Journal of Neurology (2024) 271:2119–2124

https://doi.org/10.1007/s00415-023-12163-6

LETTER TO THE EDITORS

Progressive multifocal leukoencephalopathy in patients with chronic

liver disease successfully treated with pembrolizumab
Lina Jeantin1 · Natalia Shor2 · Marc Coustans3 · Damien Roos‑Weil4 · Isabelle Quintin‑Roué5 · Agnès Bellanger6 ·
Magali Le Garff‑Tavernier7 · Rahma Ben Jemaa9,10 · Dominique Thabut8,9,10 · Valérie Pourcher10,11 ·
Nicolas Weiss1,12,13

Received: 21 November 2023 / Revised: 14 December 2023 / Accepted: 16 December 2023 / Published online: 24 December 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2023

Dear Sirs,
Progressive multifocal leukoencephalopathy (PML), an
often fatal opportunistic infection of the central nervous
system (CNS) caused by the John Cunningham (JC) virus,
is commonly observed in severe immunosuppression.[1]
No specific treatment other than immune reconstitution is
currently available. However, immune checkpoint inhibi-
tors (ICI) such as pembrolizumab have recently emerged
as potential treatments [2–4]. Pembrolizumab targets the
programmed-cell death 1 (PD-1) pathway, which is thought
to impair viral clearance in the CNS [5].
Chronic liver diseases, particularly severe fibrosis/cirrho-
sis, are associated with multifactorial immunosuppression,
including reduced T-lymphocyte proliferation [6], altered
phagocytosis [7] and natural killer activity [8]. Only eight
cases of PML have been described in patients with cirrho-
sis [9, 10], and, to date, no use of ICI for PML has been
reported in these patients. We describe two cases of PML in
patients with newly diagnosed liver fibrosis, in whom PML
progression was halted with pembrolizumab.
Patient 1 A 55-year-old male was recently diagnosed
with alcoholic liver cirrhosis (Child–Pugh score of A6 and
MELD score of 8) and stopped alcoholic consumption. Few
weeks later, he presented with rapidly progressive apraxia,
gait instability and speech impairment. Brain MRI showed
bilateral T2-FLAIR white matter hyperintensity with dif-
fusion leading-edge hyperintensity, consistent with PML
(Fig. 1A1-4). The cerebrospinal fluid (CSF) was positive
for JC virus DNA (JCVQ-PCR Alert Kit, ELITech), with

8
* Nicolas Weiss Brain Liver Salpêtrière Study Group, Sorbonne Université,
nicolas.weiss@aphp.fr INSERM UMR_S 938, Centre de Recherche Saint-Antoine
& Institute of Cardiometabolism and Nutrition (ICAN),
1
Département de Neurologie, Sorbonne Université, Médecine 75013 Paris, France
Intensive Réanimation à Orientation Neurologique, AP-HP. 9
Liver Intensive Care Unit, Hepatogastroenterology
Sorbonne Université, Hôpital Pitié-Salpêtrière, 47‑83,
Department, AP-HP, Sorbonne Université, Pitié-Salpêtrière
Boulevard de L’hôpital, 75013 Paris, France
Hospital, 47‑83 Boulevard de L’Hôpital, 75013 Paris, France
2
Department of Neuroradiology, Pitié–Salpétrière University 10
Sorbonne Université, 75005 Paris, France
Hospital, AP-HP, 47‑83 bd de L’hôpital, 75013 Paris, France
11
3 Sorbonne Université, INSERM, Institut Pierre Louis
Department of Neurology, CHIC Quimper-Concarneau, 14
d’Epidémiologie et de Santé Publique (IPLESP UMRS
Avenue Yves Thépot ‑ BP 1757, 29107 Quimper, Cedex,
1136), AP-HP, Hôpital Pitié Salpêtrière, Service Des
France
Maladies Infectieuses et Tropicales, Paris, France
4
Sorbonne Université, Department of Clinical Hematology, 12
Brain Liver Pitié‑Salpêtrière (BLIPS) Study Group, INSERM
Pitié–Salpétrière University Hospital, AP-HP, 47‑83 bd de
UMR_S 938, Centre de Recherche Saint-Antoine, Maladies
L’hôpital, 75013 Paris, France
Métaboliques, Biliaires et Fibro-Inflammatoire du Foie,
5
Département de Pathologie Cellulaire et Tissulaire, CHRU Institute of Cardiometabolism and Nutrition (ICAN), Paris,
Brest, Brest, France France
6 13
Pharmacie hospitalière, Sorbonne Université, AP-HP, Hôpital Groupe de Recherche Clinique en REanimation et Soins
Pitié Salpêtrière, 75013 Paris, France Intensifs du Patient en Insuffisance Respiratoire aiguE
7 (GRC-RESPIRE) Sorbonne Université, Paris, France
Department of Biological Hematology, Pitié–Salpétrière
University Hospital, AP-HP, 47‑83 bd de L’hôpital,
75013 Paris, France

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a detectable but unquantifiable viral load. The only immu-
nosuppression was lymphopenia (negative HIV serology,
polyclonal hypergammaglobulinemia, no evidence of
hemopathy or solid cancer, no history of immunosuppressive
medication, see Table 1). The patient received pembroli-
zumab at 2 mg/kg intravenously 1 month after the onset of
symptoms. One month later, brain MRI showed widening of
white matter hypersignals, peripheral and perivascular gado-
linium enhancement consistent with immune reconstitution
Fig. 1  MRI data for Patient #1. Baseline (A) and follow-up brain
MRIs (B, C) of Patient #1: diffusion B1000 (A-D1), apparent diffu-
sion coefficient (ADC) (A-D2); T2 FLAIR (A-D3) and T1-post-gado-
linium (A-D4)-weighted sequences. A1–A4: initial MRI (A) demon-
strates T2 FLAIR and diffusion white matter bilateral hyperintensities
including subcortical U-fibers, without gadolinium enhancement
(A3). The lesions core has low B1000 (A1) and high ADC values
(A2), whereas the rim of the lesions presents with lower ADC value
(A2, arrow). B1–B4 MRI performed 1 month after the first pembroli-
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Journal of Neurology (2024) 271:2119–2124
inflammatory syndrome (Fig. 1, B1-4). The patient received
a second cycle of pembrolizumab at 2 mg/kg intravenously,
and JC viral load in the CSF was still detectable but unquan-
tifiable. Two months after the first dose of pembrolizumab,
brain MRI (Fig. 1, C1-4) showed regression of the lesions.
The patient showed mild improvement and received a third
and final cycle of pembrolizumab at 2 mg/kg intravenously.
At that time, JC viral load was still detected and unquantifi-
able. Lymphopenia remained constant over time, suggesting
zumab infusion (B) shows an extension of the white matter abnor-
malities (B3), but also a vanishing leading-edge diffusion hyperin-
tensity (B1). Peripheral and perivascular gadolinium enhancement
(B4, arrows) in favor of immune reconstitution inflammatory syn-
drome can also be seen. C1–C4 2-month follow-up MRI (C) shows
the diffusion hyperintensity disappearance and a noticeable T2FLAIR
hyperintensity and gadolinium enhancement reduction. D1–D4 2-year
follow-up MRI (D) demonstrating the preexisting lesion reduction
and a complete disappearance of the gadolinium enhancement
Journal of Neurology (2024) 271:2119–2124 2121

Table 1  Biological data

Patient 1 Patient 2

CSF data
White blood cells, no./mm3 0 0
Proteins, g/L 0.24 0.37
JCV PCR Positive Negative
Lymphocytes
Lymphocytes, total (G/L) 0.68 1.51
CD19 + , no./mm3 (% of total lymphocyte count) 40 (4.2%) 184 (12.2%)
CD4 + , no./mm3 (% of total CD3 + count) 132 (19%) 675 (44.7%)
CD8 + , no./mm3 (% of total CD3 + count) 385 (55%) 532 (35.2%)
Lymphocytes/neutrophils ratio 0.68/2.15 (32%) 1.51/4.2 (36%)
Liver tests
Prothrombin levels (%) 64 88
APTT 1.25 0.94
Albumin (g/L) 26 38.9
AST (UI/L) 24 18
ALT (UI/L) 14 34
Gamma-GT (UI/L) 64 40
Alkaline phosphatase 59 39
Total bilirubin (µmol/L) 14 –
Ammonium (µmol/L) (N 16–60 µmol/L) 42 –
Creatinine (µmol/L) 57 59
Serology testing HIV, HBV, HCB: negative HIV, HBV, HCB, HEV,
EBV, CMV: past infection TPHA, VDRL, Borrelia:
negative

APTT activated partial thromboplastin time, ALT alanine transaminase, AST aspartate transaminase, CSF cerebrospinal fluid, Gamma-GT
gamma glutamyltransferase, JCV John Cunningham virus

a role for pembrolizumab in stabilizing PML rather than
spontaneous immune restoration, which could account for
PML improvement (see Suppl. Table 1). One year later, the
neurological examination remains stable, and brain MRI
shows a further regression of the PML lesions (Fig. 1, D1-4).
Patient 2. The second patient, a 63-year-old male with a
history of arterial hypertension, atrial fibrillation, obesity
(BMI 31.25 kg/m2), hypertriglyceridemia, no diabetes and
moderate alcohol consumption was diagnosed with meta-
bolic steatohepatitis. Elastometry showed F2–F3 grade
fibrosis at 10 kPa (IQR 1.8), and liver echography showed
S3 fibrosis without cirrhosis or portal hypertension. Three
months later, he presented with progressively worsening
motor deficit of the right hand, followed by gait, memory and
speech impairment. A brain MRI performed 8 months after
the onset of the symptoms showed frontoparietal white mat-
ter T2-FLAIR hyperintensities. CSF study showed no white
blood cells, proteins level at 0.37 g/L, and a negative PCR
for JC virus (Table 1). A stereotactic parietal brain biopsy
showed perivascular lymphocytic infiltrates and nuclei with
cytopathogenic viral aspects, confirming the diagnosis of
JC virus infection (Fig. 2). No cause for immunosuppres-
sion was found, including no solid cancer or hemopathy,
negative HIV serology, normal immunoglobulin dosage and
lymphocyte immunophenotyping. The patient was scheduled
to receive monthly intravenous infusions of pembrolizumab
at 2 mg/kg. The CSF study was not controlled, as the ini-
tial JC virus PCR in the CSF was negative. A follow-up
brain MRI (Fig. 2A) showed mild enlargement of the PML
lesions, but the symptoms had stabilized by the time of the
third pembrolizumab cycle. Treatment with pembrolizumab
was therefore continued monthly for a total of seven infu-
sions, before increasing the interval between infusions from
4 to 6 weeks. The patient currently receives one infusion of
pembrolizumab every 6 weeks due to stabilization, no other
available therapy, and the absence of ICI-related side effects.
One year after the onset of symptoms, the patient remains
stable with a slight radiological improvement (Fig. 2B).
We report two cases of PML in patients with liver fibro-
sis and no other cause of immunosuppression, successfully
treated with pembrolizumab. These cases highlight several
important pitfalls for clinicians.
Firstly, although chronic liver disease is associated with
multifactorial immunosuppression, few cases of PML have
been reported in these patients. PML has been previously
described in a patient with alcoholic cirrhosis, who died

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◂Fig. 2  MRI data for Patient #2. Patient#2 brain MRIs: diffusion
B100 (A1, B1), ADC (A2, B2), T2 FLAIR (A3, B3) and T1-post-
gadolinium (A4, B4)-weighted sequences. A1–A4 The first MRI
shows T2 FLAIR and diffusion white matter bilateral asymmetrical
hyperintensities including subcortical U-fibers without any noticeable
gadolinium enhancement. Foci of low ADC (A2, arrow) within the
lesion’s rim reflecting diffusion restriction can also be seen. B1–B4
The abnormalities appear less extensive on the 3-month follow-up
MRI (B). C1 Histopathologic analysis in hematoxylin/eosin/saffron
stain. Cerebral tissue shows perivascular lymphocytic infiltrates and
increased cellularity. Some oligodendrocytes show nuclear enlarge-
ment with glassy magenta chromatin corresponding to cytopatho-
genic viral aspects, nonspecific but compatible with JC virus infec-
tion. Black scale bar corresponds to 50 µm. C2 Immunohistochemical
study with anti-Simian virus 40 (SV40) antibodies, an immunostain
for polyomavirus targeting JC virus antigens. The immunostain shows
nuclear labeling of infected cells (in blue), confirming JC virus pres-
ence and PML caused by JC virus reactivation. Black scale bar cor-
responds to 50µm
without specific treatment [9]. In a report of 38 patients
with PML and minimal or occult immunosuppression, seven
(18.4%) patients had cirrhosis, two of which were of alco-
holic origin [10]. None of the seven cases received any spe-
cific treatment, except for one who died after treatment with
interferon and cytarabine. A total of four patients died, two
stabilized or improved, and one outcome was not specified.
Attention must be raised on rapidly progressive neurological
symptoms in patients with liver disease, as PML could be
mistaken for encephalopathy in these patients.
Secondly, data on the use of ICI in patients with chronic
liver disease are lacking. In a study of eight patients with
PML, pembrolizumab improved or stabilized five patients
and reduced JC viral load in the CSF, while three wors-
ened [2]. In a prospective series of six immunocompromised
patients with PML, three patients died after treatment with
pembrolizumab, while three stabilized or improved [3]. An
international retrospective study of 79 patients with PML
treated with ICI reported a 1-year survival rate of 52% [4].
However, in all of these studies, no patient had liver fibrosis
or cirrhosis as the sole cause of immunosuppression.
In both cases, the patients had recently been diagnosed
with liver fibrosis, and although the second patient did not
meet all histological criteria for PML [11], the neurological
symptoms and disease course in both patients were highly
suggestive of an early JC virus reactivation, which occurred
rapidly after the diagnosis of liver disease. In these cases,
pembrolizumab appears to have stopped the progression of
PML rather than reversed it. Furthermore, in our first patient,
we could not observe whether pembrolizumab therapy
decreased JC viral load in the CSF because the initial viral
load was low (detectable, but unquantifiable). As the CSF
analysis was not controlled at a later time (e.g., 6 months or
1-year follow-up), it is also possible that the JC viral load
continued to decrease until it became negative. As this is
still an experimental and compassionate therapy, there is no
2123
consensus on the duration of pembrolizumab treatment. One
of the two patients stabilized with ongoing cycles of pem-
brolizumab, while the other patient did not experience PML
reactivation on discontinuation. These reports suggest the
interest of pembrolizumab with low risk of adverse events.
However, more evidence is needed to support the use of
ICI in PML, and their indication should be discussed in a
multidisciplinary team on a case-by-case basis according to
the possibility of immune restoration.
Supplementary Information The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00415-0​ 23-1​ 2163-6.
Author contributions LJ wrote the first draft of the manuscript. NS
and LJ designed the figures. All authors participated in the diagnosis
and therapy deliberation. All authors reviewed and approved the final
manuscript. The patients provided informed consent for the publication
of this report. Data was collected and managed in accordance with the
CARE statement checklist (https://​www.​care-​state​ment.​org/​check​list).
Funding This study did not receive any funding.
Declarations
Conflicts of interest The authors have no conflict of interest to declare.
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