This 10-day-old infant was transferred for evaluation of seizures. He was the 7pound product of a 38-week gestation to a 37-year-old gravida 4 para 4 woman. His mother had normal prenatal laboratory testing and tested negative for group B streptococcus (GBS). The pregnancy was uncomplicated, except for a maternal cough and sore throat 10 days prior to delivery, which was treated with azithromycin. There was no history of maternal fever. Membranes were ruptured at delivery. The baby stayed for one day in the hospital without problems.
On the 10th day of life, he was noted to have "rhythmic jerking" movements of both the upper and lower extremities lasting for 2 minutes. His mother stated that his eyes were rolling back. He had a similar episode 2 hours later while he was being evaluated in the emergency department at an outside hospital. There was no history of fever, vomiting, diarrhea, or irritability. He had been eating well and acting normally until these episodes. An AccuCheck was 40 mg/dL, and computerized tomography of the head was normal prior to transfer.
The family history was remarkable in that the father has dermatomyositis. The baby has three healthy siblings and a maternal great-uncle who has seizures.
On examination, he was an irritable boy who was not easily consoled. His temperature was 36.9°C rectally, pulse 154, blood pressure 76/46, respiratory rate 40. Pulse oximetry was 100% on room air. The anterior fontanel was open and soft. There was bilateral periorbital edema. There were no dysmorphic features. The palate was intact. S1 and S2 were normal. There was a II/VI midsystolic murmur heard best at the left upper sternal border. Femoral and brachial pulses were normal. There were bilateral subcostal retractions with intermittent grunting. He had good breath sounds bilaterally. The abdomen was soft but mildly distended. The liver edge was palpable 5 cm below the right costal margin. The spleen tip was palpable. He had normal male genitalia. Both testes were descended. The anus was patent. The back was straight without dimples. On neurologic examination, he was described as having slightly increased tone in all his extremities. There were large ecchymoses over both antecubital fossae with bruising over the chest; there was active bleeding from the right heel from phlebotomy sites.
Robert Listemick, MD, moderator: It sounds as if he's sick and having seizures. What should we be thinking?
Mark Wainwright, MD, PhD, pediatrie neurologist: Infantile seizures may be extremely subtle and difficult to recognize. Specific manifestations may include a sudden arrest of ongoing behavior, automatisms such as lip-smacking or "bicycling" movements of the lower extremities, or even mild cyanosis and tachycardia. Tonic or clonic seizures are unusual in a neonate.
The differential diagnosis includes infections (bacterial meningitis, viral encephalitis), metabolic disease such as hypoglycemia, hypocalcemia, or inborn errors of metabolism, structural disorders of the brain (cerebral dysgenesis), and hypoxic-ischemic insults. Timing of the onset of the seizures may be helpful in distinguishing among these etiologies. Infants do not start seizing at 10 days of age from a perinatal hypoxic-ischemic insult; those seizures almost always occur immediately after birth or within the first 24 hours after birth. Obviously in this child, the enlarged liver and the presumed coagulopathy place a disseminated infection highest on the list.
Dr. Listemick: Could he have a primary liver disease to account for those findings?
Peter Whitington, MD, pediatric hepatologist: After seeing the child and reviewing the laboratory data, I felt that he had acute liver failure and an overwhelming viral infection. So it would certainly be conceivable that this was primarily a liver disease. The etiology of acute liver failure in the newborn includes metabolic disease, viral infections, and neonatal hemochromatosis.
Dr. Listemick: Before we talk about liver failure, how should we treat his seizures?
Dr. Wainwright: The standard treatment of seizures in a neonate would be phenobarbitol, attempting to maintain a therapeutic level around 20 mg/dL. Given that we suspect liver failure, I would discuss the use of phenobarbitol with the hepatologist first because we would probably have to follow the level closely and alter the maintenance dose if the drug wasn't being properly metabolized by the liver.
Stanford T. Shulman, MD, pediatrie infectious disease specialist: Just so we don't lose sight of the patient, this baby appears to have both fulminant liver failure and encephalitis. Right off the bat, we should be thinking about a disseminated viral infection, either herpes simplex virus (HSV) or enterovirus. We need to see the initial laboratory evaluation to confirm this, but I certainly would want to start antiviral therapy as soon as possible.
Dr. Listemick: Is there an effective therapy for enterovirus?
Dr. Shulman: Pleconaril, which does have anti-enteroviral activity, is not on the market. Certainly, we would start acyclovir to treat possible HSV.
Dr. Listemick: Here is the initial laboratory evaluation: hemoglobin 9.8 g/dL, white blood count 9,000/ mm3 with 61% lymphocytes, 2% monocytes, 32% neutrophils, 5% immature neutrophils; platelet count 105,000/mm3; prothrombin time 44 seconds, partial thromboplastin time greater than 150 seconds, fibrinogen 64 mg/dL (decreased), d-dimers 3.15 (elevated); SGPT 717 IU/L, SCOT 7143 IU/L, total bilirubin 5.1 mg/dL, direct bilirubin 3.6 mg/dL, GTT 243 IU/L, ammonia 149 µmol/ L. The serum electrolytes were unremarkable save for a mild acidosis, BUN 37 mg/dL, creatinine 1.5.
What's your gestalt now?
Dr. Whitington: Of all the patients with acute liver failure whom I've cared for, this baby was the first who had a seizure while I was examining him. Encephalopathy from acute liver failure generally correlates with an extremely high bilirubin in the range of 30 mg/dL. In addition, this child's ammonia was only mildly elevated. Although this child's seizures conceivably could have the result of an intracranial hemorrhage secondary to the coagulopathy, I believed that a primary CNS and liver infection was much more likely. The correct diagnosis was found pretty quickly.
Dr. Listerai ck: However, for the sake of discussion, can we broaden the differential diagnosis to the metabolic causes of acute liver failure in the newborn?
Dr. Whitmgton: Neonatal hemochromatosis is the most frequently recognized cause of neonatal liver failure and is characterized by an abnormal distribution of iron in the liver and extrahepatic tissues. Although this is similar to adult-type hemochromatosis, the pathophysiology is entirely different. It is an alloimmune disease caused by an autoantibody directed against a hepatocyte surface protein. This leads to marked structural damage with fibrosis and cirrhosis. Over 90% of these infants have oligohydramnios and intrauterine growth retardation and are extremely sick at birth.
The other metabolic diseases to consider include tyrosinemia, galactosemia, and hereditary fructose intolerance. This infant was breastfed and was not exposed to fructose, eliminating hereditary fructose intolerance as a possibility. Although they may present with liver failure, disorders of fatty acid oxidation don't generally present in the neonatal period. Finally, rarely infants with mitochondrial cytopathies such as cytochrome c oxidase deficiency may have neonatal liver failure. However, infection was 1 through 10 on my list.
Dr. Listernick: So let's go back to infections. What about disseminated enteroviral disease?
Dr. Shulman: Enteroviral disease peaks in May and June and lasts through the summer until the first frost. Disseminated neonatal enteroviral infections generally present around days 2 to 4 of life. The mother often has a history of fever and lower abdominal pain a week prior to delivery, often interpreted as "false labor." The echoviruses and group B Coxsackie viruses are the usual culprits. The severity of neonatal disease is related to the level of passively transferred maternal antibody. If the maternal infection occurs several weeks prior to delivery, more antibody crosses the placenta, potentially quelling the neonatal disease. These infants may develop severe hepatitis, encephalitis, myocarditis, and pneumonia.
Dr. Listerai ck: How did the neonatologists approach this baby?
Kama Murthy, MD, neonatologist: We certainly discussed all these possibilities. We would have wanted the information that a lumbar puncture would have provided, but we were never able to control the coagulopathy sufficiently so as to provide an adequate safety margin. He was started on intravenous antibiotics and acyclovir. Twelve hours after admission upon reexamination several vesicles were noticed. We obtained a viral culture and a direct fluorescent antibody (DFA) test on material obtained from the base of an unroofed vesicle; both were ultimately positive for herpes simplex virus type 1 (HSV-I).
Dr. Listeraick: In general, how can we confirm the diagnosis of HSV infection?
Dr. Shulman: Usually babies who have overwhelming systemic disease will develop vesicles at some time during the course. A DFA test will confirm the diagnosis. In babies who just have encephalitis, a polymerase chain reaction (PCR) test performed for HSV DNA on cerebrospinal fluid will be diagnostic; it has a sensitivity and specificity of approximately 90% each. This test is more sensitive and specific outside of the neonatal period; blood in the cerebrospinal fluid may interfere with the assay. PCR testing of other body fluids such as blood is less well standardized.
Dr. Listernick: What about a baby with acute systemic disease who has no cutaneous manifestations?
Dr. Shulman: You have to have a high index of suspicion for HSV. An IgM anti-HSV test has been utilized with the caveat that the patient may not have had an opportunity to develop antibody; in other words, there are a significant number of false negative tests in this situation.
Dr. Listernick: At what postnatal age are infants not at risk for the development of disseminated HSV disease?
Dr. Shulman: Once an infant is past 12 to 14 days old, disseminated disease is extremely rare. Those older neonates either get isolated CNS disease (encephalitis) or develop the "skin-eye-mucous membrane" triad of disease.
Dr. Listernick: Is it surprising that this child is infected with HSV-I rather than HSV-2?
William Grobman, MD, perinatologist: Not really, because HSV-I is thought to cause 20% to 30% of new genital infections. The risk of transmission of HSV-I or HSV-2 to the neonates is exponentially greater if it's a primary infection in a seronegative mother; the neonatal infection rate in this scenario may be as high as 50% if the baby is delivered vaginally.
Dr. Lis ter nick: Could this baby have been infected from an oral lesion or asymptomatic oral shedding?
Dr. Shulman: Absolutely. There have even been case reports of neonatal HSV infection in Jewish male babies who have undergone ritual circumcision during which a mohel with an asymptomatic oral HSV infection sucked a bit of blood from the circumcision site to stop the bleeding. This is a ritual called "metzitzah b'peh" practiced by a particular sect of Orthodox Jews.
Dr. Grobman: Even though the risk of neonatal infection is exceedingly low in babies born of mothers who have recurrent HSV infections, perinatal disease with both HSV-I and HSV-2 has been described in such settings. Moreover, the risk is higher with HSV-I. Interestingly, the majority of women who have a genital infection are not aware of their first episode, so a history of genital lesions is a poor predictor of disease. Many women who have recurrent genital HSV infections aren't even aware of the problem because the symptoms may be extremely mild.
Dr. Listerai ck: How do perinatologists approach women who have a history of HSV infections?
Dr. Grobman: The good news is those babies are at extremely low risk. Although it's never been shown to reduce perinatal transmission, we generally place such women on acyclovir prophylaxis during the third trimester. Women who arrive in labor with active genital lesions are offered Cesarean section It has been shown that women who receive acyclovir prophylaxis have a lower risk of having a Cesarean sectioa Although anecdotal data suggest otherwise, there has never been a randomized controlled trial to demonstrate that this reduces the risk of neonatal HSV infectioa Cost analyses have shown that this is not a cost-effective strategy.
Dr. Listerai ck: Let's talk about prognosis briefly.
Dr. Shulman: The prognosis of an infant who presents with this degree of liver involvement, coagulopathy, and encephalopathy is extremely grim. However, there have been a few infants treated successfully with liver transplantation.
Dr. Listeraick: Aside from giving acyclovir, how do we keep this infant alive?
Dr. Whitington: From a hepatologist's perspective, his greatest issue is the coagulopathy, which is impossible to treat given the massive amounts of fresh frozen plasma that he would need. Options that might be considered would be to give the plasma and treat the volume overload with either hemofiltration or dialysis. Alternately, one might try exchange transfusions. These measures are extreme and have little hope of success. My opinion was to treat the baby with acyclovir, support him as best as possible, and hope that this will successfully combat the infection.
Dr. Murthy: We felt that heroic measures, such as renal replacement therapy, at this stage of the illness would be futile and, at best, experimental. Neonatal dialysis is fraught with both mechanical and infectious complications and has a nearly uniform dismal outcome. In addition, there's no evidence that exchange transfusion in an infant with both disseminated and CNS disease would be helpful. We administered acyclovir and counseled the parents accordingly. The baby remained in the hospital for 4 days during which the seizures were adequately controlled with phenobarbitol but the severe coagulopathy persisted. He developed renal failure presumably from HSV involvement of the kidney. Ultimately, he died on the fifth day of hospitalization.
Dr. Listeraick: That's a tragedy. I have one final question. Should all febrile neonates be started on acyclovir until the HSV status is determined?
Dr. Shulman: That's an extremely difficult question. There are no good prospective data to adequately answer the question as to whether early use of acyclovir will change morbidity or mortality in that situation. It certainly isn't the standard of care in 2006. However, I would certainly recommend its use in any "sick" neonate or any neonate who has suspected encephalitis.
Dr. Murthy: A recent Canadian study of more than 18,000 infants in a 3-year period identified 56 infants with either disseminated or CNS HSV disease. Interestingly, twothirds of the babies were relatively well during the first 24 hours of illness, suggesting that there might be a role for the early institution of acyclovir. But I certainly agree with Dr. Shulman that there are no data that the acyclovir would necessarily have a positive effect.
Dr. Listeraick: Thank you, everybody.