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Recent observations on central nervous system lupus erythematosus
Recent Observations on Central Nervous System Lupus Erythematosus David A. Bennahum
and Ronald P Messner
T
HIS PAPER will review recent observations on the central nervous system (CNS) manifestations of systemic lupus erythematosus (SLE). Central nervous system involvement in SLE was first reported in detail by Kaposi’ in 1872. Twenty-three years later Sir William Osler2 distinguished SLE from the septic erythemas such as subacute bacterial endocarditis. Between 1949 and 1966 the clinical spectrum of central nervous system systemic lupus erythematosus (CNS-SLE) was further clarified by Harvey and his co-workers3.4 and by Dubois.5-7 A thorough review of the pathology and symptomatology of CNS-SLE was published by Johnson and Richardsonsin 1968. In the past 6 years there has been a remarkable increase in interest in the neurologic and psychiatric manifestations of SLE. Early diagnosis and proper treatment now offer the individual with CNS-SLE a much improved prognosis over that of 10 years ago. It is the purpose of this paper to summarize the available theoretical and practical knowledge necessary for the best care of these patients. INCIDENCE
AND
SURVIVAL
OF PATIENTS
WITH
CNS-SLE
Many authors have presented data on the incidence and survival of patients with SLE. The reports of CNS-SLE are summarized in Table 1. The percentage of patients with neurologic and psychiatric symptoms ranges from 14% to 75% and from 25% to 70% respectively. The incidence of psychiatric manifestations depends to some extent on the psychiatric sophistication of the observer. The survival of all patients with SLE has been reported as between 5 1% and 77% at 4 years.28-31 Estes and Christian” found a 4-year survival rate of 55% for patients with CNS-SLE compared to 76.9% for all SLE patients. In their study, patients with neurologic signs or organic mental syndromes had approximately 47% 4-year survival rates, compared to 85% for seizures or functional psychoses. Two other recent reports have stressed that CNS disease is a major cause of death in SLE patients. Feng, Cheah, and Lee32 report that one-third of the 30 deaths in their series of 167 patients in Singapore were due to CNS disease, while Cheatum et a1.14found that death in 70% of patients without renal disease was From rhe Department of Medicine, University of New Mexico Center for the Health Sciences, Albuquerque, N’. Mex. David A. Bennahum, MD.: Rheumarologist: Director, Medicine Clinics; Assistant Professor of Medicine; Department of Medicine. University of New Mexico Center for the Health Sciences. Ronald P. Messner, M.D.: Rheumatologist: Director. Rheumatology Clinic; Associate Professor of Medicine; Departmenr of Medicine, Universiry of New Mexico Center/or rhe Health Sciences. This work was supported in part by grants AM 13789-m and AM 70301-01 from the National Instirutefor Arthriris and Metabolic Disease. Requests for reprints may be addressed lo David A. Bennahum. M.D.. Bernalillo County Medical Cenrer. General Medicine Clinic, 221 I Lomas Blvd., N.E.. Albuquerque, N. Mex. 87106. 0 1974 by Grune & Slratron. Inc.
Semmars
,n Arrhriris
and Rheumatism,
Vol 4. No. 3 (Februan/). 1975
253
254
BENNAHUM
Table 1. Previous Reports on the Incidence Number
of Neuropsychiatric of
Percent
Patients Date
with
SLE
Dubois6
1964
520
O’Connor9
1966
1066t
Total
l
Symptoms with
in Patients with SLE
Neuropsychiatric Neurologic
25.5
150$
AND MESSNER
Symptoms Psychiatric
_
_
14
25
60
14
51
Johnsons
1968
24
75
75
33
Heinelc
1969
38
50
13
44
Estes” Quismoriol2
1971 1972
150 137
59 34
48 -
42
Ganzls
1972
68
Cheatumt4 Jessepls
1972 1973
30 130
66 25
Cadal
1973
28
-
-
33
Baker17
1973
17
-
-
41
Bennahum
1974
54
705
57
59
lPercentage tSummary
of patients with either neurologic of literature
or psychiatric
-
71
-
43
symptoms.
prior to 1965.4,6,1s-27
$O’Connor’s
own patients.
§Neurologic
and organic-psychiatric
symptoms.
Patients
with functional
psychiatric
symptoms
are excluded.
CNS-SLE. Jessep,15 in a series of 130 patients from South Africa, most of whom were Bantu, found that 25% had neurological symptoms. Of these, 9.2% had convulsions and 4.6% had psychoses. The 5-year survival of his patients was 65.5%. Cerebral vascular disease was the second most common cause of death. Dubois33+34has described a definite change in the prognosis of CNS-SLE over the past 23 years. He notes that from 1950 to 1973 the percentage of deaths due to CNS-SLE decreased from 27% to 8%. During the same period deaths from renal disease decreased from 27% to 13%, while the mean survival for all SLE patients rose from less that 1 year to 8.5 years. He attributes the change in survival to corticosteroids, hemodialysis, and renal transplantation. A trend to better prognosis with combined treatment with corticosteroids and immunosuppressive drugs such as azathioprine and chlorambucil has also recently been observed.35*36 due to
PATIENTS WITH
SLE FOLLOWED
AT THE UNIVERSITY
OF NEW MEXICO
CENTER FOR THE HEALTH SCIENCES
In a retrospective review of our records at the University of New Mexico Center for the Health Sciences, 54 patients met the criteria for SLE as suggested by the ARA37 or as modified by David and his co11eagues.38The results are summarized in Table 1 and are similar to those found in the literature. The variety of symptoms and laboratory findings in our patients are summarized in Table 3 and again are much like those reported elsewhere and shown in Table 2. Of our patients, 88.8% were female. Neurological findings were seen in 57.4%, organic psychiatric symptoms in 16.6%, and functional psychiatric symptoms in 53.7%. By organic, we mean overt thought disorder, hallucinations, delerium, confusion, and so forth. Functional is considered to include the oriented patient without a thought disorder, disorientation, or confusion who is anxious and depressed and who may have various somatic complaints. Of our patients, 16.6% died.
CNS LUPUS ERYTHEMATOSUS
Table 2. Neurologic
Symptoms
255
in Central
Nervous System Systemic Lupus Erythematosus~8,11,45 Totals
59%
Psychoses
TOtals 5%
Paralysis
Delerium
Paraplegia Hemiplegia
Schizophrenia
Aphasia
Catatonia
Transverse
Paranoia Confusion
Movement
Hypomania
Chorea Hemiballismus
Progressive dementia 13.8%-509/o
Epilepsy
Cerebellar
ataxia
Parkinson-like
Grand mal
Dysphagia
Petit mal
Peripheral
Focal Temporal
5%-33%
Cranial Nerve
11.7%
glove
Mixed sensory and motor pain Hyperesthesia
Visual defects Homonomous
Neuropathy
Stocking
lobe
Dysesthesia
hemianopia
Burning
Blindness Papilledema Extraoccular Tinnitus
myelitis Disorder
movement
abnormalities
multiplex
Guillan-Barre
type
Neurogenic
and vertigo
Pupillary
Mononeuritis
bladder
Loss of sphincter control
disturbance
Nystagmus Ptosis Optic atrophy Facial palsy
Table 3. Clinical Systemic
Findings in 54 Cases of SLE* Neurological
Psychiatric
Anemia
35
Convulsions
Rash
34
Coma
Arthritis
33
Headache
Renal disease
21
Hyperesthesia
6
Nervousness
Hypertension
18
Decreased vision
8
Emotional
Cardiac involvement
13
Hemiplegia
7
Confusion
Fever
15
Aphasia (expressive)
4
Hallucinations
3
Pleural effusion
11
Burning or itching of face
4
Anxiety
3
7
Ataxia
3
Staring
2
4
Retinitis
3
Shaking
2
4
Pain of tongue or mouth
2
Catatonia
2
4
Slurred speech
2
Loss of memory
2
3
Opthalmoplegia
1
Somatization
2
2
Optic atrophy
Dementia
2
Hemiballismus
1 1
Grinding
2
Chorea
1
Suicide attempt
1
2
Neurogenic
1
Insomnia
1
2
Pain of hands and feet
Urinary-tract Family
infection
history
Weight loss Alopecia Abdominal
pain
Hemoptysis Spontaneous
abortion
Dysphagia Tracheolaryngeal Hepatomegally
edema
Splenomegally
2
Telangiectasia
2
12 8 10
bladder
*A finding is recorded only once for each patient.
1
Depression
13
Altered
11
reality testing
Fatigue
7 5 lability
5 4
1 teeth
1
256
BENNAHUM
AND
MESSNER
It is important to note that almost all patients seen by authors (that is, since 1969) have been thought to have functional psychiatric symptoms at one time or another. Such symptoms were rarely mentioned when the records prior to 1969 were reviewed. Our patients, however, would seem to correlate well with the findings of other observers, as noted in Tables 1 and 2. NEUROLOGIC
FINDINGS
SLE is a disease that has been compared to syphilis because of the variety of neurologic and psychiatric symptoms that it can display (Table 2). Dubois7 in his 520 cases of SLE found that 13.8% had seizures, 12.1% psychoses, 11.7% peripheral neuritis, 10% retinal hemorrhages, and 9.6% fundic lesions. Eventually, 25.5% of his patients had CNS damage. In most series, seizures are the most common single neurologic symptom. In some patients, a history of epilepsy may antedate the onset of classical SLE by several years. This often creates a diagnostic problem for several of the hydantoin and primidone drugs used in the control of epilepsy are known to activate or induce the symptoms of SLE. 3QWithdrawal of the anticonvulsant or change to another medication may result in a clearing of the SLE and thus allow a diagnostic separation of drug-induced SLE from idiopathic SLE. Other drugs used in the treatment of CNS disease that may induce SLE include ethusuccimide40-42 and the phenothiazines. 43Fabius44 found 10 cases of SLE among 1800 mental patients. In eight of these patients the SLE was thought to be due to phenothiazine. Cranial nerve involvement is most frequently manifested as opthalmoplegia, but may take many forms. A review by Bennett and his associates45 arrived at an incidence of cranial nerve involvement between 5% and 33%. Lundberg and Werner46 have found five females with SLE with trigeminal sensory neuropathy. In 4 patients symptoms were bilateral, and vascular lesions in the medulla oblongata were suspected. A variety of symptoms occurred, including numbness, decreased sensibility, pain of the face, a bulky feeling of the tongue, loss of articulation, burning of the teeth, scintillation at the borders of the visual fields, numbness of the nose, horizontal-rotary nystagmus, and intense shooting pains triggered by touch. All 5 patients responded to treatment with carbamazepine alone. Other neurological manifestations are paralysis of one or several motor groups, neuralgia, headaches, chorea, hemiballismus aphasia, and peripheral neurpathy.47-52 Retinal lesions are also frequent in SLE, but loss of vision has become rare with the use of corticosteroids. Bisko53 reported a case of the rapid onset of blindness in a young black woman with a presenting complaint of blurred vision and frontal headaches. The retina revealed poor perfusion of the capillary bed, exudates, edema, hemorrhages, arteriolar spasm, and venous stasis. Steroid treatment was followed by regression of the lesions, but no improvement of vision. The authors have a similar case in one of their clinic patients. Pfaffenback and Hollenhorst54 have also described 2 young white women with SLE involving the CNS who developed microangiopathy of the retinal vessels. One had return of vision after prednisone therapy, while the other did not. Chorea is an uncommon finding in SLE, but must be distinguished from that
CNS LUPUS
257
ERYTHEMATOSUS
Table 4.
Neurological
at the University
and Psychiatric of New Mexico
Patient
Findings in 54 Patients with SLE Center for the Health Sciences
No.
Percentage
Total
54
Female
48
Male Neurological
symptoms
Organic psychiatric
symptoms
Functional
psychiatric
symptoms
Neurologic
and organic psychiatric
symptoms
combined
Death
100% 88.8%
6
11.1%
31
57.4%
9
16.6%
29
53.7%
38
70%
9
16.6%
occurring with rheumatic fever. Only 27 cases were found in a recent review of the literature.55 We have seen 1 case of chorea in our clinical practice. The patient was a 16-year-old white schoolgirl whose symptoms developed while receiving 60 mg of prednisone and 150 mg of azathioprine each day. The chorea remitted when the prednisone was increased to 200 mg a day and then was tapered slowly to her usual dose. We are also following a 27-year-old Spanish-American female with recurrent hemiballism and a permanent expressive aphasia who responds to increased corticosteroids. A peculiar CNS response to phenothiazines and to tricyclic antidepressants is that of extrapyramidal symptoms (EPS). Shaaf and Payne5fi reported that this occurs in hypoparathyroidism. A recent study suggests that the tendency for these drugs to produce EPS is enhanced in SLE when renal failure lowers ionized calcium.57 Corticosteroids also decrease intestinal calcium absorption and increase renal calcium excretion. Eight patients were on prednisone when given trifluoperazine, which then induced EPS in 4. Of the 4,3 had SLE. Lastly, a fascinating case was reported by Kaplan and his colleagues”* of a 2% year-old white female with SLE who developed tinnitus, vertigo, right auditory nerve deafness, mononeuritis multiplex, central hyperventilation, inappropriate secretion of antidiuretic hormone, and left-sided hemiparesis. Autopsy revealed random foci of vascular encephalopathy, including the pontine portions of the brain. Both supraoptic and paraventricular hypothalamic nuclei exhibited gliosis, acute neuronal degeneration, and a decrease in neurosecretory cells. PSYCHIATRIC
OBSERVATIONS
In a thorough review of the literature, Heine”’ noted that “many reports are of limited value as psychiatric diagnostic categories are not clearly used.” He found that the incidence of organic-toxic states was approximately the same 29% in the reports of four separate authors.4J*23.25 On the other hand, the incidence of “functional” mental illness varied widely and was often omitted entirely. In 38 cases he found an incidence of 24% for organic-toxic states and of 18% for functional depressive illness. His impression is that corticosteroids rarely are at fault in the genesis of the psychiatric complaints of SLE. He notes, however, that the organic-toxic states are associated with a worsening of the systemic manifestations of SLE, whereas the functional depressive states are not. The former requires intensive medical treatment, the latter psychotherapeutic intervention. Gurland5g and his colleagues have also noted that frequent errors are made by
258
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AND
MESSNER
various examiners when looking at the psychiatric symptoms found in SLE. They observed that the psychiatric symptoms found in SLE rarely last more than 6 months and are commonly of less than 6 week’s duration. They also noted that a worsening of the general physical condition of patients tended to accompany psychiatric disorders. An increase in the dosage of corticosteroids, however, rarely preceded the onset of psychiatric symptoms. In their review of the literature it was found that psychiatric signs and symptoms were described in less than 20% of the patients before 1960 and more than 40% of the patients after 1960, and they postulated that this may be due to more psychiatric examinations being applied to patients with SLE. In reporting psychiatric data on SLE patients, they strongly recommended using standard diagnostic criteria. They suggest that a distinction must be made between the various psychiatric syndromes in order to distinguish a reactive depression from a CNS-SLE-induced psychosis, and they discovered a clear distinction between these two entities. In a second paper continuing the earlier study, Ganz and her colleagues13 compared 68 patients with SLE to 36 patients with rheumatoid arthritis. The patients with SLE indeed had more psychiatric symptoms than those with rheumatoid arthritis. This confirms what Nissenso reported in 1936: that only three of 500 patients with rheumatoid arthritis had major psychiatric disorders. The point that Ganz and her colleagues stress is that many SLE patients suffer from depression, which must be distinguished from organic psychoses. In our haste to treat neurological and psychotic manifestations with increased corticosteroids, we should not forget that most of these patients have a situational depression, which often needs psychotherapeutic intervention. In two recent papers in this journal, Baker and his colleagues17*61pointed out that psychopathology is extremely frequent in SLE. In their 17 patients they found a wide variety of psychiatric symptoms, which they grouped into four basic groups: pure affective syndromes, pure organic brain syndromes, pure schizophreniform syndromes, and mixed syndromes. Serious psychiatric syndromes were observed in 41% of the patients. A mixed syndrome characterized by a combination of organic symptoms and either affective or schizophreniform symptoms was the most common, occurring in 45% of the patient episodes. The other syndromes were less frequent. In the second paper, Baker and his associates attempted to differentiate between psychopathology due to organic disease and corticosteroid administration. They found no correlations between psychopathology and either the severity of SLE or the associated CNS manifestations. They did not find that corticosteroid therapy could be implicated as the cause of the majority of psychiatric manifestations, and they came to the conclusion that it was the SLE itself that was responsible for the majority of the psychiatric symptomatology. The occurrence of corticosteroid-induced psychosis cannot, however, be totally excluded, as Cade and his co-workers16 state that a psychosis occurred in 9 of 28 patients with SLE receiving prednisone. The psychoses cleared in 6 patients when the prednisone was decreased. Other psychiatrists have questioned the degree to which the course of SLE is affected by emotional factors. A report from the Menninger FoundatioiP suggests that the mind’s protective response to the organic changes in the brain de-
CNS LUPUS
259
ERYTHEMATOSUS
pends on the patient’s premorbid personality, ego strength, and environmental stress and that these factors affect the symptom complex seen in each patient. Graemee3 reminds us that the work of Solomon64*65 and others suggests that “there is considerable evidence to show that the emotions influence the immunologic system, with the hypothalamus playing an important role.” He speculates as to whether SLE is a psychoimmunological disorder and notes a case of Janeway in which a patient with severe SLE was cured through psychotherapy.66*67 He supports his argument with Engel’s view that a “giving-up-given-up” complex will lead to a physiologically hypoactive state that renders an individual more susceptible to disease. The theory that psychologic factors may influence a disease such as SLE may find some physiologic basis in recent work that suggests that the autonomic nervous system through its effects on leukocyte and lymphocyte cyclic AMP and GMP may play a role in regulating immunologic responses.6g RECENT OBSERVATIONS
ON THE PATHOPHYSIOLOGY
OF CNS-SLE
Classically, patients with CNS-SLE have had cerebral spinal fluid pleocytosis, rarely exceeding 200 cells per cubic millimeter. A slight increase in cerebral spinal fluid protein may occur, but the opening and closing pressures are usually normal. The light-microscopic pathologic lesion appears to result from degenerative and proliferative changes of the small arterioles and capillaries, followed by microinfarction and hemorrhage and proliferation of the perivascular glial cells.R,70Large hemorrhages can result from this process, but are less common. True arteritis is rare. The lesions are peculiar in that varied states of evolution may coexist, and the correlation between pathologic and clinical findings is often poor. Dubois,’ reporting on autopsy material, noted that hemorrhagic foci of necrosis, thickened and hyahnized arterial walls, cellular degeneration, mononuclear and polymorphonuclear infiltration, and formation of corpora amylacea and dark-staining granular material throughout the brain were common to 10 of these autopsies. In 1971 Petz and his co11eagues7omeasured cerebral spinal fluid complement. They found that the fourth component of complement (C4) is low in the cerebral spinal fluid of patients with CNS-SLE and that this drop is not a reflection of a low serum complement. All of their 11 patients with clinical findings indicating CNS involvement had abnormally low levels of cerebral spinal fluid C4, while the CSF C4 was normal in 90 of 95 patients with diseases other than SLE. They noted that other workers have observed deposits of gammaglobulin and complement within and around the small vessels of the brain in animals. They suggest that the neuropsychiatric manifestations of CNS-SLE are mediated by the biological activities of the activated complement system within the CNS. Immunological reactions occurring at different locations within the CNS are thus presented as one explanation for the variety of bizarre neuropsychiatric manifestations of SLE. Hadler and his co-workers have made a similar observation.” In 1972 Levin et a1.72reported on immunoglobulin G (IgG) levels in cerebrospinal fluid. They ascertained that patients with active SLE without CNS
260
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AND MESSNER
symptoms had normal IgG levels. This included one patient who had a corticosteroid-induced encephalopathy. Twelve patients with active CNS-SLE, however, had significant lowering of the CSF IgG at some time during the active phase of disease. They felt that this strengthened the concept that CNS manifestations in SLE have an immune pathogenesis and might be the product of locally produced antibody fixing to the CNS tissue with subsequent complement fixation. Alternately, they proposed that immune complexes, possibly DNA anti-DNA could be trapped in the basement membranes of the choroid plexus with subsequent complement fixation. Of note is that in demyelinating diseases, such as multiple sclerosis, the IgG level is usually above normal; therefore, in the differential diagnosis of these disorders from that of SLE, the low IgG found in the latter may be quite useful. Another interesting observation on CSF in CNS-SLE was recently made by Harbeck and his associates.73 They reported on the occurrence of DNA antiDNA complexes in the spinal fluids of 3 patients with CNS-SLE, but they did not find them in patients with SLE without cerebritis or in non-SLE patients. Keeffe and his co-workers74 have also described a single SLE patient with meningitis in whom no microorganisms were found. The patient’s CSF had a polymorphopleocytosis, a low complement, antibodies to DNA, and DNA anti-DNA complexes. In support of the idea that immune complexes may be involved in CNS-SLE, Atkins and his col1eagues75 have demonstrated complexes in the choroid plexus of patients dying of SLE. This fascinating finding has also been noted in (NZB/ NZW) F, mice, who develop an illness similar to human SLE. With immunofluorescence and electron microscopy, Lampert and Oldstone were able to demonstrate IgG and the third component of complement in the mouse choroid plexus. These deposits appeared shortly after the development of antinuclear and anti-DNA antibody in the circulation. They therefore suggested, extrapolating from mice to man, that the neuropsychiatric findings in patients with SLE may be due to immune-complex disease of the choroid plexus. In addition to immune complexes, antibodies directed against neuronal tissue have also been found in SLE patients. Using an indirect immunofluorescent technique, Quismorio and Friou’* demonstrated antineuron antibodies in 23 of 137 patients with SLE. Forty-one percent of the patients with active CNS-SLE and 24% of patients with a history of CNS-SLE had these antibodies in their serum, compared to 9% of SLE patients who had no history of CNS involvement. Antineuronal antibodies have also been found in a patient with drug-induced SLE,77 as well as other diseases such as carcinomatous neuropathy, multiple sclerosis, myasthenia gravis, and Mycoplasmapneumoniae infections. In search of specific infectious agents, Phillips and Christian’* have found significantly increased antibodies to measles and parainfluenza type I viruses in SLE. Seventy-five percent of those SLE patients with the highest titer of measles antibody had neurological disease. Measles is a paramyxovirus, and one sees myxolike microtubular structures in the skin, kidneys, and lymphocytes of SLE patients. Similar structures are seen in subacute sclerosing panencephalitis (SSPE), now thought to be caused by measles. 7QOne of these SLE patients with neurologic findings had detectable antibody to measles in his CSF, which is ap-
CNS LUPUS
ERYTHEMATOSUS
261
parently unusual except in SSPE. This suggested to them three explanations: (1) persistent viral infection, (2) nonspecific immunologic hyperactivity, and (3) increases in antibody due to antigens shared by host cell and virus. Hurd*O has also found elevated serum measles virus titers in SLE. Other observers have seen tuboreticular structures in lymphocytes from SLE patientsx’,“2 and in endothelial cells from uninvolved skin and elsewhere in SLE patients.83-R8 The question that arises is whether these structures are true virus particles or a response of the endoplasmic reticulum to viral invasion. Myxoviruslike particles have been seen in the brain of 1 patient with probable SLE who was on corticosteroids and who at autopsy was found to have a hamartoma infected by these particles.8g Patients with SLE are usually receiving corticosteroids and often cytotoxic agents. A word of caution is in order, as several unusual infections such as one of toxoplasmosis,go a case of systemic cytomegalic inclusion disease, epidural Aspergillus fimigatus, and a cerebral reticulum-cell sarcoma have been reported.g’ Cerebral malignancy is being seen with increasing frequency in immunosuppressed patients. Previous authors have described the cerebral vault as immunologically inaccessible. g2It is interesting that half of the lymphomas found in transplant patients are cerebra1.g3 There has been great interest in histocompatibility antigens in many diseases in the past few years. A recent report of the familial occurrence of SLE in siblings supports the impression of many experienced clinicians that a familial factor is present in SLE. g4 The reports of human leukocyte antigen (HL-A) determinations in patients with SLE, however, have been conflicting. Thus Grumet and his co-workersg5 have found that HL-A8 was present in 33% and HL-WI5 in 40% of their SLE patients. Arnettg6 and others observed HL-A 13 in 5 of 15 black patients with CNS disease, as compared to 4 of 45 patients without CNS involvement. Goldberg,g7 on the other hand, found HL-A8 increased in white and HL-A 1 in black patients. HL-Al, HL-A8 were more frequent in whites with renal or CNS involvement. Whether people with certain HL-A types are more susceptible to SLE, and in particular to CNS involvement in SLE, remains an open question at this time. The diagnosis of CNS-SLE is often difficult. Measurement of cerebrospinai fluid complement and immunoglobulins should prove useful, but this requires a lumbar puncture and sophisticated laboratory technology. The brain scan has been used in the diagnosis of a wide variety of CNS diseases.gR.ggIts utility in the diagnosis of CNS-SLE has recently been reported.‘OO Eleven positive and I negative brain scans were found during 12 episodes of CNS-SLE in 6 patients. When the same patients were in remission and not experiencing neurologic symptoms, 5 of 5 scans were negative. The data suggests that the brain scan may be a useful tool to differentiate the patient with increasing cerebral arteritis from one who has a steroid psychosis, electrolyte disturbance, or functional mental disorder. Several investigators have speculated on the role of virus infection in the pathogenesis of SLE. In a paper reviewing the possibility of a viral etiology in several chronic diseases of man, Roth and Williams’o’ suggest that “in SLE we may be witnessing an adjuvant effect of one or more viruses superimposed on an alteration of cellular antigenicity produced by intracellular viruses.” Recently the
262
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concept has emerged that many of the immunologic abnormalities in SLE may be the result of an imbalance of thymic-dependent (T) and bone-marrow-dependent (B) lymphocyte function.102 Suppression of T-cell function has been noted in NZB mice and patients with SLE, while B-cell functions are augmented. It has been suggested that viral infection of T lymphocytes might explain this state of affairs.lo3 A viral etiology has also been proposed in SLE occurring in mice and dogs.lo4*lo5Whether these agents, if they exist, may cross from species to species is a question of great interest. TREATMENT
The treatment of CNS-SLE remains controversial, as does the treatment of lupus nephritis. There are no controlled studies on the use of corticosteroids or cytotoxic agents in CNS lupus. The evidence for the usefulness of these drugs is based on case reports and the experience of individual clinicians. The data of Dubois34 appear to show a clear trend toward improvement over the past 20 years, which he attributes, in part, to high-dose corticosteroids. The work of Cheaturn’* might also be interpreted to show a trend toward less CNS-SLE in patients on higher doses of corticosteroids. Sergent and Lockshin’06 found that their CNSSLE patients had less neurologic death when on high-dose corticosteroids, but they were impressed with the high incidence of complications such as sepsis, osteonecrosis, severe diabetes, myopathy, and gastrointestinal perforation. Caperton and Epstein36 have both suggested that two-drug therapy (that is, a corticosteroid and a cytotoxic agent) improves survival in SLE. Gelfand and colleagues107 have shown that similar therapy prolongs survival in the mouse. It has also been reported that SLE patients on cyclophosphamide require less corticosteroid.lOs Brook and Evans loghave successfully treated an 1 l-year-old with an SLE-induced psychosis with cyclophosphamide alone. These reports offer a basis on which to design future trials using varying doses of corticosteroids in conjunction with cytostatic drugs. While awaiting the data from such controlled studies it has been our clinical impression that patients with CNS-SLE require different doses of medication to control their symptoms. Some require high-dose corticosteroid therapy, while others may do very well with much lower doses. In support of the concept that some patients require high-dose corticosteroid treatment we have observed 3 patients who developed CNS-SLE while on 40 to 80 mg of prednisone and azathioprine 3 mg/kg per day. Two of 3 patients, 1 with chorea and 1 with an organic psychosis and ataxia, responded to an increase of their prednisone to 200 mg a day; the other, who had an organic psychosis, lapsed into coma and died when the prednisone was decreased from 80 to 60 mg a day on the supposition that she had a corticosteroid psychosis. A 4th patient developed hemiballismus, ataxia, and aphasia while on 5 to 10 mg of prednisone. Increasing the dose to 80 mg daily for 2 weeks had no effect on the neurologic symptoms. Her symptoms did respond dramatically to 300 mg of prednisone per day. In contrast to these patients, we have successfully treated another patient with headache and amnesia with 20 mg of prednisone daily. Unfortunately, at the present time we know of no way to distinguish those patients requiring high-dose treatment. Because of the devastating effect CNS-SLE can have, we recently treated 7 patients with acute neurologic
263
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signs or an organic psychosis, 1 on three separate occasions, with high-dose corticosteroids (200-300 mg prednisone and 3 mg/kg azathioprine per day). Once each patient’s symptoms had remitted, we decreased the prednisone slowly at first and then more rapidly while following the serologic and clinical indicators of disease activity. Using this treatment schedule, 5 of these patients have had remission of CNS symptoms and are now on low-dose corticosteroids and azathioprine. Two patients died, one of coexisting renal failure and one of septicemia. SUMMARY
The recent literature on CNS-SLE has been reviewed. An improved prognosis is noted that is thought to be due to the use of high-dose corticosteroids. The frequencies of the various neurologic and psychiatric findings are discussed, and a distinction is noted between organic psychoses and functional psychiatric complaints. The question of corticosteroids versus cerebral vasculitis as the cause of the neuropsychiatric symptomatology in SLE is examined, and the necessity of clear psychiatric diagnosis and treatment is stressed. Recent observations on HL-A antigens, complement, immunoglobulins, virus, and immunocomplexes suggest that the latter are prominent in CNS-SLE, but that an infectious agent may be etiologic in the genesis of SLE. Fifty-four patients not previously reported are discussed. Thirty-eight of them had neuropsychiatric manifestations. The treatment of CNS-SLE with cytotoxic agents, in addition to corticosteroids, is considered, and the experience of the authors with such treatment is presented. ACKNOWLEDGMENTS We wish to thank Mrs. Nancye Lee Yacher, their assistance in the preparation of this article.
Mrs. Mary Chazin,
and Mrs. Judith
Bennahum
for
REFERENCES I. Kaposi MK: Neue beitrage zur kenntnis des lupus erythematosus (New findings in lupus erythematosus). Arch Derm Syph 4:36-78, 1872 2. Osler W: On the visceral complications of erythematosus multiform. Am J Med Sci 110:629, 1895 3. Tumultey PA, Harvey AM: Clinical course of disseminated lupus erythematosus. Johns Hopkins Hospital Bulletin 85:47 -86. 1949 4. Harvey AM, Shulman LE. Tumulty PA, et al: Systemic lupus erythematosus: Review of the literature and clinical analyses of 138 cases. Medicine 33:291-437, 1954 5. Dubois EL: The effect of the L.E cell test on the clinical picture of systemic lupus erythematosus. Ann Intern Med 3X.1265- 1294, 1953 6. Dubois EL. Tuffanneli DL.: Clinical manifestations of systemic lupus erythematosus. JAMA 190:104-Ill, 1964 7. Dubois EL: The clinical picture of systemic lupus erythematosus, in: Lupus Erythematosus. New York, McGraw-Hill, 1966, pp 129-176
8. Johnson RT, Richardson EP: The neurological manifestations of systemic lupus erythematosus. Medicine 47:337-369, 1968 9. O’Connor JF, Musher DM: Central nervous system involvement in systemic lupus erythematosus. Arch Neural 14:157-64, 1966 IO. Heine BE: Psychiatric aspects of SLE. Acta Psychiatr Stand 45:307-326, 1969 I I. Estes D, Christian CL: The natural history of SLE by prospective analysis. Medicine 50:85-95, 1971 12. Quismorio FP, Friou GJ: Antibodies reactive with enurons in SLE patients wrth neuropsychiatric manifestations. Int Arch Allergy Appl Immunol43:740-748, 1972 13. Ganz VH, Gurland BJ, Demmg WE, Fisher B: The study of the psychiatric symptoms of systemrc lupus erythematosus: A biometric study. Psychosom Med 34:2077220, 1972 14. Cheatum DE, Hurd ER. Strunk SW, et al: Renal histology and clinical course of systemic lupus erythematosus: A prospective study. Arthritis Rheum 16:67&676, 1973
264
IS. Jessep S, Meyers OL: Systemic lupus erythematosus in Capetown. S Afr Med J 471222-225, 1973 16. Cade R, Spooner G, Schlein E, et al: comparison of azothiaprin, prednisone and heparin alone or combined in treating lupus nephritis. Nephron 10:37-56. 1973 17. Baker M: Psychopathology in SLE. Semin Arthritis Rheum 3:95-l 10, 1973 18. Sjearn MA, Pirofsky B: Disseminated lupus erythematosus: Analysis of 34 cases. Arch Intern Med 90:790, 1952 19. Jessar RA, Lamont-Havers RW, Ragan C: Natural history of lupus erythematosus disseminatus. Ann Intern Med 38:717, 1953 20. Clark EC, Bailey AA: Neurological and psychiatric signs associated with systemic lupus erythematosus. JAMA 160:455, 1956 21. Hill LC: Systemic lupus erythematosus. Br Med J 2:655, 1957 22. Armas-Cruz et al: Clinical diagnosis of systemic lupus erythematosus. Am J Med 25:409, 1958 23. O’Connor JF: Psychoses associated with systemic lupus erythematosus. Ann Intern Med 5 1:526-536, 1959 24. Rupe CE, Nickel SN: New clinical concept of systemic lupus erythematosus: Analysis of 100 cases. JAM A 171:1055, 1959 25. Stern M, Robbins ES: Psychoses in systemic lupus erythematosus. Arch Gen Psychiatry 3:205-211, 1960 26. Larson D: Systemic Lupus Erythematosus. Boston, Little Brown, 1961 27. Bennett et al: Clinical manifestations of systemic lupus erythematosus: A study of 45 patients. J Chronic Dis 13:41I, 1961 28. Kurland TL, Hauser WA, Gerguson RH, Holley KE: Epidemiologic features of diffuse connective tissue disorders in Rochester, Minnesota, 1951 through 1967, with special reference to systemic lupus erythematosus, Symposium on Systemic Lupus Erythematosus. Mayo Clin Proc 44:649-663, 1969 29. Lee SL, Blum L, Grishman E, Porush J: Guides to prognosis in systemic lupus erythematosus. Arthritis Rheum 15: 115-I 16, 1972 30. Merrell M, Shulman LE: Determination of prognosis in chronic disease. J Chron Dis 1:12-32, 1955 3 I. Kellum RE, Haserick JR: Systemic lupus erythematosus: A statistical evaluation of mortality based on a consecutive series of 299 patients. Arch Intern Med 113:20&207, 1964 32. Feng PH, Cheah PS, Lee YK: Mortality in systemic lupus erythematosus. Br Med J 41772-774, 1973
BENNAHUM
AND
MESSNER
33. Dubois EL, Wierzchowiecki M, Cox MB, Weiner JM: Causes of death in 212 cases of systemic lupus erythematosus. Arthritis Rheum 16:54&541, 1973 (abstract) 34. Dubois EL, et al: Causes of death in 212 cases of systemic lupus erythematosus. Arthritis Rheum 24:742, 1973-1974 35. Caperton E, Mulhn G, Dick FR, et al: Successful results with an aggressive approach to systemic lupus erythematosus. Arthritis Rheum 15:432, 1972 (abstract) 36. Epstein WV, Grausz H: Systemic lupus erythematosus. Arthritis Rheum 17:129-142, 1974 37. Cohen A, Canoso JJ: Criteria for the classification of systemic lupus erythematosus status. Arthritis Rheum 15:540-543, 1972 38. David P, Alkins B, Josse RG, Hughes GRV: Criteria for classification of SLE. Br Med J 3:90-91, 1973 39. Alacron-Segovia D: Drug induced lupus syndromes. Symposium on systemic lupus erythematosus. Mayo Clin Proc 44:66+681, 1969 40. Dabbous IA, Idriss HM: Occurrence of systemic lupus erythematosus in association with ethosuccimide therapy. J Pediatr 76:617-620, 1970 41. Livingston S, Rodriguez H, Green CA, Pauli LL: Systemic lupus erythematosus: Occurrence in association with ethosuccimide therapy. JAMA 204:185, 1968 42. Monnet P, Salle B, Poncet J, et al: Lupus erythemateux dissemine induit par I’ethosuccimide chez une fille de 6 ans. Rev Med Dijon 5:319, 1967 43. Alacron-Segovia D, Wakim KG, Loorthington JW, Ward LE: Clinical and experimental studies on the hydralazine syndrome and its relationship to systemic lupus erythematosus. Medicine 46: 1, 1967 44. Febius AJM, Gaulhofer WK: Systemic lupus erythematosus induced by psychotropic drugs. Acta Rheum Stand 17:137-147, 1971 45. Bennett R, Hughes GRV, Bywaters EGL, Holt PJL: Neuropsychiatric problems in systemic lupus erythematosus. Br Med J 4:342-345, 1972 46. Lundberg PO, Werner I: Trigeminal sensory neuropathy in SLE. Acta Neural Stand 48:33&340, 1972 47. Greenhouse AH: On chorea, lupus, erythematosus, and cerebral arteritis. Arch Intern Med 117:383-389, 1966 48. Antin SP, Prockop LD, Cohen SM: Transient hemiballism. Neurology 17:10681072, 1967
CNS LUPUS
265
ERYTHEMATOSUS
49. Myers R: Ballismus. Handbook of Clin Neuro. North Holland Publishing Co., 6:479, 1968 50. Rowe PB: Disseminated lupus erytbematosus with Sydenham’s chorea report of a case with review of the literature. Med J Aust 2:586588, 1963 51. Thompson S: Ballistic movements of the arm in systemic lupus erythematosus (unpublished) 52. Ashworth B, Tait GBW: Trigeminal neuropathy in connective tissue disease. Neurology 21:509 614, 1971 53. Bisko F: Retinopathy in SLE. Arthritis Rheum l5:57~ 63, 1972 54. Pfaffenback DD, Hollenhorst RW: Microangiopathy of the retinal arterioles. JAM A 225:48&485, 1973 55. Donaldson IMG, Espines EA: DISseminatcd lupus erythematosus presenting as chorea grandarum. Arch Neurol 25:240-244, 1971 56. Schaaf M, Payee CA: Distonic reactions to prochorperazine in hypothyroidism. N Engl J Med 275:991, 1966 57. Boston collaborative drug surveillance program. JAMA 224:889-89 I, 1973 58. Kaplan AP, Curl FD, Decker JL: Central hyperventilation and inappropriate antidiuretic hormone secretion in systemic lupus erytbematosus. Am J Med 48:661-667, 1970
hypothalamus and immune process. Ann NY Acad Sci 164:464, 1969 67. Weil RJ: Emotions and immunity. Can Psychiatr Assoc J 13:475, 1968 68. Engel GE: A life setting conducive to illness: The giving-up-given-up complex. Ann Intern Med 69:293, 1968 69. Bourne HR, Lichtenstein LM, Melmon KL, et al: Modulation of inflamation and immunity by cyclic AMP. Science 184: 19-28, 1974 70. Petz LD, Sharp GC, Cooper NR, Irvin WS: Serum and CSF complement. Medicine 50:259-275, 1971 71. Hadler NM, Gerawin RD. Frank MM, et al: The fourth component of complement (C4) in the cerebrospinal fluid (CSF) in systemic lupus erythematosus (SLE). Arthritis Rheum 16:5075 18, 1973 72. Levin SA, Fudenburg HH, Petz LD, Sharp GC: IgG levels in cerebrospinal fluid of patients with central nervous system manifestations of systemic lupus erythematosus. Clin Immunol Immunopathol l:ll5, 1972 73. Harbeck RJ, Hoffman AA, Carr RI, Bardana EJ: Bull Rheum Dis 24:742, l973- 1974 74. KeelTe EB, Bardana EJ, Harbeck RJ, et al: Lupus meningitis. Ann Intern Med 80:58-60, 1974
59. Gurland BJ, Ganz VH, Fleiss JL, Zubin J: The study of the psychiatric symptoms of systemic lupus erythematosus. Psychosom Med 34: 1999206, 1972
75. Atkins CJ, Kondon JJ, Quismorio F. Friou GJ: The choroid plexus in systemic lupus erythematosus. Ann Intern Med 76:65-72, 1972 76. Lampert PW, Oldstone MBA: Host immunoglobulin G and complement deposits in the choroid plexus during spontaneous immune complex disease. Science 180:408, 1973
60. Nissen HA, Spencer KA: The psychogenic problem (endocrinal and metabolic) in chronic arthritis. N Engl J Med 214:67&581, 1936
77. Dieaerichsen H, Cosmos PI: Antibodies against neurons in a patient with SLE, cerebral palsy and epilepsy. Brain 93:407-412, 1970
61. Baker M, Hadler N, Whitaker JN, et al: Psychopathology in systemic lupus erythematosus: II. Relation to clinical observations, corticosteroid administration and cerebrospinal fluid C4. Semin Arthritis Rheum 3:1 I I, 1973
78. Phillips PE, Christian CL: Myxovirus antibody increases in human connective tissue disease. Science 168:982-984, 1970
62. Kreindler S, Cancro R: psychological approach to psychiatric tions in systemic lupus erythematosus. syst 31:103, 1970 63. Graeme JT: tosus. Can Psychiatr
An ego manifestaDis Nerv
Systemic lupus erythemaAssoc J 17:26l, 1972
64. Solomon GF: Emotion, stress, the central nervous system and immunity. Ann NY Acad Sci 164:335, 1969 65. Solomon GF, Moos RH: Emotions, immunity and disease: A speculative theoretical integration. Arch Gen Psychiatry 11:657, 1964 66. Stein M, Schiavi RC, Luparello TJ: The
79. Abinanti FR: Further evidence to support role of infectious agents and/or immunologic sequelae in the causality of the chronic and degenerative disease of man. Ann NY Acad Sci 174:967-978. 1970 80. Hurd ER, Dowdle W, Casey H, Zig M: Virus antibody levels in systemic erythematosus. Arthritis Rheum 15:267 274, 1972 81. Grimley PJ, Frantz MM, Michelitch HJ, Decker JL: Tubuloreticular structures of circulating lymphocytes in systemic lupus erythematosus (SLE). Arthritis Rheum 15:112, 1972 82. Goodman JR, Sylvester RA, Talal N, Tuffanelli DL: Virus-like structures in lymphocytes of patients with systemic and dis-
266
cord lupus 79:396-402,
BENNAHUM
erythematosus. 1973
Ann
Intern
Med
83. Neiland NW, Hashimoto K, Masi A: Microtubular inclusions in normal skin systemic lupus erythematosus 15:193-200, 1972
patients.
Arthritis
Rheum
84. Gyorkey F, Min KW, Sincovics JG, et al: Systemic lupus erythematosus and myxovirus. N Engl J Med 280:333, 1969 85. Kiwano K, Miller L, Kimmelstiel Virus-like structures in lupus erythematosus. Engl J Med 28 1:I229- 1230, 1969
P: N
86. Norton WL: Endothelial inclusions active lesions of systemic lupus erythematosus. Lab Clin Med 74:369-379, 1969
in J
87. Grauz H, Earley LE. Stephens BG, et al: Diagnostic import of virus-like particles in the glomerular endothelium of patients with systemic lupus erythematosus. N Engl J Med 283:506--5 I 1, 1970 88. Garancis JC, Komorowski RA, Bernard GC, et al: Singificance of cytoplasmic microtubules in lupus nephritis. Am J Pathol 64:1-g, 1971 89. Norris, FH, Aguilzr MJ, Harmon CE: Virus-like particles in a case of vasculitis with brain tumor. Arch Neural 26:212-217, 1972 90. Dubin HV, Courter MH, Toxoplasmosis. Arch Dermatol 1971
Hanell RE: 104:547 -550,
9 I Ltpsmeyer EA: Development of mahgnant cerebral lymphoma in a patient with systemtc lupus erythematosus treated with immunosuppression Arthritis Rheum 15:183- 186, 1972 92 Green HSN: The transplantation mors to the brains of heterologous Cancer Res 11:529-534, 1951 93. Schneck SA, Penn mors in renal-transplant 1:983-986,
of tuspecies.
I: De novo brain turecipients. Lancet
197 I
94. Spector DA, Jampol LM, Hayslett JP: Report of the familial occurrence of systemic lupus in male siblings. Arthritis Rheum 16:221 224, 1973 95. Grumet, McDevitt HO: bility (HL-A) antigens associated
Histocompatiwith systemic
AND
MESSNER
lupus erythematosus. N Engl J Med 285:193196, 1971 96. Arnett FC, Bias WB, Shulman LE: HL-A antigens in SLE. Arthritis Rheum 15:455, 1972 97. Goldberg M, Arnett FC, Bias WB, Shulman LE: Histocompatibility (HL-A) antigens in systemic lupus erythematosus. Arthritis Rheum 16546-547, 1973 98. Morely BJ: Nuclear medicine in neurological diagnosis. Med J Aust 2:81-85, 1973 99. Ferris EJ, Levine HL: Cerebral arteritis: Classification. Radiology 109:327-341, 1973 100. Bennahum DA, Messner RP, Shoop JD: Brain scan findings in central nervous system involvement by lupus erythematosus. Bull Rheum Dis 241742, 1973 101. Roth EM, Williams RC: Viral-host relationships in chronic diseases of man. J Chronic Dis 26:55-61, 1973 102. Talal N: Lymphocyte heterogeneity and function Arthritis Rheum 16:422-425, 1973 103. Messner RP: Clinical aspects of T and B lymphocytes in rheumatic diseases. Arthritis Rheum (in press) 104. Lewis RM, Andre-Schwartz J, Harris GS, et al: Canine systemic lupus erythematosus: Transmission of serologic abnormalities by all free filtrates. J Clin Invest 52:1893- 1907, 1973 105. Lewis R, Tannerberg W, Smith C, Schwartz R: Human systemic lupus erythematosus and C-type RNA viruses. Clin Res 22:422, 1974 106. Sergent JS, Lockshin MD: Treatment of central nervous system lupus erythematosus: Editortal notes. Ann Intern Med 8:413-414, 1974 107. Gelfand MC, Steinberg AD, Nagle R, Knepshiled JH: Therapeutic studies in NZB-W mice 1. Synergy of azothiaprin, cyclophosand methylprednisolone in comphamide bination. Arthritis Rheum 15:239-246, 1972 108. Steinberg AD, Kalterider HB, Staples PG, et al: Cyclophosphamide in lupus nephritis: A controlled trial. Ann Intern Med 75:1655171, 1971 109. Brook CGD, Evans PR: Psychosis in systemtc lupus erythematosus (SLE) and the response to cyclophosphamide. Proc R Sot Med 62:9 12, 1969
and Ronald P Messner
T
HIS PAPER will review recent observations on the central nervous system (CNS) manifestations of systemic lupus erythematosus (SLE). Central nervous system involvement in SLE was first reported in detail by Kaposi’ in 1872. Twenty-three years later Sir William Osler2 distinguished SLE from the septic erythemas such as subacute bacterial endocarditis. Between 1949 and 1966 the clinical spectrum of central nervous system systemic lupus erythematosus (CNS-SLE) was further clarified by Harvey and his co-workers3.4 and by Dubois.5-7 A thorough review of the pathology and symptomatology of CNS-SLE was published by Johnson and Richardsonsin 1968. In the past 6 years there has been a remarkable increase in interest in the neurologic and psychiatric manifestations of SLE. Early diagnosis and proper treatment now offer the individual with CNS-SLE a much improved prognosis over that of 10 years ago. It is the purpose of this paper to summarize the available theoretical and practical knowledge necessary for the best care of these patients. INCIDENCE
AND
SURVIVAL
OF PATIENTS
WITH
CNS-SLE
Many authors have presented data on the incidence and survival of patients with SLE. The reports of CNS-SLE are summarized in Table 1. The percentage of patients with neurologic and psychiatric symptoms ranges from 14% to 75% and from 25% to 70% respectively. The incidence of psychiatric manifestations depends to some extent on the psychiatric sophistication of the observer. The survival of all patients with SLE has been reported as between 5 1% and 77% at 4 years.28-31 Estes and Christian” found a 4-year survival rate of 55% for patients with CNS-SLE compared to 76.9% for all SLE patients. In their study, patients with neurologic signs or organic mental syndromes had approximately 47% 4-year survival rates, compared to 85% for seizures or functional psychoses. Two other recent reports have stressed that CNS disease is a major cause of death in SLE patients. Feng, Cheah, and Lee32 report that one-third of the 30 deaths in their series of 167 patients in Singapore were due to CNS disease, while Cheatum et a1.14found that death in 70% of patients without renal disease was From rhe Department of Medicine, University of New Mexico Center for the Health Sciences, Albuquerque, N’. Mex. David A. Bennahum, MD.: Rheumarologist: Director, Medicine Clinics; Assistant Professor of Medicine; Department of Medicine. University of New Mexico Center for the Health Sciences. Ronald P. Messner, M.D.: Rheumatologist: Director. Rheumatology Clinic; Associate Professor of Medicine; Departmenr of Medicine, Universiry of New Mexico Center/or rhe Health Sciences. This work was supported in part by grants AM 13789-m and AM 70301-01 from the National Instirutefor Arthriris and Metabolic Disease. Requests for reprints may be addressed lo David A. Bennahum. M.D.. Bernalillo County Medical Cenrer. General Medicine Clinic, 221 I Lomas Blvd., N.E.. Albuquerque, N. Mex. 87106. 0 1974 by Grune & Slratron. Inc.
Semmars
,n Arrhriris
and Rheumatism,
Vol 4. No. 3 (Februan/). 1975
253
254
BENNAHUM
Table 1. Previous Reports on the Incidence Number
of Neuropsychiatric of
Percent
Patients Date
with
SLE
Dubois6
1964
520
O’Connor9
1966
1066t
Total
l
Symptoms with
in Patients with SLE
Neuropsychiatric Neurologic
25.5
150$
AND MESSNER
Symptoms Psychiatric
_
_
14
25
60
14
51
Johnsons
1968
24
75
75
33
Heinelc
1969
38
50
13
44
Estes” Quismoriol2
1971 1972
150 137
59 34
48 -
42
Ganzls
1972
68
Cheatumt4 Jessepls
1972 1973
30 130
66 25
Cadal
1973
28
-
-
33
Baker17
1973
17
-
-
41
Bennahum
1974
54
705
57
59
lPercentage tSummary
of patients with either neurologic of literature
or psychiatric
-
71
-
43
symptoms.
prior to 1965.4,6,1s-27
$O’Connor’s
own patients.
§Neurologic
and organic-psychiatric
symptoms.
Patients
with functional
psychiatric
symptoms
are excluded.
CNS-SLE. Jessep,15 in a series of 130 patients from South Africa, most of whom were Bantu, found that 25% had neurological symptoms. Of these, 9.2% had convulsions and 4.6% had psychoses. The 5-year survival of his patients was 65.5%. Cerebral vascular disease was the second most common cause of death. Dubois33+34has described a definite change in the prognosis of CNS-SLE over the past 23 years. He notes that from 1950 to 1973 the percentage of deaths due to CNS-SLE decreased from 27% to 8%. During the same period deaths from renal disease decreased from 27% to 13%, while the mean survival for all SLE patients rose from less that 1 year to 8.5 years. He attributes the change in survival to corticosteroids, hemodialysis, and renal transplantation. A trend to better prognosis with combined treatment with corticosteroids and immunosuppressive drugs such as azathioprine and chlorambucil has also recently been observed.35*36 due to
PATIENTS WITH
SLE FOLLOWED
AT THE UNIVERSITY
OF NEW MEXICO
CENTER FOR THE HEALTH SCIENCES
In a retrospective review of our records at the University of New Mexico Center for the Health Sciences, 54 patients met the criteria for SLE as suggested by the ARA37 or as modified by David and his co11eagues.38The results are summarized in Table 1 and are similar to those found in the literature. The variety of symptoms and laboratory findings in our patients are summarized in Table 3 and again are much like those reported elsewhere and shown in Table 2. Of our patients, 88.8% were female. Neurological findings were seen in 57.4%, organic psychiatric symptoms in 16.6%, and functional psychiatric symptoms in 53.7%. By organic, we mean overt thought disorder, hallucinations, delerium, confusion, and so forth. Functional is considered to include the oriented patient without a thought disorder, disorientation, or confusion who is anxious and depressed and who may have various somatic complaints. Of our patients, 16.6% died.
CNS LUPUS ERYTHEMATOSUS
Table 2. Neurologic
Symptoms
255
in Central
Nervous System Systemic Lupus Erythematosus~8,11,45 Totals
59%
Psychoses
TOtals 5%
Paralysis
Delerium
Paraplegia Hemiplegia
Schizophrenia
Aphasia
Catatonia
Transverse
Paranoia Confusion
Movement
Hypomania
Chorea Hemiballismus
Progressive dementia 13.8%-509/o
Epilepsy
Cerebellar
ataxia
Parkinson-like
Grand mal
Dysphagia
Petit mal
Peripheral
Focal Temporal
5%-33%
Cranial Nerve
11.7%
glove
Mixed sensory and motor pain Hyperesthesia
Visual defects Homonomous
Neuropathy
Stocking
lobe
Dysesthesia
hemianopia
Burning
Blindness Papilledema Extraoccular Tinnitus
myelitis Disorder
movement
abnormalities
multiplex
Guillan-Barre
type
Neurogenic
and vertigo
Pupillary
Mononeuritis
bladder
Loss of sphincter control
disturbance
Nystagmus Ptosis Optic atrophy Facial palsy
Table 3. Clinical Systemic
Findings in 54 Cases of SLE* Neurological
Psychiatric
Anemia
35
Convulsions
Rash
34
Coma
Arthritis
33
Headache
Renal disease
21
Hyperesthesia
6
Nervousness
Hypertension
18
Decreased vision
8
Emotional
Cardiac involvement
13
Hemiplegia
7
Confusion
Fever
15
Aphasia (expressive)
4
Hallucinations
3
Pleural effusion
11
Burning or itching of face
4
Anxiety
3
7
Ataxia
3
Staring
2
4
Retinitis
3
Shaking
2
4
Pain of tongue or mouth
2
Catatonia
2
4
Slurred speech
2
Loss of memory
2
3
Opthalmoplegia
1
Somatization
2
2
Optic atrophy
Dementia
2
Hemiballismus
1 1
Grinding
2
Chorea
1
Suicide attempt
1
2
Neurogenic
1
Insomnia
1
2
Pain of hands and feet
Urinary-tract Family
infection
history
Weight loss Alopecia Abdominal
pain
Hemoptysis Spontaneous
abortion
Dysphagia Tracheolaryngeal Hepatomegally
edema
Splenomegally
2
Telangiectasia
2
12 8 10
bladder
*A finding is recorded only once for each patient.
1
Depression
13
Altered
11
reality testing
Fatigue
7 5 lability
5 4
1 teeth
1
256
BENNAHUM
AND
MESSNER
It is important to note that almost all patients seen by authors (that is, since 1969) have been thought to have functional psychiatric symptoms at one time or another. Such symptoms were rarely mentioned when the records prior to 1969 were reviewed. Our patients, however, would seem to correlate well with the findings of other observers, as noted in Tables 1 and 2. NEUROLOGIC
FINDINGS
SLE is a disease that has been compared to syphilis because of the variety of neurologic and psychiatric symptoms that it can display (Table 2). Dubois7 in his 520 cases of SLE found that 13.8% had seizures, 12.1% psychoses, 11.7% peripheral neuritis, 10% retinal hemorrhages, and 9.6% fundic lesions. Eventually, 25.5% of his patients had CNS damage. In most series, seizures are the most common single neurologic symptom. In some patients, a history of epilepsy may antedate the onset of classical SLE by several years. This often creates a diagnostic problem for several of the hydantoin and primidone drugs used in the control of epilepsy are known to activate or induce the symptoms of SLE. 3QWithdrawal of the anticonvulsant or change to another medication may result in a clearing of the SLE and thus allow a diagnostic separation of drug-induced SLE from idiopathic SLE. Other drugs used in the treatment of CNS disease that may induce SLE include ethusuccimide40-42 and the phenothiazines. 43Fabius44 found 10 cases of SLE among 1800 mental patients. In eight of these patients the SLE was thought to be due to phenothiazine. Cranial nerve involvement is most frequently manifested as opthalmoplegia, but may take many forms. A review by Bennett and his associates45 arrived at an incidence of cranial nerve involvement between 5% and 33%. Lundberg and Werner46 have found five females with SLE with trigeminal sensory neuropathy. In 4 patients symptoms were bilateral, and vascular lesions in the medulla oblongata were suspected. A variety of symptoms occurred, including numbness, decreased sensibility, pain of the face, a bulky feeling of the tongue, loss of articulation, burning of the teeth, scintillation at the borders of the visual fields, numbness of the nose, horizontal-rotary nystagmus, and intense shooting pains triggered by touch. All 5 patients responded to treatment with carbamazepine alone. Other neurological manifestations are paralysis of one or several motor groups, neuralgia, headaches, chorea, hemiballismus aphasia, and peripheral neurpathy.47-52 Retinal lesions are also frequent in SLE, but loss of vision has become rare with the use of corticosteroids. Bisko53 reported a case of the rapid onset of blindness in a young black woman with a presenting complaint of blurred vision and frontal headaches. The retina revealed poor perfusion of the capillary bed, exudates, edema, hemorrhages, arteriolar spasm, and venous stasis. Steroid treatment was followed by regression of the lesions, but no improvement of vision. The authors have a similar case in one of their clinic patients. Pfaffenback and Hollenhorst54 have also described 2 young white women with SLE involving the CNS who developed microangiopathy of the retinal vessels. One had return of vision after prednisone therapy, while the other did not. Chorea is an uncommon finding in SLE, but must be distinguished from that
CNS LUPUS
257
ERYTHEMATOSUS
Table 4.
Neurological
at the University
and Psychiatric of New Mexico
Patient
Findings in 54 Patients with SLE Center for the Health Sciences
No.
Percentage
Total
54
Female
48
Male Neurological
symptoms
Organic psychiatric
symptoms
Functional
psychiatric
symptoms
Neurologic
and organic psychiatric
symptoms
combined
Death
100% 88.8%
6
11.1%
31
57.4%
9
16.6%
29
53.7%
38
70%
9
16.6%
occurring with rheumatic fever. Only 27 cases were found in a recent review of the literature.55 We have seen 1 case of chorea in our clinical practice. The patient was a 16-year-old white schoolgirl whose symptoms developed while receiving 60 mg of prednisone and 150 mg of azathioprine each day. The chorea remitted when the prednisone was increased to 200 mg a day and then was tapered slowly to her usual dose. We are also following a 27-year-old Spanish-American female with recurrent hemiballism and a permanent expressive aphasia who responds to increased corticosteroids. A peculiar CNS response to phenothiazines and to tricyclic antidepressants is that of extrapyramidal symptoms (EPS). Shaaf and Payne5fi reported that this occurs in hypoparathyroidism. A recent study suggests that the tendency for these drugs to produce EPS is enhanced in SLE when renal failure lowers ionized calcium.57 Corticosteroids also decrease intestinal calcium absorption and increase renal calcium excretion. Eight patients were on prednisone when given trifluoperazine, which then induced EPS in 4. Of the 4,3 had SLE. Lastly, a fascinating case was reported by Kaplan and his colleagues”* of a 2% year-old white female with SLE who developed tinnitus, vertigo, right auditory nerve deafness, mononeuritis multiplex, central hyperventilation, inappropriate secretion of antidiuretic hormone, and left-sided hemiparesis. Autopsy revealed random foci of vascular encephalopathy, including the pontine portions of the brain. Both supraoptic and paraventricular hypothalamic nuclei exhibited gliosis, acute neuronal degeneration, and a decrease in neurosecretory cells. PSYCHIATRIC
OBSERVATIONS
In a thorough review of the literature, Heine”’ noted that “many reports are of limited value as psychiatric diagnostic categories are not clearly used.” He found that the incidence of organic-toxic states was approximately the same 29% in the reports of four separate authors.4J*23.25 On the other hand, the incidence of “functional” mental illness varied widely and was often omitted entirely. In 38 cases he found an incidence of 24% for organic-toxic states and of 18% for functional depressive illness. His impression is that corticosteroids rarely are at fault in the genesis of the psychiatric complaints of SLE. He notes, however, that the organic-toxic states are associated with a worsening of the systemic manifestations of SLE, whereas the functional depressive states are not. The former requires intensive medical treatment, the latter psychotherapeutic intervention. Gurland5g and his colleagues have also noted that frequent errors are made by
258
BENNAHUM
AND
MESSNER
various examiners when looking at the psychiatric symptoms found in SLE. They observed that the psychiatric symptoms found in SLE rarely last more than 6 months and are commonly of less than 6 week’s duration. They also noted that a worsening of the general physical condition of patients tended to accompany psychiatric disorders. An increase in the dosage of corticosteroids, however, rarely preceded the onset of psychiatric symptoms. In their review of the literature it was found that psychiatric signs and symptoms were described in less than 20% of the patients before 1960 and more than 40% of the patients after 1960, and they postulated that this may be due to more psychiatric examinations being applied to patients with SLE. In reporting psychiatric data on SLE patients, they strongly recommended using standard diagnostic criteria. They suggest that a distinction must be made between the various psychiatric syndromes in order to distinguish a reactive depression from a CNS-SLE-induced psychosis, and they discovered a clear distinction between these two entities. In a second paper continuing the earlier study, Ganz and her colleagues13 compared 68 patients with SLE to 36 patients with rheumatoid arthritis. The patients with SLE indeed had more psychiatric symptoms than those with rheumatoid arthritis. This confirms what Nissenso reported in 1936: that only three of 500 patients with rheumatoid arthritis had major psychiatric disorders. The point that Ganz and her colleagues stress is that many SLE patients suffer from depression, which must be distinguished from organic psychoses. In our haste to treat neurological and psychotic manifestations with increased corticosteroids, we should not forget that most of these patients have a situational depression, which often needs psychotherapeutic intervention. In two recent papers in this journal, Baker and his colleagues17*61pointed out that psychopathology is extremely frequent in SLE. In their 17 patients they found a wide variety of psychiatric symptoms, which they grouped into four basic groups: pure affective syndromes, pure organic brain syndromes, pure schizophreniform syndromes, and mixed syndromes. Serious psychiatric syndromes were observed in 41% of the patients. A mixed syndrome characterized by a combination of organic symptoms and either affective or schizophreniform symptoms was the most common, occurring in 45% of the patient episodes. The other syndromes were less frequent. In the second paper, Baker and his associates attempted to differentiate between psychopathology due to organic disease and corticosteroid administration. They found no correlations between psychopathology and either the severity of SLE or the associated CNS manifestations. They did not find that corticosteroid therapy could be implicated as the cause of the majority of psychiatric manifestations, and they came to the conclusion that it was the SLE itself that was responsible for the majority of the psychiatric symptomatology. The occurrence of corticosteroid-induced psychosis cannot, however, be totally excluded, as Cade and his co-workers16 state that a psychosis occurred in 9 of 28 patients with SLE receiving prednisone. The psychoses cleared in 6 patients when the prednisone was decreased. Other psychiatrists have questioned the degree to which the course of SLE is affected by emotional factors. A report from the Menninger FoundatioiP suggests that the mind’s protective response to the organic changes in the brain de-
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pends on the patient’s premorbid personality, ego strength, and environmental stress and that these factors affect the symptom complex seen in each patient. Graemee3 reminds us that the work of Solomon64*65 and others suggests that “there is considerable evidence to show that the emotions influence the immunologic system, with the hypothalamus playing an important role.” He speculates as to whether SLE is a psychoimmunological disorder and notes a case of Janeway in which a patient with severe SLE was cured through psychotherapy.66*67 He supports his argument with Engel’s view that a “giving-up-given-up” complex will lead to a physiologically hypoactive state that renders an individual more susceptible to disease. The theory that psychologic factors may influence a disease such as SLE may find some physiologic basis in recent work that suggests that the autonomic nervous system through its effects on leukocyte and lymphocyte cyclic AMP and GMP may play a role in regulating immunologic responses.6g RECENT OBSERVATIONS
ON THE PATHOPHYSIOLOGY
OF CNS-SLE
Classically, patients with CNS-SLE have had cerebral spinal fluid pleocytosis, rarely exceeding 200 cells per cubic millimeter. A slight increase in cerebral spinal fluid protein may occur, but the opening and closing pressures are usually normal. The light-microscopic pathologic lesion appears to result from degenerative and proliferative changes of the small arterioles and capillaries, followed by microinfarction and hemorrhage and proliferation of the perivascular glial cells.R,70Large hemorrhages can result from this process, but are less common. True arteritis is rare. The lesions are peculiar in that varied states of evolution may coexist, and the correlation between pathologic and clinical findings is often poor. Dubois,’ reporting on autopsy material, noted that hemorrhagic foci of necrosis, thickened and hyahnized arterial walls, cellular degeneration, mononuclear and polymorphonuclear infiltration, and formation of corpora amylacea and dark-staining granular material throughout the brain were common to 10 of these autopsies. In 1971 Petz and his co11eagues7omeasured cerebral spinal fluid complement. They found that the fourth component of complement (C4) is low in the cerebral spinal fluid of patients with CNS-SLE and that this drop is not a reflection of a low serum complement. All of their 11 patients with clinical findings indicating CNS involvement had abnormally low levels of cerebral spinal fluid C4, while the CSF C4 was normal in 90 of 95 patients with diseases other than SLE. They noted that other workers have observed deposits of gammaglobulin and complement within and around the small vessels of the brain in animals. They suggest that the neuropsychiatric manifestations of CNS-SLE are mediated by the biological activities of the activated complement system within the CNS. Immunological reactions occurring at different locations within the CNS are thus presented as one explanation for the variety of bizarre neuropsychiatric manifestations of SLE. Hadler and his co-workers have made a similar observation.” In 1972 Levin et a1.72reported on immunoglobulin G (IgG) levels in cerebrospinal fluid. They ascertained that patients with active SLE without CNS
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symptoms had normal IgG levels. This included one patient who had a corticosteroid-induced encephalopathy. Twelve patients with active CNS-SLE, however, had significant lowering of the CSF IgG at some time during the active phase of disease. They felt that this strengthened the concept that CNS manifestations in SLE have an immune pathogenesis and might be the product of locally produced antibody fixing to the CNS tissue with subsequent complement fixation. Alternately, they proposed that immune complexes, possibly DNA anti-DNA could be trapped in the basement membranes of the choroid plexus with subsequent complement fixation. Of note is that in demyelinating diseases, such as multiple sclerosis, the IgG level is usually above normal; therefore, in the differential diagnosis of these disorders from that of SLE, the low IgG found in the latter may be quite useful. Another interesting observation on CSF in CNS-SLE was recently made by Harbeck and his associates.73 They reported on the occurrence of DNA antiDNA complexes in the spinal fluids of 3 patients with CNS-SLE, but they did not find them in patients with SLE without cerebritis or in non-SLE patients. Keeffe and his co-workers74 have also described a single SLE patient with meningitis in whom no microorganisms were found. The patient’s CSF had a polymorphopleocytosis, a low complement, antibodies to DNA, and DNA anti-DNA complexes. In support of the idea that immune complexes may be involved in CNS-SLE, Atkins and his col1eagues75 have demonstrated complexes in the choroid plexus of patients dying of SLE. This fascinating finding has also been noted in (NZB/ NZW) F, mice, who develop an illness similar to human SLE. With immunofluorescence and electron microscopy, Lampert and Oldstone were able to demonstrate IgG and the third component of complement in the mouse choroid plexus. These deposits appeared shortly after the development of antinuclear and anti-DNA antibody in the circulation. They therefore suggested, extrapolating from mice to man, that the neuropsychiatric findings in patients with SLE may be due to immune-complex disease of the choroid plexus. In addition to immune complexes, antibodies directed against neuronal tissue have also been found in SLE patients. Using an indirect immunofluorescent technique, Quismorio and Friou’* demonstrated antineuron antibodies in 23 of 137 patients with SLE. Forty-one percent of the patients with active CNS-SLE and 24% of patients with a history of CNS-SLE had these antibodies in their serum, compared to 9% of SLE patients who had no history of CNS involvement. Antineuronal antibodies have also been found in a patient with drug-induced SLE,77 as well as other diseases such as carcinomatous neuropathy, multiple sclerosis, myasthenia gravis, and Mycoplasmapneumoniae infections. In search of specific infectious agents, Phillips and Christian’* have found significantly increased antibodies to measles and parainfluenza type I viruses in SLE. Seventy-five percent of those SLE patients with the highest titer of measles antibody had neurological disease. Measles is a paramyxovirus, and one sees myxolike microtubular structures in the skin, kidneys, and lymphocytes of SLE patients. Similar structures are seen in subacute sclerosing panencephalitis (SSPE), now thought to be caused by measles. 7QOne of these SLE patients with neurologic findings had detectable antibody to measles in his CSF, which is ap-
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parently unusual except in SSPE. This suggested to them three explanations: (1) persistent viral infection, (2) nonspecific immunologic hyperactivity, and (3) increases in antibody due to antigens shared by host cell and virus. Hurd*O has also found elevated serum measles virus titers in SLE. Other observers have seen tuboreticular structures in lymphocytes from SLE patientsx’,“2 and in endothelial cells from uninvolved skin and elsewhere in SLE patients.83-R8 The question that arises is whether these structures are true virus particles or a response of the endoplasmic reticulum to viral invasion. Myxoviruslike particles have been seen in the brain of 1 patient with probable SLE who was on corticosteroids and who at autopsy was found to have a hamartoma infected by these particles.8g Patients with SLE are usually receiving corticosteroids and often cytotoxic agents. A word of caution is in order, as several unusual infections such as one of toxoplasmosis,go a case of systemic cytomegalic inclusion disease, epidural Aspergillus fimigatus, and a cerebral reticulum-cell sarcoma have been reported.g’ Cerebral malignancy is being seen with increasing frequency in immunosuppressed patients. Previous authors have described the cerebral vault as immunologically inaccessible. g2It is interesting that half of the lymphomas found in transplant patients are cerebra1.g3 There has been great interest in histocompatibility antigens in many diseases in the past few years. A recent report of the familial occurrence of SLE in siblings supports the impression of many experienced clinicians that a familial factor is present in SLE. g4 The reports of human leukocyte antigen (HL-A) determinations in patients with SLE, however, have been conflicting. Thus Grumet and his co-workersg5 have found that HL-A8 was present in 33% and HL-WI5 in 40% of their SLE patients. Arnettg6 and others observed HL-A 13 in 5 of 15 black patients with CNS disease, as compared to 4 of 45 patients without CNS involvement. Goldberg,g7 on the other hand, found HL-A8 increased in white and HL-A 1 in black patients. HL-Al, HL-A8 were more frequent in whites with renal or CNS involvement. Whether people with certain HL-A types are more susceptible to SLE, and in particular to CNS involvement in SLE, remains an open question at this time. The diagnosis of CNS-SLE is often difficult. Measurement of cerebrospinai fluid complement and immunoglobulins should prove useful, but this requires a lumbar puncture and sophisticated laboratory technology. The brain scan has been used in the diagnosis of a wide variety of CNS diseases.gR.ggIts utility in the diagnosis of CNS-SLE has recently been reported.‘OO Eleven positive and I negative brain scans were found during 12 episodes of CNS-SLE in 6 patients. When the same patients were in remission and not experiencing neurologic symptoms, 5 of 5 scans were negative. The data suggests that the brain scan may be a useful tool to differentiate the patient with increasing cerebral arteritis from one who has a steroid psychosis, electrolyte disturbance, or functional mental disorder. Several investigators have speculated on the role of virus infection in the pathogenesis of SLE. In a paper reviewing the possibility of a viral etiology in several chronic diseases of man, Roth and Williams’o’ suggest that “in SLE we may be witnessing an adjuvant effect of one or more viruses superimposed on an alteration of cellular antigenicity produced by intracellular viruses.” Recently the
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concept has emerged that many of the immunologic abnormalities in SLE may be the result of an imbalance of thymic-dependent (T) and bone-marrow-dependent (B) lymphocyte function.102 Suppression of T-cell function has been noted in NZB mice and patients with SLE, while B-cell functions are augmented. It has been suggested that viral infection of T lymphocytes might explain this state of affairs.lo3 A viral etiology has also been proposed in SLE occurring in mice and dogs.lo4*lo5Whether these agents, if they exist, may cross from species to species is a question of great interest. TREATMENT
The treatment of CNS-SLE remains controversial, as does the treatment of lupus nephritis. There are no controlled studies on the use of corticosteroids or cytotoxic agents in CNS lupus. The evidence for the usefulness of these drugs is based on case reports and the experience of individual clinicians. The data of Dubois34 appear to show a clear trend toward improvement over the past 20 years, which he attributes, in part, to high-dose corticosteroids. The work of Cheaturn’* might also be interpreted to show a trend toward less CNS-SLE in patients on higher doses of corticosteroids. Sergent and Lockshin’06 found that their CNSSLE patients had less neurologic death when on high-dose corticosteroids, but they were impressed with the high incidence of complications such as sepsis, osteonecrosis, severe diabetes, myopathy, and gastrointestinal perforation. Caperton and Epstein36 have both suggested that two-drug therapy (that is, a corticosteroid and a cytotoxic agent) improves survival in SLE. Gelfand and colleagues107 have shown that similar therapy prolongs survival in the mouse. It has also been reported that SLE patients on cyclophosphamide require less corticosteroid.lOs Brook and Evans loghave successfully treated an 1 l-year-old with an SLE-induced psychosis with cyclophosphamide alone. These reports offer a basis on which to design future trials using varying doses of corticosteroids in conjunction with cytostatic drugs. While awaiting the data from such controlled studies it has been our clinical impression that patients with CNS-SLE require different doses of medication to control their symptoms. Some require high-dose corticosteroid therapy, while others may do very well with much lower doses. In support of the concept that some patients require high-dose corticosteroid treatment we have observed 3 patients who developed CNS-SLE while on 40 to 80 mg of prednisone and azathioprine 3 mg/kg per day. Two of 3 patients, 1 with chorea and 1 with an organic psychosis and ataxia, responded to an increase of their prednisone to 200 mg a day; the other, who had an organic psychosis, lapsed into coma and died when the prednisone was decreased from 80 to 60 mg a day on the supposition that she had a corticosteroid psychosis. A 4th patient developed hemiballismus, ataxia, and aphasia while on 5 to 10 mg of prednisone. Increasing the dose to 80 mg daily for 2 weeks had no effect on the neurologic symptoms. Her symptoms did respond dramatically to 300 mg of prednisone per day. In contrast to these patients, we have successfully treated another patient with headache and amnesia with 20 mg of prednisone daily. Unfortunately, at the present time we know of no way to distinguish those patients requiring high-dose treatment. Because of the devastating effect CNS-SLE can have, we recently treated 7 patients with acute neurologic
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signs or an organic psychosis, 1 on three separate occasions, with high-dose corticosteroids (200-300 mg prednisone and 3 mg/kg azathioprine per day). Once each patient’s symptoms had remitted, we decreased the prednisone slowly at first and then more rapidly while following the serologic and clinical indicators of disease activity. Using this treatment schedule, 5 of these patients have had remission of CNS symptoms and are now on low-dose corticosteroids and azathioprine. Two patients died, one of coexisting renal failure and one of septicemia. SUMMARY
The recent literature on CNS-SLE has been reviewed. An improved prognosis is noted that is thought to be due to the use of high-dose corticosteroids. The frequencies of the various neurologic and psychiatric findings are discussed, and a distinction is noted between organic psychoses and functional psychiatric complaints. The question of corticosteroids versus cerebral vasculitis as the cause of the neuropsychiatric symptomatology in SLE is examined, and the necessity of clear psychiatric diagnosis and treatment is stressed. Recent observations on HL-A antigens, complement, immunoglobulins, virus, and immunocomplexes suggest that the latter are prominent in CNS-SLE, but that an infectious agent may be etiologic in the genesis of SLE. Fifty-four patients not previously reported are discussed. Thirty-eight of them had neuropsychiatric manifestations. The treatment of CNS-SLE with cytotoxic agents, in addition to corticosteroids, is considered, and the experience of the authors with such treatment is presented. ACKNOWLEDGMENTS We wish to thank Mrs. Nancye Lee Yacher, their assistance in the preparation of this article.
Mrs. Mary Chazin,
and Mrs. Judith
Bennahum
for
REFERENCES I. Kaposi MK: Neue beitrage zur kenntnis des lupus erythematosus (New findings in lupus erythematosus). Arch Derm Syph 4:36-78, 1872 2. Osler W: On the visceral complications of erythematosus multiform. Am J Med Sci 110:629, 1895 3. Tumultey PA, Harvey AM: Clinical course of disseminated lupus erythematosus. Johns Hopkins Hospital Bulletin 85:47 -86. 1949 4. Harvey AM, Shulman LE. Tumulty PA, et al: Systemic lupus erythematosus: Review of the literature and clinical analyses of 138 cases. Medicine 33:291-437, 1954 5. Dubois EL: The effect of the L.E cell test on the clinical picture of systemic lupus erythematosus. Ann Intern Med 3X.1265- 1294, 1953 6. Dubois EL. Tuffanneli DL.: Clinical manifestations of systemic lupus erythematosus. JAMA 190:104-Ill, 1964 7. Dubois EL: The clinical picture of systemic lupus erythematosus, in: Lupus Erythematosus. New York, McGraw-Hill, 1966, pp 129-176
8. Johnson RT, Richardson EP: The neurological manifestations of systemic lupus erythematosus. Medicine 47:337-369, 1968 9. O’Connor JF, Musher DM: Central nervous system involvement in systemic lupus erythematosus. Arch Neural 14:157-64, 1966 IO. Heine BE: Psychiatric aspects of SLE. Acta Psychiatr Stand 45:307-326, 1969 I I. Estes D, Christian CL: The natural history of SLE by prospective analysis. Medicine 50:85-95, 1971 12. Quismorio FP, Friou GJ: Antibodies reactive with enurons in SLE patients wrth neuropsychiatric manifestations. Int Arch Allergy Appl Immunol43:740-748, 1972 13. Ganz VH, Gurland BJ, Demmg WE, Fisher B: The study of the psychiatric symptoms of systemrc lupus erythematosus: A biometric study. Psychosom Med 34:2077220, 1972 14. Cheatum DE, Hurd ER. Strunk SW, et al: Renal histology and clinical course of systemic lupus erythematosus: A prospective study. Arthritis Rheum 16:67&676, 1973
264
IS. Jessep S, Meyers OL: Systemic lupus erythematosus in Capetown. S Afr Med J 471222-225, 1973 16. Cade R, Spooner G, Schlein E, et al: comparison of azothiaprin, prednisone and heparin alone or combined in treating lupus nephritis. Nephron 10:37-56. 1973 17. Baker M: Psychopathology in SLE. Semin Arthritis Rheum 3:95-l 10, 1973 18. Sjearn MA, Pirofsky B: Disseminated lupus erythematosus: Analysis of 34 cases. Arch Intern Med 90:790, 1952 19. Jessar RA, Lamont-Havers RW, Ragan C: Natural history of lupus erythematosus disseminatus. Ann Intern Med 38:717, 1953 20. Clark EC, Bailey AA: Neurological and psychiatric signs associated with systemic lupus erythematosus. JAMA 160:455, 1956 21. Hill LC: Systemic lupus erythematosus. Br Med J 2:655, 1957 22. Armas-Cruz et al: Clinical diagnosis of systemic lupus erythematosus. Am J Med 25:409, 1958 23. O’Connor JF: Psychoses associated with systemic lupus erythematosus. Ann Intern Med 5 1:526-536, 1959 24. Rupe CE, Nickel SN: New clinical concept of systemic lupus erythematosus: Analysis of 100 cases. JAM A 171:1055, 1959 25. Stern M, Robbins ES: Psychoses in systemic lupus erythematosus. Arch Gen Psychiatry 3:205-211, 1960 26. Larson D: Systemic Lupus Erythematosus. Boston, Little Brown, 1961 27. Bennett et al: Clinical manifestations of systemic lupus erythematosus: A study of 45 patients. J Chronic Dis 13:41I, 1961 28. Kurland TL, Hauser WA, Gerguson RH, Holley KE: Epidemiologic features of diffuse connective tissue disorders in Rochester, Minnesota, 1951 through 1967, with special reference to systemic lupus erythematosus, Symposium on Systemic Lupus Erythematosus. Mayo Clin Proc 44:649-663, 1969 29. Lee SL, Blum L, Grishman E, Porush J: Guides to prognosis in systemic lupus erythematosus. Arthritis Rheum 15: 115-I 16, 1972 30. Merrell M, Shulman LE: Determination of prognosis in chronic disease. J Chron Dis 1:12-32, 1955 3 I. Kellum RE, Haserick JR: Systemic lupus erythematosus: A statistical evaluation of mortality based on a consecutive series of 299 patients. Arch Intern Med 113:20&207, 1964 32. Feng PH, Cheah PS, Lee YK: Mortality in systemic lupus erythematosus. Br Med J 41772-774, 1973
BENNAHUM
AND
MESSNER
33. Dubois EL, Wierzchowiecki M, Cox MB, Weiner JM: Causes of death in 212 cases of systemic lupus erythematosus. Arthritis Rheum 16:54&541, 1973 (abstract) 34. Dubois EL, et al: Causes of death in 212 cases of systemic lupus erythematosus. Arthritis Rheum 24:742, 1973-1974 35. Caperton E, Mulhn G, Dick FR, et al: Successful results with an aggressive approach to systemic lupus erythematosus. Arthritis Rheum 15:432, 1972 (abstract) 36. Epstein WV, Grausz H: Systemic lupus erythematosus. Arthritis Rheum 17:129-142, 1974 37. Cohen A, Canoso JJ: Criteria for the classification of systemic lupus erythematosus status. Arthritis Rheum 15:540-543, 1972 38. David P, Alkins B, Josse RG, Hughes GRV: Criteria for classification of SLE. Br Med J 3:90-91, 1973 39. Alacron-Segovia D: Drug induced lupus syndromes. Symposium on systemic lupus erythematosus. Mayo Clin Proc 44:66+681, 1969 40. Dabbous IA, Idriss HM: Occurrence of systemic lupus erythematosus in association with ethosuccimide therapy. J Pediatr 76:617-620, 1970 41. Livingston S, Rodriguez H, Green CA, Pauli LL: Systemic lupus erythematosus: Occurrence in association with ethosuccimide therapy. JAMA 204:185, 1968 42. Monnet P, Salle B, Poncet J, et al: Lupus erythemateux dissemine induit par I’ethosuccimide chez une fille de 6 ans. Rev Med Dijon 5:319, 1967 43. Alacron-Segovia D, Wakim KG, Loorthington JW, Ward LE: Clinical and experimental studies on the hydralazine syndrome and its relationship to systemic lupus erythematosus. Medicine 46: 1, 1967 44. Febius AJM, Gaulhofer WK: Systemic lupus erythematosus induced by psychotropic drugs. Acta Rheum Stand 17:137-147, 1971 45. Bennett R, Hughes GRV, Bywaters EGL, Holt PJL: Neuropsychiatric problems in systemic lupus erythematosus. Br Med J 4:342-345, 1972 46. Lundberg PO, Werner I: Trigeminal sensory neuropathy in SLE. Acta Neural Stand 48:33&340, 1972 47. Greenhouse AH: On chorea, lupus, erythematosus, and cerebral arteritis. Arch Intern Med 117:383-389, 1966 48. Antin SP, Prockop LD, Cohen SM: Transient hemiballism. Neurology 17:10681072, 1967
CNS LUPUS
265
ERYTHEMATOSUS
49. Myers R: Ballismus. Handbook of Clin Neuro. North Holland Publishing Co., 6:479, 1968 50. Rowe PB: Disseminated lupus erytbematosus with Sydenham’s chorea report of a case with review of the literature. Med J Aust 2:586588, 1963 51. Thompson S: Ballistic movements of the arm in systemic lupus erythematosus (unpublished) 52. Ashworth B, Tait GBW: Trigeminal neuropathy in connective tissue disease. Neurology 21:509 614, 1971 53. Bisko F: Retinopathy in SLE. Arthritis Rheum l5:57~ 63, 1972 54. Pfaffenback DD, Hollenhorst RW: Microangiopathy of the retinal arterioles. JAM A 225:48&485, 1973 55. Donaldson IMG, Espines EA: DISseminatcd lupus erythematosus presenting as chorea grandarum. Arch Neurol 25:240-244, 1971 56. Schaaf M, Payee CA: Distonic reactions to prochorperazine in hypothyroidism. N Engl J Med 275:991, 1966 57. Boston collaborative drug surveillance program. JAMA 224:889-89 I, 1973 58. Kaplan AP, Curl FD, Decker JL: Central hyperventilation and inappropriate antidiuretic hormone secretion in systemic lupus erytbematosus. Am J Med 48:661-667, 1970
hypothalamus and immune process. Ann NY Acad Sci 164:464, 1969 67. Weil RJ: Emotions and immunity. Can Psychiatr Assoc J 13:475, 1968 68. Engel GE: A life setting conducive to illness: The giving-up-given-up complex. Ann Intern Med 69:293, 1968 69. Bourne HR, Lichtenstein LM, Melmon KL, et al: Modulation of inflamation and immunity by cyclic AMP. Science 184: 19-28, 1974 70. Petz LD, Sharp GC, Cooper NR, Irvin WS: Serum and CSF complement. Medicine 50:259-275, 1971 71. Hadler NM, Gerawin RD. Frank MM, et al: The fourth component of complement (C4) in the cerebrospinal fluid (CSF) in systemic lupus erythematosus (SLE). Arthritis Rheum 16:5075 18, 1973 72. Levin SA, Fudenburg HH, Petz LD, Sharp GC: IgG levels in cerebrospinal fluid of patients with central nervous system manifestations of systemic lupus erythematosus. Clin Immunol Immunopathol l:ll5, 1972 73. Harbeck RJ, Hoffman AA, Carr RI, Bardana EJ: Bull Rheum Dis 24:742, l973- 1974 74. KeelTe EB, Bardana EJ, Harbeck RJ, et al: Lupus meningitis. Ann Intern Med 80:58-60, 1974
59. Gurland BJ, Ganz VH, Fleiss JL, Zubin J: The study of the psychiatric symptoms of systemic lupus erythematosus. Psychosom Med 34: 1999206, 1972
75. Atkins CJ, Kondon JJ, Quismorio F. Friou GJ: The choroid plexus in systemic lupus erythematosus. Ann Intern Med 76:65-72, 1972 76. Lampert PW, Oldstone MBA: Host immunoglobulin G and complement deposits in the choroid plexus during spontaneous immune complex disease. Science 180:408, 1973
60. Nissen HA, Spencer KA: The psychogenic problem (endocrinal and metabolic) in chronic arthritis. N Engl J Med 214:67&581, 1936
77. Dieaerichsen H, Cosmos PI: Antibodies against neurons in a patient with SLE, cerebral palsy and epilepsy. Brain 93:407-412, 1970
61. Baker M, Hadler N, Whitaker JN, et al: Psychopathology in systemic lupus erythematosus: II. Relation to clinical observations, corticosteroid administration and cerebrospinal fluid C4. Semin Arthritis Rheum 3:1 I I, 1973
78. Phillips PE, Christian CL: Myxovirus antibody increases in human connective tissue disease. Science 168:982-984, 1970
62. Kreindler S, Cancro R: psychological approach to psychiatric tions in systemic lupus erythematosus. syst 31:103, 1970 63. Graeme JT: tosus. Can Psychiatr
An ego manifestaDis Nerv
Systemic lupus erythemaAssoc J 17:26l, 1972
64. Solomon GF: Emotion, stress, the central nervous system and immunity. Ann NY Acad Sci 164:335, 1969 65. Solomon GF, Moos RH: Emotions, immunity and disease: A speculative theoretical integration. Arch Gen Psychiatry 11:657, 1964 66. Stein M, Schiavi RC, Luparello TJ: The
79. Abinanti FR: Further evidence to support role of infectious agents and/or immunologic sequelae in the causality of the chronic and degenerative disease of man. Ann NY Acad Sci 174:967-978. 1970 80. Hurd ER, Dowdle W, Casey H, Zig M: Virus antibody levels in systemic erythematosus. Arthritis Rheum 15:267 274, 1972 81. Grimley PJ, Frantz MM, Michelitch HJ, Decker JL: Tubuloreticular structures of circulating lymphocytes in systemic lupus erythematosus (SLE). Arthritis Rheum 15:112, 1972 82. Goodman JR, Sylvester RA, Talal N, Tuffanelli DL: Virus-like structures in lymphocytes of patients with systemic and dis-
266
cord lupus 79:396-402,
BENNAHUM
erythematosus. 1973
Ann
Intern
Med
83. Neiland NW, Hashimoto K, Masi A: Microtubular inclusions in normal skin systemic lupus erythematosus 15:193-200, 1972
patients.
Arthritis
Rheum
84. Gyorkey F, Min KW, Sincovics JG, et al: Systemic lupus erythematosus and myxovirus. N Engl J Med 280:333, 1969 85. Kiwano K, Miller L, Kimmelstiel Virus-like structures in lupus erythematosus. Engl J Med 28 1:I229- 1230, 1969
P: N
86. Norton WL: Endothelial inclusions active lesions of systemic lupus erythematosus. Lab Clin Med 74:369-379, 1969
in J
87. Grauz H, Earley LE. Stephens BG, et al: Diagnostic import of virus-like particles in the glomerular endothelium of patients with systemic lupus erythematosus. N Engl J Med 283:506--5 I 1, 1970 88. Garancis JC, Komorowski RA, Bernard GC, et al: Singificance of cytoplasmic microtubules in lupus nephritis. Am J Pathol 64:1-g, 1971 89. Norris, FH, Aguilzr MJ, Harmon CE: Virus-like particles in a case of vasculitis with brain tumor. Arch Neural 26:212-217, 1972 90. Dubin HV, Courter MH, Toxoplasmosis. Arch Dermatol 1971
Hanell RE: 104:547 -550,
9 I Ltpsmeyer EA: Development of mahgnant cerebral lymphoma in a patient with systemtc lupus erythematosus treated with immunosuppression Arthritis Rheum 15:183- 186, 1972 92 Green HSN: The transplantation mors to the brains of heterologous Cancer Res 11:529-534, 1951 93. Schneck SA, Penn mors in renal-transplant 1:983-986,
of tuspecies.
I: De novo brain turecipients. Lancet
197 I
94. Spector DA, Jampol LM, Hayslett JP: Report of the familial occurrence of systemic lupus in male siblings. Arthritis Rheum 16:221 224, 1973 95. Grumet, McDevitt HO: bility (HL-A) antigens associated
Histocompatiwith systemic
AND
MESSNER
lupus erythematosus. N Engl J Med 285:193196, 1971 96. Arnett FC, Bias WB, Shulman LE: HL-A antigens in SLE. Arthritis Rheum 15:455, 1972 97. Goldberg M, Arnett FC, Bias WB, Shulman LE: Histocompatibility (HL-A) antigens in systemic lupus erythematosus. Arthritis Rheum 16546-547, 1973 98. Morely BJ: Nuclear medicine in neurological diagnosis. Med J Aust 2:81-85, 1973 99. Ferris EJ, Levine HL: Cerebral arteritis: Classification. Radiology 109:327-341, 1973 100. Bennahum DA, Messner RP, Shoop JD: Brain scan findings in central nervous system involvement by lupus erythematosus. Bull Rheum Dis 241742, 1973 101. Roth EM, Williams RC: Viral-host relationships in chronic diseases of man. J Chronic Dis 26:55-61, 1973 102. Talal N: Lymphocyte heterogeneity and function Arthritis Rheum 16:422-425, 1973 103. Messner RP: Clinical aspects of T and B lymphocytes in rheumatic diseases. Arthritis Rheum (in press) 104. Lewis RM, Andre-Schwartz J, Harris GS, et al: Canine systemic lupus erythematosus: Transmission of serologic abnormalities by all free filtrates. J Clin Invest 52:1893- 1907, 1973 105. Lewis R, Tannerberg W, Smith C, Schwartz R: Human systemic lupus erythematosus and C-type RNA viruses. Clin Res 22:422, 1974 106. Sergent JS, Lockshin MD: Treatment of central nervous system lupus erythematosus: Editortal notes. Ann Intern Med 8:413-414, 1974 107. Gelfand MC, Steinberg AD, Nagle R, Knepshiled JH: Therapeutic studies in NZB-W mice 1. Synergy of azothiaprin, cyclophosand methylprednisolone in comphamide bination. Arthritis Rheum 15:239-246, 1972 108. Steinberg AD, Kalterider HB, Staples PG, et al: Cyclophosphamide in lupus nephritis: A controlled trial. Ann Intern Med 75:1655171, 1971 109. Brook CGD, Evans PR: Psychosis in systemtc lupus erythematosus (SLE) and the response to cyclophosphamide. Proc R Sot Med 62:9 12, 1969