Higher Cortical Dysfunction, Antiphospholipid Antibodies and Neuroradiological Examinations in Systemic Lupus Erythematosus Etsuko Maeshima, Yoichi Yamada, Susumu Yukawa and Hiroshi Nomoto We performed neuropsychological tests to investigate higher cortical dysfunction in 21 patients with systemic lupus erythematosus (SLE). We also measured antiphospholipid anti bodies (APA), performed brain computed tomography (CT), and obtained a single photon emission CT (SPECT) to measure regional cerebral blood flow (rCBF) in order to elucidate a possible relationship between APA and higher cortical dysfunction. Higher cortical dysfunction Although between and cases. higherAPA cortical dysfunction not significant, was notedthe in relationship as many as 16 (76%) APA out of21 were positive inwas 8 (38%) out of21 cases. patients positive for lupus anticoagulant (LA) were found to have higher cortical dysfunction. Brain CT revealed at least one abnormality in 6 cases (29%) but none had a localized lesion, SPECT disclosed a reduced rCBF in 9 cases (43%). The findings on brain CT and SPECT were unrelated to higher cortical dysfunction. (Internal Medicine 31: 1169-1174, 1992) Key words: neuropsychological examinations, brain CT, single photon emission CT, lupus anticoagulant , anticardiolipin antibodies

Introduction of SLE (5) and who were under medical treatment, consisting of 21 females, with a mean age of 33.0 ± 10.9 Among collagenfrom diseases, is known to patient be as- was years (ranging 13 to SLE 50 years). Every sociated with a high incidence of CNS disorders and right-handed. As controls, healthy ranging may, occasionally, be fatal.16 These CNSsubjects disorders may in age from20to53 (mean age: 29.2 ± 9.1; all females) were include hemjplegia, convulsion, thought derangement, involuntary studied andmovement, compared with cranial thenerve SLE group. palsy and All headache under (1), and suggested in a few reports, higher cortical went theas following neuropsychological examinations: dysfunction (1-4). To investigate higher cortical dysfunction in SLEand in this study, we performed neuro1) Intelligence mental function psychological examinations SLE We also Mini-Mental State (MMS): on This testpatients. was examined measured "Kana"-pick antiphospholipid upwith test:the Themethod examinees antibodies, were performed instructed brain in accordance of Folstein et al (6). CT, andout obtained a single"A, photon (SPECT) to pick kana letters, I, U, emission E and O" CT (Japanese to assess and regional bloodwritten flow (rCBF) in an vowels) circlecerebral in sentences laterally in kana attempt to elucidate a possible relationship between which they could understand. If more than 20 such letters antiphospholipid antibodies (APA) and higher cortical were selected within the time limit of two minutes, the dysfunction. result waspaired considered normal. Miyake's associated memory scale: This test Subjects and Methods was performed in accordance with the method of Miyake introducted by Hasegawa (7). The subjects Word recall: The included examinees 21 patients were with instructed SLE who to pro fulfilled the 1982 revised criteriaasfor the classification vide as many names of animals possible during one

From the Third Department of Internal Medicine, Wakayama Medical College, Wakayama Received for publication September 2, 1991; Accepted for publication July 28, 1992 Reprint requests should be addressed to Dr. Etsuko Maeshima, the Third Department of Internal Medicine, Wakayama Medical College, 7Wakayama 640, Japan Internal Medicine Vol. 31, No. 10 (October 1992) 1169

Maeshima et al minute. If more than 12 names were listed, the result was considered normal. Digit span (forward): After the examiner named figures with three to nine digits (723, 4258, , 146897530) the examinee was asked to recite the numbers. Correct recitation of more than 5 digits was considered normal. 2) Linguistic function Aural comprehension, subjective speech, recitation, reading aloud, reading and understanding, writing, and dictation were examined in accordance with the method of Watamori (8). 3) Recognition and praxis Line-bisection test: The subjects were asked to bisect a 20 cm line. Deviation of more than 1 cm was considered abnormal. Line-cancellation task: Forty lines were drawn on a blank sheet of paper 29.6 X 21 cm in size, and the subject was asked to cancel out all of these lines. If more than 3 lines were left uncancelled the result was considered abnormal. Recognition of intricate pictures: The subjects were asked to name objects by tracing their pictures with their fingers. If more than 3 out of 5 objects went unnoticed, the test was considered abnormal. Perspective cube copying test: The subject was asked to copy the perspective drawing of a cube depicted on the upper half of a blank sheetof paper sized 29.6 x 21cm. The drawing was made by the more skillful hand. The criteria used to assess the result were those of Kato Table 1.

Pt 2


10 ll 13 14 15 16 17 18 19 20 21


Age 13 23 26 26 34 17 26 27 27 27 28 29 32 36 39 42 42 49 50 50 50




et al (9). The following blood and neuroradiological examin ations were also performed in studying the SLE patients. 1) Antiphospholipid antibodies (APA) Lupus anticoagulant (LA): The diluted prothrombin time (PT) was used to screen for LA in accordance with the method of Sirridge and Shannon (10). The ratios of coagulation time (diluted PT/ordinary PT) obtained were used to make the assessment. A ratio of less than 3.0 was considered negative, and that of 3.0 or more, positive. Anticardiolipin antibodies (ACA): A microplate ELISA method was used to detect ACA in accordance with the method of Hayama et al (ll). Any value ex ceeding the cut-off index of 1.0 was considered positive. 2) Neuroradiological examinations Brain CT: Slices were cut at 10mm from the OM line using a Toshiba TCT60-A. Low and high absorption fields were assessed. Atrophy of the cerebral cortex and expansion of cerebral ventricles were also noted. SPECT: Regional cerebral blood flow (rCBF) was measured by single photon emission computed tomo graphy (SPECT) using a Starcam 3000XC/T. 123I-IMP (N-isopropyl-p-iodoamphetamine) was used as a tracer of cerebral blood flow. Data was collected beginning 15 minutes after i.v.reduction injectioninofrCBF lll MBq the tracer. Assessment ofan any wasofmade by a neuroradiologist who was unaware of the patient's condition. The results of these examinations were com pared using Fisher's exact test or the grouped t-test.

and Results of Neuropsychological

Subjective symptoms and Dose of steroid on neurological findings the day of testing (mg/day)


H eadach e


H eadach e


H eadach e


D izziness

H ead ach e


H ead ach e D izziness,h eadache


D izziness,h eadach e D izzin ess

in 21 Patients

with SLE

Neuropsychological examinations with an abnormal findings

30 17.5 10 10 10 30 2 .5 30 15




10 7 .5 15 15 10

Cube copying test Cube copying test Miyake's memoryscale, cube copying test Cube copying test Miyake's memoryscale, cube copying test

Cube copying test Miyake's memory scale, word recall, cube copying test Miyake's memory scale lvnyaKe s memoryscaie, cuoe copying test Miyake's memoryscale, cube copying test Miyake's memoryscale Miyake's memory scale, cube copying test Cube copying test Miyake's memory scale, cube copying test Miyake's memory scale, cube copying test Miyake's memoryscale, word recall, cube copying test Internal


Vol. 31, No. 10 (October


Higher Cortical Results 1. Neuropsychological examinations A marked incidence (16/21, 76%) of higher cortical dysfunction, in some form, was noted (Table 1). On intelligence and mental function tests, an abnormality in word recall was seen in 2 cases (9.5%), and on Miyake's paired associated memory scale in ll cases (52.4%). Linguistic function test results were normal in each case. On recognition and praxis tests, all subjects were normal on the line-bisection test, line-cancellation test and recognition of intricate pictures, whereas in the perspective cube copying test, 14 subjects (66.7%) displayed abnormal responses. Out of these 14 cases, 9 had an unskillful response and 7 had para praxis. In comparison, abnormalities on Miyake's paired associated memory scale were noted only in 3 (18.7%) out of 16 healthy controls (Fig. 1). The incidence of higher cortical dysfunction was significantly (p < 0.002) higher in the SLE group. While there was no significant relationship between clinical symptoms, including subjective symp toms, the neurological findings or abnormalities of neuropsychological testing, 10 (62.5%) out of 16 patients who had no clinical symptoms had abnormalities on neuropsychological tests. There was no relationship between prednisolone (PSL) orally and higher cortical dysfunction (p = 1.3892). In addition to PSL, one patient (case 9) used sleep inducers, none used tranquilizers,


in SLE

and two (cases 5 and 21) used nonsteroidal antiinflam matory drugs. There were no significant differences in age, duration of SLE, duration of steroid treatment and dose of steroid on the day of testing between the groups with and without abnormal findings on neuro psychological examinations (Table 2). At the time of testing, only one patient (# 10) had active SLE according to the lupus activity criteria count (12). 2. Antiphospholipid antibodies (APA) The APA were positive in 8 (38%) of 21 cases (Table 3). Of these 8 positive APA cases, 6 had LA and 4 had ACA (IgG plus IgM in 1 case, IgG alone in 2 cases, and IgM alone in 1 case). No significant relation ship was noted between LA or ACA and higher cortical dysfunction. All of the patients who had a positive LA were found to have higher cortical dysfunction (Fig. 2).

Fig. 2. Correlation between higher cortical dysfunction and anti phospholipid antibodies. Fisher's exact test was used for analysis. LA: lupus anticoagulant, ACA: anticardiolipin antibodies, NS: not significant.

Patient 7 Patient 8 Patient 20 Fig. 1. Results of perspective cube copying test.

Table 2. Comparison between Groups with and without an Abnormal Finding on Neuropsychological Examinations

G roup N orm al fi n din gs

D u ration

D uration of steroid

D ose o f stero id o n

adm in istratio n (M o nths)

th e d ay of testin g (m g/day)

65 .6 ア 81.6

13 .5 ア 11.1

N o.

A ge

of SL E (M on th s)


24 .4 ア 7 .6

68 .4 ア 79 .0

N S A b no rm al fi n din gs


35 .7 ア 10 .5

NS 44 .1 ア 52 .5



42.8 ア 52 .」

For statistical analysis, the grouped t-test was used. Values are presented as the mean ± SD NS: not significant. Internal


Vol. 31, No. 10 (October



Maeshima et al Table 3.



1 23


of Antiphospholipid



and Neuroradiological


CT findings


of 21 Patients

with SLE

SPECT findings

+ (IgG, M) Cortical atrophy + (IgG)


Cortical atrophy

Reduced rCBF in rt-parietal, rt-temporal and It-frontal lobes Reduced rCBF in bil-parietotemporal lobes

Cortical atrophy 78 9 10 ll 12 13 14 15 16 17 18 19 20 21

Reduced rCBF in bil-frontal lobes Reduced rCBF in rt-temporoparietal lobes

+ (IgM)




cavumsepti pellucidi



Reduced rCBF in bil-frontal



Reduced rCBF in rt-temporoparietal lobes

+ (IgG)

Reduced rCBF in rt-frontoparietal



Reduced rCBF in bil-temporooccipital lobes Reduced rCBF in bil-frontal lobes

Pt: patient, LA: lupus anticoagulant, ACA: anticardiolipin antibodies, CT: computed tomography, SPECT: single photon emission computed tomography, rCBF: regional cerebral blood flow. 3. Neuroradiological examinations Brain CT revealed cortical atrophy in 6 cases and cavum septi pellucidi in 1 case (Table 3). No patient had a focal lesion. SPECT revealed reduced rCBF in 9 cases (43%). In 3 of these patients, reduced rCBF was noted in the right hemisphere and in the other 6 patients, rCBF reduction to both right and left was noted (Fig. 3). Of the patients with higher cortical dysfunction, 8 had no abnormal finding on brain CT and SPECT, 1 had abnormalities only on brain CT, 4 had abnormalities only on SPECT, and 4 had abnormalities on both brain CT and SPECT. Thus, abnormal radiological test results were obtained in 8 out of 16 patients who had higher cortical dysfunction. The findings on brain CT and SPECT were not found to be related to higher cortical dysfunction. Discussion

dated memory scale, word recall and digit span, an abnormality was noted in 52.4% (ll/21) of the patients studied. On the constructional praxis test using cube copying, 61.9% (13/21) of the patients demonstrated constructional apraxia. The incidence of such abnor malities on the described neuropsychological tests was significantly higher in the SLE group than in the healthy control group. Treatment with oral PSL was unrelated to higher cortical dysfunction. Furthermore, there were One these three patients wastaking foundorally to have no higher onlyofthree patients who were drugs such as sleep inducers cortical dysfunction and nonsteroidal and anotherantiinflammatory one was found todrugs. have been given antiinflammatory drugs only occasionaly, thus making it inconceivable that the drugs would have influenced the test results. Thus, the higher cortical dysfunction detected in the present study was considered to be associated SLE itself. Carbotte et al (3)with and Nagaoka et al (4) studied intel

SLE is known, among collagen diseases, as a disease likely complicated by a CNS disorder. However, studies of higher cortical dysfunction in SLE patients are few (1 -4). Moreover, these studies used a fragmented neuro psychological approach, and no systematic approach has been completed. In the present study, we performed neuropsychological tests of intelligence, mental function, linguistic function and recognition and praxis to investi gate higher cortical in SLE patients. On intelligence and dysfunction mental function tests, including

ligence and mental function in SLE patients, using the Wechsler adult intelligence scale (WAIS), Wechsler memory scale, and Miyake's paired associated memory scale. In the present study, the incidence of abnormalities was the highest on the Miyake's paired associated memory scale test, suggesting that effects on the limbic system, the hypothesized center of memory, are common in SLE. The present report is the first to document con structional apraxia in patients with SLE. Constructional apraxia, which is reported to occur in the presence of both focal and diffuse lesions in the cerebrum, seems to

the MMS, "Kana"-pick up test, Miyake's paired asso1172



Vol. 31, No. 10 (October


Higher Cortical


in SLE

improvement or worsening of higher cortical dysfunction was observed after remission or exacerbation of SLE activity. In these cases, higher cortical dysfunction is believed to have resulted from reversible changes, such as hypo function of cranial nerve cells, rather than from an irreversible process, such ascortical cerebral infarction. 8 Out of 16 patients with higher dysfunction, were found to have abnormalities on brain CT or SPECT. The relationship between these abnormalities and higher AXIAL AXIAL cortical dysfunction was not clear. This result would reflect that CT and SPECT detected morphological changes or organic abnormalities, whereas neuropsycho logical tests detected functional abnormalities. However, the finding of an abnormality on the neuropsychological tests may be thought to definitely indicate some disorder in the cerebral cortex. Therefore, even when no lesion is found on brain CT or SPECT, it cannot be concluded The that etiology no abnormality of CNSexists disorders in the in CNS. SLE may result from 1) cerebral vasculitis, 2) autoantibody reaction with nerve cells, or 3) thrombosis involving APA (13). SAGITTAL SAGITTAL However, cerebral vasculitis has actually been noted in only approximately ten percent of autopsied patients (13, 14). It seems, therefore, that CNS cerebral vasculitis is uncommon. On the other hand, there have recently been several cases regarding APA (15-21) and much attention has been drawn to cerebrovascular obstruction due to this factor. In the binding of phospholipid in vascular endothelial cell membranes, APA is thought to inhibit the production or release of PG-I2, thereby inducing platelet aggregation to produce a thrombus (22-24). Alternatively, APA may act by inducing platelet CORONAL CORONAL aggregation following reaction with phospholipid in Patient 7 Patient 8 platelet membranes (25, 26), inhibition of prekallikrein Fig. 3. SPECT studies of two patients. In case 7, reduced (27), reducing anti-thrombin III (28) and inhibiting rCBF was noted bilaterally in the frontal lobes. In case 8, reduced rCBF was noted in the right temporoparietal lobes. protein C (29). Among APA, the LA and IgG type of ACA seem to play an important role in causing throm bosis (30-33). Of the present subjects studied, only 4 be a useful indicator of cerebral dysfunction. had ACA. Furthermore, in 2 patients who had IgG On the other hand, there was no relationship between ACA no higher cortical dysfunction was noted. On the higher cortical dysfunction and the patients' subjective other hand, all 6 patients who were positive for LA had symptoms, and cerebral disorders were present even in higher cortical dysfunction. In LA positive patients, it patients who had no complaints. Thus, neuropsycholog This thatcranial the LAnerve may be thewere cause of the higher was suggests thought that cells damaged by ical tests seem to be useful for detecting such disorders. In most of the present patients, SLE was inactive and a cortical dysfunction. In conclusion, in SLE patients, chronic brain circulation disturbances due to thrombi. higher incidence of higher cortical dysfunction was noted a high incidence of higher cortical dysfunction such as in these patients. Therefore, higher cortical dysfunction lowered intelligence, mental function and constructional is believed to be exist in SLE irrespective of the activity apraxia, is found. Further, LA may be an important factor of SLE. During follow-up observations, however, the in the pathogenesis of this higher cortical dysfunction. ability of one patient (# 8) to copy a cube varied with Acknowledgement: The authors wish to thank Shinichiro Maeshima the SLE activity/ In one patient (# 10), memory and for his helpful suggestions and cooperation in neuropsychological constructional apraxia were improved after remission of examinations. the SLE activity was induced by treatment and in one patient (# 20), improvement of cube copying was noted after treatment. Thus, there were also cases in whom Internal


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Maeshima et al

References Dubois EL, Wallace DJ. Clinical and Laboratory Manifestations of Systemic Lupus Erythematosus. in: Dubois, Lupus Erythematosus. Third edition. Dubois EL, Ed. Lea & Febiger, Philadelphia, 1987.

Dalmas JF, Mandilaharsu C. Lupus eritematoso diseminado comenzando por desestructuracion de las funciones superiores del sistema nervioso central. Acta Neurol Latinoamer 26: 39, 1980 (abstract in English). Carbotte RM, Denburg SD , Denburg JA. Prevalence of cognitive impairment in systemic lupus erythematosus. J Nerv Ment Dis 174:



Nagaoka S, Tani K, Chiba J, et al. Study on psychological applied to patients with systemic lupus erythematosus.

tests The

Ryumachi 23: 12, 1983 (in Japanese). Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25: 1271, 1982. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12: 189, 1975. Hasegawa K. Examination of senile psychological function. Sandoz Press, Tokyo, 1977, p. 43 (in Japanese). Watamori T. Assessment of higher cortical functions. 1. Aphasia. Sogo Reh abiriteshon 10: 771, 1982 (in Japanese). Kato M, Sano Y, Uno A. Constructive deficits in brain damaged patients. Effect of the localized and/or duffuse cerebral lesions. Higher Brain Function Research 8: 305, 1988. Sirridge MS, Shannon R. Lupus anticoagulant (Tissue thromboplastin ihibitor test) , in: Laboratory Evaluation of Hemostasis and Thrombosis. Third edition. Sirridge MS, Shannon R, Eds. Lea & Febiger, Philadelphia, 1983, p. 198. Hayama K, Yamamoto S, Ozaki Y, Takahashi M. Fundamental examination and the reference values of anticardiolipin antibodies. Jpn J Clin Pathol 37; 1181, 1989 (in Japanese). Urowitz MB, Gladman DD, Tozman ECS, Goldsmith CH. The lupus activity criteria count (LACC). J Immunol ll: 783 , 1984. McCune WL, Golbus J. Neuropsychiatric lupus. Rheum Dis Clin North Am 14: 149, 1988. Bresnihan B. CNS lupus. Clin Rheum Dis 8: 183, 1982. Tobelem G, Cariou R, Camez A. The lupus anticoagulant and its role in thrombosis. Blood Reviews 1: 21, 1989. Kushner M, Simonian N. Lupus anticoagulants, anticardiolipin antibodies, and cerebral ischemia. Stroke 20: 225, 1989. Buchanan RRC, Wardiaw JR, Riglar AG, Littlejohn JO, Miller MH.Antiphospholipid antibodies in the connective tissue diseases. The relation to the antiphospholipid syndrome and forme fruste diseases.


J Rheumatol

16: 757,


Alarcon-Segovia D, Deles M, Oria CV, et al. Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus. A prospective analysis of 500 consecutive patients. Medicine 68: 353, 1989. Asherson RA, Khamashta MA, Gil A, et al. Cerebral vascular disease and antiphospholipid antibodies in systemic lupus ery thematosus, lupus-like disease, and the primary antiphospholipid syndrome. Am J Med 86: 391, 1989. Kitagawa Y, Gotoh F, Koto A, Okayasu H. Stroke in systemic lupus erythematosus. Stroke 21: 1533, 1990. Coull BM, Goodnight SH. Antiphospholipid antibodies, pre thrombotic state, and stroke. Stroke 25: 13, 1990. Carreras LO, Defreyn G, Machin SJ. Arterial thrombosis, intra uterine death and "lupus" anticoagulant: Detection of immuno globulin interfering with prostacyclin formation. The Lancet 31: 244, 1981. Carreras LO, Vermylen JG. "Lupus" anticoagulant and throm bosis - Possible role of inhibition of prostacyclin formation. Thromb Haemostas 48: 38, 1982. de Wolf F, Carreras LO, Moerman P, Vermyelen J, van Assche A, Renaer M. Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent fetal loss, and a lupus anticoagulant. Am J Obstet Gynecol 142: 829, 1982. Harris EN, Gharavi GRV. Antiphospholipid antibodies. Clin Rheum Dis ll: 591, 1985. Feinstein DI. Lupus anticoagulant, thrombosis and fetal loss. N Engl J Med 313: 1348, 1985. Sanfelippo MJ, Drayna CJ. Prekallikrein inhibition associated with the lupus anticoagulant: A mechanism of thrombosis. Am J Clin Pathol 77: 275, 1982. Cosgriff TM, Martin BA. Low functional and high antigenic antithrombin III level in a patient with the lupus anticoagulant and recurrent thrombosis. Arthritis Rheum 24: 94, 1981. Comp PC, DeBault LE, Esmon NL, et al. Human thrombomodulin is inhibited by IgG from two patients with non-specific antico agulants. Blood Suppl 1: 229a, 1983. Mueh JR, Henneth KD. Thrombosis in patients with lupus anticoagulant. Ann Intern Med 92: 156, 1980. Boey ML, Colaco CB, Gharavi AE, Elkon KB, Loizou S, Hughes GRV. Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med J 287: 1021, 1983. Jude B, Goudemand J, Doile I, et al. Lupus anticoagulant: a clinical and laboratory study of 100 cases. Clin Lab Haematol 10: 41, 1988. Font J, Cervera R, Lopez-soto A, et al. Anticardiolipin antibodies in patients with autoimmune diseases: Isotype distribution and clinical associations. Clin Rheum 8: 475, 1989.



Vol. 31, No. 10 (October


Higher cortical dysfunction, antiphospholipid antibodies and neuroradiological examinations in systemic lupus erythematosus.

We performed neuropsychological tests to investigate higher cortical dysfunction in 21 patients with systemic lupus erythematosus (SLE). We also measu...
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