Dr. Mansoureh Togha Professor of Neurology Tehran University of Medical sciences

CHANGES IN EPIDEMIOLOGY OF BRAIN ABSCESS (in the last 2-3 decades) Lower incidence of otogenic brain abscesses With increase in # of immunocompormised patients (transplant, AIDS,…), increased incidence of brain abscess seen in that population, including those caused by opportunistic pathogens (e.g., fungi, toxo, Nocardia)

PATHOGENESIS Direct spread from contiguous foci (40-50%) Hematogenous spread (25-35%) Penetrating trauma/surgery (10%) Cryptogenic (15-20%)

DIRECT SPREAD From: By: Otitis media & mastoiditis Sinusitis Dental infection (<10%), typically with molar infections Meningitis rarely complicated by brain abscess (more common in neonates with Citrobacter diversus meningitis, of whom 70% develop brain abscess) By: Direct extension through infected bone Spread through emissary/diploic veins, local lymphatics

HEMATOGENOUS SPREAD (from remote foci) empyema, lung abscess, bronchiectasis endocarditis, wound infections, pelvic infections, intra-abdominal source, etc… may be facilitated by cyanotic HD, AVM. Abscess mostly at middle cerebral artery distribution, and often multiple

PREDISPOSING CONDITION LOCATION OF ABSCESS Otitis/mastoiditis Temporal lobe, Cerebellum Frontal/ethmoid sinusitis Frontal lobe Sphenoidal sinusitis Frontal lobe, Sella turcica Dental infection Frontal > temporal lobe. Remote source Middle cerebral artery distribution (often multiple)

MICROBIOLOGY OF BRAIN ABSCESS AGENT FREQUENCY (%) Streptococci (S. intermedius, including S. anginosus) 60–70 Bacteroides and Prevotella spp. 20–40 Enterobacteriaceae 23–33 Staphylococcus aureus 10–15 Fungi * 10–15 Streptococcus pneumoniae <1 Haemophilus influenzae <1 Protozoa, helminths † (vary geographically) <1 *Fungi (Aspergillus Agents of mucor Candida Cryptococci Coccidiodoides Cladosporium trichoides Pseudallescheria boydii) †Protozoa, helminths (Entamoeba histolytica, Schistosomes Paragonimus Cysticerci) CTID,2001

PREDISPOSING CONDITION USUAL MICROBIAL ISOLATES Lung abscess, empyema, bronchiectasis Fusobacterium, Actinomyces, Bacteroides Prevotella spp., streptococci, Nocardia Bacterial endocarditis S. aureus, streptococci Congenital heart disease Streptococci, Haemophilus spp. Neutropenia Aerobic gram-negative bacilli, Aspergillus Mucorales, Candidaspp. Transplantation Aspergillus spp., Candida spp., Mucorales, Enterobacteriaceae, Nocardia spp., Toxoplasma gondii HIV infection Toxoplasma gondii, Nocardia spp., Mycobacterium spp., Listeria monocytogenes, Cryptococcus neoformans PPID, 2000

PATHOPHYSIOLOGY of Brain Abscess Begins as localized cerebritis (1-2 wks) Evolves into a collection of pus surrounded by a well-vascularized capsule (3-4 wks) Lesion evolution (based on animal models): Days 1-3: “early cerebritis stage” Days 4-9: “late cerebritis stage” Days 10-14: “early capsule stage” > day14: “late capsule stage”

Effect of Brain Abscess Direct destruction Compression of parenchyma Elevation of intracranial pressure Interfering with blood &/or CSF flow

CLINICAL MANIFESTATIONS OF BRAIN ABSCESS Headache 70% Fever 45-50 Focal neurologic findings >60 Triad of above three <50 Altered mental status <70 Nausea/vomiting 25-50 Seizures 25–35 Nuchal rigidity 25 Papilledema 25 PPID,2005

HEADACHE in Brain Abscess Usually non-specific, dull, and poorly localized. If abrupt & extremely severe headache: consider meningitis or SAH. Sudden worsening in H/A w meningismus: consider rupture of brain abscess into ventricle.

Diagnostic work-up MRI is the procedure of choice more sensitive especially for early cerebritis, satellite lesions, necrosis, ring, edema, especially for posterior fossa & brain stem abscesses CT scan with contrast enhancement is 95% sensitive Skull roentgenograms usually normal Biopsy or aspiration needed for definitive diagnosis Laboratory findings often not helpful Lumbar puncture contraindicated

LABORATORY TESTS BRAIN ABSCESS Aspirate: Gram/AFB/fungal stains & cultures, cytopathology (+/-PCR for TB) WBC Normal in 40%, only moderate leukocytosis in ~ 50%, & only 10% have WBC >20,000 CRP almost always elevated ESR Usually moderately elevated BC Often negative, BUT Should still be done AVOID LP!! Risk of herniation 15-30% May even have normal CSF findings, but: Usually elevated CSF protein & cell count (lymphs) Unremarkable CSF glucose CSF culture rarely positive

DIFFERENTIAL DIAGNOSIS Malignancy Abscess has hypodense center, with surrounding smooth, thin-walled capsule, & areas of peripheral enhancement. Tumor has diffuse enhancement & irregular borders. PET scan may differentiate. CRP?? CVA Hemorrhage Aneurysm Subdural empyema Epidural abscess

TREATMENT Medical & surgical Obtain Neurosurgical Consult ASAP Aspiration or excision Antibiotics Initially selected based on: -Likely pathogen: considering primary source, underlying condition, & geography -Antibiotic characteristics: MICs for usual pathogens, CNS penetration, activity in abscess cavity Duration of abx: usually 6-8 wks After surgical excision, a shorter course may suffice

ANTIBIOTICS TREATMENT ONLY (WITHOUT SURGERY) Only in pts with prohibitive surgical risk: poor surgical candidate, multiple abscesses a dominant location Abscess size <2.5 cm concomitant meningitis, ependymitis early abscess (cerebritis?) In pt already showing improvement on abx

MONITOR RESPONSE CLOSELY WITH SERIAL IMAGING

USUAL APPEARANCE OF CEREBRAL ABSCESS ON MRI Post-Gd T1WI: Abscess in the right thalamus shows low signal intensity within its cavity and an enhancing rim. Note subtle hypointense outer rim, corresponding to edema.

USUAL APPEARANCE OF CEREBRAL ABSCESS ON MRI T2WI: Same patient with right thalamic abscess. There is high signal in the abscess cavity and in the surrounding edema. Note low signal intensity in the rim surrounding the cavity which is thought to be secondary to susceptibility artifact from presence of local free radicals, and indicates a mature abscess.

USUAL APPEARANCE OF CEREBRAL ABSCESS ON MRI DWI: Same patient in previous two slides. There is marked high signal intensity in the abscess corresponding to restricted diffusion of water molecules in the cavity. Note mild hyperintensity surrounding the cavity due to “T2 shine through” from edema.

USUAL APPEARANCE OF CEREBRAL ABSCESS ON MRI Left and right frontal abscesses: Another example of the expected appearance of abscesses on MRI. The abscess cavities show low and high signal on T1- and T2WI, respectively. There is surrounding vasogenic edema and mature capsules. There is corresponding high signal on trace DWI. Dark signal on ADC map confirms restricted diffusion. 35-year-old male presenting with seizure, left sided weakness, and urinary incontinence. Drainage was performed and cultures grew Streptococcus anginosus.

ATYPICAL APPEARANCE OF BACTERIAL ABSCESS ON DWI Mixed signal: Abscess located in the left temporooccipital region. There is a hypointense cavity with an enhancing rim on the post-Gd T1WI. FLAIR image (middle) shows high signal in the rim, surrounding tissues and in the anterior part of the cavity corresponding to areas of edema and pus. There are also isointense areas in the cavity. (Continued)

ATYPICAL APPEARANCE OF BACTERIAL ABSCESS ON DWI Mixed signal: (Continued) DWI (right) shows high signal in the cavity corresponding to the region of hyperintensity on the FLAIR image and decreased signal corresponding to isointense region which indicates either free diffusion or susceptibility, such as that from focal hemorrhage.

TUBERCULOMA Early lesions are usually isointense on T1- and T2WI, and have variable Gd enhancement. Mature lesions have ring enhancement on post-Gd T1WI and low signal centrally on T2WI. Normal DWI signal is common even in mature tuberculomas.

TUBERCULOMA Normal DWI signal: Images show a tuberculoma in the left frontotemporal region. There is bright rim enhancement, characteristic hypointensity in its central portion on T2WI and vasogenic edema. The central area is isointenste to gray matter DWI and there is mild “T2 shine through” from edema. ADC map (far right) shows minimally restricted diffusion. 3-year-old female with miliary TB. At biopsy, fluid could noto be aspirated from the cavity.

TUBERCULOMA Two examples of tuberculomas with low signal on DWI: DWI of right occipital (top) and right cerebellar (bottom) show that neither of these lesions have restricted diffusion.

NOCARDIA Renal transplant patient: Post-Gd T1WI (top) shows multiple punctate lesions. Note that individual lesions are not discriminated on the trace DWI and that the abnormalities are seen as confluent areas of high signal due to “T2 shine through.”

Nocardia Genus : aerobic actinomycetes G+ branching filamentous bacteria Subgroup: aerobic nocardiform actinomycetes -Mycobacterium -Corynebacterium -Nocardia -Rhodococcus -Gordona -Tsukamurella

Nocardia :ECOLOGY& EPIDEMIOLOGY The risk of pulmonary or disseminated disease *deficient cell-mediated * -Alcoholism -Diabetes -Lymphoma -Transplantation -Glucocorticoid therapy -AIDS CD4+ < 250 Transmission Inhalation Skin

CLINICAL MANIFESTATIONS : 4 main form Lymphocutaneous syndrome Pulmonary :Pneumonia CNS : Brain abscess Disseminated disease CNS Eyes (particularly the retinaKeratitis), Skin& subcutaneous Kidneys, Joints, bone Heart

Pulmonary disease Pneumonia Endobronchial inflammatory mass Subacute(more acute in immunosuppressed) Cough** Small amounts of thick, purulent sputum Fever, anorexia, weight loss, malaise Endobronchial inflammatory mass Lung abscess Cavitary disease Inadequate therapy Progressive fibrotic diseaseฆ Cerebral imaging,should be performed in all cases of pulmonary and disseminated nocardiosis

Nocardial pneumonia. Discrete nodular in midlung on both sides

CT scan (A),CXR (B) from : multiple abscesses : Nocardia farcinica

CNS : Brain abscess Insidious presentations : mistaken for neoplasia !!! Granulomatous , abscesses Cerebral cortex, basal ganglia and midbrain*** Less commonly: spinal cord or meninges. Brain tissue diagnosis in pulmonary nocardiosis : not necessary However, cerebral biopsy:considered early in immunocompromised

brain abscess ; Nocardia farcinica Nocardial abscess :rt. occipital lobe

LABORATORY DIAGNOSIS Gram-positive, beaded, branching filaments usually weak acid fast+ve . Standard blood culture :48 hrs to several wks, but typical = 3 to 5 days Colonization of sputum :underlying pulmonary dz + not receiving steroid therapy no specific therapy Susceptibility testing -Deep-seated /disseminated dz. fail initial therapy -Relapse after therapy -Alternatives to sulfonamides are being considered

MANAGEMENT :Medication Sulfonamides : the mainstay of therapy treatment of choice :N. brasiliensis N. asteroides complex N. transvalensis. severely ill patients, CNS /disseminated/ immunosuppressed patients =/> 2 drugs Amikacin and Carbapenem or 3rd generation cephalosporin.

MANAGEMENT :Medication TMP-SMX :currently preferred :drugs in serum:CSF = 1:20 :high MICs  good therapeutic responses -General:5-10 mg/kgTMP & 25-50 mg/kgSMX divide2- 4times -Cerebral abscesses,severe,disseminated,AIDS :15 mg/kg TMP and 75 mg/kg SMX) -Cutaneous infection: 5 mg/kg/day (TMP) + DB Hypersensitivity reactions :Desensitization

MANAGEMENT Medication:alternative therapeutic drugs Failed sulfonamide Rx: N. otitidiscaviarum Intolerant : hypersensitivity,GI toxicity, myelotoxicity) Parenteral : Imipenem & amikacin : Meropenem : 3rd-gen cephalosporins Ceftriaxone, cefotaxime Oral:Amoxicillin clavulanate :Minocycline(100–200 mg twice daily) :Linezolid :new oxazolidinone ;effective orally (bioavailability~100%), good CSF penetration

MANAGEMENT Surgical drainage: depend on site Extraneural aspirate,drainage, excision Brain abscesses 1) Accessible and relatively large AND 2.1) Lesions progress within 2 wks or 2.2) No reduction in abscess size within a month.

Duration of Therapy : at least 12 mo. + Clinical improvement: most 7 -10 days Parenteral 3 to 6 wks oral regimen Primary cutaneous infection :1-3 mo. Nonimmunosuppressed -Pulmonary /systemic nocardiosis: at least 6 mo -CNS involvement : for 12 months Immunocompromised HIV-negative immunosuppressed :12 mo or longer if there are intercurrent increases in immunosuppression AIDS : at least 12 mo. + low-dose maintenance (long life)

Outcome of therapy Cure rates -skin or soft tissue : almost 100% -pleuropulmonary disease : 90% -disseminated infection : 63% -brain abscess : 50% Mortality -brain abscesses :31% -multiple abscesses :41% -immunocompromised patients :55%

MONITORING TREATMENT WITH DWI The following are three examples of cerebral abscesses which were followed with serial MRI examinations, including DWI after surgical drainage. The appearance of the abscess cavity on DWI can indicate success or failure of treatment.

Example 1: 2-year-old female with seizures and right-sided paraparesis Example 1: 2-year-old female with seizures and right-sided paraparesis. Initial MRI shows a left posterior frontal abscess. The edema is best seen on T2WI (far left) and the mild peripheral enhancement on post-Gd T1WI (2nd from left). There is restricted diffusion in the cavity (DWI image, 3rd from left) confirmed on ADC map (far right). (Continued)

Example 1: (Continued) Images obtained approximately 2 months after surgery. In the region of the abscess there is a non-enhancing linear area without abnormal signal on DWI, consistent with focal gliosis (no recurrence). Clinically, the patient was cured.

Example 2: Serial MRI studies (post-Gd T1WI, DWI, ADC) obtained at one-week intervals in a 40-year-old man presenting with fever, headache and vision disturbance. The left occipital abscess was drained. The lesion has similar characteristics to that shown in the previous case with a notable change on DWI following drainage and resolution of the lesion over time.

CONCLUSIONS Pyogenic abscesses have a typical appearance on DWI TB and toxoplasmosis usually little restriction of water motion when compared to pyogenic abscesses Fungal abscess have a variable DWI appearance DWI can be use to monitor cerebral abscesses during the course of therapy