Rhino-orbital-cerebral mucormycosis in type 1 diabetes mellitus
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《美国医学杂志》
1 Department of Endocrinology, PGIMER, Chandigarh, India
2 Department of Radiodiagnosis, PGIMER, Chandigarh, India
3 Department of Otolaryngology, PGIMER, Chandigarh, India
Abstract
AIM: To describe the presentation and outcome of rhino-orbital-cerebral mucormycosis (ROCM) in adolescents with type 1 diabetes mellitus (T1DM). Methods: The medical records of six patients of T1DM with ROCM admitted between October 2001 to January 2004 were analysed. Results: The mean (± SD) age and duration of DM of these patients were 16.1±3.0 years and 26.3 ± 24.9 months respectively. Four patients had ROCM at presentation, while two developed it during their hospital stay when recovering from diabetic ketoacidosis. Proptosis (100%) and ptosis (100%) were the most common symptoms, and ophthalmoplegia (85%) and vision loss (85%) were the most common signs. Maxillary sinus (85%) was the commonest paranasal sinus to be involved. All patients received amphotericin B and had appropriate surgery except one. Four patients survived. Patients who had altered sensorium, facial necrosis, palatal perforation and cerebral involvement at presentation had poor outcome. Conclusion: High index of suspicion of ROCM in T1DM and combined approach with amphotericin B and appropriate surgery is rewarding.
Keywords: Diabetes mellitus; Ketoacidosis; Mucormycosis
Key messages
1. Ophthalmoplegia and vision loss are common morbidities of rhino-orbital-cerebral mucormycosis (ROCM).
2. Poor prognostic factors at presentation included sonsorium, facial necrosis, palatal perforation and cerebral involvement.
3. High index of suspicion and combined approach with amphotericin B and appropriate surgery is rewarding.
Mucormycosis is a rare but an acute and frequently fatal infection in young patients with type 1 diabetes mellitus (T1DM) with or without diabetic ketoacidosis (DKA).[1],[2] High fatality with this disorder is due to angioinvasive character of the mucor, thereby causing thrombosis of blood vessels and tissue necrosis. It can invade many organs of the body including sinuses, orbit, brain, kidney, gastrointestinal tract and rarely skin and subcutaneous tissues.[3],[4]
Diabetes is the most common predisposing factor for rhino-orbital-cerebral mucormycosis (ROCM).[1],[2],[5] Other predisposing factors include malignant hematological disorders, chronic renal failure (CRF), metabolic acidosis[3],[5] and deferoxamine and glucocorticoid therapy. ROCM originates in the nasal/sinus mucosae following inhalation of fungal spores and takes a rapidly progressive course extending to neighboring tissues including orbit, cavernous sinus and sometimes to the brain.
The clinical and biochemical predictors of poor prognosis and fatality with ROCM are not well known in young patients with T1DM due to its rarity. We report complete profile and outcome of six young patients with T1DM. To the best of our knowledge no Indian data is available on ROCM in T1DM in children.
Material and methods
Six consecutive patients with a diagnosis of ROCM with T1DM were analyzed from medical records. This study was conducted at Nehru Hospital, Postgraduate Institute of Medical Education and Research, Chandigarh from October 2001 to January 2004. Patients up to 19 years of age and having smear and/or histopathological evidence of mucormycosis were included in the study protocol.
All patients had T1DM and were receiving insulin for their metabolic control. Their clinical, biochemical, radiological (CT/MRI) and treatment profile (amphotericin B and appropriate surgical intervention) were recorded in a special data sheet and analyzed.
Results
The mean ± SD age of our patients was 16.1 ± 3.0 years and it ranged between 11 to 19 years. The mean ±SD duration of diabetes was 26.3 ± 24.9 months and it ranged from 2 to 60 months. Four patients had clinical features suggestive of ROCM at presentation, while two patients developed it during hospital stay while recovering from diabetic ketoacidosis. Only in one out of six patients, diagnosis of ROCM was suspected prior to hospitalization at our centre. Compliance with insulin injections and follow-up was poor in two patients. Out of six patients, two were literate and remaining were illiterate. The mean ±SD plasma glucose at presentation was 14.6 ± 6 mmol/L and it ranged between 8.3 to 25mmol/L. Only two patients had diabetic ketoacidosis (plasma glucose > 14mmol/L, pH ￡ 7.3, HCO3 ￡ 15 mEq/L and ketonuria) at presentation. None of them had micro- or macro-vascular complications. Fever and headache were recorded in three patients. Proptosis and ptosis were the most common symptoms seen in all patients. Ophthalmoplegia and vision loss were recorded in all patients except one. Altered sensorium and brain involvement Figure1 were observed in two and three patients respectively. Neck rigidity and hemiparesis were observed in two (#1,6) and one (#1) patient respectively. Palatal perforation and facial necrosis Figure2 were seen in one patient (#4). These observations are summarized in table1.
On imaging (CT or MRI), all patients had evidence of involvement of sinuses. Most commonly involved sinus was maxillary (85%) followed by ethmoid (68%), frontal (34%) and sphenoid (17%) sinuses Figure3. None of the patients had cavernous sinus involvement. Orbital involvement Figure4 was seen in all patients except one.
Mucormycosis was diagnosed by direct microscopy of aspirate/crusts from nasal or sinus mucosae in three, by histopathology in two and by both in two. Finding of aseptate hyphae with right-angled branching was considered as a criterion for mucor. Mucorales culture on Sabroud's media was performed in four patients, which grew Rhizopus arrizus in two patients.
All patients were treated with intravenous amphotericin B (1.0 to 1.5 mg/kg/day) with total doses varying from 2.5 to 3g. Appropriate surgery was performed in all except one who died before surgery, including rhinotomy in five and orbital exenteration in two patients. Mean ±SD duration of hospital stay was 24.3 ± 18.9 days and ranged between 9 to 60 days. Out of six patients, four survived and two died. The mean ±SD duration of follow-up in these patients was 18 ± 6 months.
Patients who died were illiterate, poorly compliant to treatment for diabetes and had altered sensorium as well as brain involvement in the form of massive cerebral infarct at presentation. Patients who survived had mean lag time of 2.5 days between onset of symptoms and initiation of amphotericin B. However, those patients who died had mean lag time of 6.5 days. Patients who died had mean blood glucose of 19.9 mmol/L at presentation compared to 13 mmol/L, in those who survived.
Discussion
Mucormycosis is an acute, often rapidly fatal fungal infection that is an important but preventable cause of death in young patients with DM who have poor glycemic control. In the majority of instances ROCM was associated with DM (60-80%) as seen in different series.[1],[2] Mucorales are ferrophilic fungi. Acidosis reduces the binding of iron to transferrin; in turn available free iron helps in proliferation of the mucorales.[6] Mortality from mucormycosis was 90% or higher until the introduction of amphotericin B and radical surgery, which has reduced the mortality remarkably.[7]
Present study is an observational analysis of ROCM exclusively in adolescents with T1DM. Our patients had severe and extensive ocular, naso- facial and central nervous system involvement, primarily because of low index of suspicion and delayed diagnosis. In the present study diabetic ketoacidosis/ketosis did not affect the outcome primarily because of extensive involvement and late presentation in the patients. Mean blood glucose at presentation possibly affected the survival outcome, however others have not observed it.[8]
Proptosis and ophthalmoplegia were observed in majority of our patients as compared to reports by Yohai et al[1] and Ferry et al.[2] Majority (83%) of our patients had vision loss, however it was less common in series of Ferry et al.[2] Vision loss was attributed to orbital vascular involvement. However, none had central retinal artery occlusion and endophthalmitis. Face and eyelid necrosis were observed in one patient as reported by Yohai et al.[1] Central nervous system involvement in form of infarct involving fronto-parietal lobe and cerebellum were observed in three patients whereas Yohai reported in 8% of their patients. Altered sensorium (34%) and meningeal signs (34%) were more common in our patients, however hemiparesis was comparable with others.[1]
Newer modalities of imaging (CT Scan, MRI) are useful in diagnosis as well as assessment of the extent of disease. All our patients had involvement of paranasal sinuses. Ferry et al[2] and Yohai et al[1] reported sinus involvement in 69% and 79% respectively. Cavernous sinus thrombosis appears as filling defect within the enhancing sinus or as a lateral convexity. None of our patients had cavernous sinus thrombosis. Orbital involvement was observed in form of proptosis, thickening of recti, and soft tissue mass in apex of the orbit. Out of six patients, four had unilateral and one had bilateral soft tissue mass in apex of the orbit.
The detection of aseptate hyphae with right-angled branching is pathognomonic of mucormycosis.[2] All our patients had tissue diagnosis either on smear and/or by histopathology. However, culture for mucorales was positive in only two patients.
Medical management alone is not effective because of poor drug delivery to the site of infection due to extensive vascular thrombosis.[9] All of our patients received amphotericin B and appropriate surgery was performed. Potentiation of amphotericin with other drugs (such as rifampicin, azoles, flucytosine) is of unproven benefit, but given the poor results with conventional therapy, this should be considered if susceptibility testing can be done in vitro with the patient's isolate to show synergy and exclude antagonism. Some have used rifampicin (10 mg/kg/day for 3 weeks) for its additive antifungal effect.
Factors associated with poor survival in ROCM include delay in diagnosis and treatment, hemiparesis, bilateral sinus involvement and facial necrosis.[1] Moye et al[8] reported that poor compliance, risk taking behavior and frequent hospital admissions were predictors of increased susceptibility to infection with mucormycosis in patients with T1DM. Poor survival in our patients was associated with altered sensorium, brain involvement, and high blood glucose at presentation, poor compliance to treatment, poor socioeconomic status and illiteracy. Survival outcome was not affected in our patients by ketoacidosis at presentation because of extensive disease and delayed presentation. Survival rate in our patients was 68% which was comparable to other series of ROCM.[1],[10]
References
1. Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino-orbital-cerebral mucormycosis: Major Review. Surv Ophthalmol 1994; 39: 3-22.
2. Ferry AP, Abedi S. Diagnosis and management of rhino-orbital cerebral mucormycosis (phycomycosis): a report of 16 personally observed cases. Ophthalmology 1983; 90: 1096-1104.
3. Parfrey AN. Improved diagnosis and prognosis of mucormycosis: A clinicopathological study of 33 cases. Medicine 1986; 65: 113-123.
4. West BC, Oberle AD, Chung KJK. Mucormycosis caused by Rhizopus microsporus var. microsporus: cellulitis in the leg of a diabetic patient cured by amputation: J Clin Microbiol 1995; 33: 3341-3344.
5. Kline HW. Mucormycosis in children: review of the literature and report of cases. Pediatr Infect Dis 1985; 4: 672-676.
6. Artis WM, Fountain JA, Delcher HK. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability. Diabetes 1982; 31: 109-114.
7. Marchevskey AM, Bottone EJ, Geller SA. The changing spectrum of disease etiology and diagnosis of mucormycosis. Human Pathology 1980; 11: 457.
8. Moye J, Rosenbloom AL, Silverstein J. Cinical predictors of mucormycosis in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2002; 15: 1001-4.
9. Smith JL, Stevens DA. Survival in cerebro-rhino-orbital zygomycosis and cavernous sinus thrombosis with combined therapy. South Med J 1986; 79: 501-504.
10. Abramson E, Wilson D, Arky RA. Rhinocerebral phycomycosis in association with diabetic ketoacidosis . Ann Intern Med 1984; 1060-1062.(Bhadada S, Bhansali Anil,)
2 Department of Radiodiagnosis, PGIMER, Chandigarh, India
3 Department of Otolaryngology, PGIMER, Chandigarh, India
Abstract
AIM: To describe the presentation and outcome of rhino-orbital-cerebral mucormycosis (ROCM) in adolescents with type 1 diabetes mellitus (T1DM). Methods: The medical records of six patients of T1DM with ROCM admitted between October 2001 to January 2004 were analysed. Results: The mean (± SD) age and duration of DM of these patients were 16.1±3.0 years and 26.3 ± 24.9 months respectively. Four patients had ROCM at presentation, while two developed it during their hospital stay when recovering from diabetic ketoacidosis. Proptosis (100%) and ptosis (100%) were the most common symptoms, and ophthalmoplegia (85%) and vision loss (85%) were the most common signs. Maxillary sinus (85%) was the commonest paranasal sinus to be involved. All patients received amphotericin B and had appropriate surgery except one. Four patients survived. Patients who had altered sensorium, facial necrosis, palatal perforation and cerebral involvement at presentation had poor outcome. Conclusion: High index of suspicion of ROCM in T1DM and combined approach with amphotericin B and appropriate surgery is rewarding.
Keywords: Diabetes mellitus; Ketoacidosis; Mucormycosis
Key messages
1. Ophthalmoplegia and vision loss are common morbidities of rhino-orbital-cerebral mucormycosis (ROCM).
2. Poor prognostic factors at presentation included sonsorium, facial necrosis, palatal perforation and cerebral involvement.
3. High index of suspicion and combined approach with amphotericin B and appropriate surgery is rewarding.
Mucormycosis is a rare but an acute and frequently fatal infection in young patients with type 1 diabetes mellitus (T1DM) with or without diabetic ketoacidosis (DKA).[1],[2] High fatality with this disorder is due to angioinvasive character of the mucor, thereby causing thrombosis of blood vessels and tissue necrosis. It can invade many organs of the body including sinuses, orbit, brain, kidney, gastrointestinal tract and rarely skin and subcutaneous tissues.[3],[4]
Diabetes is the most common predisposing factor for rhino-orbital-cerebral mucormycosis (ROCM).[1],[2],[5] Other predisposing factors include malignant hematological disorders, chronic renal failure (CRF), metabolic acidosis[3],[5] and deferoxamine and glucocorticoid therapy. ROCM originates in the nasal/sinus mucosae following inhalation of fungal spores and takes a rapidly progressive course extending to neighboring tissues including orbit, cavernous sinus and sometimes to the brain.
The clinical and biochemical predictors of poor prognosis and fatality with ROCM are not well known in young patients with T1DM due to its rarity. We report complete profile and outcome of six young patients with T1DM. To the best of our knowledge no Indian data is available on ROCM in T1DM in children.
Material and methods
Six consecutive patients with a diagnosis of ROCM with T1DM were analyzed from medical records. This study was conducted at Nehru Hospital, Postgraduate Institute of Medical Education and Research, Chandigarh from October 2001 to January 2004. Patients up to 19 years of age and having smear and/or histopathological evidence of mucormycosis were included in the study protocol.
All patients had T1DM and were receiving insulin for their metabolic control. Their clinical, biochemical, radiological (CT/MRI) and treatment profile (amphotericin B and appropriate surgical intervention) were recorded in a special data sheet and analyzed.
Results
The mean ± SD age of our patients was 16.1 ± 3.0 years and it ranged between 11 to 19 years. The mean ±SD duration of diabetes was 26.3 ± 24.9 months and it ranged from 2 to 60 months. Four patients had clinical features suggestive of ROCM at presentation, while two patients developed it during hospital stay while recovering from diabetic ketoacidosis. Only in one out of six patients, diagnosis of ROCM was suspected prior to hospitalization at our centre. Compliance with insulin injections and follow-up was poor in two patients. Out of six patients, two were literate and remaining were illiterate. The mean ±SD plasma glucose at presentation was 14.6 ± 6 mmol/L and it ranged between 8.3 to 25mmol/L. Only two patients had diabetic ketoacidosis (plasma glucose > 14mmol/L, pH ￡ 7.3, HCO3 ￡ 15 mEq/L and ketonuria) at presentation. None of them had micro- or macro-vascular complications. Fever and headache were recorded in three patients. Proptosis and ptosis were the most common symptoms seen in all patients. Ophthalmoplegia and vision loss were recorded in all patients except one. Altered sensorium and brain involvement Figure1 were observed in two and three patients respectively. Neck rigidity and hemiparesis were observed in two (#1,6) and one (#1) patient respectively. Palatal perforation and facial necrosis Figure2 were seen in one patient (#4). These observations are summarized in table1.
On imaging (CT or MRI), all patients had evidence of involvement of sinuses. Most commonly involved sinus was maxillary (85%) followed by ethmoid (68%), frontal (34%) and sphenoid (17%) sinuses Figure3. None of the patients had cavernous sinus involvement. Orbital involvement Figure4 was seen in all patients except one.
Mucormycosis was diagnosed by direct microscopy of aspirate/crusts from nasal or sinus mucosae in three, by histopathology in two and by both in two. Finding of aseptate hyphae with right-angled branching was considered as a criterion for mucor. Mucorales culture on Sabroud's media was performed in four patients, which grew Rhizopus arrizus in two patients.
All patients were treated with intravenous amphotericin B (1.0 to 1.5 mg/kg/day) with total doses varying from 2.5 to 3g. Appropriate surgery was performed in all except one who died before surgery, including rhinotomy in five and orbital exenteration in two patients. Mean ±SD duration of hospital stay was 24.3 ± 18.9 days and ranged between 9 to 60 days. Out of six patients, four survived and two died. The mean ±SD duration of follow-up in these patients was 18 ± 6 months.
Patients who died were illiterate, poorly compliant to treatment for diabetes and had altered sensorium as well as brain involvement in the form of massive cerebral infarct at presentation. Patients who survived had mean lag time of 2.5 days between onset of symptoms and initiation of amphotericin B. However, those patients who died had mean lag time of 6.5 days. Patients who died had mean blood glucose of 19.9 mmol/L at presentation compared to 13 mmol/L, in those who survived.
Discussion
Mucormycosis is an acute, often rapidly fatal fungal infection that is an important but preventable cause of death in young patients with DM who have poor glycemic control. In the majority of instances ROCM was associated with DM (60-80%) as seen in different series.[1],[2] Mucorales are ferrophilic fungi. Acidosis reduces the binding of iron to transferrin; in turn available free iron helps in proliferation of the mucorales.[6] Mortality from mucormycosis was 90% or higher until the introduction of amphotericin B and radical surgery, which has reduced the mortality remarkably.[7]
Present study is an observational analysis of ROCM exclusively in adolescents with T1DM. Our patients had severe and extensive ocular, naso- facial and central nervous system involvement, primarily because of low index of suspicion and delayed diagnosis. In the present study diabetic ketoacidosis/ketosis did not affect the outcome primarily because of extensive involvement and late presentation in the patients. Mean blood glucose at presentation possibly affected the survival outcome, however others have not observed it.[8]
Proptosis and ophthalmoplegia were observed in majority of our patients as compared to reports by Yohai et al[1] and Ferry et al.[2] Majority (83%) of our patients had vision loss, however it was less common in series of Ferry et al.[2] Vision loss was attributed to orbital vascular involvement. However, none had central retinal artery occlusion and endophthalmitis. Face and eyelid necrosis were observed in one patient as reported by Yohai et al.[1] Central nervous system involvement in form of infarct involving fronto-parietal lobe and cerebellum were observed in three patients whereas Yohai reported in 8% of their patients. Altered sensorium (34%) and meningeal signs (34%) were more common in our patients, however hemiparesis was comparable with others.[1]
Newer modalities of imaging (CT Scan, MRI) are useful in diagnosis as well as assessment of the extent of disease. All our patients had involvement of paranasal sinuses. Ferry et al[2] and Yohai et al[1] reported sinus involvement in 69% and 79% respectively. Cavernous sinus thrombosis appears as filling defect within the enhancing sinus or as a lateral convexity. None of our patients had cavernous sinus thrombosis. Orbital involvement was observed in form of proptosis, thickening of recti, and soft tissue mass in apex of the orbit. Out of six patients, four had unilateral and one had bilateral soft tissue mass in apex of the orbit.
The detection of aseptate hyphae with right-angled branching is pathognomonic of mucormycosis.[2] All our patients had tissue diagnosis either on smear and/or by histopathology. However, culture for mucorales was positive in only two patients.
Medical management alone is not effective because of poor drug delivery to the site of infection due to extensive vascular thrombosis.[9] All of our patients received amphotericin B and appropriate surgery was performed. Potentiation of amphotericin with other drugs (such as rifampicin, azoles, flucytosine) is of unproven benefit, but given the poor results with conventional therapy, this should be considered if susceptibility testing can be done in vitro with the patient's isolate to show synergy and exclude antagonism. Some have used rifampicin (10 mg/kg/day for 3 weeks) for its additive antifungal effect.
Factors associated with poor survival in ROCM include delay in diagnosis and treatment, hemiparesis, bilateral sinus involvement and facial necrosis.[1] Moye et al[8] reported that poor compliance, risk taking behavior and frequent hospital admissions were predictors of increased susceptibility to infection with mucormycosis in patients with T1DM. Poor survival in our patients was associated with altered sensorium, brain involvement, and high blood glucose at presentation, poor compliance to treatment, poor socioeconomic status and illiteracy. Survival outcome was not affected in our patients by ketoacidosis at presentation because of extensive disease and delayed presentation. Survival rate in our patients was 68% which was comparable to other series of ROCM.[1],[10]
References
1. Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino-orbital-cerebral mucormycosis: Major Review. Surv Ophthalmol 1994; 39: 3-22.
2. Ferry AP, Abedi S. Diagnosis and management of rhino-orbital cerebral mucormycosis (phycomycosis): a report of 16 personally observed cases. Ophthalmology 1983; 90: 1096-1104.
3. Parfrey AN. Improved diagnosis and prognosis of mucormycosis: A clinicopathological study of 33 cases. Medicine 1986; 65: 113-123.
4. West BC, Oberle AD, Chung KJK. Mucormycosis caused by Rhizopus microsporus var. microsporus: cellulitis in the leg of a diabetic patient cured by amputation: J Clin Microbiol 1995; 33: 3341-3344.
5. Kline HW. Mucormycosis in children: review of the literature and report of cases. Pediatr Infect Dis 1985; 4: 672-676.
6. Artis WM, Fountain JA, Delcher HK. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability. Diabetes 1982; 31: 109-114.
7. Marchevskey AM, Bottone EJ, Geller SA. The changing spectrum of disease etiology and diagnosis of mucormycosis. Human Pathology 1980; 11: 457.
8. Moye J, Rosenbloom AL, Silverstein J. Cinical predictors of mucormycosis in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2002; 15: 1001-4.
9. Smith JL, Stevens DA. Survival in cerebro-rhino-orbital zygomycosis and cavernous sinus thrombosis with combined therapy. South Med J 1986; 79: 501-504.
10. Abramson E, Wilson D, Arky RA. Rhinocerebral phycomycosis in association with diabetic ketoacidosis . Ann Intern Med 1984; 1060-1062.(Bhadada S, Bhansali Anil,)