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Reversible encephalopathy secondary to paratyphoid infection and concomitant acute hepatitis A.

Abstract: Reversible encephalopathy has been described in association with typhoid fever as well as nontyphoidal salmonella infections. A diagnostic dilemma as to the cause of encephalopathy may arise when there is coexistent acute viral hepatitis and suspicion of fulminant liver failure. The authors report a patient who presented with acute icteric hepatitis A infection and a concomitant febrile illness due to Salmonella paratyphi associated with progressive encephalopathy and coma. The young man developed high-grade fever and coma. Concomitant infection with S paratyphi was diagnosed and the patient's encephalopathy resolved rapidly with antibiotic therapy. This is the first report of a putative association of S paratyphi infection and reversible encephalopathy. Salmonella and hepatitis A virus infection are both transmitted via the fecal-oral route, and awareness of this association is important in the management of such patients.

Key Words: coma, enteric, liver, viral

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Although encephalopathy in the absence of infection of the central nervous system or metabolic derangements is well described in enteric fever, (1-3) it is very rare in infections with nontyphoidal salmonella serotypes and has not been previously described in association with Salmonella paratyphi infection. Herein we describe a young man who presented with acute hepatitis A infection and a concomitant febrile illness due to S paratyphi associated with progressive encephalopathy and coma. His neurologic symptoms resolved rapidly on antimicrobial therapy. The difficulty in differentiating the cause of encephalopathy in this case is highlighted.

Case Report

A 23-year-old healthy male presented for evaluation of high-grade fever, chills, and upper abdominal pain associated with heartburn and belching for 3 days. Blood tests showed a white blood cell count of 4,200 cells/[mm.sup.3], with 74% neutrophils, 20% lymphocytes, and the hemoglobin and platelet counts were normal. Aspartate aminotransferase (AST) was 3,004 IU/L, and alanine aminotransferase (ALT) was 2,411 IU/L with a positive hepatitis A virus (HAV) immunoglobulin M (IgM) antibody. The patient was empirically given a dose of levofloxacin and amoxicillin orally but developed rapid confusion and was transferred to the American University of Beirut Medical Center. At arrival, the patient was comatose and in respiratory distress. He was intubated and admitted to the intensive care unit. There was no history of alcoholism, drug abuse, or blood transfusions. It was reported that 1 month earlier, the patient was cleaning the sewage system at home. Physical examination showed a temperature of 40[degrees]C, pulse of 130 per min, and blood pressure of 150/60 mm Hg. The patient was sweating profusely. He was comatose and nonresponsive to verbal or painful stimuli. Mild scleral icterus was noted. The neck was supple with no evident meningismus. His pupils were symmetric and reactive; however, his eyes were "sun downing." He also had generalized spasticity, hyperreflexic deep tendon reflexes, and bilateral Babinski signs. Heart, lung, and abdominal examinations were normal with no evidence of hepatosplenomegaly. Studies at admission (day 5 of illness) revealed a white blood cell count of 10,300 cells/[mm.sup.3] (neutrophils 55%, lymphocytes 35%, monocytes 7%, reactive lymphocytes and Downey cells), hemoglobin 12 g/dL, hematocrit 38%, and normal platelet count. Blood glucose was 127 mg/dL; serum urea nitrogen 14 mg/dL; creatinine 1.1 mg/dL; total bilirubin of 8.2 mg/dL; direct bilirubin of 6.5 mg/dL; AST of 1,720 U/L; ALT 4,070 U/L; gama-glutamyl transpeptidase 152 U/L; alkaline phosphatase of 173 U/L; creatinine kinase 1,491 U/L; albumin 3.5 g/dL; prothrombin time international normalized ratio 1.3; partial thromboplastin time 28 seconds. IgM antibodies to hepatitis A were positive. Chest x-ray and urine drug screening were negative. Nonenhanced CT of the brain revealed mild diffuse brain edema. Cerebrospinal fluid (CSF) examination demonstrated clear fluid with no cells or microorganism by Gram stain (opening pressure not recorded). An electroencephalogram showed diffuse bilateral slowing. Because of high-grade fever, the patient was started empirically on IV ceftriaxone (2 g daily) and vancomycin. On the second day of admission to the intensive care unit, empiric therapy with acyclovir was initiated for possible herpes simplex encephalitis. He did not receive any dexamethasone, mannitol, or sedatives. Three days later, the patient's neurologic status improved, and he became responsive to verbal commands and progressively regained full consciousness. He was extubated and discharged home on the fifth day of admission on no therapy. A repeat electroencephalogram was normal. His transaminases had dropped to an ALT of 1.251 IU/L. AST 530 IU/L, prothrombin time international normalized ratio 1.1, total bilirubin 6.8 mg/dL, and direct bilirubin 5.4 mg/dL. S paratyphi BH antigens were positive at > 1:6,400, with negative S paratyphi B and O antigens. Blood and stool cultures were negative. Serology for hepatitis B and C, monospot, leptospira, brucella, cytomegalovirus, and herpes simplex virus (HSV) were all negative. Similarly, HAV IgM, HSV IgM, cytomegalovirus IgM, HSV polymerase chain reaction, and Brucella antibodies were also negative in the cerebrospinal fluid. The patient remained asymptomatic with complete normalization of his blood tests. S paratyphi titers repeated after 4 weeks showed a greater than fourfold reduction (S paratyphi BH 1:400).

Discussion

We describe a patient who suffered from acute hepatitis A and S paratyphi infection resulting in a severe but rapidly-reversible encephalopathy. It is highly unlikely that the reversible encephalopathy was a result of fulminant liver failure, usually characterized by the rapid development of hepatocellular dysfunction (jaundice, coagulopathy) and encephalopathy in an individual with no prior history of liver disease. Patients suffering from fulminant liver failure are usually considered for rapid intervention, including artificial liver support devices and/or liver transplantation, and rarely make a rapid or spontaneous recovery. The absence of clinical evidence of substantial liver dysfunction in our patient (eg, severe coagulopathy, marked and worsening jaundice) and the rapid resolution of encephalopathy within 2 days argues strongly against liver failure. (4) An element of mild hepatic encephalopathy may have been contributory. However, transient or clinically significant encephalopathy is not commonly seen in acute self-limited viral hepatitis. Hepatitis A encephalitis in this case is unlikely in the presence of the negative CSF findings, the rapid recovery and the absence of sequelae. A case of hepatitis A encephalitis coexistent with hepatitis C has been described in the literature associated with negative CSF findings, normal CT of the brain and a rapid recovery in 3 days. (5) We do not agree with this conclusion, especially as in all the previous case reports of presumed hepatitis A encephalitis, (6,7) CSF pleocytosis was present. Rapid recovery has been reported in one of them but within 14 days.

Reversible encephalopathy has been described in association with typhoid fever as well as nontyphoidal salmonella infections. (8-10) In one study by Arii et al, (8) primary nontyphoidal encephalopathy was identified based on strictly defined criteria: 1) encephalopathic feature defined as altered state of consciousness, altered cognition or personality, or seizures; 2) detection of nontyphoidal salmonella species in stool; 3) absence of other viral or bacterial infection associated with central nervous system abnormalities; and 4) absence of alternative explanation by underlying neurologic or systemic disease. The exact cause of the diffuse encephalopathy in typhoid fever and nontyphoidal salmonella infection is unclear but is felt to be due to release of endotoxins. (11)

The most plausible explanation is that the reversible encephalopathy in this case was primarily related to the salmonella infection. In support of this are the presence of high-grade fever, response to antibiotics, and the rapid resolution of symptoms. The incubation period of salmonella (1-8 weeks) is similar to HAV which suggests that both could have been contracted at the same time. Cases of typhoid fever associated with fulminant hepatitis A, E, and non-A non-B infection have been reported in the literature and the emphasis made that in all cases of presumed fulminant hepatic failure, typhoid should be considered especially in endemic areas. (12) In our patient, the absence of O-agglutinin titers and the absence of positive blood cultures could be explained by the previous antibiotics taken before transfer to our hospital which could have aborted the growth of the S paratyphi in the blood and the stools. Furthermore, in endemic areas, H-agglutinin titers were found to be more specific than O-agglutinin titers for salmonella infection, especially in the absence of positive blood cultures. (13) The clinical course of our patient and the greater than fourfold decline in S paratyphi titers further supports our diagnosis.

References

1. Kapoor AK, Mathur A, Chaturvedi UC, et al. Acute encephalopathy due to salmonella infection. J Indian Med Assoc 1973;60:307-308.

2. Santhanakrishnan BR, Baliga R, Raju VB. Typhoid encephalopathy in children. Indian J Pediatr 1973;40:39-43.

3. Uysal H, Karademir A, Kilinc M, Erturk O. Salmonella encephalopathy with seizure and frontal intermittent rhythmic delta activity. Infection 2001;29:103-106.

4. Lee WM. Acute liver failure. N Engl J Med 1993;329:1862-1872.

5. Thomas WJ, Bruno P, Holtzmuller K. Hepatitis A virus anicteric encephalitis coexistent with hepatitis C virus infection. Am J Gastroenterol 1993;88:279-281.

6. Breningstall GN, Belani KK. Acute transverse myelitis and brainstem encephalitis associated with hepatitis A infection. Pediatr Neurol 1995;12:169-171.

7. Davis LE, Brown JE, Robertson BH, et al. Hepatitis A post-viral encephalitis. Acta Neurol Scand 1993;87:67-69.

8. Arii J, Tanabe Y, Miyake M, et al. Clinical and pathologic characteristics of nontyphoidal salmonella encephalopathy. Neurology 2002;58:1641-1645.

9. Daras M, Blankfein R, Singh BM. Salmonella choleraesuis encephalopathy. NY State J Med 1980;80:1606-1607.

10. Martin K, Sharland M, Davies EG. Encephalopathy associated with Salmonella enteritidis infection. Scand J Infect Dis 1994;26:486-488.

11. Nag AK, Saha K, Mehrotra AN, et al. Endotoxemia in typhoid encephalopathy. Indian J Med Res 1975;63:1273-1279.

12. Pandey CK, Singh N, Kumar V, et al. Typhoid, hepatitis E, or typhoid and hepatitis E: the cause of fulminant hepatic failure--a diagnostic dilemma. Crit Care Med 2002;30:376-378.

13. Parry CM, Hoa NT, Diep TS, et al. Value of a single-tube Widal test in diagnosis of typhoid fever in Vietnam. J Clin Microbiol 1999;37:2882-2886.
It is curious that physical courage should be so common in the world and
moral courage so rare.
--Mark Twain


From the Department of Internal Medicine, Divisions of Infectious Diseases, Neurology and Gastroenterology, American University of Beirut Medical Center, Beirut, Lebanon.

Reprint requests to Ala I. Sharara, MD, FACP, Associate Professor of Medicine, Head, Division of Gastroenterology, Box 16-B, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh 110 72020, Beirut, Lebanon. Email: as08@aub.edu.lb

Accepted January 24, 2005.

RELATED ARTICLE: Key Points

* Reversible encephalopathy occurs in association with typhoid fever as well as nontyphoidal salmonella infections.

* The exact cause of this associated diffuse encephalopathy is unclear, but may be due to release of endotoxins.

* Typhoid and nontyphoidal salmonella infection should be considered in all cases of presumed fulminant hepatic failure, especially in endemic areas.
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Title Annotation:Case Report
Author:Sharara, Ala I.
Publication:Southern Medical Journal
Date:Jul 1, 2005
Words:1826
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