Case report and literature review: A hiccup patient developed encephalitis and duodenal perforation

Abstract

Brainstem encephalitis is rare and this study aims to report the clinical course, imaging features, and therapeutic response of hiccup patient with gastric ulcer who developed brainstem encephalitis with Epstein–Barr virus (EBV) detected in cerebrospinal fluid and then subsequently followed by development of duodenal perforation. Data of a gastric ulcer patient who suffered from hiccups, with brainstem encephalitis detected and then subsequently suffered from duodenal perforation were collected retrospectively and analyzed. A literature search was conducted on Epstein–Barr virus associated encephalitis using keywords like “Epstein–Barr virus encephalitis” and “brainstem encephalitis,” “hiccup.” The etiology of EBV-related brainstem encephalitis in this case report is not clear. However, from the initial hiccup to the presentation of both brainstem encephalitis and duodenal perforation during the course of hospitalizations builds up an uncommon case.

Background

Brainstem encephalitis (BE) is rare, the etiology and causes of encephalitis are often difficult to identify. ¹ In a study to investigate the etiology of brainstem encephalitis, the etiology determined in 58 of 81 cases, are possibly related to inflammatory or autoimmune reasons, where corticosteroid were mainly given as a treatment and less frequently administered in the rest 23 cases as no confirmed diagnoses were given. ² Epstein–Barr virus (EBV) infects 90% of the world human population and most infections are asymptomatic, carried lifelong and are unaware of. Infection symptoms can include fever, sore throat, lymphadenopathy, and splenomegaly. ³ Young children are affected mainly by primary EBV infection due to oral secretions as they might exchange toys and bottles. ⁴ EBV associated encephalitis can be rare, can affect adults and mostly children, but imaging findings can range from normal to display of diffuse edema and inflammation. ⁵ The most common symptoms of Epstein–Barr associated encephalitis are fever, confusion, headache, focal neurological deficits, and antiviral medications against the disease usually include ganciclovir, valganciclovir, or valaciclovir. ⁶ In this case study, a 58 year old male patient was admitted into the hospital for three times to find cure for hiccups. He had gastric ulcer identified during his first hospitalization and subsequently developed aspirated pneumonia and then had brainstem encephalitis detected, followed by duodenal perforation but recovered eventually without any permanent neurological deficits.

Case presentation

First hospitalization

A male, 58 years old, was hospitalized for “acid reflux with hiccup after food intake for more than 2 months” and was in good health. More than 1 month ago, before his first hospitalization at the thoracic surgery department on the 6th of May 2021, until which time he lost weight from approximately 70 kg to 50 kg. The patient’s choice of ward was due to personal reasons. Though there was no obvious cause, but the patient had sensations of gastric acid reflux after food intake, accompanied by belching, hiccups, but had no obvious choking feeling during food intake. Since the first hospitalization he was provided with supportive care and symptomatic care, such as medications to suppress the gastric acid and protect stomach, but there was no apparent improvement as he continued to suffer from hiccups, occasional diarrhea, poor appetite, and did not gain weight post treatment, however, he was discharged on the 11th May 2021 as no cause was found. The computed tomography (CT) exams of his lungs, ultrasound of the abdomen and heart, and colonoscopy demonstrated normal results, only the gastroscopy showed that there was a gastric ulcer and then he was discharged.

Second hospitalization

On the 2nd of June, the patient continued to experience sensations of gastric acid reflux and discomfort after food intake, hiccups accompanied by belching, and vomiting with manifestation of ataxia. The patient vomited gastric contents, accompanied by more frequent hiccups, occasional diarrhea, poor appetite, weight loss, fatigue, and experienced syncope twice before admission into the thoracic surgery department. The brain CT was still normal then, but received similar treatment as his last hospitalization.

Third Hospitalization

On the third admission to hospitalization on 18th June in the same ward as the last two, the patient experienced frequent sensations of gastric acid reflux. The hiccups became heavy, and he still did not gain weight. The rough sounds can be auscultated in both lungs with wet rales, but with no obvious wheezing. Interventions included 1). Oxygen flow rate 50L/min, FiO2 80%, SpO2 95%. 2). cefoperazone sodium and sulbactam sodium 3.0 g every 8 hours + moxifloxacin 0.4 g once every day for anti-infection. 3). Omeprazole 40 mg twice a day was administered to protect the stomach.

On 20th June, patient had fever, the highest was 38.5 degree Celsius, antifebrile was given.

On 24th June, the patient was transferred to the intensive care unit due to severe pneumonia and respiratory failure. Oxygenation index was 136, moderate ARDS, intra-abdominal pressure 7-8 cmH2O, acute gastrointestinal injury score II, the patient was intubated and treated with mechanical ventilation with respiratory support mode: SIMV + PS, fiO2 was 55%, PEEP was 7 cmH2O, PS was 12cmH2O. Antibiotics were given for pneumonia. Moreover, nasogastrointestinal tube was inserted and connected to a bag to draw out the gas and liquid in order to relieve abdominal pressure. Enteral nutrition were given. PPI such as omeprazole 40 mg per 12 h was given till the 27th June, medications to promote bowel movement included mosapride citrate tablet 5 mg tid. According to the patient condition at the time, he couldn’t leave the mechanical ventilator for an MRI scan of the brain. Moreover, on 24th June, the patient underwent fiberoptic bronchoscopy, there was congestion and edema in his left and right bronchial mucosa. The lavage sample drawn out was pink. Sputum in the suction tube lumen observed were pink and watery which were cultured for bacteria testing and metagenomic next-generation sequencing (mNGS). However, the lab results of the sputum culture were inconsistent from the results derived from bronchoalveolar lavage (BALF) sample. The BALF lavage derived sample solution revealed heamophilus influenzae sequence was 480 which often cause acute pneumonia and streptococcus anginosus sequence was 278. Streptococcus anginosus are found in the normal flora of the gastrointestinal and genital tracts and the oral cavity, the colonization in an acidic environment due to the acidity of S. anginosus could be the etiology of the systemic infection of the bacteria^7,8 thus the bacterial culture showed different result which included pseudomonas aeruginosa that often causes infection in intensive care units and are usually resistant to antimicrobial medications. ⁹ According to the patient’s symptoms and CT characteristics, the physician was more inclined to consider that the patient had aspiration pneumonia caused by common bacteria in the pharyngeal isthmus, seemed to believe that the results from BALF were more reliable. The anti-infection regimen included meropenem 1.0 g every 8 hours + linezolid 0.6 g every 12 hours + fluconazole 0.4 g every day. Ganciclovir 0.25 g very 12 h + oseltamivir 75 mg very 12 h. Moreover, the nasogastrointestinal tube was replaced with an enteral nutrition tube.

On the 30th June, the patient underwent an MRI test of the brain, but the result issued by the MRI department was normal. However, the next day, on 1st July the physicians decided to accompany the patient for a second MRI, because they considered an alternative result according to the whiteness around the brain stem area on the MRI neuroimage. On 1st of July, the patient was diagnosed with brainstem encephalitis, as he underwent brain MRI for a second time and then lumber puncture was conducted. The intracranial pressure was 12 cmH2O, the biochemistry laboratory results of the cerebrospinal fluid showed that it was transparent, Pandy test was negative, microprotein was 0.73 g/L, and serum chlorine was 119.8 mmol/L, serum glucose was 3.22 mmol/L, red blood cell count was 1000 × 10^⁶/L, karyocyte cell count was 19 × 10^⁶/L, mononuclear leukocyte 84.2%, and multinuclear leukocyte 15.8%. Moreover, the cerebrospinal fluid was tested for metagenomic next-generation sequencing (mNGS). The results showed that the human gammaherpesvirus 4 (Epstein–Barr virus) sequence was 34, lymphocryptovirus (related to EBV) sequence was 35, candida sequence was 2, candida tropicalis sequence was 2. The physicians did not consider fungal encephalitis at the time but were more inclined to believe that the fungi were due to contamination. The anti-infection interventions included ceftazidime 2g every 8 hours + amikacin 0.5 g every day. The tracheotomy was ordered. Subglottic vacuum suction was utilized to clear the airway. Antiviral ganciclovir 0.25 g was administered every 12 hours, methylprednisolone 120 mg administered once a day for 3 days, then reduced to 80 mg once a day for 3 days, and then 40 mg for 7 days, human immunoglobulin 10g was given once a day intravenously and then thymosin 1.6 mg was administered once per day subcutaneously to boost the immune system. On the 8th July, omeprazole was restarted and given 40 mg intravenously every 8 h. See Figure 1.

Figure 1.

The CT and MRI results during the third hospitalization. Images a and b show lung CT on 24th June upon admission into intensive care unit. Lung markings in both lungs increase, pulmonary stria disorder, interlobular septa thickening, and large patches of plaque high density shadows, grid like alterations, local consolidation, air bronchogram. Watery like density shadows gathered in bilateral thoracic cavities. Images c and d show lung CT on 7th September. Lung markings and stria disorder in both lungs are absorbed, local are grid like alterations. Obviously Absorbed in comparison to previous lung CT. No bilateral pleural effusion. Images from e to g show the head MRI on 30th June. Medulla oblongata with abnormal plaque like signal shadow. Images h to i show head MRI results on 25th August. Medulla oblongata with abnormal plaque like signal shadow. Shows absorbed in comparison to the previous head MRI. Lesion clearly absorbed.

There was a health condition change of the patient on 9th of July T: 37.2°C, P: 142 times/min, R: 12 times/min, BP: 99/54mmHg (nail removal 52ug/min), SpO2 97%, the patient went into a coma, the total 24 h intake was 3693 mL and when minus the 24 h output of 630 mL (385 mL of urine, 165 mL of subglottic suction), equaled 3063 mL. Emergency biochemistry: TBIL 41.6 μ mol/L, DBIL 17.84 μ mol/L, ALB 27.9 g/L, ALT 200u/L, serum potassium 5.77 mmol/l. Blood routine: WBC: 38.3 × 10^9/L, N: 94. 3%. CRP: 276.76 mg/L, lactic acid: 3.3 mmol/l. The urine amount suggested oliguria which implicated kidney dysfunction and the patient had a few hemodialysis sessions until the 16th of July. The lab results of peritoneal effusion amylase level were 12,700U/L indicating ascites. The patient suffered from duodenum perforation and underwent operation to have it repaired and the vital signs were returning nearly to its normal state but he was still confused post-surgery but returned to consciousness.

The patient health condition changed again on the 15th of July, 300 mL fluids drawn out through the nasogastrointestinal tube were brown, Blood routine exam showed that the hematocrit 26. 8%, red blood cell count 2. 87 × 10^12/L, hemoglobin level 86 g/L. Thus gastrointestinal bleeding was implicated, medications to cease the duodenal bleeding were administered and the patient underwent digital subtraction angiography (DSA) twice to cease the bleeding. Supportive care was given post DSA. Post DSA, infection prevention care was provided and the treatment focused the following points.

1. Anti infection issues: early–late (aeruginosa)

2. Primary diagnosis and treatment: Bickerstaff’s brainstem encephalitis

3. Organ function maintenance: respiration, circulation, gastrointestinal tract, and kidney

4. Management of complications: stress ulcer

From 21st of July onwards, the patient was off the ventilator occasionally and on 22nd July, he was off mechanical ventilator entirely. The patient seemed to recover from the complications and of the brainstem encephalitis as according to the findings from the MRI on 25th August. On the 16th of September, the tracheotomy ceased. The patient was discharged on 11th October. See Figure 2.

Figure 2.

The timeline of the three hospitalizations. The patients discharged after symptomatic treatments in the first and second hospitalizations. The encephalitis was detected after the second MRI during the third hospitalization and underwent operation for duodenum perforation.

Follow up

Patient was followed up once every month and there were no symptoms of discomfort or abnormality.

Discussion

Meningitis is the inflammation of the meninges, whereas encephalitis is the inflammation of the cerebral parenchyma. The viruses that can cause meningitis and encephalitis include enterovirus, herpes simplex virus-1 and -2, human herpesvirus type-6, measles, mumps, lymphocytic choriomeningitis virus, human parechovirus, varicella-zoster, EBV virus, HIV etc. ¹⁰ Although viral meningitis and encephalitis share a similarity in manifestations, the outcome of viral meningitis is often benign. For instance, during infection by herpes simplex virus types 1 and 2, minimal or no antiviral treatment is required in meningitis but patients with encephalitis, antiviral treatment of acyclovir, hospitalization, intensive care unit admission, and supportive care is required, and permanent neurologic damage might occur. ¹¹ In Tyler et al., serological results suggests that infections, meningitis, and encephalitis of West Nile virus both cause cerebrospinal fluid pleocytosis, but patients with encephalitis have higher cerebrospinal fluid protein concentrations are inclined to suffer adverse outcomes, in need of hospitalization or can even suffer from mortality after acute onset of encephalitis. ¹² Viral encephalitis is directly caused by the virus infection, whereas post-infectious encephalitis can develop post the infection or as a result of an infection. For instance an elder male patient suffered from severe COVID-19 pneumonia, recovered and was discharged, but he developed COVID-19 post-infectious encephalitis a week later with delirium as initial symptom. ¹³

In this case study, the encephalitis was covered by gastrointestinal symptoms until the third admission due to several reasons. Primary EBV infection can be diagnosed with suitable laboratory tests. Patients who are mildly ill are unlikely to be discovered because either they do not seek medical attention or EBV infection is not considered as diagnosis. Patients with a typical infectious mononucleosis syndrome are still a diagnostic challenge because their signs and symptoms are not very sensitive or specific for EBV infection. For example, a recent report found that the classic triad of fever, sore throat, and lymphadenopathy had a sensitivity of 68.2% and a specificity of 41.9% for EBV infection.14 In this case, EBV infection was not identified at the beginning, as the hiccups led to suspicion of a gastrointestinal disease from the beginning and MRI of the brain was not conducted until the patient was transferred to the ICU on his third hospitalization making the etiology of the patient’s brainstem encephalitis difficult to determine as inflammation of the duodenal could also have reactivated EBV infection in the brainstem. However, the hiccup reflex center is considered to be in the hypothalamus, the brainstem, and the cervical spinal cord (segments C3–C5). The afferent impulses are relayed to the hiccup center via the vagal and phrenic nerve, and the afferent nerve fiber of 6–12 thoracic sympathetic nerve but the physicians considered gastrointestinal disease as the cause of hiccups before the patient was transferred into the ICU due to pneumonia and respiratory failure. ¹⁵ In literature, the main manifestations of EBV encephalitis were dizziness, headache, epilepsy, disturbance of consciousness, fever, fatigue, weight loss, and other systemic symptoms, ¹⁶ whereas in this case study, the patient also suffered from syncope, weight loss although it might be caused by the gastric ulcer and related poor nutrition, making it difficult to determine whether encephalitis or EBV infection existed simultaneously with gastric ulcer on his first hospitalization or after the first hospitalization not as no MRI of the brain with contrast or no other exams to determine encephalitis or EBV were conducted, until his stay in the ICU, due to factors that the patient wished to save hospital expenses in addition to that both the patient and physician were merely suspicious of a gastrointestinal disease.

Moreover, central respiratory failure can occur when the brainstem is involved in EBV infection. ¹⁷ In this case, brainstem encephalitis was not even considered until the third hospitalization. During the third hospitalization, it took two MRI scans of the brain to suspect EBV encephalitis, because the first physician from the MRI department who read the first MRI test result decided that the result was normal, but the physicians responsible for the patient’s care suspected EBV encephalitis, this demonstrate the subjective factor of test results reading and that there should be more training provided in this aspect. Epstein–Barr virus associated encephalitis showed MRI findings of high signal intensities in basal ganglia along with serologic tests.^18–22 Nucleosides, including acyclovir and ganciclovir are also used against EBV infection. ²³ Although most patients of Epstein–Barr virus encephalitis have a good prognosis post symptomatic treatment, but Huang et al. reported of a patient who deceased due to progression into brain stem hemorrhage. ²⁴ The sophisticated complications such as pneumonia, encephalitis, and duodenum perforation could be due to the combined harm of EBV and bacteria as Helicobactor pyloric. In addition, methylprednisone as a corticosteroid might cause side effects to the gastrointestinals which might also be the harmful cause of the duodenal perforation as their doses were not ceased before the duodenal perforation whereas the antacid medication doses for the stomach was not enough.

Conclusions

There are a general lack of awareness, knowledge, or training in treating such cases among physicians due to the rarity of EBV related encephalitis. The patient himself in this case didn’t realize the seriousness of his symptoms either until he experienced syncope and dyspnea. The current clinical system in this case study lack the tool, methods, or capacity to predict or prevent the possible worsening progression of the condition, the pneumonia, encephalitis, and subsequently the duodenal perforation, and it was only able to observe the result. The co-presentation of both brainstem encephalitis and duodenal perforation during the patient’s course of hospitalization build up a rare case. However, the activeness of both Helicobactor pylori and EBV led to the deterioration of patient health condition. The contribution in sharing this case study could be that it may provide data for future preventative medicine data pool by computational modeling^25,26 to predict the advancement of diseases before they progress, serving as a tool that health providers could utilize to prevent a deteriorating condition. Moreover, it might serve as a tool to train physicians.