Volume 7, Case 9
Kevin H. Higashigawa, Medical Student
Loren G. Yamamoto, MD, MPH
Kapiolani Medical Center For Women And Children
University of Hawaii John A. Burns School of Medicine
An 8-month-old female is brought into the emergency department by her mother. The infant was in her usual state of good health until three days ago, when her mother noted that she felt warm. She was less active, but eating well and had no vomiting, diarrhea, or other complaints. The following day (2 days ago), she refused to eat. She continued to have fevers and remained less active than normal. That evening she was taken to the ED and was found to have a temperature of 39.5 degrees C. She was described by her mother as being less active, not eating well, and having a decreased urine output. CBC showed a white count of 12.1 (32 segs, 2 bands, 53 lymphs, 9 monos), hemoglobin 11.1, and hematocrit 32.8. A blood culture was obtained. A chest radiograph was felt to be normal. The infant was given antipyretics and discharged home.
The next day (yesterday), she continued to have fevers. Her temperature was 38.5 degrees C. She was less active and was not eating or drinking. She had not voided according to her mother. There was no vomiting, diarrhea, or respiratory symptoms. Her mother also noted on this morning that she had some skin lesions which resembled insect bites. They were red and raised. She was taken to see her primary care physician, who evaluated her and discharged her.
She is brought to the ED today because of increasing lethargy, very poor oral intake, no urine output for 24 hours and continued fever.
Past Medical History: She was born via normal spontaneous vaginal delivery. Prenatal and postnatal courses were uncomplicated. She is usually on formula but has taken some solid foods. Her immunizations are up to date. She had one prior hospitalization at 4 weeks of age for fever during which time a sepsis workup was negative. Her family history is unremarkable.
Exam: VS T 39 degrees C, P 160, R 35, BP 95/46. She is very lethargic. She is not cooing, smiling, or vocalizing. She has a weak cry and is tachypneic. She does not respond to painful stimuli. She assumes a position of comfort, in which her lower and upper extremities are flexed and her head is turned to the right. Attempts to place her head midline result in a weak cry. There is slight nuchal rigidity. She is pale with mottling of her lower extremities. There are multiple skin lesions across her face and a few on her arm. They are irregularly crusted (questionably pustular) centrally, surrounded by some erythema. She appears to have a facial droop on the right. Her anterior fontanelle is small but sunken. Her mucus membranes are sticky and she does not produce any tears when she cries. She does open her eyes, but will not follow objects and has a dysconjugate gaze. Breath sounds are bilaterally coarse. She has some upper airway rhonchi. She has no wheezes, crackles, or rales. Heart regular without murmurs. Abdomen flat and soft. Radial pulses are 2-3+ bilaterally and equal. Her hands and feet are cool.
An IV is started and IV fluid is infused. She is also given an IV dose of ceftriaxone. She begins to have extensor posturing with arching of her back. She keeps her head to the right. She also develops tonic-clonic movements of her left upper extremity, and is therefore given a IV lorazepam followed by phenytoin.
What work-up would you recommend?
Because of the infant's fever, nuchal rigidity, lethargy, and focal neurologic abnormalities, a diagnosis of meningitis and/or encephalitis is suspected. A lumbar puncture is performed which shows fluid that is questionably hazy (minimally). She is given IV acyclovir and vancomycin (ceftriaxone was given earlier). The laboratory analysis of the CSF shows 105 RBCs and 40 WBCs per cubic mm with 10% segs, 80% lymphs, and 10% monos, glucose 75, protein 59. The Gram stain shows no organisms.
These clinical and laboratory findings are most consistent with which of the following possibilities:
The CSF analysis is consistent with aseptic meningitis, but since this is usually a benign clinical entity, this child who is very sick, is not likely to have just aseptic meningitis. Bacterial meningitis is not likely (practically not possible) given this CSF analysis. Tuberculous meningitis is possible, but the clinical course is too acute for this. Viral encephalitis is the most likely since the CSF analysis suggests a viral picture and the patient's poor neurological status is consistent with an acute encephalitis. Additionally, the skin lesions on the patient's face may be herpes simplex lesions. Brain abscess is another possibility which needs to be ruled out by imaging. Cerebrovascular accident cannot be ruled out, but it is less likely. Shaken infant syndrome is usually associated with CSF which is grossly bloody. Brain imaging studies will help to obtain a more definitive diagnosis. A CT and a MRI are performed.
View her CT scan.
The CT scan without contrast demonstrates (upper two images) some hypodensity in the thalami and temporal lobes, indicative of bilateral cortical and subcortical edema. After the administration of IV contrast (lower two images), there is meningeal enhancement at the margins of the abnormal parenchyma, as well as mild central enhancement. This is consistent with a breach in the blood-brain barrier following vasculitis. There is no evidence of herniation.
View her MRI scan.
The areas of increased signal intensity in the MRI scan indicate the presence of abnormal water, consistent with the CT scan findings of cortico-medullary edema in the bilateral temporoparietal lobes. There is also meningeal enhancement over the affected areas of the brain.
The above findings are compatible with bilateral temporoparietal lobe meningoencephalitis.
What additional tests would you request?
The CSF sample is positive for herpes simplex virus (HSV) DNA by polymerase chain reaction (PCR) although the viral culture of the CSF is negative. Her EEG is abnormal. It is diffusely slow for her age. These results are compatible with a diffuse encephalopathic process. In addition, there are some sharp waves emanating from the right frontotemporal and right frontal central regions, consistent with seizure foci in the affected areas shown on her brain CT and MRI.
What is the classic presentation for an infant with HSV encephalitis? What is the relationship between HSV encephalitis and the presence of mucocutaneous skin lesions? What is the prognosis for HSV encephalitis?
Discussion
Encephalitis is an infection of the parenchyma of the brain (in contrast to meningitis, an infection of the meninges). The most common cause of viral meningitis is enterovirus infection, whereas one of the more common causes of viral encephalitis is HSV. The major manifestations of viral meningitis include fever, headache, irritability, mild lethargy or drowsiness, and some degree of nuchal rigidity. On the other hand, encephalitis often presents with significant neurologic signs and symptoms in addition to an acute febrile illness. In the usual case of viral meningitis, the disease is relatively benign and self-limiting. Encephalitis, however, is a disease which can be associated with significant morbidity and mortality (1). It is not unusual for encephalitis and meningitis to coexist in the same patient as meningoencephalitis.
Encephalitis must also be distinguished from cerebritis. Cerebritis is a highly destructive inflammatory condition of the brain, which may be bacterial in origin, often leading to abscess formation. Encephalitis is most commonly viral in nature and the extent of parenchymal damage is variable.
Arboviruses are the most common cause of episodic viral encephalitis. Two of the most common forms of arboviral encephalitis are: 1) St. Louis encephalitis, which is mainly found in urban areas around the Mississippi River, and 2) California encephalitis, which is principally found in rural areas of the northern Midwest and East. Eastern equine encephalitis is one of the most severe causes of arboviral encephalitis, but it is uncommon (mostly in the New England area). Western equine encephalitis is most prevalent in the rural areas west of the Mississippi (2). The arboviruses tend to have a seasonal preference for the summer and early fall months because they are largely transmitted via arthropod vectors.
HSV is the most common cause of sporadic viral encephalitis in the United States, accounting for approximately 10 to 20 percent of all cases. It is estimated that about 2 persons per million per year will suffer from HSV encephalitis. HSV-1 is acquired more frequently and earlier in life than HSV-2. By the fifth decade of life, more than 90 percent of adults will be HSV-1 seropositive. It has been also estimated that about 22 percent of the adults in the United States are HSV-2 seropositive. HSV-1 accounts for more than 95 percent of all cases of HSV encephalitis (3). Unlike other sources of viral encephalitis, HSV encephalitis has no seasonal pattern. HSV encephalitis is most prevalent in the neonatal, 5 to 30, and over 50 age groups.
Neonates (infants less than 6 weeks old) have the highest incidence of HSV visceral and/or CNS infection among all age groups. Untreated, neonatal herpes infection disseminates or invades the CNS in greater than 70 percent of cases. In contrast to childhood/adult HSV encephalitis, 70 percent of neonatal HSV infection is caused by HSV-2, acquired from contact with infected genital secretions at time of birth (3). The incidence is about 1:3500-5000 deliveries, with signs and symptoms manifesting 4-11 days after delivery (4). The herpes virus can also be acquired postnatally from contact with immediate family members who may be shedding virus from a symptomatic or asymptomatic oral-labial infection.
Varicella-zoster virus causes a deadly encephalitis in immunocompromised patients and has an incidence of 1:2000 infected persons. Toxoplasma encephalopathy is prevalent among HIV+ patients. Measles is responsible for two types of encephalitis, post-infectious, with an incidence of 1:1000 infected persons, and subacute sclerosing panencephalitis, with an incidence of 1:100,000 infected persons. Rabies accounts for 0-3 cases of encephalitis yearly in the US. The most common form of encephalitis outside the US is Japanese encephalitis, which affects persons in Japan, SE Asia, China, and India (2).
Arboviruses require a mosquito or tick vector (hence the name "arthropod borne" virus). In general, the virus replicates outside the CNS and gains entry by hematogenous spread.
The herpes simplex virus (HSV) is a double-stranded DNA virus which can infect mucocutaneous surfaces, the central nervous system, and, less commonly, visceral organs. The virus may remain latent in neuronal ganglia and may subsequently be reactivated, resulting in viral replication. HSV is usually transmitted via contact with active ulcerative lesions. However, individuals with subclinical disease may also shed infectious virus. Subclinical transmission of HSV may partially account for the continued rise in worldwide seroprevalence.
HSV gains entry at mucosal surfaces or abraded skin and replicates within the epidermis and dermis. Often, the primary infection is subclinical. However, sufficient numbers of virus may still be present to infect peripheral sensory or autonomic nerve endings. Once inside the neuron, the virus travels intraaxonally to the nerve cell bodies in ganglia, where replication occurs. The virus can also migrate to other tissues either proximally, by contiguous spread, or distally through a neuronal network. After the primary infection has resolved, the herpes simplex virus can no longer be found in the ganglia. However, about 10 to 50 percent of ganglion cells in the area of the initial infection may harbor viral DNA. Approximately 1 percent of these cells possess latency-associated transcripts of RNA. The molecular mechanisms of latency and reactivation are not well understood. Factors linked to reactivation include: ultraviolet light, immunosuppression, and trauma to the skin or ganglia. The maintenance of latency, the frequency of reactivation, and the severity of illness ultimately depend upon the host immune response (3).
The exact pathogenesis of HSV encephalitis is not well known. One hypothesis is that the virus gains entry into the CNS directly from a peripheral route via either the trigeminal or olfactory nerve. HSV encephalitis is the result of a primary infection in about 1/3 of cases (4). In children and in adults, HSV encephalitis is generally localized to the inferior and medial regions of the temporal lobe and the orbital gyri of the frontal lobes. In neonates, brain involvement tends to be more diffuse. The disease is necrotizing and often hemorrhagic in the most severely affected regions (5).
In general, a patient with encephalitis presents with diffuse or focal neurologic signs and symptoms, including an altered mental state and level of consciousness, behavioral or personality changes, nuchal rigidity, photophobia, and generalized or focal seizures. Depending upon the type of virus, the patient may present with additional signs and symptoms. For example, patients with varicella zoster or measles encephalitis will typically have a rash, lymphadenopathy, hepatosplenomegaly, and parotid enlargement. Patients with St. Louis encephalitis will present with dysuria and pyuria (2).
In the case of HSV encephalitis, the patient will generally present with an altered state of consciousness, an abnormal mental state, and focal neurologic signs and symptoms, in addition to the acute febrile illness characteristic of viral meningitis. The level of consciousness may vary from mild lethargy to a comatose state. The patient is not mentally alert and is often confused, delirious, or disoriented. The patient may also suffer hallucinations and exhibit personality and/or behavioral changes, sometimes escalating into frank psychosis. Focal neurologic changes depend upon the site of infection within the brain. Common neurologic abnormalities include: aphasia, ataxia, cranial nerve deficits, hemiparesis, hyperactive tendon reflexes, and involuntary movements, such as myoclonic jerks (1). Prolonged seizures, or status epilepticus, which are refractory to anticonvulsants are also common in the presentation of encephalitis.
In children and adults, there is no relationship between the presence of mucocutaneous lesions and HSV encephalitis (4). In fact, only about 10% of patients have a positive history of prior labial herpes (5). Thus, the presence or absence of such lesions is of no diagnostic value.
By contrast, neonates often have pathognomonic lesions. Neonates with HSV encephalitis may present with lethargy, poor feeding, irritability, tremors, seizures, temperature instability, a bulging fontanelle, and pyramidal tract signs. With disseminated disease, the neonate may present with systemic signs and symptoms such as jaundice, shock, bleeding, or respiratory distress (4).
Once the diagnosis of encephalitis is suspected, the patient should be given intravenous acyclovir immediately. The cause of the encephalitis is assumed to be HSV until proven otherwise. HSV encephalitis has specific antiviral chemotherapy and the patient's prognosis relies heavily upon the expediency of this treatment.
The clinician must be wary of non-viral causes of encephalopathy, including infectious and non-infectious agents. Among the non-viral infectious etiologies are abscesses, as well as bacterial, fungal, parasitic, rickettsial, and tuberculous infections. Non-infectious causes of encephalopathy include tumors, hematomas, vascular insults, toxic encephalopathy, and systemic lupus erythematosus.
Hundreds of viruses have been implicated in viral encephalitis and it is difficult to clinically distinguish HSV encephalitis from the other viral forms. Therefore, confirmation of HSV encephalitis depends upon laboratory work-up; however, this should not delay the immediate initiation of acyclovir treatment. The CSF profile in viral encephalitis mimics that of viral meningitis, with a lymphocytic pleocytosis, an elevated protein content, and a normal glucose level. The lymphocytic pleocytosis is found in more than 95 percent of patients with viral encephalitis. Thus, given an immunocompetent patient, the absence of a pleocytosis should raise the suspicion of a non-viral cause of the encephalopathy. Similarly, a decreased glucose level should also prompt the search for a non-viral cause. About 20 percent of patients with encephalitis will have RBCs in their CSF profile following a non-traumatic tap, indicating a hemorrhagic encephalitis such as that associated with HSV, Colorado tick fever virus, and sometimes California encephalitis virus (1).
PCR amplification of viral nucleic acid in the CSF is a sensitive (75-98%) and specific (100%) test for HSV encephalitis within the first 25-45 hours (2). PCR analysis of the CSF is less invasive and less costly than the traditional brain biopsy, and is therefore becoming the diagnostic test of choice. A brain biopsy does have the advantage, however, of potentially identifying alternative causes of the encephalopathy (1). The PCR test for HSV is not routinely done on CSF samples and must be specifically requested. Results are usually available within 24 hours (4). The initial result may return negative and should be redone if clinical suspicion remains high (6,7).
HSV antibody detection in the CSF yields the best results after a week into the illness. Thus, its usefulness is limited to a retrospective confirmation of HSV infection rather than for acute diagnostic purposes. CSF culture for HSV is unreliable and is invariably negative in cases of HSV-1 encephalitis (1).
CT, MRI, and EEG are helpful to identify or exclude alternative diagnoses and in determining whether the disease is focal or widespread. Such tests for HSV encephalitis tend to yield focal abnormalities, such as: 1) periodic focal spikes and slow-wave or periodic sharp wave patterns over the temporal lobes on EEG; 2) areas of low absorption, mass effect, and contrast enhancement in the temporoparietal regions of the brain on CT; 3) areas of increased signal intensity in the frontotemporal, cingulate, or insular regions on T2-weighted spin-echo MRI images. The aforementioned findings, however, are not pathognomic for HSV encephalitis (1,4).
MRI is a more sensitive test than CT. However, CT is fast and is useful to rule out other causes of encephalopathy, such as acute hemorrhage, shaken infant syndrome, brain tumor, or some conditions that requires immediate neurosurgery. Many authorities recommend performing a CT scan of the head, with and without contrast, prior to obtaining a lumbar puncture (2).
A patient with encephalopathy should be evaluated and treated for shock or hypotension. The clinician may place the patient on prophylactic anticonvulsant medication and also consider airway protection in patients with altered states of consciousness. For patients with signs of hydrocephalus and increased intracranial pressure, coughing and straining should be controlled. If the patient is stable, the head should be elevated and neurologic status should be monitored. When aggressive intervention is required, the clinician may consider the use of diuretics (if the patient's circulatory volume is protected) or hyperventilation in an emergency situation. Cerebral edema can also be controlled with steroids, but the use of steroids in HSV encephalitis is controversial (4). Intracranial pressure monitoring is also controversial (2).
In general, with the exception of HSV and varicella zoster virus, the viral encephalitides lack specific treatment (Cytomegalovirus and toxoplasma encephalitis do have specific treatments, but they are not usually initiated in the ED) (2).
The consensus report on the diagnosis of HSV encephalitis published in 1996 recommends that intravenous acyclovir be given to the patient as soon as the diagnosis is suspected, since early intervention is key (6). Even if the CSF PCR returns negative for HSV, treatment with acyclovir should continue if clinicial suspicion remains high, since the drug is relatively non-toxic, with the major side-effect being transient renal insufficiency (8). Acyclovir should be given at a dose of 10 mg/kg every 8 hours (for a total of 30 mg/kg per day) for 14 days (Acyclovir should be infused slowly over one hour to minimize the risk of renal insufficiency. The dose of 30 mg/kg per day is double that for mucocutaneous/visceral infections because CSF levels of acyclovir only reach 30-50 percent of plasma levels). The dosage should be adjusted for patients with existing renal dysfunction (3). For HIV+ patients, foscarnet (Foscavir), may be a suitable substitute for acyclovir, given the increased incidence of acyclovir-resistant strains of HSV (2).
Patient prognosis is dependent upon several host factors as well as the virulence of the virus. For example, rabies, eastern equine encephalitis, and Japanese encephalitis are associated with significant mortality and morbidity, including severe neurologic sequelae. California encephalitis and western equine encephalitis tend to be milder diseases (2).
Mortality in untreated patients with HSV encephalitis is about 70%, and many survivors are left with neurologic abnormalities (4). According to National Institute of Allergy and Immune Diseases-Collaborative Antiviral Study Group (NIAID-CASG) trials, of 32 acyclovir treated patients, 81 percent survived. Among the survivors, 46 percent suffered little or no neurologic sequelae, 12 percent were moderately impaired, and 42 percent were severely impaired, requiring continuous supportive care (1). 5-10 percent of surviving patients relapse days to weeks after completion of treatment (4).
Factors important in the prognosis of HSV encephalitis are the timeliness of intervention, the age of the patient, and the level of consciousness at the initiation of therapy. For example, patients with a Glasgow coma score of less than or equal to 6, either died or suffered severe neurologic sequelae. Acyclovir can reduce neonatal death by 25 percent, but the rate of morbidity, especially with HSV-2 infections, is still very high (1,3). 40-60 percent of neonatal survivors have developmental abnormalities after 2 years of follow-up care (4).
CLINICAL PEARLS:
References: