Clinical Problem Solving: A 38-year-Old Woman With Systemic Lupus Erythematosus Presenting With Headache, Nausea, and Vomiting

Abstract

A 38-year-old woman with migraine headaches and systemic lupus erythematosus with recent cessation of her immunosuppressive therapy presents with prolonged headache and hypertensive emergency. Her examination is notable for a peripheral right facial palsy and stable malar rash. There are no signs of systemic infection nor systemic symptoms of a lupus flare. Initial CT head reveals bilateral hypodensities in the basal ganglia. Within 8 hours of presentation, she develops right hemiplegia and becomes encephalopathic. MRI shows multifocal acute infarcts (most notably in the left basal ganglia), enhancement of the right facial nerve, and multifocal vessel wall enhancement in the anterior and posterior circulation. We discuss the differential diagnosis, comprehensive workup, and subsequent treatment decisions in the management of this immunocompromised patient with encephalopathy, headache, and rapidly progressing focal neurologic deficits.

A 38-year-old female with systemic lupus erythematosus (SLE), hypertension, and migraines presented with 11 days of persistent headache. The headache began gradually as a typical migraine with photophobia. However, it lasted several days longer than usual and was refractory to acetaminophen, ketorolac, ibuprofen, and sumatriptan. Progressive nausea and vomiting, which had never before accompanied her migraines, prevented the patient from taking her oral prednisone and mycophenolate mofetil.

She was diagnosed with SLE 15 years prior with positive antinuclear antibody (ANA) and anti-double stranded DNA antibody (dsDNA) titers. She previously tested negative for antiphospholipid antibody syndrome (APLS). Four years prior, she endured a flare marked by worsening malar rash and inflammatory arthritis (Figure 1). Her laboratory studies at the time demonstrated an elevated erythrocyte sedimentation rate (ESR), anti-dsDNA titer, worsened hypocomplementemia, and worsened proteinuria. After increasing prednisone and starting weekly belimumab, the flare resolved. However, when symptoms progressed several months prior to presentation, she transitioned from belimumab to anifrolumab. She received one dose of this medication and missed subsequent infusions. In the interim, because of facial hyperpigmentation, she discontinued hydroxychloroquine.

Figure 1.

Timeline of patient's salient clinical history and pertinent medications with respect to her diagnosis of systemic lupus erythematosus (SLE). MMF: mycophenolate mofetil; HCQ: hydroxychloroquine; CTX: cyclophosphamide (roughly 7 years prior to presentation, the patient underwent 6 rounds of cyclophosphamide 500 mg every 2 weeks with significant improvement in proteinuria, rash, and arthritis).

On initial exam, the patient was afebrile but hypertensive to 280/110 mmHg. She was ill-appearing with a prominent malar rash and mild neck stiffness, but no other systemic abnormalities. Neurological exam was notable for right facial palsy involving the upper and lower face. Mental status, motor, sensory, coordination, and gait assessments were normal.

Non-contrast computed tomography of the head (CTH) showed new bilateral basal ganglia hypodensities, prompting neurological consultation (Figure 2A).

Figure 2.

(A) On HCT, new ill-defined basal ganglia hypodensities were non-specific, reflecting acute to subacute infarcts, atypical posterior reversible encephalopathy syndrome, or infection. (B) Diffusion-weighted imaging (DWI) revealed patchy multifocal lesions that were DWI-bright and dark on the apparent diffusion coefficient (ADC) sequence, suggestive of multifocal strokes. (C) These lesions were hyperintense on T2 FLAIR. (D) T1 post-contrast sequence revealed enhancement of the right facial nerve (white arrow). (E) MRA showed abnormal enhancement along the left A2 segment (red arrow) as well as patchy irregular enhancement along the lenticulostriate arteries (black arrows); additional vessel wall enhancement was noted in the bilateral posterior cerebral arteries (not shown). (F) Subsequent MRI brain (DWI sequence) following overnight stroke code for acute right hemiparesis showed progression of left basal ganglia infarction.

The patient exhibited at least 5 alarming headache features. While nausea/vomiting may accompany migraines, the following were deemed red flags: (1) atypically prolonged duration, (2) pain refractory to multiple medications, (3) neck stiffness, (4) focal neurologic deficit, and (5) features atypical of the patient's migraine semiology (in this case, nausea/vomiting).

In a patient with persistent headache, nausea/vomiting, and a focal neurologic deficit, the differential is broad. It includes infectious, infiltrative, autoimmune, vascular, and neoplastic etiologies. In an immunocompromised patient, infectious etiologies are of special consideration; these should remain high on the differential even in the absence of fever or leukocytosis in vulnerable populations. ¹

Initial exam was notable for a cranial neuropathy: a right peripheral facial palsy. The pattern of facial weakness could alternatively localize to the facial nucleus in the pons, though there were no co-localizing brainstem findings. Infectious etiologies like varicella zoster virus (VZV), herpes simplex virus (HSV), and Lyme disease commonly cause cranial neuropathies. ² Pathogens with posterior fossa predilection (ie, basilar meningitides), such as mycobacterium tuberculosis and fungi (eg, cryptococcus, coccidioides, candida), are known to cause headache and cranial neuropathies, in addition to hydrocephalus and subcortical strokes. ³ Inflammatory conditions like SLE, sarcoidosis, and granulomatosis with polyangiitis, or a compressive or infiltrative neoplasm (eg, neuroma, meningioma, leptomeningeal carcinomatosis) may similarly cause a cranial neuropathy and headache. ² To refine pretest probabilities for these conditions, additional risk factors should be elicited ‒ for example, travel history, infectious exposures, substance use, and signs/symptoms of occult malignancy. The patient had no additional risk factors identified. Of note, a recent clinical trial investigating anifrolumab efficacy in patients with SLE demonstrated higher frequency of VZV infection in patients receiving anifrolumab. ⁴ As VZV is classically associated with cranial neuropathies, often a peripheral facial palsy, and vasculopathy with associated infarcts, this was an important consideration. ³

Lastly, possible vascular etiologies include cerebral venous sinus thrombosis, posterior reversible encephalopathy syndrome, primary vasculitides such as primary CNS angiitis, and secondary vasculitides. Examples of the latter include systemic or autoimmune vasculitides (ANCA-associated, lupus, rheumatoid, and sarcoid-associated), drug-induced vasculitis (amphetamines, cocaine, heroin, sympathomimetic-associated), and infectious vasculitides (VZV, fungal, mycobacterial). Though many of the classic systemic vasculitides present with systemic manifestations, many cases present with exclusively neurologic symptoms. ⁵

Laboratory studies from serum and cerebrospinal fluid (CSF) as well as neuroimaging are necessary next steps. Empiric meningitis coverage was initiated with acyclovir, ceftriaxone, vancomycin and ampicillin, as early treatment of possible meningitis is critical. ³

Complete blood count with differential, metabolic studies, thyroid stimulating hormone, HIV antigen/antibody, syphilis screen, and blood cultures were obtained. Lupus flare screening is also essential; this includes ESR, C-reactive protein (CRP), D-dimer, anti-dsDNA titer, complement levels, urinalysis, and 24-hour urine protein.^6,7 Although the patient previously tested negative for APLS, an APLS antibody panel (including lupus anticoagulant, anticardiolipin antibodies, anti-β2 glycoprotein I antibodies) was re-sent in the setting of suspected new infarcts to assess for hypercoagulability and was negative. Laboratory workup was significant for 14.0 K/μL white blood cells, elevated ESR of 70 mm/hr, elevated CRP 1.9 mg/dL, nephrotic range proteinuria, and stable but not worsened hypocomplementemia and anti-dsDNA titers.

Magnetic resonance imaging with angiography and venography (MRI/MRA/MRV brain) and intracranial vessel wall imaging were obtained. MRI brain demonstrated multifocal diffusion restricting lesions with associated fluid-attenuated inversion recovery (FLAIR) hyperintensity throughout the bilateral basal ganglia, subcortical temporal lobes, right cingulate gyrus, and left fornix (Figure 2B and C). There was enhancement of the right facial nerve (Figure 2D) and vessel wall enhancement in the region of the bilateral basal ganglia strokes and the anterior and posterior cerebral arteries (Figure 2E). There was no hemorrhage, mass, or venous sinus thrombosis.

CSF should be obtained in an expedited manner. CSF protein, glucose, cell count, oligoclonal bands, a meningitis/encephalitis (ME) panel that includes HSV and VZV PCR testing, CSF bacterial and fungal cultures, and CSF VZV antibodies were sent. Lumbar puncture yielded 30 cmH₂O opening pressure, glucose of 72 mg/dL, elevated protein of 75 mg/dL, 6 white blood cells/mm (21% neutrophils, 43% lymphocytes), and 100 red blood cells. The ME panel was negative. CSF oligoclonal bands were not present, comparable to similar cases.^7-9 CSF VZV IgM and IgG were negative.

Finally, with diffusion restricting lesions on MRI that were chiefly concerning for multifocal subcortical strokes, a stroke workup was pursued, with special consideration to the patient's history of SLE. Echocardiogram excluded septal defects and valvular heart disease, such as non-bacterial thrombotic endocarditis (sometimes referred to as marantic or Libman-Sacks endocarditis). Electrocardiogram and telemetry monitoring revealed no arrhythmias, such as atrial fibrillation. Vessel imaging excluded atherosclerotic disease, which can be accelerated in SLE, and as mentioned, repeat APLS testing was negative. Low-density lipoprotein (LDL) and hemoglobin A1c levels were normal. There was no microangiopathic hemolytic anemia or thrombocytopenia to suggest thrombotic thrombocytopenic purpura.

Vessel wall enhancement throughout the bilateral lenticulostriate, anterior, and posterior arteries raised concern for vasculitis, particularly lupus vasculitis given the clinical history of tapering off immunosuppression. Importantly, imaging alone cannot exclude infectious vasculitides, rendering serum and CSF essential in excluding pertinent pathologies like VZV vasculopathy. While the clinical picture was initially concerning for possible meningitis (eg, headache, neck stiffness, elevated opening pressure), the CSF profile and neuroimaging most strongly supported vasculitis and multifocal strokes as the cause of the patient's clinical presentation. It is also worth noting that CSF is abnormal in 80-90% of patients with CNS vasculitis; while our patient may have been uncomfortable or suboptimally positioned for opening pressure measurement, elevated intracranial pressure may be present in up to 50% of CNS vasculitis cases.^5,10

Ultimately, a constellation of data from clinical history, neurological exam, neuroimaging, laboratory and CSF studies, indicated a diagnosis of lupus vasculitis ‒ inability to obtain second anifrolumab infusion, tapering off hydroxychloroquine, inability to tolerate prednisone and mycophenolate, worsened proteinuria, elevated inflammatory markers (though persistently low-normal complement levels and stable anti-dsDNA titer), multifocal strokes with multifocal vessel enhancement, and a comprehensive negative infectious workup.

The patient's hypertension was thought to be compensatory in the setting of acute infarct, but despite permissive hypertension on the first night of hospitalization, the patient endured significant neurological deterioration with acute right hemiparesis and encephalopathy, prompting stroke code activation. Emergent imaging revealed progressive infarction of the left basal ganglia (Figure 2F). Permissive hypertension was continued for the first 24 hours post-stroke, alongside immunosuppression, daily aspirin, and aggressive rehabilitation therapies.

Though the patient lacked overt systemic involvement compared to a prior lupus flare (noting solely her worsened proteinuria during this admission), isolated CNS SLE vasculitis does occur. ⁷ The patient promptly underwent pulse-dose methylprednisolone, followed by cyclophosphamide once CSF studies including a negative ME panel and VZV PCR resulted.^6,7,11

One week after induction, there was gradual improvement in her right hemiparesis, resolution of encephalopathy, and return of ESR, CRP, C3, and C4 to baseline levels.

Discussion

The American College of Rheumatology delineates 19 neuropsychiatric syndromes related to SLE, including stroke, seizure, psychosis, and cognitive function abnormalities.^12,13 Cerebrovascular disease is seen often in neuropsychiatric SLE (NPSLE), with thrombosis, embolism, and atherosclerosis underlying most SLE-related infarctions. In fact, as suggested by our extensive workup, all stroke subtypes are possible in SLE. In our case, repeat testing excluded APLS, which is strongly associated with thromboembolism in NPSLE. ⁶ Echocardiogram and vessel imaging did not support cardioembolic nor atherosclerotic stroke etiologies.

CNS SLE vasculitis represents a unique and rare stroke etiology with unknown incidence, although one center published a 10-year incidence of <1% of 403 patients with SLE. ⁷ The diagnosis of vasculitis inciting stroke in the context of SLE and headache reflects an exceptional case and presentation. To make a definitive diagnosis of cerebral vasculitis, brain biopsy has historically been considered gold standard. However, digital subtraction or MR angiography with vessel wall imaging can substantiate the diagnosis without biopsy, particularly with the advent of high-resolution MR imaging.^7,14

Regarding pathophysiology, isolated CNS vasculitis in NPSLE typically affects small arterioles and capillaries, for example, the lenticulostriate arteries as seen in this patient. ⁷ There are only case reports regarding large vessel cerebral vasculitis in SLE.^8,11,15 Moreover, while it may seem odd for SLE to flare in such an isolated fashion (limited to the cerebrovasculature without dramatic changes in the patient's rash, arthritis, or inflammatory markers), similar cases of CNS SLE vasculitis have demonstrated systemically quiescent lupus activity, although this presentation has been noted to be extremely rare.^7,8 In agreement with those reports, this case highlights the importance of considering active rheumatologic disease in the relative absence of clinical systemic activity and/or alarming immunologic markers.

One final interesting point was our patient's concomitant facial nerve enhancement. Cranial neuropathies are common in NPSLE, and similar treatment with methylprednisolone and cyclophosphamide is recommended. ⁶

This case emphasizes a common deliberation between infectious and autoimmune diagnoses, wherein treating one process may wield the inimical potential to worsen the other. A high index of suspicion was required to diagnose CNS SLE vasculitis alongside thorough testing to reassure against infection. After weighing risks vs benefits, prompt initiation of immunosuppressive therapy prevented ongoing cerebrovascular inflammation from further increasing stroke burden.

ORCID iDs

Andrew Silverman https://orcid.org/0000-0003-1464-0415

Paul M. George https://orcid.org/0000-0002-1080-098X