Anti-Cholinergic Receptors Antibodies, Autonomic Profile and Dysautonomia Symptoms in PAF, ALS and POTS (DISAUT-AB)

Anti alfa-3 and alfa-7 ganglionic cholinergic receptors (anti-AChRs) antibodies (Abs) plasma removal by plasmapheresis (1,2) acutely improved dysautonomia symptoms in case reports with Pure Autonomic Failure (PAF) (3). We shall assess the prevalence of anti-AChRs Ab and the relationship among Ab titer, cardiovascular autonomic profile and symptoms in neurodegenerative diseases characterized by similar dysautonomia symptoms such as PAF, Amyotrophic Lateral Sclerosis (ALS) and Postural Orthostatic Tachycardia Syndrome (POTS) (4). Ab positive patients will undergo selective immunoabsorption once a week up to achievement of Ab titer lower than 65% of baseline followed by immunosuppressive therapy with prednisone. Both Ab positive and negative groups will undergo anti-AChR Abs, autonomic profile and dysautonomia symptoms assessment, every 4 months up to 3 years. Evidence of correlation among reduced Ab titer and autonomic profile and symptoms improvement may result in new effective therapy.

PAF is a rare neurodegenerative disorder characterized by symptoms due to sympathetic failure, such as orthostatic hypotension and syncope, and deficient parasympathetic activity such as constipation, urinary retention and decreased salivation (3). Plasma anti-AChRs Abs were found in PAF (1, 2, 5) and in POTS (6), raising the possibility that Ab mediated alterations in the ganglionic cholinergic function might induce autonomic abnormalities and related symptoms. Anti-AchRs Abs removal by plasmapheresis was associated with acute improvement of orthostatic tolerance in PAF single case report (2).

There is no data on the medium/long term clinical follow-up of these patients. Nothing is known about the time course of the relationships among Abs plasma titer, neural autonomic profile and symptoms if a selective immunoabsorption procedure is combined with drug immunosoppression (Prednisone) to lower Ab levels and potentially ameliorate ganglionic function.

Finally, it is unknown whether a neurodegenerative disease with concomitant dysautonomia symptoms such as the Amyotrophic Lateral Sclerosis (ALS) may share an analogous anti-AChRs Ab profile. Variations in cholinergic receptor subunits 3 and 4 were observed in ALS but no plasma anti-AChRs Abs were searched for (7). Abs removal by immunoabsorption technique combined with drug immunosoppression might represent a new effective therapy for dysautonomia symptoms in ALS as well as in POTS and PAF.

Hyphotesis and Significance:

* Changes in anti-AChR Abs plasma titer may be mirrored by modifications in the cardiovascular autonomic profile, as assessed by spectrum analysis of RR and arterial pressure variability, and be related to fluctuations in the magnitude of dysautonomia symptoms in PAF, ALS and POTS patients.
* Plasma anti-AChR Abs might underlie dysautonomia symptoms associated to neurodegenerative disorders such as ASL and POTS
* Plasma anti-AChR Abs removal by selective immunoabsorption techniques may improve ganglionic transmission leading to clinical amelioration and represent a new effective etiologic therapy for these diseases.

Specific Aim:

Aim 1: To evaluate the prevalence of plasma anti-AChR Abs in patients affected by PAF, ALS and POTS .

Aim 2: To address the time course and relationships of anti-AChR Abs plasma titers, cardiovascular autonomic profile and dysautonomia symptoms before and after anti-AChR Abs plasma removal by selective immunoabsorption technique in PAF, ALS and POTS patients. The core laboratory of the Neuroimmunology Unit of Istituto Neurologico Besta will provide expertise and facilities for assessing plasma anti-AChR Abs. The clinical laboratory of Clinica Medica Syncope Unit (Humanitas) will provide the know-how and facilities for patients neural autonomic assessment.

Aim 3:To set up a new therapeutic strategy based on selective immunoabsorption technique sessions combined with drug immunosuppression (Prednisone) in patients with anti-AChR Abs.

Eligibility Criteria:
Inclusion Criteria:

• Patients, older than 18 years affected by PAF, ALS and POTS, with dysautonomia symptoms assessed by clinical evaluation and by the Composite Autonomic Scoring Scale (CASS)

Exclusion Criteria:

* Hepatic, renal, heart and other secondary causes of autonomic dysfunction
* History/familiarity with seizures
* Atrial fibrillation and other relevant cardiac rhythm disturbances
* Diabetes
* Other neurological or psychiatric diseases
* Pacemakers or other electronic implants inserted into the body
* Coronary disorders, elevated intracranial blood pressure
* Assumption of drugs facilitating seizures, psychiatric drugs, alcohol abuse