The recently published seventh edition of the “Guidelines on the Use of Therapeutic Apheresis in Clinical Practice” outlines the available evidence supporting and refuting the use of therapeutic apheresis as a medical treatment.1 The authors are to be congratulated for their important contribution to the medical literature, which helps to ensure that peer‐reviewed medical literature is used to guide the care of patients who are being evaluated as possible apheresis candidates. Now that the seventh edition of these guidelines has been available for several months, most apheresis practitioners have had an opportunity to begin to appreciate how the current recommendations vary from previous iterations. One key difference is the new, category I classification for the use of therapeutic plasma exchange (TPE) as a treatment for N‐methyl d‐aspartate receptor encephalitis (NMDAr). In the sixth edition, NMDAr was grouped with other paraneoplastic neurological syndromes (eg, paraneoplastic cerebellar degeneration, etc.), which were collectively assigned a category III rating.2 The technical notes of the sixth edition of the guidelines even contained an unusual caveat to the use of TPE for these indications, “TPE cannot be considered standard therapy for autoimmune paraneoplastic neurologic syndromes.” The fifth edition (published in 2010) does not mention NMDAr.3 Given the rareness of the diagnosis of NMDAr, and the lack of any published clinical trials over this time period, we were surprised at the rapidly shifting recommendations for this indication. Recurring themes in the treatment of NMDAr include early treatment, tumor removal (if present), and the recognition that patients without tumors are more likely to require second‐line treatment with cyclophosphamide or rituximab. The medical literature provides only very limited assessments as to whether patient outcomes are even improved when TPE is pursued as a first‐line treatment. As a reflection of the lack of published evidence, the authors of the Guidelines have assigned a 1C grade to the recommendation, which reflects that the evidence to support TPE in this setting is of low or very low quality. This, in conjunction with the fact that fewer than half of patients seem to actually undergo TPE, and virtually all patients who are treated with TPE are simultaneously treated with steroids, makes it difficult to understand the “strong” recommendation for TPE to be used as “first line” therapy for NMDAr.4-6 One report explicitly recommends against TPE due to the increased risks of adverse outcomes in patients with autonomic instability.7 Therefore, the role of TPE as a treatment for NMDAr appears to require further study and carefully planned individual treatment schemas. At present, the decision to include TPE as a treatment modality should depend on patient‐specific factors, such as age, presence of tumor, nature of symptoms, risk of infection, and the degree of autonomic instability.8 In light of this, we feel that a category III classification continues to be appropriate. While the Guidelines makes the point that the low grade of evidence can be used to “soften” a category I classification, in our collective experience, a category I classification is widely interpreted by the medical community to mean that apheresis‐based treatment is an effective treatment that represents the standard of care. Admittedly, this is an unintended consequence of the Guidelines, but it nonetheless has important implications for the management of these patients. For example, facilities without TPE may feel compelled to transfer these patients to centers that offer apheresis. In addition, in some cases, treatment with second‐line immunotherapy such as cyclophosphamide and rituximab may be unnecessarily delayed while a weeks‐long therapeutic trial of apheresis is completed. We are also aware of at least one instance where unjustified enthusiasm regarding the efficacy of TPE led to hesitation to perform definitive surgery. While there are other indications besides NMDAr that have a category I indication despite only limited evidence to support the efficacy of the treatment, those conditions have generally been treated by apheresis for decades (eg, myasthenia gravis). In contrast, NMDAr has had a rapid ascent from to an uncategorized condition, to a category III condition, to a category I condition over the past 7 years. We also note that, consistent with the published literature, we have successfully treated many myasthenia gravis patients with TPE. However, our use of TPE to treat NMDAr has been frustrated by frequent treatment failure. Furthermore, we fear that this new, category I indication may lead to increased reluctance (in addition to the general bias against reporting negative results) to publish cases of TPE treatment failure in NMDAr, potentially codifying the use of this controversial therapy for the long term. For all of these reasons, we ask the authors to re‐consider their recommendation in future editions of the guidelines, until additional data to support (or refute) the use of TPE are available.
Some of the brightest minds in neuroscience recently converged on the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital for its fourth biennial symposium and workshop, in partnership with Baylor College of Medicine. The special two-day event brought together nearly 300 physicians, scientists, patients, patient advocacy groups, pharmaceutical industry experts and leaders from the National Institutes of Health (NIH), the National Institute of Neurological Disorders and Stroke, and the National Institute for Mental Health, to address key issues in the field of neuropsychiatry, an intersectional branch of medicine that deals with mental illnesses caused by organic disorders of the nervous system. Neuropsychiatric disorders are a leading cause of disability and take a tremendous toll on society. In the United States alone, one out of five adults lives with mental illness. The spectrum of mental illnesses is vast, ranging from the extremely rare to more well-known conditions such as depression, anxiety, schizophrenia, ADHD, addiction and sleep disorders. Symptoms and their severity can vary widely from patient to patient, which makes them difficult to physiologically measure. For these reasons, neuropsychiatric disorders are some of the least understood – and some of the most difficult to treat. “These disorders are a major health issue all over the world, however, therapeutic interventions remain limited,” said NRI/Baylor investigator and child neurologist Dr. Hsiao-Tuan Chao. “There is a growing need to understand the organic factors behind mental illness to facilitate a better understanding of the brain, as well as to develop more effective treatment strategies.” The symposium opened with a welcome address from Dr. Huda Zoghbi, director of the NRI, and this year’s co-organizer, Dr. Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. The pair stressed the importance of identifying new research paths in order to develop targeted therapies that could not only help treat neuropsychiatric symptoms, but could also help mitigate or eliminate side effects and toxicities that far too many patients experience. Over the course of the first day, presentations from leading experts addressed hot topics in neuropsychiatry. These included a discussion on how genetic mutations contribute to neuropsychiatric disorders; the involvement of neuronal networks in neuropsychiatric phenotypes; the impact of immune cells on these disorders; and a look into how adaptive deep brain stimulation could potentially help specific conditions. Each session gave way to a 20-minute moderated panel discussion on the topic at hand. This feature of the symposium is unique in that it leads to immediate discussion and active participation among the many different types of stakeholders present. A highlight of the event was guest speaker Stephanie Arditte, who told of her experience with a sudden and inexplicable bout with autoimmune encephalitis, a condition in which the body’s immune system mistakenly attacks healthy brain cells, causing swelling and potentially numerous neurologic and/or psychiatric symptoms. Arditte had no prior medical history, which made it all the more alarming when she suddenly began experiencing memory loss, hallucinations and the inability to speak. She told the audience about her harrowing “diagnostic odyssey,” a term physicians use to describe the all-too-common ordeal patients and families endure in their search for a diagnosis, which can take months, years or even longer. And she also emphasized the need for a sea change in society’s understanding of the organic nature of mental illnesses in order to overcome the unconscious bias and negative stigma associated with them. Following a day of stellar research presentations, the investigators split into three working groups that focused on Molecular Bases of Disease and Human studies, Circuits and Neuromodulation, and Young Investigators. The groups discussed not only everything they had heard over the course of the day, but also their vision for the next 20 years in neuropsychiatry, including the obstacles that currently exist and what is needed to overcome them. The next morning, key points that had emerged from these discussions were shared with the audience. The working groups identified increased access to resources and funding as a major need. But unanimously, all of the young investigators noted the critical importance of building interdisciplinary, multi-institutional collaborations, with a focus on team science and data sharing. “Building bridges between various disciplines aids in the identification of important areas of neuropsychiatry that require further investigation and therapeutic development,” said Chao. “Neuropsychiatry itself is an interdisciplinary field, and unraveling the causes for these conditions will require continued interdisciplinary collaborations to accelerate the pace of discovery.” The proceedings will be published as a white paper in Science Translational Medicine, a leading weekly online journal and one of the event sponsors. Print PDF