Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Rhinocerebral Mucormycosis This fungus is ordinarily saprophytic, but can become an aggressive pathogen under the appropriate conditions, usually a serious predisposition in the host. It has been reported in healthy patients, but generally occurs in patients with debilitating disease. In these instances it is an aggressive and oftentimes fatal infection, seen most commonly in diabetics with flagrant ketoacidosis. Historical Review Mucormycosis can manifest itself in 6 distinct syndromes; the most common and that which I will devote my talk to today is a rhinocerebral form, seen in 38% of cases. The next 2 most common forms are the pulmonary form, or disseminated form. These are more commonly seen in patients with underlying hematologic malignancies during states of neutropenia. Patients who have underlying metabolic acidosis are also prone to develop mucor and 9% of cases are GI in nature . This is most commonly seen in underdeveloped countries with malnourished children who are prone to acidotic states from diarrhea and dehydration. A cutaneous form can be seen in burn patients. The rarest form is the isolated CNS form, which is rare without any underlying sinus disease or endocarditis. This is most commonly seen in IV drug users. Mucor is most always seen in patients with immunodeficient states. The most common risk factors is those patients with diabetes mellitus. These patients comprise about 70% of patients with mucor. These patients are usually ketoacidotic from poorly controlled disease. The second most common underlying predisposing factor is underlying renal disease, which is either chronic renal failure or those patients who are post-transplant and on desferroxamine, an iron or aluminum chelating agent. Other hematologic malignancies are predisposing conditions as are patients with steroid therapy from underlying immunosuppression after transplantation, other hematologic disorders. 4% of patients have no underlying disease. The most common risk factor is diabetes mellitus. Diabetics comprise about 60-80% of cases, especially those with poorly controlled disease. Mucor occur sin these patients because the acidotic and hypoglycemic environment is ideal for fungal growth. This environment also inhibits the effectiveness and affinity of macrophages. The second most common predisposition is renal disease – both transplant and patients with chronic renal failure. These patients also have a similar environment and are prone to similar states of acidosis, hyperglycemia and malnutrition, which also favor fungal growth. Patients with chronic renal failure also have reduced immunologic competence with lymphocytopenia and abnormal leukocyte function, specific defective chemotaxis. As I mentioned, desferroxamine is an important risk factor and as of 1991 there had been 49 dialysis patients on desferroxamine therapy with mucor that have been identified in the literature. The physiology behind this is that iron is a growth factor for the fungus. Normally transferrin binds serum iron in the body and this deprives the fungus and other pathogens of this nutrient. In order to use the iron, microorganisms, such as mucor, secrete iron-binding compounds known as siderophores. Iron, in the form bound by siderophores can be utilized by the fungus, while iron bound by transferrin cannot. Desferroxamine is a naturally occurring siderophores, so desferroxamine in its iron-chelated form provides iron to the mucoceles. This drug is also eliminated renally so its circulation time is prolonged in renal failure, increasing iron availability to the fungus. This drug also inhibits peroxidase production of free radicals, which is important for eradication of the fungus. About 4% of patients have no underlying disease, although a complete immunologic workup should be undertaken in these patients. Interestingly, there is no mortality difference in those patients without any underlying predisposition. One would hypothesize that those patients with AIDS would have an increased incidence of this disease, but this has actually not been the case. As of 1995, there had been about 10 cases reported in the literature, 8 of the 10 were IV drug users. The most common form was the cutaneous form. This disease can affect any age group. It has been found in patients from 2 months of age to 75-years old. There is no apparent racial, gender or occupational predilection. Incidence has risen for a number of reasons. One is the increased use of steroids and cytotoxic drugs associated with increased immunosuppression from transplantation. There is also increased recognition of the disease. So as far as pathophysiology, The disease process begins in the nose, paranasal sinuses, or palate. The nasal or oral mucosa is colonized with the airborne mucor spores. In the normal host there is a phagocytic response that prevents any infection. But in diabetics and those with impaired immune systems, this response is suboptimal. Diabetics and those patients with weakened neutrophils and macrophage response to the spores or an increased unbound iron present situations that favor fungal growth. Germination ensues and mucor thrives in this environment because it has a ketone reductase system that allows it to proliferate and grow in a glucose-rich acidotic ketotic environment. Mucor then has a strong predilection for growth into arteries, lymphatics and nerves. Vascular invasion produces a fibrin reaction and the development of a mucor thrombus, which occludes blood vessels. Vascular occlusion results in ischemia and infarction. Infarction produces the characteristic black necrotic eschars seen in these patients. This results in more acidotic tissue, which is ideal for fungal growth and is protected from IV antifungal agents. This vicious cycle continues allowing the fungal organisms to proliferate and damage more blood vessels. From the sinuses, the infection can spread rapidly to adjacent sinuses or to the orbit. Orbital findings are common in these patients and are due to ischemic necrosis of the orbital cranial nerves from fungal invasion of the orbital blood vessels. The infection can then spread intracranially by 2 main routes. The first is through the ethmoid sinus and the cribriform plate into the frontal lobe. The second is through the orbital apex directly under the cavernous sinus. In the process these patients, they will develop the characteristic orbital apex syndrome of ophthalmoplegia and 5 th cranial nerve symptoms which can lead to cavernous sinus thrombosis, internal carotid artery thrombosis, massive stroke, coma and death. Coma and death in these patients can also result from direct brain extension and cerebral vessel thrombosis. The disease process generally begins unilaterally and remains so. The clinical history is classically described as an acute fulminating infection with a violent and often catastrophic course unless recognized early and managed with aggressive surgical and medical treatment. The typical patient is a diabetic with a 1 to 7 day history of unilateral headache or facial pain, eye irritation with lacrimation, visual difficulties, nasal congestion, rhinorrhea or epistaxis. On physical examination the patient is generally more debilitated than one would expect for a simple acute sinusitis. There may be a purulent nasal discharge with a black necrotic material. The nasal turbinates will be black and crusting from dry gangrene. There may be necrotic ulcers on the palate from through and through passage to the nasal cavity or maxillary sinus. These patients also have orbital findings and can present with periorbital edema or cellulitis. This edema is classically described as being cool, soft and non-tender vs. a warm and more taught than tender edema of a cellulitis. Further invasion of the orbit results in proptosis and chemosis, leading to visual changes and ophthalmoplegia and subsequent nerve palsies associated with the orbital apex syndrome. This ptosis in these patients is described as paralytic; meaning the eye can be easily raised versus a ptosis of cellulitis, which is more resistant to opening. Further invasions to the central nervous system results in lethargy and increase in headache, the pain of which is usually out of proportion to the physical examination findings. Fever is the most common symptom, and other than the ocular symptoms, the most common symptoms or signs are the nasal necrosis or ulcerations and sinusitis. Laboratory studies are usually non-specific. Typically they will reveal a diabetic in ketoacidosis with underlying hyperglycemic state. A white blood cell count can reveal a neutrophilic leukocytosis with a mild bandemia. CSF studies are generally not helpful. They can reveal mild pleocytosis as well as elevations in glucose and protein. CSF cultures have never grown out before and blood cultures are rarely positive. Radiologic studies can be of benefit to document the extent of sinus disease, as well as the presence of orbital infiltrates. CT findings would include a thickened mucosa, or some sinus opacification. MR shows a hyperintense signal and is best used to document intracranial spread of disease and to visualize internal carotid or cavernous sinus thrombosis. MRI can also be helpful to detect early intracranial spread before a patient develops any symptoms of the disease. Making the diagnosis in these patients requires a high index of suspicion. The finding of nasal or palate necrosis would strongly suggest this diagnosis. A biopsy should be sent for frozen and permanent section. Nasal swab cultures should be avoided because these have a high rate of false positives. Mucor can inhabit the nasal cavities of healthy individuals. Histologically there is a thick wall of non-septate hyphae with branching at right angles and culture can identify the specific species. Here are some histologic pictures. Diagnosis can be made on H&E or frozen section, but these organisms are best seen on a silver stain. The key to diagnosis is not so much the presence of mucor itself, since it can a contaminant or colonizer in patients. The hallmark is arterial involvement. This organism has a predilection for invading arteries of all sizes with invasion in the elastic lamina. Although this disease is most commonly described as acute and rapid, there is a form of chronic disease. This is well documented here at Baylor in a paper by Drs. Harrill and Stewart in 1996, that included a literature review of 18 cases, including 2 seen at Ben Taub General Hospital. This phenomenon of the disease was first identified in 1964 in a 39-year-old patient with a 24-year history of a slowly progressive soft tissue destruction of the nose. They defined this entity as a patient with signs or symptoms lasting for greater than 4 weeks. About 5% of all cases of rhinocerebral mucormycosis present with a chronic form of the disease. The underlying patient demographics or the underlying predispositions are the same. There was an average of a 7-month median duration of symptoms prior to diagnosis, and it seemed that these patients were not toxic because of their disease. They seemed to coexist with it. Interestingly, along those lines, there was a high percentage of internal carotid and cavernous sinus involvement without significant cerebrovascular ischemia. Not surprisingly, because of the less indolent disease course, these patients have higher survival rate of 84%. The only patients who died with chronic disease had a recurrence. Treatment can be broken down into 4 main concomitant approaches. These involve rapid correction of the underlying host conditions, such as diabetic ketoacidosis, antifungal therapy, surgical debridement of devitalized tissue and the use of adjunctive therapies, such as hypobaric oxygen. The overall treatment should be guided by the severity of the disease. The mainstay of antifungal therapy is amphotericin B. It exerts its antifungal effects by binding to ergosterol, a component in fungal cell membranes. This alters membrane permeability. The important thing to remember about this drug is that it is fungistatic and not fungicidal. The dose should be rapidly advanced to the highest possible tissue levels, approximately 1 mg/kg dose per day. Patients generally receive a cumulative dose of 3 to 5 grams, and the duration of therapy depends on the extent of the infection and the clinical response, averaging around 6 weeks. The extended duration of treatment is because the drug is fungistatic and not fungicidal. The effectiveness of amphotericin B can compliment surgery by allowing demarcation of necrotic areas for a more limited surgical debridement. Amphotericin B can be a very toxic drug. Some of the common side effects include acute febrile reactions, azotemia, nephrotoxicity, wheezing and hypotension. Pretreatment of these patients with steroids, antihistamines or antipyretics can minimize some of these side effects. The most worrisome side effect is renal toxicity, which is generally rare in cumulative doses of less than 5 grams. These patients require frequent blood work. General treatment guidelines are that the BUN and creatinine can be allowed to arise to 50 and 3 respectively, before the dose needs to be reduced. Because this drug has the potential to be so toxic, there has been impetus to develop less toxic, but no less efficacious, formulations that can be used as a higher dose. A liposomal formulation has been developed that is associated with a lipid colloidal dispersion or lipid complex, rather that the bile salts allowing for a higher dosing with fewer side affect. Average doses using this formulation can reach 4 mg/kg per day. There are fewer side effects, specifically reduce renal toxicity. Pharmacologically the incorporation of the drug into liposomes, alters the pharmacological distribution, and enhances its delivery to fungus-infected organ and phagocytes, while the renal delivery is decreased. There have been a number of alternate delivery systems described in the literature, mostly to improve drug delivery in those patients with intracranial extension. These include local irrigation, intrathecal injection, intraventricular injection and even the application of impregnated sponges directly to infected cerebral tissue. Using the drug in this manner is not without side-effects including nausea, vomiting, meningitis or cranial nerve palsies. These risks must be balanced against the outcome of untreated disease. And also, the majority of these are case reports and anecdotal in nature. There have been case reports of survival with adjunctive use of ketoconazole, rifampin or tetracycline; but there has been no consistent in vivo or in vitro activity against mucor demonstrated with any of these drugs. These agents can be used, but should not be used alone in the treatment of this disease. Medical management alone produces poor outcomes compared to combined modalities. Surgery is a very important part of the treatment of these patients, largely because of difficulty of medically clearing disease in necrotic tissue. The principle of surgical treatment is to débride until one encounter normal bleeding tissue. The infected mucor tissue bleeds very little because of the vaso-occlusive effect of the fungus. Patients may need repetitive debridements. Iimaging studies can be helpful here to document the extent of disease after initial surgery. Surgical options include debridement with Caldwell Luc, medial maxillectomy, ethmoidectomies, sphenoidotomies, and even radical maxillectomy with orbital exenteration. One must analyze each case individually and weigh the morbidity of potential mutilating surgery with the potential benefits. Much has been written about an orbital exenteration in these patients. Because of the propensity for rapid invasion and local extension to the orbit, debridement has often included an orbital exenteration, which should be considered for a patient with an actively inflamed orbit and blind immobile eye. This usually indicates underlying retinal artery thrombosis, orbital apex necrosis, or even frank ocular invasion. Orbital exenteration usually is not indicated if a seeing eye is present, unless there is extensive fungal invasion identified. Some have even advocated that orbital exenteration may be helpful after intracranial spread has occurred by decreasing the overall fungal burden. Surgical treatment depends on the aggressiveness of the disease and the response to initial therapy. In those patients with less aggressive disease, the orbit can be spared. Endoscopic sinus surgery is also been described. The aim of ESS in these patients would be to remove only necrotic tissue and restore sinus drainage. Benefits of using endoscopic sinus surgery include improved visibility, minimal invasiveness, and less operative morbidity especially in some of these patients that can be acutely ill or who also need preoperative staging of the disease. ESS will need adjunctive procedures with it if there is extension of the mucor beyond the medial wall of the maxillary sinus or hard palate extension. The only report in the literature identified was a report from Taiwan and this involved 9 patients since 1985, treated with endoscopic sinus surgery. Six had ESS alone and 3 required additional procedures because of the spread of disease. All patients received amphotericin B, and 8 of 9 of these survived. Hyperbaric oxygen is an adjunctive therapy that has been prescribed. The principle behind this is that lengthy exposure and high pressures of oxygen are fungicidal in vitro. Hyperbaric oxygen should reduce tissue hypoxia and acidosis that occur with vascular invasion of mucormycosis. The use of hyperbaric oxygen may be able to salvage hypoxic marginally viable tissue. It can also augment the fungal effects of amphotericin B against other pathogens. The increased oxygen tension allows the fibroblasts to lay down new collagen providing a framework for new vessel formation and facilitates wound healing. The largest study is from Duke, by Ferguson in 1988, and this involved 6 patients since 1983 treated with surgery, amphotericin-B and hyperbaric oxygen; and they were compared with 6 patients prior to that time, treated only with surgery and medical therapy. All but one of these patients were diabetics, and the hyperbaric oxygen was initiated within 12 to 24 hours of diagnosis. They found that 4 of 6 patients that received hyperbaric oxygen recovered within 1 to 3 months; 2 of 6 survived without hyperbaric oxygen therapy. Hyperbaric oxygen therapy is not without its risks as it can be quite mutagenic, and can be associated with significant CNS and pulmonary toxicity. Prospective studies are precluded here because of the paucity of patients. This disease was once universally fatal. But now with aggressive medical and surgical management and early diagnosis, the mortality has been reduced to 20 to 30%. Blitzer et al in 1979 reviewed 179 patients identified in the literature up until that time. Prior to 1960, the patients did quite dismally. Once amphotericin B was prescribed and used more frequently, survival rose to about 70%. Specifically, they found that amphotericin B increased survival from 27% to 76% and that radical surgery increased survival from 57% to 87%. One thing that most researchers don’t talk about is the residual deficits that are left in these patients. They frequently focus on survival, but Blitzer found that 70% of these patients had significant residual deficits. The most common of these was complete blindness. Yohai et al in 1994 reviewed 200 patients treated since 1970. Those patients who received amphotericin-B within the first 6 days, had a survival of about 70-80%. Moving out to 7-12 days and 13 to 30 days from symptom onset, there was a linear decrease in survival. The same results are seen with those patients who were operated on or débrided earlier. They also showed that diabetics do about 40% better than non-diabetics. The reason for the easy correctibility of their underlying disease state versus those patients other general immune compromised states. This study also looked at the type of organism involved and found no significant difference in virulence. They also looked at the extent of sinus involvement and found that no statistically significant differences with the absolute number of sinuses involved. They did find that radiographic presents of bilateral sinus disease was a poor prognosticator. Specifically, those patients with unilateral disease had a 74% survival, while those patients with bilateral radiographic disease had a 32% survival. They identified these survival factors as factors being associated with the worst survival: hemiparesis or hemiplegia, bilateral sinus infection, renal disease or desferroxamine therapy, leukemia, and non-malignant hematologic disease. Orbital involvement is another important prognosticator that is common in these patients and can be seen 67-85% of cases – and, not surprisingly, one would guess these patients have a higher mortality because orbital involvement would indicate a more aggressive disease and spread to the orbit also provides a direct path for intracranial extension. Peterson et al showed that those patients who had orbital involvement in their series had a 33% mortality versus 14% mortality in those patients without orbital involvement. Many have looked at the effect of intracranial extension and whether it precludes surgical debridement or more aggressive management. Is aggressive debridement, including orbital exoneration and craniotomies combined with antifungal drugs and other adjunct therapies justified in these patients? Anand et al in 1992 reviewed the literature and found that 55% of cases since 1943 had intracranial extension. The mortality in these patients ranged from 50% to 67%. Since 1980, those patients who underwent craniotomies combined with orbital exenterations and sinus surgery had the best outcomes. But one must reflect on these data with caution because, even though it may appear here that craniotomies improve survival rates, oftentimes it is not documented if there is direct fungal invasion or abscess formation versus underlying inflammatory or ischemic events. Survival associated with a fungal abscess would be relatively less common. So, in conclusion, this is an aggressive disease with a formidable mortality rate. And the keys to survival are rapid diagnosis, correction of the underlying disease states, and prompt anti-fungal therapy combined with surgical debridement. Case Presentation: JC is a 34-year-old African American male with a seven day history of worsening headache. His past medical history is significant for insulin dependent diabetes mellitus for seven years. Of note, 10 days prior he was treated for an episode of diabetic ketoacidosis. He improved, but left against medical advice after refusing incision and drainage of a perirectal abscess. He denied any neck pain, diplopia, rhinorrhea, nausea, vomiting, or fevers. Past Medical/Surgical History: As above. Medications: Insulin, Levaquin, Amitryptilene. No known drug allergies. Social History: no tobacco, alcohol, or intravenous drug use. Physical Examination showed general-awake and alert, in no acute distress. Ears - tympanic membranes clear and intact; Eyes - pupils equal and reactive, extra-ocular movements intact; Nose - clear; Oral cavity/Oropharynx - clear; Neck - no lymphadenopathy or masses; Cranial nerves intact. Pertinent Labs: WBC- 42 with 97% neutrophils, glucose- 455 Hospital Course: The patient was admitted to the medical intensive care unit at BTGH on May 23, 2000 with a diagnosis of diabetic ketoacidosis. He was started on Maxipime and Flagyl empirically. He was transferred to the floor after 48 hours of treatment, which included hydration and insulin therapy with improvement in his glycemic control and leukocytosis. Examination by the Medicine service on hospital day six revealed a necrotic oral ulcer. Subsequent Otolaryngology consultation revealed necrosis and crusting of the lateral nasal wall, nasal floor and septum. Oral cavity examination revealed a necrotic black eschar involving most of the hard palate. Frozen section pathology revealed fungal non-septate hyphae and vascular invasion consistent with mucormycosis. The patient was taken to the OR that day for wide local debridement of the palatal and nasal mucosa and a septectomy. Amphotericn B therapy was also initiated. The patient was discharged on post-operative day seven. He was seen in follow-up in the otolaryngology clinic two weeks later, and his wounds were healing appropriately without evidence of infection. 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Yousem DM, Galetta SL, Gusnard DA, Goldberg HI. MR findings in rhinocerebral mucormycosis. J Comput Assist Tomogr 1989;13:878-882. Zapico ADV, Suarez AR, Encinas PM, Angulo CM, Pozuelo EC. Mucormycosis of the sphenoid sinus in an otherwise healthy patient. Case report and literature review. J Laryngol Otol 1996;110:471-473. Grand Rounds Archive | Department Home page BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2005 Baylor College of Medicine
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