Case History
A 34-year-old woman presented to the emergency room after an episode of loss of consciousness and bilateral tonic-clonic movements accompanied by urinary incontinence and followed by postictal confusion. She had experienced seven similar episodes in the last 10 days and also reported several months of headache.
She had 6 months of progressively more frequent and severe migraine headaches without aura. She described these headaches as bilateral in the frontal region, pulsating, and with photophobia and phonophobia, though no nausea or vomiting. She had no fever, weight loss, weakness, numbness, visual changes, or other neurologic deficits.
She had a history of systemic lupus erythematosus (SLE) diagnosed 5 years prior and treated with hydroxychloroquine 600 mg/day for 3 years, azathioprine 200 mg/day for 3 years, and deflazacort for 2 years (a corticosteroid with approximately 3:2 prednisone equivalence 1 - i.e., patient was on equivalent of about 13 mg of prednisone daily). Nine months before her presentation, she developed lupus nephritis and was treated with monthly methylprednisolone 1 g/day for 3 days and cyclophosphamide, 0.75 mg/m2 monthly for 6 months. She had no prior infections on this immunosuppressant regimen. She also had a history of hypothyroidism, hypertension, obesity, fibromyalgia, major depressive disorder, osteoporosis, and pre-diabetes.
On physical examination, her blood pressure was 140/90 mmHg, heart rate 80 bpm, SpO2 98% on room air, and temperature 36.3oC. There was no lymphadenopathy, and her pulmonary, cardiac, abdominal, and musculoskeletal exams were normal. She had a malar rash, alopecia, and a Cushingoid appearance (moon face and buffalo hump). Her neurological examination was completely normal, and no papilledema was found.
Laboratory and Imaging Data
Fingerstick glucose, serum electrolytes, and complete blood count were unremarkable (Table 1). Brain MRI demonstrated a 1.8 by 1.6 cm lesion in the left medial frontal gyrus that was heterogeneously enhancing with surrounding T2 hyperintensity and internal regions of hyperintensity on diffusion weighted imaging and hypointensity on apparent diffusion coefficient sequences (Figure 1). A separate 7 x 7 mm ring-enhancing lesion was seen in the anterior portion of the septum pellucidum. Vessel imaging is not available locally.
Table 1.
Serum Laboratories.
| Serum laboratories | Reference range, adults | Result |
|---|---|---|
| Sodium | 137–145 mmol/L | 139 mmol/L |
| Potassium | 3.5–5.1 mmol/L | 4.0 mmol/L |
| Magnesium | 1.6–2.3 mg/dL | 2.1 mg/dL |
| Urea | 15–37 mg/dL | 34 mg/dL |
| Creatinine | .52–1.04 mg/dL | .7 mg/dL |
| Glucose | 70–99 mg/dL | 113 mg/dL |
| White blood cells | 4000–11 000/mm3 | 8900/mm3 |
| Neutrophils | 2120–7370/mm3 | 5700/mm3 |
| Lymphocytes | 920–3630/mm3 | 2200/mm3 |
| Monocytes | 120–880 mm3 | 780/mm3 |
| Eosinophils | 80–160/mm3 | 100/mm3 |
| Basophils | <110/mm3 | 40/mm3 |
| Hemoglobin | 12–16 g/dL | 11.1 g/dL |
| Platelets | 140 000–440 000/mm3 | 361 000/mm3 |
| C-reactive protein | <1.0 mg/dL | 2.4 mg/dL |
| C3 | 80–160 mg/dL | 40 mg/dL |
| C4 | 20–50 mg/dL | 16.5 mg/dL |
| Lupus anticoagulant | Negative | Negative |
| Cardiolipin antibody—IgM | <12.5 MPL/UmL | 2 MPL/UmL |
| Cardiolipin antibody—IgG | <15 CLP/UmL | 7 GLP/UmL |
Abbreviations: IgM, immunoglobulin M; IgG, immunoglobulin G.
Figure 1.
Brain MRI. Axial T1-weighted (A), T2-weighted (B), T1-weighted post contrast (C) and (D), diffusion weighted imaging (E), and apparent diffusion coefficient MRI images (F) demonstrating a left frontal heterogeneously enhancing lesion (C) with surrounding edema (A–B) that demonstrates central diffusion restriction (E) and (F). There is also a ring-enhancing lesion in the septum pellucidum (D).
The patient underwent serum infectious serology testing (Table 2) and cerebrospinal fluid analysis (Table 3). Serum serology for HIV, syphilis, Hepatitis B and C, Paracoccidioides, and Chagas were negative. CSF demonstrated mildly elevated protein (52 mg/dl), 2 WBC/mm3, and unremarkable glucose. Bacterial and mycobacterial culture of the CSF were negative as well as latex agglutination tests for Cryptococcus neoformans, N. meningitidis, S. agalactiae, S. pneumoniae, E. coli, H. influenzae. Fungal markers such as ß-D-Glucan and galactomannan and viral PCRs (such as for herpes simplex, varicella zoster, CMV, enterovirus, parechovirus, and JC virus) are not available locally. Chest radiograph, transthoracic echocardiogram, and electroencephalogram were normal.
Table 2.
Serologies.
| Serologies (serum) | Reference range | Result |
|---|---|---|
| Cryptococcus neoformans antigen (Latex Agglutination Test) | Negative | Negative |
| Treponema pallidum (FtAbs and VDRL) | Negative | Negative |
| HIV 1 and 2 (Antibody Test) | Negative | Negative |
| Aspergillosis sp (Direct Immunofluorescence) | Negative | Negative |
| Histoplasmosis capsulatum (Direct Immunofluorescence) | Negative | Negative |
| Paracoccidioidomicosis brasiliensis (Direct Immunofluorescence) | Negative | Negative |
| Hepatitis B (AntiHBc AgHBs, AntiHBS) | Negative | Negative |
| Hepatitis C (Antibody Test) | Negative | Negative |
| Chagas (Chemiluminescence Test) | Negative | Negative |
| Toxoplasmosis (IgG) | Positive if ≥3 UI/mL | 6.4 UI/mL |
| Toxoplasmosis (IgM) | Positive if ≥ .60 UI/mL | .11 UI/mL |
Table 3.
CSF Analysis.
| CSF analysis | Reference range | Result |
|---|---|---|
| White blood Cells | 0–5/mm3 | 2/mm3 |
| Red blood Cells | 0–rare/mm3 | 10/mm3 |
| Protein | 5–40 mg/dL | 52 mg/dL |
| Glucose | (in reference to serum glucose) | 52 mg/dL |
| India Ink | Negative | Negative |
| Cryptococcus neoformans antigen (Latex Agglutination Test) | Negative | Negative |
| N. meningitidis, S. agalactiae, S. pneumoniae, E. coli, H. influenzae (Latex Agglutination Test) | Negative | Negative |
| Culture for bacteria, fungi, and tuberculosis | Negative | Negative |
Given the morphology of the lesions and the patient’s immunocompromised status, she was treated empirically for toxoplasmosis with trimethoprim/sulfamethoxazole. Her seizures were treated with phenytoin. She initially improved with no seizures for 8 days, but then began to have seizures again. Clobazam was added. Resource limitations precluded repeat imaging. A biopsy of the lesion was performed.
Clinical Discussion
This patient presented with seizures and a worsening headache in the context of SLE and immunosuppression. Although headache is a common symptom in patients with SLE and is most commonly due to migraine,2,3 specific etiologies should be considered including venous sinus thrombosis, vasculitis, and CNS infections. 4
Another cause of neurologic symptoms to be considered in patients with SLE is neuropsychiatric lupus, which can cause central nervous system manifestations such as cognitive dysfunction, headache, mood disorder, seizure, aseptic meningitis, and movement disorders, as well as peripheral nervous system manifestations including polyneuropathy (which may be acute, i.e., Guillain-Barré syndrome), cranial neuropathy, and myasthenia gravis.5,6 Relevant to our patient, seizures can occur in 10% of patients with neuropsychiatric lupus, and headache in 28–57%.4-6 The pathogenesis for neurologic involvement in lupus involves non-inflammatory vasculopathy, antiphospholipid antibody-mediated cerebral infarction, and immune complexes and cytokines that may gain access to the CNS via increased blood–brain barrier permeability due to ongoing inflammation.5,6
In patients receiving immunosuppressive therapy, infectious etiologies of headache should also be considered, including meningitis, encephalitis, and intracranial abscess (eg, epidural and cerebral). In patients who are immunocompromised, bacterial, viral, fungal, mycobacterial, and parasitic etiologies must all be considered, including both infections unique to this population as well as those that can affect the general population. Patients who are immunocompromised pose several challenges related to diagnosing CNS infections as they may lack meningeal signs, fever, and significant CSF inflammatory findings due to disease- or treatment-related diminished immune response. 7
Any of these vascular or infectious etiologies can also cause seizures. The lack of clear focal onset of the seizures and lack of focal deficits on clinical examination do not provide additional localizing clues. The lack of papilledema despite months of worsening headache argues against a venous sinus thrombosis, and the subacute evolution of her headache over months would be inconsistent with a viral or bacterial infection, raising concern for an atypical infection. A brain neoplasm could have a similar presentation in terms of symptoms and evolution, but her age, lupus, and medications do not put her at particularly increased risk for primary or metastatic brain neoplasm.
Neuroimaging revealed two brain lesions. The differential diagnosis for multifocal brain lesions in general includes embolic infarction, metastatic neoplasm, demyelinating disease, and infections. In immunocompromised individuals, some of the most common opportunistic infectious conditions to consider include toxoplasmosis, progressive multifocal leukoencephalopathy (PML) due to JC virus, EBV-associated primary CNS lymphoma (PCNSL), tuberculoma/tubercular abscess, cryptococcoma (most commonly seen with concurrent cryptococcal meningitis), and molds such as Aspergillus and Mucor, the latter two often associated with concurrent vasculitis and resultant infarction due to angioinvasion. These infectious etiologies have distinct imaging characteristics. PML causes multifocal white matter lesions in juxtacortical regions and the middle cerebellar peduncles, usually without enhancement or mass effect, although these may be seen in the context of immune reconstitution inflammatory syndrome (IRIS). Diffusion restriction can be seen in abscess, but may also be seen in lymphoma as both are highly dense lesions restricting diffusion of water molecules. The combination of central diffusion restriction and ring enhancement is highly suggestive of abscess. 8 However, although this patient’s most prominent lesion was diffusion-restricting, it was heterogenously enhancing rather than ring enhancing.
In patients who are immunocompromised presenting with one or more ring enhancing lesions, toxoplasmosis and EBV-associated PCNSL are primary considerations, which are difficult to distinguish radiologically. Many patients have been exposed to toxoplasmosis and therefore have a positive serum antibody test. Therefore, whereas a negative toxoplasma serology would generally exclude toxoplasmosis in this context, positive serology does not confirm that a brain lesion is due to toxoplasmosis. Nuclear imaging studies such as Thallium-201-Labeled SPECT and FDG PET/CT of the brain can be used to differentiate toxoplasmosis from PCNSL as the latter has higher metabolic activity. 9 However, nuclear imaging is often unavailable in resource-limited settings such as the one where this patient presented. Therefore, patients who are immunocompromised and develop one or more ring-enhancing lesions are treated empirically for toxoplasmosis and followed with serial clinical and radiologic evaluation. 10 Further clinical or radiologic progression on anti-toxoplasma treatment suggests a need for biopsy. Resource limitations did not permit repeat neuroimaging in this patient, but the persistence of seizures on two antiseizure medications and toxoplasmosis treatment appropriately led to the decision to perform a biopsy.
With the exception of mildly elevated total protein, the CSF was unremarkable in this case. However, the CSF can be challenging to interpret in patients who are immunocompromised or who have localized infections that do not involve the meninges or CSF compartment. Notably ruled out is Cryptococcus due to negative antigen, which is highly specific (93–100%) and sensitive (83–97%). 11 CNS tuberculosis is not excluded since it is notoriously challenging to diagnose due to limited sensitivity of commonly available tests (around 15% for CSF culture); PCR-based assays have a sensitivity of 60% and specificity of 100%,11,12 but are not available locally. Resource limitations precluded testing for fungal markers such as ß-D-Glucan (which can be positive with many fungi including Candida with a sensitivity of 80% and specificity of 82%) 11 and galactomannan (which is specific for Aspergillus—around 96%, with a sensitivity of 88%), 11 which could have been useful in this case. In Brazil, a common endemic fungal infection is Paracoccidioides brasiliensis, which can present with seizures and/or focal deficits and also causes ring-enhancing lesions, commonly with a dual rim sign on SWI sequences (outer intense rim with inner hyperintense rim), 13 and less specific findings such as meningeal enhancement and abscess with diffusion restriction. However, this patient’s test result for this infection was negative. Therefore, remaining possibilities to consider in this patient are fungi such as Candida, Aspergillus, and Mucor, or tuberculosis (given relative insensitivity of culture). Aspergillus and Mucor often cause a more acute presentation due to their angioinvasive nature. Therefore, Candida or tuberculosis seems more likely given the time course of the patient’s headaches worsening over months.
Pathological Discussion
Pathological analysis of the left frontal lobe revealed reactive gliosis and necrosis accompanied by a moderate neutrophilic infiltrate, suggestive of abscess. Numerous yeast spore forms were visualized, some with a budding appearance giving rise to pseudohyphae, consistent with Candida species (Figure 2).
Figure 2.
Brain biopsy. Hematoxylin and eosin (A) and (B), Grocott-Gomori methenamine silver (C) and (D) and Periodic Acid-Schiff stained (E) and (F) sections of left frontal lobe lesion at 400x (A), (C), (D) and 600X (B), (D), (F) demonstrating reactive gliosis accompanied by a moderate acute inflammatory infiltrate, rich in neutrophils, associated with suppurative and necrotic microabscesses (A) and (B), as well as numerous pseudohyphae and budding spores ([C], [D], [E], [F], red arrows) consistent with Candida.
Discussion of Final Diagnosis
Candida mainly causes superficial (mucosal or skin) infections, usually due to Candida albicans, 14 and is the fourth most common cause of positive blood cultures in hospitalized patients. 15 Candida infection in the CNS is uncommon, but some studies suggest that CNS involvement can be present at autopsy in nearly 50% of patients who died of systemic candidiasis. 16
Risk factors for developing CNS candidiasis are neutropenia, HIV, malignancy, surgery, burns, indwelling catheters, injection drug use, immunosuppressive medications, total parenteral nutrition, and critical illness.14,16 The mortality from CNS candidiasis is as high as 31% in HIV-positive patients and 11% in neurosurgical patients. 14
CNS candidiasis can be divided into 4 categories: cerebral microabscesses, meningitis, cerebral macroabscesses, and vascular complications. 15 Cerebral microabscesses are the most common manifestation though these are often diagnosed postmortem since symptoms may be absent or subtle, CSF analysis is typically normal, and CSF culture can be negative. Candida meningitis can be challenging to diagnose as the CSF can be normal in individuals who are immunocompromised.14,15 Candida macroabscesses are rare, and generally require biopsy to diagnose as their neuroimaging appearance is non-specific and the differential diagnosis for enhancing brain lesions in patients who are immunocompromised is broad. CSF may be unremarkable in cases of isolated abscess without meningitis, though ß-D-Glucan may be elevated providing a clue to the diagnosis. Cerebrovascular complications of Candida infection include cerebral infarction, subarachnoid hemorrhage, and mycotic aneurysms. 15
CNS Candida infection is treated with amphotericin B and flucytosine followed by azole therapy. Treatment efficacy is measured by clinical evolution and follow-up neuroimaging in the case of abscess. 14
Clinical Outcome
The patient was treated with liposomal amphotericin B followed by fluconazole. Flucytosine was not used because of the risk of renal toxicity and bone marrow suppression given her underlying renal disease and need for ongoing immunosuppression. Her seizures were treated with clobazam and topiramate, the latter to provide migraine prophylaxis as well. At 3 month follow-up, she was seizure- and headache-free. Repeat imaging 6 months after treatment showed complete resolution of the lesions.
This case report reviews the approach to new neurologic symptoms in a patient with SLE, the differential diagnosis of multifocal brain lesions in a patient who is immunocompromised, and the test characteristics of various diagnostic assays in making a microbiologic diagnosis in a patient with a CNS infection.
Footnotes
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD
Gabriela Figueiredo Pucci, MD https://orcid.org/0000-0002-6597-6106
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