Carolinas Research Day 2021

Autoimmune Encephalopathy Dr. Michaeleena Carr, DO, Joseph Filek, OMS IV. Edward Via College of Osteopathic Medicine – Carolinas Campus, Spartanburg, SC.

CBR-13

Diagnosis

Discussion

Case Summary

References Treatment • Prioritize ruling out any other causes of encephalitis and underlying malignancies by testing for pertinent autoantibodies. • First-line immunotherapies, such as IVIG, plasmapheresis (PLEX), or steroids may be given empirically. 4 • If first-line immunotherapies prove to be ineffective, second-line treatment, such as rituximab or cyclophosphamide may be considered. 1, 2 • Patients who have had a malignancy found, need to have the tumor removed. If tumor screening was initially negative, it is important to continue screening the patient for more than 5 years. 1 Prognosis • Earlier diagnosis and treatment lead to a better prognosis. 8 • Autoimmune encephalopathy overall has been shown to be associated with a higher rate of relapse and malignancy than infectious encephalopathy. 9 • Classification of autoimmune encephalopathy determines prognosis: Intracellular Antigens • Poor Prognosis • Associated with cancer • Irreversible 4, 8 Extracellular Antigens • Better Prognosis • Less associated with cancer • Reversible 4, 8 Conclusion Autoimmune encephalopathy is an important diagnostic consideration in patients presenting with a new, subacute onset of altered mental status. Regarding this patient’s results, antibody test on both blood and CSF were unrevealing. This patient did improve with methylprednisolone therapy, noted to be more appropriately conversant and interactive at discharge. She did have multiple subsequent admissions with a simar presentation and improvement with steroids. The patient was also found to have low thiamine levels which can contribute to neuropsychiatric symptoms and was replenished. She was to be followed by neurology and psychiatry as an outpatient. The research on this topic reveals that it may also be beneficial for her to continue a new first-line immunotherapy regimen and continue to be screened for cancer for at least 5 years from the diagnosis. Although great strides are being made in the field of autoimmune encephalitis, there is still much to be discovered. Research on intra- and extracellular antibody groups and their correlations to each other and specific malignancies would be of particular benefit in caring for these patients. Earlier diagnosis leads to sooner implementation of specific therapy and an improved patient prognosis. 1. Graus, Francesc, et al. “A Clinical Approach to Diagnosis of Autoimmune Encephalitis.” The Lancet. Neurology, U.S. National Library of Medicine, Apr. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5066574/. 2. Shin YW;Lee ST;Park KI;Jung KH;Jung KY;Lee SK;Chu K; “Treatment Strategies for Autoimmune Encephalitis.” Therapeutic Advances in Neurological Disorders, U.S. National Library of Medicine, 2017, pubmed.ncbi.nlm.nih.gov/29399043?dopt=Abstract. 3. Oldham, Mark. “Autoimmune Encephalopathy for Psychiatrists: When to Suspect Autoimmunity and What to Do Next.” Psychosomatics, vol. 58, no. 3, 2017, pp. 228–244., doi:10.1016/j.psym.2017.02.014. 4. Lancaster, Eric. “The Diagnosis and Treatment of Autoimmune Encephalitis.” Journal of Clinical Neurology (Seoul, Korea), Korean Neurological Association, Jan. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC4712273/. 5. “Autoimmune Encephalitis.” Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, rarediseases.info.nih.gov/diseases/11979/autoimmune-encephalitis. 6. Kamei, S. “Autoimmune Encephalopathy.” Journal of the Neurological Sciences, vol. 381, 2017, pp. 19–20., doi:10.1016/j.jns.2017.08.090. 7. Mayo Clinic Laboratories, 2020, www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/92116. 8. Kelley, B.P., et al. “Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis.” American Journal of Neuroradiology, American Journal of Neuroradiology, 1 June 2017, www.ajnr.org/content/38/6/1070. 9. SJ;, Tobin WO;Pittock. “Autoimmune Neurology of the Central Nervous System.” Continuum (Minneapolis, Minn.), U.S. National Library of Medicine, 2017, pubmed.ncbi.nlm.nih.gov/28570322?dopt=Abstract. 10. Ariño H;Armangué T;Petit-Pedrol M;Sabater L;Martinez-Hernandez E;Hara M;Lancaster E;Saiz A;Dalmau J;Graus F; “Anti-LGI1-Associated Cognitive Impairment: Presentation and Long-Term Outcome.” Neurology, U.S. National Library of Medicine, 2016, pubmed.ncbi.nlm.nih.gov/27466467?dopt=Abstract. 11. van Sonderen A;Petit-Pedrol M;Dalmau J;Titulaer MJ; “The Value of LGI1, Caspr2 and Voltage-Gated Potassium Channel Antibodies in Encephalitis.” Nature Reviews. Neurology, U.S. National Library of Medicine, 2017, pubmed.ncbi.nlm.nih.gov/28418022?dopt=Abstract. 12. Dubey, Divyanshu, et al. “The Incidence and Prevalence of Autoimmune Encephalitis and a Comparison to Infectious Encephalitis: A Population-Based Study (P5.401).” Neurology, Wolters Kluwer Health, Inc. on Behalf of the American Academy of Neurology, 10 Apr. 2018, n.neurology.org/content/90/15_Supplement/P5.401. 13. Dogan L;Kaya D;Sarikaya T;Zengin R;Dincer A;Akinci IO;Afsar N; “Plasmapheresis Treatment in COVID-19-Related Autoimmune Meningoencephalitis: Case Series.” Brain, Behavior, and Immunity, U.S. National Library of Medicine, 2020, pubmed.ncbi.nlm.nih.gov/32389697. 14. Peery HE;Day GS;Dunn S;Fritzler MJ;Prüss H;De Souza C;Doja A;Mossman K;Resch L;Xia C;Sakic B;Belbeck L;Foster WG; “Anti-NMDA Receptor Encephalitis. The Disorder, the Diagnosis and the Immunobiology.” Autoimmunity Reviews, U.S. National Library of Medicine, 2012, pubmed.ncbi.nlm.nih.gov/22440397?dopt=Abstract. 15. Gaillard, F. (n.d.). Paraneoplastic limbic encephalitis: Radiology case. Retrieved March 04, 2021, from https://radiopaedia.org/cases/paraneoplastic-limbic-encephalitis?lang=us 16. Dixon, A. (n.d.). Limbic encephalitis - small cell lung cancer: Radiology case. Retrieved March 04, 2021, from https://radiopaedia.org/cases/limbic-encephalitis-small-cell-lung-cancer?lang=us

A 42-year-old Caucasian female presented to the emergency department on several occasions for abnormal behavior. On the patient’s first visit, she was brought to the emergency department by EMS for bizarre behavior. She was described as very combative when touched and noncooperative to commands. EMS reported that the patient was in her home naked reading the Bible and claiming to be able to communicate with the dead. Patient’s fiancé reported that she had been acting odd for the past 2 weeks. She had experienced psychological trauma from her daughter passing away in a motor vehicle accident, as well as from her son with a traumatic brain injury caused by a car accident. Her fiancé also reported a history of cocaine and “pill” use, but none recently. On a subsequent ED visit, the patient was brought in by her fiancé who stated that her behavior was becoming more bizarre. Patient was again unable to provide any meaningful history. She was placed in the psychiatric holding unit where she experienced aggressive outbursts, hyperreligiosity, delusions, and hallucinations. Her initial diagnoses were anemia and bipolar disorder. However, after continued lack of improvement, the patient was admitted to medical service for further work up and evaluation. Extensive evaluation with CT Head, MRI Brain, numerous laboratory evaluations on blood and CSF, revealed positivity for Sjogren antibodies and antinuclear antibodies, suggesting a diagnosis of autoimmune encephalitis. • Autoimmune encephalopathy is a rare autoimmune disorder • Incidence rate of 0.8/100,000 people • Patient’s own immune system attacks brain cells, leading to inflammation • Associated conditions: herpes simplex virus (HSV), systemic lupus erythematosus (SLE), Sjogren syndrome, and Behcet syndrome 4 • Subtypes (each with own predilection for certain population subtypes) • Antibodies to intracellular antigens – paraneoplastic association (for example Anti- HU(anti-neuronal nuclear antibody 1) 3, 4, 8 • Antibodies to extracellular antigens (for example Anti-NMDAR (N-methyl-D-aspartate receptor) 3, 4, 8 • Each of these antigens serve vastly different roles within the central nervous system • Pathophysiology can be quite different depending on the autoantibodies involved • Example: anti-AMPAR and anti-LGI1: antigens vital in maintaining fast excitatory neuronal transmission  long-term plasticity within the hippocampus. 11 • Hippocampal dysfunction can eventually lead to short and long-term memory deficits as well as issues in temporarily storing and manipulating information. 1 • Of note, this patient was negative anti-NMDAR during the CSF autoimmune encephalitis panel Pathophysiology

Diagnostic Labs and Imaging • Antibody panels – many times send away to specialty labs, adds time to diagnosis • CSF studies, including HSV (important in differential) • Thiamine • Heavy metal testing • RPE/Treponema antibody • MRI – normal MRI does not exclude this diagnosis 15 • Findings present in about ½ individuals with autoimmune encephalitis • Old term “limbic encephalitis”  mesial temporal lobe and limbic system • Cortical thickening and increased T2/Flair signal intensity • Bilateral the most common findings, although asymmetric • Note: HSV encephalitis usually spares basal ganglia • True diffusion restriction and hemorrhage are NOT common  suggests other diagnosis • PET-CT – may show increased FDG update

The hippocampal head and the medulla, and to a lesser degree, hippocampal body on the right demonstrate increased T2 signal and appear bulkier than the counterpart on the left. 15

Markedly FDG avid abnormality within the left mesial temporal lobe corresponding to the MRI abnormality. 16

Differential Diagnoses 1, 3, 4 • HSV encephalitis – more acute, associated fever • Acute disseminated encephalomyelitis (ADEM) • CNS infections • Septic encephalopathy • Metabolic encephalopathy • Drug toxicity • Cerebrovascular disease • Neoplastic disorders • Creutzfeldt-Jakob disease

• Wernicke encephalopathy • Epileptic disorders • Vasculitis • Rheumatologic disorders (e.g., lupus, sarcoidosis, other) • Kleine-Levin, mitochondrial diseases • Heavy metal poisoning

• Wilson's disease • Multiple sclerosis

• Bickerstaff encephalitis • Miller Fisher syndrome.

Signs and Symptoms

Diagnostic Criteria 5, 6 • Subacute onset (<3 months) of memory deficits, altered mental status, or psychiatric symptoms • New focal CNS finding, seizures, CSF pleocytosis, or MRI features need to be present • All other differential diagnoses need to be excluded. 5, 6

• Subacute deficit in memory • Subacute deficit in cognition • Psychosis • Seizures

• Altered mental status • Psychiatric symptoms

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