Check Your Diagnosis — Patient 48
Jennifer Lynch, M.D. and Dennis R. Mosier, M.D., Ph.D.
Systemic Lupus Erythematosus with Cerebral Edema and Leukoencephalopathy
The patient was admitted to the Neurology Service at Ben Taub General Hospital. An initial CT and MRI showed diffuse white matter signal changes and brain swelling with sulcal effacement. Following a lumbar puncture, she was treated with dexamethasone and mannitol boluses for increased intracranial pressure, with rapid improvement of her neurologic symptoms. At the time of admission, immune-inflammatory, postinfectious, and paraneoplastic disorders were all considered as possible causes for her disorder. Two days into her initial hospital stay, the patient amended the history with additional detail: her knee pain, initially described vaguely despite directed questioning, was better characterized as episodic, with swelling of the knee joints and pain in several other joints. She also described hemoptysis as an early feature of her recent "pneumonia." CT scans detected a left pelvic mass, confirmed by ultrasound to be a cystic lesion (cystadenoma, less likely cystadenocarcinoma). At this point, the patient decided to leave the hospital.
She returned to the Ben Taub emergency room two days later with tachypnea, and was readmitted to the hospital with left ear pain, dizziness, tachycardia (to 120/min), and progressive hypoxemia. Records of her recent "pneumonia" (not available on the first admission) described considerable pleuritic chest pain, with no causative organisms isolated. Her condition rapidly declined, and she was intubated for mechanical ventilation, with bright red blood evident upon initial suctioning. Bronchoscopy was performed, but did not detect any sites of ongoing bleeding, and no growth of bronchial washings or atypia of cells was found. The patient had been empirically treated with valacyclovir in view of her history of herpes simplex, but no conclusive evidence of viral infection was found.
Together with the clinical or historical features of CNS dysfunction, episodic polyarthralgias, anemia of chronic disease, transient skin rash, and recurrent pneumonitis, the laboratory reports of high-titer antinuclear antibodies and antibodies to double-stranded DNA (available by the patient's second admission) were felt to support a clinical diagnosis of systemic lupus erythematosus (SLE). Her CNS dysfunction was characterized as aseptic meningitis and cerebral edema, together with anosmia from cranial nerve I dysfunction, abducens palsies presenting as false-localizing signs of her cerebral edema, and diffuse white matter disease accompanied by mild slowing of mentation but otherwise very little cognitive impairment. The patient was treated with intravenous high-dose methylprednisolone and cyclophosphamide, with rapid improvement and extubation. An extensive search for other illnesses revealed no alternative causes for her clinical syndrome. During the following week, she again became hypoxic, requiring intubation, but gradually recovered and was discharged from the hospital 20 days later. Over her hospitalizations and with subsequent outpatient studies, her adnexal mass did not enlarge, and was felt to represent a benign process.
The diagnosis of systemic lupus is made as a syndrome, by observing clinical evidence of polyserositis and autoimmune dysfunction affecting multiple organ systems, together with supporting laboratory evidence of antibodies against cellular nuclei and double-stranded DNA. Exclusion of alternative causes is an important component of establishing a diagnosis.
The differential diagnosis of diffuse white matter disease includes inherited, early-onset leukoencephalopathies such as Krabbe's disease (globoid cell leukodystrophy), metachromatic leukodystrophy, and X-linked adrenoleukodystrophy, which typically present in infancy or childhood, but rarely may present in young adults. These disorders are unlikely in this patient due to the absence of signs of peripheral neuropathy accompanied by marked elevation of CSF protein (frequently present in the first two disorders), lack of significant optic atrophy, radiographic involvement of arcuate or U-fibers (unusual in the inherited leukodystrophies), and absence of a suggestive family history. The patient's gender argues against the latter condition, although occasionally mild forms of adrenoleukodystrophy have been reported in females. Acute disseminated encephalomyelitis (ADEM) typically presents with a monophasic course, prominent mental status changes (minimal in this patient) and radiographic evidence of multifocal, confluent white matter lesions, unlike the diffuse white matter changes evident in this patient. Atypical presentations of multiple sclerosis could exhibit cerebral edema and white matter lesions together with a remitting-relapsing course, but the diffuse rather than multifocal nature of this patient's radiographic findings, the initial presentation with cranial nerve I dysfunction (anosmia), and the absence of oligoclonal banding on CSF electrophoresis argue against this diagnosis. Progressive multifocal leukoencephalopathy (PML) may present with multifocal white matter lesions in severely immunocompromised patients; we found no clinical or laboratory evidence suggesting marked immunosuppression in this patient, and the clinical response to steroids with concomitant radiographic resolution of edema would be unusual for PML. Sickle cell disease may present with confluent white matter abnormalities, but often has gray matter accompaniment, and usually occurs in patients with established clinical disease. The extent of this patient's lesions would be highly unlikely in a young, previously healthy subject with sickle cell trait. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, resulting from mutations in the Notch3 gene) may have premonitory migraine headaches, and occasionally present with the appearance of diffuse white matter disease, but a significant subcortical dementia typically accompanies the radiographic lesions. The presence of cranial nerve deficits and cerebral edema in this patient also make a diagnosis of CADASIL unlikely. There was no history of radiation therapy, which may also produce diffuse white matter abnormalities. Finally, the reported rare cases of diffuse white matter disease as an asymptomatic radiographic finding would not account for the widespread evidence of CNS dysfunction in this patient. In addition, few of the above disorders could explain the patient's prominent multisystem involvement.
Tumor-associated syndromes are another consideration in patients presenting with cerebral edema and cranial nerve deficits. Paraneoplastic encephalomyelitis typically involves gray as well as white matter, with significant mental status alterations in most cases; cranial nerve findings are uncommon in this disorder. We initially entertained the possibility of an unusual paraneoplastic presentation of malignancy due to the early CT finding of an adnexal mass, but could not find evidence of a primary tumor with numerous investigations. We did not find evidence of a primary brain tumor or of multifocal glial neoplasms (gliomatosis cerebri) on MR imaging. A hematologic neoplasm (e.g., leukemia or lymphoma) would be unlikely in view of the initial screening studies and imaging findings.
This patient's multisystem involvement, cerebral edema, cranial nerve deficits, and diffuse white matter changes are best explained by an immune-inflammatory or infectious disorder. We did not find serologic evidence of syphilis on testing, nor did the patient travel to an area in which Lyme disease is endemic. Tuberculosis could explain some of the multisystem findings and evidence for chronic meningeal inflammation, but the appearance of diffuse white matter abnormalities would be unusual, and no growth of acid-fast bacilli was evident from a previous bronchoscopic study. In the presence of higher clinical suspicion, however, a single negative bronchoscopic study would not rule out mycobacterial infection.
Given the above considerations, this patient's chronic anemia, immunoglobulin studies, protein electrophoresis, elevated erythrocyte sedimentation rate, and depressed complement levels increased the clinical concern for an active inflammatory process. Prominent lower respiratory symptoms and cranial nerve abnormalities in this patient raised the possibility of Wegener's granulomatosis, but screens for anti-neutrophil cytoplasmic antibodies (ANCA) did not support this possibility, and the diffuse white matter abnormalities seen in this patient would be highly atypical for Wegener's granulomatosis. Other forms of systemic vasculitis (including Churg-Strauss vasculitis), granulomatous disorders such as sarcoidosis, and other inflammatory disorders such as Behcet's disease were considered but deemed unlikely due to lack of suggestive clinical or laboratory findings or inability to provide a unifying explanation for the patient's findings.
Neurologic involvement in SLE is common, occurring in 14-75% of patients, in different series, and accounts for 10-20% of SLE-related deaths and decreased survival rates in affected patients. While it is rarely the presenting symptom, it usually occurs within one year of a definite diagnosis of disease. Neurologic involvement is more common in patients with antiphospholipid antibody syndrome. The most common symptoms are headache and peripheral neuropathy. True CNS vasculitis, while often discussed, is relatively rare and was not classified as a distinct syndrome by the American College of Rheumatology's Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. Aseptic meningitis, cerebrovascular disease, demyelinating disease, headache (including migraine and benign intracranial hypertension), movement disorders, myelopathy, seizure disorders, acute confusional states, anxiety disorders, cognitive dysfunction, mood disorders and psychosis, are all recognized as common manifestations of CNS lupus. The pathological correlates of neuropsychiatric lupus are often mild and nonspecific. The brain usually appears histologically normal in SLE involving the CNS. Bland vasculopathy, characterized by vascular hyalinization, vessel tortuosity, endothelial proliferation and perivascular gliosis are probably the most common findings on biopsy, but are nonspecific. Perivascular cuffing of arterioles or venules with inflammatory cells may be seen, but these findings are rare. Gross and microscopic infarcts may occur due to thrombi or emboli resulting from active lupus, antiphospholipid antibody syndrome, cardiac lesions, arterial dissection, large or medium-vessel vasculitis or accelerated atherosclerosis. Diffuse neuropsychiatric SLE may be manifested by clinically subtle cerebral edema without an obvious autopsy correlate.
As biopsy findings are of limited value and require an invasive procedure, neuroimaging is the primary diagnostic tool for CNS lupus. While CT is readily available, it is relatively insensitive to chronic white matter disease, small infarcts, cerebral edema diffuse brain injury and leukoencephalopathy, which is obvious by MRI or MR spectroscopy. Angiography is also limited in SLE, due to the frequent small-vessel nature of the disease, and is frequently negative even in the presence of infarcts. MRI abnormalities are seen in 15-78% of patients with active neuropsychiatric SLE, but differentiation of old and new lesions is difficult, and is not aided by the addition of PET or SPECT. Many different neuroimaging presentations of CNS lupus can occur. These can include atrophy, infarct, discrete gray matter lesions, diffuse gray matter hyperintensities, focal, diffuse or periventricular white matter hyperintensities, and cerebral edema. MRI may show extensive bilateral white matter abnormalities suggestive of edema in the cerebral hemispheres, the brain stem, in the cerebellum, which may be associated with hypertension, benign intracranial hypertension, immunosuppression or other signs of active CNS lupus. Confluent white matter edema has been reported, and of note, very mild neurological manifestations were present despite prominent MRI findings in one case report. While findings such as these are seen in hypertensive encephalopathy, our patient never had any evidence of increased blood pressure. It was felt that our patient most likely had cerebral edema due to microangiopathic disease, perhaps related to immune complex deposition.
CSF findings are often non-specific as well. A modest protein elevation and pleocytosis are seen in the cerebrospinal fluid of 25-60% of patients with CNS lupus, as was evident in this patient. Damage to the blood-brain barrier is present in about one-third of CNS lupus patients, as evidenced by elevated Q-albumin. An elevated IgG index, indicating the presence of intrathecal IgG production, is present in 25-60% of these patients, and although rarely checked, an elevated IgM index is reportedly even more common. Oligoclonal banding is present in 20-80% of CNS lupus patients in different reports, indicating that only a few B-cell clones may be responsible for CNS IgG production.
Autoantibodies, useful in the diagnosis of lupus itself, have not shown a consistent relationship with CNS involvement. Antineuronal antibodies have been reported to correlate with CNS disease, and were present in this patient (data not shown). The presence of anticardiolipin antibodies and the lupus anticoagulant have also been suggested as risk factors for CNS involvement in SLE.
CNS involvement in SLE is often reversible. Recovery from the CNS symptoms is observed in 70-85% of episodes. Long-term prognosis, however, is clearly worsened when the CNS is involved. Treatment for CNS lupus involves high-dose steroids and cytotoxic agents such as cyclophosphamide, as is usually the case in patients with renal glomerular disease or other significant organ system involvement. Although this patient's radiographic findings of cerebral edema resolved quickly with corticosteroid therapy, concomitant with clinical improvement, her white matter findings have persisted. It remains to be seen if her findings on neuroimaging will fully normalize with long-term immunosuppressive therapy.
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