Clinical manifestations

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.

Biological basis

Etiology and pathogenesis

Aberrant thermoregulation has been implicated as the instigating factor for the full syndrome of HSES. Seasonal clusters occurring in late winter/early spring are perhaps worsened by overwrapping the infant (24). In addition, infants may be more vulnerable to overheating due to lack of mature sweating mechanisms and higher heat production per surface area than in older children and adults (11).

It is theorized that release of proteolytic enzymes (17) and impaired downregulation of cytokine release either triggered by the fever itself or due to release of environmental or intestinal toxin are causative of the syndrome (05). In several ways, the findings resemble those of heat stroke (29). An isolated case of occurrence in an older child with high spinal lesion suggested dysautonomic response causing aberrant temperature control (03). Another child diagnosed with HSES at the age of 10 months had previously had an evaluation for fever of unknown origin, again suggesting abnormal temperature regulation (13). Some have suggested an underlying metabolic disorder causing a malignant hyperthermia picture (26).

Epidemiology

The overall incidence is unknown. Sofer and colleagues reported 20 patients in the Negev area of Israel in a predominantly Jewish and Bedouin population of approximately 400,000 over an 11-year period (24). However, this may reflect a population bias due to higher rates of consanguinity in the area. It was the fourth most common cause of an acute encephalopathy syndrome in children in Japan during the years 2007 to 2010, accounting for 2% of the cases reported (10).

Prevention

There are no known preventative measures. However, overwrapping infants has been associated with HSES, particularly if the head is covered (01).

Differential diagnosis

The differential diagnosis includes Reyes syndrome, hemolytic uremic syndrome (HUS), toxic shock syndrome, septic shock, overwhelming viremia, febrile seizures, Dengue hemorrhagic fever, malignant hyperthermia, and heat stroke. Unlike Reyes syndrome, the onset of HSES is abrupt, and vomiting is not prominent. Reyes syndrome typically occurs in older children, 8 to 9 years of age on average, and elevations of ammonia are quite striking. In HSES, mild elevation in ammonia may occur, but most commonly ammonia is normal. Unlike HUS, the hematologic findings in HSES are not hemolytic. HUS is more protracted in onset, with diarrhea preceding events. Renal failure in HSES is prerenal and typically resolves rapidly. Elevated liver function tests are not a part of HUS, and encephalopathy, if present, is mild and late in onset. Toxic shock syndrome is caused by staphylococcal infection and typically presents with rash. However, one case of toxic shock in an infant without a rash closely resembled HSES (28). The child was ultimately diagnosed with toxic shock when toxin-producing staphylococci were cultured from the child’s lymph nodes. Dengue hemorrhagic fever occurs more often in endemic areas, and as it is a mosquito-borne illness, occurs more often in the rainy season and warmer months. CNS involvement in Dengue hemorrhagic fever is low, up to 5%. In endemic areas, rising titers for the virus are diagnostic (21). Febrile seizures are difficult to exclude at initial presentation, especially when status epilepticus is present. The presence of shock and elevated liver function tests at presentation is not seen in febrile seizures. The bacterial cultures are the differentiating factor for septic shock. Hemodynamically, the course of HSES resembles septic shock; however, bacterial cultures are negative. Malignant hyperthermia also manifests similar findings, with high fever and rhabdomyolysis. An underlying metabolic disorder or defect such as in malignant hyperthermia could play a role in HSES, but this has yet to be elucidated. The course of heat stroke is similar, and it is still debated whether the HSES cascade of events is triggered by the high core body temperature producing “heat stroke.”

Diagnostic workup

Initial laboratory studies should include complete blood count (CBC), chemistries, and blood gases to document acidosis. Pan culture should include blood, urine, sputum, stool, and if no cerebral edema to preclude spinal tap, CSF, to rule out bacterial etiology. Viral culture and herpetic and other viral PCR studies should also be done. Serial chemistries and hematologic studies showing rising liver transaminases and CPK and falling hematocrit and platelets within the first 36 hours of presentation should be done. Initial pH should be determined. Kidney function should be monitored. Serum ammonia should be measured. Serial CT should be done to document evolving cerebral edema, which should be aggressively treated.

Management

Treatment is supportive. Shock in these infants will often respond to large volumes of isotonic fluids and/or blood products. Vasopressor support is needed in slightly less than half of the patients (13). Treatment of the hyperthermia may require external cooling in addition to antipyretics. However, the extremely high temperature seen at presentation tends to resolve the first day. The patient should be closely observed for the development of diffuse intravascular coagulopathy, and blood product should be used as necessary to treat. Treatment of the encephalopathy includes control of the seizures and intracranial pressure. Seizures are difficult to control, but may respond to typical anticonvulsant drugs. Intracranial pressure monitoring is indicated in severe cases. Treatment in individual cases with dantrolene (Chaves-Carbello et al 1990) and plasmapheresis (22) have also been reported.