Continuing Education Activity

Rhinocerebral mucormycosis, also known as zygomycosis, is a rare and potentially life-threatening disease caused by filamentous fungi that primarily affects the nose, paranasal sinuses, and brain. This condition predominantly targets individuals with compromised immune systems, such as those with diabetic ketoacidosis, severe burns, organ transplants, prolonged corticosteroid therapy, hemochromatosis, HIV, neutropenia, malnutrition, and hematological malignancies. However, it's crucial to note that mucormycosis can also occur in patients without any predisposing factors.

This continuing education activity aims to provide healthcare professionals with comprehensive insights into the diagnosis, assessment, and treatment of rhinocerebral mucormycosis. Given the rapid and aggressive nature of this fungal infection, timely intervention is paramount to prevent severe complications.

Objectives:

• Identify the clinical signs and symptoms of rhinocerebral mucormycosis to facilitate early recognition and diagnosis.
• Assess the severity and extent of rhinocerebral mucormycosis in patients using imaging techniques such as CT scans and MRI to guide treatment decisions.
• Select the most suitable antifungal therapy, such as amphotericin B, and prescribe its dosage based on patient factors and current clinical guidelines.
• Collaborate with infectious disease specialists to monitor high-risk patients, ensuring treatment response and preventing recurrence with long-term management.

Introduction

Rhinocerebral mucormycosis, also known as zygomycosis, is a rare disease caused by filamentous fungi that affect the nose, paranasal sinuses, and brain. Filamentous fungi are opportunistic pathogens that frequently infect individuals with weakened immune systems. Due to its association with individuals who are already immunocompromised, this fungus exhibits rapid and aggressive growth, leading to a well-defined, fulminant, and potentially life-threatening condition. Timely intervention is imperative to save lives and prevent permanent neurological complications in affected patients. Although, in most cases, this condition presents as an acute fungal infection, chronic presentations have also been described. These chronic forms are indolent and slowly progressive, occurring over several weeks.[1]

Commonly associated medical conditions include diabetic ketoacidosis, severe burns, steroid therapy, solid organ transplantation, prolonged corticosteroid therapy, hemochromatosis, HIV-infected patients, neutropenia, malnutrition, and hematological malignancies.[2] However, it is noteworthy that the absence of predisposing factors does not rule out the possibility of mucormycosis. Research has shown that approximately 9% of rhinocerebral mucormycosis cases occur in patients without identifiable predisposing factors.[3] 

Etiology

The causative agent of rhinocerebral mucormycosis is saprophytic fungi belonging to the class Phycomycetes, order Mucorales, and family Mucoraceae. These saprophytic fungi are Apophysomyces elegans and members of the genera Mucor, Rhizopus, Absidia, and Cunninghamella.[4] The most prevalent fungal invasion route is the inhalation of spores from fungi residing in soil or organic matter, particularly among immunocompromised patients.[5]

As an opportunistic infection, fungal invasion is facilitated by diminished host immunity and a conducive host environment, such as hyperglycemia or iron overload. This infection is particularly prolific in hot and humid climates and environments, particularly in tropical regions and during the summer season.

Epidemiology

The incidence of mucormycosis varies depending on the prevalence of various high-risk populations, making it challenging to report and estimate its prevalence accurately. In the United States, the rhinocerebral form is the most prevalent type of mucormycosis. In India, uncontrolled diabetes ranks as the leading cause of mucormycosis.[5] The overall incidence of mucormycosis is approximately 4 cases per 100 patients with hematological malignancies.[6][7] Acute myeloid leukemia accounts for 62% of all hematologic malignancies.

Pathophysiology

The fungal infection initiates in the nasal cavity and subsequently spreads to the adjacent paranasal sinuses, where it implants itself and proliferates. The humid conditions within the nasal cavity and paranasal sinuses create a favorable environment that promotes fungal growth and invasion. The extent of mucosal and bone invasion depends on the infection's duration, the host's immune response, and the disease's severity. Early fungal implantation is frequently observed in the maxillary sinus, characterized by a mass of fungal growth but without evident bone erosion. The most commonly affected site in Mucor infections is the middle turbinate, followed by the middle meatus and the septum. In cases where bone infiltration goes undiagnosed or untreated, it can spread to adjacent tissues. This progression can lead to brain involvement through various routes, including the ethmoid sinuses, orbital apex, bone erosion, or angioinvasion.

The rapid progression of mucormycosis is due to its unique pathogenesis. Fungal hyphae invading blood vessels damage the endothelium, cause blood clots that obstruct the blood vessels, and ultimately lead to ischemia and necrosis of adjacent tissues. This necrotic tissue is the nidus for the organism's growth, where it thrives and subsequently invades the surrounding tissues through the bloodstream. In rhinocerebral mucormycosis cases, the invasion of the brain and orbit occurs through the involvement of the sphenopalatine and internal maxillary arteries. The involvement of the internal carotid artery and cavernous sinus thrombosis typically occurs in long-standing cases and is less common in the early stages of the infection.

Patients with diabetes, particularly those with diabetic ketoacidosis, exhibit an increased incidence of infection. Hyperglycemia compromises the body's immunity by suppressing various processes in individuals with diabetes, including leukocyte phagocytosis, neutrophil chemotaxis, and local inflammatory responses.

Rhizopus thrives in a glucose-rich medium with low oxygen tension and in the presence of a ketone-reductase system, which is common in diabetes. Iron is essential for both bacterial and fungal growth. Iron chelators, such as deferoxamine, increase fungal virulence by making iron available in a form suitable for growth.[8] In addition, iron chelators modify the fungistatic activity of transferrin and inhibit the iron-catalyzed peroxidase-dependent free radical production, which kills fungi. Unsaturated serum transferrin functions as a fungistatic agent by inhibiting fungal growth. Deferoxamine also masks the antifungal effect of amphotericin B.

Histopathology

Microscopic examination reveals aseptate fungal hyphae, branching at 90-degree angles, irregularly wide, and accompanied by regions of necrosis and hemorrhage.[5] Invaded brain tissue exhibits necrosis, polymorphonuclear infiltration, multinucleated giant cells, and aseptate hyphae.[9]

History and Physical

History

Clinical signs of rhinocerebral mucormycosis are often nonspecific, hindering early diagnosis. Most symptoms are primarily associated with the affected head region. The initial presentations typically include one-sided headaches behind the eyes and lethargy. Other symptoms, such as nausea, fever, nasal congestion, rhinorrhea, epistaxis, nasal hypoesthesia, facial pain, numbness, a history of black nasal discharge, and sinusitis, are common. Frequent eye-related complaints include retro-orbital or periorbital pain, amaurosis, diplopia, and blurred vision. Central nervous system (CNS) involvement manifests in symptoms such as convulsions, dizziness, altered mental status, and gait disturbances. In extensive cases, respiratory involvement may result in difficulty breathing, coughing, and hemoptysis. Gastrointestinal involvement often leads to vomiting and abdominal pain.

Physical Examination

Typical findings in rhinocerebral mucormycosis include nasal and orbital cellulitis, redness, and swelling of the nasal bridge and cheek skin in later stages, which may eventually darken due to tissue necrosis. A black eschar may become visible on the nasal or palatine mucosa. Bleeding from the nose may be evident in severe cases. An intraoral examination can reveal palatal ulceration. Several studies have indicated that proptosis is the most prevalent orbital sign, followed by ophthalmoplegia and visual impairment. Other ocular symptoms include conjunctival chemosis, nystagmus, and fixed pupil. Patients with cerebral involvement and vascular compromise may present in a coma or display signs indicative of a stroke. During a neurological assessment, it is feasible to identify second to seventh cranial nerve palsies, which may manifest as muscle weakness or sensory loss. 

Evaluation

Due to the nonspecific nature of clinical signs, it is crucial to maintain a high index of suspicion when risk factors are present. Upon suspicion, a biopsy of antral necrotic tissue should be performed immediately for histopathological study to confirm the diagnosis. An accurate parallel comparison of clinical and histological features is vital in aiding the diagnosis. Several clinicians opt for a computed tomography (CT) scan before a biopsy, as it can be time-consuming.[10] Therefore, to assess the extent of the disease and obtain a quick overview of the condition, a CT scan is usually conducted immediately before getting histopathology results. Imaging typically reveals bone erosion and sinus obliteration, and magnetic resonance imaging is a preferred choice for viewing soft tissue changes despite its higher cost.[5]

The preferred diagnostic tool for early detection of infection is a CT scan, which can reveal double-density sinuses caused by mucosal thickening and hyperdense areas. A CT scan typically exhibits sinus opacification and bone erosion signs during the chronic invasive sinusitis phase. These findings aid in determining the appropriate surgical modality. Notably, CT scan findings are not specific to mucormycosis. A false-positive result can occur in other invasive diseases, whereas false negatives, such as a seemingly normal sinus CT, may still indicate invasive disease.

Nasal scrapings and fine-needle aspiration cytology are conducted to obtain a diagnostic result, which typically reveals the presence of fungal hyphae. Blood cultures are not the preferred diagnostic method because they rarely yield positive results. Similarly, swabs taken and cultured from the sinuses often yield negative results in most cases. The findings from the cerebrospinal fluid analysis may be negative or nonspecific for fungal hyphae. In such cases, an endoscopic examination of the sinuses proves valuable in identifying tissue necrosis and aiding in the biopsy procedure.

Treatment / Management

Medical Treatment

Rhinocerebral mucormycosis spreads rapidly and is highly invasive, necessitating aggressive therapy. However, definitive treatment and a sequential management plan are currently unavailable. Therefore, a comprehensive clinical trial is needed to establish clear and effective treatment strategies. Upon suspicion of a fungal infection, amphotericin B should be promptly administered to patients, and a 4- to 6-week course of this therapy is necessary to eradicate the disease. Although amphotericin B is a consistently effective antifungal drug, the ideal dose has not yet been conclusively defined. In the contemporary study, a daily dose of 50 mg amphotericin B was used, which was well tolerated by all patients. Several studies recommend a daily dosage of 1 mg/kg of amphotericin B for patients with rhinocerebral mucormycosis. Amphotericin B can be mixed with distilled water to achieve a 5 mg/mL concentration. The treatment typically begins with a daily dose of 5 mg amphotericin B, which is then doubled each day until a daily dosage of 1 mg is attained.[11]

Liposomal amphotericin B is preferred for its reduced toxicity compared to the high nephrotoxicity of amphotericin B alone. This liposomal form allows for the administration of more substantial doses. However, the limited availability and cost constraints associated with liposomal amphotericin B may restrict its usage, necessitating the utilization of plain amphotericin B in specific regions.[5][12] Monitoring of serum electrolytes, creatinine, and urea is conducted to assess renal function. Warfarin may be used to prevent clotting, particularly in cases involving arterial or venous thrombosis.

Surgical Treatment

Surgical removal of the fungal mass is recommended after drug therapy. However, several studies advocate immediate surgical debridement after diagnosis, followed by a gradual intravenous administration of amphotericin B.[5] Surgical intervention is an invasive procedure that involves the removal of affected body tissue and fungal growth, supervened by sinus drainage and irrigation. In certain cases, surgery can alter the configuration of body parts, especially when it necessitates the removal of structures such as the palate, eye components, and nasal cavity. Multiple surgical interventions may be required, and the specific procedure is chosen based on the location or sinuses affected. Maxillectomy or ethmoidectomy procedures are performed as needed, depending on the site of involvement. The extent of maxillectomy or ethmoidectomy is determined by the degree of bone and surrounding tissue involvement.

Extensive palate ulceration and oroantral fistula formation may require a complete maxillectomy, whereas swelling with minimal bone erosion may necessitate only a partial maxillectomy. To effectively eliminate the disease, it is essential to excise the affected tissue with a proper clearance of more than 1 cm, including removing the surrounding healthy tissue. Orbital exenteration becomes necessary in cases of severe orbital involvement. However, when the orbital contents are unaffected, orbital floor preservation can be achieved. In cases of intracranial involvement, craniotomy and debridement are necessary procedures.

Endoscopic sinus surgery and topical administration of antifungal in the debrided area have proven beneficial in treating rhinocerebral mucormycosis. Endoscopic sinus surgery has been possible due to technological advancements, including the availability of microsurgical instruments designed for precise procedures at specific sinuses or sites. This approach is particularly valuable for removing obstructions at the sinus ostia and enhancing ventilation. In addition, endoscopes provide improved illumination and visualization during the surgical procedure. A more effective approach to managing rhinocerebral mucormycosis is to prevent invasive progression by addressing earlier sinusitis phases. This involves thoroughly understanding the pathophysiology and focusing on ventilation and drainage to reduce the risk of recurrence. 

Alternative and Subsidiary Treatments

Hyperbaric oxygen therapy delivers sufficient oxygen to neutrophils, enabling them to combat the fungi effectively. Rifampicin serves as an adjunct to systemic amphotericin B therapy. Swiftly addressing the underlying cause and managing immunosuppression is imperative. The best way to treat the underlying causes of rhinocerebral mucormycosis is with the help of relevant specialties. For instance, diabetic ketoacidosis should be treated with insulin and oral hypoglycemic agents after consulting physicians. Steroids and chemotherapeutic immunosuppressants should be promptly discontinued or their doses minimized as per physicians' recommendations. Immunity can be enhanced by administering granulocyte colony-stimulating factors, which increase leukocyte production.[2] Antifungal agents such as azoles can sometimes serve as a salvage therapy. Iron chelators may be beneficial when the infection is caused by hemochromatosis, although the advantages of chelators remain uncertain.

Differential Diagnosis

Clinicians must maintain a high index of suspicion to differentiate rhinocerebral mucormycosis from other diseases with similar overlapping symptoms and involving similar anatomical sites.

Bacterial Sinusitis and Allergic Fungal Sinusitis

The initial stages of mucormycosis cause sinusitis, which is often misdiagnosed as other forms of sinusitis. Patients diagnosed with mucormycosis should discontinue taking antibiotics for bacterial sinusitis. Allergic fungal sinusitis can manifest with signs and symptoms such as proptosis and the presence of a sizeable rhinocerebral mass. However, a diagnosis pointing toward allergic sinusitis can be established when there is a history of recurrent allergic rhinitis and sinusitis, nasal polyps, and elevated IgE levels. In the allergic form of sinusitis, bone erosion may be present due to pressure, but no fungal invasion is observed, unlike the invasive rhinocerebral form.

Aspergillosis

In immunocompromised individuals with fulminant fungal sinusitis, aspergillosis may exhibit similar symptoms of rhinocerebral mucormycosis, such as the invasion of the CNS and other tissues. Although clinical differentiation of the 2 infections can be challenging, histological stains can help distinguish between rhinocerebral mucormycosis and aspergillosis. Furthermore, on gross examination, the formation of a black eschar is not usually seen in cases of aspergillosis. Aspergillosis can be effectively treated with itraconazole, whereas amphotericin B is the primary treatment for mucormycosis.[13]

Nasal and Paranasal Malignancies

Because of the highly invasive nature of mucormycosis, it can sometimes resemble malignancies. The presence of a nasal mass and bleeding upon gross examination can be misleading in both malignancies and mucormycosis, making the diagnosis challenging.

Proptosis

Proptosis is one of the most common manifestations of rhinocerebral mucormycosis. Ruling out other conditions that cause proptosis is crucial. Conditions such as Graves disease, orbital tumors, cellulitis, and subperiosteal hematoma can result in proptosis and should be considered in the differential diagnosis.

Brain Tumor and Pseudotumor Cerebri

Pseudotumor cerebri, characterized by increased intracranial pressure, shares similar symptoms with brain tumors and rhinocerebral mucormycosis, including headaches, dizziness, nausea, and vision problems.

Cavernous Sinus Thrombosis

Mucormycosis is one of the causes of cavernous sinus thrombosis. Other potential causes include spreading infection from the nose, eyes, face, ear, and pharynx. This condition often affects both eyes, leading to proptosis, chemosis, and cranial nerve palsies.

Migraine Headache

Migraine headache is a primary headache disorder characterized by recurrent episodes accompanied by nausea, vomiting, and light sensitivity. The one-sided nature of this headache can resemble the presentation of rhinocerebral mucormycosis.

Prognosis

Although the prognosis for this condition in most cases is poor, even with aggressive therapy, early diagnosis and prompt treatment can significantly improve the prognosis. The mortality rate varies depending on the severity and extent of the disease. For the rhinocerebral form, mortality rates range from 30% to 70%, whereas in the disseminated form, it can be as high as 90%. In cases involving AIDS, the mortality rate may reach 100%. Research indicates that combining surgical debridement and antifungal therapy results in a higher survival rate of 70%, compared to 57% for surgery alone and 61% for chemotherapy alone.

Another study concluded that patients have a higher survival rate of 85% when treatment is initiated within 5 days of diagnosis and a lower survival rate of 49% when treatment is initiated after 6 days of diagnosis.[5] The overall mortality rate can range from 80% to 145%, depending on individual factors and the timing of diagnosis and treatment. Research findings conclude that patients with predisposing factors and cerebral involvement tend to have a higher mortality rate than those without such factors.

Complications

Brain Infarction and Hematoma after Hemorrhage

Vascular invasion is a distinctive feature of rhinocerebral mucormycosis. The development of intravascular thrombi results in ischemia and infarction of various parts of the brain, including the cerebrum, cerebellum, and brainstem.[9][14] Diffuse vasculitis can weaken the walls of blood vessels, potentially leading to the formation of aneurysms. The rupture of aneurysmal blood vessels can result in the formation of hematomas in subarachnoid and subdural regions, as well as intracerebral hemorrhages, which further complicate the disease.

Orbital Apex Syndrome

Ophthalmoplegia can occur due to damage to motor nerves, whereas vision loss may result from optic nerve involvement.[15] Ptosis can be caused by damage to the third cranial nerve, and decreased corneal sensation can also be observed. Proptosis may occur due to venous congestion in cases of cavernous thrombosis, increased retrobulbar pressure, and loss of tone in the eyeball.[16][17][18] Additional ocular complications may include conjunctival hemorrhage and edema. Orbital cellulitis can arise due to secondary bacterial infection, fungal invasion, or ophthalmic artery thrombosis.

Meningitis

Meningitis is a rare manifestation of rhinocerebral mucormycosis. The cause of meningitis in cases of rhinocerebral mucormycosis is thought to be either diffuse vasculitis or fungal infection of the meninges.[9]

Brain Abscesses

Brain tissue involvement of mucormycosis can lead to the formation of brain abscesses, particularly in chronic cases.[19][20] Brain abscess formation in rhinocerebral mucormycosis cases may be complicated by secondary bacterial infections,[21] leading to hemiplegia.

Garcin Syndrome

Garcin syndrome is characterized by unilateral cranial nerve palsies without involvement of sensory and motor tracts.[22] The unilateral involvement observed in Garcin syndrome is attributed more to mycelium growth along the cranial nerves or invasion of leptomeningeal blood vessels rather than direct brain tissue pathology.[23]

Facial and Nasal Deformities

Permanent damage to the maxillary and nasal bones can result in alterations to the cosmetic facial appearance. Orbital exenteration, in particular, can lead to disfigurement of facial structures.

Deterrence and Patient Education

As immunocompromised individuals are particularly susceptible to invasive mucormycosis, they should be prioritized for early intervention. Awareness of rhinocerebral mucormycosis can prompt individuals to seek medical attention early, thereby facilitating early diagnosis and improving their survival chances. Patients feel at ease and well-informed when disease-related information is presented in an understandable manner. 

Furthermore, patients with a higher level of education can be offered more comprehensive information. Providing patients with information about the signs and symptoms of the disease can aid them in identifying early warning signs of the condition. Patients have the right to choose the mode of investigation and treatment, including accepting or rejecting recommended interventions. However, providing counseling and thorough instructions to patients is crucial to ensure they fully understand the advantages and disadvantages, necessity, and potential complications associated with these interventions.

Enhancing Healthcare Team Outcomes

The collaboration of a multidisciplinary healthcare team can enhance healthcare outcomes for patients affected by rhinocerebral mucormycosis. Some complex diseases necessitate interprofessional collaboration to establish accurate diagnoses and treatment plans. Highly invasive and extensive conditions, such as rhinocerebral mucormycosis, demand prompt diagnosis and immediate treatment. This can be achievable through the simultaneous efforts of multiple healthcare professionals, particularly in developed countries and tertiary care hospitals.

The management of rhinocerebral mucormycosis through an interprofessional approach necessitates collaboration among various healthcare professionals, including medical intensivists, otolaryngologists, physicians, ophthalmologists, radiologists, histopathologists, neurosurgeons, pharmacists, and neurologists. This collaborative effort ensures comprehensive patient care and enhances the diagnostic and treatment processes, ultimately reducing mortality and morbidity rates. Despite these efforts, the prognosis often remains poor. Therefore, it is crucial to maintain high suspicion in high-risk individuals and implement a multifaceted approach to improve outcomes.[24] Delivering high-quality nursing care to patients during their post-treatment recovery is of utmost importance.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Harrill WC, Stewart MG, Lee AG, Cernoch P. Chronic rhinocerebral mucormycosis. Laryngoscope. 1996 Oct;106(10):1292-7. [PubMed: 8849804]

2.

Gonzalez CE, Couriel DR, Walsh TJ. Disseminated zygomycosis in a neutropenic patient: successful treatment with amphotericin B lipid complex and granulocyte colony-stimulating factor. Clin Infect Dis. 1997 Feb;24(2):192-6. [PubMed: 9114146]

3.

Elinav H, Zimhony O, Cohen MJ, Marcovich AL, Benenson S. Rhinocerebral mucormycosis in patients without predisposing medical conditions: a review of the literature. Clin Microbiol Infect. 2009 Jul;15(7):693-7. [PubMed: 19624514]

4.

Brown SR, Shah IA, Grinstead M. Rhinocerebral mucormycosis caused by Apophysomyces elegans. Am J Rhinol. 1998 Jul-Aug;12(4):289-92. [PubMed: 9740925]

5.

Ramadorai A, Ravi P, Narayanan V. Rhinocerebral Mucormycosis: A Prospective Analysis of an Effective Treatment Protocol. Ann Maxillofac Surg. 2019 Jan-Jun;9(1):192-196. [PMC free article: PMC6585200] [PubMed: 31293952]

6.

Noorifard M, Sekhavati E, Jalaei Khoo H, Hazraty I, Tabrizi R. Epidemiology and clinical manifestation of fungal infection related to Mucormycosis in hematologic malignancies. J Med Life. 2015;8(Spec Iss 2):32-37. [PMC free article: PMC5327702] [PubMed: 28255394]

7.

S Sarvestani A, Pishdad G, Bolandparvaz S. Epidemiology and Clinical Characteristics of Mucormycosis in Patients with Leukemia; A 21-year Experience from Southern Iran. Bull Emerg Trauma. 2014 Jan;2(1):38-43. [PMC free article: PMC4771258] [PubMed: 27162862]

8.

Anand VK, Alemar G, Griswold JA. Intracranial complications of mucormycosis: an experimental model and clinical review. Laryngoscope. 1992 Jun;102(6):656-62. [PubMed: 1602914]

9.

Ho KL. Acute subdural hematoma and intracerebral hemorrhage. Rare complications of rhinocerebral mucormycosis. Arch Otolaryngol. 1979 May;105(5):279-81. [PubMed: 107935]

10.

Mnif N, Hmaied E, Oueslati S, Rajhi H, Hamza R, Marrakchi M, Kaffel N, Kooli H, Ben Salah M, Ferjaoui M. [Imaging of rhinocerebral mucormycosis]. J Radiol. 2005 Sep;86(9 Pt 1):1017-20. [PubMed: 16224341]

11.

Raj P, Vella EJ, Bickerton RC. Successful treatment of rhinocerebral mucormycosis by a combination of aggressive surgical debridement and the use of systemic liposomal amphotericin B and local therapy with nebulized amphotericin--a case report. J Laryngol Otol. 1998 Apr;112(4):367-70. [PubMed: 9659500]

12.

Spellberg B, Walsh TJ, Kontoyiannis DP, Edwards J, Ibrahim AS. Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis. 2009 Jun 15;48(12):1743-51. [PMC free article: PMC2809216] [PubMed: 19435437]

13.

Arndt S, Aschendorff A, Echternach M, Daemmrich TD, Maier W. Rhino-orbital-cerebral mucormycosis and aspergillosis: differential diagnosis and treatment. Eur Arch Otorhinolaryngol. 2009 Jan;266(1):71-6. [PubMed: 18470529]

14.

Sasannejad P, Ghabeli-Juibary A, Aminzadeh S, Olfati N. Cerebellar infarction and aneurysmal subarachnoid hemorrhage: An unusual presentation and rare complications of rhinocerebral mucormycosis. Iran J Neurol. 2015 Oct 07;14(4):222-4. [PMC free article: PMC4754602] [PubMed: 26885342]

15.

Mattingly JK, Ramakrishnan VR. Rhinocerebral Mucormycosis of the Optic Nerve. Otolaryngol Head Neck Surg. 2016 Nov;155(5):888-889. [PubMed: 27352893]

16.

Umemura A, Suzuka T. [A case of rhinocerebral mucormycosis presenting orbital apex syndrome]. No Shinkei Geka. 1998 May;26(5):439-42. [PubMed: 9621358]

17.

Lim CC, Liao IC, Lee WA. Orbital apex syndrome secondary to fungal sinusitis. QJM. 2020 Mar 01;113(3):205-206. [PubMed: 31665453]

18.

Badakere A, Patil-Chhablani P. Orbital Apex Syndrome: A Review. Eye Brain. 2019;11:63-72. [PMC free article: PMC6913296] [PubMed: 31849556]

19.

Tay AG, Tan CT. Mucormycosis and chronic brain abscess. Med J Aust. 1986 Jun 23;144(13):725-6. [PubMed: 3724609]

20.

Pellacchia V, Terenzi V, Moricca LM, Buonaccorsi S, Indrizzi E, Fini G. Brain abscess by mycotic and bacterial infection in a diabetic patient: clinical report and review of literature. J Craniofac Surg. 2006 May;17(3):578-84. [PubMed: 16770203]

21.

Cano P, Horseman MA, Surani S. Rhinocerebral mucormycosis complicated by bacterial brain abscess. Am J Med Sci. 2010 Dec;340(6):507-10. [PubMed: 20861715]

22.

Mutsukura K, Tsuboi Y, Imamura A, Fujiki F, Yamada T. [Garcin syndrome in a patient with rhinocerebral mucormycosis]. No To Shinkei. 2004 Mar;56(3):231-5. [PubMed: 15112447]

23.

Yang H, Wang C. Looks like Tuberculous Meningitis, But Not: A Case of Rhinocerebral Mucormycosis with Garcin Syndrome. Front Neurol. 2016;7:181. [PMC free article: PMC5075765] [PubMed: 27822198]

24.

Palejwala SK, Zangeneh TT, Goldstein SA, Lemole GM. An aggressive multidisciplinary approach reduces mortality in rhinocerebral mucormycosis. Surg Neurol Int. 2016;7:61. [PMC free article: PMC4882964] [PubMed: 27280057]

Disclosure: Jenish Bhandari declares no relevant financial relationships with ineligible companies.

Disclosure: Pawan Thada declares no relevant financial relationships with ineligible companies.

Disclosure: Shivaraj Nagalli declares no relevant financial relationships with ineligible companies.