3. Differential diagnosis and treatment
From March 8, 2024, to March 12, 2024, based on the clinical
manifestations, the patient has a history of hypertension combined with
cerebral infarction, and transient ischemic attacks (TIAs), indicating
cerebral blood insufficiency. The patient is prescribed oral aspirin
(enteric-coated), clopidogrel sulfate, and atorvastatin calcium tablets
to provide antiplatelet therapy, lipid stabilization, and
antihypertensive treatment. After initiating treatment, the symptoms
initially improved, and there was no significant worsening. However, on
March 13, 2024, the patient experienced a progressive aggravation in
consciousness and drowsiness and was given a red injection Chinese
medicine to promote blood circulation and remove blood stasis to prevent
and treat cerebral infarction. On March 15, 2024, the patient entered a
shallow coma. On March 15, 2024, a cranial plain MRI (Fig. 1) revealed
the following findings: (Artifacts) (1) Left temporoparietal swelling
and abnormal signal, nature to be determined, recommended for follow-up
review; (2) Ponte, bilateral thalamus, basal ganglia, lateral ventricle,
hemioval center, and frontal multiple lacunar cerebral infarctions, with
partial softening noted; (3) bilateral lateral paraventricular ischemia
demyelination changes; (4) senile brain changes; and (5) occipital
arachnoid cyst. Clinical considerations indicated the possibility of
immune-related encephalitis or brain metastases. On the same day, the
patient was given methylprednisolone sodium succinate 40 mg IV hormone
treatment once and mannitol injection 125 mL ivgtt q12h once. On March
16, 2024, the patient regained consciousness and was able to eat
autonomously. Hormonal and mannitol therapies were continued, and the
patient was able to move independently and maintain a normal diet.
Cranial MRI of March 19, 2024 (Fig. 2): 1. Multiple lacunar cerebral
infarctions in the brainstem and bilateral basal ganglia; 2. diffuse
swelling of the left temporoparietal gyrus and mild enhancement in the
left temporal lobe. The review found that there was no obvious
enhancement, and brain metastasis was excluded. Given the clinical
characteristics and the comparison of imaging examination, immune
encephalitis was finally considered. March 19, 2024 CT chest scan (Fig.
3): 1. Left hilar space (5.0*3.9 cm), considering malignancy; 2.
Multiple slightly large lymph nodes in the mediastinum; 3. Left lower
lobe inflammation, mild interstitial changes; 4. Multiple micro and
small nodules in both lungs (larger short diameter of approximately 1.1
cm) are recommended for regular review; 5. Left 5,6 anterior rib, left
7,10 posterior rib, and right 6-8 side ribs irregular, suggestive of old
fractures; 6. The left adrenal gland shown is slightly thickened. Chest
CT revealed inflammation of the left lower lung lobe, considering
immunological pneumonia, except for infectious pneumonia, and adding
cefoperazone sulbactam sodium for injection based on hormone
(methylprednisolone sodium succinate 40 mg iv) treatment.
Outcome and follow-up
On April 3, 2024,during ward rounds, the patient presented with a
stable general condition, clear consciousness, and the ability to
exercise independently, while cooperating in the physical examination.
Cranial MRI findings (April 3, 2024) (Fig. 4): 1. Possible necrosis of
the left parietal and temporal cortex, combined with clinical practice;
2. bilateral cerebral hemisphere white matter changes indicative of
cerebral ischemia and demyelination; 3. Abnormalities in the left
lateral paraventricular region, thalamus, and pons; 4. senile brain
changes; 5. posterior fossa cyst. Chest CT scan (April 3, 2024) (Fig. 5)
findings: 1. Left hilar occupancy (4.8*3.6 cm), Considering the
malignancy, Compared with images March 19,2024, Similar to before; 2.
Larger lymph nodes are seen in the mediastinum, Part is slightly smaller
than before; 3 inflammation of the original left lower lobe. This time,
the absorption is significantly improved; Mild interstitial changes in
the lower lobe of both lungs, and the left side is clearly visible
compared with the front; 4. Multiple micro and small nodular foci in
both lungs, some have reduced in size, while others have newly appeared,
regular follow-up is recommended; 5. left 5 and 6 anterior ribs, left 7
and 10 posterior ribs, and right 6-8 lateral ribs with irregular
morphology, suggestive of an old fracture, consistent with the prior
scans; 6. The left adrenal gland slightly thickened, similar to previous
assessments.
After treatment on April 3, 2024, the patient was allowed to be
discharged. The regimen included oral prednisone acetate tablets 15 mg
(3 tablets) once daily for 3 days, followed by a reduction to 10 mg (2
tablets) once daily and 5 mg (1 tablet) once daily before
discontinuation. Blood routine analysis and coagulation function were
monitored for 1 week. The patient was reviewed after 1 month to assess
the potential for surgery.
Case Discussion
This patient is an elderly male with a history of hypertension for 30
years and an old cerebral infarction for 2 years. Based on the clinical
manifestations, he had an early diagnosis of new lacunar cerebral
infarction or a primary infarction leading to the recurrence of cerebral
infarction dementia (MID), but improved cerebral circulation treatment
after consciousness, drowsiness symptoms have not been significantly
improved. Later, the patient was treated with the PD-1 checkpoint
inhibitor tirellizumab. This treatment activated T cell-mediated tumor
cell killing, which led to the release or stimulation of numerous
inflammatory mediators, enhancing the immune response and promoting the
inflammatory response. A brain MRI of the patient showed patchy lesions
in the brain, indicative of brain parenchymal inflammation. The
laboratory examination of the patient during the onset. The laboratory
tests revealed increased CSF cell count, elevated protein levels, and
increased IL-6 levels, all of which are clinically relevant. This
patient’s immune-mediated encephalitis manifested on day 10 after the
second cycle of treatment. Through the clinical manifestations, the
encephalitis patient has rapid onset, the pathological activity
developed rapidly in a short period, abnormal consciousness, accompanied
by drowsiness and other symptoms, more atypical. The patient developed
immunoencephalitis and immunopneumonia, both of which improved
significantly following small-dose hormone treatment (0.5-1 mg/kg).
Patients with mild to moderate irAEs have found significant improvements
in progression-free survival, overall survival, and overall response
rate compared with patients without irAEs[4].
Immune-related adverse events caused by ICIs can affect any organ, most
commonly in the skin, colon, endocrine organs, liver, and lung.
Neurological disorders are rare and even
life-threatening[5]. During the first 4 weeks of
treatment, the risk of first developing irAEs was 3 times higher than
between 4 weeks of treatment and end of
treatment[6]. Neurological irAEs are estimated in
4.2% of patients with diverse clinical manifestations with central and
peripheral dysfunction[7]. In central irAEs,
encephalitis should be considered ICIs infusiona rare, sometimes occult,
and potentially fatal AE[8]. Patients of any age
and sex can experience acute encephalitis as an irAE, which can be
life-threatening. In a multicenter cohort analysis of ”lung cancer
immunotherapy-related encephalitis”, 9 male patients, all smokers, with
a median age of 67 (48-77) years were studied. Of these, 78% had
adenocarcinoma, and 5 patients were treated with second-line ICIs. Two
patients had inactive brain metastases at the onset of ICIs. A median of
5 (1-22) ICIs infusions preceded the onset of neurological symptoms,
most commonly confusion (78%), fever (45%), and cerebellar ataxia
(33%)[8]. Case fatality rate was reported between
6% and 12%)[9]. In addition, the unfavorable
prognosis of encephalitis may lead to neurological sequelae, such as
cerebrovascular diseases and epilepsy. The pathogenesis of
immune-related encephalitis is unclear. The inhibition of immune
checkpoints by PD-1, PD-L1, and CTLA-4 may induce or aggravate irAEs
through various mechanisms, such as tumor and normal nerve, muscle
tissue cross immune reaction, interactions between specific intestinal
microbes and immune system, immune cell changes, and genetic factors
(genetic susceptibility and polygenic risk), all of which are potential
mechanisms contributing to irAEs.
At present, the diagnosis of irAEs, which is mainly based on the
experience of autoimmune neurological diseases. Reference to the Chinese
autoimmune encephalitis diagnosis and treatment of autoimmune
encephalitis expert consensus[10](2022 edition),
summarizes the following four conditions: A. With acute onset, use of
immune checkpoint inhibitors within 1 year, clinical characteristics of
consciousness disorders, autonomic dysfunction; severe coma, seizures,
and mental behavior abnormalities. B. Early imaging examination can
improve the accuracy and timeliness of the diagnosis of immune-related
encephalitis, and brain MRI shows leptomeningeal enhancement or brain
parenchyma inflammation. C. Histological examination of brain biopsy is
the gold standard for the diagnosis of encephalitis, but there are
clinical risks and realization. Therefore, inflammatory reaction in
cerebrospinal fluid (CSF), brain parenchymal abnormalities in CSF
bacterial culture, or neuroimaging can be used as surrogate indicators
of immune-related encephalitis; IL-6, IL-17, C-reactive protein are the
three inflammatory mediators related to immune-related encephalitis for
monitoring and evaluating the condition. D. Antineuronal antibodies were
negative, while reasonably excluding other causes. The diagnostic
conditions include four aspects: clinical manifestations, auxiliary
examination, confirmed experiment, and exclusion of other causes. First,
comprehensive analysis is needed to identify the encephalitis with
irAEs. In addition, the diagnosis of ICIs-related encephalitis requires
sufficient exclusion of meningeal carcinoma, infectious diseases (such
as viral encephalitis, neurosyphilis, CNS infections caused by bacteria,
fungi, and parasites), and metabolic encephalopathy (Wernick
encephalopathy, hepatic encephalopathy, and pulmonary encephalopathy).
In a case of atenlibizumab and bevacizumab for advanced hepatocellular
carcinoma-associated encephalitis, high-dose hormone shock was selected
and multiple plasmapheresis was performed, resulting in improvement of
clinical symptoms and abnormal remission of
CSF[11]. In one case of autoimmune encephalitis
during Nivolumab monotherapy (Nivolumab 3 mg/kg Q14d), the symptoms
occurred 28 weeks after treatment, with no significant improvement
despite antiepileptic treatment. After methylprednisolone 80 mg, the
patient’s neurological symptoms disappeared within 24
hours[12]. Glucocorticoid shock therapy is
commonly used as the first line treatment for irAEs encephalitis,
methylprednisolone 1000 mg/day, continuous intravenous infusion for 3
days, followed by 500 mg/day, intravenous infusion for 3 days.
Afterward, the treatment transitioned to oral prednisone acetate 1 mg
kg-1·day-1. After 2 weeks, the
amount was reduced by 5 mg every 2 weeks, and the total course was
approximately 6 months[13]. Although most of the
irAEs are usually controlled with corticosteroids, serious events that
induce the development of immune encephalitis, or even final death, may
complicate treatment[14]. The best treatment
strategy is based on drug efficacy and its dose (hormones, infliximab,
IVIG, rituximab, and plasma exchange).
Therefore, patients receiving PD-1 or PD-L1 inhibitor drugs should be
alert to sleep abnormalities and altered consciousness, and the
possibility of encephalitis after ICIs treatment. An early
multidisciplinary approach to diagnosis and management is crucial in
effectively addressing this condition. Referring to this patient, MRI
examination mostly showed leptomeningeal enhancement or brain
parenchymal inflammation, showing abnormal signals in one or both medial
temporal lobes, which provided a more reliable and effective imaging
basis for the early diagnosis and prognosis evaluation of irAEs. Early
detection of immune-mediated encephalitis and early administration is
likely to avoid large hormonal impact, and low-dose hormone use may be
used as an early clinical path. At present, it is difficult to measure
and evaluate individual-level exposure to immune-related encephalitis in
large-scale population studies. The vast majority of studies are from
animal experimental data. Just like other pharmacovigilance studies, it
is necessary to conduct prospective clinical studies for long-term
validation of ICI-induced irAEs in the future. Due to the lack of
detailed clinical information and clear diagnostic criteria, it is
currently difficult to evaluate cases reported by clinicians (for
example, cerebrospinal fluid data to confirm the reported diagnosis).
The natural outcome of adverse events under standard supportive care,
comparing the impact of nonspecific and targeted immunomodulatory
therapy on the clinical outcomes of patients with tumors developing
irAEs still needs further exploration[15].