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71-Year-Old Woman With Fever and Altered Mental Status
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71-Year-Old Woman With Fever and Altered Mental Status CHENG E. CHEE, MD,* AND DAVID N. MOHR, MD†
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71-year-old woman with a history of type 2 diabetes mellitus, hypertension, and hyperlipidemia was hospitalized at our institution because of a sudden change in mental status. Two months previously, she had been hospitalized elsewhere for nausea, vomiting, and diarrhea. At that time, a duodenal ulcer and acute renal failure attributed to volume depletion were diagnosed, although renal biopsies performed during hospitalization showed focal segmental glomerulosclerosis with collapsing features, acute tubular necrosis, and thrombotic microangiopathy with glomerular capillary wall remodeling (double contours). No medication was administered for the renal failure. A dialysis catheter was placed and dialysis initiated, but the patient’s symptoms persisted. During the next 2 months, she experienced an 11.25-kg weight loss. Two days before the current admission, the patient noted neck and shoulder pain after sleeping on a new pillow and took benzodiazepine for symptom relief. During the 24 hours before admission, her daughter noted a change in behavior, somnolence, and during the last few hours before presentation, agitation and confusion. The patient did not have chills, dysuria, or pain. On physical examination, the patient was not oriented to time, place, or person but was able to follow some 1-step commands. Her temperature was 38.4ºC, blood pressure was 130/80 mm Hg, and pulse rate was regular at 100/min. Cardiovascular examination revealed a nonradiating 2/6 systolic murmur at the right upper sternal border. No erythema or discharge was evident at the dialysis catheter exit site on the anterior aspect of the chest wall. Neurological examination showed nuchal rigidity but no photophobia. The pupils were equal and reactive, and a single left conjunctival petechia was noted. No focal neurological deficits were identified, and the patient had a downward response to plantar stimulation. Initial laboratory tests yielded the following results (reference ranges shown parenthetically): hemoglobin, 13.5 g/dL (12.0-15.5 g/dL); white blood cell count, 9.2 × 109/L (3.510.5 × 109/L) with a left shift; thrombocytopenia (platelet count, 120 × 109/L); hyperkalemia (potassium, 5.4 mEq/L); *Resident in Internal Medicine, Mayo School of Graduate Medical Education, Mayo Clinic College of Medicine, Rochester, Minn. †Adviser to resident and Consultant in General Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn. See end of article for correct answers to questions. Address reprint requests and correspondence to David N. Mohr, MD, Division of General Internal Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2007 Mayo Foundation for Medical Education and Research
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creatinine, 3.9 mg/dL; and serum urea nitrogen, 31 mg/dL. Urinalysis revealed the presence of nitrates and more than 100 erythrocytes per high-power field but no leukocytes. Gram stain yielded negative results. However, urinalysis performed 4 days before admission had shown pyuria and 51 to 100 white blood cells per high-power field. 1. Which one of the following should not be considered in the differential diagnosis of this patient? a. Meningitis b. Urosepsis c. Endocarditis d. Thrombotic thrombocytopenic purpura (TTP) e. Malignancy The patient had the classic triad of fever, nuchal rigidity, and altered mental status that is characteristic of meningitis. The previously identified pyuria, urinalysis positive for nitrates, and fever make urosepsis another possibility. Endocarditis should also be considered in the differential diagnosis because the patient had a cardiac murmur in the setting of fever and a conjunctival hemorrhage. In addition, neurological manifestations can be presenting symptoms of endocarditis. Thrombotic thrombocytopenic purpura should be included in the differential diagnosis as well because it can present with thrombocytopenia, fever, and changes in mental status. Furthermore, the previous renal biopsy results were compatible with thrombotic microangiopathy. Although malignancy can present with mental status changes, it is unlikely to occur in an acute setting and therefore should not be considered in this patient’s differential diagnosis. The patient underwent computed tomography (CT) of the head, which showed old ischemic changes in the right thalamus. However, an emerging infarct in the thalamus and brainstem could not be excluded. The CT scan showed evidence of a previous small right lentiform and cerebellar infarct, but no hemorrhage was identified. A lumbar puncture was performed, and cerebrospinal fluid (CSF) analysis revealed the following: total nucleated cells, 471/µL (99% neutrophils); glucose, 37 mg/dL; and total protein, 45 mg/ dL. The serum glucose level was 77 mg/dL. 2. Which one of the following empirical antibiotic treatment regimens is the best choice for the patient at this time? a. Ceftriaxone, ampicillin, and vancomycin b. Ceftriaxone, acyclovir, and vancomycin c. Ceftriaxone and gentamicin d. Vancomycin, gentamicin, and rifampin e. Vancomycin and ceftriaxone
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The CSF results, including the leukocytosis with neutrophilic predominance, and the low CSF glucose–plasma glucose ratio of 0.48 (0.6) are consistent with primary bacterial meningitis. In patients with suspected meningitis, treatment should never be delayed. Empirical therapy against the most likely pathogens should be instituted immediately. In patients older than 50 years, common bacterial causes of meningitis include Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, and aerobic gram-negative bacilli.1 Third-generation cephalosporins such as ceftriaxone and cefotaxime have potent activity against the major pathogens of bacterial meningitis with the notable exception of L monocytogenes, for which ampicillin is effective. With the worldwide increase in the prevalence of penicillin-resistant pneumococci, vancomycin should be added to cefotaxime or ceftriaxone as empirical treatment until culture and susceptibility results are available1 even though CSF levels of these third-generation cephalosporins are generally adequate for pneumococci that are intermediately sensitive to penicillins or cephalosporins. Acyclovir as early therapy is associated with a considerable decrease in morbidity and mortality and should be included in the treatment regimen if meningitis due to herpes simplex virus 1 is suspected.2 In our patient, the predominance of neutrophils and the extremely low CSF glucose level made viral meningitis less likely, and the addition of acyclovir to ceftriaxone and vancomyin would be inappropriate. Ceftriaxone and gentamicin are reasonable empirical therapies for prosthesis-associated endocarditis caused by viridans group streptococci or Streptococcus bovis. A regimen of vancomycin, gentamicin, and rifampin is indicated for endocarditis caused by staphylococci in patients with prosthetic devices.3 Because we were treating our patient empirically for meningitis due to an as yet unknown cause, these antibiotics would not provide broad enough coverage. Furthermore, gentamicin would be a poor choice for suspected central nervous system (CNS) infection because of its poor penetration into the CSF. The combination of vancomycin and ceftriaxone would also not be the best choice at this time because it does not provide adequate antimicrobial coverage. Blood was withdrawn for culture studies, and empirical therapy with intravenous ceftriaxone, ampicillin, and vancomycin was instituted. The patient’s platelet count continued to decrease to 74 × 109/L. Coagulation studies yielded the following results: D-dimer, >2000 ng/mL (<301 ng/ mL); fibrinogen, 604 mg/dL (175-430 mg/dL); activated partial thromboplastin time, 39 seconds (21-33 seconds); prothrombin time, 10.9 seconds (8.4-12.0 seconds); and soluble fibrin monomer complex, positive. A peripheral blood smear showed no schistocytes. 238
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3. Given this new clinical information, which one of the following would be the most appropriate next step in the management of this patient? a. Transfusion with fresh frozen plasma b. Platelet transfusion c. Transfusion with cryoprecipitate d. Continuation of antibiotics e. Plasma exchange The clinical picture of sepsis and the abnormal coagulation profile with elevated D-dimer levels, prolonged activated partial thromboplastin time, and the presence of soluble fibrin monomers are consistent with disseminated intravascular coagulation (DIC). However, because the platelet count was only moderately reduced, the prothrombin time was within normal limits, and the fibrinogen level was increased, this scenario is most consistent with chronic DIC, in which the slower rate of consumption of coagulation factors may be balanced by enhanced synthesis of these proteins. Of note, because the patient had leukocytosis and pyuria 4 days before admission, the infection could have preceded her admission by many days. Disseminated intravascular coagulation was suspected as the cause of the patient’s coagulopathy. Because she had no signs of bleeding or thrombosis and the prothrombin time was not prolonged, specific treatment for coagulopathy with transfusions of fresh frozen plasma, platelets, or cryoprecipitate is unnecessary. In patients with DIC, the underlying cause should be treated. Therefore, continuing antibiotic treatment of the meningitis is the most appropriate choice at this time. Also, TTP should be considered because the patient presented with 4 of the pentad of features characteristic of this disorder: fever, renal failure, mental status changes, and thrombocytopenia. However, the absence of schistocytes and the strong evidence of an infectious etiology suggested that the patient’s condition was unlikely to be secondary to TTP, and hence plasma exchange is not indicated. The patient subsequently experienced tachycardia with an intermittently irregular heart rhythm and a pulse rate of approximately 130/min. Electrocardiography confirmed new atrial fibrillation, compared to admission tracings that showed sinus tachycardia. Additionally, within 24 hours of admission, both CSF and blood cultures grew Staphylococcus aureus. 4. At this stage in the patient’s work-up, which one of the following diagnostic tests would be most helpful? a. Magnetic resonance imaging of the head b. Transesophageal echocardiography (TEE) c. Transthoracic echocardiography d. CT of the abdomen and pelvis e. Electroencephalography
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Taking into account the clinical picture of meningitis, the pathogen involved in this case, the presence of a dialysis catheter, and the new-onset arrhythmia, a diagnosis of endocarditis must be entertained. Magnetic resonance imaging of the head could be helpful because the patient had mental status changes and possible evidence of infarction on head CT. However, this modality would simply confirm the suspicion of an infarct and would not reveal its cause, which would clarify the primary diagnosis. In the diagnosis of endocarditis, TEE is more sensitive (>90%) than transthoracic echocardiography (55%-63%) for detecting vegetations and cardiac abscess and thus is the diagnostic test of choice.4-6 Computed tomography of the abdomen and pelvis would be more useful in the evaluation of the patient’s earlier symptoms of nausea, vomiting, diarrhea, and weight loss and is not the most helpful study at this point in the evaluation. Electroencephalography would not be helpful in a patient with no history of seizures. Transesophageal echocardiography revealed multiple large mobile masses in the left ventricular outflow tract and the anterior and posterior mitral valve leaflets. In addition, thrombi were detected at the tip of the dialysis catheter and at the junction of the right atrium and the superior vena cava. 5. Which one of the following would be the most important next step in this patient’s management? a. Change antibiotics b. Remove the dialysis catheter c. Change antibiotics and remove the dialysis catheter d. Perform cardioversion e. Obtain surgical consultation for valve replacement With identification of the infecting organism, the antibiotic regimen should be changed to include the drugs most effective against the particular pathogen. In our patient, the source of the infection was most likely the dialysis catheter, and TEE showed thrombi at its tip. In a setting of sepsis, appropriate antibiotic therapy along with removal of the source of the infection is the most important next step. Cardioversion for treatment of atrial fibrillation is unnecessary at this point in a patient whose vital signs are stable. The presence of congestive heart failure in the setting of endocarditis is a major reason to proceed with surgery because studies have shown that valve surgery improves survival.7 Our patient had no clinical evidence of congestive heart failure, and a surgeon was not consulted. The patient’s antibiotic regimen was changed to vancomycin, gentamicin, and rifampin. Her heart rate was controlled with β-blockers. Subsequently, respiratory failure and septic shock developed. Pulseless electrical activity ensued, and resuscitative efforts were unsuccessful. The patient died on day 4 of hospitalization. At autopsy, the diagnosis of infective endocarditis (IE) was confirmed, and Mayo Clin Proc.
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an acute fatal occlusion of the left main coronary artery by septic embolus was discovered. Systemic embolization, associated with splenic and cerebral infarcts, microabscesses in the brain, heart, pancreas, and both kidneys, and splinter hemorrhages in multiple fingers and toes were also identified. We hypothesized that thrombotic thrombocytopenic purpura–hemolytic uremic syndrome might have been the cause of the patient’s previous renal failure. The renal biopsy finding of double contours in the glomerular basement membranes is known as tram-tracking. It is found in type I and type II membranoproliferative glomerulonephritis and results from basement membrane reduplication. 8 One condition associated with this membranoproliferative pattern of injury is immune complex–mediated disease such as chronic and recovered thrombotic microangiopathy. 9 However, features of membranoproliferative glomerulonephritis can also be seen in patients with IE, including renal biopsy findings similar to those found in patients with TTP. DISCUSSION This case highlights the neurological manifestations and complications associated with IE. In 1885, Osler10 provided the first clear description of the frequent involvement of the brain in the morbid complications of bacterial endocarditis. Cerebral and other neurological complications have been reported to occur in 20% to 40% of cases of IE.11 They include stroke, intraparenchymal hemorrhage, subarachnoid hemorrhage, abscess, mycotic aneurysm, seizure, encephalopathy, and meningitis.12 Bacterial meningitis, a serious complication of IE, is an unusual first manifestation.13 The reported frequency of meningitis in patients with IE varies from 0% to 20%,14,15 and the most frequent pathogen is S aureus.13 In 1939, Smith16 described 3 mechanisms for the pathogenesis of meningitis in patients with IE: (1) a mycotic aneurysm may leak, and the blood in the CSF may then cause aseptic meningitis; (2) after embolic infarction, meningeal irritation occurs in the adjacent area or results from rupture of softened brain tissue into the CSF; and (3) deeply situated infarcts cause congestion of the pia-arachnoid membrane resulting in aseptic meningitis. In our patient, these aseptic causes of meningeal irritation certainly could not explain the positive CSF cultures and the severity of her meningismus. Emboli containing bacteria can occur in patients with acute endocarditis, especially those with staphylococcal endocarditis.17 In these cases, purulent or suppurative meningitis is common,18 and the proposed mechanism includes blood-borne implantation of septic emboli in meningeal vessels and suppurative extension from brain infarcted by septic emboli.10 Early recognition of neurological manifestations of IE is important because
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mortality rates are higher in patients with neurological complications than in those without such complications (50.0% vs 20.9%).19 In addition, neurological complications of IE markedly increase the operative risk associated with open heart surgery.20 Valve replacement should be delayed for 2 to 3 weeks after a nonhemorrhagic CNS event and for a month after an intracerebral bleed.20 In cases involving native valves, anticoagulation is not recommended until the septic phase of the disease has passed because of the risk of hemorrhagic CNS complications.21 Our patient’s cause of death was coronary artery embolism, which has been seen in as many as 60% of cases of IE at autopsy.22 In 1856, Virchow23 provided the first description of coronary arterial occlusion complicating acute bacterial endocarditis. Experience with thrombolytics in the setting of IE-related myocardial infarction has largely been unfavorable because of the high risk of major intracerebral hemorrhage.22 In patients with myocardial infarction, prompt primary percutaneous coronary intervention is regarded as superior to thrombolytic therapy,24 and it appears to be a safer option in the setting of IE, although only case reports documenting such treatment are available in the literature. Because IE vegetations are normally firm, placement of a coronary stent may be required to prevent restenosis.22 The risk-benefit ratio of stent placement must be considered, especially in the setting of bacteremia.22 The differential diagnosis of thrombotic microangiopathy was interesting in this case. Thrombotic microangiopathies are microvascular occlusive disorders characterized by systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes.25 Examples of the disorders are TTP and hemolytic uremic syndrome. The literature also contains reports of TTP-like syndromes associated with IE.26 In these cases, the chief presentation was a TTP-like syndrome with compatible laboratory findings, and the syndrome was rapidly reversed with specific antimicrobial therapy. The authors postulated that the high levels of circulating immune complexes that declined as TTP abated supported the concept that the TTP syndrome in these patients resulted from immune complex–mediated vasculitis.26 In our patient with S aureus IE, a dialysis catheter was the most likely source of the infection. The patient later developed complications of septic emboli, including meningitis and cerebral and myocardial infarction, and died. We appreciate the helpful review of the submitted manuscript by Larry M. Baddour, MD.
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REFERENCES 1. van de Beek D, de Gans J, Tunkel, AR, Wijdicks, EF. Communityacquired bacterial meningitis in adults. N Engl J Med. 2006;354:44-53. 2. Whitley RJ. Viral encephalitis. N Engl J Med.1990;323:242-250. 3. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association. Circulation. 2005;111: e394-e434. 4. Reynolds HR, Jagen MA, Tunick PA, Kronzon I. Sensitivity of transthoracic versus transesophageal echocardiography for the detection of native valve vegetations in the modern era. J Am Soc Echocardiogr. 2003;16:67-70. 5. Erbel R, Rohrmann S, Drexler M, et al. Improved diagnostic value of echocardiography in patients with infective endocarditis by transoesophageal approach: a prospective study. Eur Heart J. 1988;9:43-53. 6. Mugge A, Daniel WG, Frank G. Lichtlen PR. Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and transesophageal approach. J Am Coll Cardiol. 1989;14:631-638. 7. Vikram HR, Buenconsejo J, Hasbun R, Quagliarello VJ. Impact of valve surgery on 6-month mortality in adults with complicated, left-sided native valve endocarditis: a propensity analysis. JAMA. 2003;290:3207–3214. 8. Cotran RS, Kumar V, Collins T. The kidney. In: Cotran RS, Kumar V, Collins T, eds. Robbins Pathologic Basis of Disease. 6th ed. Philadelphia, Pa: WB Saunders; 1999:959. 9. Rennke HG. Secondary membranoproliferative glomerulonephritis. Kidney Int. 1995;47:643-656. 10. Osler W. Gulstonian lectures on malignant endocarditis. Lancet. 1885; 1:415-418, 459-464, 505-508. 11. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-1330. 12. Selky AK, Roos KL, Neurologic complications of infective endocarditis. Semin Neurol. 1992;12:225-233. 13. Angstwurm K, Halle E, Wetzel K, Schultze J, Schielke E, Weber JR. Isolated bacterial meningitis as the key syndrome of infective endocarditis. Infection. 2004;32:47-50. 14. Harrison MJ, Hampton JR. Neurological presentation of bacterial endocarditis. BMJ. 1967;2:148-151. 15. Le Cam B, Guivarch G, Boles JM, Garre M, Cartier F. Neurologic complications in a group of 86 bacterial endocarditis. Eur Heart J. 1984;5(suppl C):97-100. 16. Smith WF. Meningitis secondary to subacute bacterial meningitis. N Engl J Med. 1939;220:587. 17. Ziment I. Nervous system complications in bacterial endocarditis. Am J Med. 1969;47:593-607. 18. Bergen SS Jr, Dermksian G. Meningeal manifestations of subacute bacterial endocarditis. N Y State J Med. 1957;57:3683-3685. 19. Chen C, Lo MC, Hwang KL, Liu CE, Young TG. Infective endocarditis with neurologic complications: 10-year experience. J Microbiol Immunol Infect. 2001;34:119-124. 20. Bashore TM, Cabell C, Fowler V Jr. Update on infective endocarditis. Curr Probl Cardiol. 2006;31:274-352. 21. Tornos P, Almirante B, Mirabet S, Permanyer G, Pahissa A, Soler-Soler J. Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy. Arch Intern Med. 1999;159:472-475. 22. Khan F, Khakoo R, Failinger C. Managing embolic myocardial infarction in infective endocarditis: current options. J Infect. 2005 Oct;51:e101-e105. Epub 2004 Nov 11. 23. Virchow RC. Gesammelte Abhandlungen zur wissenschaftlichen Medicin. 1856;219-732. 24. Zeymer U, Schroder R, Machnig T, Neuhaus KL. Primary percutaneous transluminal coronary angioplasty accelerates early myocardial reperfusion compared to thrombolytic therapy in patients with acute myocardial infarction. Am Heart J. 2003;146:686-691. 25. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347:589-600. 26. Bayer AS, Theofilopoulos AN, Eisenberg R, Friedman SG, Guze LB. Thrombotic thrombocytopenic purpura-like syndrome associated with infective endocarditis: a possible immune complex disorder. JAMA. 1977;238:408-410.
Correct answers: 1. e, 2. a, 3. d, 4. b, 5. c
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71-Year-Old Woman With Fever and Altered Mental Status CHENG E. CHEE, MD,* AND DAVID N. MOHR, MD†
A
71-year-old woman with a history of type 2 diabetes mellitus, hypertension, and hyperlipidemia was hospitalized at our institution because of a sudden change in mental status. Two months previously, she had been hospitalized elsewhere for nausea, vomiting, and diarrhea. At that time, a duodenal ulcer and acute renal failure attributed to volume depletion were diagnosed, although renal biopsies performed during hospitalization showed focal segmental glomerulosclerosis with collapsing features, acute tubular necrosis, and thrombotic microangiopathy with glomerular capillary wall remodeling (double contours). No medication was administered for the renal failure. A dialysis catheter was placed and dialysis initiated, but the patient’s symptoms persisted. During the next 2 months, she experienced an 11.25-kg weight loss. Two days before the current admission, the patient noted neck and shoulder pain after sleeping on a new pillow and took benzodiazepine for symptom relief. During the 24 hours before admission, her daughter noted a change in behavior, somnolence, and during the last few hours before presentation, agitation and confusion. The patient did not have chills, dysuria, or pain. On physical examination, the patient was not oriented to time, place, or person but was able to follow some 1-step commands. Her temperature was 38.4ºC, blood pressure was 130/80 mm Hg, and pulse rate was regular at 100/min. Cardiovascular examination revealed a nonradiating 2/6 systolic murmur at the right upper sternal border. No erythema or discharge was evident at the dialysis catheter exit site on the anterior aspect of the chest wall. Neurological examination showed nuchal rigidity but no photophobia. The pupils were equal and reactive, and a single left conjunctival petechia was noted. No focal neurological deficits were identified, and the patient had a downward response to plantar stimulation. Initial laboratory tests yielded the following results (reference ranges shown parenthetically): hemoglobin, 13.5 g/dL (12.0-15.5 g/dL); white blood cell count, 9.2 × 109/L (3.510.5 × 109/L) with a left shift; thrombocytopenia (platelet count, 120 × 109/L); hyperkalemia (potassium, 5.4 mEq/L); *Resident in Internal Medicine, Mayo School of Graduate Medical Education, Mayo Clinic College of Medicine, Rochester, Minn. †Adviser to resident and Consultant in General Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn. See end of article for correct answers to questions. Address reprint requests and correspondence to David N. Mohr, MD, Division of General Internal Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2007 Mayo Foundation for Medical Education and Research
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creatinine, 3.9 mg/dL; and serum urea nitrogen, 31 mg/dL. Urinalysis revealed the presence of nitrates and more than 100 erythrocytes per high-power field but no leukocytes. Gram stain yielded negative results. However, urinalysis performed 4 days before admission had shown pyuria and 51 to 100 white blood cells per high-power field. 1. Which one of the following should not be considered in the differential diagnosis of this patient? a. Meningitis b. Urosepsis c. Endocarditis d. Thrombotic thrombocytopenic purpura (TTP) e. Malignancy The patient had the classic triad of fever, nuchal rigidity, and altered mental status that is characteristic of meningitis. The previously identified pyuria, urinalysis positive for nitrates, and fever make urosepsis another possibility. Endocarditis should also be considered in the differential diagnosis because the patient had a cardiac murmur in the setting of fever and a conjunctival hemorrhage. In addition, neurological manifestations can be presenting symptoms of endocarditis. Thrombotic thrombocytopenic purpura should be included in the differential diagnosis as well because it can present with thrombocytopenia, fever, and changes in mental status. Furthermore, the previous renal biopsy results were compatible with thrombotic microangiopathy. Although malignancy can present with mental status changes, it is unlikely to occur in an acute setting and therefore should not be considered in this patient’s differential diagnosis. The patient underwent computed tomography (CT) of the head, which showed old ischemic changes in the right thalamus. However, an emerging infarct in the thalamus and brainstem could not be excluded. The CT scan showed evidence of a previous small right lentiform and cerebellar infarct, but no hemorrhage was identified. A lumbar puncture was performed, and cerebrospinal fluid (CSF) analysis revealed the following: total nucleated cells, 471/µL (99% neutrophils); glucose, 37 mg/dL; and total protein, 45 mg/ dL. The serum glucose level was 77 mg/dL. 2. Which one of the following empirical antibiotic treatment regimens is the best choice for the patient at this time? a. Ceftriaxone, ampicillin, and vancomycin b. Ceftriaxone, acyclovir, and vancomycin c. Ceftriaxone and gentamicin d. Vancomycin, gentamicin, and rifampin e. Vancomycin and ceftriaxone
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The CSF results, including the leukocytosis with neutrophilic predominance, and the low CSF glucose–plasma glucose ratio of 0.48 (0.6) are consistent with primary bacterial meningitis. In patients with suspected meningitis, treatment should never be delayed. Empirical therapy against the most likely pathogens should be instituted immediately. In patients older than 50 years, common bacterial causes of meningitis include Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, and aerobic gram-negative bacilli.1 Third-generation cephalosporins such as ceftriaxone and cefotaxime have potent activity against the major pathogens of bacterial meningitis with the notable exception of L monocytogenes, for which ampicillin is effective. With the worldwide increase in the prevalence of penicillin-resistant pneumococci, vancomycin should be added to cefotaxime or ceftriaxone as empirical treatment until culture and susceptibility results are available1 even though CSF levels of these third-generation cephalosporins are generally adequate for pneumococci that are intermediately sensitive to penicillins or cephalosporins. Acyclovir as early therapy is associated with a considerable decrease in morbidity and mortality and should be included in the treatment regimen if meningitis due to herpes simplex virus 1 is suspected.2 In our patient, the predominance of neutrophils and the extremely low CSF glucose level made viral meningitis less likely, and the addition of acyclovir to ceftriaxone and vancomyin would be inappropriate. Ceftriaxone and gentamicin are reasonable empirical therapies for prosthesis-associated endocarditis caused by viridans group streptococci or Streptococcus bovis. A regimen of vancomycin, gentamicin, and rifampin is indicated for endocarditis caused by staphylococci in patients with prosthetic devices.3 Because we were treating our patient empirically for meningitis due to an as yet unknown cause, these antibiotics would not provide broad enough coverage. Furthermore, gentamicin would be a poor choice for suspected central nervous system (CNS) infection because of its poor penetration into the CSF. The combination of vancomycin and ceftriaxone would also not be the best choice at this time because it does not provide adequate antimicrobial coverage. Blood was withdrawn for culture studies, and empirical therapy with intravenous ceftriaxone, ampicillin, and vancomycin was instituted. The patient’s platelet count continued to decrease to 74 × 109/L. Coagulation studies yielded the following results: D-dimer, >2000 ng/mL (<301 ng/ mL); fibrinogen, 604 mg/dL (175-430 mg/dL); activated partial thromboplastin time, 39 seconds (21-33 seconds); prothrombin time, 10.9 seconds (8.4-12.0 seconds); and soluble fibrin monomer complex, positive. A peripheral blood smear showed no schistocytes. 238
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3. Given this new clinical information, which one of the following would be the most appropriate next step in the management of this patient? a. Transfusion with fresh frozen plasma b. Platelet transfusion c. Transfusion with cryoprecipitate d. Continuation of antibiotics e. Plasma exchange The clinical picture of sepsis and the abnormal coagulation profile with elevated D-dimer levels, prolonged activated partial thromboplastin time, and the presence of soluble fibrin monomers are consistent with disseminated intravascular coagulation (DIC). However, because the platelet count was only moderately reduced, the prothrombin time was within normal limits, and the fibrinogen level was increased, this scenario is most consistent with chronic DIC, in which the slower rate of consumption of coagulation factors may be balanced by enhanced synthesis of these proteins. Of note, because the patient had leukocytosis and pyuria 4 days before admission, the infection could have preceded her admission by many days. Disseminated intravascular coagulation was suspected as the cause of the patient’s coagulopathy. Because she had no signs of bleeding or thrombosis and the prothrombin time was not prolonged, specific treatment for coagulopathy with transfusions of fresh frozen plasma, platelets, or cryoprecipitate is unnecessary. In patients with DIC, the underlying cause should be treated. Therefore, continuing antibiotic treatment of the meningitis is the most appropriate choice at this time. Also, TTP should be considered because the patient presented with 4 of the pentad of features characteristic of this disorder: fever, renal failure, mental status changes, and thrombocytopenia. However, the absence of schistocytes and the strong evidence of an infectious etiology suggested that the patient’s condition was unlikely to be secondary to TTP, and hence plasma exchange is not indicated. The patient subsequently experienced tachycardia with an intermittently irregular heart rhythm and a pulse rate of approximately 130/min. Electrocardiography confirmed new atrial fibrillation, compared to admission tracings that showed sinus tachycardia. Additionally, within 24 hours of admission, both CSF and blood cultures grew Staphylococcus aureus. 4. At this stage in the patient’s work-up, which one of the following diagnostic tests would be most helpful? a. Magnetic resonance imaging of the head b. Transesophageal echocardiography (TEE) c. Transthoracic echocardiography d. CT of the abdomen and pelvis e. Electroencephalography
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Taking into account the clinical picture of meningitis, the pathogen involved in this case, the presence of a dialysis catheter, and the new-onset arrhythmia, a diagnosis of endocarditis must be entertained. Magnetic resonance imaging of the head could be helpful because the patient had mental status changes and possible evidence of infarction on head CT. However, this modality would simply confirm the suspicion of an infarct and would not reveal its cause, which would clarify the primary diagnosis. In the diagnosis of endocarditis, TEE is more sensitive (>90%) than transthoracic echocardiography (55%-63%) for detecting vegetations and cardiac abscess and thus is the diagnostic test of choice.4-6 Computed tomography of the abdomen and pelvis would be more useful in the evaluation of the patient’s earlier symptoms of nausea, vomiting, diarrhea, and weight loss and is not the most helpful study at this point in the evaluation. Electroencephalography would not be helpful in a patient with no history of seizures. Transesophageal echocardiography revealed multiple large mobile masses in the left ventricular outflow tract and the anterior and posterior mitral valve leaflets. In addition, thrombi were detected at the tip of the dialysis catheter and at the junction of the right atrium and the superior vena cava. 5. Which one of the following would be the most important next step in this patient’s management? a. Change antibiotics b. Remove the dialysis catheter c. Change antibiotics and remove the dialysis catheter d. Perform cardioversion e. Obtain surgical consultation for valve replacement With identification of the infecting organism, the antibiotic regimen should be changed to include the drugs most effective against the particular pathogen. In our patient, the source of the infection was most likely the dialysis catheter, and TEE showed thrombi at its tip. In a setting of sepsis, appropriate antibiotic therapy along with removal of the source of the infection is the most important next step. Cardioversion for treatment of atrial fibrillation is unnecessary at this point in a patient whose vital signs are stable. The presence of congestive heart failure in the setting of endocarditis is a major reason to proceed with surgery because studies have shown that valve surgery improves survival.7 Our patient had no clinical evidence of congestive heart failure, and a surgeon was not consulted. The patient’s antibiotic regimen was changed to vancomycin, gentamicin, and rifampin. Her heart rate was controlled with β-blockers. Subsequently, respiratory failure and septic shock developed. Pulseless electrical activity ensued, and resuscitative efforts were unsuccessful. The patient died on day 4 of hospitalization. At autopsy, the diagnosis of infective endocarditis (IE) was confirmed, and Mayo Clin Proc.
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an acute fatal occlusion of the left main coronary artery by septic embolus was discovered. Systemic embolization, associated with splenic and cerebral infarcts, microabscesses in the brain, heart, pancreas, and both kidneys, and splinter hemorrhages in multiple fingers and toes were also identified. We hypothesized that thrombotic thrombocytopenic purpura–hemolytic uremic syndrome might have been the cause of the patient’s previous renal failure. The renal biopsy finding of double contours in the glomerular basement membranes is known as tram-tracking. It is found in type I and type II membranoproliferative glomerulonephritis and results from basement membrane reduplication. 8 One condition associated with this membranoproliferative pattern of injury is immune complex–mediated disease such as chronic and recovered thrombotic microangiopathy. 9 However, features of membranoproliferative glomerulonephritis can also be seen in patients with IE, including renal biopsy findings similar to those found in patients with TTP. DISCUSSION This case highlights the neurological manifestations and complications associated with IE. In 1885, Osler10 provided the first clear description of the frequent involvement of the brain in the morbid complications of bacterial endocarditis. Cerebral and other neurological complications have been reported to occur in 20% to 40% of cases of IE.11 They include stroke, intraparenchymal hemorrhage, subarachnoid hemorrhage, abscess, mycotic aneurysm, seizure, encephalopathy, and meningitis.12 Bacterial meningitis, a serious complication of IE, is an unusual first manifestation.13 The reported frequency of meningitis in patients with IE varies from 0% to 20%,14,15 and the most frequent pathogen is S aureus.13 In 1939, Smith16 described 3 mechanisms for the pathogenesis of meningitis in patients with IE: (1) a mycotic aneurysm may leak, and the blood in the CSF may then cause aseptic meningitis; (2) after embolic infarction, meningeal irritation occurs in the adjacent area or results from rupture of softened brain tissue into the CSF; and (3) deeply situated infarcts cause congestion of the pia-arachnoid membrane resulting in aseptic meningitis. In our patient, these aseptic causes of meningeal irritation certainly could not explain the positive CSF cultures and the severity of her meningismus. Emboli containing bacteria can occur in patients with acute endocarditis, especially those with staphylococcal endocarditis.17 In these cases, purulent or suppurative meningitis is common,18 and the proposed mechanism includes blood-borne implantation of septic emboli in meningeal vessels and suppurative extension from brain infarcted by septic emboli.10 Early recognition of neurological manifestations of IE is important because
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mortality rates are higher in patients with neurological complications than in those without such complications (50.0% vs 20.9%).19 In addition, neurological complications of IE markedly increase the operative risk associated with open heart surgery.20 Valve replacement should be delayed for 2 to 3 weeks after a nonhemorrhagic CNS event and for a month after an intracerebral bleed.20 In cases involving native valves, anticoagulation is not recommended until the septic phase of the disease has passed because of the risk of hemorrhagic CNS complications.21 Our patient’s cause of death was coronary artery embolism, which has been seen in as many as 60% of cases of IE at autopsy.22 In 1856, Virchow23 provided the first description of coronary arterial occlusion complicating acute bacterial endocarditis. Experience with thrombolytics in the setting of IE-related myocardial infarction has largely been unfavorable because of the high risk of major intracerebral hemorrhage.22 In patients with myocardial infarction, prompt primary percutaneous coronary intervention is regarded as superior to thrombolytic therapy,24 and it appears to be a safer option in the setting of IE, although only case reports documenting such treatment are available in the literature. Because IE vegetations are normally firm, placement of a coronary stent may be required to prevent restenosis.22 The risk-benefit ratio of stent placement must be considered, especially in the setting of bacteremia.22 The differential diagnosis of thrombotic microangiopathy was interesting in this case. Thrombotic microangiopathies are microvascular occlusive disorders characterized by systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes.25 Examples of the disorders are TTP and hemolytic uremic syndrome. The literature also contains reports of TTP-like syndromes associated with IE.26 In these cases, the chief presentation was a TTP-like syndrome with compatible laboratory findings, and the syndrome was rapidly reversed with specific antimicrobial therapy. The authors postulated that the high levels of circulating immune complexes that declined as TTP abated supported the concept that the TTP syndrome in these patients resulted from immune complex–mediated vasculitis.26 In our patient with S aureus IE, a dialysis catheter was the most likely source of the infection. The patient later developed complications of septic emboli, including meningitis and cerebral and myocardial infarction, and died. We appreciate the helpful review of the submitted manuscript by Larry M. Baddour, MD.
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REFERENCES 1. van de Beek D, de Gans J, Tunkel, AR, Wijdicks, EF. Communityacquired bacterial meningitis in adults. N Engl J Med. 2006;354:44-53. 2. Whitley RJ. Viral encephalitis. N Engl J Med.1990;323:242-250. 3. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association. Circulation. 2005;111: e394-e434. 4. Reynolds HR, Jagen MA, Tunick PA, Kronzon I. Sensitivity of transthoracic versus transesophageal echocardiography for the detection of native valve vegetations in the modern era. J Am Soc Echocardiogr. 2003;16:67-70. 5. Erbel R, Rohrmann S, Drexler M, et al. Improved diagnostic value of echocardiography in patients with infective endocarditis by transoesophageal approach: a prospective study. Eur Heart J. 1988;9:43-53. 6. Mugge A, Daniel WG, Frank G. Lichtlen PR. Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and transesophageal approach. J Am Coll Cardiol. 1989;14:631-638. 7. Vikram HR, Buenconsejo J, Hasbun R, Quagliarello VJ. Impact of valve surgery on 6-month mortality in adults with complicated, left-sided native valve endocarditis: a propensity analysis. JAMA. 2003;290:3207–3214. 8. Cotran RS, Kumar V, Collins T. The kidney. In: Cotran RS, Kumar V, Collins T, eds. Robbins Pathologic Basis of Disease. 6th ed. Philadelphia, Pa: WB Saunders; 1999:959. 9. Rennke HG. Secondary membranoproliferative glomerulonephritis. Kidney Int. 1995;47:643-656. 10. Osler W. Gulstonian lectures on malignant endocarditis. Lancet. 1885; 1:415-418, 459-464, 505-508. 11. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-1330. 12. Selky AK, Roos KL, Neurologic complications of infective endocarditis. Semin Neurol. 1992;12:225-233. 13. Angstwurm K, Halle E, Wetzel K, Schultze J, Schielke E, Weber JR. Isolated bacterial meningitis as the key syndrome of infective endocarditis. Infection. 2004;32:47-50. 14. Harrison MJ, Hampton JR. Neurological presentation of bacterial endocarditis. BMJ. 1967;2:148-151. 15. Le Cam B, Guivarch G, Boles JM, Garre M, Cartier F. Neurologic complications in a group of 86 bacterial endocarditis. Eur Heart J. 1984;5(suppl C):97-100. 16. Smith WF. Meningitis secondary to subacute bacterial meningitis. N Engl J Med. 1939;220:587. 17. Ziment I. Nervous system complications in bacterial endocarditis. Am J Med. 1969;47:593-607. 18. Bergen SS Jr, Dermksian G. Meningeal manifestations of subacute bacterial endocarditis. N Y State J Med. 1957;57:3683-3685. 19. Chen C, Lo MC, Hwang KL, Liu CE, Young TG. Infective endocarditis with neurologic complications: 10-year experience. J Microbiol Immunol Infect. 2001;34:119-124. 20. Bashore TM, Cabell C, Fowler V Jr. Update on infective endocarditis. Curr Probl Cardiol. 2006;31:274-352. 21. Tornos P, Almirante B, Mirabet S, Permanyer G, Pahissa A, Soler-Soler J. Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy. Arch Intern Med. 1999;159:472-475. 22. Khan F, Khakoo R, Failinger C. Managing embolic myocardial infarction in infective endocarditis: current options. J Infect. 2005 Oct;51:e101-e105. Epub 2004 Nov 11. 23. Virchow RC. Gesammelte Abhandlungen zur wissenschaftlichen Medicin. 1856;219-732. 24. Zeymer U, Schroder R, Machnig T, Neuhaus KL. Primary percutaneous transluminal coronary angioplasty accelerates early myocardial reperfusion compared to thrombolytic therapy in patients with acute myocardial infarction. Am Heart J. 2003;146:686-691. 25. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347:589-600. 26. Bayer AS, Theofilopoulos AN, Eisenberg R, Friedman SG, Guze LB. Thrombotic thrombocytopenic purpura-like syndrome associated with infective endocarditis: a possible immune complex disorder. JAMA. 1977;238:408-410.
Correct answers: 1. e, 2. a, 3. d, 4. b, 5. c
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