Ganglionic Antibody Level as a Predictor of Severity of Autonomic Failure

Abstract

Objective: To assess antibody level as a test of autonomic failure (AF) associated with ganglionic nicotinic acetylcholine receptor antibody (AChR-Ab) autoimmunity.

Patients and methods: We searched the Mayo Clinic laboratory database of 926 ganglionic AChR-Ab-seropositive patients seen at our institution between October 1, 1997, and April 1, 2015, for initial level of 0.05 nmol/L or higher and contemporaneous autonomic reflex screen (standardized evaluation of adrenergic, cardiovagal, and sudomotor functions) from which Composite Autonomic Scoring Scale (CASS) scores could be calculated.

Results: Of 289 patients who met inclusion criteria, 163 (56.4%) were women, median age was 54 years (range, 10-87 years), median antibody level was 0.11 nmol/L (range, 0.05-22.10 nmol/L), and median CASS total score was 2.0 (range, 0-10). Using receiver operating characteristic curve analysis, a level above 0.40 nmol/L predicted severe AF (CASS score, ≥7) with 92% specificity and 56% sensitivity. For at least moderate AF (CASS score ≥4 and anhidrosis ≥25%), a level of at least 0.20 nmol/L had 80% specificity and 59% sensitivity. Levels below 0.20 nmol/L were not predictive of the presence or absence of AF. For predicting orthostatic hypotension, ganglionic AChR-Ab level had excellent specificity above 0.4 nmol/L but lacked sensitivity. Autoantibodies to additional targets were present in 61 patients (21.1%).

Conclusion: Ganglionic AChR-Ab level of at least 0.40 nmol/L is a moderately sensitive and highly specific marker for severe AF, as is a level of at least 0.20 nmol/L for moderate AF if CASS score is coupled with anhidrosis of 25% or more, among patients with suspected ganglionic AChR-Ab autoimmune autonomic ganglionopathy. Antibody levels of less than 0.20 nmol/L have little clinical importance in the absence of clinical AF.

Figure 1:. Ganglionic AChR Ab level versus degree of autonomic failure as measured by Composite Autonomic Scoring Scale.

Higher CASS scores indicate more severe autonomic failure. Higher antibody levels were generally associated with more severe AF, but there were exceptions. Occasional high levels (>1.00 nmol/L) were seen in patients with no or only mild autonomic impairment, and several patients with severe AF had low levels (<0.20 nmol/L). Ganglionic AChR Ab indicates antibodies to α3 subunit of nicotinic ganglionic acetylcholine receptor; CASS, composite autonomic scoring scale.

Figure 2.. ROC curves for Ganglionic AChR Ab antibody level as test of (A) severe autonomic failure, (B) moderate autonomic failure, and (C) orthostatic hypotension.

Ganglionic AChR Ab level of 0.40 nmol/L predicted severe AF by CASS alone with 92% specificity and 56% sensitivity. Sensitivity was somewhat better with severe AF defined as the combination of CASS ≥7 and anhidrosis ≥50% (A). Antibody level poorly predicted moderate AF (B). Antibody level above 0.40 nmol/L predicted OH with excellent specificity (91%) but poor sensitivity (38%, C). Ganglionic AChR Ab indicates antibodies to α3 subunit of nicotinic ganglionic acetylcholine receptor; AUC, area under curve; CASS, composite autonomic scoring scale; ROC, receiver operator characteristic; TST, thermoregulatory sweat test.