Need for combined therapy for a rare case of autoimmune autonomic ganglionopathy: A case report

Abstract

BACKGROUND

Autoimmune autonomic ganglionopathy (AAG), formerly known as acute pandysautonomia, is a rare, acquired, antibody-mediated, potentially curable autonomic disorder that presents with diffuse autonomic failure. High levels of anti-ganglionic nicotinic acetylcholine receptor (gAChR) serum antibodies are detected in approximately 50% of AAG cases, confirming the diagnosis.

CASE SUMMARY

We present the case of a 68-year-old man who developed autonomic failure gradually over a 2-year period. Recently, the patient was unable to stand upright for more than a few seconds before fainting. Additionally, he presented with decreased sweating, dry mouth, urinary retention, early satiety, weight loss, bloating, constipation, and erectile dysfunction. Neurological examination revealed dilated pupils that were unresponsive to light. Deep tendon reflexes were absent or diminished. Serologic evaluation revealed the presence of gAChR autoantibodies. An orthostatic hypotension test yielded a positive result. The patient did not respond to symptomatic therapy, including midodrine, fludrocortisone and atomoxetine. Second-line therapy with immunoadsorption produced a noticeable clinical improvement; however, orthostatic hypotension persisted. Sequential rituximab infusion therapy successfully led to a significant improvement in symptoms.

CONCLUSION

Our case report supports the benefit of combined immunomodulatory therapy for refractory AAG cases that are unresponsive to single-agent treatment.

Key Words: Autoimmune autonomic ganglionopathy; Immunoadsorption; Combined immunomodulatory therapy; Refractory autoimmune symptoms; Rituximab; Case report

Core Tip: This case highlights the potential benefit of combined immunoadsorption and rituximab therapy in refractory autoimmune autonomic ganglionopathy. Despite first-line therapy failure, the patient achieved significant long-term improvement, suggesting that a stepwise immunomodulatory approach may be necessary in resistant cases.

INTRODUCTION

Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure, first described by Young et al[1] in 1969. It is defined by the presence of ganglionic nicotinic acetylcholine receptor (gAChR) antibodies, which are implicated in approximately half of all cases[2]. These receptors, composed of two α3 and three β4 subunits, mediate fast synaptic transmission across the sympathetic, parasympathetic, and enteric autonomic ganglia, with AAG-associated antibodies specifically targeting the α3 subunit[2]. The severity of autonomic dysfunction correlates with serum gAChR antibody titers; however, these titers do not reliably predict whether the disease will manifest acutely, subacutely, or chronically[3]. The pathological mechanisms involve functional receptor blockade, receptor internalization, and complement-mediated neuronal damage, leading to severe dysautonomia[3]. In some cases, T-cell-mediated autoimmunity and neuronal inflammation may also contribute to disease progression[3].

Clinically, AAG is characterized by widespread autonomic failure, affecting multiple organ systems. Patients typically present with severe orthostatic hypotension, recurrent syncope, anhidrosis, sicca syndrome (xerostomia and reduced lacrimation), neurogenic bladder, and gastrointestinal dysmotility, including gastroparesis and severe constipation[4]. Additionally, pupillary abnormalities, such as tonic or poorly reactive pupils, are commonly observed[4]. The disease predominantly affects middle-aged individuals (mean age 45-61 years), with a female predominance[4]. While idiopathic in most cases, AAG can also arise as a paraneoplastic syndrome or in association with autoimmune conditions such as Sjögren’s syndrome or systemic lupus erythematosus[5].

We present a case of AAG with severe autonomic dysfunction, including profound orthostatic hypotension, neurogenic bladder, and gastrointestinal dysmotility, that was refractory to standard symptomatic first-line therapies. Despite limited improvement with immunoadsorption alone, the patient exhibited substantial clinical recovery following the introduction of rituximab alongside pyridostigmine. This case highlights the potential role of combined immunotherapy in refractory AAG and suggests a possible advantage of immunoadsorption over plasma exchange (PE) in select cases.

CASE PRESENTATION

Chief complaints

A 68-year old man presented to the Emergency Department of Internal Medicine, Hippokration University Hospital (Thessaloniki, Greece), with a 2-year history of progressively worsening orthostatic syncope. Recently, he was unable to stand upright for more than a few seconds before experiencing a syncopal episode. He also reported autonomic dysfunction symptoms, including decreased sweating, sicca syndrome, urinary retention, erectile dysfunction, early satiety, abdominal distention, and severe constipation that resulted in weight loss.

History of present illness

The patient reported a 2-year history of progressively worsening orthostatic syncope.

History of past illness

No preceding acute illness, including diabetes mellitus, Guillain Barré, or amyloidosis, nor identifiable cause had been found in a previous workup.

Personal and family history

The patient had no significant past medical history. He was an active smoker. His father had a history of arterial hypertension, and his mother had diabetes mellitus.

Physical examination

On physical examination, he weighed 60 kg (with a body-mass index, defined as the weight in kilograms divided by the square of the height in meters, of 19.6) and had warm, dry skin. His supine blood pressure was 150/70 mmHg, with a marked postural drop to 80/40 mmHg upon standing, without compensatory tachycardia. He experienced syncope within one minute of standing. His pupils were dilated and unresponsive to light. Deep tendon reflexes were absent or diminished in both upper and lower extremities, though muscle strength and sensation remained intact. The abdomen was distended with sparse bowel sounds and tympanitic percussion. Nerve conduction studies were normal.

Laboratory examinations

Serum samples for antibody detection were collected before treatment. Antibodies binding to neuronal gAChR were detected using a radioimmunoprecipitation assay (RIA)[6]. This assay utilizes a solubilized acetylcholine receptor (AChR) from a human neuroblastoma cell line (IMR-32) that is labeled with a high-affinity radioligand, ¹²⁵I-labeled epibatidine[7] and was performed by the Institute Pasteur Hellenique, Athens, Greece. The threshold for a definite positive result for gAChR antibodies targeting α3 subunit was set at 15 pmol per liter (pmol/L). Our patient’s antibody level was 235 pmol/L.

Testing for myasthenia gravis, including measurement of muscle AChR antibodies, antibodies to membrane-linked muscle-specific kinase (MuSK) and antibodies to lipoprotein receptor-related protein 4 (LRP4), was negative (Table 1). Comprehensive diagnostic anti-neuronal antibodies panels were also negative (Table 2).

Table 1 Autoantibody control for myasthenia gravis.

Exam	Method	Result	Result classification
			Negative	Grey-zone	Positive
Anti-AChR	RIA	< 0.1 nmol/L	≤ 0.1	0.2-0.5	≥ 0.6
Anti-MuSK	RIA	< 0.015 nmol/L	< 0.015 nmol/L	0.015-0.03	> 0.03
Anti-LRP4	IFA (cell based assay)		< 10	10	> 10

Anti-AChR: Acetyl-Choline receptor ganglionic neuronal auto-antibodies; Anti-MuSK: Muscle-specific tyrosine kinase auto-antibodies; Anti-LRP4: Low-density lipoprotein receptor-related protein autoantibodies; RIA: Radioimmunoprecipitation assay, IFA: Indirect immunofluorescence assay.

Table 2 Antineuronal antibodies control.

Exam	Method	Result	Result classification
			Negative	Grey-zone	Positive
NMDA-R	IFA (cell based assay)	< 10	< 10	10	> 10
AMPA-R1		< 10
GABAB-R		< 10
LGI1		< 10
DPPX		< 10
CASPR2		< 10	< 10	10	≥ 100

NMDA-R: N-Methyl D-aspartate Receptor; AMPA-R1: A-amino-3-hydroxy-5-Methyl-4-isoxazolepropionic acid Receptor; GABAB-R: Gamma-amino butyric acid B Receptor; LGI1: Leukin-rich glioma inactivated; DPPX: Dipeptidyl-peptidase-like protein 6; CASPR2: Contactin-associated protein-like 2.

Imaging examinations

Abdominal computed tomography scan revealed thickening of the right colon at the ileocolic junction and in the ascending colon and a suspected renal pelvis tumor (likely originating from transitional epithelium). The biopsy was inconclusive and a pigtail catheter was placed. However, repeated urinary cytology showed no evidence of malignant cells. Moreover, a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed no metabolic activity suggestive of malignancy.

First-line therapy, including volume expansion (normal saline and fludrocortisone), vasoconstrictors (midodrine and atomoxetine), and nonpharmacologic measures (such as compression stockings), were ineffective. Given the persistent orthostatic intolerance and refractory symptoms, sequential therapy with pyridostigmine, immunoadsorption (second-line therapy), and rituximab (third-line therapy) was initiated, leading to symptomatic improvement, as described below.

FINAL DIAGNOSIS

The patient presented with progressive autonomic dysfunction, prompting an extensive differential diagnosis. Primary and secondary causes of autonomic dysfunction were systematically excluded, including neurodegenerative disorders (e.g., multiple system atrophy), metabolic and endocrine abnormalities (e.g., diabetic autonomic neuropathy and adrenal insufficiency), infectious and paraneoplastic syndromes, and medication-induced autonomic impairment. The presence of high-titer anti-gAChR antibodies strongly supports an immune-mediated pathogenesis. The exclusion of alternative causes and the presence of these disease-specific autoantibodies confirmed AAG as the most likely etiology of the patient’s autonomic failure.

TREATMENT

The patient exhibited no response to first-line therapy, which included volume expansion, vasoconstrictors (midodrine and atomoxetine), and nonpharmacologic strategies. Severe orthostatic dizziness and syncope persisted, significantly impairing his mobility. Notably, he experienced several head trauma episodes due to falls when attempting to stand and walk unassisted, despite medical advice to remain supine. Given the refractory nature of his symptoms and limited literature on the optimal management of AAG, we chose immunoadsorption as a second-line therapy[7]. The patient underwent nine cycles of immunoadsorption, after which he exhibited neurological improvement. Specifically: (1) Cranial nerve function: Hoarseness improved, and lacrimal gland function showed partial recovery, leading to decreased ocular dryness; (2) Deep tendon reflexes: Previously absent lower limb reflexes became detectable, suggesting improved ganglionic synaptic transmission; (3) Autonomic function: He reported improvement in constipation, indicating partial recovery of enteric nervous system activity; and (4) Orthostatic tolerance: The patient was able to stand and walk without severe dizziness, though orthostatic hypotension remained abnormal on testing.

OUTCOME AND FOLLOW-UP

One month after immunoadsorption, a reassessment was performed, and given the incomplete symptomatic response, we initiated four cycles of intravenous rituximab as third-line therapy, while continuing pyridostigmine. During a 12-month follow-up, his symptoms markedly improved: He remained syncope-free, constipation resolved, and lacrimation and salivation normalized. Most notably, orthostatic hypotension testing was normal, indicating substantial autonomic recovery.

DISCUSSION

The traditional second-line approach to AAG treatment includes PE, which functions by removing pathogenic antibodies and other inflammatory plasma components. However, PE is associated with several complications, including thrombosis, bleeding, hypotension, sepsis, and allergic reactions[8]. More recently, immunoadsorption has been recognized as a promising alternative to PE, with the advantage of selectively removing immunoglobulins while preserving other plasma components, thereby reducing the need for volume replacement solutions[9]. In our case, we opted for immunoadsorption over PE, given its favorable safety profile and theoretical advantages in selectively reducing pathogenic autoantibodies, and we observed neurological improvement following nine treatment cycles. Another second-line treatment choice, widely used in immune-mediated neuropathies, is intravenous immunoglobin, though its efficacy in AAG remains variable[7].

When either PE, immunoadsorption, or intravenous immunoglobulin is used as a single therapy, subsequent treatments are required in most relapsing patients to maintain the improvement[7]. Other immunosuppressants, including azathioprine, cyclophosphamide, and mycophenolate mofetil, have been used in some cases, but their success is inconsistent[5]. In our patient, first-line symptomatic therapies failed to provide any benefit, leading us to escalate to second-line therapy with immunoadsorption, which resulted in partial neurological recovery but persistent orthostatic hypotension. As a result, the addition of other immunomodulatory therapies, particularly B-cell depleting agents, has emerged as a rational treatment strategy. Limited data exist on the efficacy of combination therapy in AAG, and only a few cases have reported the use of rituximab or immunoadsorption in seropositive AAG[3,5,7,10,11].

Rituximab, a monoclonal antibody targeting the CD20 antigen on B cells, has been successfully used in autoimmune neurological diseases, including AAG, but its use remains off-label and is based on case reports[8]. Rituximab is thought to deplete B cells, reduce disease-specific antibody production, and exert immunomodulatory effects on T cell signaling[8]. Some reports indicate that rituximab may induce clinical remission even in cases where antibody titers remain elevated, suggesting that pathogenic mechanisms beyond gAChR autoantibodies-such as postganglionic sympathetic dysfunction-may contribute to AAG[12,13]. In our case, the addition of rituximab as third-line therapy resulted in marked improvement in orthostatic tolerance, resolution of syncope, and recovery of autonomic functions, an effect that persisted during 12 months of follow-up.

In our case we evaluated the patient based solely on clinical improvement and not on serological control. According to existing data, serum antibody levels are not always correlated with the clinical course with some cases indicating discordance between clinical severity and antibody titers[4]. The results by Gibbons and colleagues[3] were consistent with prior reports that reveal no relationship between the temporal profile (acute, subacute, or chronic) and antibody titers, symptom complex, response to therapy or clinical course. The patient described by Iodice et al[7] had significantly elevated antibody titers after intravenous immunoglobulin therapy. In an earlier report, rapid clinical improvement of AAG with rituximab occurred without a significant decline in gAChR antibody level[12]. This discrepancy may imply that perhaps other pathogenic mechanisms besides gAChR antibodies exist, such as the dysfunction of postganglionic sympathetic pathways[14]. Quantitative testing with validated autonomic biomarkers has been recently proposed to guide clinical management and monitor treatment response in patients with AAG[15]. Our case provides valuable insights into the treatment approach for refractory AAG. Specifically, combination therapy with immunoadsorption and rituximab may be an effective option in patients resistant to first-line symptomatic therapy. Immunoadsorption may serve as a safer and more targeted alternative to PE, including other autoimmune neurological disorders. The long-term benefit of rituximab in our patient highlights the potential for sustained remission with B-cell depletion therapy, warranting further investigation into its role as a second- or third-line treatment.

Although promising, the use of rituximab in AAG remains limited by several factors, including high cost, potential immune escape leading to reduced efficacy over time, and the risk of severe complications such as progressive multifocal leukoencephalopathy[9,10]. Further prospective studies are required to establish optimal treatment strategies, determine the most effective combination of immunotherapies, and evaluate the long-term safety and efficacy of rituximab in AAG and related autonomic disorders.

CONCLUSION

In conclusion, we present a patient with AAG of Greek origin who demonstrated resistance to initial first-line symptomatic therapy. Second-line therapy with immunoadsorption was not enough alone to control symptoms adequately and therefore third-line therapy with rituximab was added. This case presentation adds to the understanding of combined therapy in AAG and highlights a possible benefit of the implementation of immunoadsorption instead of PE. Further studies are essential to clarify the ideal treatment options for AAG.