Clinical manifestations

Presentation and course

Intracranial subdural empyema is significantly more common in males than in females and is predominantly a condition of children and young adults; 70% of cases occur in the second and third decades of life (47; 89; 76; 35; 81). In a series including cases occurring after craniotomy, the male-to-female ratio was 56:44, and the mean age was older (32). In many series, there has been a bimodal distribution of infection: cases in infancy associated with meningitis or mastoiditis, and cases in older children, adolescents, and young adults associated with sinusitis (37). The onset of symptoms in subdural empyema is often abrupt (48; 47; 76; 09; 32). If the diagnosis of subdural empyema is not made early in the course of infection, progression of neurologic injury occurs over hours to days, producing signs that indicate involvement of an entire cerebral hemisphere or widespread involvement of posterior fossa structures (22; 54; 20; 48; 72; 89; 35; 32). Rapidity of progression was emphasized by a case in which an empyema was observed by MRI to triple in size within a period of 12 hours (110). In cases following neurosurgical procedures, however, more gradual onset of symptoms over a period of up to 3 weeks may be seen (20; 83; 32; 81). Forty percent of patients will present with nausea and vomiting (81). Early symptoms include fever (present in over 70% to 80% of patients), localized cranial pain, focal or generalized headache, and symptoms of nasal or sinus congestion (20; 48; 32). Roughly a quarter of patients will present with seizures (48; 47; 76; 09; 32). Lin and colleagues have reported a patient in whom development of subdural empyema and meningitis was preceded by symptoms consistent with trigeminal neuralgia (61). Nuchal rigidity is often present and may suggest meningitis (48; 09). Enlargement of the empyema is accompanied by signs of increased intracranial pressure and alteration in mental status. Focal neurologic deficits, particularly hemiplegia, are present in the majority of patients, and subdural empyemas overlying the dominant hemisphere may produce aphasia (20; 48). Focal symptoms, however, are often overshadowed by more ominous findings produced by mass effect of the empyema. Subdural empyema is extremely irritating to underlying brain and is accompanied by focal or generalized seizures in approximately 50% of cases (48). Enlargement of the empyema may be so rapid that coma and death may occur before papilledema becomes clinically evident. Venous extension of infection inward may produce meningitis, brain abscess, or septic intracranial venous thrombosis (54; 48; 09). Parafalcine subdural empyemas may present without clear localizing symptoms or signs other than headache, signs of meningeal irritation, or increased intracranial pressure (98). Rare patients may develop a subtentorial subdural empyema, with danger of hydrocephalus and upward as well as transtentorial herniation (97; 92; 71). These patients, who are at extreme risk for rapid decompensation, may be without cerebellar or brainstem signs, although sixth nerve palsies may be present (97; 71). The clinical course of subdural empyema in children older than 6 years of age and in adolescents is similar to that seen in adults (35; 52; 74; 65). Subdural empyema in infants and small children is usually a complication of bacterial meningitis (80; 99). Diagnosis in these young patients is often more difficult because early symptoms may be masked by those of meningitis, and the subdural empyema may come to be suspected only as the patient fails to improve despite successful treatment of meningitis (90; 62; 65). In infants, a bulging fontanelle may be present. The empyema may be sufficiently turbid; however, that transillumination may be negative.

Prognosis and complications

Untreated subdural empyema is rapidly fatal. With therapy, overall mortality in subdural empyema in older children and adults has fallen from 20% to 40% in the late 1970s, to 7% to 25% at present (48; 89; 82; 101; 12; 27; 76; 58). Germiller and colleagues, in a review of nine cases of intracranial subdural empyema in children and adolescents, reported no deaths (35), as did French and colleagues in a series of 36 patients presenting from 2001 to 2011 (32), and Otto and colleagues in a series of 54 patients between 1 and 21 years of age (81). Morbidity rates in reported studies have varied from 14% to 58% (40; 82; 101; 12; 27; 32); up to 30% of survivors may be left with severe neurologic deficits. Likelihood of death and severity of neurologic injury are functions of delay in diagnosis and of patient neurologic status at the presentation. A minority of patients may require repeat surgical intervention (32). In a study, intracranial subdural empyemas related to sinogenic infection were found to have significantly more severe clinical presentation, a higher morbidity, and need for a longer duration of antibiotic therapy than that those associated with otogenic infection (84).

Clinical vignette

A 47-year-old male was in excellent health until 1 week prior to admission, when he developed an upper respiratory infection with accompanying severe nasal congestion. Over the next several days the patient repeatedly instrumented his nasal mucosa in an effort to improve his ability to breathe. On the morning of admission, his wife found him unresponsive, with irregular respirations, and brought him to the hospital. On examination, the patient was comatose, without response to voice, loud noise, or pain. The patient initially had Cheyne-Stokes respirations. Respirations became rapid and irregular during the examination. Pulse was 75 per minute and regular. Blood pressure was 150/90. Temperature was 39.5°C. General physical examination was unremarkable except for nuchal rigidity; optic discs were flat. Cranial nerve examination revealed a right third nerve palsy involving the pupil and a left facial weakness. Motor examination revealed a flaccid left hemiparesis. Reflexes were depressed on the left. Babinski sign was present bilaterally. Emergent CT scanning showed bilateral frontal and maxillary sinusitis. A large hypodense space-occupying lesion was present over the left hemisphere, extending along the falx cerebri. The patient was begun on nafcillin, metronidazole, and cefotaxime. Emergent craniotomy resulted in drainage of over 75 mL of purulent material. Cultures grew out microaerophilic streptococci, sensitive to penicillin. The patient's antibiotics were changed to intravenous penicillin G. The patient awakened and made a gradual recovery but was left with a mild right hemiparesis and mild intellectual impairment.

Biological basis

Etiology and pathogenesis

The causative agents of subdural empyema are similar to those associated with intracranial epidural abscess and brain abscess. Aerobic, microaerophilic, and anaerobic streptococci, including Streptococcus milleri and Streptococcus anginosus, are common in epidural abscesses associated with sinusitis or otitis (48; 47; 109; 89; 04; 27; 44; 76; 52; 19; 32; 81). Mirza and colleagues reported isolation of Escherichia coli from a subdural empyema associated with mastoiditis and cholesteatoma (70). Streptococcus pneumoniae has been identified as the most common organism in cases of intracranial subdural empyema complicating meningitis (46). Multiple additional organisms, including Bacteroides species and enteric bacteria such as Escherichia coli, Proteus species, or Pseudomonas species may also be present in this setting (109; 90; 04; 15; 76). Nontyphoidal Salmonella species have been associated with intracranial subdural empyema in the setting of advanced AIDS or, occasionally, in children (02; 26). Anaerobic organisms may be detected in up to 100% of cases in which meticulous care is taken in obtaining cultures (109). Staphylococcus aureus is the most common organism in cases associated with cranial trauma or surgical procedures and can also be seen in a minority of nonsurgical patients. Subdural empyema following neurosurgical procedures may also be caused by coagulase-negative strains of Staphylococcus; Propionobacterium acnes; Mycoplasma hominis; Eikenella corrodens; anaerobes, including S milleri; or Gram-negative organisms, including Campylobacter fetus (107; 90; 04; 69; 32). Infections due to P acnes and M hominis are particularly likely to occur in immunosuppressed patients or to be associated with implanted surgical devices. In such cases, presentation of the empyema may be significantly delayed (36). Subdural empyema associated with internal jugular vein thrombosis and septic pulmonary vein thrombosis (Lemierre syndrome) has been associated with Fusobacterium septicemia (94). In a minority of patients, multiple organisms may be present (107; 90; 04; 69; 32). As noted above, subdural empyema in infants and small children is almost always a complication of meningitis, and isolates from subdural fluid are usually identical to those causing the meningitis (29; 90; 57; 95; 32). In older children, as in adults, subdural empyema is most commonly a complication of sinusitis or otitis (57; 99). Tuberculous subdural empyema has been reported in children but is extremely rare (05).

Subdural empyema represents infection within the potential space that lies between the dura and arachnoid (08; 09). This space surrounds the brain and is interrupted only where the arachnoid and dura are joined along the falx cerebri, the tentorium cerebelli, and the base of the brain. Infection within the subdural space can, thus, spread rapidly (at times within hours) over an entire cerebral hemisphere or most of the posterior fossa to behave as a large, rapidly expanding mass lesion (08; 09). Historically, subdural empyema has most commonly occurred as a complication of sinusitis or otitis and develops following septic thrombophlebitis of the emissary veins that connect the venous drainage of facial structures, sinuses, middle ear, and mastoid with the deep cerebral venous system (54; 48; 102; 33; 09). In this setting, subdural empyema is frequently preceded or accompanied by epidural abscess (48). Empyemas along the falx (parafalcine subdural empyemas) or the tentorium most commonly arise as complications of otitis media (86; 100). In a series of 10 patients, Salunke and colleagues found parafalcine subdural empyemas as most commonly representing a complication of otitis media, with a minority of cases appearing to have been hematogenous in origin (86). Subdural empyema may also develop following cranial trauma or neurosurgical procedures (107; 90; 04; 75; 73), and in a series by French and colleagues, this was the most common setting in which subdural empyema was found, followed by sinusitis and otitis (32). In this series and that by Kim and colleagues, the most common setting was following drainage of a subdural hematoma (32; 51). A small number of cases have occurred following dental procedures (16). At times, subdural empyema may occur months or years after cranial injury (93). In infants, subdural empyema most commonly occurs as a complication of bacterial meningitis (57; 32). In children, subdural empyema may occur as a complication of otitis or mastoiditis, with a small number of cases associated with bacterial meningitis or sinusitis (06; 57). Rarely, subdural empyema will develop after bacteremic seeding of a preexisting subdural hematoma, transforming an indolent pathologic process into a fulminantly progressive one (20; 14; 59; 50; 23). Extension of infection inward from the subdural empyema may result in meningitis, cortical vein or venous sinus thrombophlebitis, or brain abscess. The empyema frequently produces intense cortical encephalitis within underlying brain (54; 89).

A number of cases of intracranial subdural empyema have been reported in both adults and children in association with SARS-CoV-2 (COVID-19) virus (17; 10; 63; 108; 03; 39). Two of these studies suggest an increased incidence of intracranial subdural empyema in association with COVID-19 (03; 39). The relationship, if any, between the development of empyemas and SARS-CoV2 infection with its ability to target endothelial cells and its possible accompanying hypercoagulable state is not known.

Epidemiology

Intracranial subdural empyema accounts for 15% to 25% of space-occupying intracranial infections (89; 40). The condition is predominantly a disorder of males and, outside of neurosurgical settings, most commonly occurs in two age groups: during infancy as a complication of bacterial meningitis or, in late adolescence and young adulthood, as a complication of sinusitis or otitis. The more frequent occurrence of subdural empyema in adolescents and young adults is thought to possibly reflect the rapid enlargement of the paranasal sinuses during that period of life (47; 32; 99).

Prevention

No specific measures have been described for prevention of intracranial subdural empyema. Specific risk factors do exist, however, and proper treatment of these conditions remains the key to prevention of subdural empyema. Sinusitis, in particular involving the frontal or sphenoidal sinuses, is the major risk factor for development of a subdural empyema (48; 47; 24; 07; 101; 27; 35). A smaller number of cases are associated with otitis media or mastoiditis (48; 47; 88), or as a consequence of cranial trauma or surgery involving the skull, sinuses, middle ear, or mastoid (107; 48; 47; 90; 04; 75; 32). The possibility of subdural empyema should be kept in mind in a patient who worsens following burr hole drainage of a subdural hematoma (32; 51).

Differential diagnosis

Confusing conditions

Early symptoms of intracranial subdural empyema may be masked by those of a severe sinusitis or otitis or a preceding epidural abscess, with fever and local pain (20; 55; 89; 76; 32). The symptoms of the empyema itself (focal pain, generalized headache, signs of increased intracranial pressure) may suggest epidural abscess, brain abscess, or meningitis (89; 09; French et at 2014).

Diagnostic workup

The possibility of intracranial subdural empyema should be kept in mind in any patient with sinusitis or otitis who develops fever accompanied by focal cranial pain, or diffuse headache, or both. The presence of sinusitis or otitis should heighten suspicion that a subdural empyema might be present, although the sinusitis or otitis that led to the empyema may be clinically silent.

Fever and leukocytosis are often present but may be attributed to the sinusitis or otitis. Frontal subperiosteal swelling, indicative subperiosteal abscess (Pott’s puffy tumor) is most often associated with intracranial epidural abscess but may occasionally be seen when infection has spread into the subdural space (11). Experience in children suggests that elevation in erythrocyte sedimentation rate or C-reactive protein may help in distinguishing epidural abscess or subdural empyema from uncomplicated sinusitis (01). CSF procalcitonin, although used for rapid diagnosis of bacterial meningitis, appears to be insensitive in the diagnosis of subdural empyema (43). The diagnostic procedure of choice, however, is MRI with gadolinium enhancement (103; 104; 53; 68; 85; 41; 77).

This procedure, used with a high level of suspicion, may diagnose subdural empyema at a time when symptoms are confined to headache and fever (25). Work by Tsuchiya and colleagues and by Wong and colleagues suggests that diffusion-weighted imaging, together with comparison of images with apparent diffusion coefficient studies may be of value in differentiating subdural from epidural intracranial infections, and in differentiating subdural empyemas from subdural effusions (96; 106; 13). Patient sedation, with careful monitoring of vital signs, may be essential to achieve an adequate study. CT will also reveal the presence of an empyema in many cases.

It should be kept in mind, however, that although CT is superior to MRI in providing information about actual injury to adjacent bone (103), it may fail to detect empyemas easily visible by MRI (42; 53; 68; 09). For this reason, angiography should be strongly considered on an emergency basis in cases in which MRI is not available, and subdural empyema is suspected despite negative CT. Radiological imaging should be studied with care for evidence of sinusitis or otitis, osteomyelitis, or brain abscess. Spinal fluid in older children and in adults is usually sterile, with nonspecific changes in cell count, glucose concentration, and protein level. Superficial review of imaging studies may be misleading: a small subdural or parafalcine ribbon of abscess, given its extent over much of the subdural space may contain a large volume of pus and produce mass effect. Intracranial subdural empyema is almost invariably accompanied by significant elevation of intracranial pressure, and lumbar puncture may precipitate brain herniation and death (48; 41).

Management

Immediate surgical drainage of the empyema and antibiotic coverage remain the mainstays of treatment. Neurosurgical approaches to subdural empyema have included drainage by craniotomy and drainage through multiple burr holes. Although the merits of both approaches have been discussed in articles spanning more than 40 years, the efficacy and morbidity of the two approaches have never been compared in a carefully controlled study (89; 30; 82; 101; 12; 41). In the series reported by French and colleagues, however, three of the four patients treated with burr holes alone required subsequent craniotomy (32). MRI-guided stereotactic surgery has been successfully used in selected cases (18; 64), as has use of flexible endoscopy (31). One elderly patient was successfully treated by drainage through burr holes followed by prolonged intracranial irrigation (28). Surgery may also be required for treatment of the associated sinusitis or otitis. Material obtained at surgery should be submitted for both aerobic and anaerobic culture. Reaccumulation of pus may require repeat surgery (52). In occasional, carefully selected cases, the diagnostic sensitivity of MRI allows diagnosis of subdural empyema at a time when the empyema is too small to permit surgical drainage. In such cases, therapy is undertaken with antibiotics alone, and the empyema is scrupulously followed with serial MRI scans to document resolution of infection and exclude enlargement of the empyema despite antibiotic therapy. Where surgical drainage is deferred, it is imperative that the treating neurologist and neurosurgeon monitor the patient together so that neurosurgical intervention can be initiated on an emergency basis at any time.

Controlled studies of antibiotic treatment of subdural empyema do not exist as of yet. The similarity in the bacterial culture of subdural empyema and that of brain abscess suggests the following approach to treatment (09; 45; 38). Because many abscesses contain a mixed culture of organisms, two or more agents may be required.

Table 1. Antibiotics for Empiric Therapy of Intracranial Subdural Empyema

For initial therapy, where no information exists as to the source of infection, the combined use of vancomycin and ceftriaxone, plus metronidazole should be considered (09). Ceftazidime should be used in place of ceftriaxone if P aeruginosa is strongly suspected (105). Linezolid has been used in individual cases to treat central nervous system infections with methicillin-resistant Staphylococcus aureus (MRSA) and other multidrug-resistant organisms and has been used, both with and without rifampin, in selected cases of subdural empyema not responding to more conventional agents (49; 66; 34; 56). The antibiotic regimen used in a given patient may need to be revised as data become available from cultures obtained at surgery. Length of therapy is determined by patient course and follow-up MRI or CT. In general, antibiotics should be continued for at least 4 weeks if surgery is not undertaken, or 6 to 8 weeks if osteomyelitis is present. The mean duration of antibiotic therapy in the series by Cole and colleagues was 14.4 weeks (19). Careful follow-up of the infection by MRI or, if MRI is not available, by CT is essential if the empyema is treated with antibiotics only.

Special considerations

Pregnancy

Incidence, clinical symptoms, and treatment of intracranial subdural empyema in pregnancy do not differ from those seen in nonpregnant individuals.

Anesthesia

Intracranial subdural empyema is not a contraindication to the use of anesthesia. Large subdural empyemas can be expected to cause significant elevation in intracranial pressure. In such cases, the use of anesthetic agents such as halothane, methoxyflurane, or ketamine should be approached with caution. These agents cause intracranial vasodilatation and may, thus, further increase intracranial pressure and the risk of herniation.