Brief Report Y.'T. Cheng, C.-T. Huang, H. S. Leu, J.-S. Chen, M.-C. Kiu Central Nervous System Infection due to Clostridium septicum: A Case Report and Review of the Literature Summary: A patient with end stage breast cancer was admitted to hospital due to fever, chills, multiply eroded discharging wounds, and sudden onset of left hemiparesis. Clostridium septicum bacteremia and brain abscess were diagnosed. The patient was treated successfully with intravenous penicillin and clindamycin and stereotactic aspiration of the abscess. Eleven cases of C. septicum central nervous system infection are reviewed. They showed an extremely fulminant course and high fatality. Nevertheless, some relationship seems to exist between outcome and type of brain lesion. Hemolytic-uremic syndrome associated with central nervous system infection is also discussed, because all these cases in the literature were due to this organism. Early diagnosis and aggressive treatment, including surgical drainage and appropriate antibiotics, are the key to improving the prognosis. A long-term prophylactic oral antimicrobial agent is suggested for patients who survive this infection. Introduction Clostridium septicum, an a n a e r o b i c g r a m - p o s i t i v e r o d c o m m o n l y a s s o c i a t e d with gas g a n g r e n e a n d m a l i g n a n c y , is a r a r e cause o f c e n t r a l n e r v o u s s y s t e m ( C N S ) infection. W e p r e s e n t a case of b r e a s t c a n c e r with C. s e p t i c u m b a c t e r e m i a a n d b r a i n abscess which has n e v e r b e e n r e p o r t e d b e fore, a n d r e v i e w 11 p r e v i o u s case r e p o r t s of this infection. Case Report A 40-year-old female was treated with modified radical mastectomy in 1990 for left breast cancer. Metastatic lymph nodes developed over the left neck and right axillary regions 6 months later. Two courses of chemotherapy (cyclophosphamide, mitomycin and 5-FU) and local radiotherapy were performed. Recurrent metastatic lymph nodes of the left neck and multiple cutaneous nodules of the left anterior chest wall were noted in January 1994. Three courses of chemotherapy and palliative local radiotherapy to the left side of the neck and bilateral anterior chest wall were performed. Painful swelling and perforation of the left neck mass occurred after radiotherapy. Sudden onset of left side weakness with fever and chills occurred on 8 October 1994. On physical examination, the patient was oriented and alert, but febrile (38.5°C) and tachypneic (24 times/min). Her neck was supple, but with a very large eroded discharging left neck lymph node (about 5×6 cm 2 in size). Besides, two big and deep ulcerated wounds, surrounded by multiple small cutaneous nodules, were noted over the right anterior chest wall with foul purulent discharge. Neurological examination revealed right central facial palsy and hemiparesis. Her white cell count was 9,500/mm 3 (94% segments and 1% band forms), hematocrit was 37 % and platelet count Was 22,900/mm 3. Further laboratory tests, including liver and renal function, were normal. Computerized tomography (CT) of the brain showed a white matter swelling over the left frontal-parietal region (Figure 1). Suspecting brain metastasis, lumbar puncture was not carried out. After two sets of blood cultures were drawn, she was treated empirically with cephalothin and gentamicin intravenously for probable sepsis. Intravenous penicillin was added later due to persistent fever and probable aspiration pneumonia suggested by chest X-ray. Magnetic resonance imaging (MRI) of the brain, performed on day 5 after admission, revealed a space occupying lesion over the left frontal-parietal region (Figure 2). On day 7 after admission, C. septicum was isolated from the blood cultures which was susceptible to ticarcillin, chloramphenicol, cephalothin, erythromycin, clindamycin, piperacillin, moxalactam, penicillin, tetracycline and metronidazole. Treatment was changed to combination therapy with penicillin and clindamycin, but the patient was still febrile after 6 days of the combination therapy. A neurosurgeon was consulted and stereotactic biopsy of the brain lesion was performed on 21 October 1994, day 13 after admission. Twenty ml of brisk pus-like fluid was aspirated and the result of culture also showed C. septicum with the same susceptibility test as blood culture. After stereotactic aspiration, fever subsided gradually. A total of 6 weeks of combination antibiotic therapy was completed, and the follow-up computerized tomography of the brain showed resolution of the brain abscess. The patient was discharged on 29 November 1994, day 53 after admission, in a stable condition but with mild left side hemiparesis. Two months later, she was admitted again due to superior vena cava syndrome and severe dyspnea. Despite treatment with two courses of N L F (mitoxanthrone, leucovorin and 5-Fu) with intravenous dexamethasone, her condition deteriorated rapidly. She was discharged in a critical state against advice on 23 March 1995 and died at home on the same day. Received: 1 July 1996/Revision accepted: 25 September 1996 Y.-T. Cheng, M. D., C.-T. Huang, M. D., H.-S. Leu, M. D., Div. of Infectious Diseases; J.-S. Chen, M. D., M.-C. Kiu, M. D., Div. of Oncology, Dept. of Internal Medicine, Chang Gung Memorial Hospital, 199 Tun Hwa North Road, Taipei, Taiwan, Republic of China. Reprint requests to: Dr. H.-S. Leu. Infection 25 (1997) No. 3 © MMV Medizin Verlag GmbH Miinchen, Mtinchen 1997 171/41 Yo-T. Cheng et al.: Clostridiumsepticurn Figure 1: Brain CT showing white matter swelling over left frontal-parietal region. Discussion C. septicum, first isolated by Louis Pasteur 100 years ago [1], is an exotoxin-producing, strictly anaerobic, and sporeforming gram-positive bacillus. The major toxin produced by C. septicum is alpha toxin, which is lethal, necrotizing, hemolytic and possibly leukocidic [2]. Invasive infections due to C. septicum include muscular necrosis and abscess formation in solid organs [3]. Such infections are usually fulminant and spontaneous without obvious infectious focus. Malignancies, including colonic adenocarcinoma and leukemia, or non-malignant hemotologic disorder were reported to be associated closely with C. septicum infection [4-6]. Damage of the bowel wall, particularlyin the distal ileum or ascending colon, was presumed to be the portal of entry of C. septicum [7, 8]. The antibiotic most widely used for this infection was penicillin, but cephalothin, carbencillin, chloramphenicol, clindamycin and metronidazole have been used alternatively [9]. Due to the high risk of recurrent infection, life-long prophylactic oral penicillin was suggested [10]. The mortality rate was as high as 50 to 70% [71. With the improved techniques for identifying anaerobic pathogens, C. septicum infection has been recognized more often in recent years. However, C~S infection due to this organism is still rare. In our literature review, only 12 patients were retrieved (Table 1). Their ages ranged from 16 months to 85 years. Eight were males and three 42 / 172 were females. Among these 12 patients, six (50 %) were associated with malignant diseases and the other six cases had non-malignant hematologic disorders. Three of 12 (25%) patients had occult colonic adenocarcinoma. The clinical manifestations were fever, chills, pain in the extremities, and variable neurological symptoms, including facial twitching, seizure, hemiparesis, and confusion. There were two types of CNS lesion in these 12 cases: four (33%) brain abscesses and eight (67%) hemorrhagic, necrotizing, and gas-forming cerebritis. A high rate of positive blood cultures is noted. The antibiotics used were varied. Penicillin, combined with various antibiotics, was most common. Eight of 12 (67%) died directly due to this infection, and the other four (33%) survived. The mean duration from the onset of symptoms to mortality was 77 h. Colorectal lesions were found in eight of nine (89%) patients who were examined by autopsy. Hemolytic-uremic syndrome (HUS) is a clinical entity consisting of acute microangiopathic hemolytic anemia, thrombocytopenia, and oligouric renal failure. Complications in the gastrointestinal tract (emesis, diarrhea and cramping abdominal pain) and CNS (seizure, stroke and cerebral hemorrhage) are common and considered to be due to systemic vasculopathy [3, 7, 11]. HUS-associated CNS infection is extremely rare. In our literature review, four cases were reported, all of which were due to C. septicum (as presented in Table 1 ) [3, 7, 9, 11]. HUS-related colitis is presumed to play a key role in the entity [3, 7, 11]. Frequent neurologic manifestations related to HUS make it difficult tb find C. septicum CNS infection early. Therefore, when neurologic symptoms develop in HUS, CNS infection due to C. septicum should be considered. In the review of the literature, we found a close relationship between the outcome and the type of CNS lesion. The patients with documented cerebritis or meningoencephalitis presented an extremely fulminant course. All of them died within 3 days, some even within several hours. On the other hand, four patients with brain abscess formation exhibited a relatively benign course and had the chance to receive surgical therapy. Bacteremia and CNS infection due to C. septicum associated with breast cancer is reported for the first time in this article. The possibility of CNS metastasis often causes confusion and makes early diagnosis impossible. However, for a cure, we should remain highly suspicious of C. septicum CNS infection when neurologic symptoms develop in patients with underlYing malignant diseases. According to the literature, penicillin is the preferred antibiotic for this infection, and its minimal inhibition concentration is among the lowest [9]. Combination therapy with gentamicin, cephalothin, clindamycin or metronidazole was common. The suggested length of antibiotic therapy was 4-6 weeks [10, 1t]. However, the effectiveness of combination therapy is still uncertain. Further study is needed on this issue. In conclusion, when infections associated with neurological symptoms and signs develop in a patient with malig- Infection 25 (1997)No. 3 © MMVMedizinVerlag GmbH Mtinchen, Mianchen1997 Y.-T. Cheng et al.: Clostridium septicum Table 1: Summary of patients with CNS infections due to Clostridium septicum. 1 [4] 32 years M Myelogenous leukemia Fever, N/V and abdominal pain Meningitis (?) Pos P, C, M Survived (?) None 2 [12] 73 years F Colonic carcinoma Fever and right hemiparesis Cerebritis with gas Pos G, CTZ Died 4h Ulceration and necrotizing polyps 3 [6] 33 years M Sptenectomized Fever, for aplastic right leg anemia myonecrosis Cerebritis with gas Pos To, E Died 36 h None 4 [6] 76 years M Occult colonic carcinoma Fever, diarrhea and mental confusion Cerebritis with gas Pos AM Died 14 h Perforation with pericolonic abscess 5 [9] 16 months M HUS Bloody diarrhea, fever and seizure Cerebritis with gas (?) AM, G, CC Died 1 day Massive necrosis 6 [13] 67 years F Occult rectal carcinoma Fever, diarrhea and confusion Meningoencephalitis with gas Pos (?) Died several h Necrotic rectal tumor 7 [10] 71 years M MDS Fever, Brain abscess confusion and myonecrosis Pos P, CTZ, CC Survived 6 weeks None 8 [14] 85 years M Occult carcinoma of the caecum Fever, left Brain abscess weakness and confusion Pos P, MET, aspiration Died t6 days Multiple tumors 9 [3] 4 years M HUS Bloody diarrhea, seizure and coma IVleningoencephalitis with gas Pos (?) Died 70 h Microangiopathy with necrosis 10 [7] 2 years F HUS Fever, vomiting, Cerebritis diarrhea and and seizure meningitis Pos P, MET Died 6h Transmural inflammation and necrosis 11 [11] 2 years M HUS Bloody Brain abscess diarrhea and facial twitching (?) P, MET, Survived aspiration 6 weeks None *'12 40 years F Breast cancer Fever and left hemiparesis Pos 6 weeks None Brain abscess P, CC Survived HUS: hemolytic-uremic syndrome; MDS: myelodysplastic syndrome; N/V: nausea and/or vomiting; Pos: positive; P: penicillin; C: cephalothin; M: methicillin; G: gentamicin; CTZ: ceftazidime; To: tobramycin; E: erythromycin; AM: ampicillin; CC: clindamycin; MET: metronidazole; *: died 4 months later due to recurrent septicemia without residual brain lesion by autopsy; **: our presented case. Infection 25 (1997) No. 3 © MMV Medizin Verlag GmbH Mttnchen, Mtinchen 1997 173 / 43 Y.-T. Cheng et al.: Clostridium septicum Figure 2: MRI revealing a space-taking lesion over left frontal-parietal lobe in T1 (A) and T2 (B) images and ring-like contrast enhancement with perifocal edema (C). n a n c y or n o n - m a l i g n a n t h e m a t o l o g i c disorder, C. septicum CNS i n f e c t i o n s h o u l d b e considered. T h e p r o g n o s i s is poor, b u t it m a y b e i m p r o v e d by early diagnosis. T h e n a t u r a l course of disease d e p e n d s o n the types of CNS lesion. Penicillin c o m b i n e d with various antibiotics is the preferred m e d i c a l t h e r a p y at p r e s e n t . If p a t i e n t s survive this infection, l o n g - t e r m p r o p h y l a c t i c oral penicillin is indicated b e c a u s e of the high risk of r e c u r r e n c e . References 1. MacLennan, J. D.: The histotoxic clostridial infections of man. Bact. Rev. 26 (1962) 177-276. 2. Johnson, S., Driks, M. R., Tweten, R. K., Ballard, J., Stevens, D. L., Anderson, D. L., Janoit; E. N.: Clinical course of seven survivors of Clostridium septicum infection and their immunologicresponse to alpha toxin. Clin. Infect. Dis. 19 (1994) 761-764. 3. Randall, J. M., Hall, K., Couithard, M. G.: Diffuse pneumocephalus due to Clostridium cerebritis in hemolytic uremic syndrome: CT demonstration. Neuroradiology 35 (1993) 218-220. 4. AIpern, R. J., Dowell, V. R. Jr.: Clostridium septicum infections and malignancy. JAMA 209 (1969) 386-388. 5. Kornbluth, A. A., Danzig, J. B., Bernstein, L H.: Clostridium septicure infection and associated malignancy: report of 2 cases and review of the literature. Medicine 68 (1989) 30-37. 6. Gorse, G. J., Siater, L. M., Sobol, E., Kim, R. C., Wishnow, R. M., Cesario, T. C.: CNS infection and bacteremia due to Ctostridium septicum. Arch. Neurol. 41 (1984) 882-884. 7. Bronghton, R. A., Lee, E. Y.: Clostridium septicum sepsis and meningitis as a complication of the hemolytic-uremic syndrome. Ctin. Pediatr. 32 (1993) 750-752. 44 / 174 8. Kirehner, J. T.: Clostridium septicum infection. Postgrad. Med. 90 (1991) 157-160. 9. Riccio, J. A., Oberkircher, O. R.: Clostridium septicum sepsis and cerebritis: a rare complication of the hemolytic-uremic syndrome. Pediatr. Infect. Dis. J. 7 (1988) 342-345. 10. Kolbeinsson, M. W., Holder, W. D., Aziz, S.: Recognition, management, and prevention of Closlridium septicum abscess in immunosuppressed patients. Arch. Surg. 126 (1991) 642-645. 11. Chiang, V., Adelson, P. D., Poussaint, T. Y., Hand, M., Churchwell, K. B.: Brain abscess caused by Clostridium septicum as a complication of hemolytic-uremic syndrome. Pediatr. Infect. Dis. J. 14 (1995) 72-74. 12. Roeltgen, D., Shugar, G., Towfighi, J.: Cerebritis due to Clostridium septicum. Neurology 30 (1980) 1314-1316. 13. Ragland, IL L, Knorr, J. R., Lee, G. M., DeGirolami, U., Gelber, N. D.: Clostridium septicum meningoencephalitis: an usual presentation of occult rectal carcinoma. AJNR 13 (1991) 1487-1488. 14. Marangou, A. G., Joske, R. A , Kaard, A. O, Thomas, W.: Cerebral abscess due to Clostridium septicum. J. R. Soc. Med. 85 (1992) 641. Infection 25 (1997) No. 3 © MMV Medizin Verlag GmbH Mtinchen, Mtinchen 1997