J Neurosurg 51:408-414, 1979
Primary eerebellar noeardiosis Report of two cases
GEORGE W. TYSON, M.D., JOSEPH E. WELSH, M.D., ALBERT B. BUTLER, M.D., JOHN A. JANE, M.D., AND H. RICHARD WINN, M.D.
Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, Virginia v,' The authors describe two cases of primary cerebellar nocardiosis. Confinement of Nocardia abscesses to a localized, accessible portion of the central nervous system should favor surgical cure of this aggressive and often fatal disease. In our two cases multilocularity, tenuous encapsulation, and proximity to the brain stem prevented complete primary excision. Nevertheless, the infections were effectively treated by intensive postoperative antibiotic therapy and, in one case, a second operation to excise the residual abscess. The need for the latter was suggested by the results of sequential computerized tomographic brain scans that were used to monitor the response to antibiotic therapy. In the absence of any apparent extracranial focus of infection and any overt condition that might impair immunological competence, nocardiosis is likely to be omitted from the preoperative differential diagnosis of a posterior fossa space-occupying lesion. KEY WORDS 9 cerebellar abscess 9 computerized tomography primary cerebellar nocardiosis 9 surgical treatment
XTRACRANIAL Nocardia asteroides infections have a tendency to disseminate to the brain. In a review of 147 cases of nocardiosis, Presant, et al., TM found a 36% incidence of secondary cerebral abscesses. Since these abscesses occur ubiquitously within the brain 25 and are frequently multiple, aa confinement of intracranial nocardiosis to the posterior fossa is uncommon. In the few cases that have been reported, the primary infection has been extracranial, usually in the lung. 8,~a,27 In the absence of an extracranial infective focus, the preoperative diagnosis of the cerebral lesion is likely to be erroneous, and the initial surgical management of the Nocardia abscess may therefore be incorrect. 26 Fortunately, primary cerebral Norcardia infections are rare, accounting for only 5% to 7% of cases of nocardiosis. 14'~6'~8 We are reporting two unprecedented cases in which the cerebellum was the only discernible focus of Nocardia infection.
9
Case Reports
E
408
9 nocardiosis
Case 1 This 67-year-old, right-handed farmer was admitted for evaluation of headaches, confusion, and difficulty in walking. He first noted difficulty with memory and concentration 1 month before admission. Two weeks later, he began having increasingly severe frontal headaches associated with attacks of visual obscuration, each of which lasted no more than 5 to 10 seconds. He had lost 20 lbs during the course of his illness. Except for hypertension and chronic congestive heart failure, the patient had been well his entire life. He had a 25-year history of cigarette smoking. Examination. The patient was lethargic but could be aroused by voice, and was then conversational although confused. The oral temperature was 37.4 ~ C; blood pressure, 150/90 mm Hg; pulse, 76/min; and
J. Neurosurg. / Volume 51 / September, 1979
Primary cerebellar nocardiosis
Fro. 1. Case 1. Contrast-enhanced computerized tomography scans. Left: Preoperative study demonstrates a serpiginous lesion in the vermis. Right: Postoperative scan shows only multiple, punctate areas of decreased attenuation in the vermis and left cerebellar hemisphere. The white dot marks the largest of these areas.
respiratory rate 18. General physical examination was remarkable only for signs of chronic obstructive pulmonary disease and a 1 • 1 cm scrotal skin papule. Neurological signs included bilateral papilledema, horizontal nystagmus to the left on left lateral gaze, generalized weakness and hyperreflexia with bilateral Babinski signs, and a left hemi-ataxia. In addition, the patient demonstrated a truncal ataxia while sitting and could not stand, even with support. Hemoglobin was 14.9 gm/dl and white blood cell count 8100/cu mm with 92% polymorphonuclear leukocytes (PMN's). Normal admission laboratory studies included: serum electrolytes, calcium, phosphorus, uric acid, blood urea nitrogen (BUN), creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, glutamic oxaloacetic transaminase (SGOT), lactic dehydrogenase (LDH), cholesterol, prothombin time, and partial thromboplastin time. Urinalysis was also normal. Electrocardiogram showed right bundle-branch block. Chest film demonstrated only signs of chronic obstructive disease. A computerized tomographic (CT) brain scan performed on the day of admission disclosed an irregular, contrast-enhancing mass within the cerebellar vermis (Fig. 1 left). The fourth ventricle was not demonstrated but the other ventricles were enlarged. A diagnosis of obstructive hydrocephalus secondary to primary or secondary cerebellar neoplasm was made.
J. Neurosurg. / Volume51 / September, 1979
Operations. A right-sided ventriculoperitoneal shunt was inserted. The ventricular fluid protein was 8 mg%, and the glucose was 88 mg% (simultaneous serum glucose 111 mg%). There were no leukocytes. Gram and acid-fast stains and bacterial and fungal cultures were negative. The patient became more alert and his headache abated. Subsequent cerebral angiography demonstrated no abnormal vascularity associated with the vermal lesion. Eight days after placement of the shunt, dexamethasone therapy (16 mg/day) was initiated, and 2 days later a suboccipital craniectomy was performed. Incision of the posteroinferior portion of the vermis disclosed a multiloculated abscess with a poorly formed capsule. The loculi were incised and drained, but in the absence of a discernible plane between the abscess and the cerebellum, it was impossible to completely excise the lesion. An intraoperative Gram stain disclosed no definite organisms and intravenous nafcillin (2 gm) and chloramphenicol (1 gm) were given. Immediately after surgery, branching hyphae were seen in a specimen stained by a modified acid-fast technique. The antimicrobial regimen was changed to intravenous sulfisoxazole (12 gin/day) and ampicillin (6 gm/day), and dexamethasone was discontinued. Culture subsequently confirmed the diagnosis of Noeardia asteroides sensitive to the above agents. Postoperative Course. On the first postoperative day, the patient developed acute left ventricular 409
G. W. Tyson, et al. failure. In addition, he was noted to have a left hemiplegia and hemihypalgesia. Results of a CT scan were consistent with cerebral infarction in the distribution of the right middle cerebral artery. The patient subsequently developed Pseudomonas pneumonia and septicemia and required a tracheostomy. A C T scan performed 2 weeks after craniectomy showed several irregular areas of decreased attenuation in the vermis and adjacent portion of the left cerebellar hemisphere (Fig. 1 right). The patient remained critically ill for 6 weeks after his operation, but then gradually improved. A thorough search was made for an extracerebral focus of Nocardia infection, including incision and culture of the scrotal lesion and polytomography of the petrous bones, but all studies were negative. Immunoglobulin electrophoresis was normal. Cerebrospinal fluid (CSF) obtained via lumbar puncture was repeatedly sterile. At the time of discharge, the CSF protein was 111 mg% and the glucose was 60 mg% (serum glucose, 94 mg%). Lymphocyte count was 1/cu mm. The posterior fossa appeared normal on a CT scan obtained 8 weeks after craniectomy. At that time, the patient was alert, fully oriented, and could converse. His neurological deficits included a spastic left hemiparesis, a left hemihypesthesia, and a left hemiataxia. He could sit without support but could not walk. Eight months after craniectomy, the patient could walk with a cane and was being cared for by his wife at hime. He continued taking oral sulfisoxazole (8 gin/day) and ampicillin (4 gm/day), as well as medications for chronic congestive heart failure. He died suddenly of an apparent myocardial infarction 12 months after craniectomy. Permission for an autopsy was not obtained.
Comment Since as many as 64% of patients with localized cutaneous Nocardia infections eventually develop disseminated disease, 18 there is a possibility that this patient's scrotal lesion was the primary site of infection but was subsequently sterilized by antibiotic therapy.
Case 2 This 22-year-old, right-handed woman was admitted because of progressive headache, vomiting, and lethargy. One month before admission, she began having intermittent, throbbing occipital headaches. Within 2 weeks these headaches became constant and were associated with a stiff neck. The head pain increased with coughing and exertion, and awakened her from sleep. One week before admission, the patient developed constant nausea with intermittent vomiting, dizziness, and diplopia. She noted progressive difficulty with walking and with using her left hand. She became somnolent on the day of admission. 4"]0
Examination. The patient could be aroused by being gently shaken, and was then conversational and fully oriented, although her attention span was short and she was severely dysarthric. The rectal temperature was 37.3 ~ C; blood pressure, 135/90 mm Hg; pulse, 88/min; and respiratory rate 24. General physical examination was remarkable only for marked stiffness of the neck. Neurological abnormalities included phasic horizontal nystagmus in primary position which increased in the direction of lateral gaze. The nasolabial fold was effaced on the left, and there was mild pronator drift of the left arm. Deep tendon reflexes were normal and no pathological reflexes were elicited. There was severe dysmetria in the left upper extremity and fine finger movements were impaired out of proportion to the mild paresis. The patient fell to the left while standing and demonstrated retropulsion when she attempted to walk. The pupils and fundi were unremarkable. The admission hemoglobin was 14.6 gm/dl and the white blood cell count was 6600/cu mm with a normal differential. Serum electrolytes, calcium, phosphorus, uric acid, creatinine, BUN, total protein, albumin, bilirubin, liver enzymes, and clotting studies were all normal, as was urinalysis, electrocardiogram, and chest film. The erythrocyte sedimentation rate was 59 mm/hr (normal: 0 to 20 mm/hr). A C T scan (Fig. 2 upper left) demonstrated a 2-cm contrast-enhancing lesion in the superomedial portion of the left cerebellar hemisphere. It appeared to extend into the rostral vermis adjacent to the upper brain stem. The fourth ventricle and quadrigeminal plate cistern were not demonstrated, but the other ventricles were enlarged. The preliminary diagnosis was cerebellar neoplasm. Intravenous dexamethasone therapy (16 mg/day) was initiated and a right-sided ventriculoperitoneal shunt was inserted. Postoperatively the patient was alert and no longer nauseated, but neurological examination was otherwise unchanged. A vertebral angiogram showed no abnormal vascularity and relatively little vessel displacement. First Operation. Five days after insertion of the shunt, the patient underwent a suboccipital craniectomy. A multiloculated, thinly encapsulated abscess was found in the superior vermis and adjacent left cerebellar hemisphere. It was adherent to the petrous apex and adjacent tentorium. The lesion was drained and partially excised. A Gram stain of the pus demonstrated Gram-positive organisms consisting of branched filaments. Nocardia asteroides infection was subsequently confirmed by culture. Therapy was initiated with intravenous sulfadiazine (12 gm/day) and ampicillin (6 gm/day). Dexamethasone was tapered over the course of 5 days. Postoperative Course. On the fourth postoperative day, the patient began vomiting and developed increasing abdominal tenderness in the region of the distal shunt catheter. The Rickham reservoir was tapped percutaneously and the shunt found to be patent. The J. Neurosurg. / Volume 51 / September, 1979
Primary cerebellar nocardiosis
FIG. 2. Case 2. Contrast-enhanced computerized tomography scans. Upper Left." The preoperative study shows an annular lesion in the rostral left cerebellopontine angle that extends into the adjacent vermis and cerebellar hemisphere. Note that the lateral aspect of the lesion is "molded" by the left tentorial leaf and is entirely medial to it, indicating that the lesion is confined to the posterior fossa. Upper Center." Scan performed 1 week after the first operation still demonstrates a unilocular lesion. The ventricles are normal in size following a shunting procedure. Upper Right." The study obtained 1 week later shows a daughter abscess posterior to the original lesion. Lower Left." Scan 18 days later: the lesion remains biloculated, but has decreased slightly in size. Ventricular size remains normal despite removal of the shunt. Lower Right: Scan 13 days after the second operation showing a residual area of contrast enhancement anterior to the fourth ventricle.
ventricular C S F contained 35 cells/cu mm, of which 26% were P M N ' s . The glucose and protein were 56 and 45 mg/dl, respectively. The C S F obtained by lumbar puncture demonstrated 1700 cells/cu m m (68% PMN's), a glucose of 32 mg/dl, and a protein of 391 mg/dl. A diagnosis of meningitis was made and the shunt was externalized. The vomiting and abdominal
J. Neurosurg. / Volume51 / September, 1979
tenderness resolved over the next 48 hours. G r a m and modified acid-fast stains as well as cultures of the ventricular and lumbar CSF failed to demonstrate any organisms. Comparison of CT scans obtained 7 and 14 days postoperatively disclosed that the residual abscess had increased slightly in size (Fig. 2 upper center and 41 ]
G. W. T y s o n , et al.
right). Nevertheless, the patient remained symptomatically improved. Minocycline (200 mg/day) was added to the treatment regimen. The patient tolerated clamping of her external ventriculostomy which was subsequently removed. Second Operation. A C T scan performed 1 month postoperatively showed only a minor decrease in the size of the abscess (Fig. 2 lower left). The following day, the posterior fossa was re-explored. The abscess was now well encapsulated, but was densely adherent to the left petrous bone, and extended into the tentorial incisura where the left trochlear nerve was embedded in the abscess wall. The lesion was removed in piecemeal fashion. Biopsy of the left petrous bone demonstrated multiple microabscesses, but selective stains and cultures failed to demonstrate any organisms. Postoperative Course. The patient was discharged 14 days later on a regimen of oral sulfisoxazole (12 mg/day), ampicillin (4 gm/day), and minocycline (200 mg/day). A C T scan at that time demonstrated a small area of enhancement adjacent to the left petrous apex (Fig. 2 lower right). She was readmitted 3 weeks later because of dizziness. Evaluation by an otolaryngologist disclosed no vestibular or auditory impairment. Polytomography of both petrous bones was normal. A lumbar puncture demonstrated CSF with a glucose of 48 mg/dl and a protein of 97 mg/dl. There were 3 PMN's/cu mm. A C T scan demonstrated no significant interval change. Minocycline was discontinued. Her symptoms subsequently resolved. The patient has continued on sulfisoxazole and ampicillin, and will ultimately have received a 12-month course of therapy. She has remained asymptomatic in the ensuing 9 months. Her nystagmus, dysarthria, and gait ataxia have gradually resolved, although she remains slightly dysmetric in her left upper extremity, and has a left trochlear nerve palsy. The CT scan appeared normal 3 months after her second operation. Comment Unlike most cerebellar abscesses, which are usually otogenic, s~ previously reported Nocardia cerebellar abscesses have been the result of hematogenous dissemination from a primary extracranial infection. 8,13a7 However, the fact that this patient's abscess was adherent to the petrous bone superior and medial to the internal auditory meatus suggests that the lesion may have been otogenic. According to Krayenbuhl, TM and also Shaw and Russell, s~ this finding implies that the abscess may have originated from an infective thrombophlebitis involving the venous connections between the superior and inferior petrosal sinuses. However, the superior petrosal sinus receives veins from the anterosuperior portion of the cerebellum. 7 The cerebellar abscess may, therefore, have been the cause rather than the result of the thrombophlebitis. The fact that this patient had a marked dysarthria associated with a lesion involving mainly the superior 4]2
and medial portions of the left cerebellar hemisphere supports the conclusions of Lechtenberg and Gilman TM concerning localization of speech function within the cerebellum. Furthermore, the absence of dysarthria in our first case is consistent with these investigators' observation that speech is usually normal with predominantly vermal lesions. Discussion
Nocardia asteroides is normally a weak human pathogen, 14,27 and 50% to 85% of infections occur in compromised hosts? ,17 Nevertheless, the organism behaves aggressively in established intracranial infections. Invasion of the blood stream often occurs early in the disease, 1 and mortality is closely correlated with extracranial dissemination.? 8 Furthermore, prolific growth within the rapidly expanding abscess usually renders puncture and drainage ineffective? s,19 and this procedure may facilitate dissemination of the organism into the adjacent brain or CSF. ~9,s6Cure of the resulting meningitis is exceptional; ~' therefore, radical extracapsular excision is usually advocated, and this technique has accounted for the majority of reported cures, a,daa,~a,~5,2x.2a,2e Nocardia cerebral abscesses are often multiloculated, 4,~s and may be only minimally encapsulated, se Such characteristics may render complete excision difficult, s~ especially in the posterior fossa where proximity to the brain stem may make radical excision of an irregular, poorly circumscribed lesion particularly hazardous. We thus doubt that we would have attempted to completely excise either patient's abscess as a primary procedure, even if we had known the correct diagnosis at the time of surgery. However, failure to establish the diagnosis prior to surgery caused us to omit appropriate preoperative antibiotic therapy. This probably increased the risk of dissemination of the infections as a result of either the CSF shunt procedures or the subsequent incomplete, piecemeal excisions. It is very difficult to establish a preoperative diagnosis of cerebral nocardiosis in the absence of a discernible extracranial focus of infection. Goodman and Koenig 5 reported that in more than half of their cases surgical drainage or biopsy was required for diagnosis. They also noted that in most cases of nocardiosis the diagnosis is first suggested by the bacteriology laboratory. In both of our cases microscopic examination and culture of CSF obtained prior to institution of proper antibiotic therapy failed to suggest Nocardia infection. Indeed, organisms are seldom isolated from the CSF of patients with Nocardia cerebral abscesses, t4ad,ss and in 20% of these patients the CSF is normal in every respect? 8 Intracranial Nocardia abscesses produce no distinct clinical syndrome TM or pathognomonic CT scan findings.' In fact, as our two cases illustrate, it is possible to confuse the clinical presentation and CT scan J. Neurosurg. / Volume51 / September, 1979
Primary eerebellar nocardiosis appearance of a Nocardia abscess with that of a neoplasm. Despite the fact that the surgical management of our two patients was imperfect, it is possible that one or both were ultimately cured. In both cases the contrast-enhanced CT scan eventually became normal. Our first patient was still improving neurologically and complained of no new symptoms of posterior fossa disease at the time of his sudden death from an apparently unrelated cause. Studies of tissue excised during the posterior fossa re-exploration of our second patient suggested that the abscess had been sterilized by antibiotic therapy. This patient remains well with only mild neurological deficits 9 months later. Successful treatment of a Nocardia cerebral abscess without complete excision of the lesion is not unprecedented. Turner and Whitby ~2 reported a patient who was cured by aspiration of an abscess and antibiotic therapy. Antibiotic treatment alone was successful in single cases reported by Viroslav and Williams 24 and by Kirmani, et al. 9 However, all reported cures, including our own, should be accepted with caution, since patients with cerebral nocardiosis may relapse and die a year or more after the termination of what was thought to be adequate treatment: ~ It is likely that the use of sequential CT scans will diminish the mortality of recurrent cerebral nocardiosis. This technique can be used not only to monitor the progress of medical therapy, 9 but also to improve decisions concerning the need for and timing of operative intervention. For example, the posterior fossa of our second patient was re-explored because there was only minimal change on consecutive CT scans despite almost 3 weeks of intervening intensive antibiotic therapy. Her clinical signs had not changed during that interval. On the other hand, our first patient was spared further surgery as a result of serial CT scans which showed unexpected resolution of his residual lesion. Conclusions
It is possible that primary cerebral nocardiosis will become a more common neurosurgical problem, since the incidence of Nocardia infections appears to be gradually increasing. 2,16 However, in the absence of an identifiable extracranial focus of infection, preoperative diagnosis of this disease is likely to remain exceptional. Because the association between nocardiosis and impaired immunological competence is often emphasized, 2 Nocardia infection may be inadvertently omitted from the differential diagnosis of cerebral abscess in patients who have no apparent underlying disease. Our two patients exemplify the fact that as many as 50% of patients with nocardiosis have no obvious predisposing condition. 17 We suggest that high-dose sulfonamides, which inhibit growth of 95% to 100% of Nocardia strains,: be considered in the preoperative antibiotic regimen of any patient with a J. Neurosurg. / Volume51 / September, 1979
presumed brain abscess if a likely organism has not already been identified. On the basis of our limited experience, we offer the following tentative guidelines for the management of primary cerebellar nocardiosis. 1. Since reports of success with alternative forms of therapy are only anecdotal, complete extracapsular excision of a Nocardia brain abscess remains the primary procedure of choice. 2. If safe extracapsular excision is impossible, careful aspiration of the abscess followed by a trial of intensive antibiotic therapy may be preferable to incomplete, fragmentary removal, particularly if proper antibiotic coverage was not initiated preoperatively. However, our own cases indicate that clinically significant meningitis is not an inevitable complication of the latter course of action. 3. If the diagnosis is established only after the operation is completed, immediate re-operation and further removal of a partially excised lesion is not indicated. Instead, intensive antibiotic therapy should be initiated and the progress of treatment monitored by clinical response and sequential CT scans. Acknowledgment The authors wish to express their appreciation to Lucille
Staiger for her technical assistance with the manuscript. References
1. Bach MC: The chemotherapy of infections due to Nocardia. Int J Clin Pharmacol Biopharm 11:283-285, 1975
2. Beaman BL, Burnside J, Edwards B, et al: Nocardial infections in the United States, 1972-1974. J Infect Dis 134:286-289, 1976 3. Brine JAS: Human nocardiosis: a developing clinical picture. Med J Aust 1:339-342, 1965 4. Claveria LE, du Boulay GH, Moseley IF: Intracranial infections: investigation by computerized axial tomography. Neuroradioiogy 12:59-71, 1976 5. Goodman JS, Koenig MG: Nocardia infections in a general hospital. Ann NY Acad Sci 174:552-567, 1970 6. Hoeprich PD, Brandt D, Parker RH: Nocardial brain abscess cured with cycloserine and sulfonamides. Am J Med Sci 255:208-216, 1968 7. Kaplan HA, Ford DH: The Brain Vascular System. Amsterdam/New York: Elsevier, 1966, pp 115-118 8. Kirby WMM, McNaught JB: Actinomycosis due to Nocardia asteroides. Report of two cases. Arch Intern Med 78:578-591, 1946 9. Kirmani N, Tuazon CU, Ocuin JA, et al: Extensive cerebral nocardiosis cured with antibiotic therapy alone. Case report. J Neurosurg 49: 924-928, 1978 10. Krayenbuhl HA: Abscess of the brain. Clin Neurosurg 14:25-44, 1967 11. Krueger EG, Norsa L, Kenney M, et al: Nocardiosis of the central nervous system. J Neurosurg 11:226-233, 1954 12. Lechtenberg R, Gilman S: Speech disorders in cerebellar disease. Ann Neuroi 3:285-290, 1978 413
G. W. Tyson, et al. 13. List CF, Williams JR, Beeman CB, et al: Nocardiosis with multilocular cerebellar abscess. Report of a cured case. J Neurnsurg 11:394-398, 1954 14. Lope ES, Gutierrez DC: Nocardia asteroides primary cerebral abscess and secondary meningitis. Acta Neurochir 37:139-147, 1977 15. Munslow RA: Actinomycotic (Nocardia asteroides) brain abscess with recovery. Case report. J Neurosurg l1:399-402, 1954 16. Murray JF, Finegold SM, Froman S, et al: The changing spectrum of nocardiosis. A review and presentation of nine cases. Am Rev Respir Dis 83:315-330, 1961 17. Palmer DL, Harvey RL, Wheeler JK: Diagnostic and therapeutic considerations in Nocardia asteroides infection. Medicine 53:391-401, 1974 18. Presant CA, Wiernik PH, Serpick AA: Factors affecting survival in nocardiosis. Am Rev Respir Dis 108: 1444-1448, 1973 19. Rankin J, Javid M: Nocardiosis of the central nervous system. Neurology 5:815-820, 1955 20. Shaw MDM, Russell JA: Cerebellar abscess. A review of 47 cases. J Nenrol Neurosurg Psychiatry 38:429--435, 1975 21. Supena R, Karlin D, Strate R, et al: Pulmonary alveolar proteinosis and Nocardia brain abscess. Report of a case. Arch Nenroi 30:266-268, 1974
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22. Turner E, Whitby JL: Nocardial cerebral abscess with systemic involvement successfully treated by aspiration and sulfonamides. Case report. J Nenrosnrg 31: 227-229, 1969 23. Tveten L: Cerebral mycosis. A clinico-pathological report of four cases. Acta Neurol Stand 41:19-33, 1965 24. Viroslav J, Williams TW Jr: Nocardial infection of the pulmonary and central nervous system: successful treatment with medical therapy. South Med J 64:1382-1385, 1971 25. Weintraub MI, Glaser GH: Nocardial brain abscess and pure motor hemiplegia. NY State J Med 70: 2717-2721, 1970 26. Weiss MH, Jane JA: Nocardia asteroides brain abscess successfully treated by enucleation. Case report. J Neurosurg 30:83-86, 1969 27. Young LS, Armstrong D, Blevins A, et al: Nocardia asteroides infection complicating neoplastic disease. Am J Med 50:356-367, 1971
Address reprint requests to: George W. Tyson, M.D., Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, Virginia 22908.
J. Neurosurg. / Volume51 / September, 1979
Primary eerebellar noeardiosis Report of two cases
GEORGE W. TYSON, M.D., JOSEPH E. WELSH, M.D., ALBERT B. BUTLER, M.D., JOHN A. JANE, M.D., AND H. RICHARD WINN, M.D.
Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, Virginia v,' The authors describe two cases of primary cerebellar nocardiosis. Confinement of Nocardia abscesses to a localized, accessible portion of the central nervous system should favor surgical cure of this aggressive and often fatal disease. In our two cases multilocularity, tenuous encapsulation, and proximity to the brain stem prevented complete primary excision. Nevertheless, the infections were effectively treated by intensive postoperative antibiotic therapy and, in one case, a second operation to excise the residual abscess. The need for the latter was suggested by the results of sequential computerized tomographic brain scans that were used to monitor the response to antibiotic therapy. In the absence of any apparent extracranial focus of infection and any overt condition that might impair immunological competence, nocardiosis is likely to be omitted from the preoperative differential diagnosis of a posterior fossa space-occupying lesion. KEY WORDS 9 cerebellar abscess 9 computerized tomography primary cerebellar nocardiosis 9 surgical treatment
XTRACRANIAL Nocardia asteroides infections have a tendency to disseminate to the brain. In a review of 147 cases of nocardiosis, Presant, et al., TM found a 36% incidence of secondary cerebral abscesses. Since these abscesses occur ubiquitously within the brain 25 and are frequently multiple, aa confinement of intracranial nocardiosis to the posterior fossa is uncommon. In the few cases that have been reported, the primary infection has been extracranial, usually in the lung. 8,~a,27 In the absence of an extracranial infective focus, the preoperative diagnosis of the cerebral lesion is likely to be erroneous, and the initial surgical management of the Nocardia abscess may therefore be incorrect. 26 Fortunately, primary cerebral Norcardia infections are rare, accounting for only 5% to 7% of cases of nocardiosis. 14'~6'~8 We are reporting two unprecedented cases in which the cerebellum was the only discernible focus of Nocardia infection.
9
Case Reports
E
408
9 nocardiosis
Case 1 This 67-year-old, right-handed farmer was admitted for evaluation of headaches, confusion, and difficulty in walking. He first noted difficulty with memory and concentration 1 month before admission. Two weeks later, he began having increasingly severe frontal headaches associated with attacks of visual obscuration, each of which lasted no more than 5 to 10 seconds. He had lost 20 lbs during the course of his illness. Except for hypertension and chronic congestive heart failure, the patient had been well his entire life. He had a 25-year history of cigarette smoking. Examination. The patient was lethargic but could be aroused by voice, and was then conversational although confused. The oral temperature was 37.4 ~ C; blood pressure, 150/90 mm Hg; pulse, 76/min; and
J. Neurosurg. / Volume 51 / September, 1979
Primary cerebellar nocardiosis
Fro. 1. Case 1. Contrast-enhanced computerized tomography scans. Left: Preoperative study demonstrates a serpiginous lesion in the vermis. Right: Postoperative scan shows only multiple, punctate areas of decreased attenuation in the vermis and left cerebellar hemisphere. The white dot marks the largest of these areas.
respiratory rate 18. General physical examination was remarkable only for signs of chronic obstructive pulmonary disease and a 1 • 1 cm scrotal skin papule. Neurological signs included bilateral papilledema, horizontal nystagmus to the left on left lateral gaze, generalized weakness and hyperreflexia with bilateral Babinski signs, and a left hemi-ataxia. In addition, the patient demonstrated a truncal ataxia while sitting and could not stand, even with support. Hemoglobin was 14.9 gm/dl and white blood cell count 8100/cu mm with 92% polymorphonuclear leukocytes (PMN's). Normal admission laboratory studies included: serum electrolytes, calcium, phosphorus, uric acid, blood urea nitrogen (BUN), creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, glutamic oxaloacetic transaminase (SGOT), lactic dehydrogenase (LDH), cholesterol, prothombin time, and partial thromboplastin time. Urinalysis was also normal. Electrocardiogram showed right bundle-branch block. Chest film demonstrated only signs of chronic obstructive disease. A computerized tomographic (CT) brain scan performed on the day of admission disclosed an irregular, contrast-enhancing mass within the cerebellar vermis (Fig. 1 left). The fourth ventricle was not demonstrated but the other ventricles were enlarged. A diagnosis of obstructive hydrocephalus secondary to primary or secondary cerebellar neoplasm was made.
J. Neurosurg. / Volume51 / September, 1979
Operations. A right-sided ventriculoperitoneal shunt was inserted. The ventricular fluid protein was 8 mg%, and the glucose was 88 mg% (simultaneous serum glucose 111 mg%). There were no leukocytes. Gram and acid-fast stains and bacterial and fungal cultures were negative. The patient became more alert and his headache abated. Subsequent cerebral angiography demonstrated no abnormal vascularity associated with the vermal lesion. Eight days after placement of the shunt, dexamethasone therapy (16 mg/day) was initiated, and 2 days later a suboccipital craniectomy was performed. Incision of the posteroinferior portion of the vermis disclosed a multiloculated abscess with a poorly formed capsule. The loculi were incised and drained, but in the absence of a discernible plane between the abscess and the cerebellum, it was impossible to completely excise the lesion. An intraoperative Gram stain disclosed no definite organisms and intravenous nafcillin (2 gm) and chloramphenicol (1 gm) were given. Immediately after surgery, branching hyphae were seen in a specimen stained by a modified acid-fast technique. The antimicrobial regimen was changed to intravenous sulfisoxazole (12 gin/day) and ampicillin (6 gm/day), and dexamethasone was discontinued. Culture subsequently confirmed the diagnosis of Noeardia asteroides sensitive to the above agents. Postoperative Course. On the first postoperative day, the patient developed acute left ventricular 409
G. W. Tyson, et al. failure. In addition, he was noted to have a left hemiplegia and hemihypalgesia. Results of a CT scan were consistent with cerebral infarction in the distribution of the right middle cerebral artery. The patient subsequently developed Pseudomonas pneumonia and septicemia and required a tracheostomy. A C T scan performed 2 weeks after craniectomy showed several irregular areas of decreased attenuation in the vermis and adjacent portion of the left cerebellar hemisphere (Fig. 1 right). The patient remained critically ill for 6 weeks after his operation, but then gradually improved. A thorough search was made for an extracerebral focus of Nocardia infection, including incision and culture of the scrotal lesion and polytomography of the petrous bones, but all studies were negative. Immunoglobulin electrophoresis was normal. Cerebrospinal fluid (CSF) obtained via lumbar puncture was repeatedly sterile. At the time of discharge, the CSF protein was 111 mg% and the glucose was 60 mg% (serum glucose, 94 mg%). Lymphocyte count was 1/cu mm. The posterior fossa appeared normal on a CT scan obtained 8 weeks after craniectomy. At that time, the patient was alert, fully oriented, and could converse. His neurological deficits included a spastic left hemiparesis, a left hemihypesthesia, and a left hemiataxia. He could sit without support but could not walk. Eight months after craniectomy, the patient could walk with a cane and was being cared for by his wife at hime. He continued taking oral sulfisoxazole (8 gin/day) and ampicillin (4 gm/day), as well as medications for chronic congestive heart failure. He died suddenly of an apparent myocardial infarction 12 months after craniectomy. Permission for an autopsy was not obtained.
Comment Since as many as 64% of patients with localized cutaneous Nocardia infections eventually develop disseminated disease, 18 there is a possibility that this patient's scrotal lesion was the primary site of infection but was subsequently sterilized by antibiotic therapy.
Case 2 This 22-year-old, right-handed woman was admitted because of progressive headache, vomiting, and lethargy. One month before admission, she began having intermittent, throbbing occipital headaches. Within 2 weeks these headaches became constant and were associated with a stiff neck. The head pain increased with coughing and exertion, and awakened her from sleep. One week before admission, the patient developed constant nausea with intermittent vomiting, dizziness, and diplopia. She noted progressive difficulty with walking and with using her left hand. She became somnolent on the day of admission. 4"]0
Examination. The patient could be aroused by being gently shaken, and was then conversational and fully oriented, although her attention span was short and she was severely dysarthric. The rectal temperature was 37.3 ~ C; blood pressure, 135/90 mm Hg; pulse, 88/min; and respiratory rate 24. General physical examination was remarkable only for marked stiffness of the neck. Neurological abnormalities included phasic horizontal nystagmus in primary position which increased in the direction of lateral gaze. The nasolabial fold was effaced on the left, and there was mild pronator drift of the left arm. Deep tendon reflexes were normal and no pathological reflexes were elicited. There was severe dysmetria in the left upper extremity and fine finger movements were impaired out of proportion to the mild paresis. The patient fell to the left while standing and demonstrated retropulsion when she attempted to walk. The pupils and fundi were unremarkable. The admission hemoglobin was 14.6 gm/dl and the white blood cell count was 6600/cu mm with a normal differential. Serum electrolytes, calcium, phosphorus, uric acid, creatinine, BUN, total protein, albumin, bilirubin, liver enzymes, and clotting studies were all normal, as was urinalysis, electrocardiogram, and chest film. The erythrocyte sedimentation rate was 59 mm/hr (normal: 0 to 20 mm/hr). A C T scan (Fig. 2 upper left) demonstrated a 2-cm contrast-enhancing lesion in the superomedial portion of the left cerebellar hemisphere. It appeared to extend into the rostral vermis adjacent to the upper brain stem. The fourth ventricle and quadrigeminal plate cistern were not demonstrated, but the other ventricles were enlarged. The preliminary diagnosis was cerebellar neoplasm. Intravenous dexamethasone therapy (16 mg/day) was initiated and a right-sided ventriculoperitoneal shunt was inserted. Postoperatively the patient was alert and no longer nauseated, but neurological examination was otherwise unchanged. A vertebral angiogram showed no abnormal vascularity and relatively little vessel displacement. First Operation. Five days after insertion of the shunt, the patient underwent a suboccipital craniectomy. A multiloculated, thinly encapsulated abscess was found in the superior vermis and adjacent left cerebellar hemisphere. It was adherent to the petrous apex and adjacent tentorium. The lesion was drained and partially excised. A Gram stain of the pus demonstrated Gram-positive organisms consisting of branched filaments. Nocardia asteroides infection was subsequently confirmed by culture. Therapy was initiated with intravenous sulfadiazine (12 gm/day) and ampicillin (6 gm/day). Dexamethasone was tapered over the course of 5 days. Postoperative Course. On the fourth postoperative day, the patient began vomiting and developed increasing abdominal tenderness in the region of the distal shunt catheter. The Rickham reservoir was tapped percutaneously and the shunt found to be patent. The J. Neurosurg. / Volume 51 / September, 1979
Primary cerebellar nocardiosis
FIG. 2. Case 2. Contrast-enhanced computerized tomography scans. Upper Left." The preoperative study shows an annular lesion in the rostral left cerebellopontine angle that extends into the adjacent vermis and cerebellar hemisphere. Note that the lateral aspect of the lesion is "molded" by the left tentorial leaf and is entirely medial to it, indicating that the lesion is confined to the posterior fossa. Upper Center." Scan performed 1 week after the first operation still demonstrates a unilocular lesion. The ventricles are normal in size following a shunting procedure. Upper Right." The study obtained 1 week later shows a daughter abscess posterior to the original lesion. Lower Left." Scan 18 days later: the lesion remains biloculated, but has decreased slightly in size. Ventricular size remains normal despite removal of the shunt. Lower Right: Scan 13 days after the second operation showing a residual area of contrast enhancement anterior to the fourth ventricle.
ventricular C S F contained 35 cells/cu mm, of which 26% were P M N ' s . The glucose and protein were 56 and 45 mg/dl, respectively. The C S F obtained by lumbar puncture demonstrated 1700 cells/cu m m (68% PMN's), a glucose of 32 mg/dl, and a protein of 391 mg/dl. A diagnosis of meningitis was made and the shunt was externalized. The vomiting and abdominal
J. Neurosurg. / Volume51 / September, 1979
tenderness resolved over the next 48 hours. G r a m and modified acid-fast stains as well as cultures of the ventricular and lumbar CSF failed to demonstrate any organisms. Comparison of CT scans obtained 7 and 14 days postoperatively disclosed that the residual abscess had increased slightly in size (Fig. 2 upper center and 41 ]
G. W. T y s o n , et al.
right). Nevertheless, the patient remained symptomatically improved. Minocycline (200 mg/day) was added to the treatment regimen. The patient tolerated clamping of her external ventriculostomy which was subsequently removed. Second Operation. A C T scan performed 1 month postoperatively showed only a minor decrease in the size of the abscess (Fig. 2 lower left). The following day, the posterior fossa was re-explored. The abscess was now well encapsulated, but was densely adherent to the left petrous bone, and extended into the tentorial incisura where the left trochlear nerve was embedded in the abscess wall. The lesion was removed in piecemeal fashion. Biopsy of the left petrous bone demonstrated multiple microabscesses, but selective stains and cultures failed to demonstrate any organisms. Postoperative Course. The patient was discharged 14 days later on a regimen of oral sulfisoxazole (12 mg/day), ampicillin (4 gm/day), and minocycline (200 mg/day). A C T scan at that time demonstrated a small area of enhancement adjacent to the left petrous apex (Fig. 2 lower right). She was readmitted 3 weeks later because of dizziness. Evaluation by an otolaryngologist disclosed no vestibular or auditory impairment. Polytomography of both petrous bones was normal. A lumbar puncture demonstrated CSF with a glucose of 48 mg/dl and a protein of 97 mg/dl. There were 3 PMN's/cu mm. A C T scan demonstrated no significant interval change. Minocycline was discontinued. Her symptoms subsequently resolved. The patient has continued on sulfisoxazole and ampicillin, and will ultimately have received a 12-month course of therapy. She has remained asymptomatic in the ensuing 9 months. Her nystagmus, dysarthria, and gait ataxia have gradually resolved, although she remains slightly dysmetric in her left upper extremity, and has a left trochlear nerve palsy. The CT scan appeared normal 3 months after her second operation. Comment Unlike most cerebellar abscesses, which are usually otogenic, s~ previously reported Nocardia cerebellar abscesses have been the result of hematogenous dissemination from a primary extracranial infection. 8,13a7 However, the fact that this patient's abscess was adherent to the petrous bone superior and medial to the internal auditory meatus suggests that the lesion may have been otogenic. According to Krayenbuhl, TM and also Shaw and Russell, s~ this finding implies that the abscess may have originated from an infective thrombophlebitis involving the venous connections between the superior and inferior petrosal sinuses. However, the superior petrosal sinus receives veins from the anterosuperior portion of the cerebellum. 7 The cerebellar abscess may, therefore, have been the cause rather than the result of the thrombophlebitis. The fact that this patient had a marked dysarthria associated with a lesion involving mainly the superior 4]2
and medial portions of the left cerebellar hemisphere supports the conclusions of Lechtenberg and Gilman TM concerning localization of speech function within the cerebellum. Furthermore, the absence of dysarthria in our first case is consistent with these investigators' observation that speech is usually normal with predominantly vermal lesions. Discussion
Nocardia asteroides is normally a weak human pathogen, 14,27 and 50% to 85% of infections occur in compromised hosts? ,17 Nevertheless, the organism behaves aggressively in established intracranial infections. Invasion of the blood stream often occurs early in the disease, 1 and mortality is closely correlated with extracranial dissemination.? 8 Furthermore, prolific growth within the rapidly expanding abscess usually renders puncture and drainage ineffective? s,19 and this procedure may facilitate dissemination of the organism into the adjacent brain or CSF. ~9,s6Cure of the resulting meningitis is exceptional; ~' therefore, radical extracapsular excision is usually advocated, and this technique has accounted for the majority of reported cures, a,daa,~a,~5,2x.2a,2e Nocardia cerebral abscesses are often multiloculated, 4,~s and may be only minimally encapsulated, se Such characteristics may render complete excision difficult, s~ especially in the posterior fossa where proximity to the brain stem may make radical excision of an irregular, poorly circumscribed lesion particularly hazardous. We thus doubt that we would have attempted to completely excise either patient's abscess as a primary procedure, even if we had known the correct diagnosis at the time of surgery. However, failure to establish the diagnosis prior to surgery caused us to omit appropriate preoperative antibiotic therapy. This probably increased the risk of dissemination of the infections as a result of either the CSF shunt procedures or the subsequent incomplete, piecemeal excisions. It is very difficult to establish a preoperative diagnosis of cerebral nocardiosis in the absence of a discernible extracranial focus of infection. Goodman and Koenig 5 reported that in more than half of their cases surgical drainage or biopsy was required for diagnosis. They also noted that in most cases of nocardiosis the diagnosis is first suggested by the bacteriology laboratory. In both of our cases microscopic examination and culture of CSF obtained prior to institution of proper antibiotic therapy failed to suggest Nocardia infection. Indeed, organisms are seldom isolated from the CSF of patients with Nocardia cerebral abscesses, t4ad,ss and in 20% of these patients the CSF is normal in every respect? 8 Intracranial Nocardia abscesses produce no distinct clinical syndrome TM or pathognomonic CT scan findings.' In fact, as our two cases illustrate, it is possible to confuse the clinical presentation and CT scan J. Neurosurg. / Volume51 / September, 1979
Primary eerebellar nocardiosis appearance of a Nocardia abscess with that of a neoplasm. Despite the fact that the surgical management of our two patients was imperfect, it is possible that one or both were ultimately cured. In both cases the contrast-enhanced CT scan eventually became normal. Our first patient was still improving neurologically and complained of no new symptoms of posterior fossa disease at the time of his sudden death from an apparently unrelated cause. Studies of tissue excised during the posterior fossa re-exploration of our second patient suggested that the abscess had been sterilized by antibiotic therapy. This patient remains well with only mild neurological deficits 9 months later. Successful treatment of a Nocardia cerebral abscess without complete excision of the lesion is not unprecedented. Turner and Whitby ~2 reported a patient who was cured by aspiration of an abscess and antibiotic therapy. Antibiotic treatment alone was successful in single cases reported by Viroslav and Williams 24 and by Kirmani, et al. 9 However, all reported cures, including our own, should be accepted with caution, since patients with cerebral nocardiosis may relapse and die a year or more after the termination of what was thought to be adequate treatment: ~ It is likely that the use of sequential CT scans will diminish the mortality of recurrent cerebral nocardiosis. This technique can be used not only to monitor the progress of medical therapy, 9 but also to improve decisions concerning the need for and timing of operative intervention. For example, the posterior fossa of our second patient was re-explored because there was only minimal change on consecutive CT scans despite almost 3 weeks of intervening intensive antibiotic therapy. Her clinical signs had not changed during that interval. On the other hand, our first patient was spared further surgery as a result of serial CT scans which showed unexpected resolution of his residual lesion. Conclusions
It is possible that primary cerebral nocardiosis will become a more common neurosurgical problem, since the incidence of Nocardia infections appears to be gradually increasing. 2,16 However, in the absence of an identifiable extracranial focus of infection, preoperative diagnosis of this disease is likely to remain exceptional. Because the association between nocardiosis and impaired immunological competence is often emphasized, 2 Nocardia infection may be inadvertently omitted from the differential diagnosis of cerebral abscess in patients who have no apparent underlying disease. Our two patients exemplify the fact that as many as 50% of patients with nocardiosis have no obvious predisposing condition. 17 We suggest that high-dose sulfonamides, which inhibit growth of 95% to 100% of Nocardia strains,: be considered in the preoperative antibiotic regimen of any patient with a J. Neurosurg. / Volume51 / September, 1979
presumed brain abscess if a likely organism has not already been identified. On the basis of our limited experience, we offer the following tentative guidelines for the management of primary cerebellar nocardiosis. 1. Since reports of success with alternative forms of therapy are only anecdotal, complete extracapsular excision of a Nocardia brain abscess remains the primary procedure of choice. 2. If safe extracapsular excision is impossible, careful aspiration of the abscess followed by a trial of intensive antibiotic therapy may be preferable to incomplete, fragmentary removal, particularly if proper antibiotic coverage was not initiated preoperatively. However, our own cases indicate that clinically significant meningitis is not an inevitable complication of the latter course of action. 3. If the diagnosis is established only after the operation is completed, immediate re-operation and further removal of a partially excised lesion is not indicated. Instead, intensive antibiotic therapy should be initiated and the progress of treatment monitored by clinical response and sequential CT scans. Acknowledgment The authors wish to express their appreciation to Lucille
Staiger for her technical assistance with the manuscript. References
1. Bach MC: The chemotherapy of infections due to Nocardia. Int J Clin Pharmacol Biopharm 11:283-285, 1975
2. Beaman BL, Burnside J, Edwards B, et al: Nocardial infections in the United States, 1972-1974. J Infect Dis 134:286-289, 1976 3. Brine JAS: Human nocardiosis: a developing clinical picture. Med J Aust 1:339-342, 1965 4. Claveria LE, du Boulay GH, Moseley IF: Intracranial infections: investigation by computerized axial tomography. Neuroradioiogy 12:59-71, 1976 5. Goodman JS, Koenig MG: Nocardia infections in a general hospital. Ann NY Acad Sci 174:552-567, 1970 6. Hoeprich PD, Brandt D, Parker RH: Nocardial brain abscess cured with cycloserine and sulfonamides. Am J Med Sci 255:208-216, 1968 7. Kaplan HA, Ford DH: The Brain Vascular System. Amsterdam/New York: Elsevier, 1966, pp 115-118 8. Kirby WMM, McNaught JB: Actinomycosis due to Nocardia asteroides. Report of two cases. Arch Intern Med 78:578-591, 1946 9. Kirmani N, Tuazon CU, Ocuin JA, et al: Extensive cerebral nocardiosis cured with antibiotic therapy alone. Case report. J Neurosurg 49: 924-928, 1978 10. Krayenbuhl HA: Abscess of the brain. Clin Neurosurg 14:25-44, 1967 11. Krueger EG, Norsa L, Kenney M, et al: Nocardiosis of the central nervous system. J Neurosurg 11:226-233, 1954 12. Lechtenberg R, Gilman S: Speech disorders in cerebellar disease. Ann Neuroi 3:285-290, 1978 413
G. W. Tyson, et al. 13. List CF, Williams JR, Beeman CB, et al: Nocardiosis with multilocular cerebellar abscess. Report of a cured case. J Neurnsurg 11:394-398, 1954 14. Lope ES, Gutierrez DC: Nocardia asteroides primary cerebral abscess and secondary meningitis. Acta Neurochir 37:139-147, 1977 15. Munslow RA: Actinomycotic (Nocardia asteroides) brain abscess with recovery. Case report. J Neurosurg l1:399-402, 1954 16. Murray JF, Finegold SM, Froman S, et al: The changing spectrum of nocardiosis. A review and presentation of nine cases. Am Rev Respir Dis 83:315-330, 1961 17. Palmer DL, Harvey RL, Wheeler JK: Diagnostic and therapeutic considerations in Nocardia asteroides infection. Medicine 53:391-401, 1974 18. Presant CA, Wiernik PH, Serpick AA: Factors affecting survival in nocardiosis. Am Rev Respir Dis 108: 1444-1448, 1973 19. Rankin J, Javid M: Nocardiosis of the central nervous system. Neurology 5:815-820, 1955 20. Shaw MDM, Russell JA: Cerebellar abscess. A review of 47 cases. J Nenrol Neurosurg Psychiatry 38:429--435, 1975 21. Supena R, Karlin D, Strate R, et al: Pulmonary alveolar proteinosis and Nocardia brain abscess. Report of a case. Arch Nenroi 30:266-268, 1974
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22. Turner E, Whitby JL: Nocardial cerebral abscess with systemic involvement successfully treated by aspiration and sulfonamides. Case report. J Nenrosnrg 31: 227-229, 1969 23. Tveten L: Cerebral mycosis. A clinico-pathological report of four cases. Acta Neurol Stand 41:19-33, 1965 24. Viroslav J, Williams TW Jr: Nocardial infection of the pulmonary and central nervous system: successful treatment with medical therapy. South Med J 64:1382-1385, 1971 25. Weintraub MI, Glaser GH: Nocardial brain abscess and pure motor hemiplegia. NY State J Med 70: 2717-2721, 1970 26. Weiss MH, Jane JA: Nocardia asteroides brain abscess successfully treated by enucleation. Case report. J Neurosurg 30:83-86, 1969 27. Young LS, Armstrong D, Blevins A, et al: Nocardia asteroides infection complicating neoplastic disease. Am J Med 50:356-367, 1971
Address reprint requests to: George W. Tyson, M.D., Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, Virginia 22908.
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