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sugestoes ao manual de alta suspeição MS 

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Systemic Therapy for Melanoma: ASCO Guideline Update - PubMed

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Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a pot …

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Correspondence to Dr Anna C Pavlick; acp9008med.cornell.edu ✉Corresponding author.

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Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0

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Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination…

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Current Treatment Paradigms for Advanced Melanoma with Brain Metastases

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The therapeutic management of melanoma brain metastases has undergone a profound revolution during recent decades. Optimal integration of systemic therapies with local treatments seems to represent the strategy to pursue in order to maximize clinical outcomes, stressing the need for real multidisciplinary care in this setting of patients. However, the current approach in the clinics does not necessarily reflect what the current guidelines state, and several pending issues are present, from the ideal therapeutic sequence between stereotactic radiosurgery (SRS) and drug administration to the current role of surgery and whole brain radiotherapy (WBRT), all of which need to be addressed. This narrative review aims to provide practical help for navigating the current controversies, with an eye towards possible future advancements in the field, which could help to obtain a comprehensive molecular characterization of the tumor and a more personalized patient-centered therapeutic approach.

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by 1,2 1,2,3,* and

Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, 1011 Lausanne, Switzerland

Lundin Family Brain Tumor Research Centre, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, 1011 Lausanne, Switzerland

Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, 1011 Lausanne, Switzerland

Author to whom correspondence should be addressed.

1. Introduction

1.1. Encephalitis

Encephalitis is an inflammation of the brain parenchyma, often involving the cortical or deep gray matter, with or without the involvement of white matter, meninges, or spinal cord. It generally results from a direct viral infection or an autoimmune process that may be postinfectious, paraneoplastic, or idiopathic. The typical clinical presentation is a combination of fever, headache, and altered mental status (behavior, personality, cognition, and consciousness). Focal neurological deficits, seizures, movement disorders, and/or autonomic instability are often associated. Unfortunately, symptoms remain largely nonspecific, and given the multiple etiologies, diagnosis of encephalitis remains challenging [ 1]. The typical diagnosis relies mostly on clinical symptoms and workup requires serum and cerebrospinal fluid (CSF) analysis, neuroimaging, and electroencephalography (EEG) [ 2]. Autoantibody testing should be considered in all cases, especially those with a recognizable autoimmune encephalitis phenotype [ 3].

Based on the International Encephalitis Consortium [ 4], encephalitis is defined as an altered mental status lasting 24 h or more, without alternative cause and at least two of the following:

Fever above 38 °C within the last 72 h.

New focal neurological signs.

New epileptic seizure activity, unrelated to a pre-existing condition

Signs of encephalitis on MRI.

Abnormal EEG findings consistent with encephalitis.

However, most patients with encephalitis will not present a severely depressed Glasgow coma scale (GCS) score on admission and may even perform well on basic cognitive assessments such as mini-mental-status (MMS), or Montreal Cognitive Assessment (MoCA) tests, and might, especially in autoimmune or paraneoplastic forms, lack fever or CSF pleocytosis [ 1].

Encephalitis can be broadly classified as infectious or autoimmune [ 5, 6]. Infectious encephalitis is beyond the scope of this review, is mostly viral in origin, and has been reviewed by Tyler et al. in the New England Journal of Medicine [ 2]. Autoimmune encephalitis (AE) is a group of non-infectious immune-mediated inflammatory diseases. In some (but not all) cases of AE, a specific autoantibody directed against a CNS antigen can be detected in the serum or cerebrospinal fluid [ 7]. The most common etiologies are associated with antibodies against leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), and in patients under 50, autoantibodies against the N-methyl-D-aspartate receptor (NMDAR) are observed at similar frequencies [ 8]. In addition to these two autoantibodies, more than a dozen new types of autoantibodies have been identified in the last 15 years, and their incidence is increasing [ 7]. These antibodies are typically directed against extracellular domains of neuroglial proteins [ 9].

Autoimmune encephalitis is often observed as a paraneoplastic syndrome. One of the best and most comprehensively described models for this is the association of ovarian teratomas with anti-NMDAR AE [ 10], with up to 25% of patients with anti-NMDAR AE having an ovarian teratoma [ 11]. Paraneoplastic neurological disorders are usually subacute at onset, progressive due to accelerated neuronal death, have a poor prognosis, and are typically detected months to years before a tumor is diagnosed [ 12, 13]. Brain imaging may show no abnormal findings. Testing for anti-NMDAR antibodies in the cerebrospinal fluid may be useful, but is not necessary to make a diagnosis of CNS toxicity related to an autoimmune process [ 14]. In contrast to classical autoimmune encephalitis, patients with paraneoplastic etiology show significantly less clinical improvement when treated with steroids and intravenous immunoglobulin [ 15]. In paraneoplastic encephalitis, a cancer elicits an immune-mediated response directed against CNS antigens, primarily by molecular mimicry. Specific autoantibodies associated with particular tumors ( Table 1) are typically directed against intracellular targets [ 13]. For example, up to 50% of patients with gamma-aminobutyric acid B receptor [GABABR] [ 16] and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) [ 17] encephalitis have been shown to have cancer. Notably, the presence of onconeural antibodies such as anti-Hu and anti-Ma2 are almost always associated with an underlying cancer in adults [ 13]. Interestingly, the incidence of such paraneoplastic encephalitis increases with checkpoint inhibitors [ 18, 19] and is discussed below.

In addition to the encephalitis described above, which is better defined as limbic encephalitis, paraneoplastic neurologic syndromes may include encephalomyelitis, sensory neuronopathy, opsoclonus-myoclonus, enteric neuropathy, rapidly progressive cerebellar syndrome, and Lambert-Eaton myasthenic syndrome. These conditions have been reviewed by Graus et al. [ 13]. The term encephalomyelitis (EM) only applies to patients presenting neurological dysfunction at multiple sites, affecting both central and peripheral nervous systems, including dorsal root ganglia, peripheral nerve, or nerve roots [ 13]. Rapidly progressive cerebellar syndrome (RPNS), as its name suggests, is a rapidly progressive, severe, and bilateral cerebellar syndrome limiting daily activities in less than 3 months and is characterized by the absence of substantial cerebellar atrophy on imaging [ 13]. RPNS has only been described in small patient series but appears to be associated with anti-Yo and Tr/delta/notch-like epidermal growth factor-related receptor (DNER) antibodies [ 13]. Opsoclonus-myoclonus syndrome (OMS) consists of involuntary, chaotic, multidirectional, high-frequency, saccadic movements of the head, trunk, and limbs. Signs of encephalopathy (ranging from confusion to coma) and cerebellar involvement (dysarthria or truncal ataxia) have also been reported. Paraneoplastic OMS in adults is most often associated with SCLC or breast cancer and is mostly associated with anti-Ri antibodies [ 13].

Finally, acute demyelinating encephalomyelitis (ADEM) also constitutes an important cause of non-infectious encephalitis. ADEM is defined as an autoimmune demyelinating disease caused by an autoimmune response. This immune response is thought to be post-infectious or following vaccination, although this has never been proven. It presents as an acute onset encephalopathy associated with polyfocal neurologic deficits preceded by fever, malaise, irritability, somnolence, headache, nausea, and vomiting. It is seen primarily in pediatric populations and is often associated with antibodies to myelin oligodendrocyte glycoprotein [ 20].

1.2. Immune Checkpoint Inhibitors

Over the past two decades, immune checkpoint inhibitors (ICIs) have become a mainstay of cancer therapy, with up to half of metastatic patients in economically developed countries now receiving ICIs [ 21]. ICIs enhance antitumor immunity by blocking immune checkpoint molecules expressed on the surface of T lymphocytes and tumor cells, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) [ 22]. Today, more than 50 different malignancies can be treated with 10 approved ICIs either as monotherapy or in combination in the neoadjuvant, adjuvant, or palliative setting [ 23, 24] ( Table 2). The introduction of ICIs into routine oncology practice has led to increased survival and long-term remissions, even in patients with extensive metastatic cancer [ 21].

ICIs are surface receptors expressed by immune cells that regulate immune homeostasis. PD-1 and its primary ligand PD-L1 are expressed on T cells and tumor cells, respectively, resulting in T cell exhaustion upon interaction. This mechanism is exploited by tumor cells to avoid immune elimination [ 21]. Thus, PD-1/PD-L1 like LAG-3 inhibition acts directly at the tumor site, whereas CTLA-4 inhibition acts mainly during T cell priming when antigen-presenting cells (APC) and the T cells interact in lymph nodes.

2. Checkpoint Inhibitor-Induced Encephalitis

The exact mechanism by which checkpoint inhibitors lead to CIIE is not fully understood. It is thought to involve an immune response to brain tissue, as seen in autoimmune and paraneoplastic encephalitis. Risk factors for developing CIIE include a history of autoimmune disease, prior radiation therapy, and concurrent infections.

There is growing interest in the relationship between the gut-brain axis, neuroinflammation, and the role of ICIs. The microbiota-gut-brain axis is a complex and multi-faceted network that connects the brain and gut through a variety of immunological, hormonal, and neural signals. An imbalance in gut microbiota (dysbiosis) can affect and trigger neuroinflammation and microglial activation [ 39]. In murine models, alteration in the gut-brain axis has been shown to disrupt the blood-brain barrier and to be linked to CNS autoimmune diseases such as encephalomyelitis and multiple sclerosis [ 40]. Similarly, it is postulated that the gut microbiota may influence the effectiveness of ICIs by directly regulating immune cells and modulating the immune system through the gut-brain axis [ 41]. Whether the gut-brain axis and the microbiota play a role in CIIE remains largely unknown but represents an important emerging topic of research.

2.1. Diagnosis of CIIE

Diagnosis of CIIE can be challenging because symptoms can be subtle and indistinguishable from other causes of encephalitis, including viral infections. Any patient with altered mental status and fever without an obvious cause should be treated as having a central nervous system (CNS) infection until proven otherwise [ 42]. CIIE remains a diagnosis of exclusion ( Table 3), but it is important for healthcare providers to consider CIIE in the differential diagnosis of patients receiving checkpoint inhibitors who present with a decreased level of consciousness, confusion, headache, fever, seizures, and/or focal neurologic deficits. The time interval between initiation of ICI therapy and the onset of symptoms is highly variable, ranging from less than a week to up to 2 years, with a median of 6 to 9 weeks [ 27, 37]. In cases of uncertainty, neuronal damage biomarkers such as neurofilament light chain (NfL) and S100B can quickly signal neuroaxonal damage. These markers, though non-specific, help in flagging patients for further neurological evaluation, particularly when antibody tests are negative [ 43].

Diagnosis is usually based on a combination of clinical presentation, imaging studies, and laboratory tests. CSF analysis must be performed to rule out infectious etiologies (bacterial, fungal, or viral meningoencephalitis) and leptomeningeal disease. Typical CSF findings in patients with CIIE are pleocytosis with predominantly lymphocytes and elevated protein concentrations. Glucose levels are unaffected. CSF polymerase chain reaction (PCR) for herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus (VZV) should be ordered. Since we are dealing with cancer patients, a cytological examination of the cerebrospinal fluid is recommended.

A cerebral MRI is part of the workup to rule out brain metastases, ischemia, and intracranial hemorrhage. An EEG can rule out nonconvulsive status epilepticus. A complete laboratory work-up is performed, including a complete blood count, a C-reactive protein (CRP) test, a comprehensive metabolic panel (including ammonia), blood concentrations of vitamins (B1, B12), an evaluation of the pituitary hormonal axes with thyroid-stimulating hormone (TSH) and cortisol. Blood and urine cultures should be obtained. Antineutrophil cytoplasmic antibody (ANCA) titers should be measured to rule out vasculitis. If intoxication is suspected, a toxicology screen should be performed [ 28, 44]. There are no specific tests for CIIE; in the case series by Stuby et al., less than 50% of performed MRIs revealed findings consistent with encephalitis. No encephalitis-specific EEG pattern was found, although epileptiform spikes were seen in 30% of EEGs. CSF pleocytosis and elevated CSF protein levels were found in a majority of patients [ 37]. A summary of the diagnostic approach and workup is illustrated in Figure 1.

2.2. Management of CIIE

Immune-mediated encephalitis is generally graded from 3 to 4 and requires permanent discontinuation of ICI. The standard of care is corticosteroids, which should be started as soon as possible after differential diagnoses have been ruled out. The search for autoimmune encephalitis or paraneoplastic antibodies should not delay the initiation of treatment, as they can be quantified even in the presence or after corticosteroids. Intravenous methylprednisolone at a dose of 1 to 2 mg/kg body weight/day is recommended initially [ 45, 46]. In severe cases, the corticosteroid dose may be increased to ≥10 mg/kg daily. With such doses of corticosteroids, adverse events such as delirium, insomnia, hyperglycemia, or immunosuppression should be expected. As usual, in immunosuppressed patients, prophylaxis with trimethoprim/sulfamethoxazole (300 mg, three times a week) and acyclovir (500 mg daily) is indicated. In some cases, corticosteroid treatment becomes chronic, but ideally, treatment should be discontinued if possible. In this case, the steroids should be slowly tapered over a period of at least four weeks [ 45, 46].

In steroid-refractory cases, treatment with intravenous immunoglobulins (IVIG), plasmapheresis, or rituximab should be considered [ 1, 45, 47]. We have successfully treated an NSCLC patient with anti-Hu-positive autoimmune limbic encephalitis on ipilimumab and nivolumab with natalizumab, an antibody that blocks the α4β1 integrin on blood-brain barrier endothelial cells, limiting lymphocyte recruitment into the CNS [ 36].

It is important for healthcare providers to be aware of the risk of CIIE and to closely monitor patients receiving checkpoint inhibitor immunotherapy for signs or symptoms of this complication. Early detection and treatment of CIIE can help improve patient outcomes. Early diagnosis and appropriate treatment improve patient outcomes, and symptom control is achieved in the majority of patients (82%). However, despite optimal management and supportive care, CIIE remains a serious complication with an in-hospital mortality of nearly 20%, depending on the series [ 37].

2.3. Monitoring of the Evolution of CIIE

Neural antibodies are well-recognized biomarkers of autoimmune and paraneoplastic encephalitis and treatment response and outcome largely depend on the targeted antigen. Antibodies against intracellular antigens (anti-Hu, Ma2, Yo) are associated with poor outcomes whereas antibodies against cell-surface antigens (anti-NMDAR, LGI1, CASPR2) are associated with more favorable outcomes [ 43]. Likewise, the prognostic value of neural antibodies has also been demonstrated in CIIE. Paraneoplastic antibodies were found associated with a lower probability of treatment response and higher risk of mortality as opposed to GFAP or neuron-surface antibodies [ 38].

3. Immunotherapy-Induced Acute Demyelinating Encephalomyelitis

Although atypical, Zafar et al. described a case of nivolumab-induced acute demyelinating encephalomyelitis (ADEM) [ 15]. Two weeks after starting palliative nivolumab immunotherapy, a patient with relapsed and metastatic laryngeal squamous cell carcinoma exhibited progressive weakness, altered mental status, and progressive dyspnea requiring intubation. A cMRI showed multiple hyperintense T2 flair white matter lesions without contrast enhancement or restricted diffusion, consistent with acute demyelinating encephalomyelitis. Similar to the encephalitis cases above, 5 days of intravenous methylprednisolone and immunoglobulin (IVIg) therapy allowed gradual improvement of motor symptoms.

4. Activated T Cell-Induced Encephalitis

4.1. Chimeric Antigen Receptor T-Cells

Chimeric antigen receptor T-cells (CAR-T cells) are a new approach in clinical cancer therapy and a form of tumor immunotherapy. The basic idea behind this approach is to harvest the patient's T cells, provide them with receptors specific for tumor surface markers, and return them to the patient where they will eliminate tumor cells.

CAR-T cells are genetically engineered to express a chimeric transmembrane receptor that includes an extracellular single-chain variable fragment (scFv) targeting tumor antigens. This scFv fragment is linked via a hinge and transmembrane domain to intracellular T cell signaling domains. These signaling domains comprise the CD3 zeta chain (CD3ξ) of the T-cell receptor (TCR), which contains the immunoreceptor tyrosine-based activation motif (ITAM), as well as costimulatory domains from CD28 and 4-1BB. To date, all approved CAR-T cell therapies treat hematologic malignancies [ 48]. In total, six CAR-Ts have been approved, four of which are directed against CD19 in B-cell malignancies, primarily diffuse large B-cell lymphoma (DLBCL): axicabtagene ciloleucel (YESCARTA ®) [ 49], tisagenlecleucel (KYMRIAH ®) [ 50], brexucabtagene autoleucel (TECARTUS ®) [ 51]. Lisocabtagene maraleucel (BREYANZI ®) [ 52] and two directed against BCMA in multiple myeloma idecabtagene vicleucel (ABECMA ®) [ 53] and ciltacabtagene autoleucel (CARVYKTI ®) [ 54].

4.2. Chimeric Antigen Receptor T-Cell Related Encephalopathy

CAR-T-related encephalopathy (CRES) is a CAR-T-mediated CNS toxicity associated with significant morbidity and mortality that may hinder the expansion of CAR-T therapies. CRES has recently been renamed immune effector cell-associated neurotoxicity syndrome (ICANS) because similar neurotoxic symptoms have been reported with other immune effector cell-engaging therapies, such as bi-specific T-cell engagers (blinatumomab) [ 55].

ICANS is relatively common, affecting up to 45% of patients with severe, sometimes fatal, neurological symptoms [ 56, 57, 58, 59]. This syndrome has been observed not only with CARs targeting CD19 but also with those targeting CD22 and BCMA. ICANS can occur with CARs containing either CD28 or 4-1BB costimulatory domains, although the incidence varies: up to 45% in patients with CD28-based CARs compared to only 13% with 4-1BB-based constructs [ 60, 61, 62]. The underlying mechanisms of these toxicities are not fully understood, but key features of ICANS include endothelial activation and disruption of the blood-brain barrier, leading to brain edema due to cytokine release by CAR-T cells [ 58, 59, 60, 63, 64, 65]. Indeed, a report by Norelli et al. showed that proinflammatory cytokines and myeloid cells are involved in addition to activated T cells [ 66]. This leakage leads to cerebral edema, hemorrhage, infarction, and necrosis due to intravascular coagulation (DIC) [ 59]. The latter can be measured in the blood of patients with severe neurotoxicity, as they have significantly elevated DIC markers [ 60]. Elevated levels of the excitatory NMDA receptor agonists glutamate and quinolinic acid have also been shown in the cerebrospinal fluid of patients with neurotoxicity [ 67].

Although ICANS can develop without the presence of cytokine release syndrome (CRS), patients typically experience both conditions concurrently (91%). Clinically, CRS resembles septic shock and is characterized by high fever, tachycardia, hypotension, myalgia, respiratory failure, vascular leakage, coagulopathy (disseminated intravascular coagulation, or DIC), and oliguria, which can lead to multiple organ failure in severe cases [ 45, 61, 62]. It is a systemic phenomenon that has the potential to affect any organ, including the nervous system. The severity of ICANS is proportional to that of the CRS and is, therefore, closely related to in vivo T-cell expansion, with ICANS occurring when CAR-T levels are highest [ 59, 60]. ICANS typically present 4-5 days after CAR T-cell administration, but delayed onset occurring 3-4 weeks after CAR T-cell treatment has been reported [ 57]. Clinically, ICANS follows a stereotypical progression, beginning with somnolence, confusion, attention deficit, disorientation, and mild aphasia. These symptoms can then worsen to include aphasia, hallucinations, delirium, myoclonus, and tremors. In severe cases, patients may experience generalized seizures and encephalopathy, leading to coma and potentially death [ 45, 60, 66]. EEG findings typically show nonspecific diffuse generalized slowing triphasic waves. Such patients risk developing posterior reversible encephalopathy syndrome (PRES) and acute necrotizing encephalopathy [ 59, 64].

Unlike conventional CRS, for which tocilizumab is routinely used, ICANS does not respond well to IL-6R blockade. Intravenous methylprednisolone and antiepileptic drugs (levetiracetam) appear more effective in this situation [ 60, 64]. Plasmapheresis has been proposed as it is used in thrombotic thrombocytopenic purpura, which shares similar endothelial cell activation mechanisms, but this approach has yet to be validated [ 68].

ICANS grading and management guidelines have been published by the American Society of Bone Marrow Transplantation ( Table 4) [ 64].

4.3. Bispecific T Cell Engager Immunotherapy (BiTEs)

Bi-specific T-cell engagers (BiTEs) can be considered at the interface between ICI and CAR-T, as they are an antibody-based, infused drug, but directly confer a novel T-cell specificity. To date, five BiTEs have been approved, blinatumomab (BLINCYTO ®), a CD-19-targeting construct indicated as second-line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia [ 69], tebentafusp (KIMMTRAK ®), a bispecific gp100 peptide-HLA-directed CD3 T-cell engager indicated for the treatment of HLA-A*02: 01-positive adult patients with unresectable or metastatic uveal melanoma [ 70], glofitamab, (COLUMVI ®) a bispecific CD20-CD3 monoclonal antibody used for the treatment of diffuse large B-cell lymphoma [ 71], mosunetuzumab, (LUNSUMIO ®), also a CD20-CD3 BiTE is used for the treatment of follicular lymphoma [ 72], and finally talquetamab, (TALVEY ®), a humanized GPRC5D-CD3 BiTE is used in the treatment of multiple myeloma [ 73]. Many more are under development and will reach the market soon [ 74].

BiTEs induce systemic AEs similar to CAR T cell toxicity with the typical development of fever, headache, neutropenia, and cytokine release syndrome. However, this therapy is also known to induce neurologic adverse events in up to half of treated patients. These include tremors, seizures, confusion, febrile delirium, (leuko)encephalopathy, and cerebellar ataxia. Up to 30% of patients experience Grade 3 symptoms [ 75, 76]. These nAEs typically occur early in treatment (median onset = 9 days) and are generally reversible and manageable with high-dose dexamethasone (3 × 8 mg/day for 4 days) and interruption of the BiTE infusion. Premedication with 20 mg of dexamethasone IV, administered 1 h prior to BiTE infusion, is recommended to minimize the risk of nAE development. Patients experiencing grade 4 symptoms or seizures should be permanently discontinued. Otherwise, treatment may be resumed once symptoms have resolved to grade 1 or have disappeared. Although not fully understood, BiTE nAEs are thought to result from transient neuroinflammation in the CNS due to endothelial adherence of BiTE-activated T cells [ 75].

5. Chemotherapy-Induced Encephalitis

Chemotherapy is known to induce chemotherapy-induced toxic (leuko)encephalopathy, or "chemobrain", which is clinically characterized by progressive cognitive dysfunction. However, this chronic and progressive form of neurotoxicity is not the only one induced by chemotherapy regimens. In fact, several cytostatic drugs can damage the central nervous system after systemic (intravenous, oral) or topical (i.e., intrathecal, intraventricular, or intraarterial) administration. Cytotoxic drug-associated clinical syndromes are classified into 11 categories: acute encephalopathy, aseptic meningitis, cerebellar dysfunction, cerebral infarction, chronic encephalopathy, cortical blindness, multifocal leukoencephalopathy, posterior reversible (leuko)encephalopathy syndrome (PRES), thrombotic microangiopathy, seizure, and subacute encephalopathy [ 77]. For the scope of this review, we will only discuss systemic chemotherapy applications and acute complications.

As above, a broad differential diagnosis including infectious encephalitis, non-convulsive epileptic status, paraneoplastic syndrome, metabolic disorders, and brain metastasis is to be excluded [ 78]. Cytotoxics commonly associated with acute encephalopathy are 5-fluorouracil (5-FU), cytosine arabinoside (Ara-C), etoposide/VP16 (high dose), ifosfamide (10-15% of patients treated with doses > 1 g/m ²), interferon-α, interleukin-2, methotrexate (MTX), nitrosoureas (high dose), paclitaxel, procarbazine, and tamoxifen (high dose) [ 78]. Table 5 provides a non-exhaustive summary of medications, associated symptoms, risk factors, and management.

Cases of acute encephalopathy and focal neurological deficits require urgent intervention to prevent the development of chronic leukoencephalopathy. Once established, there is no treatment available to reverse the chronic changes. Keeping in mind the absence of consensus on the best management of acute toxicity, several treatment approaches have been investigated with variable success rates. Treatment of MTX complications includes CSF drainage, ventriculo-lumbar perfusion with saline, and glucarpidase, a drug catabolizing an enzymatic cleavage degrading MTX into a non-toxic metabolite [ 81, 82]. Unfortunately, leucovorin, routinely given to rescue patients from systemic MTX toxicities, cannot be given intrathecally. One fatal case has been reported [ 83].

Subacute encephalopathy is rare but may develop days to weeks after administration of certain cytostatic agents such as cisplatin or MTX, presenting as an abrupt onset of confusion, seizures, and focal signs such as hemiparesis or aphasia. It primarily affects children, but isolated cases have been reported in adults [ 86]. The mechanism of neurotoxicity is not well understood. Symptoms usually resolve spontaneously, but fatal outcomes have been observed [ 77].

Cerebellar and brain stem dysfunction with dysarthria, oculomotor disorders, and ataxia are typical complications of cytarabine, usually at cumulative doses over 36 g/m ² [ 77]. Autopsies have revealed widespread Purkinje cell loss. Fortunately, only isolated cases of complication have been reported at lower doses. Risk factors for the development of cerebellar dysfunction include advanced age, renal insufficiency, and elevated alkaline phosphatase. A similar cerebellar syndrome may be seen after treatment with high-dose 5-FU, which is reversible after interruption of therapy, but may recur with re-exposure to the drug [ 77].

Chemotherapy-induced autoimmune-mediated encephalitis is rare but has recently been described. A case of autoimmune encephalitis with oligoclonal bands in the cerebrospinal fluid has been reported in a 10-year-old patient treated for a pure germinoma in the suprasellar region. Her clinical status improved rapidly with steroids [ 87]. Similarly, a rare case of anti-Yo autoimmune encephalitis with confusion, behavioral changes, and seizures was reported in a 66-year-old patient receiving a capecitabine/oxaliplatin treatment [ 88]. Recently, chemotherapy for colorectal cancer has been shown to induce autoantibodies, although the pathophysiology is not yet understood [ 89].

Finally, radiation-induced CNS toxicity continues to be a significant cause of morbidity among cancer patients. Although there have been advances in creating more precise and safer radiation techniques, these improvements have been counterbalanced by the growing use of combined radio-chemotherapy regimens, the advent of radiosurgery, and the rising number of long-term survivors. However, these effects tend to develop over the long term and are due to general cerebral toxicity rather than encephalitis [ 98].

6. Conclusions

Although immunotherapy is revolutionizing cancer treatment and its use is rapidly expanding, it is associated with specific and often serious side effects that must be understood by treating physicians. Immunotoxicity and autoimmunity are common complications of checkpoint inhibitors and CAR T cells. Among the wide range of immune-related adverse events, neurological AEs, particularly encephalitis, are rare but represent an adverse outcome if not managed appropriately. The timing of symptom onset is highly variable, making patient monitoring and diagnosis difficult. Patients developing rapidly evolving confusion under ICI treatment should be suspected of having encephalitis. The diagnostic workup should include blood tests, CSF analysis, cerebral MRI, and an EEG. The treatment of choice relies on intravenous corticosteroids. Alternative treatment options include IVIG, rituximab, natalizumab, and plasma exchange therapy. However, current consensus guidelines are based on empirical data. Prospective clinical trials remain an important priority. Targeted therapies and chemotherapy can also induce encephalopathies to a lesser extent, some specific treatments have been discussed, but the main intervention remains treatment discontinuation.

Author Contributions

Writing-original draft preparation, N.P.D.; writing-review and editing, A.F.H.; funding acquisition, A.F.H. All authors have read and agreed to the published version of the manuscript.

Funding

Lundin Family Brain Tumor Research Centre covered the costs of publication of this review.

Acknowledgments

The authors thank Stéphanie Viguet-Carrin and Frédérique Landuyt for their administrative and editorial support.

Conflicts of Interest

The authors declare no conflicts of interest.

References

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Figure 1. Diagnosis of ICI-induced encephalitis. ( A) Early symptoms, especially confusion, must raise suspicion of encephalitis. ( B) Differential diagnosis to be evoked; ( C) workup to be done. ¹ Metabolic panel: electrolytes, glucose, creatinine, bilirubin, liver enzymes, ammonia, arterial blood gas analysis, vitamins B1 and B12, thyroid function tests, basal cortisol concentration, ANCA; ² autoantibody panel: autoantibodies: AGNA (SOX1), AMPAR1/2, Amphiphysin, CRMP5 (CV2), DPPX, GABAR, GAD65, Hu (ANNA1), Ma1, Ma2, Ri (ANNA2), TG, TPO, TR, VGKC (anti-LGI1, anti-CASPR2), Yo (PCA1), ZIC44; Paraneoplastic antibodies: NMDAR, AMPAR1/2, VGKC (anti-LGI1, anti-CASPR2), Gly, GABAR. Abbreviations: ANCA = antineutrophil cytoplasmic antibody; CRP = C-reactive protein; CSF = cerebrospinal fluid, EEG = electroencephalogram > HSV-1 = herpes simplex virus type 1; HSV-2 = herpes simplex virus type 2, MRI = magnetic resonance imaging; PCR = polymerase chain reaction; SS = sedimentation speed; VZV = varicella-zoster virus. Adapted from [ 37].

Selection of High and Intermediate-Risk Tumor-Associated Autoantibody-Mediated Encephalitis

Autoantibody-Mediated Encephalitis

Related Tumor

High-risk antibodies (>70% paraneoplastic)

Hu

Small and non-small cell lung cancer, neuroendocrine tumors, and neuroblastoma

CV2/CRMP5

Small cell lung cancer and thymoma

Yo

Small and non-small cell lung cancer, breast cancer

Ma2

Testicular cancer, non-small cell lung cancer

SOX1

Small cell lung cancer

PCA2/MAP1B

Small and non-small cell lung cancer, breast cancer

Ri

Small and non-small cell lung cancer, breast cancer

Tr

Hodgkin's lymphoma

KLHL11

Testicular cancer

Intermediate-risk antibodies (30-70% paraneoplastic)

NMDAR

Ovarian or extraovarian teratomas

AMPAR

Small cell lung cancer, malignant thymoma

GABA A/B

Small cell lung cancer

CASPR2

Malignant thymoma

mGluRs

Hodgkin's lymphoma

Approved Checkpoint Inhibitors and Their Indications

Drug Name

Target

First Approval

Indications

Differential Diagnosis and Work-Up

Differential Diagnosis

Work-Up

Infection (sepsis-induced encephalopathy; bacterial,
fungal or viral meningoencephalitis; brain abscess)

Blood tests including culture, CSF analysis including culture and viral PCR (herpes simplex, varicella-zoster), MRI

Brain Metastasis/Leptomeningeal tumor dissemination

CSF analysis, MRI

Metabolic encephalopathy

Blood tests *

Nonconvulsive status epilepticus

EEG

Paraneoplastic limbic encephalitis

Blood tests **, CSF analysis ***, MRI

PRES

MRI

Stroke (ischemia/intracerebral hemorrhage)

MRI

Vasculitis

Blood tests (ANCA), MRI

Grading and Management ICANS
1. Grading of ICANS

ICANS Grade 1 ICANS Grade 2 ICANS Grade 3 ICANS Grade 4

Neurological assessment score (by ICE score)

7-9 (mild
impairment)

3-6 (moderate impairment)

0-2 (severe
impairment)

0 patients in critical condition and/or unable to perform assessment

Depressed level of consciousness (not attributable to other factors (sedation...)

spontaneous awakening

awakens to voice

Awakens only to tactical stimulus

Patient is unarousable or needs vigorous/
repetitive tactical
stimulus.
Stupor or coma

Raised intracranial pressure

NA

NA

Focal/local edema on neuroimaging

Diffuse cerebral edema on neuroimaging; decerebrate or decorticate posturing or cranial nerve VI palsy; or papilledema or Cushing's triad

Seizure

NA

NA

Any clinical seizure that resolves rapidly or non-convulsive seizure on EEG that resolves with
intervention

Life-threatening generalized seizure (>5 min) or repetitive clinical or electrical seizures without return to baseline in between

Motor findings

NA

NA

NA

Deep focal motor weakness such as hemi or paraparesis

2. Management recommendations for ICANS

Grade 1

IV hydration, vigilant supportive care, aspiration precautions

Withhold oral intake of food, fluids & medicines, assess swallowing

Avoid all medications that may cause CNS depression

Agitated patients may be controlled with low-dose lorazepam (0.25-0.5 mg IV q8h) or haloperidol (0.5 mg IV q6h)

Search for and follow a possible papilledema

Cerebral MRI + MRI of the spine if focal peripheral neurological deficits

Lumbar puncture with measurement of opening pressure

Daily 30 min EEG until toxicity symptoms resolve, in the absence of seizure prophylactic levetiracetam q12h

Consider Tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV if concomitant CRS

Grade 2

Consider transferring the patient to ICU if CRES associated with ≥grade 2 ICANS

Supportive care and neurological work-up as indicated for grade 1 ICANS

Tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV if concurrent CRS

Dexamethasone 10 mg IV q6h if refractory to anti-IL-6 or for ICANS without CRS

Grade 3

Transfer to ICU

Supportive care and neurological work-up as indicated for grade 1 ICANS

Anti-IL-6 therapy if associated with concurrent CRS

Dexamethasone 10 mg IV q6h if CRES symptoms worsen despite anti-IL-6 therapy or for ICANS without CRS. Taper once ICANS is resolved to grade 1

Follow papilledema

consider repeat MRI every 2-3 days if persistent CRES ≥ grade 3

Grade 4

ICU monitoring-consider mechanical ventilation for airway protection.

Supportive care and neurological work-up as indicated for grade 1 ICANS.

Anti-IL-6 therapy and repeat neuroimaging as described for grades 2 and 3 ICANS.

High-dose corticosteroids continued until improvement to ICANS grade 1 (methylprednisolone IV 1g/day, followed by a rapid taper: 250 mg q12h for 2 days, 125 mg q12h for 2 days, 60 mgq12h for 2 days).

Stage ≥ 3 papilledema with CSF opening pressure ≥ 20 mmHg: High dose corticosteroids (methylprednisolone IV 1g/d); elevate the head end of patient's bed to 30°; hyperventilation to achieve a partial pressure of arterial carbon dioxide (PaCO ₂) of 28-30 mmHg, but maintained for no longer than 24 h; hyperosmolar therapy with mannitol or hypertonic saline; consider neurosurgery consultation for Ommaya reservoir/drain; consider anesthetics for burst-suppression pattern on EEG; metabolic profiling and daily imaging of the brain to prevent rebound cerebral edema, renal failure, electrolyte abnormalities, hypovolemia, and hypotension

Table 5. Therapy/prophylaxis of chemotherapy-induced CNS toxicity. Adapted from [ 78].

Acute Chemotherapy-Induced CNS Toxicity and Management

Drug

Symptoms

Frequency

Threshold Dosage

Risk Factors

Therapy/
Prophylaxis

Methotrexate (MTX)

Acute reversible encephalopathy

Rare

>0.5 g/m ²

Whole-brain radiotherapy

Frequently self-limiting

Subacute
encephalopathy

Very rare

After 2nd or 3rd iv
application

Increased levels of
Homocysteine

Dextromethorphan

Chronic
encephalopathy

Infrequent after MTX alone

>0.5 g/m ²

Whole-brain radiotherapy, intrathecal MTX

None

Ara-C

Cerebellar dysfunction plus possible acute encephalopathy

Frequent, if dose > 36 g/m ²

cumulative dose
>36 g/m ²

Renal insufficiency,
increased alkaline phosphatase, age > 60, neurological comorbidity

Frequently self-limiting

5-Fluorouracil

Acute
encephalopathy

Rare

Low dihydropyridine dehydrogenase

None

Cerebellar dysfunction plus facultative additional CNS symptoms

Rare

Allopurinol increase,
N-Phosphonoacetyl-
aspartate (PALA)
thymidine

Often self-limiting

Inflammatory
multifocal
leukoencephalopathy

Rare

Levamisole

None

Ifosfamide

Acute encephalopathy

Up to 30%

High dose, renal and
hepatic insufficiency, low albumin

Frequently
self-limiting.
methylene-blue, thiamine

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AMA Style

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APA Style

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Encephalitis associated with cancer therapies is a rare but serious complication that can significantly impact patients' quality of life and it requires prompt identification and management. Over the past two decades, immunotherapy-particularly immune checkpoint inhibitors-has become a cornerstone of cancer treatment, with up to half of metastatic cancer patients in economically developed countries now receiving these therapies.

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Case report

Open access

Published:

Vincent Pillonel 1,2,

Vincent Dunet 3,

Andreas F. Hottinger 1,4,

Gregoire Berthod 1,5,

Luis Schiappacasse 6,

Solange Peters 1,

Olivier Michielin 1,7 &

...

Veronica Aedo-Lopez orcid.org/0000-0003-0629-4508 1

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Journal for ImmunoTherapy of Cancer 7, Article number: 336 (2019) Cite this article

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Abstract

Background

Immune checkpoint inhibitors (ICPis) have revolutionised the treatment of melanoma by significantly increasing survival rates and disease control. However, ICPis can have specific immune-related adverse events, including rare but severe neurological toxicity.

Case presentation

We report a 44-year-old man diagnosed with stage IIIB melanoma who developed metastatic disease (pulmonary and brain metastases) and was treated with stereotactic radiosurgery and nivolumab immunotherapy. He developed asymptomatic multifocal diffuse white matter lesions consistent with active central nervous system demyelination seen on brain MRI. One month after cessation of the immunotherapy, spontaneous regression of the demyelinating lesions was observed, suggesting a nivolumab-related toxicity.

Conclusion

We report the first case of a melanoma patient with an asymptomatic and spontaneously reversible central nervous system demyelination following nivolumab immunotherapy. This case highlights the need for better recognition of such atypical and rare neurological toxicities which could be mistaken for progressive brain metastases. Early recognition and appropriate management are crucial to reduce severity and duration of these toxicities, especially for patients with less favourable evolution.

Background

Immune checkpoint inhibitors (ICPis), ipilimumab and nivolumab, are recombinant human monoclonal antibodies which target cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1) receptor, respectively. By blocking these key immune suppressive molecules on T cell surface, they elicit a potent immune response against cancer cells that managed to hijack these natural inhibitory signals [ 1]. Ipilimumab and nivolumab provide significant clinical benefits in patients with advanced melanoma [ 2, 3, 4, 5, 6, 7, 8, 9] and multiple other tumor types, leading to FDA-approval of ipilimumab in 2011 and nivolumab in 2014 [ 1]. However, immunotherapies may elicit imbalances in immunologic tolerance which can result in excessive unregulated immune response with inflammatory or autoimmune side effects [ 10]. Hence, despite significant clinical benefit, the use of ICPis is frequently associated with a large spectrum of immune-related adverse events (irAEs) [ 2, 3, 4, 5, 6, 7, 8, 9, 11], including rare but severe (grade 3-4) neurological toxicities [ 12, 13, 14]. Patients may develop a variety of neurological disorders including transient peripheral neuropathies, Guillain-Barré syndrome, myositis, myasthenia gravis, or less frequently central nervous system (CNS) toxicity such as hypophysitis, immune encephalitis, vasculitis, aseptic meningitis and multiple sclerosis. These neurological irAEs are yet extensively reviewed [ 12, 13, 14, 15]. However, there has been only few scarce reports of CNS demyelination in association with ICPIs. One case was reported after nivolumab [ 16] and one after ipilimumab [ 17], which were both severe and eventually fatal. One more case of CNS demyelination resulting in neurological symptoms was reported after pembrolizumab, another PD-1 inhibitor [ 18]. Here, we present the first case of a melanoma patient with asymptomatic and spontaneously reversible CNS demyelination following nivolumab immunotherapy.

Case presentation

A 44-year-old Caucasian man was diagnosed in March 2017 with a stage IIIB cutaneous nodular melanoma on the right forearm, with a tumor Breslow thickness of 3.43 mm, without ulceration (pT3a), one clinically detected tumor-involved axillary lymph node (pN1b), and no evidence of distant metastasis (cM0). He was treated with wide local excision, axillary lymph node dissection, and then with high-dose adjuvant ipilimumab monotherapy at 10 mg/kg i.v., according to EORTC 18071 protocol [ 7, 19]. Two days after the first ipilimumab infusion, he developed a persistent grade 2 colitis, which was corticosteroid-resistant, treated with infliximab, and that imposed termination of the treatment.

In September 2017, a follow-up computed tomography (CT) scan revealed pulmonary progression (one unique lesion) and wedge resection of segment 10 of the left inferior lobe was performed. The pathology confirmed metastatic melanoma, programmed death-ligand 1 (PD-L1) positive (60%) and wild-type BRAF. Three months later, subsequent imaging by CT scan and brain magnetic resonance imaging (MRI) revealed metastatic progression in lung with multiple lesions in the left superior and inferior lobe, hilar lymph nodes, and brain with one cerebellar and 4 millimetric contrast enhancing lesions in the frontal white matter. A CyberKnife (Accuray Incorporated, Sunnyvale, California) stereotactic radiosurgery (SRS) was administered 2 weeks later to the 5 cerebral lesions in one single fraction of 24 Gy and an immunotherapy anti-PD1 with nivolumab (3 mg/kg as monotherapy) was initiated. The decision to administer nivolumab as monotherapy was based on the very high PD-L1 positivity (60% of tumor cells), but also to minimize the risk of new irAEs, given his previous ipilimumab-induced corticosteroid-resistant colitis, and knowing that combination of ipilimumab and nivolumab result in more complications [ 3, 12, 13].

Two weeks after the first nivolumab infusion the patient presented with asthenia, headache, and apraxia of the upper right limb with impaired coordination of the right hand, and later developed a grade 1 erythematous maculopapular rash. A brain MRI showed multiple new metastatic brain lesions in the cerebellum, the left frontoparietal cortex, and the brain stem. The lesions were all complicated by perilesional oedema, for which he was administered dexamethasone (1 mg i.d. for 7 days and 5.25 mg tapered over 14 days). There was no evidence of infection and thyroid function studies were normal. Within 1 week, he presented at the hospital after a generalized epileptic seizure with clonic movements of the right-hand side of his body. Electroencephalogram (EEG) recording, performed after the seizure, was considered normal despite the presence of a discreet left temporal slowing. MRI revealed no changes in the known brain metastases and no evidence of ischemic or haemorrhagic events. He was hospitalized and an anti-epileptic treatment was introduced (Levetiracetam 500 mg bid) which prevented a recurrence of the seizures. In January 2018, CyberKnife SRS was administered to treat 7 new small metastasis (24 Gy in one fraction) and 3 large ones (35 Gy in five fractions) (Fig. 1 a).

Comparison of the appearance of metastasis and demyelinating lesion in this patient. a The patient was treated by stereotaxic radiotherapy in January 2018 for several brain metastases, the largest being located at the cortico-subcortical junction of the left precentral gyrus. The lesion appeared hypointense with central necrosis and large perilesional oedema on T2-weighted images, had complete ring enhancement on post-contrast T1-weighted images, and increased normalized cerebral blood volume (nrCBV = 1.2) and cerebral blood flow (nrCBF = 1.7) ratios on perfusion weighted images. b In June 2018, he developed several demyelinating lesions, the largest being located in the left superior frontal gyrus. Contrary to the brain metastasis, the lesion was juxtacortical, had little perilesional oedema, partial ring enhancement (i.e. open ring sign), and low nrCBV and nrCBF

In February 2018, the immunotherapy with nivolumab was resumed (3 mg/kg, every 2 weeks). Follow-up brain MRI in April 2018 showed early evidence of good response with decrease in size or disappearance of the multiple pre-existing lesions without any new metastasis (Fig. 2a). In June 2018, after 11 cycles of nivolumab, a routine follow-up brain MRI showed multiple new diffuse white matter lesions, consistent with active CNS demyelination with a patient that was completely asymptomatic (Fig. 2b). These lesions consisted of multiple, well-defined, ovoid, T2-hyperintense lesions with incomplete ring enhancement (i.e. open ring sign) after i.v contrast administration and hypovascularization on perfusion weighted imaging (Fig. 1b). In addition, there was no abnormal diffusion restriction on diffusion-weighted imaging (DWI) in these lesions. They were mainly located in the juxtacortical and periventricular white matter of the fronto-parietal lobes, respecting Dawson fingers distribution, classical of demyelinating lesions (Fig. 2b). In contrast, previously treated brain metastases were T2-hypointense with central necrosis and large perilesional oedema, had complete ring enhancement on post-contrast T1-weighted imaging and hypervascularization on perfusion weighted imaging (Fig. 1a). Hence, demyelinating lesions could radiologically clearly be distinguished from brain metastases. The patient was asymptomatic and there were no findings indicating an infection or progression of his melanoma. Systematic neurological examination did not reveal any cranial or peripheral nerve abnormalities and he showed no cognitive function impairment. The EEG was repeated and was found unchanged from previous exams. Cerebrospinal fluid (CSF) analysis showed clear appearance with normal glucose and lactate levels. Elevated white blood cells (14 × 10 ⁶/l) and lymphocytes (13 × 10 ⁶/l) counts were found. Elevated protein level (594 mg/l, normal range: 150-450) and elevated albumin level (316 mg/l, normal range: 80-300) were observed. The CSF thus revealed a disrupted blood-brain barrier. Oligoclonal bands were absent, Immunoglobulins gamma (IgG) pattern and total IgG levels were normal in the CSF. Protein electrophoresis was normal, and serum autoantibody testing (anti-CNS, anti-LGT1, anti-CASPR2, anti-NMDA-R, anti-GluR1-2 AMPA) was negative. No tumor cell could be identified. Nivolumab immunotherapy was discontinued due to these demyelinating lesions. Since the patient was asymptomatic, it was decided not to give him any immunosuppressive treatment.

Display of demyelinating lesions evolution over 6 months. Successive brain MRI are displayed on axial T2-weighted images (top row), axial (middle row) and sagittal (bottom row) T1-weighted images after i.v. infusion of gadolinium contrast media. a Baseline in April 2018 before CNS demyelination. b Demyelinating lesions were diagnosed in June 2018. The largest lesion was located in the juxtacortical white matter of the left superior frontal gyrus (arrows) while numerous small ovoid lesions (arrows' head) were located deep in the periventricular fronto-parietal white matter with a long axis perpendicular to the ventricle, corresponding to the typical "Dawson fingers" pattern. c After nivolumab discontinuation, lesions enhancement progressively decreased in September 2018. d The lesions disappeared in December 2018, leading to the characteristic "black hole" pattern on T1-weighted images

Strikingly, 1 month after cessation of nivolumab, the multiple demyelinating lesions spontaneously regressed (Fig. 2c), strongly suggesting an IrAEs of the immunotherapy, which was permanently discontinued. The patient has been followed by close monitoring for neurological symptoms and remained asymptomatic. Follow-up brain MRI every 3 months revealed complete resolution of these demyelinating lesions 6 months after initiation of nivolumab treatment (Fig. 2d and Fig. 3) along with stability in size and appearance of the prior identified cerebral metastases without new lesions. Tumor evaluation every 3 months by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan did not reveal any hypermetabolic lesions and confirmed a complete systemic and cerebral response over 12 months after occurrence of his irAE.

Timeline of the patient's clinical, therapeutic, and radiological course. The 11 cycles of nivolumab administration and its related onset and resolution of CNS demyelinating lesions are highlighted in red. A time reference has been included, with Day 0 referring to the day of onset of nivolumab treatment. Abbreviations: LN: lymph node; C: cycle; SRS: stereotactic radiosurgery; Dx: diagnosis; TT: treatment; DEX: dexamethasone; PD: progressive disease; PR: partial response; MRI: magnetic resonance imaging; CT: computed tomography; CNS: central nervous system. *5 mg/kg; **1 mg i.d. for 7 days, and 5.25 mg tapered over 14 days

Discussion and conclusions

Neurological complications of ICPis are rare, but often severe and may be life threatening, making its management challenging. This case study provides the first description of asymptomatic CNS demyelination after anti-PD1 blockade with nivolumab for metastatic melanoma with a spontaneous reversible course.

The patient reported here underwent an immunotherapy with nivolumab subsequent to adjuvant ipilimumab, which had to be discontinued after one dose of 10 mg/kg due to autoimmune colitis. Overall, the patient had been tolerating well the 11 cycles of nivolumab and was fully asymptomatic at the time of detection of lesions, radiologically compatible with CNS demyelinating lesions. Multiple juxta-cortical and periventricular white matter lesions with Dawson fingers distribution, open ring sign on post-contrast T1-weighted imaging and hypovascularization on perfusion weighted imaging were typical for demyelinating lesions.

Neurological adverse events of ICPis remain a complex diagnosis of exclusion [ 13]. In our case, all other differential diagnoses have been ruled out, including brain metastasis and leptomeningeal carcinomatosis for progressive oncologic disease, but also other demyelinating diseases of the CNS like multiple sclerosis as well as vascular, and infectious causes. The long interval of 12 months between the unique dose of ipilimumab and the occurrence of CNS demyelination argues against a role of this antibody. In previous case reports, the median time to onset of neurological irAEs following ICPis (mainly ipilimumab) was approximately 6 weeks (range: 1 to 74 weeks) and mostly occurs during the induction phase [ 20]. However, spontaneous regression of the radiological CNS lesions after nivolumab cessation strongly suggests a direct relationship between the two. Indeed, the onset and improvement of radiological lesions correlates with the administration and discontinuation of nivolumab, respectively. This, along with the absence of any other possible etiology, indicates that CNS toxicity is most likely nivolumab-related. Considering the asymptomatic course, nivolumab immunotherapy was discontinued without administration of immunosuppression to avoid dampening of the anti-tumor activity. Remarkably, even without treatment all demyelinating lesions completely resolved 6 months after nivolumab discontinuation.

So far, CNS demyelination in association with ICPis treatment have not been reported in large cohorts of patients [ 21, 22], but only in few isolated cases [ 16, 17, 18]. Unlike in the case reported here, they were all severe, symptomatic and not spontaneously reversible. In addition, in two of these case reports, patients had either clinical or radiographic evidence of preexisting multiple sclerosis flares. Interestingly, PD1-blockade was previously shown to worsen demyelinating disease in animal models of multiple sclerosis [ 23, 24]. Moreover, a PD-1 gene polymorphism was found to be associated with disease progression in multiple sclerosis patients [ 25]. Taken together, these pre-clinical studies and the CNS demyelinating toxicity of PD-1 inhibitors observed in 3 case reports including this case [ 16, 18], suggest that the PD-1 pathway may play a regulatory role in the development of CNS demyelination.

This case report highlights the need for better recognition of atypical and rare neurological toxicities such as CNS demyelination under anti-PD1 treatment. It is essential to recognize such lesions as they may be mistaken for progressive brain metastases. Early recognition and appropriate management are crucial to reduce severity and duration of these toxicities, especially for patients with less favourable evolution [ 13, 15]. Atypical neurological irAEs like CNS demyelination may be more prevalent than expected and their real incidence has been possibly underestimated due to lack of recognition and/or underreporting, as these irAEs could be transient [ 12] and possibly asymptomatic like reported in this case. Of note, patients with active brain metastases were excluded from most pivotal clinical trials and hence, such rare asymptomatic CNS adverse events may have been missed in this particular setting. It is important, that oncologists, neurologists and radiologists are aware of such atypical and rare neurological toxicities, which are anticipated to rise given the increased use of ICPIs to treat melanoma and other malignancies. Further clinical trials are needed to evaluate the exact neurological safety profile and clarify the risk-benefit ratio of these ICPis in order to determine optimal management guidelines.

Availability of data and materials

Abbreviations

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CT:

Computed tomography

CTLA-4:

Cytotoxic T-lymphocyte-associated antigen-4

FDA:

Food and Drug Administration

FDG:

18F-fluorodeoxyglucose

ICPis:

Immune checkpoint inhibitors

irAEs:

Immune-related adverse events

MRI:

Magnetic resonance imaging

PD-1:

Programmed death-1

PET:

Positron emission tomography

SRS:

Stereotactic radiosurgery

References

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Acknowledgements

The author would like to thank the patient and his family for entrusting us with his care.

Author information

Authors and Affiliations

1. Department of Medical Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland

Vincent Pillonel, Andreas F. Hottinger, Gregoire Berthod, Solange Peters, Olivier Michielin & Veronica Aedo-Lopez

2. Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland

Vincent Pillonel

3. Department of Diagnostic and Interventional Radiology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland

Vincent Dunet

4. Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland

Andreas F. Hottinger

5. Department of Oncology, Hôpital du Valais, Sion, Switzerland

Gregoire Berthod

6. Department of Radiation Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland

Luis Schiappacasse

7. Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland

Olivier Michielin

Contributions

VP: analyzed and interpreted the patient case, wrote and edited the manuscript. VD: performed radiological data analysis and interpretation, provided the imaging figures and reviewed the manuscript. AFH: treated the patient, interpreted the case and reviewed the manuscript. BG: treated the patient, and reviewed the manuscript. LS: treated the patient, reviewed and confirmed the accuracy of the radiotherapy history. SP: interpreted the case and reviewed the manuscript. OM: treated the patient, interpreted the case and reviewed the manuscript. VLA: was the main treating physician, collected and interpreted the patient's data, and supervised this case report. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Veronica Aedo-Lopez.

Ethics declarations

Ethics approval and consent to participate

Not Applicable.

Consent for publication

The patient provided full consent for participation and publication.

Competing interests

Solange Peters has received education grants, provided consultation, attended advisory boards, and/or provided lectures for: Abbvie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Incyte, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics and Takeda, from whom she has received honoraria (fees to institution). The remaining authors declare that they have no competing interests.

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Pillonel, V., Dunet, V., Hottinger, A.F. et al. Multiple nivolumab-induced CNS demyelination with spontaneous resolution in an asymptomatic metastatic melanoma patient. j. immunotherapy cancer 7, 336 (2019). https://doi.org/10.1186/s40425-019-0818-3
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Multiple nivolumab-induced CNS demyelination with spontaneous resolution in an asymptomatic metastatic melanoma patient - Journal for ImmunoTherapy of Cancer

# data[].attributes.attachment_link.description
Background Immune checkpoint inhibitors (ICPis) have revolutionised the treatment of melanoma by significantly increasing survival rates and disease control. However, ICPis can have specific immune-related adverse events, including rare but severe neurological toxicity. Case presentation We report a 44-year-old man diagnosed with stage IIIB melanoma who developed metastatic disease (pulmonary and brain metastases) and was treated with stereotactic radiosurgery and nivolumab immunotherapy.

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Frontiers | Fatal Necrotizing Encephalopathy after Treatment with Nivolumab for Squamous Non-Small Cell Lung Cancer: Case Report and Review of the Literature

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Immune checkpoint inhibitors are antibodies which enhance cellular and humoral immune responses and are approved for the treatment of various tumors. Immune-…

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Fatores que contribuem para o surgimento e a carga de irAEs.

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Martins, F., Sofiya, L., Sykiotis, G.P. et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 16, 563–580 (2019). https://doi.org/10.1038/s41571-019-0218-0

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Martins, F., Sofiya, L., Sykiotis, G.P. et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 16, 563–580 (2019). https://doi.org/10.1038/s41571-019-0218-0

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