arthritis in myastheniagravisserum contained antibodies of igg class to some...

Journal of Neurology, Neurosurgery, and Psychiatry, 1975, 38, 1048-1055

Arthritis in myasthenia gravisJ. A. AARLI1, E.-J. MILDE, AND S. THUNOLD

From the Departments of Neurology and Pathology, School of Medicine, University of Bergen,and the Rheumatic Disease Unit, The Deaconesses' Hospital, Bergen, Norway

SYNOPSIS Seven patients with myasthenia gravis developed clinical signs of arthropathy. In twopatients, the symptoms were due to a deforming rheumatoid arthritis and the myasthenic symptomsappeared as a transitory phase during the course of the disease. Muscle antibodies of IgG class weredemonstrated with sera from both patients. Autoreactivity between muscle antibodies and rheuma-toid factor was detected in one patient. Both patients died from sudden cardiac failure. Necropsywas performed in one and revealed a spotty myocardial necrosis. One patient had juvenile rheumatoidarthritis. Two patients had mild articular symptoms with indices of multivisceral disease and sero-logical findings indicating a systemic lupus erythematosus. One patient had classical ankylosingspondylitis, and one, unspecified arthropathy.

The concept of myasthenia gravis as a puredisorder of the neuromuscular transmission hasprobably been an obstacle to the full delineationof the clinical picture of this disease. Thus, care-ful clinical examination has revealed a series ofsigns and symptoms connected with myastheniagravis which cannot be attributed to the defect oftransmission of the neuromuscular junction(Simpson, 1960). Some patients with myastheniagravis develop arthritis, even to a disablingdegree. The occurrence of coincidental myas-thenia gravis and rheumatoid arthritis may indi-

I Address for correspondence: Dr Johan A. Aarli, Departmentof Neurology, 5016 Haukeland sykehus, Bergen, Norway.(Accepted 9 June 1975.)

cate a clinical overlap (Oosterhuis and de Haas,1968). The aim of the present paper is a re-appraisal of the relationship between myastheniagravis and arthritis. Seven patients are describedand the data compared with relevant literature.

METHODS

Patients were selected from among those treated atthe Department of Neurology for myasthenia gravis(MG). The numerals refer to corresponding nu-merals in earlier publications (Aarli and T0nder,1970; Aarli, 1970-1972b).The diagnosis of MG was based mainly upon the

criteria given by Schwab and Perlo (1966). Clinicaldata are presented in Table 1.

BLE 1

CLINICAL DATA IN SEVEN PATIENTS WITH MYASTIENIA GRAVIS (MG) AND ARTHROPATHY

Pctient Sex Age at onset Type ofMG* Age when first Type of arthropathy Other diseasesno. ofMG (yr) arthropathy appeared

(yr)1 CT 51 IIBA 60 Classical RA Cardiac insufficiency2 31 IIBA 17 Classical RA Cardiac insufficiency3 18 IIBA 17 Juvenile RA Iridocyclitis4 17 IIBA 37 Probable SLE Bell's palsy5 22 HA 23 Probable SLE6 CT 47 I 20 Ankylosing spondylitis -

7 V 34 IIA 36 Unspecified arthropathy -

* Classification according to Oosterhuis (1964).1048

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The diagnosis of rheumatoid arthritis (RA) and ofsystemic lupus erythematosus (SLE) followedcriteria given by the American Rheumatism Asso-ciation (1959).

SEROLOGICAL TESTS The antiglobulin consumptiontest (AGCT) for muscle antibodies was performed asdescribed earlier (Aarli and T0nder, 1970). When thetissue was treated with normal human serum, a smallconsumption of antiglobulin serum occurred (normalconsumption). A consumption four or more timesgreater than normal was designated 'pathologicalconsumption' (PC) (Aarli and T0nder, 1970).

Indirect haemagglutination test (IHA) for muscleantibodies was performed using tannic acid-treatedred cells sensitized with citric acid extract (CAantigen) of skeletal muscle (Aarli, 1972b).

Waaler's test for rheumatoid factor (RF) andabsorption of RF were performed as earlier (Aarli,1971b).

DIRECT IMMUNOFLUORESCENCE (IF) Quick frozenmyocardial tissue was stained as described previously(Thunold et al., 1973) with monospecific FITClabelled rabbit antisera against human albumin, IgA,IgG, IgM, fibrinogen, and /l3c/1A-globulin (C3)obtained from Behringwerke AG, Marburg Lahn,West Germany and against Clq (Thunold et al.,1970).

HISTOLOGY Myocardial tissue was fixed in 10%formalin and sections were stained with haema-toxylin and eosin, Elastin van Gieson, periodic acidSchiff (PAS), and Mallory's phosphotungstic acid(PTAH).

FIG. 1 Case 1. Male, aged 72years. Anteroposterior radio-graph of hands. There isnarrowing with subluxationsand ulnar deviation of theMCP joints. Erosive lesions inthe metacarpal heads. Slightnarrowing of the PIP jointsand a few erosive lesions.

CASE REPORTS

Myastheliia gravis and classical rheumatoid arthritisCASE 1 (MG-3) A male patient, born in 1903, hadno family history of neurological or rheumaticdisease. He was previously of good health but, at theage of 51 years, noted intermittent but increasingpainless fatiguability of both legs when walking.After a few months he also developed ptosis anddiplopia. On admission to the Department ofNeurology in 1957, bilateral ptosis was present whichdisappeared temporarily after injection of edropho-nium. There was nasal regurgitation of fluid. Thespeech fatigued easily. There was symmetricalmuscular weakness without wasting. Tendon reflexeswere normal and there was no sensory loss. Generalexamination and examination of the joints revealednothing pathological. Except for a moderate eleva-tion of ESR (21 mm in one hour), the routinelaboratory investigations were normal. Tests forRF were not performed. There was no radiographicevidence of thymoma. He was treated with neostig-mine and was able to work on a dose of 225-300 mgdaily, but he was severely incapacitated for severalyears.During 1964, he experienced a remarkable

remission of myasthenic symptoms with only aslight left-sided ptosis on upwards gaze and amoderate reduction of motor power on repeatedcontractions of the muscles in the forearm and hand.From the same time, however, he started sufferingfrom pains, swelling, and stiffness in metacarpo-phalangeal (MCP) and proximal interphalangeal(PIP) joints in both hands. Gradually his arthritisbecame worse, fulfilling the criteria of definite RA.

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J. A. Aarli, E.-J. Milde, and S. Thunold

TABLE 2SEROLOGICAL DATA IN SEVEN PATIENTS WITH MYASTHENIA GRAVIS AND ARTHROPATHY

Patient Muscle antibodies RF test ANF Thyroglobulinno. AGC IHA antibodies

1 128 N 1280/20 P N2 128 - 340/20 N N3 128 - N N N4 8 - N P N5 64 - N P N6 16 - N N N7 8 - N N N

N= negative. P= positive.

Radiographs showed typical rheumatic destructionof finger joints (Fig. 1). From the beginning of 1972,he also suffered from cardiac insufficiency withincreasing dyspnoea, crural oedema, and tachycardia.Electroconversion was performed. In 1973 he washospitalized for acute anteroseptal cardiac infarction.He died in his home, in January 1975, from suddencardiac failure. Necropsy was not performed.

Serological findings IgG antibodies to striatedmuscle were demonstrated by the AGCT (PC= 128).Antibodies to the CA antigen of skeletal muscle werenot detected by IHA test (Table 2). Accordingly, hisserum contained antibodies of IgG class to someother component of striated muscle.

His RF titre of 1 280 remained constant until1974, when a significant fall in titre occurred (titre20-40). All sera were tested simultaneously.When the patient's serum was absorbed with

homogenized human skeletal muscle sensitized withhis own serum after prior treatment with mercapto-ethanol to destroy 19S RF, a significant reduction ofRF titre occurred (Aarli, 1971b). This indicatesautoreactivity between IgG muscle antibodies andRF.

Neither LE cells nor antinuclear factors (ANF)were detected.

CASE 2 (MG-1) A female patient, born in 1921,had a mother with RA. The patient had polyarthritisfrom the age of 17 years with increasing and severeaffection of multiple joints, fulfilling the criteria ofclassical RA.At the age of 31 years, she noticed that her voice

became nasal when talking. She also became pro-gressively weaker in the facial and neck muscles.During a mild respiratory infection she developedleft ptosis and deglutition difficulties. These symptomspersisted after the infection had subsided.On admission to the Department of Neurology in

1953, there was a slight left ptosis in the basal state,

but bilateral ptosis developed after looking upwardsfor less than two minutes. Tongue and facial muscleswere weak.The clinical condition was, however, dominated

by the rheumatic disorder. There was swelling andsymmetrical deformity of MCP and PIP joints, withtypical ulnar deviation of the hands and rheumatoidaffections of several other joints. Radiographs of herjoints showed rheumatoid destruction.

Subcutaneous injection of neostigmine resulted infull but transitory improvement of muscle strength.She was treated with neostigmine, later pyridostig-mine, with a satisfactory control of the myasthenicsymptoms. She had intermittent diplopia but noother symptoms of muscular fatigue.There was no radiological evidence of thymic

enlargement in 1953 or at later examinations.She received gold injections, was treated with

chloroquine for six years (after manifestation ofMG), but was never treated with ACTH or steroids.She died from sudden cardiac failure at the age of

52 years. The heart was removed at a partial necrop-sy. It was enlarged (weight 440 g) but showed nosigns of valvular defects or obstructing coronaryatheromatosis or thrombosis. There were no signsof old or recent infarcts. However, microscopyrevealed hypertrophic muscle fibres and small areasof fibrosis (Fig. 2a). In addition, multiple focal areasof muscle cell vacuolization and necrosis were seen,often accompanied by a slight infiltration of lympho-cytes and histiocytes (Fig. 2b, c). In the pericardium,small perineural lymphocyte infiltrations were found(Fig. 2d). There were no signs of vasculitis or rheu-matoid granulomas. Direct IF microscopy revealedno deposits of serum proteins or complement factors.

Serologicalfindings In 1958, a positive Waaler's testfor RF was found (titre 320). Serum was not stored.On all occasions from 1966, negative Waaler's testswere recorded. A positive latex RF test was found in1969, but was negative in 1974.

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FIG. 2 Case 2. Myocardium and pericardium stained with haematoxylin and eosin. (a) ( X 280). Fibrotic

area surrounded by slightly hypertrophic muscle fibres. (b) ( x 280). Muscle fibres showing degenerative

changes (arrows). (c) (x 280). Muscle fibres with oedema, vacuolar degeneration (arrows), and hyper-

chromatic nuclei surroundedby mononuclear inflammatory cells. (d) ( x 70). Pericardium with a perineural

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FIG. 3 Case 6. Male, aged 47 years. Anteroposteriorradiograph of lumbar spine and sacroiliac joints.Advanced sacroiliitis with complete obliteration ofsacroiliac joints and 'bambooing' of the lumbar spine.

Muscle antibodies of IgG class were demonstratedby the AGCT. IHA test for muscle antibodies was

negative (Table 2). Numerous LE cells were demon-strated in 1969 and 1972 but not in 1968. ANF, whichwas not detected in 1966, was demonstrated in 1968by IF test (homogeneous fluorescence at 1:128).

Myasthenia gravis andjuvenile rheumatoid arthritisCASE 3 (MG-6) This patient was a woman of

healthy family, born in 1941. At the age of 14 yearsshe had juvenile RA, starting with acute arthritis inthe neck. In the same year she had iridocyclitis.Three months later she had pain and swelling of theleft knee and right first toe as well as restrictedmobility and pains in the iliosacral joints. The ESRwas elevated (78 mm) and there was a slight anaemia.Her juvenile RA gradually subsided without

treatment and went into a complete clinical remissionuntil 1965. She had then a brief exacerbation, withpainful swelling in the left ankle. Later observationshave disclosed no rheumatic signs.From the age of 18 years she noticed ptosis,

increasing difficulty in swallowing, and generalizedmuscular weakness. She was admitted to theDepartment of Neurology and bilateral ptosis andfacial weakness were found. There was a moderateweakness of both legs without muscular wasting. Themuscular weakness was promptly but temporarilyremoved with injection of edrophonium. She wastreated with anticholinesterase drugs with excellenteffect. The course of the disease varied with remis-sions during the last two trimesters of two suc-ceeding pregnancies and recurrence of symptomsduring the puerperium. The symptoms of MG havegradually faded and she is at present (1975) almostfree from muscular symptoms.

Serological findings Muscle antibodies of IgG classwere demonstrated by the AGCT but not by IHA(Table 2). RF and ANF were not detected.

Myasthenia gravis and probable systemic lupuserythematosus (SLE)

CASE 4 (MG-20) This female patient was born in1934 of a healthy family. Her second child was bornwith neonatal myasthenia. At the age of 17 years,she had transient ptosis and diplopia. For severalyears she only had fluctuating ocular symptoms butfrom the age of 33 years she also suffered from facialweakness, deglutition, and speech difficulties andfatiguability when walking for a while. Radiographygave no evidence of thymoma. A diagnosis of MGwas made in 1966 and treatment with pyridostigminecommenced. After a period with serious myasthenicsymptoms, the weakness gradually faded and shebecame able to manage on a low dose of pyridostig-mine.

In 1967 she had a left peripheral facial palsy ofBell's type with spontaneous recovery.From the age of 37 years she had had migrating

arthralgia with painful swelling and limitation ofmovements in various joints (PIP, shoulder, elbows).She also had periodic fever of unknown origin. Onclinical examination, she presented synovitis in thesecond and fourth PIP of the left hand.

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FIG. 4 Case 6. Lateral radiograph of lumbar spine,showing moderately advanced ossification deep to theanterior longitudinal ligament. Advanced osteoporosis.

Serological findings Muscle antibodies were notdetected by IHA or AGCT. LE cells, which were notfound in 1967, were present in several specimens in1974. ANF was demonstrated in 1974 but not in1967. Serum values of C 3 and C 4 were depressedand there was a leucopenia with 1 800 cells/mm3.RF and thyroid antibodies were not detected.

CASE 5 (MG-25) A female patient, born in 1947noticed weakness in arms and legs from the age of

22 years. She developed transient ptosis and diplopia.An edrophonium test was positive and she wastreated with anticholinesterase drugs, at first withgood response but with decreasing effect during thenext months. A thymectomy was performed at age23 years. Histology showed thymic hyperplasia butno thymoma. She had a short course of ACTH twomonths after the operation with moderate effect.Before she noticed the muscular weakness, she hadperiods with arthralgia. During improvement ofmyasthenic symptoms, she noticed swelling of bothankles, PIP and MCP joints of second and thirdfingers of both hands. She also had haematuria.There was a slight enlargement of the thyroid gland.Renal and thyroid functions were normal.

Serological findings Muscle antibodies of IgG classwere detected by the AGCT but not by IHA.Numerous LE cells were detected on several occa-sions and ANF was demonstrated (titre 512). Therewas a false positive Wassermann reaction. RF andthyroid antibodies were not detected.

Myasthenia gravis and ankylosing spondylitisCASE 6 (MG-28) This man was born in 1922. Fromthe age of 20 years he noticed the first symptoms ofankylosing spondylitis with increasing low back painand progressive stiffness of the spine. Radiographsshowed iliosacral arthritis (Fig. 3) and extensiveligamentous calcification (Fig. 4). He received x-raytreatment and later indomethacin. Nonetheless, thedisease progressed.From the age of 47 years he noticed diplopia and

bilateral ptosis. The ocular symptoms fluctuatedduring the day and disappeared temporarily afterinjection of edrophonium. His myasthenic symptomswere confined to the extraocular muscles. Nothymoma was demonstrated on radiological investi-gation. Renal and thyroid functions were normal.

Serological findings Muscle antibodies, RA andANF were not detected.

Myasthenia gravis and unspecified arthralgiaCASE 7 (MG-32) A female patient, born in 1937,noticed from the age of 34 years, intermittentdiplopia and weakness of both shoulders and legs.An edrophonium test was positive and she receivedanticholinesterase medication with excellent effect.There was a total clinical remission during pregnancybut the disease recurred during the puerperium.From the age of 36 years, she had migrating

arthralgia and intermittent swelling of small jointsof the hands and feet. Clinical examination, how-ever, has on several occasions revealed no sign of

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synovitis. Radiographs revealed no signs of thymo-ma. Renal and thyroid function were normal.

Serologicalfindings Muscle and thyroid antibodies,RF and ANF have not been detected.

DISCUSSION

Seven patients with myasthenia gravis (MG)developed clinical signs of arthropathy. One ofthese had ankylosing spondylitis and one arthral-gia without objective signs of arthritis. Theother five patients all showed clinical signs ofpolyarthritis.The degree of polyarthritis varied from a

slight, non-deforming articular affection to amanifest and deforming rheumatoid arthritis(RA) in two of the patients (case 1 and 2). Thecourse of the rheumatoid disease was, from thestart, progressively destructive, advancing to anincapacitating stage with ankylosis and severedeformation of several joints. With both patients,the diagnosis was a definite RA, with themodification that high concentrations of LEcells were demonstrated in the serum of case 2.

In these two patients, the myasthenic symp-toms were a transitory clinical phase during thedevelopment of rheumatoid disease. As thearticular symptoms progressed, the myasthenicweakness became less prominent. Similaramelioration of myasthenic symptoms in con-nection with the appearance of RA has beenreported by Oosterhuis and Haas (1968). Anothercase of regression of myasthenic symptomsduring the development of RA is reported byStorm-Mathisen (1961).Serum from case 1 contained both IgG

muscle antibodies and RF. In an earlier study,evidence for autoreactivity between the muscleantibodies and RF was presented. Furthermore,RF was also demonstrated in eluates preparedfrom muscle tissue sensitized with autologousserum (Aarli, 1971b). These results indicate invitro autoreactivity. The titre reduction of RFobserved in case 1 during 1974 may thereforerepresent in vivo binding of RF to skeletalmuscle tissue.The muscle antibodies in sera from cases 1 and

2 reacted with skeletal as well as heart muscle.Such cross-reactivity was first described byBeutner et al. (1962). A recent theory postulatesthat muscle antibodies may be indicators of

autoimmune muscle disease (Dawkins andZilko, 1975). Case 2 died from sudden cardiacfailure and necropsy revealed an enlargement ofthe heart. There were no signs of rheumatoidmyocarditis. The histological findings were aspotty myocardial necrosis accompanied by amild inflammatory reaction-a common lesionin myasthenia gravis (Russell, 1953; Genkins etal., 1961). However, IF did not reveal antibodyprotein or complement factors within themyocardial lesions.The relationship between muscle pathology

and muscle antibodies is not clarified. Beutneret al. (1965) have described in vivo-binding ofgamma-globulin only to the sarcolemmal-subsarcolemmal region of skeletal muscle fibresfrom patients with MG. The concomitanthistological lesion was abnormally large num-bers of subsarcolemmal nuclei. But this pheno-menon was observed only when the IHA test formuscle antibodies was positive. Antibodies ofthis type are probably directed towards antigensin the sarcolemmal/subsarcolemmal region(Aarli, 1972a). Such antibodies were notdemonstrated in sera from case 1 and 2.

Several patients with concomitant MG andRA are reported in the literature. Sera from anumber of these patients are reported to givenegative reactions in IF or IHA tests for muscleantibodies (Downes et al., 1966; Szobor et al.,1969; Durance, 1971). Recent reports haveshown that the AGCT also detects antibodies toother muscle antigens (Aarli and T0nder, 1970;Aarli, 1972b). Therefore, the specificity of themuscle antibodies in MG patients who developRA seem to differ from that described in otherMG patients.

It has been discussed whether the arthritisoccurring in MG represents RA or a differentform of polyarthritis (Simpson, 1960, 1964).The results of the present study clearly show thatboth definite RA and juvenile RA (case 3) maydevelop during myasthenia. There are, however,forms of arthropathy, seen in MG (case 7) whichare probably not of rheumatoid nature.

In the two patients with SLE (cases 4 and 5)the articular symptoms were mild. In bothpatients, MG preceded the SLE by several years.The initial symptoms were from extrinsic ocularmuscles, a finding indicating that the muscularsymptoms were not due to a polymyositis. It is of

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interest that one of these patients (case 4) gavebirth to a child with neonatal myasthenia. Inboth patients, the myasthenic symptoms gradu-ally faded as indices of SLE appeared. Bothexacerbation and remission of muscular symp-

toms during development of SLE have beenreported by several authors (Harvey et al., 1954;Alarcon-Segovia et al., 1963; Goldin andRobbins, 1963; Piemme, 1964; Oosterhuis andde Haas, 1968). Thymectomy was performed incase 5 without influencing the course of SLE.The progression of MG in case 6 resembled

that of case 2. The former developed a classicalankylosing spondylitis. During the disease, hehad a period with myasthenic, edrophonium-sensitive ocular symptoms followed by spon-

taneous remission of the muscular symptoms.Coexisting ankylosing spondylitis and MG is alsoreported by Simpson (1960). The data are

however, insufficient to exclude the possibilityof this being a pure coincidence.To summarize, arthritis may develop during

the course of MG. The clinical and serologicaldata demonstrate a close relationship betweenthe two disorders. In some patients, the articularsymptoms indicate the development of RA. In

other patients, the myasthenia may be a preludeto SLE. In still other patients, unspecifiedarthralgia occurs, where only the future clinicaldevelopment may reveal the definite diagnosis.

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Aarli, J. A. (1971b). Demonstration of antibodies to muscleby absorption of rheumatoid factor. Acta Pathologica et

Microbiologica Scandinavica, Section B., 79, 365-371.Aarli, J. A. (1972a). Localization and properties of an acid-

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