From the Archives: Summer 2005 Issue of Lupus Now Magazine
Association Between Multi-Infarct Dementia, SLE, and Antiphospholipid Antibody Syndrome
An SLE Case Study
by Gary M. Kammer, M.D.
Arthritis Associates, Inc., Willoughby, OH
Introduction
Antiphospholipid antibody syndrome (APLS) is a hypercoagulable state characterized by spontaneous intravascular clotting that results in arterial and venous thrombosis, ischemia, and infarction. APLS exists as a primary disorder or associated with other autoimmune disorders, particularly systemic lupus erythematosus (SLE). Among the clinical sequelae, neurologic complications include epileptic seizures, chorea/ ballismus, headache, and cerebrovascular accidents. It has been estimated that cerebrovascular disease is the second leading complication of APLS. Recurrent, often asymptomatic, strokes can lead to impaired cognition and memory loss, a condition referred to as multi-infarct dementia. This case illustrates the presenting features and evaluation of multi-infarct dementia associated with APLS and SLE.
History of the Present Illness
A 61-year-old Caucasian female was found wandering and confused about three hours from her home. She recalled driving on a highway, but did not recognize that she had driven this distance. She was admitted to Lake West Hospital in Willoughby, OH for evaluation of her mental status.
Family, Social, and Past Medical History
The patient was educated through high school and had been employed as a beautician and in a plant nursery. She had been widowed one month earlier. She has smoked a pack of cigarettes daily for 20 years. There is no prevailing familial history of cerebrovascular disease or autoimmunity. There was a remote history of a minor stroke for which the patient was taking no long-term therapy. Within several days prior to admission, the patient believed she was treated for a urinary tract infection. The patient denied a history of miscarriage, hypertension, cardiac arrhythmia, or hypercoagulability.
Physical Examination
The patient was an asthenic, middle-age woman with apparent enophthalmos sitting up in bed, conversant, cooperative, and in no acute distress.
Vital Signs: blood pressure—134/78, respirations—15, temperature—37.1 C, pulse—88 and regular, pain—0/10.
Skin and Appendages: physiologic; no livedo reticularis, rashes, petechiae, purpura, or ecchymoses.
Head, Eyes, Ear, Nose, and Throat: physiologic; no evidence of xerophthalmia, conjunctival hemorrhage or petechiae, or retinopathy.
Nodes: physiologic; no systemic lymphadenopathy.
Neck: physiologic; no thyromegaly or masses.
Thorax: symmetric, reduced breath sounds bilaterally, bibasilar scattered, crepitant rales.
Cardiovascular: no stigmata of Raynaud’s or Burger’s; equal pulses bilaterally except absent pedal pulses; no carotid or aortic bruits; regular pulse, S1 and S2 physiologic, no gallop, rub, or murmur.
Abdomen: scaphoid, non-tender, no hepatosplenomegaly, no masses.
Musculoskeletal: generalized reduced muscle mass, fair muscle tone, physiologic muscle strength for age, ectomorphic body habitus; joints showed mild nodal osteoarthritis but no evidence of active synovitis. Gait was intact.
Central Nervous System: The patient was garrulous but demonstrated loose associations. Remote memory more than one year ago appeared to be intact. She knew her place of birth, her street address, her phone number, her daughters’ names, her city and state of residence. She was oriented to person, but not to place, date, season, or president. She could not interpret aphorisms or perform serial sevens. When asked about how she drove three hours away from her home without recalling the trip, she could not answer. Her sentences and thoughts were often incomplete and left hanging. Yet, her affect was appropriate, she expressed some humorous statements, and was generally in good spirits. She did not appear agitated, hostile, or uncooperative. Sensory examination was intact. Motor examination showed intact cranial nerves, 1+ DTRs, no pathologic reflexes, no ankle clonus, and normal cerebellar responses.
Laboratory Tests Results
Hemoglobin 9.7 gm/dl, hematocrit 29%, white blood count 8200, normal differential.
Platelets 382K.
ESR 60 mm/hr.
C-reactive protein 0.4 mg/dl.
RPR negative.
Urinalysis 30 mg/dl protein, no blood, no casts, culture negative.
Complete metabolic panel: electrolytes normal, creatinine 0.7 mg/dl, BUN (blood urea nitrogen) 22 mg/dl, glucose 86 mg/dl, calcium 8.7 mg/dl, magnesium 1.6 mg/dl; ammonia 23 µmol/L; TSH 1.33 miu/L.
Prothrombin time 13.2 sec, INR 1.1, A-PTT 58.1 sec.
Urine drug screen negative.
IgG and IgM anti-cardiolipin antibody positive; dilute RVVT 66 sec; dRVVT ratio 1.85; dRVVT 1:1 mix 50.5 sec.
Platelet neutralization positive; homocysteine 10.6 µmol/L; total protein S 108% and free protein S 85%; functional protein C 118%.
Immunologic protein C100%; factor V Leiden was normal; anti-thrombin III 119%; methylmalonic acid 400 nmol/ L; prothrombin 20210 mutation was normal; blood alcohol negative; vitamin B12 262.7 pg/ml; folic acid 11.2 ng/ml; C4 complement 21 mg/dl; C3 complement 80 mg/dl; ANA 1:640 homogeneous; anti-DNA 857 IU/ml; anti-RNP, anti-Smith, anti-SS/A and B, anti-microsomal antibodies negative.
CSF: protein 36 mg/dl, glucose 56 mg/dl, WBC 0, negative
CSF cytology, and HSV 1 and 2 DNA not detected.
Other Studies
An EEG was normal. An MRI of the head revealed parenchymal atrophy, small vessel ischemic disease, small remote infarcts of the parietal lobes and occipital lobes bilaterally, as well as the pole of the right temporal lobe. An MRV was negative. A Duplex ultrasound of the carotid vessels was normal. An MRA of the brain revealed findings of subacute ischemic infarcts, possibly embolic in origin. A transthoracic echocardiogram showed no pericardial effusion, intracardiac clots or masses, mild mitral regurg, EF 50%, and no evidence of pulmonary hypertension.
Hospital Course
Neurologic and psychiatric consultations interpreted the findings as consistent with multi-infarct dementia. Rheumatologic consultation identified the presence of an autoimmune process most consistent with SLE associated with APLS and hypercoagulability. Anticoagulation was initiated. The patient signed out of the hospital against medical advice.
Discussion
Although the patient denied a familial history of autoimmunity or hypercoagulability and had no history of clinical stigmata of SLE, repeated questioning revealed a possible history of polyarthralgias, headaches, and photosensitivity. Because of the patient’s memory deficit and the physicians’ inability to obtain or verify information from a family member, the diagnosis of definite SLE cannot be substantiated despite the presence of high concentrations of anti-DNA autoantibody and low concentrations of proteinuria. However, the presence of IgG and IgM anticardiolipin antibodies, prolonged A-PTT and positive dRVVT, with positive platelet neutralization in the presence of brain imaging studies consistent withsmall vessel disease and multiple bilateral infarcts, suggests the diagnosis of multi-infarct dementia secondary to APLS. The absence of elevated levels of CSF protein and cells, demyelinization by MRI, and a normal EEG militate against a diagnosis of concurrent lupus cerebritis.
Analyses of patient cohorts with SLE and/or anti-phospholipid antibody syndrome have demonstrated the association of multi-infarct dementia with hypercoagulability. Mechanisms by which hypercoagulability causes infarcts include embolization, in situ clot formation, and a non-inflammatory vasculopathy. It has been hypothesized that endothelial damage may be an early event predisposing to vasculopathy. Treatment of the hypercoagulable state to prevent in situ clot formation (particularly in the heart affected by Libman-Sachs endocarditis or valvular disease) and embolization resulting in ischemic stroke may be appropriate.
Glossary
A-PTT -- activated partial thromboplastin time.
CSF -- cerebrospinal fluid.
dRVVT -- dilute Russell Viper venom time.
EF -- ejection fraction, or percentage of blood in heart chamber that is pumped out with every heartbeat; EF of 55–75% is normal.
enophthalmos -- sunken eyes.
MRA -- magnetic resonance angiography.
MRV -- magnetic resonance venography.
physiologic -- normal.
thyromegaly -- enlarged thyroid gland.
xerophthalmia -- dry eyes.
References
Westerman EM, Miles JM, Backonja M, and Sundstrom WR. Neuropathologic findings in multi-infarct dementia associated with anticardiolipin antibody. Evidence for endothelial injury as the primary event. Arthritis Rheum 1992; 35: 1038–1041.
Asherton RA and Cervera R. CFS and/or FM as a Variation of APLS. Lupus 1994; 3:253–257.
Sastre-Garriga J and Montalban X. APS and the Brain. Lupus 2003; 12:877–882.