The case is a 67-year-old female with hypertension, hyperlipidemia, and left breast cancer for which she underwent a mastectomy and adjuvant chemotherapy from 2016 to 2017. In July 2020, she was diagnosed with a second malignancy:locally advanced pancreatic head adenocarcinoma, received neoadjuvant chemotherapy from August 2020 to January 2021, surgical resection (total pancreatectomy, extended right hemicolectomy and portal vein resection) in May 2021, and adjuvant chemotherapy from 18 October 2021 to 31 October 2021.
In December 2021, she attended a routine clinic review and was found to be significantly malnourished:she had extremely poor oral intake, wasting of muscle bulk, a body mass index of 18.9, and severe hypoalbuminemia (albumin 15 g/L; reference range 40-50 g/L). Her vital signs were stable:temperature of 36.2 degrees Celsius, blood pressure was 103/67 mmHg, heart rate of 91 beats per minute, and SpO2 96% on room air. She was admitted for inpatient enteral nutrition support. She remained well for a week before developing acute AMS. Clinical examination revealed a gradual decline of her Glasgow Coma Scale (GCS) from 15 to 11 over several days, but was otherwise unremarkable with no focal neurological deficits.
An extensive biochemistry panel revealed hyperammonemia (with an initial ammonia level of 144 umol/L; reference range 16-53 umol/L), hypophosphatemia (0.57 mmol/L; reference range 0.94-1.50 mmol/L), and micronutrient (zinc, copper, selenium, vitamin A, vitamin D2, vitamin D3, vitamin E) deficiencies. There was suspicion of an acute coronary syndrome in view of new anterolateral ST segment elevations on her electrocardiogram and raised troponin levels, but this was ruled out with a negative coronary angiogram and attributed to stress cardiomyopathy with a depressed ejection fraction of 25%. Neuroimaging (computed tomography and magnetic resonance imaging of brain, magnetic resonance angiogram of brain) was normal. An electroencephalogram showed severe diffuse encephalopathy with generalized triphasic waves suggestive of metabolic encephalopathy. Basic microbiological investigations including aerobic and anaerobic blood cultures, she was initially managed for metabolic encephalopathy, likely contributed by constipation, hyperammonemia, electrolyte imbalance, and stress cardiomyopathy. Her mental status improved to normal with regular opening of bowels and electrolytes correction.
However, her neurological status gradually deteriorated from a GCS of 15 to 3 over the next 2 weeks, associated with multiple episodes of hypoglycemia. There was no improvement to her mental status after correction of hypoglycemia. Thus, a repeat workup including neuroimaging, electroencephalogram and lumbar puncture was performed. A comprehensive panel of microbiological investigations---including aerobic and anaerobic bacterial blood cultures, fungal blood cultures, viral serology panel,1 sputum cultures, urine cultures, cerebrospinal fluid (CSF) cultures, CSF meningoencephalitis panel,2 tests for syphilis infection and tuberculosis infection:was also sent. The investigations were significant for hyperammonemia (234 umol/L), positive urine cultures for Escherichia coli, and positive sputum cultures for Klebsiella pneumoniae and Stenotrophomonas maltophilia. She was started on intravenous (IV) Meropenem and Minocycline to cover for these organisms, and concomitantly worked up for the underlying etiology of hyperammonemia.
A liver duplex ultrasound revealed possible right portal vein thrombosis. Hence, she underwent a percutaneous transhepatic biliary drainage, portal vein angioplasty and stenting. Her ammonia levels improved transiently to 74 umol/L but rose back up again after several days post-procedure with no improvement in neurology. Her blood and endotracheal aspirates were sent for Ureaplasma and Mycoplasma cultures. She had earlier been commenced on a course of Minocycline (IV Minocycline 200 mg loading dose, followed by 100 mg every 12 h for a week) to cover for the Stenotrophomonas pulmonary infection, as well as for empirical coverage of possible Ureaplasma infection. The blood culture eventually returned positive for Ureaplasma urealyticum. By this time, she had completed a week of Minocycline, and was continued on another week of Azithromycin (Oral Azithromycin 500 mg once daily). A repeat Ureaplasma blood culture thereafter was negative. The patient had undergone chemotherapy with TS-One (Tegafur, Gemeracil, Oteracil) in October 2021. However, her medical oncologist felt that the time frame (TS-One was given more than 6 weeks before her presentation of hyperammonemia) was not compatible with TS-One as the cause of her current encephalopathy or hyperammonemia. Finally, a metabolic panel for urea cycle disorders was sent and returned negative.
Simultaneously, supportive treatment was initiated to promote ammonia clearance with lactulose, rifaximin, sodium benzoate, and hemodialysis, as well as to reduce ammonia production through dietary protein restriction.
Retrospectively, we found that her mentation improved most dramatically with a combination of: (1) lowering her ammonia levels with dialysis, (2) treatment of Ureaplasma infection with the appropriate anti-microbials, (3) treatment with high dose thiamine for presumed thiamine deficiency, and (4) nutritional replacement for micronutrient deficiencies. The final diagnosis was metabolic encephalopathy contributed by thiamine deficiency (causing a Wernicke-like state), exacerbated by hyperammonemia from Ureaplasma infection, and micronutrient deficiencies related to a post-pancreatectomy state. Subsequently, with the appropriate treatment and normalization of ammonia levels, she recovered to full neurology and was able to follow instructions. However, her protracted intensive care unit (ICU) stay was complicated by critical illness myopathy. She was discharged from ICU after 41 days but eventually succumbed to nosocomial infections and passed on day 83 of her hospital stay.
Table 1 shows the timeline of events that occurred.