EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Neurologic complications after solid-organ transplant reveal a great spectrum of pathologies. Intracranial hemorrhages, cerebral ischemic lesions, infarctions, lymphoproliferative disorders, and infections, including aspergillosis, have been observed after liver transplant. Fungi constitute nearly 5% of all central nervous system infections, mainly occurring in immunocompromised patients. The most common causative agent is Aspergillus species. It presents either as maxillary sinusitis or pulmonary infection. Brain involvement of Aspergillus carries a high rate of mortality. Aspergillosis presents in the forms of meningitis, mycotic aneurysms, infarctions, and mass lesions. Aspergillosis does not have a specific radiologic appearance. Parenchymal aspergillosis has heterogenous signal intensity (hypointense on T1-weighted and hyperintense on T2-weighted images). Here, we present 3 patients who underwent solid-organ transplant and developed central nervous system aspergillosis. Different modalities of neurosurgical intervention were performed in combination with chemotherapy as part of their fungal therapy.

Key words : Liver transplantation, Neurosurgical intervention, Renal transplantation

The term "aspergillosis" refers to a clinical condition related to Aspergillus species infection, most commonly A. fumigatus, A. niger, A. flavus, or A. terreus.¹ Liver transplant recipients are particularly vulnerable to aspergillosis infection.^2,3 If aspergillosis is further complicated by central nervous system (CNS) involvement, neurosurgical procedures may be required.

Neurosurgical interventions aim to relieve neurologic symptoms by removing mass lesions, to aid with diagnosis in suspicious cases, and to treat increased intracranial pressure by cerebrospinal fluid diversion techniques and placement of reservoirs. Patients who undergo neurosurgical procedures during treatment of fungal CNS infections have significantly improved survival. Preoperative antifungal treatment, particularly with itraconazole, has been reported to have a positive effect on outcome.⁴ The Infectious Diseases Society of America has stated that the response to antifungal therapy is closely associated with host factors, including resolution of neutropenia, control of immunosuppression, and return of graft function after organ transplant.⁴

Here, we present 3 patients, one who demonstrated histopathologic verification after intracranial fungal infection was considered, based on radiologic scan, and who showed a positive response to medical treatment.

Patient 1
In January 2017, a 46-year-old male patient underwent a deceased-donor liver transplant at the Ankara Hospital of Ba?kent University. He was discharged on postoperative day 16 with medical therapy prescription. Three months later, he was again hospitalized because of high fever. The patient showed disturbance of consciousness; therefore, cranial magnetic resonance imaging (MRI) was performed, revealing thickening of the maxillary sinus, contrast enhancement around the fourth ventricle, and abscesses, including in the corpus callosum and vicinity of the left lateral ventricle (Figure 1, A and B). He received 6 cycles of intrathecal antifungal therapy. A cranial computerized tomography showed hydrocephalus (Figure 1C). An external ventricular drainage was inserted, with subsequent insertion of a ventricular-peritoneal shunt. The patient was discharged 1 month later in good neurologic condition, with recommendation to continue oral antifungal therapy.

Patient 2
In January 2017, a 61-year-old male patient underwent deceased-donor liver transplant at the Ankara Hospital of Ba?kent University. The patient presented with right hemiplegia and fluctuation of consciousness. A cranial MRI showed a hemorrhagic lesion in the left thalamic region. Ring-enhancing lesions suggestive of abscess were observed in the right occipital and right temporal lobes (Figure 2). Serum galactomannan was positive. The right occipital lesion was totally removed via craniotomy. Culture from the surgical specimen and histopathologic evaluation both confirmed aspergillosis. The patient received antifungal therapy and rehabilitation. The patient is in stable condition with minimal neurologic deficit.

Patient 3
In 2006, a 38-year-old female patient received a living-donor renal transplant at the Ankara Hospital of Ba?kent University. She was treated for chronic renal disease after kidney rejection in 2011. She was readmitted to the nephrology clinic in March 2017 with high fever and severe headache. Cranial MRI showed bilateral thalamic enhancing abscesses (Figure 3). Urgent brain scan was performed because of sudden unconsciousness. The scan revealed acute hydrocephalus. Urgent external ventricular drainage was inserted. The following day, she experienced intraparenchymal hemorrhage, which was followed by death the next day. Table 1 summarizes the 3 cases.

A wide variety of complications may be seen during the postoperative period after transplant. Intracranial hemorrhages, cerebral ischemic lesions, infarctions, lymphoproliferative disorders, infections, including aspergillosis, lymphoma, and progressive multifocal leukoencephalopathy have been reported after liver transplant.^5,6 In a retrospective study of 200 liver transplant patients, 3% were diagnosed with aspergillosis.⁷

Fungal CNS infections are rare and are secondary in nearly all cases to a primary pathology in a different location of the body. Individuals with acquired immunodeficiency syndrome, posttransplant patients, and patients with diabetes of long duration are prone to CNS fungal involvement. In a study of 595 patients with proven or probable invasive aspergillosis, major risk factors included bone marrow transplant (32%) and hematologic malignancy (29%). Solid-organ transplants accounted for 9%, acquired immunodeficiency syndrome for 8%, and pulmonary disease for 8%.⁸

Walsh and associates⁹ studied the clinical, laboratory, and pathologic features of aspergillosis of the CNS in a series of 17 patients at autopsy. In 8 patients, diseases and events associated with CNS aspergillosis included leukemia, aplastic anemia, and renal transplant. The remaining 9 patients had illnesses not generally known to be associated with aspergillosis. On the basis of the study, the authors suggested considering CNS aspergillosis as a cause of new-onset focal neurologic deficits in patients who have illnesses not usually associated with aspergillosis.

Donor-derived fungal infections in organ transplant recipients are also possible.⁴ The infection reaches the CNS either by direct extension from nasal sinuses or by hematogenous spread from lungs and gastrointestinal tract.¹⁰

The clinical symptoms and signs are generally nonspecific, and fever may be absent. For this reason, diagnosis in most cases is difficult. Other infectious pathologies or neoplastic diseases may present with similar clinical and radiologic features. Neurologic symptoms due to aspergillosis are mental status changes, epileptic fits, and focal neurologic deficits. Diagnosis of aspergillosis relies on radiology, presence of fungi elsewhere in the body, and microbiologic investigations. There may be clinical symptoms similar to meningitis and subarachnoid hemorrhage. The pathology of CNS aspergillosis has been classified in 3 forms: infarction, granulomas, and meningitis.

Aspergillosis does not have a specific radiologic appearance. Computed tomography and MRI are the primary tools for radiologic diagnosis. Computed tomography scans demonstrate isodense to hyperdense attenuation of primary sinus disease with bony destruction. Dural-based lesions show isodense to hyperdense attenuation. Magnetic resonance imaging scans show iso- to hypointense signal intensity on T1-weighted and T2-weighted images in cases of sinonasal origin and duralbased lesions. Primary parenchymal lesions are reported to show heterogenous signal intensity with mainly hypointense signal on T1-weighted and hyperintense on T2-weighted images.¹¹

The radiologic features of aspergillosis have been reported as edematous lesions, hemorrhagic lesions, and solid lesions (called aspergilloma or tumoral form).10 Multiple areas of hypointensity on computed tomography or hyperintensity on T2-weighted MRI involving the cortex and/or subcortical white matter consistent with multiple areas of infarction have been reported as a common radiologic finding in Aspergillus infection.¹⁰

Intracranial aspergillosis has been noted in 4% of children and 10% of adults after liver transplant.⁶ In a Mayo Clinic report, of 405 liver transplant patients, 13% had aspergillosis as an invasive form of fungal infection.¹²

Brain involvement of Aspergillus has a mortality rate of up to 90.9% (20/22) in patients after organ transplant.¹³ A study from our center reported 75% (6/8) mortality in patients with invasive fungal infection after solid-organ transplant.¹⁴

In a report from Wasay and associates¹⁵of 25 cases of confirmed cerebral aspergillosis, overall mortality was 40%. The author suggested preoperative administration of antifungal therapy based on their results.

Therapy includes total removal of the aspergilloma combined with chemotherapy. Srinivasan¹⁶ reported the long-term outcomes of 3 patients treated with radical surgery followed by oral itraconazole. A dose of oral itraconazole 200 mg twice daily for at least 6 months was recommended; this chemotherapy combined with surgery resulted in nearly complete cure in 5 years.

In a study from Schwartz and associates,¹⁷ of 81 patients, 48 patients had definite diagnosis of aspergillosis and 33 had probable diagnosis. In 31 patients, various neurosurgical treatments were conducted (abscess removal in 14, abscess drainage in 12, ventricular shunt in 4, and Ommaya reservoir placement in 1). Overall evaluation revealed that neurosurgical interventions were associated with improved survival. The authors concluded that voriconazole treatment combined with neurosurgical intervention, whenever possible, is the best approach to treat patients with CNS aspergillosis.

Experimental data and case reports agree that underlying immunosuppression is one of the most important factors regarding outcomes of invasive aspergillosis.^18,19 Among the various factors affecting the outcomes of patients with aspergillosis, hematopoietic stem cell transplant has a high mortality rate. Complete and partial responses have been reported only in 15% of patients with bone marrow transplant and invasive aspergillosis at any site.¹⁸ Surgery has been advocated for patients with invasive aspergillosis of the lung, sinuses, and bone.²⁰ Surgical experience for CNS involvement of aspergillosis is limited; however, neurosurgical interventions are needed for better neurologic outcomes and decreased mortality.^16,17,21

Volume: 16 Issue: 1 March 2018 - Supplement - 1

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