Severe Neurological Dysfunction Causing Respiratory Complications in a 2-year-old Male with Zellweger Spectrum Disorder: Initiating End-of-life Care

Introduction: Zellweger spectrum disorders (ZSD) are a group of peroxisome biosynthesis disorders with clinical manifestations including craniofacial abnormalities, hepatorenal involvement, and profound neurological dysfunction, predominately distinctive hypotonia. The majority of infants with ZSD do not survive past one year of life with the most common causes of death being respiratory failure, apnea, and infection. However, there are few case reports that document the presentation of and differential diagnosis for apneic episodes in ZSD. Our objective is to add to current literature on the presentation of neurologic respiratory compromise in ZSD and how this can be used to initiate end-of-life care discussion and appropriate management.

Case Description: We present a 2-year-old male with ZSD with characteristic leukodystrophy and chronic liver disease who was admitted for progressive feeding intolerance and worsening “breath-holding” episodes. His apneic episodes occurred multiple times per day, lasting 30 to 60 seconds and were associated with decreases in oxygen saturation to as low as 20%, resolving with blow-by oxygen and physical stimulation. He also demonstrated stiffening and perioral cyanosis during these episodes. An EEG demonstrated that some, but not all, episodes were associated with rhythmic discharges thought to represent reflex anoxic tonic seizures. Brain MRI prior to hospitalization demonstrated findings consistent with characteristic leukodystrophy. The frequency of the patient’s apneic episodes decreased and there were no electrographic associations following initiation of levetiracetam and supplemental oxygen by nasal cannula. He was discharged with hospice care on supplemental oxygen and anti-epileptic therapy and passed away four months later.

Discussion: The differential diagnosis for apnea in this patient included cyanotic breath-holding spells, seizures, and central apnea due to progression of CNS dysfunction. Our patient’s apnea spells were unprovoked and not associated with strong emotional stimuli as typically seen with cyanotic breath-holding spells. Given the presence of leukodystrophy involving the brainstem on MRI, it was concluded his apnea spells heralded the onset of impending central respiratory failure. This case highlights the importance of distinguishing between apnea due to epileptic seizures, which would be managed with anti-epileptics, and apnea due to decreased central respiratory drive, which has more serious implications for disease progression and setting goals of care. In this setting, levetiracetam was used to decrease the frequency of anoxic seizures and improve patient comfort.

Conclusion: A thorough evaluation of apnea in ZSD patients allows us to distinguish between causes that can be managed medically versus causes that are indicative of poor prognosis and would benefit from a palliative care discussion. This case also reinforces the role for anti-epileptics and supplemental oxygen in treatment of ZSD especially in children who are at high-risk for anoxic seizures. Properly identifying the root of apnea in ZSD patients allows us to better counsel families regarding disease progression and guide palliative care.