cerebrospinal fluid immunoglobulin abnormalitiesin ... · cerebrospinalfluid immunoglobulin...

Journal of Neurology, Neurosurgery, and Psychiatry 1985;48:807-813

Cerebrospinal fluid immunoglobulin abnormalities insystemic lupus erythematosusJAN ERNERUDH,* TOMAS OLSSON,t FOLKE LINDSTROMt AND THOMAS SKOGH§

From the Department ofNeurology, University Hospital, Linkoping. * Department ofNeurology, KarolinskaInstitute, Huddinge University Hospital, Stockholm. t Department ofInternal Medicine, University Hospital,Linkoping. t Department ofMicrobiology, University Hospital, Linkoping, § Sweden.

SUMMARY Central nervous system (CNS) involvement is a common and important complicationin systemic lupus erythematosus. The mechanisms for CNS involvement are poorly understoodand reliable diagnostic procedures are lacking. Pairs of serum and cerebrospinal fluid (CSF)specimens from 17 patients with clinical and serological manifestations of systemic lupuserythematosus were analysed. All 11 patients with definite or suspect clinical CNS disorderrevealed some kind of abnormality in the CSF, in contrast to three of sev.en systemic lupuserythematosus patients without CNS disorder. The most prominent findings in systemic lupuserythematosus patients with CNS disorder were immune aberrations with oligoclonal bands onagarose isoelectric focusing (AIF) and elevation of IgG and IgM index, probably reflectingintrathecal production of IgG and IgM respectively. Intrathecal production of antiviral antibodieswas found in four of 12 patients by AIF followed by immunofixation and subsequent autoradio-graphy. An enzyme-linked immunoabsorbent assay (ELISA) could not detect autoantibodiesagainst structural brain antigens.

Involvement of the central nervous system (CNS)has been reported in 50%' and 70%2 of patientswith systemic lupus erythematosus. The mechanismsleading to CNS involvement are, however, poorlyunderstood and reliable laboratory diagnostic pro-cedures are lacking. Thus, humoral immune vari-ables in cerebrospinal fluid (CSF) have hithertobeen studied only to a minor extent. This contrastswith diseases such as multiple sclerosis and CNSinfections, where CSF immunoglobulin aberrationhave been extensively investigated. One prominentfinding in these disorders is the frequent occurrenceof intrathecal synthesis of IgG which is manifestedby elevated CSF IgG index ((CSF IgG/serum IgG):(CSF albumin/serum albumin) )3 and by oligoclonalbands demonstrable by electrophoresis or isoelectricfocusing of CSF4 In multiple sclerosis, the biologicalsignificance of these phenomena is not clear, butthey are of diagnostic aid.4-7 In CNS infections it has

Address for reprint requests: Dr Jan Emerudh, Department ofNeurology, University Hospital, S-581 85 Linkoping, Sweden.

Received 27 July 1984 and in revised form 7 January 1985.Accepted 14 January 1985

been shown that some of the intrathecally producedimmunoglobulins have specificity against the causa-tive microorganism (see ref 8 for review).

In systemic lupus erythematosus with clinical CNSinvolvement, it has been shown in one previousstudy that 42% of the patients had oligoclonal bandsin CSF demonstrable by isoelectric focusing.9 Find-ings in systemic lupus erythematosus patients with-out CNS involvement were, however, not reported.CSF IgG index was determined in another study andfound to be elevated in 10 out of 20 systemic lupuserythematosus patients with CNS involvement,while normal values were found in patients withoutCNS disease.'0The present study was done in order to study

more extensively the occurrence of humoralimmune aberrations in CSF from systemic lupuserythematosus patients with and without clinicalevidence for CNS involvement. We have analysedpairs of CSF and serum from 17 patients with sys-temic lupus erythematosus, 11 of whom had definiteor probable CNS involvement. Isoelectric focusingwas performed to demonstrate oligoclonal IgGbands, and the CSF IgG was determined, as werethe corresponding indices of IgA and IgM. Further-more, IgG fractions separated by isoelectric focusing

807

Protected by copyright.

on February 13, 2020 by guest.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.48.8.807 on 1 August 1985. D

ownloaded from

http://jnnp.bmj.com/

Table 1 Survey of clinical and serological data

Patients Age Clinical manifestations Serological findings

(yr) CNS Extra-CNS ANA Other antibodies

1 16 Psychosis; seizures Nephritis rash; Raynaud; hypertension 1/400 IgG: homog2 18 Seizures Autoimmune thyroiditis; 'lupus" 1/100 IgG; speckled Parietal cell

anticoagulant; deep vein thrombosis;diabetes mellitus

3 39 Vertigo; vestibular Arthralgia; alopecia; leukopenia 1/100 IgG; speckled Parietal cell,dysfunction; aseptic rheumatoidmeningitis factor

4 34 Hemiparesis (cerebral Arthritis; nephritis; pleuritis 1/1600 IgG; homog Smooth musclehaematoma)

5 35 Transient hemiparesis; Arthritis; nephritis; rash; 1/10(0 IgG; homog Thyroid; falseamaurosis fugax photosensitivity; thrombocytopenia positive test for

syphilis6 40 Seizures Arthritis; nephritis; pleuritis: 1/1600 IgG; homog ds DNA*

fever episodes7 34 Migraine Arthritis; nephritis; pleuritis; 1/1600 IgG; homog ds DNA*

leukopenia; fever episodes8 34 Myelitis; optic neuritis Arthralgia; rash; fever episodes 1/400 IgG; homog Reticuline9 64 Myelitis; optic neuritis Arthralgia; fever episodes; myalgia; 1/100 IgG; homog

thrombocytopenia10 51 Exacerbations and Diabetes mellitus; asthma; 1/6400 IgG; homog

remissions resembling polyneuropathiaMS

11 52 Headache; confusion Arthritis; hypertonia; nephritis 1/100 IgG; speckled LE cells; ds DNA*12 33 - Arthritis; pleuritis; fever episodes 1/100 IgG; homog13 18 - Arthritis; photosensitivity; purpura 1/400 IgG; speckled14 40 - Arthritis; nephritis; fever episodes 1/6400 IgG; homog ds DNA*

leukopenia15 34 - Arthritis; discoid lupus; chronic 1/100 IgG; peripheral

bronchitis speckled16 24 - Arthritis; Raynaud 1/1600 IgG; homog17 53 - Arthritis; pleuritis; pericarditis; 1/1600 IgG; homog Positive Coombs

leukopenia test

*ds DNA = double stranded DNA.

were examined for antiviral and antinuclear anti-bodies, and an enzyme-linked immunosorbent assay

(ELISA) was used to demonstrate any anti-brainIgG antibodies.

Materials and methods

PatientsSeventeen patients (14 women) with clinical and serologi-cal evidence for systemic lupus erythematosus were

included (table 1). Eight of them met the 1982 revisedAmerican Rheumatism Association diagnostic criteria,"six displayed clinical and serological evidence strongly sug-

gesting systemic lupus erythematosus, two (nos 7, 8) hadsigns and symptoms consistent with neuromyelitis opticaand had clinical and serological findings suggesting prob-able systemic lupus erythematosus, and one (no 10) dis-played serological findings consistent with systemic lupuserythematosus while the clinical picture was not conclusivefor this diagnosis.

Definite systemic lupus erythematosus-related CNS dys-function was defined as the presence of unequivocalneurological or psychiatric abnormalities not attributableto non-systemic lupus erythematosus causes including cor-

ticosteroid therapy. One patient with classical migraine butlacking heredity (No 7) was classified as having probableCNS dysfunction.'2 CSF and serum used for the presentstudy were always obtained during episodes of neuro-

psychiatric symptoms. From one patient (No 6), CSF andserum were obtained during a period when he had no his-tory or signs of CNS dysfunction, and also when he haddeveloped seizures.Of the 17 patients, 11 (Nos 1-11. table 1) had definite or

probable clinical CNS dysfunction (group I), while theremaining six patients (Nos 12-17) as well as patient No 6examined twice, lacked evidence of CNS involvement(group II).

Control CSF and serum specimens were obtained fromfour patients who sought advice because of tensionheadache. The physical and neurological examinationswere normal, as were the routine CSF studies.

Routine CSF studies15 ml of CSF was obtained by lumbar puncture, examinedfor cell numbers by phase contrast microscopy, and cen-trifuged at 200 g for 10 min. The erythrocyte count in CSFdid not exceed 100 x 101 cells/l. Determinations of albu-min, IgG and IgA were carried out by immunoprecipita-tion nephelometry on unconcentrated CSF and on serumobtained in parallel. IgM in unconcentrated CSF and inserum was determined by ELISA.'3 The CSF IgG indexwas calculated,3 as were the corresponding CSF IgA andCSF IgM indices. The upper reference limit in our laborat-ory is 0 7 for the CSF IgG index, 0-6 for the CSF IgA indexand 0-06 for the CSF IgM index. As indicator of theblood-brain barrier's status, the CSF albumin/serum albu-min ratio was calculated. Age-adjusted upper reference

Ernerudh, Olsson, Lindstrbm, Skogh808



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ownloaded from


Cerebrospinal fluid immunoglobulin abnormalities in systemic lupus erythematosusvalues previously described were used.3 For demonstrationof oligoclonal bands, agarose isoelectric focusing was per-formed on pairs of CSF and serum.'4 To confirm the pres-ence of oligoclonal IgG bands, unconcentrated CSF anddiluted serum were also examined by agarose isoelectricfocusing, followed by transfer to cellulose nitrate mem-

brane,'5 16 and double antibody avidin biotinperoxidaselabelling.'"

Antigen immunofixation and autoradiography forcharacterisation ofantibody specificity ofagarose isoelectricfocusing separated lgGAntigen immunofixation and autoradiography'8 1' was per-formed to identify antibodies in agarose isoelectric focus-ing separated CSF and serum IgG against deoxyribonucleicacid (DNA), extractable nuclear antigens (ENA) and vari-ous viruses. Briefly, CSF and serum were run by agaroseisoelectric focusing and the unstained agarose isoelectricfocusing plate was covered with plates containing the anti-gen dissolved in agarose. Previous experiments using posi-tive and negative serum samples had revealed the follow-ing optimal antigen concentrations per ml of agarose; 30 ,ulmeasles (suspension of Lec strain, National BacteriologicalLaboratories, SBL, Stockholm, Sweden); 2 ,ul herpes simp-lex virus type 1 (SBL); 10 ,ul mumps (Orion, Helsinki,Finland); 10,u1 rubella (Orion); 10 gl varicella (SBL);200 ,u1 DNA (Sigma, St Louis, MO, USA); 200 ,ul ENA, alyophilised phosphate-buffer extract of homogenised calfthymus.20 IgG complexed to the antigen was detected byincubation with radiolabelled rabbit anti-human IgG iodi-nated with 125 I (code IMS 30; the Radiochemical Centre,Amersham, England) using the chloramine-T method,2'and exposed to autoradiography. Patterns on autoradio-grams were compared with those on stained agaroseisoelectric focusing plates which had been used forimmunofixation, and also with agarose isoelectric focusingseparated specimens run as reference and stained immedi-ately. Intrathecal antibody production was considered tooccur when the most pronounced antibody activity on

autoradiography was found in the CSF compared to serum,or when one or more oligoclonal bands on autoradiogra-phy were observed in the CSF only, and not in the corres-ponding serum.

ELISA for identification ofIgG antibodies against braincomponentsAn ELISA previously used in our laboratory to detectautoantibodies in serum and CSF was modified and applied

for the detection of any antibodies against the followingbrain antigens; myelin isolated from CNS of guineapigS;13 24 myelin basic protein (MBP) isolated from CNS ofhuman brain from a patient without neurological disease,dying from acute myocardial infarction; water solubleextracts of human grey and white matter, both supernatantand pellet.25 The antigens were consistently diluted in0.05 M sodium carbonate buffer pH 9-6. Optimal concen-trations of CSF and serum, antigens, antisera and incuba-tion times were determined in experiments using positiveand negative sera obtained from guinea pigs with chronicrelapsing experimental allergic encephalomyelitis (r-EAE). Microtitre plates were coated with 0-1 ml per wellof the following antigens; 0-5 ,ug myelin; 0-3 ,ug MBP;1 p.g extract of white matter; 1 ,ug extract of grey matter;1 p.g pellet of white matter; 1 ,ug pellet of grey matter. CSFcontaining 0-8, 4 and 20 mg/l of IgG and serum with 0-8, 4,20, 100 and 500 mg/l of IgG were examined.

Demonstration of autoantibodies against DNA and ENAby indirect immunofluorescence (IF) microscopy100 pl. of serum diluted 1:25 in phosphate buffered saline(PBS, pH 7 6) and undiluted CSF were allowed to reactwith 5 pum cryostat sections of rat kidney, rat liver and ratstomach for 30 min at room temperature in a moistchamber. The slides were washed with PBS for 10 min.100 ILI fluorescein isothiocyanate-(FITC-) conjugatedrabbit anti-human IgG (The Wellcome Foundation Ltd,London, England) was applied to the sections for 30 min.The slides were then washed with PBS, mounted withPBS-buffered glycerine, and examined in a Zeiss Standardmicroscope equipped with incident halogen lamp illumina-tion and filters for FITC activation/emission. In this way,we looked for antinuclear antibodies (ANA), anti-mitochondrial antibodies (AMA), anti-smooth muscleantibodies (SMA) and anti-parietal cell antibodies. AllANA-positive sera (1:10) and CSF samples were alsotested for presence of antibodies against double-stranded(ds) DNA using the flagellate Crithidia luciliae as source ofds-DNA for indirect immunofluorescence microscopy.Sera giving rise to the speckled type ofANA were analysedfor presence of antibodies against ENA, using doubleimmunodiffusion in agarose.

Results

CSF findingsAll 11 patients belonging to group I with systemic

Table 2 Summary ofCSFfindings in systemic lupus erythematosus patients with (I) CNS dysfunction (CNS-SLE) and (II)without CNS dysfunction (non CNS-SLE)

n Pleocytos (>5 Blood-brain barrier Intrathecal Ig synthesismononuclear cells dysfunction (T CSF/Sx 106/l) albumin ratio) IgG IgA IgM Oligoclonal IgG

index index index on isoelecticfocusing

I CNS-systemic lupuserythematosus 11 3 7 6 1 7 9

II non CNS-systemiclupus erythematosus 7 0 1 0 0 2 0

809



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ownloaded from


Ernerudh, Olsson, Lindstrom, Skogh

Fig 1 Examples ofserum and CSF agarose isoelectric focusing (left 1-8) with corresponding antiviral immunofixation and

subsequent autoradiography (right 1-8). 1-2 show normal findings on agarose isoelectric focusing and also on

autoradiography, where serum shows some antibody activity, but CSF to a lesser extent. The next patient (sample 3-4) was

one with CNS involvement where CSF reveals oligoclonal bands, indicated with arrows. Autoradiography findings are

similar to the first patient. Autoradiogram of the next patient (5-6) shows a more pronounced activity (indicated with

arrows) in CSF compared to serum. The last patient (7-8) was one with CNS involvement. CSF reveals oligoclonal bands on

agarose isoelectric focusing. Arrows on autoradiogram denote zones ofpronounced activity compared to serum.

lupus erythematosus and definite or probable CNSdysfunction displayed some abnormality on routineCSF studies, in contrast to three of the sevenpatients in group II with systemic lupuserythematosus and no CNS dysfunction (table 2).Among the patients of group I, three had mononuc-lear pleocytosis, seven slight blood-brain barrierdamage, nine had oligoclonal bands which werefound in CSF only and not in serum by agaroseisoelectric focusing (fig 1), and which were provedto consist of IgG when CSF was re-examined byagarose isoelectric focusing and subsequent doubleantibody avidin-biotin-peroxidase labelling. Six ofthe patients of group I had elevated CSF IgG index(fig 2), one of them in the absence of oligoclonalbands, while one had increase of CSF IgA index andseven out of nine examined from group I had ele-vated CSF IgM index (fig 3). Among the patients ofgroup II, one displayed slight blood-brain barrierdamage and two had elevated CSF IgM index. Fromsix of the patients belonging to group I, three ormore pairs of CSF and serum were obtained duringa period of one to five years. The oligoclonal bandpattern persisted unchanged in one patient (No 3),showed the appearance of one band and the loss of

three other bands in another patient (No 9) andrevealed oligoclonal bands only in the first of threeconsecutive CSF samples in a third patient (No 11).In a fourth patient (No 8) no oligoclonal bands werepresent in the first CSF sample. Five years later,

12-0 10-

. 8-En 6-

(1) 4-lLu 2

0

0

0

* 00

0-2 0-4 0-6IgG- index

IIII0111111110111

0-8

00

0

0

I A1-0

Fig 2 IgG-index versus CSFIS albumin ratio illustratesintrathecal IgG synthesis and blood-brain barrierdysfunction respectively. Open symbols represent systemiclupus erythematosus patients with clinical CNS involvementand closed symbols represent systemic lupus erythematosuspatients without clinical CNS involvement.

810



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ownloaded from


Cerebrospinal fluid immunoglobulin abnormalities in systemic lupus erythematosus

12-

0 10

I-

6-

4LU.

(t

*00

0 0

0

0

0

0

OJ0

0 i

0.1 0-2 0-3 014IgM-index

Fig 3 IgM index and CSFIS albumin ratio in systemiclupus erythematosus patients with clinical CNS dysfunction(open symbols) and without clinical CNS involvement(closed symbols).

after additional CNS symptoms (transitory sensorydisturbances as in ischaemic attacks), an oligoclonalIgG band pattern was found. The two remainingpatients who were followed longitudinally (Nos 1and 6) did not display oligoclonal bands at any occa-

sion. One of these patients (No 6) was evaluatedprior to, during and after occurrence of CNS dys-function. While having no CNS symptoms, an eleva-tion of the CSF IgM index was the only abnormality.After CNS symptoms had occurred, the CSF IgMindex was further raised and CSF IgG index was alsoelevated. The CSF/serum albumin ratio was alsoincreased, but not high enough to explain the ele-vated CSF IgM and IgG indices.26 After treatmentwith steroids and plasmapheresis, the CSF IgGindex became normal, while the CSF IgM index aswell as the CSF/serum albumin ratio remained ele-vated.

Intrathecal antibody productionAgarose isoelectric focusing of CSF and serum from12 of the systemic lupus erythematosus patientsand the four control patients, and subsequentimmunofixation with viral antigens and autoradio-graphy revealed IgG antibodies against one or moreof the viruses tested in most sera. The same anti-bodies, displaying identical migration properties,were mostly detected in the corresponding CSF, butthey appeared less pronounced indicating transuda-tion from serum to CSF. However, in four patients(three with CNS involvement) the CSF revealedstronger bands than in the corresponding serumagainst herpes simplex virus or varicella, indicatingintrathecal antibody synthesis. These viral anti-

bodies corresponded to oligoclonal IgG in two of thepatients (fig 1).None of the 14 systemic lupus erythematosus

patients examined for intrathecal production ofantibodies against DNA or ENA was positive whenantigen immunofixation and autoradiography wasperformed on agarose isoelectric focusing separatedCSF and serum, while indirect immunofluorescencerevealed DNA-ENA antibodies in CSF in onepatient, but at a lower titre than in the correspond-ing serum.

Using ELISA for identification of IgG antibodiesagainst structural brain components in the form ofmyelin, myelin basic protein and water solubleextracts of grey and of white matter did not revealsuch autoantibodies in CSF or serum from any of the12 patients examined.

Discussion

The present study clearly demonstrates aberrationsof CSF immunoglobulins in a majority of systemiclupus erythematosus patients with clinical CNSinvolvement compared to patients without CNSsymptoms. The occurrence of these aberrationsshows that a thorough examination of CSF includingdetermination of CSF IgG, CSF IgA and CSF IgMindices as well as separation by agarose elec-trophoresis or preferably agarose isoelectric focus-ing should be performed in patients with systemiclupus erythematosus who develop clinical evidenceof CNS involvement. Cell counting and evaluationof the blood-brain barrier preferably also withdetermination of the CSF/serum albumin ratio3should be included. Notably, systemic lupuserythematosus patients without clinical CNSinvolvement lacked CSF IgG abnormalities. On theother hand, systemic lupus erythematosus patientswith CNS involvement may lack CSF IgG abnor-malities, and normal findings on CSF studies doesnot exclude CNS involvement in systemic lupuserythematosus.

The immunoglobulin abnormalities observed insystemic lupus erythematosus with CNS involve-ment are not restricted to IgG but include elevationof the CSF IgM index and occasionally of the CSFIgA index. It is not clear why two of our patientswithout clinical CNS involvement also had increasedCSF IgM index values. IgM may appear early duringimmune response and the observed intrathecal IgMsynthesis in these patients could indicate early "sub-clinical" CNS involvement. In fact, one of the sys-temic lupus erythematosus patients with an elevatedCSF IgM index later developed CNS symptoms, andhad at that time also an elevated CSF IgG index.The CSF abnormalities observed in systemic lupus

811



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ownloaded from


812

erythematosus with CNS involvement, namelymononuclear pleocytosis, slight blood-brain barrierdamage and intrathecal IgG and IgM synthesis, aresimilar to those in multiple sclerosis.4 13 14 26 Itremains to be established whether intrathecal IgGand IgM production in multiple sclerosis has anypathogenetic importance or represents an epi-phenomenon. Studies hitherto reported have failedto define antibody specificity of the major portion ofintrathecally produced IgG which migrates as oligo-clonal bands on electrophoresis or isoelectric focus-ing.28 A minor portion represents a variety of viralantibodies which are most probably synthesisedintrathecally, but their relevance to the pathogenesisof multiple sclerosis is unknown. Autoantibodieshave not been traced to oligoclonal IgG in multiplesclerosiS.2Our results obtained with immunofixation and

autoradiography, using viruses as antigens, revealedsimilarities with the situation in multiple sclerosis.Patients with systemic lupus erythematosus andCNS involvement are thus able to synthesise viralantibodies intrathecally. In the present study noneof four normal control patients showed intrathecalantiviral antibody production. In a previous studyusing the same method, intrathecally produced anti-viral antibodies were found in two of 11 controlpatients, and in 21 of 25 multiple sclerosis patients.28For structural brain antigens, our ELISA techni-

que has successfully demonstrated autoantibodiesagainst various antigens in r-EAE.3 It has also beenapplied to CSF and serum samples from multiplesclerosis patients, where about one third of thepatients showed low levels of antibodies againstmyelin basic protein.Regarding antiviral antibodies four of 12 patients

showed intrathecal production. Judged from previ-ous experiments in multiple sclerosis, these antiviralantibodies account for only a minor proportion ofthe oligoclonal IgG.'8 1' Present observations ofintrathecal antiviral antibody synthesis represent afurther similarity with multiple sclerosis whereintrathecal synthesis of antibodies against 17 differ-ent viruses have been detected.3" The deversity ofhitherto detected antibody specificities and the largeproportion of IgG with unknown antibodyspecificity (at least, it is not directed against putativeautoimmune target antigens) may be interpreted asa random selection of B cells into the CNS com-partment during the inflammatory process, and thatthey for some reason continued to produce IgG(Emerudh, Olsson, unpublished observations).

In conclusion, the present study showedintrathecal synthesis of IgG and IgM in a largeproportion of systemic lupus erythematosus patientswith CNS involvement, in contrast to patients with-

Ernerudh, Olsson, Lindstrom, Skoghout CNS symptoms. CSF studies with regard tomononuclear pleocytosis, CSF IgG and IgM indices,and oligoclonal IgG bands are therefore useful clini-cally. The biological and pathogenetic implicationsof this immune response are unclear.

We thank Professor Hans Link, Department ofNeurology, Huddinge University Hospital, Stock-holm, for valuable critical review of the manuscript.The excellent technical assistance of Mrs MonicaDufmats, Mrs Ingela Lilja and Mrs Gunnel Rosen isgratefully acknowledged. The work was supportedby grants from the Swedish Medical ResearchCouncil (project 3381) and Ostergotlands LansLandsting (project 83/28 and 83/26).

References

'Grigor R, Edmond J, Lewkonia R. Systemic lupuserythematosus. A prospective analysis. Ann RheumDis 1978;37:121-8.

2 Estes D, Christian CL. The natural history of systemiclupus erythematosus by prospective analysis. Medicine197 1;50:85-95.

Tibbling G, Link H, Ohman S. Principles of albumin andIgG analyses in neurological disorders. I. Establish-ment of reference values. Scand J Clin Lab Invest1 977;37:385-90.

Link H, Muller R. Immunoglobulins in multiple sclerosisand infections of the nervous system. Arch Neurol1971;25:326-44.

Trotter JL, Brooks BR. Pathophysiology of cerebrospi-nal fluid immunoglobulins. In: Neurobiology of cere-brospinal fluid; Wood JH, ed. New York: PlenumPress, 1980:465-85.

6 Link H, Tibbling G. Principles of albumin and IgG anal-yses in neurological disorders. III. Evaluation of IgGsynthesis within the central nervous system in multiplesclerosis. Scand J Clin Lab Invest 1977;37:397-401.

7Thompson EJ, Kaufmann P, Shortman RC, Rudge P,McDonald WI. Oligoclonal immunoglobulins andplasmacells in spinal fluid of patients with multiplesclerosis. Br Med J 1979; 1: 16-27.

8 Link H, Kam-Hansen S, Forsberg P, Henriksson A.Humoral and cellular immunity in patients with acuteaseptic meningitis. Immunology of nervous systeminfections. Prog Brain Res 1983;59:29-46.

Winfield JB, Shaw MBS, Silverman LM, Eisenberg RA,Wilson HA, Koffler D. Intrathecal IgG synthesis andblood-brain barrier impairment in patients with sys-temic lupus erythematosus and central nervous systemdysfunction. Am J Med 1983;74:837-44.

Seibold JR, Buckingham RB, Medsger Jr TA, Kelly RH.Cerebrospinal fluid immune complexes in systemiclupus erythematosus involving the central nervoussystem. Semin Arthritis Rheum 1982; 12:68-76.

"Tan EM, Cohen AS, Fries JF, Alfonse TM, et al. The1982 revised criteria for the classification of systemiclupus erythematosus. Arthritis Rheum 1982; 25:1271-7.



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ownloaded from


Cerebrospinal fluid immunoglobulin abnormalities in systemic lupus erythematosus2 Brandt KD, Lessell S. Migrainous phenomena in sys-

temic lupus erythematosus. Arthritis Rheum 1978;21:7-16.

3 Forsberg P, Henriksson A, Link H, Ohman S. Referencevalues for CSF-IgM, CSF-IgM/S-IgM ratio and IgMindex, and its application to patients with multiplesclerosis and aseptic meningoencephalitis. Scand JClin Lab Invest 1984;44:7-12.

'4 Link H, Kostulas V. Utility of isoelectric focusing ofcerebrospinal fluid and serum on agarose evaluatedfor neurological patients. Clin Chem 1983;29:810-5.

Glynn P, Gilberg H, Newcombe JIA, Cuzner ML. Rapidanalysis of immunoglobulin isoelectric focusing pat-terns with cellulose nitrate sheets and immunoperox-idase staining. J Immunol Methods 1982; 51:251-7.

6 Walker RWH, Keir G, Johnson MH, Thompson EJ. Arapid method for detecting oligoclonal IgG in uncon-centrated CSF, by agarose isoelectric focusing, trans-fer to cellulose nitrate and immunoperoxidase stain-ing. J Neuroimmunol 1983;4: 14 1-8.

7 Olsson T, Kostulas V, Link H. Detection of oligoclonalIgG in unconcentrated CSF by agarose isoelectricfocusing and double antibody avidin-biotin-peroxidase labelling. Clin Chem 1984;30: 1246-9.

8 Nordal HJ, Vandvik B, Norrby E. Multiple sclerosis:local synthesis of electrophoretically restrictedmeasles, rubella, mumps and herpes simplex virusantibodies in the central nervous system. Scand JImmunol 1978;7:473-9.

9 Shorr J, Rostrom B, Link H. Antibodies to viral andnon-viral antigens in subacute sclerosing panen-cephalitis and multiple sclerosis demonstrated bythin-layer polyacrylamide gel isoelectric focusing,antigen immunofixation and autoradiography. JNeurol Sci 1981;49:99-108.

2(1 Sharp GL, Williams SI, Tan EM, Gould RG, HolmanHR. Mixed connective tissue disease - an apparentlydistinct rheumatic disease with a specific antibody toan extractable nuclear antigen (ENA). Am J Med

1972;52: 148-59.21 Garvey JS, Cremer NE, Sussdorf DH. Methods in

Immunology. Reading: Benjamin WA Inc, 1977:175-8.

22 Olsson T, Henriksson A, Link H, Kristensson K. IgMand IgG responses during chronic relapsing allergicencephalomyelitis (r-EAE). J Neuroimmunol1984;6: 265-81.

23 Norton WT, Poduslo SE. Myelination in rat brain-changes in myelin composition during brain matura-tion. J Neurochem 1973; 21:759-73.

24 Kadlubowski M, Hughes RA, Greyson NA. Experimen-tal allergic neuritis in Lewis rat. - Characterization ofthe activity of peripheral myelin and its major basicprotein P2. Brain Res 1980;184:439-54.

25 Vandenbark AA, VanRompaey F, Heyligen H, Nijst D,Raus J. CSF autoantibodies defect brain antigens.Protides Biological Fluids. XXX colloquim 1982:231-4.

26 Levfert AK, Link H. IgG production within the centralnervous system - a critical review of proposed for-mulae. Protides Biological Fluids. XXXII colloquium1984;6:27.

27 Sindic CJM, Cambinso CL, Depre A, Laterre EC, Mas-son PL. The concentration of IgM in the cerebrospinalfluid of neurological patients. J Neurol Sci 1982;55:339-50.

28 Rostrom B. Specificity of antibodies in oligoclonal bandsin patients with multiple sclerosis and cerebrovasculardisease. Acta Neurol Scand Suppl 86 1981:63.

29 Rostrom B, Link H, Laurenzi MA, Kam-Hansen S,Norrby E, Wahren B. Viral antibody activity of oligo-clonal and polyclonal immunoglobulins synthesizedwithin the central nervous system in multiple sclerosis.Ann Neurol 1981;9:569-74.

31 Salmi A, Reunanen M, Ilonen J, Panelius M. Intrathecalantibody synthesis to virus antigens in multiplesclerosis. Clin Exp Immunol 1983;52:241-9.

813



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ownloaded from


cerebrospinal fluid immunoglobulin abnormalitiesin ... · cerebrospinalfluid immunoglobulin...

Documents