Severe Chemoradiotherapy Toxicity in a Pediatric Patient with Leigh Syndrome and Grade IV Isocitrate Dehydrogenase-Mutant Astrocytoma: A Case Report

Introduction

We present a case of a pediatric patient with Leigh syndrome and a grade 4 isocitrate dehydrogenase (IDH)-mutant astrocytoma, a previously undescribed co-occurrence. Leigh syndrome is a necrotizing encephalomyelopathy, typically presenting within the first 2 years of life [1]. It is a mitochondrial disorder caused by at least 75 different gene mutations involving both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). These mutations lead to disruption of all 5 oxidative phosphorylation complexes (Figure 1A) and manifest clinically as diffuse spongiform lesions throughout the basal ganglia, thalamus, cerebellum, brainstem, and spinal cord [2–4]. Clinical presentation begins with loss of head control, developmental delay, hypotonia, feeding difficulty, and decreased growth [3]. Disease progression leads to dysarthria, dystonia, dysphagia, failure to thrive, ataxia, epilepsy, and respiratory muscle weakness [3]. As brainstem involvement and encephalopathy worsens, patients with Leigh syndrome have a high incidence of death from respiratory failure [3]. Leigh syndrome generally has a poor prognosis and the median age of death is 2.4 years [5].

Gliomas with IDH 1/2 mutations are rare in pediatric populations, occurring in only 9% of pediatric gliomas [6]. In pediatric patients, IDH-mutant astrocytomas have a better prognosis than their wild-type IDH counterparts [7]. This explanation is multifactorial; however, one factor is the role of the IDH mutations in regulating the tumor-mediated immune response [8]. IDH-mutant gliomas have been found in 0.5% of glioma patients aged 0–9 years and in 16.1% of glioma patients aged 10–21 years [6]. Therefore, the frequency of IDH-mutant gliomas increases with age. High-grade IDH 1/2-mutant astrocytomas have 5-year and 10-year overall survival rates of 84% and 22%, respectively, whereas low-grade IDH 1/2-mutant astrocytomas have 5-year and 10-year overall survival rates of 95% and 88%, respectively [6]. The treatment regimen includes gross total resection followed by a combination of temozolomide and radiotherapy. IDH 1/2-mutant astrocytomas have a relatively high sensitivity to radiation [9].

We present a case of a pediatric patient with Leigh syndrome and a grade 4 IDH-mutant astrocytoma. To our knowledge, this is the first case documented in the literature of a pediatric patient with both Leigh syndrome and a grade 4 IDH-mutant astrocytoma. Over the course of the patient’s treatment with chemoradiotherapy, excessive toxicity was observed. We aim to explore the connections between the patient’s response to the toxicity of the chemoradiotherapy, the IDH-mutant astrocytoma, and his underlying mitochondrial disorder.

Case Report

The objective of this case report is to outline the unusual clinical course of a patient with Leigh syndrome and an astrocytoma, which resulted in excessive toxicity from chemoradiotherapy. The patient was a 10-year-old boy with a complex medical history of craniosynostosis, epilepsy, infantile spasms, mitochondrial myopathy/Leigh syndrome, global developmental delay, G-tube dependence, obstructive sleep apnea, nephrolithiasis, and echogenic kidneys with normal kidney function. He initially presented to the Children’s Hospital Emergency Department (CH ED) via Emergency Medical Services (EMS) in May 2024 for a chief concern of congestion and oxygen desaturation to 84%. He was admitted to the Pediatric Intensive Care Unit (PICU) for acute hypoxic respiratory failure and upper respiratory infection. On hospital day 4, the patient was discharged home after being treated for viral pneumonia; however, he re-presented the next day to the CH ED via EMS for evaluation of hypoxemia and increased oxygen requirement. During his second hospitalization, he developed acute anisocoria and a brain CT was ordered. The CT showed a right frontoparietal subcortical mass with a 9-mm right-to-left midline shift (Figure 2A). The neurosurgery team performed a craniotomy and gross total resection, noting that the tumor had cystic and solid components as well as surrounding vasogenic edema. The pathology report confirmed a WHO grade 4 IDH-mutant anaplastic astrocytoma. The patient was started on chemoradiotherapy per the described standard of care (Children’s Oncology Group protocol ACNS0423) with 42 days of temozolomide 100 mg daily, administered via gastrostomy tube, and 60 Gy radiation over 30 fractions [10]. Lomustine (CCNU) was planned to be added following completion of chemoradiotherapy. The patient started chemoradiotherapy 22 days after the craniotomy.

Approximately 1 month after starting chemoradiotherapy, the patient’s platelets dropped below 25 000. A platelet transfusion was given for grade IV platelet toxicity and the decision was made to stop temozolomide with 4 doses remaining in the treatment cycle. The radiation consisted of 4600 cGy in 23 fractions to the area of T2 signal abnormality and a 1400 cGy boost in 7 fractions to the tumor resection bed. Brain MRI conducted at the end of the chemoradiotherapy treatment revealed post-surgical changes in the right frontoparietal astrocytoma resection, with increased nodular enhancement and diffusion thought to be secondary to post-radiation changes or radiation necrosis (Figure 2B).

Approximately 1 month after stopping temozolomide (2 months after starting chemoradiotherapy), the patient’s platelet levels improved. A decision was made to start maintenance chemotherapy per ACNS0423 with 160 mg oral temozolomide for 5 days every 6 weeks and a single 90 mg oral dose of CCNU every 6 weeks, with close platelet monitoring. Within 1 month of starting maintenance therapy, bleeding from the gums and bruising were noted, likely secondary to grade II platelet toxicity, and a platelet transfusion was given. One week later, the patient presented to the oncology clinic for follow-up with hematuria and grade III platelet toxicity, which prompted a platelet transfusion and decision to decrease chemotherapy dosage.

Six days later, the patient presented to the CH ED via EMS for epistaxis and desaturations, which required resuscitation and packed red blood cell and platelet transfusions and initiation of mechanical ventilation. Neutropenia was also noted and vancomycin, cefepime, and azithromycin were started for empiric antimicrobial coverage. He subsequently developed hypovolemic shock due to alveolar hemorrhage, which was complicated by acute respiratory distress syndrome. Sputum cultures were ultimately positive for Stenotrophomonas maltophilia and Pseudomonas aeruginosa and antibiotics were changed to monotherapy with levofloxacin. Brain MRI on admission showed hemorrhage within the surgical bed with stable peripheral enhancement, likely representing post-radiation changes (Figure 2C).

Over the next month, the patient developed breakthrough seizures and new central apnea. A repeat brain MRI was obtained which showed new enhancement adjacent to the resection cavity and along the right corticospinal tracts at the cerebral peduncle (Figure 2D). Following conversations with neurosurgery and radiation oncology, MRI changes were felt to represent tumor recurrence rather than radiation necrosis, and a 6-week course of dexamethasone 4 mg twice daily was started to treat potential post-radiation toxicity/necrosis.

Six weeks later, a repeat brain MRI was obtained due to loss of gag and cough reflex and decreased response to painful stimuli. It showed significant disease progression, with increased size and mass effect of a right hemispheric mass and extension into the right thalamus, cerebral peduncles, and new involvement of the pons. Increased mass effect at the foramen of Monro with early right uncal herniation was also noted (Figure 2E). Dexamethasone was increased to 4 mg, 4 times daily for management of cerebral edema, and goals of care conversations were continued with the family with a decision to continue full supportive care. The patient continued to have progressive neurologic deterioration and intermittent transfusion requirements. His platelet counts never normalized, more than 3 months after discontinuation of chemotherapy. Significant decompensation developed on hospital day 110, with a drop in Glascow Coma Scale score to 3–4, with concern for continued tumor progression and loss of brainstem function. On hospital day 129, the patient was compassionately extubated, and he died peacefully with his family at his bedside. A timeline of all key events and toxicities is outlined in Figure 3.

Discussion

RELATIONSHIP BETWEEN MITOCHONDRIAL DISORDERS AND IDH-MUTATED GLIOMAS:

Due to a dearth of research published on patients with mitochondrial disorders like Leigh syndrome and IDH-mutant astrocytoma, little is known about the connection between these diseases. However, the relationship between mitochondrial dysfunction and IDH-mutant gliomas in general has been explored more closely. Leigh syndrome leads to a disruption of all 5 complexes involved in oxidative phosphorylation, due to mtDNA mutation, limiting the efficacy of oxidative phosphorylation in energy production (Figure 1A). However, gliomas are known to shift energy metabolism from oxidative means to glycolytic pathways outside the mitochondria, which is known as the Warburg effect [11]. In our patient’s case, however, the glycolytic pathway was also compromised due to an IDH mutation. Under normal conditions, mitochondrial IDH isoforms are essential for the reductive carboxylation of alpha-ketoglutarate to isocitrate, which eventually is transformed into citrate [11]. This role of IDH makes the enzyme critical to mitochondrial energy metabolism under hypoxic conditions (Figure 1B). Gliomas are commonly accompanied by mitochondrial abnormalities that alter standard energy production through mechanisms like apoptotic pathway dysregulation, alterations in membrane potential, and mutations to enzymes in the citric acid cycle [11]. Additionally, dysfunction of microtubules in mitochondria may promote glioma cell motility, leading to metastasis [11].

Additionally, there is a link between oxidative stress-related genes and prognosis for glioma patients. Reactive oxygen species (ROS) can alter genetic material and lead to tumorigenesis [12]. Mitochondrial dysfunction and mutations in oxidative stress-related genes can lead to an inability to balance redox equilibrium, causing an increase in ROS, which can alter various pathways for cellular function like proliferation and metabolism [12]. Therefore, oxidative stress can have a strong influence on glioma progression.

Given the known correlation between mitochondrial dysfunction and glioma proliferation, we hypothesize that the patient’s mitochondrial disorder impacted oxidative phosphorylation and enhanced the Warburg effect by prematurely shifting the metabolic pattern of the glioma from oxidative phosphorylation to glycolytic metabolism for survival. To investigate this further, more research needs to be done into the molecular mechanism by which mitochondrial disorders may increase the survival of IDH-mutant gliomas, and the possibility of increased susceptibility to gliomas in patients with mitochondrial disorders.

RELATIONSHIP BETWEEN MITOCHONDRIAL DISORDERS AND CHEMOTHERAPY AND RADIATION TOXICITY:

Mitochondria are the main producers of ROS. Mitochondrial dysfunction caused by Leigh syndrome increases patient risk for oxidative damage, which results in deficits to cellular functions (Figure 1A) [13]. Additionally, IDH-mutant cells compensate for the dysfunction by increasing the number of mitochondria in IDH-mutated cells, which can pose a risk for further increased ROS production [14]. One function of the mitochondria is to mediate cell death through mitochondrial outer membrane permeabilization, which allows for cytochrome c release to stimulate the apoptotic cascade [13]. In cells with excessive ROS, this apoptotic signaling may be compromised, which could lead to toxicity during treatments that stimulate cell death, such as radiation and chemotherapy (Figure 1C).

Multiple drugs have been shown to cause mitochondrial toxicity through a variety of different mechanisms. Antineoplastic agents are known to cause increased production of ROS, leading to oxidative stress and damage to mitochondria [15]. In regard to our patient, he received temozolomide, which is an alkylating agent known to cause damage to mtDNA, affecting the respiratory chain [16]. As Leigh syndrome also affects all the complexes in the respiratory chain, it is possible he exhibited increased toxicity from temozolomide due to compounded deficits in oxidative phosphorylation. Additionally, oxidative stress is known to lead to temozolomide resistance through the NF-kB signaling cascade [12]. The combination of temozolomide resistance implicated by oxidative stress and direct damage of temozolomide to mtDNA and the respiratory chain may also explain the excessive toxicity our patient experienced from chemoradiotherapy. To our knowledge, there is no literature describing the mitochondrial effects of CCNU; however, as it is also an alkylating agent, we suspect there are similar effects to those seen with temozolomide.

Conclusions

Overall, this case represents a novel presentation of a pediatric patient with Leigh syndrome and an IDH-mutant grade 4 astrocytoma. This patient experienced excessive toxicity to chemoradiotherapy, which manifested as platelet toxicity, radiation necrosis, and neurological decline. Our analysis of the current literature highlights a likely correlation between mitochondrial dysfunction, IDH-mutant gliomas, and toxic sensitivity to chemotherapy and radiation therapy that should be further explored. More research into these relationships is warranted to guide future treatment of pediatric patients with mitochondrial disorders and IDH-mutant gliomas. Due to limited research into these relationships, clinicians should use caution in extrapolating practices based on single-case data as presented in this case report.