J Med Cases

Journal of Medical Cases, ISSN 1923-4155 print, 1923-4163 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Med Cases and Elmer Press Inc

Journal website https://www.journalmc.org

Case Report

Volume 12, Number 9, September 2021, pages 359-365

Pembrolizumab-Induced Meningoencephalitis: A Brain Autopsy Case

Figure 1. Chest computed tomography imaging of the primary tumor in the left lower lobe (shown by black arrow) before the start of pembrolizumab (a), and brain magnetic resonance imaging (MRI) of metastasis in the cerebellum (shown by white arrow) in T1-weighted image with gadolinium enhancement at the first visit to our hospital in March 2018 (b).

Figure 2. Chest computed tomography imaging did not show regrowth of the primary tumor in the left lower lobe (shown by black arrow) on admission (a). Brain magnetic resonance imaging (MRI) in plain T2-weighted image on the hospital day 4 did not suggest a diagnosis of encephalitis and meningitis (b).

Figure 3. Medulla oblongata obtained through autopsy: infiltration of lymphocytes, plasma cells and macrophages in the meninges (Hematoxylin and Eosin stain).

Figure 4. Immunohistochemistry of medulla oblongata stained by anti-CD3 (a), CD4 (b), CD8 (c) and CD20 (d) antibodies. CD: cluster of differentiation.

**Table 1.** Summary of Previous Brain Autopsy Cases of Encephalitis Induced by Immune Checkpoint Inhibitors
Authors (year)	Age/sex	Cancer	Initial symptoms	ICIs (course)/(response)	Timing^a	Brain mets	PNS antibody	Treatment	Symptom to death^b	Main lesion	Lym type
^aInterval from the start of ICI to symptom presentation. ^bInterval from symptom presentation to death. ^cBefore nivolumab treatment and after the onset of encephalitis. ACV: acyclovir; Ad: adenocarcinoma; CR: complete remission; F: female; ICI: immune checkpoint inhibitor; Ig: immunoglobulin; Ipi: ipilimumab; Lym: lymphocyte; LC: lung cancer; mets: metastasis; M: male; mPSL: methylprednisolone; Nivo: nivolumab; PC: pleomorphic carcinoma; PE: plasma exchange; Pem: pembrolizumab; PNS: paraneoplastic syndrome; PR: partial response; SQ: squamous cell carcinoma; CD: cluster of differentiation.
Bossart et al, 2017 [5]	60/M	Melanoma	Generalized tiredness, weakness, appetite loss	Ipi (4)→Pem (1)/(CR)	6 months	Yes	Not evaluated	None	> 2 wks	Pons, medulla	CD8-positive T cells
Leitinger et al, 2018 [4]	67/F	LC, SQ	Dyspnea, confusion, anxiety	Nivo (1)/(not described)	17 days	No	Negative	mPSL, Ig, ACV	40 days	Thalami, left central region	Few CD3-positive T cells
Matsuoka et al, 2018 [3]	60/M	LC, PC	Daytime drowsiness, memory disturbance	Nivo (2)/(PR)	33 days	No	Hu^c	High-dose mPSL, PE	6 mo	Hippocampus, pons, spinal cords, temporal lobe, thalamus, cerebellum	CD8-positive T cells, macrophage
Ours	67/F	LC, Ad	Fever	Pem (13)/(PR)	8 months	Yes	Not evaluated	mPSL pulse, ACV	10 days	Brain stem, temporal lobes	CD8-positive T cells

Table 1. Summary of Previous Brain Autopsy Cases of Encephalitis Induced by Immune Checkpoint Inhibitors

Authors (year)

Age/sex

Cancer

Initial symptoms

ICIs (course)/(response)

Timing^a

Brain mets

PNS antibody

Treatment

Symptom to death^b

Main lesion

Lym type

^aInterval from the start of ICI to symptom presentation. ^bInterval from symptom presentation to death. ^cBefore nivolumab treatment and after the onset of encephalitis. ACV: acyclovir; Ad: adenocarcinoma; CR: complete remission; F: female; ICI: immune checkpoint inhibitor; Ig: immunoglobulin; Ipi: ipilimumab; Lym: lymphocyte; LC: lung cancer; mets: metastasis; M: male; mPSL: methylprednisolone; Nivo: nivolumab; PC: pleomorphic carcinoma; PE: plasma exchange; Pem: pembrolizumab; PNS: paraneoplastic syndrome; PR: partial response; SQ: squamous cell carcinoma; CD: cluster of differentiation.

Bossart et al, 2017 [5]

60/M

Melanoma

Generalized tiredness, weakness, appetite loss

Ipi (4)→Pem (1)/(CR)

6 months

Yes

Not evaluated

None

> 2 wks

Pons, medulla

CD8-positive T cells

Leitinger et al, 2018 [4]

67/F

LC, SQ

Dyspnea, confusion, anxiety

Nivo (1)/(not described)

17 days

Negative

mPSL, Ig, ACV

40 days

Thalami, left central region

Few CD3-positive T cells

Matsuoka et al, 2018 [3]

60/M

LC, PC

Daytime drowsiness, memory disturbance

Nivo (2)/(PR)

33 days

Hu^c

High-dose mPSL, PE

6 mo

Hippocampus, pons, spinal cords, temporal lobe, thalamus, cerebellum

CD8-positive T cells, macrophage

Ours

67/F

LC, Ad

Fever

Pem (13)/(PR)

8 months

Yes

Not evaluated

mPSL pulse, ACV

10 days

Brain stem, temporal lobes

CD8-positive T cells

**Table 2.** Summary of Previous Cases of Non-Small Cell Lung Cancer With Encephalitis Induced by Immune Checkpoint Inhibitors
Authors (year)	Age/sex	Histology	Fever symptom	ICIs (courses)/(response)	Timing	Brain mets	Treatment	PNS-Ab	CSF protein	CSF cells	Outcome
ACV: acyclovir; Ad: adenocarcinoma; anti-TB: anti-tuberculous drugs; Atezo: atezolizumab; CR: complete remission; CSF: cerebrospinal fluid; Dex: dexamethasone; F: female; GAD65: glutamic acid decarboxylase 65-isoform antibody; Ig: immunoglobulin; Ipi: ipilimumab; Large: large cell carcinoma; Lym: lymphocyte; LymMono: lymphomonocytic cells; M: male; Mono: monocyte; mPSL: methylprednisolone; ND: not described; Neu: neutrophil; Nivo: Nivolumab; NSCLC: non-small cell lung carcinoma; PC: pleomorphic carcinoma; PD: progressive disease; PE: plasma exchange; Pem: pembrolizumab; PNS-Ab: paraneoplastic syndrome antibody; PR: partial response; SQ: squamous cell carcinoma.
Kawamura et al, 2016 [6]	54/F	Ad	No	Nivo (1)/(ND)	> 4 weeks	ND	Dex, mPSL pulse	Negative	56 mg/dL	10/µL	Dead
Richard et al, 2017 [7]	74/M	NSCLC	No	Nivo (1)/(ND)	1 week	Yes	Dex	ND	ND	ND	Recovered
Raskin et al, 2017 [8]	58/M	SQ	No	Nivo (17)/(PR)	8 - 9 months	No	Dex	Hu	74 mg/dL	63/µL (96.8% mononuclear)	Recovered
Schneider et al, 2017 [9]	78/F	SQ	No	Nivo (14)/(PR)	28 weeks	No	mPSL	Negative	1,027 mg/L	Lym 16/µL	Recovered
Leitinger et al, 2018 [4]	67/F	SQ	No	Nivo (1)/(ND)	17 days	No	mPSL, Ig, ACV	Negative	56 mg/dL	LymMono 30/μL	Dead
Shah et al, 2018 [10]	66/F	Ad	No	Nivo (ND)/(ND)	4 months	No	mPSL pulse, PE	Novel and unclassified	56 mg/dL	Normal	Clinically declined
	44/F	Ad	No	Nivo (5)/(ND)	2.5 months	No	mPSL pulse, PE, rituximab	GAD65	Normal	19 nucleated cells/ (97% Lym)	Clinically declined
Matsuoka et al, 2018 [3]	60/M	PC	No	Nivo (2)/(PR)	33 days	No	High-dose mPSL, PE	Hu	162 mg/dL	16/µL	Dead
Niki et al, 2019 [11]	51/M	SQ	Yes	Pem (ND)/(ND)	8 months	No	High-dose mPSL	Negative	446 mg/dL	58/µL (Lym predominant)	Recovered
Honjo et al, 2019 [12]	59/M	Large	Yes (mild)	Nivo (22)/(CR)	16 months	No	mPSL pulse	Negative	144 mg/dL	61/µL (Mono 85%)	Recovered
Yonenobu et al, 2019 [13]	61/M	SQ	Yes	Pem (2)/(ND)	26 days	No	mPSL pulse, anti-TB, ACV	Negative	209.2 mg/dL	79/µL (Mono 100%)	Recovered
Fujiwara et al, 2019 [14]	70/M	Ad	Yes (slight)	Nivo (ND)/(PR)	5 months	No	High-dose mPSL, anti-TB, ACV	Negative	166 mg/dL	50/µL	Recovered
Arakawa et al, 2019 [15]	78/M	Ad	Yes	Atezo (1)/(ND)	13 days	Yes	mPSL pulse, ACV	Negative	106 mg/dL	6/µL	Recovered
Yamaguchi et al, 2020 [16]	56/M	Ad	Yes	Atezo (1)/(ND)	17 days	No	mPSL pulse	Negative	166 mg/dl	20/µL	Recovered
Robert et al, 2020 [17]	48/F	Ad	Yes	Atezo (1)/(ND)	13 days	No	mPSL pulse	ND	ND	62 nucleated cells/µL (Neu predominant)	Recovered
	57/M	Ad	No	Pem (3)/(ND)	4 months	No	mPSL pulse	ND	1.41 g/L	40 nucleated cells/µL (Lym 98%)	Recovered
Singh et al, 2021 [18]	72/F	Ad	Yes	Ipi + Nivo (4)/(PD)	13 weeks	Yes	High-dose mPSL	Negative	> 180 mg/dL	ND (Lym predominant)	Recovered
Ours	67/F	Ad	Yes	Pem (13)/(PR)	8 months	Yes	mPSL pulse, ACV	ND	317.6 mg/L	197 cells/µL (Mono 93%)	Dead

Table 2. Summary of Previous Cases of Non-Small Cell Lung Cancer With Encephalitis Induced by Immune Checkpoint Inhibitors

Authors (year)

Age/sex

Histology

Fever symptom

ICIs (courses)/(response)

Timing

Brain mets

Treatment

PNS-Ab

CSF protein

CSF cells

Outcome

ACV: acyclovir; Ad: adenocarcinoma; anti-TB: anti-tuberculous drugs; Atezo: atezolizumab; CR: complete remission; CSF: cerebrospinal fluid; Dex: dexamethasone; F: female; GAD65: glutamic acid decarboxylase 65-isoform antibody; Ig: immunoglobulin; Ipi: ipilimumab; Large: large cell carcinoma; Lym: lymphocyte; LymMono: lymphomonocytic cells; M: male; Mono: monocyte; mPSL: methylprednisolone; ND: not described; Neu: neutrophil; Nivo: Nivolumab; NSCLC: non-small cell lung carcinoma; PC: pleomorphic carcinoma; PD: progressive disease; PE: plasma exchange; Pem: pembrolizumab; PNS-Ab: paraneoplastic syndrome antibody; PR: partial response; SQ: squamous cell carcinoma.

Kawamura et al, 2016 [6]

54/F

Nivo (1)/(ND)

> 4 weeks

Dex, mPSL pulse

Negative

56 mg/dL

10/µL

Dead

Richard et al, 2017 [7]

74/M

NSCLC

Nivo (1)/(ND)

1 week

Yes

Dex

Recovered

Raskin et al, 2017 [8]

58/M

Nivo (17)/(PR)

8 - 9 months

Dex

74 mg/dL

63/µL (96.8% mononuclear)

Recovered

Schneider et al, 2017 [9]

78/F

Nivo (14)/(PR)

28 weeks

mPSL

Negative

1,027 mg/L

Lym 16/µL

Recovered

Leitinger et al, 2018 [4]

67/F

Nivo (1)/(ND)

17 days

mPSL, Ig, ACV

Negative

56 mg/dL

LymMono 30/μL

Dead

Shah et al, 2018 [10]

66/F

Nivo (ND)/(ND)

4 months

mPSL pulse, PE

Novel and unclassified

56 mg/dL

Normal

Clinically declined

44/F

Nivo (5)/(ND)

2.5 months

mPSL pulse, PE, rituximab

GAD65

Normal

19 nucleated cells/ (97% Lym)

Clinically declined

Matsuoka et al, 2018 [3]

60/M

Nivo (2)/(PR)

33 days

High-dose mPSL, PE

162 mg/dL

16/µL

Dead

Niki et al, 2019 [11]

51/M

Yes

Pem (ND)/(ND)

8 months

High-dose mPSL

Negative

446 mg/dL

58/µL (Lym predominant)

Recovered

Honjo et al, 2019 [12]

59/M

Large

Yes (mild)

Nivo (22)/(CR)

16 months

mPSL pulse

Negative

144 mg/dL

61/µL (Mono 85%)

Recovered

Yonenobu et al, 2019 [13]

61/M

Yes

Pem (2)/(ND)

26 days

mPSL pulse, anti-TB, ACV

Negative

209.2 mg/dL

79/µL (Mono 100%)

Recovered

Fujiwara et al, 2019 [14]

70/M

Yes (slight)

Nivo (ND)/(PR)

5 months

High-dose mPSL, anti-TB, ACV

Negative

166 mg/dL

50/µL

Recovered

Arakawa et al, 2019 [15]

78/M

Yes

Atezo (1)/(ND)

13 days

Yes

mPSL pulse, ACV

Negative

106 mg/dL

6/µL

Recovered

Yamaguchi et al, 2020 [16]

56/M

Yes

Atezo (1)/(ND)

17 days

mPSL pulse

Negative

166 mg/dl

20/µL

Recovered

Robert et al, 2020 [17]

48/F

Yes

Atezo (1)/(ND)

13 days

mPSL pulse

62 nucleated cells/µL (Neu predominant)

Recovered

57/M

Pem (3)/(ND)

4 months

mPSL pulse

1.41 g/L

40 nucleated cells/µL (Lym 98%)

Recovered

Singh et al, 2021 [18]

72/F

Yes

Ipi + Nivo (4)/(PD)

13 weeks

Yes

High-dose mPSL

Negative

> 180 mg/dL

ND (Lym predominant)

Recovered

Ours

67/F

Yes

Pem (13)/(PR)

8 months

Yes

mPSL pulse, ACV

317.6 mg/L

197 cells/µL (Mono 93%)

Dead