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Publication: MMWR. Morbidity and Mortality Weekly Report
Date published:
Language: English
PMID: 15976
ISSN: 01492195
Journal code: IMMW

In late December 2010, a male resident of Wisconsin, aged 70 years, sought treatment for progressive right shoulder pain, tremors, abnormal behavior, and dysphagia at an emergency department (ED). He was admitted for observation and treated with benzodiazepines and haloperidol, a neuroleptic, for presumed alcohol withdrawal syndrome. The next day, he had rhabdomyolysis, fever, and rigidity, and neuroleptic malignant syndrome was diagnosed. The neuroleptic was discontinued, but the patient's clinical status worsened, with encephalopathy, respiratory failure, acute renal failure requiring hemodialysis, and episodes of cardiac arrest. With continued clinical deterioration, additional causes were considered, including rabies. On hospital day 12, rabies virus antigens and nucleic acid were detected in the nuchal skin biopsy and rabies virus nucleic acid in saliva specimens sent to CDC. A rabies virus variant associated with silver-haired bats (Lasionycteris noctivagans) was identified. The patient died on hospital day 13. His spouse reported that they had been selling firewood, and bats had been present in the woodpile; however, the man had not reported a bat bite. Two relatives and five health-care workers potentially exposed to the man's saliva received postexposure prophylaxis. This case highlights the variable presentations of rabies and the ease with which a diagnosis of rabies can be missed in a clinically challenging patient with comorbidities. Clinicians should consider rabies in the differential diagnosis for patients with progressive encephalitis or neurologic illness of unknown etiology and caregivers should take precautions to avoid exposure to body fluids. Continued public education regarding risks for rabies virus exposure during interactions with wildlife, particularly bats, is important.

Case Report

During December 2010, a male Wisconsin resident aged 70 years experienced right shoulder pain after mixing cookie dough. Two days later, he became tremulous and had difficulty swallowing. Although coherent and alert, his family reported he appeared fatigued and exhibited abnormal behavior, including a prolonged staring spell. The following day, the patient complained of ongoing right shoulder pain and became increasingly tremulous and diaphoretic, without reported fever. His swallowing difficulties persisted, and he could eat only small pieces of food. Four days after symptom onset, after an evening of insomnia, he requested evaluation at hospital As ED.

At the ED, the patient was agitated, restless, and complained of weakness, right shoulder pain, and difficulty swallowing. He was alert and afebrile, with a blood pressure of 208/121 mmHg and a respiratory rate of 16 breaths per minute. Physical examination was remarkable only for diaphoresis and tremors. The initial differential diagnosis included cerebral vascular injury, transient ischemic attack, acute coronary syndrome, and alcohol withdrawal syndrome. Laboratory tests included a complete blood count, complete metabolic panel, urinalysis, serum alcohol, urine drug screen, liver function, and cardiac enzymes. Abnormal test results included a white blood cell (WBC) count of 13.7 ? IO3 cells//żL (normal: 4.2-11.07 ? IO3 cells/^L) with 81% neutrophils, asparate aminotransferase (AST) of 87 IU/L (normal: <38 IU/L), B-type natriuretic peptide of 133 pg/mL (normal: <100 pg/mL), creatine kinase-MB of 49.9 ng/mL (normal: <5.1 ng/mL), myoglobin >500 ng/mL (normal: <170 ng/mL), creatine Phosphokinase (CPK) of 5,589 IU/L (normal: 39-308 IU/L), and blood glucose of 103 mg/dL (normal: 65-99 mg/dL). An electrocardiogram (ECG) demonstrated sinus tachycardia (ST) with no ST segment changes. A computerized tomography scan of the patient's head and chest radiograph were unremarkable. The Clinical Institute Withdrawal Assessment (CIWA-Ar) protocol was followed for presumed alcohol withdrawal syndrome (1). The patient received thiamine, lorazepam, and folic acid, but his agitation and restlessness worsened, and he became confused and eventually nonverbal. He began to have muscle spasms, twitches, and abnormal body movements. A consulting neurologist determined the patient's signs and symptoms were more consistent with alcohol withdrawal syndrome than seizures. The patient was admitted to the intensive-care unit for management of severe alcohol withdrawal syndrome and possible rhabdomyolysis.

During hospital day 2, the patient's agitation, confusion, and tremors continued; twitching was noted in his arms and legs, and his muscle strength was diminished in all extremities. Based on CIWA-Ar protocol, he was given both diazepam and haloperidol for severe alcohol withdrawal symptom control. During evaluation of his swallowing difficulties, the patient coughed immediately; with consumption of thin liquids, he was unable to consistently swallow on command. Abnormal laboratory test results included WBC of 13.8 ? 103 cells//żL, serum ammonia of 55 //mo 1/L (normal: 9-33/żmol/L), alanine aminotransferase of 112 IU/L (normal: <66 IU/L), AST of 460 IU/L, CPK of 26,780 IU/L, and blood urea nitrogen of 21 mg/dL (normal: 10-20 mg/dL). The patient's temperature was 1020F (38.90C) and he had onset of generalized rigidity. Antibiotic therapy was initiated because of fever and leukocytosis. A diagnosis of neuroleptic malignant syndrome related to haloperidol (day 2; cumulative dose: 10 mg) was considered because of the patient's rigidity, fever, and rhabdomyolysis. Neuroleptic medications were discontinued, and aggressive intravenous hydration was started.

Early on day 3, the patient became unresponsive with respiratory failure and required intubation and mechanical ventilation. A chest radiograph revealed a focus of atelectasis or infiltrate in the lower lobe of the right lung, and antibiotic therapy was continued. The patient experienced acute renal failure secondary to rhabdomyolysis and his cardiac enzyme levels increased. An ECG revealed a normal ejection fraction with diastolic dysfunction but no regional wall motion abnormalities. The ECG demonstrated no evidence of ischemia; non-ST elevation myocardial infarction was diagnosed and anticoagulation therapy administered.

During day 5, the patients urinary output decreased. Despite sedation, he spontaneously opened his eyes and intermittently had 2-second, full body tonic contractions during physical examinations. A chest radiograph revealed worsened bibasilar areas of the atelectasis or infiltrates. On day 6, the patient was transferred by ambulance to hospital B for hemodialysis because of acute renal failure.

During days 7-10, the patient had hypotensive episodes that required vasopressor support. These included full-body tonic contractions that increased in duration to 20-30 seconds and rhabdomyolysis that continued despite cessation of neuroleptic medications. On two occasions, minor tactile stimulation or body manipulation was followed by cardiac arrest. An electroencephalogram showed diffuse nonspecific cortical dysfunction without seizure activity consistent with a toxic metabolic or hypoxemic encephalopathy. Other diagnoses associated with encephalopathy and rhabdomyolysis were considered, including tetanus, Lyme disease, West Nile virus (WNV) infection, syphilis, and rabies. The glutamic acid decarboxylase antibody test for stiff-person syndrome was negative, as were serologic tests for Lyme disease, WNV, and syphilis. The patients tetanus antibody level was considered protective.

On day 1 1 , a nuchal skin biopsy, serum, and saliva were sent to CDC for rabies diagnostic evaluation. Because of the patients clinical instability, cerebrospinal fluid was unobtainable. The next day, CDC detected rabies virus antigens in the nuchal skin biopsy. Infection with a silver-haired bat rabies virus variant was confirmed in a saliva sample and the nuchal biopsy tissue by using nucleic acid amplification and sequencing. No rabies virus antibodies were detected in the serum. The patient died soon after rabies was confirmed. Analysis of postmortem brain tissue confirmed the diagnosis by detection of rabies virus antigens. Antigenic typing with monoclonal antibodies was consistent with a rabies virus variant associated with silverhaired and tricolored (Perimyotis subflavus) bats.

Public Health Investigation

On hospital day 9, hospital B infection control staff notified the Wisconsin Division of Public Health (DPH) of a suspected case of rabies and inquired about the process for antemortem testing. During a follow-up interview of the patient's family about possible sources of rabies exposure, the patient's wife stated that they had been selling firewood and her husband mentioned the presence of bats in the woodpile. When the rabies diagnosis was confirmed, infection control staff members at both hospitals and DPH staff members initiated contact investigation interviews with the patient's family, friends, and health-care providers to determine the extent of exposure and need for postexposure prophylaxis (PEP) consistent with the Advisory Committee on Immunization Practices (ACIP) recommendations (2). To assist with the health-care providers' evaluation, DPH provided assessment material and an information sheet on rabies virus exposure in a health-care setting to both hospitals. No animal bites were reported by the patient or his wife, and no other family members or friends had any likely exposures to bats or other potentially rabid animals.

Among 176 health-care workers assessed at both hospitals, five (2.8%) were advised to receive postexposure prophylaxis because they were exposed to the patient's saliva during intubation, cardiopulmonary resuscitation, or teeth brushing, or were exposed to aerosols emitted from a dislodged ventilator tube while not using appropriate personal protective equipment. Among friends and family members, the patient's wife and a grandchild were exposed to the patient's saliva and received postexposure prophylaxis. Among the persons who had had contact with the patient, none have experienced rabies to date.

Editorial Note

Human rabies is a vaccine-preventable disease that is almost universally fatal in unimmunized persons (3,4). Prompt and thorough wound cleaning, administration of human rabies immune globulin, and vaccination using a 4-dose schedule of a cell culture rabies vaccine as soon as possible after rabies virus exposure can eliminate the risk for rabies in nearly all cases (2,5,6). This case underscores the importance of seeking timely medical intervention after suspected rabies virus exposure. Administration of postexposure prophylaxis might have been recommended in this case if rabies virus exposure had been suspected, although little is known about the patient's interactions with animals, including any bats or others animals associated with the woodpile. Additionally, persons might not seek timely medical care if a bat bite appears insignificant or a minor wound is not thought to be linked to an animal exposure.

Although human rabies occurs rarely in the United States, this is the third case reported in Wisconsin since 2000, all of which involved known or inferred interaction with bats before illness onset; only one of the three patients survived (2,7)· During 1995-2010, among 30 previously reported patients with human rabies whose rabies virus exposures occurred in the United States and were not associated with transplanted organs or tissues, 29 (96.6%) had infections associated with a bat rabies virus variant and only one with the raccoon rabies virus variant (8,9).

This case highlights the varied clinical presentations of human rabies and the need to consider a diagnosis of rabies for any patient with unexplained progressive encephalitis of unknown etiology. Obtaining information regarding exposure to animals in the United States and during foreign travel is a crucial component of the medical history. Continued public education regarding the risk for rabies after exposures to wildlife, particularly to bats, is needed. Health-care providers are reminded to use personal protective equipment when the possibility of exposure to infectious body fluids exists. The use of guidelines specific to the risks for rabies virus transmission within health-care facilities might reduce unnecessary postexposure prophylaxis in such settings.*


Brian Buggy, MD, Charles Brummitt, MD, LyAnne Halverson, Aurora Health Care, Milwaukee; Gail Zavadsky, Aurora Health Care, West Allis, Wisconsin. Kristine Bisgard, DVM, Scientific Education and Professional Development Program Office; Richard Franka, DVM, PhD, Ivan Kuzmin, MD, PhD, Michael Niezgoda, MS, Felix Jackson MS, Andres Velasco-Villa, PhD, Lillian Orciari, MS, and Pamela Yager, Div of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC.

* Additional information and resources prepared by DPH are available at http:// www. dhs. Wisconsin, gov/com m unicab Ie/ rab ies/ resources . htm .


1. Mayo-Smith MF. Pharmacological management of alcohol withdrawal: a meta-analysis and evidence-based practice guideline. JAMA 1997;278(2): 144-51.

2. CDC. Human rabies prevention - United States, 2008: recommendations of the Advisory Committee on Immuni2ation Practices (ACIP). MMWR 2008;57(No. RR-3).

3. Willoughby RE Jr, Tieves KS, Hoffman GM, et al. Survival after treatment of rabies with induction of coma. N Engl J Med 2005;352:2508-14.

4. CDC. Presumptive abortive human rabies - Texas, 2009. MMWR 2010;59:185-90.

5- CDC. Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies. MMWR 2010;59(No. RR-2).

6. World Health Organi2ation. WHO expert consultation on rabies. First report. Geneva, Switzerland: World Health Organization; 2005. WHO Technical Report Series, no. 931. Available at trs931_%2006_05.pdf. Accessed August 25, 201 1.

7. CDC. Human rabies - California, Georgia, Minnesota, New York and Wisconsin, 2000. MMWR 2000;49: 1 1 1 1-5.

8. Blanton JD, Palmer P, Rupprecht CE. Rabies surveillance in the United States during 2009. J Am Vet Med Assoc 2010;237:646-57.

9. CDC. Human rabies. Adanta, GA: US Department of Healm and Human Services, CDC; 2011. Available at usa/surveillance/human_rabies.html. Accessed March 17, 2011.

Author affiliation:

Reported by

James J. Kazmierczak, DVM, Jeffrey P. Davis, MD, Wisconsin Div of Public Health. Ernesto Brauer, MD, Aurora Health Care, Milwaukee, Wisconsin. Sergio Recuenco, MD, Charles E. Rupprecht, VMD, PhD, Div of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC; Michael L. Bartholomew, MD, EIS Officer, CDC Corresponding contributor: Michael Bartholomew,, 608-266-0392.

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