Article In Brief
More than one in five patients diagnosed with autoimmune encephalitis turned out to actually have a psychiatric or functional neurologic disorder, neurodegenerative disease, or other condition instead.
Autoimmune encephalitis often is misdiagnosed in patients, leading to the unnecessary use of immunotherapies and delays in treating the correct condition, according to a multicenter study published online Nov. 28 in JAMA Neurology.
The retrospective study indicated that more than 1 in 4 patients diagnosed with autoimmune encephalitis did not have the disorder; rather, they had a psychiatric or functional neurologic disorder, neurodegenerative disease, or other condition.
Misdiagnoses of autoimmune encephalitis even occurred at the subspecialty centers participating in the study, suggesting that the problem occurs in all kinds of clinical settings. Autoimmune encephalitis, a rare condition, has received increased attention in recent years along with the discovery of antibody biomarkers that can indicate the condition.
“Neurologists should be aware of the potential for autoimmune encephalitis misdiagnoses and consider a broad differential diagnosis including common disorders when evaluating suspected cases,” the study authors wrote.
Lead author Eoin Flanagan, MD, professor of neurology at Mayo Clinic in Rochester, MN, said the findings suggest that “clinicians need to use their clinical acumen” when assessing a patient with possible signs of autoimmune encephalitis and not rely only on serum antibody test results, which sometimes lead to misleading results.
Misdiagnoses can have serious consequences for patients since taking immunosuppressants does have risks, he said. At the same time, delaying treatment for a correct diagnosis, such as a brain tumor, can be detrimental.
“You might end up treating a glioma later rather than earlier,” Dr. Flanagan said.
Autoimmune encephalitis is a broad diagnosis that includes a group of immune-mediated brain diseases frequently associated with antibodies against neuronal or glial proteins, according to an editorial that accompanied the paper. Possible signs include rapidly deteriorating memory, psychosis, altered mental status, involuntary movements, and seizures, though such symptoms can indicate other neurologic or psychiatric conditions.
The medical literature has focused on cases in which autoimmune encephalitis was missed but said there are little data on misdiagnosed cases.
“The increased awareness of autoimmune encephalitis and discovery of novel autoantibody diagnostic biomarkers is a success story in neurology, but this study serves as a reminder about the potential for misdiagnosis of autoimmune encephalitis and to watch out for red flags that may suggest alternative diagnoses,” Dr. Flanagan said.
The study drew on a series of 363 patients with an autoimmune encephalitis diagnosis referred to one of six subspecialty centers—Mayo Clinic; University of Oxford; University of Texas Southwestern; University of California, San Francisco; Washington University, St. Louis; and University of Utah—between Jan. 1, 2014, and Dec. 31, 2020.
Of that patient pool, 286 patients were excluded from the analysis because they had true autoimmune encephalitis. The remaining 107 (more than one in four of the total pool) had been misdiagnosed and met the criteria for inclusion in the study: they were adults 18 or older with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis made at an in-person visit at one of the six centers.
The researchers collected data on clinical features, testing results, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions. The average age of the patients was 48, and 61 percent were female.
Of the 107 misdiagnosed patients, 77 (72 percent) did not fulfill basic diagnostic criteria for autoimmune encephalitis, including whether the symptoms had progressed rapidly (less than three months) or whether there were signs of brain inflammation on imaging.
Twenty-five percent were correctly diagnosed with functional neurologic disorder, 20.5 percent with neurodegenerative disease, 18 percent with primary psychiatric disease, 10 percent with cognitive deficits from comorbidities, 9.5 percent with cerebral neoplasm, and 17 percent with other conditions.
“An insidious rather than subacute onset and lack of magnetic resonance imaging or cerebrospinal fluid findings suggestive of inflammation were clues to misdiagnosis,” the researchers reported. Also, “overinterpretation of nonspecific antibodies was a major contributor to misdiagnosis.”
Many patients experienced a delay of more than a year to a correct diagnosis, and one in five experienced adverse reactions to unnecessary treatment with therapies such as corticosteroids, intravenous immunoglobulin, plasma exchange, and rituximab. Adverse reactions included steroid-related psychosis or agitation, aseptic meningitis, confusion, and headache.
The paper included a list of “red flags” clinicians should look for when considering a possible diagnosis of autoimmune encephalitis with the points divided into four categories: clinical, MRI of the head, cerebrospinal fluid (CSF), and serology.
“With neural antibody biomarkers, the diagnostic accuracy varies by pretest probability, sample assessed (serum or CSF), antibody type, assay methodology, and antibody titer,” the study said.
Some antibodies used to diagnose autoimmune encephalitis are found in the general population. For instance, “thyroid peroxidase antibodies occur in 13 percent of people [overall] and 20 percent [of people] older than 60 years, which drastically reduces their diagnostic utility in autoimmune encephalitis,” the authors wrote.
Among misdiagnosed cases, the researchers also found that “low-end titer serum GAD65 antibody positives were often overinterpreted as supporting autoimmune encephalitis but occur in 8 percent of the population (particularly individuals with diabetes), and only high titer ... serum positives or CSF detection are neurologically relevant.”
In the accompanying editorial, coauthor Josep Dalmau, MD, PhD, a neurologist at Hospital Clinic at the University of Barcelona in Spain and an adjunct professor of neurology at the University of Pennsylvania, said “the high frequency of missed diagnoses comes as no surprise,” adding that the problem likely is underestimated in the study because of its design limitations.
Dr. Dalmau helped write a clinical algorithm for the diagnosis of autoimmune encephalitis published in the Lancet in 2016 and noted that if doctors followed it, misdiagnoses would go down.
The three minimal requirements for a possible diagnosis of autoimmune encephalitis are rapid progression—less than or equal to three months—of memory deficits, altered mental status, or psychiatric symptoms; one or more of the indicated features (new focal central nervous system deficits, unexplained seizures, CSF pleocytosis, or MRI findings suggesting encephalitis); and exclusion of a specific list of alternative disorders.
“This exclusion step is extremely important though rarely well implemented,” the editorial said. Clinicians should “favor clinical reasoning over antibody results,” it said, but in the context of a suspected neuronal antibody-associated encephalitis, they should pick CSF over serum testing if they have to choose.
“In my opinion, the fields of autoimmune neurology and immune psychiatry are driven by antibody testing (frequently using serum only) rather than by clinical judgment; this is an important source of misdiagnoses and will be very difficult to correct,” Dr. Dalmau told Neurology Today.
Complex to Sort Out
Hesham Abboud, MD, PhD, associate professor of neurology at Case Western Reserve University School of Medicine, said autoimmune encephalitis is “actually one of the toughest diagnoses in neuroimmunology.”
“It is a relatively new entity (diagnosis), and it became better recognized after the recognition of the NMDA receptor antibody in 2007” by Dr. Dalmau, said Dr. Abboud, director of the multiple sclerosis and neuroimmunology program at University Hospitals of Cleveland Medical Center.
In 2021, Dr. Abboud and colleagues published two-part “best practice recommendations” on the diagnosis and management of autoimmune encephalitis in the Journal of Neurology, Neurosurgery, and Psychiatry.
He said many clinicians are unfamiliar with the complexities of diagnosing autoimmune encephalitis, which can lead to both misdiagnoses and missed diagnoses. If he suspects autoimmune encephalitis after taking a patient history and a clinical exam, he would start with a brain MRI followed by a spinal tap to look for evidence of inflammation in general.
Even then, “you have to consider competing diagnoses,” Dr. Abboud said. He includes the possibility of other inflammatory diseases and certain types of cancer, like lymphoma, on that list.
“Even after diagnosing autoimmune encephalitis, the clinician must identify possible triggers, like viral infections, iatrogenic causes, and the presence of underlying cancer somewhere else in the body,” he said. The latter refers to patients with “paraneoplastic autoimmune encephalitis” in which the immune system can attack the brain while trying to detect the cancer.
“While trying to rule things in, you have to rule things out,” Dr. Abboud said.
Michael Lane, MD, a neurohospitalist at Oregon Health and Science University, said there should be a rationale for ordering antibody testing.
“We really need to rely on the diagnostic criteria and not order these tests willy-nilly,” Dr. Lane said, adding that it can be both a relief and a struggle for patients to learn they were misdiagnosed with autoimmune encephalitis.
“It can be challenging to remove that diagnosis if you've come to identify with it,” he said.
John Probasco, MD, FAAN, professor of neurology and co-director of the Encephalitis Center at Johns Hopkins University, said there is still a lot to be learned about diagnosing and managing autoimmune encephalitis, particularly when it comes to interpreting the significance of antibodies associated with the condition.
“One cannot assume that everyone with autoimmune encephalitis is going to have a detectable antibody level, nor that a detected antibody means someone has autoimmune encephalitis,” he said. “Our experience has been that roughly half of patients who meet consensus criteria for possible autoimmune encephalitis are negative on commercial antibody testing. Also, in this study, nearly half of the patients who did not have autoimmune encephalitis were antibody positive.”
“Though it is a difficult diagnosis to make, it is an important one,” he said. If left untreated for long, autoimmune encephalitis can cause irreversible brain damage.
Dr. Probasco said it is not clear how long patients should be placed on immunosuppressants for autoimmune encephalitis and the role of follow-up antibody testing for specific syndromes.
The new study is a good reminder, however, that making a correct diagnosis is very doable, he added.
“We just need to take a step back and consider that the diagnostic criteria are helpful right off the bat,” he said.
Dr. Flanagan has served on advisory boards for Alexion, Genentech, UCB, and Horizon Therapeutics outside the submitted work and has a patent for DACH1-IgG as a biomarker of paraneoplastic autoimmunity pending. Dr. Abboud has received consulting fees and speaking honoraria from Biogen, Genentech, BMS, Horizon, and Alexion. He received research support (paid to institution) from Genentech, BMS, Novartis, and Sanofi. Dr. Dalmau reported grants from Euroimmun and SAGE outside of the submitted work; in addition, Dr. Dalmau had a patent for antibody testing with royalties paid from Euroimmun. Dr. Lane had no disclosures.