blindness, a grant from the Myasthenia Gravis Foundation and GrantCA-02332 from the National Cancer Institute . Requests for reprints should be addressed to Lewis P. Rowland, M.D.Manuscript received April 9, 1968 .

t Present address : Department of Neurology, Hospital of the University of Pennsylvania, 3400 Spruce Street,Philadelphia, Pennsylvania 19104 .

I Faculty Research Associate of the American Cancer Society .

vol . . 46, APRIL 1969

599

600 Myasthenia Gravis with Myeloma-l'ype Protein-Rosaland et al.

N«mol Serum

Y2

9

-2Y1

H . H . serum

rl

r2

02Alb .

FIG. 1 . Cellulose acetate electrophoretie analyses ofnormal serum and the patient's serum on September28, 1964 . The patient's serum shows an abnormal, elec-trophoretically homogeneous protein of fast gammamobility and a decrease in normal gamma globulin .

nopathy and no palpable hepatic or splenic enlarge-ment. There was slight ptosis of the left eyelid andslight symmetric weakness of horizontal eye move-ments. There was weakness of upper and lowerfacial muscles. Speech was dysarthric, and the pa-tient supported his jaw manually while talking .There was slight cervical weakness and prominentweakness of the deltoid muscles, but other limbmuscles were normal. Myotatic reflexes and sensa-tion were normal .

The following laboratory studies were normal :hemoglobin, hematocrit, white blood cell count,erythrocyte sedimentation rate, urinalysis, bloodsugar and urea nitrogen, serologic test for syphilis,latex fixation test for rheumatoid factor, Coombs'test, heterophil antibodies, antinuclear antibodies,thyroglobulin antibodies, immunofluoreseence testfor muscle antibodies (performed by Dr . A. J. L .Strauss), bone marrow (slight erythroid hyperpla-sia), muscle biopsy and electrocardiogram .

Quite unexpectedly, routine serum protein elec-trophoresis (Fig. 1) demonstrated an abnormal,electrophoretically homogeneous peak of fastgamma(,/,) mobility, comprising 1 .5 gm. per 100ml. The serum total protein was normal (7 .4 gm .per 100 ml .) . In addition to the abnormal M-typeconstituent, the serum pattern also demonstrateda decrease in normal gamma (y,) globulin. By im-munoelectrophoretic analyses (Fig . 2), the M-typeglobulin was identified as a 7S IgG globulin withtype I . (II) light chains. Quantitation of the serumimmunoglobulins by the Immunoplate® method(Hyland Laboratories, Los Angeles) confirmed anincrease in total IgG and a decrease in IgA andIgM (Table I) .

In plain lateral roentgenograms, 10 degreeoblique films and lateral laminagrams, a soft tissuemass was overlying the pulmonary artery ; it mea-sured 5 cm . in vertical dimension, 6 cm . antero-posteriorly, and it was 2 cm . thick (Fig . 3) .At the time of admission the patient was given

edrophonium (Tensilon®) intravenously ; after 5mg. there was slight improvement of speech andptosis but no effect on deltoid strength ; after 10tog. all symptoms were worse . These results werecompatible with myasthenia gravis affected by treat-ment with cholinergic drugs. Because of the ab-normality seen on chest roentgenogram, a thorn .cotomy was performed by Dr . Robert Wylie onJune 10, 1964 . A thickened substernal fat padaccounted for the roentgenographic appearance,but there was no thymoma . The thymus itself wasfatty and was totally removed . Sections of the thy-mus were reviewed by Dr. R. Lattes . The thymushad been generally replaced by adipose tissue withonly a few microscopic islands of thymus remain-ing. These, however, showed characteristic Hassal'scorpuscles . In addition, there were scattered lym-phoid follicles in the adipose tissue,At operation a tracheostomy was performed .

Respiration was maintained postoperatively by in-termittent positive pressure, with no cholinergicmedication, for seventy-two hours . Pyridostigminetherapy was resumed on June 13, and the patient'scondition improved continuously . At the time ofdischarge on July 4 he was able to eat a full diet(not possible previously), could read without an eyepatch, did not have to support his jaw while talk-ing and was less dysarthric; his deltoid musclestrength was normal . The only residual manifesta-tions of myasthenia were slight limitation of lateraleye movements and weakness of eye closure ; hewas taking pyridostigmine. 120 nrg . every fourhours .

The improvement persisted throughout the sum-mer, but at the end of August all the originalsymptoms recurred and became more severe despitean increase in the pyridostigmine dose to 180 mg.every three hours . The patient was readmitted on

AMERICAN JOURNAL OE MEDICINE

15 10 5 58relel

cmm.% 1 .2 .3 .8 .6 7 .6

T rolul

%

11 30 12 12 ProteinOmm .%

.6 7.4

September 25 with bilateral ptosis, overt weaknessof medial and lateral recti, weakness of all facialmuscles, severe dysarthria and jaw weakness, weak-ness of the deltoid muscles and diffuse weaknessthroughout the arms, with slight weakness of thepsoas muscles as well . Once again routine labora-tory studies were normal, including hemoglobin,hematocrit, erythrocyte sedimentation rate, uri-

VO1. . 46, APRIL 196 9

Myasthenia Gravis with Myeloula=l vpe Protein-Row/and et a/,

Fu : . 2. IDURUDOelectrophoretic analysis of normal serum and the patient'sserum demonstrating the M-type IgG globulin abominably . I he precipitationof this protein by the antiserum to the Fe and Fal) fragments of IgG globulinand by the anti -type L antiserum establishes its identity as a complete 1g$globulin with type l, light chains, Alb . . albumin : '1' Ii r'ansferriu .

TABLE ISERUM PROTEINS IN PATIENT WITH M3'ASTHENIA GRAVIS AND M-TYPE MVELOMA PROTEIN

601

naly'sis, blood nrea nitrogen, electrocardiogram,roentgenograms of skull, spine and pelvis, antinu-clear antibodies, skin tests with tuberculin (inter-mediate strength) and mumps antigen . The serumprotein pattern again demonstrated the abnormalR-r-type peak which was quantitatively unchangedfrom the original analysis . Electrodiagnostic studieswere performed by Dr . R . E . l .ovelace ; conduction

1964 1965

Uau . Normal 6/10 9/28 12,:13 1/25 4/6 7/8 9/24 10/29

1 1 28

Strum protein dectrophc.resis (gm./ 100 00 .)Total 6 .5-8 .2 7 .4 74 80 8 .4 8 .1 80 7 .6 7 .8

Albumin 3 .5-4 .8 3 .5 18 3 .7 4 4 4 .6 4 .1 4 .5 37 LO 0Alpha, 0 .2-0 .4 0 .4 0 .4 0 .3 0 .4 0 .3 02 0,3 (L2 0 .4 X1 .3Alpha, 0 .5-0 .9 0 .8 0 .8 0 .6 0 .6 0 .8 0 .8 0 .7 0 6 09 0 .9Be, . 0 .7-1 .2 0 .4 0 .6 0 .6 0 .7 0.6 0 .8 0 .5 0 .7 0 .7 0 .7M-type + gamma, 0 0 .3 1 .6 12 1 5 1 .4 1 .5 1 .8 1 .5 1 .'2 4SGamma, 0 .9-1 9 0 .7 0 .6 06 06 0 .5 0 7 0 .s 09

Serum immunnglobulins*(% normal adult)

igG (including M.protein) 270 153 170 200 230 161 176 140tgA 48 45 48 48 41 32 26 26IgM 36 57 41 29 21 17 32 40

602 Myasthenia Gravis with Myeloma-Type Protein-lowland et al .

velocity was normal in motor nerves . The ampli-tude of evoked potentials fell rapidly after stim-ulation of the median nerve at 2 per second ; therewas increased insertional activity with sharp, re-ducedduration, rapidly firing potentials on voli-tional contraction . The findings were compatiblewith a myasthenic defect, with some myopathicfeatures as well . Chest roentgenograms again re-vealed a globular density in the anterior mediasti-num similar in shape and position to the massseen prior to operation. Pyridostigmine dosage wasincreased with no definite benefit, and the patientwas discharged on October 6. During the nextmonth the daily dose of pyridostigmine was grad-ually increased to 1,800 mg . a, the weakness be-came more severe .

On November 10, 1964, the patient was admittedto the Albany Medical Center Hospital in markeddistress. There was bilateral ptosis, virtually com-plete ophthalmoplegia, oropharyngeal weaknessand weakness of all limbs . Because of his desperatecondition and the possible relationship betweenthe immunoglobulin abnormality and the myasthe-nia, a trial of melphalan (L-phenylalanine mus-tard, Alkeran®) was started on November 12 . Ini-tially he was given 10 mg . daily for seven days ;forty-eight hours after starting this therapy therewas distinct diminution in myasthenic symptoms .In the ensuing weeks there was progressive im-provement in the patient's condition . The dailypyridostigmine dosage was reduced gradually from1,800 mg. to 400 mg. by April. Six weeks after thefirst course of melphalan, the white blood cellcount was 3,600 per cu . Turn ., and continuous main-tenance therapy with 2 mg. daily was institutedon January 3, 1965 . This therapy was well toler-ated for the next seven months during which timeth^ hemoglobin levels were normal, and the whiteblood cell counts remained in the range of 3,500to 4,500 cu . mm. The patient was essentially asymp-tomatic and resumed a full teaching schedule . Hetook 20 mg. pyridostigmine daily .

In August 1965 his hemoglobin was rioted tohave decreased from the prior 13 to 14 gm . per100 nil. range to 11 .2 gm . per 100 ml., although thewhite blood cell Count remained in the range of4,000 per cu. men. In the next two months thehemoglobin level fell progressively to 7 .5 gm. per100 ml., but the white blood cell count was still4,000 per cu . mm. Headaches, dyspnea and palpi-tations developed, apparently related to anemia,but the patient remained essentially free of my-asthenic symptoms ; pyridostigmine therapy wasdiscontinued .

Because of the progressive hematologic abnor-mality, the patient returned to the NeurologicalInstitute on November 7, 1965 . He was pale andthere was a small ecchymosis in the left inguinalregion. There was no palpable adenopathy orsplenomegaly . The liver edge was felt 2 cm . below

Fn: . 3 . The mediastinal mass indicated by ar-rows in anterior (A), lateral (B) and oblique (C)views had the appearance of thymoma . It provedto be an unusual fat pad and there was no evi-dence of thymoma when the mediastinum wasexplored or subsequently at autopsy. Photographscourtesy of Dr . Kent Ellis.

AMERICAN JOORNAI. Of' MEDICINE

tht costal margin ; neurologic examination wascompletely normal . The hemoglobin concentrationwa s 6.5 gin . per 100 ml . ; hematocrit, 18 per cent ;reel blood cell count 2.0 million per cu . mm .; whiteblood cells 2,350 per cat mm . (neutrophils 56 per(e«, lymphocytes 11 per cent, monocytes 3 per(ent) : platelets 86,000 per cu . mm . ; serum directbilirubin 0.48 mg. per 100 ml . ; indirect bilirubin0 .10 mg. per nil . ; Coombs' test negative. Bone mat-row aspirate showed a marked diminution inervthropoicsis and only rare megakaryocytes . Chestroentgenograms again demonstrated the anteriormediastinal mass .

In view of the peripheral blood and bone mar-row patterns, it was presumed that the pancyto-penia was related to the melphalan therapy, andaccordingly administration of the drug was discon-tinued on November 10 . The patient's progresswas subsequently followed at the Albany MedicalCenter Hospital .

Despite discontinuation of melphalan therapy,there was progressively severe anemia and throm-bocytopenia although the white blood cell countrose during the next several weeks to the rangeof 5,000 per cu, mnl ., with a normal differentialcount. A total of twenty-five transfusions of wholeblood was required between November 1965 and_little 1966 . Prednisone, 20 rig. daily, and testosterone enanthate, 600 mg. intramuscularly weekly,were given in an attempt to improve his hema-tologic status . 'Throughout this period there wereno invasthenic symptoms and no further pyridostig-mine was given .

On June 18, 1966, the patient was readmitted tothe Albany Medical Center because of fatigue,low grade fever, anorexia and icterus. He had alsonoted dark urine and light stools during the pre-ceding week . 'There was scattered purpura and hewas deeply icteric The liver edge was palpable 4cin. below the costal margin but the spleen wasriot palpable . Neurologic examination was nor-mal. Laboratory studies showed a hemoglobin of143 gm. per 100 ml .; the hematocrit was 31 perwrit; white blood cell count 6,470 per cu . rum .,with a normal differential ; platelets 259,000 perc it . mm.; serum total bilirubin 6 .4 mg. per 100 ml .(direct, 4 .4 mg. per 100 ml .) ; thymol turbidity 7 .9units : alkaline phosphatase 9.5 Bessey-Lowry units ;glutamic oxalacetic transaminase (COl) 520 units ;glutamic pyruvic transaminase (GPT) 95 units ;test for acid heniolysis, negative ; serum iron . 540pg. per 100 ml .; total iron-binding capacity, 540pg. per 100 ml . A bone marrow aspirate again dem-onstrated a marked decrease in erythropoiesis withscattered plasma cells and lymphocytes. The granu-locytic and megakaryocytic series showed normalmaturation . Skeletal roentgenograms did not re-seal any abnormalities .

it was presumed that serum hepatitis, secondarym multiple transfusions, was responsible for the

,ot . . 46, avan. 1969

Myasthenia Gravis with Myeloma-Type Protein --Rowland el al-

o(13

clinical and laboratory abnormalities, and the pa-tient was treated with bedrest . In mid-Jitly he be-came progressively more febrile and a cough de-veloped productive of large quantities of purulentsputwu- A chest roentgenogram disclosed a densityin the tight mid-lung field with an air-fluid level ;sputum culture revealed Streptococcus fecal is andcoliform organisms. 'the hemoglobin was 8.6 gnu .per 100 nil . ; hematocrit 26 per cent ; white bloodcell count 4 .150 per cu. mm . ; platelets ..,03,000 percu. mm .; blood glucose 346 mg . per 100 nil .; bloodurea nitrogen 21 mg . per 100 ml . ; serum totalbilirubin 2.4 mg- per 100 ml . ; direct 1 .5 tug . per1011 ml . ; alkaline phosphatase 8 to 9 Bessey-Lowryunits; GOT 93 units ; GPT 249 units and lacticdehydrogenase 520 units. Despite vigorous treat-ment with antibiotics, blood transfusions, predni-sone and insulin . the patient died on August. 27,466,At postmortem examination both arms showed

multiple ecchymoses . There were serous effusionsof 500 nil . in the right pleural cavity and 750 ml .in the left . The lungs weighed 1,100 gm. andshowed congestion and edema . There was a largeabscess measuring 9 by 6 cm, in the upper lobe ofthe right lung and an organizing infarct 3 by 1 .5cm . in the lower lobe of die right lung. There wasno tumor mass in the anterior mediastinutn . Asmall remnant of fibrotic tissue with areas of hem-orrhage was present- 1 - 11C peritoneal cavity con-tained 1 .200 ml. of serous fluid . The liver weighed900 gin . and showed moderate atrophy and (lark,red brown, patchy necrosis scattered on cut sur-faces, particularly in the lobe of the right lung .Sultiple small nail owl erosions were present inthe stomach . The pancreas was the site of fat ne-crosis . The bone marrow appeared grossly normal.

On microscopic examination, the liver sectionsshowed massive necrosis of the hepatic cells, pro-liferation of bile ducts, infiltration in portal areaswith lvniphocvtes and brown piginentatiun of manyhepatic cells and Kupffer cells. There was somefibrosis extending between the portal triads . Thepancreas showed marked autolvsis with extensivebrown pigmentation. Prussian-blue stain for ironwas positive in the liver and pancreas . The bonemarrow sections were normally cellular, Abundanterythroevtic, granulocytic and megakaryocytic pro-duction was present . The spleen and lymph nodesappeared to be normal .

In summary, the postmortem findings indicateddeath from extensive hepatic cellular destruction,complicated by lung abscess. The normal marrowfindings were evidence of recovery of ervthro-poictic function .

COMMENTS

There is increasing evidence that immuno-logic abnormalities occur in patients with my-

604

Myasthenia Gravis with Myeloma-Type Protein-Rowland et al.

asthenia gravis . The thymus gland, now knownto play a role in the development of immunecapacity, is frequently the site of tumor inmyasthenia and germinal centers are oftenpresent when there is no tumor [5] . Improve-ment of myasthenia frequently follows thy-mectotny [6] . In addition, antibodies to musclehave been demonstrated in about 30 per centof myasthenic patients by the immunofluores-cent technic [7], hemagglutination [81 andgel diffusion [9] . These antibodies are presentin almost all patients with myasthenia andthymoma [7,10] but are less common in pa-tients with no tumor . Other circulating anti-bodies (e .g ., antinuclear factor, thyroglobulinantibodies) have been found in myasthenic pa-tients [11-13] . In one study [13,14] there wasa tendency for myasthenic subjects to havediminished capacity for delayed hypersensi-tivity, but this was not true in another study[15] . In exceptional patients with myasthenia,impaired immunologic mechanisms may resultin chronic infection [16] .

In the patient reported herein myastheniagravis was associated with a plasma cell dys-crasia manifest by an abnormal M-type serumgamma globulin and a decrease in normalgamma globulin [17] . This coincidence hasnot been reported previously although Ander-son and Vye [18] described a case in whichplasma cell dyscrasia with an M-type IgG se-rum globulin abnormality was associated withthymoma, but no myasthenia gravis .

Throughout the course of the illness in thepresent patient there was no evidence of skele-tal destruction consistent with multiple my-eloma. The myasthenia initially subsided afterthymectomy, then relapsed and became life-threatening. At that time treatment with mel-phalan (L-phenylalanine mustard) was initi-ated because of the possibility that there mightbe some connection between the abnormal M-type globulin and the myasthenia . Withinforty-eight hours there was unequivocal im-provement in the patient's condition ; essen-tially complete remission of the myastheniaensued within a few weeks and was sustainedfor twenty months until the patient died .

For the first nine months following institu-tion of ntelphalan therapy there was moderateleukopenia but no anemia or thrombocytope-nia. Thereafter there was a profound sup-pression of erythropoiesis, unassociated with acomparable decrease in leukopoiesis . This fail-

arc of erythropoiesis persisted even after theadministration of ntelphalan was discontinued .Although it is impossible to exclude a directrelationship between the drug and the hema-tologic failure, this type of reaction has notbeen observed in a series of more than fiftycases of various kinds of plasma cell dyscrasiatreated with melphalan at the Francis Dela-field Hospital. The possibilities that the fail-tire of erythropoiesis might be associated withthymoma [19] or marrow invasion by mye-loma [ 17] were excluded by autopsy.Although the temporal relationship was

highly suggestive, there is no proof that theremarkable remission of myasthenia was ac-tually due to therapy with ntelphalan . Therapidity of symptomatic improvement in thiscase (within forty-eight hours) is difficult to ex-plain since objective evidence of improvementin myeloma (decrease in M-proteins, hema-tologic improvement) is usually not demon-strable for two to four weeks . As shown inTable t, significant concentrations of the ab-normal M-protein persisted in the serum ofthis patient even during the period of majormyasthenic remission, and myasthenia did notrecur after melphalan therapy was discon-tinued. The apparent decline of serum IgG,as determined by the Immunoplate® method,is difficult to interpret because both the M-protein and normal IgG are included in thisanalysis and also because the patient receivedmany blood transfusions during the terminalphase of his illness .It has been suggested that myasthenia may

be an autoimmune disease [20], but theevidence at present is that antimuscle anti-bodies bind primarily to A or I bands ratherthan to the neuromuscular junction [21,22] .and this is inconsistent with physiologic dataindicating an abnormality of neuromusculartransmission [23] . Furthermore, antibodies arenot always present in symptomatic cases and .when present, there is no consistent relation-ship between the titer of muscle antibodies andthe severity of symptoms [22,24] . There is nocon-elation between the presence of muscleantibodies in mother or infant in cases ofneonatal myasthenia [25] . In a detailed studyby Strauss and associates [7] the presence ofantimuscle antibodies was quite specific formyasthenia since they were not detected in theserum of patients with neuromuscular diseasesother than myasthenia or in cases of multiple

AMERICANJOURN .A L OF MEDICINE

in' elonla or other plasma cell dyscrasias . How-ever. muscle antibodies have been found insolve patients with thymoma but no evidenceof myasthenia [h] .

Chore have been no extensive trials of im-mnnosuppressive therapy in myasthenia, but

we have treated four patients with 6-mercap-topurine 12] : in three there was no effect onthe wvasthenia and in the remaining one therewas a fatal exacerbation of myasthenia at a

time wh'n the marrow was maximally de-pressed. Recent reports on the benefit ofACTH therapy in severe myasthenia, how-ever, have again raised the question that

irnmunosuppression may be of therapeuticvalue [26-28] .

REFERENCES

I. KoRNFE1D, P . Serum proteins in myasthenia gravis .J.A .M.A . . 190 : 463, 1964 .

2 . WOLF. S. M ., ROWLAND, L. P., SCHOTLAND, L ., Me.KINNFY, A . S ., HOEFER, P. F. A. and ARANOW, H .,JR. Myasthenia as an autoimmune disease. Clinicalaspects. Ann. New York Acad . Sc., 135 : 517, 1966.

3. OOSTERHPIS, H . 1 . G. H., VAN DER GELD, H ., FELT-KAMP. T . E. W. and PEETOM, F. Myasthenia graviswith hypergammaglobulinemia and antibodies. J .Neural . Neurosurg. & Psychiat, 27 : 345, 1964 .

4 . TE VPrDE . K., BARER, J. and VAN DER SLIKKE, L . B .Primary acquired hypogammaglobulinemia, my-asthenia and thymoma . Arm. In!. Med ., 65 : 554,1966-

1 . PFRLO . V., SCHWAB, R. S. and CAST[FMAN, B .Myasthenia gravis and thymoma . In : The RemoteEffects of Cancer on the Nervous System, p . 55 .Edited by Lord Brain and Norris, F. H ., Jr . NewYork . 1965 . Grune & Stratton, Inc.

6 . PFRLO. V .. POSKANZER, D . C., SCHWAB, R . S ., VIETS,H, R . . OssERMAN, K . E. and GENKINS, G. Myasthe-nia gravis. Evaluation of treatment in 1,355patients . Neurology, 16: 431, 1966 .

7 . STRAUSS, A . J . I . . . VAN DER GELD, H . W .R, KEMP,P. O. . 1R., Exum, E . O. and GOODMAN, H, C .Immunological concomitants of myasthenia gravis .Ann . New York Acad . Sc, 124 : 744, 1965 .

8. DJ.ANIAN, A . Y., BENTNER, E . H . and WITEBSKY, E .W. Tanned cell hemagglutination test for detec-tion of antibodies in sera of patients with myas-thenia gravis . 1 . Lab . & Clin . Med, 63: 60, 1964 .

9. RICRFN, 1) . Myasthenia gravis and humoral anti-bodies against human skeletal muscle proteins .Dent,rlre . rued. Wchnschr., 90: 1717, 1965 .

10. Smnrss. A . 1 . I . ., SMrr., C. W., CAGE, G . W, VAN PERGELD. H. W. R., MCFARLIN, D . E. and B.ARLOW,M. Further studies on the specificity of presumedimmune associations of myasthenia gravis andconsideration of possible pathogenic implications .Ann- New York Acad . Sc ., 13 .5 : ,557, 1966 .

I1 . VAN DER GELD, H. W. R., FELTKAMP, T. E. W, VANGOcHEM, 1 . 1 . . OOSTERHDIs, H, J. G. H. andBRIEMOND, A . Multiple antibody production inmyasthenia gravis. Lancet, 2 : 373, 1963 .

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Myasthenia Gravis with Myeloma=type Protein -Rorwland ei al .

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12. STI'RcILI ., B, C ., CARPENTER, R. R . . STRAOss, A . 1. L.and GOODMAN, FT . C. Antibodies in systemic lupuservthematosus and myasthenia gravis which reactwith thermally denatured DNA-coated bentonite.Proc . Soc . Exper . Rio!. '& Med ., 115 : 246 . 1.964.

13. ADNPR, M. M., SHERMAN, J. D-, 1SE, C., SCHWAS, R.S. and DAMESHEK, W. An immunologic survey of48 patients with myasthenia gratis . New EnglandJ . Med„ 271 : 1327, 1964 .

14 . ADNF :R, M . M ., IsE, C., SCHWAB, R ., SHERMAN, J . P .and DAMESHEK, W . Immunologic studies of thy-mectomized and nonthymectomized patients withmyasthenia gravis . Arm. New York Arad. 5'c., 135 :536, 1966.

15. KORNFELD, P . . SIECAL, S ., WEINER, L . B. and OssER .MAN, K. E. Studies in myasthenia gravis . Im .munologic response in thymectomized and non-thymcctomized patients . Ann. Int . Med, 63: 416,1965 .

16. RON'LAND, 1 . . P ., GRIFF'ITHS, C . and KARAT, E . A.Myasthenia gravis, thymoma and cryptocoecalmeningitis . New England J, Med., 273 : 620, 1965 .

17. OSSFRM .AN, E . F . Plasma cell dyscrasias, In : Cecil andLoch's Textbook of Medicine. 12th ed ., p . 1101 .Edited by Beeson . P. B . and McDermott, W,Philadelphia, 1967 . W. B. Saunders Co .

18. ANDERSON, E . T- and VYF, M. V. Dysproteinemia ofthe myeloma type associated with a thymoma .Ann, lot . Med., 66 : 142, 1967 .

19 . SCHMID, J. R., KIELY, J . M., HARRISON, E. G ., JR.,BASRD, E . D. and PEASE, P . L. Thymoma associ-ated with pure red cell agenesis. Review of litera-ture and report of 4 cases. Cancer, I8 : 216, 1965 .

20. SlsrrsoN, J. A. Myasthenia as an autoimmune dis-case . Clinical aspects . Ann. New York Aced . Sc,135 : 506 . 1966 .

21. McFARI .IN, D . E., ENGEL, W. K. and STRAUSS, A . J . L .Does myasthenia serum bind to the neuromuscu-lar junction? Ann. New York Acad . Sc ., 135 : 656,1966.

22. NASTUK, W . L., KESSLER, If . J ., GRYNBAUM, A .,SMITH, M. and HERRMANN, C ., JR. Immunologicalchanges following thymectomv in myastheniagravis . Arch . Neurol, 15 : 1, 1966 .

23. ELMgvIST, I) ., HOFMANN, W. W ., KUDELBERC, J . andf)FASIEL, 1), M, J . An electrophysiological investi-gation of neuromuscular transmission in myas-thenia gravis. J. Physiol., 174 : 417, 1964.

24. WEINER, L . B. and OSSERMAN, K. F.. Demonstrationof presence of immnnofluorescencc in scrums cor-related with clinical findings . Arm- New YorkAcad . Se ., 135 : 644 . 1966 .

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