Granulomatous amebic encephalitis in a patient treated with chemotherapy: a case report and literature review

Article information

J Neurocrit Care. 2024;17(2):88-93

Publication date (electronic) : 2024 December 18

doi : https://doi.org/10.18700/jnc.240032

Marcos R. Flores, BS^,1, Miranda G. Montion, BS, MA², Aneesha N. Usman, BS, MS¹, Munachiso A. Ngene, MPH³, Samir Ruxmohan, DO⁴

¹Department of Clinical Sciences, University of Medicine and Health Sciences, Basseterre, Saint Kitts and Nevis

²Department of Clinical Sciences, Ross University School of Medicine, Bridgetown, Barbados

³Department of Clinical Sciences, St. George’s University, School of Medicine, True Blue, Grenada

⁴Division of Neurocritical Care, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Corresponding author: Marcos R. Flores, BS Department of Clinical Sciences, University of Medicine and Health Sciences, Basseterre, KN1201, Saint Kitts and Nevis E-mail: 6marcos@gmail.com

Received 2024 October 2; Revised 2024 November 28; Accepted 2024 December 2.

Abstract

INTRODUCTION

Several species of microscopic free-living amoebas (FLAs; such as Acanthamoeba species, Balamuthia mandrillaris, and Naegleria fowleri) are commonly found worldwide in soil, dust, and water, including lakes, rivers, swimming pools, hot tubs, and even tap water [1-3]. Acanthamoeba species have been implicated in different types of human infections involving the eye (Acanthamoeba keratitis), brain, and spinal cord (granulomatous encephalitis), and in some cases, these can spread throughout the entire body (disseminated infection) [1,2]. B. mandrillaris infects the cutaneous and central nervous system (CNS) [3]. In the nervous system, these FLAs can cause two distinct syndromes, primary amebic meningoencephalitis (PAM) and granulomatous amebic encephalitis (GAE) [4]. PAM is caused by N. fowleri, and GAE is caused by the Acanthamoeba species and B. mandrillaris [3,4]. Acanthamoeba and B. mandrillaris have only two stages, cysts and trophozoites, with the latter being the infective form, but both forms are found in tissues [1,3,4]. The organism causing GAE most commonly enters through the respiratory system or skin and will then invade the CNS [1-3,5]. Once in the CNS, the parasite causes abscess and focal granuloma formation. Disseminated disease, skin disease, and keratitis can also occur [3,4].

Owing to the rarity of the disease and lack of clinical trials, a definitive treatment plan for GAE has not been determined [4,5]. Often, a combination of drugs is used to improve treatment outcomes. The Infectious Disease Society of America recommends a combination treatment comprising fluconazole, sulfadiazine, pyrimethamine, or trimethoprim–sulfamethoxazole, rifampin, and ketoconazole [5,6]. Here, we describe a case of GAE with significant insights into its clinical presentation and diagnostic challenges in immunocompromised patients. Though rare, this case reinforces the importance of GAE recognition in immunosuppressed patients and the critical need for prompt interventions to improve survival rates.

CASE REPORT

We present the case of a 71-year-old woman undergoing chemotherapy for previously diagnosed chronic lymphocytic leukemia (CLL) who arrived at the emergency department with bilateral tonic–clonic movements of the arms and legs with spared awareness. Initially, a seizure was suspected, and levetiracetam was administered (500 mg every 12 hours intravenously). However, an electroencephalogram (EEG) during these movements showed no epileptic discharges, leading to the discontinuation of levetiracetam.

Two weeks prior, she experienced decreased motor strength in her right upper extremity. Her speech difficulties began 2 days before her emergency department visit. Initially, her speech consisted of incomprehensible sounds, including mumbling, and then it became nonverbal. A head computed tomography (CT) conducted at the transferring facility revealed multiple intracranial lesions, primarily affecting the left frontal lobe, accompanied by vasogenic edema.

Of note, the patient was subjected to nasal surgery 2 months prior, after which she went swimming in a Texas lake. Subsequently, she was transferred to an academic hospital for further evaluation. Based on her CLL being well-controlled and being treated as an outpatient by her oncologist, the presence of leukocytosis led to a CNS infection being part of the differential diagnosis. A CNS infection workup was performed, but it was not diagnostic. Magnetic resonance imaging (MRI) scans confirmed bilateral cerebral masses with central necrosis and hemorrhage (Fig. 1). Treatment commenced with dexamethasone for cerebral edema and 3% saline for hyponatremia. Table 1 provides details of the treatment protocol during the hospital course. Further investigation involved endoscopic sinus surgery with a biopsy to assess a nasal mass discovered during the examination because of suspected tumor involvement. The initial biopsy was negative for malignancy and, therefore, a subsequent frontal open-brain biopsy was performed. This biopsy confirmed Acanthamoeba or B. mandrillaris infection, with the presence of FLA cysts and trophozoites, prompting adjustments to the treatment plan.

Fig. 1.

Brain magnetic resonance imaging with T2 fluid-attenuated inversion recovery. (A) A lesion with central necrosis, where the ameba is located, surrounded by vasogenic edema (arrow). (B) Vasogenic edema causing a compression of the left lateral ventricle (arrow). (C) A parenchymal lesion (arrow).

Table 1.

Treatment protocol and indications during the patient’s hospital course

Sulfadiazine, flucytosine, and fluconazole were initiated with scheduled miltefosine and pentamidine to treat the patient’s newly diagnosed GAE. Medications were chosen following the recommendation of the Centers for Disease Control and the Doctors of Pharmacy. Polymerase chain reaction test result was sent to the Mayo Clinic, confirming GAE based on pathology. Brain MRI was completed 12 days post-initial imaging, shown in Fig. 2. The MRI revealed enhancement and improvements in the hemorrhage and vasogenic edema. EEG monitoring at this time was negative for abnormal epileptiform findings.

Fig. 2.

Brain magnetic resonance imaging with T2 fluid-attenuated inversion recovery following the treatment protocol. (A) The necrotizing lesion with an improved surrounding vasogenic edema (arrow). (B, C) Improved vasogenic edema based on the size and mass effect decreased (arrows) when compared to Fig. 1.

Though improvements were detected on MRI, the patient, unfortunately, experienced rapid neurological decline and became non-verbal, with minimal responses to pain and touch. The patient was intubated, and the scheduled antimicrobial regimen was continued. Her renal function began to decline, and goals of care and hospice planning were discussed with her family at that time.

DISCUSSION

Acanthamoeba is a free-living, microscopic amoeba found in various environments, such as soil, dust, and different water sources, including swimming pools, hot tubs, drinking water systems, and HVAC (heating, ventilation, and air conditioning) systems. It can cause three primary types of infections, Acanthamoeba keratitis (which affects the eye), GAE, which affects the brain and spinal cord, and disseminated infections through skin lesions. GAE, in particular, can lead to rapidly fatal CNS infections, especially in immunocompromised hosts [2,3].

GAE caused by Acanthamoeba species was first reported in humans in 1971 and has since been reported mainly in patients with immunosuppression caused by chemotherapy, alcohol abuse, or chronic disease [1]. It is a rare infection, affecting 3–12 people annually in the United States, with the mortality rate ranging from 82% to 98% [2,4,5]. In contrast, for Balamuthia, 109 cases have been reported in the United States between 1974 and 2016 with a high Hispanic representation and 90% mortality [3]. B. mandrillaris cases are more common in the Americas, particularly Latin America and the southeastern states of the United States [7]. Table 2 provides a comparative reference of the various clinical courses of infections caused by Acanthamoeba species.

Table 2.

Comparison of three amoebae species and two clinical presentations of PAM and GAE [3,5,6]

Patients with GAE will present with progressive disease from weeks (subacute) to months (chronic), and the infected individual can have a headache, low-grade fever, visual/smell/taste disturbances, behavioral abnormalities with or without hallucinations, irritability, and focal neurologic deficits. Further, it can progress to increase the intracranial pressure, resulting in seizures, coma, and death [3-5]. It is presumed that many cases are not recognized or are incorrectly diagnosed [5]. In the human immunodeficiency virus (HIV)-affected population, the lesions can be confused with Toxoplasma encephalitis [4]. A biopsy is necessary to diagnose GAE, in contrast to PAM, which can be diagnosed via a lumbar puncture [4]. The tissue biopsy must show trophozoites and cysts, with optional granulomatous inflammation [3,4]. Balamuthia and Acanthamoeba are distinct organisms but are difficult to distinguish in tissue sections using light microscopy only [3]. Although the cerebrospinal fluid (CSF) analysis is not diagnostic, mild pleocytosis with lymphocytic predominance, a high protein concentration, and a low or normal glucose concentration may be present [4].

Though a tissue biopsy is essential for diagnosing and confirming GAE, most cases are diagnosed post-mortem during autopsy, leading to many cases being missed. Brain tissue examined after death typically reveals significant edema and hemorrhage [4]. The presence of trophozoites and cysts is crucial, and the tissue may also exhibit moderate granulomatous inflammation with prominent vascular involvement [4]. Typical findings of a CSF analysis include mild pleocytosis with a predominance of lymphocytes, elevated protein levels, and low-to-normal glucose concentrations [4]. An MRI usually demonstrates one or more space-occupying lesions with ring enhancement. In contrast, head CT may show progressive hydrocephalus, meningeal thickening, pseudotumoral lesions, or multifocal ring-enhancing lesions [4].

In contrast, the diagnosis of PAM involves a lumbar puncture followed by CSF analysis. Laboratory findings typically reveal leukocytosis with a left shift, elevated CSF opening pressure, and increased white cell counts with a predominance of polymorphonuclear cells (ranging from 300 to 25,000 cells/mm) [4]. Hemorrhagic fluid and the presence of red blood cells may also be noted. A definitive diagnosis is confirmed through the visualization of motile trophozoites in a centrifuged CSF wet mount preparation [4]. Additionally, PAM can be identified through a nucleic acid or antigen evaluation of CSF, biopsy, or tissue specimens [4].

Immunosuppressed individuals, such as those undergoing cancer treatments or those with conditions such as HIV/acquired immunodeficiency syndrome (AIDS), are at heightened risk of CNS infections. Despite the frequency of these infections, they are often diagnosed late or missed entirely, partly owing to the nonspecific symptoms and the compromised immune status of the patients. Such cases can include neutropenia, B-lymphocyte or immunoglobulin deficiencies, and impaired T lymphocyte-mediated immunity [8].

The case discussed provides significant insights into the clinical presentation and diagnostic challenges of GAE in immunocompromised patients. Most reported cases involve individuals with HIV/AIDS and generally have poor outcomes compared to those with a healthy immune system [8]. The patient in this case presented with seizure-like activity and multifocal intracranial lesions during chemotherapy. Initial treatment included dexamethasone and hypertonic saline, followed by a brain biopsy, which confirmed GAE. Unfortunately, the patient declined further treatment and moved to hospice care before additional therapies could be administered.

Similarly, a 2023 study reported a 49-year-old male with AIDS and neurosyphilis who was diagnosed with GAE but died 19 days later despite empirical treatment with antituberculosis drugs and sulfadiazine [8]. Another case involved a 53-year-old male with HIV/AIDS who was diagnosed post-mortem after an initially unremarkable biopsy [9,10]. These two cases further emphasize the importance of the early diagnosis of and intervention for GAE in an immunocompromised host.

In contrast, a 2020 study highlighted a male with chemotherapy-resistant stage IV-B classical Hodgkin lymphoma. The patient had headaches and mass-like lesions identified on MRI. A prompt biopsy resulted in a diagnosis of GAE. Immediate treatment was started, and it included miltefosine, metronidazole, azithromycin, fluconazole, pentamidine isethionate, and co-trimoxazole. The patient achieved complete remission, and continued rehabilitation led to improvements during their 1-year follow-up. This case is notable, as it is the only known case of survival from GAE in an immunocompromised patient, demonstrating that early diagnosis and immediate treatment can result in favorable outcomes [11].

Nitroxoline, a metal-chelating antibiotic, has been used for several cases of B. mandrillaris infection, as an additional agent in treatment regimens. It demonstrates in vitro activity against this organism at low concentrations, with a half-maximal concentration of 2.8 µM. Although nitroxoline is not approved by the Food and Drug Administration (FDA) and is not commercially available in the United States, it has been utilized under emergency authorization in specific cases [3-5,9]. Clinical and radiologic improvements have been observed in several instances when nitroxoline has been integrated into existing treatment regimens. Furthermore, it has been safely used to treat urinary tract infections in Europe and China, with minimal side effects [10,11].

One notable case involved a male patient in his 50s with no significant past medical history who was diagnosed with GAE due to B. mandrillaris. Remarkably, he survived following a treatment regimen that included nitroxoline. His initial MRI revealed a single hyperintensity in the left temporal lobe, along with enhancement and surrounding edema, which are consistent with typical GAE findings. A brain biopsy confirmed the presence of well-formed granulomata with acute inflammation [12]. The patient was initially treated with a seven-drug regimen, including sulfadiazine, fluconazole, flucytosine, pentamidine, azithromycin, miltefosine, and albendazole, leading to an initial improvement in MRI findings. However, he experienced severe adverse effects, necessitating the discontinuation of pentamidine and sulfadiazine. A follow-up MRI a few days later indicated disease progression, prompting the decision to trial nitroxoline, given its favorable tolerance profile and international availability. This treatment required emergency FDA authorization. After 1 week of nitroxoline therapy, in conjunction with his other medications, MRI showed a reduction in the size of the lesions, and subsequent scans continued to demonstrate improvements [12].

However, whether nitroxoline can effectively penetrate the blood–brain barrier or whether it is effective against Acanthamoeba species remains unclear [13]. Because of these uncertainties, we do not recommend the clinical use of nitroxoline at this time. Instead, we advocate for continued research on its potential role in the treatment of GAE, alongside exploration of other novel agents that may improve survival rates. The limited but positive clinical data on nitroxoline, combined with its safety profile, warrant further investigations, particularly concerning its effectiveness in the CNS. Ultimately, expanding our understanding of nitroxoline and other emerging therapies could lead to significant advancements in the management of GAE.

Overall, GAE, caused by either Acanthamoeba or B. mandrillaris, is rare and is often associated with nonspecific symptoms that can mimic other conditions, such as brain abscesses, encephalitis, or meningitis. The cases discussed highlight the variability in GAE presentations and the crucial need for timely brain biopsies and treatment. Early diagnosis is essential, as delays often result in poor outcomes [8]. The case presented reinforces the importance of vigilance in recognizing GAE in immunosuppressed patients and the critical need for prompt interventions to improve survival rates.

Limitations of this study include, but are not limited to, the limited evidence, unclear causal relationships, and limited comparability. This infection and condition are rare, limiting the use of the findings of this study in similar scenarios. As stated, limited evidence is present regarding the use of antibiotics that are novel to these specific case settings. Positive correlation results based on the use of these agents may not be causal owing to the very limited number of cases in which these agents were used. Finally, owing to limited published case studies, comparisons with our case are difficult.

Acanthamoeba species are FLAs ubiquitous in our environment. They present a significant threat, particularly to immunocompromised patients, such as the one described in this case, who is currently undergoing chemotherapy for CLL. Unfortunately, even with the appropriate therapy, CNS involvement in GAE leads to rapid deterioration, with immunocompromised patients facing a significantly higher risk of mortality compared to immunocompetent individuals. This case underscores the importance of early recognition and aggressive management to improve GAE outcomes. Despite advancements in diagnostic and treatment approaches, the prognosis for this condition remains poor, highlighting the urgent need for further research into more effective therapeutic options, even though it is a rare disease.

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