The authors have declared that no competing interests exist.
Conceived and designed the experiments: J. Sejvar EL SM J. Schier B. Barr MH GA. Performed the experiments: J. Sevjar EL JN AL RM SM SL LC KD DT YR J. Schier B. Barr SK B. Blount MH. Analyzed the data: J. Sejvar EL BN J. Schier MH GA EM. Contributed reagents/materials/analysis tools: BN SK B. Blount MH DT GA EM. Wrote the paper: J. Sejvar EL JN AL RM BN SM TK SL LC KD DT YR J. Schier B. Barr AD MM SK B. Blount MH DT EM.
The bacterium
Describe neurologic features complicating typhoid fever during an outbreak in Malawi-Mozambique
Persons meeting a clinical case definition were identified through surveillance, with laboratory confirmation of typhoid by antibody testing or blood/stool culture. We gathered demographic and clinical information, examined patients, and evaluated a subset of patients 11 months after onset. A sample of persons with and without neurologic signs was tested for vitamin B6 and B12 levels and urinary thiocyanate.
Between March – November 2009, 303 cases of typhoid fever were identified. Forty (13%) persons had objective neurologic findings, including 14 confirmed by culture/serology; 27 (68%) were hospitalized, and 5 (13%) died. Seventeen (43%) had a constellation of upper motor neuron findings, including hyperreflexia, spasticity, or sustained ankle clonus. Other neurologic features included ataxia (22, 55%), parkinsonism (8, 20%), and tremors (4, 10%). Brain MRI of 3 (ages 5, 7, and 18 years) demonstrated cerebral atrophy but no other abnormalities. Of 13 patients re-evaluated 11 months later, 11 recovered completely, and 2 had persistent hyperreflexia and ataxia. Vitamin B6 levels were markedly low in typhoid fever patients both with and without neurologic signs.
Neurologic signs may complicate typhoid fever, and the diagnosis should be considered in persons with acute febrile neurologic illness in endemic areas.
Typhoid fever is a bacterial disease caused by infection with
Beginning in June 2009, an outbreak of unexplained febrile illness occurred in villages along the border region between southern Malawi and western Mozambique. This area was known to have a high rate of general mild malnutrition, with most diets high in consumption of wheat, corn, and leafy vegetables. Cassava is consumed, but infrequently. Initial reports described many persons who presented with acute neurologic illness including mental status changes, headache, “difficulty walking”, dysarthria, and hyperreflexia. Other neurologic features including seizures and neck stiffness were also described. Gastrointestinal complaints were not prominent among patients early in the outbreak. The investigators initially suspected common etiologies of such neurologic abnormalities in sub-Saharan Africa such as acute encephalitis or heavy metal toxicity, as well as less common etiologies such as neurolathyrism and konzo. However, subsequent investigation revealed the outbreak to be caused by typhoid fever, and after the etiology was determined, persons with signs and symptoms more typical of typhoid fever were increasingly recognized.
We describe the results of an investigation into the clinical, neurologic and laboratory features of persons with typhoid fever during this outbreak. Our investigation suggests that signs of upper motor neuron dysfunction were predominant, neurologic features were generally a later manifestation of typhoid fever, and outcome was generally favorable.
The outbreak was first noted in June 2009 by health personnel in Neno District, Malawi, who observed an increase in patients hospitalized at Neno District Hospital with fever and neurologic illness. Ill patients were from villages in Neno District and neighboring Tsangano District, Mozambique. The outbreak occurred in a remote location; the closest health center, Nsambe Health Centre, is approximately 8.5 km away by dirt road over rough terrain. As cases continued, a larger investigation was initiated by the Malawi Ministry of Health (MOH).
Between July and November, 2009, an epidemiologic investigation was conducted
We identified patients with neurologic illness by several methods. We reviewed medical records at Neno District Hospital for admissions during March through November 2009 for descriptions of objective neurologic findings. From July 22 through November 13, 2009, we prospectively gathered data on persons presenting with illness, and hospitalized patients meeting the case definition underwent neurologic evaluation by one of the authors, a U.S. board-certified neurologist (JJS). When possible, suspected patients meeting clinical case criteria but not hospitalized were evaluated in their villages. When possible, hospitalized patients were serially re-evaluated in order to document progression of illness; a subset of patients underwent re-evaluation approximately 11 months after acute illness to detect the presence of long-term neurologic sequelae.
Cerebrospinal fluid (CSF) white blood cell count (WBC), glucose, and protein level results were reviewed when available. Clinical specimens obtained from acutely ill patients, including serum, blood, urine, and CSF, initially underwent testing for a number of infectious agents including various viruses, bacteria, parasites, and rickettsiae, as well as various toxins at laboratories at CDC (
Because some of the neurologic features observed in the patients were similar to those seen in some micronutrient abnormalities, we tested serum specimens on a subset of patients with and without neurologic illness for vitamin B6 and B12 concentrations. Serum B12 concentrations were assessed by electrochemiluminescence immunoassay (ECLIA; Roche Diagnostics Modular Analytics E170) at CDC. Serum B6 concentrations [pyridoxal 5′-phosphate (PLP) and 4-pyridoxic acid (4PA)] were assessed by high-performance liquid chromatography with fluorometric detection
Three patients with neurologic illness underwent brain and spinal cord magnetic resonance imaging (MRI) at the Malawi MRI Facility in Blantyre. Autopsy was performed on one decedent with neurologic illness; tissue from central nervous system, meninges, lung, spleen, kidney, and liver was assessed by routine histology at University of Malawi Medical School, and immunohistochemical staining for leptospira and flaviviruses at CDC.
Data were entered into an Access™ database. Mean and median concentrations of vitamins B6 and B12 and urinary thiocyanate were calculated; comparisons between patients with and without neurologic illness were made using Wilcoxon rank-sum analysis. SAS software version 9.2 (SAS Institute Inc, Cary, NC) was used for analyses.
To determine the possible presence of subclinical or mildly clinical upper motor neuron findings among village populations, persons in two affected villages, who were approximately representative of age group and sex distribution of typhoid cases were evaluated for the presence of objective neurologic findings during two village-wide evaluations. These persons underwent a screening neurological evaluation by one of the authors (JJS).
The Malawi MOH conducted the investigation in the context of an outbreak response and a public health intervention, and it was determined by human subjects review at CDC to be public health response evaluation and not research. Verbal consent was obtained from patients or guardians for collection of biological specimens and physical examination.
Between March 1 and November 13, 2009, we identified 303 persons meeting the case definition for typhoid fever, including 212 suspected, 45 probable, and 46 confirmed cases. Of these, 40 (13%) persons had objective, focal neurologic findings documented in the medical chart (n = 6) or elicited on examination (n = 34); an additional 27 persons had encephalopathy or altered mental status but did not demonstrate focal neurologic findings and were not included in subsequent analysis. Twenty-six of the 40 cases with neurologic signs met criteria for a suspected case, 10 for a probable case, and 4 for a confirmed case. The median age was 18 years (range: 3–57 years); 53% were female. Age and sex distribution were not significantly different between patients with and without neurologic illness (data not shown). Twenty-seven persons (68%) with neurologic illness were hospitalized, and there were five (13%) deaths; one decedent underwent autopsy. Twenty-one (53%) persons were treated with a variety of antimicrobials at some point during their illness, generally upon hospital admission. The most commonly administered antimicrobials included chloramphenicol (n = 15), lumefantrine-artemether (n = 9), and penicillin G (n = 7). Specific information on dose and duration of antimicrobial therapy was not available.
Neurologic signs among cases are shown in
Neurologic Sign/Symptom | N | % |
Upper Motor Neuron Signs | ||
Hyperreflexia | 22 | 55 |
Sustained ankle clonus | 16 | 40 |
Spasticity | 10 | 25 |
Babinski's sign | 5 | 13 |
Dysarthria | 21 | 53 |
Ataxia | 22 | 55 |
Encephalopathy/altered mental status | 15 | 38 |
Headache | 15 | 38 |
Hearing loss (subjective) | 9 | 23 |
Parkinsonism | 8 | 20 |
Tremor | 4 | 10 |
Eleven patients had CSF examination; WBC, protein, and glucose levels were within normal limits in all. No routine blood laboratory parameters were consistently abnormal among patients. Extensive diagnostic testing for other viral, bacterial, parasitic, and rickettsial pathogens, including broad-spectrum polymerase-chain reaction (PCR) testing and random-primer sequencing, was performed on 16 of the 303 patients overall and included four patients with neurologic illness. Viral cultures, serologic assays for infectious agents, and PCR for pathogen-specific nucleic acid sequences were negative, and random-primer PCR assays in serum were unremarkable or nonspecific. Autopsy specimens from one decedent with focal neurologic findings, including ataxia, spasticity, and clonus, showed patchy necrosis in the liver; histopathology of cerebral cortex, cerebellum, pons, and medulla were unremarkable and without perivascular cuffing or other signs of acute inflammation. Immunohistochemical assays for leptospira and flaviviruses in all tissues were negative.
Although chronic malnutrition was present in this poor and rural area, there had been no acute changes in food availability or food type consumption reported by villagers. Cassava consumption was reported in all affected areas, including both bitter and sweet cultivars, but no recent changes in cassava processing were reported. We were unable to elicit a history of pea or legume consumption, or other plants that would be suggestive of
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Assay | N | Median | Mean (95% CI) | N | Median | Mean (95% CI) | Referent Range |
|
13 | 400 | 597 (367–828) | 10 | 377 | 415 (280–550) | 211–946 |
|
8 | 2.1 | 12.6 (0–30.8) |
9 | 3.2 | 6.5 (0.6–12.3) | 11.0–337 |
|
8 | 20.0 | 72.6 (0–202.2) |
9 | 12.5 | 26.1 (1.2–51.0) | 8.8–464 |
|
5 | 112.5 | 209.6 (0–446.2) | 16 | 1,185.0 | 1,407.0 (806.7–2008.5) | 1,000–4,000 |
Referent ranges for vitamin B12 obtained from kit manufacturer, based upon presumably healthy US population
Referent ranges for vitamin B6 (PLP and 4PA) obtained from a subset of samples from US National Health and Nutrition Examination Survey (NHANES) data among a presumably healthy US population
Referent ranges for urine thiocyanate levels obtained from a sample of non-smoking US residents
PLP – Pyridoxal 5′ phosphate.
4PA – 4-pyridoxic acid.
Calculated lower confidence interval limits for PLP and 4PA resulted in negative values; for the purposes of reporting, a lower limit of 0 was used as the lower 95% confidence interval limit.
MRI of the brain and spinal cord was performed on three symptomatic persons (two probable, one suspect) with neurologic signs including spasticity, ataxia, and parkinsonism, during their acute illnesses. No signal abnormalities were present, however all three demonstrated generalized cerebral atrophy disproportionate to age (5, 7, and 18 years) (
Coronal T1 FLAIR (A) and axial T2 FLAIR (B) MRI Images demonstrating generalized cerebral atrophy, 7 year-old male with neurologic illness associated with acute typhoid fever, Malawi.
Seventeen typhoid fever patients hospitalized with neurologic illness were serially evaluated for at least 1 week following onset. All had upper motor neuron signs in combination with other neurologic features; seven had parkinsonism. By 1 month after onset, seven had normal neurologic examinations and were symptomatically well with complete resolution of neurologic signs. By 2 months, an additional 6 had resolution of neurologic signs (
Age | Sex | Initial Signs/Symptoms | Interval, Illness Onset to Neurologic Signs (Approx.) | Neurologic features | Follow-Up | Additional Studies/Comment |
5 | M | Fever, abdominal pain | 5 | Hyperreflexia, sustained ankle clonus, diffuse kinetic tremors, severe ataxia | Normal exam at 2 and 11 month evaluations | CSF: WBC 0 cells/mm3, protein 16 mg/dL, glucose 64 mg/dLMRI: moderate generalized cerebral atrophy |
7 | M | Fever, headache | 12 | Hyperreflexia, lower extremity spasticity, sustained ankle clonus, truncal ataxia | Normal exam at 2 and 11 month evaluations | MRI: mild generalized cerebral atrophy |
7 | M | Fever, abdominal pain, back pain | NK | Lower extremity hyperreflexia, sustained ankle clonus, mild truncal ataxia | Persistent lower extremity hyperreflexia, clonus, spasticity at 1 month; unchanged at 11 months | |
10 | M | NK | Hyperreflexia, lower extremity spasticity, sustained ankle clonus, parkinsonism | Normal exam at 2 and 11 month evaluations | ||
13 | M | Fever, abdominal pain, backache, leucopenia | 28 | Lower extremity hyperreflexia, sustained ankle clonus, parkinsonism | Normal exam at 2 and 11 month evaluations | |
13 | M | Fever, myalgias, back and neck pain, “difficulty walking” | NK | Lower extremity hyperreflexia, sustained ankle clonus, left Babinski's sign | Normal exam at 1 and 11 month evaluations | |
14 | F | Fever, leg pain | 3 | Diffuse hyperreflexia, truncal and appendicular ataxia,parkinsonism | Persistent ataxia and parkinsonism at 1 month | |
14 | M | Fever, myalgias, cough, leg pain | 4 | Lower extremity hyperreflexia, sustained ankle clonus, truncal ataxia, parkinsonism | Normal exam at 1 and 11 month evaluations | CSF: WBC ND, protein 21 mg/dL, glucose 66 mg/dL |
16 | F | Fever, abdominal pain, leg pain | 13 | Lower extremity hyperreflexia, sustained ankle clonus, spasticity, diffuse myoclonus, orthostatic tremor | Persistent lower extremity hyperreflexia, clonus, spasticity at 1 month; unchanged at 11 months | |
17 | F | Fever, neck and back pain, loose stools | 14 | Lower extremity hyperreflexia, sustained ankle clonus, altered mental status/encephalopathy | Normal exam at 2 and 11 month evaluations | |
18 | F | Fever, headache, abdominal pain, dizziness | 21 | Lower extremity hyperreflexia, sustained ankle clonus,parkinsonism, myoclonus | Normal exam at 2 and 11 month evaluations | |
18 | F | Headache | 7 | Hyperreflexia, sustained ankle clonus, truncal and appendicular ataxia, parkinsonism, confusion/altered mental status, ataxic dysarthria, diffuse kinetic tremors | Normal exam at 2 and 11 month evaluations | CSF: WBC 1 cell/mm3, protein 20 mg/dL, glucose 52 mg/dLMRI: moderate generalized cerebral and cerebellar atrophy |
18 | M | Fever, myalgias, back pain, headache, “difficulty walking” | NK | Lower extremity hyperreflexia, lower extremity spasticity, diffuse myoclonus, subjective hearing loss | At 1 month evaluation: clinical status unchanged | |
19 | M | Fever, backache | 35 | Hyperreflexia, sustained ankle clonus, truncal ataxia, diffuse kinetic tremors | Normal exam at 2 and 11 month evaluations | |
26 | F | Fever | 30 | Hyperreflexia, sustained ankle clonus, truncal and appendicular ataxia,mild parkinsonism | Normal exam at 2 and 11 month evaluations | |
52 | F | Fever, headache, myalgias, abdominal pain, joint pain | 3 | Lower extremity hyperreflexia, sustained ankle clonus, lower extremity spasticity, truncal ataxia; subjective hearing loss | Normal exam at 1 month evaluation | |
57 | F | Fever, chills, general body pain, “difficulty walking” | 21 | Lower extremity hyperreflexia, sustained ankle clonus; severe hip flexor and extensor weakness | Normal exam at 1 month evaluation |
CSF: Cerebrospinal fluid.
WBC: White blood cell count.
NK: Not known.
Sixty-five persons from two affected villages who were without a history of illness compatible with typhoid within the previous 6 months, and did not describe a prior history of possible neurologic illness, underwent screening neurologic examination, 35 from Dackson, Mozambique, and 30 from Nseula, Malawi. Median age of these persons was 16 years (range, 4–78 years), and 54% were female, which was similar to the age and sex distribution of patients with neurologic illness (data not shown). Three (5%) persons (median age, 19 years) had brisk deep tendon reflexes with crossed adductors; 1 of these had sustained (>5 beats) ankle clonus. No history of prior neurologic illness could be elicited from these persons. Other nonspecific findings, including physiologic tremors and lower extremity areflexia, were observed in 9 persons.
This outbreak of typhoid fever in an area along the Malawi- Mozambique border was associated with a range of objective neurologic findings. Although neurologic complications of typhoid fever have been previously described, the prominence of neurologic illness early in the outbreak initially led to diagnostic confusion and caused investigators to consider numerous other etiologies thought more likely to result in acute febrile neurologic illness. Our investigation benefitted from detailed clinical information, extensive testing for other possible etiologies of neurologic illness, and laboratory confirmation of a large number of temporally and spatially clustered cases.
Thirteen percent of the 303 persons meeting case definition criteria for typhoid fever in this outbreak demonstrated objective neurologic illness. Neurologic signs have been previously described in association with typhoid fever, and have commonly included spasticity and clonus, ataxia, and dysarthria, and less frequently, neuropsychiatric features
The most common manifestations in our patients were related to upper motor neuron dysfunction, including spasticity, clonus, and hyperreflexia; a bradykinetic–rigid syndrome; and ataxia. Other manifestations, including seizures, tremors, and dysarthria, were also observed. The presence of variable neurologic manifestations suggests that typhoid produces dysfunction at numerous sites within the nervous system. Many patients presented with neurologic findings in the absence of encephalopathy or other alteration in mental status, indicating that typhoid may produce focal, as well as generalized, neurologic dysfunction. With few exceptions, the neurologic findings in these subjects resolved over time, sometimes within weeks of acute illness, and long-term or recurrent neurologic sequelae were largely absent among a subset of persons we were able to assess in extended follow-up. Notably, we did not observe some of the other neurologic manifestations that have been frequently mentioned in the setting of typhoid fever, such as acute psychosis
The reason for the high proportion of cases with neurologic illness during this outbreak is unclear, but there are several possibilities. Surveillance bias is possible; early surveillance and case detection efforts focused on those persons hospitalized with neurologic features. Following recognition of typhoid as the cause of the outbreak, more persons with features typical of typhoid fever, including abdominal pain and other gastrointestinal symptoms, were detected. The involvement of neurologists in the outbreak investigation possibly led to detection of neurologic features that might not be typically assessed or noted by other clinicians. Neurologic manifestations of typhoid have been described as a late manifestation of illness
The mechanism by which typhoid fever may produce neurologic illness is unknown. Rare cases of
An underlying host factor or environmental exposure that may predispose persons to develop neurologic illness in the setting of severe systemic infection due to typhoid is possible. Many of the predominant signs and symptoms observed in these patients, including spasticity, clonus, hyperreflexia, and ataxia, may be seen with micronutrient abnormalities including vitamin B6 toxicity/deficiency and B12 deficiency
Production of a bacterial toxin may lead to neurologic illness, with toxins produced by
Our study has limitations. We did not perform neurologic examinations on all outbreak patients, and the number of cases of neurologic illness may have been underestimated or otherwise biased. Not all patients with suspected illness were positive for or underwent testing for
Our study demonstrates that persons with typhoid fever may develop acute and severe neurologic illness. The underlying pathophysiological mechanisms producing these features remain unknown. The varying neurologic manifestations observed in this group of patients with typhoid-associated neurologic illness suggest involvement of multiple nervous system localizations. Neurologic illness associated with typhoid fever appears to resolve over time, with few ongoing sequelae, a feature that is important in the prognostic assessment of cases. Acute infection with
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The authors would like to thank the following individuals for their valuable contributions to this manuscript: Malawi Ministry of Health: Secretary Chris Kang'ombe, Ben Chilima, Kundai Moyo, and Kapangaza Ntonya; the Neno District Rapid Response Team; Partners in Health: Keith Joseph and Annemarie Ackerman; World Health Organization: F. R. Zawaira, Kelias Msyamboza, and Reggis Kasande; Population Services International; United Nations International Children's Fund; United States Agency for International Development; CDC-Malawi: Dr. Thomas Warne, Rankin Thamanda, Laston Thamangira, Victor Samidu, Ethel Mpagaja, CDC-Mozambique: Amy DuBois, Lisa Nelson; CDC-Nutritional Biomarkers Branch: Christine Pfeiffer, Michael Ryback, Usha Mandava, Huiping Chen, Donna LaVoie, Usha Mandava, Christine Pfeiffer, Daniel Rabinowitz, Michael Rybak, Rosemary Schleicher, Mary Xu, Mindy Zhang; CDC-DASH Laboratory: Nicole Burcher, Michael Dillon; CDC-NCEH Laboratory: Charles Dodson; CDC-Global Disease Detection: Ray Arthur, Rohit Chitale, Kira Christian; CDC-NCEZID: Cheryl Bopp, Michele Parsons, Ermias Belay, Katie Schilling, Sherif Zaki, Wun-Ju Shieh; CDC-NCIRD: Lauren Stockman; and the CDC Emergency Operations Center staff.
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry.