Multifocal disseminated necrotizing leukoencephalopathy as severe central nervous system toxicity from nivolumab therapy for Hodgkin lymphoma: a case report
Article information
Abstract
Nivolumab, a monoclonal antibody approved in 2014 as an immune checkpoint inhibitor, offers benefits in cancer treatment but can cause serious neurological complications, including multifocal disseminated necrotizing leukoencephalopathy. We report a case of severe central nervous system toxicity in a 13-year-old boy with Hodgkin lymphoma who was treated with nivolumab following an inadequate response to multiple lines of chemotherapy. After six cycles of nivolumab, the patient developed multifocal disseminated necrotizing leukoencephalopathy, presenting with altered mental status, seizures, and neurological deficits with magnetic resonance imaging (MRI) findings of extensive white matter involvement, rendering him completely disabled. This case highlights the potential for disabling neurological complications associated with immune checkpoint inhibitors, emphasizing the importance of early detection through regular neurological assessment and MRI surveillance. The case also underscores the need for careful patient selection and monitoring when using nivolumab to mitigate the risk of severe central nervous system toxicity.
Introduction
Nivolumab is a human monoclonal antibody (immunoglobulin G4) that has been utilized as an oncologic drug in the immune checkpoint inhibitor class since its U.S. Food and Drug Administration (FDA) approval in 2014, providing unprecedented and durable clinical benefits in patients with metastatic melanoma and other malignancies [1]. Immune checkpoints, such as programmed cell death-1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), are receptors on the surface of activated CD8-positive T cells that function as brakes on the immune system’s anticancer response. By targeting these inhibitory or stimulatory T-cell molecules, immune checkpoint inhibitors like nivolumab activate T cells to attack and kill tumor cells. However, this unrestrained immune activation can also lead to the immune system attacking healthy tissue, resulting in autoimmune diseases, including neurological complications [2]. In this case report, we present a severe and disabling complication of nivolumab-related central nervous system toxicity following six cycles of treatment as an escalation therapy for Hodgkin lymphoma.
Case Report
A 13-year-old boy, previously healthy until the age of 7 years, presented to our institute with a previous diagnosis of stage IV-B Hodgkin lymphoma. His history started with a comprehensive evaluation at a specialized tertiary care center, based on which he was treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, followed by radiation for bulky disease in the mediastinum and neck. One year later, a whole-body positron emission tomography-computed tomography (PET-CT) scan revealed recurrent fluorodeoxyglucose (FDG)-avid disease, prompting a second-line chemotherapy regimen with gemcitabine and vinorelbine, which led to a partial response. Due to persistent disease, the patient underwent salvage therapy with brentuximab and ICE (ifosfamide, carboplatin, and etoposide). Subsequent progression of the porta hepatis lesion necessitated treatment with nivolumab, which resulted in a partial response. After six cycles of nivolumab (3 mg/kg every 2 weeks), a PET-CT scan showed no FDG-active uptake, and the patient maintained independent daily activities, including communication and ambulation.
One month after completing nivolumab therapy, the patient developed vision disturbances, potentially indicative of Anton syndrome, accompanied by confusion and inappropriate responses, such as misidentifying his father as his mother. Clinical examination revealed hemodynamic stability, decreased power in all limbs, intermittent disorientation, and a Glasgow Coma Scale score of 13 to 14; the patient maintained the ability to obey commands and open his eyes spontaneously. Despite walking with assistance and clear speech production, his answers were often unrelated to the posed questions. Initial brain magnetic resonance imaging (MRI) showed bilateral cortical and subcortical hyperintensities in the posterior parietal, occipital, temporal, and left frontal regions, as well as in the corpus callosum splenium, with associated hemorrhagic areas. Postcontrast imaging demonstrated diffuse cortical/pachymeningeal enhancement extending bilaterally to the tentorial leaflet (Figure 1).
Brain magnetic resonance imaging showing extensive loss of gray-white matter differentiation and parenchymal swelling predominantly involving the left frontal lobe, with lesser involvement of the left medial thalamus, right medial frontal lobe, and cortical-subcortical regions of the bilateral parietal lobes
There are patchy areas of involvement in the cortical temporal lobes, accompanied by diffuse cortical swelling and T2/fluid-attenuated inversion recovery (FLAIR) signal alteration. Additionally, cystic encephalomalacia with gliosis is observed within the bilateral parietal, temporal, and occipital lobes, extending into the bilateral temporal lobes, more prominently on the right side. Postcontrast imaging shows diffuse cortical/pachymeningeal enhancement extending bilaterally to the tentorial leaflet. The images are T2-weighted (A), FLAIR images (B), diffusion-weighted imaging (C), and contrast-enhanced T1-weighted (D).
Two weeks later, the patient’s condition worsened, and he was admitted to the hospital with right-sided hemiplegia, aphasia, and encephalopathy. He also exhibited persistent head movements that suggested seizure activity, and that were confirmed by electroencephalogram as subclinical seizures. Despite treatment with midazolam and escalating doses of multiple antiseizure medications, his seizures remained refractory. His serum paraneoplastic antibody panel was negative. Comprehensive cerebrospinal fluid analysis showed white blood cells (WBC) of 62 cells/µL (mainly lymphocytic), red blood cells (RBC) of 3 cells/µL, protein of 539 mg/dL, and glucose of 2.43 mg/dL with negative cultures, polymerase chain reaction for viral panel (cytomegalovirus, enterovirus, herpes simplex virus type [HSV] 1, HSV-2, human herpesvirus 6, human parechovirus, varicella-zoster virus), acid-fast bacilli, gram stain, and paraneoplastic/autoimmune antibodies. A follow-up MRI showed significant swelling in the right frontal lobe, right insular cortex, left basal ganglia, and anterior corpus callosum, with loss of gray-white matter differentiation and diffuse heterogeneous enhancement. New hyperintense foci were noted in the left cerebral peduncle and left midbrain/pons, raising concerns for acute necrotizing encephalopathy rather than primary disease recurrence (Figure 2). Despite receiving empiric antibacterial, antiviral, and antifungal treatments to address potential infectious causes, four antiepileptic medications to manage seizures, along with dexamethasone and intravenous immunoglobulin for suspected autoimmune involvement, the patient’s condition showed no improvement.
Brain magnetic resonance imaging demonstrating significant swelling of the right frontal lobe, right insular cortex, left basal ganglia, and anterior corpus callosum, with marked loss of gray-white matter differentiation
There are T2 hyperintense foci in the left cerebral peduncle and left aspect of the midbrain/pons. The image also shows cortical atrophy and cystic encephalomalacia in the left frontal lobe, insular cortex, and areas of abnormal signal intensity in the left thalamus, with confluent T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity in the left frontal parenchyma. Additional findings include cortical atrophy and cystic encephalomalacia in the bilateral parietal, temporal lobes, and hippocampi. Postcontrast imaging shows heterogeneous cortical and subcortical enhancement. The images are T2-weighted (A), FLAIR images (B), diffusion-weighted imaging (C), and contrast-enhanced T1-weighted (D).
A subsequent MRI 1 month later revealed evolving bilateral multifocal cerebral parenchymal cystic encephalomalacia and gliosis with hemosiderin deposition and without new diffusion restriction or enhancement (Figure 3). A repeated cerebrospinal fluid analysis showed WBC of 2 cells/µL, RBC of 1 cells/µL, protein of 394 mg/dL, and glucose of 5.03 mg/dL with negative cultures. Given the extensive necrotizing brain lesions and the lack of response to treatments, the medical team transitioned him to palliative care due to the poor prognosis.
Brain magnetic resonance imaging illustrating extensive gliosis and cystic encephalomalacia involving the bilateral frontal and insular regions, bilateral temporal and parietal lobes, insular cortex, hippocampi, left basal ganglia, and anterior corpus callosum
There is also evidence of global brain volume loss with ventriculomegaly. Postcontrast imaging shows no new enhancement. The images are T2-weighted (A), fluid-attenuated inversion recovery images (B), diffusion-weighted imaging (C), and contrast-enhanced T1-weighted (D).
The patient was transferred to his local hospital where his condition remained static, characterized by uncontrolled seizures, generalized spasticity, loss of communication abilities, and complete dependence on others for all activities of daily living. He remained alive and managed by both local hospital and home health care for 2 years.
Written informed consent was obtained for publication of this case report and accompanying images.
Discussion
Since its FDA approval in 2014, nivolumab has been associated with a spectrum of serious neurological adverse events. The overall incidence of neurological complications in patients receiving nivolumab is reported to be between 2% to 4%, with more severe events occurring in fewer than 0.2% to 0.4% of cases. When nivolumab is used in combination with CTLA-4 inhibitors, such as ipilimumab, the rate of complications may increase significantly, reaching up to 14% [3]. The autoimmune neurological complications resulting from nivolumab use can affect any part of the neuraxis, including the brain, spinal cord, nerve roots, neuromuscular junction, muscles, and peripheral nerves. A significant majority (60%–80%) of these complications occur early, within the first 4 months of therapy initiation. The severity of these neurological complications varies, with mild events (grades 1–2) presenting as nonspecific neurological symptoms, such as headache, dizziness, or paresthesia. In contrast, more severe events (grades 3–4) can manifest as debilitating conditions, including myasthenia gravis, inflammatory myopathies, autoimmune encephalitis, vasculitis, and multiple sclerosis-like diseases [4].
Multifocal disseminated necrotizing leukoencephalopathy is a rare but serious neurological complication associated with nivolumab therapy, characterized by a broad spectrum of clinical symptoms including altered consciousness, confusion, fever, headaches, seizures, cognitive impairment, and focal neurological deficits. Diagnosis is typically made after excluding other potential causes, such as infections, postinfectious encephalitis, metastatic or paraneoplastic syndromes, and vasculitis. Radiologically, this condition is identified by high signal intensity on imaging that involves at least 25% of the white matter [5]. In our patient, more than 70% of the white matter was affected, indicating a particularly severe form of this complication. The extensive involvement underscores the critical and aggressive nature of this condition.
To minimize the neurological side effects of nivolumab, early detection and continuous monitoring are crucial. Regular, thorough neurological examinations are mandatory for all patients undergoing this therapy. Early recognition of side effects allows prompt intervention before the condition worsens. In cases of mild neurological complications, therapy interruption can be considered; however, permanent discontinuation of nivolumab is mandatory in life-threatening complications, such as encephalitis [6]. Unfortunately, in our patient, catastrophic complications occurred one month after the last dose of nivolumab.
Typical MRI findings associated with nivolumab-related neurological complications include demyelinating lesions, encephalitis, and vasculitis. A careful review of MRI results, correlated with clinical symptoms and the timing of nivolumab infusions, is important, as these neurological changes can mimic metastatic disease. Patients who develop new white matter lesions should be seriously considered for discontinuation of nivolumab therapy, with an alternative agent allocated [4-6]. Patients treated with nivolumab may benefit from regular MRI surveillance to detect potential neurological complications early, particularly in high-risk cases, even in the absence of neurological symptoms.
Once neurological complications of nivolumab, particularly encephalitis and multifocal necrotizing leukoencephalopathy, occur, the drug should be permanently discontinued. High-dose intravenous corticosteroids, such as methylprednisolone at 1 to 2 g daily for 5 days, should be initiated promptly. This may be followed by a course of oral prednisolone at 1 mg/kg/day, with a slow taper over 4 to 6 weeks. If symptoms persist despite steroid use, other immunosuppressive therapies, such as intravenous immunoglobulin or plasma exchange, may be warranted to manage ongoing neurological complications [4-6]. In our patient, immunomodulatory therapies, including dexamethasone and intravenous immunoglobulin, were administered over the course of management. However, the patient’s condition remained unchanged, likely due to the irreversible brain damage caused by multifocal necrotizing leukoencephalopathy.
This case underscores the critical importance of recognizing the potential for severe and disabling central nervous system toxicity as a rare but serious complication of nivolumab therapy. While nivolumab and other immune checkpoint inhibitors have revolutionized the treatment of various malignancies by harnessing the body’s immune system, this case illustrates the substantial risks associated with their use. The development of multifocal disseminated necrotizing leukoencephalopathy in this patient serves as a stark reminder of the necessity for vigilant monitoring throughout treatment, as well as the need for heightened awareness among clinicians to detect early signs of neurological involvement. Prompt intervention is crucial when such symptoms arise, as early identification and management may mitigate the extent of central nervous system damage and improve patient outcomes. This case also highlights the importance of a multidisciplinary approach, including neurology, oncology, and critical care teams, to optimize care for patients experiencing severe adverse effects of immunotherapy. The therapeutic benefits of nivolumab must be balanced against the risk of severe toxicity, especially in patients with pre-existing neurological risk factors, emphasizing the need for close monitoring and early intervention to maintain a reasonable safety profile.
Notes
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Conceptualization, Project administration, Supervision, Validation: Algahtani H; Data curation: all authors; Formal analysis: Algahtani H, Shirah B, Bin Saeed A; Visualization: Algahtani H, Shirah B; Writing - original draft: Algahtani H, Shirah B, Alameen MN, Alqahtani AA; Writing - review & editing: all authors