A 63-year-old male with a 10-year history of cocaine abuse presented with hyperpyrexia, seizures, and left hemiparesis. On admission, blood tests showed significant neutrophilic leukocytosis (28 × 103) and high C-reactive protein levels (346 mg/L). Once vital functions were stabilized and seizures were arrested, he underwent contrast-enhanced computed tomography (CT) of the head, which showed a right intra-axial temporopolar lesion (35 × 33 mm) with non-homogeneous contrast enhancement associated with digitiform perilesional edema and another large extra-axial bilateral frontal-basal lesion, which also presented non-homogeneous contrast enhancement. Moreover, extensive remodeling of the nasal and paranasal cavities, recognizable as cocaine-induced midline destructive lesions (CIMDL), and a hyperdense collection in the posterior aspect of the right maxillary sinus, spreading beyond the sphenopalatine foramen and pterygopalatine fossa through the orbital cavity and intracranial compartment were detected []. Subsequent contrast-enhanced MRI of the head confirmed the presence of a round lesion on the right temporal pole, with central necrosis and peripheral ring contrast enhancement []. Spectroscopy sequences showed a choline spike, altered choline/creatine ratio, and elevated N-acetyl-aspartate and lactate levels. These findings were suggestive of the temporopolar abscess. Furthermore, a vast subdural empyema was detected in the bilateral frontal-basal and right paraclinoidal regions. The images also showed an infective process pathway through the intracranial compartment and right orbital cavity. There were no appreciable bony defects in the middle basicranium or clinically clear rhinoliquorrhea. The hyperintensity of the right pterygopalatine fossa and posterior aspect of the right orbital cavity on MRI suggested direct spreading of the suppuration. Indeed, the hypothesized dissemination pathway of the inflammatory process started from the maxillary sinus, proceeding through the sphenopalatine foramen toward the pterygopalatine fossa, and then upward through the inferior orbital fissure toward the posterior aspect of the orbital cavity and, lastly, spread posteriorly, and superiorly, through the superior orbital fissure, toward the middle cranial fossa []. Blood cultures showed no bacterial infection in the bloodstream, consequentially osmotic and empiric antibiotic therapy was administered. Endoscopic endonasal exploration was performed, which confirmed almost total erosion of the nasal septum and turbinates, destruction of medial walls of maxillary sinuses, and absence of ethmoidal cells; thus, during the procedure, nasal cavities were cleaned with abundant and repeated H2O2 and antibiotic washings. Osseous erosion toward the middle cranial fossa was not observed. Two days later, a second surgical intervention was performed using the frontal-temporal approach. Yellowish liquid from the underlying subdural compartment was detected above the dura mater and collected for microbiological and cultural examination. As a plausible consequence of this inflammatory reaction, the dura mater appeared taut, thick, and yellowish. The right frontal basal side of the outer membrane of the subdural empyema was opened, revealing an organized purulent collection. The anterior and basal portions of the lesion were removed in fragments. They presented parenchymatous consistency and yellowish color and were tenaciously adherent to the underlying tissues. Therefore, minimal temporal corticectomy was performed, and the abscess capsule content was aspirated []. Cultural examination revealed the presence of S. anaerobium susceptible to meropenem and levofloxacin. The postoperative course was regular, and the patient was free from further complications. A contrast-enhanced postoperative MRI scan demonstrated resolution of the bilateral subdural empyhematous collection and reduction in the diameter of the right temporopolar abscess. Targeted therapy reduced the contrast-enhanced lesion in the right temporal pole and remaining phlogistic tissue within the pterygopalatine and orbital cavities. Regression of radiological signs and clinical symptoms related to cerebritis in the temporal and right frontal areas has been previously reported. Blood tests on the 1st postoperative day showed a considerable decrease in C-reactive protein blood levels (49.84 mg/L) and white blood cell count (6.81 × 103). Postoperative head CT showed a sharp volume reduction of the extra-axial empyema collections and intra-axial abscess associated with regression of the central necrotic part and decreased intralesional septation. The patient’s neurological status progressively improved. Targeted antibiotic therapy successfully resolved the intraparenchymal abscess. The patient was dismissed due to an intact neurological status and an indication to follow targeted antibiotic treatment for the following 6 weeks. The 1-month postoperative MRI confirmed that the inflammation resolved in the pterygopalatine fossa and orbital cavity and showed a meaningful reduction in diameter on the axial plane of the temporopolar abscess (1.23 × 0.53 cm). Moreover, the subdural empyema located bilaterally in frontal-basal areas showed almost complete resolution, as well as infection of the right pterygopalatine fossa [].