JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Supplement No. 43 Volume 96 2003

Autonomic dysfunction in cystic fibrosis

AMirakhur MB MRCP MJWalshaw MD FRCP

J R Soc Med 2003;96(Suppl. 43):11–17 SECTION OF PAEDIATRICS & CHILD HEALTH, 26 NOVEMBER 2002

INTRODUCTION thetic nervous system, has both pre- and postganglionic The autonomic nervous system (ANS) is a complex neural fibres. However, in general, the preganglionic fibres pass network largely responsible for the regulation of visceral uninterrupted to the organ that is to be controlled; function and maintenance of homeostasis of the internal postganglionic neurons are located in the wall of the organ.3 environment.1 This is achieved primarily through interac- The neurotransmitter for all preganglionic and para- tions with the and via autonomic reflexes. sympathetic postganglionic fibres is acetylcholine. All The latter comprise specialized sensory receptors in the postganglionic sympathetic nerves are adrenergic except viscera which provide information regarding visceral for those fibres innervating the sweat glands which are function to higher ANS centres in the brain. At these sites cholinergic.1 sensory information is processed and integrated, and appropriate autonomic motor responses to the viscera are Higher centres relayed through the ANS efferent system. In many The supraspinal integration of ANS function is accomplished circumstances, the ANS reflexes are capable of responding by a complex interaction of many brainstem, mesencephalic very quickly to alterations in the internal environment and and cortical areas, the hypothalamus being the principal can rapidly return the system to its homeostatic baseline. higher centre for integration of ANS function. It receives sensory afferents as well as connections from the limbic GENERAL ANATOMICAL ORGANIZATION system and sensorimotor cortex, and exerts its effects via The ANS has two major divisions: the sympathetic and interactions with the endocrine system and through 2 parasympathetic nervous systems. A third division has also descending pathways to the brainstem and spinal cord. been recognized: the enteric ANS. This consists of neurons located in the wall of the that function CLASSIFICATION OF AUTONOMIC NEUROPATHY relatively independently of the sympathetic and parasympa- Autonomic neuropathy may be primary (pure autonomic thetic systems to regulate motility and fluid and electrolyte failure, autonomic failure with multi-system atrophy, homeostasis within the gut.2 autonomic failure with Parkinson’s disease) or more commonly secondary to chronic diseases (diabetes, amyloid, Anatomy of the sympathetic nervous system chronic renal failure, chronic liver disease, nutritional disorders, malignancy).4,5 Preliminary observations suggest Sympathetic nerves originate in the spinal cord between that it also exists in cystic fibrosis (CF) (see later). segments T1 and L2 (the so-called thoracolumbar outflow), and pass from here first into the sympathetic chain, thence PATHOGENESIS OF AUTONOMIC NEUROPATHY to the tissues and organs that are stimulated by the IN CF sympathetic nerves; preganglionic fibres are short whereas the postganglionic fibres are long.1,3 Evidence that autonomic neuropathy exists in CF comes from several sources. It is known that in CF there exists a state of increased Anatomy of the parasympathetic nervous sensitivity to a-adrenergic stimulation of pupil dilatation and system increased responsiveness to cholinergic stimulation of pupil The cell bodies of the parasympathetic efferent system lie in constriction.6 In addition, the reduced cardiovascular the nuclei of cranial nerves III, VII, IX and X, and in the sensitivity to b-adrenergic stimulation in CF patients is intermediolateral cell column of the sacral spinal cord (the confirmed by a reduced leucocyte response to isoproterenol, craniosacral outflow). The parasympathetic, like the sympa- a b-receptor agonist.7 More recently, preliminary work has demonstrated the existence of autonomic neuropathy in a Adult Regional CF Unit, Cardiothoracic Centre, Thomas Drive, Liverpool L14 3PE, UK group of adult CF patients on the basis of abnormal heart 8 Correspondence to: Dr Martin Walshaw rate variability which correlates with increasing disease E-mail: [email protected] severity as determined by spirometric indices. 11 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Supplement No. 43 Volume 96 2003

Possible mechanisms for the pathogenesis of autonomic supine blood pressure, fall in blood pressure on standing neuropathy in CF are: and impaired thermoregulation; increased energy intake is associated with the opposite changes.26 Many CF patients . metabolic are malnourished, as a result of a high metabolic rate, . nutritional malabsorption, and general ill health. . immunological. Vitamin E deficiency Metabolic causes Malabsorption of fat-soluble vitamins in CF may result in 27 Diabetes mellitus vitamin E deficiency. Several authors have reported that this may cause neurological deficits in this patient group.28,29 In classic diabetes, several metabolic mechanisms have been However, the presence of autonomic neuropathy was not proposed to explain the relationship between the extent and specifically investigated. Nevertheless, vitamin E is known severity of hyperglycaemia and the development of to contribute to the development of autonomic neuropathy autonomic neuropathy. For example, activation of the in non-CF patients30 and may be improved with vitamin E polyol pathway by glucose via aldose reductase which administration; certainly in diabetes vitamin E improves the results in sorbitol and fructose accumulation, myo-inositol ratio of cardiac sympathetic to parasympathetic tone as depletion and slowing of nerve conduction by alteration of assessed by analysis of heart rate variability.31 neural Na/K ATPase activity.9–12 Other mechanisms include local ischaemia resulting in lipid peroxidation of nerve membranes leading to nerve Immunological factors fibre death,13–15 decreased nitric oxide production with The identification of autoantibodies to b2-adrenergic receptors impaired endothelium dependent vasodilatation and Na/K in the serum of three patients with allergic respiratory disease ATPase activity,16 increased homocysteine levels17 and was described by Venter et al.32 These autoantibodies inhibited abnormal amino acid metabolism and protein glycation.9 adrenergic ligand binding to the receptor, providing a Approximately 20% of adult CF patients have difficulty in molecular basis for b-adrenergic hyporesponsiveness. A handling glucose, a condition labelled CF related diabetes potential role for these autoantibodies has also been mellitus.18 demonstrated in a CF patient with autonomic dysfunction.33 A positive correlation between high levels of antibodies Chronic liver disease specific for nicotinic acetylcholine receptors in autonomic Autonomic dysfunction also exists in chronic liver disease19 ganglia and the severity of autonomic dysfunction has been and is independent of aetiology.20 It is implicated in the reported in subjects with idiopathic autonomic neuro- development of portal hypertension.21 Impairment of pathy.34 A similar relationship exists between complement- axoplasmic transport, thiamine and pyridoxine deficiencies, fixing sympathetic ganglia autoantibodies and defective enhanced lipid peroxidation of nerve membranes and cardiac innervation in type I diabetes.35 circulating immune complexes are important pathogenic Antibodies against nerve growth factor have also been mechanisms.22 Chronic liver disease, in the form of identified.36 Nerve growth factor is essential for the secondary biliary cirrhosis, occurs as a sequel to altered development and maintenance of autonomic nerves.37 in CF patients, with diffuse hepatic nodularity Deficiency of this leads to autonomic neuropathy.38 developing in only 2–5% of patients, although fatty changes are much more common.23 SYSTEMS REVIEW

Uraemia Autonomic nerves innervate virtually every body system, and so the symptoms of autonomic dysfunction are quite Widespread autonomic dysfunction has been demonstrated varied. These include orthostatic hypotension, abnormal in chronic uraemic patients using a battery of six sweating, gastroparesis, impotence and bladder and bowel cardiovascular tests.24 CF patients who receive repeated dysfunction.39 The significant associated mortality and courses of nephrotoxic antibiotics may develop renal morbidity due to silent myocardial ischaemia,40 sudden disease.25 cardiac death,41 which may be related to a prolonged QT interval,42 and anaesthetic complications43 emphasize the Nutritional factors need for accurate, sensitive and specific tests of autonomic Malnutrition function. The systems which lend themselves most easily to In general, an alteration in nutritional status with examination are cardiovascular, gastrointestinal, ophthalmic subsequent reduced energy intake is accompanied by and urinary and these will now be discussed in more 12 evidence of reduced sympathetic activity and decreased detail. JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Supplement No. 43 Volume 96 2003

CARDIOVASCULAR SYSTEM An alternative to this classification of severity is to give Autonomic fibres innervate the atria, ventricles, coronary each individual test a score of 0, 1, or 2, depending on arteries and resistance vessels of the peripheral circulation.44 whether it is normal, borderline or abnormal, respectively. Essentially, sympathetic activity increases heart rate and An overall autonomic test score of 0–10 can then be myocardial contractility, dilates the coronary vessels and obtained. constricts the resistance vessels; parasympathetic activity does the converse, except that it has little effect on the The sequence of abnormalities in autonomic peripheral vasculature. neuropathy Autonomic damage is not simply present or absent, it can also be anywhere on the spectrum from minimal to severe. TESTS OF CARDIOVASCULAR AUTONOMIC FUNCTION Cardiac parasympathetic function is impaired before sympathetic function, possibly because the parasympathetic Historically, the assessment of cardiovascular autonomic fibres are longer and therefore more liable to damage.47 neuropathy is based on a battery of five tests known as Watkins and Mackay48 confirmed that reduced heart rate Ewing’s tests. These have traditionally most often been variability can be the earliest sign of diabetic neuropathy and performed on diabetics, but are equally applicable in the in fact can predate the symptoms of autonomic neuropathy 45 diagnosis of autonomic damage caused by other disorders. by several years.49 Cardiovascular tests also deteriorate with time, an observation supported by several investigators.46,50,51 Tests of parasympathetic function Disadvantages of Ewing’s tests These are: Although historically our assessment of cardiovascular . Heart rate variability with respiration (sinus arrhythmia) autonomic function has been based on Ewing’s tests, it is . Heart rate response to the Valsalva manoeuvre increasingly apparent that these have several disadvantages. . Heart rate response to standing from the supine First, they have been criticized as being insensitive to position. early changes in autonomic function, particularly sympa- thetic nervous system dysfunction.52 Secondly, the tests of sympathetic function have poor reproducibility with Tests of sympathetic function coefficients of variation in excess of 30%53 and, therefore, These are: are much less reliable. Thirdly, they require active patient participation54,55 which is difficult to standardize. Lastly, . conventional scoring systems rely on being able to perform The diastolic blood pressure response to isometric 47 exercise (sustained handgrip) all five tests. However, the Valsalva manoeuvre is difficult to . The systolic blood pressure response to standing from perform particularly in the presence of chronic lung disease. the supine position. The technique of power spectral analysis may answer some of these criticisms.

Classification of severity of autonomic Power spectral analysis damage Heart rate variability (the continual change in heart rate One cardiovascular test alone does not distinguish the even under stable conditions) is mainly a reflection of the degree or severity of autonomic damage,46 a combination of influence of the ANS on the sinus node of the heart.56 These tests must be used. heart rate fluctuations can be quantified and displayed using Autonomic neuropathy can be classified, according to power spectral analysis. the severity of damage, into one of four groups:47 Any biological rhythm such as heart rate, or an ECG RR time interval series, can be broken down into a series of sine . Normal—all five tests normal, or one borderline waves of different amplitudes and frequencies.55 Spectral . Early involvement—one of the three heart rate tests analysis, using fast Fourier transformation, separates the RR abnormal time interval series into groups of identical discrete . Definite involvement—two or more of the heart rate tests frequencies generating a graph known as a power abnormal spectrum.47 This displays the amplitude squared of these . Severe involvement—two or more of the heart rate tests sine waves against frequency. Power spectral analysis may abnormal plus one or both of the blood pressure tests thus provide a useful non-invasive technique for analysing abnormal. the autonomic mechanisms that control heart rate.57 13 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Supplement No. 43 Volume 96 2003

Spectral analysis of the resting heart rate commonly Extrinsic (sympathetic and parasympathetic) produces several prominent peaks. These peaks can be nervous system further quantified by measuring the area under each, known This modulates the intrinsic reflexes and integrates impulses as the power. from higher nerve centres and the gut.70 Therefore The peak found at the highest frequency (greater than autonomic dysfunction of the gastrointestinal tract can be 0.15 Hz) reflects oscillations of heart rate that occur with due to disturbances of the intrinsic or extrinsic systems. respiration—the respiratory sinus arrhythmia. This is a Diagnosis of autonomic dysfunction in the gastrointest- reflection of parasympathetic (vagal) activity and is inal tract is difficult for several reasons: (1) The symptoms abolished by atropine.58 The peaks found at lower of autonomic dysfunction are non-specific and in fact some frequencies (below 0.15 Hz) represent baroreceptor patients are symptom-free. (2) With the exception of two feedback activity and fluctuations in vasomotor tone tests (pancreatic polypeptide response to sham feeding or associated with thermoregulation. These provide an hypoglycaemia [i.e. parasympathetic test]71 and superior index of sympathetic activity and are abolished by mesenteric artery blood flow studies in response to stress propranolol.59 [i.e. sympathetic test]),72 there are no specific tests for the Thus spectral analysis provides a single test of autonomic detection of autonomic neuropathy of the gastrointestinal function, measuring both parasympathetic and sympathetic tract. Diagnostic workup is therefore usually restricted to divisions of the ANS.60 the investigation of sequelae of autonomic dysfunction, e.g. The power spectrum of heart rate variation has disturbed motility. This may be assessed by means of previously been characterized in several conditions such as manometry (oesophageal, small bowel and colonic diabetes,54 congestive cardiac failure,43 sudden cardiac motility), scintigraphy (gastric emptying) or measuring death,61 chronic liver disease62 and chronic renal failure.63 transit times of radio-opaque markers (colonic transit).73 More recently, in CF patients, heart rate recordings It can be seen that the above investigations are complex made over 15 minutes using a modified orthostatic load and invasive. They also involve radiation exposure and have shown a strong correlation between global autonomic transfer of the patient to a specialized unit. Therefore, a tone and FEV1% predicted.8 potentially simpler, non-invasive test will now be described.

Other techniques looking at cardiovascular The investigation of bowel sounds autonomic function Bowel sounds are generated by which is under Some methods take a more global look at heart rate autonomic control.68 Essentially sympathetic activity causes variability than those that interpret heart rate variability in slowing of motility whilst parasympathetic activity stimulates terms of sympathetic and parasympathetic control of the motility.44 cardiovascular system. These include Poincare´ plots,64 Bowel sounds were first recorded by Cannon in 190574 fractal dimension65 and apparent entropy.66 Direct as a means of studying the mechanical activity of the scintigraphic assessment of cardiac sympathetic integrity gastrointestinal tract. Historically they have most often been has also recently become possible with the introduction of studied in the context of obstruction. radiolabelled analogues of noradrenaline.67 Arnbjornsson75 looked at bowel sounds in patients with documented mechanical small bowel obstruction. The most striking observations were the regular occurrence of GASTROINTESTINAL SYSTEM clustered bowel sounds, defined as 3–10 regular sounds The gastrointestinal tract is the organ system with the occurring one every 5 seconds, preceded and followed by at largest surface in the body, serving motor, secretory, least 1 minute of silence, and also a high motility index (an storage and excretory functions. These are under the indication of the motor activity of the intestine). A further control of the ANS.68 There are two main control study demonstrated bowel sounds of higher frequency in a systems: group of obstructed patients compared to controls.76 Sugrue and Redfern77 found that bowel sounds were longer and of greater amplitude when compared to controls. Intrinsic (enteric) nervous system The above results may be of relevance when looking at This consists of approximately 108 semiautonomous bowel sounds in CF where the basic cellular defect is neurons located in the wall of the gastrointestinal tract, reduced, or defective expression of the CF transmembrane and provides specific programmes and reflexes for the conductance regulator gene (CFTR).78 This is found in the control of gastrointestinal motility (e.g. the peristaltic , colon and . Therefore, reduced 14 reflex) and other functions.69 CFTR expression in those regions would result in the JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Supplement No. 43 Volume 96 2003 production of thick, tenacious secretions which could Only the first of these will be described as the others potentially lead to constipation and/or obstruction. require specialist equipment and interpretation. However, not all patients develop so-called distal intestinal obstruction syndrome. Therefore, there may be an Resting pupil darkness diameter additional mechanism involved, e.g. autonomic neuropathy; In the human eye, light reflex latencies are in excess of certainly diabetics with severe constipation show a complete 0.2 s, and so conventional flash light photographs can be loss of the normal post-prandial rise in colonic electrical and taken even in darkness before the pupil starts to constrict. A motor activity, the so-called gastrocolic reflex which can, convenient way of expressing pupil size is pupil darkness nevertheless, be stimulated pharmacologically indicating the 79 diameter per cent (PD%). This is the ratio of the pupil to presence of autonomic neuropathy. iris diameter as a percentage of the latter. Using flash light photographs Smith and Dewhirst86 demonstrated that in URINARY SYSTEM diabetes, for example, a large proportion of patients had abnormally small pupils. The autonomic innervation to the bladder is complex, but Pharmacological pupil tests are a useful supplement to essentially during bladder filling (urine storage) sympathetic the above. They rely on the principle of denervation activity results in detrusor muscle inhibition and internal hypersensitivity whereby an organ, e.g. the eye, deprived of sphincter contraction; parasympathetic outflow is inactive. its innervation becomes more sensitive to the transmitter During voiding, sympathetic outflow becomes inactive normally released from those nerves. In sympathetic whilst parasympathetic activity causes detrusor muscle 80 dysfunction the pupil is supersensitive to the mydriatic contraction. effect of topical 2% phenylephrine,87 whereas in para- Bladder dysfunction has been recognized as a frequent sympathetic dysfunction the pupil is supersensitive to the complication of diseases affecting the ANS such as multiple 88 81 82 83 miotic effect of pilocarpine. system atrophy, pure autonomic failure and diabetes. Similar results have been demonstrated in patients with In the latter, compared with control subjects, cystometro- CF in response to phenylephrine and carbachol.89 grams show significant increases in bladder volume at first desire to void and maximum bladder capacity, a decrease in CONCLUSION detrusor contractility and a larger residual volume of urine. This is due to parasympathetic dysfunction. The bladder Autonomic dysfunction is a well-documented finding in neck, which is principally innervated by sympathetic fibres, several chronic diseases. 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