autoimmune encephalitis from check point inhibitor

Complications of checkpoint inhibitor therapies (anti-PD1 and CTLA-4 antibody therapy), when severe, lead to ICU admission. Despite substantial study of complications of these relatively new drugs, the severe manifestations occur infrequently, making it challenging for intensivists to become comfortable with their treatment. The most common side effects of checkpoint inhibitors are skin reactions, such as rashes, followed by GI problems, including colitis, all of which are often self-limited. Of the severe complications, myocarditis, pneumonitis, enteritis, and neurological dysfunction lead the list. A grading scale for these complications ranges from grade 1 (mild) to grade 4 (life-threatening). Typically, grade 3 (severe) and grade 4 patients are the patients who are admitted to an ICU.

Among the neurological complications, many forms of autoimmune disease have been described. Myasthenic syndromes, myopathies, and Guillain-Barré are most commonly noted. In patients with underlying neurological conditions such as multiple sclerosis or myasthenia gravis, worsening of symptoms has also been described. In addition, autoimmune paraneoplastic disorders, which may be subtle or unrecognized, can become more severe.

In this case, the patient presents with weakness progressing to confusion and frank encephalopathy. On examination, he has rotary nystagmus on passive upward gaze and absent deep tendon reflexes. This is a typical presentation for a paraneoplastic syndrome, likely caused by anti-Ma2 antibodies against both central and peripheral neurons and associated with renal cell carcinoma (choice C is correct).

Myasthenic syndrome would be unlikely lead to confusion unless hypercapnia ensued from ventilatory failure and would not have would not have absent reflexes (choice A is incorrect). Similarly, the inflammatory myopathy syndrome, in some reports the most common neurological complication, would not have absence of deep tendon reflexes (choice B is incorrect). Likewise, confusion and nystagmus would not be expected findings, nor would a history of delusions, in a patient with Guillain-Barré syndrome (choice D is incorrect).

Treatment for patients with grades 2 through 4 neurological complications after checkpoint inhibitors should include discontinuation of the medication, diagnosis of the syndrome, and initiation of treatment specific for the diagnosed syndrome. In some cases, the discontinuation of the medication is sufficient to improve the patient. In patients who continue to progress, because all the disorders are autoimmune in nature, treatment with glucocorticoids, plasmapheresis, and immunosuppressants is often tried. There is not enough experience with the complications of these medicines to make very strong recommendations about cancer-specific therapies.

Paraneoplastic disorders are a particular challenge because the antibodies are present in as many as one-third of patients who have associated cancers, and disease manifestation is believed to be exacerbated by treatment with the checkpoint inhibitor, not initiated by it. In addition, although paraneoplastic disorders have off-target effects on neurons, it is clear that the immune response works as an effective anticancer treatment. For this reason, in the little experience published with autoimmune paraneoplastic syndromes after checkpoint inhibitors, discontinuation of the medication has little effect to ameliorate symptoms. In a few isolated cases, natalizumab therapy has been initiated without discontinuation of the checkpoint therapy. Natalizumab is an α4 integrin blocker that prevents the entry of immune cells into the brain. If there is no evidence of cancer in the CNS, it is postulated that the neurological effects can be stopped without inhibiting the systemic anticancer effects. This has not been tested in a clinical trial.123

Footnotes

  1. Dalakas MC. Neurological complications of immune checkpoint inhibitors: what happens when you ‘take the brakes off’ the immune system. Ther Adv Neurol Disord. 2018;11:1756286418799864. PubMed ↩

  2. Manson G, Maria ATJ, Poizeau F, et al. Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study. J Immunother Cancer. 2019;7(1):337. PubMed ↩

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