Syncope in Patients with Autonomic Nervous System Disturbances:Which Diagnosis and Treatment? C.J. MATHIAS Introduction Syncope is a condition in which there is transient loss of consciousness due to reduction in cerebral blood flow. The term syncope is often used synony- mously with fainting, blackouts, passing out, and swooning. It is a common condition with both neurological (autonomic and non-autonomic) and car- diac causes. Psychologic and psychiatric conditions resulting in pseudosyn- cope are difficult to separate from true syncope [1]. There is increasing recognition that disturbances of the autonomic ner- vous system account for a large proportion of syncope cases. This was emphasised in a study of 641 patients with recurrent syncope and presyn- cope, in whom major neurological (non-autonomic) and cardiac causes had been previously excluded [2]. Following autonomic and allied investigations, half of the patients had an autonomic cause (Fig. 1). This highlighted the role that the autonomic nervous system plays–in part through the baroreceptor reflex, with efferents to the heart and sympathetic efferents to blood vessels in the heart – in the maintenance of blood pressure and thus in the causation of syncope. This review provides a classification of disturbances of the autonomic nervous system that result in syncope. An outline of treatment options fol- lows. Neurovascular Medicine Unit, Faculty of Medicine; Imperial College London at St Mary’s Hospital, Autonomic Unit, National Hospital for Neurology & Neurosurgery, Queen Square; Institute of Neurology, University College London, London, United Kingdom 644 C.J.Mathias Fig. 1. Flow diagram showing investigations and diagnosis in 641 patients with recurrent syncope and presyncope. (Adapted from [2]) Diagnosis and Evaluation Autonomic disturbances resulting in syncope may be intermittent (neurally mediated syncope and the postural tachycardia syndrome) (Table 1), due to drugs (Table 2), or the result of damage to the autonomic nervous system as a result of primary or secondary autonomic failure [3, 4] (Table 3). Diagnosis is dependent on a precise history, detailed clinical examination, and appro- priate tests [5, 6] (Table 4). Table 1. Intermittent disturbances of the autonomic nervous system that cause syncope Neurally mediated syncope Vasovagal syncope Carotid sinus hypersensitivity Miscellaneous causes (situational syncope) Postural tachycardia syndrome (PoTS) Syncope in Patients with Autonomic Nervous System Disturbances:Which Diagnosis and Treatment? 645 Table 2. Mechanisms by which drugs, chemicals, poisons, and toxins may cause syncope. (adapted from [3]) By decreasing sympathetic activity Centrally acting Clonidine, reserpine, anaesthetics Peripherally acting via Sympathetic nerve endings (guanethidine, bethanidine) α-Adrenoceptor blockade (phenoxybenzamine) β-Adrenoceptor blockade (propranolol) By increasing cardiac parasympathetic activity Organophosphates Ciguatera (reef fish) poisoning By vasodilatation Jellyfish and marine animal venoms By a first-dose effect Prazosin, Captopril By causing an autonomic neuropathy Alcohol, thiamine (vitamin B1) deficiency Vincristine, perhexiline maleate Table 3. Disorders of the autonomic nervous system that cause syncope (adapted from [4]). Primary autonomic failure Acute/subacute dysautonomias Pure pandysautonomia Pandysautonomia with neurological features Chronic autonomic failure syndromes Pure autonomic failure Multiple system atrophy (Shy-Drager syndrome) Autonomic failure with Parkinson’s disease Secondary autonomic failure Congenital Nerve growth factor deficiency Hereditary Autosomal dominant trait Familial amyloid neuropathy continue ➝ 646 C.J.Mathias Table 3. continue Autosomal recessive trait Familial dysautonomia, Riley-Day syndrome Dopamine beta-hydroxylase deficiency Metabolic Diabetes mellitus Chronic renal failure Chronic liver disease Alcohol-induced Inflammatory Guillain-Barre syndrome Transverse myelitis Infections Bacterial: Tetanus Viral: Human immunodeficiency virus infection Neoplasia Brain tumours, especially of the third ventricle or posterior fossa Paraneoplastic, including adenocarcinomas of lung and pancreas Trauma Cervical and high thoracic spinal-cord transection Table 4. Outline of investigations used in the evaluation of syncope due to disturbances of the autonomic nervous system (adapted from [6]) Head-up tilt (60°)a; standinga; Valsalva manoeuvrea Pressor stimulia (isometric exercise, cold pressor, mental arithmetic) Heart rate responses to: deep breathinga, hyperventilationa, standinga, head-up tilta Liquid meal challenge Modified exercise testing Carotid sinus massage aIndicates screening autonomic tests used in our London Units Additional autonomic and allied tests, as described in [6], may need to be performed if relevant to diagnosis and management Syncope in Patients with Autonomic Nervous System Disturbances:Which Diagnosis and Treatment? 647 Treatment of Syncope Caused by Autonomic Nervous System Disturbances The key components of treatment revolve around non-pharmacological mea- sures, drug treatment when appropriate, and the introduction of interven- tions such as cardiac pacemaker when relevant. Neurally Mediated Syncope This depends upon the cause, the most common being vasovagal syncope (Fig. 2). Reducing or preventing exposure to precipitating causes is of impor- tance, along with educating the patient about the disorder. A combination of non-pharmacological approaches, especially if supine blood pressure is low, should include a high-salt diet; fluid repletion; exercise to strengthen lower limb muscles; measures that activate the sympathetic nervous system, such as sustained hand grip, the use of the calf muscle pump to prevent pooling; and various manoeuvres such as leg crossing [8–11]. Patients who have symptoms suggestive of an oncoming attack should sit and ideally lie head down, if needed with the legs upright. Pharmacological measures are used when non-pharmacological measures alone are not successful, especially if the supine blood pressure is low. These include low-dose fludrocortisone and Fig. 2. Blood pressure and heart rate with continuous recordings from the Portapres II in a patient with the mixed (cardio-inhibitory and vasodepressor) form of vasovagal syn- cope. (Adapted from [7]) 648 C.J.Mathias the sympathomimetics ephedrine and midodrine. 5-Hydroxytryptamine uptake release inhibitors have been used with varying success. In the cardio- inhibitory form of vasovagal syncope, a cardiac demand pacemaker is of value [12]. In some patients, especially those with phobias, cognitive behav- ioural psychotherapy is recommended. In carotid sinus hypersensitivity, which is diagnosed more often in older patients, a cardiac pacemaker often is of benefit, both in the cardio-inhibito- ry and in the mixed forms (Fig. 3). In the vasodepressor form, non-pharma- cological and drug treatment as outlined above for vasovagal syncope often is needed. In unilateral hypersensitivity, denervation of the carotid sinus nerves has been employed. In the miscellaneous (situational) group of syncope cases, treatment is tailored to the provoking cause. Thus, in patients with high spinal cord lesions on an artificial respirator, vagal activity is not opposed by sympathet- ic activity and tracheal stimulation can cause bradycardia and syncope; ade- quate oxygenation, atropine and, in some patients, a temporary cardiac demand pacemaker is indicated [14, 15]. In micturition-induced syncope, avoidance of precipitating factors, such as alcohol, and advice to empty the urinary bladder while sitting rather than standing may be all that is required. Fig. 3. Continuous blood pressure and heart rate measured non-invasively (by Portapres II) in a subject with falls of unknown cause. Left carotid sinus massage caused a fall in both heart rate and blood pressure. The findings indicate the mixed (cardioinhibitory and vasodepressor) form of carotid sinus hypersensitivity. (Adapted from [13]) Syncope in Patients with Autonomic Nervous System Disturbances:Which Diagnosis and Treatment? 649 Postural Tachycardia Syndrome In this condition (Fig. 4), non-pharmacological measures are of particular importance and include avoiding hypovolaemia and contributory factors such as hyperventilation. Drugs such as fludrocortisone and midodrine are of value in some patients. Beta-adrenergic blockers, especially those that are cardioselective, reduce tachycardia. Specific approaches may be needed depending upon the cause and association; thus, in the joint hypermobility syndrome, the underlying collagen disorder (Ehlers-Danlos type III) needs to be addressed. Drug-Induced Syncope The pharmacological effect of drugs, their interactions with other agents, and modification of their actions in certain disease states, need to be borne in mind when syncope results from drugs. The ideal is withdrawal of drugs, but this may not always be possible, as in the treatment of parkinsonian syn- dromes (Table 5). Drugs such as alcohol and perhexiline maleate cause an autonomic neuropathy, and withdrawal alone may not result in recovery. Fig. 4. Blood pressure and heart rate measured continuously before, during, and after 60° head-up tilt by Portapres II in a normal subject (uppermost panel) and in a subject with postural tachycardia syndrome (PoTS) (lowermost panel). (Adapted from [16]). The middle panel is from a subject with orthostatic hypotension due to autonomic failure 650 C.J.Mathias Table 5. The causative or contributory causes