Diagnosing Autoimmune Psychosis

Katlyn Nemani, MD, explores how autoimmune and inflammatory brain disorders can present as first-episode psychosis—and why some patients diagnosed with schizophrenia may actually have a treatable immune-mediated illness. She explains the clinical features that should prompt suspicion for autoimmune psychosis, including subacute onset, subtle neurologic signs, and poor response to antipsychotics, even when standard imaging and antibody tests are unrevealing.

Dr. Nemani also discusses the limits of current biomarkers, how to think clinically when diagnostic certainty is incomplete, and why early immunotherapy can dramatically alter outcomes. The conversation closes with a forward-looking discussion of emerging research suggesting that a meaningful subset of schizophrenia-like illness may ultimately be reclassified as autoimmune in origin.

Katlyn Nemani, MD, is a Research Assistant Professor in the Departments of Psychiatry and Neurology at NYU Grossman School of Medicine and a graduate of NYU’s combined Neurology-Psychiatry residency program.

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00:00 When Psychosis May Be an Autoimmune Disease
01:18 Early Psychiatric Symptoms of Autoimmune Encephalitis
02:47 Why Subtle Neurologic Clues Matter
04:00 A Case of Rapidly Reversible Psychosis
06:37 The Limits of Antibody Testing
07:51 Why Early Treatment Changes Outcomes
08:18 Rethinking the Heterogeneity of Schizophrenia
09:31 How Common Is Autoimmune Contribution to Psychosis?
10:48 Network-Level Brain Effects and Open Research Questions

This episode is intended for psychiatrists, neurologists, and other clinicians interested in psychosis, neuroinflammation, and complex diagnostic presentations at the psychiatry–neurology interface.

This discussion is for educational purposes and does not substitute for individual clinical judgment or patient care.

Senior Producer: Jon Earle

Transcript

[00:00:00] CHARLES MARMAR, MD: Do you think 10 years from now we'll realize that 20, 30, 40 percent of people suffering with a schizophrenic-like illness have some degree of autoimmune contribution?

[00:00:11] KATLYN NEMANI, MD: I'd approximate about 30 percent of patients might have a treatable autoimmune form of illness. That estimate is partially coming from the work that we're doing now to identify novel autoantibodies that target the brain in schizophrenia, and partly from the work of others that have identified staining patterns, looking at antibodies in the blood and the spinal fluid of patients with schizophrenia on brain slices, which show that about 30 percent of them have antibodies that do target the brain.

[00:00:46] CHARLES MARMAR, MD: I am Dr. Charlie Marmar, chair of the Department of Psychiatry at NYU Grossman School of Medicine and Langone Health network. Today I'm in conversation with Dr. Katlyn Nemani. She is an Assistant Professor in the Department of Psychiatry. She is by training both a neurologist and psychiatrist, having been one of the distinguished graduates of our double board Neurology-Psychiatry program, a six-year residency that prepares our doctors to be both certified in neurology and psychiatry. And she also has a developing, very important research career with other colleagues here at NYU, including Dr. Goff, on trying to understand and advance the understanding of the underlying molecular basis for psychotic illness and how we can do much better in the future to treat it. So welcome, Katlyn. It's a real pleasure to speak with you.

[00:01:48] KATLYN NEMANI, MD: It's an honor to be here.

[00:01:49] CHARLES MARMAR, MD: You're doing very important research on neuroinflammatory mechanisms or autoimmune mechanisms in psychosis, and so please tell us a little bit about that. Will the day come when we can say the same thing about autoimmune forms of schizophrenia or psychosis that we can say about neurosyphilis—that we have found a clear understanding of the mechanism and we can provide very robust treatment?

[00:02:20] KATLYN NEMANI, MD: The really exciting field of autoimmune neuropsychiatry really requires some knowledge that spans both specialties because patients typically present in the early stages of disease with symptoms that would typically be treated by a psychiatrist: some subtle personality changes, psychosis, sometimes impulsivity and aggression, some subtle cognitive changes, before progressing to typically more neurologic symptoms—seizures, dysautonomia, things that a neurologist would see. And so putting all of that together and getting the right diagnosis by someone who understands the full clinical picture can make a world of difference to patients, because these patients who would've normally been diagnosed with some untreatable form of chronic psychosis become patients who have a treatable immune-mediated disease. And it was really treating patients like this and seeing them go from really floridly psychotic and not responding to the treatments that we were offering to essentially back to their baseline after immunotherapy.

[00:03:39] CHARLES MARMAR, MD: Could you tell us briefly about maybe a composite patient that presented with a complex picture of the kind you described that turned out to have an underlying autoimmune basis? How did you arrive at that diagnostic conclusion, and specifically, how would you treat them?

[00:04:00] KATLYN NEMANI, MD: So imagine a grad student in her twenties who presents with a couple of weeks of anxiety and some subtle mood changes, followed by some psychotic symptoms. The family says she's getting a little bit paranoid. She's having trouble following conversations, and they eventually bring her to the emergency room when she starts having some bizarre hallucinations. She comes in, she's a little bit aggressive. She is reporting hearing voices, and there's no obvious neurologic symptoms when she first comes in. And so the emergency team recommends an admission to psychiatry. Psychiatry thinks this is most likely first-episode psychosis that will progress to schizophrenia, but then they notice a few unusual symptoms. She's complaining about persistent headaches. She is having some fluctuating levels of consciousness—not full-out delirium, but sometimes she just looks out of it and stares. There's some subtle lapses in her memory. The treatment team notices that one morning she doesn't remember her family visiting. This is raising suspicion for something that might not be what we would call typical schizophrenia. So she gets a full medical neurologic workup, but her MRI is normal. Blood work shows nothing. EEG shows a little bit of slowing, but nothing obvious. And she even has a spinal tap and we see a little bit of inflammatory changes, but nothing that's screaming towards the diagnosis—enough to raise suspicion, though. And the standard antibody panels that we check for autoimmune encephalitis are negative. So at that point, some clinicians would stop there: no antibody, no autoimmune-mediated illness. But there are features of this case that suggest potential autoimmune etiology. She had the sort of subacute course. Her symptoms came on fast. She has these subtle neurologic symptoms, and she's not responding to antipsychotics very well. So the team tries immunotherapy, says, "We don't know what this antibody is or if it is an antibody-mediated illness, but clinically it looks like it could be." And she receives a course of IVIG and steroids, and within a few days her psychosis has resolved. She's back to herself.

[00:06:36] CHARLES MARMAR, MD: Amazing.

[00:06:37] KATLYN NEMANI, MD: And I think the key insight from cases like this is that we are really working at the edge of our diagnostic capabilities. We can look for, say, 12 different antibodies that we know cause this type of illness, but there are potentially many others. Our biomarkers have to catch up to that in order to definitively know what we're treating.

[00:07:02] CHARLES MARMAR, MD: It's remarkable because had you and the team not persisted—and I think part of it is your ability to consult as a neurologist and psychiatrist and be very sensitively attuned to the shifting psychiatric and neurological symptoms that are interplaying in someone with an autoimmune encephalitis or related disorder—that allowed you to persist. And I think, unfortunately, in many settings that might not occur and the patient might then unfortunately experience a prolonged period of misdiagnosis. In essence, multiple failed trials of neuroleptic and other medications, which have very significant side effects and, worse, prolonged suffering.

[00:07:51] KATLYN NEMANI, MD: Absolutely. And time is brain.

[00:07:53] CHARLES MARMAR, MD: Exactly. And the earlier you can—I presume another advantage of that early trial of IVIG was that the sooner you can intervene in the autoimmune encephalitic process, the less neurological damage will occur.

[00:08:11] KATLYN NEMANI, MD: Absolutely.

[00:08:12] CHARLES MARMAR, MD: As a neuropsychiatrist, how do you think about the heterogeneity of schizophrenia?

[00:08:18] KATLYN NEMANI, MD: I think there's a number of different pathways that could lead to the symptoms of schizophrenia. Some of those might be neurodevelopmental. Some people might just be very genetically predisposed. I think the number of patients who have a clearly genetically defined illness are far and few between. For some patients, I think there's probably a combination of genes and environmental risk factors that put them at higher risk. And those environmental risk factors can include stressors of all types. When I say stress, that can be physiologic stress, such as from an infection. That can be trauma. And the combination of that genetic risk with those environmental exposures can contribute to the onset of schizophrenia. Ultimately, we're looking for mechanisms that are treatable and reversible, and those might be far and few between, but they might not be. I think we don't know yet.

[00:09:20] CHARLES MARMAR, MD: Do you think 10 years from now we'll realize that 20, 30, 40 percent of people suffering with a schizophrenic-like illness have some degree of autoimmune contribution?

[00:09:31] KATLYN NEMANI, MD: So it's hard to say based on the limited amount of data that we have, but I am a betting woman, and so I would say I'd approximate about 30 percent of patients might have a treatable autoimmune form of illness. That estimate is partially coming from the work that we're doing now to identify novel autoantibodies that target the brain in schizophrenia, and partly from the work of others that have identified staining patterns, looking at antibodies in the blood and the spinal fluid of patients with schizophrenia on brain slices, which show that about 30 percent of them have antibodies that do target the brain, even if we don't know what those exact antibodies are.

[00:10:16] CHARLES MARMAR, MD: And do they typically, you think, target a limited set of brain regions or receptors, or is it much more complicated than that?

[00:10:25] KATLYN NEMANI, MD: It is all over the place, and it's really hard to synthesize across studies because everyone is using different slices of the brain. Some people are focused on the hippocampus. Some people are looking at frontal cortex. I don't think that we are gonna find a smoking gun in one specific brain region. I think we are probably looking at something that is operating on more of a network level.

[00:10:48] CHARLES MARMAR, MD: I often think, Katlyn, if you've been ill for a week with a bad flu or something, or you've been injured and you're not feeling well for a while, it's very difficult to even feel unwell for days, weeks, or a month. Imagine having to feel unwell for a lifetime of illness. It's an enormous burden and really tragic in many ways. And hopefully we'll have, with your help and others in the field, we'll be able to offer real care, real treatment, and real hope to patients who, in some sense, have been condemned to a lifetime of pain and disability. So I just want to say how wonderful it is that you are committing to this. What a great pleasure it is and privilege to have you working with us in our department, and we're really hopeful about the future with your help. And thank you so much for joining me in conversation today.

[00:11:54] KATLYN NEMANI, MD: Thank you so much, and thank you so much for being so supportive of neuropsychiatry here at NYU.