sometimes, it *is* lupus

June 8, 2023 5:17 PM

After a traumatic experience in college, April Burrell was catatonic for twenty years. She was diagnosed with a severe form of schizophrenia which did not respond to treatment. “She was the first person I ever saw as a patient,” said Sander Markx, director of precision psychiatry at Columbia University, who was still a medical student in 2000 when he first encountered April. “She is, to this day, the sickest patient I’ve ever seen.”

Burrell initially presented with psychosis, and was soon "lost in a constant state of visual and auditory hallucinations," unable to communicate, care for herself, or bathe unassisted. After re-encountering this unforgettable patient, Markx assembled a multidisciplinary team of more than 70 experts from around the world to re-evaluate Burrell. It was discovered that "although April’s illness was clinically indistinguishable from schizophrenia, she also had lupus, an underlying and treatable autoimmune condition that was attacking her brain. After months of targeted treatments — and more than two decades trapped in her mind — April woke up." (Washington Post, June 1, 2023; gift article; archive link).

Members of the team then searched for patients with psychiatric diagnoses and antibody markers for autoimmune disease, and found 20-year-old Devine Cruz. At age nine, she'd started hearing voices and having hallucinations, and was diagnosed with schizoaffective disorder (which can result in symptoms of both schizophrenia and bipolar disorder) and an intellectual disability. Cruz also has lupus, which was identified when she was about 14 years old.

"Last August, the medical team prescribed monthly immunosuppressive infusions of corticosteroids and chemotherapy drugs, a regime similar to what April had been given a few years prior. By October, there were already dramatic signs of improvement. [...] Her recovery is remarkable for several reasons, her doctors said. The voices and visions have stopped. And she no longer meets the diagnostic criteria for either schizoaffective disorder or intellectual disability."

On April 25, 2023, Columbia University announced the creation of The SNF Center for Precision Psychiatry and Mental Health at Columbia (established with a $75 million grant from the Stavros Niarchos Foundation (SNF), an international philanthropic organization). "The goal of the center is to develop new treatments based on specific genetic and autoimmune causes of psychiatric illness."

Clinical manifestations and immunomodulatory treatment experiences in psychiatric patients with suspected autoimmune encephalitis: a case series of 91 patients from Germany. Mol Psychiatry 27, 1479–1489 (2022). https://doi.org/10.1038/s41380-021-01396-4

Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry 7:93–108. https://doi.org/10.1016/S2215-0366(19)30290-1

Autoantibody-associated psychiatric symptoms and syndromes in adults: A narrative review and proposed diagnostic approach. Brain Behav Immun Health. 2020 Oct 1;9:100154. doi: 10.1016/j.bbih.2020.100154.

Autoimmune encephalitis as a differential diagnosis of schizophreniform psychosis: clinical symptomatology, pathophysiology, diagnostic approach, and therapeutic considerations. Eur Arch Psychiatry Clin Neurosci. 2020 Oct;270(7):803-818. doi: 10.1007/s00406-020-01113-2.

Inflammation in Schizophrenia: Pathogenetic Aspects and Therapeutic Considerations. Schizophr Bull. 2018 Aug 20;44(5):973-982. doi: 10.1093/schbul/sby024.

Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis. Transl Psychiatry. 2021 Nov 5;11(1):566. doi: 10.1038/s41398-021-01701-3.

Catatonia and the immune system: a review. Lancet Psychiatry. 2019 Jul;6(7):620-630. doi: 10.1016/S2215-0366(19)30190-7.

Catatonia with GABAA receptor antibodies, Practical Neurology 2020;20:139-143. http://dx.doi.org/10.1136/practneurol-2019-002388

Psychosis in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study. Arthritis Rheumatol. 2019 Feb;71(2):281-289. doi: 10.1002/art.40764.

Autoimmune Diseases and Psychotic Disorders. Front Psychiatry. 2019 Mar 20;10:131. doi: 10.3389/fpsyt.2019.00131.

Clinical Diagnosis of an Autoimmune Encephalitis Presented as a Manic Episode with Psychotic Symptoms: A Case Report. Rep Psychiatry. 2022 Feb 16;2022:2460492. doi: 10.1155/2022/2460492.

Autoimmune Encephalopathies and Dementias. Continuum (Minneap Minn). 2016 Apr;22(2 Dementia):538-58. doi: 10.1212/CON.0000000000000299.

Dysbiosis, gut-blood barrier rupture and autoimmune response in rheumatoid arthritis and schizophrenia. Reumatologia. 2021;59(3):180-187. doi: 10.5114/reum.2021.107588.

Immunological causes of obsessive-compulsive disorder: is it time for the concept of an "autoimmune OCD" subtype? Transl Psychiatry. 2022 Jan 10;12(1):5. doi: 10.1038/s41398-021-01700-4.

Autoimmune obsessive-compulsive disorder with novel anti-CNS autoantibodies in cerebrospinal fluid. Mol Psychiatry 27, 3926–3928 (2022). https://doi.org/10.1038/s41380-022-01688-3

Autoimmunity in narcolepsy. Curr Opin Pulm Med. 2017 Nov;23(6):522-529. doi: 10.1097/MCP.0000000000000426.

Repositioning synthetic glucocorticoids in psychiatric disease associated with neural autoantibodies: a narrative review. J Neural Transm (2022). https://doi.org/10.1007/s00702-022-02578-2

Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody Encephalitis, A Meta-analysis. JAMA Neurol. 2021;78(11):1333-1344. doi:10.1001/jamaneurol.2021.3188

Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome. J Neurol. 2020 Jul;267(7):2101-2114. doi: 10.1007/s00415-020-09814-3.

posted by Iris Gambol (31 comments total)

Somewhat related: How inflammation in the body may explain depression in the brain (ungated)
posted by BungaDunga at 5:30 PM on June 8, 2023 [12 favorites]

slow. clap. terrific fpp. now. for a few hours of reading.
posted by j_curiouser at 5:56 PM on June 8, 2023 [16 favorites]

Well done headline. Dr. House reference for the uninitiated.
posted by beckybakeroo at 6:06 PM on June 8, 2023 [11 favorites]

This is unbelievably important. Thank you for this post.
posted by mhoye at 6:36 PM on June 8, 2023 [6 favorites]

An incredible improvement, but how do you move on after something that takes a decade or more from your life? Where do you even start educating someone who missed that many years of school?
posted by ockmockbock at 6:42 PM on June 8, 2023 [2 favorites]

One day at a time. Or many, on better days.
posted by Callisto Prime at 7:03 PM on June 8, 2023 [17 favorites]

You start by showing them Encino Man?

But really, this is amazing. We're only starting to wake up to things like this. And we're going to be finding more and more of them with what we've learned so far.

We think we know so much, but we're really only just toddlers in many ways.
posted by hippybear at 8:02 PM on June 8, 2023 [8 favorites]

You start by showing them Encino Man?

Haven't they suffered enough?
posted by star gentle uterus at 8:20 PM on June 8, 2023 [19 favorites]

As an autoimmune patient, though not with this kind of presenting issue, this is mind-blowing. Thanks for doing all the work to present the research.
posted by gentlyepigrams at 8:53 PM on June 8, 2023 [5 favorites]

The first conclusive evidence was in her bloodwork: It showed that her immune system was producing copious amounts and types of antibodies that were attacking her body. Brain scans showed evidence that these antibodies were damaging her brain’s temporal lobes, areas that are implicated in schizophrenia and psychosis.

This is really, really cool, but also... How new are these technologies? What was the state of the art in 1995 when she first got sick? What about in 2000? Why didn't anyone do this kind of bloodwork sooner? Or we were just not thinking this way at all?

(I guess I'm still personally angry at the GI who, in 2006, laughed at me and told me I was just taking "too many math and computer science classes" to explain my chronic vomiting, brain fog, depression, and debilitating fatigue, instead of just doing a simple fucking blood test for celiac disease which would have spared me a decade of suffering and damage. I'm hoping medicine is growing out of that kind of attitude.)

I'm glad Dr. Markx was willing and able to assemble a large multidisciplinary team to take the patient seriously, look under every rock, and figure this out. Looking forward to digging into this post!
posted by cnidaria at 8:56 PM on June 8, 2023 [26 favorites]

Thank you, Iris Gambol. This is an amazing FPP. This part was heartening: “Researchers working with the New York state mental health-care system have identified about 200 patients with autoimmune diseases, some institutionalized for years, who may be helped by the discovery.”

The news that April had regressed because she had not received the maintenance treatment she needed was heartbreaking. Patients are basically hostages of the healthcare system and specific places where they get treatment. But that is a different issue. I am so glad to have learned about this development.
posted by Bella Donna at 11:32 PM on June 8, 2023 [11 favorites]

Or we were just not thinking this way at all?

I think a lot of people have had the experience of being told by doctors that their fatigue must be due to depression, that their heart or sleep issues must be anxiety, and so on. That can be right part of the time, but the idea that psychosomatic effects can cut both ways, with the body affecting the mind, has 100% not been part of the thinking of any doctor I have ever met. Even though there's been plenty of research on the subject.

That, plus the tendency to go with the most obvious explanation ("it looks like schizophrenia") and not dig any further even when treatments that should work don't. To me the most surprising thing in this story is that somebody did say "wait, this warrants another look."
posted by trig at 12:42 AM on June 9, 2023 [18 favorites]

Excellent post; thank you!
posted by cool breeze at 4:45 AM on June 9, 2023 [1 favorite]

How new are these technologies?

I was curious about this as well because, as a woman with many women friends with dismissive doctors, I was shocked when my husband got a diagnosis in two doctor's visits in under two months, with a GP who took one look at his bloodwork and said his "inflammation markers were sky-high", in I think 2016.

Someone smarter than me may come along and explain this with more accuracy, but it looks like we've had some tests for these markers since the 1920s, but we didn't know what they were telling us and not much real research went into it until the 00s and 10s, and honestly it still kind of reads like we find those dang markers high all over the place - like just maybe inflammation really is a factor in a lot of disease - but we know that if we see them it's bad, and then if we see them in the presence of other specific symptoms/bloodwork that means X. As an example, the CRP markers were added to the Rheumatoid Arthritis diagnostic criteria in 2010, which probably means they were being tracked for some years previous but possibly in a way that GPs wouldn't have been especially aware of.

But also some doctors get into the business because it gives them free reign to be abusive, so I am sorry to everyone who has had that kind of experience trying to figure out what's wrong with them.
posted by Lyn Never at 4:54 AM on June 9, 2023 [6 favorites]

Once a patient has a diagnosis of a mental health condition on their health record, especially a serious one like schizophrenia, nothing else they say is ever taken seriously by any doctor (or often anyone else). Doctors like those in this story are truly rare.
posted by hydropsyche at 5:08 AM on June 9, 2023 [27 favorites]

I feel like the real miracle here is that someone actually noticed symptoms and tested for autoimmune disease. It's often pretty subtle and goes undiagnosed for years in people who are very vocal about their symptoms.

I would bet that she was on a biologic, and relapsed when the insurance denied it. That's another too-common story with autoimmune disease.

I'm very heartened that her case has widened into a "this test is easy, let's test more people!".

Given that there is no actual biological underpinning of many mental diseases, it's almost certain that people get lumped into a category they don't actually belong in, and a real, treatable biological condition is missed.
posted by Dashy at 6:15 AM on June 9, 2023 [2 favorites]

Or we were just not thinking this way at all?

I think a lot of people have had the experience of being told by doctors that their fatigue must be due to depression, that their heart or sleep issues must be anxiety, and so on. That can be right part of the time, but the idea that psychosomatic effects can cut both ways, with the body affecting the mind, has 100% not been part of the thinking of any doctor I have ever met. Even though there's been plenty of research on the subject.

That, plus the tendency to go with the most obvious explanation ("it looks like schizophrenia") and not dig any further even when treatments that should work don't. To me the most surprising thing in this story is that somebody did say "wait, this warrants another look."

It's a Bayes theorem problem combined with signal detection theory. The number of cases that probably meet this criteria are vanishingly small in the population as a whole and the percentage of medical experts with the updated knowledge and the drive to make the connections are probably very small in the profession. Medicine as a field despite a lot of peoples beliefs about scientific progression and rationality is only just starting to climb out of being almost entirely dependent on lucky guess hypothesis generation. This is one of the things made the Covid-19 mrna vacines so incredible.
posted by srboisvert at 6:16 AM on June 9, 2023 [4 favorites]

I believe that doctor's who could truly advertise "doctor who listens and thinks" could get a lot of patients-- though that might not be the problem, such doctors might already be swamped.

I suspect without evidence that sleep deprivation during med school and internship is apt to cause both brain and emotional damage. Doctors might even resent that patients are at least not in med school.
posted by Nancy Lebovitz at 6:40 AM on June 9, 2023 [4 favorites]

Doctors are just people who went to medical school. All of the same personal failings apply to them that apply to every other profession, with the extra added bonus that they are trained to believe they are right all the time.

I went to an ENT for tinnitus and, apropos of nothing, he declared that I had Meniere's Disease, despite the fact that I did not present with two of the three symptoms (vertigo and low frequency hearing loss) necessary for a diagnosis. I would, he said, eventually lose my sense of balance and the quality of my life would severely deteriorate. Spoiler alert: I don't have Meniere's and my vestibular system is in ace condition. But the only reason I didn't spiral into depression over that misdiagnosis was that I looked it up and realized he was wrong. Dr. Google gets a bad rap for a good reason, but Reference Librarian Google is a good friend and true.

The world needs more doctors like Sander Markx. The world needs more doctors, period.
posted by grumpybear69 at 7:00 AM on June 9, 2023 [5 favorites]

The world needs more doctors who are given time to think.

We train them so carefully in thinking. And then we stand over them with a stopwatch. Which as anyone with a working brain knows, is a sure-fire way to limit that brain.
posted by Dashy at 7:18 AM on June 9, 2023 [28 favorites]

In addition to the lupus tie-in, House featured a substantially similar plot in S1E6, "The Socratic Method". A woman who has been diagnosed with schizophrenia is found instead to be suffering from Wilson's disease, a rare condition characterized by a build-up of copper in the body, causing (among other things) neurological symptoms. House's "a-ha" moment is punctuated by the line: "Pick your specialist, pick your disease".
posted by kjh at 10:31 AM on June 9, 2023 [1 favorite]

"April, who is turning 50 this year, [...] has recently regressed because she was not receiving adequate maintenance care" -- Women/AFAB people make up around 80% of identified autoimmune-disease cases (and these diseases are underdiagnosed); per the article, "autoimmune disorders like lupus disproportionately affect women and people of color with more severity."

I'd wondered whether menopause (which occurs earlier in this population) was a factor in the recent regression, because hormonal changes often call for medication changes. (For many patients with lupus, disease activity decreases after menopause.) If meds recalibration didn't happen in a timely fashion, or was a rocky process, Burrell would have suffered setbacks.
posted by Iris Gambol at 10:51 AM on June 9, 2023 [2 favorites]

This echos a bit of Susannah Callahan’s Brain on Fire-and that was a month, not 20 years! I’m so glad they are moving forward with checking on other people.
posted by childofTethys at 12:01 PM on June 9, 2023 [1 favorite]

Amazing. Truly amazing. Much reading in store.
posted by Splunge at 2:09 PM on June 9, 2023 [1 favorite]

Encouraging results from a recent US clinical trial:

- Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant).

- Participants: 25,871 participants, consisting of 12,786 men ≥50 years and 13,085 women ≥55 years at enrollment.

- Supplements: vitamin D (cholecalciferol [D3]; 2000 IU/day) and marine omega 3 fatty acids (1 g/day as a fish oil capsule containing 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid). [Current Vitamin D RDA for ages 1-70 is 600 IU, and 800 IU for people 71 and older. Recommendation chart for omega 3 fatty acids; it's 1.1 to 1.6g/day for adults.]

- Blood samples from a subgroup at one year found mean 25-hydroxyvitamin D levels (n=1644) increased by 40% (from 29.8 ng/ml at baseline to 41.8 ng/ml at one year) in the vitamin D group and changed minimally in the placebo group; the mean omega 3 index (n=1583) increased 54.7% (to 4.1% at one year in the omega 3 group) and changed by less than 2% in the placebo group.

- This trial did not intend to examine vitamin D supplementation in a population that was vitamin D deficient, but in participants representative of vitamin D levels in other large trials and in the general older adult population in the United States.

- This was a randomized controlled trial inspired by physicians’ awareness of limited choices for treating patients with autoimmune disease, and desire by patients for effective treatments.

from Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ 2022; 376 :e066452 doi:10.1136/bmj-2021-066452

See also: Effects of Vitamin D on Systemic Lupus Erythematosus Disease Activity and Autoimmunity: A Systematic Review and Meta-Analysis. Cureus. 2022 Jun 13;14(6):e25896. doi: 10.7759/cureus.25896.
Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors? Mol Aspects Med. 2012 Feb;33(1):77-82. doi: 10.1016/j.mam.2011.10.014.
Involvement of the secosteroid vitamin D in autoimmune rheumatic diseases and COVID-19. Nat Rev Rheumatol. 2023 May;19(5):265-287. doi: 10.1038/s41584-023-00944-2. "[A] low serum concentration of 25(OH)D3 is considered to be a risk factor for autoimmune rheumatic diseases and vitamin D3 supplementation seems to improve the prognosis; moreover, long-term vitamin D3 supplementation seems to reduce their incidence (i.e. rheumatoid arthritis). In the setting of COVID-19, 1,25(OH)2D3 seems to downregulate the early viral phase (SARS-CoV-2 infection), by enhancing innate antiviral effector mechanisms, as well as the later cytokine-mediated hyperinflammatory phase."

However: "It has been noted that excessive amounts of vitamin D are associated with a worse clinical outcome in sarcoidosis;" calcium metabolism is altered in sarcoidosis.
posted by Iris Gambol at 2:20 PM on June 9, 2023 [2 favorites]

What level is an excessive amount, though?
posted by eviemath at 3:34 PM on June 9, 2023 [2 favorites]

this is a truly great post. thank you so much, Iris Gambol! much reading to be done, all worthwhile.
posted by lapolla at 7:02 PM on June 9, 2023 [1 favorite]

In sarcoidosis, "ergocalcitrol levels of 10 to 20 ng/ml was associated with the lowest fracture risk for patients. One possible explanation for the lower ideal ergocalcitrol level in sarcoidosis is the enhanced activity of 1-alpha hydroxylase in sarcoidosis granulomas." That enhanced activity can spur calcium absorption to the point of hypercalcemia -- leading to osteoporosis (and bone fractures), kidney stones, arrhythmia, etc. (Sarcoidosis News: Vitamin D Supplements in Sarcoidosis Patients Linked to Risk of High Blood Calcium Levels.) The main thing seems to be that if you have sarcoidosis, you'd definitely get your levels checked first and discuss supplement appropriateness with your doctor. The research I'd linked was blanket pro-D3 supplementation to deter or ameliorate several autoimmune diseases, so I wanted to specify an exception in that category.

Autoimmune Rheumatic Diseases Masquerading as Psychiatric Disorders: A Case Series. Mediterr J Rheumatol. 2021 Jun 30;32(2):164-167. doi: 10.31138/mjr.32.2.164. [The cases: Sjogren's syndrome, systemic sclerosis, lupus, sarcoidosis; one of the sclerosis patients dies within one year of diagnosis, still in her 30s.] "Conclusion: Any patient, particularly females, with a newly detected psychiatric disorder that responds poorly to medical management should be properly examined for underlying primary systemic autoimmune diseases."

Adolescent Sjogren's syndrome presenting as psychosis: a case series. Pediatr Rheumatol Online J. 2020 Feb 11;18(1):15. doi: 10.1186/s12969-020-0412-8.
posted by Iris Gambol at 9:03 PM on June 9, 2023 [2 favorites]

Yes, but what does that translate to in terms of an upper limit for amount of vitamin D supplement to take? Or, what egocalcitrol levels result from taking daily vitamin D supplements of 600 vs 2000 IU? Without having a commensurate measurement unit, it is impossible to tell whether the two pieces of information about benefits and risks of vitamin D supplementation are incommensurate or present no conflict with each other.
posted by eviemath at 9:26 AM on June 10, 2023

Sorry, I'd thought the "excessive amount" question was about supplementation in sarcoidosis.

I'm not sure. At that NIH fact sheet with the 600 IU rec, which sets the upper limit for adults as 4,000 IU, "You get vitamin D from food, sunshine, and dietary supplements," with a broad list of people "more likely than others to have trouble getting enough vitamin D," plus "almost one out of four people have vitamin D blood levels that are too low or inadequate for bone and overall health." Of course, US healthcare is a shell game, and few people get regular vitamin D testing -- the test may be ordered for the patient in one or more of the known risk categories, a person already showing signs of deficiency?

In the VITAL trial, "Eligible participants, recruited throughout the US, were required to limit vitamin D use from outside sources to no more than 800 IU/day, and to forego the use of fish oil supplements;" baseline serum levels for 16,956 people and any pre-trial D supplementation are in Table 1. There are people in the placebo group continuing their pre-trial under-800 IU/day supplements, more than meeting the RDA, but it's the 2K IU/day group that sees the dramatic rise in their serum levels and experiences the statistically-significant reduced rate of autoimmune disease.
posted by Iris Gambol at 11:08 AM on June 10, 2023

Just checked the dosage on the vit D I take over winter and the fish oil I take 2 of daily as per the dosage:

D: 4000IU per pill
Fish oil 1g omega fatty acids per pill

Looks like I'd benefit from halving the fish oil and getting a lower dose vit D that I take daily (I don't get enough sun as it is really given I live somewhere with 300+ days of cloud or rain a year lol).
posted by daysocks at 12:25 PM on June 12, 2023