Nicotinic ganglionic acetylcholine receptor autoantibodies associated with paraneoplastic disease in a neuropsychiatric patient

Nicotinic ganglionic acetylcholine receptor autoantibodies (alpha-3-AChR Ab) are associated with paraneoplastic syndromes when present in low elevations. These antibodies can be tested for as part of an autoimmune encephalopathy panel in neuropsychiatric patients; a mildly elevated titre of alpha-3-AChR Ab that may start as an incidental finding can lead to the diagnosis of a previously undetected cancer. While alpha-3-AChR Ab are most typically associated with thymomas and small cell lung cancer, the presence of these antibodies can suggest a diverse range of other cancers. This case presents a patient with longstanding neuropsychiatric symptoms and possible functional hypothyroidism for whom a low elevation in alpha-3-AChR Ab led to the finding of papillary thyroid carcinoma.

Brain dysfunction and thyroid antibodies: autoimmune diagnosis and misdiagnosis

Hashimoto encephalopathy, also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis, has been defined by subacute onset encephalopathy, with elevated thyroid antibodies, and immunotherapy responsiveness, in the absence of specific neural autoantibodies. We aimed to retrospectively review cases referred with suspected Hashimoto encephalopathy over a 13 year period, and to determine the clinical utility of thyroid antibodies in the course of evaluation of those patients. One hundred and forty-four patients (all thyroid antibody positive) were included; 72% were women. Median age of symptom onset was 44.5 years (range, 10-87). After Mayo Clinic evaluation, 39 patients (27%) were diagnosed with an autoimmune CNS disorder (autoimmune encephalopathy [36], dementia [2] or epilepsy [1]). Three of those 39 patients had neural-IgGs detected (high glutamic acid decarboxylase-65, AMPA-receptor and neural-restricted unclassified antibody), and 36 were seronegative. Diagnoses among the remaining 105 patients (73%) were functional neurological disorder (n = 20), neurodegenerative disorder (n = 18), subjective cognitive complaints (n = 14), chronic pain syndrome (n = 12), primary psychiatric (n = 11), sleep disorder (n = 10), genetic/developmental (n = 8), non-autoimmune seizure disorders (n = 2), and other (n = 10). More patients with autoimmune CNS disorders presented with subacute symptom onset (p < 0.001), seizures (p = 0.008), stroke-like episodes (p = 0.007), aphasia (p = 0.04) and ataxia (p = 0.02), and had a prior autoimmune history (p = 0.04). Abnormal brain MRI (p = 0.003), abnormal EEG (p = 0.007), CSF inflammatory findings (p = 0.002) were also more frequent in the autoimmune CNS patients. Patients with an alternative diagnosis had more depressive symptoms (p = 0.008), anxiety (p = 0.003), and chronic pain (p = 0.002). Thyoperoxidase antibody titer was not different between the groups (median 312.7 vs 259.4 IU/mL, p = 0.44, normal range <9 IU/mL). None of the non-autoimmune group and all but three of the CNS autoimmune group (two with insidious dementia presentation, one with seizures only) fulfilled the autoimmune encephalopathy criteria proposed by Graus et al (sensitivity 92%, specificity 100%). Among patients who received an immunotherapy trial at our institution and had objective post-treatment evaluations, the 16 responders with autoimmune CNS disorders more frequently had inflammatory CSF, compared to 12 non-responders, all eventually given an alternative diagnosis (p = 0.02). Seventy-three percent of patients referred with suspected Hashimoto encephalopathy had an alternative non-immune mediated diagnosis, and more than half had no evidence of a primary neurological disorder. Thyroid antibody prevalence is high in the general population, and does not support a diagnosis of autoimmune encephalopathy in the absence of objective neurological and CNS-specific immunological abnormalities. Thyroid antibody testing is of little value in the contemporary evaluation and diagnosis of autoimmune encephalopathies.

A Shared Diagnostic Stewardship Approach toward Improving Autoimmune Encephalopathy Send-out Testing Utilization

Background For many laboratories, autoimmune encephalopathy (AE) panels are send-out tests. These tests are expensive, and ordering patterns vary greatly. There is also a lack of consensus on which panel to order and poor understanding of the clinical utility of these panels. These challenges were presented to our newly formed, multidisciplinary, diagnostic stewardship committee (DSC). Through this collaboration, we developed an algorithm for ordering AE panels; combining diagnostic criteria with practice guidelines. Methods We analyzed test-ordering patterns in 2018 and calculated a true-positive rate based on clinical presentation and panel interpretation. An evidence-based approach was combined with input from the Department of Neurology to synthesize our algorithm. Efficacy of the algorithm (number of panels ordered, cost, and true positives) was assessed before and after implementation. Results In 2018, 77 AE-related panels were ordered, costing $137 510. The true-positive rate was 10%, although ordering multiple, similar panels for the same patient was common. Before implementing the algorithm (January 1–July 31, 2019), 55 panels were ordered, costing $105 120. The total true-positive rate was 3.6%. After implementation, 23 tests were ordered in a 5-month period, totaling $50 220. The true-positive rate was 13%. Conclusion With the DSC-directed mandate, we developed an algorithm for ordering AE panels. Comparison of pre- and postimplementation data showed a higher true-positive rate, indicating that our algorithm was able to successfully identify the at-risk population for AE disorders. This was met with a 43% decrease in the number of tests ordered, with total cost savings of $25 000 over 5 months.

A Shared Diagnostic Stewardship Approach to Autoimmune Encephalopathy Send-Out Testing

As part of our laboratory testing utilization at University of Louisville Hospital (ULH), any send-out test ≥$500 must be assessed by the clinical chemistry fellow or pathology resident for clinical necessity and as a way to provide consultation to the ordering physician on appropriate test utilization. In 2018, we noticed a prominent increase in the volume of panels for autoimmune encephalopathy (AE) and related disorders being ordered. This was met with considerable cost to the hospital, a lack of consensus on which panels should be ordered, and poor understanding of the clinical utility of these panels. These challenges presented an ideal project for our newly-formed diagnostic stewardship committee (DSC) at ULH. Through collaboration with the DSC, we were able to form a sub-committee with the Department of Neurology to develop an algorithm-based approach for ordering of these AE panels. Our goals were to improve diagnostic utility for the betterment of patient care, improve test utilization, and decrease cost associated with panel ordering. Prior to involvement of the DSC, we analyzed the number and cost of all AE panels ordered in 2018. We also calculated the number of positive panels and reviewed patient data to determine if a positive panel corresponded with a clinical outcome. After presenting our data to the DSC, an evidence-based approach was taken in collaboration with the Department of Neurology to develop an algorithm for AE test ordering. Results were analyzed for true positive rate, defined as a patient testing positive for an antibody with known etiology or association with AE based on result interpretation provided by Mayo Clinical Laboratories. The total cost of tests was also analyzed before implementation of the algorithm (January 1, 2019-July 31, 2019) and post-implementation (August 1, 2019-December 31, 2019). In 2018, 77 AE panels were ordered with an estimated charge to the laboratory of $137,510. The true positive rate was 10%. Based on these test ordering patterns, we projected that 120 tests would be ordered in 2019, totaling >$200,000. Prior to the implementation of the algorithm in 2019, 55 tests were ordered, totaling $105,210. Total true positive rate was 3.6%. After implementation of the algorithm, 23 tests were ordered, totaling $50,220. The true positive rate was 13%. Using a shared diagnostic stewardship approach, we were able to develop an evidence-based algorithm for guiding physicians for AE panel ordering. Comparing test ordering patterns pre and post-implementation in 2019, our true positive rate more than tripled (3.6% to 13%), indicating that our algorithm was able to successfully identify the at-risk population for development of AE disorders. This was met with a >50% decrease in the number of tests ordered, and a total cost savings of $54,990 compared to the first half of 2019.