Immunocompetent isolated cerebral mucormycosis presenting with obstructive hydrocephalus: illustrative case

Abstract

BACKGROUND

Isolated cerebral mucormycosis is rare in immunocompetent adults and is only sparsely reported to be associated with obstructive hydrocephalus.

OBSERVATIONS

Here, the authors report a case of obstructive hydrocephalus secondary to central nervous system mucormycosis without other systems or rhino-orbital involvement and its technical surgical management. A 23-year-old, incarcerated, immunocompetent patient with history of intravenous (IV) drug use presented with syncope. Although clinical and radiographic findings failed to elucidate an infectious pathology, endoscopy revealed an obstructive mass lesion at the level of the third ventricle, which, on microbiological testing, was confirmed to be Rhizopus fungal ventriculitis. Perioperative cerebrospinal fluid diversion, endoscopic third ventriculostomy, endoscopic biopsy technique, patient outcomes, and the literature are reviewed here. The patient received intrathecal and IV amphotericin B followed by a course of oral antifungal treatment and currently remains in remission.

LESSONS

The patient’s unique presentation and diagnosis of isolated cerebral mucormycosis reveal this pathogen as a cause of ventriculitis and obstructive hydrocephalus in immunocompetent adult patients, even in the absence of infectious sequelae on neuroimaging.

Rhizopus, family Mucoraceae, one of the most common genus fungi causing mucormycosis of the central nervous system (CNS),^1–3 has the potential to create a unique surgical problem. Pathogenic Rhizopus species are considered opportunistic infections, mainly affecting immunocompromised patients. This disease disproportionately afflicts patients in African and Asian continents, with a global incidence of 910,000 cases annually, most commonly in India.⁴ The estimated annual incidence in the United Sates is 1.7 cases per million persons.⁵ Mucormycosis typically manifests in rhino-orbito-cerebral, gastrointestinal, cutaneous, pulmonary, or disseminated forms of disease.^2,5–9

The symptomatic rhino-orbito-cerebral triad spreads hematogenously to the paranasal sinuses or the orbit and then intracranially through the ophthalmic artery, veins, or superior orbital fissure or directly through the cribriform plate or sinus walls.^2,10–15 Isolated CNS disease via hematogenous spread without rhino-orbital involvement is uncommon. There are 59 reports of isolated cerebral mucormycosis in immunocompetent adult patients.^16–20 Among those, the vast majority had a focal mass lesion or radiographic infectious sequelae on magnetic resonance imaging (MRI).^{3,8,17,19,21–23} Only three to date have reported obstructive hydrocephalus secondary to mucormycosis without an evident infectious process on neuroimaging, although all occurred in the 1980s before the advent of MRI^24–26 and only one was diagnosed and appropriately treated before death.²⁵

Here, we present our experience with a rare case of adult obstructive hydrocephalus caused by Rhizopus infection in an immunocompetent patient, with the obstruction and infection both diagnosed only at the time of surgery. This case is unique for the indeterminate clinical and radiographic findings, a novel report in the modern neuroimaging era, along with the focally obstructive nature of the infectious process.

Illustrative Case

Clinical Presentation

A 23-year-old incarcerated male with a history of remote traumatic brain injury, attention-deficit/hyperactivity disorder, substance abuse, and chronic pain presented to the emergency department after being found unresponsive. On arrival, he was arousable but amnestic to recent events, nonseptic, afebrile, hemodynamically stable, and without focal neurological deficit. The patient reported a similar episode the prior week with associated headache and nausea. He endorsed blurry vision while standing. He denied recent travel, existing malignancy, and prior infectious disease. His white blood cell count, inflammatory markers, and drug panel were normal.

Imaging Findings

Neuroimaging was remarkable for triventricular hydrocephalus with transependymal edema and query of aqueductal stenosis given the normal size of the fourth ventricle, although no specific cause of obstruction was evident (Figs. 1–3).

FIG. 1.

Axial head computed tomography (CT) without contrast showing marked enlargement of the lateral and third ventricles with associated transependymal edema.

FIG. 2.

Brain fluid-attenuated inversion recovery (A), diffusion-weighted (B), and contrast T1-weighted (C and D) MRI showing triventricular ventriculomegaly, transependymal flow, and normal size of the fourth ventricle, although there is no abnormal enhancement suggestive of infection or a mass lesion.

FIG. 3.

Coronal (A) and sagittal (B) high-resolution T2 constructive interference in steady state sequences showing triventricular hydrocephalus, possible aqueductal stenosis, and no focal lesion or web contributing to obstruction.

Operation and Procedural Intervention

A right frontal external ventricular drain (EVD) was placed with initial intracranial pressure elevated at 35 mm Hg. Cerebrospinal fluid (CSF) had slightly elevated protein (59), normal glucose, and elevated white blood cells (286) out of proportion to red blood cells (2,000) on cell count. The differential resulted in 8% neutrophils, 65% lymphocytes, and 27% monocytes. Cultures were negative. Four days later, the patient underwent planned endoscopic third ventriculostomy (ETV). An intraoperative decision was made to also complete an endoscopic biopsy.

Induction of general anesthesia, endotracheal intubation, and patient head fixation in a neutral 30° elevated position were completed in typical fashion. After the usual surgical preparation, a right frontal burr hole was made at Kocher’s point, and the dura was completely opened to allow for the introduction of a peel-away sheath followed by a 30° endoscope (KARL STORZ SE & Co. KG) to the frontal horn of the right lateral ventricle. A frameless stereotactic navigation system guided the intraventricular portion of the procedure, which revealed a grossly abnormal, whitish, thick material obstructing the posterior third ventricle just behind the foramen of Monro and extending to the floor of the third ventricle. The material had a consistency possibly representing a colloid cyst, although it was not clearly encased in a single membrane (Fig. 4A–C). The material was sampled for further pathological analysis. Additional obstructive material was freed from the choroid plexus of the roof and lateral walls of the third ventricle. After clearance of the material allowed for anatomical identification of the infundibular recess and mamillary bodies, the ETV was performed without complication. Total operative time was 123 minutes.

FIG. 4.

Endoscopic view of a well-circumscribed homogeneous-appearing white lesion at the posterior third ventricle that was resected (A and B). Endoscopic view of the third ventricle, demonstrating a layer of friable white material posteriorly (C). Microscopic examination of the biopsied obstructive material revealing fragmented nonseptate fungal hyphal forms (D). I = infundibulum; MB = mamillary bodies; TC = tuber cinereum.

Pathological Assessment

The biopsied white membranous material was fungi with accompanying acute inflammation. Subsequent broth culture and microscopic examination revealed a Rhizopus species (Fig. 4D), although the fungal culture itself remained negative.

Postoperative Course

Postoperative MRI revealed improvement of the hydrocephalus and still no evidence of abnormal parenchymal enhancement (Fig. 5).

FIG. 5.

Postoperative MRI with and without contrast illustrating decreased lateral and third ventricle sizes, near resolution of transependymal CSF flow, and no evidence of abnormal parenchymal enhancement (A–C).

The CD4 cell count was mildly low, but all additional immunological lab work including fourth-generation human immunodeficiency virus testing, immunoglobulins, and blood cultures were normal. No mucosal biopsy was pursued given the lack of radiographically abnormal nasal tissue. Postoperative CSF samples were negative for any pathogens. Our infectious disease colleagues considered the patient immunocompetent and decided to treat him with amphotericin B.

Procedural complications included iatrogenic infection of the initially placed EVD by Propionibacterium acnes, which resolved with a course of ceftriaxone with no further sequelae. The initial EVD catheter was replaced once, and after diagnosis of the mucormycosis, additional contralateral catheters were placed for passive debridement of the ventricular system and administration of intrathecal (IT) amphotericin B. After 6 days of IT administration, the patient developed persistent headache, so amphotericin B was converted to an intravenous (IV) route and combined with oral isavuconazole sulfa. The headaches resolved, and the EVD was removed. Antifungal complications included treatment-related acute kidney injury and transaminitis, both of which resolved with discontinuation of the amphotericin B after a total of 3 weeks of IV administration and fluids.

The patient was hospitalized for 35 days. At discharge, neurological examination was normal. He was given a 7-day supply of daily isavuconazole sulfate to complete the planned total of 4 weeks postoperative antifungal treatment course. He re-presented to the emergency department one time in the first 90 days after surgery for missing medications but no new medical concerns or diagnoses. He had no readmissions to inpatient care.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Here we describe the novel presentation of a patient with acute obstructive hydrocephalus secondary to isolated cerebral mucormycosis for the purpose of contributing to treatment recommendations in an immunocompetent adult. The patient’s nontoxic appearance and imaging findings made the differential diagnosis broad and uncertain until the intraoperative microbiological results were finalized.

Observations

Typically, neurological manifestations of Rhizopus infection present with the classic triad of rhino-orbital-cerebral symptoms^5,10,11; occasionally, however, isolated cerebral disease can occur, as in our case. As with many neurological fungal infections, mucormycosis is typically an opportunistic infection, especially in those with poorly controlled diabetes mellitus, which is possibly attributable to the promotion of an acidic environment and increased iron availability that the fungal pathogens can bind.^14,27–30 Our patient did not have diabetes, but his low CD4 count could be a risk factor or, alternatively, a sequelae of the fungal infection itself. The patient’s history of IV drug use put him at higher risk, as it presents a direct mode of transmission for opportunistic infection via inoculation of fungal spores and hematogenous dissemination of fungi. IV drug use is the most significant risk factor for isolated intracerebral mucormycosis.^{2,3,8,16,17,31}

Meyerowitz et al.¹⁷ published case reports and a literature review of isolated cerebral mucormycosis in immunocompetent nondiabetic adult patients in 2020, identifying 55 total cases. To our knowledge, four additional cases of isolated intracerebral mucormycosis that would have met their inclusion criteria have been published since.^9,18–20 We believe that our case marks the 60th case and, notably, is the only one in the modern era of MRI with obstructive hydrocephalus but without specific infectious radiographic findings.

The existing three case reports of obstructive hydrocephalus secondary to mucormycosis in an immunocompetent patient all were reported in the 1980s before the advent of MRI.^24–26 One case did diagnose focal obstructive pathology on ventriculography,²⁴ one was not specified as communicating or obstructive hydrocephalus,²⁶ and only one of the three cases was diagnosed and appropriately treated before death.²⁵

Regarding obstructive hydrocephalus secondary to infection, the majority of the literature describes a bacterial etiology including gram-negative rods³² or tuberculosis basal meningitis^33,34 or is opaquely nonspecific with regard to the nuances of fungal infectious hydrocephalus.^5,10 Single case reports of obstructive hydrocephalus secondary to other fungal infections in both immunocompromised³⁵ and immunocompetent³⁶ adult patients have been described, but these too were in the setting of clear infectious sequelae and focal obstructive pathology on MRI.

The intraventricular obstructive material in this case, localized to the level of the third ventricle, initially presented similar to a cyst intraoperatively. On gross examination, the obstructive material apparently matched almost all the characteristics expected for a colloid cyst except the single-layer membrane.³⁷ This emphasizes the necessity of a complete pathological and microbiological analysis for diagnoses of obstruction with uncertain etiology. The lack of radiographic findings consistent with a well-circumscribed cyst or infection made the interpretation of these intraoperative findings less clear.

Lessons

An infectious etiology of hydrocephalus can generally be suspected on preoperative clinical or radiographic workup. This case subverted an initial consideration for a broad infectious disease workup. In fact, the preoperative MRI revealed a normally sized fourth ventricle and small cerebral aqueduct but an acute clinical presentation. Ultimately, mucormycosis was the cause of CSF obstruction and presumably the etiology of secondary aqueductal stenosis on preoperative MRI. It is also possible that this was an incidental congenital finding with radiographically nonapparent infectious matter being the sole cause of the obstruction or contributing to the obstruction in an already high-risk patient.

This somewhat benign presentation caused a 9-day delay in diagnosis and treatment with IT and IV amphotericin B. The current survival of patients without intracranial involvement ranges between 50% and 80%; survival decreases to 20% with intracranial involvement. Morbidity and death in CNS mucormycosis is influenced by the reversibility of underlying risk factors, time to initiation of treatment with IV amphotericin, and time to surgical debridement.^{3,15,17,30,38–40}

A treatment regimen was extrapolated from transplant patients and specialty guidelines recommending amphotericin B for Rhizopus infection in immunocompromised and/or patients with diabetes for our nondiabetic and immunocompetent patient’s rare CNS infection.^10,15 IT amphotericin B was utilized, which has been reported in a few case reports.^41–45 Complications were minor, and the patient has been in complete remission for several years. This reaffirms the efficaciousness of amphotericin B in treating mucormycosis regardless of the patient’s immunocompetency and/or diabetic comorbidity. Moreover, it reveals that the sequelae of obstructive hydrocephalus may be amenable to treatment by ETV and/or passive CSF drainage.

When dealing with triventricular hydrocephalus with nonspecific imaging findings, the modern neurosurgeon should consider a broad differential that includes an obstructive infectious etiology. Treatment should not only aim to ameliorate symptoms, but also to decipher and directly address the underlying cause. Here, neuro-endoscopy may serve as a potent diagnostic and therapeutic option that circumnavigates the need for a ventriculoperitoneal shunt. Prompt and efficacious care is necessary to minimize sequelae and complications. Collaborative, multidisciplinary insights and adaptation of existing guidelines are crucial for the treatment of rare infectious presentations.

The limitations of our report include the unclear significance of a slightly low CD4 count, which could be significant to the patient’s risk level and could have aided in an earlier diagnosis, although newest-generation testing revealed no specific diagnosis. Additionally, the numerous antifungal/antibacterial agents the patient received throughout his hospitalization hindered the applicability of a treatment algorithm to a similar case. The intentional egress of CSF by the EVD for the first 6 days postoperatively was not standardized or reliably documented, making the significance of this portion of the treatment plan difficult to evaluate.

Infectious obstructive hydrocephalus is a very rare presentation of isolated cerebral mucormycosis, itself a rare entity in immunocompetent nondiabetic patients. Diagnosis can be difficult without specific clinical or radiographic findings. Early, broad infectious, inflammatory, neoplastic, and vascular workup must be considered for patients with acute hydrocephalus. Further studies are required to better understand the pathophysiology of this disease. This report demonstrates the importance of early tissue diagnosis and the viability of treatment techniques in infectious obstructive hydrocephalus including ETV and passive debridement of infectious debris in conjunction with well-established antifungal therapy.

Acknowledgments

We express our appreciation to the infectious disease team at Denver Health for their multidisciplinary contributions to the care of our patient.

Author Contributions

Conception and design: Nguyen, Ung, Ojemann, Grassia. Acquisition of data: Nguyen, Freeman, Ojemann. Analysis and interpretation of data: Nguyen, Ung, Ojemann. Drafting the article: Nguyen, Freeman, Ung. Critically revising the article: Nguyen, Freeman, Ung, Ojemann. Reviewed submitted version of manuscript: Nguyen, Ung, Ojemann. Approved the final version of the manuscript on behalf of all authors: Nguyen. Study supervision: Ung, Ojemann.