**2. Methods**

#### **2.1 Case definition and data sources**

This review includes all cases of human rabies reported to the Centers for Disease Control and Prevention (CDC) that occurred within the United States and its territories between the years 1960–2010. These cases include both indigenous cases occurring in United States nationals as well as imported cases in foreign nationals diagnosed and treated within the United States and it territories. All cases were confirmed using standard diagnostic laboratory tests performed by CDC or by a state laboratory and were reported by health authorities as part of ongoing national surveillance. The clinical and laboratory findings were taken from CDC's Morbidity and Mortality Reports, published journal articles, and unpublished CDC notes. In addition, this review contains clinical data from patients with suspected rabies submitted to the CDC for laboratory diagnostic testing between the years 2007–2010 for whom rabies was subsequently ruled out (non-rabies cases).

#### **2.2 Variable definitions**

Onset of illness was defined as either the first day of reported symptoms attributable to rabies or, when this date was unknown, the date when medical care was first sought prior to the confirmation of rabies. Signs and symptoms attributable to rabies included aerophobia, hydrophobia, paresthesia or localized pain, priapism or spontaneous ejaculation, dysphagia, localized weakness, fever, muscle spasm, hypersalivation, anxiety, hallucinations, autonomic instability, agitation or combativeness, nausea or vomiting, ataxia, anorexia, insomnia, seizures, confusion or delirium, malaise or fatigue, and headache. When a bite from a known species, laboratory RABV exposure, or transplantation of infected organs or tissue was reported the species of biting animal or type of exposure and the location of the exposure incident are indicated in the exposure history. Probable exposures where no known bite occurred but physical contact with an animal or close proximity to an animal was reported are also indicated. All other exposures were defined as "unknown." The RABV variant determined by antigenic or molecular typing also provides evidence of the likely source of infection and is particularly useful when no exposure history is known. The type of case was defined as indigenous if the bite incident occurred in the United States or its territories or if the RABV variant identified matched an indigenous source. Imported cases were defined by an exposure occurring outside of the United States or its territories or by identification of a RABV variant not found within the United States. The diagnosis of rabies was considered antemortem when samples were obtained specifically for rabies diagnostic testing before death or when the signs, symptoms, and clinical history were deemed sufficient by the clinicians involved to establish the diagnosis.

### **2.3 Statistical analysis**

248 Non-Flavivirus Encephalitis

provides the patient with the opportunity for treatment and possible survival. Insights gained from each attempt at treatment further our understanding of the disease and add to the body of knowledge that can be applied to future cases. When rabies is ruled out, efforts can be focused on identifying more treatable causes of encephalitis. With these goals in mind, this review will describe the epidemiology of human rabies, examine the signs and symptoms of disease, and review the laboratory diagnostic testing and results for all

This review includes all cases of human rabies reported to the Centers for Disease Control and Prevention (CDC) that occurred within the United States and its territories between the years 1960–2010. These cases include both indigenous cases occurring in United States nationals as well as imported cases in foreign nationals diagnosed and treated within the United States and it territories. All cases were confirmed using standard diagnostic laboratory tests performed by CDC or by a state laboratory and were reported by health authorities as part of ongoing national surveillance. The clinical and laboratory findings were taken from CDC's Morbidity and Mortality Reports, published journal articles, and unpublished CDC notes. In addition, this review contains clinical data from patients with suspected rabies submitted to the CDC for laboratory diagnostic testing between the years

Onset of illness was defined as either the first day of reported symptoms attributable to rabies or, when this date was unknown, the date when medical care was first sought prior to the confirmation of rabies. Signs and symptoms attributable to rabies included aerophobia, hydrophobia, paresthesia or localized pain, priapism or spontaneous ejaculation, dysphagia, localized weakness, fever, muscle spasm, hypersalivation, anxiety, hallucinations, autonomic instability, agitation or combativeness, nausea or vomiting, ataxia, anorexia, insomnia, seizures, confusion or delirium, malaise or fatigue, and headache. When a bite from a known species, laboratory RABV exposure, or transplantation of infected organs or tissue was reported the species of biting animal or type of exposure and the location of the exposure incident are indicated in the exposure history. Probable exposures where no known bite occurred but physical contact with an animal or close proximity to an animal was reported are also indicated. All other exposures were defined as "unknown." The RABV variant determined by antigenic or molecular typing also provides evidence of the likely source of infection and is particularly useful when no exposure history is known. The type of case was defined as indigenous if the bite incident occurred in the United States or its territories or if the RABV variant identified matched an indigenous source. Imported cases were defined by an exposure occurring outside of the United States or its territories or by identification of a RABV variant not found within the United States. The diagnosis of rabies was considered antemortem when samples were obtained specifically for rabies diagnostic testing before death or when the signs, symptoms, and clinical history were

reported human rabies cases in the United States between 1960 and 2010.

2007–2010 for whom rabies was subsequently ruled out (non-rabies cases).

deemed sufficient by the clinicians involved to establish the diagnosis.

**2. Methods** 

**2.2 Variable definitions** 

**2.1 Case definition and data sources** 

Data analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, North Carolina). Data were summarized using descriptive statistics and comparisons between human rabies cases and cases of encephalopathy with negative rabies diagnostic testing were made using Chi-square or Fisher's exact test. Some variables were dichotomized before statistical comparisons for determination of odds ratios (OR) and 95% confidence intervals (CI). Associations were considered statistically significant at p-values less than 0.05.
