What is Rhino-Orbital Cerebral Mucormycosis?
‘Zygomycosis’ was a term used to categorize a type of fungal infection caused by Zygomycetes. Zygomycetes are molds that look like ribbons, around 5-15 microns wide, with few or no divisions. They reproduce by forming zygospores, a type of spore. Eventually, these fungi were reclassified into two groups known as Mucorales and Entomopthorales.
Mucormycosis is a term specifically used to describe infections that progress quickly and are caused by fungi in the Mucorales group, though instances of it progressing slowly have been noted. This type of fungus is notorious for causing severe disease in patients with diabetes that isn’t well-managed, and in those with compromised immune systems. The disease can lead to significant health complications and even death. While it’s rare, there have been cases of mucormycosis in healthy individuals with strong immune systems. The most commonly seen manifestation of this disease is rhino-orbital cerebral mucormycosis, which affects the nose, eye socket, and brain.
Mucormycosis can cause a range of clinical conditions with involvement from the digestive system, skin, kidneys, and the central nervous system. However, the most common and severe manifestations usually involve the nose, eye socket, brain, and lungs. There have also been individual instances of mucormycosis mainly affecting the middle ear, parotid gland (a major salivary gland), mediastinum (the area between the lungs), heart and valves, uterus, urinary bladder, and lymph nodes. Widespread mucormycosis, where the disease is spread across the body, is rare and usually seen in patients with compromised immune systems and premature babies.
What Causes Rhino-Orbital Cerebral Mucormycosis?
Fungi that belong to the Mucorales order are found everywhere, often thriving on decaying plant debris and soil. The ones that frequently cause infections in humans include Rhizopus, Lichtheimia, Apophysomyces, Mucor, and Rhizomucor. However, it’s less common for humans to be infected by the Cunninghamella and Saksenaea fungi.
The type of fungus that causes an infection can vary around the world. Worldwide, the most commonly found species is Rhizopus arrhizus. But in Asia, Apophysomyces variabilis is most common, while in Europe, it’s often Lichtheimia species.
A review of 929 patients from 1940 to 2003 found that uncontrolled diabetes was the most common risk factor for these infections, followed by blood cancers and transplantation of stem cells or organs. A separate study in France found that nearly half of the patients had blood cancer, followed by diabetes and physical injuries.
The most common symptoms are related to a condition called rhino-orbital-cerebral mucormycosis, usually caused by a fungus called Rhizopus oryzae. This condition is most likely to occur in people with weakened immune systems due to uncontrolled diabetes, use of steroids, organ or stem cell transplants, chemotherapy, certain blood disorders, HIV, and malnourishment. Other risk factors include an excess of iron in the body, intravenous drug use, and certain surgical procedures. Rhino-orbital-cerebral mucormycosis has been reported in otherwise healthy individuals, but it’s rare.
These fungi grow quickly and release a large number of spores into the surrounding environment. People often breathe in these spores, which are then directed by the body’s natural defenses to the throat and are eliminated by the digestive system. These spores can also settle in the mouth, nose, throat, and sinuses but typically don’t cause disease in people with a healthy immune system that can effectively contain any infection.
When the immune system isn’t working properly, the spores can start to grow and invade the body’s tissues including blood vessels. This often starts in the nose and sinuses. If untreated, sinusitis can progress to affect the palate, orbit, and even the brain, and cause serious damage due to the tissue-destroying nature of the fungus.
Risk Factors and Frequency for Rhino-Orbital Cerebral Mucormycosis
Mucormycosis, or fungal infection, is a disease that isn’t easily tracked, which makes it hard to study. But from the data we do have, we know this disease not only affects more people now than before, but it also involves new types of fungi and impacts different groups of people. This has been noticed worldwide, but it’s especially true in Asia, particularly in India and China. The Leading International Fungal Education (LIFE) portal projects that there are roughly 10,000 cases worldwide each year, excluding India. When we factor in the data from India, the number jumps to 910,000 cases each year.
Case numbers vary globally; for instance, the rate in the United States is about 3 in every 1 million people, while in the United Kingdom it’s 0.9, and in Canada and Australia, it’s 1.2 and 0.6 respectively. Even within Europe, the rates differ greatly. For instance, Denmark sees 0.2 cases per million, while Portugal sees a striking 95 cases per million. Rhino-orbital cerebral mucormycosis is the most common form of this disease, making up about 40% of all cases. There seems to be no specific age or gender that is more susceptible to this disease.
- A review of 851 cases over 7 years shows the highest incidence in Europe (34%), followed by Asia (31%), North and South America (28%), Africa (3%), and Australia and New Zealand (3%).
- The unequal numbers could be attributed to under-diagnosis and under-reporting in Asia during the review period.
- Diabetes is the most prevalent risk factor worldwide for the rhino-cerebral type of mucormycosis. However, lung mucormycosis is more commonly found in individuals with cancers of blood cells or those who have undergone organ transplants.
- In Asia, new risk factors have emerged, including chronic kidney disease and post-tuberculosis health concerns.
- In France, a study named RetroZygo identified blood cancers as the major risk factor for mucormycosis (50% of cases), followed by diabetes (23%) and physical trauma (18%).
Signs and Symptoms of Rhino-Orbital Cerebral Mucormycosis
Rhino-orbital cerebral mucormycosis is a disease that often shows a range of non-specific symptoms that can vary greatly in severity. Often, people who get this disease have a history of conditions like diabetes or have a weakened immune system. Initial signs may include fever, headache, nausea, or feeling generally unwell. Additional symptoms may start with a runny nose, nosebleeds, a stuffy nose or a change in sensation inside the nose. Other nasal symptoms might include ulcers and dying tissue. Facial discomfort and numbness are also common.
Eye symptoms include pain around the eye, double or blurred vision, or even partial or total vision loss that can lead to blindness. In some people, the disease can also affect the brain, causing symptoms like altered consciousness, difficulty walking, or seizures. In rare cases, the disease can affect the retina in the eye and be mistaken for another condition called Coats’ disease.
- Fever
- Headache
- Nausea
- General weakness
- Runny nose or nosebleeds
- Change in nasal sensation
- Nasal ulcers
- Dying tissue in the nose
- Facial pain and numbness
- Eye pain
- Double or blurred vision
- Partial or total vision loss (may progress to blindness)
- Altered consciousness
- Unsteady walk
- Seizures
Physical examinations can reveal symptoms that include, but are not limited to, mucous membrane discoloration, skin death (necrosis), eyelid tenderness and swelling, and potentially infected interior parts of the eye. Notably, a lack of necrosis does not necessarily mean that the disease is not present. Patients can experience different symptoms like eyelid droopiness, corneal numbness, and swelling, among other things. Features of a more severe disease, such as inflammation inside the eye, swelling of the optic nerve, or signs of an infection inside the eye, may also be visible upon closer inspection.
A severe form of this disease can mean loss of muscle function in the eye, abnormal pupil responses, uncontrolled eye movements, and vision loss due to the fungal invasion or a blockage in the blood supply to the retina. Additionally, symptoms relating to syndromes of the eye region and conditions affecting the veins in the eye region can also occur. Furthermore, varying degrees of nerve damage can cause paralysis of the eye muscles. More serious complications can involve the brain, potentially leading to coma or stroke-like symptoms. Mucormycosis can also result in a blockage in a large vein at the base of the skull which can cause vision loss, often considered a characteristic of this disease.
Testing for Rhino-Orbital Cerebral Mucormycosis
When you’re not feeling well, your doctor will typically conduct various tests to diagnose the health problem correctly. This is even more important for conditions that have serious implications if not diagnosed and treated early. One such condition may require lab tests, which look for signs such as abnormal levels of sugar in the blood and excess acid in the body fluids. Your doctor might also recommend blood gas, electrolyte and ketone tests for further investigation.
Imaging techniques, like computed tomography (CT) scans, can also be used to look at your body’s tissues and structures for signs of illness. A CT scan does an excellent job at looking for abnormal changes in areas like your face sinuses, the orbits around the eyes, and on your brain. It can even determine whether an infection has spread to the bones. Unfortunately, such severe issues usually mean the condition has advanced, which might hinder recovery.
Magnetic Resonance Imaging (MRI) can also be used to see more subtle changes in the body. It can show if an infection has moved or spread along the nerves, or show early signs of blood vessel changes.
The final diagnosis, however, relies heavily on collecting tissue samples. These are examined under a microscope for specific abnormalities. For example, a tissue test may show the presence of abnormal growths called ‘hyphae’, which is a key feature of some diseases. If suspicious areas are safe to reach, a doctor might also look at a blood vessel sample if other tests aren’t clear.
While it can be beneficial to identify the type of organism in a disease process, it is important to know that in some cases, it can be difficult and even misleading. This is because some organisms can naturally exist in the body without causing an issue or may have contaminated the tissue sample during testing. Your doctors will take care in interpreting these results.
With the help of PCR techniques, even if the culture from tissue samples is negative, the cause of disease can be detected. Other fancy techniques such as ‘MALDI -TOF mass spectrometry’ are also used to identify the types of organisms in culture samples tested in the laboratory.
Treatment Options for Rhino-Orbital Cerebral Mucormycosis
Treating rhino-orbital cerebral mucormycosis, a type of fungal infection in the sinuses, eyes, and brain, requires immediate medical attention due to its severity. However, reaching a quick diagnosis can be difficult, and any delay in treatment can significantly increase the risks and potential complications.
Treatment generally starts as soon as the infection is suspected by relying on a combination of reversing the patient’s immune-suppressive state, giving IV antifungal drugs, and performing extensive surgical cleaning of the infected area.
To reverse the immune-suppressive state, this involves managing health conditions that weaken the immune system. This includes regulating blood sugar levels, correcting low blood oxygen, and balancing electrolytes in the bloodstream. Sometimes, doctors also consult with specialists to discuss reducing or stopping the use of medications that weaken the immune system.
To treat the infection, an IV antifungal medication called amphotericin is typically used. If the patient shows significant progress after several weeks of amphotericin treatment, the medication may be changed to either oral posaconazole or isavuconazole. Posaconazole and isavuconazole are alternative antifungal medications that can be used in patients who can’t take amphotericin or are not responding to it.
Alongside medical treatments, the infected and dead tissues are also surgically removed. This helps control the source of the infection and reduce the amount of fungus in the body. Notably, this surgery may cause significant changes in the patient’s appearance as it sometimes involves removal of parts of the nose, palate, or eyes.
If the eyes are involved, surgical interventions may also include orbital decompression or exenteration, both of which focus on relieving pressure or removing the eye and surrounding tissue. However, deciding when to perform these surgeries isn’t always certain, and some cases with eye involvement have been managed successfully without these procedures.
Other treatment options, such as iron-chelating drugs and hyperbaric oxygen therapy, still remain under investigation. Iron-chelating drugs, like deferasirox and deferiprone, remove excess iron from your body and might help fight infection, but their effectiveness for mucormycosis is still unclear. Hyperbaric oxygen therapy, which involves breathing pure oxygen in a pressurized room or tube, could theoretically help alleviate severe low oxygen levels and reduce acidity, thereby potentially inhibiting fungal growth. However, the definite benefit of this therapy is yet to be established for this condition.
What else can Rhino-Orbital Cerebral Mucormycosis be?
Being aware and suspecting a certain condition is crucial because delaying its diagnosis and treatment can lead to worse health outcomes. The potential conditions a doctor may consider when diagnosing a case can vary depending on the symptoms and signs presented. These could include:
- Allergic fungal sinusitis: This happens due to an allergic reaction to certain types of fungi. It can cause symptoms like sinusitis, eye bulging, and a mass in the nasal and cerebral area in people with normal immune system. This condition doesn’t invade the tissue and often lasts from months to years. Many affected individuals could also have asthma, allergies, nasal polyps, and high IgE levels. The thick, eosinophil-rich fungal substance produced can erode into the surrounding orbit and intracranial space, sometimes even causing bony erosions due to pressure.
- Invasive aspergillosis in the form of rhino-orbital cerebral aspergillosis: Like the previous condition, this can also mimic sinusitis with orbit and brain involvement, but it’s more common in patients with a compromised immune system. The outcome of this condition is usually quite severe. Treatment often involves IV amphotericin and surgical debridement. An affected individual may experience eye pain due to inflamed eyelids, conjunctivitis, or preseptal and orbital cellulitis. This can also be a consequence of migraine, gingival or dental infections, or chronic sinusitis.
- Other conditions like subperiosteal hematomas, inflammatory pseudotumors, cavernous sinus thrombosis, and orbital neoplasms can all lead to the protrusion of the eyeball (exophthalmos).
- Graves disease: This is an immune system disorder that can also cause exophthalmos.
What to expect with Rhino-Orbital Cerebral Mucormycosis
Patients without signs of brain involvement in a condition called rhino-orbital cerebral mucormycosis have a survival rate of about 50-80%. In cases where it spreads to the brain, survival rates unfortunately drop to about 20%.
The patient’s chances of surviving this condition rely on things like how quickly treatment began, if their risk factors (things that put them at higher risk of contracting the illness) can be managed, and how soon they were given a certain type of medication, IV amphotericin, and surgical intervention. Any delays in treatment can impact survival rates.
Interestingly, before 1954 when we starting using amphotericin, survival wasn’t reported at all. It’s also important to note that waiting longer than 6 days to start treatment after diagnosis is linked to a lower survival rate.
Certain patients may also have a lower survival rate due to their specific conditions or treatments, such as being diagnosed late, experiencing hemiparesis or hemiplegia (paralysis or weakness on one side of body), having two-sided sinus involvement, being diagnosed with blood cancer or kidney disease, or receiving deferoxamine treatment.
The prognosis is generally poor if the brain, cavernous sinus, and carotid artery are involved. However, if the disease remains confined to the sinuses, the prognosis is better. People with the history of diabetes tend to have a better survival rate compared to those without diabetes or those with CNS (central nervous system) involvement.
A recent study found that despite little change in the overall survival rate of these patients over the past 20 years, patients with chronic kidney disease have had improved outcomes. This is likely related to the use of newer medication, liposomal amphotericin, which is less harmful to the kidneys.
However, survivors can face long-term effects. Patients may have to undergo antifungal treatment for approximately 7 months. Post-surgery deformity can often cause emotional stress for patients and their families. Neurological deficits, meaning problems with the way their brain, nerves, or muscles function, may endure if the treatment gets delayed. In some cases, long-term preventative treatment might be needed for patients with compromised immune systems.
Possible Complications When Diagnosed with Rhino-Orbital Cerebral Mucormycosis
The serious complications that may arise include a blood clot forming in the cavernous sinus (a large vein at the base of the brain), blockage of the carotid artery (major blood vessels in the neck that carry blood to the brain), stroke as a result of a fungal infection causing a blood clot, resulting in partial paralysis of the body, full paralysis, coma, or even death. Other problems include bleeding in the brain, abscesses (pockets of pus), inflammation, and loss of sight. Blockage of the airway can also occur from infections around the head and neck.
The antifungal drug, amphotericin administered via IV is often linked with major damage to the kidneys and problems with electrolyte balance particularly when given in the traditional form of the drug. Disfigurement is commonplace among survivors post-surgery and there is often a need for psychological or psychiatric support. Lasting aftereffects of the disease can be seen in up to two-thirds of patients.
Possible Complications:
- Blood clot in the large vein at the brain’s base
- Blockage of major blood vessels in the neck
- Stroke from blood clots caused by a fungal infection
- Potential paralysis or coma
- Bleeding in the brain
- Abscesses or pockets of pus
- Inflammation and loss of sight
- Blockage of the airway from head and neck infections
- Kidney damage and electrolyte imbalance due to antifungal medication
- Physical disfigurement post-surgery needing psychological support
- Lasting aftereffects seen in up to two-thirds of patients
Preventing Rhino-Orbital Cerebral Mucormycosis
Rhino-orbital cerebral mucormycosis is a serious infection that affects the sinuses, eyes, and brain. Despite available treatments, it can lead to very severe health problems and even death. It’s important that patients and their families understand their risk factors and the signs of this infection to catch it early. This is because early diagnosis and treatment can prevent the condition from getting worse.
This infection is most likely to show up in people who have diabetes, especially if they’re having a hard time controlling their blood sugar. That’s why it’s so important for these patients to keep a close eye on their blood sugar levels. This wouldn’t just help them, but it could help reduce the number of new cases in the general public.
People who have weakened immune systems and their families should also be informed about the importance of seeking immediate medical help for any issues related to the ears, nose, or eyes–even if symptoms seem minor. This is particularly true for patients with neutropenia, a condition where you have low levels of a type of white blood cells, as they might not display normal signs of inflammation. So, both patients and their families should always be alert to even small changes in their health.
If a patient is diagnosed with rhino-orbital cerebral mucormycosis, it’s crucial to speak openly with the patients and their families about what to expect. This is a serious infection, and surgical treatment may lead to significant changes in appearance. Moreover, even after the surgery, up to two-thirds of the patients can experience some type of lasting effects on their nervous system.
