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 cardiac causes. Psychologic and psychiatric conditions resulting in pseudosyncope are difficult to separate from true syncope [1]. There is increasing recognition that disturbances of the autonomic nervous system account for a large proportion of syncope cases. This was emphasised in a study of 641 patients with recurrent syncope and presyncope, 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 appropriate 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 measures, 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 importance, 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 syncope. (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 cardioinhibitory 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-inhibitory and in the mixed forms (Fig. 3). In the vasodepressor form, non-pharmacological 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 sympathetic 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 syndromes (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 of syncope in a patient with parkinsonism (adapted from [5])

Side effects of anti-parkinsonian therapy: L-DOPA, bromocriptine, pergolide Combination of L-DOPA and COMT inhibitors (tolcapone) MAO ‘b’ inhibitor, selegiline

Coincidental disease causing autonomic dysfunction Diabetes mellitus

Coincidental administration of drugs for an associated condition Antihypertensives α-Adrenoceptor blockers (for benign prostatic hypertrophy) Vasodilators (for ischaemic heart disease) Diuretics (for cardiac failure) Sildenafil (for erectile failure)

Autonomic failure Multiple system atrophy (Shy-Drager syndrome) Parkinson’s disease with autonomic failure Diffuse Lewy body disease

Primary and Secondary Autonomic Failure These conditions usually require a combination of approaches. The original disorder needs to be addressed, and orthostatic hypotension (Fig. 4 middle panel), which is the usual cause of syncope, must be treated. A combination of approaches often is needed (Table 6). Drugs used for the treatment of orthostatic hypotension act in different ways and frequently can be combined in lower dosages to provide benefit while reducing side effects (Table 7).

Table 6. Non-pharmacological and major pharmacological measures used in the management of neurogenic orthostatic hypotension (adapted from [17])

Non-pharmacological measures

To be avoided Sudden head-up postural change (especially on waking) Prolonged recumbency Straining during micturition and defaecation High environmental temperature (including hot baths) ‘Severe’ exertion Large meals (especially with refined carbohydrate) Alcohol Drugs with vasodepressor properties continue ➝ Syncope in Patients with Autonomic Nervous System Disturbances:Which Diagnosis and Treatment? 651

Table 6. continue

To be introduced Head-up tilt during sleep Small frequent meals High salt intake Judicious exercise (including swimming) Body positions and manoeuvres

To be considered Elastic stockings Abdominal binders Water ingestion

Pharmacological measures

Starter drug: Fludrocortisone Sympathomimetics: Ephedrine, midodrine Specific targeting: Octreotide, desmopressin, erythropoietin

Table 7. Outline of the major actions by which a variety of drugs may reduce orthostatic hypotension (adapted from [17])

Reducing salt loss/plasma volume expansion Mineralocorticoids (fludrocortisone)

Reducing nocturnal polyuria

V2-receptor agonists (desmopressin)

Vasoconstriction: sympathetic On resistance vessels (ephedrine, midodrine, phenylephrine, noradrenaline, clonidine, tyramine with monoamine oxidase inhibitors, yohimbine, L-dihydroxyphenylserine)

On capacitance vessels (dihydroergotamine)

Vasoconstriction: non-sympathomimetic V1 receptor agents – terlipressin

Ganglionic nicotinic-receptor stimulation Anticholinesterase inhibitors: pyridostigmine

Preventing vasodilatation Prostaglandin synthetase inhibitors (indomethacin, flurbiprofen) Dopamine receptor blockade (metaclopramide, domperidone)

Beta2-adrenoceptor blockade (propranolol) continue ➝ 652 C.J.Mathias

Table 7. continue

Preventing postprandial hypotension Adrenosine receptor blockade (caffeine) Peptide release inhibitors (somatostatin analogue: octreotide)

Increasing cardiac output Beta-blockers with intrinsic sympathomimetic activity (pindolol, xamoterol) Dopamine agonists (ibopamine)

Increasing red cell mass Erythropoietin

References

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