The patient was a 15-year-old girl who rescued and released a bat that struck an interior window. She sustained a 5-mm laceration to her left index finger from the bat. The wound was washed with peroxide. No medical attention was sought, and no rabies postexposure prophylaxis was administered. The patient continued to excel in school and play sports until one month after exposure, when she experienced generalized fatigue and paresthesia of the left hand. Two days later diplopia developed and she felt unsteady. The next day, she had nausea and vomiting without fever. A neurologist noted partial bilateral sixth-nerve palsy and ataxia. The results of magnetic resonance imaging and angiography of her brain were unremarkable. By the fourth day after the onset of symptoms, blurred vision, weakness of the left leg, and a gait abnormality were present. On the fifth day, fever (38.8°C), slurred speech, nystagmus, and tremors of the left arm developed. With the progression of symptoms and an elicited history of a bat bite, the patient was transferred to our facility.

On the first hospital day, the patient was febrile (temperature, 38.2°C) and semiobtunded but answered simple questions and complied with simple commands during diagnostic maneuvers. She had scanning speech, bilateral sixth-nerve palsies, decreased upward gaze, dysarthria, myoclonus, intention tremor of the left arm, and ataxia. Samples of serum, cerebrospinal fluid, nuchal skin, and saliva were submitted to the Centers for Disease Control and Prevention (CDC) for the diagnosis of rabies. Repeated brain magnetic resonance imaging and angiography showed no abnormalities. The patient began salivating, with uncoordinated swallowing, and was intubated for airway protection. On the second hospital day, the presence of rabies virus–specific antibody in her cerebrospinal fluid and serum was confirmed by the CDC. Attempts to isolate rabies virus, detect viral antigen, and amplify viral nucleic acid from two skin biopsies and nine saliva samples were unsuccessful.

The patient's parents were counseled about her diagnosis and prognosis. We offered both hospice care and an aggressive approach on the basis of an untested strategy that combined antiexcitatory and antiviral drugs with supportive intensive care. We provided information about the probable failure of antiviral therapy and the unknown effect of the proposed therapy, as well as the possibility of severe disability if the patient were to survive. The patient's parents requested that we institute aggressive care on the basis of the principles we had discussed.

Figure 1. Figure 1. Relationship between Vital Signs in a Patient with Rabies and the Treatment Regimen. Panel A shows the relationship between temperature and titers of total rabies virus–specific antibody and neutralizing antibody in cerebrospinal fluid (CSF), according to hospital day. A pronounced febrile inflammatory syndrome in the second week was associated with the emergence of neutralizing antibodies in the CSF. Panel B shows the effects of the administration of ketamine, benzodiazepines (in midazolam equivalents, with 3 mg midazolam equal to 1 mg diazepam), phenobarbital, amantadine, and ribavirin. Burst suppression was achieved after an initial sleep pattern was established by electroencephalography. In Panel C, a loss of variability in pulse and respiratory rate and salivary secretions (with an arbitrary score of 4) was followed by a return of heart-rate variability (with a score of 5) and then hyperreactivity (including tearing of the eyes, the production of thick secretions, coughing, and gagging, with a score of 6) and later bronchospasm (with a score of 7).

We administered ketamine at 2 mg per kilogram of body weight per hour with midazolam at 1 to 3.5 mg per kilogram of body weight per hour to suppress background activity on electroencephalography so that only one to two seconds of cerebral activity were interspersed (Figure 1). Oxygen delivery was optimized without inotropic agents by red-cell transfusion to maintain the hemoglobin level at more than 10 g per deciliter, appropriate volume loading, and mechanical ventilation targeting arterial normoxia and mild hypercapnia.5 Adequacy of oxygen delivery to organs was monitored by intermittent assessment of venous saturation, and brain and somatic oxygenation by near-infrared spectroscopy.6 Heparin (10 U per kilogram per hour) was administered prophylactically.7

Table 1. Table 1. Evolution of Inflammation and Levels of Rabies Virus–Specific Antibody in Cerebrospinal Fluid, According to Hospital Day.

After the induction of coma and on the basis of discussions with scientists at the CDC, we instituted antiviral therapy. Studies in animals have shown little penetration of ribavirin into the central nervous system, and it has had little effect in animal models, but we administered the drug with the rationale that elevated protein levels in the cerebrospinal fluid indicated permeability of the blood–brain barrier (Table 1) and that ribavirin might protect against rabies myocarditis.3 Ribavirin was administered on the third hospital day, with a loading dose of 33 mg per kilogram followed by a maintenance dose of 16 mg per kilogram every six hours. Interferon alfa was not used because of its neurotoxicity. Neither rabies vaccine nor rabies immune globulin was administered because of the patient's demonstrated immune response and the potential for harm from a potentiated immune response.8 Amantadine (200 mg per day, administered enterally) was added on the fourth hospital day because of its in vitro activity against rabies virus, as well as its antiexcitotoxic activity, which is distributed more rostrally in the brain than is that of ketamine.9,10

High doses of benzodiazepines with supplemental barbiturates were necessary to maintain burst suppression. Limited availability of preservative-free midazolam necessitated the use of midazolam containing 1 percent benzyl alcohol. Biochemical evidence of hemolysis and acidosis was detected by the fifth hospital day. The hemoglobin level declined from 13.7 to 10.9 g per deciliter, whereas the lactate dehydrogenase level rose from 420 to 1020 U per liter over seven days, a finding that was consistent with hemolysis, probably after a cumulative total of 276 mg per kilogram of ribavirin had been administered. An arterial base excess of 2.7 mmol per liter declined to –3.8 mmol per liter over five days, which was consistent with metabolic acidosis, without a change in the blood lactate level, probably reflecting the cumulative total of 362 mg per kilogram of benzyl alcohol. Ribavirin was reduced to 8 mg per kilogram for nine doses, and midazolam was tapered to 1.5 mg per kilogram per hour, with phenobarbital supplementation to maintain burst suppression.

There were minimal systemic effects of brain-stem and peripheral neuropathy. The patient had transient evidence of both deficiency and excess of antidiuretic hormone on the fifth through seventh hospital days. Clinical autonomic denervation developed on the fifth hospital day, with reduced cardiac variability (Figure 1) and higher central venous pressure.1,11-13 Salivation decreased on the eighth hospital day. The patient's skin became flushed, and ileus developed. Increased levels of liver aminotransferase (52 IU per liter), lipase (1193 U per milliliter), and amylase (288 U per milliliter) were noted. Lipase and amylase peaked on the 15th to 18th hospital days (at 2532 U and 539 U per milliliter, respectively), but without enlargement of the pancreas on sonography. A lumbar puncture on the eighth hospital day showed an increased level of rabies-virus antibody in both the serum and cerebrospinal fluid (Figure 1 and Table 1). Ketamine was tapered over 24 hours, and diazepam was given to replace midazolam.

On the 10th hospital day, the patient responded to suctioning with increases in pulse and blood pressure. A high fever developed on the 12th hospital day, without leukocytosis or culture evidence of infection. The patient's fever did not respond to acetaminophen, ibuprofen, ketorolac, or external cooling. On the 14th day, therapy was intensified with ketamine, high-dose diazepam, and amantadine, without effect on her fever (Figure 1). Studies in both animals and humans describe marked poikilothermia in rabies.1,14 A reduction in the room temperature by 5.5°C on the 15th day was followed by a 3.6°C drop in core body temperature. Ketamine and diazepam were lowered and amantadine continued for one week.

Although the electroencephalographic findings improved after the initial tapering of drugs, the patient had briskly reactive pupils but no other cranial-nerve function on the ninth day. Motor examination showed complete flaccidity, without spontaneous movement or movement in response to pain and the absence of deep-tendon reflexes. Patellar deep-tendon reflexes developed on the 12th day, when the patient also opened her mouth in response to sternal pressure. She blinked when eyedrops were administered and regained eye movements on the 14th day. By the 16th day, she opened her mouth to assist with care and raised her eyebrows in response to speech. On the 19th day, she wiggled her toes and squeezed hands in response to commands, fixed her gaze preferentially on her mother, and had an apneustic breathing pattern associated with dystonic opening of her jaw. Computed tomography of her head was normal.

On the 20th day, patellar and ankle deep-tendon reflexes became hyperreflexic, and deep-tendon reflexes in the biceps and triceps developed. Her attention span was 10 to 30 seconds. On the same day, the patient had respiratory distress associated with diaphoresis, tearing of the eyes, the production of thick secretions, and prolonged episodes of coughing and gagging. This condition responded to applications of lidocaine to her hypopharynx. On the 22nd day, she had episodes of prolonged expiratory phase, responsive to albuterol or suctioning. On the 23rd day, she sat in bed, holding her head erect. On the 26th day, she clearly objected to new staff members, a tremor developed in her jaw, and she showed passive tone when her extremities were moved. She was extubated on the 27th day and later slept for 8 consecutive hours and had 60 seconds of sustained alertness. There was persistent jaw dystonia and limited spontaneous movement. On the 30th day, she cried spontaneously and acknowledged sadness as opposed to fear or pain. Deep-tendon reflexes in her biceps and triceps became hyperreflexic, whereas patellar and ankle reflexes normalized. She reported having no skin hyperesthesia or dysesthesia.

Figure 2. Figure 2. Timeline by Hospital Day from the Time of Inoculation with Rabies Virus until Two Months after Discharge from the Hospital. The incubation period extends from the day on which the patient was bitten by a bat until her first symptoms appeared. Hospitalization includes both the referral and accepting hospitals. The therapeutic coma induced by ketamine and midazolam and the period of burst suppression are shown for reference. Disorders of temperature (more than 38.9°C) and the syndrome of inappropriate antidiuretic hormone (SIADH) or diabetes insipidus are indicated. The patient was transferred from intensive care on the 32nd hospital day. A selected list of rehabilitation milestones is shown.

Given her continued neutralizing antibody response to rabies virus in cerebrospinal fluid and blood and our inability to isolate the virus or detect viral nucleic acid in saliva, the patient was considered cleared of transmissible rabies and removed from isolation on the 31st day. After rehabilitation, she was discharged to her home on the 76th day (Figure 2). In a clinic visit 131 days after her initial hospitalization, she smiled, laughed, and interacted with the examiner; her speech was dysarthric ( , available with the full text of this article at www.nejm.org). The patient was able to dress herself, ate a normal diet, slept well, and attended high school part-time. She had constant buccolingual choreoathetosis with generalized choreoathetosis and intermittent dystonia and ballismus, which produced a lurching gait and fine-motor difficulties ( ). She was able to write legibly but slowly and to type with her index fingers. She had normal extremity tone, bilateral upward-going toes, and no clonus. She had decreased dorsiflexion in the left ankle and decreased grip in the left hand. She had intact sense of position and light touch.