The patient was a 72-year-old male who presented to the emergency department (ED) with complaints of headache and seizure-like activity with shaking of his bilateral upper extremities. His past medical history was significant for CLL with 13q deletion diagnosed 6 years prior to presentation. He was treated at that time with fludarabine and rituximab for 4 cycles; however, he was not able to complete a 5th cycle due to prolonged cytopenia. Two years later due to progression of disease, he was started on ibrutinib 420 mg daily and continued for 2 years. He developed severe neutropenia while on ibrutinib, and treatment was held for two months until resolution. He presented to the ED one month after resuming ibrutinib.
At presentation, the patient was alert with the only examination finding of episodic shaking movements. He was afebrile and had a leukocytosis of 15,200/microL with 66% lymphocytes. Initial workup included computed tomography (CT) of the head without contrast which showed no findings to explain presenting symptoms. Continuous electroencephalography (EEG) evaluation was negative for epileptiform activity. With persistent symptoms he was started on anticonvulsants with levetiracetam and phenytoin. A magnetic resonance imaging (MRI) of the brain with contrast was obtained, and it showed a nonspecific focal area of increased signal involving the right frontal cortex (Figure 1(a)). He was transferred to our institution for further workup and management.
On arrival, the patient was evaluated for progression of CLL by the chest, abdomen, and pelvis CT which was negative for any evidence of disease with no lymphadenopathy or splenomegaly. MRI of the spine was performed and was negative for any disease other than degenerative changes. Ophthalmological evaluation was unrevealing for any intraocular pathology. He was worked up for autoimmune processes with ANA, CRP, and ESR, all of which were insignificant. Infectious workup with blood culture, urine culture, quantiferon-TB, histoplasma, blastomyces, influenza, RPR screen, and HIV were negative. He had a lumbar puncture which showed cerebrospinal fluid (CSF) with elevated WBC 97/microL, polysegmented neutrophils (PMN) 2%, lymphocytes 82%, red blood cells (RBC) 4/microL, elevated protein 93 mg/dL, and normal glucose of 44 mg/dL. FilmArray meningitis and encephalitis panel was negative for all the following tested agents: Escherichia coli, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus group B, Streptococcus pneumoniae, Cytomegalovirus, Enterovirus, Herpes simplex virus 1 and 2, Human herpesvirus 6, Human parechovirus, Varicella zoster virus, and Cryptococcus neoformans. Gram stain and culture also turned out to be negative. Cytologic analysis of CSF was negative for malignant cells or large cell transformation. CSF flow cytometry showed a minute population of 0.04% CD5+ B-CLL cells, which was not felt to be clinically significant and sufficient to explain the acute changes the patient was experiencing. Other CSF tests, which were negative, included angiotensin-1-converting enzyme, John Cunningham (JC) polyomavirus, cryptococcal antigen, fungal culture, and CSF toxoplasma serologies.
The patient became increasingly lethargic and started complaining of worsening headache. He also started having high fevers which persisted despite treatment with broad-spectrum antibiotics with vancomycin and piperacillin/tazobactam and antivirals with acyclovir. His neurological status continued to decline and repeat MRI brain showed new and increase in size of previously known scattered hyperintensities with associated rim enhancement (Figure 1(c)). At this time, infectious etiology was favored, given the acuity of changes seen on imaging and patient status. The infectious coverage was expanded and included IV vancomycin, cefepime, and ampicillin for bacterial meningitis; IV amphotericin B for atypical fungal meningitis; and IV acyclovir was continued for viral encephalitis. The patient continued to decompensate clinically, and a repeat CT of the head showed hydrocephalus. An external ventricular drain was placed which did not improve his status. A leptomeningeal biopsy was not performed considering the difficult location and size of the lesions. As all workup continued to be unrevealing, progressive multifocal leukoencephalopathy (PML) was thought to be the most likely diagnosis to fit the patient's medical history and imaging and laboratory results; however, JC polyomavirus was tested negative on two separate CSF analyses, making this diagnosis unlikely. The patient ultimately expired within two weeks after he presented with the neurologic symptoms after support was withdrawn per family request, and an autopsy was performed.
Autopsy of the brain showed diffuse cerebral edema with right-sided predominance on gross findings. There were multiple areas of hemorrhagic necrosis including the bilateral frontal lobe, right parasagittal posterior frontal lobe, left temporal lobe, bilateral medial occipital lobe, and paraventricular areas. Microscopic findings revealed parenchymal necrosis with mixed inflammation, amebic trophozoites, and occasional cysts (Figures 2(a) and 2(b)). This mixed infiltrate was seen involving the meninges. The amebas were prominent around vessels, and occasional multinucleated giant cells were seen (Figures 2(c) and 2(d)). The autopsy brain was sent to the Centers for Disease Control and Prevention (CDC) and immunohistochemical stains were performed, which identified Acanthamoeba species with no evidence of Naegleria fowleri. His final diagnosis based on autopsy was necrotizing meningoencephalitis with morphologic and immunohistochemical evidence of Acanthamoeba species.