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

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.

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

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

AIMS & OBJECTIVES Compare the epidemiology and clinical characteristics of

bacterial and fungal SBO

Aiming to identify unique risk factors and clinical associations

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

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

Materials & MethodsResults 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.

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.

Materials & MethodsProbable 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.

Materials & MethodsStatistical 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

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

RESULTSPredisposing 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%

RESULTS Median time to presentation:

i. Bacterial - 26.3 weeks (4.2-28.5)

ii. Fungal - 8.1 weeks (0.6-15.5)

RESULTS

CLINICAL FEATURES

BACTERIAL FUNGAL SIGNIFICANCE

FEVER 3 (30.0%) 6 (54.5%) NS

HEADACHE 4 (40.0%) 8 (72.7%) NS

DEAFNESS 7 (70.0%) 2 (18.2%) p 0.03

EAR PAIN 8 ((80.0%) 2 (18.2%) p<0.009

EAR DISCHARGE 8 (80.0%) 1 (9.1%) p<0.002

SINONASAL PAIN 1 (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

0 2 (18%) -

BRAIN PARENCHYMAL INFECTION

0 1 (9%) -

RESULTSSITE OF INFN BACTERIAL FUNGAL SIGNIFICANCE

EAR DISEASE 8 (80.0%) 2 (18.2%) p<0.02

SINUS DISEASE

0 9 (81.8%) p<0.04

TRAUMATIC/UNCERTAIN

2 (20.0%) 0 NS

RESULTS

THERAPY RECEIVED

BACTERIAL FUNGAL SIGNIFICANCE

SURGERY 5 (50.0%) 11 (100%) p<0.02

ANTIBACTERIAL THERAPY

10 (100%) 6 (54.5%) P<0.04

ANTIFUNGAL THERAPY

0 11 (100%) p<0.001

HYPERBARIC O2 THERAPY

0 2 (18.2%) NS

RESULTSOUTCOME BACTERIAL FUNGAL SIGNIFICANCE

SURVIVAL(6 MONTHS)

7/7 (100%) 7/11 (63.7%) NS

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

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.

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

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

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

DISCUSSIONFungal 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

DISCUSSIONTREATMENT 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

DISCUSSIONTREATMENT 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

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.

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 1st C.N

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

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

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

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

Data analysis:

Retrospective analysis of hospital records

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

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

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

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%

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

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%

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

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

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

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

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

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

Cohen’s diagnostic criteria:

B. Occasional :

i. Diabetes mellitus

ii. Cranial nerve involvement

iii. Positive radiograph

iv. Debilitating condition

v. Old age

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

Staging System Levenson’s

Davis’s staging system(1992)

Dr A. Thakar, D. A. Tandon, S. Bahadur, S. K. Kacker (1996)

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)

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,

ETIOLGY

AGE DIABETES

IMMUNOSUPPRESSION

GRANULATION TISSUE

ME/MASTPID INVOLVEMENT

HISTOLOGY

BACTERIA(pseudomona)

older common common+ -

Gm-rod

FUNGAL(aspergillus)

younger Less common

More common

- + Branching septated hyphae, calcium oxalate crystal

Diagnosis :

A. History

B. Clinical examination

C. Laboratory studies: CRP , ESR

D. Imaging studies

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

Imaging :

CT

MRI

NUCLEAR IMAGING

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

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

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

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

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

CONDITION GALLIUM TECHNETIUM CT

OTITIS EXTERNA + - -

MOE + + MAY BE(-)

SBO + + +

RECURRENT MOE

(-) AFTER TREATMENT THEN +

+ + IF SBO

RESOLVED MOE - + + IF SBO

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

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

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

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

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

Monitoring progress in infectionClinical features in monitoring Severe otalgia, exudates,

granulations

Serial inflammatory markers CRP, ESR

Monitoring glycaemic control Capillary blood glucose

Monitoring imaging Gallium citrate scan/SPECTMRICT

Complications Facial +/- other cranial neuropathy, dural sinus thrombosis, meningitis, cerebral abscess, other