Encephalopathy After a High-Dose Dexamethasone Suppression Test in a Woman With X-Linked Ornithine Transcarbamylase Deficiency.

Background/Objective: The high-dose dexamethasone suppression test is a common and usually benign endocrine procedure. We report a patient with ornithine transcarbamylase deficiency (OTCD) who developed hyperammonemic encephalopathy after a high-dose dexamethasone suppression test. Case Report: A 46-year-old woman with a 1.3-cm right adrenal incidentaloma causing mild autonomous cortisol secretion underwent a high-dose dexamethasone suppression test for confirming adrenocorticotropic hormone independency. On the next day, she presented to the emergency room with confusion and somnolence. Her Glasgow Coma Scale score was 10 on arrival. The initial laboratory results showed ammonia, alanine transaminase, creatinine, and blood urea nitrogen levels of 289.51 (18.73-54.5) µg/dL, 21 (≤33) IU/L, 0.6 (0.6-1.1) mg/dL, and 13 (7-20) mg/dL, respectively. Electroencephalography showed triphasic morphology with no pathologies on brain imaging. Her husband told us that her brother and son had died in the neonatal period. On further review of medical records, we found that she was diagnosed as an OTCD carrier. We administered L-arginine, L-carnitine, rifaximin, and continuous renal replacement therapy. After 3 days, the serum ammonia level was 78.34 µg/dL with an increased Glasgow Coma Scale score of 15, and electroencephalography abnormalities disappeared. Discussion: Liver diseases and urea cycle disorders are the leading causes of hyperammonemia. This causes encephalopathy and death if the ammonia levels are too high. X-linked OTCD urea cycle disorder affects men more severely as they have only the carrier X chromosome. Glucocorticoids can exacerbate this disorder because they increase protein substrates converted to ammonia. Conclusion: This case reminds that it may be particularly important to have a complete medical history when administering glucocorticoids.

Mitochondrial targets in hyperammonemia: Addressing urea cycle function to improve drug therapies.

The urea cycle (UC) is a critically important metabolic process for the disposal of nitrogen (ammonia) produced by amino acids catabolism. The impairment of this liver-specific pathway induced either by primary genetic defects or by secondary causes, namely those associated with hepatic disease or drug administration, may result in serious clinical consequences. Urea cycle disorders (UCD) and certain organic acidurias are the major groups of inherited rare diseases manifested with hyperammonemia (HA) with UC dysregulation. Importantly, several commonly prescribed drugs, including antiepileptics in monotherapy or polytherapy from carbamazepine to valproic acid or specific antineoplastic agents such as asparaginase or 5-fluorouracil may be associated with HA by mechanisms not fully elucidated. HA, disclosing an imbalance between ammoniagenesis and ammonia disposal via the UC, can evolve to encephalopathy which may lead to significant morbidity and central nervous system damage. This review will focus on biochemical mechanisms related with HA emphasizing some poorly understood perspectives behind the disruption of the UC and mitochondrial energy metabolism, namely: i) changes in acetyl-CoA or NAD+ levels in subcellular compartments; ii) post-translational modifications of key UC-related enzymes, namely acetylation, potentially affecting their catalytic activity; iii) the mitochondrial sirtuins-mediated role in ureagenesis. Moreover, the main UCD associated with HA will be summarized to highlight the relevance of investigating possible genetic mutations to account for unexpected HA during certain pharmacological therapies. The ammonia-induced effects should be avoided or overcome as part of safer therapeutic strategies to protect patients under treatment with drugs that may be potentially associated with HA.

Hyperammonemic encephalopathy after tyrosine kinase inhibitors: A literature review and a case example.

OBJECTIVE: To review the evidence of uncommon but fatal adverse event of hyperammonemic encephalopathy by tyrosine kinase inhibitors (TKI) and the possible mechanisms underlying this condition and to describe the case of a patient that developed drug-induced hyperammonemic encephalopathy related to TKI. DATA SOURCES: Literature search of different databases was performed for studies published from 1 January 1992 to 7 May 2023. The search terms utilized were hyperammonemic encephalopathy, TKI, apatinib, pazopanib, sunitinib, imatinib, sorafenib, regorafenib, trametinib, urea cycle regulation, sorafenib, carbamoyl-phosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase 1, Mitogen activated protein kinases (MAPK) pathway and mTOR pathway, were used individually search or combined. DATA SUMMARY: Thirty-seven articles were included. The articles primarily focused in hyperammonemic encephalopathy case reports, management of hyperammonemic encephalopathy, urea cycle regulation, autophagy, mTOR and MAPK pathways, and TKI. CONCLUSION: Eighteen cases of hyperammonemic encephalopathy were reported in the literature from various multitargeted TKI. The mechanism of this event is not well-understood but some authors have hypothesized vascular causes since some of TKI are antiangiogenic, however our literature review shows a possible relationship between the urea cycle and the molecular inhibition exerted by TKI. More preclinical evidence is required to unveil the biochemical mechanisms responsible involved in this process and clinical studies are necessary to shed light on the prevalence, risk factors, management and prevention of this adverse event. It is important to monitor neurological symptoms and to measure ammonia levels when manifestations are detected.

Sunitinib-induced hyperammonemic encephalopathy in metastatic gastrointestinal stromal tumors: A case report.

BACKGROUND: Sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI), has been approved for the salvage treatment of gastrointestinal stromal tumors (GIST). Hyperammonemic encephalopathy is a rare but severe complication of sunitinib use. Here, we present the case of a 66-year-old male with metastatic GIST without underlying liver cirrhosis who developed sunitinib-induced hyperammonemic encephalopathy. CASE SUMMARY: A 66-year-old male with metastatic GIST was admitted because of reduced consciousness. Imatinib was administered as the first-line systemic therapy. He experienced repeated episodes of peritonitis due to tumor perforation, and surgery was performed. Progressive disease was confirmed based on increased liver metastasis, and sunitinib was initiated as a salvage treatment. However, 23 d after the third course of sunitinib, he presented to the emergency room with an episode of altered consciousness and behavioral changes. Based on the patient clinical history and examination findings, sunitinib-induced encephalopathy was suspected. Sunitinib was discontinued, and the patient was treated for hyperammonemia. The patient had a normal level of consciousness four days later, and the serum ammonia level gradually decreased. No further neurological symptoms were reported in subsequent follow-ups. CONCLUSION: TKI-induced hyperammonemic encephalopathy is potentially life-threatening. Patients receiving TKIs experiencing adverse reactions should undergo systemic evaluation and prompt treatment.

Monocrotophos-Induced Intermediate Syndrome Complicated by Hyperammonemic Encephalopathy: A Case Report.

Organophosphorus (OP) poisoning is the most common type of poisoning in India. Amongst the OP, monocrotophos poisoning has the highest lethality and need for mechanical ventilation. Monocrotophos is also implicated in causing OP-induced intermediate syndrome, the prevalence of which is 10-40% of all OP poisoning. The other neurological manifestations are delayed neuropathy and neuropsychiatric syndrome. We herein discuss a case of a 58-year-old male who presented with monocrotophos poisoning and intermediate syndrome. During the hospitalisation course, the patient developed hyperammonemic encephalopathy, resulting in difficulty in weaning from mechanical ventilation. After ruling out all possible causes of hyperammonemia, it was attributed to monocrotophos poisoning. The patient improved significantly after initiating lactulose and was successfully weaned off from the ventilator. This report highlights the high index of suspicion of hyperammonemic encephalopathy in monocrotophos toxicity, which can be easily missed due to other commoner neurological manifestations of organophosphorus poisoning.

Histopathological examination of characteristic brain MRI findings in acute hyperammonemic encephalopathy: A case report and review of the literature.

INTRODUCTION: Acute hyperammonemic encephalopathy is associated with distinct brain MRI findings, namely, hyperintensity in T2-weighted sequences as well as restricted diffusion in diffusion-weighted imaging with accentuation in the insular cortex and cingulate gyrus. The pathophysiology and the histopathological correlates of these characteristic MRI findings are largely unknown. CASE REPORT: We present a 57-year-old male with a history of chronic alcohol abuse, liver cirrhosis and portal hypertension, and a clinical syndrome (variceal bleeding, depression of consciousness, seizures), elevated plasma ammonia levels, and characteristic brain MRI abnormalities suggestive of acute hyperammonemic encephalopathy. A postmortem histopathological examination revealed extensive hypoxic ischemic encephalopathy without evidence for metabolic encephalopathy. No episodes of prolonged cerebral hypoxemia were documented throughout the course of the disease. We conducted a review of the literature, which exhibited no reports of hyperammonemic encephalopathy in association with characteristic brain MRI findings and a consecutive histopathological examination. CONCLUSION: This is the first report of a patient with acute hyperammonemic encephalopathy together with characteristic brain MRI findings and a histopathological correlation. Although characteristic MRI findings of acute hyperammonemic encephalopathy were present, a histopathological examination revealed only hypoxic pathology without signs of metabolic encephalopathy.

Challenges in the Clinical Diagnosis of Lithium Toxicity: A Case Report.

Lithium, a medication commonly used to treat bipolar disorders, has a narrow therapeutic index, putting patients at risk of lithium toxicity. Such toxicity could entail neurological-related complications and could be precipitated by several factors. In this paper, the authors discuss a case of a middle-aged woman taking lithium for bipolar disorder who presented to the emergency department with altered mental status, tremors, generalized weakness, and dysarthria. Multiple differential diagnoses were considered during her hospitalization, which included an admission to the intensive care unit. This case highlights the variability of lithium toxicity presentations and its management challenges. Further research is needed to understand such manifestations, potential precipitating factors, differential diagnoses, and effective detection and management.

Valproate-related hyperammonemic encephalopathy with generalized suppression EEG: a case report.

BACKGROUND: Valproic acid (VPA) is a prevalent antiseizure medication (ASM) used to treat epilepsy. Valproate-related hyperammonemic encephalopathy (VHE) is a type of encephalopathy that can occur during neurocritical situations. In VHE, the electroencephalogram (EEG) displays diffuse slow waves or periodic waves, and there is no generalized suppression pattern. CASE PRESENTATION: We present a case of a 29-year-old female with a history of epilepsy who was admitted for convulsive status epilepticus (CSE), which was controlled by intravenous VPA, as well as oral VPA and phenytoin. The patient did not experience further convulsions but instead developed impaired consciousness. Continuous EEG monitoring revealed a generalized suppression pattern, and the patient was unresponsive. The patient's blood ammonia level was significantly elevated at 386.8 µmol/L, indicating VHE. Additionally, the patient's serum VPA level was 58.37 µg/ml (normal range: 50-100 µg/ml). After stopping VPA and phenytoin and transitioning to oxcarbazepine for anti-seizure and symptomatic treatment, the patient's EEG gradually returned to normal, and her consciousness was fully restored. DISCUSSION: VHE can cause the EEG to display a generalized suppression pattern. It is crucial to recognize this specific situation and not to infer a poor prognosis based on this EEG pattern.

Hyperammonemic Encephalopathy in Multiple Myeloma: A Case Report.

Multiple myeloma (MM) typically presents as lytic bony lesions, hypercalcemia, anemia, and renal failure. Only a few cases of hyperammonemic encephalopathy (HE) attributed to multiple myeloma have been reported. We report a case of a 68-year-old Hispanic female diagnosed with multiple myeloma and presented with altered mental status and elevated ammonia levels found to have HE. The pathology behind HE is associated with higher ammonia levels produced by myeloma cell lines in the absence of liver disease. Due to the wide range of differentials for altered mental status (AMS), HE often gets missed and causes delayed treatment and the associated higher mortality. The primary treatment is chemotherapy. Lactulose and rifaximin must be initiated; however, it is ineffective if solely used. In our case, chemotherapy was not considered a treatment option in light of the patient's pancytopenia and infection. Our case is unique, as despite adequately treating other commonly suspected causes of AMS such as infection, there was no expected improvement in the patient's clinical status noticed, eventually leading to intubation due to worsening AMS. Given the patient's history of multiple myeloma, non-compliance with chemotherapy before presentation, and elevated ammonia levels raised suspicion for HE. Clinicians are encouraged to acquaint themselves with HE as a differential for patients presenting with MM flare and AMS, specifically when other potential causes of AMS are ruled out and addressed.

Valproate-Induced Encephalopathy Presenting at Therapeutic Blood Concentrations: A Case Report and Literature Review.

Patients presenting with hyperammonemic encephalopathy are likely to have hepatic encephalopathy. However, valproate (an anticonvulsant and mood stabilizer) can also cause hyperammonemic encephalopathy and belongs on the differential for patients taking it, especially if there are recent contributory medication changes. We present a case report of a 61-year-old woman with valproate-induced hyperammonemic encephalopathy but with an initial valproate level within the therapeutic range (50-100 mcg/dL). After withholding valproate and before additional treatment could be initiated, she became fully alert and oriented. We present a literature review exploring valproate toxicity and treatment. Our case shows that clinical suspicion for valproate-induced hyperammonemic encephalopathy is warranted even if the valproate level is within the therapeutic range.

Brain MR imaging in acute hyperammonemic: Case report.

Acute hyperammonemic encephalopathy is rare and generally is not widely known; only a few pediatric cases were found in the literature. These lesions' clinical presentation differs significantly so they can mimic other lesions. In this case report, we discuss a 5-year-old boy who presented with generalized seizures and was unconscious in an apyretic context, for which she had a cranial computed tomographic and magnetic resonance imaging, both objectified an acute hyperammonemic encephalopathy resulting from an enzyme deficiency. Magnetic resonance imaging revealed lesions throughout the cortex, with the perirolandic and occipital cortices spared. This distribution of cerebral signal abnormalities on magnetic resonance imaging with an abrupt and profound neurological disorder is secondary to hyperammonemic. The knowledge of the magnetic resonance imaging results of this entity is essential to accelerate the diagnosis, and treatment, also to prevent sequelae.

Idiopathic hyperammonemic encephalopathy secondary to gemcitabine-cisplatin treatment.

Idiopathic hyperammonemic encephalopathy is a rare complication of chemotherapy, which has previously mainly been associated with L-asparaginase, cytarabine and 5-FU. We present a case following treatment with gemcitabine-cisplatin in a patient with cholangiocarcinoma. The etiology of chemotherapy-induced idiopathic hyperammonemic encephalopathy remains unclear and existing theories differ per chemotherapeutic agent. Physicians treating patients with gemcitabine-cisplatin should be aware of the possibility of this complication, especially because it is treatable when recognized early.

Liver transplantation for late-onset ornithine transcarbamylase deficiency: A case report.

BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) is an X-linked inherited disorder and characterized by marked elevation of blood ammonia. The goal of treatment is to minimize the neurological damage caused by hyperammonemia. OTCD can be cured by liver transplantation (LT). Post-transplant patients can discontinue anti- hyperammonemia agents and consume a regular diet without the risk of developing hyperammonemia. The neurological damage caused by hyperammonemia is almost irreversible. CASE SUMMARY: An 11.7-year-old boy presented with headache, vomiting, and altered consciousness. The patient was diagnosed with late-onset OTCD. After nitrogen scavenging treatment and a protein-free diet, ammonia levels were reduced to normal on the third day of admission. Nevertheless, the patient remained in a moderate coma. After discussion, LT was performed. Following LT, the patient's blood ammonia and biochemical indicators stabilized in the normal range, he regained consciousness, and his nervous system function significantly recovered. Two months after LT, blood amino acids and urine organic acids were normal, and brain magnetic resonance imaging showed a decrease in subcortical lesions. CONCLUSION: LT can significantly improve partial neurological impairment caused by late-onset OTCD hyperammonemic encephalopathy, and LT can be actively considered when early drug therapy is ineffective.

Case Report: Hyperammonemic Encephalopathy Linked to Ureaplasma spp. and/or Mycoplasma hominis Systemic Infection in Patients Treated for Leukemia, an Emergency Not to Be Missed.

Background: Hyperammonemic encephalopathy caused by Ureaplasma spp. and Mycoplasma hominis infection has been reported in immunocompromised patients undergoing lung transplant, but data are scarce in patients with hematological malignancies. Case Presentation: We describe the cases of 3 female patients aged 11-16 years old, developing initially mild neurologic symptoms, rapidly evolving to coma and associated with very high ammonia levels, while undergoing intensive treatment for acute leukemia (chemotherapy: 2 and hematopoietic stem cell transplant: 1). Brain imaging displayed cerebral edema and/or microbleeding. Electroencephalograms showed diffuse slowing patterns. One patient had moderate renal failure. Extensive liver and metabolic functions were all normal. Ureaplasma spp. and M. hominis were detected by PCR and specific culture in two patients, resulting in prompt initiation of combined antibiotics therapy by fluoroquinolones and macrolides. For these 2 patients, the improvement of the neurological status and ammonia levels were observed within 96 h, without any long-term sequelae. M. hominis was detected post-mortem in vagina, using 16S rRNA PCR for the third patient who died of cerebral edema. Conclusion: Hyperammonemic encephalopathy linked to Ureaplasma spp. and M. hominis is a rare complication encountered in immunocompromised patients treated for acute leukemia, which can lead to death if unrecognized. Combining our experience with the few published cases (n=4), we observed a strong trend among female patients and very high levels of ammonia, consistently uncontrolled by classical measures (ammonia-scavenging agents and/or continuous kidney replacement therapy). The reversibility of the encephalopathy without sequelae is possible with prompt diagnosis and adequate combined specific antibiotherapy. Any neurological symptoms in an immunocompromised host should lead to the measurement of ammonia levels. If increased, and in the absence of an obvious cause, it should prompt to perform a search for Ureaplasma spp. and M. hominis by PCR as well as an immediate empirical initiation of combined specific antibiotherapy.

Extrahepatic portosystemic shunts as an unusual but treatable cause of hyperammonemic encephalopathy in a noncirrhotic patient - a case report.

We report a case of hyperammonemic encephalopathy due to extrahepatic portosystemic shunts in a noncirrhotic patient. A 79-year-old woman suffered from episodic confusion, disorientation, dysphasia and fluctuating level of consciousness. Electroencephalography (EEG) showed encephalopathic changes and serum levels of ammonia were elevated. Further investigation revealed mesenterorenal and mesenterocaval shunts, which had possibly evolved after pancreatic surgery 5 years ago. After shunt obliteration, the symptoms completely resolved, ammonia levels dropped to the normal range and EEG findings normalized. Clinicians should be aware of this rare but treatable cause of encephalopathy in noncirrhotic patients.

Aggressive Plasmablastic Myeloma With Extramedullary Cord Compression and Hyperammonemic Encephalopathy: Case Report and Literature Review.

BACKGROUND: Plasmablastic myeloma is an aggressive subtype of multiple myeloma with overall poor prognosis. Spinal cord compression and hyperammonemic encephalopathy are two grave complications of multiple myeloma with significantly poor survival outcomes. CASE REPORT: A 49-year-old male presented with a 5-day history of worsening abdominal distention with inability to walk, urinate or defecate. Imaging findings of innumerable spinal osteolytic lesions with paraspinal masses coupled with a bone marrow biopsy of ≥70% plasmablasts confirmed the diagnosis of plasmablastic myeloma. Despite spinal decompression surgery, the patient remained paraplegic. Three myeloma-directed chemotherapies failed, eventually leading to him developing hyperammonemic encephalopathy culminating in his death. CONCLUSION: Plasmablastic myeloma is a rare entity which poses therapeutic challenges especially in patients with negative prognosticators, including high-risk cytogenetic markers, extraosseous involvement with cord compression and hyperammonemic encephalopathy. Early aggressive management with consideration of novel therapeutic alternatives, especially in treatment refractory disease, can be worthwhile.

Hyperammonemic encephalopathy associated with post-radiotherapy vesicointestinal fistula following cervical cancer.

The majority of hyperammonemic encephalopathy is due to liver cirrhosis. However, urinary tract infection caused by urease-producing bacteria increases ammonia in urine and can lead to hyperammonemic encephalopathy, especially in cases with obstructive uropathy and vesicointestinal fistula. This is the first case report of hyperammonemic encephalopathy in a cervical cancer patient associated with postradiotherapy vesicointestinal fistula. A 52-year-old woman developed diarrhea due to vesicosigmoidal fistula 14 years after radical hysterectomy and radiotherapy to treat cervical cancer. She refused urinary and/or fecal diversion. Twelve months after the diagnosis of fistula, she was admitted due to somnolence. Blood examination showed hyperammonemia without liver dysfunction. Urine culture showed Proteus rettgeri and Klebsiella pneumoniae. She recovered after intravenous antibiotics. Eight months after recovery, she was readmitted due to somnolence reoccurring with failed intravenous, but successful oral antibiotic treatment. She finally agreed to undergo percutaneous nephrostomy and hyperammonemia never recurred during 7 years of follow-up.

Delayed Cerebral Abnormalities in Acute Hyperammonemic Encephalopathy.

Acute hyperammonemic encephalopathy (AHE) is a rare but life-threatening condition. We present a case of an 81-year-old woman with cirrhotic AHE who presented with prolonged disorientation. Her magnetic resonance (MR) images were normal on the third hospital day, which showed bilateral abnormalities in the insular and cingulate cortices on day 13. The imaging abnormalities were slightly improved but remained on day 24. The imaging abnormalities seemed correlated with her persistent disorientation. AHE can present as delayed cerebral abnormalities, and follow-up imaging tests are useful in detecting such conditions. Further reports are needed to investigate the correlation between imaging abnormalities and clinical outcomes in patients with AHE.

Incidence, Presentation, and Risk Factors for Sodium Valproate-Associated Hyperammonemia in Neurosurgical Patients: A Prospective, Observational Study.

OBJECTIVE: Sodium valproate (VPA) is a commonly prescribed antiepileptic drug (AED) in daily neurosurgical practice. However, the incidence of VPA-associated hyperammonemia (VAH) and its life-threatening consequence, VPA-induced hyperammonemic encephalopathy (VHE), in neurosurgical patients is unknown. We determined the incidence, clinical presentation, and risk factors for VAH. METHODS: This prospective cohort study was performed on adult neurosurgical patients prescribed VPA for at least a week over a 22-month period. Blood tests for ammonia, VPA, and liver function were performed at the time of recruitment. The primary end point was VAH. Secondary end points were VHE and liver dysfunction. RESULTS: In total, 252 patients were recruited. The commonest disease etiology was brain tumors (27%, 69), followed by aneurysmal subarachnoid hemorrhage (SAH; 26%, 65). VPA was prescribed for primary seizure prophylaxis in 110 patients (44%). The mean daily dose was 1148 mg for a mean duration of 48 months. The mean serum VPA level was 417 µmol/L. In total, 92 patients (37%) were prescribed an additional AED, the most common being phenytoin (65%, 60/92). The mean serum ammonia level was 47 µmol/L. In total, 28% (71/252) of patients had VAH and only 0.7% had VHE. Independent factors were aneurysmal SAH (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.1-4.2), concomitant phenytoin (aOR 1.9; 95% CI 1.0-3.5), and phenobarbital (aOR 4.6; 95% CI 1.1-20.0). No associations with VPA dose, duration, serum levels, and liver function were observed. CONCLUSIONS: Although VAH is common among neurosurgical patients, VHE is rare. Patients with aneurysmal SAH or on concomitant enzyme-inducing AEDs are at risk. Clinicians should be vigilant for VHE symptoms in these patients.