Lung Cancer 109 (2017) 74–77

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Lung Cancer
journal homepage: www.elsevier.com/locate/lungcan

Case report

Recurrent dysphasia due to nivolumab-induced encephalopathy with
presence of Hu autoantibody

MARK

⁎

Jo Raskina, , Pegah Masrorib, Antonin Cantb, Annemie Snoeckxc, Birgitta Hiddingaa, Sisca Kohla,
Annelies Janssensa, Patrick Crasb,d, Jan P. Van Meerbeecka,e
a

Department of Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium
Department of Neurology, Antwerp University Hospital, Edegem, Belgium
c
Department of Radiology, Antwerp University Hospital, Edegem, Belgium
d
Born Bunge Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
e
Center for Oncological Research, University of Antwerp, Antwerp, Belgium
b

A R T I C L E I N F O

A B S T R A C T

Keywords:
Nivolumab
Non-small-cell lung cancer
Immune-related adverse event
Hu paraneoplastic antibody
Neurological toxicity
Dysphasia

A 58-year-old man was being treated for squamous non-small-cell lung cancer with nivolumab. At the 17th of
biweekly administrations he presented with global dysphasia, dysarthria and myoclonus in the right upper
extremity. MRI showed multiple T2/FLAIR hyperintense lesions in the left hemisphere; lumbar puncture showed
lymphocytic pleiocytosis in the CSF without identifiable pathogens. Hu antibodies were present in serum and
CSF. Nivolumab was discontinued and corticosteroids were administered. The neurological symptoms gradually
improved; MRI showed complete remission of cerebral lesions. After rechallenge with nivolumab his symptoms
and cerebral lesions recurred, proving the causal relationship with nivolumab. After tapering of corticosteroids, a
second relapse occurred.

1. Introduction
Nivolumab (Opdivo•, Bristol-Myers Squibb, New York, NY) is a
genetically engineered, fully human immunoglobulin G4 monoclonal
antibody which binds PD-1 (short for programmed death-1) with high
affinity, thus blocking interaction with its ligands PDL-1 and PDL-2 [1].
PD-1 is an immune regulatory protein (checkpoint inhibitor) expressed
by a variety of immune cells (CD4+ and CD8+ T-lymphocytes,
regulatory T-lymphocytes, B-lymphocytes and natural killer cells). Its
ligands PDL-1 (CD274/B7-H1) and PDL-2 (CD273/B7-DC) are expressed by macrophages and dendritic cells; additionally, PDL-1 is
expressed by lymphocytes [2]. PDL-1 is upregulated on solid tumour
cells by activation of interferon by cytotoxic T-lymphocytes and via
oncogenic signalling through MAPK, PIK3 and EGFR pathways, thus
downregulating effector T-cells, leading to immune tolerance of cancer
cells and even escape from the immune system. Under normal
circumstances, the PD1-ligand interaction forms an immune checkpoint, preventing auto-immunity and excess inflammation by suppression of effector T-cells [3,4]. Nivolumab is currently approved for
treatment of metastatic malignant melanoma and non-small-cell lung
cancer, but has demonstrated antitumoural activity in several other
cancers. Inhibition of immune checkpoints raises concern for auto-

⁎

immune mediated adverse effects of treatment with nivolumab. Neurotoxicity is reported to be rare [5].
2. Case presentation
A 58-year-old man had received the 17th of biweekly administrations of nivolumab for stage IV squamous non-small-cell lung cancer
(NSCLC), pre-treated with 2 lines of chemotherapy. Evaluation after 16
cycles showed confirmed partial response, with continuation of treatment.
He suddenly presented with new-onset speech impairment and mild
myoclonus in the right arm since one week. No cerebral or leptomeningeal metastases had ever been found, and no existing neurological
disease was known. His medication (denosumab, omeprazole and
bisoprolol) had not been changed for the last 2 years.
He predominantly suffered from global dysphasia, limited speech
(single words, stuttered three-word sentences) to almost complete
muteness. His symptoms seemed to be worsened by stress, and by
forcibly trying to explain himself. Neurological exam further revealed
mild dysarthria, difficulties in performing complex tasks, reduced right
forearm rolling and discrete flattening of the right nasolabial fold. His
comprehension was not affected.

Corresponding author at: Antwerp University Hospital. Wilrijkstraat 10, 2650 Edegem, Belgium.
E-mail address: jo.raskin@uza.be (J. Raskin).

http://dx.doi.org/10.1016/j.lungcan.2017.05.002
Received 10 March 2017; Received in revised form 26 April 2017; Accepted 2 May 2017
0169-5002/ © 2017 Elsevier B.V. All rights reserved.

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Fig. 1. MRI of the brain at first presentation. Axial FLAIR images show a large area of hyperintensity in the left insular cortex (A) and a small area of hyperintensity (B) in the left frontal
operculum (white arrow). Axial FLAIR image (C) after discontinuation of Nivolumab shows normal findings with complete resolution of all T2 hyperintensities. At axial diffusionweighted MR image (b = 1.000 s/mm2) only very slight increase in signal intensity in the area of the left insular cortex and slight decrease of signal intensity on the apparent diffusion
coefficient (ADC) map, corresponding to only very mild diffusion restriction (D-E). No diffusion restriction is seen in the lesion in the left operculum (F).

physin, anti-PNMA2, anti-Ri, anti-Yo, anti-recoverin, anti-SOX1, antititin, anti-zic4, anti-GAD65, anti-Tr, anti-CASPR2, anti-LGI1 and antiNMDA-receptor, anti-AMPA1-receptor, anti-AMPA2-receptor, anti-GABAb-receptor) were not present.
Empirical treatment with ceftriaxone (2 g/12 h) and ampicillin
(2 g/4 h) was initiated, with association of levetiracetam (1000 mg/
12 h); nivolumab was discontinued and dexamethasone (8 mg/24 h)
administered. Over the next few weeks, his speech progressively
improved, with disappearance of the brain lesions five weeks later on
MRI (Fig. 1C), and normal speech eight weeks after diagnosis.
Corticosteroids were gradually tapered and discontinued after twelve
weeks of treatment. At this moment a new chest computed tomography
(CT) unfortunately showed significant tumour progression.
As no valid other treatment was available, rechallenge with
nivolumab was proposed, in accordance with successful rechallenges
reported in other patients [6]. An identical aphasia syndrome occurred
after three cycles of nivolumab. Relapse of lesions was present at MRI
(Fig. 2A), although less pronounced, on EEG, in spite of ongoing
treatment with levetiracetam, and with similar lymphocytic pleiocytosis and anti-Hu antibodies in the CSF. Dexamethasone was restarted.
With this, his EEG normalized and his speech slowly returned to

A work-up with EEG, magnetic resonance imaging (MRI), blood
analysis and lumbar puncture was performed. Full blood count showed
no abnormalities. EEG showed moderate diffuse slowing with focal
epileptic activity in the temporal cortex, corresponding at MRI to areas
of increased T2/FLAIR relaxation time in the left hemisphere: in the
frontal operculum, in the posterior part of the sylvian fissure and insula
and in the parafalcine superior parietal cortex and subcortical white
matter (Fig. 1A–C). The large lesion in the insula showed very slight
diffusion restriction (Fig. 1D-E), too limited to be compatible with
ischemic stroke. No diffusion restriction was seen in the smaller lesions
(Fig. 1F). Cerebral ischaemia or vasculitis was considered very unlikely
and not further investigated. No cerebral or leptomeningeal metastases
were found. A repeat MRI one week later showed a fourth lesion in the
parietal subcortical white matter and a more pronounced diffusion
restriction.
A lumbar puncture showed an inflammatory cerebrospinal fluid
(Table 1); this finding was confirmed on a second sample one week
later. Extensive cultures with viral and microbial PCRs remained
negative. No malignant cells were found. Anti-Hu antibodies in serum
and CSF (immunofluorescence and confirmation with immunoblot),
would later return positive. Other antineuronal antibodies (anti-am75

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J. Raskin et al.

Table 1
Results of cerebral fluid analysis on day 1 and day 10 of first presentation, at first (FR) and second (SR) recurrence.
Lumbar puncture

1

10

FR

SR

Units

WBCs
RBCs
(/mm3)
Cultures
Glucose [40–70]
Protein
[15–40]
IgG [ < 5.5]
Lactic acid [0.6–2.2]
Oligoclonal bands
Flow cytometry

63 (96.8% mononuclear)
< 1000

24 (100% mononuclear)
< 1000

61 (70.5% mononuclear)
< 1000

3
< 1000

/mm3
/mm3

negative
90
74

negative
108
67

negative
75
77

negative
78
49

mg/dl
mg/dl

6.0
ND
YES
ND

ND
2.7
ND
ND

5.4
2.6
YES
normal

7.73
ND
YES
ND

mg/dl
mmol/l

Abbreviations: RBC = red blood cell, WBC = white blood cell, ND = not determined.

paraneoplastic antibody and has been associated with several neurological syndromes, including sensory neuropathy, cerebellar ataxia and
(limbic) encephalitis [10].
PD-(L)1-inhibitor treatment-related grade 3/4 adverse events are
not uncommon, being reported in 7–10% in phase III studies in nonsmall-cell lung cancer [1,11]. Neurological adverse events are very rare,
phase III studies only reporting 5 cases in 564 patients (0.89%) treated
with nivolumab, of which 2 minor (dizziness) and 3 grade ≥3 (lethal
encephalitis, initially not attributed to nivolumab; cerebrovascular
accident; and myasthenic syndrome) [1,11].
Case reports describing several neurological syndromes, such as
dysgeusia, in- and hypersomnia, restless legs syndrome, tremor,
lethargy, impaired memory, vertigo, dysarthria, cerebral oedema,
peripheral neuropathy, optic neuritis, myasthenia gravis, multifocal
CNS demyelination, … are summarized by Zimmer, with additionally
describing 16 cases of neurological adverse events in melanoma, of
which 5 grade ≥3 [4]. This gives an incidence of 5/496 (1.0%). Median
time to onset of symptoms was 9.5 weeks after first administration
(range 1–68 weeks).
Mandel reported a case of ataxia, vertigo and numbness in the left
arm in a melanoma patient receiving pembrolizumab, another PD-1
inhibitor, who had previously also been treated with ipilimumab. He
developed FLAIR hyperintensities in the claustrum, right frontal and
left occipital lobes. EEG showed partial motoric status epilepticus, but
no lymphocytic pleiocytosis was found at lumbar puncture [12]. These

normal.
Corticosteroids were gradually tapered over the next twelve weeks.
Once corticosteroid-free, a second relapse of aphasia took place, more
than fifteen weeks after the last administration of nivolumab. Again,
EEG findings were similar. Hu autoantibodies were confirmed. The
initial lesion in the left thalamus had increased in size (Fig. 2B).
Dexamethasone was restarted, with dose increase of levetiracetam and
association of valproic acid. Currently his speech remains normal with a
maintenance dose of 6 mg dexamethasone.
3. Discussion
Inhibitors of the PD-1/PD-L1 pathway, also called checkpoint
inhibitors, have been shown to cause a wide array of immune-related
adverse events [5,7]. The exact mechanism is unknown: a central role
for unchecked T-cell activity is being assumed, possibly with a
contribution of antibody production by B-cells or cytokine release by
granulocytes [8]. As anti-Hu neuronal antibodies were present in our
patient’s CSF and serum, nivolumab-triggered antibody production or
direct cytotoxic T-cell response to tumour antigen cross-reacting with
brain epitopes, may have been responsible. Hu antigen is almost
exclusively present in neuronal tissue, but may ectopically be expressed
by cancer cells, especially in small-cell lung cancer. Expression in nonsmall-cell lung cancer is uncommon [9]. Hu antibody (also known as
type 1 anti-neuronal nuclear antibody [ANNA-1]) is a well-known

Fig. 2. Axial FLAIR image (A) after rechallenge shows a new small T2 hyperintensity lesion in the left thalamus (white arrow) and recurrence of T2-hyperintensities in the left insular
cortex. Axial FLAIR image (B) at the second recurrence of clinical relapse clearly shows an increase in size of the thalamic T2-hyperintensity lesion (white arrow).

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findings and further evolution after discontinuation of pembrolizumab
strongly resembles our case, but to our knowledge, this case is the first
in which presence of a paraneoplastic (Hu) antibody is documented.

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4. Conclusion
Severe neurological immune-related adverse events of nivolumab
are rare, with an incidence of < 1%, and might present with a wide
array of neurological syndromes, mimicking infectious, inflammatory,
vascular or malignant aetiologies. Onset might be early after first
administration, weeks or months later, or even after discontinuation of
nivolumab, as the immune activation might persist. Discontinuation of
nivolumab and slowly tapering of corticosteroids are essential in
management of this kind of neurotoxicity. A high sense of clinical
awareness coupled with appropriate neurological imaging is needed in
order to raise the diagnosis. There is presently no diagnostic test; an
empiric approach of drug discontinuation and treatment with corticosteroids is the current management of choice.
Conflicts of interest
None.
Acknowledgement
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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