The study aims at assessing that theophylline is effective in patients with no prodromes, normal heart and with low values of plasmatic adenosine compared with a propensity-score matched untreated control population who have received an implantable cardiac monitor (ICM) for diagnosis of unexplained or atypical reflex syncope.

Theophylline has been used for 3 decades in ordinary medical practice to tentatively prevent syncopal recurrences in patients affected by neurally-mediated syncope. Observational studies report a recurrence rate with this drug ranging between 12% and 22%. Theophylline was much more effective in selected patients with syncope without prodromes and normal heart who had ECG documentation of long pauses at the time of syncopal attack and low values of baseline plasmatic adenosine. Since theophylline is a non-selective antagonist of purinergic receptors, it has been hypothesized that purinergic receptors are involved in the mechanism of syncope in such patients. Conversely, theophylline was suspected to be ineffective (or less effective) in patients affected by other forms of neurally-mediated syncope.

The present study aims at assessing that theophylline is effective in patients with no prodromes, normal heart and with low values of plasmatic adenosine compared with a propensity-score matched untreated control population.

This will be a multicenter, non interventional study, verified by ICM, with 2 predefined subgroups:

Subgroup #1

• Low adenosine group: Patients with Low Adenosine values (<0.40 μmol/L)
• Normal/high adenosine (≥0.40 μmol/L) group: any other patient Subgroup #2
• Patients with no prodromes or very short prodromes (≤5 sec), normal heart and normal ECG (No prodrome group)
• Any other form of atypical neurally-mediated syncope with prodromes >5 sec. Remote or in-hospital periodic follow-up will be done according to centre's clinical practice for ICM monitoring.

Patients will be followed up until the first primary endpoint event with a maximum follow-up of 24 months since start of theophylline treatment.

Inclusion Criteria:

1. Male or female gender with age >18 years
2. Unexplained syncope without prodrome or neurally-mediated syncope with atypical prodrome, with normal heart and normal ECG
3. Two syncopes /last year or 3 syncopes /last 2 years before start of theophylline treatment
4. Having received an ICM according to conventional guideline-based indications
5. Being treated with oral theophylline therapy, while been waiting for ICM diagnosis
6. Having signed a written informed consent to the study participation and to the treatment of personal data

Exclusion Criteria:

1. Typical vaso-vagal syncope with long prodromes and situational syncope
2. Any other form of syncope/T-LOC different from reflex syncope
3. Pregnant or breast-feeding patients -

Patients who have received an implantable cardiac monitor (ICM) for diagnosis of unexplained or atypical reflex syncope