Original article

Immune checkpoint inhibitor therapy-associated encephalitis: a case series and review of the literature

DOI: https://doi.org/10.4414/smw.2020.20377
Publication Date: 23.11.2020
Swiss Med Wkly. 2020;150:w20377

Johann Stubya, Thomas Herrenb, Guido Schwegler Naumburgerc, Claudia Papetd, Alain Rudigera

a Internal Medicine, Department II, Limmattal Hospital Zurich, Schlieren, Switzerland

b Cardiology, Department II, Limmattal Hospital Zurich, Schlieren, Switzerland

c Neurology, Department II, Limmattal Hospital Zurich, Schlieren, Switzerland

d Oncology/Haematology, Department II, Limmattal Hospital Zurich, Schlieren, Switzerland

Summary

BACKGROUND

Immune checkpoint inhibitors (ICIs) can cause a wide spectrum of immune-related adverse events, including encephalitis. To date, no prospective randomised controlled trials examining the patient characteristics, treatment and outcomes of ICI-associated encephalitis have been published. Therefore, we aimed to review case reports and to provide recommendations for the management of ICI-associated encephalitis.

METHODS

A literature search using Google Scholar and PubMed was performed in December 2019. Published case reports and case series of ICI-associated encephalitis were reviewed, and a case series from the Limmattal Hospital in Schlieren, Switzerland was added. The results are presented as numbers and medians (ranges).

RESULTS

Five different ICIs caused encephalitis in the 47 patients included in this case series. Nivolumab was the most frequently involved drug (27/47, 57%). The median time between treatment and onset of symptoms was 65 (4–630) days. Patients presented with rapidly evolving confusion, reduced level of consciousness, headache, seizures and focal neurological deficits. A total of 19 out of the 44 (43%) magnetic resonance imaging (MRI) scans performed revealed findings suggestive of encephalitis. No specific electroencephalogram (EEG) pattern consistent with encephalitis was found, but epileptiform discharges were detected in 7/20 (35%) of all tested patients. Typical findings of cerebrospinal fluid (CSF) analysis were pleocytosis, elevated protein levels and normal glucose concentrations. Forty-four out of 47 (94%) patients received corticosteroids. Intravenous immunoglobulins (IVIG), rituximab and plasma exchange therapy were less frequently prescribed. Nine out of 47 (19%) patients died during the index hospitalisation.

CONCLUSIONS

Encephalitis should be suspected in patients treated with ICIs who present with rapidly evolving confusion. Blood tests, CSF analysis, cerebral MRI and an EEG should be performed. Therapy with intravenous corticosteroids is recommended. Steroid unresponsiveness is rare and should lead to a review of the diagnosis. Alternative treatment options are IVIG, plasma exchange therapy and rituximab.

Keywords: immune checkpoint inhibitor, nivolumab, pembrolizumab, ipilimumab, encephalitis

Abbreviations

ANCA: anti-neutrophil cytoplasmic antibody

AGNA: anti-glia nuclear antibody, SOX1

Anti-AchR antibody: anti-acetylcholine receptor antibody

Anti-AMPAR 1 antibody: anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor 1 antibody

Anti-AMPAR 2 antibody : anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor 2 antibody

Anti-CASPR2 antibody: anti-contactin-associated protein-like 2 antibody

Anti-CRMP5 antibody: anti-collapsin response mediator protein 5 antibody, CV2

Anti-DPPX antibody: anti-dipeptidyl-peptidase-like protein 6 antibody

Anti-GABAR antibody: anti-gamma aminobutyric acid B receptor antibody

Anti-GAD65 antibody: anti-glutamate decarboxylase 65 kDa isoform antibody

Anti-Gly antibody: anti-glycine antibody

Anti-Hu antibody: anti-neuronal nuclear antibody-1, ANNA1

Anti-LGI1 antibody: anti-leucine-rich glioma-inactivated 1 antibody

Anti-NMDAR antibody: anti-N-methyl-D-aspartate receptor antibody

Anti-Ri antibody: anti-neuronal nuclear antibody-2, ANNA2

Anti-TG antibody: anti-thyroglobulin antibody

Anti-TPO antibody: anti-thyroid peroxidase antibody

Anti-TR antibody: anti-human thrombin receptor antibody

Anti-Yo antibody: anti-Purkinje cell cytoplasmic antibody type 1, PCA-1

Anti-VGKC antibody: anti-voltage-gated potassium channel antibody

Anti-VGCC antibody: anti-voltage-gated calcium channel antibody

Anti-ZIC4 antibody: anti-zic family member 4 antibody

EEG: electroencephalogram

CSF: cerebrospinal fluid

CTLA-4: cytotoxic T-lymphocyte-associated antigen 4

FLAIR: fluid-attenuated inversion recovery

HSV-1: herpes simplex virus type 1

HSV-2: herpes simplex virus type 2

ICI: immune checkpoint inhibitor

ICU: intensive care unit

IV: intravenous

IVIG: intravenous immunoglobulins

MRI: magnetic resonance imaging

NAEs: neurological adverse events

NSCLC: non-small cell lung cancer

PCR: polymerase chain reaction

PD-1: programmed cell death protein 1

PRES: posterior reversible encephalopathy syndrome

SCLC: small cell lung cancer

VZV: varicella zoster virus

Introduction

Immune checkpoint inhibitors (ICIs) re-establish the antitumour activity of T-lymphocytes by blocking immune inhibitory receptors such as programmed cell death protein 1 (PD-1, e.g., nivolumab, pembrolizumab and lambrolizumab), programmed cell death ligand 1 (e.g., atezolizumab, durvalumab and avelumab) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, e.g., ipilimumab) [13]. They are effective in patients with melanoma, lung cancer, renal cell cancer, urothelial cancer and other tumour types [46].

ICIs have been associated with various neurological immune-related adverse events, including peripheral neuropathies, Guillain-Barré syndrome, myasthenia gravis, Tolosa-Hunt syndrome and autoimmune encephalitis. According to the literature, less than 1% of patients will develop autoimmune encephalitis when treated with ICIs [4, 6, 7], with higher risks during concurrent or sequential ICI use [6].

In the absence of prospective randomised controlled trials examining the patient characteristics, treatment and outcomes of ICI-associated encephalitis, we reviewed the published case reports of ICI-associated encephalitis and added our own five cases. Recommendations for the management of ICI-associated encephalitis are presented.

Methods

A literature search using Google Scholar and PubMed and focusing on publications in English was performed in December 2019. The following search terms were used: “immune checkpoint inhibitors”, “checkpoint inhibitor therapy”, “checkpoint inhibitor treatment”, “ipilimumab”, “pembrolizumab”, “atezolizumab”, “nivolumab”, “durvalumab”, “avelumab”, “encephalitis”, “encephalopathy”, “case report” and “case series”. Additionally, the bibliographies of the retrieved publications were screened. The patient characteristics, treatments and outcome parameters were entered into a Microsoft Excel® (2011) worksheet.

Five patients with ICI-associated encephalitis treated at the Limmattal Hospital in Schlieren, Switzerland were added to this case series. Written consent was obtained from the patients or their next of kin. Data were collected from electronic medical records.

Results

Five cases of ICI-associated encephalitis were diagnosed in the Limmattal Hospital in Schlieren, Switzerland from 2016 to 2020. One case was previously described by Schneider et al. [6]. Detailed descriptions of the four remaining patients are provided in appendix 1. All five patients were included in the case series. The literature search identified 29 published cases. A bibliography screening revealed 13 additional publications. Overall, 47 cases were analysed.

Five different ICIs were implicated in the pathogenesis of autoimmune encephalitis, either as monotherapy or as concurrent or sequential combination therapy. These five drugs were atezolizumab (n = 4), ipilimumab (n = 14), lambrolizumab (n = 1), nivolumab (n = 27) and pembrolizumab (n = 10). No incidences of avelumab- or durvalumab-associated encephalitis were reported. The median (range) delay between the start of ICI treatment and the onset of symptoms was 65 (4–630) days.

The median (range) patient age was 63 (18–83) years. Patients presented with reduced levels of consciousness, confusion, headache, fever, seizures and/or focal neurological deficits (e.g., motor deficits, paraesthesia, aphasia or ataxia). Other symptoms or signs included asterixis, myoclonus, memory loss, nausea, vomiting and abnormal behaviours (e.g., inappropriate laughter). The patient characteristics are summarised in table 1.

Table 1

Patient characteristics.

Case reportYear of publicationCountryAgeSexCancer typeBrain metastasesCancer therapySteroid dose*Hospital survival
Limmattal Hospital
See appendix 1n/aCH74FPulmonary adenocarcinomaNoPembrolizumab125Yes
See appendix 1n/aCH58FCarcinosarcoma of the uterusYesPembrolizumab80No
See appendix 1n/aCH63FPulmonary adenocarcinomaNoNivolumab125Yes
Schneider et al. [6]2017CH78MPulmonary squamous cell carcinomaNoNivolumab80Yes
See appendix 1n/aCH79MMerkel cell carcinomaYesNivolumab + Ipilimumab125Yes
Literature search
Larkin et al. [4]2017USA53FMalignant melanomaNoNivolumab + Ipilimumab200Yes
Larkin et al. [4]2017USA61MMalignant melanomaNoNivolumab + Ipilimumab → Nivolumab alone1000Yes
Larkin et al. [4]2017USA57MMalignant melanomaNoNivolumab → Ipilimumab → Nivolumabn.r.Yes
Larkin et al. [4]2017USA83MMalignant melanomaNoNivolumab24No
Larkin et al. [4]2017USA58FMalignant melanomaYesNivolumab1000Yes
Shah et al. [8]2018USA66FPulmonary adenocarcinomaNoNivolumab1000No
Shah et al. [8]2018USA44FPulmonary adenocarcinomaYesNivolumab1000Yes
Williams et al. [9]2016USA55FMalignant melanomaYesNivolumab + Ipilimumab1000Yes
Williams et al. [9]2016USA65MSmall cell lung cancerYesNivolumab + Ipilimumab48Yes
Niki et al. [10]2016Japan51MPulmonary squamous cell carcinomaYesPembrolizumab2 mg/kgYes
Cook et al. [11]2017USA72MMalignant melanomaYesPembrolizumabHigh doseNo
Kim et al. [12]2019Korea49MUrothelial carcinoma of the bladdern.r.Atezolizumab1000Yes
Mandel et al. [13]2014USA66MMalignant melanomaNoLambrolizumabNoneYes
Laserna et al. [14]2018USA53FCervical squamous cell carcinomaNoAtezolizumab90Yes
Levine et al. [15]2017USA59FUrothelial carcinoma of the bladderYesAtezolizumab200Yes
Bossart et al. [7]2017CH60FMalignant melanomaYesIpilimumab + PembrolizumabNoneNo
Arakawa et al. [16]2019Japan78MPulmonary adenocarcinoman.r.Atezolizumab1000Yes
Salam et al. [17]2016UK64MMalignant melanomaNoPembrolizumabHigh doseYes
Ito et al. [18]2017Japan75MSmall cell lung cancerYesNivolumab + Ipilimumab500Yes
Conry et al. [19]2015USA41MMalignant melanomaNoIpilimumab160Yes
Burke et al. [20]2018USA64FOvarian clear cell carcinomaNoNivolumab12,000Yes
Boyd et al. [21]2015UK71MMalignant melanomaNoIpilimumab1000Yes
Voskens et al. [22]2013DE50MMalignant melanomaNoIpilimumabHigh doseYes
Cao et al. [23]2016USA76FMalignant melanomaYesIpilimumabHigh doseYes
Khoja et al. [24]2016Canada51FMalignant melanomaNoPembrolizumab1000Yes
Kazandjian et al. [25]2016USA70FNon-small cell lung cancern.r.Nivolumab2–4 mg/gNo
Carl et al. [26]2015DE64MProstate cancerNoIpilimumab1000Yes
Richard et al. [27]2017USA74MPulmonary squamous cell carcinomaYesNivolumabn.r.Yes
Matsuo et al. [28]2018Japan60MPulmonary pleomorphic carcinoman.r.NivolumabHigh doseNo
Brown et al. [1]2017Australia67MMalignant melanoman.r.PembrolizumabHigh doseYes
Feng et al. [29]2017Australia66MPulmonary adenocarcinomaYesPembrolizumab1000Yes
Strik et al. [30]2017DE53MNon-Hodgkin lymphomaNoNivolumab1000Yes
Chaucer et al. [31]2018USA44MRenal cell carcinomaNoNivolumabn.r.Yes
Leitinger et al. [32]2018Austria67FPulmonary squamous cell carcinoman.r.Nivolumab1000No
Zurko et al. [33]2018USA20MHodgkin lymphomaNoNivolumab160Yes
Kopecký et al. [34]2018Czech Republic63MRenal cell carcinomaNoNivolumab2 mg/kgYes
De la Hoz et al. [35]2018USA28FHodgkin lymphoman.r.Nivolumab1 mg/kgYes
Shibaki et al. [36]2019Japan78MMalignant pleural mesotheliomaNoNivolumabn.r.Yes
Zafar et al. [37]2019USA59FLaryngeal squamous cell carcinoman.r.Nivolumab1000Yes
Gill et al. [38]2019USA68FMerkel cell carcinomaNoNivolumab1000No
Hottinger et al. [39]2018CH71FSmall cell lung cancern.r.Nivolumab + Ipilimumab1000Yes
Gill et al. [38]2019USA71FPulmonary adenocarcinoman.r.Pembrolizumabn.r.Yes

F = female; M = male; n/a = not applicable; n.r. = not reported * Daily methylprednisolone dose or equivalent (mg) † Intracranial epidermoid with R2 resection previously

Cerebral magnetic resonance imaging (MRI) was performed in 44/47 (94%) patients. In 25/44 (57%) patients, cerebral MRI was normal or showed nonspecific abnormalities. In 19/44 (43%) patients, cerebral MRI findings were consistent with encephalitis. These findings included leptomeningeal enhancement, bilateral hyperintensities in the mesial temporal area or in the basal ganglia, and diffuse encephalitis resembling disseminated demyelination.

An electroencephalogram (EEG) was obtained in 20/47 (43%) patients. No specific EEG pattern was found. Epileptic activity was recorded in 7/20 (35%) patients.
The findings of the cerebral MRIs and EEGs are summarised in table 2.

Table 2

MRI and EEG findings.

Case reportYear of PublicationBrain MRIEEG
Limmattal Hospital
See appendix 1n/aNo signs of encephalitis or meningitis.Moderate background slowing, focal slowing over the right temporal region, some epileptiform activity with bilateral frontal sharp waves.
See appendix 1n/a25 × 24 mm metastatic lesion subcortically located in the left medial frontal gyrus. Otherwise, normal MRI.n.r.
See appendix 1n/aDiffuse white matter changes, most likely due to whole brain radiation.n.r.
Schneider et al. [6]2017No signs of encephalitis, carcinomatous meningitis, metastases or stroke.Moderate background slowing and focal delta slowing over the left temporal region with singular sharp waves in this region.
See appendix 1n/aNo signs of encephalitis, hypophysitis or ischaemia.Mild background slowing, moderate focal slowing over the left temporal region. No epileptiform activity.
Literature search
Larkin et al. [4]2017No signs of metastasis or stroke.Diffuse, marked cerebral slowing.
Larkin et al. [4]2017Abnormally high fluid-attenuated inversion recovery (FLAIR) signal without evidence of brain metastasis.Epileptic activity.
Larkin et al. [4]2017No signs of brain metastasis.Diffuse slowing and triphasic waves and phase reversal in the right frontal region. No sign of seizure activity.
Larkin et al. [4]2017Some areas of hypersignal on the supratentorial white matter and FLAIR without a break in the haematocephalic barrier, probably caused by microangiopathy.n.r.
Larkin et al. [4]2017No signs of stroke, brain metastases unchanged, no new lesions.n.r.
Shah et al. [8]2018Symmetric T2 hyperintense and T1 hypointense basal ganglia abnormalities. A repeat brain MRI three weeks later re-demonstrated symmetric T2 hyperintense basal ganglia but with a transition to T1 hyperintensities in the same location.n.r.
Shah et al. [8]2018T2 signal hyperintensities of the bilateral mesial temporal lobes compatible with limbic encephalitis. Additionally, there were two enhancing foci within the left occipital and right temporal lobes, concerning for metastatic disease.n.r.
Williams et al. [9]2016Stable encephalomalacia at sites of prior radiosurgery with no additional metastases. No changes were noted at previously irradiated tumour sites.Serial EEG showed intermittent bilateral slowing, then a subclinical seizure of left temporo-occipital origin. Continuous EEG monitoring showed intermittent periods of rhythmic epileptiform activity in the left temporal lobe without clinical correlations.
Williams et al. [9]2016New nonspecific T2 hyperintensities in the right mesial temporal lobe.n.r.
Niki et al. [10]2016No abnormality other than the previous surgical resection.Slow wave in the right frontal lobe, which indicated encephalitis or the aftermath of the previous brain metastasis.
Cook et al. [11]2017Restricted diffusion in the basal ganglia and right temporal lobe.n.r.
Kim et al. [12]2019Diffuse leptomeningeal enhancement.Status epilepticus.
Mandel et al. [13]2014Unremarkable but limited due to motion artefact. A follow-up brain MRI scan showed stable T2 FLAIR hyperintensities in the right frontal and left occipital lobes, with improvement in the signal originating from both external capsules.Periodic epileptiform discharges.
Laserna et al. [14]2018Diffuse leptomeningeal enhancement.No acute abnormalities. The EEG was repeated and showed non-convulsive status epilepticus.
Levine et al. [15]20171.0 × 0.9 cm mildly enhancing lesion in the left frontal lobe with no vasogenic oedema or mass effect.n.r.
Bossart et al. [7]2017n.r.n.r.
Arakawa et al. [16]2019No abnormal findings other than the left temporal lobectomy.n.r.
Salam et al. [17]2016Bilateral symmetrical T2 signal change with atrophy within the hippocampi, extending into the anterior temporal lobe and insula. This was more extensive on the left side, with significant volume loss. Previous MRI performed at the referring hospital in November 2014 was reviewed and showed a bilateral high T2 signal affecting the limbic structures, again predominantly on the left, though without volume loss.No epileptic activity.
Ito et al. [18]2017No recurrence of brain metastasis, haemorrhage or infarction.No epileptic activity.
Conry et al. [19]2015New area of restricted diffusion in the posterior splenium of the corpus callosum, with corresponding T2 hyperintensity on FLAIR and no abnormal enhancement or evidence of melanoma metastasis.n.r.
Burke et al. [20]2018No signs of encephalitis or metastasis.n.r.
Boyd et al. [21]2015Unchanged.n.r.
Voskens et al. [22]2013Enhancement in both trigeminal nerves and, additionally, three parenchymal lesions with no indication of meningeosis carcinomatosa or pituitary enlargement.n.r.
Cao et al. [23]2016New signal abnormalities in the left optic nerve, left inferior frontal lobe, and splenium of the corpus callosum, which extended into the parietal lobe and bordered on the stereotactic radiosurgery-treated lesion that by now was no longer enhancing.n.r.
Khoja et al. [24]2016Hyperintense white matter foci in both subcortical (enhancing on FLAIR) and periventricular areas (non-enhancing). There were ovoid lesions perpendicular to the ventricles and lesions involving the corpus callosum. All lesions showed restricted diffusion. The findings were consistent with either demyelination or an ischemic process. A repeat brain MRI after 10 days of steroid treatment showed increased enhancement in the previously noted lesions and lesions involving the cortex, changes more suggestive of multiple infarctions and possibly a vascular process.n.r.
Kazandjian et al. [25]2016n.r.n.r.
Carl et al. [26]2015Mild microangiopathic changes, an old lacunar infarction in the right thalamus and a normal pituitary gland.Generalised slowing with prevailing slow theta and delta waves.
Richard et al. [27]2017n.r.Mild slowing and no evidence of seizure activity.
Matsuo et al. [28]2018High-intensity areas in the inner aspect of the temporal lobe, thalamus, cerebral aqueduct and spinal cord.n.r.
Brown et al. [1]2017T2 hyperintensity of the medial temporal lobes bilaterally with contrast enhancement.Background slowing (6–7 Hz) with intermittent delta slowing.
Feng et al. [29]2017FLAIR hyperintensity adjacent to the resection site, which was consistent with the postoperative changes.Generalised, intermittent slowing consistent with mild diffuse encephalopathy.
Strik et al. [30]2017Small, scattered, T2 and FLAIR hyperintense contrast-enhancing lesions dorsal to the left lateral ventricle and in the midbrain and brain stem.n.r.
Chaucer et al. [31]2018No evidence of metastases or lymphoreticular disorder.n.r.
Leitinger et al. [32]2018Multiple and confluent cortical and subcortical FLAIR hyperintensities within both cerebral hemispheres.Moderate slowing.
Zurko et al. [33]2018Diffusely oedematous cerebellum with patchy enhancement, signs of early tonsillar herniation, and early hydrocephalus.n.r.
Kopecký et al. [34]2018No signs of any tumour lesion. MRI revealed a symmetrical, pathologically increased signal within the basal ganglia consistent with possible inflammatory involvement of these structures.n.r.
De la Hoz et al. [35]2018No abnormalities.n.r.
Shibaki et al. [36]2019T2 high signal intensity in the mesencephalon and medial thalami (typical findings in anti-Ma2-associated encephalitis).n.r.
Zafar et al. [37]2019Multifocal cerebral demyelination, primarily involving the parietal lobe: multiple hyperintense T2 FLAIR signal white matter lesions, primarily in the parietal lobes but also involving the posterior frontal lobes, corpus callosum and right brachium ponti. None of these lesions were enhanced following contrast administration. No restricted diffusion was present. No significant mass effect or midline shift was identified. These findings were suggestive of acute demyelinating encephalomyelitis.Diffuse, generalised slowing with practically no significant reactivity to external stimuli.
Gill et al. [38]2019T2/FLAIR hyperintensities bilaterally in the medial temporal lobes.No seizure activity.
Hottinger et al. [39]2018Severe abnormalities in both hippocampi with contrast-enhancing lesions.n.r.
Gill et al. [38]2019No signal abnormality or enhancement.n.r.

EEG = electroencephalogram; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging; n/a = not applicable; n.r. = not reported

Cerebrospinal fluid (CSF) was analysed in 37/47 (79%) patients. Pleocytosis was found in 30/37 (81%) patients. An increased leucocyte count was found in 24/37 (65%) patients, of whom 16/37 (43%) had lymphocytosis, 2/37 (5%) had monocytosis and 1/37 (3%) had an increased proportion of neutrophils. In 5/37 (14%) patients, the leukocytes were not further differentiated. Protein levels were increased in 24/32 patients (75%, 270 to >6,000 mg/l), but glucose levels were normal in the majority of patients (19/24 patients, 79%). The detailed results of the CSF analyses are provided in table 3.

Table 3

CSF analyses.

Case reportYear of publicationCSF cell countCSF protein levelCSF glucose level
Limmattal Hospital
See appendix 1n/a59/μl589 mg/l4.1 mmol/l
See appendix 1n/an.r.n.r.n.r.
See appendix 1n/an.r.n.r.n.r.
Schneider et al. [6]201716/μl1027 mg/l1.1 mmol/l
See appendix 1n/a83/μl1065 mg/l2.7 mmol/l
Literature search
Larkin et al. [4]2017Elevated3120 mg/l2.4 mmol/l
Larkin et al. [4]201714/μl850 mg/l11.8 mmol/l
Larkin et al. [4]201752/μln.r.n.r.
Larkin et al. [4]2017n.r.n.r.n.r.
Larkin et al. [4]201718/μln.r.n.r.
Shah et al. [8]2018Normal560 mg/lNormal
Shah et al. [8]201819/μlNormalNormal
Williams et al. [9]20168/μlNormalNormal
Williams et al. [9]201618/μl980 mg/lNormal
Niki et al. [10]201658/μl4460 mg/ln.r.
Cook et al. [11]2017ElevatedElevatedNormal
Kim et al. [12]2019Elevatedn.r.n.r.
Mandel et al. [13]20148/μl1030 mg/l5.6 mmol/l
Laserna et al. [14]2018667/μl>6000 mg/l5.1 mmol/l
Levine et al. [15]20179/μl1000 mg/l4.4 mmol/l
Bossart et al. [7]2017n.r.n.r.n.r.
Arakawa et al. [16]2019139/μl1320 mg/lNormal
Salam et al. [17]201617/μl530 mg/ln.r.
Ito et al. [18]201758/μl1280 mg/ln.r.
Conry et al. [19]2015n.r.n.r.n.r.
Burke et al. [20]2018NormalNormalNormal
Boyd et al. [21]2015Normal1370 mg/ln.r.
Voskens et al. [22]2013n.r.n.r.n.r.
Cao et al. [23]2016n.r.n.r.n.r.
Khoja et al. [24]2016n.r.270 mg/l4.4 mmol/l
Kazandjian et al. [25]2016n.r.n.r.n.r.
Carl et al. [26]2015Normal850 mg/lNormal
Richard et al. [27]2017Normaln.r.Normal
Matsuo et al. [28]201816/μl1620 mg/ln.r.
Brown et al. [1]2017Elevatedn.r.n.r.
Feng et al. [29]20170/μlNormalNormal
Strik et al. [30]201715/μlNormaln.r.
Chaucer et al. [31]2018n.r.n.r.n.r.
Leitinger et al. [32]201830/μl560 mg/lNormal
Zurko et al. [33]201831/μl1610 mg/l4.1 mmol/l
Kopecký et al. [34]2018Elevatedn.r.n.r.
De la Hoz et al. [35]2018136/μl600 mg/l2.9 mmol/l
Shibaki et al. [36]201915/μl900 mg/ln.r.
Zafar et al. [37]201974/μlElevatedn.r.
Gill et al. [38]20193/μl330 mg/l6.4 mmol/l
Hottinger et al. [39]201816/μl1145 mg/ln.r.
Gill et al. [38]201910/μl400 mg/ln.r.

CSF = cerebrospinal fluid; n/a = not applicable; n.r. = not reported

One or more antibodies could be detected in 13/25 (52%) patients. The following antibodies were found: anti-CASPR2 (n = 1), anti-GAD65 (n = 2), AGNA (n = 1), anti-Hu (n = 3), anti-NMDAR (n = 2), anti-Ma2 (n = 2), anti-Ri (n = 1), an uncharacterised antibody against Purkinje cells (n = 1) and an unclassified antibody (n = 1). One patient with steroid-responsive encephalopathy associated with autoimmune thyroiditis presented with anti-TPO and anti-TG antibodies. In 12/25 patients (48%), testing for antibodies was negative.

Brain metastases were present in 14/47 (30%) patients. Antibiotics and/or antiviral therapy were initially prescribed in 16/47 (34%) patients. Intravenous treatment with corticosteroids was started in 44/47 (94%) patients. Typically, “high” (>30 mg) and “very high” (>100 mg) daily corticosteroid doses were used [40]. The mean (range) dose was 997 (24–12,000) mg methylprednisolone or equivalent per day. Usually, the intravenous regimen was changed to oral administration after five days and then tapered over several weeks. In 6/47 patients (13%) the corticosteroid dose was simply specified as “high-dose”; in another 4/47 patients (9%), the dose was not specified at all. In addition, twelve patients (26%) received intravenous immunoglobulins (IVIG), six patients (12%) were given rituximab, and four patients (9%) underwent plasma exchange therapy.

Nine out of 47 (19%) patients died during hospitalisation, of whom six patients received a mean (range) corticosteroid dose of 541 (24–1000) mg, two patients received “high-dose” corticosteroids (not further specified), and the remaining patient received no corticosteroid therapy at all.

Discussion

In this study, we analysed five patients treated in our hospital and combined these findings with those of 42 patients described in published case reports and case series. Based on these findings, we provide recommendations for the management of ICI-associated encephalitis.

The ICIs nivolumab, ipilimumab, pembrolizumab, atezolizumab and lambrolizumab were involved in the pathophysiology of ICI-associated encephalitis. Less than half of the MRIs performed revealed findings suggestive of encephalitis. No specific EEG pattern consistent with encephalitis was found, but epileptiform discharges were detected in approximately one third of the EEGs. The majority of patients had CSF pleocytosis, elevated CSF protein levels and normal CSF glucose concentrations. The patients usually received therapy with corticosteroids, whereas IVIG, rituximab and plasma exchanges were less frequently administered.

Risk factors

In general, CTLA-4 inhibitors (e.g., ipilimumab) are associated with a higher incidence of immune-related adverse events than PD-1 inhibitors (e.g., nivolumab, pembrolizumab and lambrolizumab). When two ICIs (e.g., nivolumab + ipilimumab or pembrolizumab + ipilimumab) are given concurrently, the risk seems to be even higher [4143]. In our review, 29/47 cases (62%) were caused by PD-1 inhibitor monotherapy, and 5/47 cases (11%) were caused by CTLA-4 inhibitor monotherapy. The concurrent or sequential use of ICIs caused encephalitis in 9/47 cases (19%).

Paraneoplastic antibodies (e.g., anti-Hu, anti-Yo, anti-Ma2, anti-CRMP5, anti-amphiphysin, anti-Ri, anti-NMDA, anti-VGKC, anti-VGCC and anti-AchR) can develop in tumour patients and are associated with various neurological diseases [44]. The presence of paraneoplastic antibodies may increase the risk of developing ICI-associated encephalitis [38].

In our case series, one or more antibodies could be detected in 52% of the patients tested (anti-CASPR2, anti-GAD65, anti-AGNA, anti-Hu, anti-NMDAR, anti-Ma2, anti-Ri and anti-TPO/TG). Shah et al. [8] reported a patient with pulmonary adenocarcinoma and type 1 diabetes who developed GAD65 antibody-positive encephalitis after treatment with nivolumab. GAD65 is located on pancreatic islet cells as well as on GABAergic neurons of the central nervous system. This patient had a higher risk for ICI-associated encephalitis, as he presumably had pre-existing GAD65 antibodies in association with his diabetes.

Presentation and diagnosis

In our experience, ICI-associated encephalitis should be suspected in patients with rapidly evolving confusion. Other symptoms associated with immune-mediated encephalitis include reduced level of consciousness, headache, seizures and focal neurological deficits. One third of patients presented with fever. The time interval between the start of immune checkpoint blockade and the onset of symptoms was wide, ranging from less than a week to 21 months, with a median of 9 weeks. In the case series of Cuzzubbo et al. [2], the median (range) time of onset was 6 (1–74) weeks.

To establish a diagnosis of ICI-associated encephalitis, potential differential diagnoses must be excluded (table 4). Consultation with a neurologist is advised. Infectious aetiologies (bacterial, fungal or viral meningoencephalitis, especially herpes simplex) and leptomeningeal disease can be ruled out by analysing CSF. Typical CSF findings in patients with ICI-associated encephalitis are elevated white blood cell counts with predominant lymphocytes and elevated protein concentrations. The glucose concentration is usually normal. Polymerase chain reaction assays of CSF for herpes simplex virus type 1, herpes simplex virus type 2 and varicella zoster virus must be ordered. In addition, cytological examination of CSF is recommended.

Table 4

Differential diagnosis of ICI-associated encephalitis.

Differential diagnosisDiagnostic tests
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
Intracerebral haemorrhageMRI
IschaemiaMRI
Leptomeningeal disseminationCSF analysis, MRI
Metabolic disturbancesBlood tests*
Nonconvulsive status epilepticusEEG
Paraneoplastic limbic encephalitisBlood tests, CSF analysis, MRI
PRESMRI
VasculitisBlood tests (ANCA), MRI

AGNA (SOX1) = anti-glia nuclear antibody; AMPAR1/2 = alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors 1 and 2; ANCA = anti-neutrophil cytoplasmic antibody; CASPR2 = contactin-associated protein-like 2; CRMP5 (CV2) = collapsin response mediator protein 5; CSF = cerebrospinal fluid; DPPX = dipeptidyl-peptidase-like protein 6; EEG = electroencephalogram; GABAR = gamma aminobutyric acid B receptor; GAD65 = glutamate decarboxylase 65 kDa isoform; gly = glycine; Hu = neuronal nuclear antibody-1; ICI = immune checkpoint inhibitor; LGI1 = leucine-rich glioma-inactivated 1; MRI = magnetic resonance imaging; NMDAR = N-methyl-D-aspartate receptor; PCR = polymerase chain reaction; PRES = posterior reversible encephalopathy syndrome; Ri (ANNA2) = neuronal nuclear antibody-2; TG = thyroglobulin; TPO = thyroid peroxidase; TR = human thrombin receptor; VGKC = voltage-gated potassium channel; Yo (PCA1) = anti-Purkinje cell cytoplasmic antibody type 1; ZIC4 = zic family member 4 * Glucose, creatinine, bilirubin, liver enzymes, ammonia, electrolytes, arterial blood gases; additionally, in non-responders to therapy: vitamins B1/12, thyroid function tests, cortisol concentrations, toxicological screening † Antibodies against 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) and ZIC4 ‡ Antibodies against NMDAR, AMPAR1/2, VGKC (anti-LGI1, anti-CASPR2), Gly, GABAR, etc.

A cerebral MRI should be performed to detect brain metastases and to exclude ischemia or intracranial haemorrhage. Nonconvulsive status epilepticus must be ruled out by recording an EEG. Blood and urine cultures must be drawn. A complete blood count, a C-reactive protein test and a comprehensive metabolic panel (including ammonia) should be obtained, and arterial blood gases should be analysed. In selected patients, especially in those not responding to corticosteroid therapy, blood concentrations of vitamins (B1, B12), thyroid-stimulating hormone and cortisol should be measured. Toxicological screening should be performed if an intoxication is suspected. Measurement of the anti-neutrophil cytoplasmic antibody concentration can help to exclude vasculitis [3, 4]. The recommended diagnostic approach is illustrated in figure 1.

fullscreen
Figure 1

Diagnosis of ICI-associated encephalitis.

1 For differential diagnoses, see table 4.

2 Glucose, creatinine, bilirubin, liver enzymes, ammonia, electrolytes, arterial blood gas analysis; additionally, in non-responders to therapy: vitamins B1/12, thyroid function tests, cortisol concentration, toxicological screening, ANCA

3 Antibodies against 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), ZIC4

4 Antibodies against NMDAR, AMPAR1/2, VGKC (anti-LGI1, anti-CASPR2), Gly, GABAR, etc.

ANCA = anti-neutrophil cytoplasmic antibody; CSF = cerebrospinal fluid; HSV-1 = herpes simplex virus type 1; HSV-2 = herpes simplex virus type 2; ICI = immune checkpoint inhibitor; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; VZV = varicella zoster virus

Management

The severity of neurological adverse events (nAEs) is graded from 1 to 4. In patients with grade 1 nAEs (asymptomatic or mild symptoms), ICI therapy can be continued. However, in patients with grade 2 (moderate symptoms), grade 3 (severe symptoms) and grade 4 (life-threatening symptoms) nAEs, ICIs should be stopped [27, 45].

In our experience, immune-mediated encephalitis is usually graded 3 to 4. Therefore, permanent discontinuation of ICI therapy is advisable, and treatment with corticosteroids should be established. We recommend an initial intravenous dose of 1 to 2 mg/kg body weight/day of methylprednisolone (or equivalent), as suggested in the literature [46, 47]. If symptoms persist, other diagnoses must be entertained, as shown in figure 1. In this case, an extended metabolic panel should be ordered, and paired samples of plasma and CSF should be tested for both paraneoplastic and autoimmune encephalitis antibodies. Autoimmune encephalitis antibodies can be quantified even after an initial treatment with corticosteroids [48]. Data on the time courses of autoimmune encephalitis or paraneoplastic antibodies before and after ICI treatment are not available, however. In the most severe cases, the corticosteroid dose can be increased to ≥1000 mg daily. Due to the long half-life of ICIs, steroids should be tapered slowly over at least four weeks. Potential adverse effects of corticosteroid therapy must be anticipated, including delirium, arterial hypertension, hyperglycaemia and lower resistance to infection. Coadministration of trimethoprim/sulfamethoxazole therapy should be considered, especially if long-term treatment is necessary. In steroid-refractory cases and after careful review of the results of (neuro-)imaging studies, blood tests, CSF analysis, EEG, and titres of paraneoplastic and autoimmune encephalitis antibodies, treatment with IVIG, plasma exchange therapy or rituximab should be considered [4, 45, 46, 4951]. According to the case report by Hottinger et al. [39], natalizumab, an antibody directed at α4β1 integrin which thus limits lymphocyte recruitment to the CNS, may be considered to treat ICI-associated encephalitis. An algorithm for the management of ICI-associated encephalitis is shown in figure 2.

fullscreen
Figure 2

Management of ICI-associated encephalitis.

ICI = immune checkpoint inhibitor; ICU = intensive care unit; IV = intravenous; IVIG = intravenous immunoglobulins; PCR = polymerase chain reaction

Prognosis

Most patients with ICI-associated encephalitis respond to intravenous corticosteroids. Due to early diagnosis and appropriate management, the majority of patients (82%) included in this review improved significantly. However, nine patients (18%) died during their hospital stay.

Limitations of the study

The study design is descriptive and retrospective. As there are no prospective randomised controlled trials examining the diagnosis and therapy of ICI-associated encephalitis, the current data provide the best available basis for treatment recommendations. Prospective studies are needed to identify the optimal treatment.

Implications for further research

New indications for ICI therapy and combinations with other therapeutic strategies (e.g., chemotherapy) are in preclinical and clinical testing. The incidence of and risk factors for ICI-associated encephalitis will be reported accordingly. To date, ICI encephalitis is a diagnosis of exclusion. However, we propose that the diagnosis can be made after clinical evaluation and performing basic laboratory analysis, MRI and EEG. Expanded testing for rare autoimmune diseases of the brain should be reserved for therapy-refractory cases.

It would be interesting to study whether the concomitant administration of ICIs and corticosteroids could prevent the development of encephalitis. It remains unclear whether the presence of paraneoplastic antibodies is a risk factor for ICI-associated encephalitis, whether the antibodies are possibly induced by ICI therapy, or whether they lead to an alternative diagnosis, e.g., paraneoplastic limbic encephalitis. Further studies are needed to determine the role of paraneoplastic antibodies in ICI encephalitis.

Conclusions

The use of ICIs for multiple tumour types is increasing. In patients treated with ICIs presenting with rapidly evolving confusion, encephalitis should be suspected. Blood tests, CSF analysis, cerebral MRI and an EEG should be ordered. The treatment of choice is intravenous corticosteroids. Steroid unresponsiveness is rare and should lead to a review of the diagnosis. Alternative treatment options are IVIG, plasma exchange therapy and rituximab.

Potential competing interests

CP has received honoraria from Roche and MSD. The other authors declare no conflicts of interest.

Correspondence

Johann Stuby, MD, Internal Medicine, Limmattal Hospital, Urdorferstrasse 100, CH–8952 Schlieren, johann.stuby[at]spital-limmattal.ch

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Appendix 1

Descriptions of the four unpublished cases

Case 1

A 74-year-old woman with pulmonary adenocarcinoma (cT2a, Nx, cM1c, stage IVB, no brain metastases) presented to the emergency room with sudden onset of fever, confusion and a reduced level of consciousness. First-line therapy with carboplatin, pemetrexed and pembrolizumab was established 17 days before. Due to elevated inflammatory markers and opacities in a chest X-ray, pneumonia was suspected for which antibiotic treatment was started. The patient’s condition continued to deteriorate. Computerised tomography (CT) of the brain, chest and abdomen did not show any signs of infection. Blood cultures were negative. Lumbar puncture revealed leucocytosis (85% monocytes) and increased values of protein (589 mg/l, normal value 150–450 mg/l), glucose (4.1 mmol/l, normal value 2.2–3.9 mmol/l) and lactate (2.9 mmol/l, normal value 1.2–2.1 mmol/L). PCR assays for herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and varicella zoster virus (VZV) were negative. Serological tests showed a positive IgG result and negative IgM result for tick-borne encephalitis (TBE), which was due to a vaccination. Meningoencephalitis was suspected, and the patient was transferred to the intensive care unit (ICU) with a reduced Glasgow Coma Scale (GCS) of 11. Since antibiotic and antiviral treatment (ceftriaxone, amoxicillin, metronidazole, and aciclovir) did not improve the patient’s condition, an electroencephalogram (EEG) was obtained. The EEG showed focal findings in the parieto-temporal region, suggesting encephalopathy. An MRI scan of the brain did not show any signs of encephalitis or meningitis. Nevertheless, a diagnosis of immune-mediated encephalitis due to cancer treatment with pembrolizumab was established. Antimicrobial therapy was stopped, and the patient was treated with intravenous steroids (methylprednisolone, 125 mg daily) and intravenous immunoglobulins (IVIG, 30 g/300 ml). The patient’s condition improved rapidly within five days in the ICU, and she was transferred back to the ward. The corticosteroid therapy was changed to oral prednisone 50 mg daily, followed by a steroid taper over several weeks. The patient was discharged from the hospital after 17 days.

Case 2

A 58-year-old woman with stage IV carcinosarcoma of the uterus received third-line therapy with lenvatinib and pembrolizumab. She was previously treated with carboplatin, paclitaxel and bevacizumab well as with hormonal therapy with medroxyprogesterone acetate and later tamoxifen. A solitary brain metastasis was treated with radiosurgery. She developed diffuse pain, fever, aphasia, agitation and confusion 13 days after starting the new therapeutic regimen with pembrolizumab. She was intubated and transferred to the intensive care unit. A CT scan of the brain did not show signs of intracerebral haemorrhage or another new pathology. Neurology consultation was obtained. Herpes simplex encephalitis or limbic encephalitis were suspected, and treatment with aciclovir and methylprednisolone (80 mg IV) was established. Furthermore, the dose of her seizure prophylaxis with levetiracetam was increased. A brain MRI, electroencephalogram (EEG) and analysis of CSF were not performed. The patient’s condition promptly improved with steroid treatment, and she was transferred back to the ward after 3 days. Due to further progression of the carcinosarcoma with infiltration of the ureters with consecutive severe renal failure, further cancer treatment was stopped, and the regimen changed to palliation. The patient died a couple of days later.

Case 3

A 63-year-old woman with advanced pulmonary adenocarcinoma (cT1, cN2, M1c, UICC stage IV without brain metastases) that had progressed despite chemotherapy with carboplatin and pemetrexed was treated with nivolumab. The patient developed muscle weakness and dysarthria after approximately 10 months. She was admitted to the emergency room with a reduced level of consciousness but without fever. An MRI scan of the brain that was performed in the rehabilitation clinic prior to hospitalisation did not reveal signs of ischaemia, encephalitis or meningitis. An electroneuromyography (ENMG) study did not show signs of myositis or demyelinating polyneuropathy. An EEG was not obtained, and CSF was not analysed. Clinically, autoimmune encephalitis was suspected, and the patient received intravenous steroids (125 mg of methylprednisolone daily), which led to a clear improvement of her condition. Steroid treatment was changed to oral prednisone, and the patient was discharged home after 11 days in the inpatient ward with a steroid taper regimen.

Case 4

A 79-year-old man with stage IV Merkel-cell carcinoma was brought to the emergency room with aphasia, visual disturbance and memory loss. There was no sign of intracerebral haemorrhage, aneurysm or vascular stenosis in the CT scan of the brain. Brain MRI did not detect encephalitis, hypophysitis, or ischaemia. An EEG showed mild background slowing with moderate focal slowing over the left temporal region but no epileptiform activity. CSF analysis revealed an increased cell count (83/μl, normal value <5/μl) with 90% monocytes, an increased level of protein (1065 mg/l, normal value 150–450 mg/l) and a normal concentration of glucose (2.7 mmol/l, normal value 2.2–3.9 mmol/l). The patient was treated with fourth-line therapy with ipilimumab and nivolumab, which was started 12 days prior to admission. Previously, he received cisplatin/etoposide, avelumab and talimogene laherparepvec. Due to a clinical diagnosis of encephalitis, intravenous immunosuppressive therapy with 125 mg methylprednisolone was initiated, and the patient was transferred to the ICU. Additionally, the patient received aciclovir until the PCR assays for HSV-1, HSV-2 and VZV were negative. Given the rapid improvement of his clinical condition, intravenous methylprednisolone was changed to oral prednisone and tapered over a few weeks. The patient was discharged from the ICU and the hospital after three and six days, respectively.

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