A case study on Rhino-Orbital-Cerebro- Mucormycosis

Yazhini. N

MEM Resident, Kauvery Hospital, Cantonment, Trichy

Background

Mucormycosis (previously called zygomycosis) is a serious but rare fungal infection caused by a group of molds called mucormycetes.

These molds/fungi live throughout the environment-they live in soil and in decaying organic matter, such as leaves, compost piles, or rotten wood. People get mucormycosis by coming in contact with the fungal spores in the environment.

Mucormycosis mainly affects people who have uncontrolled diabetes or immunocompromised patients. After the fungal spores are inhaled from the air they most commonly affect the sinuses or the lungs. It can also occur on the skin after a cut, burn, or other type of skin injury.

Types of Mucormycosis

Rhinocerebral (sinus and brain) mucormycosis is an infection in the sinuses that can spread to the brain. This is most common in people with uncontrolled diabetes and in people who have had a kidney transplant and are immune-suppressive.
Pulmonary (lung) mucormycosis is the most common type of mucormycosis in people with cancer, and in people who have had an organ transplant or a stem cell transplant.
Gastrointestinal mucormycosis is more common among young children than adults. Premature and low-birth-weight infants less than 1 month of age are at risk if they have had antibiotics, surgery, or medications that lower the body’s ability to fight germs and sickness.
Cutaneous (skin) mucormycosis occurs after the fungi enter the body through a break in the skin. This type of infection might occur after a burn, scrape, cut, surgery, or other types of skin trauma. This is the most common form of mucormycosis among people who do not have weakened immune systems.
Disseminated mucormycosis occurs when the infection spreads through the bloodstream to affect another part of the body. The infection most commonly affects the brain, but also can affect other organs such as the spleen, heart, and skin.

Types of fungi that most commonly cause mucormycosis

Several different types of fungi can cause mucormycosis. These fungi are called mucormycetes and belong to the scientific order Mucorales.

The most common types that cause mucormycosis are Rhizopus species and Mucor species. Other examples include Rhizomucor sp., Syncephalastrum sp., Cunninghamel la bertholletiae, Apophysomyces, Lichtheimia (formerly Absidia), Saksenaea, and Rhizomucor.

Case Presentation

A 65-year-old female, with Type 2 diabetes mellitus, systemic hypertension and dyslipidemia, on irregular medications, with also a history of coronary artery disease with severe LV dysfunction, presented to the emergency room with complaints of headache for 10 days, blurring of vision, ptosis of left eye and ophthalmoplegia, culminating in complete loss of vision since day one. The patient had a previous surgical history for cataracts in both eyes in 2015, with good visual rehabilitation. She had no history of fever.

On ophthalmic examination:

	R EYE	L EYE
Bedside vision	> 3/60	Denies perception to light
EOM	Free full range	Total ophthalmoplegia
Fundus	Normal study	Central retinal artery occlusion
Intra Ocular Pressure	Digitally normal	Digitally increased

Management and treatment

Patient was admitted in IMCU care for further management.

On evaluation:

MRI Brain and CT PNS showed: Sphenoid Sinusitis with intra-orbital extension, Left orbital proptosis with thrombosis of the Left Superior Ophthalmic Vein and Cavernous Sinus.

As advised by the neurosurgeon and cardiologist antiepileptics, anticoagulants and statins were added.

Patient underwent Endoscopic Sinus Debridement with Left medial maxillectomy and left orbital exentration under general anaesthesia.

Findings

Histopathology revealed features of Mucormycosis in periorbital soft tissue, ethmoid, sphenoid, bilateral middle turbinate and septum.

KOH mount from pus in the left nasal cavity, sinuses and exenterated orbital apex contents revealed many broad aseptate fungal hyphae with right angle branching suggestive of Mucormycosis.

Patient was the started on Inj. Liposomal Amphotericin 250 mg IV OD and monitored. Blood parameters showed Dyselectrolemia, acute kidney injury, UTI and high sugars. Urine cultures revealed growth of E. coli MDR. Antibiotics according to culture sensitivity Inj. Meropenem 1g IV TDS, and T. Nitrofurantoin 100 mg BD were started along with insulin infusion for sugar control with adequate electrolytes correction and fluid resuscitation. Diuretics, antiviral agent, anticoagulants, and anti-epileptics analgesics were continued.

Repeat MRI brain imaging showed minimal residual mucosal thickening in the right maxillary, ethmoid, and sphenoid sinuses, and disease not progressing compared to previous scans.

Sugars were controlled, insulin infusion was stopped and adjusted to fixed doses. The patient was then shifted to the ward, followed up and closely monitored.

The patient clinically improved over the course of time. After obtaining reviews from the Ophthalmologist, ENT and Neurosurgeon, the patient was discharged with T. Posaconazole 100 mg and antibiotics, anticoagulants, antiepileptics, diuretics continued till review.

Diagnosis:

A definitive diagnosis of mucormycosis typically requires histopathological evidence or positive culture from a specimen from the site of infection. Specimens from sterile body sites offer stronger evidence of invasive infection compared to colonization. Culture of non-sterile sites (e.g., sputum) may be helpful in patients with infection that is clinically consistent with mucormycosis.

Mucormycetes may be difficult to differentiate from other filamentous fungi in tissue; experienced pathological and microbiological assistance is often helpful. No routine serologic tests for mucormycosis are currently available, and blood tests such as beta-D- glucan or Aspergillus galactomannan do not detect mucormycetes.

DNA-based techniques for detection are promising but are not yet fully standardized or commercially available.

Histopathology

Smears can be examined under potassium hydroxide (KOH) wet preparation. Hematoxylin-eosin (HE) and Papanicolaou stains are used in scrape smears, and air-dried smears are examined with periodic acid Schiff (PAS) and May-Grnwald-Giemsa stains. Surgical sections are processed in paraffin and examined with HE 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-Gomoris methenamine silver staining demonstrates twisted septate hyphae.

Treatment

Early recognition, diagnosis, and prompt administration of appropriate antifungal treatment are important for improving outcomes for patients with mucormycosis. Amphotericin B, Posaconazole, and Isavuconazole are active against most mucormycetes. Lipid formulations of Amphotericin B are often used as first-line treatment. Medications active against Aspergillus such as Voriconazole are not active against mucormycetes, and there is some evidence to suggest that pre-exposure to Voriconazole may be associated with increased incidence of mucormycosis in some patients. In addition, surgical debridement or resection of infected tissue is often necessary, particularly for rhinocerebral, cutaneous, and gastrointestinal infections. Control of the underlying immunocompromising condition should be attempted when possible. The efficacy of other treatments such as hyperbaric oxygen therapy is uncertain but has been useful in certain situations.

IV Amphotericin B (liposomal) is administered in the dose of 5-10 mg per kg body weight per day.

Plain Amphotericin b deoxycholate is administered in the dose of 1-1.5 mg per kg body weight.

Amphotericin B lipid complex is administered in the dose of 5 mg per kg body weight.

Amphotericin B cholesterol sulfate complex is administered in the dose of 3-4 mg per Kg body weight.

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 300 mg 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 100 mg capsules) thrice daily for two days, followed by 200 mg once daily.

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. 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 diseases

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 are 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. A delay from diagnosis to treatment for more than 6 days is associated with poor survival. 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. 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.

Conclusion

A patient with Mucormycosis- Sphenoid Sinusitis with Intraorbital extension, Left orbital proptosis with thrombosis of Left Superior Ophthalmic Vein and Cavernous Sinus- and her management is discussed.

There was no association with COVID-19.

Dr. Yazhini. N

MEM Resident

A case study on Rhino-Orbital-Cerebro- Mucormycosis