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Nicotinic ganglionic acetylcholine receptor autoantibodies associated with paraneoplastic disease in a neuropsychiatric patient
  1. Catherine Stauffer1,2,
  2. Daniel A Llano3 and
  3. Suzanna Kitten4
  1. 1Carle Foundation Hospital, Urbana, Illinois, USA
  2. 2Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA
  3. 3Carle Neuroscience Institute, Carle Foundation Hospital, Urbana, Illinois, USA
  4. 4Psychiatry, Carle Foundation Hospital, Urbana, Illinois, USA
  1. Correspondence to Ms Catherine Stauffer; ces10{at}illinois.edu

Abstract

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.

  • mood disorders (including depression)
  • endocrine cancer
  • screening (oncology)
  • neuroendocrinology
  • anxiety disorders (including OCD and PTSD)

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Background

Nicotinic ganglionic acetylcholine receptor autoantibodies (alpha-3-AChR Ab) are well-documented to be associated with autoimmune dysautonomia, with a direct relationship between antibody titre and severity of dysautonomia occurring in both experimental animals and patients.1 2 Moderate to high elevations of alpha-3-AChR Ab (0.10–0.99 nmol/L and ≥1.00 nmol/L, respectively) are often found in patients with neurological autoimmunity and pandysautonomia. In fact, the alpha-3-AChR Ab is the most commonly detected marker of autoimmune dysautonomia, and one study found that alpha-3-AChR Ab levels above 0.40 nmol/L were moderately sensitive (56%) and highly specific (92%) for severe autonomic failure, with predictive value decreasing as antibody levels fell below 0.20 nmol/L and in the absence of clinical symptoms.3 4 What is less well understood is the relationship between low elevations of alpha-3-AChR Ab (0.03–0.09 nmol/L) and cancer. While alpha-3-AChR Ab has previously been associated with thymomas and small cell lung cancer, McKeon et al found an association with a diverse number of cancers, most notably adenocarcinomas.2 Patients with low titres may also exhibit more limited symptoms of dysautonomia that can manifest as mild autonomic, somatic or central nervous system dysfunction.2

There are few reports in the literature of elevated alpha-3-AChR Ab in conjunction with thyroid carcinoma, including papillary thyroid carcinoma.2 5 Papillary thyroid carcinoma is the most common type of thyroid cancer with an excellent prognosis if detected early.6 However, papillary thyroid carcinoma is often undetected due to lack of overt clinical symptoms.7 Although the exact mechanism has not been elucidated, the thyroid is known to play a role in neuropsychiatric symptoms as evidenced by the prevalence of depressive symptoms in patients with hypothyroidism.8 We present a case of a neuropsychiatric patient with a constellation of psychiatric, neurological and systemic symptoms who was found to have mild functional hypothyroidism and a low elevation of alpha-3-AChR Ab on an autoimmune encephalopathy panel and was subsequently diagnosed with papillary thyroid carcinoma. This case demonstrates a possible connection between thyroid dysfunction and neuropsychological symptomatology and the utility of the autoimmune panel in patients with otherwise unexplained symptoms.

Case presentation

A 68-year-old female patient was referred to psychiatry after continued anxiety and depression that was only minimally responsive to medications. At the initial presentation she reported multiple life stressors and was being seen for a long list of medical issues including migraines, vertigo, fatigue, obstructive sleep apnoea, insomnia, neuropathic pain and diarrhoea-predominant irritable bowel syndrome (IBS) with constipation between episodes (table 1). Review of systems was notable for heat intolerance and a 40 lb weight gain over 8 years. She endorsed psychiatric symptoms including sadness and anxiety, crying spells, anhedonia, guilt, concentration issues, irritability and fluctuating periods of ‘up and down’ moods. Seizures, fevers and altered consciousness were absent. A routine laboratory panel ruled out medical causes of depression and anxiety and the patient’s thyroid stimulating hormone (TSH) levels were in normal laboratory range.

Table 1

List of patient’s symptoms

At the time of the initial consultation, the patient was taking venlafaxine, gabapentin and sumatriptan for her psychological symptoms, neuropathic pain and migraines, respectively. She was tapered off venlafaxine and started on duloxetine. Lamotrigine was added for mixed depressive symptomatology which was detected during psychiatric evaluation. Nortriptyline was also tried for IBS and migraines. Quetiapine was added after the patient failed to achieve mood stabilisation on lamotrigine alone. At this time the patient was given a formal diagnosis of bipolar II disorder due to meeting full Diagnostic Statistical Manual 5 criteria for hypomania (specifically, distinct periods of irritability along with decreased need for sleep, distractibility, pressured speech, and perseverative thought process).9

On follow-up approximately 1 year later, the patient reported improvement in her migraines and sleep apnoea, with some improvement in her dizziness. While her mood had improved, she still experienced periods of anxiety, especially following continued life stressors. She also experienced constipation interspersed with bouts of diarrhoea and abdominal cramping and reported ongoing heat intolerance and overeating along with non-specific right eye ‘weakness’. Additionally, she had acquired a bilateral hand tremor and right arm rigidity (Abnormal Involuntary Movement Scale (AIMS) score: 2). Repeat labs showed an increased TSH of 3.56 (nL 0.358–3.740 mcIU/mL) which was higher than her baseline of 3.00 the year prior. Although the patient’s TSH continued to rise, it was found to be outside of normal laboratory limits on only one occasion (figure 1), and her T4 remained on the lower end of normal limits. Regardless, a referral was made to the patient’s primary care provider about starting levothyroxine which has been shown to be beneficial for patients with depression with TSH >2.5.8 However, the patient’s ongoing neurological and somewhat severe psychiatric symptoms prompted further investigation.

Figure 1

Graph of patient’s thyroid stimulating hormone (TSH) levels over a period of 30 months after the first encounter with the patient. Green dotted line shows a cut-off of 3.74 mcIU/mL, the laboratory upper limit of normal. Orange dashed line shows a cut-off of 2.50 mcIU/mL, the recommended upper bound for patients with depression.

Investigations

As indicated by the patient’s constellation of neurological, psychiatric and systemic symptoms, an autoimmune encephalopathy panel was ordered through Mayo Medical Laboratories, Rochester, Minnesota. This panel is useful in the investigation of possible encephalopathy manifesting with symptoms as varied as confusion, psychosis, movement disorders, dyssomnias and gastrointestinal complaints. The serum autoimmune encephalopathy panel was normal except for slightly elevated ganglionic acetylcholine receptor neuronal antibodies (table 2). The patient’s alpha-3-AChR Ab were 0.04 nmol/L (nL ≤0.02). This result was concerning for a possible underlying carcinoma, since low elevations of single antibodies are more associated with paraneoplastic syndromes than autoimmune dysautonomia.2 10 The patient was sent for repeat testing 1 month later, and her alpha-3-AChR Ab had increased to 0.07 nmol/L. At the time of evaluation, the testing laboratory reported that low levels of alpha-2-AChR Ab have a positive predictive value of 46% for an autoimmune neurological diagnosis, and a positive predictive value of 30% for a cancer diagnosis.11 The patient was referred to haematology and oncology for evaluation. Table 2 includes the methodology used by the laboratory.11

Table 2

Results of autoimmune encephalopathy panel

Differential diagnosis

With the patient’s mildly elevated alpha-3-AChR Ab on autoimmune encephalopathy panel, the investigations shifted to determining if she had an underlying carcinoma (figure 2). While she had no history of cancer, nor of risk factors like smoking or radiation exposure, she did have a history of benign adenomatous colonic polyps and was overdue for a mammogram. With both colon and breast cancer high on the differential, a colonoscopy and mammography were performed; both tests were negative. An oncological blood panel was unremarkable; serum protein electrophoresis did not reveal any monoclonal peak and the kappa/lambda free light chain ratio was normal.

Figure 2

Decision tree for working through patient’s diagnosis. Solid blue rectangle, symptoms and past medical history; orange oval, labs; green hexagon, test results; rounded red rectangle, differential diagnoses. TSH, thyroid stimulating hormone; PET, positron emission tomography; FNA, fine needle aspiration; US, ultrasound.

At this point, the patient’s history of rising TSH along with fatigue, weight gain and heat intolerance was recalled and the possibility of thyroid cancer suggested. She had no history of palpable thyroid nodule and denied neck pressure, dysphagia, breathing problems and hoarseness; nevertheless, a referral was made for a thyroid ultrasound. The ultrasound showed a 10 mm irregular nodule in the left lobe of the thyroid along with a small right thyroid nodule; the left thyroid nodule was subsequently biopsied via fine needle aspiration. Biopsy revealed a stage 1 follicular variant papillary carcinoma involving the left lobe and isthmus and anterior margin. A CT scan with contrast of the chest, abdomen and pelvis was negative, and a positron emission tomography (PET) scan/CT from skull base to upper thigh showed no abnormalities, suggesting the cancer was limited to the thyroid gland.

Treatment

After consulting with endocrinology and oncology the patient decided on surgical intervention. She underwent a total thyroidectomy that confirmed the diagnosis of follicular variant papillary carcinoma in the left lobe and showed classic type papillary microcarcinoma in the right lobe. The patient remained on levothyroxine postoperatively and her thyroid levels stabilised. She continued to follow with endocrinology to monitor response to the levothyroxine and with psychiatry to manage her depression, anxiety and mood fluctuations. Had there been symptoms of autoimmune encephalitis, which has been associated with positive alpha-3-AChR Ab, steroids and immunotherapy would have been considered as treatment options. However, in this case, thyroidectomy and stabilisation of thyroid hormone were sufficient without immunosuppression.12

Outcome and follow-up

The patient did well overall following her thyroidectomy. Her IBS became controlled, with regular bowel movements and significant symptoms only a few times per year. Her severe insomnia also improved and she was instructed to follow-up with sleep medicine for her remaining sleep difficulties secondary to obstructive sleep apnoea. Her tremor resolved and her dizziness became less severe. She continued to experience some anxiety and depression, especially in association with life stressors, but overall her mood stabilised and she reported satisfaction with her medication regimen.

Discussion

Nicotinic ganglionic acetylcholine receptor autoantibodies are most commonly associated with autoimmune dysautonomia where symptom severity is positively correlated with the magnitude of the antibody titre. However, studies have shown that in some cases, especially for patients with mildly elevated titres, alpha-3-AChR Ab markers can be secondary to neoplasms. Most studies have examined the association between alpha-3-AChR Ab and thymomas and small cell lung carcinomas, but a growing body of evidence suggests that these antibodies are associated with a diverse range of cancers. The clinical utility of alpha-3-AChR Ab is not well established due to the highly varied presentations of autoimmune dysautonomia, neurologic autoimmunity, and paraneoplastic syndromes. However, Tebo et al argue for further examination of the utility of autoantibody screening in patients with poorly defined symptoms and specific risk factors for paraneoplastic syndromes.13 The fact that alpha-3-AChR Ab has a positive predictive value of 30% for a cancer diagnosis warrants further investigation in patients with a positive titre.2

Although the elevations of serum alpha-3-AChR Ab could be a marker for other forms of seronegative encephalitis, we think that this is unlikely. Most forms of autoimmune encephalitis have detectable serum antibodies.10 Those cases with only cerebrospinal fluid antibodies are marked by fever, alterations in consciousness and seizures, none of which were observed in this case.14 There were also no imaging findings on subsequent MRI brain, which are often observed in autoimmune encephalitis. Therefore, although cerebrospinal fluid (CSF) was not obtained and autoimmune encephalitis cannot be ruled out definitively, the absence of clinical or imaging criteria for this diagnosis make it unlikely.

This case report emphasises a potential role for alpha-3-AChR Ab titres as a diagnostic tool in the setting of neurological symptoms superimposed on psychiatric symptoms. In this case, increased alpha-3-AChR Ab levels may have provided a medical explanation for symptoms that first appeared unrelated and which were only minimally responsive to medical therapy. While it is difficult to determine with any certainty, it is possible that some of the patient’s symptoms may have been the manifestation of a mild dysautonomia; some symptoms could also have been the result of her functional hypothyroidism as indicated by elevated TSH. The positive alpha-3-AChR Ab led to a diagnosis of papillary thyroid carcinoma that was previously undetected and caught in time to administer successful treatment. This case supports the screening value of alpha-3-AChR Ab in identifying paraneoplastic syndromes; however, additional studies are needed to examine the relationship between alpha-3-AChR Ab and various cancer types beyond thymomas and small cell lung cancers, especially in adenocarcinomas like papillary thyroid cancer. Nevertheless, an autoimmune encephalopathy panel appears to be useful in the assessment and management of complicated neuropsychological diseases.

Patient’s perspective

Going through this process was a really long haul. I was sent for bloodwork, then something showed up in the bloodwork, and then it was recommended I get all these follow-up tests. It took about 2 months to go through all the tests, and I was especially worried to get the colonoscopy and mammogram because I have a family history of colon and breast cancer. My most anxious point was probably the first time I went to meet with the oncologist. But then when I found out all these tests came back negative, there was a feeling of relief. By the time I went to get the thyroid ultrasound and found out that I had thyroid cancer, I was able to get it removed really quickly and they caught it very early. I was thankful that it was a simple surgery and that everything has looked good since then.

I surprised myself, but I remember feeling pretty calm throughout most of my testing and procedures. Maybe I kept my feelings suppressed, but I come from a very resilient family and I think that I was preparing for the worst, so when I found out that I had a very treatable cancer, I was thankful. For most of my life I have just figured I would get cancer as almost everyone in my family has cancer. My husband and son were very supportive. I also liked my surgeon and everybody on the team was great. I do wish that the process was more streamlined and didn’t take so long to get all of the testing done, but I think if anyone else was in my shoes they should be optimistic because thyroid cancer is usually quite treatable, especially if it is caught early like mine was.

Learning points

  • Diagnostic panels such as the autoimmune encephalopathy panel may play an important role in the management of patients with complex and treatment-resistant neuropsychiatric disease.

  • Nicotinic ganglionic acetylcholine receptor autoantibodies have a significant association with underlying carcinoma, and low elevations in these antibodies should be further explored for their association with a diverse range of cancers, including thyroid carcinoma.

  • Thyroid stimulating hormone (TSH) levels should be routinely monitored in patients with depression, especially when depression is coupled with other signs and symptoms suggestive of hypothyroidism, and stabilisation of thyroid hormone levels should be a treatment goal for psychiatric patients.

References

Footnotes

  • Contributors CS completed a chart review and prepared the manuscript draft. SK treated the patient, proposed the case review, lent medical expertise and contributed to drafting and revising the manuscript. DAL was involved in patient care and advised on neurological aspects of the case as well as contributed to the writing and editing of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.