Neurologic Manifestations Associated with an Outbreak of Typhoid Fever, Malawi - Mozambique, 2009: An Epidemiologic Investigation

2009: An Epidemiologic Investigation. PLoS ONE 7(12): e46099. doi:10.1371/journal.pone.0046099 Neurologic Manifestations Associated with an Outbreak of Typhoid Fever, Malawi - Mozambique, 2009: An Epidemiologic Investigation James Sejvar 0 Emily Lutterloh 0 Jeremias Naiene 0 Andrew Likaka 0 Robert Manda 0 Benjamin Nygren 0 Stephan Monroe 0 Tadala Khaila 0 Sara A. Lowther 0 Linda Capewell 0 Kashmira Date 0 David Townes 0 Yanique Redwood 0 Joshua Schier 0 Beth Tippett Barr 0 Austin Demby 0 Macpherson Mallewa 0 Sam Kampondeni 0 Ben Blount 0 Michael Humphrys 0 Deborah Talkington 0 Gregory L. Armstrong 0 Eric Mintz 0 Martyn Kirk, The Australian National University, Australia 0 1 Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, United States of America, 2 Scientific Education and Professional Development Program Office, Epidemic Intelligence Service, CDC, Atlanta, Georgia, United States of America , 3 Current Position , New York State Department of Health , Albany , New York, United States of America, 4 Ministry of Health , Maputo, Mozambique, 5 Ministry of Health , Lilongwe, Malawi, 6 Division of Foodborne , Waterborne, and Environmental Infectious Diseases, NCEZID, CDC, Atlanta , Georgia , United States of America, 7 Division of Environmental Hazards and Health Effects, National Center for Environmental Health (NCEH), CDC, Atlanta, Georgia, United States of America , 8 Global AIDS Program, CDC, Lilongwe, Malawi, 9 Malawi-Liverpool-Wellcome Trust , College of Medicine, Blantyre, Malawi, 10 Division of Viral Diseases, National Center for Immunization and Respiratory Diseases , CDC, Atlanta, Georgia , United States of America Background: The bacterium Salmonella enterica serovar Typhi causes typhoid fever, which is typically associated with fever and abdominal pain. An outbreak of typhoid fever in Malawi-Mozambique in 2009 was notable for a high proportion of neurologic illness. Objective: Describe neurologic features complicating typhoid fever during an outbreak in Malawi-Mozambique Methods: 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. Results: 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. Conclusions: Neurologic signs may complicate typhoid fever, and the diagnosis should be considered in persons with acute febrile neurologic illness in endemic areas. - Funding: U.S. government funding, Centers for Disease Control and Prevention. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Typhoid fever is a bacterial disease caused by infection with Salmonella enterica serovar Typhi (Salmonella Typhi). It is transmitted through the fecal-oral route, generally by contaminated water or food. Typically, it presents as an acute febrile illness often accompanied by signs and symptoms such as headache, abdominal pain, diarrhea or constipation, and malaise [1]. Other, more severe complications of typhoid fever include intestinal perforation, hepatitis, pneumonia, and tissue abscesses [1,2]. Neurologic illness has also been described, most frequently as acute encephalopathy or meningitis [3]. A variety of objective neurologic signs have been documented, including acute neuropsychiatric illness [4,5,6], spasticity and clonus [4,7], ataxia [8,9,10,11,12,13], aphasia [14,15,16], and cerebritis [3,17]. However, these findings have generally appeared as case reports or small case series. 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. Patient Identification 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 [18] that included structured retrospective interviews of previously ill individuals to determine initial signs and symptoms, risk factors (...truncated)