A relatively new strategy for treating certain cancers involves increasing the activity of host antitumor immunity through inhibition of intrinsic down-regulators of T-cell immunity. Several drugs have been approved for the treatment of melanoma, non-small-cell lung cancer, and other malignancies; these include pembrolizumab, ipilimumab, nivolumab, and others. These drugs are monoclonal antibodies that target immune down-regulators such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). As reviewed by Postow and colleagues, the inhibition of intrinsic immune downregulation results in an increase in immune activity that is accompanied by inflammation. This inflammation can adversely affect any organ; from a neurological perspective, the main problems encountered are encephalitis, aseptic meningitis, hypophysitis, uveitis, and a Guillain-Barré type of generalized neuropathy. We have encountered cases of the last of these with widely varying severity but most have slowly, if incompletely, improved. These problems typically occur a few weeks to months after therapy is initiated. The susceptibility to these complications is variable and it is unclear whether the presence of complications correlates with improved treatment efficacy. The excessive inflammation can be treated with glucocorticoids or, if needed, additional immunosuppressive agents.
Another strategy for treating certain malignancies, mostly hematologic, involves the use of host T-cells that have been genetically engineered to express an antigen receptor that binds specifically to tumor cells. This binding facilitates cytotoxic destruction of tumor cells by the modified T-cells, and several trials have demonstrated not only a favorable response rate in patients with otherwise refractory malignancies but also occasional durable remissions. The most common toxicity associated with CAR-T-cell therapy is a cytokine-release syndrome that can manifest on a spectrum from mild constitutional symptoms to severe multi-organ dysfunction including, rarely, hemophagocytic lymphohistiocytosis. An encephalopathy termed CAR-T-cell-related encephalopathy syndrome (CRES) is the second most common toxicity and is associated with a confusional state and seizures that result from cerebral edema and elevated intracranial pressure. The disorder most often occurs about 5 days after initiation of therapy, coincident with other cytokine-release symptoms, but may occur later as well. Efforts aimed at identifying and grading the symptoms have been established, as reviewed by Neelapu and colleagues. Current recommendations include obtaining a baseline brain MRI and initiating seizure prophylaxis before initiation of CAR-T-cell therapy, and frequent neurological assessments thereafter. Symptoms of cytokine-release syndrome and CRES can be managed with glucocorticoids, though at the expense of suppressing T-cell function. Interestingly, a high serum level of interleukin-6 (IL-6), one of the many cytokines released by activated T-cells, has been associated with more severe neurotoxicity. Antibody drugs that bind to and inhibit the IL-6 receptor, such as tocilizumab, have been shown to reduce CRES, particularly in the early period following initiation of CAR-T-cell therapy.
Numerous antibiotics, cardioactive medications, and other drugs may have adverse effects on the central or peripheral nervous system. Some of the latter are addressed in
Chap. 43. Here we mention mainly that penicillin and its derivatives such as imipenem, and to a lesser degree, the cephalosporins, are capable of causing seizures when high serum concentrations are attained. Cefepime, for example, has often been presumptively implicated in otherwise unexplained encephalopathies in patients we see as consultants on the wards and ICU. This complication is favored in most instances by concomitant renal failure.