Transient Hyperammonemic Encephalopathy in a Child with Relapsed Acute Lymphoblastic Leukemia and Severe Tumor Lysis Syndrome

Abstract Idiopathic hyperammonemia (IHA) is a severe condition, which has been reported in intensive chemotherapy and bone marrow transplantation. This case elucidates the diagnostic dilemma in children undergoing initiation of chemotherapy and developing severe disorders of qualitative and quantitative consciousness in the presence of hyperammonemia (HA) and lactic acidosis. The role of mitoxantrone as a causative agent for IHA in children is elusive. Children undergoing chemotherapy are often in a poor general condition, and the clinical presentation of HA is heterogeneous. This case should be a reminder for clinicians to check for HA in children with tumor lysis syndrome and acute neurological deterioration.


Introduction
Hyperammonemia (HA) is defined as an elevation of plasma ammonia concentrations above the normal range.2][3][4] The clinical presentation is heterogeneous ranging from mild symptoms like nausea to acute life-threatening conditions with encephalopathy, cerebral edema, and coma. 1 Since the 1980s, there have been reports on HA following intensive chemotherapy and bone marrow transplantation.The term idiopathic hyperammonemia (IHA) has been suggested to describe this condition. 2,3IHA is defined as elevated concentration of ammonia in serum with normal test results for liver enzymes, and no evidence for inborn errors of metabolism or other identifiable causes. 2,3[5][6][7][8][9][10] There are several available treatment options for HA.Many of them were adopted from the management of inborn

Abstract
Idiopathic hyperammonemia (IHA) is a severe condition, which has been reported in intensive chemotherapy and bone marrow transplantation.This case elucidates the diagnostic dilemma in children undergoing initiation of chemotherapy and developing severe disorders of qualitative and quantitative consciousness in the presence of hyperammonemia (HA) and lactic acidosis.The role of mitoxantrone as a causative agent for IHA in children is elusive.Children undergoing chemotherapy are often in a poor general condition, and the clinical presentation of HA is heterogeneous.This case should be a reminder for clinicians to check for HA in children with tumor lysis syndrome and acute neurological deterioration.
errors of metabolism with HA, such as arginine (improvement/stimulation of nitrogen excretion by the Krebs-Henseleit cycle).The main goals are the removal of nitrogen by enhancing nitrogen excretion by hemodialysis and ammonia-trapping therapy (alternate pathway therapy with sodium benzoate, sodium phenylacetate or sodium phenylbutyrate) and the reduction of exogenous nitrogen load (optimization of enteral/parenteral nutrition).To reduce the intestinal source of ammonium lactulosis and neomycin/rifaximin are used.Treatment should be started early and be regularly reevaluated. 4e describe a unique clinical phenotype of IHA associated with marked tumor lysis syndrome (TLS) after the administration of dexamethasone and mitoxantrone.The role of mitoxantrone as a causative agent for IHA in children is elusive.

Case Presentation
Our patient, an 8-year-old male, presented with common lymphoblastic leukemia (central nervous system [CNS] not involved) and received chemotherapy according to the CoALL-08/09 protocol (German Co-operative Study Group for Treatment of Acute Lymphoblastic Leukemia 08-09, Low-Risk group) from March 2017 to October 2017.From October 2017 to February 2018, he was on oral maintenance chemotherapy with methotrexate and 6-mercaptopurine.In February 2018, our patient presented with progressive fatigue and reduced general condition.Laboratory analysis revealed anemia (7.5 g/dL, reference range (RR): 11.8-14.8),thrombocytopenia (7.0 G/L, RR: 195-464), and leukopenia (2.73 G/L, RR: 3.50-14.00).The diagnostic workup revealed a relapse of common acute lymphoblastic leukemia.The treatment was started according to the IntReALL-HR protocol (International Study for Treatment of High Risk Childhood Relapsed Acute Lymphoblastic Leukemia 2010, High-Risk group) with dexamethasone (20 mg/m 2 , intravenously, twice a day) from therapy day 0 to 5 and mitoxantrone (10 mg/m 2 , intravenously, once a day) on therapy day 0. Furthermore, he received a concomitant intravenous hydration therapy (4,000 mL/m 2 per day).He developed severe TLS with hyperuricemia (9.2 mg/dL, RR: 1.9-5.0),hyperphosphatemia (7.4 mg/dL, RR: 3.0-5.4),hyperkalemia (6.6 mmol/L, RR: 3.3-4.7),and lactic acidosis (pH ¼ 7.22, RR: 7.35-7.43,lactate ¼ 13.3 mmol/L, RR: 0.5-2.2,base excess: À14.6 mmol/L, RR: À1.5 to 3.0).The coagulation parameters were slightly abnormal (international normalized ratio: 1.5, RR: 0.8-1.2, and partial thromboplastin time: 45 seconds, RR: 25-42).The liver function studies were normal (total bilirubin, alanine-aminotransferase, and γ-glutamyltransferase).There was no evidence for acute kidney injury.Repeated blood cultures remained sterile.On therapy day 1, he developed a qualitative and quantitative disorder of consciousness in an undulating manner with confusion, agitation, disorientation, anxiousness, and somnolence, respectively.An electroencephalography revealed a generalized slowing, consistent with metabolic encephalopathy (►Fig. 1).A computed tomography of the brain showed no apparent morphological involvement of the CNS.A magnetic resonance imaging on the following day confirmed the results.A sonography of the abdomen revealed a hepatosplenomegaly and diffuse leukemic infiltration of liver, spleen, gut, and kidneys.There was no evidence for hepatic veno-occlusive disease.With a lumbar puncture, malignant cells and a CNS infection could be excluded.Strikingly, the concentration of ammonia in serum was significantly elevated (213 µmol/L, RR: 16-53).Sampling was performed by using a triple-lumen Hickman catheter.The sample was transported refrigerated.The measurement was performed immediately upon arrival at the laboratory.Additionally, analysis of organic acids in urine, amino acids, and carnitine/acylcarnitine in plasma did not indicate an inborn error of metabolism associated with HA.Moreover, a comprehensive workup for hepatotropic infectious diseases and autoimmune liver diseases showed no significant findings.
The TLS could be managed sufficiently with hydration, rasburicase, and forced diuresis.The patient received crystalloid fluids only.Our management of HA comprised lactulosis three times a day (3 Â 3.3 g) and rifaximin twice a day (2 Â 200 mg) via nasogastral tube to reduce the intestinal source of ammonium and sodium benzoate (100 mg per kg per day, continuously) intravenously for ammonia-trapping therapy.After a subsequent plateau phase with slightly elevated and fluctuating results for the concentration of

Discussion
IHA is generally regarded as a diagnosis of exclusion.Since we do not have any identifiable causes for HA in our patient, we suspect a case of IHA.IHA was previously described in the literature in the context of high-dose chemotherapy for hematological malignancies, [3][4][5][6][7] chemotherapy in solid tumors, 11 bone marrow transplantation for malignant, 2,3,8-10 and nonmalignant diseases (Hurler syndrome) and solid organ transplants (lung transplant). 12,13IHA is a rare, but frequently lethal complication, despite ammoniatrapping therapy and hemofiltration. 5,6Thus, we hypothesize a mild and unusually early-onset form of IHA in our patient, who received dexamethasone and mitoxantrone on the first therapy day.
The occurrence of IHA during initiation of chemotherapy for leukemia is highly unusual and was described in a pediatric population only twice: once on day 15 in a 15year-old male with newly diagnosed acute lymphoblastic leukemia and initiation of chemotherapy with steroids only 14 and another time in a case of a 13-month-old male with a lethal IHA on day 35 after induction therapy with seven different chemotherapeutic drugs. 6he only report of IHA in combination with mitoxantrone described the case of a 59-year-old woman who received a polychemotherapy including mitoxantrone. 15However, mitoxantrone was linked to mitochondrial cardio toxicity in a dose-dependent manner during long-term use in a mouse model. 16An acute adverse reaction to mitoxantrone cannot be ruled out in our patient.Yet, a study in de novo diagnosed lymphoblastic leukemia could not show a higher toxicity for mitoxantrone compared with daunorubicin. 17any chemotherapeutic agents have been linked to IHA: vinciristine, busulfan, cyclophosphamid, etoposide, methotrexate, cytarabain, daunomycin, and amsacrine. 4,5,18However, some chemotherapeutic agents seem to cause less devastating outcomes when it comes to HA, as for instance asparaginase and 5-Fluorouracil. 4Some reports suggest specific adverse drug effects in these cases.For instance, treatment with asparaginase for acute leukemia has been linked to transient HA. [19][20][21] Asparaginase hydrolyses asparagine in aspartic acid and ammonia as a mechanism of action.3][24] The intermediate product of 5-Fluorouracil, fluoracetate, is regarded as a direct inhibitor of the urea cycle, thus leading to elevated plasmatic ammonia concentrations. 4,25or a functioning homeostasis of ammonia a functioning Krebs-Henseleit cycle and a balanced ratio of protein anabolism and catabolism are crucial. 26The capacity of the Krebs-Henseleit cycle varies in humans without clinical relevance. 19,27However, when HA is combined with a previously unknown latent ornithine transcarbamylase deficiency, a defect of the urea cycle, lethal outcomes have been reported. 23Since we do not have evidence for underlying enzymatic defects in the Krebs-Henseleit cycle in our patient and no chemotherapeutic agents with known transient HA as a side-effect were used, we hypothesize that our patient had a mild form of IHA.A transient form of HA due to massive acute protein breakdown in TLS should be considered as a differential diagnosis.In addition, liver infiltration with leukemia blasts may have exaggerated the metabolic decompensation.

Conclusion
Children undergoing chemotherapy are often temporarily in a poor general condition and the clinical presentation of HA is heterogeneous.This could be one explanation for HA being potentially under-recognized and thus under-diagnosed in TLS.
This case report should be a reminder for pediatric intensive care doctors to check for HA in children with TLS and acute neurological deterioration.Routine measurements of plasma ammonia concentrations in high-risk patients could lead to earlier diagnosis.
In addition, latent metabolic disorders and drug-induced HA should be taken into consideration.
To conclude, in children with acute alterations in consciousness of unknown origin during chemotherapy and especially with TLS, HA should be considered and closely monitored.

Fig. 1
Fig. 1 Electroencephalography with generalized slowing and periodic pattern well consistent with metabolic encephalopathy.

Fig. 2
Fig. 2 Plasmatic concentration of ammonia versus hours since onset of clinical symptoms.The dashed line indicates the threshold (¼ 53 µmol/L) of pathological concentration of ammonia in serum.