Rhinocerebral mucormycosis: A rare fungal infection linked to diabetes case report

 case report
Rhinocerebral mucormycosis: A rare
fungal infection linked to diabetes
Although usually prevented by the immune system, this disease is common in patients who
are immunocompromised. As in this case, early detection and treatment are key.
Sarah Asman, MPA, PA-C;
Mehrdad M. Behnia, MD, FACP, FCCP
CASE
A 37-year-old male presented to his primary care physician with acute onset periorbital edema, tinnitus, and
nasal congestion. He attributed his symptoms to ongoing
chronic sinusitis. On physical examination, the patient
was afebrile and had ptosis of the right eyelid with periorbital edema and erythema. Edema and hypertrophy of the
nasal turbinates and posterior pharynx were also present.
His history included hypertension and chronic anxiety.
The patient denied smoking but admitted to drinking
alcohol socially. His physician made the primary diagnosis
of periorbital cellulitis and admitted him to the hospital
for treatment, where he was started on clindamycin, vancomycin, and piperacillin-tazobactam.
Two days after admission, the patient exhibited altered
mental status. On neurologic examination, he had facial
asymmetry due to complete ptosis and significant edema
of the right eyelid. Extraocular movements were intact
but limited during upward gaze in the right eye. CT of
the brain showed cavernous sinus thrombosis with similar
changes to the orbit, a semiacute right frontal lobe infarct,
and diffuse sinusitis (Figure 1). Heparin was started in
conjunction with ceftriaxone for the cavernous sinus thrombosis, and the patient’s previous antibiotic regimen was discontinued. Based on an elevated hemoglobin A1C level of
7.8% and random blood glucose level of 260 mg/dL, a presumptive diagnosis of type 2 diabetes mellitus was made.
On hospital day 3, the patient’s neurologic condition
began to deteriorate acutely. He exhibited some posturing with blindness of the right eye; the right pupil became
dilated and nonreactive. CT of the head showed hemorrhage in the area where the right frontal lobe infarct
had been (Figure 2). Left pupillary response was intact.
Heparin was stopped, and the patient was intubated
because of concern that the airway was compromised.
The following day, repeat CT of the head showed a large
frontal bleed with surrounding edema and mass effect as
well as subarachnoid hemorrhage (Figure 3).
A
B
FIGURE 1. CT showing cavernous sinus thrombosis (a) and
orbit thrombosis (b), with the red arrow indicating the
pathologic area
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case report | Rhinocerebral mucormycosis
The patient underwent a frontal lobectomy with removal
of the blood clot. A complete right ethmoidectomy, right
maxillary sinus antrostomy, frontal sinusotomy, and sphenoidectomy were also performed. Intraoperatively, significant devitalized mucous membranes were seen within the
nasal cavity that were suspicious for an acute fungal process. The area was debrided, and pathology was consistent
with mucormycosis. The patient was started on IV amphotericin B and anidulafungin. Multiple debridements of the
right nasal cavity were subsequently performed. Bilateral
myringotomy with insertion of a tympanostomy was also
performed, and he was started on hyperbaric oxygen therapy (HBO). His condition started to improve dramatically,
and he was subsequently discharged to an outpatient rehabilitation program on posaconazole after 21 days of treatment with amphotericin B, anidulafungin, and ceftriaxone.
FIGURE 2. Left, CT demonstrating right frontal lobe hemorrhage (red arrow)
FIGURE 3. Right, CT showing frontal hemorrhage (red arrow)
and surrounding edema and mass effect (yellow arrow)
DISCUSSION
Rhinocerebral mucormycosis is a rare fungal infection that
historically is seen in the immunocompromised. Previously
referred to as zygomycosis, changes in high-level taxonomy
in reference to molecular phylogenetic analyses led to the
class Zygomycota being renamed as Glomeromycota.1 Although
this fungus is ubiquitous in the environment, the disease
is usually prevented by the immune system and is therefore rare. As with other types of fungi, the most desirable
environment for rhinocerebral mucormycosis to grow is in
wet, damp places such as soil, composting vegetation, and
bread. Well-recognized risk factors for the disease include
diabetes mellitus, leukemia, aplastic anemia, myelodysplastic
syndrome, blood dyscracias, immunosuppressive therapy
in organ transplantation, renal disease, sepsis, and severe
burns.2 The disease is primarily found in those who are
immunocompromised, but it may also manifest in immunocompetent persons.3 In fact, in one study, nearly 20% of
mucormycosis cases occurred in patients with “no underlying medical condition,” although the latter group had a history of penetrating trauma, surgery, or burns.3
Disease progression Rhinocerebral mucormycosis generally progresses in three stages.2 The first stage occurs after
the fungal spores have been inhaled and infect the paranasal sinuses, resulting in formation of necrotic lesions in
the nasal mucosa, turbinates, or hard palate.2 The second
stage is characterized by direct extension of the disease into
the maxillary sinus or invasion of the surrounding vasculature. During the last stage, the fungus spreads into the
cribriform plate or the orbital apex.2
Rhinocerebral mucormycosis usually manifests as an
acute sinus infection but can lead to serious complications
such as cavernous sinus thrombosis and vascular invasion
if not treated early.4,5 Table 1 lists the distinguishing features
of both bacterial sinusitis and rhinocerebral mucormycosis.
Delayed treatment may also cause the disease to spread rapidly to adjacent structures such as the brain and orbits or to
occlude the carotid artery, causing an internal carotid artery
pseudoaneurysm.2,4,5 If the fungus invades the blood vessels
extensively, infarction and necrosis of the involved tissue
will eventually result.2
Treatment As of now, treatment options for rhinocerebral
mucormycosis are still being optimized. Current therapy for
the invasive disease includes treating the underlying predisposing factors, antifungal therapy, and surgical debridement
of the affected tissues. Early recognition of the disease and
treating the underlying cause of mucormycosis, such as
diabetes, are key to improving outcomes. The antifungal
treatment of choice for mucormycosis is amphotericin B,
although very high doses are required because of the relative resistance of the fungus to the drug.
TEACHING POINTS
■■ Rhinocerebral mucormycosis is a rare fungal infection that historically is seen in the immunocompromised.
■■ Well-recognized risk factors for the disease include diabetes mellitus, leukemia, aplastic anemia, myelodysplastic syndrome, blood
dyscracias, immunosuppressive therapy in organ transplantation, renal disease, sepsis, and severe burns.
■■ The infection progresses in three stages and usually manifests as an acute sinus infection. If not treated early, it can lead to serious
complications such as cavernous sinus thrombosis and vascular invasion.
■■ Current therapy for the invasive disease includes treating the underlying predisposing factors, antifungal therapy, and surgical debridement of the affected tissues.
■■ Early recognition of the disease and treating the underlying cause of mucormycosis are key to improving outcomes.
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case report | Rhinocerebral mucormycosis
TABLE 1. Features of bacterial sinusitis and rhinocerebral
mucormycosis10
Sinusitis
Rhinocerebral mucormycosis
Presentation
• Unilateral facial pain
• Severe facial pain
over maxillary dentition
• Clear- to strawor maxillary sinuses,
colored nasal
between eyes (ethmoid
drainage
sinuses), over forehead
• Visual symptoms
(frontal sinuses) or head
may be noted
vertex (sphenoid sinuses) at presentation
• Acute onset (1-4 weeks),
in absence of
purulent green or yelsignificant nasal
low nasal discharge or
findings
expectoration
• Associated symptoms
including cough, malaise, nasal congestion,
fever, and headache
Examination
• Tenderness to palpation
of the affected sinuses
• Red, swollen nasal
turbinates
• Pathognomic finding: black eschar on the
middle turbinate
• Nasal mucosa can
also appear normal
or slightly pale
Treatment
• Two-thirds of untreated
patients with acute
bacterial rhinosinusitis
will improve symptomatically within 2 weeks
• Consider antibiotics
when symptoms last longer than 10-14 d or when
symptoms are severe • First-line therapy is
amoxicillin, trimethoprim-sulfamethoxazole,
or doxycycline
• Prompt wide surgical debridement
and amphotericin
B by IV infusion
or lipid-based
amphotericin B in patients with
renal insufficiency
• Some evidence
to suggest iron
chelator therapy
as adjunct treatment
Amphotericin B works by binding to ergosterol, increasing
the permeability of the fungal cell mebranes.6 Amphotericin
B can be nephrotoxic, and renal indices should be monitored
during therapy. Several studies have indicated that lipid formulations of amphotericin B, such as liposomal amphotericin
B, may result in improved response rate and survival, reduction of fungal burden, and lesser nephrotoxicity.1 Surgical
debridement is fundamental in combination with antifungal
therapy because patients treated with antifungal therapy
alone have very low cure rates.5
HBO has been reported by some to improve treatment
outcomes in patients with rhinocerebral mucormycosis.
Although no definitive evidence exists that this treatment
can lower mortality, it has been used to ameliorate tissue
hypoxia and lactic acidosis associated with mucormycosis.2
In one case study, three presumptive benefits of HBO were
as follows: a) increased oxygenation to the vessels and tissues distal to the affected sites with resulting improvement
in acidosis; b) inhibited growth of the fungus caused by the
decrease in acidosis; and c) fungicidal properties of oxygen
when provided in high quantities.7
Outcome In our patient, treatment was initiated with
amphotericin B, anidulafungin (Eraxis), and ceftriaxone.
Anidulafungin is an echinocandin antifungal that inhibits
fungal cell wall synthesis by inhibiting beta 1,3 glucan.8 We
thought that the combination of antifungals would be most
beneficial to this patient based on the extent of the disease
while the ceftriaxone would provide simultaneous broad
spectrum coverage for other opportunistic bacteria. In addition, the additive effects of the two antifungals from different classes could potentiate a greater response to both drugs
while attenuating the need for higher doses of amphotericin
B required for extensive disease involvement.
Posaconazole is a triazole oral antifungal with a good
safety profile that blocks the synthesis of ergosterol. It can
be used as salvage therapy or in conjunction with amphotericin B or echinocandin in the treatment of mucormycosis, although randomized trials are not available to prove
its complete efficacy.9 Deferasirox, an oral iron chelator
used for treatment of iron overload, has in vitro fungicidal
activity against Mucorales. A phase II study, “DefrasiroxAmbisome Therapy for Mucormycosis,” has been completed, but results are yet to be published (NCT00419770).
CONCLUSIONS
This report summarizes the case of a patient with mucormycosis of the sinuses requiring extensive sinus debridement
and cavernous sinus thrombosis. The hospital course was
complicated by a large, frontal intracranial bleed with mass
effect requiring craniotomy. He was treated with 21 days of
IV amphotericin B, anidulafungin, and ceftriaxone in conjunction with HBO and outpatient posaconazole.
Although mucormycosis is rare, clinicians must hold a
high index of suspicion when dealing with patients who
present with symptoms like those in our patient. Although
complaints such as nasal congestion and periorbital edema
are common in the primary care setting, the health care
provider must take into account the patient’s underlying
comorbidities when formulating a differential diagnosis. In
this case report, undiagnosed diabetes mellitus was the precursor to the development of mucormycosis. Recognition
and correction of the factors that predispose patients to
rhinocerebral mucormycosis are critical in order to avoid
serious complications of this rare infection. JaApa
At the time this article was written, Sarah Asman was a PA student at Georgia Health Sciences University, Augusta, Georgia. She currently practices at Southern Surgical Group, West Columbia, South Carolina. Mehrdad Behnia is clinical associate professor of medicine at Georgia
Health Sciences University. The authors have indicated no relationships to
disclose relating to the content of this article.
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case report | Rhinocerebral mucormycosis
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