1. SKULL BASE OSTEOMYELITIS: Fungal vs Bacterial infection ( C.C Blyth et al, Clin Microbiol Infect 2011;17:306-311 DR KAMLESH K DUBEY Deptt. Of Otorhinolaryngology AIIMS, New Delhi

2. INTRODUCTION  First described in 1959 by Meltzer and Kelemen  Skull-base osteomyelitis (SBO) is an uncommon condition  Associated with significant morbidity and mortality  Described most often as a complication of malignant otitis externa secondary to Pseudomonas aeruginosa infection  May also occur in the absence of malignant otitis externa and with pathogens other than Pseudomonas aeruginosa, including fungi.  Fungal SBO : Aspergillus, Scedosporium spp.

3. INTRODUCTION  RISK FACTORS: a)Increasing age b)Diabetes mellitus c)Microvascular disease d)Immunodeficiencies: primary / acquired  Fungal SBO has also occurred in the absence of these traditional risk factors

4. INTRODUCTION  ESSENTIALS OF MANAGEMENT OF SBO: I.Early diagnosis II.Identification of the causative pathogens III.Prompt initiation of appropriate antimicrobial or surgical therapies IV.Continuation of therapy for an adequate period

5. AIMS & OBJECTIVES  Compare the epidemiology and clinical characteristics of bacterial and fungal SBO  Aiming to identify unique risk factors and clinical associations

6. Material and Methods  Study design: retrospective study over 18 years(1990-2007).  Cases identified following interrogation of medical records using International Statistical Classification of Diseases and related Health Problems definitions  Otorhinolaryngology, Histopathology and Microbiology data bases were also queried for cases of SBO.  Approval for the study was obtained from Sydney West Area Health Service Human Research Ethics Committee

7. Material & Methods  For each patient clinical information was recorded on a standardized form and included: a)Patient demographics b)Comorbidities & predisposing factors within 90 days c)Likely source of infection : ear, sinuses, other d)Clinical features e)Results of microbiological and histopathological investigations f)Treatment g)Hospital length of stay h)Clinical outcomes

8. Materials & Methods Results of computed tomography(CT), magnetic resonance imaging (MRI) and bone scan Technitium-99m/gallium citrate (Ga)-67 were assessed by radiologist who was blinded to other results.

9. Materials & Methods  Definitions : A. Definite : skull base infection in patients with localizing symptoms/signs at presentation who had: i.Radiological or scintigraphic features indicative of bone erosion and/or infection. ii.Isolation and/or visualization of pathogen from affected bone(s) and surrounding tissue.

10. Materials & Methods Probable SBO: Infection in patients with localizing symptoms/signs with evidence of SBO on imaging studies, but from whom a pathogen was recovered from clinical specimens other than bone or tissue (e.g. ear swabs) or in whom a definitive response to antimicrobial therapy was evident. Primary source of pathogen: Assigned according to patient clinical features in context of accompanying microbiological and radiological results.

11. Materials & Methods Statistical analysis : I.Clinical data analyzed using SPSS, version 15.0.0 ( SPSS Inc., Chicago, IL USA). II.Variables associated with SBO caused by bacteria were compared with those associated with fungal SBO III.Analyses were also performed to examine risk factors, presenting symptoms, causative pathogen, and treatments administered associated with survival at 6 months. IV.Univariate analyses were performed using a Student’s t-test (for continuous variables) or Chi-square or Fisher’s exact tests( for categorical variables) V.p<0.05 was considered statistically significant

12. RESULTS  DEMOGRAPY: i.-From over 500 patients identified through search, 21 patients met the case definition of SBO. ii. 15 had proven SBO and six had probable infection. iii.Mean patient age was 58 years (range 26-80 years) iv.66.7% -male

13. RESULTS Predisposing factors: i.Diabetes mellitus was most frequent predisposing factor--- -12 patients ; 57% ii.Chronic otitis externa 33% iii.chronic sinusitis 29% iv.Immunosuppression 10% v.Trauma or surgery 30%

14. RESULTS  Median time to presentation: i.Bacterial - 26.3 weeks (4.2-28.5) ii.Fungal - 8.1 weeks (0.6-15.5)

15. RESULTS CLINICAL FEATURES BACTERIALFUNGALSIGNIFICANCE FEVER3 (30.0%)6 (54.5%)NS HEADACHE4 (40.0%)8 (72.7%)NS DEAFNESS7 (70.0%)2 (18.2%)p 0.03 EAR PAIN8 ((80.0%)2 (18.2%)p<0.009 EAR DISCHARGE8 (80.0%)1 (9.1%)p<0.002 SINONASAL PAIN1 (10.0%)8 (72.7%)p<0.008 FACIAL OR PERIORBITAL SWELLING 1 (10.0%)7 (63.6%)P 0.024 NASAL STUFFINES OR DISCHARGE 3 (30.0%)9 (81.8%)p 0.03 CRANIAL NERVE INVOLVEMENT 5 (50.0%)5 (45.5%)NS EYE/ORBIT INFECTION 02 (18%)- BRAIN PARENCHYMAL INFECTION 01 (9%)-

16. RESULTS SITE OF INFNBACTERIALFUNGALSIGNIFICANCE EAR DISEASE8 (80.0%)2 (18.2%)p<0.02 SINUS DISEASE 09 (81.8%)p<0.04 TRAUMATIC/U NCERTAIN 2 (20.0%)0NS

17. RESULTS THERAPY RECEIVED BACTERIALFUNGALSIGNIFICANCE SURGERY5 (50.0%)11 (100%)p<0.02 ANTIBACTERI AL THERAPY 10 (100%)6 (54.5%)P<0.04 ANTIFUNGAL THERAPY 011 (100%)p<0.001 HYPERBARIC O2 THERAPY 02 (18.2%)NS

18. RESULTS OUTCOMEBACTERIALFUNGALSIGNIFICANCE SURVIVAL(6 MONTHS) 7/7 (100%)7/11 (63.7%)NS

19. DISCUSSION  SBO is uncommon infection  Complication of uncontrolled otogenic, odontogenic or sinus infection  Large adequately powered epidemiological studies have not been published  Present study, using strict case definitions for SBO, reveals that fungi accounted for a significant proportion : approx. 50% of SBO  Significant morbidity of SBO in the present study is consistent with previous reports

20. DISCUSSION  Almost half (48%) of patients had persistent cranial nerve abnormalities, other reports 21-43%.  Extension into brain uncommon.  Cerebral involvement has been associated with high mortality in reported cases despite surgical intervention.  As reported in other studies, diabetes mellitus and chronic ear disease.  Confirmation of underlying chronic sinusitis as a risk factor for SBO is required.

21. DISCUSSION  Otogenic Pseudomonas aeruginosa infection accounted for 50% of bacterial SBO.  SBO complicating malignant otitis externa is almost uniformly caused by this bacterium  Other bacteria and fungi are also important causes of SBO  Fungal SBO is increasingly reported in literature  Apparent rise reflect apparent rise in use of immunosuppressive therapy  Importantly however fungal SBO may also occur in immunocompetent individuals

22. DISCUSSION  Most cases of fungal SBO has been due to Aspergillus or Scedosporium spp., reportedly arising from contiguous spread of ear infection  Authors observed that fungal SBO occurred primarily as a result : i.Underlying sinus infection ii.Zygomycetes were most frequent pathogen  Reasons fro relative prevalence Zygomycetes not readily apparent but are of interest  Zygomycetes are well known pathogens of invasive fungal sinus

23. DISCUSSION  Although not statistically significant, majority >70% fungal SBO patients had diabetes (known risk factor for zygomycetes)  There may be differences in clinical risk factors and associations for bacterial and fungal SBO

24. DISCUSSION Fungal SBO features:  More likely to have underlying chronic sinus disease  Symptoms attributable to invasive sinus infection a. Sino-facial pain b. Periorbital swelling c. Nasal stuffiness/discharge  Absence of purulent ear discharge was a sensitive (91%) predicator of underlying fungal SBO  Clinical failure with antibacterial therapy should also promt similar considerations

25. DISCUSSION TREATMENT OPTIONS:  Antimicrobial therapy i.Because P. aeruginosa infection predominates in most case series of bacterial SBO ii.Initiation of antibiotics with activity against P. aeruginosa is appropriate pending microbiological diagnosis iii.Because zygomycetes were responsible for >50% of fungal SBO use of regimens including high-dose amphotericin B formulations is advised pending definitive diagnosis

26. DISCUSSION TREATMENT OPTIONS: ROLE OF SURGERY: I.Likely influenced by pathogen II.Early surgery is associated with improved survival in patients with improved survival in patients with zygomycosis III.Aggressive surgical debridement is recommended in fungal SBO IV.Probably unnecessary in patients with bacterial SBO

27. Skull base osteomyelitis: diagnostic and therapeutic challenges in atypical presentation( A. Singh et al. Otolaryngology head and neck surgery volume 133, Issue 1, july 2005;121-125  Objectives : To document diagnostic and management difficulties in masked skull base osteomyelitis secondary to malignant otitis externa, emphasis on establishing diagnostic criteria in recurrence.  Study design: Retrospective analysis of 3 cases of inadequately treated malignant otitis externa in elderly diabetic individuals leading to recurrence and atypical manifestations of skull base osteomyelitis on contralateral side with or without multiple cranial nerve involvement.

28.  Result : i.Two of 3 cases died despite aggressive treatment ii.One case treated successfully with combination of antipseudomonal microbial drugs for 8-12 weeks and hyperbaric oxygen therapy iii.Major complications observed were: a. thrombosis of lateral sinus and IJV thrombosis b.Meningitis c.Ophthalmoplegia d.Blindness e.Cervical spine erosion f.Paralysis of all cranial nerve except 1 st C.N

29. Management of osteomyelitis of anterior skull base and craniovertebral junction (Yadranko Ducic. Otolaryngology Head Neck Surg 2003;128:39-42)  Objectives : To determine patient demographics, identify predisposing factors and determine efficacy of treatment for nonotologic osteomyelitis of skull base and craniovertebral junction  Study design: All patients with biopsy proven diagnosis of osteomyelitis of skull base treated by author from 1997 through 2001 were retrospectively evaluated

30.  Results : i.Six patients were identified on review ii.Average age of presentation was 56.7 years (38-70 yrs.) iii.All except one had immunocompromising condition (DM, HIV, Steroid use) iv.Most presented with neurologic deficits associated with a destructive lesion of osseous skull base v.Aggressive debridement of involved bone enabled through use of broad field standard skull base approaches were associated with clinical resolution in each case vi.Systemic antibacterial/antifungal therapy and medical optimization remain important adjuncts in treatment of this group of patients vii.In the absence of any persistent neurologic deficit and in the presence of a normal ESR, reasonable to discontinue systemic therapy after 6 weeks viii.Persistent elevation of ESR or a return of symptoms would mandate repeat imaging, including gallium scanning

31.  Conclusion: i.Nonotologic osteomyelitis of skull base and craniovertebral junction is a locally aggressive disorder causing lytic destruction of skull base bone often with underlying dural enhancement ii.Systemic immunocompromise i.e. is usually noted iii.Aggressive surgical debridement of all affected bone achieved through broad field exposure afforded by modern skull base approaches iv.Culture guided antifungal or antibiotic therapy

32. Cranial nerve involvement in malignant external otitis: implication for clinical outcome (Mani N et.al. Laryngoscope.2007 May;117(5):907-10)  Objective : To determine whether cranial nerve involvement in malignant external otitis affects or predicts clinical outcome in terms of morbidity and mortality Methods: Diagnosis of malignant otitis externa established in 23 patients based on inclusive criteria: i.Severe pain ii.Otitis externa refractory to conventional treatments iii.Diabetes mellitus iv.Pseudomonas aeruginosa infection detection

33.  Data analysis: Retrospective analysis of hospital records

34.  Results : i.Ten of 23(43.5%) patients showed cranial nerve involvement ii.Cranial nerve affected were: a. facial nerve (6/10) b.Lower cranial nerves (combination of IX,X,XI,XII) c.Extended nerve palsy(VI,VII,IX,X,XI)(1/10) d.13/23(56.5%) patients displayed no cranial nerve involvement e.All patients treated with long term, high dose antibiotic treatment dependent on the microbiological findings

35.  Conclusions: i.All patients with lower cranial nerve palsy recovered normal function ii.Facial nerve palsy was significantly less likely to improve by medical treatment iii.Cranial nerve involvement did not affect patient survival rate under an optimized medical treatment

36.  Objectives: To review presentation, microbiology, and long term results of treating otogenic cranial base osteomyelitis to develop a prognosis based classification system  Patients & Method: i.38 patients with otogenic cranial base osteomyelitis treated between 1989-2002 ii.Patient demographics, presentation, pathogens, details of therapy, and disease specific survival were recorded iii.Patients stratified using Tc-99 single photon emission computerized tomography(SPECT) at presentation in to 4 grades: grade I- mild uptake, grade II- focal mastoid/temporal bone uptake not reaching midline grade III- petrous temporal bone uptake reaching midline grade IV- uptake crossing midline, involving contralateral temporal bone Otogenic cranial base osteomyelitis: a proposed prognosis-based system for disease classification (Lee S. et.al. Otol Neurotol.2008 Aug;29(5):666-72

37.  Results : i.27/38 men ii.Average age at presentation 65+/- 16 yrs iii.Mean adjusted charlson comorbidity score was 5 & 63% of patients were diabetic iv.Most common presenting symptoms: pain, otorrhea v.8 patients had cranial nerve neuropathy vi.Antibiotics were administered for 161 days, 6 patients had concomitant surgery vii.Avg. f/u was 33 months viii.3 year disease-specific survival was 76%

38. Results : -Univariate predictors of survival were: i.SPECT grade ii.Fungal/mixed infections iii.Charlson score iv.Immune compromise v.Cranial nerve neuropathy -only independent predictor of survival on multivariate Cox regression was SPECT stage at presentation Conclusion : Cranial base osteomyelitis is associated with significant morbidity, mortality and requires prolonged treatment Long term outcome can be predicted from initial SPECT scan

39. Outcomes of malignant external otitis: survival vs mortality (Chen CN. Acta Otolaryngol.2010;130(1):89-94)  Objectives : To analyze factors that affect survival of patients with MEO in todays era of advanced antibiotics  Patients & Methods: Patients with a diagnosis of MEO from 1993-2005 were collected  Results: i.26 patients with mean age 63.7±10.2 years were included ii.All had history of diabetes mellitus iii.Most frequent pathogens: Pseudomonas aeruginosa 26.9% Klebsiella pneumoniae 19.2% Fungus 15.4%

40.  Results cranial nerves were involved in 11 patients Facial nerve was most frequently(38.46%) involved Complications such as intracranial involvement were noted Mastoidectomy performed in 12 patients Total of five patients died  Conclusion: i.Mortality was not related to age, sex, degree of glucose intolerance, duration of diabetes mellitus, microorganism, comorbid disease or involvement of a single cranial nerve ii.Intracranial involvement and multiple cranial nerves involvement were correlated with mortality

41. Malignant otitis externa (Matthew J. Carfrae. Et.al. Otolaryngol Clin N Am.41;(2008):537-549  Results : i.With current cranial nerve involvement does not preclude cure ii.Patient may have incomplete recover of facial nerve function iii.Lower cranial nerves exhibited good recovery  Conclusion : Poor prognostic factor include i.Fungal infection ii.MRI finding of middle cranial fossa and foramen magnum dural inhancement

42. Final Discussion  Skull base osteomyelitis: infection spread to skull base beyond external auditory canal  Diabetes mellitus remains most important associated condition: Because of associated: i.Endarteritis ii.Microangiopathy iii.Small vessel obliteration Pathophysiology: Pseudomonas aeruginosa has ability to invade vessel walls and cause a vasculitis with thrombosis and coagulation necrosis of surrounding tissue Cellulitis->chondritis->osteitis->osteomyelitis

43.  Pathophysiology: i.Infection from EAC spreads to skull base through fissures of santorini, small perforations in cartilaginous portion of EAC along floor of canal ii.Compact bone of skull base becomes replaced with granulation tissue leading to bone destruction iii.Progressive spread of infection to skull base foramina causes cranial neuropathies iv.Most common nerve involved Facial nerve because of proximity of stylomastoid foramen to EAC v.Nerves of jugular foramen next to get affected vi.More medial spread to petrous apex can affect abducens and trigeminal nerves & further medial optic nerve vii.Spread of infection to sigmoid sinus can lead to septic thrombosis of sigmoid and internal jugular vein viii.Intracranial complication: meningitis, cerebral abscess

44.  Levenson’s criteria: i.Refractory otitis externa ii.Severe nocturnal otalgia iii.Purulent otorrhea iv.Granulation tissue in external canal v.Growth of pseudomonas aeruginosa from EAC vi.Presence of diabetes and other immunocompromised state vii.Positive bone scan

45. Cohen D, Fredman P. The diagnostic criteria of malignant external otitis. J Laryngol Otol 1987;101:216-21 A.Obligatory : i.Pain ii.Edema iii.Exudates iv.Granulations v.Microabscess(when operated) vi.Positive bone scan vii.Failure of local treatment after >1week treatment viii.Possibly pseudomonas in culture

46.  Cohen’s diagnostic criteria: B. Occasional : i.Diabetes mellitus ii.Cranial nerve involvement iii.Positive radiograph iv.Debilitating condition v.Old age

47. Staging system  Corey (1985) i.Stage I: infection ii.Stage II: involving cranial nerves iii.Stage III: intradural spread  Benecke (1989): i.Stage I: Necrotizing otitis externa: soft tissue infection ii.Stage II: limited skull base osteomyelitis iii.Stage III: extensive skull base osteomyelitis with involvement of occipital bones, facial bones, and contralateral extension

48. Staging System  Levenson’s  Davis’s staging system(1992)  Dr A. Thakar, D. A. Tandon, S. Bahadur, S. K. Kacker (1996)

49.  Scott-Brown’s Otorhinolaryngology Head n Neck Surgery staging (by combining three staging system published between 1985-1991) Stage 1: clinical evidence of malignant otitis externa with soft tissue infection beyond external auditory meatus, but negative 99mTc bone scan Stage 2: soft tissue infection beyond external auditory meatus with positive 99mTc bone scan Stage 3: as stage 2 but with cranial neuropathy 3a: single 3b: multiple Stage 4: as stage 2/3 with intracranial complications (meningitis, empyema, sinus thrombosis, brain abscess)

50.  Microbiology : A.Bacterial : P. aeruginosa, S. aureus, S. epidermis, P. mirabilis, K. oxytoca, P. cepacia Features of pseudomonas: gram negative obligate aerobe contain mucoid surface layer protecting against phagocytosis Produce: lytic enzymes- collagenase, elastase, also endotoxin B. Fungal : Aspergillus fumigatus, A. flavus, A. niger, Scedosporium apiospermum,

51. ETIOLG Y AGEDIABET ES IMMUN OSUPP RESSIO N GRANU LATION TISSUE ME/MA STPID INVOLV EMENT HISTOL OGY BACTE RIA (pseudo mona) oldercommon +- Gm-rod FUNGA L (aspergil lus) youngerLess common More common -+Branchin g septated hyphae, calcium oxalate crystal

52. Diagnosis : A.History B.Clinical examination C.Laboratory studies: CRP, ESR D.Imaging studies

53.  Clinical examination: i.Tympanic membrane usually normal ii.EAC skin soggy, edematous iii.Scanty and foul smelling discharge iv.Foul smelling discharge the onset of osteomyelitis v.Patients usually dose not have fever or other constitutional symptoms vi.Cranial nerve palsies

54.  Imaging : CT MRI NUCLEAR IMAGING

55.  CT: i. Sensitive to bone erosion and decreased skull base density ii. Sensitive in diagnosing: abscess formation, involvement of mastoid, temporomandibular joint, infratemporal fossa, petrous apex, carotid canal iii. Demineralization of skull base of ≥30% is identifiable on CT scan iv. These changes persist despite resolution of disease, therefore poor choice for measuring treatment response v. Inadequate for showing intracranial extension and bone marrow involvement

56.  MRI: i.Shows changes in soft tissue (particularly dural enhancement and involvement of medullary spaces) ii.Persistence of these changes despite resolution makes MRI poor study for determining disease resolution

57.  Nuclear imaging: Technetium Tc99m methylene diphosphonate (MDP) scintigraphy: i.Concentrate in areas with osteoblastic activity ii. Allows earlier diagnosis of osteomyelitis than CT iii.Not specific for infection

58.  Gallium Ga67 citrate : Concentrates in areas of active inflammation through attaching to lactoferrin (present in large quantities in leukocytes -Binding to transferrin -Binding to bacteria directly -Positive for soft tissue and bone infections -Uptake returns to normal after infection has cleared  Several studies have suggested repeating gallium studies every 4 weeks -to assess treatment response -as reliable test to stop treatment if negative

59.  Indium scan: i.Type of white blood cell scintigraphy ii.More reliable than CT in detection iii.Can be used to monitor response to treatment iv.Further work needs to be performed on this modality to elucidate its role in skull base osteomyelitis

60. CONDITIONGALLIUMTECHNETIUMCT OTITIS EXTERNA+-- MOE++MAY BE(-) SBO+++ RECURRENT MOE (-) AFTER TREATMENT THEN + ++ IF SBO RESOLVED MOE-++ IF SBO

61. treatment  Long process  Meticulous aural toilet  Antibiotic or antifungal agents: length of treatment dictated by patients clinical picture and inflammatory markers  Hyperbaric oxygen: a.For cases of intracranial spread b.When disease is recurrent or refractory to antibiotics c.Not enough data to provide recommendations

62. Role of surgery  Central or atypical skull base osteomyelitis: diagnosis and treatment( Matthew P.A et.al. Skull Base 2009;19:247-254) a.Providing tissue that helps exclude a neoplastic pathology b.Allowing reliable culture of microorganism responsible

63. Anti pseudomonal antibiotics  Aminoglycosides: gentamicin, amikacin, tobramycin  Quinolones: ciprofloxacin, levofloxacin  Cephalosporin: ceftazidim, cefepime, cefoperazone, cefpirome, ceftobiprole  Antipseudomonal penicillins: i.Carboxypenicillins: carbenicillin, ticarcillin ii.Ureidopenicillins: piperacillin, azlocillin, mezlocillin iii.Carbapenems: meropenem, imipenem, doripenem iv.Polymyxins: plymyxinB, colistin v.Monobactams: aztreonam Route : all I.V except Oral : fluroquinolones Aerosolized: tobramycin, aztreonam

64. Role of surgery  Malignant otitis externa with skull base osteomyelitis (E. Illing et.al. JSCR.2011;5:6) a.Surgical resection of diseased bone not recommended due to disease spread through fascial and vascular planes b.Biopsies can be obtained c.Any abscess can drained d.In the presence of facial nerve palsy, decompression is not indicated

65. Final Conclusion  Cranial nerve palsies in elderly diabetic or immunocompromised patient imaging finding of a lesion causing bony destruction in skull base should raise concern of a diagnosis of SBO  Past history of otitis externa even if resolved before onset of presenting symptoms should raise suspicion of an underlying infective cause  Prompt diagnosis with nuclear and CT imaging, biopsy to rule out malignancy and culture (aerobic, anaerobic, and fungal) is essential  High dose oral quinolones can be started in established pseudomonal infection  Early diagnostic sampling recommended in patients at increased risk of fungal SBO to enable optimal antimicrobial and surgical management  The length of time of therapy continued guided by clinical findings, normalization of inflammatory markers, resolution on MRI, gallium scan findings  Intracranial extension and multiple cranial nerves can be correlated with mortality

66. Monitoring progress in infection Clinical features in monitoringSevere otalgia, exudates, granulations Serial inflammatory markersCRP, ESR Monitoring glycaemic controlCapillary blood glucose Monitoring imagingGallium citrate scan/SPECT MRI CT ComplicationsFacial +/- other cranial neuropathy, dural sinus thrombosis, meningitis, cerebral abscess, other