A review of the literature showed that the incidence of neurological adverse events (nAEs) was 3.8% with anti-CTLA4 inhibitors, 6.1% with anti-PD1 inhibitors, and 12.0% with the combination of anti-CTLA4 + anti-PD1 inhibitors [3]. Another review of 7604 patients treated with immune checkpoint inhibitors (ICI) revealed a 7.7% overall incidence of nAEs and 0.1% incidence of GBS/MFS (Miller-Fisher syndrome)[4]. GBS is an acute autoimmune disorder affecting peripheral nervous system. T cell mediated immunity is considered as a trigger factor of GBS, and antibodies and complement are thought to be involved in the process. In addition, ganglioside antibodies that target macrophages are thought to play a crucial role[5].
Anti-PD1 agents were initially developed for blocking the PD1/PDL1 (programmed death–ligand 1) signaling pathway, which was confirmed to be involved in tumor immune escape. However, PD1 also expressed on activated B cells, natural killer cells and regulatory T cells (Tregs) [6]. Combination with anti-VEGF drugs does promote anti-tumor response, but it may trigger more complex autoimmunity. Macrophages-mediated ADCP (antibody-dependent cellular phagocytosis) can cause depletion of target cell. Fc region of tislelizumab is genetically engineered to lower affinity for Fc receptor on macrophages, which is different from nivolumab or pembrolizumab [2]. Currently, tislelizumab is approved by the National Medical Products Administration (NMPA, formerly the China Food and Drug Administration) for the treatment of classical Hodgkin Lymphomas, Urothelium Carcinoma and Lung Squamous Cell Carcinoma. So far, tislelizumab-related GBS has not been reported.
Due to the complicated action mechanism of ICI, it is difficult to elucidate the causes of ICI-related GBS. Fortunately, there has been a proposed diagnostic and treatment paradigm for ICI high-grade neurological complications [7]. CSF and EMG analysis are critical diagnostics steps. IVIG (intravenous immunoglobulin), plasmapheresis and glucocorticoid treament are effective therapies for ICI-related GBS [7–22].
16 ICI-related GBS patients (15 publications) were found via PubMed with median age 63 years (range: 45–81 years) [8–22], including 1 bladder, 1 nasal, 1 kidney, 5 lung and 8 melanoma cancer patients. Male patients accounted for 75%. Prognosis of these cases varies, 5 patients were confirmed dead (age range: 63–81 years) [9–10, 12, 19, 21]. Patient in our case refused CSF analysis, so he was diagnosed with GBS-like syndrome. Glucocorticoid and IVIG treament improved clinical symptoms. However, he developed severe pneumonia during treatment and died after 3 days ICU admission. Additionally, CT on Day58 showed disease progression of lung and bone.
In summary, we reported the first GBS-like syndrome case related with tislelizumab. Rapid diagnosis and treatment of GBS are crucial because irAEs can initiate serious sequelae or death. A multidisciplinary approach is necessary for patients who received immunotherapies.
Table 1. Nerve electrophysiological tests results part1
Nerve
|
Electrophysiological sites
|
Latency(ms)
|
Amplitude(mv)
|
Conduction velocity(m/s)
|
F wave latency(ms)
|
L
|
R
|
NL
|
L
|
R
|
NL
|
L
|
R
|
NL
|
L
|
R
|
NL
|
median nerve(motor )
|
wrist
|
3.17
|
3.6
|
≤4.4
|
10.3
|
9.5
|
≥4
|
|
|
|
|
|
≤25
|
cubital fossa
|
7.54
|
7.96
|
|
9.4
|
9.1
|
|
50.3
|
50.5
|
≥50
|
|
|
|
Ulnar nerve(motor)
|
wrist
|
2.56
|
2.79
|
≤3.3
|
7.7
|
7.3
|
≥6
|
|
|
|
25.5
|
27.2
|
≤25
|
elbow
|
8.54
|
8.56
|
|
7.7
|
6.6
|
|
50.2
|
50.3
|
≥50
|
|
|
|
Ulnar motor facilitation
|
wrist
|
|
|
|
7.5preexercise
|
|
|
|
|
|
|
|
|
|
|
7.8postexercise
|
|
|
|
|
|
|
|
radial nerve(motor)
|
forearm
|
|
|
≤3.0
|
|
|
≥2
|
|
|
|
|
|
|
elbow
|
|
|
|
|
|
|
|
|
≥50
|
|
|
|
peroneal nerve(motor)
|
ankle
|
4.08
|
3.81
|
≤6.5
|
5.0
|
2.7
|
≥2
|
|
|
|
|
|
≤50
|
fibular head
|
13.1
|
12.8
|
|
4.7
|
1.78
|
|
38.8
|
36.7
|
≥45
|
|
|
|
tibial nerve(motor)
|
ankle
|
3.98
|
3.85
|
≤5.8
|
6.6
|
5.8
|
≥4
|
|
|
|
57.7
|
53.5
|
≤50
|
popliteal fossa
|
14.2
|
13.1
|
|
5.0
|
3.3
|
|
40.1
|
41.1
|
≥40
|
|
|
|
median nerve(reverse sense)
|
wrist
|
2.15
|
2.44
|
-
|
26.1
|
15.6
|
≥20
|
59.1
|
58.3
|
≥50
|
|
|
|
Ulnar nerve(reverse sense)
|
wrist
|
2.02
|
2.03
|
-
|
13.2
|
14.4
|
≥10
|
55.0
|
57.5
|
≥50
|
|
|
|
radial nerve(reverse sense)
|
wrist
|
|
|
-
|
|
|
≥15
|
|
|
≥50
|
|
|
|
sural nerve(reverse sense)
|
shank
|
3.35
|
3.33
|
-
|
11.1
|
12.1
|
≥6
|
41.2
|
42.4
|
≥40
|
|
|
|
ms=milliseconds; mv=millivolts; m/s=meters/second; L=left; R=right; NL=Normal value
|
Table 2. Nerve electrophysiological tests results part2
L/R
|
Muscle
|
Innervation
|
Insertion potential
|
Spontaneous potential
|
Voluntary MUP
|
fibrillation
|
positive sharp
|
fasciculation
|
other
|
time limit(↑↓%)
|
amplitude
|
polyphase wave
|
recruitment
|
L
|
trapezius
|
accessory
|
NL
|
+
|
+
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
R
|
biceps brachii
|
C5/6, musculo
|
NL
|
-
|
-
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
R
|
first interosseous muscle
|
C8/T1, ulnar
|
NL
|
-
|
-
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
L
|
first interosseous muscle
|
|
NL
|
-
|
-
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
L
|
vastus medialis
|
L3/4, femoral
|
NL
|
+
|
+
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
L
|
tibialis anterior muscle
|
L4/5, peroneal
|
NL
|
+
|
+
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
L
|
gastrocnemius
|
S1/2, tibial
|
NL
|
-
|
-
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
R
|
tibialis anterior muscle
|
L4/5, peroneal
|
NL
|
2+
|
2+
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
R
|
gastrocnemius
|
|
NL
|
-
|
-
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
R
|
vastus medialis
|
|
NL
|
-
|
-
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
L
|
paravertebral muscle
|
T9
|
NL
|
2+
|
2+
|
-
|
-
|
NL
|
NL
|
NL
|
NL
|
L=left; R=right; NL= Normal value
|