Meningoencephalitis in a Child Complicated by Myocarditis, Quadriparesis and Respiratory Failure

An 8-year-old Hispanic male resident of Maryland developed fever to 38°C, diffuse abdominal pain and dizziness in August 2005. He was previously healthy, born and raised in the United States, but had traveled to Mexico a few years prior. He was treated for sinusitis by his physician, but was hospitalized 5 days later because of persistent fever, neck stiffness, nausea, vomiting and generalized weakness. On admission, vital signs showed a temperature of 38.5°C, heart rate of 126 beats/min, respiratory rate of 28 breaths/min, blood pressure of 102/45 mm Hg and oxygen saturation >95% in room air. Physical examination was notable for stiff neck, diffuse abdominal tenderness and a focal petechial rash over his left anterior chest. Neurologic examination was normal. A complete blood count revealed a white blood cell count of 4.2/μL (87% neutrophils, 2% band forms, 9% lymphocytes and 2% monocytes), hemoglobin concentration of 11 g/dL and platelet count of 161,000/μL. Cerebrospinal fluid (CSF) analysis showed 530 leukocytes/μL (88% granulocytes, 12% lymphocytes), red blood cells 20, with glucose 61 mg/dL and protein 148 mg/dL. A Gram-stained smear of the CSF and bacterial cultures of the CSF and blood revealed negative results. Aspartate aminotransferase was 218 units/L (normal, <26), and alanine aminotransferase was 109 units/L (normal, <44). Serum electrolyte concentrations, urinalysis, urine toxicology screen and urine culture were normal. The patient was empirically treated with vancomycin and ceftriaxone for suspected bacterial meningitis. On the second hospital day, the child's temperature increased to 39°C, and he continued to have abdominal pain and persistent nonbilious, nonbloody emesis. Neurologic examination remained normal, and mental status was appropriate. A chest radiograph and computed tomography of the brain were normal. Contrast-enhanced abdominal computed tomography examination revealed a mildly fatty liver with no focal lesions and a moderate quantity of retained stool. Early the next morning, the patient's cardiorespiratory monitor alarm was activated, and he was found to be unresponsive with agonal breathing and weak gag and cough reflexes. He was hypothermic (34.5°C), heart rate was 145 beats/min and oxygen saturation was not detectable by pulse oximetry. The patient was intubated. Cardiology evaluation that morning demonstrated decreased electrocardiographic voltages throughout all leads and a prolonged QTc interval. Echocardiography showed a reduced shortening fraction of 23% (normal, 28–44%) and an ejection fraction of 40% (normal, 55–70%), consistent with myocarditis. Later in the afternoon, neurologic examination was remarkable for a comatose state and complete flaccid, areflexic quadriparesis. An electroencephalogram revealed diffuse slowing, consistent with meningoencephalitis. A repeat complete blood count showed a white blood cell count of 14,280/μL (44% neutrophils, 2% band forms, 35% lymphocytes, 11% monocytes, 1% basophils and 7% reactive lymphocytes), hemoglobin 10.5 g/dL and platelet count 210,000/μL. Aspartate aminotransferase and alanine aminotransferase were improved slightly to 117 and 76 units/L, respectively. Sodium had decreased to 126 mmol/L, and chloride was 93 mmol/L as a result of inappropriate antidiuretic hormone production and cerebral salt wasting. The other electrolytes were normal. Polymerase chain reaction tests on the CSF obtained from a repeat lumbar puncture on hospital day 4 for herpes simplex virus and enteroviruses yielded negative results. T2 magnetic resonance imaging on hospital day 6, obtained because of concern for cerebral damage resulting from hypoperfusion, demonstrated mild leptomeningeal enhancement and enhancing ventral nerve roots from thoracic level spine through the cauda equina. Antimicrobial therapy was empirically broadened on hospital day 4 when the patient developed respiratory failure and demonstrated an evolving flaccid paralysis. Acyclovir (for herpes simplex virus), doxycycline (for Rocky Mountain spotted fever), rifampin, isoniazid, pyrazinamide (for tuberculosis) and fluconazole (for cryptococcal meningitis) were added. Intravenous immunoglobulin (2 g/kg; Polygam SD; Baxter, Westlake Valley, CA) was administered on the fifth hospital day, after no neurologic improvement was noted because of concern for atypical Guillain-Barré syndrome. Increased alertness was observed over the next several days, during which time ptosis was noted that improved slightly over his hospital course. On the sixth hospital day, nerve conduction studies and an electromyogram suggested an early peripheral demyelinating polyneuropathy. By the eighth hospital day, the patient was able to open his eyes slightly to pain and had minimal ability to visually track from side to side. On hospital day 9, follow-up electrocardiogram revealed low, but improved, voltages and echocardiography showed improvement of the shortening fraction to 29% and ejection fraction to 52%. For denouement, see p. 855. Denouement Continued from p. 853 Serum polymerase chain reaction obtained before treatment with intravenous immunoglobulin (IVIG) for West Nile virus (WNV) RNA (Roche Molecular Systems, Pleasanton, CA), including WNV IgM and IgG, as well as WNV IgM of the CSF were all positive. Serum IgG for St. Louis encephalitis virus, known to demonstrate extensive cross-reactivity with other viruses in the Flaviviridae family, was also positive; however, serum and CSF IgM as well as CSF IgG for St. Louis encephalitis virus were negative. Additional IVIG containing high anti-West Nile virus antibody titers (Omr-IgG-am; Omrix Biopharmaceutical, Tel Hashomer, Israel) was obtained from the National Institute of Allergy and Infectious Diseases for compassionate use and administered in 4 doses of 0.5 g/kg on his 9th–12th hospital day. Antibody titers against WNV in the Omr-IgG-am preparation were 1/150 by plaque neutralization assay. At 2 months postadmission, the patient remained ventilator-dependent with minimal additional improvement: bilateral movement of his toes; wrist extension; and plantar flexion. Four months postadmission, he could breathe independently and could speak around his tracheostomy, but he had severe oropharyngeal dysphagia necessitating continued gastric tube feedings. He had muscle wasting in his weak extremities but was able to hold objects in his hands; he was unable to lift his arms at his shoulders. His lower extremity movement was still limited to bilateral toe wiggling. Public health representatives identified old tires with standing water in the child's yard that may have contributed to the risk of mosquito exposure. WNV, a predominantly mosquito-transmitted infection, was first isolated in 1937 and detected in the Western Hemisphere in 1999. Most WNV infections are asymptomatic; however, 20% of individuals will have symptomatic disease, mostly uncomplicated viral syndromes, and <1% will have severe neuroinvasive disease.1 Symptomatic disease is reported most commonly in older patients. Children younger than 10 years of age comprised only 1% of the 4,146 cases with clinical and demographic information reported to the Centers for Disease Control (CDC) between 2000 and 2002.2 WNV infections among hospitalized patients manifests most commonly as neuroinvasive disease. Encephalitis occurs in 58–63%, and 16–29% are diagnosed with meningitis.3,4 The number of WNV meningitis cases (40) among United States children younger than 18 years of age reported to the CDC in 2002 exceeded the number of WNV encephalitis cases (29); however, 36 cases were categorized as “unspecified neuroinvasive disease.”2 Focal paralysis or weakness may accompany either encephalitis or meningitis or may present as an isolated finding, as was seen in 2.7% of 219 cases during an outbreak in the United States described by Sejvar et al.5 Chowers et al3 found age ≥70 years old to be an independent risk factor for severe WNV disease; therefore, it is not surprising that patients younger than 10 years of age comprised <2% of 233 patients hospitalized for WNV disease. Acute flaccid paralysis (AFP) involving all 4 extremities (quadriparesis), such as that manifested by our patient, is among the most severe sequelae of WNV disease. Of the 219 cases of neuroinvasive disease identified during a 2003 WNV epidemic in Colorado, only 32 (14%) experienced acute flaccid paralysis.5 Among these, poliomyelitis-like syndrome (84%) occurred much more commonly than Guillain-Barré-like syndrome (13%). Our patient's nerve conduction studies were suggestive of early peripheral demyelinating polyneuropathy typically found with the Guillain-Barré-like syndrome, which is the less common presentation of AFP. Follow-up electromyographic and nerve conduction studies demonstrated typical findings of motor neuron injury, indicating that our patient actually had the poliomyelitis-like syndrome rather than the Guillain-Barré-like syndrome. For patients with documented poliomyelitis-like syndrome, there is 1 report of 11 patients in which the majority of motor recovery occurred by 6 months in most patients. Recovery is variable from minimal to full recovery and is not based upon the initial degree of paralysis.6 Our case has several unique features. First, our patient represents the youngest reported case of WNV-associated acute flaccid paralysis. In a review of 32 patients with AFP by Saad et al,7 a single case occurred in a patient in the 15- to 19-year age category, and no cases occurred in younger children. Since this review, an additional 8 cases of WNV-associated AFP have been reported in the literature, and the youngest among these was 33 years old.8–10 We identified a case report of a 4-year-old child with “motor aphasia” who became “completely bedridden,”11; but the neurologic basis of his paralysis is unclear from the case description. The child was not ventilator-dependent and had recovered to the point of hospital discharge 1 month after admission. Secondly, our patient had cardiac findings consistent with myocarditis, which is not usually associated with WNV. During a 1999 WNV epidemic in Russia, “hydropericarditis with flabbiness of the cardiac muscle” was described among 40 fatal cases. However, the number of patients with these cardiac findings and their ages were not specified.12 Thirdly, our patient had evidence of mild hepatitis, also not commonly described with WNV. We were able to identify only one other case of WNV-associated hepatitis in the literature, a pediatric patient with fulminant hepatitis.13 Agrawal and Petersen14 reviewed several animal studies of WNV infection that demonstrated increased survival with use of anti-WNV immunoglobulin. This treatment was less efficacious if administration was delayed until after viral entry into the brain, but survival among treated animals remained better than among untreated controls. An experiment with golden hamsters infected with WNV showed 100% survival among younger hamsters (4–5 weeks old) given Israeli IVIG (known to have high anti-WNV antibody titers), whereas older hamsters (older than 8 weeks of age) all died despite this treatment. This child with ventilator dependence, quadriparesis, myocarditis and hepatitis represents the most severe manifestation of West Nile virus infection in a surviving child reported in the English medical literature. This case illustrates that children can suffer the same devastating, long-term paralytic manifestations as adults. Additionally the rapid deterioration of this initially hemodynamically stable child with meningitis into one with meningoencephalitis, respiratory and cardiac failure within 48 hours of admission emphasizes the need for close monitoring of any child admitted with suspicion for West Nile disease. Systematic clinical trials of IVIG therapy for children with WNV infection are needed.