Journal of Neuroimmunology 385 (2023) 578248

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Journal of Neuroimmunology
journal homepage: www.elsevier.com/locate/jneuroim

Short Communication

Progressive multifocal leukoencephalopathy secondary to idiopathic CD4

lymphocytopenia treated with pembrolizumab
Kyriakoula Varmpompiti a, *, Andrew J. Westwood b, Aaron Ben-Joseph b, Naomi Sibtain a,
Mohammad A.A. Ibrahim a, Biba Stanton a, Mark Zuckerman a, Robert Hadden a, b,
Laura Mantoan Ritter a
a
King’s College Hospital NHS Foundation Trust, London, United Kingdom
b
Maidstone and Tunbridge Wells NHS Tust, Hermitage Lane Maidstone, Kent, United Kingdom

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic
Progressive multifocal leukoencephalopathy infection of oligodendrocytes caused by John Cunningham polyoma virus (JCV) infection. Idiopathic CD4+ T-
John Cunningham Virus cell lymphocytopenia (ICL) is a very rare cause of PML.
Idiopathic lymphocytopenia
Methods: We present an individual with PML secondary to ICL treated with 3 doses of pembrolizumab, a
Neuroinflammation
Programmed-Death-1 Immune Checkpoint Inhibitor following with complete resolution of symptoms and
Pembrolizumab
PD-1 Checkpoint Inhibitor conduct a review of the literature.
Conclusion: This report illustrates the objective clinical and radiological improvement in a patient with PML due
to ICL and suggests further study of immune checkpoint inhibitors as potential treatment for patients with PML.

1. Introduction are susceptible to opportunistic infections (Lisco et al., 2023). It has

Progressive multifocal leukoencephalopathy (PML) is a progressive
and often fatal disease of the central nervous system (CNS) caused by
John Cunningham virus (JCV) (Berger, 2014). Depending on the coun­
try, the JCV seropositivity rate in the general population ranges from
33% to 91% (Wollebo et al., 2015; Bartsch et al., 2019). In immuno­
compromised patients, JCV may reactivate and cause a lytic infection of
the subcortical white matter oligodendrocytes, producing focal demye­
linating white matter lesions on imaging and neurological disability.
PML is particularly seen in patients with impaired cell-mediated im­
munity caused by HIV infection, immunosuppressive drugs, hemato­
logical and autoimmune disease as well as idiopathic forms of
lymphopenia (Cortese et al., 2019; Berger, 2014).
Idiopathic CD4+ lymphocytopenia (ICL) is a syndrome described in
Human Immunodeficiency Virus (HIV) negative patients with an abso­
lute CD4+ T-lymphocyte count of <300 cells/μL or of <20% total T-cells
on more than one occasion and absence of any immunodeficiency or
immunosuppressive therapy. Patients with reduced CD4+ T cell counts
been described as a rare cause of PML, with only 28 cases in the liter­
ature, without specific treatment and variable outcome (Table 3).
Treatment strategies so far include withdrawal of immunosuppressive
therapies, plasma exchange, mirtazapine, mefloquine, immunomodu­
latory drugs (Castle and Robertson, 2019), antiviral agents including
cidofovir, chemotherapy agents such as cytarabine as well as combina­
tions of multiple agents (Patel et al., 2010 with variable outcomes. More
recently, the focus has been on therapeutic strategies that promote the
recovery of antiviral immune responses, such as interleukin-7 (Lajaunie
et al., 2022) and immune checkpoint inhibitors (ICIs) (Boumaza et al.,
2023; Cortese et al., 2019; Walter et al., 2019).
Cortese et al. demonstrated a potential effect of PD-1 inhibition on
JCV in the CNS and possibly survival, using pembrolizumab 2 mg per kg
every 4 to 6 weeks in five out of eight patients with PML, with or without
HIV infection (Cortese et al., 2019). A more recent retrospective review
of 79 PML patients secondary to various predisposing conditions
including ICL, hematological malignancies, HIV, cancer and transplant
patients showed that cerebrospinal fluid (CSF) JCV DNA load decreased

Abbreviation: PML, Progressive multifocal leukoencephalopathy; CNS, Central Nervous System; JCV, John Cunningham virus; ICL, Idiopathic Lymphocytopenia;
PD1, Programmed cell death 1; ICIs, Immune Checkpoint Inhibitors; HIV, Human Immunodeficiency virus; CSF, Cerebrospinal fluid; IRIS, Immune Reconstitution
Syndrome; OCB, Oligoclonal Bands.
* Corresponding author at: King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom.
E-mail address: k.varmpompiti@nhs.net (K. Varmpompiti).

https://doi.org/10.1016/j.jneuroim.2023.578248
Received 26 September 2023; Received in revised form 9 November 2023; Accepted 13 November 2023
Available online 18 November 2023
0165-5728/© 2023 Elsevier B.V. All rights reserved.
K. Varmpompiti et al. Journal of Neuroimmunology 385 (2023) 578248

significantly 1-month post-treatment with an immune checkpoint in­

hibitor in survivors compared to non-survivors (p < 0.0001) (Boumaza
et al., 2023).
In this paper, we report an individual with ICL and PML who was
successfully treated with pembrolizumab and review the literature,
summarizing the associated clinical features and prognostic indicators.

2. Case summary

A 67-year-old right-handed previously independent man presented

Fig. 1. Axial T2w image shows confluent T2 hyperintensity the right cerebellar
peduncle with extension into the adjacent pons and cerebellar hemisphere
(orange arrow).
to his local hospital with worsening left-sided weakness, dysarthria, and
ataxia. Past medical history included hypertension and hypercholes­
terolemia. He was treated as having had a cerebellar infarct after
computed tomography (CT) head imaging showed right cerebellar
hypodensity. Three months later, he presented again with progressive
bulbar weakness complicated by aspiration pneumonia, worsening
dysarthria and ataxia. A magnetic resonance imaging (MRI) brain scan
showed cerebellar and brainstem signal abnormalities and a low level of
JCV DNA was detected in the CSF (623 copies/mL). He was HIV-
negative and had no risk factors for immunosuppression and was
transferred to the tertiary neurosciences centre for further
investigations.
Clinical examination revealed marked bulbar weakness, dysphagia
and non-sustained gaze-evoked nystagmus toward the right. There was
bilateral asymmetric (right more than left) gross ataxia with dysmetria
and intention tremor with brisk reflexes.
Serial MRI brain imaging showed progressive posterior fossa T2
hyperintensity and T1 hypointensity with right sided predominance,
without mass effect, restricted diffusion or contrast enhancement
(Fig. 1), overall suggesting PML. No inflammatory changes were seen on
the MRI spine. Laboratory results (Table 1) revealed mild lymphopenia
(0.9 × 109/L, normal range 1-10 × 109/L) with a low CD4 count (263
cell/μL, normal range 300–1400 cell/μL), low CD8 cells (170 cells/μL,
normal range 200–900 cells/ μL) and NK cells (59 cells/μL, normal range
90–600 cells/μL). Previous blood analyses showed persistent lympho­
penia (0.9 × 109/L) one year prior to the current presentation, hence

Table 1
Blood tests.
Lymphocyte subsets Immunoglobulins and serum electrophoresis Immunological and infection
screen

Before 1st After 2nd Normal range Normal Range

dose dose

CD3% 75 80 55–83% IgG 1 3.662 3.80–9.30 g/L Anti CASPR2 Negative

700-
CD3 Cells 421 780 IgG2 2.346 2.40–7.00 g/L Anti-LGi1 abs negative
2100cells/Ul
CD4% 44 41 28–57% IgG3 0.707 0.20–1.80 g/L Anti- haemophillus ab 0.69
300-1400cell/ 0.052–1.250 g/ Pneum cap polysac IgG 44.1 mg/
CD4 cells 263 406 IgG4 0.006
Ul L total L
CD8% 28 37 10–39% IgG 7.21 6.0–16.0 g/L Nuclear abs negative
200–900 cells/
CD8 cells 170 369 Serum kappa light chains 21.19 3.3–19.4 mg/L MPO/ PR3 negative
Ul
5.71–26.3 mg/
B cells % 6 1 6–19% Serum lamba light chains 26.9 IgG2 Pneumococcal abs 24.7
L
100–500 cells/
B Cells absolute counts 35 13 kappa:lamda ratio 0.86 0.26 to 1.65 anti tetanus toxoid IgG <0.10
Ul
0.70–1.80 μg/
NK% 11 12 7–31% b2 microglobulin 3.07 B-D Glucan negative
mL
90–600 cells/ IgM lambda monoclonal
NK cells 59 N/a present Aspergillus EIA Negative
Ul paraprotein
Lymphocyte Sum 515 N/a paraprotein concentration 3 (g/L) Treponemal antibody Negative
Virology test results
HIV type 1&2 antibody
HIV-1 RNA
antigen Negative <20 copies/mL
SARS CoV-2 RNA Negative
HCV antibody
HTLV type 1&2 Negative Negative
HCV RNA
antibody

Abbreviations: NK: Natural Killers; Ig; Immunoglobulin; CASPR2: Contacting Associated Protein Like 2; LGi1: Leucine Rich Glioma inactivated 1; VGKC; Voltage Gated
Potassium Channel; EIE; Enzyme Immunoassay; HTLV: Human T-lymphotropic Virus; HIV; Human Immunodeficiency Virus;

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K. Varmpompiti et al. Journal of Neuroimmunology 385 (2023) 578248

Table 2 DNA antibodies, anti-La and anti-Ro antibodies, complement levels,

CSF results VDRL and ACE were normal. CSF analysis showed no cells, normal
CSF tests At presentation Prior to starting protein, and glucose, however JCV DNA was positive on two occasions
pembrolizumab one month apart (623 copies/mL and 76 IU/mL) (Table 2). Intrathecal
Glucose 3.9 mmol/L 3.9 mmol/L JCV antibodies were also present. Incidentally, the patient was found to
Protein 0.51 g/L (0.25–0.45 g/L) 0.43 g/L (0.25–0.45 g/L) have raised κ and λ light chains on serum electrophoresis with a normal
CSF IgG 0.060 g/L (<0.026 g/L) Not done ratio and IgM λ monoconal paraprotein present at 3 g/dL, diagnosed as
CSF albumin 0.26 g/L (0.00–0.24 g/L) Not done monoclonal gammopathy of unknown significance.
WBC count <5 (/cmm) <5 (/cmm)
RBC count 5(/cmm) 7 (/cmm)
Despite extensive investigations, we were unable to find a predis­
Oligoclonal Unmatched intrathecal Not done posing cause for the low CD4 counts in our patient, leading to its cate­
bands OCB gorization as Idiopathic CD4+ T-cell Lymphopenia (ICL). He continued
Virologya Negative Negative to deteriorate clinically and radiologically (Fig. 2), became bedbound
JCV DNA Positive (623 copies DNA. Positive (76 IU/mL)
and a PEG tube was inserted to avoid further aspirations. The patient
mL)
JCV antibody Not done Positive was treated with 3 doses of pembrolizumab 2 mg/kg (Cortese et al.,
Cytology Negative Negative 2019). The first pembrolizumab dose was tolerated without any com­
a plications and led to mild improvement in his tremor and ataxia in his
CSF Virology includes CMV DNA, Adenovirus DNA, HSV1 and 2 DNA,
Varicella zoster virus DNA, Enterovirus DNA, EBV DNA, JCV. Abbreviations:
arms after a week. He continued to improve after further inpatient
CSF: Cerebrospinal Fluid; IgG: Immunoglobulin G; WBC: White Blood Cells; RBC: neurorehabilitation and 4 weeks later he received a second infusion. One
Red Blood Cells; OCB: Oligoclonal Bands; JCV: John Cunningham Virus month later, his gait improved to allow him to use a zimmer frame, his
dysphagia resolved, and he was able to eat. A repeat MRI brain showed
transient lymphopenia due to a possible concurrent infection was un­ improvement in the extent of the T2 hyperintensity in the pons, right
likely. The patient received a 2-week course of steroids for suspected middle cerebellar peduncle and the right cerebellar hemisphere (Fig. 3).
paraneoplastic autoimmune encephalitis without response. An extensive At this time, he developed allodynia in the right upper limb, affecting
work up including infective, autoimmune and paraneoplastic screen the soft tissue and joints and his right arm was stiff with mild oedema.
(Table 1), body CT scan and Positron Emission Tomography scan were There was no evidence of erythema or cellulitis. Blood tests showed a
negative. Blood tests including haemoglobin, renal function, bone pro­ raised ESR at 47, with normal Rheumatoid Factor and Full Blood Count.
file, antinuclear antibodies, antineutrophil cytoplasmic antibodies, anti- This was treated as an inflammatory arthritis with steroids for two weeks
extractable nuclear antigen, rheumatoid factor, anti-double-stranded and resolved.

Fig. 2. a) Repeat MRI performed 4 weeks later showed progression of signal change into the pons (orange arrow) and both cerebellar hemispheres (blue arrow),
without mass effect. b) Axial T1 post gadolinium image shows corresponding T1 hypointensity with absent enhancement (yellow arrow). (For interpretation of the
references to colour in this figure legend, the reader is referred to the web version of this article.)

3
K. Varmpompiti et al.
Fig. 3. Follow up MRI performed 6 months later shows a marked reduction in
the extent of T2 hyperintensity in the pons, right middle cerebellar peduncle
and right cerebellar hemisphere (blue arrow). (For interpretation of the refer­
ences to colour in this figure legend, the reader is referred to the web version of
this article.)
Four months after the second dose he began to deteriorate with
unsteadiness and bulbar symptoms. In view of the previous improve­
ment, a third dose of pembrolizumab was administered 5 months after
the second dose. However, at that time he was unable to chew or speak,
unable to walk, had developed diarrhea and fecal incontinence. He was
too unwell to tolerate a repeat MRI. Around three months after the last
dose of pembrolizumab he developed sepsis, aspiration pneumonia,
Clostridium difficile colitis and died.
3. Discussion
This is a patient with HIV negative PML in the context of ICL. The
clinical spectrum of ICL ranges from an incidental laboratory finding
(Zonios et al., 2008) to life-threatening complications that mimics the
clinical course of individuals with HIV infection (Luo and Li, 2008).
According to recent reports, PML has been described in several patients
who were eventually diagnosed with ICL (Boumaza et al., 2023; Cortese
et al., 2019). Our patient had a significantly long period of lymphopenia
starting at least 1 year prior to his presentation. Additionally, there was
also no history of previous immunosuppressive treatment as the patient
received 2 weeks of steroids. This is consistent with a primary cause for
his persistent lymphopenia. Genetic testing to rule out known causes of
inborn errors of immunity or constitutional bone marrow failure syn­
dromes was not carried out which is one of the limitations of our report
(Lisco et al., 2023).
In a recent literature review studying PML treated with ICIs, only 5
out of 53 patients had underlying HIV infection; four of whom had a
good outcome (Corey et al., 2022). Pembrolizumab has been suggested
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Journal of Neuroimmunology 385 (2023) 578248
to benefit individuals with HIV infection whilst on antiretroviral ther­
apy, However, there is a risk of immune reconstitution inflammatory
syndrome (IRIS) (Pinnetti et al., 2022). In a recent case report, pem­
brolizumab was seen to be effective in treating PML in an individual
with HIV infection whilst off antiretroviral therapy (Sim et al., 2022).
Table 3 includes those HIV negative individuals with PML caused by
ICL. The literature review was conducted by searching the Pubmed
database using the combination of keywords with the Mesh terms
(“Leukoencephalopathy, Progressive Multifocal”[Mesh] OR “Progres­
sive multifocal leukoencephalopathy “ OR “PML”) AND (“T-Lympho­
cytopenia, Idiopathic CD4-Positive”[Mesh] OR “Idiopathic CD4
lymphocytopenia” OR “ICL”). We identified 28 patients, the majority
were male (24 cases), two female and two of unknown gender. The
patients’ ages ranged between 30 and 87 years (median 56, Inter­
quantile range 24.25). CD4 counts varied between 39 and 294/μL (mean
161.75, SD 81.02). Treatments used included mirtazapine, mefloquine,
methylprednisolone alone or in combination, as well as cidofovir,
cytarabine interferon, and IL-7, but no clear conclusions could be drawn
on their efficacy. Over a variable follow-up period of up to 5 years, 10
out of 28 patients died, and 16 survived out of which 9 were stable, 4
were worse and 3 improved. Two cases had an unknown outcome.
Pembrolizumab has been used to treat individuals with HIV-
associated PML with (Coltart et al., 2023) and without IRIS (Sim
et al., 2022) and clinical improvement was reported. The possible
mechanism is that the Programmed Cell Death Protein-1 (PD-1) blocking
by Pembrolizumab inhibits down-regulatory signals toward T-cells,
leading to T-cell upregulation. The PD1 expressed on CD4+ and CD8+ T
lymphocytes has been shown to be elevated in patients with PML.
Moreover, blocking of the PD-1 receptor resulted in increased JCV-
specific T-cell immune response in a subgroup of patients with PML.
(Tan et al., 2012). Cortese described 8 individuals with PML, and 5
clinically improved or stabilized and had a reduction in the JCV DNA
load. A large multicenter retrospective “real-world” survey included
both published and unpublished reports about patients who received
ICIs as an add-on to standard care for PML (Boumaza et al., 2023). This
included 79 patients with PML due to various causes including hema­
tological malignancies, primary immunodeficiencies, HIV/AIDS,
chronic inflammatory diseases, solid neoplasm and transplant re­
cipients. 14 patients had primary immunodeficiencies, 2 out of whom
had ICIs, namely pembrolizumab and nivolumab. One-year survival
following ICI initiation was 51.9% and was similar across all causes
except for kidney transplant recipients (48.1% died, 18.4% from PML-
IRIS).
Our patient received 3 doses of pembrolizumab 2 mg/kg (Cortese
et al., 2019). Although our patient sadly died from complications of his
illness shortly after his third infusion, we believe his response to treat­
ment provides support for the efficacy of Pembrolizumab in PML in the
context of ICL. There were no significant side effects including IRIS.
Nevertheless, the patient developed right arm allodynia with soft tissue
and joint pain and stiffness, without any infective features. This was
improved with a short course of steroids. Arthritis in the context of IRIS
has been described in individuals with HIV infection (Eyer-Silva Wde
et al., 2012). It is difficult to rule out completely the possibility of IRIS
contributing to his clinical deterioration after the 3rd pembrolizumab
dose. In fact, the progressive deterioration of the pre-existing neuro­
logical deficits along with the immune reconstitution against the JC
virus favours this scenario, even in the absence of new brain imaging.
The increase observed in CD4 count and the improved viral load (CSF
PCR for JC negative) could mount an IRIS response. Indeed, PML - IRIS
cases are reported in the literature in patients undergoing treatment
with ICIs, but most of them concerned HIV patients or chronic inflam­
matory diseases, two subgroups in which immune recovery may be more
readily achieved (Corey et al., 2022). On the other hand, a rheumatic
K. Varmpompiti et al. Journal of Neuroimmunology 385 (2023) 578248

Table 3
Literature review of PML in the context of ICL.
Author, date age/ Underlying CD4 clinical MRI PML JCV treatment outcome
sex disorder count/ manifestations lesion diagnosis
μLbefore distribution
treatment

Fukumoto 54/ ICL and alcoholism 78 progressive pons and middle CSF and positive in cytarabine Remained in
et al., 2021 male dysarthria and cerebellar MRI CSF vegetative
gait disturbance peduncles state and
for over one death from
month, acute
hemifacial obstructive
dysesthesia, cholangitis
dysarthria, after 11 year
ataxia. Akinetic
mutism after 4
months
Dato et al., 40/ ???? 210 progressive parietal and CSF and positive in mirtazapine Mild
2020 male speech occipital lobe, MRI CSF deterioration
disturbance extending to the in cognitive
over 3 months, splenium of the impairment
Gerstmanns corpus after 2 years
syndrome, callosum, the
cognitive inner temporal
impairment lobe WM and
the left external
capsula
Sutton et al., 87/ ICL 259 unsteadiness, bilateral CSF and positive in supportive care died 15 days
2020 male diplopia, severe cerebellar MRI CSF after
dysarthria, hemispheres, admission
ataxia left brachium
pontis and left
pons
Aggarwal 45/ ICL 217 behavioral left brain Positive PCR mirtazapine died of
et al., 2019 male alteration, frontoparietal biopsy in CSF aspiration
progressive and right consistent pneumonia
right-sided temporoparietal with PML
weakness
Harel et al., 63/ ICL 140 progressive left na JCV in negative IL-7 and Maraviroc improved
2018 female hemiparesis x6 brain twice in CSF after 11
months biopsy and months
CSF
Kano et al., 75/ ICL 217 dysarthria and left brain mirtazapine died of
2018 male left facial frontoparietal biopsy aspiration
paralysis and right consistent pneumonia
temporoparietal with
Aghoram and 36/ ICL 50 Left-sided right precentral brain negative CSF Mirtazapine + Died
Narayan, male weakness, gyrus bioppsy 4 times mefloquine 29 months
2018 cognitive consistent after onset
dysfunction, with PML
anarthria,
dysphagia,
stridor, and
right-sided
cerebellar signs
Nambirajan 44/ ICL 110 impaired vision, Right parietal brain PCR positive Mirtazapine and Died
et al., 2017 male behavioral subcortical area, biopsy in CSFMi Mefloquine 11 months
changes, left followed by consistent after onset of
hemiparesis cerebellar with illness
hemispheres,
left medulla,
both thalami,
and internal
capsule
Aotsuka 66/ ICL 140 progressive gait right JCV positive PCR IL-7 and Stable 2 years
et al., 2016 male and speech frontoparietal positive in in CSF dmaraviroc after onset
impairement lobe CSF
x1.5 months
Gupta et al., 33/ ICL and failure 84 Right visual left cerebellum, brain positive in Mefloquine + Died 3 months
2020 male field deficit, brainstem, and biopsy CSF methylprednisolone after onset
headache, middle consistent
memory cerebellar with pml
problems × peduncle and JCV
3 weeks positive
Izaki et al., 77/ ICL 181 Slowly Left parietal, MRI and na Mirtazapine + Stable
2015 female progressive temporal, CSF mefloquine 12 months
cerebellar after onset
(continued on next page)

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K. Varmpompiti et al. Journal of Neuroimmunology 385 (2023) 578248

Table 3 (continued )
Author, date age/ Underlying CD4 clinical MRI PML JCV treatment outcome
sex disorder count/ manifestations lesion diagnosis
μLbefore distribution
treatment

ataxia × occipital, and

6 months insular regions
Alstadhaug 61/ ICL 110 Expressive Left parietal Brain Positive PCR Mirtazapine + Initial clinical
et al., 2014 male aphasia, a right- lobe biopsy in serum human improvement
sided spastic recombinant IL-7 and then
hemiparesis, deterioration
dysarthria due to
epilepsy
continua
partialis
Kobayashi 81/ ICL and CKD on 294 3 week history left frontal and CSF and positive in mefloquine Died 4 months
et al., 2013 male dialysis, HF of worsesning parietal lobes MRI CSF after onset
gait and right
disturbance, parietal lobe
right muscle
cramp and
hemiparesis,
following left
hemiparesis and
dysphagia
Delgado- 72/ ICL and biliary 247 dysarthria, B/L cerebellar MRI and positive PCR mefloquine Stable
Alvarado male cystadenocarcinoma ataxia and peduncles and CSF in CSF 22 months
et al., 2013 of liver cognitive upper left dorsal after onset
impairment. pons
Acute onset
with further
progression
Moloney 55/ ICL 242 Gradual onset Right na positive PCR mirtazapine clinical and
et al., 2012 male upper limb frontoparietal in CSF +mefloquine radiological
weakness × region, improvement
3 months cerebellum persisting 34
Dysarthria + and midbrain months after
onset
Patel et al., na ICL 39 Progressive right na positive PCR na na
2010 right-sided hemisphere in CSF
weakness,
numbness,
aphasia
Puri et al., 30/ ICL 87 Progressive Throughout brain Positive PCR Cidofovir, Stable 8 weeks
2010 male cognitive brain biopsy in serum risperidone, after therapy
decline, acute consistent mefloquine,
right-sided with pml brincidofovir, IL-7
weakness and JCV
positive
Gheuens 49/ ICL 81 progressive Left temporal brain na Supportive care Died within
et al., 2010 male expressive lobe extending biopsy 3 months of
aphasia to left parietal onset of
and frontal lobe illness
Gheuens 61/ ICL 80 progressive frontal lobes brain JCV-specific mirtazapine slowly
et al., 2010 male right bilaterally biopsy lymphocytes worsening 2
hemiparesis and showed in blood months after
expressive PML onset
aphasia
Hayashi 71/ ICL and Sjogren 272 dementia, right left frontal CSF JCV CSF JCV Steroid pulse Stable after
et al., 2008 male hemiparesis, white matter PCR, PCR, Biopsy therapy Cytarabine 18 months
ataxia, akinetic thalamus, Biopsy iv,
mutism after 3 cerebellum and
months brainstem.
Melzi et al., na ICL, previous syphilis 294 Right left na negative CSF IFNa recovery 5
2008 and psoriasis hemiplegia frontoparietal years after
lobes corpus onset
callosum and
left brainstem
Inhoff et al., 82/ ICL reduced Difficulty left frontal lobe na na cidofovir Alive after 1
2007 male but na swallowing, month of
severe admission but
dysarthria, worsening
nystagmus on
lateral gaze, and
ataxia
Rueger et al., 39/ Kaposi sarcoma, ICL 201 Vertigo and left frontal lobe na JCV DNA in na died 3 months
2006 male progressively CSF and after
unsteady gait, admission
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K. Varmpompiti et al. Journal of Neuroimmunology 385 (2023) 578248

Table 3 (continued )
Author, date age/ Underlying CD4 clinical MRI PML JCV treatment outcome
sex disorder count/ manifestations lesion diagnosis
μLbefore distribution
treatment

slurred speech, serum, PCR from

diplopia + antibodies pneumonia
Kokubun 61/ ICL 80 mild dementia Medial JCV IHC JCV DNA in amantadine Alive
et al., 2005 male and left cerebellar on biopsy serum 20 months
hemiparesis peduncle and sample after onset of
cerebellum illness
Haider et al., 49/ ICL 119 diplopia, right frontal brain JCV IHC on na na
2000 male progressive lobe biopsy biopsy
right upper limb consistent sample
weakness, with PML
paresthesias
and cognitive
decline,
impaired speech
Iwase et al., 57male ICL 202 Dysarthria, gait left subcortical, Na NA cidofovir died 4 months
1998 abnormalities, thalamic and from
ataxia cerebellar symptom
regions onset of
aspiration
pneumonia
Chikezie and 47/ TB and ICL 139 Confusion and Brainstem and Na JCV DNA in ATT + high-dose Alive 3 years
Greenberg, male speech cerebellum peripheral steroid therapy after onset of
1997 difficulty × blood illness, no
4 days improvement
Chikezie and 47/ MI (4 years back) <100 Confusion and left frontal lobe na ISH for JCV na Stable
Greenberg, male and ICL speech on biopsy 2 months after
1997 difficulty × onset of
4 days illness, but
developing
new lesions

reaction can also be considered, as irAEs are relatively common with PD-
1 inhibitor therapy and appear to be associated with a good response to
ICI therapy. The median time for the first rheumatic irAE is reported as
3–12 months, can be de novo autoimmune phenomena or exacerbations
of pre-existing autoimmune conditions (Cappelli et al., 2022; Liew et al.,
2019). The patient also developed Clostridium difficile colitis 5 months
after the 3rd dose of pembrolizumab. Clostridium difficile colitis has
never been described as a result of IRIS and was probably secondary to
the long courses of antibiotics for the recurrent aspiration pneumonias.
Pembrolizumab-Induced Immune-Mediated Colitis in a Patient with
Concurrent Clostridium Difficile Infection (CDI) comes second as a dif­
ferential. According to a recent review and meta- analysis on the Fatal
Toxic Effects Associated With Immune Checkpoint Inhibitors, fatal co­
litis appears to be the most common toxic adverse effect after Ipilimu­
mab and among the most common after PD-1 inhibitor (Wang et al.,
2018). Cases of concurrent pembrolizumab-induced colitis and CDI have
also been reported (Zhou et al., 2019). However, these usually are
documented 40 days after treatment initiation and rarely occur above
three months after the last dose.
Taken together, we would advocate considering pembrolizumab for
PML treatment earlier, to prevent or delay longer term morbidity and
mortality.
The natural history of ICL has not been well described. In Boumaza’s
case series some patients continued to demonstrate progression of
lymphocytopenia over time, however seven out of 39 had shown
spontaneous remission after 3 years follow up (Boumaza et al., 2023). In
our patient, CD4 cells normalised after the second dose of pem­
brolizumab. In Boumaza’s review, survival was not associated with
normalisation of the CD4 or CD8 T-cell counts. While CD4 counts are an
excellent way to estimate the severity of immunodeficiency in AIDS,
they are less reliable predictors of PML risk or outcomes than in many
other co-infectious complications. A progressive increase in CD4+ T cell
counts was observed in 2 patients during follow up, which was a
significant increase by a factor of 1.044 per year (Lisco et al., 2023) ICL
can be associated with a reduction of all lymphocyte subsets (Zonios
et al., 2008).
4. Conclusion
This report adds to the growing body of evidence that the intro­
duction of immunomodulators, especially pembrolizumab, have shown
promising results. Further research and clinical trials, such as in the form
of “n-of-1 trials” for rare diseases, which are single case studies, are
needed to assess their efficacy for this disease.
Declaration of Competing Interest
None.
Data availability
Data will be made available on request.
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