Literature Review

Cranial Osteomyelitis: A Comprehensive Review of Modern Therapies

Martin M. Mortazavi1,2, Muhammad Adnan Khan1, Syed A. Quadri1, Sajid S. Suriya1,2, Kian M.
Fahimdanesh3, Salman A. Fard1,2, Tania Hassanzadeh4, M. Asif Taqi1,2, Hannah Grossman5, R. Shane
Tubbs1,6

Key words
- Central skull base osteomyelitis - BACKGROUND: Cranial osteomyelitis is a rare but potentially life-
- Cranial osteomyelitis threatening condition that requires early diagnosis with prompt and
- Iatrogenic osteomyelitis appropriate manage- ment by neurosurgeons to prevent further central
- Posttraumatic osteomyelitis nervous system complications.
- Skull base osteomyelitis (SBO)
- Temporal bone osteomyelitis - METHODS: The literature in the Medline database was comprehensively
Abbreviations and Acronyms reviewed with the keywords “cranial osteomyelitis,” “skull base osteomyelitis
ASBO: Anterior skull base osteomyelitis (SBO),” “central skull base osteomyelitis,” and “temporal bone osteomyelitis.”
CT: Computed tomography Items in the reference list of each article relevant to the objective of
CRP: C-reactive protein
this study were reviewed.
EAC: External auditory canal
ESR: Erythrocyte sedimentation rate - RESULTS: This review produced 183 articles: 13 book chapters, 24 case
MOE: Malignant otitis externa
MRI: Magnetic resonance imaging reports, 17 case series, 98 original articles, 30 review articles, and 1 meta-
MSBO: Middle skull base osteomyelitis analysis. We classified cranial osteomyelitis as sinorhino-otogenic, including
NSRO: Nonsinorhino-otogenic anterior, middle, and posterior skull base osteomyelitis; and non-sinorhino-
PSBO: Posterior skull base osteomyelitis
otogenic, including iatrogenic, posttraumatic, hematologic, and
SBO: Skull base osteomyelitis
SPECT: Single-photon emission computed osteomyelitis with other causes.
tomography
SRO: Sinorhino-otogenic
- CONCLUSIONS: New diagnostic modalities, the introduction of
SSI: Surgical site infections broad- spectrum antibiotics, and recent advances in neurosurgical
Tc 99m: Technetium 99m procedures have led to a decrease in the rate of treatment failure in
WBC: White blood cell cranial osteomyelitis. Early recognition of initial nonspecific symptoms is
From the 1National Skull Base Center, Thousand Oaks, key to diagnosing and managing this treatable but life-threatening
California; 2California Institute of Neuroscience, Thousand condition. Early identification of the causative pathogen, appropriate broad-
Oaks, California; 3UNIVERSITy of California IRVINe Medical spectrum antibiotic therapy over a period of 8e20 weeks, and aggressive
Center, IRVine, California; 4UNIVERSITY of Arizona College of
Medicine, Tucson, Arizona; 5Los Robles Hospital and Medical surgical debridement are essential for managing cranial osteomyelitis. On
Center, Thousand Oaks, California; and 6Seattle Science the other hand, inadequate treatment is responsible for re- fractory cases
Foundation, Seattle, Washington, USA and poses a great diagnostic challenge. A new classification dividing
To whom correspondence should be addressed: cranial osteomyelitis into sinorhino-otogenic versus nonsinorhino- otogenic
groups could prove valuable for clinical communication and treatment.

Martin M. MortazaVI, M.D.

otics, and new diagnostic modalities, management of cranial osteomyelitis re-
[E-mail: M_MORTAZAVI@hotmail.com]
mains a great challenge. The aim of this
Citation: World Neurosurg. (2018) 111:142-153.
article is to catalog various types of osteo-
https://doi.org/10.1016/j.wneu.2017.12.066
myelitis along with modern management of
Journal homepage: www.WORLDNEUROSURGERY.org
the disease.
AVAILABLE online: www.sciencedirect.com
1878-8750/$ - see front matter ª 2017 ELSEVier Inc. All
rights RESERVED.
METHODS
The published literature in PubMed,
INTRODUCTION
Medline, and EMBASE was comprehen-
In 1959, Meltzer and Kelemen were the sively reviewed. Cross-checking of refer-
first to describe skull base osteomyelitis ences identified additional relevant
(SBO) in a patient with pyocyaneus references. “Cranial osteomyelitis,” “skull
chondritis and osteomyelitis of the base osteomyelitis (SBO),” “central SBO,”
external auditory canal (EAC).1 Cranial and “temporal bone osteomyelitis” were
osteomyelitis includes a spectrum of used as search terms. The final decision to
various causes.2,3 include or exclude reviews and data
Despite advances in neurosurgical extraction were completed by the authors,
procedures, introduction of new antibi-
WORLD NEUROSURGERY 111: 142-153, MARCH 2018 WWW.WORLDNEUROSURGERY.ORG 1
and any disagreements were settled by discussion. Articles related to the key-
words were thoroughly searched and
later the articles focusing mostly on
cranial/ calvarial, infectious, iatrogenic,
post- traumatic, tuberculous pediatric-
clival, Garré and sclerosing osteomyelitis
and their diagnostic modalities and
treatment were included. No date
restrictions were imposed. Studies with
the possibility of blurred/mixed and
confusing data were excluded. Moreover,
the animal data studies were also
excluded to maintain the study totally
human focused.

RESULTS
A total of 2522 articles were
initially recovered. Of these articles,
183 Were included on the basis of their
relevance to

2 WWW.SCIENCEDIRECT.COM WORLD NEUROSURGERY, HTTPS://DOi.org/10.1016/J.WNEU.2017.12.066


MARTIN M. MORTAZAVI ET AL.
skull osteomyelitis and our
objectives. These articles comprised 13
book chap- ters, 24 case reports, 17
case series, 98 original articles, 30
review articles, and 1 meta-analysis. The
relevant available in- formation was
then used to describe the classification,
prevalence, risk factors, clinical
course, diagnostic modalities, and
investigative techniques along with
management in all classifications. On the
basis of the information available, we
propose a new classification of cranial
osteomyelitis into sinorhino-otogenic
(SRO) and non-SRO (NSRO)
categories. The SRO group is
subdivided into ante- rior SBO (ASBO),
middle SBO (MSBO), and posterior SBO
(PSBO) and the NSRO group into
iatrogenic, posttraumatic, he- matologic,
and osteomyelitis with other causes
(Figure 1).
Causes and Risk Factors of Cranial
Osteomyelitis
The most common causes of cranial
osteomyelitis in developing countries are
paranasal sinusitis, direct head injuries,
and scalp infections. Postoperative
craniotomy-related infections are the pre-
dominant source of cranial osteomyelitis
in developed countries. 2,4-6 SBO mainly
involves the middle skull base and usually
occurs as a complication of malignant
otitis externa (MOE) or chronic mastoid
infections or secondary to sphenoidal
sinusitis.7-9
Cranial osteomyelitis is also influenced
by systemic diseases that decrease bone
vascularity, change the course of disease,
and alter host defense mechanism. 2,10-17
The causative infections and predispos-
ing comorbidities are summarized in
Tables 1 and 2. Common organisms
causing cranial osteomyelitis are
summarized in Table 3.
Classification of Cranial Osteomyelitis
Depending on the originating site of
infection, cranial osteomyelitis can be
classified primarily into 2 broad clinical
entities: SRO origin and NSRO origin (see
Figure 1).
SRO Origin. We differentiate the SRO
origin of osteomyelitis into 3 types
to guide with definitive diagnosis and
selec- tion of appropriate therapy.
1)ASBO. ASBO develops as
complication of paranasal sinusitis, acute
bacterial rhinitis, skull base trauma, or
previous surgical procedures, or it can be
idio- pathic.17-18 The most common
causative pathogens are Staphylococcus
aureus, strep- tococci, and anaerobes.19
Prasad et al.2 determined that chronic
rhinosinusitis is the main source of frontal
bone osteomyelitis. Undertreatment of
infection is also an important risk factor
for recurrence of ASBO.20 However,
direct extension involving the external
wall of the frontal bone leads to bone
erosion, subperiosteal abscess, epidural
empyema, subdural collections,
meningitis, and encephalitis.21-24 On the
other hand, hematogenous spread can
also occur by valveless diploic veins
causing sagittal sinus thrombophlebitis,
brain abscess, and subdural empyema. 22,24
This process leads to bone sequestration,
which assists in harboring bacteria, and
also produces an area of low oxygen
tension. This area effectively reduces the
bactericidal activity of leukocytes and the
rate of diffusion of the antibiotic into the
dead bone. These pathologic changes make
it impossible for the antibiotic to reach
the site of infection, despite a therapeutic
serum concentration.24-25 Frontal
osteomyelitis is generally a polymicrobial
infection; however, if the intracranial
complications
LITERATURE REVIEW
CRANIAL OSTEOMYELITIS
are the initial presentation of frontal
osteomyelitis, then, anaerobic or fungal
infections are the leading cause.21,22,26,27
Clinically, ASBO can present acutely as
fever, frontal headache, frontal
edema, retro-orbital pain, photophobia,
purulent rhinorrhea, seizures, and focal
neurologic signs.2,18,21-23,28 However,
chronic ASBO is characterized by
progressive frontal head- ache along
with decreased mentation,
a sinocutaneous fistulas, and infectious
complications such as meningitis and
extradural, subdural, or
intraparenchymal abscess, leading to
significant morbidity and mortality.2 1 -
23,28 -31
ASBO is frequently a
complication of frontal sinusitis or
posttraumatic infection. Other less
frequent risk factors are osteocartilaginous
necrosis secondary to chronic intranasal
cocaine abuse, dental abscess, or delayed
complications of neurosurgery.32-33
Another rare clinical entity that causes
frontal bone osteomyelitis and is
commonly found in the adolescent and
young adult group is Pott puffy tumor.30-31
This disease is characterized by forehead-
localized nonneoplastic swelling caused
by a subperiosteal abscess associated with
osteomyelitis of the frontal bone
second- ary to either direct or
hematologic spread of the infection.30-31
2) MSBO. Although relatively uncommon,
MSBO is a frequent clinical entity among
SBO cases, associated with significant
functional morbidity and mortality.15,34 In
1838, Toulmouche35 was the first to report
a case of progressive temporal bone
osteomyelitis. However, Chandler in 1968
introduced the term malignant otitis
externa.36,37 Many studies suggest that
Pseudomonas aeruginosa infection is a
leading cause of MOE and MSBO,
responsible for up to 98% of all cases.38
However, MSBO can also develop as a
complication of paranasal sinusitis,
 LITERATURE REVIEW
MARTIN M. MORTAZAVI ET AL. CRANIAL OSTEOMYELITIS

Figure 1. Classification of cranial osteomyelitis.

 abscess formation, and contralateral the hypoglossal canal (Collet-Sicard
Table 1. Systemic Comorbid Conditions side spread with cervical spine syndrome).42 Complications such as
in Cranial Osteomyelitis involvement can also complicate the meningitis, brain parenchymal
Systemic Comorbid Conditions course of infection.39,46 involvement, abscess formation, venous
MSBO primarily involves the temporal sinus thrombosis, and lateral medullary
Nutritional Immunocompromised and sphenoid bones.47 ,4 8 Typically, MSBO syndrome can also result from the spread
imbalance state involving the temporal bone presents with of infection.51,52
Diabetes mellitus Malignancy severe and deep otalgia, spiking fever, Gradenigo syndrome or petrous apicitis is
Renal failure Postradiation exposure aural fullness, and foul purulent rarely seen since the introduction and
discharge.49 Conductive deafness, widespread use of antibiotics. However, it is
Hepatic failure Paget disease
headache, and temporomandibular joint a serious and potentially fatal intracra-
Chronic hypoxia Osteoporosis pain may also be present.50 nial complication of acute otitis media,
Small-vessel disease Prolonged hospital stay On examination, woody induration of acute mastoiditis, and cholesteatoma.5 3 It
Osteopetrosis Advanced age the pinna, preauricular cellulitis, and can also be caused by extradural
a tender EAC with granulation tissue inflammation at the petrous apex of the
Smoking/tobacco use
are the cardinal findings. In later temporal bone involving the trigeminal
stages, there can be involvement of the ganglion and abducens nerve.54
mastoid bone with granulation Gradenigo syndrome consists of the triad
chronic mastoiditis, suppurative
tissue and cutaneous fistula.49,50 of suppurative otitis media, ipsilateral
otitis media, and odontogenic
Cohen and Friedman suggested abducens nerve palsy secondary to
infections.39,40 Many other pathogens
the following diagnostic criteria: pain, involvement of the nerve as it passes
can also cause MSBO, including
exudate, edema, granulation tissue of through the Dorello canal, and unilateral
Staphylococcus aureus, Staphylococcus
EAC, and positive technetium 99m (Tc retro-orbital pain, or pain in the cuta-
epidermidis, Proteus spp, Klebsiella spp,
99m) scan.23 neous distribution of the ophthalmic and
Candida ciferri, Candida parapsilosis,
Sphenoid SBO specifically presents with maxillary divisions of the trigeminal nerve
Scedosporium apiospermum,
unremitting headaches in the absence as a result of the extension of inflamma-
mucormycosis, Aspergillus fumigatus,
of localized ear and sinus infection, tion into the Meckel cave.53-56 Other
and Aspergillus niger.41-43
posing a diagnostic challenge. If it is symptoms can include severe headache,
Pathologically, MSBO is a progressive
not treated promptly, a variety of photophobia, meningeal signs, fever,
infection spread from the EAC to the
cranial neuropa- thies, most commonly diplopia, and reduced corneal sensi-
middle skull base through the fissures of
abducens palsy, can ensue rapidly as tivity.53-57 The most common etiologic
Santorini and the osseocartilaginous
a result of the extension of infection pathogens are Staphylococcus aureus, Strepto-
junction.44 The facial nerve is the cranial
to the brainstem.34 Subtemporal spread coccus pneumoniae, group A streptococci,
nerve most commonly involved. As a
of infection in- volves the facial Pseudomonas, and nontypeable Haemophilus
result of the spread to the jugular
nerve, where further posteromedial influenzae.58 Traditionally, Gradenigo
foramen, cranial nerves IX, X, or XI are
spread can involve the ju- gular syndrome has been treated by surgery;
the next most commonly affected.44,45
foramen, carotid space, sigmoid si- nus, however, surgery is reserved for
Anterior spread of the infection can
and hypoglossal canal.51 This refractory cases. A pus sample is
involve the parotid gland and
situation implicates the cranial nerves obtained by mastoid drainage or in life-
temporomandibular joint. Septic
exiting the jugular foramen, the threatening complications.58 Recent
thrombosis of the sigmoid sinus and
glossopharyngeal, vagus, and accessory advances in imaging with new antibiotic
internal jugular vein, meningitis, cerebral
nerves (Vernet syndrome), and also treatment availability allow conservative
the hypoglossal nerve exiting through treatment to produce complete recovery
without major surgery.58
Table 2. The Main Routes of Infection in Cranial Osteomyelitis 3) PSBO. PSBO is a very rare condition
that occurs in the setting of direct spread of
Routes of Infection and Their Causes an infection involving the paranasal sinuses,
EAC, mastoid, middle ear, or oral cav-
Contiguous Spread Direct Inoculation from Iatrogenic Hematogenous Dissemination ity.39,59 Noninfectious causes are extremely
from from Local Infection or Posttraumatic Condition rare and can be secondary to posttraumatic
Remote Source of Infection and iatrogenic cau- ses.39,60-66 Various
Chronic mastoiditis Neurosurgical site infections Lung infection pathogens such Pseu- domonas,
Paranasal sinus Gunshot wounds Spine infection streptococcal pneumonia, Streptococcus spp,
infections and Staphylococcus aureus are most frequently
involved; fungal or mixed bacterial
Malignant otitis externa Postcraniofacial injuries Peripheral arthritis
infections have also been documented,
Scalp infections Cephalohematomas Meningitis although less commonly.67-69 Factors such as
Penetrating scalp wound and laceration Cryptogenic infection delayed

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 Clinically, traumatic cranial osteomye-
Table 3. Common Pathogens Causing Cranial Osteomyelitis in Different Locations litis presents as chronic infection and
of
Skull Base is usually milder than the acute
variant.89 However, osteomyelitis
Infection in Different
reported after scalp avulsion can show
Location of Skull Common Causative Pathogens
the findings of acute osteomyelitis.91
Anterior skull base Bacteria: Staphylococcus aureus, Staphylococcus epidermidis, Bacteroides The diagnostic workups include
osteomyeltis spp, Peptostreptococcus, Mycobacterium tuberculosis, microaerophilic checking erythrocyte sedimentation rate
Streptococcus spp, and nontuberculous Mycobacterium spp (ESR) and C-reactive protein (CRP)
Fungi: Candida cifferi, Candida parapsilosis, Aspergillus spp, levels and performing imaging
and mucormycosis modalities and bone biopsy.89-91 Bone
Middle skull base Bacteria: Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella spp, magnetic resonance imaging (MRI) and
osteomyelitis Nontuberculous Mycobacterium spp Bacteroides spp, Peptostreptococcus, bone single-photon emission
Mycobacterium tuberculosis, Proteus spp, and Klebsiella spp computed tomography (SPECT) are
Fungi: Aspergillus fumigates, Aspergillus niger, mucormycosis, considered the most sensitive tech-
Scedosporium apiospermum, blastomycosis, and Cryptococcus neoformans niques.92 Needle biopsy is the most
Mixed bacterial and fungal infections: occasionally
accurate diagnostic tool.
Posterior skull base Bacteria: Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella spp, Staphylococcus aureus is the most
osteomyelitis Nontuberculous Mycobacterium spp, anaerobes, Mycobacterium common pathogen, followed by other
tuberculosis, and Streptococcus spp organisms including Proteus mirabilis,
Fungi: Aspergillus fumigates, Aspergillus niger, mucormycosis,
Peptostreptococcus spp, Streptococcus
Scedosporium apiospermum, blastomycosis, and Cryptococcus neoformans
pyogenes, Streptococcus pneumoniae,
Mixed bacterial and fungal infections: occasionally
Mycobacterium tuberculosis, Klebsiella
spp, Pseudomonas spp, and Bacterioides
diagnosis or maltreatment of the primary high morbidity and mortality. Progression spp.25,53,89,93-95
origin of infection, and resistance of of iatrogenic osteomyelitis is slow and the 3) Hematologic Cranial Osteomyelitis.
the pathogen to antimicrobial therapy initial symptoms are usually subtle. Staph- Osteomyelitis can also result from hema-
or immunosuppression, are ylococcus aureus is the most common togenous spread after bacteremia or fun-
significantly implicated in PSBO. path- ogen.75-78 In countries where gemia. It can occur in immunosuppressed
Bilateral or contra- lateral SBO is very tuberculosis is endemic, direct inoculation patients who have prolonged neutropenia,
rare.23,39,63-65 of Mycobac- terium tuberculosis can also leukemia, corticosteroid use, critical
PSBO most commonly involves the happen. illness requiring intensive care, chemo-
clivus but superiorly the lesion can also Multiple studies have suggested various therapy, AIDS, or diabetes mellitus. These
extend to the sphenoid bone (Figure 2). infection prevention strategies that can chronic infections are difficult to diagnose
Headaches, atypical facial pain, and decrease the risk of SSIs. These strategies and have life-threatening complications
cranial nerve palsies are the most include adequate surgical scrub, appro- with poor prognosis.96-98 The most com-
common symptoms at the time of initial priate suture materials, antibiotic prophy- mon pathogens include Pseudomonas
presentation when the sphenoid is laxis, and preoperative correction of aeru- ginosa, Salmonella spp,
involved.39,70 Inferior extension can dehydration and poor nutrition, along nontuberculous Mycobacterium spp,
involve the prevertebral space, which with wound care procedures such as the Treponema pallidum, and fungal causes
links the base of skull to the posterior use of wound guards, drains, and surgical including Cryptococcus neo- formans,
mediastinum.68 Presentations are dressings.79-81 Alexander et al.82 showed Aspergillus spp, blastomycosis, and
persistent fever, neck pain, focal pain that careful skin preparation and surgery mucormycosis.75,99-101
and tenderness in the suboccipital performed without scalp shaving can Aspergillus is the most common fungal
area, hemiplegia and/or quadriparesis, significantly decrease the rate of SSIs. cause of cranial osteomyelitis in immu-
dyspnea, and apnea.39,69,71,72 Extension 2) Posttraumatic Cranial Osteomyelitis. nosuppressed patients, usually involving
of the disease can cause serious the temporal bone at the base of the
complications, skull.102-109 However, cranial osteomyelitis
including dural sinus thrombosis, associated with Traumatic cranial osteomyelitis is a
jugular foramen syndrome, complication of head trauma. In children,
meningitis, brain abscess, or trauma is the most common predisposing
cervical epidural abscess.39,67,70-74 factor for cranial osteomyelitis, followed
These complications are rare. by sinusitis.83,84 Cranial osteomyelitis also
occurs after infection of cepha-
NSRO Origin. NSRO comprises lohematomas in neonates, pin site infec-
iatrogenic, posttraumatic, hematologic, tion from halo traction, or after traumatic
and osteo- myelitis with other causes. scalp hematoma.85-87 In adults, it can
1) Iatrogenic Cranial Osteomyelitis. Despite occur as a complication of a wide variety of
advances in preventive procedures, head injuries ranging from minor to major
surgical site infections (SSIs) remain a cranial fractures with or without
significant clinical problem and are contamination.88-90
can also occur in immunocompetent pa-
tients. Mucormycosis is another common
fungal cause of this condition. 110,111 Very
rarely, blastomycosis and Cryptococcus
neo- formans can involve skull bones,
causing osteomyelitis, most often in the
temporal bone. A high index of suspicion
and recognition of atypical clinical
features of specific organisms are
required for diag-
nosing and treating
hematogenously spread
osteomyelitis.75,97,98,100-104,106-113
Cranial osteomyelitis caused by
Salmo- nella spp is extremely rare and
can occur in
 characterized by a unique
proliferative subperiosteal reaction in
the pediatric population.130 It

Figure 2. (A) Gadolinium-contrasted, T1-weighted axial and (B) noncontrasted T2-weighted

axial images showing a large retroclival empyema with substantial edema of the brainstem.

both immunocompetent and immuno- Clival Osteomyelitis. Clival osteomyelitis

suppressed patients.106 A few cases of
cranial osteomyelitis caused by
disseminated Mycobacterium infection have
been reported in patients with advanced
AIDS. Disseminated disease is universally
fatal, with a mean survival time of 6
months from initial diagnosis.107
4) Other Causes of Cranial Osteomyelitis.
Tuberculous Osteomyelitis. Primary
tuberculous osteomyelitis, both of the skull
vault and skull base, is a common cause of
cranial osteomyelitis in many regions of the
world.114-118 Because of widespread
malnutrition, poor socioeconomic condi-
tions, and immunodeficiency syndromes in
the developing world, the incidence of
calvarial TB is on the increase. 119 It usually
presents as painless or sometimes painful
scalp swelling with a discharging sinus,
subgaleal collections, and a variable amount
of extradural granulation tissue. 120 It
usually involves multiple cranial bones. The
radiologic forms of calvarial TB are diffuse
TB of the cranium or circumscribed lesions
of the sclerotic and lytic type.121 If the
extrapulmonary source is not found, this
may lead to delay in starting the treatment.
Posttraumatic tubercular osteomyelitis of the
cranial vault has also been reported. 122 It is
suggested that the increased vascularity and
transitory decrease in resistance at the
trauma site may result in the inoculation of
the bacilli.121
is a very rare condition observed in the
pedi- atric population. It usually occurs
secondary to the direct spread of an
infection from contiguous structures,
the paranasal sinuses, or adjacent
bones of the skull base.8,123,124 A few
case studies have reported pathogens
such Enterococcus faecium, methicillin-
resistant Staphylococcus aureus, and an
anaerobe, Fusobacterium necropho-
rum.8,123,125 Infection can also be
transmitted from the lymphatic tissue in
the pharynx through the fossa navicularis
magna to the skull base. The lymphoid
tissue of the pharyngeal tonsil and
emissary veins in the fossa navicularis are
a potential route for the spread of
infection and subsequently lead to clival
osteomyelitis.124,126,127 Because
numerous important structures lie
adjacent to the clivus, any progression of
disease can lead to an intracranial
complication.128 Contrast-enhanced
imaging studies such as MRI and
computed tomography (CT) scans with
contrast are required to assess the extent
of the disease process.123,124,127 Clival
osteomyelitis is treated by
intravenous
administration of broad-spectrum
antibi- otics over a period of 4e8 weeks.
Surgical drainage via the posterior
pharyngeal wall is necessary in patients
who are unresponsive to antibiotic
therapy.123,124,127,129
Garré Osteomyelitis. Garré
Osteomyelitis is a rare chronic disease
was first described by Carl Garré in cranial osteomyelitis, in general, can be
1893. This disease is also known as
Garré chronic sclerosing osteomyelitis
because it comprises chronic sclerosing
osteomyelitis with proliferative
periostitis, ossifying periostitis, or
other forms of osteomyelitis.13 1, 132
It predominantly affects the mandible
and long bones, with rare calvarial
involvement. However, Klisch et al.133
reported 1 case of skull involvement as
well.
Sclerosing Osteomyelitis.
Sclerosing osteomyelitis can present as
diffuse or focal forms. Diffuse forms
can involve the calvarium and are
caused by microorgan- isms; however,
in most cases, no bacterial growth can
be obtained in culture.130 Klisch et
al.133 SUGGESTED that calvarial
sclerosing osteomyelitis has to
be included as a differential
diagnosis of skull osteolytic and
sclerosing lesions with persistent
swelling of the head. The imaging
findings are not specific and
predominantly show sclerosis of
the bone and calvarial thickening.
Treatment strategies can involve
conservative approaches with antibiotic
therapy but sometimes surgery is
required to achieve a permanent cure.131
Melioidosis. Melioidosis is caused
by Burkholderia pseudomallei, a ubiquitous
soil saprophyte, and is characterized by
mul- tiple abscesses in different organs
of the body.134 Although uncommon,
cranial melioidosis can present
with either isolated involvement
of brain parenchyma in the form
of intracerebral abscesses or with
osteomyelitis without extension into
the extradural space.134 Diabetes
mellitus is a well-documented risk
factor for melioidosis.135 Other risk
factors include alcoholism, renal
disease, immunosuppression, and
thalassemia.136 Cranial melioidosis
presentation potentially mimics
tuberculosis both clinically and
radiologically.134 However, its varying
presentation can mimic Guillain-
Barré syndrome, limb weakness, and
cranial nerve palsies.137 This
condition is relatively
asymptomatic, especially in the context
of an extradural empyema; however, it
can present with fever, headache,
ataxia, and generalized tonic clonic
seizures.137-139

Modern Management Strategies

Diagnostic Modalities. The diagnosis of
based on history, physical examination,
laboratory findings, tissue sampling, and
imaging studies. Laboratory workup is not
always helpful. ESR, CRP, procalcitonin,
and white blood cell (WBC) count can be
mildly increased.27 In suspicious cases,
tissue sampling is often required for
definitive diagnosis because imaging
studies are not specific except in giving
the location of infection. 48,72 Tissue can
be sampled by CT-guided fine needle
aspiration, endoscopic sphenoidotomy,
magnetic resonanceeguided biopsy, or
open craniotomy.48,140 Tissue sampling
with histopathology and microbiology is
also helpful to rule out malignant
disease.38,48
Imaging studies are generally used to
establish the location and extension of
infection. These modalities include con-
trasted CT, MRI with contrast, gallium 67
scintigraphy, and indium 111 WBC (In-111
WBC) scan, and Tc 99m bone scintig-
raphy.39,92,141-145 CT with contrast is sen-
sitive to bone erosion
periosteal remodeling; however, it is a
poor choice for monitoring
intracranial extension, bone marrow
involvement, and treatment
response.92,146 In iatrogenic osteomyelitis,
plain radiographs and CT lack initial
sensitivity but can later show
destruction in osteomyelitis (Figure 3).
In cranial melioidosis, CT lacks
sensitivity, particularly in the initial
stages of the disease.134,137,138 CT
no longer diagnostic of active
osteomyelitis after surgery or
trauma.92,147,148
MRI is more sensitive than CT for early ongoing active cranial osteomyelitis
detection of cranial osteomyelitis and de- after treatment. Gallium scintigraphy
termines the full extent of adjacent and inflammatory parameters such as
soft- tissue involvement (Figure 4). In CRP, procalcitonin, WBC, and ESR are
among the modalities for evaluating
the setting of extensive disease, the
treatment response and assessing
imaging of cranial osteomyelitis is best
recurrence and prognosis in cranial
achieved with MRI.149 Clival marrow and
osteomyelitis, because they rapidly revert
preclival soft-tissue abnormalities are
to normal as the disease
the usual MRI findings. However, it is
resolves.39,145 Strumas et al.144
uncertain whether these changes in
suggested a method for
preclival soft tissue are caused by direct
multimodality image registration
extension of an infection from the
sphenoid sinus or extension from the (fused standard CT and SPECT
clivus itself.48,149,150 MRI T2-weighted images) to locate osteomyelitis
scans show classic signs of cranial accurately in a clinically challenging
patient. This fused multimodality
melioidosis, which include calvarial
image technique also guides the need
osteomyelitis, leptomeningeal
enhancement, ring-enhancing lesions, for surgical management and limits
edema, abscesses, and a predilection unnecessary dissection and excessive
for brainstem involvement.134,137,138 debridement. At present, these novel
For patients with cranial osteomyelitis diagnostic tools are available only in the
who have not undergone previous skull developed world.
base surgery, MRI with contrast and In- In developing countries where these
111 WBC bone SPECT scintigraphy are advanced diagnostic tools are not avail-
or the most sensitive techniques for detecting able, the relevant investigation generally
osteomyelitis.92,146,151 Seabold et al.92 and performed after a clinical diagnosis in-
Weber et al.146 showed that bone SPECT cludes high-resolution CT, culture and
scintigraphy is superior to CT for sensitivity of the pus from discharging si-
detecting cranial osteomyelitis. Anatomic nuses, biopsy from the granulation tissue
localization of the disease can be further for histopathologic examination, and
improved with positron-emission tomog- routine blood examination including
raphy.144 In patients with preexisting blood sugar and human immunodefi-
cranial bone abnormalities resulting from ciency virus testing.47
surgical procedures or trauma, SPECT Multiple factors are involved in the
and Tc 99m methylene diphosphonate delayed diagnosis of the disease. Several
is bone scans have been proved to be the granulomatous diseases and other in-
most accurate methods.68,92 These flammatory conditions such as Wegener
techniques are also useful for assessing granulomatosis, tuberculosis, sarcoidosis,
fibrous dysplasia, Paget disease of bone,

Figure 3. Computed tomography of the head with and without contrast

wound. (A) A noncontrasted bone window. (B) Noncontrasted series.
in a patient who returned 40 days after craniotomy for evacuation of
intracranial hemorrhage and resection of a grade V arteriovenous (C) Contrasted series showing right frontotemporoparietal osteomyelitis
malformation. He had been picking the suture off his initially healing with underlying cerebral abscess.
 Figure 4. Brain magnetic resonance imaging. (A) Axial T2-weighted osteomyelitis and a deep frontal intracerebral abscess 100 days after
series without contrast. (B) Axial T1-weighted series with contrast. (C) awake craniotomy for resection of oligodendroglioma.
Axial fluid-attenuated inversion recovery imaging showing left frontal

and eosinophilic granuloma of the cra- culture-directed antimicrobial therapy treatment is highly effective in traumatic
nium can mimic findings of SRO SBO on for a minimum of 3 months remains skull fracture cases. The distinction is
imaging studies and must also be the general protocol because treatment that antibiotic use for an open
considered.39,48 Commonly, the disease may take up to several months for contaminated skull fracture is treatment
may be misdiagnosed as tumor on CT and complete resolution.47,59,93,145 Because of of contaminated tissue rather than
MRI.152 The bone erosion and marrow the high prevalence of Pseudomonas prophylaxis. In addition, the review158
infiltration along with a masslike soft- aeruginosa, dou- ble coverage is required. found that 7e10 days of antibiotic
tissue swelling may raise the suspicion Recent data show that carbapenems and resulted in fewer late infections than did
for underlying malignant lesion such as ciprofloxacin are suitable for short-term treatment (24e72 hours).
nasopharyngeal carcinoma or skull base adjunctive therapy.92,155 Empirical The antibiotic therapy for cranial
metastases.68 Consequently, further delays therapy with vancomycin should also melioidosis is still being debated.134,138,139
in diagnosis can occur as tissue be considered for adequate methicillin- These antibiotics include ceftazidime or
samples from surgical biopsies may be resistant Staphylococcus aureus coverage.70 carbapenems for up to 6 weeks for the
sent for histology only and yield Johnson et al.70 reported that broad- eradication phase and oral quinolone or
nondiagnostic results. Inadequate or spectrum antifungal coverage must be cotrimoxazole for 6 months for the main-
partial treatment of primary origin of considered in refractory cases in the tenance phase in patients with
infection, failure to respond to setting of appropriate empirical antibac- cranial melioidosis.134,138,139
antimicrobial treatment, and fungal terial. However, empirical antifungal Surgical Treatment. Surgical treatment
infection in susceptible individuals are therapy has not been recommended in the generally involves debridement, removal of
responsible for chronic and refractory literature. Blyth et al.1 7 recommended the necrotic bone and culture of necrotic
disease and pose a great diagnostic use of high-dose amphotericin B or tissue, removal and culture of the
challenge.18 High suspicion should be lipo- somal amphotericin B, a new infected bone, dead space management,
maintained after a failure of lipid formulation with lower toxicity and and maintaining bone stability.2,21-23,26,89,159,160
antibacterial therapy in a patient who has equal efficacy. The targeted and aggressive treatment of
classic signs and symptoms with In iatrogenic osteomyelitis, empirical the source of the original infection,
negative cultures or in patients who therapy should be directed toward Escher- either simulta- neously or as soon as
initially respond to antimicrobial ichia coli and Staphylococcus aureus.75 In these possible to prevent further dissemination
therapy but later experience cases, suction-irrigation systems, or of infected material, is one of the
recrudescence. washin washout indwelling antibiotic irri- mainstays of successful man- agement
gation methods have shown favorable re- and outcome. In cases of MOE, the role
Therapeutic Techniques. Antibiotic Therapy. sults and can save 50% of the infected of surgery is mainly limited to bi- opsy,
The mainstay of treatment for bone flaps.156,157 debridement of EAC, and possible
cranial osteomyelitis is a course of The length of antibiotic treatment for drainage of an associated abscess. In cases
culture-guided antibiotics and early traumatic open contaminated skull frac- of PSBO, surgical drainage can be per-
aggressive surgical removal of tures is a highly debated subject in formed via the posterior pharyngeal wall in
infectious sequestra.153 Different neurosurgery. The extensive review of patients who are unresponsive to antibiotic
studies have recommended various controversies in antibiotic management therapy.1 2 3 , 1 24 , 1 2 7 , 1 2 9 , 1 6 1 In addition to
treatment durations of broad- of traumatic open skull fractures by anti- biotic therapy in Pott puffy tumor,
spectrum antimicrobial agents ranging Mortazavi et al.158 found that antibiotic the sur- gical treatment includes
from 6 to 20 weeks, with an initial 6 weeks external
of intravenous therapy.15,70,154 However,
approaches such as trephination, frontal
sinus obliteration, craniotomy, and endo-
scopic sinus surgery.162,163
In the management of iatrogenic osteo-
myelitis, after debridement and removal of
infected bone flaps, delayed cranioplasty is
recommended.164,165 However, in patients
with uncomplicated postcraniotomy in-
fections, simple surgical debridement is
sufficient with preservation of bone
flaps.164,165 Posttraumatic open displaced
skull fractures into the brain parenchyma
are a distinct entity needing special atten-
tion. Despite extensive debridement and
irrigation, micropieces of contaminated
bone often remain within the brain paren-
chyma and cause late intracerebral infec-
tion, even prolonging intravenous
antibiotic treatment. Therefore, attention
and special care should be given in cases
of traumatic skull fraction.
Adjuvant Therapy in Refractory Cases.
Hyperbaric oxygen therapy is a
particularly useful adjunct to antibiotics
and surgical therapies and is vital for
managing chronic refractory cases. It is
also useful in complicated
postcraniotomy cranial oste- omyelitis
with or without bone flap that requires
repeat surgery. Treatment failures can
occur in both bacterial and fungal SBO
as a result of tissue hypoperfusion and
hypoxia, especially in diabetic patients
with microvessel disease. Hyperbaric
oxy- gen therapy leads to increase
oxygen ten- sion in the wound, enhances
the oxidative killing of pathogens, and
promotes angioneogenesis and
osteoneogenesis. Mader and Love166
suggest that it requires daily treatments
for several weeks; however, its side
generation cephalosporins and
quinolones are the drugs of choice for
treating systemic SAlmonellosis.168
However, the treatment regimen for
Mycobacterium kansasii infections
comprises isoniazid, rifampin,
and ethambutol for 18e24 months.107 For
fungal cranial osteomyelitis, amphotericin
B is the drug of choice, despite its
systemic toxicity.169 In view of the side
effects, few studies have been conducted
on newer antifungal agents such as
miconazole, fluconazole, and itraconazole.
Liposomal Amphotericin B and g
interferon are the new alternative
therapies.169-171 Prevention of aspergillosis
in immunocompromised patients has
gained some attention. Prophylactic
amphotericin B nasal spray or itraconazole
in high-risk patients can pre- vent
colonization.169
Aside from treatment, strict glucose
con- trol in diabetic patients, improvement
of immune status, and resolution of
chemotherapy-induced neutropenia are
vital for successful resolution.169,172-174
Although diabetes increases susceptibility
to infec- tion, no association between
diabetes and longer duration of
antimicrobial therapy has been shown.70
During treatment, it is important that the
reporting radiologist and physician can
detect signs of improvement on radiologic
images. These changes often lag
significantly behind clinical improvement,
resulting in premature discontinuation of
antimicrobial treatment, leading to
occurrence of refractory and chronic
osteomyelitis.175
Chandra Prasad K, Chandra Prasad S, Mouli N, Agarwal S.
Osteomyelitis in the head and neck. Acta Otolaryngol.
2007;127:194-205.
3. Barker FG. Efficacy of prophylactic antibiotics for
craniotomy: a meta-analysis. Neurosurgery. 1994;
35:484-492.
4. Nisbet M, Briggs S, Ellis-Pegler R, Thomas M,
Holland D. Propionibacterium acnes: an under-
appreciated cause of post-neurosurgical infec- TION.
J ANTIMICROB CHEMOTHER. 2007;60:1097-1103.
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vault from a human bite. Br J Neurosurg.
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8. Laurens MB, Becker RM, Johnson JK, Wolf JS,
Kotloff KL. MRSA with progression from otitis
media and sphenoid sinusitis to clival osteomy-
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Pediatr Otorhinolaryngol. 2008;72:945-951.
9. Chen J-C, Yeh C-F, Shiao A-S, Tu T-Y.
Temporal bone osteomyelitis: the relationship with
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effects include oxygen toxicity,
barotrauma, and tympanic membrane
perforation.
Therapeutic Approach for Immunosuppressant
Patients. The management of cranial
osteo- myelitis in immunosuppressed
patients is multidisciplinary. Complete and
wide sur- gical debridement with
prolonged paren- teral antimicrobial
therapy is the treatment of choice if
feasible, along with hyperbaric oxygen for
refractory patients. Recently,
incidences of chronic and subacute forms
of SBO have increased as a result of
inappro-
priate and unnecessary use of antibiotics,
especially in the immunosuppressed.
The treatment of Pseudomonas
CONCLUSIONS
We present one of the most extensive
reviews on cranial osteomyelitis and offer a
classifi- cation on the basis of the origin of
infection. On the basis of location and
cause, we have introduced a new
classification of cranial osteomyelitis: SRO
versus NSRO. This clas- sification can be
valuable for assessing the clinical course of
this condition and the diagnostic and
therapeutic challenges for its management.
the
Thorough diagnosis with prompt and
aggressive treatment is neces- sary, and
complete resolutionofthe infection is
important to decrease morbidity and
mortality among patients.
2.
43
in immunosuppressed patients includes
12. McClelland S III, Hall WA. Postoperative central
nervous system infection: incidence and associ-
ated factors in 2111 neurosurgical procedures.
Clin Infect Dis. 2007;45:55-59.
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Nouraei R. Otogenic cranial base osteomyelitis: a
proposed prognosis-based sys-
tem for disease classification. Otol Neurotol. 2008;
29:666-672.
combination antimicrobial therapy such as
ciprofloxacin and ceftazidime.167 Third-
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