PEDIATRICS Vol. 103 No. 2 February 1999, p. e18

ELECTRONIC ARTICLE:
Central Nervous System Manifestations of Childhood Shigellosis: Prevalence, Risk Factors, and Outcome

Wasif A. Khan^*, Ujjwal Dhar^*, Mohammed A. Salam^*, Jeffrey K. Griffiths, TM; William Rand, and Michael L. Bennish^{, §}

From the ^* International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh; the  Department of Family Medicine and Community Health, Tufts University School of Medicine, Boston, Massachusetts; and the ^§ Tupper Research Institute, Division of Geographic Medicine and Infectious Diseases, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts.

	ABSTRACT

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Background and Objective.    Alterations in consciousness, including seizures, delirium, and coma, are known to occur during Shigella infection. Previous reports have suggested that febrile convulsions and altered consciousness are more common during shigellosis than with other childhood infections. Those reports, however, have been from locations where S dysenteriae type 1 was not common, thus making it difficult to assess the specific contribution that S dysenteriae type 1 infection, and Shiga toxin, might make to the pathogenesis of altered consciousness in children with shigellosis. In this study we seek to determine the prevalence, risk factors, and outcome of altered consciousness in children with shigellosis in Bangladesh, a country where infection with all four species of Shigella is common. We particularly focus on the importance of metabolic abnormalities, which we have previously shown to be a common feature of shigellosis in this population.

Methods.    This study was conducted at the Diarrhea Treatment Centre of the International Centre for Diarrhoeal Disease Research, Bangladesh in Dhaka, Bangladesh, which provides care free of charge to persons with diarrhea. During 1 year, a study physician identified all inpatients infected with Shigella by checking the logs of the Clinical Microbiology Laboratory daily. Study physicians obtained demographic and historical information by reviewing the patient charts and by interviewing patients, or their parents or guardians, to confirm or complete the history of illness obtained on admission. Patients were categorized as being conscious or unconscious based on a clinical scale; having a seizure documented in the hospital; or having a seizure by history during the current illness that was not witnessed by medical personnel. Patient outcome was classified as discharged improved, discharged against medical advice, transferred to another health facility, or died in the Treatment Centre. Laboratory examinations were ordered at the discretion of the attending physician; all such information was recorded on the study form. Clinical management was by the attending physician. Factors independently predictive of a documented seizure, or of unconsciousness, were determined using a multiple logistic regression analysis. For this analysis variables associated with unconsciousness or a documented seizure in the analysis of variance or ² analyses were entered into the regression equation and eliminated in a backward stepwise fashion if the probability associated with the likelihood ratio statistic exceeded .10.

Results.    During this 1-year study, 83 402 persons with diarrhea came to the Treatment Centre for care, and 6290 patients were admitted to the inpatient unit. Shigella was isolated from a stool or rectal swab sample of 863 (13.7%) of the inpatients. Seventy-one (8%) of the inpatients with shigellosis were 15 years old; 61 (86%) were conscious; 10 (14%) were unconscious; none had either a documented seizure or a seizure by history during this illness. Seven hundred ninety-two patients were <15 years old (92%); 654 (83%) were conscious; 73 (9%) were unconscious; 41 (5%) had a documented seizure (compared with 15-year age group); 24 (3%) had a seizure by history during this illness. Of the 41 patients with documented seizures, 19 (46.3%) had a seizure at the time of admission, and 22 (53.7%) had a seizure after admission. Twenty-five (61.0%) of the 41 patients with documented seizures were reported to have a seizure during this illness before coming to the Treatment Centre.Clinical features that are known to cause altered consciousnessfever, severe dehydration, hypoglycemia, hyponatremia, or meningitiswere present in 38 (92.7%) of the 41 patients in whom a seizure was witnessed and in 67 (91.8%) of the 73 patients who were unconscious. Nineteen (46.3%) of the patients who had a seizure documented had two of these five features, 4 (9.8%) had three, and 1 (2.4%) had four of these features; among unconscious patients two of the features were present in 25 (34.2%) and three in 2 (2.7%). In a multiple regression analysis factors independently associated with a documented seizure in patients <15 years old were a shorter duration of diarrhea, higher body temperature, higher median weight-for-age, increased proportion of immature leukocytes, higher serum potassium, and lower serum sodium. Factors associated with unconsciousness were older age, a shorter duration of diarrhea, higher admission temperature, severe dehydration, and higher serum potassium. In the multiple logistic regression analysis we found no association between the infecting species of Shigella and either the occurrence of seizures or altered consciousness. Patients who were unconscious (death rate 48%) or had a documented seizure (death rate (29%) were at significantly increased risk of death compared with conscious patients (death rate 6%) or patients who had a seizure by history (no deaths). There were no deaths among patients 15 years or older.

Conclusions.    This study had a substantially larger number of patients than any of the previously published clinical studies on seizures or altered consciousness during shigellosis. The results of this study suggest that seizures in shigellosis in the population studied occur in an age groupchildren 5 years of age or lessknown to be at increased risk of seizures from fever or metabolic alterations. This study also suggests that, at least in the majority of these inpatients, altered consciousness is not related to Shiga toxin, which is produced in appreciable amounts only by the S dysenteriae type 1 serotype. Direct infection of the central nervous system also was not a major cause of altered consciousness in these patients. Both diminished consciousness and documented seizures are associated with a poor outcome in Bangladeshi children with shigellosis. Prompt attention to fever reduction and metabolic alterations may help reduce these potentially lethal complications, but often this is not easy to accomplish in the poor countries where shigellosis is endemic.  Key words:  Shigella, Shigella dysenteriae, dysentery, bacillary, central nervous system, risk factors, convulsions, unconsciousness, diarrhea, infantile, Bangladesh, developing countries.

Although shigellosis is a major cause of morbidity in more prosperous countries,¹ it is an important cause of both morbidity and mortality in poor countries.^2-4 Alterations in consciousness, including seizures, delirium, and coma, are known to occur during Shigella infection, and were described soon after the organism was identified and the clinical characteristics and epidemiology of infection were defined.^5-7 Previous reports have suggested that febrile convulsions are more common during shigellosis than with other childhood infections,^8-15 even when controlled for height of temperature,^11,15 and that seizures in patients with shigellosis may occur at older ages than typical febrile convulsions.^{8,11,12,16,17} Shiga toxin has been postulated to play a role in the pathogenesis of altered consciousness in shigellosis.¹⁸ Shiga toxin producing strains of Escherichia coli are known to cause central nervous system disease in pigs (edema disease of swine) and case reports of similar lesions, including brain edema, have been reported from children and adults.^7,19 Among Shigella species, however, Shiga toxin is produced in substantial quantities only by Shigella dysenteriae type 1.^20,21 Previous reports on seizures and altered consciousness during shigellosis, however, have been from locations where S dysenteriae type 1 was not common, thus making it difficult to assess the specific contribution that S dysenteriae type 1 infection, and Shiga toxin, might make to the pathogenesis of altered consciousness in children with shigellosis.

In this study we present information on the prevalence of, and risk factors for, altered consciousness and seizures during shigellosis in patients in Bangladesh, a country where infection with all four species of Shigella is common. We particularly focus on the importance of metabolic abnormalities, which we have previously shown to be a common feature of shigellosis in this population.^2,3

	PATIENTS AND METHODS

Patient Recruitment

This study was conducted at the Diarrhea Treatment Centre of the International Centre for Diarrhoeal Disease Research, Bangladesh in Dhaka, Bangladesh, which provides care free-of-charge to persons with diarrhea. The majority of patients coming to the Treatment Centre are cared for in an outpatient unit. Patients with more complicated disease or underlying illnesses are admitted to an inpatient unit. Bacterial cultures of a stool or rectal swab sample are done on a systematic 4% sample of outpatients (every 25th patient),²² and on all patients admitted to the inpatient unit.

Patients presented in this report were prospectively enrolled in a 12-month study of all inpatients with shigellosis conducted from March, 1987, through February, 1988. A study physician identified all inpatients infected with Shigella by daily checking the logs of the Clinical Microbiology Laboratory.

Information Collected

Study physicians obtained demographic and historical information by reviewing the patient charts and by interviewing patients, or their parents or guardians, to confirm or complete the history of illness obtained on admission. Physical examination findings on admission were noted, and a physical examination repeated. Nutritional status was determined using a weight-for-age classification.²³ Study physicians daily obtained interval histories and performed physical examinations. Laboratory examinations were ordered at the discretion of the attending physician; all such information was recorded on the study form. Clinical management was by the attending physician.

Special emphasis was given to determining the mental status of the patient before admission, at the time of admission, and during the Treatment Centre stay. This was determined both by a staff physician on admission and by a study physician at the time the patient was enrolled in the study. Both groups of physicians were familiar with the classifications of mental status that were used, which comprised 8 categories (Table 1). These 8 categories were consolidated for purposes of analysis to conscious, unconscious, and documented seizure in the Treatment Centre. An additional categorypatients with a history of seizure during this illness before coming to the Treatment Centre, but who did not have a seizure documented while in the Treatment Centrewas also used. The final classification of mental status relied on examinations done both on admission and daily during the patient's stay in the Treatment Centre. Patients who had both a documented seizure and were unconscious on admission or during their Treatment Centre stay were classified in the documented seizure category; patients who had both a history of seizure during the current illness and a documented seizure were categorized in the documented seizure category; patients who were both unconscious and had a history of seizure were categorized in the unconscious category. The remaining patients were categorized as being conscious. No attempt was made to obtain information on seizures that might have occurred before the current illness, or of a family history of seizures. Patient outcome was classified as discharged improved, discharged against medical advice, transferred to another health facility, or died in the Treatment Centre. All laboratory tests were performed using standard methods previously described.²⁴

Statistical Analysis

Data were entered onto a computer database using StatPac Gold Version 3.2 (Walonick Associates, Minneapolis, MN). Data analysis was performed in part using the Statistical Package for Social Sciences, versions 6.0 and 8.0 for Windows, (SPSS, Chicago, IL), and Epi Info (version 6.0, USD, Stone Mountain, GA). The significance of differences in proportions were tested by the ² test with continuity correction, or Fisher's exact test if an expected cell size was <5. The significance of differences between continuous variables in two groups was tested with Students t test if the data were normally distributed, or the Mann-Whitney U test if the data were not normally distributed. For normally distributed continuous variables involving three or more groups an analysis of variance was used to test the significance of differences. Differences between individual groups were tested for significance using Scheffé procedure if the overall F statistic was 0.2. For nonnormal continuous variables involving three or more groups the Kruskal-Wallis test was used, and the Mann-Whitney test then used to compare two groups.

Factors independently predictive of a documented seizure, or of unconsciousness, were determined using a multiple logistic regression analysis. For this analysis, variables associated (P < .20) with unconsciousness or a documented seizure in the analysis of variance or ² analyses were entered into the regression equation and eliminated in a backward stepwise manner if the probability associated with the likelihood ratio statistic exceeded .10. Blood glucose, serum creatinine, and blood culture results, although associated with either unconsciousness or seizure in initial analyses, were excluded from the multiple logistic regression analysis because these tests were performed on only a limited number of patients. Age was included in the multiple regression analysis even although it was not significantly associated with outcome in the analysis of variance analysis because age is known to often be an important determinant of the clinical manifestations of infection. Multivariate odds ratios and confidence intervals in the final logistic regression equation were calculated from the coefficient of the multiple regression model.

	RESULTS

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Patient Population

During this 1-year study, 83 402 persons with diarrhea came to the Treatment Centre for care. Shigella was isolated from a stool or rectal swab sample of 303 (9.2%) of the 3289 patients entered in the 4% systematic sample of outpatients. If this proportion is extrapolated to all outpatients, an estimated 7683 outpatients were infected with Shigella. Shigella was isolated from a stool or rectal swab sample of 863 (13.7%) of the 6290 patients actually admitted to the inpatient unit. Thus, an estimated 11.2% (863/7683) of all persons with shigellosis who presented to the outpatient unit were admitted to the inpatient unit during the study period.

Three hundred six (35.5%) of the inpatients with shigellosis were <1 year old (including 5 neonates), 407 (47.2%) were 1 to 4 years old, 65 (7.5%) were 5 to 9 years old, 14 (1.6%) were 10 to 14 years old, and the remaining 71 (8.2%) patients were >14 years old.

Mental Status

The mental status of inpatients with shigellosis by age group is shown in Table 2. Seizures occurred in 19 (6.2%) of the 306 patients <1 year old, 18 (4.4%) of the 407 patients 1 to 4 years old, 4 (6.2%) of the 65 patients were 5 to 9 years old (3 patients age 5 and 1 age 9), and in no patient older than 9 years. Of the 41 patients with documented seizures, 19 (46.3%) had a seizure at the time of admission, and 22 (53.7%) seized after admission. Twenty-five (61.0%) of the 41 patients with documented seizures were reported to have a seizure during this illness before coming to the Treatment Centre. Of the 73 patients <15 years of age who were unconscious, 32 (43.8%) were unconscious on admission, and 41 (56.2%) became unconscious during their stay in the Treatment Centre.

Only 4 (1.3%) of the 303 patients ages 1 month to 65 years with shigellosis who were identified as part of the 4% systematic sample of outpatients had either a seizure on arrival or gave a history of a seizure in the 24 hours before coming to the Treatment Centre. For the 180 surveillance patients <15 years of age, the rate of seizures was 1.7% (3/180).

Clinical Characteristics Associated With Altered Consciousness

Characteristics of inpatients <15 years of age by mental status are shown in Table 3. Features on admission that differed significantly (P < .05) between groups were diarrhea duration, the presence of severe dehydration, body temperature, weight-for-age, the proportion of immature leukocytes in peripheral blood, serum sodium, potassium, and creatinine, the presence of bacteremia, and the infecting species of Shigella; features that approached statistical significance (P = .05 to 0.10) were gender and blood glucose.

The proportion of males among unconscious inpatients (47%, P = .014) and inpatients with documented seizures (46%, P = .057) was lower than the proportion of males among inpatients who were conscious (59%). The proportion of all outpatients with shigellosis who were male (63%) was similar (P > .2) to that of conscious inpatients, suggesting that girls were less likely to be brought for care unless seriously (and dramatically) ill.

Spinal fluid was obtained from 34 (5.2%) of the conscious patients, 25 (34.2%) of the unconscious patients, 28 (68.3%) of the patients who had a seizure, and 16 (66.7%) of the patients who had a history of seizure. Pleocytosis, defined as either more than one polymorphonuclear cell or more than seven total leukocytes/mm³, was present in 5 (15%) of 34 conscious patients who had a spinal tap performed, 2 (8%) of 25 unconscious patients, 4 (14%) of 28 patients who had a documented seizure, and 2 (13%) of 16 patients who had a history of a seizure. One conscious patient had Haemophilus influenzae isolated from spinal fluid, and 1 patient who had a documented seizure had Neisseria meningitidis isolated.

Outcome

The outcome of patients <15 years of age by mental status category is shown in Table 4. Eighty-three (10.5%) of the 792 patients <15 years of age died, with significantly more deaths occurring among patients who were unconscious or who had a documented seizure. There were no deaths in patients 15 years of age or older.

The Presence of Features Known to Cause Altered Consciousness

Clinical features that are known to cause altered consciousnessfever, severe dehydration, hypoglycemia, hyponatremia, or meningitiswere present in 38 (92.7%) of the 41 patients in whom a seizure was witnessed and in 67 (91.8%) of the 73 patients who were unconscious. Nineteen (46.3%) of the patients who had a seizure documented had two of these five features, 4 (9.8%) had three, and 1 (2.4%) had four of these features; among unconscious patients two of the features were present in 25 (34.2%) and three in 2 (2.7%). Hypernatremia (serum sodium >150 mmol/L) was present in only 1 child, a 9 month old with a serum sodium of 161 mmol/L who was conscious.

Factors Associated With a Documented Seizure or Unconsciousness in Multiple Logistic Regression Analyses

In a multiple-regression analysis (Table 5) factors associated with a seizure were shorter illness duration, higher body temperature, higher median weight-for-age, increased proportion of immature leukocytes, higher serum potassium, and lower serum sodium. Factors associated with unconsciousness (Table 6) were older age, shorter duration of illness, higher admission body temperature, the presence of severe dehydration, and higher serum potassium.

	DISCUSSION

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In this study seizures occurred in 5.2% of 792 inpatients with shigellosis <15 years of age, and in none of the 71 patients 15 years of age or older (P = .042). Only 1 patient older than 5 years had a seizure. Seizures either by history or which were witnessed occurred in 1.3% of a systematic survey of outpatients with shigellosis of all ages, and 1.7% of outpatients <15 years of age. The prevalence of seizures among inpatients in this study is lower than in most previously reported series, in which the proportion of children with shigellosis who had a seizure ranged from 4.8% to 45.3%,^7-14,1625-27, with the lower rates generally found in studies which included outpatients (Table 7).^7,11,25 The lower prevalence of children with seizures in this study when compared with previous studies might be explained in part by the greater range of complications prompting admission of patients with shigellosis in Bangladesh. A high proportion of patients in this series were malnourished, had severe anemia or ileus, or severe or protracted dysentery. In contrast with most previous studies of seizures during shigellosis, we distinguished between children who had a seizure that was witnessed by medical personnel, and seizures that were reported by parents or other caretakers, but were not witnessed by medical personnel. It is likely that the latter included at least some children having rigors in response to a rapid rise in temperature. If patients who had a seizure reported by history in this study were combined with those who had a witnessed seizure, the prevalence of children admitted to hospital with shigellosis and seizures increases to 8.2%.

Previous studies have variously identified young age, height of temperature, and previous seizure, or family history of seizure, as being associated with seizures during shigellosis.^{8,9,11,13,16,17} In this study, which had a substantially larger number of patients than any of the previously reported clinical studies, six features were independently associated with a documented seizure in a multiple regression analysis; shorter duration of diarrhea before admission to the Treatment Centre, higher admission body temperature, higher weight-for-age, lower admission serum sodium, higher admission serum potassium, and a higher proportion of immature leukocytes in the peripheral blood. We did not obtain information on a family history of seizures, or a history of seizures in study patients before the current illness.

Why seizures are apparently more common during shigellosis than other febrile childhood illnesses is not certain. In patients in this study the high prevalence of hyponatremia, which is thought to lower the seizure threshold in children,^28,29 may have acted in concert with fever to precipitate seizures. Previous studies have found mild hyponatremia (130-134 mmol/L) in one third to one half of patients with shigellosis and seizures,^15,27 but have not identified hyponatremia as a risk factor for the development of seizures.¹⁶ Mean serum sodium values in patients with seizures in this study were 125.9 mmol/L, considerably lower than found in patients in previous studies. In patients in this study, two additional metabolic abnormalitieshypoglycemia and elevated serum creatininewere common. These two variables were not included in the logistic regression analysis because of the substantial number of patients in whom they were not measured. Patients with seizures had higher serum potassium concentrations; this may reflect their shorter duration of diarrhea and lesser loss of potassium in diarrhea stools when compared with control patients, their better nutritional status, or a higher prevalence of renal failure in these children. To our knowledge alterations in serum potassium have not been etiologically linked to the development of seizures.

Children with seizures were better nourished than those who were conscious. This might represent in part the increased ability of better nourished children, when compared with malnourished children, to generate a fever; weight-for-age and body temperature were modestly correlated in patients in this study (R = 0.23, P < .01). It may also represent an increased probability of admitting malnourished children for a variety of complications, whereas admission for better nourished children was more restricted. The longer duration of illness in conscious patients when compared with patients with documented seizures (median, 3 days versus 6 days) would not alone be sufficient to produce the marked disparity in nutritional status that existed between the two groups (mean, 57% weight-for-age versus 67% weight-for-age); the two groups of patients must have differed in nutritional state before the onset of illness. Although seizures are known to increase the peripheral leukocyte count, they are not thought to increase the proportion of immature leukocytes. The increase in the latter in patients with seizures in this study may reflect a more severe underlying disease, a finding consistent with their higher body temperature. The shorter duration of illness in patients with seizures is consistent with previous findings that seizures tend to occur early in the course of illness.^6,13,15,25 We did not find an association between age and seizures in the multiple regression analysis; this is most likely because both patients with and without seizures were predominantly <5 years old.

Factors associated with unconsciousness in a multiple regression analysis included three of the six factors associated with seizuresshorter duration of diarrhea, higher body temperature, and higher serum potassiumand two additional factorsolder age and the presence of severe dehydration. A previous study of fatal encephalopathy in 15 children with shigellosis found that hyponatremia was associated with encephalopathy and death, but that duration of diarrhea, body temperature, hydration status, and serum potassium were not associated with death and encephalopathy.³⁰ That study may have been limited in determining associations by the relatively small number of patients studied.

In the multiple logistic regression analysis we found no association between the infecting species of Shigella and either the occurrence of seizures or altered consciousness. This would suggest that, at least in the majority of these inpatients, altered consciousness is not related to Shiga toxin, which is produced in appreciable amounts only by the S dysenteriae type 1 serotype.²⁰ Direct infection of the central nervous system was also not a major cause of altered consciousness in these patients, a finding consistent with previous reports.^{6,8,11,13,1530-33} Previous studies have suggested that cerebral edema occurs in patients with shigellosis and encephalopathy.^{6,7,30,3133-35} In Ekiri, a particularly fulminant form of shigellosis that occurred in Japan in the first half of this century and was associated with seizures and encephalopathy, neuronal necrosis was reported as being a common finding.³⁶ In patients in this study neither brain imaging nor necropsies were performed.

Being unconscious or having a documented seizure were strongly associated with death; unconscious patients were 9.6 times more likely to die than conscious patients, and patients with a documented seizure 5.8 times more likely to die. The association between unconsciousness and death is not surprising, especially in the 41 (56.2%) unconscious patients who became unconscious after admission, who had a 76% death rate. In many of these patients unconsciousness was a premortal event, and was associated with clinical shock. The association between a seizure and death is more surprising. In recent studies, seizures have not been associated with a high risk of death or of subsequent complications,^13-15,17,37 although in earlier studies some deaths were noted (Table 7).^8,9 In this study it is unclear if seizures were simply a marker for more severe disease or if the seizure itself contributed to death.

This study suggests that seizures in shigellosis occur in an age group (children 5 years of age or less) known to be at increased risk of seizures from fever or metabolic alterations. Preventing the development of seizures or unconsciousness, and ultimately death, by preventing these complications is likely to be difficult. Ostensibly, the fever could be controlled with antipyretics. Acetaminophen is readily available in most countries, and is recommended by United Nations Children's Fund, (UNICEF), the World Health Organization, and the Centers for Disease Control and Prevention as part of their integrated management of the sick child initiative.³⁸ In poor countries, however, there is often inadequate monitoring of the quality of the drug supply, and fatal renal failure from ingestion of acetaminophen adulterated with diethylene glycol has occurred in a number of countries, including Bangladesh.^39-41 Treatment of hyponatremia is also problematic, as the capability to measure electrolytes is often not available at medical facilities in poor countries, and adequate treatment for this complication in shigellosis is yet to be defined. Hypoglycemia could presumably be prevented by continued feeding, but profound anorexia is one of the hallmarks of severe shigellosis. Early antimicrobial treatment of shigellosis has been shown to markedly reduce the rate of complications during shigellosis, but the increasing prevalence of resistant strains has made providing effective antimicrobial treatment difficult.

	ACKNOWLEDGMENTS

This study was supported by the International Centre for Diarrhoeal Disease Research, Bangladesh.

The International Centre for Diarrhoeal Disease Research, Bangladesh, is currently supported by the Governments of Australia, Bangladesh, Belgium, Canada, Japan, the Netherlands, Saudi Arabia, Sweden, Switzerland, the United Kingdom, and the United States; the Ford and Rockefeller Foundations, and the United Nations Children's Fund (UNICEF).

We thank Dr ASG Faruque for providing information from the surveillance study, and Mr Humayun Kabir for assistance with data entry.

	FOOTNOTES

Received for publication May 13, 1998; accepted Aug 27, 1998.

Reprint requests to (M.L.B.) New England Medical Center, 750 Washington St, Box 041, Boston, MA 02111.

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