Article 1: Physiology and Pathophysiology of the Autonomic Nervous System
Eduardo E. Benarroch, MD, FAAN. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):12–24.
PURPOSE OF THE REVIEW
This article reviews the anatomic, functional, and neurochemical organization of the sympathetic and parasympathetic outputs; the effects on target organs; the central mechanisms controlling autonomic function; and the pathophysiologic basis for core symptoms of autonomic failure.
Functional neuroimaging studies have elucidated the areas involved in central control of autonomic function in humans. Optogenetic and other novel approaches in animal experiments have provided new insights into the role of these areas in autonomic control across behavioral states, including stress and the sleep-wake cycle.
Control of the function of the sympathetic, parasympathetic, and enteric nervous system functions depends on complex interactions at all levels of the neuraxis. Peripheral sympathetic outputs are critical for maintenance of blood pressure, thermoregulation, and response to stress. Parasympathetic reflexes control lacrimation, salivation, pupil response to light, beat-to-beat control of the heart rate, gastrointestinal motility, micturition, and erectile function. The insular cortex, anterior and midcingulate cortex, and amygdala generate autonomic responses to behaviorally relevant stimuli. Several nuclei of the hypothalamus generate coordinated patterns of autonomic responses to internal or social stressors. Several brainstem nuclei participate in integrated control of autonomic function in relationship to respiration and the sleep-wake cycle. Disorders affecting the central or peripheral autonomic pathways, or both, manifest with autonomic failure (including orthostatic hypotension, anhidrosis, gastrointestinal dysmotility, and neurogenic bladder or erectile dysfunction) or autonomic hyperactivity, primary hypertension, tachycardia, and hyperhidrosis.
- The sympathetic nervous system mediates patterns of responses critical for maintenance of blood pressure, local regulation of blood flow, thermoregulation, and response to exercise and stress.
- Autonomic dysreflexia results from interruption of supraspinal pathways coordinating the activity of preganglionic sympathetic neurons.
- Norepinephrine elicits vascular and visceral smooth muscle contraction via α1 receptors, presynaptic inhibition of neurotransmitter release via α2 receptors, cardiac stimulation via β1 receptors, and vasodilation and smooth muscle relaxation via β2 and β3 receptors.
- The parasympathetic nervous system is critical for lacrimation, salivation, pupil reaction to light, beat-to-beat control of the heart rate, gastrointestinal motility and secretion, micturition, and erectile function.
- Parasympathetic neurons releasing acetylcholine activate smooth muscle contraction, exocrine gland secretion, and vasodilation via M3 receptors and inhibit cardiac function via M2 receptors; neurons releasing nitric oxide and vasoactive intestinal polypeptide elicit vasodilation and smooth muscle relaxation.
- The insula is the primary viscerosensory cortex and contributes to conscious bodily sensation.
- The anterior midcingulate cortex and the anterior insular cortex are part of the so-called salience network and are activated during tasks associated with increased sympathetic activity.
- The central nucleus of the amygdala triggers autonomic, endocrine, and motor response to emotionally salient stimuli.
- The hypothalamus initiates specific patterns of autonomic responses to internal or external stressors via projection from the paraventricular and dorsomedial nuclei and orexin/hypocretin neurons.
- The periaqueductal gray coordinates autonomic, somatomotor, and pain modulatory responses to stress.
- The parabrachial nucleus is involved in arousal, respiratory control, and modulation of cardiovascular and gastrointestinal reflexes.
- The nucleus of the solitary tract is the first relay station for medullary cardiovascular, respiratory, and gastrointestinal reflexes.
- Sympathoexcitatory neurons of the rostral ventrolateral medulla, including the C1 group, mediate the baroreflex and responses to hypoxia and other internal stressors.
- Neurons of the rostral ventromedial medulla and nucleus raphe pallidus mediate sympathoexcitatory responses to external stressors and exposure to cold.
- Arterial blood pressure is primarily regulated by the sympathetic noradrenergic input to skeletal muscle and mesenteric blood vessels, mediated by α1 receptors and driven by premotor neurons in the rostral ventrolateral medulla.
- The baroreceptor reflex is the principal mechanism for short-term, moment-to-moment control of blood pressure, buffering acute fluctuations in response to orthostatic changes or stress.
- Baroreflex-triggered sympathetic vasoconstriction mediated by α1 receptors and skeletal muscle and splanchnic vessels is critical to prevent orthostatic hypotension, which may be a manifestation of disorders affecting every step of the efferent baroreflex sympathoexcitatory pathway.
- Baroreflex afferent failure manifests with fluctuating hypertension and hypotension.
- Impaired heart rate response to deep breathing is a reliable index of cardiovagal failure.
- The sympathetic output to the sweat glands and skin blood vessels is critical for thermoregulation.
- Peripheral autonomic denervation results in exaggerated responsiveness of target organs to cholinergic or adrenergic agonists (denervation supersensitivity).
Article 2: Autonomic History, Examination, and Laboratory Evaluation
William P. Cheshire Jr, MD, FAAN. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):25–43.
PURPOSE OF REVIEW
Autonomic disorders offer a fascinating view of the complexity of the nervous system. Their impact on human health ranges from benign to severe. Deciphering autonomic symptoms and signs draws on the cognitive skills and personal interest in the plight of patients that first attracted many physicians to the field of neurology. This article provides tools to sharpen those skills.
Autonomic neuroscience and accumulated clinical knowledge have led to the categorization of autonomic disorders into specific syndromes that can be identified on the basis of clinical phenotypes and physiologic responses to standardized stimuli in the autonomic laboratory. A key development has been the ability to distinguish neurogenic orthostatic hypotension from other causes of hypotension. Quantification of sudomotor responses has proven valuable in the diagnosis of thermoregulatory disorders and small fiber neuropathies such as those related to diabetes mellitus. Increasing attention has focused on autonomic failure as a defining feature of neurodegenerative α-synucleinopathies, especially multiple system atrophy. As awareness of autonomic disorders has increased, the once obscure term dysautonomia has entered into common parlance.
With appropriate knowledge and experience, neurologists can diagnose autonomic dysfunction accurately and with confidence. The opportunity to play an important role in caring for patients with autonomic disorders is worth the effort.
- Autonomic disorders are common and diverse in character and can present with sustained or episodic hypofunction or hyperfunction of sympathetic or parasympathetic systems.
- A thoughtful autonomic history is the most important component of the evaluation of the patient with autonomic symptoms. The art of the history consists in taking a jumble of clues and formulating a coherent set of questions and conclusions.
- Key aspects of the autonomic history are timing of onset, temporal course, associated illness or context, modifying factors, and use of medications and dietary supplements.
- The impact of autonomic symptoms on daily functioning and quality of life is important. Standing activities may be limited, and tolerance of heat or cold may be impaired. Social and job-related function may also be impaired.
- Dysautonomias are syndromic and cluster into recognizable patterns of presentation that help to organize the history and examination.
- Sympathetic noradrenergic failure causes neurogenic orthostatic hypotension, which is often worse in the morning, in hot environments, after exercise, or after meals.
- Sympathetic noradrenergic hyperactivity causes hypertension, tachycardia, palpitations, pupillary dilatation, and piloerection.
- Sympathetic adrenergic failure occurs in adrenal failure and presents with fatigue. Sympathetic adrenergic hyperactivity causes palpitations, dilated pupils, facial pallor, palmar sweating, and decreased intestinal motility.
- Sympathetic cholinergic failure causes hypohidrosis or anhidrosis. When severe or widespread, patients may be at risk for heat-related illness, including heatstroke. Anticholinergic medications or carbonic anhydrase inhibitors can contribute to anhidrosis.
- Sympathetic cholinergic hyperactivity causes increased sweating. Opioids, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors may contribute to sweating. Consider serotonin syndrome in the patient who has increased the dose of a serotonergic agent.
- Orthostatic hypotension is a sustained reduction in systolic blood pressure of >20 mm Hg within 3 minutes of standing, with or without symptoms. Orthostatic hypotension cannot be diagnosed by symptoms alone but requires measurement of blood pressure.
- Postural tachycardia syndrome is a sustained increase in heart rate during standing or head-up tilt ≥30 beats/min above baseline, or, for patients younger than 20 years of age, ≥40 beats/min above baseline. The tachycardia must not be in response to orthostatic hypotension.
- About one-third of orthostatic hypotension is neurogenic, as recognized by impaired blood pressure responses to the Valsalva maneuver and by deficient reflex tachycardia. Blood pressure drops in neurogenic orthostatic hypotension can also be more profound than orthostatic hypotension that does not have a neurogenic basis.
- Harlequin syndrome consists of strikingly unilateral facial flushing provoked by heat stress. The opposite side of the face, which remains pale, is abnormal and lacks sympathetic vasomotor innervation.
- Physicians who perform autonomic testing should be knowledgeable about the autonomic nervous system and its disorders.
- The quantitative sudomotor axon reflex test evaluates distal postganglionic sudomotor neurons innervating eccrine glands. This test is a sensitive method for detecting small fiber peripheral neuropathies, but the results can be confounded by medications that inhibit sweating. Such medications should be withheld in advance of testing when it is safe to do so.
- A sensitive test of cardiovagal function is the variation in heart rate with sinusoidal deep breathing, which assesses respiratory sinus arrhythmia. Another method is the Valsalva ratio, which is the maximum heart rate divided by the minimum heart rate in response to straining.
- The Valsalva maneuver consists of four phases. Phases I and III are mechanical and occur at the beginning and end of straining. Baroreflex-sympathoneural (noradrenergic cardiovascular) function is assessed by how quickly and completely the blood pressure recovers during phases II and IV and overshoots in phase IV in response to the drop in blood pressure early in phase II that occurs in response to straining.
- Not all tilt-table tests are the same, but the duration and conditions of the test are adjusted to the goals of the test. A duration of 5 minutes is sufficient to establish neurogenic orthostatic hypotension. Longer durations of tilt are needed when assessing orthostatic intolerance and syncope.
- Personal health devices that display autonomic data such as heart rate and blood pressure are increasingly available to patients. Such data have become part of the autonomic evaluation. The numbers can be useful, but they can also be misinterpreted.
- Dysautonomia is not a specific diagnosis but rather a broad category. No one universal treatment exists for “dysautonomia.” Treatment decisions must be directed to the patient’s specific diagnosis and condition.
Article 3: Autoimmune Autonomic Disorders
Steven Vernino, MD, PhD, FAAS, FAAN. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):44–57.
PURPOSE OF REVIEW
Autonomic disorders sometimes occur in the context of systemic autoimmune disease or as a direct consequence of autoimmunity against the nervous system. This article provides an overview of autonomic disorders with potential autoimmune etiology.
Recent evidence highlights a close association between the autonomic nervous system and inflammation. The autonomic nervous system regulates immune function, and autonomic manifestations may occur in a number of systemic autoimmune diseases. In a few instances, autoimmunity directly influences autonomic function. Autoimmune autonomic ganglionopathy is the prototypic antibody-mediated autonomic disorder. Over time, a better understanding of the clinical spectrum of autoimmune autonomic ganglionopathy, the significance of ganglionic nicotinic acetylcholine receptor antibodies, other immune-mediated autonomic neuropathies, and autonomic manifestations of other systemic or neurologic autoimmune disorders has emerged.
Autoimmune autonomic disorders may be challenging, but correct identification of these conditions is important. In some cases, potential exists for effective immunomodulatory treatment.
- The autonomic nervous system regulates inflammation through a cholinergic anti-inflammatory reflex.
- Some cases of autoimmune autonomic failure are associated with antibodies against the ganglionic nicotinic acetylcholine receptor.
- Synaptic transmission in all autonomic ganglia requires acetylcholine and the ganglionic nicotinic acetylcholine receptor.
- Autoimmune autonomic ganglionopathy is an antibody-mediated disorder caused by antibodies to the ganglionic nicotinic acetylcholine receptor.
- Features of autoimmune autonomic ganglionopathy include prominent cholinergic failure, orthostatic hypotension, and abnormal pupillary light responses.
- Paresthesia (but not pain) occurs in autoimmune autonomic ganglionopathy without objective evidence of sensory neuropathy.
- Low levels of ganglionic nicotinic acetylcholine receptor (<0.2 nmol/L) antibody are nonspecific and should not be considered diagnostic of an autoimmune autonomic disorder.
- Immunotherapy may be beneficial for autoimmune autonomic ganglionopathy.
- Intermediate levels of ganglionic nicotinic acetylcholine receptor antibodies may be associated with chronic cases of autoimmune autonomic ganglionopathy or with limited forms of autonomic failure such as isolated gastrointestinal dysmotility.
- Chronic idiopathic anhidrosis is suspected to be an autoimmune disorder but is not associated with ganglionic nicotinic acetylcholine receptor antibodies.
- Acute autonomic and sensory neuropathy differs from autoimmune autonomic ganglionopathy in clinical features and response to treatment and is not associated with ganglionic nicotinic acetylcholine receptor antibodies.
- The clinical features of acute immune-mediated sensory and autonomic neuropathy are varied but often include neuropathic pain, orthostatic hypotension, and gastrointestinal dysmotility.
- Paraneoplastic autonomic neuropathy is most commonly associated with small cell lung carcinoma and anti-Hu antibodies.
- Severe gastrointestinal dysmotility with gastroparesis is the most common presentation of paraneoplastic autonomic/enteric neuropathy.
- Other clinical syndromes such as limbic encephalitis may coexist with paraneoplastic autonomic neuropathy.
- Patients with Lambert-Eaton myasthenic syndrome commonly report dry mouth, constipation, and sexual dysfunction.
- Various autonomic disturbances can be seen in patients with Guillain-Barré syndrome independent of the severity of muscle weakness.
- Autonomic hyperactivity (hypertension, tachycardia, hypersalivation) can be seen in disorders associated with voltage-gated potassium channel complex antibodies (leucine-rich glioma inactivated protein 1 [LGI1] and contactin-associated proteinlike 2 [CASPR2]).
- Central autonomic dysfunction may be seen in patients with N-methyl-d-aspartate (NMDA) receptor antibody encephalitis.
- Encephalitis associated with severe gastrointestinal dysmotility has been associated with dipeptidyl-peptidase–like protein 6 (DPPX) antibodies.
- Autonomic dysfunction may be seen in patients with Sjögren syndrome.
- Autonomic symptoms in Sjögren syndrome are mostly cholinergic. In addition to sicca symptoms, orthostatic intolerance with tachycardia and gastrointestinal symptoms are seen.
- Various degrees of autonomic dysfunction have been reported in systemic lupus erythematosus, rheumatoid arthritis, and scleroderma and may represent effects of deconditioning and chronic systemic inflammation rather than autonomic neuropathy.
- An autoimmune basis for postural tachycardia syndrome has been proposed but not yet proven.
- Various autoantibodies have been found in patients with postural tachycardia syndrome.
Article 4: Autonomic Peripheral Neuropathy
Roy Freeman, MBChB. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):58–71.
PURPOSE OF REVIEW
This article provides a summary of the autonomic neuropathies, including neuropathies associated with diabetes mellitus, neuropathies due to amyloid deposition, immune-mediated autonomic neuropathies (including those associated with a paraneoplastic syndrome), inherited autonomic neuropathies, and toxic autonomic neuropathies. The presenting features, diagnostic investigations, and natural history of these neuropathies are discussed.
Recent findings in autonomic peripheral neuropathy include data on the epidemiology and atypical presentations of diabetic autonomic neuropathy, treatment-induced neuropathy of diabetes mellitus, the presentation of immune-mediated neuropathies, and advances in hereditary neuropathy associated with amyloidosis and other hereditary neuropathies.
Knowledge and recognition of the clinical features of the autonomic neuropathies, combined with appropriate laboratory and electrophysiologic testing, will facilitate accurate diagnosis and management.
- A generalized autonomic neuropathy typically occurs in the setting of a generalized diabetic polyneuropathy but may occur in isolation.
- Treatment-induced neuropathy of diabetes mellitus should be considered when a patient with diabetes mellitus presents with the sudden onset of pain and autonomic dysfunction. This is a reversible diabetic peripheral neuropathy.
- Prominent autonomic features do not occur in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and when patients present with such features, alternative diagnoses should be considered. The peripheral neuropathy associated with hereditary amyloidosis is sometimes misdiagnosed as CIDP, particularly in nonendemic areas.
- The peripheral neuropathy associated with hereditary transthyretin amyloidosis has a heterogeneous presentation, even within families in endemic areas.
- When autonomic features occur in combination with peripheral nerve excitability and neuropsychiatric features such insomnia, agitation, hallucinations, and memory loss, antibodies to the voltage-gated potassium channel complex protein should be considered.
- Among the hereditary sensory and autonomic neuropathies (HSANs), autonomic manifestations are most prominent in HSAN III (also known as Riley-Day syndrome or familial dysautonomia). HSAN III is caused by homozygous mutations in the ELP1 gene.
- Chemotherapeutic agents are the most common cause of a toxic autonomic neuropathy. Predisposing factors to a chemotherapy-induced peripheral neuropathy include genetic factors and an underlying clinical or subclinical peripheral neuropathy.
Article 5: Synucleinopathies
Elizabeth A. Coon, MD; Wolfgang Singer, MD. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):72–92.
PURPOSE OF REVIEW
This article reviews the α-synucleinopathies pure autonomic failure, multiple system atrophy, dementia with Lewy bodies, and Parkinson disease with respect to autonomic failure.
The pattern and severity of autonomic involvement in the synucleinopathies is related to differences in cellular deposition and neuronal populations affected by α-synuclein aggregation, which influences the degree and manifestation of autonomic failure. Clinical and laboratory autonomic features distinguish the different synucleinopathies based on pattern and severity. These features also determine which patients are at risk for evolution from pure autonomic failure to the synucleinopathies with prominent motor involvement, such as multiple system atrophy, dementia with Lewy bodies, or Parkinson disease.
Autonomic failure is a key feature of the synucleinopathies, with varying type and degree of dysfunction from predominantly peripheral involvement in the Lewy body disorders to central involvement in multiple system atrophy.
- α-Synuclein aggregation in central and peripheral autonomic structures may lead to autonomic manifestations of orthostatic hypotension, urogenital dysfunction, gastrointestinal dysmotility, or thermoregulatory dysfunction.
- Rapid eye movement sleep behavior disorder is a unifying feature of the synucleinopathies and may precede autonomic or motor features in the various diseases.
- Pure autonomic failure is a sporadic, gradually progressive neurodegenerative disorder characterized by orthostatic hypotension with a tendency for syncope.
- Supine hypertension is found in approximately half of all patients with pure autonomic failure; it may be severe and often complicates treatment of orthostatic hypotension.
- The diagnosis of pure autonomic failure is based on detection of orthostatic hypotension, usually with clinical history or evaluation consistent with widespread autonomic failure.
- Evaluation in pure autonomic failure reveals peripheral involvement with decreased uptake on cardiac functional imaging and low levels of supine norepinephrine that have minimal to no increase upon standing.
- A subset of patients with pure autonomic failure phenoconvert to a synucleinopathy with motor or cognitive impairment, or both. Greater severity and earlier autonomic symptoms with central autonomic failure on autonomic testing predicts conversion to multiple system atrophy (MSA).
- MSA is characterized by autonomic failure with motor symptoms of predominant parkinsonism (MSA-P) or predominant cerebellar ataxia (MSA-C), although parkinsonism and ataxia often overlap later in disease.
- Autonomic dysfunction in MSA tends to occur early and be severe, with orthostatic hypotension that may have concomitant supine hypertension and genitourinary failure characterized by sexual dysfunction and urinary retention leading to incontinence.
- Autonomic function testing in MSA generally shows orthostatic hypotension with central autonomic dysfunction characterized by a large degree of anhidrosis on thermoregulatory sweat test with relatively preserved quantitative sudomotor axon reflex test volumes.
- Characteristic brain MRI findings in MSA include the putaminal rim sign, which is more commonly seen in MSA-P, and the hot cross bun sign, which is more commonly seen in MSA-C.
- Treatment for MSA involves a multidisciplinary team managing autonomic failure, motor features, sleep, and respiratory dysfunction.
- The neuropathologic hallmark of MSA is oligodendroglial cytoplasmic inclusions, which are frequently found in the substantia nigra, basal ganglia, brainstem, cerebellum, and spinal cord.
- The diagnosis of dementia with Lewy bodies (DLB) is based on the presence of dementia, often with early prominent deficits in attention, executive function, and visuoperceptual ability along with core clinical features that include fluctuating cognition, visual hallucinations, rapid eye movement sleep behavior disorder, and parkinsonism. Syncope and severe autonomic dysfunction are supportive clinical features.
- The degree of autonomic failure in DLB is less severe than MSA but more prominent than typically seen in Parkinson disease.
- Constipation, neurogenic bladder, and orthostasis are common nonmotor symptoms in Parkinson disease reflecting autonomic dysfunction.
- Orthostatic hypotension is found in 30% to 50% of all patients with Parkinson disease, and treatment with dopaminergic medications may contribute to blood pressure drop.
- Thermoregulatory dysfunction in Parkinson disease may manifest as heat or cold intolerance, intermittent hyperhidrosis episodes, and hypohidrosis.
- The Lewy body disorders typically have early and more extensive peripheral α-synuclein involvement, although central involvement of autonomic structures likely contributes to orthostatic hypotension in DLB.
Article 6: Postural Tachycardia Syndrome and Neurally Mediated Syncope
Jeremy K. Cutsforth-Gregory, MD. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):93–115.
PURPOSE OF REVIEW
This article reviews the diagnosis and management of the most common disorders of orthostatic intolerance: postural tachycardia syndrome (POTS) and neurally mediated syncope.
POTS is a heterogeneous syndrome caused by several pathophysiologic mechanisms that may coexist (limited autonomic neuropathy, hyperadrenergic state, hypovolemia, venous pooling, joint hypermobility, deconditioning). Neurally mediated syncope occurs despite intact autonomic reflexes. Management of orthostatic intolerance aims to increase functional capacity, including standing time, performance of daily activities, and exercise tolerance. Nonpharmacologic strategies (fluid and salt loading, physical countermaneuvers, compression garments, exercise training) are fundamental for patients with POTS, occasionally complemented by medications to raise blood pressure or slow heart rate. Neurally mediated syncope is best managed by recognition and avoidance of triggers.
Significant negative effects on quality of life occur in patients with POTS and in patients with recurrent neurally mediated syncope, which can be mitigated through targeted evaluation and thoughtful management.
- The normal response to standing, via activation of the baroreflex, is a small fall in systolic blood pressure, a small rise in diastolic blood pressure, and a small rise in heart rate.
- Orthostatic intolerance is the inability to tolerate upright posture because of symptoms of cerebral hypoperfusion or sympathetic activation, or both, which are relieved with recumbency.
- Postural tachycardia syndrome (POTS) is the most prevalent form of orthostatic intolerance.
- POTS is defined as a symptomatic and sustained heart rate increment of 30 beats/min or more within 10 minutes of standing or head-up tilt in the absence of orthostatic hypotension; the standing heart rate is often 120 beats/min or higher. For individuals 12 to 19 years of age, the required increment is at least 40 beats/min.
- The main POTS mechanisms are impaired sympathetically mediated vasoconstriction in the lower limbs (neuropathic POTS), excessive cardiac sympathoexcitatory responses (hyperadrenergic POTS), volume dysregulation, joint hypermobility, and physical deconditioning.
- A postinfectious autoimmune process is likely in many patients with POTS, as evidenced by an antecedent illness of presumed viral etiology in approximately one-half and organ-specific autoantibodies in up to one-third.
- Hyperadrenergic POTS is characterized by episodes of tachycardia, sweating, and hypertension that can be triggered by upright posture, physical activity, and emotional stimuli, and episodes may even occur during sleep.
- Most patients with POTS have some degree of hypovolemia, with low plasma and total blood volumes resulting in reduced cardiac preload upon standing.
- A sizable minority of patients with POTS have hypermobile joints consistent with an underlying disorder of the connective tissue matrix, most commonly Ehlers-Danlos syndrome hypermobility type.
- Many patients with POTS have additional chronic conditions, including inappropriate sinus tachycardia, migraine and other headaches, visceral hypersensitivity, gastrointestinal dysmotility, chronic fatigue, insomnia, and fibromyalgia.
- The syndrome of inappropriate sinus tachycardia is defined as a sinus heart rate higher than 100 beats/min at rest, with a mean 24-hour heart rate higher than 90 beats/min, accompanied by bothersome palpitations.
- Patients with suspected POTS should undergo comprehensive cardiac and neurologic examinations, supine and standing heart rate and blood pressure measurement, and a 12-lead ECG.
- The primary objective of POTS management is to improve patients’ functional capacity (ie, increase the time that they can stand, perform daily activities, and exercise).
- Physical counterpressure maneuvers for patients with POTS aim to counteract venous pooling and include crossing the legs, bending forward at the waist, rising on toes, slow marching in place, and squatting.
- Compression garments for patients with POTS should cover the abdomen and thighs.
- Patients with POTS should engage in a graduated exercise program that includes both endurance and resistance training.
- Medications should be considered for treatment of POTS only after nonpharmacologic strategies have been implemented.
- Beta-blockers are probably most beneficial for patients with hyperadrenergic POTS.
- Pyridostigmine reduces orthostatic tachycardia and improves chronic symptoms of POTS without aggravating supine hypertension.
- Syncope is a transient loss of consciousness and postural muscle tone due to global cerebral hypoperfusion, with relatively abrupt onset and spontaneous, complete, and relatively prompt recovery.
- Syncope can occur at any age, with the first peak usually occurring in the teen or young adult years and a second peak near 80 years of age. Syncope at younger age is usually the neurally mediated type.
- The typical episode of neurally mediated syncope can be divided into prodrome and unresponsive phases. The prodrome can be of variable duration, generally less than 1 minute, and is recognized or later recalled by only two-thirds of patients.
- When syncope occurs abruptly without any prodrome, the clinician should be suspicious for ventricular arrhythmia.
- Prolonged unresponsiveness in alleged syncope should raise concern for epilepsy, vertebrobasilar insufficiency, subarachnoid hemorrhage, traumatic brain injury, hypoglycemia, drug or medication intoxication, or psychogenic pseudosyncope.
- Convulsive syncope can be distinguished from an epileptic seizure by the number of myoclonic jerks: fewer than 10 in syncope, more than 20 in seizures.
- Neurally mediated syncope is associated with one or both of two hemodynamic patterns. The vasodepressor pattern is an abrupt fall in blood pressure that occurs beyond the time cutoff (3 minutes) for orthostatic hypotension; the cardioinhibitory pattern is a pronounced bradycardia of fewer than 40 beats/min or asystole of more than 3 seconds.
- Vasovagal syncope may be a protective reflex response to excessive sympathetic activity, to which the heart is particularly prone.
- Prodromal symptoms typically occur when mean blood pressure falls below 60 mm Hg. Unresponsiveness occurs below 50 mm Hg at heart level, corresponding to 30 mm Hg cerebral arterial pressure.
- In contrast to postexertional syncope, which is a benign reflex syncope, syncope during exertion points toward ventricular arrhythmias, atrioventricular block, hypertrophic obstructive cardiomyopathy, aortic stenosis, or subclavian steal syndrome.
- Patients with psychogenic pseudosyncope often deny any prodrome, report longer periods of apparent loss of consciousness (up to several minutes), and may be suggestible. A definite diagnosis of psychogenic pseudosyncope is made by recording normal blood pressure, heart rate, and EEG during an episode.
- Tilt-table test results must be interpreted with caution, as both false negatives and false positives are common.
- Neurally mediated syncope, especially vasovagal and the various situational syncopes, is most effectively managed by recognition and avoidance of triggers.
Article 7: Sweating Disorders
Elizabeth A. Coon, MD; William P. Cheshire Jr, MD, FAAN. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):116–137.
PURPOSE OF REVIEW
This article reviews disorders of sweating, including hyperhidrosis and anhidrosis due to central or peripheral autonomic nervous system causes.
Disorders of thermoregulation and sweating may manifest with hyperhidrosis or hypohidrosis/anhidrosis. Primary disorders of hyperhidrosis may significantly impact quality of life yet tend to be benign. Many sweating disorders present with compensatory hyperhidrosis due to areas of anhidrosis. Anhidrosis may occur due to either central or peripheral damage to the autonomic nervous system. The thermoregulatory control of sweating involves central pathways from the hypothalamus to the brainstem and then spinal cord as well as projections to peripheral structures, including the sympathetic chain ganglia, peripheral nerves, and eccrine sweat glands. Disruption at any point of this pathway may lead to impaired sweating. Characterization of sweating dysfunction helps localize different autonomic disorders to guide diagnosis and may allow for evaluation of treatment effect.
Sweating dysfunction manifests in myriad ways, including essential hyperhidrosis, complete anhidrosis with heat intolerance, and compensatory hyperhidrosis due to anhidrosis, and often indicates involvement of underlying central or peripheral autonomic dysfunction.
- Warm-sensitive neurons in the preoptic nucleus of the hypothalamus respond to subtle changes in core temperature to invoke a sympathetic nervous system response of generalized sweating, vasodilation, and hyperpnea triggering radiant and evaporative heat loss.
- Innervation of sweat glands is predominantly by unmyelinated C fibers to cholinergic M3-type receptors.
- The highest density of sweat glands involved in thermoregulation is on the forehead, followed by the upper limbs and then the trunk and lower limbs, whereas acral (hands and feet) sweating is chiefly triggered by emotional stimuli.
- Hyperhidrosis is defined as excessive sweating beyond the need to maintain core temperature; it tends to be more socially limiting than medically worrisome.
- Medications frequently cause hyperhidrosis, with common offenders including selective serotonin reuptake inhibitors, opioids, and prostaglandin inhibitors.
- Shapiro syndrome is characterized by episodic hypothermia and hyperhidrosis with abnormalities of midline structures, such as agenesis of the corpus callosum.
- Paroxysmal sympathetic hyperactivity after acquired brain injury is characterized by paroxysmal sympathetic overreactivity leading to diaphoresis, fever, flushing, shivering, hypertension, tachypnea, tachycardia, and, occasionally, motor involvement.
- Primary focal hyperhidrosis frequently involves palms and soles and may significantly interfere with quality of life.
- Treatment options for primary focal hyperhidrosis include topical agents, systemic medications, iontophoresis, or endoscopic thoracic sympathotomy.
- Cold-induced sweating syndrome is a genetic disorder characterized by profuse truncal sweating when exposed to cold with paradoxical anhidrosis when exposed to heat.
- Autonomic dysreflexia may occur in patients with spinal cord injuries with lesions above T6 and is characterized by hypertension with concomitant bradycardia and facial flushing with profuse sweating above the level of the spinal cord lesion.
- Treatment for autonomic dysreflexia involves fast-acting antihypertensives with urgent identification of the trigger, such as bowel or bladder distension or skin irritation.
- Harlequin syndrome is characterized by hemifacial flushing and hyperhidrosis contralateral to sympathetic denervation and may include Horner syndrome when oculosympathetic fibers are involved.
- Patients with multiple system atrophy typically have a high degree of anhidrosis, which is predominantly due to a central/preganglionic lesion.
- Patients with Parkinson disease typically have mild distal anhidrosis that is peripheral in origin, whereas patients with dementia with Lewy bodies also show a peripheral pattern of sweat loss that is to a greater degree than in patients with Parkinson disease.
- Patients with autoimmune autonomic ganglionopathy may manifest a high degree of anhidrosis, which tends to increase distally; the degree of autonomic failure may correlate with the antibody titer.
- Familial dysautonomia is characterized by episodes of orthostatic hypotension or hypertension in addition to profuse sweating related to underlying neuropathy and central sudomotor pathway hyperexcitability.
- Diabetic autonomic neuropathy is the most common cause of autonomic neuropathy and may manifest as length-dependent sweat loss and focal areas of anhidrosis or lead to global anhidrosis when severe.
- Chronic idiopathic anhidrosis is characterized by heat intolerance and widespread anhidrosis in the absence of accompanying autonomic failure; the pattern of anhidrosis may be preganglionic or postganglionic.
Article 8: Autonomic Hyperactivity
Alejandro A. Rabinstein, MD, FAAN. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):138–153.
PURPOSE OF REVIEW
Autonomic hyperactivity is a relatively common consequence of severe acute brain injury and can also be seen with spinal cord and peripheral nerve disorders. This article reviews basic pathophysiologic concepts regarding autonomic hyperactivity, its various forms of clinical presentation, and practical management considerations.
Paroxysmal sympathetic hyperactivity is most common after traumatic brain injury but can also occur after other forms of severe acute diffuse or multifocal brain injury. Formal criteria for the diagnosis and severity grading of paroxysmal sympathetic hyperactivity have now been proposed. A growing body of literature is beginning to elucidate the mechanisms underlying this disorder, but treatment remains based on observational data. Our mechanistic understanding of other distinct forms of autonomic hyperactivity, such as autonomic dysreflexia after traumatic spinal cord injury and dysautonomia after Guillain-Barré syndrome, remains rudimentary, yet clinical experience shows that their appropriate management can minimize the risk of serious complications.
Syndromes of autonomic hyperactivity can result from injury at all levels of the neuraxis. Much more research is needed to refine our understanding of these disorders and guide optimal management decisions.
- Recognition of autonomic hyperactivity is important because it can provoke dangerous complications.
- Injury at multiple levels of the neuraxis can cause autonomic hyperactivity.
- Damage causing disconnection of sympathetic centers from descending inhibitory pathways and maladaptive changes in the spinal cord can result in excessive sympathetic responses.
- Sympathetic signs predominate in most patients with central autonomic hyperactivity.
- Autonomic hyperactivity may cause exaggerated responses to various medications and therefore puts patients at risk of serious iatrogenic complications.
- Careful attention can reliably distinguish paroxysmal sympathetic hyperactivity caused by brain injury from adrenergic manifestations of sepsis, pulmonary embolism, or seizures.
- Paroxysmal sympathetic hyperactivity can be seen in up to one-third of patients with severe traumatic brain injury.
- Standardized criteria have been proposed for the diagnosis and severity assessment of paroxysmal sympathetic hyperactivity.
- Young age and coma are associated with higher risk of paroxysmal sympathetic hyperactivity.
- Deep brain lesions affecting connecting tracts, as seen with diffuse axonal injury, are commonly seen in patients with paroxysmal sympathetic hyperactivity.
- Management of paroxysmal sympathetic hyperactivity includes minimizing stimulation and using abortive (eg, morphine) and preventive (eg, gabapentin and propranolol) medications.
- Paroxysmal sympathetic hyperactivity can negatively affect the outcome of traumatic brain injury.
- Although primarily a complication of traumatic brain injury, paroxysmal sympathetic hyperactivity can occur after other forms of acute brain injury, most notably global anoxia-ischemia.
- Autonomic dysreflexia occurs after severe spinal cord injury at the cervical or upper thoracic (T5 and above) levels.
- Episodes of autonomic dysreflexia are often triggered by urinary retention, fecal impaction, or nursing care.
- Sudden hypertension is the most common and most serious manifestation of autonomic dysreflexia.
- Close attention to potential triggers is the key element in the management of autonomic dysreflexia.
- The clinical presentation of dysautonomia in Guillain-Barré syndrome is unpredictable and potentially life-threatening.
- Rapid fluctuations in blood pressure and heart rate, urinary retention, and adynamic ileus are the most prevalent expressions of dysautonomia in Guillain-Barré syndrome.
- Dysautonomic signs in patients with Guillain-Barré syndrome are best managed conservatively to prevent iatrogenic complications.
Article 9: Management of Orthostatic Hypotension
Jose-Alberto Palma, MD, PhD; Horacio Kaufmann, MD, FAAN. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):154–177.
PURPOSE OF REVIEW
This article reviews the management of orthostatic hypotension with emphasis on neurogenic orthostatic hypotension.
Establishing whether the cause of orthostatic hypotension is a pathologic lesion in sympathetic neurons (ie, neurogenic orthostatic hypotension) or secondary to other medical causes (ie, non-neurogenic orthostatic hypotension) can be achieved by measuring blood pressure and heart rate at the bedside. Whereas fludrocortisone has been extensively used as first-line treatment in the past, it is associated with adverse events including renal and cardiac failure and increased risk of all-cause hospitalization. Distinguishing whether neurogenic orthostatic hypotension is caused by central or peripheral dysfunction has therapeutic implications. Patients with peripheral sympathetic denervation respond better to norepinephrine agonists/precursors such as droxidopa, whereas patients with central autonomic dysfunction respond better to norepinephrine reuptake inhibitors.
Management of orthostatic hypotension is aimed at improving quality of life and reducing symptoms rather than at normalizing blood pressure. Nonpharmacologic measures are the key to success. Pharmacologic options include volume expansion with fludrocortisone and sympathetic enhancement with midodrine, droxidopa, and norepinephrine reuptake inhibitors. Neurogenic supine hypertension complicates management of orthostatic hypotension and is primarily ameliorated by avoiding the supine position and sleeping with the head of the bed elevated.
- Diagnosing orthostatic hypotension requires blood pressure measurements. The presence of orthostatic intolerance is not sufficient or necessary to diagnose orthostatic hypotension.
- Orthostatic hypotension is very common in the elderly, usually due to drug effects, volume depletion, or cardiovascular deconditioning.
- Neurogenic orthostatic hypotension is a feature of neurologic disorders affecting sympathetic pathways, including diabetes mellitus, neurodegenerative synucleinopathies, and amyloid neuropathies.
- Exercise, meals (postprandial hypotension), prolonged bed rest (physical deconditioning), and hot and humid environments typically worsen symptoms of neurogenic orthostatic hypotension.
- Patients with cognitive impairment may not accurately identify symptoms of orthostatic hypotension, despite low blood pressure when standing.
- A heart rate increase of at least 0.5 beats/min for each 1 mm Hg fall in systolic blood pressure (ΔHR/ΔSBP ratio ≥0.5 beats per minute/mm Hg) is sensitive and specific to diagnose non-neurogenic orthostatic hypotension.
- Treatment of orthostatic hypotension should be geared to the patients’ symptoms and their impact on daily function rather than a target blood pressure.
- The initial treatment of orthostatic hypotension focuses on nonpharmacologic measures first: removing offending medications, increasing salt and fluid intake, using compression garments, and instituting physical maneuvers and exercise.
- Drugs that reduce intravascular volume (eg, diuretics) or induce vasodilatation (eg, α-adrenergic blockers, nitrates, phosphodiesterase-5 inhibitors, tricyclic antidepressants, centrally acting α-adrenergic agonists) exacerbate orthostatic hypotension and worsen symptoms; thus, they should be reduced or discontinued.
- In patients with orthostatic hypotension, anemia should be investigated and treated.
- Because carbohydrate-rich meals trigger insulin, a potent vasodilator, patients with neurogenic orthostatic hypotension should reduce carbohydrate content, eat smaller and more frequent meals, and choose low glycemic index carbohydrates.
- Bolus water drinking produces a marked, albeit short-lived, increase in blood pressure in patients with neurogenic orthostatic hypotension.
- Waist-high compression stockings are effective to increase blood pressure in patients with neurogenic orthostatic hypotension, although compliance is very low. Elastic abdominal binders are a good alternative.
- Sleeping with the head of the bed raised 30 to 45 degrees reduces nocturnal hypertension, thus decreasing natriuresis, which, in turn, prevents volume depletion overnight and improves orthostatic tolerance the next morning.
- When medications for neurogenic orthostatic hypotension are used, patients should be taught to avoid the flat position, sleep with the head of the bed raised 30 to 45 degrees, and measure their own blood pressure.
- Determining the site of the autonomic lesion (central versus peripheral) in patients with neurogenic orthostatic hypotension has important therapeutic implications. Patients with central autonomic dysfunction (ie, decentralization) have a more pronounced pressor response to norepinephrine reuptake inhibitors, whereas patients with peripheral autonomic dysfunction (ie, denervation) have a more pronounced pressor response to norepinephrine enhancers and agonists.
- For patients who still remain symptomatic despite nonpharmacologic measures, stepwise pharmacologic treatment begins with low-dose fludrocortisone (0.1 mg/d), particularly in patients with volume depletion.
- Frequently used fludrocortisone dosages range from 0.05 mg/d to 0.2 mg/d. There is little benefit in increasing fludrocortisone to dosages higher than 0.2 mg/d. Common short-term side effects include hypokalemia; long-term side effects include left ventricular hypertrophy and renal failure.
- In patients with anemia of chronic disease and orthostatic hypotension, subcutaneous recombinant human erythropoietin increases blood pressure and improves orthostatic tolerance.
- When starting droxidopa, a careful titration is required to identify the best dose for each patient and prevent excessive supine hypertension.
- Treatment with norepinephrine reuptake inhibition is emerging as a potentially effective option for patients with neurogenic orthostatic hypotension, particularly those with autonomic dysfunction from damage to the central nervous system (eg, decentralization).
- Pyridostigmine alone has little effect to increase blood pressure. It appears to have synergistic effects when combined with midodrine or atomoxetine.
- Neurogenic supine hypertension is best treated with postural measures, ie, avoiding the flat position and sleeping with the head of the bed raised 30 to 45 degrees with the help of an electric bed or mattress. In patients with refractory supine hypertension and high risk of organ damage, short-acting antihypertensives at bedtime might be considered.
Article 10: Lower Urinary Tract and Bowel Dysfunction in Neurologic Disease
Jalesh N. Panicker, MD, DM, FRCP; Ryuji Sakakibara, MD, PhD, FAAN. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):178–199.
PURPOSE OF REVIEW
This article provides an overview of the clinical presentation, investigations, and treatment options for lower urinary tract and bowel dysfunction in patients with neurologic diseases.
The site of the neurologic lesion influences the pattern of lower urinary tract dysfunction. Antimuscarinic agents are first-line management for urinary incontinence; however, the side effect profile should be considered when prescribing them. β3-Receptor agonists are a promising alternative oral medication. Botulinum toxin injections into the detrusor have revolutionized the management of neurogenic detrusor overactivity.
Bowel dysfunction commonly presents as constipation and fecal incontinence. Gastrointestinal emergencies may arise, including intestinal pseudoobstruction, intussusception, volvulus, and stercoral ulcer (ulcer of the colon due to pressure and irritation resulting from severe, prolonged constipation). Bowel function tests in neurologic patients often show a combination of slow transit and anorectal dysfunction. Management for slow transit constipation includes bulking agents, softening agents, yogurt/probiotics, and prokinetic agents. Suppositories, botulinum toxin injections, and transanal irrigation are options for managing anorectal constipation.
Functions of the lower urinary tract and bowel are commonly affected in neurologic disease. Neurologists play an important role in assessing lower urinary tract and bowel symptoms in their patients and planning treatment strategies, often in collaboration with specialist teams.
- The site of the neurologic lesion influences the pattern of lower urinary tract dysfunction. Symptoms of an overactive bladder (urinary urgency, increased daytime frequency, nocturia, and, often, incontinence) are the most common presentation.
- The risk of developing upper urinary tract damage is considerably lower in patients with slowly progressive nontraumatic neurologic disorders than in those with spinal cord injury or spina bifida.
- Antimuscarinic agents are the first-line management of urinary incontinence; however, their side effect profile and impact on anticholinergic burden should be considered when prescribing in patients who are susceptible.
- β3-Receptor agonists are a promising new oral treatment for managing storage symptoms in patients with neurologic diseases.
- Intradetrusor onabotulinumtoxinA injections are a highly effective and minimally invasive treatment for storage dysfunctions.
- Percutaneous tibial nerve stimulation is a minimally invasive option for managing patients with mild to moderate overactive bladder symptoms and is associated with few adverse effects.
- The postvoid residual should be routinely measured during the workup of every patient with neurologic disease reporting lower urinary tract symptoms.
- A high postvoid residual is important to recognize as it may contribute to storage (overactive bladder) symptoms and can predispose to recurrent urinary tract infections.
- Bowel dysfunction is common in patients with neurologic diseases.
- Bowel dysfunction not only affects patients’ quality of life but may also lead to gastrointestinal emergencies.
- Bowel dysfunction is often a combination of slow transit–type constipation (slowed colonic transit time, loss of peristaltic contractions) and anorectal-type constipation (weak strain, anismus on defecation, and large postdefecation residuals).
- Bowel dysfunction should be managed with a combination of diet, exercise, and drugs.
- Collaboration between neurologists, urologists, and gastroenterologists is recommended to maximize the quality of life of patients with neurologic diseases who have lower urinary tract or bowel dysfunction.
Article 11: Skin Biopsy in Evaluation of Autonomic Disorders
Christopher H. Gibbons, MD, MMSc, FAAN; Ningshan Wang, MD, PhD; Jee Young Kim, MD; Marta Campagnolo, MD; Roy Freeman, MBChB. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic Disorders):200–212.
PURPOSE OF REVIEW
This article provides an up-to-date assessment of the role of skin biopsy in the evaluation of autonomic disorders. The standard methodology for completing a skin biopsy, the anatomic structures of interest detected within a skin biopsy, and the disease states in which skin biopsies may provide valuable information are reviewed.
Several recent advances in the studies of hereditary amyloidosis and the various degenerative synucleinopathies have demonstrated that simple skin biopsies can provide valuable pathologic evidence of neurologic disease. In addition to diagnosis of the underlying disorder, skin biopsies provide a quantitative structural measurement of the associated autonomic damage.
Skin biopsies are making great inroads into the study of autonomic and peripheral nerve disorders. Complex immunohistochemical staining protocols are challenging to complete, but the rich data derived from these studies in the diagnosis and monitoring of different disease states suggest that the role of skin biopsies in the study of the autonomic nervous system will continue to expand in the years to come.
- Standard punch biopsies 3 mm in diameter are used to obtain sections of tissue, generally from the distal leg, distal thigh, and proximal thigh sites.
- Although biopsies are frequently used to evaluate for small fiber neuropathy by quantifying the nerve fibers within the epidermis, autonomic innervation is all contained within the deeper dermal tissue.
- Pilomotor nerve fibers predominantly contain sympathetic adrenergic innervation.
- Sweat glands contain sympathetic cholinergic (also known as sudomotor) nerve fibers. Quantitation of sweat gland density without reporting the area of sweat glands measured is a common error by laboratories and limits the utility of this technique.
- In patients with hereditary amyloidosis, skin biopsy can provide quantitative assessment of neuropathy severity, but it can also provide pathologic confirmation of disease by detection of the presence of amyloid through Congo red staining.
- Skin biopsies are used in research studies to measure phosphorylated α-synuclein to aid in confirming a diagnosis of an α-synucleinopathy such as Parkinson disease, multiple system atrophy, pure autonomic failure, or Lewy body dementia.