What does it do?

While the evolutionary and developmental origins of the ANS may be somewhere akin to the traditional image of an all-or-nothing mediator of ‘fight or flight’ and ‘rest and digest’, it in fact underpins highly sophisticated adaptive responses (box 1).

The ANS is integral to adjustment to all to which adjustment is required, whether internal or external, environmental, physical or psychological, individual or interpersonal, or any combination of these. ‘Stressors’ may be welcome or otherwise, including light, sound, touch, heat and pain, gravity, danger and excitement, distress and pleasure, infection and injury among many. The ANS adjusts sensitivity to all modalities of sensory input and environmental conditions. It coordinates physiological, psychological and behavioural adaptation to these, and their detail, in an integrated hierarchy of centrally generated multisystem patterns, integrating the demands of extraneous stressors with intrinsic homeostasis.2 Despite having multiorgan manifestations, traditional teaching is that the ANS has little role in motor control: common experience suggests otherwise, however, as does an evolutionary role in fight and flight.

By colouring verbal and non-verbal communication, ANS function influences the quality of relationships and thus the functioning of society. It is involved in emotional regulation, and in communication of, for example, fear, anxiety and excitement.3 ,4 Parents’ regulatory capacity prominently affects that of their children and influences the quality of the attachment on which they depend, this relationship forming a template for others.5

The ANS anticipates the extent of need to adapt. It generates alertness and sensory sensitivity when danger warrants it, allowing concentration, intellectual learning and its application, reproduction or somnolence when it does not, optimising available resources through circadian rhythm, and cooperation through time perception.6 It adjusts fitness and modulates pain sensitivity according to circumstances.7 It modifies the extent to which vigilance to the environment overrides, or not, the value and possibility of sensitive attunement to others.

Sympathetic and parasympathetic functions are not merely antagonistic. Some organs are innervated by one, some by both; unexplained paradoxes remain apparent. Differential function of receptors and neurotransmitters, and cotransmitters within individual neurones, allow subtle attunement of function to need. The presumed principal sympathetic and parasympathetic neurotransmitters, noradrenaline and acetylcholine are only part of the story. For example, their precursors, including dopamine and gamma-aminobutyric acid (GABA), serve independently and synergistically; serotonin, glutamate and nitrous oxide modulate gastrointestinal function; glutamate is prominent in central ANS control.8 There are aspects hovering on the edge of practically applicable understanding—including the relevance of magnesium to the ANS9 and of the ANS to immunity,10 mast cell function,11 vasopressin and oxytocin12 and glucose metabolism.13

It follows that ANS dysfunction has potentially profound implications, touching all specialties.

Set for action? Development, programming and reprogramming

The linked ANS and hypothalamus-pituitary-adrenal (HPA) axis are thought to be programmed in utero and the early post-natal months to equip children for the environment in which they are born.14 ,15 However, at this level the system lacks specificity. Pathways whose evolutionary role ensured vigilance to, say, predators, are those which anticipate domestic aggression, or are perhaps programmed through antenatal stress or unpredictable pain during neonatal intensive care—a matter of degree.

Programming does not merely reflect ambient stress per se, but also how effectively it is controlled. With little capacity for independent regulation, babies depend on carers to do so. Programming is therefore influenced by the quality of attachment, reflecting parents’ physical and emotional ‘availability’, on a spectrum affected by, for example, post-natal depression, substance abuse or domestic violence. Parental stress regulation is necessary to achieve it for children.5 Secure early attachment equips the relationship-dependent prefrontal cortex to regulate automatic responses16: dysregulation is a common sustaining consequence of dysfunctional foundations.17

Regardless of foundations, trauma-induced or infection-induced epigenetic change offers a route to ‘baseline shifts’, as exemplified by post-traumatic stress disorder syndrome (PTSD).18 Adaptive ANS function may fail to ‘switch off’ when circumstances change, becoming counterproductive. For example, visceral function adaptive to infection or injury becomes unhelpful if it becomes fixed, generating chronic pain, inflammation and illness. Similarly, high reactivity beneficial to children living with aggression becomes problematic in safe circumstances—in school or in adoptive homes, for example. Like war veterans, children may go through life ‘set for action’ when little is needed, ‘fight or flight’ eroding self-esteem by engendering cause for discipline, peer relationship problems and sometimes parental rejection—pouring stress into a system set to respond dysfunctionally to it.19 ,20

Recognition

Exploring the relevance of the ANS in general paediatric practice involves noticing the detail of what is described and observed, how symptoms and signs cluster and what alleviates and exacerbates them. Recognition is helped by noting parallels with conditions seen in other specialties in paediatrics and adult medicine and with features of identified autonomic disorders (table 1, box 2). Comparisons show common themes, familiar also in everyday experience of ‘stress’, positive and negative, physical (eg, infection, exertion), environmental (eg, heat, altitude, hazard), psychological (eg, excitement, distress) or interpersonal (eg, anger or approval), and conveyed in idiom. Adult patients’ descriptions can shed light on children's experiences (table 2).

The task involves shedding preconceptions and building a jigsaw of pieces of varying clarity, adjusting this as experience accumulates. It means taking fresh perspectives on the familiar. For example, the sensory hypersensitivity, altered pain perception, emotional dysregulation and anxiety symptoms of autism make sense as manifestations of sympathetic activity inadequately modified by parasympathetic function22 via the relationship-driven prefrontal cortex—a pattern also common in once-abused children.23 Symptomatic parallels occur in migraine, cyclical vomiting, chronic fatigue syndrome (CFS/ME), PTSD and Ehlers-Danlos syndrome (EDS). In all, undampened sympathetic activity may generate physical and psychological manifestations of stress with ‘normal’ stressors—‘normal’ symptoms but incongruous with circumstances.

Experience in the few centres of excellence, particularly of rare familial autonomic disorders, needs to be optimally used.24 ,25 Checklists initially developed in relation to these should have increasing broad application, as should therapeutic insight.26 Indicators common in general paediatric contexts should prompt closer scrutiny (table 3).

The ANS underlies gastrointestinal disorders without local structural abnormality (eg, irritable bowel syndrome, gastroparesis, constipation, reflux, colic, cyclical vomiting, recurrent abdominal pain): it is, equally, contributory where abnormality is visible (eg, ulcerative colitis, Crohn's, Hirshprung's, megacolon, pyloric stenosis).27–33

The relationship of asthma to physical and psychological stressors suggests autonomic prominence. The ANS is integral to obesity through its interrelationship with leptins,34 to complications of diabetes35 and to migraine.36 It contributes to symptoms of cerebral palsy,37 Rett syndrome,38 Guillain-Barre syndrome39 and multiple sclerosis (MS) and to consequences of intrauterine drug and alcohol exposure40 and substance abuse.

The ANS influences immunity and autoimmunity and is integral to connective tissue disorders including rheumatoid arthritis, Sjogren's and systemic lupus erythematosus (SLE).41 EDS (notably ‘hypermobility type’—‘type 3’) is an under-recognised source of generalised ANS dysfunction, sometimes producing complex multisystem disability and one of many causes of postural tachycardia (PoTS) (figures 1⇓⇓–4).42 ,43 ANS immaturity contributes to apnoea of prematurity44 and to sudden infant death syndrome. Its dysfunction underlies sleep-related apnoea; its role in circadian rhythm and arousal underlies sleep disorder. ANS influence is prominent in poorly understood areas—CFS/ME, for example.45 It underlies many conditions currently described as ‘functional’.29

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Figure 1

Ehlers-Danlos syndrome hypermobility type: Hypermobility.

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Figure 2

Ehlers-Danlos syndrome hypermobility type: Acrocyanosis.

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Figure 3

Ehlers-Danlos syndrome hypermobility type: Unattributed bruising.

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Figure 4

Ehlers-Danlos hypermobility type: Raynaud's phenomenon.

The ANS is equally pertinent to problems of behaviour, concentration, emotional regulation and temper, and to symptoms of, or mimicking, mental health problems such as anxiety disorder, panic attacks, dissociation, PTSD, bipolar disorder, personality disorder and eating disorders.46–53 Anxiety, dissociative symptoms and panic would be unsurprising manifestations of autonomic dysfunction, fluctuating alongside others, without need, necessarily, to consider them ‘comorbidities’ or assume complex psychopathology, any more than is so of infection-related ‘delirium’.

ANS dysfunction complicates assessment of intercurrent illness. It mimics infection by generating pyrexia, pallor, malaise and lymphadenopathy, adding ambiguity by modulating and sometimes perpetuating pain, generalised or localised, as in chronic regional pain syndrome (CRPS). It accentuates medication side effects. The ubiquitous role of the ANS in illness illustrates reason to capitalise on, not reject, placebo effects.

One might predict greater risk for children programmed for hazard by, for example, antenatal stress, neonatal intensive care, post-natal depression, or abuse, on a spectrum of severity. Others’ histories might identify infection or trauma as flicking a (probably epigenetic) switch.

Preventing harm

ANS function matters at many levels in safeguarding children, including from iatrogenic harm.

Unhelpful programming of regulatory systems is among the most troublesome sustaining consequences of early abuse and neglect, often refractory even to successful adoption, affecting integration at home and school,14 ,15 so is an important consideration in safeguarding children. Protection requires consideration of the dependence of children's regulatory capacity on that of their parents and on adequate mutual attachment.16 Parents’ dysregulation, often reflecting their own early parenting, often managed through substance abuse and often manifest in temper problems, readily produces vicious circles of escalating parenting difficulty, dysregulated children's behaviour fuelling stress.20

The relevance of the ANS to ease of bruising, skin marking, healing rates and bone density, and to gastrointestinal control, immunity, growth and behaviour, make this an important consideration in assessment.10 ,54–56

ANS dysfunction carries risk of iatrogenic harm: physical and psychological.57 Harm may result from a lack of suitable—or suitably informed—services. If evidence determines, rather than guides services, those with unexplored conditions may lack provision. Disadvantage may result from over-specialisation, whereby each sees distorting fragments of the overall picture, allowing misassumption to flourish. Because the ANS straddles specialties, patients may fit nowhere. Since young people depend on others’ feedback in building their identity and self-perception, misattribution matters. Unrecognised knowledge gaps carry psychological risk. If, for example, ‘medically unexplained’ is irrationally equated with ‘medically inexplicable’, blame may be sensed.

Since the ANS integrates mind and body, ANS dysfunction may exaggerate the association. A little stress, of any modality, may go far. ‘Psychological’ symptoms may or may not accurately represent psychological concerns. Stress experienced as trivial and non-aversive may nevertheless generate symptoms—‘as though the body feels anxious’—potentially confusing for the child, family and professionals.

ANS disorder is ‘functional’: it produces malfunction of end-organs which have the potential to function normally. ‘Functional’ is, however, a loosely applied, variably understood term, often seen by default as synonymous with ‘psychological’, this merging hazardously with ‘volitional’ or ‘behavioural’ if undefined and afforded no mechanism. Without a mechanism other routes to the same end-point are overlooked. ‘Stress’ is readily equated with ‘negative psychological stress’ and psychopathology potentially erroneously implicated. ‘Functional’ may imply physical insignificance, inviting disbelief and judgement: a retrievably non-functioning computer is not necessarily a trivial problem. ‘Symptoms without known physical cause’ suggests that there is none, 'Symptoms real to the patient’ that they would not be to others. Language matters.

Therapeutic considerations

There is much to learn. Children's care meanwhile means working sometimes from first principles, learning from patients and from disciplines in adult medicine and paediatrics which see analogous problems, and extrapolating experience from the few international specialist centres of rare genetic ANS disorders and neurovascular medicine. There may be lessons from ‘complementary’ therapies, music, sports medicine, deep-sea diver and astronaut rehabilitation, meditation and yoga practitioners.58–60

Paediatrics may offer opportunity to optimise the baseline of stress responses, by reducing ambient stress and by facilitating parental attunement through which its effects are regulated—for example in neonatology and in supporting vulnerable parents. Neural plasticity provides justification for encouraging mollification of stress responses upregulated by, for example, early exposure to violence. The starting point is parental stress regulation: infants depend on this for theirs, and all children are influenced by it. Similarly important is protection of the attachment which mediates the link. The aim is to teach stress regulation through play, discussion and role model, implementing it through environmental calm, minimising anxiety, maximising calming through others and encouraging self-regulation (box 3).61

Established maladaptive ANS function is, in significant part, a problem in relation to prevalent demands—eased by adjusting them. For example, noisy schools or supermarkets may precipitate dysregulation for once-abused children, equipped for danger. Adults can choose environments which suit their regulatory capacity—children cannot. The aim is, however, adjustment to normality, not avoidance. Rewriting the ‘pacing’ principle from ‘a finite pot of energy’ to ‘a finite pot of tolerable stress of all modalities’ allows applicability to diverse routes to ANS dysfunction. A baseline of manageable stress, achieved by modifying the environment, may gradually be stretched towards tolerance of a less constrained one, capitalising on neural plasticity. For example, adoptive parents of previously abused children are encouraged to ‘attune but not too much’, easing towards normal opportunity.61 Problematic stressors may be rendered manageable by, for example, an otherwise calm environment, music, meditation, humour, diversion, choice and control. Minimising ‘unhelpful’ stressors reserves capacity for valuable ones, the distinction depending on individual priorities. Relaxation or exercise before demanding activities may increase capacity for them. Consequences of undampened sympathetic activity are modified by elevating vagal tone: relatively inexpensive approaches such as massage, yoga and music may be beneficial in, for example, diabetes, cerebral palsy, disordered attachment, prematurity, pain control, recovery from brain injury and the management of connective tissue and autoimmune disorder and autism.58–61

The impact on quality of life of diffuse ANS disorder may be profound, not least because of its unpredictability. There may be associated or secondary anxiety or depression, and predisposition to PTSD. While ANS dysfunction may distort the apparent significance of psychological stressors, managing them nevertheless matters. Low-key, pragmatic psychological support may be unavailable in overstretched CAMHS services; insightful specialist nurses can play an invaluable part. Factors underlying dysfunctional programming or subsequent epigenetic change may, or may not, be long-since resolved, and may, for some, bring associated difficulties. For example, those whose ANS responses were programmed dysfunctionally through abuse or neglect may also struggle with, for example, identity, self-esteem and relinquishing attention, influencing their responses to illness, sometimes warranting specific support.

Management of PoTS depends on its cause, severity and consequences. When attributable to deconditioning alone, reconditioning alone can correct it. For others, simple measures to protect circulatory volume, such as elastic stockings and high fluid and salt intake may adequately protect cerebral circulation, control secondary sympathetic overdrive and prevent deconditioning. Evaluated pharmacological options include midodrine, fludrocortisone, clonidine and octreotide among others.43 For some, complex multisystem disorder demands coordinated, multiprofessional care, facilities for which are however few.42 ,43 Because multiple factors interrelate, promptly addressing remediable stressors such as infections, pain, dehydration or psychological stress may prevent vicious circles whereby consequences of unregulated stress, recumbency and deconditioning perpetuate it. Adjusting remediable elements may allow to others correct.

Iatrogenic stress requires consideration. Potentially effective treatment presented without trust may flounder through generating stress. ‘Driven’ physiotherapy, or treatment offered in a busy, noisy environment, may fail when approaches encouraging regulation succeed. Time to listen, explain, tailor care individually and build trust may be wise economy. Pharmacological options remain, generally, off-licence for ANS dysfunction, despite evidence of efficacy. They usually facilitate rehabilitation rather than providing the sole solution.