Zainab [email protected], Siti Noor Ali [email protected], Amir Hamzah A. [email protected], Fadzil [email protected], Abdul Wahab [email protected], Adnan O Jwda# Kyaw Tun Wai$, Quazi Manjurul Haque%

A six year old boy with staphylococcus aureus meningo-encephalitis complicating periorbital cellulitis is reported. The presence of cavernous sinus thrombosis and the causes of the accompanying bilateral sixth nerve palsies are discussed by the ophthalmology and the neurosurgical team. The main clinical and micriobiological aspects are discussed by the paediatric and the microbiology team.

A 6-year old boy who was previously well presented to the accident and emergency department with dizziness and vomiting following a fall from a bicycle. There was no loss of consciousness. He was admitted to the surgical ward for observation. On admission, he was fully conscious but febrile. His vital signs were stable. .There was periorbital oedema and chemosis of the right eye. Vision and movement of the right eye were normal. The left eye was normal. Two days later, the fever became high grade and he developed vomiting, headache and drowsiness. He was referred to the paediatric and ophthalmology departments. The attending paediatrician found him to be drowsy with neck stiffness and positive Kernig’s sign. The right eye was proptosed with periorbital oedema, conjunctival injection and restricted ocular  movements in all directions. The left eye was normal. Both pupils were reactive to light and there was no relative afferent pupillary defect (RAPD). Fundal examination was normal. A full septic work up excluding lumbar puncture was done. He was accordingly transferred to the paediatric intensive care unit (PICU). The first blood culture taken in the surgical ward grew Staphylococcus aureus sensitive to cloxacillin. He was started on intravenous (i.v.) cefotaxime and cloxacillin. A CT scan of the brain and orbit revealed cerebral oedema and soft tissue swelling around the right orbit. There was no obvious cavernous sinus thrombosis. He was given i.v. mannitol for a total of three days. His full blood picture on admission revealed high white cell count (21,700/L with 90% polymorphonuclear leucocytes). The platelet count was normal. The next day, his level of consciousness improved and the fever subsided. However this time his left eye was noted to be swollen and inflamed. The second blood culture also grew S.aureus. A lumbar puncture requested was refused by the parents. On day 5 of his illness, he developed high-grade fever and became drowsy again. His left eye became more swollen whilst the right eye swelling subsided. There was restricted movement of the lateral gaze. Both pupils were still reactive to light with no RAPD. There was no papilloedema. Intravenous cefotaxime was changed to cefipime. MRI of the brain and orbit which was done at this stage showed no cerebral oedema or cavernous sinus thrombosis. He became apyrexial and remained stable over the next five days.

On  Day 4                                                       On Day 11

Lumbar puncture was requested repeatedly during his PICU stay and the parents consented on day 10 of illness when he was already on intravenous cefipime for 5 days. The cerebrospinal fluid (CSF) was clear and colourless with white cell count of 7,000/l. The CSF glucose was 4.2 mmol/l (random blood sugar 6.6mmol/ l), protein 3.5g/dl. Gram stain showed no organism and both latex and culture were negative. On day 11 of his illness, a bruit was heard over his left eye. His lateral gaze restrictions were more obvious. There was no restriction in any other gaze directions. He was then referred to the neurosurgical team. Connective tissue screenings done were normal. He was put on a 5-day course of 60mg oral prednisolone. On the 16th day of illness, he was transferred to the neurosurgical ward. He was later referred to the National University Malaysia Hospital in Kuala Lumpur for cerebral angiogram which was done on day 21 of illness. The result was normal. At this point the bruit was no longer heard over the left eye. He was discharged home. During outpatient follow-up 35 days after his initial admission, there was a slight improvement noted in the left lateral gaze.

The clinical history and examination at presentation to the department clearly suggest central nervous system (CNS) infection; in this case it is most likely meningitis or meningoencephalitis. The CNS infection probably originated from the right orbital cellulitis. Right orbital cellulitis most likely occurred following trauma to the right eye that he sustained one day prior to admission. It is well documented that trauma to the eye   predisposes to the development of orbital cellulitis1. The other factors which can lead to orbital cellulitis are sinusitis, dental extraction, post operative and preseptal cellulitis 1, 2

The common organisms involved in orbital cellulitis are Haemophilus inlfuenzae, S. aureus and Streptococcus spp.3. This is compatible with the patient in whom blood cultures taken prior to commencement of antibiotics grew S. aureus. The features of meningism persisted for about 5 days after the onset of clinical symptoms. He then deteriorated on day 5 of illness. However his condition improved when cefotaxime was changed to the fourth generation cephalosporin, cefipime. Cefipime is a new, injectable, x-methoxyimino aminothiazolyl cephalosporin with spectrum of activity which includes many of the Gram-positive and Gram-negative bacteria responsible for severe infection 4. The efficacy of cefipime for the treatment of bacterial meningitis had been previously demonstrated in experimental animal models with group B streptococci, S. aureus, E. coli and Pseudomonas aeruginosa as meningeal pathogens5. Xavier et. al. al. found that cefipime is safe and therapeutically equivalent to cefotaxime for management of bacterial meningitis in infants and children6. In this case, where S aureus meningitis is highly likely, cefipime has led to a tremendous clinical improvement as compared to a combination of cefotaxime and cloxacillin.

Devastating complications including meningitis or meningoencephalitis can develop if prompt and adequate treatment for orbital cellulites is not instituted7. Meningitis or meningoencephalitis carries a high mortality and morbidity rate. In one study on acute bacterial meningitis in children aged between 1 month and 12 years in our hospital, the case fatality rate is 19% with a morbidity rate of 42%8. In another studies, ocular manifestations including squint is one of the morbidities 9. However, whether the patient’s squint will improve with time or not, we will have to wait as we have not found published data on this.

Our biggest hurdle to diagnose meningitis with certainty in the paediatric population in this country is failure to get parental consent for lumbar puncture. This is especially so in the rural population .In this case several attempts were made to persuade the parents to consent for a lumbar puncture. This was only given after the child had been on intravenous cefipime for 5 days. Malik AS found that the number of days after admission does not significantly influence the decision making in giving consent for lumbar puncture10. Factors that influenced parental decision are knowledge about the purpose of lumbar puncture and knowledge about the underlying disease10. Perhaps the opportunity to ask more questions during the course of their son’s illness help to allay the parents’ anxiety on lumbar puncture and have given them some insights on the underlying disease.

We saw the case three days after admission. There was an axial proptosis in the right eye with conjunctival injection and generalised restriction of extraocular muscle movements. Both pupils were reactive to light and there was no RAPD. The left eye was normal. The child showed signs and symptoms of meningitis as explained earlier by the pediatrician. We felt that the child had right orbital cellulitis secondary to the trauma he sustained one day prior to his admission to the hospital. A retrograde infection leading to the involvement of the meninges is a well recognized complication in this situation. The CT scan finding was supportive of such a postulation. However despite the introduction of appropriate antimicrobial therapy and supportive measures his fever did not subside and his conscious level deteriorated. Further more his left eye begins to be affected with conjunctival injection, proptosis, and restricted movements. This development was alarming since the possibility of cavernous sinus thrombosis had to be considered. The changing of the antimicrobial therapy was an appropriate action which resulted in some clinical improvement. The development of bilateral six nerve palsies can be seen in cavernous sinus thrombosis and secondary to increase intracranial pressure (false localizing sign). The patient will be on regular follow-up with our eye clinic; on each visit his visual function will be assessed and also the degree of eye deviation. Only after a reasonable period of stabilization of the degree of the deviation that a surgical option may be considered.

Infections of the orbits are uncommon, but they are potentially devastating infections that can quickly result in blindness, meningitis, or death. The emergency physician must make a rapid and accurate diagnosis and then quickly initiate therapy because visual loss is associated directly with the length of time to definitive treatment. The orbit is a pyramid-shaped bony space in the anterior skull that contains the globe, the blood vessels, and the intraorbital muscles and nerves. The space is bordered on its superior, medial, and inferior sides by the facial sinuses (frontal, ethmoid, sphenoid, and maxillary, respectively). The bony septa separating the orbit from the sinuses are thin and fenestrated, particularly in the medial orbital wall, where the lamina papyracea borders the ethmoid sinus. The anterior border of the orbit is marked by the orbital septum, a fibrous band from the external bony orbit to both eyelids, which effectively separates the preseptal space from the orbital space. The posterior wall of the orbit contains the optic canal and the superior and inferior orbital fissures. The superior orbital fissure connects directly to the cavernous sinus and the intracranial space. The posterior wall is the source of the blood and nerve supply to the orbit. The optic nerve (cranial nerve [CN] II) enters the orbit with the ophthalmic artery through the optic canal. CNs III, IV, and VI; the ophthalmic branch of the trigeminal nerve (CN V1); and the superior ophthalmic vein enter the cavernous sinus after exiting the orbit through the superior orbital fissure. The superior ophthalmic vein provides the main venous drainage for the contents of the orbit. The smaller inferior ophthalmic vein exits the orbit through the inferior orbital fissure with the maxillary branch of the trigeminal nerve (CN V2) and connects with the temporal fossa. Infectious material can be inoculated directly into the orbital soft tissue secondary to trauma, surgery, or orbital foreign bodies. More rarely, orbital infections develop from hematogenous seeding secondary to sepsis or bacterial endocarditis. Orbital cellulitis may or may not progress to a subperiosteal abscess, orbital abscess, or cavernous sinus thrombosis. Cavernous sinus thrombosis is an infectious thrombosis of the cavernous sinus. (The cavernous sinus, a circular venous structure surrounding the pituitary gland, drains blood from both orbits.). Infectious thrombosis most commonly is spread from the orbit via the valveless orbital veins into the cavernous sinus. Once again, this diagnosis is confirmed by CT scan or MRI; however, the physical sign of bilateral posterior orbital disease is highly suggestive. Intracranial infection or cavernous sinus thrombosis can result from any stage of orbital infections. Meningitis is inflammation of the meninges resulting in meningeal symptoms (eg. headache, nuchal rigidity, photophobia) and an increased number of white blood cells in the cerebrospinal fluid (CSF), i.e., pleocytosis. Depending on the duration of symptoms, meningitis is classified as acute or chronic. Acute meningitis denotes the evolution of symptoms within hours to several days, while chronic meningitis has an onset of weeks to months. Cranial nerve palsies may be observed as a result of increased ICP or the presence of exudates encasing the nerve roots.

We received referral for this patient at day 11 of illness. He has bilateral divergent squint due to bilateral 6th cranial nerves palsies. A bruit was detected over the left eye. There was no evidence of orbital swellings or meningitis. He was transferred to our care when his condition remained static on day 16 of illness. The theoretical and practical background would be discussed here. The abducens nerve (6th cranial nerve) begins at the lower border of pons in the pontomedullary sulcus, 1 cm from the midline. The nerve then ascends through the ventral surface of pons, crossed by anterior inferior cerebral artery, pierces the dura of clivus 2 cm below the posterior clinoids. It passes above the inferior petrosal sinus, beneath the petroclinoid ligament. It travels through cavernous sinus freely, inferolateral to the inferior cerebral artery with attached sympathetic fibers. It exits the cranium at superior orbital fissure to innervate lateral rectus muscle. Possible anatomical aetiologies include Abducens nucleus lesion at the brain stem, lesion of medial longitudinal fasciculus (intranuclear opthalmoplegia), lesion of nucleus prepositus hypoglossi and adjacent medial vestibular nucleus, Abducens nerve lesion and muscular and eyeball lesions. Abducens nerve lesions and muscular and eyeball lesions result in abduction deficit. The examples of the lesions are Graves myopathy (fibrotic medial rectus), Myasthenia gravis, orbital pseudotumour / myositis, orbital trauma (medial rectus entrapment), congenital defects (Duane, Mobius syndrome) and convergence spasm (spasm of near reflex). Causes of localizing infranuclear sixth palsy include pontine syndrome (infarct, demyelination, tumour), cerebello pontine angle lesions (meningioma), clivus lesion (chordoma), disorders of middle cranial fossa and lesions at the cavernous sinus or superior orbital fissure (tumour, inflammation, aneurysm, orbital apex fracture). Possible aetiologies in a child with isolated 6th nerve palsy without other neurological signs are recent viral infection and middle ear infections.

The investigations that may be helpful in double pathology are tensilon test, serum glucose and glycosylated haemoglobin, ESR, contrast CT scan of orbital apex, sella, clivus and cavernous sinus and contrast MRI of cavernous sinus and clivus. Looking back, definite history of head injury leads to consideration of missed injury of brain stem, skull base fracture and untreated diffuse brain injury with marked cerebral oedema which leads to increased intracranial pressure and delayed 6th nerve palsy. The obvious clinical history of meningitis and meningism attracts one to think about basal meningitis and subarachnoid haemorrhage. Eye injury and spreading inflammation point towards cavernous sinus thrombosis and bilateral spread. However, left eye bruit definitely denotes vascular problem (dural AVM, aneurysm, indirect carotid-cavernous fistula or other concomitant connective tissue disorder flare up and orbital pseudotumour). It is not a case of double pathology of isolated 6th nerve palsy. With provisional diagnosis of vascular pathology and differential diagnosis of brain stem disorders, we referred the patient for cerebral angiogram. The result was normal. Our management plans for this patient include observation with close follow up, steroid trial (60mg prednisolone daily for 5 days) and surgical correction after 6-12 months after thorough assessment of lateral rectus and medial restus muscles.

Meningitis due to S aureus accounts for 1-9% of all cases of bacterial meningitis and is associated with mortality rate of 14-77%11,12. It usually is associated with neurosurgical interventions (such as cerebrospinal fluid [CSF] shunts), trauma or underlying conditions such as malignancy, decubitus ulcers, cellulitis, infected intravascular grafts, diabetes mellitus, osteomyelitis or perirectal abscess. S aureus meningitis has 2 different pathogenic mechanisms. In the first form, bacteria are introduced during surgery or by trauma or local spreading (especially coagulase-negative staphylococci) from contiguous infections. Bacteria introduced during surgery cause foreign body infection and subsequent postoperative meningitis. Attachment of S aureus to foreign body involves interaction with proteins of the extracellular matrix: fibrinogen, fibronectin, laminin, thrombospondin, vitronectin, elastin, bone sialoprotein and collagen. S aureus ligands for these host proteins have been characterized, cloned and sequenced. In the second form, hematogenous or spontaneous meningitis, S aureus is disseminated systemically. Infection is more often community acquired, and the incidence of positive blood culture results is higher, as is mortality rate. S aureus attachment to endothelial cells during septicaemia is complex and involves interaction with fibronectin, fibrinogen and laminin. After adhesion, phagocytosis by endothelial cells and induction of tissue factor procoagulant activity occur.

Any localized S aureus infection can lead to bacteraemia. In the preantibiotic era, mortality rate was 82%13,14. Recent studies reported mortality rates between 30% and 40% in non-drug using patients with S aureus septicaemia14. Patient with this type of infection have a lower mortality rate compared to those with hematogenous meningitis, which may be explained by early recognition and less systemic involvement Staphylococcal meningitis is associated with a high mortality rate (about 50% in adult), particularly haematogenous S aureus meningitis (mortality rate 18-56%). The prognosis for CSF shunt infections is more favourable, probably because of earlier recognition15. In one study, 38 of 154 (25%) cases of bacterial meningitis during a 7-year period were nonpneumococcal gram-positive coccal infections; the majority of cases were due to S aureus and S epidermidis15.

Laboratory identifications are: full blood count with differential demonstrates polymorphonuclear leukocytosis and CSF analysis is the diagnostic test of choice for suspected meningitis. The CSF lactate dehydrogenase (LDH) appears to be diagnostic and has a prognostic value in bacterial meningitis. Increase in total LDH is observed consistently in bacterial meningitis, mostly due to increase in fractions 4 and 5, which are derived from granulocytes. LDH fraction 1 and 2, derived presumably from brain tissue, are elevated only

We believe that the patient suffered from a septic bacteriologic process affecting central nervous system causing cerebral oedema and cranial neuropathies albeit somewhat a rare complication the bilateral sixth nerve palsies due to S aureus meningitis or meningoencephalitis can be due to the inflammatory process of the disease itself. The fall causes trauma to the right eye, which then acts as a nidus of infection (S. aureus) which later spread to the central nervous system. Although we were unable to confirm whether or not he had bacterial meningitis because the cerebrospinal fluid sample was obtained after the patient has been on intravenous cefipime for almost one week, the clinical features strongly suggest CNS infection. Meningitis is still a relatively common condition in Malaysia and a high index of suspicion should be the practical approach  in any child presenting with high fever associated with drowsiness. This is particularly important in situations where getting CSF sample is a problem. Prompt treatment with appropriate antimicrobial therapy will prevent further complications of this disease. There is a possibility of some pathology in his cavernous sinus during the acute stage of illness that which fortunately was successfully treated. But we were unable to confirm this suspicion with our radiological imaging. The child however responded fairly well to the treatment and we will continue to monitor his progress in the outpatient clinic.


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@ Department of Paediatrics, International Islamic University, Malaysia
# Department of Ophthalmology, International Islamic University, Malaysia
$ Department of Surgery, International Islamic University, Malaysia
% Department of Basic Medical Sciences, International Islamic University, Malaysia