Immune Checkpoint Inhibitor‐Associated Striatal Encephalitis Presenting with Subacute Progressive Parkinsonism

Atezolizumab, an immune checkpoint inhibitor (ICI) that targets programmed death ligand 1 ¹ has emerged as a novel immunotherapeutic agent approved for treating several cancers, but the expanding use of ICIs has led to an increase in neurological immune‐related adverse events (irAEs) such as encephalitis (ICI‐iE). However, available data on ICI‐iE is limited to a few small case series. Here, we highlight a case of ICI‐induced striatal encephalopathy manifesting with subacute progressive parkinsonism.

Case Report

A 58‐year‐old man presented with gradually progressive slowness of movement. He had developed stooped posture, shuffling gait, and festination, and also noted changes in his voice which he described as monotonous over a period of 2 months. He had no tremor and denied having any non‐motor symptoms, including those related to autonomic dysfunction. His cognition was also normal. He had been previously diagnosed (2017) with advanced‐stage bladder cancer and a single‐brain metastasis at the right frontal lobe, which was surgically removed followed by whole‐brain radiotherapy. Atezolizumab, 1200 mg intravenously every 3 weeks, had been administered since 2019. Surveillance magnetic resonance imaging (MRI) brain scans in 2019 and 2020 were unremarkable.

Physical examinations showed an alert and cooperative man. He had poor facial expressions, hypophonia, and demonstrated mild bilateral bradykinesia and rigidity. Stooped posture, gait initiation difficulty, shuffling gait with occasional freezing, and reduced arm swing were also noted (Video 1). He had mild hyperreflexia on his left knee. The eye movement examination was normal, and the MDS‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) score was 29. Further neurological examination was unrevealing.

Video 1.

The video shows hypomimia, hypophonia, and bilateral bradykinesia, slightly more prominent on the left side. Gait shows marked stooped posture, decreased arm swing on both sides, narrow‐based with shuffles, start hesitation, festination, and enbloc turning.

MRI brain demonstrated hyperintense T2/FLAIR lesions involving the left putamen extending to the left internal and external capsules, the left frontal white matter with patchy curvilinear enhancement in the left basal ganglia, and another lesion involving the right lentiform nucleus, external capsule, deep white matter of the right frontal lobe with nodular and peripheral enhancement (Fig. 1A–C). Basic cerebrospinal fluid (CSF) profiles were within normal limits (WBC 2 cell/mm3, no RBC, protein 40.6 mg/dL, glucose 64.1 mg/dL). Serum and CSF autoimmune and paraneoplastic antibodies (anti‐Yo, anti‐Hu, anti‐Ri, anti‐Ma1, Ma2, anti‐CRMP5, anti‐amphiphysin, anti‐Sox‐1, anti‐Zic‐14, anti‐Tr, anti‐CASPR2, anti‐glutamic acid decarboxylase, anti‐LgI1, anti‐N‐methyl‐d‐aspartate receptor) were unremarkable. Oligoclonal bands and myelin oligodendrocyte glycoprotein antibodies were negative in both serum and CSF. CSF cytology and metastatic workup in other sites were normal. A standard serological workup for infectious causes was also negative. Atezolizumab was subsequently withheld, and two courses of intravenous pulse methylprednisolone (IVMP) and 600 milligrams of oral levodopa/carbidopa were administered. The patient gradually improved, with reducing stoop posture and festination (Video 2). The MDS‐UPDRS score was decreased to 21. Due to the recurrent upper urinary tract infections, immunosuppressive therapy was discontinued 1 month later.

Figure 1.

Magnetic resonance imaging (MRI) brain demonstrated hypointense lesions on T1W (A), hyperintense lesions on T2W/FLAIR (B), involving the left putamen extending to the left internal and external capsules, the left frontal white matter with patchy curvilinear enhancement in the left basal ganglia, and another lesion involving the right lentiform nucleus, external capsule, and deep white matter of the right frontal lobe with nodular and peripheral enhancement (C). Seven months after withholding atezolizumab and administering intravenous pulse methylprednisolone, MRI brain demonstrated a new hypointense lesion on T1W (D), hyperintense lesions on T2W/FLAIR (E), at the cortical gray matter of the parietal lobe and left thalamus, with a gadolinium‐enhancing lesion in the left thalamus without vasogenic edema, and scattered nodular leptomeningeal enhancement lesions (F).

Video 2.

After two courses of intravenous pulse methylprednisolone and 600 milligrams of oral levodopa/carbidopa administration, the patient gradually improved, with improvement in posture and gait, however in the presence of hypomimia, hypophonia, and bradykinesia.

Despite not having received atezolizumab since the first occurrence of symptoms, a second episode of irAEs occurred after a 7‐month period of remission, presenting with progressive parkinsonism, gait difficulty, and suspected parasomnia, causing him to be bedridden within 1 month. All sets of the same previous blood and CSF examinations were normal. MRI brain showed a new gadolinium‐enhancing lesion at the left thalamus without vasogenic edema, a hyperintense T2/FLAIR lesion at the cortical gray matter of the parietal lobe, and scattered nodular leptomeningeal enhancement lesions (Fig. 1D–F). High‐dose IVMP and intravenous immunoglobulin (IVIg) were given. His consciousness gradually improved to alertness; he could perform two step‐commands, and gradually ambulated with the walker.

Discussion

Atezolizumab was approved for treating many types of cancer, including bladder cancer. ² Neurological irAEs have been reported in 2%–12.6% of patients, ³ , ⁴ , ⁵ manifesting with various presentations in the peripheral and central nervous systems (CNS). Common neurological irAEs that have been reported include CNS demyelinating disorder, myasthenia gravis, myelopathy, Guillain‐Barre‐like syndrome, and peripheral neuropathy. ⁴ , ⁶ ICI‐iE is a rare, but increasingly recognized complication with encephalitis phenotypes divided into two main groups: focal encephalitis and meningoencephalitis syndrome. ³ The most common presentations in the reported cases include alteration of consciousness, memory disturbance, headache, and seizures. ² The occurrence of movement disorders is less frequently reported with chorea/ballism, ataxia, and parkinsonism reported in patients receiving nivolumab. ⁷ , ⁸ , ⁹ , ¹⁰ To our knowledge, no cases with a movement disorder and striatal encephalitis associated with atezolizumab have been reported. In fact, literature review identified a single case with thalamic lesion following exposure to atezolizumab. ¹¹ All previously reported cases with atezolizumab‐induced encephalitis are presented in Table 1. Importantly, MRI may be unrevealing in some of the cases with clinical features consistent with encephalopathy, and hence a normal MRI does not exclude the possibility of an ICI‐iE. Although neurologic irAEs may occur at any time during the course of this treatment, the median time to the onset is usually 5–8 weeks, after two ICI treatment cycles, ¹ with 14% of patients developing symptoms after 6 months. ³ The mechanism by which ICI induces neurotoxicity is still unknown. It has been postulated that it is due to the restoration of anti‐tumor activity of cytotoxic T cells against antigens that are also expressed in healthy tissues, which resemble classic paraneoplastic syndromes. Moreover, an anti‐neural autoimmune response precipitated by immunotherapy or a direct reaction to the expressed antigen, activating the complement system, can also lead to inflammation. ⁴ , ¹² To date, no controlled therapeutic trials have been conducted. Management of ICI‐iE involves first withholding the offending agent and then administering IVMP to those with progressive neurological symptoms. However, management may often be challenging as approximately half of the patients diagnosed with ICI‐iE may continue to clinically worsen. ¹⁰

TABLE 1.

Characteristics of previously reported cases of encephalitis following atezolizumab therapy.

Characteristics	Case 1 5	Case 2 13	Case 3 14	Case 4 15	Case 5 2	Our case
Age	59	53	78	56	42	58
Sex	Female	Female	Male	Male	Female	Male
Underlying cancer	Metastatic bladder cancer	Metastatic cervical squamous cell carcinoma	Metastatic lung adenocarcinoma	Metastatic lung adenocarcinoma	Hepatocellular carcinoma	Metastatic bladder cancer
ICI treatment	Atezolizumab	Atezolizumab plus bevacizumab	Atezolizumab	Atezolizumab with carboplatin plus nab‐paclitaxel	Atezolizumab plus bevacizumab	Atezolizumab
Cycle	1st cycle	1st cycle	1st cycle	1st cycle	1st cycle	47th cycle
Onset of symptoms	12 days	13 days	13 days	17 days	17 days	55 days
Presentation	Confusion, fatigue, spastic, tremor, vomiting	Alter mental status, headache, and meningeal sign	Confusion and fever	Confusion, motor aphasia, and fever	Alter mental status, fever, convulsion	Parkinsonism with gait difficulty
MRI findings	Mildly enhancing lesion at left frontal lobe	Diffuse leptomeningeal enhancement	Normal	Normal	T2/FLAIR hyperintense lesion in the splenium of corpus callosum	T2 hyperintense lesion with patchy curvilinear enhancement in left basal ganglia
CSF profiles	High protein	Pleocytosis, high protein	Pleocytosis, high protein	Pleocytosis, high protein	Pleocytosis, high protein	Normal
Paraneoplastic antibodies	Negative	Negative	Negative	Negative	Not performed	Negative
Treatment	Dexamethasone	Dexamethasone	Methylprednisolone	Methylprednisolone	Methylprednisolone	Methylprednisolone
Outcome	Partial recovery	Partial recovery	Recovery	Recovery	Partial recovery	Partial recovery with relapse

Abbreviation: CSF, cerebrospinal fluid.

In our case, the patient experienced a second episode of neurologic deterioration even after atezolizumab had been removed for over 6 months. Although the reasons behind that remain unclear, the fact that there was no long‐term follow‐up of oral steroids treatment due to his active infection, may require even more intense immunosuppressive therapy or even the possibility of an unidentified paraneoplastic antibody even though we intensively investigated.

Conclusion

ICI‐iE is increasingly recognized in clinical practice with diverse neurological presentations, including both hypo‐ and hyperkinetic movement disorders. This potential complication should be highlighted to medical professionals who are involved in the use of these new ICIs. Prompt recognition, as demonstrated in our case, leads to improved outcomes. However, relapses are possible and a consensus is needed on proper therapeutic management of this new complication.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

T. P.: 1A, 3A

N. T.: 1A, 3B

R. B.: 1C, 3B

J. S.: 1A, 3B.

Disclosures

Ethical Compliance Statement: The authors confirm that the Ethics board clearance of Chulalongkorn University was not required for this work. The subject has provided written video consent. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work, and the authors declare no conflicts of interest relevant to this work.

Financial Disclosures for Previous 12 Months: The authors declare no additional disclosures to report.