Nivolumab Induced Encephalopathy in a Man With Metastatic Renal Cell Cancer

A Case Report

Jindřich Kopecký; Ondřej Kubeček; Tomáš Geryk; Birgita Slováčková; Petr Hoffmann; Miroslav Žiaran; Peter Priester


J Med Case Reports. 2018;12(262) 

In This Article

Case Presentation

A 63-year-old white man with no significant comorbidities was diagnosed as having mRCC affecting his right kidney with metastatic spread in the Th11 vertebra and multiple pulmonary sites (Figs. 1a–c, 2a). He underwent a cytoreductive nephrectomy in December 2015. A histological examination was consistent with clear cell carcinoma, predominantly grade 2–3 (focally grade 4) with small areas of sarcomatoid differentiation and necrosis. The tumor stage was assessed as pT1b pN1 cM1. He was sent to the Comprehensive Cancer Center of the University Hospital in Hradec Králové, where he started therapy with sunitinib (50 mg daily, 4 weeks on/2 weeks off schedule) in December 2015. Considering the bone metastases, treatment with denosumab was started simultaneously. Owing to poor tolerability (nausea, fatigue, and anorexia) of the treatment, the schedule was changed to 2 weeks on/1 week off. Due to progressive back pain, combined analgesic therapy with opiates was required (oxycodone, transdermal fentanyl patches). Disease progression was documented in his lungs and spine after 4 months on sunitinib in April 2016. His progressive back pain resulted in hospital admission to perform analgesic radiotherapy to the Th 9–12 area with a dose of 20 Gy in five fractions on 5 consecutive days. He developed diarrhea during the hospitalization. A possible infectious etiology was ruled out with microbiological stool examination, as well as examination for Clostridium difficile and its toxin, and he was started on symptomatic therapy with an antidiarrheal treatment (diphenoxylate hydrochloride 2.5 mg three times a day) and probiotics.

Figure 1.

Frontal, sagittal, and axial computed tomography scan demonstrating a destructive mass affecting Th11body (see arrows) from April 2016 (ac) and August 2016 (df)

Figure 2.

Axial contrast-enhanced computed tomography scans of the thorax showing tumor regression (see arrows) April 2016 (a) and August 2016 (b)

After finishing radiotherapy, nivolumab therapy was started in May 2016 within an expanded access program at an absolute dose of 300 mg every 14 days. Both diarrhea and back pain were gradually resolving during treatment, enabling dose reduction of the opiates. Our patient completed a total of six doses of nivolumab with no laboratory or clinical signs of adverse effects.

However, 14 days following the last dose of nivolumab, he reported a change in behavior and a history of uncontrollable movements. His family started to say that he was strange and restless. He personally felt very well when taking nivolumab and the pain was even improving. He was fully aware of the uncontrollable movements, and although he could think rationally, he was not able to influence or stop them.

There was no family history of neurological or mental illness, and he denied any head trauma or neurological disorders in the past. A physical neurological examination revealed no significant findings in his head and peripheral nerves, but there were mild generalized choreatic movements of his upper extremities and head. A psychiatrist described our patient as cooperative, with pronounced choreatic movements of the entire body. His behavior was described as social, without signs of hostility or aggression, and at a reasonable psychomotor tempo. His mood was described as mildly dysphoric in response to the current situation of somatic manifestations. Laboratory tests showed no marked abnormalities. The only medication he was on at that time was a transdermal fentanyl patch (100 mcg/hour changed every 3 days), and he intermittently used antidiarrheal medications (diphenoxylate hydrochloride 2.5 mg or probiotics based on Lactobacillus acidophilus metabolites); during the sunitinib treatment, he irregularly used metoclopramide 10 mg, but he denied any history of neuroleptic use. Because of a serious suspicion of a possible side effect associated with immunotherapy, he was admitted to our hospital on 11 August 2016. A general overview of the timeline of the case report is shown in an additional file (see Additional file 1).

Additional File 1

CT (computed tomography) of his chest, abdomen, and pelvis showed signs of tumor regression in his lungs and bones (Figs. 1d–f, 2b). CT of his brain ruled out brain lesions or infiltrative brain damage. Because of the deterioration of choreatic movements, a magnetic resonance imaging (MRI) of his brain was performed. There were no signs of any tumor lesion. However, the MRI revealed a symmetrical, pathologically increased signal within the basal ganglia consistent with possible inflammatory involvement of these structures (Figure 3).

Figure 3.

Susceptibility-weighted imaging magnetic resonance imaging of the brain showing (see arrows) an areaof inflammatory increased signal within the basal ganglia (August 2016)

Serum laboratory tests for infection and autoimmune diseases were negative. A cerebrospinal fluid (CSF) examination yielded negative results for bacterial and viral involvement and for the presence of malignant cells. Specific neuroimmunological examination of the CSF showed only mild inflammatory changes without any evidence of tissue destruction and no signs of primary infectious etiology. Anti-paraneoplastic antigen Ma2 (anti-PNMA2) IgG class autoantibodies were the only positive findings. Flow cytometry of CSF demonstrated a majority of lymphocytes (approximately 61%); most of the lymphocyte population was represented by T cells (approximately 95%), with the dominant proportion being CD4+ helper T cells (Figure 4).

Figure 4.

Flow cytometry gating of cerebrospinal fluid. a Side scatter versus CD45 plot for identification of basic population of leucocytes. b Identification of T (CD3+) and B (CD19+) cells. c Identification of Th (helper) cells (CD4+) and d Tc (cytotoxic) cells (CD8+). SS side scatter

According to the recommendations for the management of irAE, high-dose intravenously administered corticosteroid therapy was started: Solu-Medrol (methylprednisolone) 2 mg/kg per day. Trimethoprim/sulfamethoxazole was administered simultaneously to prevent possible infectious complications: 960 mg twice a day (BID) twice a week. Despite the high dose of intravenously administered corticosteroid therapy, there was further deterioration of choreiform movements. The choreiform, athetoid, and ballistic movements spread to his lower limbs and trunk. The choreiform movements were so intense that our patient was unable to rest or lie on a bed. Furthermore, he developed a paranoid hallucinatory syndrome with suicidal thoughts. He was started on antipsychotic therapy (clonazepam 2 mg per day, haloperidol 15 mg per day, olanzapine 20 mg per day) after consultation with a psychiatrist and a neurologist and he experienced partial improvement. Considering the lack of a significant effect of corticosteroid therapy, the administration of infliximab at a dose of 5 mg/kg was started. However, infliximab did not achieve any clinical effect.

Our patient and his family insisted on discharge from our hospital. According to the conclusion of a psychiatric examination, he was pronounced capable of signing an against-medical-advice discharge form and was discharged on 23 August 2016. An early out-patient visit to administer a further dose of infliximab was scheduled, and he was duly informed about the importance of doing so. However, he did not come to visit and refused any further treatment despite the provided information about possible adverse consequences.

He was eventually admitted to the standard ward on 13 September 2016, presenting with a fever and soporific state (Glasgow Coma Scale 5) on admission. Because of urinary retention (initially 1000 ml) and elevated levels of C-reactive protein, we suspected urinary infection, and he was started on intravenously administered amoxicillin/clavulanic acid 3.6 g/day and intravenously administered hydration. No other laboratory abnormalities were found. He partially regained consciousness after 2 days of treatment, with clinical manifestations of aggression and choreiform movement as described above. Therefore, therapy with antipsychotics and corticosteroids was reintroduced. However, his condition started to deteriorate again, and he developed bronchopneumonia. His level of consciousness started to deteriorate again, and he died 4 days following admission.

An autopsy confirmed the histology of clear cell renal cancer with metastatic para-aortic lymph nodes and necrotic Th11 vertebra, probably due to necrotic metastasis rather than radiotherapy-induced focal necrosis. Considering the clinical suspicion of aseptic meningitis, his brain was extensively examined. Its weight was 1480 g, and there were no macroscopically notable findings. A histological examination revealed inconclusive areas, suggesting focal lymphocytic meningitis of the entire brain—the cerebrum, brainstem, and cervical spinal cord (Figure 5a)—and multiple perivascular lymphocytic infiltrates, which were most prominent in the basal ganglia on both sides; these findings were consistent with the MRI examination (Figure 6a). The perivascular infiltrates localized in the frontal lobe and basal ganglia were immunohistochemically analyzed for surface markers of CD4 and CD8 T cells (Figs. 5b, c and 6b, c). The ratio of CD4+/CD8+, which is typically 3:1 in aseptic meningitis, was unusually low (approximately 1:1) in both sections.

Figure 5.

Histological samples of the brain (× 100 magnification). a Hematoxylin and eosin staining showing lymphocytic meningitis. b Immunohistochemical staining of affected brain tissue for CD4+ and c CD8+ markers

Figure 6.

Histological samples of the basal ganglia (× 100 magnification). a Hematoxylin and eosin staining of perivascular infiltration. b Immunohistochemical staining of perivascular area of basal ganglia for CD4+ and c CD8+ markers