Chien-Liang  Chen

CASE REPORT:
A 62-year-old man presented to our hospital with right facial palsy, left arm and leg weakness, and mild fever; he was diagnosed with a stroke in the emergency room. The patient had a history of cadaveric renal transplantation 2 years prior, for which he was prescribed tacrolimus- based immunosuppressive drugs. Multiple myeloma was diagnosed 18 months after renal transplant. He was treated with bortezomib and steroids for the multiple myeloma, and low-dose TMP/SMX for pneumocystis prophylaxis. A listeria brain abscess was diagnosed based on a comprehensive medical history, magnetic resonance images, positive blood culture, and brain biopsy. He underwent ampicillin therapy and achieved full recovery after a 3-month follow-up period.

DISCUSSION:
Listeria monocytogenes is a gram-positive facultative intracellular food-borne pathogen that can cause serious infections in the elderly, neonates, and the immunocompromised populations. Listeria brain abscesses are rare, even among transplant patients. The diagnosis of brain abscesses developing after renal transplant is important. They may lead to temporary neurological deficits that resolve without requiring surgical intervention, in contrast to true strokes, which are associated with permanent neurological deficits. Which population subset is more susceptible to Listeria infection with central nervous system involvement? Opportunistic infections and the reactivation of chronic listeriosis typically occur in immunocompromised populations. Listeria has been identified in a broad range of foods, including raw milk, cheese, raw meat products, and salads. Its typical route of transmission is the consumption of contaminated food. Listeria penetrates the intestinal epithelium via enterocytes and Peyer’s patches. These organisms are well-adapted to the various microenvironments of the gastrointestinal tract, suggesting their ability to cause chronic infections (3). Reactivation of listeriosis may occur in transplant recipients taking immunosuppressants. Renal transplant recipients often receive regular immunosuppressants to prevent graft rejection; poor compliance with immunosuppressant medication can lead to limited graft survival (4). Current guidelines recommend that maintenance immunosuppression should consist of a calcineurin inhibitor and an anti-proliferative agent with or without corticosteroids (5). Our patient was treated with tacrolimus, with everolimus as maintenance therapy for renal transplant, and bortezomib for multiple myeloma. Tacrolimus negatively affects infection-stimulated T cells (6), everolimus is associated with more frequent infections in patients with neuroendocrine diseases (7), and evidence has shown that bortezomib enhances the apoptosis of antibody-secreting cells such as plasma cells or memory B cells, and decreases the function of other immune cells, resulting in mild neutropenia, decreased T cell proliferation, decreased NK and CD8+T cell function, inhibition of dendritic cell function and viability, and alteration of cytokine secretion (8, 9). Long-term immunosuppressant use poses a great risk for opportunistic infection and reactivation of chronic listeriosis because of a deficiency in antibody-related bacterial opsonization and dysfunctions of other immune cells. What is the typical presentation of brain abscesses in transplant patients? Impaired inflammatory responses due to immunosuppressant use may obscure the clinical and radiological findings of microbial invasion. Consequently, patients are often minimally symptomatic, present late, and are diagnosed late (10), resulting in more severe infection in the central nervous system. Listeria penetrates the intestinal barrier through internalin A and internalin B by binding to the cellular receptors E-cadherin and a receptor tyrosine kinase for which the natural ligand is hepatocyte growth factor (11). These receptors are also expressed on the surface of choroid plexus epithelial cells and brain endothelial cells (12), thereby allowing Listeria to invade the central nervous system. Our case raises one important question; why did the patient develop a Listeria infection while being prophylactically treated with TMP/SMX? TMP/ SMX prophylaxis is consistently included in the post- transplant regime for varying durations, from 3 months to a lifetime, according to the patient's comorbidities and physical conditions. This treatment prevents infections from a wide range of opportunistic agents such as Pneumocystis pneumonia, Toxoplasma gondii, Isospora belli, Cyclospora cayetanensis, and many Nocardia and Listeria species. Low-dose TMP/SMX is well tolerated and should be used unless the patient exhibits evidence of an allergy or interstitial nephritis (13). Oral TMP/ SMX therapy has excellent bioavailability, and is widely used in clinical practice. A low dose of trimethoprim (80 mg/kg/day) plus sulfamethoxazole (400 mg/kg/day) has comparable efficacy in Pneumocystis pneumonia. Our patient was administered low-dose TMP/SMX for Pneumocystis prophylaxis, but nevertheless experienced a breakthrough Listeria infection that caused their brain abscess. More evidence is required on the dosage of TMP/SMX required for prophylaxis during tacrolimus- based immunosuppressive medications and bortezomib treatments. How do we distinguish stroke from brain abscess or other stroke mimics? Common characteristics for brain abscess including fever, headache, and changes in the level of consciousness, as well as elevated C-Reactive protein level, are often insufficient to precisely identify brain abscess and stroke (14, 15). Despite a striking similarity in the clinical manifestation of stroke and brain abscess, several factors can aid their differentiation. First, anatomical localization based on neurological examination may suggest multiple lesions. For example, right peripheral- type facial palsy may suggest lesions over the right pons involving an infratentorial lesion, while left hemiparesis may suggest the involvement of the supratentorial lesion. MRI-confirmed brain abscesses can be located in a variety of regions, including right frontotemporal, basal ganglion, and periventricular white matter region, to the mid-posterior midbrain and pons, compatible with the clinical presentation described above. Lesions with these multifocal brain findings include cardioembolic stroke or infectious disorders, such as brain abscesses or congenital cytomegalovirus infection, and inflammatory disorders, such as multiple sclerosis (16). Second, appropriate brain imaging studies should be selected. MRI or contrast CT should be performed, as these enable the visualization of unusual presentations, such as vessel territory distribution to detect the brain abscess. Cerebral abscesses with contrast enhancement such as ring signs may also be helpful (17).