BRIEF REPORT. ELIZABETH REINITZ, DAVID HUBBARD, and ARTHUR 1. GRAYZEL

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1 ~ 583 BRIEF REPORT CENTRAL NERVOUS SYSTEM SYSTEMIC LUPUS ERYTHEMATOSUS VERSUS CENTRAL NERVOUS SYSTEM INFECTION: LOW CEREBRAL SPINAL FLUID GLUCOSE AND PLEOCYTOSIS IN A PATIENT WITH A PROLONGED COURSE ELIZABETH REINITZ, DAVID HUBBARD, and ARTHUR 1. GRAYZEL Since infection in patients with systemic lupus erythematosus (SLE) is a major cause of morbidity and mortality, differentiating between infection and active SLE is often a vital part of the care of these patients. The symptoms and signs of SLE can often be mimicked by infection and vice versa. Although new serologic methods are available to help diagnose SLE, these are not always helpful in differentiating a lupus flare from infection in a specific organ. In addition, patients with active disease, regardless of whether they are receiving immunosuppressive therapy, are more susceptible to infection (1). Cultures are helpful, but in acutely ill patients, treatment often needs to be initiated before results are available. Also, some infectious agents are difficult to culture. Central nervous system SLE (CNS-SLE) has been especially difficult to diagnose in the absence of specific laboratory tests, whereas certain laboratory data are generally used to decide whether a CNS episode is caused by infection. Typically, cerebral spinal fluids (CSF) with low glucose and pleocytosis From the Department of Medicine, Division of Rheumatology, and Department of Neurology, Montefiore Hospital and Medical Center, and the Albert Einstein College of Medicine. Supported by a Clinical Research Center Grant from the Arthritis Foundation. Elizabeth Reinitz, MD: Instructor, Department of Medicine, Division of Rheumatology, Albert Einstein College of Medicine; David Hubbard, MD: Instructor, Department of Neurology, Montefiore Hospital and Medical Center; Arthur I. Grayzel, MD: Professor, Department of Medicine, Head of the Division of Rheumatology, Montefiore Hospital and Medical Center. Address reprint requests to Dr. Reinitz, Department of Medicine, Room 360, Albert Einstein College of Medicine, 1165 Moms Park Avenue, Bronx, NY Submitted for publication July 24, 1981; accepted in revised form October 15, are considered indicative of infectious diseases although other diseases, including meningeal carcinoma and sarcoid, can cause hypoglycorrhacia. There is a report (2) of these findings in patients with SLE without infection. We present a patient who had SLE and CNS pathology, as well as CSF pleocytosis and low glucose. For 5 months, we could find no infectious etiology for this patient. We report this case to emphasize the importance of continuously searching for infections in SLE patients who have episodes atypical of SLE flare. Case report. In 1977, our patient (then 14 years old) was diagnosed as having SLE at another institution after she had developed fever, malar rash, and arthralgias. A renal biopsy showed mild proliferative lesions. At that time, the patient had been treated with prednisone. Over the next 2 years, followup was poor, and medication compliance was intermittent. One and one-half years before admission to our hospital, she came to our lupus clinic because of total body pain. She had not taken any medication for 2 months. She was afebrile and had a prominent malar rash and small effusions in both knees. Hematocrit was 35%, and white blood cell (WBC) count was 8,000/ mm3; results of platelet count, renal function test, and urinalyses were normal. Total hemolytic complement (C') was 120 CH50 units (normal >150), and anti-dna was 110 pg DNA bound/ml serum (normal <3). Prednisone (60 mg daily) was started. Results of purified protein derivative (PPD) (5 tu), candida, and trichophyton skin tests were negative. The patient improved clinically and serologically. After she stopped her medication, however, she was admitted to the hospital with fever to 103"F, vasculitic skin lesions, and a stiff back. She refused lumbar puncture but responded Arthritis and Rheumatism, Vol. 25, No. 5 (May 1982)

2 584 BRIEF REPORTS quickly and dramatically when steroids were started again. Similar episodes occurred over the next several months. Treatment with azathioprine 100 mg was started, but the patient probably never took the drug at home. A course of plasmapheresis was attempted but the patient only kept 2 appointments. In January 1980, she became pregnant. She became more compliant with clinic visits and medication (prednisone only), and she was clinically well. Complement was 156 CH5O units and anti-dna 13.5 pg DNA bound/ml serum. Urinalysis results remained normal, and creatinine clearance was 110 ml/minute. On August 26, she was admitted to the hospital because of a headache. Temperature was 100.2"F rectally. She was not cushingoid, and the results of the rest of the physical examination were normal. Results of other routine lab tests and urine and blood cultures were normal or negative. She refused lumbar puncture. She was given prednisone 60 mg daily. On August 27, she no longer had a headache and was afebrile, but she stayed in the hospital for observation. On the following day, she had a worse headache, as well as photophobia and meningisumus with fever to 102 F. There were no rashes or joint effusions. She permitted us to perform a lumbar puncture, which yielded an opening pressure (OP) 110 mmh20, glucose 22 mg/dl, protein 11 1 mg/dl, and WBC 400/mm3 with 40% lymphocytes and 60% polymorphonuclear leukocytes (PMN). Results of counterimmunoelectrophoresis for pneumococcal and meningococcal bacterial antigens, studies for cryptococcal antigen, Gram stain, and acid-fast bacilli stain were all negative. We gave her penicillin, but later changed the treatment to ampicillin. Results of a repeat lumbar puncture the following day were: CSF OP 100 mmh20, glucose 16 mgldl, protein 135 mg/dl, WBC 385/mm3 with 60% lymphocytes and 40% PMN. Results of all other studies were negative. Findings from routine cultures from both lumbar punctures were negative. On a computed tomography (CT) scan (Figure 1 A), left parietal occipital lesion was shown; there was some enhancement with contrast. Results of a chest roentgenogram were normal. A PPD (250 tu) was strongly positive. (The patient's stepfather had a positive PPD for many years. Results of his chest roentgenogram were also normal.) Complement was 250 CH50 units; anti-dna was 4 pg DNA boundlml serum. The patient did not improve. On September 4, ampicillin was discontinued, and isoniazid, ethambutol, and rifampin were started. Within 72 hours, there was improvment: no headache, fever, or photophobia. She again refused lumbar puncture and was discharged on antituberculous medication and prednisone 60 mg/day. We planned to see her as an outpatient and slowly decrease the dosage. On September 22, she was hospitalized in labor and gave birth to a girl of low birth weight with apgar 9/ 10. Our patient was doing well when she went home on September 26. During following week, she took the baby home; the baby was doing well and receiving isoniazid. Cultures for mycobacteria from the CSF samples gave negative results at 6 weeks. On October 23, the patient again had fever, headache, and photophobia, but no localizing neurologic signs. She insisted that she was taking all her medications, but she was not cushingoid. Lumbar puncture results were: OP 100 mmh20; WBC 270/ mm3, with 25% lymphocytes and 75% PMN; glucose 34 mgldl (simultaneous blood glucose 120 mg/dl); and protein 176 mg/dl. Findings from all cultures and stains for organisms were negative. On a CT scan performed October 25 (Figure IB), an increase in the lesion was apparent. Symptoms resolved, but there was no change in the lesion. On November 4, she again had headache with nausea, vomiting, and left ear pain. No ear problems were found. On another CT scan on November 5, further increase in the lesion was shown. On November 7, with the patient under general anesthesia, a cerebral angiogram was performed, followed by a spinal puncture (CLC2 interspace) to obtain CSF for more cultures. The angiogram (Figure 1C) showed abnormal vessels in the area of the CT scan lesion. The neuroradiologist thought these vessels were more consistent with a granulomatous process than with vasculitic lesions. The CSF showed glucose 38 mg/dl (blood glucose 75 mg/dl), protein 140 mg/dl, negative cytology for malignant cells, and WBC 60/mm3, with 85% lymphocytes and 15% PMN. Bacterial, tuberculous, and fungal smears, as well as routine cultures, gave negative results. Neurosurgical consultation was obtained to evaluate the patient for a procedure to obtain tissue. It was concluded that, because she was clinically well except for occasional headaches, any procedure involving the left paretal-occipital area would be too risky, and any other procedure would be unlikely to give a diagnosis. She was receiving prednisone and isoniazid when she was discharged from the hospital on November 10. Late in December she again had fever and headache. On a CT scan, some improvement of the lesion was shown, and her symptoms disappeared. On

3 BRIEF REPORTS 585 A B C D Figure 1. A, computed tomography (CT) scan (8/29/80) of left posterior parietal lesion. B, CT scan (10/25/80) of an increase in the lesion. C, Cerebral angiogram (11/7/80) of abnormal vasculature in the area of the lesion. D, CT scan (1/7/81) of hydrocephalus.

4 ~ ~ ~ ~~ ~ 586 BRIEF REPORTS Table 1. Date 9/79 11/79 1/80 8/28/80 8/29/80 10/23/80 11/7/80 1/7/81 Patient s signs, symptoms, and laboratory findings Opening Signs and Complement pressure Glucose Protein WBCI symptoms anti-dna* mmh20 mgldl mg/dl %PMN Comments Malar rash, No medications for joint effusions past 2 months Asymptomatic, Prednisone 60 mg physical exam daily since 9/79 normal Asymptomatic, physical exam normal Headache Photophobia fever, After receiving IV meningismus ampicillin for 24 hours Fever photophobia, headache Rifampin, isoniazid, and ethambutol as an outpatient since 9/4/80 Slight intermittent Spinal puncture (ClX2 headache interspace) Uncommunicative, CT scan communicating right Babinski s hydrocephalus sign CSF culture + at 3 weeks for M tuberculosis * Total hemolytic complement CH5O units (normal ); anti-dna antibodies, Fg DNA boundml serum (normal < 3.0). t CSF = cerebral spinal fluids; WBC = white blood cell count; PMN = polymorphonuclear leukocytes; CT = computed tomography. CSFt January 2, she was hospitalized with fever, anorexia, lethargy, and disorientation. She became more alert and oriented when she was treated with hydration and intravenous steroids, but continued to fabricate answers to questions and have difficulty with calculations. On January 7, she became more lethargic and developed a right Babinski s sign. Results of lumbar puncture were: OP 500 mmh20, WBC 320/mm3, with 60% lymphocytes and 40% PMN; glucose 27 mg/dl, and protein 199 mg/dl. On CT scan (Figure ld), a communicating hydrocephalus was shown. Triple antituberculous medication was started again on January 8, and high-dose intravenous steroids were continued. She was again somewhat responsive 2 days later. CSF pressure was lowered by daily lumbar puncture. Mental status improved and then degenerated but was never normal. Intermittent fever persisted. On January 21, an Omaya reservoir was placed to make drainage of CSF easier. At the same time, a right frontal meningeal biopsy was done. Results of cultures and histologic studies were negative. On January 28, the tuberculosis laboratory reported growth of a mycobacterium from the CSF specimen from January 7. This was later identified as Mycobacterium tuberculosis resistent to isoniazid, pyrazinamide, cycloserine, and usual concentrations of rifampin (sensitive to streptomycin, ethambutol, and high concentrations of rifampin). Results of chest roentgen- ogram remained negative. For several months, the patient remained disoriented with persistent hydrocephalus, despite placement of a ventriculoperitoneal shunt. Antituberculous medication was continued but the prednisone was tapered to 20 mg daily without evidence of a clinical or serologic lupus flare. The hydrocephalus then gradually decreased, and there was a concomitant improvement in her mental status. In July 1981, she was discharged from the hospital, and she was able to care for herself and her child. The patient s signs, symptoms, and laboratory results from September 1979 through January 7, 1981 are shown in Table 1. Discussion. Though CNS-SLE can be the sole or first manifestation of a disease flare and even the first presentation of SLE (3), it usually occurs when disease activity is manifested in other organs (4). Gibson and Myers (2) reported their experience with 80 SLE patients, 41 (51%) of whom had CNS disease. None of the neurologic features appeared in the absence of other features of SLE. Analysis of CSF obtained during 51 episodes from their 41 patients showed abnormalities in 18 (33%) and low glucose in 4 (8%). White cells were also found in the CSF of 2 of these patients, 1 of whom had paraplegia (WBC 3/ mm3) and 1 of whom had seizures (WBC 22/mm3). The latter also had increased CSF protein (154 mg/dl). The other 2 patients who had low CSF glucose, 1 with

5 BRIEF REPORTS 587 psychosis and ataxia and the other with psychosis only, had no other CSF abnormalities. Andrianakos et a1 (5) reported 3 patients who had transverse myelitis associated with SLE, all of whom had reduced CSF glucose concentration. These authors also reviewed the records of 81 patients with SLE, 19 of whom had neurologic episodes attributed to SLE, CSF had been examined during these episodes. One patient had low CSF glucose but not transverse myelitis. In the literature, they found reports of 20 other patients with transverse myelitis due to lupus. A reduced CSF glucose had been mentioned in only one of these reports. In their review of neuropsychiatric manifestations of SLE in 140 patients, Feinglass et a1 (4) found 52 patients (37%) had such manifestations, and CSF was examined in 37 of them during 44 episodes. Fourteen (32%) were abnormal. Although it was mentioned that CSF findings were occasionally suggestive of an infectious process, glucose abnormalities were not mentioned. CSF pleocytosis is reported in association with CNS-SLE in 10-30% of episodes in which CSF is obtained (2,4,6). Usually, this pleocytosis consists of only a few cells, though occasionally WBC/ mm3 have been reported. Feinglass et a1 (4) reported a 4,900-WBC CSF sample from a patient thought to have CNS-SLE. When serial lumbar punctures are done, fluctuating or transient pleocytosis is shown (7,8). Recurrent sterile meningitis (7,9) has been reported as a manifestation of SLE, but not with reduced CSF glucose concentration. Persistent elevations of 'SF WBC to the hundreds has not been the pattern' In patients for whom high CSF WBCs have been considered to be a symptom Of CNS-SLE9 tissue was not obtained. Thus, hypoglycorrhacia and CSF pleocytosis with persistently elevated protein are unusual for SLE, especially in the absence of myelopathy. Even after 5 months without the discovery of an infectious agent, we wondered if our patient's course could be attributed to SLE alone, especially in this immunosuppressed patient. Because of the studies described in the paragraphs above, we were reluctant to start further immunosuppressive therapy, such as azathioprine, or to begin plasmapheresis. We continued to search for infection. The efforts at diagnosis were hampered by the patient; her family finally informed us of that she had not taken the antituberculous medication. (Lack of cushingoid habitus was not helpful because even after months on high-dose ste- roids in the hospital, the patient was not cushingoid.) The difficulty of culturing tuberculosis from the CSF, especially in a partially treated patient, further impeded our ability to make the diagnosis. The patient probably got worse initially because she did not take her medications regularly and later because of the emergence of drug resistance, likely caused by the intermittent treatment. When she did not improve but claimed she took her medications, the diagnosis of tuberculosis was in doubt. Until we cultured the organism, we could not know that it was resistent to usual medications. CNS-SLE remains a diagnosis of exclusion because there are no generally available tests to diagnose it. It is also difficult to treat, and there is no agreement about which, if any, treatments are effective. There is specific treatment for many CNS infections, however, and these are often effective. Though hypoglycorrhacia can be caused by SLE alone, it is rare, especially in the absence of transverse myelitis or in the presence of marked CSF pleocytosis. We hope our report will encourage others to search for infectious etiologies in patients with SLE and CNS disease that is atypical for the underlying lupus. A continued search is always warranted when results of early studies are negative. REFERENCES 1. Staples PJ, Gerding DN, Decker JL, Gordon RS: Incidence of infection in SLE. Arthritis Rheum 17:l-10, Gibson T, Myers AR: Nervous system involvement in SLE. Ann Rheum Dis 35: , Siekert RG, Clark EC: Neurologic signs and symptoms as early manifestations of SLE. Neurology , Feinglass EJ, Arnett FC, Dorsch CA, Zizic M, Stevens MB: Neuropsychiatric manifestations of SLE: diagnosis, clinical suectrum and relationship to other features of the disease. Medicine 55: , Andrianakos AA, Duffy J, Suzuki M, Sharp JT: Transverse myelopathy in SLE. Ann Intern Med 83: , Abel T, Gladman D, Urowitz M: Neuropsychiatric lupus. J Rheumatol 7: , Canoso JJ, Cohen AS: Aseptic meningitis in SLE. Arthritis Rheum 18: , Keeffe EB, Bardana EJ, Harbeck RJ, Pirofsky B, Carr RI: Lupus meningitis: antibodies to deoxyribonucleic acid (DNA) and DNA: anti-dna complexes in the CSF. Ann Intern Med 80:58-60, Welsby P, Smith C: Recurrent sterile meningitis as a manifestation of SLE. Scand J Infect Dis 9: , 1977