Case Records of the Massachusetts General Hospital

Richard C. Cabot, Founder, Nancy Lee Harris, M.D., Editor, Eric S. Rosenberg, M.D., Editor, Jo-Anne O. Shepard, M.D., Associate Editor, Alice M. Cort, M.D., Associate Editor, Sally H. Ebeling, Assistant Editor, Emily K. McDonald, Assistant Editor

Case 1-2013 — A 63-Year-Old Man with Paresthesias and Difficulty Swallowing

David M. Greer, M.D., Gregory K. Robbins, M.D., M.P.H., Virginia Lijewski, M.P.H., R. Gilberto Gonzalez, M.D., Ph.D., and Declan McGuone, M.B., B.Ch.

N Engl J Med 2013; 368:172-180January 10, 2013DOI: 10.1056/NEJMcpc1209935

Article

Presentation of Case

Dr. Andrew M. Brunner (Medicine): A 63-year-old man was admitted to this hospital because of paresthesias, difficulty drinking liquids, and anxiety.

The patient had been well until 4 days before admission, when aching developed in the left elbow, which improved with ibuprofen. The next day, right-elbow discomfort occurred, and he had decreased appetite. Two days before admission, he noted difficulty forming words, mild light-headedness, and mild recurrent pain in both elbows. An attempt to drink a glass of water precipitated a gagging sensation. He had difficulty breathing and could not swallow the water. The choking sensation resolved when he spat out the water, but it recurred with subsequent attempts. He stopped drinking liquids and became increasingly anxious. One day before admission, he was unable to shower because of increased anxiety and noted intermittent decreased fluency in his speech and pruritus at the nape of his neck. He was concerned that he was having a stroke, and he drove to the emergency department at a local hospital.

On examination, the temperature was 37.8°C, the blood pressure 111/81 mm Hg, the pulse 97 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 96% while the patient was breathing ambient air. He was intermittently very anxious and hyperventilating. When given a cup of water or juice, he gagged as the cup neared his mouth and coughed while attempting to drink, with improvement after he expectorated the liquid. He was able to swallow solids. The remainder of the examination was normal. The blood levels of hemoglobin, electrolytes, total protein, albumin, creatine kinase isoenzymes, and troponin T were normal, as were the hematocrit, platelet count, and red-cell indexes; tests of coagulation and renal and liver function were also normal. Other test results are shown in Table 1Table 1Laboratory Data.. An electrocardiogram (ECG) showed sinus rhythm at a rate of 87 beats per minute, left ventricular hypertrophy, and a QRS-complex duration of 134 msec, without evidence of acute ischemia. A chest radiograph was normal. Lorazepam and intravenous fluids were administered, with some reduction in anxiety. Computed tomography (CT) of the head without the administration of contrast material was reportedly normal. The patient was transferred to this hospital.

The patient reported intermittent tremulousness during the previous 2 days, retching when thinking about drinking water, and a transient pruritic rash on his left shoulder 2 weeks before this presentation, without recent fever, chills, vomiting, diarrhea, pharyngitis, or focal motor deficits. He had hypertension, chronic ptosis of the right eyelid, and, 6 months earlier, a tick bite for which doxycycline had been administered. Medications included hydrochlorothiazide and low-dose aspirin daily; he had received influenza and tetanus vaccinations within the past year. He had no allergies. He drank alcohol occasionally, had stopped smoking 25 years earlier, and did not use illicit drugs. He lived with his wife in an old house in a semirural region of New England. He had no history of animal bites; however, bats had been seen in his home and in a barn where he had worked several times during the previous year. He had not traveled internationally in the past decade. His father had had lung cancer.

On examination, the patient appeared anxious, with dry mucous membranes. The blood pressure was 171/80 mm Hg, the pulse 86 beats per minute, the temperature 36.4°C, the respiratory rate 16 breaths per minute, and the oxygen saturation 98% while he was breathing ambient air. Other findings included ptosis of the right eyelid, mild facial twitching, postural hand tremors, and dysmetria on finger–nose–finger and heel-to-shin testing, without truncal ataxia. Deep-tendon reflexes were symmetrically hyperactive throughout; plantar reflexes were flexor. There was mild difficulty with tandem walking. The patient's speech was rushed and fluent, except for occasional slurred words and pauses for word finding; the remainder of the general and neurologic examination was normal. The hematocrit, platelet count, erythrocyte sedimentation rate, and levels of hemoglobin, C-reactive protein, and troponin T were normal, as were tests of renal and liver function; toxicologic screening and testing for antibodies to Ro and La were negative. Other test results are shown in Table 1. Lorazepam was administered.

Magnetic resonance imaging (MRI) of the brain without the administration of contrast material and magnetic resonance angiography (MRA) of the head and neck revealed abnormal signal hyperintensity scattered in the periventricular and subcortical white matter on T₂-weighted and fluid-attenuated inversion recovery (FLAIR) images and was otherwise normal. A chest radiograph was normal. The patient was admitted to the hospital.

During the first day, the patient was conversant and had increasing anxiety and discomfort from ambient noises, including hospital monitor alarms. Evaluation by a speech and language pathologist revealed severe anxiety related to swallowing liquids (characterized by physically aversive behaviors when liquids began to approach his facial area), without evidence of focal dysphagia, dysarthria, or an anatomical contraindication to swallowing.

Overnight, anxiety increased. Lorazepam and haloperidol were administered. Early in the morning of the second day, the temperature rose to 38.2°C. The patient was tremulous, agitated, oriented but confused, and unable to give a clear history. After premedication with additional lorazepam and haloperidol, a lumbar puncture was performed. The opening pressure was 33 cm of water. Results of cerebrospinal fluid (CSF) analysis and other test results are shown in Table 1. Cytologic examination and flow cytometry of the CSF showed no abnormalities.

Immediately after the procedure, cyanosis developed; the systolic blood pressure was 240 mm Hg, the pulse 160 beats per minute, the respiratory rate 40 breaths per minute, and the oxygen saturation 40 to 49%. An ECG showed supraventricular tachycardia at a rate of 150 beats per minute, with regular rhythm and right bundle-branch block, without ischemic changes. The pulse suddenly decreased from 150 beats per minute to 60, then returned to 150 beats per minute before pharmacologic intervention. Oxygen was administered, and the oxygen saturation rose to 95%. Metoprolol and furosemide were administered intravenously, followed by diltiazem. A repeat chest radiograph showed perihilar fullness and loss of definition of the pulmonary vasculature, consistent with pulmonary edema. The trachea was intubated, and the patient was admitted to the cardiac care unit. An electroencephalogram (EEG) showed moderate generalized background slowing without focal features, epileptiform activity, or correlation to episodes of arm tremors and twitching. CT of the brain showed no evidence of acute injury.

Diagnostic procedures were performed.

Differential Diagnosis

Dr. David M. Greer: May we see the imaging studies?

Dr. R. Gilberto Gonzalez: MRI of the brain without the administration of contrast material, along with MRA of the head and neck, revealed abnormal signal hyperintensity scattered in the periventricular and subcortical white matter on T₂-weighted and FLAIR images and was otherwise normal. No vascular abnormalities were identified. A chest radiograph was normal.

Dr. Greer: The approach to a patient with an altered sensorium involves a careful history taking, with particular attention to the time course. This patient had a subacute but rapidly progressive deterioration over a period of 4 days. Environmental exposure was possible owing to the bats in his house and the history of a tick bite. Psychiatric features were prominent, including agitation, anxiety, and confusion. He had systemic features, including aching in the elbows, a previous rash, low-grade fever, and later, autonomic dysfunction. Other than chronic ptosis of the right eyelid, the neurologic examination did not reveal any focal features (e.g., brain-stem dysfunction or lateralizing weakness), sensory changes, or abnormalities in coordination. Most important, the patient had severe hydrophobia without an anatomical cause.

There are several considerations in the formulation of the differential diagnosis. These include tetanus, diphtheria, botulism, delirium tremens, drug intoxication or reaction, and rabies.

Bacterial Toxins

Does this patient have tetanus? Patients who have tetanus present with muscle rigidity (with early involvement of the masseter and facial muscles) and can have laryngospasm, which can cause difficulty swallowing. Trismus and spasms of deglutition muscles may result in difficulty with swallowing and verbal expression. Patients with tetanus commonly have autonomic instability and a hyperadrenergic state,1 and the disease can occur after an animal bite. However, this patient had recently received a tetanus vaccine. Furthermore, the absence of the generalized muscle rigidity characteristic of tetanus and of laryngospasm or another anatomical or physical explanation for the hydrophobia makes tetanus less likely. The alteration in mental status, a prominent feature in this case, is not consistent with tetanus.

Infection with Corynebacterium diphtheriae results in a toxin-mediated illness that causes an acute demyelinating polyneuropathy. Diphtheria usually affects the oropharynx and larynx, and palatal paralysis occurs in more than 10% of cases. Bulbar dysfunction can occur early in the disease process, and weakness in the trunk and extremities later. Perioral numbness, nasal speech, nasal regurgitation, diplopia, anisocoria, ptosis, mydriasis, dysphagia, and weakness of the tongue and sternocleidomastoid muscle are common.2 Later in the disease course, patients have a generalized peripheral neuropathy, with sensory, motor, and autonomic features. Although this patient has difficulty swallowing, he does not have cranial neuropathies or evidence of other neuropathy, which makes diphtheria unlikely.

Botulism, another toxin-mediated infection, is caused by blocking the transmission of acetylcholine across cholinergic synapses of the peripheral nervous system, which results in a descending, flaccid, symmetric pattern of paralysis, with prominent bulbar palsies. Loss of ocular accommodation, blurred vision, diplopia, dysarthria, dysphonia, and facial weakness are also seen.3 The sensorium is unaffected, sensation is normal, and hyperthermia is unusual.4 In the absence of bulbar palsies or paralysis, it is unlikely that this patient has botulism.

Alcohol Withdrawal

Patients with delirium tremens present with generalized tremulousness, agitation, delirium, and visual or auditory hallucinations. Autonomic hyperactivity is the rule, with tachycardia, hypertension, hyperthermia, and sweating. Seizures can occur.5 Delirium tremens typically manifests 6 to 8 hours after the last exposure to alcohol and is most pronounced at 24 to 72 hours. Patients with chronic alcoholism have a sensorimotor polyneuropathy, with prominent distal paresthesias. This patient does not have a history of alcohol consumption or evidence of chronic alcohol exposure (e.g., neuropathy), and he did not respond to medications, such as lorazepam, that would commonly treat delirium tremens.

Drug Reactions

Occasionally, the administration of a drug such as a phenothiazine may cause an acute dystonic reaction that is characterized by involuntary, sustained muscle contractions, typically involving the cranial and cervical muscles. The head may be flexed, extended, or rotated, and the jaw, tongue, and face are commonly involved, affecting the ability to swallow. This patient has no history of exposure to phenothiazines or similarly acting drugs, and he does not have sustained focal muscle contractions.

This patient has no history of amphetamine use. Amphetamines commonly cause anxiety, hyperactivity, bruxism, tachycardia, hypertension, word-finding difficulties, and tremors and would not have resulted in this patient's progressive and fulminant course.

Rabies

Does this patient have rabies? Although a dog bite is responsible for most rabies infections in humans in the developing world, bats are responsible for most infections in humans in the United States. Transmission is usually through a bite, which is often unrecognized. Rabies can also be transmitted by aerosolized exposure, such as could occur in a cave with a very large density of bats,6 and there have also been reports of the transmission of rabies in association with organ or tissue transplantation. 7

Disease progression occurs in five stages: incubation, prodrome, acute neurologic phase, coma, and death (or, rarely, survival). There are two varieties of rabies: encephalitic (or “furious,” accounting for 80% of cases and consistent with this case) and paralytic (or “dumb,” accounting for 20% of cases).8 On the basis of the patient's history, it appears that he has a classic rabies prodrome consisting of malaise and irritability, as well as paresthesias, pain, and pruritus. We are told that he had pruritus at the nape of his neck. Although he has no known history of an animal bite, pruritus due to rabies typically occurs at the site of infection. The prodrome may last a few days to weeks. This patient also presented with signs and symptoms that commonly occur in the encephalitic phase of rabies, including hyperexcitability, agitation, and hydrophobia, which is a fear of swallowing liquids. Hydrophobia is unique to rabies, and conditioning can occur, in which the sight of liquids can trigger laryngeal, pharyngeal, or diaphragmatic spasms. I suspect that this patient also has aerophobia, or fear of air, in which the force of air on the face or airway can trigger spasms.9 In addition, hallucinations and excessive salivation may occur in this phase of infection, although these findings were not reported in this patient. Death typically occurs within 5 days after the start of the acute neurologic phase. Autonomic dysfunction is common, with hypertension, cardiac dysrhythmias, priapism, sweating, and fever. This patient has classic autonomic dysfunction, most prominent immediately after the lumbar puncture.

Since rabies is rare in the United States, one must have a strong suspicion that rabies is the diagnosis. The diagnosis can usually be confirmed by the patient's clinical history, presentation, and supporting information. Although this patient did not report an animal bite, his history of possible exposure to bats and his distinctive clinical presentation are sufficient to lead one to think of rabies. MRI can reveal increased T₂-weighted signal in the brain stem, hippocampus, basal ganglia, hypothalamus, and thalamus, or it can be normal.10 In this case, imaging studies are consistent with the diagnosis of rabies. The presence of abnormal signal enhancement is a worrisome prognostic sign, since this occurs late in the course of the disease.11 In persons infected with rabies, the CSF may reveal a mildly increased protein level but a normal glucose level; a mononuclear-predominant pleocytosis is commonly seen, typically fewer than 100 white cells per cubic millimeter.12 This patient's CSF formula falls neatly within these ranges and is consistent with rabies, but it is not diagnostic. The presence of rabies-specific neutralizing antibodies in the serum and CSF of unvaccinated patients is useful in confirming the diagnosis. Rabies virus antigen can be detected on skin-biopsy specimens,13 and reverse-transcription or real-time polymerase chain reaction (PCR) testing of saliva, tears, or skin-biopsy specimens can provide supporting evidence.14

This patient's history and clinical presentation, especially the severe hydrophobia, are consistent with a diagnosis of rabies. Furthermore, the lack of a plausible alternative diagnosis makes rabies the most likely diagnosis in this case.

Dr. Anne M. Neilan (Infectious Diseases): The patient's wife and I stood outside the patient's room. His wife handed me a sheet of paper with a message that the patient had typed 24 hours before admission that described his inability to swallow. He wrote, “While I ate breakfast and drank coffee without incident, at midday, an attempt to drink a glass of water resulted in an immediate gagging sensation, with a sensation that I couldn't breathe. I could not swallow the water. This sensation went away when I spit it out, but happened again repeatedly on subsequent attempts.” And later in the day he wrote, “Just bringing a glass of water to my lips starts the gagging sensation.” His wife recalled that 2 to 3 months before this admission, she and her husband had awakened in the night to a bat flapping around the room. On the morning of the lumbar puncture, the patient seemed worried about rabies and had written a list of all the animals he had seen in the neighborhood, although he did not report any animal bites. We initially considered atypical Guillain–Barré syndrome and infectious causes of encephalitis, including West Nile virus, arboviruses, herpes simplex virus, influenza virus, Lyme disease, and Mycoplasma pneumoniae. No cases of rabies have been described as endemic in Massachusetts for more than 80 years. Nevertheless, we were concerned about rabies and called the Massachusetts Department of Public Health (MDPH) and the Centers for Disease Control and Prevention (CDC) immediately after evaluating the patient.

Clinical Diagnosis

Human rabies.

Dr. David M. Greer's Diagnosis

Human rabies.

Pathological Discussion

Dr. Declan McGuone: The diagnostic test was a biopsy of nuchal skin. Rabies virus antigen was detected on direct fluorescence antibody testing of the biopsy specimen, and sequence analysis identified a variant found in insectivorous bats in the myotis (mouse-eared) species. Rabies virus nucleic acids were detected by heminested PCR. Rabies virus IgM and IgG antibodies were present in the patient's serum and CSF, and a small, neutralizing antibody response was detected in the serum but not in the CSF. His saliva remained PCR-positive for rabies throughout the disease course. All tests were performed by the CDC.

Discussion of Management

Dr. Gregory K. Robbins: Postexposure prophylaxis is highly efficacious, but once rabies encephalitis has begun, there is unfortunately no proven treatment and the mortality rate approaches 100%. Therefore, for most patients with symptomatic rabies, the standard of care is palliation. However, in this patient, after discussing treatment options (including palliative care) with his family, we elected to pursue a more aggressive approach. In collaboration with the CDC and investigators at the Medical College of Wisconsin, we began treatment according to the Milwaukee protocol (www.chw.org/display/PPF/DocID/33223/router.asp), a strategy developed to minimize brain injury while allowing the patient's immune response to eradicate the virus. Key features of the protocol are sedation and other supportive measures designed to suppress brain activity and minimize injury from catecholamine storm and cerebral vasospasm. In addition, it is important to avoid the administration of glucocorticoids, rabies IgG, and the rabies vaccine.

This patient was intubated and sedated with ketamine and midazolam to induce coma. He had a hectic hospital course notable for cerebral vasospasms, fluctuating blood pressure, flash pulmonary edema, diabetes insipidus, and unexplained fevers. Rabies-neutralizing antibodies were detected in the serum on hospital day 18 but not in the CSF. On hospital day 27, neutralizing antibodies were still absent in the CSF, and interferon beta was administered to stimulate the development of antibody. Three days later, the patient had fixed pupils, progressive multisystem organ failure, and a flat EEG while not under sedation. The patient's family and caregivers agreed to withdraw care, and he died on hospital day 30.

Dr. McGuone: An autopsy limited to the cranial cavity revealed a swollen, dusky-gray brain weighing 1535 g. Coronal slicing revealed a diffusely thin, dark, soft granular cortex with blurring of the white-matter interface (Figure 1AFigure 1Pathological Examination of the Brain.). The hippocampi and the amygdalae were small. The cerebral white matter and basal ganglia were soft. The periventricular medial thalamus, hypothalamus, and cerebellar dentate nuclei were dark gray (Figure 1A). The mammillary bodies were normal. The descending white-matter tracts of the basis pontis and the medulla lacked differentiation. The substantia nigra of the midbrain was pale. The cerebellum was mildly atrophic. Cranial nerves and trigeminal ganglia were grossly normal.

Neurohistologic examination confirmed viral encephalitis, with widespread microglial activation, microglial nodules, perivascular lymphocytic inflammation, and frequent Negri bodies in the brain stem, confirming the antemortem diagnosis of rabies encephalitis (Figure 1B). There was diffuse neuronal necrosis and a macrophage response throughout the cortical ribbon, hippocampus, basal ganglia, thalamus, and brain stem. Neurons of the lateral geniculate nucleus and a lateral thalamic nucleus were relatively preserved. Neuronal necrosis was particularly severe in the basis pontis, with an associated macrophage response (Figure 1C). In the cerebellum, there was prominent loss of Purkinje cells, with a striking preservation of neurons in the granule-cell layer (Figure 1D). The dentate nucleus had an occasional Negri body. This pattern of pontocerebellar damage is not easily explained by global hypoxic–ischemic injury and is much more suggestive of a direct viral cytolytic effect. The distribution of the gray-matter necrosis (i.e., in the medial thalamus, hypothalamus, and periaqueductal region) also suggests a superimposed nutritional deficiency. There was mild chronic trigeminal ganglionitis with dropout of occasional ganglion cells. No Negri bodies in the trigeminal ganglia were identified. One branch of the trigeminal nerve showed marked wallerian degeneration.

Discussion of Epidemiology

Ms. Virginia Lijewski (Massachusetts Department of Public Health): In 2011 in Massachusetts, 110 animals with rabies were identified. Bats accounted for 20 (18%) of the animals that tested positive. Most of the bats with rabies were identified in the summer and early fall, which was when this patient was probably exposed.

The MDPH received more than 1000 calls about potential rabies exposures in 2011. Exposures are assessed individually, and management recommendations are made on the basis of current guidelines published by the Advisory Committee on Immunization Practices (ACIP).15 In this patient, exposure information was obtained from the family after diagnosis. It was reported that several weeks before the onset of symptoms, the patient had awoken to a bat flying around his face during the night and that he had direct contact with the bat. The reported exposure scenario meets the ACIP criteria for the recommendation of the administration of postexposure prophylaxis.

The patient was seen at two health care facilities, and 122 health care workers involved in his care were assessed. Any person with exposure to the patient's saliva, CSF, or brain tissue, through the mucous membranes or through open wounds, within 10 days before the onset of symptoms is considered a candidate for postexposure prophylaxis. Nine health care workers were considered to have had sufficient exposure to warrant postexposure prophylaxis. Twenty-one of the patient's close contacts were questioned about potential exposure (e.g., through kissing or sharing food, drinks, or cigarettes), and five received postexposure prophylaxis.

A Physician: If well patients report seeing a bat flying around the house, what should they do?

Ms. Lijewski: We recommend postexposure prophylaxis only in situations in which contact with a bat cannot be ruled out, such as when a person awakens to find a bat in the room they are sleeping in. That is what happened in this case.

Dr. Eric S. Rosenberg (Pathology): If we encounter a patient with symptomatic rabies, should we implement the Milwaukee protocol?

Dr. Robbins: There have been several reports of patients who survived rabies,16 although none had detectable rabies antigen or virus. Of these, the most tantalizing case was a 15-year-old teenager from Wisconsin who survived after she was treated according to the Milwaukee protocol.17,18 Subsequent reports of the use of this strategy have not shown similar success,19 and there is no good evidence to support the use of the protocol, although there are no other reasonable alternatives outside of palliative care. This protocol should be considered only for persons early in the course of symptomatic disease who are otherwise in good health. It is critically important that patients and family members understand that this approach is unlikely to be successful and that there is a high risk of neurologic sequelae if the patient survives.

Anatomical Diagnosis

Rabies encephalitis.

This case was presented at Medical Grand Rounds.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

This article was updated on January 17, 2013, at NEJM.org.

We thank Dr. E. Tessa Hedley-Whyte for review of an earlier version of the manuscript; Drs. Ann Neilan, James Kimo Takayesu, Stephen Neil Gomperts, Nicholas A. Morris, and Eyal Kimchi and Ms. Rebecca Santos for their assistance with the case history; Dr. Catherine Brown of the MDPH; Dr. Rodney E. Willoughby of the Medical College of Wisconsin for assistance with implementation of the Milwaukee protocol; and Dr. Charles E. Rupprecht of the CDC. All rabies diagnostic testing was performed at the CDC.

Source Information

From the Department of Neurology, Yale University School of Medicine, New Haven, CT (D.M.G.); and the Departments of Medicine (G.K.R.), Radiology (R.G.G.), and Pathology (D.M.), Massachusetts General Hospital; the Departments of Medicine (G.K.R.), Radiology (R.G.G.), and Pathology (D.M.), Harvard Medical School; and the Division of Epidemiology and Immunization, Massachusetts Department of Public Health (V.L.) — all in Boston.

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Citing Articles (2)

Citing Articles

1. 1

   Alan C. Jackson. (2013) Current and future approaches to the therapy of human rabies. Antiviral Research 99:1, 61-67
   

2. 2

   Alan C. Jackson. Therapy of Human Rabies. In: Rabies. Elsevier, 2013:575-589.