Rhino-Orbital Cerebral Mucormycosis

Etiology

The ubiquitous fungi in the order Mucorales often thrive on decaying plant debris and soil. The most common genera causing human infections include Rhizopus, Lichtheimia, Apophysomyces, Mucor, and Rhizomucor. Human infections are less commonly caused by Cunninghamella and Saksenaea. The most commonly isolated mucormycosis species in the world is Rhizopus arrhizus, though Apophysomyces variabilis is most common in Asia, and Lichtheimia species is predominant in Europe.[5] A large review of 929 patients from 1940 to 2003 identified poorly controlled diabetes mellitus as the commonest risk factor (36%), followed by hematologic cancers (17%), and hematopoietic stem cell or solid organ transplant (12%).[4] Subsequently, the RetroZygo study done over 3 years in France has shown hematologic malignancy as the risk factor in almost half of the patient population followed by diabetes mellitus (23%) and trauma(18)%.[6]

The most common clinical presentation is rhino-orbital cerebral mucormycosis, and the commonest etiology for rhino-orbital cerebral mucormycosis is Rhizopus oryzae. Rhino-orbital cerebral mucormycosis almost always occurs in immunocompromised persons, including uncontrolled diabetes mellitus, especially with acidosis or ketoacidosis, steroid therapy, solid organ or hematopoietic stem cell transplant recipients, chemotherapy, hematologic dyscrasias, retroviral disease, and malnourishment. The preponderance is also noted in patients on deferoxamine therapy, iron overload state, and intravenous drug abuse. Cases of rhino-orbital cerebral mucormycosis occurring following facial burns or scleral buckling procedures have been reported. Rare reports of rhino-orbital cerebral mucormycosis have also been published in immunocompetent hosts.

The rapidly growing saprophytic fungi release a large number of spores into the environment. These sporangiospores are commonly inhaled by the host, and in hosts with normal immune status, the ciliary system directs the spores towards the pharynx, thereby eliminating them via the gastrointestinal system. The spores might also get colonized in the oral mucous membranes, nose, throat, and paranasal sinuses. Mucorales do not cause disease in the host with an intact immune system where phagocytosis could effectively contain the invasion and infection. When the phagocytosis is impaired due to immune deficiency, the germination of spores into hyphae with resultant angioinvasion is initiated. The initial site of infection in rhino-orbital cerebral mucormycosis is the nasal turbinates. An acute episode of sinusitis progresses into pan sinus involvement within a few days with contiguous spread to the palate, orbit, and brain resulting in severe tissue ischemia and necrosis due to the angioinvasive nature of the fungus.

Epidemiology

Accuracy of epidemiologic analysis is challenging since mucormycosis is not a notifiable disease and is further compounded by considerable variation of risk factors among the different populations. With the available data, the global epidemiology of mucormycosis has been showing not only an increase in the incidence but also reporting of new causative agents along with a change in the susceptible population characteristics. Though the rise has been noted globally, it is significantly higher in the Asian continent, especially in India and China. The Leading International Fungal Education (LIFE) portal estimates the annual global prevalence of mucormycosis approximately as 10,000 cases when Indian data is not included. When Indian data is added, it becomes 910,000 cases annually.[5] The estimated incidence burden in the USA is about 3 cases per million population, the UK being 0.9 cases per million, and Canada and Australia being 1.2 and 0.6 cases per million, respectively. Wide variation has been noted among European countries, e.g. an incidence of 0.2 cases per million in Denmark versus 95 cases per million in Portugal. Rhino-orbital cerebral mucormycosis is the commonest presentation seen in 40% of the cases.[7][8] There is no age or sex predilection.

A 7-year review of 851 cases showed that the incidence is higher in Europe at 34 %, and 31 % in Asia, 28 % in North and South America, 3% in Africa, and 3% in Australia and New Zealand.[9] The higher values in the European continent could have been due to under-diagnosis and under-reporting in the Asian continent during the study period. The most common risk factor for rhino-cerebral mucormycosis all over the world is diabetes mellitus, whereas hematologic malignancies and transplants more commonly predispose to pulmonary mucormycosis. Though diabetes mellitus has been the most common susceptibility factor in Asia, post-tuberculosis state and chronic renal failure have emerged as new risk factors. The RetroZygo study in France found hematologic malignancy as the major predisposition to mucormycosis in 50 % of the cases, followed by diabetes mellitus (23 %) and trauma (18%).[6]

Pathophysiology

Rhizopus grows rapidly in the hyperglycemic environment because phagocytosis is significantly impaired in a high blood sugar state. The ketone reductase system in the fungus helps to successfully survive the acidotic environment in diabetic ketoacidosis. Moreover, acidosis causes dissociation of iron from sequestering proteins in the serum, which could promote virulence and survival. Phagocytosis is notoriously impaired also in neutropenia and steroid therapy. The iron-rich state caused by deferoxamine, an iron-chelating agent, also favors the fungal growth by acting as a siderophore to the fungus. Many patients with diabetes mellitus with rhino-orbital cerebral mucormycosis present with minimal or no acidosis. The hyperglycemia itself favors fungal growth by at least three mechanisms, which include hyper-glycation of iron sequestering proteins with impaired iron sequestration, enhanced expression of GRP 78, a mammalian protein receptor, which increases binding to Mucorales, and finally the decreased phagocytosis associated with high blood sugar state. 

Mucormycosis is an angiotropic fungus having a high tendency to damage the internal elastic lamina of blood vessels, especially the arteries by mechanical and toxic means, and subsequently spreading to lymphatics and veins. After inhalation of spores into the sinuses, the angioinvasive infection gets established via the spores germinating into multiple hyphae in the immunocompromised patient. The pterygopalatine fossa is believed to be the largest reservoir. Vascular and neuronal spread along with vessel wall infiltration ensues rapidly in the coming hours. Direct invasion results in thrombosis and nerve dysfunction. The involvement of blood vessels, bone, cartilage, nerves, perineural areas, and meninges are quite common. The tissue necrosis at the palate results in palatine eschars and the destruction of nasal turbinates. The bone is eroded by the spread of infection from the sinuses, which subsequently extends into the orbital structures, thereby spreading to the brain via a retro-orbital route. Spread to the frontal lobes could also happen via the ethmoid sinuses. Infection spreading along the sphenoid sinuses to the nearby cavernous sinus results in cranial nerve palsies. This is followed by extensive thrombosis of the cavernous sinus, jugular veins, and carotid artery. Blockage of the carotid artery is well reported.

Histopathology

Smears can be examined under potassium hydroxide (KOH) wet preparation. Hematoxylin-eosin (H&E) and Papanicolau stains are used in scrape smears, and air-dried smears are examined with periodic acid Schiff (PAS) and May-Grünwald-Giemsa stains. Surgical sections are processed in paraffin and examined with H&E and PAS stains. Histopathology evaluation of the debrided tissue will reveal elongated broad ribbon-like hyphae irregularly branching at right or obtuse angles, with no or scanty septations. Thrombosed blood vessels with significant necrotic areas and giant cells are also noted. Widespread infiltration with lymphocytes, eosinophils, and occasional plasma cells is seen. Calcofour-white or Grocott-Gomori's methenamine silver staining demonstrates twisted septate hyphae.

History and Physical

The symptoms of rhino-orbital cerebral mucormycosis are often non-specific with varying spectrum and severity. Background history of diabetes mellitus or underlying immunosuppression is usually revealed. Fever, headache, nausea, and generalized weakness may be the initial complaints. Purulent discharge with or without epistaxis might be present with the onset of sinusitis, along with congestion and decreased sensation inside the nose. Nasal ulceration and necrosis are often reported. Facial symptoms include pain and numbness. Periorbital or retro-orbital pain, double or blurred vision, and partial or complete loss of vision in one or both eyes might progress to blindness. The involvement of the brain can manifest with altered consciousness, unstable gait, and/or seizures. Rare reports of rhino-orbital cerebral mucormycosis leading to mucormycosis of the retina misdiagnosed as coats disease in young patients exist.

Nasal or palatine findings of rhino-orbital cerebral mucormycosis include grey or reddish mucosa, which will progress to black areas of eschar as necrosis ensues. Eschar may be seen in the nasal septum, palate, eyelid, face, or orbital areas. The absence of eschar does not rule out rhino-orbital mucormycosis. Examination of the eyes may reveal tenderness and swelling of the eyelids, and evidence of orbital invasion in the form of painful proptosis. Ptosis, abscess of eyelids, and corneal numbness with edema are often noticed. A closer examination may reveal features of vitritis and/or endophthalmitis, and optic disc edema. Evidence of ophthalmoplegia (internal as well as external) with the latter being partial or complete, afferent pupillary abnormalities, fixed pupils, nystagmus, and a loss of vision secondary to fungal invasion or retinal artery occlusion can occur. Superior orbital fissure syndrome and superior ophthalmic vein thrombosis have been known to occur. A painless orbital apex syndrome has also been well described. Cranial nerve palsies with varying involvement of II, III, IV, V, VI, and VII nerves are common. Cerebral edema may lead to coma, and vascular occlusion progresses to cerebral infarcts. Cavernous sinus thrombosis with loss of vision is believed to be a characteristic feature of mucormycosis where cavernous sinus thrombosis without loss of vision is observed in bacterial infections.

Evaluation

A high index of suspicion in the appropriate clinical setting and a low threshold for further evaluation is imperative for early diagnosis and treatment, which significantly reduces morbidity and mortality. Laboratory findings are often non-specific and may show a high blood sugar reading with/without evidence of acidosis or ketoacidosis. An arterial blood gas report can rule out acidosis, dyselectrolytemia, and serum or urine ketone tests can screen for ketone bodies. A complete blood cell count can rule out a neutropenic state. Iron studies might be required to rule out suspected iron overload states in the form of low total iron-binding capacity and high ferritin values.

Computed tomography (CT) scan can demonstrate the nature and extent of soft tissue abnormalities in the sinuses, orbits, and brain. Mucosal thickening of sinuses along with opacification is often noted. Edema, inflammation, and infarcts in the brain are also detected. CT scan is advantageous over magnetic resonance imaging (MRI) due to its ability to detect bony erosion and necrosis though such findings indicate an advanced disease with a poor prognosis. A contrast CT scan also shows evidence of cavernous sinus thrombosis and enhancement of vessels. MRI is more helpful over the CT brain in clearly delineating early vascular invasion, intracranial spread, and also in the assessment for early perineural spread. A T2 weighted MRI with fat saturation sequences or short- TI inversion recovery (STIR) images is ideal.

Definite diagnosis is arrived at only by demonstrating the characteristic ribbon-shaped non-septate or pauciseptate, irregularly branching hyphae in the tissue specimens, and the finding is further strengthened by demonstrating thrombosis of the vessels signifying angioinvasion. Fresh tissue specimens subjected to PCR techniques often show high sensitivity and specificity in the diagnosis. The biopsy specimens could be fresh, frozen, and/or permanent. If safe and feasible, an arterial biopsy needs to be considered, if all the available tissue specimens come back negative for fungal hyphae despite a high degree of suspicion.

Tissue cultures are rarely positive, and extreme caution needs to be exercised to avoid the homogenization process, which will destroy the fragile hyphae. Fine mincing of the tissues is preferred over-grinding or crushing to preserve the hyphae. The culture positivity could be challenging at times since the differentiation between colonization versus contamination versus pathogenicity could be difficult. It is a well-accepted fact that Mucorales could be a colonizer in airways or could often contaminate microbiology specimens.

PCR techniques can help in identifying the fungal species in histologic specimens, even when the culture is negative. MALDI -TOF mass spectrometry can be used for species identification in culture specimens.[10][11][12]

Treatment / Management

Management of rhino-orbital cerebral mucormycosis is a medical as well as surgical emergency. Reaching an early definite diagnosis is pragmatically challenging, whereas the delay in initiating the treatment will further aggravate the morbidity and mortality. Early antifungal administration and extensive surgical debridement are carried out empirically whenever the possibility of rhino-orbital cerebral mucormycosis is suspected based on risk factors, clinical features, and/or radiologic findings. A three-pronged approach of reversal of immunosuppressive state, administration of IV antifungals, and extensive surgical debridement is usually undertaken.

The immune-suppressive factors are reversed by reversal of hyperglycemia, acidosis, hypoxemia, and dyselectrolytemia. Discussions are made with relevant experts regarding reducing or stopping of immunosuppressive agents. Granulocyte colony-stimulating factor may increase white cell count and may help to improve host defenses.

IV amphotericin (liposomal) is administered in the dose of 5-10 mg per Kg body weight per day. After initial treatment with IV amphotericin for several weeks along with the achievement of clinical improvement, the amphotericin is usually stepped down to oral posaconazole or isavuconazole. In the step-down therapy, oral posaconazole (delayed-release tablet) is given at a dose of 300mg twice daily on the first day, followed by 300 mg once daily. Oral posaconazole suspensions are not advisable since their bioavailability is inadequate and requires fatty meals for better absorption. Serum trough concentration of oral posaconazole needs to be monitored after a week of treatment and has to be kept at least above 1 mcg/ml. Oral isavuconazole is given at a dose of 200 mg (2 x 100mg capsules) thrice daily for two days, followed by 200 mg once daily.

IV or oral posaconazole or isavuconazole has been used as salvage therapy in certain patients who do not tolerate amphotericin or who do not respond to it. There is no evidence for the benefit of a combination of drug therapy in the form of combining amphotericin with an echinocandin at this stage. Although echinocandins do not have an in vitro activity against mucormycosis, R.oryzae, the commonest etiology for mucormycosis, expresses the target enzyme for echinocandins raising the theoretical possibility for a potential benefit. A retrospective study had observed a potential benefit for the above combination therapy in mucormycosis patients with brain involvement, though the conclusion is debatable.[13] Amphotericin is also used for local instillation or irrigation of debrided cavities in surgical management.(B2)

Surgical debridement includes extensive resection of infected and necrotic tissues as a part of source control and reduction of fungal load. Debridement also provides adequate tissue biopsy specimens for definite histopathologic confirmation. Dissection is usually continued until normal, well-perfused bleeding tissue is reached since mucormycotic tissues are less likely to bleed due to extensive thrombosis of vessels. Removal of the palate, nose cartilage, and orbit would cause significant disfigurement. The orbital involvement may need orbital decompression or exenteration. The role of routine orbital exenteration or the timing of exenteration is currently unclear, and cases with orbital involvement have also been successfully managed without exenteration.[14][15][16](B3)

Deferasirox and deferiprone are iron-chelating agents which do not act as a siderophore to the fungus. The studies have been small, and the results have been mixed. The DEFEAT mucor (Deferasirox-AmBisome Therapy) for Mucormycosis randomized trial showed increased mortality in patients who received a combination of amphotericin and deferasirox than those who received amphotericin alone.[17](B3)

The role of hyperbaric oxygen therapy is yet to be established, though hyperbaric oxygen is expected to alleviate severe hypoxia and acidosis, thereby inhibiting fungal multiplication.[18][19][20](B2)

Differential Diagnosis

A high degree of suspicion is a must and any delay in diagnosis with the subsequent delay in initiation of IV amphotericin can worsen morbidity and mortality.[21] The differential diagnosis may vary based on the presenting symptoms and signs and include:

• Allergic fungal sinusitis manifesting due to allergic reaction to dematiaceous fungi can produce a clinical picture of sinusitis with proptosis and rhino cerebral mass in immunocompetent hosts. But it never invades the tissue and often lingers for months to years. Many patients could have underlying asthma, allergy, mucosal polyps, and elevated IgE levels. The eosinophil-rich fungal mucin can erode into adjacent orbit and intracranial space. Bony erosions have been reported due to the pressure effect of thick mucin.
• Invasive aspergillosis in the form of rhino-orbital cerebral aspergillosis can produce a sinusitis-like picture with orbit and brain involvement and is increasingly reported in immunocompromised patients, and the outcome is extremely poor. IV amphotericin, along with surgical debridement, is the key management strategy.
• Painful eyes could be due to inflamed lids, conjunctivitis, or preseptal and orbital cellulitis.
• Migraine, gingival or dental infections, or long-standing sinusitis
• Subperiosteal hematomas, inflammatory pseudotumors, cavernous sinus thrombosis, and orbital neoplasms can produce protrusion of the eyeball
• Graves disease

Pertinent Studies and Ongoing Trials

DEFEAT Mucor was a small randomized double-blinded placebo-controlled study where 20 patients with proven or probable mucormycosis were randomly given IV liposomal amphotericin alone or liposomal amphotericin plus deferasirox for the first 2 weeks of therapy. The 90-day mortality was found to be significantly higher in the deferasirox group (82% versus 22%). Adverse events were similar in both groups. It is difficult to make strong conclusions given the population imbalances in this small phase II trial. The patients who received deferasirox were having hematologic cancers, neutropenia, or/and pulmonary involvement where the expected mortality is significantly high.[17]

Prognosis

The current survival of patients without brain involvement can be up to 50%-80% but the survival drops to 20% with brain involvement. The morbidity and mortality in rhino-orbital cerebral mucormycosis is determined by the reversibility of underlying risk factors, the time of initiation of IV amphotericin, and the time of initiation of surgical debridement. A delay in any of the above measures could affect survival.[21][22][23][24] No survival was reported before 1954 when amphotericin was not in use. Delay from diagnosis to treatment for more than 6 days is associated with poor survival.[18] The factors associated with poor survival include delay in initiation of treatment, hemiparesis or hemiplegia, sinus involvement on both sides, blood cancer, renal disorder, and deferoxamine treatment. The involvement of the brain, cavernous sinus, and carotid artery is usually associated with poor outcomes. The best prognosis is expected in those patients where the disease is confined to the sinuses. Patients with diabetes mellitus have better survival than patients with no history of diabetes mellitus or patients with CNS involvement. A recent meta-analysis observed no change in overall survival of rhino-orbital cerebral mucormycosis patients in the past 20 years although the mortality in patients with chronic renal disease is better (decreased from 52% to 19%), likely due to the use of liposomal amphotericin which is less nephrotoxic.[25] The study also found enhanced survival in patients with leukemia (from 13% to 50%). Facial necrosis and hemiplegia continue to be poor prognosticators.

There is significant associated morbidity in survivors. The duration of antifungal treatment can be approximately 7 months. Significant post-surgical disfigurement can psychologically impair many patients as well as relatives. Neurologic deficits of variable degrees could persist if there is a delay in treatment. Long-term prophylaxis may be required in certain immunosuppressed patients.

Complications

Major complications include cavernous sinus thrombosis, carotid artery obstruction, central nervous system infarction secondary to mycotic intravascular thrombosis, manifesting with hemiparesis, hemiplegia, coma, and death. CNS hemorrhage, abscess, inflammation, and blindness have been well reported. Airway obstruction from head and neck infections is possible.

The antifungal agent IV amphotericin is associated with significant nephrotoxicity and dyselectrolytemia, especially when given in the conventional amphotericin B deoxycholate form. Disfigurement following surgical debridement is common in survivors who often need psychological or psychiatric support. Residual sequelae of the disease occur in up to two-thirds of the patients.