Continuing Education Activity

Rhinocerebral mucormycosis, also called zygomycosis, is a rare disease caused by filamentous fungi involving the nose, paranasal sinuses, and brain. It is an opportunistic pathogen commonly found in immunocompromised individuals. Commonly associated diseases include diabetic ketoacidosis, severe burns, steroid therapy, solid organ transplantation, prolonged corticosteroid therapy, hemochromatosis, patients with HIV, neutropenia, malnutrition, hematologic malignancies, etc. But the absence of predisposing factors does not exclude mucormycosis. This activity reviews the role of the interprofessional team in diagnosing, evaluating, and managing the patients with this condition.

Objectives:

• Identify the etiology of rhinocerebral mucormycosis.
• Review the appropriate evaluation of rhinocerebral mucormycosis.
• Outline the management options available for rhinocerebral mucormycosis.
• Describe interprofessional team strategies for improving care coordination and communication to advance the care of patients with rhinocerebral mucormycosis and improve outcomes.

Introduction

Rhinocerebral mucormycosis, also called zygomycosis, is a rare disease caused by filamentous fungi involving the nose, paranasal sinuses, and brain. It is an opportunistic pathogen commonly found in immunocompromised individuals. Because of its involvement with already immunocompromised patients, the fungus grows rapidly and aggressively, causing a well-defined fulminant and life-threatening disease. Early intervention is a must to save lives and prevent permanent neurological complications. It is an acute fungal infection in most cases, but chronic presentations have also been described, which is indolent and slowly progressive, occurring over several weeks.[1]

Commonly associated diseases include diabetic ketoacidosis, severe burns, steroid therapy, solid organ transplantation, prolonged corticosteroid therapy, hemochromatosis, patients with HIV, neutropenia, malnutrition, hematologic malignancies, etc.[2] But the absence of predisposing factors does not exclude the presence of mucormycosis. Some research demonstrated that about 9% of Rhinocerebral mucormycosis was found in patients without any predisposing factors.[3] 

Etiology

The causative agent of the rhinocerebral mucormycosis is saprophytic fungi of the class Phycomycetes, order Mucorales, and the family Mucoraceae. These fungi include Mucor, Rhizopus, Absidia, Cunninghamella genera, and Apophysomyces elegans.[4] Inhalation of spores from fungi living in soil or organic matter in immunocompromised patients is the most common route of invasion.[5] Being an opportunistic infection, reduced host immunity and appropriate host environment such as hyperglycemia, iron overload favor the fungal invasion. It flourishes more in hot and humid climate and environment especially in tropical areas and summer season.

Epidemiology

The frequency of mucormycosis varies depending upon the prevalence of different high-risk populations; thus, it is difficult to report and estimate its prevalence. In the United States, Rhinocerebral form is the most common form of mucormycosis. In India, uncontrolled diabetes is the most common cause of mucormycosis.[5] The overall frequency of mucormycosis is about 4 per 100 patients having hematologic malignancies.[6][7] Among all hematologic malignancies, acute myeloid leukemia (AML) is the most commonly involved (62%).

Pathophysiology

The infection starts in the nasal cavity and extends to adjoining paranasal sinuses. It gets implanted and grows in the nasal cavity and sinuses. The humid environment of the nose and paranasal sinuses favors the growth and invasion of fungi. Invasion of mucosa and bone depends upon the duration, host immunity, and severity of the disease. Early implantation of fungi is common in maxillary sinus with a mass of fungal growth called a fungal ball and no bone erosion. The most common site involved in mucor is middle turbinate, followed by middle meatus and septum. In undiagnosed or untreated cases, the infiltration of bone is common. It almost extends in all surrounding tissues. It then progresses to the brain via either ethmoid sinuses, orbital apex, and through bone erosion or through angioinvasion.

Rapid progression of mucormycosis is due to its unique pathogenesis. Invasion of blood vessels by fungal hyphae damages the endothelium causing blood clots that occlude the blood vessels leading to ischemia and necrosis of surrounding tissue. This necrotic tissue is the nidus for organism growth, and it thrives there and subsequently invades the surrounding tissues through blood vessels. In Rhinocerebral mucormycosis, invasion of brain and orbit is through the involvement of sphenopalatine and internal maxillary arteries. The involvement of the internal carotid artery and cavernous sinus thrombosis is common only in long-standing cases.

There is an increased incidence of infection in diabetic patients, especially diabetic ketoacidosis. Hyperglycemia depletes the immunity of the body. Phagocytosis of leukocytes, neutrophils chemotaxis, and local inflammatory response is depressed in patients with diabetes mellitus. Rhizopus is found to thrive in the ketone-reductase system, glucose-rich medium, and low oxygen tension typical of diabetes. Iron is required for the growth of bacteria and fungi. The use of iron chelator (deferoxamine) makes the iron available in an appropriate form for fungal growth, thus increases fungal virulence.[8] Unsaturated serum transferrin acts as a fungistatic agent by suppressing fungal growth. Iron chelators modify the fungistatic activity of transferrin and also inhibit the iron-catalyzed peroxidase dependent production of free radicals, which kills fungi. Deferoxamine also conceals the antifungal effect of amphotericin B.

Histopathology

Microscopic examination shows fungal hyphae, which are aseptate, branching with 90 degrees, irregularly wide, and areas of necrosis and hemorrhage.[5] Invaded brain tissue exhibit necrosis, infiltration of polymorphonuclear, and multinucleated giant cells along with aseptate hyphae.[9]

History and Physical

History

Clinical signs of rhinocerebral mucormycosis are nonspecific, impeding early diagnosis. Symptoms are mostly associated with the involvement of the head region. One-sided headache behind the eyes and lethargy are the earlier presentation. Other general presentation includes nausea, fever, nasal congestion and rhinorrhea, epistaxis, nasal hypoesthesia, facial pain and numbness, history of black nasal discharge and sinusitis. Common eye complaints are retro-orbital or periorbital pain, amaurosis, diplopia, blurring of visions. CNS involvement presents with convulsions, dizziness, altered mental status, and gait. In widespread cases, respiratory involvement shows the difficulty in breathing, cough, and hemoptysis. Vomiting and abdominal pain are common in gastrointestinal involvement.

Physical Examination

Nasal and orbital cellulitis, reddened and swelling of nasal bridge and skin of cheek in later stages, and eventually turn black due to cell death are the common findings. Black eschar visible on nasal mucosa or palatine mucosa. Bleeding from the nose may be present in severe cases. Intraoral examination can show palatal ulceration. Some series of studies revealed proptosis as the most common orbital sign followed by ophthalmoplegia and visual loss. Other eye signs are conjunctival chemosis, nystagmus, and fixed pupil. Patients with cerebral involvement and vascular compromise may be in a coma or may show signs of a stroke. Neurological examination may reveal palsies of loss of second to seventh cranial nerves.

Evaluation

Because of nonspecific clinical signs, a high index of suspicion should be made in the existence of risk factors. Biopsy of antral necrotic tissue should be performed immediately after suspicion for histopathological study to confirm the diagnosis. And the correct parallel comparison between clinical and histological features helps in diagnosis. Some clinicians prefer CT scan before biopsy because biopsy may take time.[10] So, to appraise the extent of disease and to get a quick picture of disease CT scan is done immediately before histopathology results. Imaging reveals the erosion of bones, obliteration of sinuses, and MRI is favored to visualize the soft tissue changes but is more expensive.[5]

Investigation of choice in early fungal ball detection is a CT scan. CT-scan shows double density sinuses due to the thickening of mucosa with hyperdense areas. The chronic invasive sinusitis phase shows the opacification of sinuses with bone erosion on CT scan. This helps in manipulating surgical modality. But CT findings are not specific to mucormycosis. A false-positive result may be obtained in other invasive diseases and false negatives i.e., even normal sinus CT may have invasive disease.

Nasal scrapings and fine-needle aspiration cytology performed to give the diagnostic result, which shows fungal hyphae. Blood cultures are not preferred because it is rarely positive. Even swab taken and cultured from sinuses are negative in most of the cases. Spinal fluid findings may be negative and nonspecific. Endoscopic observation of sinuses is beneficial to look for tissue necrosis and also to take a biopsy.

Treatment / Management

Medical Treatment

It spread rapidly and highly invasive, so, needs aggressive therapy. Yet, definitive therapy and a sequential plan of management are unavailable. A comprehensive clinical trial is required to confirm the unambiguous therapy and define optimal management strategies. Amphotericin B should be administered straight away when suspected. 4 to 6 weeks of Amphotericin B therapy is required to eradicate the disease. Amphotericin B is the consistently effective antifungal; however, the exact ideal dose is not defined yet. The contemporary study used a daily dose of 50mg, which is tolerated by all patients. Some study recommends 1mg/kg/day dose of amphotericin B. Amphotericin B can be mixed with distilled water to achieve a concentration of 5mg/ml. It is started with 5mg/day doubling daily until 1mg/day is achieved.[11]

Liposomal amphotericin B is endorsed due to its less toxicity as compared to the high nephrotoxicity of amphotericin B alone. Therefore liposomal form allows foe higher doses; however, due to lack of accessibility of this formulation and expensive, it is not always used everywhere and compelled to use plain amphotericin B.[5][12] The monitoring of serum electrolytes, creatinine, and urea are accomplished to evaluate the status of renal function. Because of arterial or venous thrombosis, warfarin is used to prevent clotting.

Surgical Treatment

Surgical removal of the fungal ball is indicated after drug therapy. But some studies defined immediate surgical debridement after diagnosis followed by slow intravenous administration of amphotericin B.[5] Surgical intervention is an invasive technique that involves the removal of involved body tissue and fungal growth supervened by drainage and irrigation of sinuses. Sometimes surgery changes the configuration of body parts when it involves removal of the palate, eye structures, nasal cavity. Multiple surgeries may be needed. The type of surgical procedure depends upon the site or sinuses involved. Maxillectomy or ethmoidectomy is performed according to the site involved. The extent of maxillectomy or ethmoidectomy depends upon the degree of bone and surrounding tissue involvement.

Extensive palate ulceration and oroantral fistula formation may necessitate complete maxillectomy, and just swelling with minimal bone erosion need only partial maxillectomy. Proper clearance of involved tissue needs (>1 cm) excision of healthy tissue is required to eradicate the disease. Orbital exenteration is needed in cases of severe orbital involvement. In cases of uninvolved orbital contents, orbital floor preservation is achieved. Intracranial involvement necessitates craniotomy and debridement. Endoscopic sinus surgery and topical administration of antifungal in the debrided area is also useful. Endoscopic sinus surgery has been possible due to advances in technology such as the availability of microsurgical instruments for precise surgery at specific sinuses or sites, especially to remove the obstruction at sinus Ostia which improves ventilation and endoscopes for better illumination and visualization. Prevention of progressive invasion by restricting at earlier sinusitis phases by understanding pathophysiology and recurrence through ventilation and drainage has better. 

Alternative and Subsidiary Treatment

Hyperbaric oxygen provides sufficient oxygen to neutrophils to kill fungi, and rifampicin are the adjuncts to systemic amphotericin B. Rapid reversal of underlying cause and immunosuppression is inevitable. Treatment of underlying cause is best appreciated if managed after consultation of respective specialty. For example, diabetic ketoacidosis should be treated with insulin and oral hypoglycemic agents after consulting physicians. Steroids and chemotherapeutic immunosuppressants should be discontinued immediately or minimize dose. Immunity can be heightened by administering granulocyte colony-stimulating factors, which increases the production of leukocytes.[2] Azoles can be used as salvage therapy. Iron chelators are useful in those cases caused by hemochromatosis, but the benefits of chelators are not certain.

Differential Diagnosis

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

Bacterial Sinusitis and Allergic Fungal Sinusitis

Initial stages of mucormycosis cause sinusitis, which is confusing with other forms of sinusitis. Patients taking antibiotics for bacterial sinusitis should discontinue after diagnosis of mucormycosis. Allergic fungal sinusitis may cause proptosis and shows large rhinocerebral mass, but a history of recurrent allergic rhinitis and sinusitis, nasal polyp, elevated IgE level directs the diagnosis of allergic sinusitis. There may be bone erosion due to pressure but no fungal invasion in an allergic form, unlike in invasive Rhinocerebral form.

Aspergillosis

Among the fulminant fungal sinusitis in immunocompromised individuals, aspergillosis like rhinocerebral mucormycosis shows similar characteristics such as CNS invasion and other tissue invasion. It is difficult to distinguish clinically. So, histologic stains can figure out between these two, and there is no black eschar formation of gross examination in aspergillosis. Aspergillosis is responsive to itraconazole, whereas amphotericin B is the primary treatment of mucormycosis.[13]

Nasal and Paranasal Malignancies

Due to the high invasiveness of mucormycosis, malignancies resemble mucormycosis. Nasal mass and bleeding on gross examination both in malignancies and mucormycosis mislead the diagnosis.

Proptosis

Proptosis is one of the most common manifestations of the of rhinocerebral mucormycosis, any other diseases causing proptosis should be ruled out. Graves disease, orbital tumor, and cellulitis, subperiosteal hematoma result in proptosis.

Brain Tumor and Pseudotumor Cerebri

Pseudotumor cerebri is due to increased intracranial pressure has similar symptoms as a brain tumor and Rhinocerebral mucormycosis i.e., headaches, dizziness, nausea, and vision problems.

Cavernous Sinus Thrombosis

Mucormycosis is one of the causes of cavernous sinus thrombosis. Other causes of cavernous sinus thrombosis are spread of infection from nose, eyes, face, ear, and pharynx. It usually involves both eyes precipitating proptosis, chemosis, and cranial nerve palsies.

Migraine Headache

It is a primary headache disorder that is recurrently associated with nausea, vomiting, and sensitivity to light. One-sided nature of headache mimics that of rhinocerebral mucormycosis.

Prognosis

Prognosis is poor in most cases despite aggressive therapy. Prognosis can be enhanced comparatively by early diagnosis and prompt treatment. The mortality rate depends upon the severity and expansion of the disease. Mortality in rhinocerebral form is high around 30% to 70%, in disseminated form is up to 90%, and with AIDS has up to 100%. It is demonstrated that the survival rate of a combination of surgical debridement and antifungal therapy is greater (70%) than the surgery (57%) and chemotherapy alone (61%).

One study concluded that survival of patients is 85% when managed within 5 days of diagnosis as compared to 49% when treatment initiated after the 6th day of diagnosis.[5] The overall mortality rate extends from 145 to 80%, depending upon the individual status and time of diagnosis and treatment. It is concluded that the mortality rate is higher in predisposed and cerebral involved patients than in patients without predisposing factors.

Complications

Brain Infarction and Hematoma after Hemorrhage

Vascular invasion is characteristic of rhinocerebral mucormycosis. The formation of intravascular thrombi leads to ischemia and infarction of the brain, including the cerebrum, cerebellum, and brainstem.[9][14] Diffuse vasculitis weakens the walls of blood vessels forming aneurysms. Rupture of aneurysmal blood vessels causes hematoma formation in subarachnoid and subdural regions and intracerebral hemorrhages, which further complicates the disease.

Orbital Apex Syndrome

Ophthalmoplegia due to damage of motor nerves, vision loss due to optic nerve involvement[15], ptosis caused by damage of third cranial nerve, decreased corneal sensation, and proptosis due to venous congestion in cases of cavernous thrombosis, increased retrobulbar pressure and loss of tone in the eyeball.[16][17][18] Other ocular complications include conjunctival hemorrhage and edema, and orbital cellulitis may be due to secondary bacterial infection or fungal invasion, ophthalmic artery thrombosis.

Meningitis

Meningitis is a rare manifestation of rhinocerebral mucormycosis. Diffuse vasculitis or fungal infection of meninges is supposed to be the cause of meningitis.[9]

Brain Abscesses

Brain tissue involvement of mucormycosis gives rise to brain abscess formation, especially in chronic cases.[19][20] Brain abscess formation in rhinocerebral mucormycosis cases may be complicated by a secondary bacterial infection.[21] It may lead to hemiplegia.

Garcin Syndrome

It is the unilateral cranial nerve palsies without the involvement of sensory and motor tracts.[22] Mycelium growth along the cranial nerves or invasion of leptomeningeal blood vessels is estimated as the strict cause of unilateral involvement rather than direct brain tissue pathology.[23]

Facial and Nasal Deformity

Permanent destruction of maxillary and nasal bones changes the cosmetic facial configuration. Orbital exenteration gives disfigurement of facial structures.  

Deterrence and Patient Education

Since the major victims of the invasive mucormycosis are immunocompromised individuals, they should be under consideration for early intervention. Knowledge of rhinocerebral mucormycosis among these individuals allows an early visit to the hospital or clinic. It assists in early diagnosis and increases survival. Information about the disease comforts the patients, and the level of information provided should be parallel to the understanding level of patients. More educated patients must be provided with more extensive details. Details of signs and symptoms help the patients before self-assessing the warning of disease. Patients have the right to choose the mode of investigation and treatment, accept or reject the intervention upon them. But first, they should be counseled and instructed about the merits, necessity, demerits, and complications in the absence of the interventions.

Enhancing Healthcare Team Outcomes

Healthcare outcomes can be enhanced by the collaboration of multi-professional health workers. Some extensive diseases require interprofessional cooperation to make the correct diagnosis and treatment. Highly invasive and extensive diseases like rhinocerebral need quick diagnosis followed by immediate treatment. This would be possible if multiple healthcare workers are available and work simultaneously, especially in developed countries and tertiary care hospitals.

The interprofessional approach to rhinocerebral mucormycosis with infectious disease and medical intensivists, otolaryngologists, physicians, ophthalmologists, radiologists, histopathologists, neurosurgeons, pharmacists, neurologists escalate the diagnosis and treatment which reduce mortality snd morbidity. Even despite these measures, the result remains poor. So a high degree of suspicion is made in high-risk individuals to accomplish a multifaceted approach.[24] Nursing care is inevitable, and post-treatment recovery depends partly upon the effectiveness of nursing care.