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Therapeutic intervention
Neurological immune-related adverse events of ipilimumab
  1. Ilja Bot1,2,
  2. Christian U Blank3,
  3. Willem Boogerd1,
  4. Dieta Brandsma1
  1. 1Department of Neurology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands
  2. 2Department of Neurology, University Medical Centre Nijmegen St Radboud, Nijmegen, The Netherlands
  3. 3Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands
  1. Correspondence to Dr Ilja Bot, Department of Neurology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands; i.bot{at}neuro.umcn.nl

https://doi.org/10.1136/practneurol-2012-000447

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    Introduction

    Until recently, dacarbazine was the only registered chemotherapeutic drug for systemic treatment of metastatic melanoma. Patients with progressive metastatic melanoma during dacarbazine treatment can now be treated with ipilimumab, a human monoclonal antibody directed against the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor. Due to the binding of ipilimumab to the CTLA-4 receptor, the T lymphocyte mediated immune inhibition is decreased, enhancing the immune offensive against the tumour. In two phase III studies, patients with metastatic melanoma treated with ipilimumab had increased median survival compared to those in control groups (median overall survival: 6.4 vs 10.1 months (ipilimumab), hazard ratio for death 0.66; p=0.003;1 median overall survival: 9.1 (dacarbazine) vs 11.2 (dacarbazine+ipilimumab) months, HR for death 0.72; p<0.001).2 Currently, ipilimumab is first line therapy for metastatic melanoma in the USA and second line therapy in Europe. There are ongoing studies of ipilimumab treatment in prostate, small cell and non-small cell lung cancer.

    However, the increased immune response can also lead to immune-related adverse events (irAEs). Clinicians should be aware that neurological symptoms in patients with metastatic melanoma are not always due to central nervous system metastases, but can also be caused by ipilimumab. Here, we describe three patients with metastatic melanoma who developed neurological symptoms due to irAEs induced by ipilimumab.

    Case 1

    In January 2011, a 66-year-old man received ipilimumab to treat a lymph node metastasised melanoma. After three courses, he developed continuous, severe headache. Neurological examination was normal. He had decreased serum levels of sodium, thyroid-stimulating hormone, free T4, luteinising hormone and testosterone. MRI scan of the brain showed clear enlargement of the pituitary gland and thickening of the infundibulum with homogenous contrast enhancement. We diagnosed ipilimumab-induced immune-related hypophysitis with diabetes insipidus. We stopped his ipilimumab and started oral prednisone (60 mg/day), with testosterone and thyroid hormone supplementation. Within 2 days of starting prednisone, the headache improved completely. At last follow-up, in December 2011, he had no complaints but still depended on testosterone and corticosteroid supplementation. After ipilimumab treatment, he has had no other antitumour treatment, as the melanoma metastases were stable.

    Case 2

    In January 2011, a 51-year-old man known to have progressive metastasised melanoma started ipilimumab treatment. After one course, he developed severe headache and fever (temperature=40°C). Neurological and blood examinations were normal. MRI of the brain showed a known, stable, small cerebellar metastasis. Cerebrospinal fluid (CSF) opening pressure was increased (29 cm H2O), with an increased total protein (0.87 g/l (0.15–0.45)), a mild pleocytosis (20 white blood cells/µl (≤5)) but with no malignant cells. PCRs for neurotrophic viruses and bacterial cultures of the CSF were negative. We diagnosed an immune-related meningitis induced by ipilimumab. One day after starting oral dexamethasone (8 mg/day), his body temperature normalised, and 2 days later the headache disappeared. At last follow-up in October 2011, he had no neurological complaints. The cerebellar metastasis and liver metastases were stable, but there was a new metastasis in the adrenal gland.

    Case 3

    In January 2008, a 63-year-old man started ipilimumab because of a progressive metastasised melanoma. Three weeks after the fourth course, he developed paraesthesias of his feet and fingertips and an unsteady gait. On examination, he had a mild dyspnoea, normal muscle strength, normal tendon reflexes at the arms, absent tendon reflexes in the legs and decreased gnostic and vital sensibility of the feet. His gait was unsteady and Romberg's test was positive. The following day, he developed a mild tetraparesis, with sensory loss in both hands and feet and generalised areflexia. MRI of the cervical spine was normal. CSF examination showed an increased total protein level (0.89 g/l) and no malignant cells. Nerve conduction studies found median and ulnar sensory responses were absent with low amplitude compound muscle action potentials, increased distal motor latencies and normal conduction velocity in median and ulnar nerves. H-reflexes of the tibial nerve were prolonged. This acute sensorimotor axonal neuropathy with increased CSF protein and normal cells was diagnosed as axonal Guillain–Barré syndrome. He started on intravenous immunoglobulin treatment (0.4 g/kg, five consecutive days). The muscle strength of all limbs slightly increased. However, 3 days after starting intravenous immunoglobulin he died from respiratory insufficiency. We did not institute artificial resuscitation because of lack of treatment options for the progressive metastatic melanoma and through following his own wishes.

    Discussion

    These three patients indicate that neurological symptoms in metastasised melanoma in the new ipilimumab treatment era are not always due to central nervous system metastases. We have described patients with hypophysitis, meningitis and Guillain–Barré syndrome, all irAEs induced by ipilimumab.

    To understand the antitumour and immune-related mechanisms of action of ipilimumab, one should know about the normal T lymphocyte response. During a normal T lymphocyte response, the T lymphocyte receptors TCR and CD28 have to bind the antigens on the surface of antigen presenting cells in order to stimulate T cell proliferation. During this phase, the CTLA-4 receptors are upregulated and move to the cell surface of the T lymphocytes. Subsequently, the CTLA-4 receptor binds the antigen presenting cells antigen B7 with a higher affinity than the CD28 receptor, inactivating the T lymphocyte proliferation. Ipilimumab binds to the CTLA-4 receptor on T lymphocytes. This binding blocks the inhibitory feedback system of the T cell mediated immune response. This leads to an ongoing T cell proliferation and a highly activated T cell response to the tumour, but also potentially to the patient's own tissue.3 The latter explains the high incidence of irAEs in patients treated with ipilimumab. In previous studies, 14%–77% of patients treated with ipilimumab developed irAEs, most frequently enterocolitis, dermatitis and hypophysitis. About half of the irAEs were reported as Common Toxicity Criteria grade III or IV.1 ,2 Approximately 5%–17% of patients treated with ipilimumab develop a hypophysitis. Hypophysitis can cause severe headache, nausea, vomiting, fatigue and visual field defects.4 Approximately 20% of hypophysitis patients develop diabetes insipidus due to inflammation of the posterior pituitary gland, as in our patient.5 The diagnosis of a hypophysitis is based on MRI of the brain and abnormal serum endocrine markers. On MRI, the pituitary gland and infundibulum are usually enlarged and enhance homogeneously or heterogeneously with gadolinium.6 Endocrine disturbances include depressed adrenocorticotropic hormone, testosterone (male subjects), thyroid-stimulating hormone, cortisol and free T4 serum levels.5 After stopping ipilimumab and treating with glucocorticosteroids, the symptoms usually diminish within days or weeks. On MRI, the pituitary gland normalises and pituitary functions often partially recover. Nearly all patients show prolonged adrenocortical insufficiency and many need long term cortisol replacement.7

    Two previously reported patients developed immune-related meningitis while taking ipilimumab.7 ,8 The symptoms of immune-related meningitis are headache, mild neck-stiffness and fever. Contrast MRI of the brain may show meningeal enhancement. CSF examination usually shows a mild lymphocytic pleocytosis and increased protein level.

    Previous studies of Guillain–Barré syndrome found increased levels of ganglioside directed T lymphocytes.9 Therefore, the enhanced T lymphocyte proliferation from ipilimumab probably plays a role in the pathogenesis of ipilimumab-induced Guillain–Barré syndrome. The same applies to hypophysitis and immune-related meningitis, as T lymphocytes are important in the pathogenesis of these illnesses.10 ,11 There have been only two reported cases of Guillain–Barré syndrome during ipilimumab treatment so far.12 ,13 In retrospect, we would have treated our patient with prednisolone in addition to intravenous immunoglobulin. Furthermore, the treatment was incomplete as the patient declined artificial respiration.

    Finally, there are two other rare neurological irAEs induced by ipilimumab: myositis and inflammatory autonomic neuropathy.14 ,15

    Ipilimumab treatment should be stopped and glucocorticosteroids (prednisone or dexamethasone) started in patients with Common Toxicity Criteria grade III and IV neurological irAEs. Neurological symptoms often diminish within a few days or weeks and glucocorticosteroids can be tapered. However, unrecognised neurological ipilimumab-induced irAEs can be life-threatening.

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    Footnotes

    • Contributors IB: wrote the paper. DB: supervisor. CUB and WB: minor revisions.

    • Competing interests None.

    • Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Neil Scolding, Bristol, UK.

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