|ORIGINAL RESEARCH PAPER
|Year : 2022 | Volume
| Issue : 1 | Page : 16-22
Post-COVID, neurosurgical interventions in rhinocerebral mucormycosis, an institutional experience
Samrendra Kumar Singh1, Dhananjay Kumar1, Brajesh Kumar1, Brajesh Kumar1, Niraj Kanaujia1, OP Gupta1, KM Jha1, Rakesh Kumar Singh2
1 Department of Neurosurgery, IGIMS, Patna, Bihar, India
2 Department of Otorhinolaryngology, IGIMS, Patna, Bihar, India
|Date of Submission||29-Aug-2021|
|Date of Decision||04-Feb-2022|
|Date of Acceptance||07-Feb-2022|
|Date of Web Publication||25-Feb-2022|
Department of Neurosurgery, IGIMS, Patna, Bihar
Source of Support: None, Conflict of Interest: None
Objective: Mucormycosis is an opportunistic, fungal infection, often lethal fungal infection which occurs in immunocompromised patients. However, in this second phase of COVID-19, we faced many post-COVID mucormycosis cases at our institution, IGIMS, Patna. We present our experience in eight patients with this condition who underwent neurosurgical interventions.
Patients and Methods: A prospective study for eight patients underwent neurosurgical interventions for rhinocerebral mucormycosis. All cases were operated by same surgeons from ENT and Neurosurgery.
Results: Total 42 patients referred for neurosurgical opinion, out of that eight patients taken for neurosurgical interventions. Out of 8, seven patients had COVID reverse transcription-polymerase chain reaction (RT-PCR) positive and treated with steroid and oxygen inhalation and one patient had fever but COVID RT-PCR was negative and treated at home with oxygen cylinder. All of them were treated with either liposomal amphotericin B/amphotericin B or oral posaconazole. Sinus surgery was performed in all eight patients by ENT surgeons, two underwent orbital exenteration by eye surgeon, five patients underwent open craniotomy for cerebral infection while in two patients, cerebral exploration done endoscopically. Six patients survived, while two patients died.
Conclusion: Patients with rhino-cerebral mucormycosis spreading outside the sinonasal cavity to the base of brain can be treated successfully to some extent by neurosurgical interventions.
Keywords: Covid-19, covid-19 RT-PCR, rhinocerebral mucormycosis, PNS- paranasal sinuses
|How to cite this article:|
Singh SK, Kumar D, Kumar B, Kumar B, Kanaujia N, Gupta O P, Jha K M, Singh RK. Post-COVID, neurosurgical interventions in rhinocerebral mucormycosis, an institutional experience. J Indira Gandhi Inst Med Sci 2022;8:16-22
|How to cite this URL:|
Singh SK, Kumar D, Kumar B, Kumar B, Kanaujia N, Gupta O P, Jha K M, Singh RK. Post-COVID, neurosurgical interventions in rhinocerebral mucormycosis, an institutional experience. J Indira Gandhi Inst Med Sci [serial online] 2022 [cited 2022 May 28];8:16-22. Available from: http://www.jigims.co.in/text.asp?2022/8/1/16/338363
| Introduction|| |
Mucormycosis is an infection caused by Mucorales fungi, within the class zygomycetes. The most common pathogens are from the genera mucorales, rhizopus, mucor, and absidia. Clinically, there are five forms of mucormycosis: rhinocerebral, pulmonary, gastrointestinal, cutaneous, and disseminated.
Rhinocerebral mucormycosis is the most common type and classically occurs in immunocompromised patients with diabetic ketoacidosis, neutropenia, uremia, burns, chronic corticosteroid therapy or severe malnutrition.,,
Inoculation occurs by inhalation; spores enter the nose and then spread to the paranasal sinuses and subsequently to the hard palate, orbit, meninges, and brain by direct extension.,
The diagnosis is made from clinical, radiological, microbiological, and histopathological findings.
The clinical manifestations of rhinocerebral mucormycosis are fever, headache, lethargy, decreased vision, ophthalmoplegia, and nasal or black palatal eschar. Death may follow in a few days, especially in undiagnosed and severely immunocompromised patients. Pathologically, the disease involves thrombosis, vascular invasion, ischemia, and infarction.
There are few published series of rhinocerebral mucormycosis containing sufficient patient numbers to enable analysis of predictors of survival.,, The purpose of this report is to share our experience with seven patients with neurosurgical interventions in rhinocerebral mucormycosis.
| Patients and Methods|| |
We prospectively studied the outcomes of patients admitted to Indra Gandhi Institute of Medical Sciences, Patna, in department of Otorhinolaryngology between June 2021 and July 2021. We analyzed the following data for all patients: age, gender, predisposing illness (es), clinical symptoms and findings, imaging results, pathological diagnosis, microbiological results, laboratory findings, surgical procedures, and treatment outcomes. Magnetic resonance imaging (MRI) scans had been obtained for all patients.
Biopsies were taken from all patients, for histopathological analysis and culture. Microbiological studies were performed on tissue biopsies inoculated onto Sabouraud's agar and incubated at 30°C. A sample was also examined under light microscopy in 20% potassium hydroxide. The histopathological diagnosis was primarily determined from tissue morphology, using hematoxylin and eosin (H and E), periodic acid Schiff, and Gomori's methenamine silver staining. In all cases, histopathological examination identified invasive, broad, thick-walled, nonseptate hyphae branching at right angles.
All patients received initial empirical treatment with liposomal amphotericin-B/amphotericin B or oral posaconazole.
Patients with localized cerebral fungal abscess with or without features of cerebral signs considered for neurosurgical interventions.
patients with disseminated cerebral involvement or involvement of cavernous sinuses, cerebral infarct or ischemia due to involvement of blood vessels by fungus were not taken for neurosurgical interventions. After histopathological diagnosis, surgical treatment was undertaken immediately.
| Results|| |
Total 42 mucormycosis patients referred from ENT department for neurosurgical opinion, 19 patients had skull base extension of mucormycosis without penetration of duramater so managed medically along with surgical debridement of paranasal sinus by ENT surgeons. Among remaining 23 patients, six patients had disseminated cerebral involvement, six patients had cavernous sinus involvement, and 3 patients had ischemic infarct (Total-15) and managed medically. Only 8 patients had localized cerebral involvement, so neurosurgical interventions done [Table 1].
|Table 1: Types of rhinocerebral mucormycosis referred to neurosurgical opinion and mode of treatment given|
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Out of eight patients operated, comprised five males and three females, with a mean age of 59.1 years (range: 30–75 years). Out of eight patients seven were diagnosed reverse transcription-polymerase chain reaction (RT-PCR) positive for COVID-19 about 1½ months back and admitted to hospital and treated with steroids and inhalational oxygen, while one was RT-PCR negative but had breathlessness and fever and treated with inhalational oxygen without steroids. All they recovered from COVID infection and discharged from hospital.
Out of eight patients, five (62.5%) were diagnosed case of DM before COVID infection and were on oral hypoglycemics, while two patients (25%) developed uncontrolled DM due to steroid during COVID treatment, they all were treated with insulin on sliding scale during treatment course in hospital and One patient (12.5%) remained euglycemic.
The common presenting symptoms in all patients were facial edema, facial pain, and nasal obstruction. On physical examination, findings were nasal discharge, gray or black nasal eschar, periorbital cellulitis, proptosis, ptosis, and altered consciousness.
On initial examination, 4 (50%) patients had cutaneous and/or palatal necrosis (one had both palatal and skin necrosis); of these, two (25%) had ophthalmoplegia and blurring of vision.
On neurological examinations, three (37.5%) patients had one or two episodes of seizure. Two (25%) patients had history of personality changes and one (12.5%) patient also had left sided hemiparesis and altered level of consciousness.
On nasal endoscopy, gray or black mucosa was observed on the middle turbinate in all patients. Four patients had large necrotic areas in the nasal cavity. Biopsies were taken from all patients. On direct light microscopy with potassium hydroxide (20 per cent), fungal microorganisms were seen for five of the eight (62.5%) patients [Figure 1]a and [Figure 1]b. All patients had a histopathological diagnosis of mucormycosis.
Computed tomography (CT) and MRI performed at initial evaluation, showed nonspecific sinusitis findings unilaterally in 6 (75%) patients and bilaterally in two (28.6%). Five (62.5%) patients had basifrontal cerebral mucormycosis while three (37.5%) had basitemporal mucormycosis [Figure 2]a and [Figure 2]b.
|Figure 2: (a) Showing magnetic resonance imaging of two patients with basifrontal and (b) basitemporal mucormycosis|
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Patients received a combination of medical and surgical treatment. In medical management, patients received either liposomal amphotericin B, plain amphotericin B or oral posaconazole. All patients underwent surgical debridement of sinuses by ENT surgeons (five endoscopic approach while three open approach). In two patients, exenteration of involved eyeball was done by eye surgeons.
Neurosurgical interventions were done in all eight patients. In six (75%) patients, craniotomy done and fungal abscess along with capsule removed, in two (25%) patients fungal abscess aspirated through endoscopic approach to basifrontal lobe through cribriform plates. None of them developed postoperative neurodeficit.
The overall mortality rate was 25% (two of eight). The age of one deceased patient was 75 years, and patient died on 3rd postoperative day due to uncontrolled diabetic ketoacidosis and electrolytes imbalance, the second patients' age was 46 years, postoperatively patient recovered and discharged, but on 3rd week, patient died at home. In surviving patients, the follow-up period ranged from 4 to 6 weeks [[Table 2] showing outcomes in patients operated for rhinocerebral mucormycosis].
|Table 2: Outcome of eight patients taken for neurosurgical interventions|
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| Discussion|| |
Mucor-mycosis usually develops in severely immunocompromised patients, e.g., those with diabetes mellitus and diabetic ketoacidosis. The other predisposing factors are hematological malignancy, chronic renal failure, severe burns, iatrogenic immunosuppression, and deferoxamine therapy.,,, However, in this COVID Era, we faced many cases of post-COVID mucor-mycosis, especially those treated with steroids and inhalational oxygen.
The disease usually commences in the nose and spreads by direct extension and intravascular propagation to involve the paranasal sinuses, orbit, cribriform plate, meninges, and brain. The clinician must entertain a high index of suspicion for the disorder when managing COVID recovered patients. It is important to be aware of early signs and symptoms.
The initial signs of infection are usually nonspecific. Facial edema, impaired vision and proptosis are the most common complaints.,, Other common symptoms are nasal obstruction or discharge, headache, epistaxis, and periorbital and/or facial pain. Orbital symptoms include loss of function of the second, third, fourth, and sixth cranial nerves, with resultant ptosis, proptosis, chemosis, orbital pain, mydriasis, and loss of vision.,,,
The physical findings in patients with rhinocerebral mucormycosis are often as subtle as the presenting symptoms. Nasal endoscopy enables effective examination of high risk patients, to detect any changes in mucosal color (i.e., white, gray or black) and/or texture (i.e., granulation or ulceration). Decreased mucosal bleeding or sensation should also alert the physician., One study observed necrotic nasal mucosa lesions in 80% of patients during the course of the disease. Head-and-neck examination should also be performed on all patients, in addition to endoscopic nasal evaluation.
The cranial nerves, afferent pupillary reflex, visual acuity, and facial sensation must be evaluated. Facial edema associated with rhinocerebral mucormycosis may be confused with periorbital cellulitis; however, the periorbital edema associated with rhinocerebral mucormycosis is soft, cool, and nontender, while the edema of cellulitis is firm, warm, and tender. Rhinocerebral mucormycosis produces a paralytic ptosis: the examiner can raise the eyelid easily, but the edematous ptosis of cellulitis resists active lid opening.
The oral cavity and oropharynx should also be examined. Unilateral gangrene and perforation of the hard and soft palates may occur due to involvement of the palatine arteries.,
The diagnosis of rhinocerebral mucormycosis is best made by histological evaluation of infected tissue. Infection usually begins along the middle or inferior turbinate. Biopsies can be taken from commonly involved areas such as the middle turbinate even in the absence of marked mucosal abnormality. Most of the patients presented in this study had evidence of necrosis on the middle or inferior turbinate.
Histologically, the fungi are characterized by broad, thick-walled, nonseptate hyphae that branch at right angles. There is a distinct proclivity for vessel wall invasion, which causes thrombosis with resultant ischemia and infarction. In contrast to most fungi, the etiological agents of mucormycosis are readily seen on H and E-stained tissue sections. Due to the possibility of contamination, the diagnosis should be verified histologically rather than by positive microbial cultures.,
Waiting for cultures may also delay the initiation of treatment. If a clinical picture of mucormycosis exists, positive direct smears may be sufficient to justify treatment.
CT and MRI scans may be suggestive of invasive mucormycosis, but they are often nondiagnostic. The most common CT findings include mild mucosal sinus thickening and extraocular muscle thickening. Later, findings may include frank abscess and sinus opacification (often without air–fluid levels), together with extension into the orbit, orbital apex, or brain. If angio-invasion is present, bone erosion may be absent even in the presence of progressive disease.
MRI evidence of sinus involvement may range from hyperintensity on T2-weighted scans to marked hypointensity on all sequences, often with obliteration of normal fat planes. The T2-weighted modality is typically more useful than T1-weighted scans for the evaluation of extension into the orbital apex, cavernous sinus, or brain. CT is considered best for the evaluation of bony involvement, while MRI is best for evaluating the cranial nerves and cavernous sinuses.,, Overall, CT and MRI may be most useful in assisting surgical planning for, rather than diagnosis of, rhinocerebral mucormycosis.
During our observations, CT scans showed nonspecific sinusitis findings unilaterally in six patients and bilaterally in two. In MRI, five (62.5%) patients had basifrontal cerebral mucormycosis while three (37.5%) had basitemporal mucormycosis. One more interesting findings were that all female patients showed right cerebral involvement while all males showed left sided involvement.
The mainstays of rhinocerebral mucormycosis therapy are reversal of the source of immunocompromise, high dose systemic amphotericin B, and surgical debridement of nonviable tissue.,,,
The predisposition of diabetes mellitus patients to rhinocerebral mucormycosis is probably related to hyperglycemia and acidosis. The acidotic environment is believed to promote both phagocytic dysfunction and a decrease in the iron-binding capacity of the blood. In previous reports, up to 60–80% of patients with mucormycosis had diabetes mellitus, and one-third to one-half of these diabetic patients were in diabetic ketoacidosis at the time of infection., Recent studies have found a decreasing incidence of diabetic ketoacidosis because the characteristic signs and symptoms of the disease are now well recognized by physicians. Patients with underlying diseases that take longer to correct are known to have a lower survival rate for mucormycosis.
During our observations, out of eight patients five (62.5%) were diagnosed case of DM before COVID infection and were on oral hypoglycemics while two patients (25%) developed uncontrolled sugar due to steroid during COVID treatment and one patient (12.5%) remained euglycemic. They all were treated with inhalation oxygen. The exact pathophysiology of mucormycosis in these post-COVID patients is still subject of debate and need more research.
Upon diagnosis of rhinocerebral mucormycosis, high-dose amphotericin B therapy should be instituted immediately. Because of the potential for nephrotoxicity, patients' renal function must be closely monitored.
Liposomal preparations of amphotericin B may allow the use of this antifungal agent while reducing systemic toxicity., In general, liposomal amphotericin B is reserved for clinically proven fungal infection in an immunocompromised patient with an elevated serum creatinine concentration (>2.5 mg/dl) or progression of fungal disease while receiving the maximal dosage of standard amphotericin B (1.25 mg/kg/day). Liposomal amphotericin B is safer but more expensive than conventional amphotericin B.
More extensive surgical treatment may include sinus surgery, wide resection of necrotic soft tissue and bone, and exenteration of the orbit if needed. The orbit is the portal of entry for infection of the central nervous system. The most difficult decision in the management of orbital mucormycosis is whether or not to undertake orbital exenteration. In general, the indications for orbital exenteration are ophthalmoplegia, proptosis, cranial nerve involvement, cranial involvement, and ocular involvement (e.g., central retinal artery occlusion).,,,
However, several reports have documented patient survival without exenteration, in the presence of clinical orbital involvement.,,
Patients with frontal sinus involvement are less likely to survive than those without such involvement. Palatal and facial necrosis are also negative factors for survival.
Aggressive surgical debridement to remove disease outside the sinonasal cavity rarely attains negative margins or improves long-term survival., Patients with intracranial spread are less likely to respond to radical surgery, and their prognosis is extremely poor., When radical surgery is considered, such patients should be appropriately counseled.
As per our observations, all the eight patients had involvement of frontal sinuses and intracranial spread. Two patients had palatal necrosis and two patients had complete ophthalmoplegia with proptosis and visual loss. Radical surgical procedures were performed (e.g., maxillectomy and orbital exenteration), in three patients. Endoscopic surgical debridement of sinuses was done in remaining five patients.
Craniotomy was done in six patients for radical excision of cerebral mucormycosis involving basifrontal or basitemporal lobe. While two patients with basifrontal mucormycosis, abscess drained endoscopically through cribriform plates [Table 3].
Our observations show that out of eight patients, six patients improved completely without any neurological deficit. One patient, who underwent endoscopic surgical debridement of maxillary, ethmoid and frontal sinuses along with endoscopic aspiration of basifrontal abscess through cribriform plate died on 3rd postoperative day due to diabetic ketoacidosis and electrolytes imbalance. Another patient with bilateral basifrontal mucormycosis recovered completely after surgery and discharged but died on 3rd week at home.
Irregular amphotericin B administration/nonavailability of liposomal amphotericin B was major challenges during the treatment. All patients discharged with tablet posaconazole 200 mg 6 hourly that tapered gradually with follow up.
| Conclusion|| |
Mucormycosis is a serious disease and may be fatal if not treated in time. A high index of clinical suspicion, early diagnosis, and immediate correction of underlying medical disorders are important factors for a favorable prognosis. Even in patients with rhino-cerebral mucor-mycosis that has spread outside the sinonasal cavity can be managed with aggressive medical and surgical therapy, especially if mucor-mycosis is localized in brain.
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| References|| |
Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol 1994;39:3-22.
Mohindra S, Mohindra S, Gupta R, Bakshi J, Gupta SK. Rhinocerebral mucormycosis: The disease spectrum in 27 patients. Mycoses 2007;50:290-6.
Sundaram C, Mahadevan A, Laxmi V, Yasha TC, Santosh V, Murthy JM, et al.
Cerebral zygomycosis. Mycoses 2005;48:396-407.
Yeung CK, Cheng VC, Lie AK, Yuen KY. Invasive disease due to mucorales: A case report and review of the literature. Hong Kong Med J 2001;7:180-8.
Luna JD, Ponssa XS, Rodríguez SD, Luna NC, Juárez CP. Intraconal amphotericin B for the treatment of rhino-orbital mucormycosis. Ophthalmic Surg Lasers 1996;27:706-8.
Blitzer A, Lawson W, Meyers BR, Biller HF. Patient survival factors in paranasal sinus mucormycosis. Laryngoscope 1980;90:635-48.
Peterson KL, Wang M, Canalis RF, Abemayor E. Rhinocerebral mucormycosis: Evolution of the disease and treatment options. Laryngoscope 1997;107:855-62.
Sims CR, Ostrosky-Zeichner L. Contemporary treatment and outcomes of zygomycosis in a non-oncologic tertiary care center. Arch Med Res 2007;38:90-3.
Gillespie MB, O'Malley BW Jr., Francis HW. An approach to fulminant invasive fungal rhinosinusitis in the immunocompromised host. Arch Otolaryngol Head Neck Surg 1998;124:520-6.
Hargrove RN, Wesley RE, Klippenstein KA, Fleming JC, Haik BG. Indications for orbital exenteration in mucormycosis. Ophthalmic Plast Reconstr Surg 2006;22:286-91.
Turunc T, Demiroglu YZ, Aliskan H, Colakoglu S, Arslan H. Eleven cases of mucormycosis with atypical clinical manifestations in diabetic patients. Diabetes Res Clin Pract 2008;82:203-8.
Pillsbury HC, Fischer ND. Rhinocerebral mucormycosis. Arch Otolaryngol 1977;103:600-4.
Bodenstein NP, McIntosh WA, Vlantis AC, Urquhart AC. Clinical signs of orbital ischemia in rhino-orbitocerebral mucormycosis. Laryngoscope 1993;103:1357-61.
Talmi YP, Goldschmied-Reouven A, Bakon M, Barshack I, Wolf M, Horowitz Z, et al
. Rhino-orbital and rhino-orbitocerebral mucormycosis. Otolaryngol Head Neck Surg 2002;127:22-31.
Gillespie MB, O'Malley BW. An algorithmic approach to the diagnosis and management of invasive fungal rhinosinusitis in the immunocompromised patient. Otolaryngol Clin North Am 2000;33:323-34.
Gravesen S. Fungi as a cause of allergic disease. Allergy 1979;34:135-54.
Alleyne CH Jr., Vishteh AG, Spetzler RF, Detwiler PW. Long-term survival of a patient with invasive cranial base rhinocerebral mucormycosis treated with combined endovascular, surgical, and medical therapies: Case report. Neurosurgery 1999;45:1461-3.
Ferguson BJ. Mucormycosis of the nose and paranasal sinuses. Otolaryngol Clin North Am 2000;33:349-65.
Jung SH, Kim SW, Park CS, Song CE, Cho JH, Lee JH, et al.
Rhinocerebral mucormycosis: Consideration of prognostic factors and treatment modality. Auris Nasus Larynx 2009;36:274-9.
Spellberg B, Edwards J Jr., Ibrahim A. Novel perspectives on mucormycosis: Pathophysiology, presentation, and management. Clin Microbiol Rev 2005;18:556-69.
Centeno RS, Bentson JR, Mancuso AA. CT scanning in rhinocerebral mucormycosis and aspergillosis. Radiology 1981;140:383-9.
Terk MR, Underwood DJ, Zee CS, Colletti PM. MR imaging in rhinocerebral and intracranial mucormycosis with CT and pathologic correlation. Magn Reson Imaging 1992;10:81-7.
Weir NW, Golding-Wood DG. Infective rhinitis and sinusitis. In: Kerr GA, MacKay IS, Bull TR, editors. Scott-Brown's Otolaryngology. 6th
ed. Oxford: Butterworth-Heinemann; 1997. p. 4/8/1-4.
Avet PP, Kline LB, Sillers MJ. Endoscopic sinus surgery in the management of mucormycosis. J Neuroophthalmol 1999;19:56-61.
Bonifaz A, Macias B, Paredes-Farrera F, Arias P, Ponce RM, Araiza J. Palatal zygomycosis: Experience of 21 cases. Oral Dis 2008;14:569-74.
Scheckenbach K, Cornely O, Hoffmann TK, Engers R, Bier H, Chaker A, et al.
Emerging therapeutic options in fulminant invasive rhinocerebral mucormycosis. Auris Nasus Larynx 2010;37:322-8.
Hejny C, Kerrison JB, Newman NJ, Stone CM. Rhino-orbital mucormycosis in a patient with acquired immunodeficiency syndrome (AIDS) and neutropenia. Am J Ophthalmol 2001;132:111-2.
Tarani L, Costantino F, Notheis G, Wintergerst U, Venditti M, Di Biasi C, et al.
Long-term posaconazole treatment and follow-up of rhino-orbital-cerebral mucormycosis in a diabetic girl. Pediatr Diabetes 2009;10:289-93.
Kohn R, Hepler R. Management of limited rhino-orbital mucormycosis without exenteration. Ophthalmology 1985;92:1440-4.
Anaissie EJ, Shikhani AH. Rhinocerebral mucormycosis with internal carotid occlusion: Report of two cases and review of the literature. Laryngoscope 1985;95:1107-13.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]