Group C streptococcal endocarditis presenting as clinical meningitis : Report of a case and review of the literature

Lancefield group C streptococci are known to be pathogenic in a number of animal species, but cause human disease much less commonly than do streptococci of scrogroups A or B. Reported cases of bacteremic infection, pneumonia or meningitis in humans have been very severe with a grave prognosis. The authors describe a patient who presented with classic clinical and laboratory evidence of bacterial meningitis which proved to be a complication of endocarditis caused by a group C streptococcus. This is the first reported case in which meningitis was the presenting manifestation of group C streptococcal endocarditis and is only the second case in which group C streptococcal meningitis and endocarditis have been associated in the same patient. A total of 13 cases of group C streptococcal meningitis have now been reported in the medical literature. Five of these patients died, and four others recovered only to be left with neurological sequelae. The current case confirms the seriousness of group C streptococcal infections in humans. Such infections are associated with a poor prognosis despite apparently adequate antimicrobial therapy.

S TREPTOCOCCI ASSOCIATED wm-1 LANCEFIELD SEROGROUP C include those classified as Streptococcus millen:.Streptococcus dysgalactiae (including Streptococcus equisimilis).and Streptococcus equi (including Streptococcus zooepidemicus) (1-4) .Streptococci of this seragroup have mainly been desctibed as pathogens in a number of animal species (2.3) .Strep equis imilis has been reported to cause septic arthtitis and septicemia in swine (3).Strep dysgalactiae causes mastitis in cattle, while Strep equi is the causative agent of stranD'Ies.a mucopurulent infection of tl1e upper respiratory tract of horses (1.4).Group C streptococci can be isolated relatively frequently from normal human skin.pharynx and female genital tract (3.4).The use of simplified latex and co-agglutination testing ratl1er than the more timeconsuming precipitin reaction originally described by Lancefield -using heat-and acid -extracted cell wall carbohydrate-has allowed routine serotyping of streptococcal isolates (3).This has led to greater awareness of infections caused by nonserogroup A streptococci.Nonserological methods of identification (including hemolysis reactions, antibiotic sensitivity and fermentation reactions) often left group C streptococci uncia sified or misclassified as group A streptococci (3) .Reports of group C streptococcal infections in humans have usually described invasion of local tissues (1.2.5).Suppurative tonsillitis and pharyngitis.as well as skin.wound and puerperal infections.have been reported (1.2.5).To the authors• knowledge.only 12 cases of meningitis in adults caused by group C streptococci (includ ing no case with pre-mortem clinical manifestations of both endocarditis and meningitis) have been previously reported in Lhe world li terature.The present autl1ors report tl1eir experience witl1 a patient with Strep equisimilis endocarditis whose clinical presentation was Lhat of meningitis.and who died despite apparenlly adequate antimicrobial therapy.

CASE PRESENTATION
A 67 -year-old female !mown to have rheumatic m itral valvular disease was brought to Lhe hospital because of shortness of breath and altered consc iousness.The patient had been previously known to have mitral stenosis associated will1 chronic altial fibrillation and had had multiple previous episodes of decompensated congestive heart failure related to atrial fibtillalion \vitll a rapid ventricular response.She had previously refused cardiac catheterization and Lhe possibility of valve replacement surgery.Medications prior to admission consisted of digoxin.cliltiazem.furosemide.warfarin and potassium supplementation.The patient had been well until two days prior to admission.There was no history of recent dental.gynecological or urological procedures.There was no history of exposure to pels or other animals.The patient was found by a neighbour who investigated after not having seen her for two days.Immediate history prior to this point was unavailable.The patient appeared short of breatl1 and confused.a nd was brought to the hospital.
On examination .the patient was an elderly cau casian female who was stuporous.Pulse was 150 beats/min and irregular, blood pressure 130/90 mmHg.respirations 40/min.and temperature 38.8°C orally.Examination of tl1e h ead a nd neck was notable for marked nuchal rigidity .The fundi were unremarkable.The patient's mouth was edentulous and her throat appeared normal .Exan1ination of the ch est revealed only a few scattered wheezes.Examination of U1e cardiovascular system revealed 8 em jugular venous distension.The apex beat was not displaced .Heart sounds were present witl1 an open ing s n ap but witl1out discernible murmur or gallop .Neurological ex-an1ination revealed a stuporous woman who moved all four limbs equally and withdrew well to painful stimulus.No focal neurological deficits or cranial nerve abnormalities were discernible.Visual fields could not be assessed.The remainder of tl1e physical examination was nom1al, with no petipheral stigmata of e ndocarditis.
Hematological evaluation was within normal limits except for a peripheral le ukocyte count of 18.900 cells /mm 3 (89% polymorphonuclear leukocytes) and a protl1rombin lime of 17.4 s.Initia l biochemistry revealed a serum glucose of 10.4 mmoi/L.creatin e kinase of 1144 U/L, alanine aminotransferase of 62 U/L.aspartate aminotransferase of 172 U/L. and lactate dehydrogenase of 590 U/L.Electrocardiography demonstrated atrial fibrillation will1 a ventricular rate averaging 150 beats/min and no acute ischemic changes.A chest radiograph was interpreted as bowing interstitial pulmonary edema.Urinalysis was vvitl1in normal limits.Lumbar puncture yielded clear cerebrosp in al fluid with 50 erythrocytes and 400 leukocytes/mm3 (98% polymorphonuclear).glucose 5.5 mmol/L.and protein 540 g/L.Gram stain of spinal fluid revealed the presence of Gram -positive cocci in c hains.Therapy with cefotaxi me 6 g/ clay was begun immediately after lumbar puncture on Lhe first hospital day.
Echocardiography showed thickened and calcified mitral valve leaflets.as well as a clilatecl left atrium.which was felt to be cons istent witl1 moderate mitral stenosis .No vegetation was id entifiable.Computed tomography of tl1e head demonstrated a hypodense area in the left patieto-occipital region associated with effacement of Lhe sulci (Figure 1).No enhancement of Ll1e reD'ion was noted after infusion of contrast material.The lesion was interpreted as being consistent \vith a cerebral infarction which had occurred within U1e past week.In addition.a number of lesions were seen in tl1e area of the basal gan glia.which were interpreted as remote lacunar infarcts.
Strep eqlLisimilis was isolated from spinal flui d culture as well as from all six blood cultures taken prior to institution of antibiotic therapy.The organism was beta-hemolytic and susceptible by disc sensitivity testing to penicillin.oxacillin .cefazolin .vancomycin .erythromycin and cotrimoxazole.The minimal inhibitory and bactericidal concentrations for penicillin G were equal to or below 0.03 U/mL.Minimal inhibitory and bactericidal concentrations were, respectively.1.0 and 2.0 ~tg/mL for gentamicin.8.0 and 8.0 pg/mL for netilmicin.6.2 and 6.2 pg/mL for tobramycin.and 4.0 and 16.0 pg/mL for amikacin.Combination therapy with penicillin G 24.000.000U/day and netilmicin 100 mg every 8 h was substituted when initial culture results became available on the second hospital day.Intubation and inotropic support became necessary on Lhe second hospital day.Nter four days of U1erapy with penicillin and neWmicin, repeat blood cu ltures were negative.and peak and trough serum bactericidal activities were both greater than 1:5096.Despite antibiotic therapy and diuresis.the patient remained febrile and in mild to moderate congestive heart failure.Repeat spinal Ouid examination on the eighU1 hospital day revealed an absence of cellular elements.a glucose concentration of 5 mmol/L, protein 620 g/L.negative Gram stain and negative cu lture.Repeat computed tomography of the head the same day was unchanged from admission .Antibiotic therapy was not a ltered.By the 10U1 hospital day U1e patient had become more Figure 2) Gross pathological appearance of recent left parietooccipital cerebral infarction in a 69-year-oldfemale with Group C streptococcal meningitis and endocarditis alert and her nuchal rigidity was improved.She remained respirator dependent.however, and on the 16th hospital day sustained a sudden cardiac arrest.Attempts at resuscitation were unsuccessful.
Au topsy revealed the immediate cause of death to be congestive heart failure and multiple pulmonary emboli.The lungs weighed 1450 g. and multiple recent pulmonary emboli were present on a background of pulmonary edema and emphysema.The h eart weighed 360 g.There was evidence of severe aU1erosclerotic changes in the aorta and coronary arteries.but no myocardial infarct was identified.The left atrium was dilated and a left atrial thrombus was present.A severely thickened mitral valve exh ibited fusion of the chordae tendinae and superimposed ulceration associated with fri able thrombotic material on the valve surfaces.Coloni es of Gran1-positive cocci were id entified in histological sections of the heart valve .There was no evidence of embolization of thrombotic material to the myocardium.Post mortem culture of the valve material was not performed.The spleen weighed 300 g and showed passive congestion.Gross examination of the lGdneys showed bilateral nephrosclerosis.Histological examination revealed focal glomerulonephritis with immune complex deposition in addition to foci of peritubular and perivascular inflammatory reaction in varying stages of organization.representing probable embolization.
Gross exan1ination of the brain revealed normal-appearing meninges, a normal circle of Willis , and slight softness of the left inferior occipital lobe.Sectioning of the brain allowed identification of an area of recent infarction in the left occipital lobe (Figure 2).Microscopic exan1ination of the brain disclosed multiple cerebral infarcts of various ages in the right frontal lobe.the left ce rebellum, and the right lateral occipital lobe.There was histological confirmation of the new left occipital infarct in proximity to a large subarachnoid artery with partial necrosis of its wall associated wiU1 a dense inflammatory infiltrate.The lumen of this a rtery contained a red cell thrombus .The les ion was interpreted as an early mycotic aneurysm despite the absence of discernible bacteria .There was no histological evidence of inflammation of llie leptomeninges.
DISCUSSIO N Lancefield group C streptococci are important pathogens in a number of animal species (1).These organisms can be iso lated from normal human skin.upper respiratory tract a nd female genital tract.Infec-tion with group C streptococci h as been associated with suppurative infection of a number of organ system s with an often protracted clinical course and a high mortality ( 1.2 .5).Clin ical infections in humans have most commo nly involved limited disease includ ing pharyngitis and tonsillitis.as well as skin .wound and puerperal infections (1.2.5 -9).Epidemic outbreaks h ave occurred involving erysipelas in Baltimore in 1924 (6).puerperal fever in London in 1931 -32 (7).and acute cellulitis in London in 1944 (8).Serious human disease caused by beta-hemolytic streptococci of serogroup C is. however.much less common llian that caused by serogroups A and B. Among 1107 patients wW1 strep-tococcal bacteremia at the Mayo Clinic b etween 1968 a nd 1977.gro up C streptococci were iden tifi ed in only eight (5).Simi larly.a serogro up C streptococcus was identi fi ed in only one of 140 pa tients with streptococcal bacteremia during a two-year period (1964-66) a t th e Massachusetts General Hospita l (1).
Beginning vvith a case of endocarditis described by Rosen thai a nd Stone in 1940 (9), 21 cases (inc! uding the present one) of group C streptococcal e ndocarditi s have been described.These cases have been partially reviewed by Salata et a l (2) .
On ly 13 cases (including the present one) of group C streptococcal meningitis in the presence or absen ce of endocardi tis have now been reported in adult s (Table 1) (10)(11)(12)(13)(14)(15)(16)(17)(18) .Five of the 13 di ed.although an apparen Uy appropriate choice of anlibiotic(s) was made in a ll but one patient (case 5. Table 1).Four of the eight patients who recovered were left with n eurological sequelae of varying degrees.Three of the cases had a histo ry or exposure to animals.Prior to the present report.only one case of meningitis associated with endoca rditi s had been reported (case 1. Table 1).This patient did not have clin ical meningitis.but s mall foci of men ingilis were noted at autopsy.The present case.U1erefore.represents U1e first report of group C streptococcal endocard itis complicated by clinical meningitis.Group C streptococci have , in a ddition.been reported as causative agents in five cases of neonatal meningitis (19)(20)(21)(22) and in three cases of intracrania l abscess or empyema wifuout meningitis (2 .23.24).
Various n eurological complicatio ns have been associated vvith infective endocarditis.The top ic has been reviewed by Lerner et a l (25) .Embolic events .both bland and septic.are most common.More than 90% of large emboli to fue b rain lodge in the ante tior ce reb ra l circulation.mainly in U1e branches of the middle cerebral artery.The present case showed evidence of embolization in llie less common distribution of the posterior cerebral circulation.Additional n eurological complications of infective endocarditis includ e U1 e development of mycotic a n ewysms.cerebral abscesses.meningoencephalitis and frank meningitis.These may manifest as an acute co nfu s ional state wiU1 or without focal neurological s igns or seizures.The present case presented to hospital wiU1 confusion a nd stupor without focal neurologi ca l signs, as a n apparent diffuse or •toxic• enceph a lopalliy associated wiU1 clinica l s igns of meningitis.Spinal fluid examin a tion revealed classic s igns of bacteria l m eningitis.and the organism was easily isola ted from spinal fluid cu lture.At a utopsy.evide n ce was found for a mycotic a n ew ys m. but no abscess form ation was found a nd no bacteria were seen in U1 e central n ervo us system.Despite classical cl inical and ce rebrospina l fluid findings of meningitis.no eviden ce of leptomeningeal infl ammation was seen 16 days after initiation of an tibiotic fuerapy.lt seems likely.U1erefore.U1 at U1e mycolic aneurysm acted as a paran1eningeal suppurative focus.and U1at U1e infection had sp read to the s ubarachnoid space not long before presentation to hospital.The c lini cal cou rse.as well as the a bsence of leptomeningeal inflammation at a utopsy.imply U1at U1e deaU1 of U1e patient could not be attributed to eiU1 er ongoing infection or inadequately aggressive antib iotic U1e rapy .
The clinical presentation or endocarditi s as frank meningitis is indeed ra re.ln a report of 385 patients with bacterial endocarditis d iagnosed at fue Mayo Clinic (26). 110patients (29%) were described as h aving centra l n ervou s system co mplications.Although 66 of the 110 (60%) ha d n e urologica l s ign s or symptoms as their initial manifestation.only seven (6.4%) h ad meningiti s. ln this seri es.U1 e presence of ne urological complications in cases of endocarditis was associated \villi a n overall mortality of 50% (ranging from 28% . in cases involving viridans streptococci.to approxi mately 75% in cases involving SiaphyLococcus aureus or Enierococcus faecaL is).
Gro up C s treptococci a re very sensilive in vitro to a number of an tibiolics including penicillin G. vancomycin, first generalio n ceph alosporins.erythromycin , azloc illin and piperacillin.and newer beta -laclam agents \vilh th e exception of moxalactan1 (27) .The present case confirms a nd adds to U1e body of litera lure indicaling U1al.while serious human in fections with this serogro up of slreptococci a re rare.they carry a grave prognosis despite apparenUy adequate antimicrobial therapy.

Figure 1 )
Figure 1) Computed tomographic scan after irifusion of contrast material showing a nonenhancing hypodense area in I he left parieto-occipital region in a 69-year-oldfemale presenting with shortness of breath and altered consciousness streptococci of serological groups C. G. L. and possibi ly rcl ateclt&'\:a.System Appl Microbial 1984:5:483-5.4. Ruoff I<L.I<u nz W. FeiTaro MJ.Occu rrcnce of Streptococcus milleri among bela-h emolytic streptococci isolated from c linical specimens.J Clin Microbial 1985 :22: 149-52.5 .Mohr ON.Feist Dj.Washington J. Hermans PE.Infections clue to gro u p C streptococci in man.Am J Mecl 1979:66:450-6.6. B irkha ug KE.Stud ies on the biology of the st reptococcu s crysipelatis.Bu ll Johns Hopkins Hosp 1925:36 :248-53 .7. Co lebrook DC.The sou rce of infection in pueq)era l fever clue to hemolytic streptococci.Special Report Series No .205.Medical Research Council of Great B rita in 1935.