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A clinical and pathologic study of cerebrovascular disease in patients with systemic lupus erythematosus
A Clinical and Pathologic Study of Cerebrovascular Disease in Patients With Systemic Lupus Erythematosus By George C. Tsokos, Maria Tsokos, Nicole G.H. le Riche, and John H.
I
NVOLVEMENT of the CNS is common in patients with systemic lupus erythematosus (SLE).‘-’ Clinical manifestations are protean and reflect a number of different pathologic processes collectively referred to as CNS lupus. Prognosis, therapy, morbidity, and mortality are dependent on the anatomy, type, and severity of the specific pathologic processes. Cerebrovascular disease (CVD) is one of the underlying pathologies responsible for CNS manifestations in lupus patients. We have studied a group of SLE patients with various forms of occlusive and hemorrhagic CVD. Clinical, demographic, laboratory, and pathologic data on these patients are presented. PATIENT POPULATION
All patients with the diagnosis of SLE and CVD evaluated at the Clinical Center of the National Institutes of Health (NIH) between 1962 and 1983 were studied. Among approximately 500 patients with SLE observed at this institution during this period, 15 carried the combined SLE and CVD diagnosis. Charts were reviewed and special emphasis was given to features pertinent to CVD. Six case studies that demonstrate different causes of CVD pathology underlying the clinical presentations in patients with SLE were selected and presented in detail. RESULTS Patients
rized
into
with SLE-CVD
occlusive
Tsokos,
were further categoor hemorrhagic forms of
MD: Kidney Section, Metabolic Dis-
eases Branch, NIADDK; Maria Tsokos, MD: Laboratory of Pathology, National Cancer Institute; Nicole G.H. le Riche, MD: Arthriiis and Rheumatism Branch, NIADDK; John H. Klippel, MD: Arthritis and Rheumatism Branch, NIADDK, Bethesda, Md. Address reprint requests io George C. Tsokos, MD, National Institutes of Health, Bldg IO, Room 3NI14, Bethesda, MD 20892. 0 1986 by Grune & Stratton, Inc. 0049-0172/86/1601-0004$5.00/O
70
Klippel
disease. Eleven patients were determined to have primarily vascular occlusive disease; three had middle cerebral artery occlusion documented by arteriography, and five had extremity paralysis consistent with the diagnosis based on the clinical picture. Two patients had brain stem artery occlusion with the diagnosis made on clinical manifestations of vertigo, ataxia, hemianesthesia, cranial nerve involvement, and paresthesias. The last patient in this group had multiple cerebral and cerebellar infarctions secondary to small artery occlusions. A case report of this patient is presented in detail (patient no. 2). Four patients were classified as having primarily hemorrhagic disease; one case each of a ruptured berry aneurysm (patient no. 3), a right cerebral hemorrhage (patient no. 5) a right cerebellar hemorrhage and generalized vasculitis, and a basal ganglion bleed diagnosed on clinical grounds and computed tomography (CT) findings. The mean patient age at time of SLE-CVD was 40 years (range, 26 to 55) in the 11 patients with occlusive disease and 37 years (range, 16 to 60) in the four patients with hemorrhagic disease. Occlusive CVD occurred 6 years (range, 2 to 14) and hemorrhagic CVD, 2.8 years (range, 1 to 4) from the time of diagnosis of SLE based on revised classification criteria.’ The clinical characteristics of patients with SLE-CVD are shown in Table 1. Frequencies of alopecia, rash, nasopharyngeal ulcers, serositis, arthritis, cutaneous vasculitis, Raynaud phenomenon, renal disease, and Sjogren syndrome were not different from those observed in large populations of patients with SLE.‘-3*8 Of the 11 patients with occlusive disease, five had evidence of lupus activity at the time of the neurologic event, as defined by the presence of several of the above clinical features; all four patients with hemorrhagic disease had active disease at the time of CVD. A summary of the laboratory data of the patient groups is shown in Table 2. The frequency of various abnormalities is not strikingly different from that reported for larger groups of patients.‘-3s8 A chronic false-positive VDRL was
Seminars in Arthritis and Rheumatism, Vol 16, No 1 (August), 1986: pp 70-78
71
CEREBROVASCULAR DISEASE IN SLE
Table 1. Clinical Characteristics of Patients With
Table 3. Predisposing Factors for the Development of
SLE-CVD
CVD in Patients With SLE
Alopecia Rash
Occlusive (%I
Hemorrhagic (%I
5/l 1 145) 10/l 1 191)
occlusive
Hemorrhagic
Positive family history CVD
7111
Of4
214 (50)
History of heavy smoking
3111
214 (50)
History of contraceptive
l/10
O/4 l/4
Nasopharyngeal ulcers
2/l 1 (18)
l/4
(25)
Serositis
6/l 1 (55)
l/4
125)
Arthritis
6/l
1 (55)
4/4 (100)
Cutaneous vasculitis
l/l
1 (9)
o/4 (0)
Hypercholesterolemia
5111
l/4
Raynaud phenomenon
3/l 1 (27)
o/4 (0)
History of diabetes
o/11
O/4
314 (75)
Prior history of drug treatPrednisone
10/l 1
414
Cyclophosphamide
l/l
l/4
Kidney involvement
10/l 1 (91)
Sjogren syndrome
l/l
1 (9)
l/4
(25)
Overall disease activity at the time of the
drug treatment History of hypertension
B/11 (O- 11 years)
214 (O-10)
ent 1
CNS event
516
Active/inactive
4/O
noted in four of the 11 patients (36%) with occlusive disease and in none of the four patients with hemorrhagic disease. Prolonged partial thromboplastin time (PTT) was recorded in only two of 11 patients with occlusive disease. Summarized in Table 3 are the presence of various predisposing risk factors pertinent to the diagnosis of CVD. A positive family history, hypertension, and hypercholesterolemia were found in many of the patients with occlusive disease and infrequently present in the group of four patients with hemorrhagic disease. The rates of recovery and death from CVD were strikingly different between the groups of patients with occlusive and hemorrhagic disease. Five patients with occlusive disease had complete recovery from the CVD, while only one (a patient with a basal ganglion bleed) from the group of patients with hemorrhagic disease showed complete neurologic recovery. Five patients with occlusive disease had partial clinical recovery. Death occurred in one patient with occlusive Table 2. Laboratory Characteristics of Patients With SLE-CVD Occlusive 1%) High serum DNA Binding
10/l
Hemorrhagic (%)
1 (91)
414 ( 100)
Low c3
3/l 1 (97)
LE cells
9/l 1 (82)
314 (75) 414 ( 100)
VDRL
4/l
1 136)
o/4 (0)
Prolonged PlT
2/l 1 (18)
o/4 (0)
Anemia
4/l
1 (36)
414 (100)
Leucopenia
4/l
1 (36)
l/4
Thrombocytopenia
6/l
1 (55)
3/4 (75)
(251
disease while three of the patients with hemorrhagic disease died. Presented below are detailed case histories of six patients who exemplify different underlying pathologies of SLE-CVD. A summary of the main clinical features of these patients is presented in Table 4 and pertinent laboratory findings are summarized in Table 5. CASE REPORTS
Patient No. I A 25-year-old white female with a IO-month history of SLE was referred for evaluation of acute left hemiparesis and expressive aphasia. The patient had rheumatic fever diagnosed at age 15 manifested by arthritis, first degree conduction block, and a holosystolic mitral valve murmur, Nine years earlier she suffered an acute right hemiparesis with receptive and expressive aphasia. Carotid angiography disclosed a left middle cerebral artery occlusion thought to be an embolus dislodged from her mitral valve. The patient fully recovered with no neurologic sequelae. Five years before admission, her only pregnancy was complicated by hypertension, proteinuria, and an acute right retinal artery occlusion. Laboratory studies at the time showed a false-positive syphilis serology and a prolonged partial thromboplastin time. Abnormal laboratory studies on admission included a positive antinuclear antibody (titer l/640, diffuse pattern), high anti-DNA binding, low serum C3 levels, thrombocytopenia (30,00O/rL), Coomb positive hemolytic anemia (hematocrit 22%), leucopenia (2,30O/rL), elevated partial thromboplastin time (74 seconds), and normal prothrombin time. Neurologic examination revealed a right gaze preference with left homonymous hemianopsia, right Horner syndrome, decreased left cornea1 reflex, decreased left facial sensation, decreased gag reflex, and decreased muscular strength of the left upper and lower extremities. Lumbar puncture was within normal limits with negative cultures. CT scan of the head without contrast showed a low density, well-defined deficit in the left parietal lobe and a low density deficit with surrounding edema in the right parietal lobe (Fig 1). An EEG showed a normal recording on the left side and
TSOKOS ET AL
72
Table 4. Summary
PatientNo.
Clinical Description
Sex/Age
1
F/25
of Clinical and Patholoaic Data
Arterioaaphic Findings
AutopsyFindings
Right middle cerebral
Right hemiparesis global aphasia
AssumedCause Emboli from mitral valve
occlusion, left mid-
prolapse
dle cerebral occlusion 2
F/42
CNS vasculitis, multiple
ND
Chronic manic-
infarcted areas
depressive illness, multiple
CNS vasculitis or emboli from Libman-Sack endocardial lesions
neurologic symptoms and signs 3
F/39
Ruptured berry aneu-
Subarachnoid
rysm
hemorrhage
Ruptured berry aneurysm
Subarachnoid hemorrhage
4
F/13
Quadriparesis
ND
Multiple brain hemor-
5
F/59
fa2.3 Left hemi-
ND
Hemorrhage of the right
Hyperviscosity, coagulo-
hemisphere, multiple
pathy, emboli, or ath-
microscopic hemor-
erosclerosis
Coagulopathy
rhages paresis
rhagic foci, athero6
F/37
Left middle cerebral
Right hemiparesis
sclerosis -
No cause identified
artery occlusion Abbreviation: ND, not determined.
slow waves on the right side; no epileptic
foci were identified. A two-dimensional echocardiogram was normal. Carotid arteriograms (Fig 2) showed complete occlusion of both the right and left middle cerebral arteries interpreted as consistent with arterial emboli. The arteriograms of the aortic arch and carotid arteries were normal. A left heart catheterization showed minimal mitral regurgitation consistent with the diagnosis of mitral valve prolapse. She was maintained on 35 mg of prednisone daily and treated with bedside physical therapy. The patient experienced slow but continuous improvement of speech with almost complete recovery of muscular strength over a 3-month period. Summary A 25-year-old white female with SLE and a history of rheumatic heart disease who experienced three separate, presumably embolic, episodes to the right middle cerebral, right retinal, and the left middle cerebral arteries Table 5. Selected
Laboratory
Findings of the Presented
Case Reports Patient No. 1
2
3
4
5
6
ANA
+
+
+
+
+
+
Prolonged PlT
+ +
ND -
ND _
+ +
~
_
Thrombocytopenia
+
+
+
Hemolytic anemia
+
Leucopenia
+
Prolonged PT
+
+
ND
+
+
+
-
+
+
+
ND
_
False positive syphilis +
+
_
-
_
Rheumatoid factor
_
_
+
-
+
-
Cryoglobulinemia
_
_
+
-
+
ND
Hyperviscosity (IgMI
-
-
-
-
+
ND
serology
Abbreviation: ND, not determined.
over a 9-year period. The apparent the mitral valve.
source of the emboli was
Patient No. 2 A 42-year-old white female with an 1 l-year history of SLE was admitted for evaluation of memory loss, gait disturbances, and rigidity. The diagnosis of SLE was made 4 months postpartum with the development of arthritis, rash, leucopenia, thrombocytopenia, and findings of a positive antinuclear antibody and a positive lupus erythematosus (LE) cell preparation. By history she had an unexplained false-positive syphilis serology, Raynaud phenomenon, and several bouts of manic-depressive psychosis. During one of the manic episodes, she was started on haloperidol and lithium and treated with electroconvulsant shock therapy. While on haloperidol and lithium she noted the onset of rigidity, gait disturbances, and decreased memory. These drugs were discontinued, yet symptoms progressed over the next 3 years. Physical examination on admission revealed good orientation and poor memory. The extremities were rigid with cogwheeling of the left arm. Deep tendon reflexes were brisk and symmetric. Pinprick sensation was decreased in the left lower extremity. There was bilateral ankle clonus. The gait was unsteady and shuffling; Romberg sign was negative. Lumbar puncture showed normal, sterile CSF. CT of the head showed prominent cortical atrophy with ischemic foci (Fig 3). EEG showed mild slowing of the background rhythms and an excessive amount of fast activity. Heart examination revealed a 2/6 systolic ejection murmur and a l/6 early diastolic blow. Echocardiographic evaluation showed normal chamber size with mild aortic stenosis and insufficiency. During the next year, the patient was treated with lithium and low doses of corticosteroids with good
CEREEROVASCULAR DISEASE IN SLE
Fig 1. Patient no. 1. CT scan without enhancement showing low density, well-defined deficit in the left parietal lope and low density deficit with surrounding edema in the right parietal lobe.
control of lupus activity. She then developed the sudden onset of pleuritic chest pain with findings on x-ray of wedgedshaped atelectasis of the right lower lobe. A pulmonary angiogram showed findings consistent with a pulmonary embolus and she was treated with heparin and warfarin sodium. During the subsequent 2 weeks, she developed acute intermittent episodes of respiratory failure associated with diffuse pulmonary infiltrates. Pulmonary wedge pressure was 12 mm Hg. Bronchoscopy and transbronchial biopsy were performed but were nondiagnostic. She was treated with broad spectrum antibiotic coverage (aminoglycosides, trimethoprim and sulfamethoxazole, and erythromycin) as well as high-dose intravenous (IV) methylprednisolone. Five days later she developed focal right upper extremity seizures. A lumbar puncture was normal and CT scan findings were unchanged from the previous study. Blood cultures were positive for a Candida species. She died 3 days later despite appropriate antibiotic treatment. A postmortem examination was performed which showed: (1) non-bacterial thrombotic vegetations of the mitral and aortic valves consistent with Libman-Sacks endocarditis; and (2) careful study of the brain showed hydrocephalus ex vacua, extensive necrosis of frontal, parietal, and occipital cortex (lamellar necrosis) (Fig 4). and minute necrotic foci in the cerebellum. Microscopic examination showed obliterative vasculitis noted on almost all sections; vasculitis lesions were associated with the presence of multifocal perisulcal infarctions. The infarcts were of different age (Fig 5). Occasional vessels of the pia showed obliterative endarteritis and intralu-
Fig 2. Patient no. 1. Carotid arteriograms. (A) Left carotid arteriogram showing complete occlusion of the middle cerebral artery. and iB) right carotid arteriogram showing complete occlusion of the middle cerebral artery.
minal thrombi; these features are consistent with the diagnosis of thrombotic thrombocytopenic purpura (TTP). Search by silver stain for Alzheimer plaques was negative. Summary A 42-year-old white female with a chronic manic depressive disorder, SLE, and multifocal neurologic symptoms and signs. She developed a fatal illness initiated by pulmonary embolus complicated by acute respiratory failure, seizures, and sepsis. Autopsy showed Libman-Sacks endocarditis, CNS vasculitis, TTP-like lesions, and multiple cerebral infarctions. CNS vasculitis was apparently responsible for the multiple cerebral and cerebellar infarcts. Sporadic emboli from the aortic and mitral valves may have contributed to some of the symptoms and signs.
TSOKOS ET AL
Patient no. 2. CT scan showing prominent cortiFig 3. cal atrophy with multiple ischemic foci.
Fig 4. Patient no. 2. Macroscopic preparation of the cerebrum showing multiple necrotic areas of the parietal (A) and frontal (6) lobes.
Patient No. 3 A 39-year-old South American female with a 4-year history of SLE presented for evaluation of arthritis, fever, and a maculopapular rash involving the hands and knees bilaterally. All studies for an infectious etiology were negative, except for an immunofluorescence titer for toxoplasmosis of l/256 which decreased two-fold after absorption with IgG. Additional laboratory studies showed an elevated antidouble-stranded DNA binding (99%), thrombocytopenia (60,0OO/j1L), and severe hemolytic anemia (hct = 20%). She was treated with 60 mg of prednisone daily and, in consideration of the possibility of cerebral toxoplasmosis, an 1I-day course of pyrimethamine and triple sulfadiazine was administered. The flare of SLE responded satisfactorily to treatment and the dose of corticosteroids was gradually reduced. Two months later, the patient developed an acute episode of loss of consciousness associated with vomiting followed by a generalized motor seizure that progressed to status epilepticus. Lumbar puncture revealed grossly bloody fluid. Cerebral angiography showed a ruptured berry aneurysm located at the junction of the right internal carotid artery and the posterior communicating artery. Over the next several days, the patient developed group D streptococcus sepsis, respiratory failure, and died. An autopsy showed extensive subarachnoid hemorrhage and a ruptured aneurysm located at the junction of the right posterior communicating artery. No vasculitis was detected in any of the brain sections. No evidence of cerebral toxoplasmosis was identified. Summary A 39-year-old female with SLE manifested by arthritis and severe hemolytic anemia. The patient died of
complications secondary to an extensive subarachnoid hemorrhage from rupture of a berry aneurysm of the circle of Willis.
Patient No. 4 A 13.year-old white girl with SLE was referred for evaluation of nephritis and several episodes of grand mal seizures. Laboratory studies showed an active urinary sediment, a serum creatinine of 1.8 mg/dL, low complement levels, high serum DNA binding, and cryoglobulinemia. The patient was treated with 30 mg prednisone daily and oral cyclophosphamide at a dose of 100 mg daily. Renal function showed significant improvement on this regimen. Prednisone and cyclophosphamide were continued for the next 30 months with little clinical or serologic evidence of active lupus. The cyclophosphamide was discontinued and a few weeks thereafter the patient developed a butterfly rash, an active urinary sediment, hypertension, and a progressive decline of renal function. Shortly after hospitalization she experienced a grand mal seizure. Renal function continued to deteriorate, necessitating peritoneal dialysis. The dialysis was complicated by the development of peritonitis with Pseudomonas aeruginosa cultured from the dialysate. She was treated with gentamicin and cefazolin. Sepsis was complicated by the development of disseminated intravascular coagulopathy with low levels of fibrinogen, elevated fibrin split products, and appropriate RBC morphology on blood smear. Two days later she developed spastic quadriparesis considered to be secondary to transverse myelopathy of the cervical cord. The patient was treated with IV heparin and showed some mild
CEREBROVASCULAR DISEASE IN SLE
Fig 5. Patient no. 2. Microscopic preparations of the cerebrum showing obliterative vasculitis associated with the presence of perisulcal infarctions of different age.
improvement in neurologic function. Five days later the patient was found flaccid and unresponsive with bilateral fixed dilated pupils. She died a few hours later. An autopsy was performed that showed extensive vasculitis characterized by perivascular infiltration and fibrinoid medial necrosis involving the kidneys, intestines, and coronary arteries. Sections of the fixed brain showed blood clots in the lateral ventricles and multiple small hemorrhages scattered throughout both cerebral hemispheres, many of which were located at the junction of gray and white matter. Hemorrhage and necrosis were also observed in the hypothalamus and midbrain. The right cerebellum was completely necrotic; the pons and medulla contained extensive large and small hemorrhagic foci (Fig 6). Vasculitic lesions were not detected microscopically in any of the sections. Summary A 13-year-old white girl with severe SLE who responded well to treatment with prednisone and oral cyclophosphamide. Her disease deteriorated fulminantly in the 3-week period after cyclophosphamide was discontinued. The flare included grand mal seizures and rapidly progressive glomerulonephritis with eventual renal failure. Peritoneal dialysis was complicated by pseudomonas sepsis and intravascular coagulopathy. Death was secondary to a massive intracerebral catastrophy which on post mortem examination was found to involve extensive hemorrhage.
plasmapheresis, which over a l-month period led to a marked reduction of the serum viscosity. This was associated with a marked improvement in mental function and abolished the bleeding episodes. Ten days after completion of apheresis, she complained of sudden severe headache and left hemiparesis which rapidly progressed to bilateral fixed pupils, flaccid quadriparesis, and evidence of decerebrate activity. She died
Patient No. 5 A 59-year-old white female with a 17-year history of Sjogren syndrome and SLE was referred for evaluation of lethargy. On physical examination the patient was mildly lethargic with findings of Roth spots in the right fundus. Serum IgM was 41.5 mg/mL (normal, 0.9 to 1.7 mg/mL) and the relative serum viscosity was 7.5. Bone marrow aspiration showed mild increase of plasmacytoid cells with normal cellularity of the other marrow cell series. While in the hospital, the patient experienced several acute episodes of confusion, disorientation, and obtundation, and complained of a mildly stiff neck. Repeated lumbar punctures were normal. EEG showed diffuse slowing as well as some transient focal changes. On several occasions, fresh hemorrhages of the fundi were noted and she experienced several severe nose bleeds. The patient was treated with
Fig 6. Patient no. 4. Macroscopic preparation of the cerebellum with extensive necrotic areas of the hypothalamus (A), midbrain (6). and the right cerebellum (Cl.
76
TSOKOS ET AL
a few hours later. The serum viscosity throughout the entire terminal phase of the illness was normal. The autopsy showed a necrotising arteritis involving the vessels of the gastrointestinal tract, mild mononuclear cell infiltrates of both liver and kidneys, and mild follicular hyperplasia of several lymph nodes. Sterile endocardial lesions consistent with Libman-Sacks endocarditis were found on the aortic valve. There was diffuse hemorrhage in the right cerebral cortex with rupture into the lateral ventricles. Microscopically multiple foci of hemorrhage and encephalomalacia were observed in the cortex, basal ganglia, brain stem, and cerebellum. No vasculitis was observed in any of the many slide preparations of the brain. Summary. A 59-year-old female with SLE, Sjogren syndrome, and hyperviscosity syndrome responded to treatment with plasmapheresis. Her terminal illness was consistent with a massive intracerebral hemorrhage that was confirmed on postmortem examination. The exact reasons for the diffuse intracerebral hemorrhages are not entirely clear and may have been secondary to hypervisocity with coagulopathy or emboli from the Libman-Sacks endocardial lesions.
Patient No. 6 A 37-year-old left-handed white woman with a 3 year history of SLE was seen for assessment of a left hemispheral cerebrovascular accident. She was considered to be in complete clinical remission for a period in excess of 2 years when one day before admission she noticed the sudden onset of slurred speech and weakness of the entire right side of her body. On neurologic examination there was mild to moderate muscular weakness on the right side; deep tendon reflexes were slightly decreased on the right side and there was a right Babinski sign. A right central VII nerve paralysis was noted. Lumbar puncture was normal. Cerebral angiography showed complete occlusion of the left middle cerebral artery approximately 2 cm past its origin with no other evidence of vessel disease. Summary. A 37-year-old white female with a 3-year history of SLE, in complete remission for 2 years, developed an acute left middle cerebral artery occlusion. The etiology of the occlusion was not identified.
DISCUSSION
The original descriptions of patients with SLE by Kaposi in 1872” and Osler in 1895” emphasized neurologic manifestations. The clinical manifestations of CNS disease in SLE are remarkably diverse and include disturbances of mental function, psychosis, seizures, neuropathies, paralysis, movement disorders, ocular dysfunction, migraine, aseptic meningitis, transverse myelopathy, and cerebrovascular accidents. Studies have suggested that as many as two thirds of patients with SLE may develop significant neuropsychiatric disease.‘-* In approximately 5% of lupus patients, neuropsychiatric manifestations are the presenting feature of
the disease and may antedate by months or years the actual diagnosis. Following the diagnosis of SLE, neuropsychiatric manifestations may develop at any time in the course of the disease, although in the majority of patients signs and symptoms most commonly develop within the first 2 years of the disease.6 The presence of CNS manifestations is generally regarded as an ominous prognostic sign. In most studies, the contribution of CNS disease to the overall mortality in SLE is exceeded only by infection and renal involvement.‘2 Among the various CNS manifestations, cranial nerve signs and organic mental disorders are thought to carry the poorest prognosis. Many of the deaths are due directly to complications from impaired neurologic function or complications from the high doses of corticosteroids used in treatmentI Although many studies have reported on the pathologic findings in SLE patients with neuropsychiatric manifestations, characteristic pathology to account for all the diverse clinical presentations has not been identified.14*15 The main pathologic features consistently recognized in autopsies of patients with SLE include vascular lesions, infarctions, and hemorrhage. True vasculitis with inflammatory cells within the vessel wall is found in only a small percentage. Large vessel disease, similar to that of polyarteritis nodosa, is a distinctly uncommon feature. More characteristic are vascular hyalinization, perivascular inflammation, and endothelial proliferation. Approximately 50% of patients with CNS disease have been shown to have multiple small infarcts. Most of these infarcts are observed in the cortex, while the cerebellum seems to be spared. The potential causes of vascular compromise and infarction are many. Emboli from valvular vegetation may be responsible. Indeed, Libman and Sacks, in describing these endocardial lesions, regarded them as important in the pathogenesis of neurologic manifestations.‘6 Also, thrombotic thrombocytopenic purpura has been documented in a number of patients with SLE. The clinical spectrum includes a characteristic hematologic and neurologic picture. At the morphologic level it is characterized by widespread hyaline occlusions in terminal arterioles and capillaries. This report describes a group of 15 patients with SLE and various forms of cerebrovascular
77
CEREBROVASCULAR DISEASE IN SLE
disease. Eleven patients could be classified as having primarily occlusive disease, whereas the remaining four had cerebrovascular disease associated with hemorrhage. There were no demographic features that distinguished the two groups, nor were there differences in the frequencies of various non-CNS or laboratory disease features. Several apparent differences between the two groups were identified. Active non-CNS lupus was present at the time of the neurologic event in all four patients with hemorrhagic lesions as compared with less than 50% of those with occlusive lesions. Of the established predisposing risk factors for cerebrovascular diseases, positive family history, history of smoking, hypertension, and hypercholesterolemia were found more frequently in the group of patients with occlusive disease. Finally, the most obvious difference between the two groups was in the mortality rate. Three of the four patients with hemorrhagic disease died, while only one of the 11 with occlusive disease had a fatal outcome. A number of different etiologies for SLECVD were identified. Six case studies representative of different forms of etiopathogenesis are presented in detail. Arterial embolic disease was demonstrated to be the cause of three isolated CNS occlusive episodes in one patient. Despite a history of apparent rheumatic heart disease, mitral valve prolapse, and not rheumatic mitral disease, was documented. Mitral valve prolapse is known to be associated with cerebrovascular embolic episodes.” Libman-Sacks endocardial lesions were identified in postmortem studies of two patients and may have contributed to the neurologic abnormalities. The clinical course of patient no. 2 is very characteristic of the process most commonly termed CNS lupus. Chronic disturbances of mental function were superimposed on intermit-
tent neurologic signs. CT revealed perisulcal atrophy thought to be secondary to microinfarction.” Postmortem examination showed a prominent obliterative vasculitis with intraluminal thrombi. The findings were consistent with the lesions that occur in thrombotic thrombocytopenic purpura although the patient had neither the clinical findings nor thrombocytopenia to support this diagnosis. Rupture of a probable congenital aneurysm led to the death of one patient. Although vasculitis has been reported to produce such aneurysms, r9.” no evidence of vasculitis or other aneurysms were found on postmortem examination. The dilemma produced by the coexistence of active lupus, infection, and CNS disease is typified by the course of several patients. Despite floridly active lupus, sepsis and disseminated intravascular coagulation was responsible for one of the fatal outcomes. Similarly, a coagulopathy produced by the hyperviscosity syndrome and responsible for mental symptoms likely led to a massive fatal intracerebral hemorrhage. Finally, the non-fatal stroke documented in eight patients is, at least in our experience, the most common form of SLE-CVD. More often than not, it develops without obvious cause in the setting of completely quiescent lupus activity for months or even years. Recent studies have called attention to the frequent presence of the lupus anticoagulant in such patients.20*23Although we have not systematically searched for evidence of the anticoagulant, it is our impression that prolongation of the partial thromboplastin time or positive serologic tests for syphilis are infrequently found in these patients. Hopefully, antibodies to cardiolipin may be more sensitive in the identification of this group of patients at risk for cerebral infarctions.24*25
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E, Sacks
B: A hitherto
undescribed
form of
valvular and mural endocarditis. Arch Intern Med 33:701737,1924 17. Schlant RC, Felner JM, Miklozek CL, et al: Mitral valve prolapse. DM 26: I-5 1, 1980 18. Bilaniuk LT. Pate1 S, Zimmerman RA: Computed tomography of systemic lupus erythematosus. Radiology 124:119-121,1977 19. Fody EP, Nersky MG, Mrak RE: Subarachnoid spinal hemorrhage in a case of systemic lupus erythematosus. Arch Neural 37:173-174, 1980 20. Kelley RE, Stokes N, Reyes P, et al: Cerebral transmural angiitis and ruptured aneurysm. A complication of systemic lupus erythematosus. Arch Neural 37:526-527, 1980 21. Mueh JR, Herbst KD, Rapaport SI: Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 92:156-159.1981 22. Boey ML, Colaco CB, Gharavi AE, et al: Thrombosis in SLE: Striking association with the presence of circulating “lupus anticoagulant.” Br Med J 287:1021-1023, 1983 23. Landi G, Calloni MV, Sabbadini MG, et al: Recurrent ischemic attacks in two young adults with lupus anticoagulant. Stroke 14:377-379, 1983 24. Harris EN, Hughes GRV: Cerebral disease in systemic lupus erythematosus. Springer Semin Immunopathol 8:251-266,1985 25. Harris EN, Gharavi AE, Asherson RA, et al: Cerebral infarction in systemic lupus: Association with anticardiolipin antibodies. Clin Exp Rheumatol 2:47-5 1, 1984
I
NVOLVEMENT of the CNS is common in patients with systemic lupus erythematosus (SLE).‘-’ Clinical manifestations are protean and reflect a number of different pathologic processes collectively referred to as CNS lupus. Prognosis, therapy, morbidity, and mortality are dependent on the anatomy, type, and severity of the specific pathologic processes. Cerebrovascular disease (CVD) is one of the underlying pathologies responsible for CNS manifestations in lupus patients. We have studied a group of SLE patients with various forms of occlusive and hemorrhagic CVD. Clinical, demographic, laboratory, and pathologic data on these patients are presented. PATIENT POPULATION
All patients with the diagnosis of SLE and CVD evaluated at the Clinical Center of the National Institutes of Health (NIH) between 1962 and 1983 were studied. Among approximately 500 patients with SLE observed at this institution during this period, 15 carried the combined SLE and CVD diagnosis. Charts were reviewed and special emphasis was given to features pertinent to CVD. Six case studies that demonstrate different causes of CVD pathology underlying the clinical presentations in patients with SLE were selected and presented in detail. RESULTS Patients
rized
into
with SLE-CVD
occlusive
Tsokos,
were further categoor hemorrhagic forms of
MD: Kidney Section, Metabolic Dis-
eases Branch, NIADDK; Maria Tsokos, MD: Laboratory of Pathology, National Cancer Institute; Nicole G.H. le Riche, MD: Arthriiis and Rheumatism Branch, NIADDK; John H. Klippel, MD: Arthritis and Rheumatism Branch, NIADDK, Bethesda, Md. Address reprint requests io George C. Tsokos, MD, National Institutes of Health, Bldg IO, Room 3NI14, Bethesda, MD 20892. 0 1986 by Grune & Stratton, Inc. 0049-0172/86/1601-0004$5.00/O
70
Klippel
disease. Eleven patients were determined to have primarily vascular occlusive disease; three had middle cerebral artery occlusion documented by arteriography, and five had extremity paralysis consistent with the diagnosis based on the clinical picture. Two patients had brain stem artery occlusion with the diagnosis made on clinical manifestations of vertigo, ataxia, hemianesthesia, cranial nerve involvement, and paresthesias. The last patient in this group had multiple cerebral and cerebellar infarctions secondary to small artery occlusions. A case report of this patient is presented in detail (patient no. 2). Four patients were classified as having primarily hemorrhagic disease; one case each of a ruptured berry aneurysm (patient no. 3), a right cerebral hemorrhage (patient no. 5) a right cerebellar hemorrhage and generalized vasculitis, and a basal ganglion bleed diagnosed on clinical grounds and computed tomography (CT) findings. The mean patient age at time of SLE-CVD was 40 years (range, 26 to 55) in the 11 patients with occlusive disease and 37 years (range, 16 to 60) in the four patients with hemorrhagic disease. Occlusive CVD occurred 6 years (range, 2 to 14) and hemorrhagic CVD, 2.8 years (range, 1 to 4) from the time of diagnosis of SLE based on revised classification criteria.’ The clinical characteristics of patients with SLE-CVD are shown in Table 1. Frequencies of alopecia, rash, nasopharyngeal ulcers, serositis, arthritis, cutaneous vasculitis, Raynaud phenomenon, renal disease, and Sjogren syndrome were not different from those observed in large populations of patients with SLE.‘-3*8 Of the 11 patients with occlusive disease, five had evidence of lupus activity at the time of the neurologic event, as defined by the presence of several of the above clinical features; all four patients with hemorrhagic disease had active disease at the time of CVD. A summary of the laboratory data of the patient groups is shown in Table 2. The frequency of various abnormalities is not strikingly different from that reported for larger groups of patients.‘-3s8 A chronic false-positive VDRL was
Seminars in Arthritis and Rheumatism, Vol 16, No 1 (August), 1986: pp 70-78
71
CEREBROVASCULAR DISEASE IN SLE
Table 1. Clinical Characteristics of Patients With
Table 3. Predisposing Factors for the Development of
SLE-CVD
CVD in Patients With SLE
Alopecia Rash
Occlusive (%I
Hemorrhagic (%I
5/l 1 145) 10/l 1 191)
occlusive
Hemorrhagic
Positive family history CVD
7111
Of4
214 (50)
History of heavy smoking
3111
214 (50)
History of contraceptive
l/10
O/4 l/4
Nasopharyngeal ulcers
2/l 1 (18)
l/4
(25)
Serositis
6/l 1 (55)
l/4
125)
Arthritis
6/l
1 (55)
4/4 (100)
Cutaneous vasculitis
l/l
1 (9)
o/4 (0)
Hypercholesterolemia
5111
l/4
Raynaud phenomenon
3/l 1 (27)
o/4 (0)
History of diabetes
o/11
O/4
314 (75)
Prior history of drug treatPrednisone
10/l 1
414
Cyclophosphamide
l/l
l/4
Kidney involvement
10/l 1 (91)
Sjogren syndrome
l/l
1 (9)
l/4
(25)
Overall disease activity at the time of the
drug treatment History of hypertension
B/11 (O- 11 years)
214 (O-10)
ent 1
CNS event
516
Active/inactive
4/O
noted in four of the 11 patients (36%) with occlusive disease and in none of the four patients with hemorrhagic disease. Prolonged partial thromboplastin time (PTT) was recorded in only two of 11 patients with occlusive disease. Summarized in Table 3 are the presence of various predisposing risk factors pertinent to the diagnosis of CVD. A positive family history, hypertension, and hypercholesterolemia were found in many of the patients with occlusive disease and infrequently present in the group of four patients with hemorrhagic disease. The rates of recovery and death from CVD were strikingly different between the groups of patients with occlusive and hemorrhagic disease. Five patients with occlusive disease had complete recovery from the CVD, while only one (a patient with a basal ganglion bleed) from the group of patients with hemorrhagic disease showed complete neurologic recovery. Five patients with occlusive disease had partial clinical recovery. Death occurred in one patient with occlusive Table 2. Laboratory Characteristics of Patients With SLE-CVD Occlusive 1%) High serum DNA Binding
10/l
Hemorrhagic (%)
1 (91)
414 ( 100)
Low c3
3/l 1 (97)
LE cells
9/l 1 (82)
314 (75) 414 ( 100)
VDRL
4/l
1 136)
o/4 (0)
Prolonged PlT
2/l 1 (18)
o/4 (0)
Anemia
4/l
1 (36)
414 (100)
Leucopenia
4/l
1 (36)
l/4
Thrombocytopenia
6/l
1 (55)
3/4 (75)
(251
disease while three of the patients with hemorrhagic disease died. Presented below are detailed case histories of six patients who exemplify different underlying pathologies of SLE-CVD. A summary of the main clinical features of these patients is presented in Table 4 and pertinent laboratory findings are summarized in Table 5. CASE REPORTS
Patient No. I A 25-year-old white female with a IO-month history of SLE was referred for evaluation of acute left hemiparesis and expressive aphasia. The patient had rheumatic fever diagnosed at age 15 manifested by arthritis, first degree conduction block, and a holosystolic mitral valve murmur, Nine years earlier she suffered an acute right hemiparesis with receptive and expressive aphasia. Carotid angiography disclosed a left middle cerebral artery occlusion thought to be an embolus dislodged from her mitral valve. The patient fully recovered with no neurologic sequelae. Five years before admission, her only pregnancy was complicated by hypertension, proteinuria, and an acute right retinal artery occlusion. Laboratory studies at the time showed a false-positive syphilis serology and a prolonged partial thromboplastin time. Abnormal laboratory studies on admission included a positive antinuclear antibody (titer l/640, diffuse pattern), high anti-DNA binding, low serum C3 levels, thrombocytopenia (30,00O/rL), Coomb positive hemolytic anemia (hematocrit 22%), leucopenia (2,30O/rL), elevated partial thromboplastin time (74 seconds), and normal prothrombin time. Neurologic examination revealed a right gaze preference with left homonymous hemianopsia, right Horner syndrome, decreased left cornea1 reflex, decreased left facial sensation, decreased gag reflex, and decreased muscular strength of the left upper and lower extremities. Lumbar puncture was within normal limits with negative cultures. CT scan of the head without contrast showed a low density, well-defined deficit in the left parietal lobe and a low density deficit with surrounding edema in the right parietal lobe (Fig 1). An EEG showed a normal recording on the left side and
TSOKOS ET AL
72
Table 4. Summary
PatientNo.
Clinical Description
Sex/Age
1
F/25
of Clinical and Patholoaic Data
Arterioaaphic Findings
AutopsyFindings
Right middle cerebral
Right hemiparesis global aphasia
AssumedCause Emboli from mitral valve
occlusion, left mid-
prolapse
dle cerebral occlusion 2
F/42
CNS vasculitis, multiple
ND
Chronic manic-
infarcted areas
depressive illness, multiple
CNS vasculitis or emboli from Libman-Sack endocardial lesions
neurologic symptoms and signs 3
F/39
Ruptured berry aneu-
Subarachnoid
rysm
hemorrhage
Ruptured berry aneurysm
Subarachnoid hemorrhage
4
F/13
Quadriparesis
ND
Multiple brain hemor-
5
F/59
fa2.3 Left hemi-
ND
Hemorrhage of the right
Hyperviscosity, coagulo-
hemisphere, multiple
pathy, emboli, or ath-
microscopic hemor-
erosclerosis
Coagulopathy
rhages paresis
rhagic foci, athero6
F/37
Left middle cerebral
Right hemiparesis
sclerosis -
No cause identified
artery occlusion Abbreviation: ND, not determined.
slow waves on the right side; no epileptic
foci were identified. A two-dimensional echocardiogram was normal. Carotid arteriograms (Fig 2) showed complete occlusion of both the right and left middle cerebral arteries interpreted as consistent with arterial emboli. The arteriograms of the aortic arch and carotid arteries were normal. A left heart catheterization showed minimal mitral regurgitation consistent with the diagnosis of mitral valve prolapse. She was maintained on 35 mg of prednisone daily and treated with bedside physical therapy. The patient experienced slow but continuous improvement of speech with almost complete recovery of muscular strength over a 3-month period. Summary A 25-year-old white female with SLE and a history of rheumatic heart disease who experienced three separate, presumably embolic, episodes to the right middle cerebral, right retinal, and the left middle cerebral arteries Table 5. Selected
Laboratory
Findings of the Presented
Case Reports Patient No. 1
2
3
4
5
6
ANA
+
+
+
+
+
+
Prolonged PlT
+ +
ND -
ND _
+ +
~
_
Thrombocytopenia
+
+
+
Hemolytic anemia
+
Leucopenia
+
Prolonged PT
+
+
ND
+
+
+
-
+
+
+
ND
_
False positive syphilis +
+
_
-
_
Rheumatoid factor
_
_
+
-
+
-
Cryoglobulinemia
_
_
+
-
+
ND
Hyperviscosity (IgMI
-
-
-
-
+
ND
serology
Abbreviation: ND, not determined.
over a 9-year period. The apparent the mitral valve.
source of the emboli was
Patient No. 2 A 42-year-old white female with an 1 l-year history of SLE was admitted for evaluation of memory loss, gait disturbances, and rigidity. The diagnosis of SLE was made 4 months postpartum with the development of arthritis, rash, leucopenia, thrombocytopenia, and findings of a positive antinuclear antibody and a positive lupus erythematosus (LE) cell preparation. By history she had an unexplained false-positive syphilis serology, Raynaud phenomenon, and several bouts of manic-depressive psychosis. During one of the manic episodes, she was started on haloperidol and lithium and treated with electroconvulsant shock therapy. While on haloperidol and lithium she noted the onset of rigidity, gait disturbances, and decreased memory. These drugs were discontinued, yet symptoms progressed over the next 3 years. Physical examination on admission revealed good orientation and poor memory. The extremities were rigid with cogwheeling of the left arm. Deep tendon reflexes were brisk and symmetric. Pinprick sensation was decreased in the left lower extremity. There was bilateral ankle clonus. The gait was unsteady and shuffling; Romberg sign was negative. Lumbar puncture showed normal, sterile CSF. CT of the head showed prominent cortical atrophy with ischemic foci (Fig 3). EEG showed mild slowing of the background rhythms and an excessive amount of fast activity. Heart examination revealed a 2/6 systolic ejection murmur and a l/6 early diastolic blow. Echocardiographic evaluation showed normal chamber size with mild aortic stenosis and insufficiency. During the next year, the patient was treated with lithium and low doses of corticosteroids with good
CEREEROVASCULAR DISEASE IN SLE
Fig 1. Patient no. 1. CT scan without enhancement showing low density, well-defined deficit in the left parietal lope and low density deficit with surrounding edema in the right parietal lobe.
control of lupus activity. She then developed the sudden onset of pleuritic chest pain with findings on x-ray of wedgedshaped atelectasis of the right lower lobe. A pulmonary angiogram showed findings consistent with a pulmonary embolus and she was treated with heparin and warfarin sodium. During the subsequent 2 weeks, she developed acute intermittent episodes of respiratory failure associated with diffuse pulmonary infiltrates. Pulmonary wedge pressure was 12 mm Hg. Bronchoscopy and transbronchial biopsy were performed but were nondiagnostic. She was treated with broad spectrum antibiotic coverage (aminoglycosides, trimethoprim and sulfamethoxazole, and erythromycin) as well as high-dose intravenous (IV) methylprednisolone. Five days later she developed focal right upper extremity seizures. A lumbar puncture was normal and CT scan findings were unchanged from the previous study. Blood cultures were positive for a Candida species. She died 3 days later despite appropriate antibiotic treatment. A postmortem examination was performed which showed: (1) non-bacterial thrombotic vegetations of the mitral and aortic valves consistent with Libman-Sacks endocarditis; and (2) careful study of the brain showed hydrocephalus ex vacua, extensive necrosis of frontal, parietal, and occipital cortex (lamellar necrosis) (Fig 4). and minute necrotic foci in the cerebellum. Microscopic examination showed obliterative vasculitis noted on almost all sections; vasculitis lesions were associated with the presence of multifocal perisulcal infarctions. The infarcts were of different age (Fig 5). Occasional vessels of the pia showed obliterative endarteritis and intralu-
Fig 2. Patient no. 1. Carotid arteriograms. (A) Left carotid arteriogram showing complete occlusion of the middle cerebral artery. and iB) right carotid arteriogram showing complete occlusion of the middle cerebral artery.
minal thrombi; these features are consistent with the diagnosis of thrombotic thrombocytopenic purpura (TTP). Search by silver stain for Alzheimer plaques was negative. Summary A 42-year-old white female with a chronic manic depressive disorder, SLE, and multifocal neurologic symptoms and signs. She developed a fatal illness initiated by pulmonary embolus complicated by acute respiratory failure, seizures, and sepsis. Autopsy showed Libman-Sacks endocarditis, CNS vasculitis, TTP-like lesions, and multiple cerebral infarctions. CNS vasculitis was apparently responsible for the multiple cerebral and cerebellar infarcts. Sporadic emboli from the aortic and mitral valves may have contributed to some of the symptoms and signs.
TSOKOS ET AL
Patient no. 2. CT scan showing prominent cortiFig 3. cal atrophy with multiple ischemic foci.
Fig 4. Patient no. 2. Macroscopic preparation of the cerebrum showing multiple necrotic areas of the parietal (A) and frontal (6) lobes.
Patient No. 3 A 39-year-old South American female with a 4-year history of SLE presented for evaluation of arthritis, fever, and a maculopapular rash involving the hands and knees bilaterally. All studies for an infectious etiology were negative, except for an immunofluorescence titer for toxoplasmosis of l/256 which decreased two-fold after absorption with IgG. Additional laboratory studies showed an elevated antidouble-stranded DNA binding (99%), thrombocytopenia (60,0OO/j1L), and severe hemolytic anemia (hct = 20%). She was treated with 60 mg of prednisone daily and, in consideration of the possibility of cerebral toxoplasmosis, an 1I-day course of pyrimethamine and triple sulfadiazine was administered. The flare of SLE responded satisfactorily to treatment and the dose of corticosteroids was gradually reduced. Two months later, the patient developed an acute episode of loss of consciousness associated with vomiting followed by a generalized motor seizure that progressed to status epilepticus. Lumbar puncture revealed grossly bloody fluid. Cerebral angiography showed a ruptured berry aneurysm located at the junction of the right internal carotid artery and the posterior communicating artery. Over the next several days, the patient developed group D streptococcus sepsis, respiratory failure, and died. An autopsy showed extensive subarachnoid hemorrhage and a ruptured aneurysm located at the junction of the right posterior communicating artery. No vasculitis was detected in any of the brain sections. No evidence of cerebral toxoplasmosis was identified. Summary A 39-year-old female with SLE manifested by arthritis and severe hemolytic anemia. The patient died of
complications secondary to an extensive subarachnoid hemorrhage from rupture of a berry aneurysm of the circle of Willis.
Patient No. 4 A 13.year-old white girl with SLE was referred for evaluation of nephritis and several episodes of grand mal seizures. Laboratory studies showed an active urinary sediment, a serum creatinine of 1.8 mg/dL, low complement levels, high serum DNA binding, and cryoglobulinemia. The patient was treated with 30 mg prednisone daily and oral cyclophosphamide at a dose of 100 mg daily. Renal function showed significant improvement on this regimen. Prednisone and cyclophosphamide were continued for the next 30 months with little clinical or serologic evidence of active lupus. The cyclophosphamide was discontinued and a few weeks thereafter the patient developed a butterfly rash, an active urinary sediment, hypertension, and a progressive decline of renal function. Shortly after hospitalization she experienced a grand mal seizure. Renal function continued to deteriorate, necessitating peritoneal dialysis. The dialysis was complicated by the development of peritonitis with Pseudomonas aeruginosa cultured from the dialysate. She was treated with gentamicin and cefazolin. Sepsis was complicated by the development of disseminated intravascular coagulopathy with low levels of fibrinogen, elevated fibrin split products, and appropriate RBC morphology on blood smear. Two days later she developed spastic quadriparesis considered to be secondary to transverse myelopathy of the cervical cord. The patient was treated with IV heparin and showed some mild
CEREBROVASCULAR DISEASE IN SLE
Fig 5. Patient no. 2. Microscopic preparations of the cerebrum showing obliterative vasculitis associated with the presence of perisulcal infarctions of different age.
improvement in neurologic function. Five days later the patient was found flaccid and unresponsive with bilateral fixed dilated pupils. She died a few hours later. An autopsy was performed that showed extensive vasculitis characterized by perivascular infiltration and fibrinoid medial necrosis involving the kidneys, intestines, and coronary arteries. Sections of the fixed brain showed blood clots in the lateral ventricles and multiple small hemorrhages scattered throughout both cerebral hemispheres, many of which were located at the junction of gray and white matter. Hemorrhage and necrosis were also observed in the hypothalamus and midbrain. The right cerebellum was completely necrotic; the pons and medulla contained extensive large and small hemorrhagic foci (Fig 6). Vasculitic lesions were not detected microscopically in any of the sections. Summary A 13-year-old white girl with severe SLE who responded well to treatment with prednisone and oral cyclophosphamide. Her disease deteriorated fulminantly in the 3-week period after cyclophosphamide was discontinued. The flare included grand mal seizures and rapidly progressive glomerulonephritis with eventual renal failure. Peritoneal dialysis was complicated by pseudomonas sepsis and intravascular coagulopathy. Death was secondary to a massive intracerebral catastrophy which on post mortem examination was found to involve extensive hemorrhage.
plasmapheresis, which over a l-month period led to a marked reduction of the serum viscosity. This was associated with a marked improvement in mental function and abolished the bleeding episodes. Ten days after completion of apheresis, she complained of sudden severe headache and left hemiparesis which rapidly progressed to bilateral fixed pupils, flaccid quadriparesis, and evidence of decerebrate activity. She died
Patient No. 5 A 59-year-old white female with a 17-year history of Sjogren syndrome and SLE was referred for evaluation of lethargy. On physical examination the patient was mildly lethargic with findings of Roth spots in the right fundus. Serum IgM was 41.5 mg/mL (normal, 0.9 to 1.7 mg/mL) and the relative serum viscosity was 7.5. Bone marrow aspiration showed mild increase of plasmacytoid cells with normal cellularity of the other marrow cell series. While in the hospital, the patient experienced several acute episodes of confusion, disorientation, and obtundation, and complained of a mildly stiff neck. Repeated lumbar punctures were normal. EEG showed diffuse slowing as well as some transient focal changes. On several occasions, fresh hemorrhages of the fundi were noted and she experienced several severe nose bleeds. The patient was treated with
Fig 6. Patient no. 4. Macroscopic preparation of the cerebellum with extensive necrotic areas of the hypothalamus (A), midbrain (6). and the right cerebellum (Cl.
76
TSOKOS ET AL
a few hours later. The serum viscosity throughout the entire terminal phase of the illness was normal. The autopsy showed a necrotising arteritis involving the vessels of the gastrointestinal tract, mild mononuclear cell infiltrates of both liver and kidneys, and mild follicular hyperplasia of several lymph nodes. Sterile endocardial lesions consistent with Libman-Sacks endocarditis were found on the aortic valve. There was diffuse hemorrhage in the right cerebral cortex with rupture into the lateral ventricles. Microscopically multiple foci of hemorrhage and encephalomalacia were observed in the cortex, basal ganglia, brain stem, and cerebellum. No vasculitis was observed in any of the many slide preparations of the brain. Summary. A 59-year-old female with SLE, Sjogren syndrome, and hyperviscosity syndrome responded to treatment with plasmapheresis. Her terminal illness was consistent with a massive intracerebral hemorrhage that was confirmed on postmortem examination. The exact reasons for the diffuse intracerebral hemorrhages are not entirely clear and may have been secondary to hypervisocity with coagulopathy or emboli from the Libman-Sacks endocardial lesions.
Patient No. 6 A 37-year-old left-handed white woman with a 3 year history of SLE was seen for assessment of a left hemispheral cerebrovascular accident. She was considered to be in complete clinical remission for a period in excess of 2 years when one day before admission she noticed the sudden onset of slurred speech and weakness of the entire right side of her body. On neurologic examination there was mild to moderate muscular weakness on the right side; deep tendon reflexes were slightly decreased on the right side and there was a right Babinski sign. A right central VII nerve paralysis was noted. Lumbar puncture was normal. Cerebral angiography showed complete occlusion of the left middle cerebral artery approximately 2 cm past its origin with no other evidence of vessel disease. Summary. A 37-year-old white female with a 3-year history of SLE, in complete remission for 2 years, developed an acute left middle cerebral artery occlusion. The etiology of the occlusion was not identified.
DISCUSSION
The original descriptions of patients with SLE by Kaposi in 1872” and Osler in 1895” emphasized neurologic manifestations. The clinical manifestations of CNS disease in SLE are remarkably diverse and include disturbances of mental function, psychosis, seizures, neuropathies, paralysis, movement disorders, ocular dysfunction, migraine, aseptic meningitis, transverse myelopathy, and cerebrovascular accidents. Studies have suggested that as many as two thirds of patients with SLE may develop significant neuropsychiatric disease.‘-* In approximately 5% of lupus patients, neuropsychiatric manifestations are the presenting feature of
the disease and may antedate by months or years the actual diagnosis. Following the diagnosis of SLE, neuropsychiatric manifestations may develop at any time in the course of the disease, although in the majority of patients signs and symptoms most commonly develop within the first 2 years of the disease.6 The presence of CNS manifestations is generally regarded as an ominous prognostic sign. In most studies, the contribution of CNS disease to the overall mortality in SLE is exceeded only by infection and renal involvement.‘2 Among the various CNS manifestations, cranial nerve signs and organic mental disorders are thought to carry the poorest prognosis. Many of the deaths are due directly to complications from impaired neurologic function or complications from the high doses of corticosteroids used in treatmentI Although many studies have reported on the pathologic findings in SLE patients with neuropsychiatric manifestations, characteristic pathology to account for all the diverse clinical presentations has not been identified.14*15 The main pathologic features consistently recognized in autopsies of patients with SLE include vascular lesions, infarctions, and hemorrhage. True vasculitis with inflammatory cells within the vessel wall is found in only a small percentage. Large vessel disease, similar to that of polyarteritis nodosa, is a distinctly uncommon feature. More characteristic are vascular hyalinization, perivascular inflammation, and endothelial proliferation. Approximately 50% of patients with CNS disease have been shown to have multiple small infarcts. Most of these infarcts are observed in the cortex, while the cerebellum seems to be spared. The potential causes of vascular compromise and infarction are many. Emboli from valvular vegetation may be responsible. Indeed, Libman and Sacks, in describing these endocardial lesions, regarded them as important in the pathogenesis of neurologic manifestations.‘6 Also, thrombotic thrombocytopenic purpura has been documented in a number of patients with SLE. The clinical spectrum includes a characteristic hematologic and neurologic picture. At the morphologic level it is characterized by widespread hyaline occlusions in terminal arterioles and capillaries. This report describes a group of 15 patients with SLE and various forms of cerebrovascular
77
CEREBROVASCULAR DISEASE IN SLE
disease. Eleven patients could be classified as having primarily occlusive disease, whereas the remaining four had cerebrovascular disease associated with hemorrhage. There were no demographic features that distinguished the two groups, nor were there differences in the frequencies of various non-CNS or laboratory disease features. Several apparent differences between the two groups were identified. Active non-CNS lupus was present at the time of the neurologic event in all four patients with hemorrhagic lesions as compared with less than 50% of those with occlusive lesions. Of the established predisposing risk factors for cerebrovascular diseases, positive family history, history of smoking, hypertension, and hypercholesterolemia were found more frequently in the group of patients with occlusive disease. Finally, the most obvious difference between the two groups was in the mortality rate. Three of the four patients with hemorrhagic disease died, while only one of the 11 with occlusive disease had a fatal outcome. A number of different etiologies for SLECVD were identified. Six case studies representative of different forms of etiopathogenesis are presented in detail. Arterial embolic disease was demonstrated to be the cause of three isolated CNS occlusive episodes in one patient. Despite a history of apparent rheumatic heart disease, mitral valve prolapse, and not rheumatic mitral disease, was documented. Mitral valve prolapse is known to be associated with cerebrovascular embolic episodes.” Libman-Sacks endocardial lesions were identified in postmortem studies of two patients and may have contributed to the neurologic abnormalities. The clinical course of patient no. 2 is very characteristic of the process most commonly termed CNS lupus. Chronic disturbances of mental function were superimposed on intermit-
tent neurologic signs. CT revealed perisulcal atrophy thought to be secondary to microinfarction.” Postmortem examination showed a prominent obliterative vasculitis with intraluminal thrombi. The findings were consistent with the lesions that occur in thrombotic thrombocytopenic purpura although the patient had neither the clinical findings nor thrombocytopenia to support this diagnosis. Rupture of a probable congenital aneurysm led to the death of one patient. Although vasculitis has been reported to produce such aneurysms, r9.” no evidence of vasculitis or other aneurysms were found on postmortem examination. The dilemma produced by the coexistence of active lupus, infection, and CNS disease is typified by the course of several patients. Despite floridly active lupus, sepsis and disseminated intravascular coagulation was responsible for one of the fatal outcomes. Similarly, a coagulopathy produced by the hyperviscosity syndrome and responsible for mental symptoms likely led to a massive fatal intracerebral hemorrhage. Finally, the non-fatal stroke documented in eight patients is, at least in our experience, the most common form of SLE-CVD. More often than not, it develops without obvious cause in the setting of completely quiescent lupus activity for months or even years. Recent studies have called attention to the frequent presence of the lupus anticoagulant in such patients.20*23Although we have not systematically searched for evidence of the anticoagulant, it is our impression that prolongation of the partial thromboplastin time or positive serologic tests for syphilis are infrequently found in these patients. Hopefully, antibodies to cardiolipin may be more sensitive in the identification of this group of patients at risk for cerebral infarctions.24*25
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TSOKOS ET AL
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E, Sacks
B: A hitherto
undescribed
form of
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