Presentation and course
A typical case is a previously healthy infant who, in the early hours or morning, is found with a high fever and is comatose, in shock, and convulsing. This progresses to multiorgan failure and diffuse intravascular coagulopathy. A mild prodromal illness is noted in 60% (25). The etiology is unknown.
As there are no biological markers for the disease, the established diagnostic criteria are based on clinical and laboratory abnormalities. Three papers have proposed criteria (04; 02; 13). All have been consistent with encephalopathy, shock, and laboratory abnormalities showing elevated liver functions (greater than 3-fold) and falling hematocrit and platelets and negative bacterial cultures. The criteria proposed by Bacon and Hall were proposed for surveillance of the disorder in the British Isles (02). Although most reported cases are in infants less than a year old with a median age of 4 months (13), the diagnostic criteria by Bacon and Hall were broadened to less than 16 years of age to increase catchment. Hyperammonemia was originally an exclusionary criterion in Chaves-Carballo and colleagues’ 1990 criteria, but later studies found that more variable. The degree of hyperammonemia is typically moderate, if present at all.
The laboratory abnormalities found are striking, but do not predict mortality (13). Liver function tests may be elevated on presentation, but tend to rise over the first 24 to 36 hours, whereas platelet counts and hematocrit may be normal at presentation but fall over the same time frame. Creatine phosphokinase (CPK) follows a similar course as the transaminases. In cases followed from very early in their courses, the first laboratory abnormalities noted were elevated CPK and liver function tests and severe acidosis. These may precede shock by 12 hours. The acidosis is quite severe and tends to be refractory to circulatory support (23). Bacterial cultures must be negative. Viral cultures have been reported positive up to approximately 50% of patients (13). However, the pathogens found are typically associated with mild disease courses – not the severe disease course seen in HSES.
Despite “hemorrhagic” being in the name, clinically significant hemorrhage is seen in less than 10% (1/17) of patients (13). Due to the lack of overt hemorrhage at presentation, many have suggested changing the name to “hyperpyrexia shock and encephalopathy syndrome” to confer that hemorrhage is not the instigating factor (06). When hemorrhage is noted, it is more often a diffuse intravascular coagulopathy picture with oozing at needle stick sites. Occasionally, gastrointestinal or pulmonary hemorrhages can occur. Hematologically, platelets and hemoglobin fall, reaching their nadir in the first 36 hours, and then tend to resolve by the end of the first week (13). Also noted are prothrombin time (PT) and partial thromboplastin time (PTT) prolongation, decrease in fibrinogen levels, and the occurrence of fibrin split products (04).
Although not a consensus part of the diagnostic criteria, extremely high fever, peaking at a median of 41.4°C in one study (13), is typically seen at initial presentation. The fever is highest at presentation and tends to rapidly defervesce. The peak temperature may be recorded at home prior to transfer. However, as the temperature may quickly normalize, it may be missed. Therefore, one cannot discount a case if fever is not present.
Encephalopathy is part of the presenting features and is typically manifest by coma, altered mental status, hypotonia, and seizures. Infants who present with status have a worse prognosis (25). Seizures peak at onset of disease process and typically become controlled in 24 to 48 hours with vigorous anticonvulsant therapy (12). In some patients, seizures may have a bimodal distribution with the initial seizures at presentation and later onset of infantile spasms or other intractable epilepsy in survivors (12).
Imaging studies may be normal on the first day of presentation, or they may show mild cerebral edema. In the largest series of neuroimaging studies in HSES, a normal CT was noted at presentation in 14 of 22 patients (78%) (15). Serial studies showed progression to bilateral watershed infarcts and global brain edema. MRI of the brain in 14 of the 22 patients confirmed cytotoxic edema in bilateral watershed zones. Others have reported cortical hemorrhagic infarctions on MRI in some patients (08; 25).
In a smaller series of 9 patients studied by CT done between 1 and 7 days after onset of symptoms, cerebral edema was universal (14). The brainstem, basal ganglia, and cerebellum were relatively spared. No abnormal enhancement was seen with contrast. In patients who underwent serial CTs, the findings stayed consistent within 1 to 7 days after disease onset, and after 7 days, evolved to encephalomalacia and compensatory ventricular enlargement. The degree of cerebral edema correlated to outcome.
CSF studies have not been consistently obtained in patients due to the presence of cerebral edema making patients at high risk for spinal tap. When CSF is obtained, it is commonly normal or has mild cellularity and/or high protein (02).
In the largest reported series of EEG findings by Harden and colleagues, EEGs in 22 patients initially showed prolonged runs of often rhythmic discharges of fluctuating amplitude that evolved over time to low amplitude and slowing (09). In 7 of the 22 patients, the EEG ultimately showed electrocerebral silence (09). Other studies have reported EEG findings of multifocal epileptiform discharges or low amplitude (23).
Other clinical features include diarrhea, hepatomegaly, renal dysfunction, and respiratory arrest. Diarrhea, which may be bloody, often occurs in the acute phase and may be associated with hypernatremia. It typically resolves within the first few days of presentation. In some patients, a diarrheal illness has been prodromal. Rotavirus has been reported in conjunction with HSES; however, the majority of stools studies are negative for pathogens (20; 12; 10). Renal function studies reveal prerenal azotemia that responds to fluids (16). Lungs are not as prominently affected as other organs, and acute respiratory distress syndrome is uncommon. Ventilatory support is commonly needed early on due to the degree of seizures and encephalopathy.
In addition to rotavirus, other reported viral pathogens that may be the initial trigger or responsible for the prodromal illness include enterovirus, adenovirus, parainfluenza (02), respiratory syncytial virus and herpes virus 6, norovirus (10), echovirus (13), and H1N1 influenza (19).
HSES has been implicated as a cause of sudden infant death syndrome (27; 18).
At autopsy, petechial hemorrhages are noted in several organs. The liver may also have fatty changes and focal or generalized necrosis. Kidneys are relatively spared. The brain at autopsy reveals herniation, congestion, liquefaction, and necrotic and hemorrhagic lesions in the cortical areas (02; 25).
Prognosis and complications
Death occurs in approximately 50% of patients, despite aggressive management. Severe neurologic impairment occurs in up to 75% of survivors. Approximately 10% to 20% of patients have reported normal neurologic outcomes (02; 25).
Clinical vignette
A 4-month-old infant girl presented to the emergency room via ambulance actively convulsing early one winter morning. The infant was put to bed healthy except for some minor congestion the night before. The parents awoke to find the child limp, unresponsive, and “burning up.” While they were trying to wake her, she began having seizures and the ambulance was called. Initial exam showed the infant to be hot to the touch and hypotonic, with intermittent seizures and poor peripheral perfusion. Initial vital signs revealed a temperature of 41.9°C. Blood pressure was 45/20 mmHg. Initial labs showed an arterial pH of 7.25, WBC of 11.3, hematocrit of 39, platelet count of 330,00, BUN of 25 mg/dl, and creatinine of 0.7 mg/dl. Glucose was 90 mg/dl. Electrolytes were normal. Liver enzymes showed serum glutamic oxaloacetic transaminase (SGOT) of 375 U/L and serum glutamic pyruvic transaminase (SGPT) of 230 U/L. CPK was also noted to be high at 410 U/L. CT of head in the emergency room was negative, as was chest x-ray. CSF was obtained and had 3 WBCs, protein of 22 mg/dl, and glucose of 62 mg/dl. She had an isolated event of a large diarrhea stool in the ER. Blood, urine, and stool cultures were obtained and remained negative. Viral cultures and stool for toxins were also done and remained negative. IVF resuscitation was started and vasopressor support was added on the first hospital day as her blood pressure did not respond to fluids alone. She was intubated and ventilated easily. Seizure control was obtained with benzodiazepines and phenytoin on the first hospital day. Initial EEG done on the first hospital day showed multifocal spike and low voltage.
Over the next 24 hours she developed a full fontanel, and repeat CT showed diffuse cerebral edema with blurring of gray white junctions but sparing the posterior fossa. She began bleeding from needle stick areas, and laboratory studies revealed a fall in hematocrit and platelets. She stabilized over the next 4 days, and by the end of the first week, all her laboratory parameters had normalized. She remained encephalopathic. Repeat EEG did not reveal any subclinical seizures, but was slow with low amplitude. MRI on day 4 showed gyral swelling with narrowing of the ventricles, and DWI and T2 changes demonstrated hyperintensity in the frontal and parietal white matter, particularly subcortically. On hospital day 7 she was extubated. At 2 weeks, she evolved from being hypotonic to spastic with increased reflexes. She did not track to face or light and had minimal purposeful movements. She had not recovered suck or swallow, so a G-tube was placed. Over the next few months she regained some facial expression and smiled, but still required G-tube feedings. At one month out, she again developed seizures, and levetiracetam was started. She is still severely neurologically impaired.
