1Hasan Abdallah, MD Children’s Heart Institute DysautonomiasHasan Abdallah, MDChildren’s Heart Institute
2DysautonomiasDefinition:altered autonomic function
3HistoryGalen(2nd Century): Nerves are hollow tubes distributing “animal spirits” to body parts enabling concerted action, or “sympathy” of the organs.Eustachius (1552): anatomy of the sympathetic nerves and the adrenal glandsAbel and Takamine(1895): identified epinephrine as the active principle of the adrenal gland.Langley ( 1898) introduced the term autonomic nervous system to denote the portion of the nervous system largely responsible for involuntary, unconscious functions of internal organs.Cannon(1920): the sympathetic nerves and adrenal medulla is a functional unit—the “sympathico-adrenal” system.
4Scope of the ProblemUp to 1% of teenagers are debilitated with chronic fatigue.Autonomic dysfunction is identified in around 50% patients with CFS
5Autonomic Nervous System ( ANS) ANATOMY AND PHYSIOLOGY Sympathetic (thoracolumbar)Parasympathetic (craniosacral)EntericThe ANS is largely involuntary motor/ effector system.The CAN (Central Autonomic Network)Maintains integral relationships with visceral sensory neurons via afferentinput from the vagus nerve and relays transmissionthrough the nucleus tractus solitarius to the hypothalamus,amygdala, and forebrain.Autonomic Outflow Discharge: Occur independently, partially regulated and integrated by the central autonomic network (CAN)
7ANSComplex System:Pervasive and integrates multiple secondary functions so that symptoms can be widespread and confounding.Autonomic Dysfunction is often associated sensory perturbations, because the development of the Autnomic and sensory systems are closely linked
8Embryologic Development Development of the ANS is intimately related to thedevelopment of the sensory nervous system;both have their embryonic origins in the multipotential neuralcrest cells. These cells migrate and eventually evolve intosensory and autonomic ganglia as well as the adrenalchromaffin cells.Their differentiation and commitmentto function in the mature nervous system is incumbenton exposure to growth factors released by structuresalong the migratory route and then within the targettissue.
10Fuctional Oraganization of the Autonomic Nervous System Inhibitory input from mechanoreceptors in the heart and aortic and carotid baroreceptors travels via afferent vagal fibers to the nucleus tractus solitarius （NTS）． Sympathetic outflow is transmitted by efferent nerve fibers to the heart， blood vesselsa nd adrenal gland via the spinal cord． Cardiac parasympathetic tone originating from the vagal nuclei is modulated by the NTS in an integrated and reciprocal fashion， The resulting autonomic tone is determined by the balance between sympathetic and parasympathetic outf1ow
11orthostatic intolerance Humans absolutely require a functionallyintact sympathetic nervous system to tolerate the “nonemergency”behavior of simply standing up. This explainswhy orthostatic intolerance constitutes a cardinal clinicalmanifestation of sympathetic neurocirculatory failure
12Autonomic Dysfunction Determine: Clinical Features Extent Severity Duration- Acute, Subacute, Chronic) Frequency- the symptoms occur (Daily, weekly, etc…) Diurnal variation Functional impact Secondary causes (e.g. Anemia, Dehydration, Deconditioning or Thyroid disorder) Possible underlying pathogenesis
13RAR = rapidly adapting receptor; SAR = slowly adapting receptor.
14Orthostatic Intolerance Symptoms occurring upon changing from the supine to the standing positions. May include: Dizziness, Lightheadedness, Blurred or Tunnel Vision Headache, Nausea Throbbing Headaches Diaphoresis Syncope
16Symptoms Associated With ANS Disorders SystemDysfunctionSymptomOphthalmologicAlacrimaDry EyeNonreactive/sluggish pupilsDark/light intolerancePtosisStrabismusAnisocoriaSevere myopiaSudomotorAltered sweatingHypohidrosis or hyperhidrosisUrologic)Delayed bladder emptyingNocturnal enuresisGIDysmotilityGasto perisis
17Gastrointestinal Symptoms NauseaEarly satiety,Abdominal cramping after meals,Frequent diarrhea or constipation (or alternating bouts of both),
18Genitourinary Symptoms May includeUrinary incontinenceUrinary frequency and urgencyUrinary retention.Erectile dysfunctionDecreased libido and inability to achieve orgasmMenstrual Disturanances
19POTS-Diagnostic Criteria Development of orthostatic symptoms associated with a heart rate (HR) increment ≥30, usually to ≥120 bpm, within 10 minutes of standing and without orthostatichypotension.Symptoms of orthostatic intolerance are those due to brain hypoperfusion and sympathetic overaction.
20POTS-Symptoms Due to Cerebral Hypoperfusion Mechanism: Cerebral autoregulation fails in relation to the onset of dyspnea, hyperpnea, and hypocarbia.Cerebral vasoconstriction in POTS ensues in affected individuals and may be diagnosed as‘‘hyperventilation syndrome’’ or ‘‘panic attack.’’ Interestingly, similar respiratory signs can beproduced in control subjects given sufficient provocation. The underlying cause oforthostatic hyperpnea remains obscure, but postural stimulation appears to be necessary, andAbnoraml interactions between carotid baroreceptor and chemoreceptors are probably the root cause.
21Acrocyanosis The distribution of color change does not mimic the distribution of discolorationin Raynaud phenomenon, which is confined to thehand and foot. Rather, as shown in Figure 1, there is morewidespread extension, especially in dependent extremities witha mottled appearance comprising islands of pink skin withnormal cutaneous blood flow interspersed among prevailingcyanosis with decreased cutaneous blood flow.
22Tachycardia of POTS could represent absolute Blood VolumeTachycardia of POTS could represent absolutehypovolemia. This has been demonstrated in some patientswith POTS41 and may relate to defective denervation of thekidneys and associated hyporeninemic hypoaldosteronism.42,43 A reflex response to fluid shifts results in thecirculatory insufficiency observed in patients.44More recentdata indicate that hypovolemia tends to be modest and maynot by itself explain orthostatic intolerance in these patients.45Nevertheless, decreased blood volume further impairs venousreturn and is at least a contributing factor:All compensatorymechanisms for orthostasis depend on circulatory volumeadequacy and all will ultimately fail during sufficiently severehypovolemia.Conversely, repletion of blood volume is oftenhelpful in orthostatic intolerance of whatever cause because itinvariably enhances postural venous return., although effects unrelated to bloodvolume may play a role. Although a primary disturbance inblood volume (or renal volume regulation) has been proposedfor some cases of POTS,47-49 volume loading may improvepatient well-being nonspecifically as well.
23physical forces comprise a primary Muscle Pumpphysical forces comprise a primarydefense against lower extremity pooling in human beings inthe form of the ‘‘skeletal muscle pump’’ in which contractionsof leg and gluteal muscles increase interstitial pressure andpropel sequestered venous blood back to the heart.Skeletalmuscle may also be involved in neurogenic compensationthrough chemoreceptors and through local controlmechanisms.Recent data indicate that while the musclepump is normal in most patients with POTS, the musclepump is defective in a subset of patients with POTS who alsohave decreased resting peripheral blood flow unrelated toexercise capability but exacerbated by bed rest.
24Neurovascular Compensation Neurovascular compensation limits dependent bloodpooling. This includes rapid peripheral arterial vasoconstrictionlimiting flow to the extremities and splanchnic vascularbed while promoting passive venous emptying.53 Activevenoconstriction occurs in the splanchnic circulation,54 butthere is little evidence for venous beds other than splanchniccontributing to active orthostatic venoconstriction; rather,recent data suggest that other veins and venules contribute tovenous return by passive elastic recoil during arterialvasoconstriction.55,56A useful way to view vascular control systems is to viewthem as long distance or local control systems.
26‘‘Local’’ Vascular Control compensatory response to orthostasisarising from local vasoactive responses are often less wellappreciated. These include endothelial vasoactive products (ie,NO, PGI-2, endothelin, EDHF)67,68 metabolites (adenosine,Ca21, CO2, H1 ions, lactate)69-71 autacoids (histamine,bradykinin, 5-HT, PAF, prostaglandins),72 local neurogenicmechanisms such as the axon reflex,73 and neurogenicinflammation (CGRP, substance P),74,75 especially withinthe cutaneous and enteric circulations. Local responsescontribute to classic myogenic, metabolic, and venoarteriolarflow control, which may be important compensatorymechanisms during
27physiologic variants of POTS distinguished on the basis of measurements of peripheralblood flow and peripheral arterial resistance in association withcharacteristic changes in regional circulations:
28ClassificationHyperadrenergic statesAutonomic neuropathy involving antiganglionic antibodiesAbsolute hypovolemiaRedistributive form of hypovolemia(central thoracic blood volume is reduced in the upright position, even though overall blood volume is normal)
31Normal-flow POTS (Pool in splanchnic circulation due to increased splanchnic blood flow) Redistributive form of hypovolemia- Splanchnic Blood flow is increased in the supine posture and during incremental tiltNormal peripheral resistance supine and enhanced peripheral resistance upright..Intact graded reflex-mediated compensatory Intense peripheral vasoconstrictionNo generalized sympathetic failure.Severe degree of gravitational dependent acrocyanosis due to stagnant hypoxiaProbable Mechanisms:Selective splanchnic denervationintact autonomic splanchnic activity confounded by local vasoactive substances e.g.Vasoactive intestinal polypeptide (VIP), substance P, or nitric oxide.
32Low-flow POTS (Uniform Hypovolemia & Reduced blood flow in multiple regional circulations ) intense peripheral vasoconstriction and low resting cardiac output while supine and decreased blood volumePallor, extensive supine and upright acrocyanosis, cool skin and extremities,Tachycardia while supine and graded tilt.Defective skeletal muscle pump commonDecreased blood flow most notable in the dependent parts of the bodysplanchnic blood flow does not change during tiltAbnormal Hyperemic blood flow indicating endothelial dysfunction and abnormal local blood flow regulation.Fluid Infusions usually helpful
33High-flow POTS (Lower body vasodilation) Increased cardiac indexIncreased peripheral blood flow,Decreased peripheral resistance in the lower extremities and pelvic segment,Unchanged peripheral blood flow during orthostatic stressMay be related to a long tract neuropathy and high cardiac output is caused by inadequate peripheral vasoconstriction supine and upright.Patients typically are acyanotic, warm to touch with extensive filtration, resulting in dependent edema.patients are peripherallyvasodilated and mildly tachycardic when supine and haverelatively increased blood volume, reduced total peripheralresistance, and high resting cardiac output compared withhealthy control subjects.1Defective Peripheral vasoconstrictionduring orthostasis remains defective, leading to excess blooddelivery to the lower limbs with enhanced microvascularfiltration and edema formation.63 Acrocyanosis does not oftenoccur. Persistent upright vasodilationresponds to vasoconstrictortherapy with midodrine or similar agents. Often suchpatients have illness after a viral infection. A perip
34POTS-ONSET, EPIDEMIOLOGY, AND NATURAL HISTORY Onset oftenfollows an infectious diseasePatients oftenslowly improve after the initial infectious illness, only tobecome ill again spontaneously or during an intercurrentinfection.1 Approximately 75% to 80% of patients are womenranging in age from 14 to 50 years22POTS is relativelyuncommon in preadolescent children and may have a distinctpathophysiology in the very young. The illness may follow a remitting andrelapsing clinical course, often enduring for years, but seems inmany instances self-limited.
35Symptoms of orthostatic intolerance LightheadednessHeadacheFatigueNeurocognitive/sleep disordersExercise intoleranceWeaknessHyperpnea/dyspneaTremulousnessNausea/abdominal painSweatingAnxiety/palpitations
36Pathophysiologic Mechanisms (not mutually exclusive) include Peripheral Autonomic DenervationHypovolemiavenous pooling,β-receptor supersensitivityImpairment of brain stem regulation.SecondaryProlonged deconditioningPsychological factorsPoor Nutrition status
37Physiological Changes upon Assuming the standing position Abrupt gravitational shift in blood volume and consequent reduction venous return to the heart. Counteracted in the normal person by activation of the baroreceptors.
38Is excessive postural tachycardia associated with deconditioning rather than merely being an independent sign of autonomic dysfunction in patients with POTS?Conclusion:HR changes in POTS are not solely because of inactivity resulting in deconditioningBarbara E. U. Burkhardt, MD, Phil R. Fischer, MD, et al- (J Pediatr 2011;158:15-9)
39Deconditioning Definition: Peak VO2 less than 80% predicted with no evidence of ventilatory limitation to exercise.Ventilatory limitation: Ratio of maximum exercise ventilation to maximum voluntary ventilation of <1
40POTS Vs. Non POTS Significantly higher resting HR Delay in HR RECOVERY 5 minutes after exerciseSignificantly lower stroke volume with increasing exercise work load.
41Medow and Stewart22 described a pathophysiological model with 3 groups of patientswith POTS—so-called ‘‘low-flow’’, ‘‘normal-flow’’, and‘‘high-flow’’ POTS—admitting that this distinction maynot be clinically relevant yet
42HR recovery after exercise shows higher HR in patients with POTS and deconditioned subjects.
43rapid eye movement (REM)-behavioral sleep disturbances Sleep DisordersInsomniaFragmented Sleeprapid eye movement (REM)-behavioral sleep disturbances
44DysautonomiaRange from transient episodes in otherwise healthy people to progressive neurodegenerative diseases;from conditions in which alteredautonomic function plays a primary pathophysiologicrole to those in which it worsens an independent pathologicstate
45Orthostatic Hypotension A decrease in systolic pressure of at least 20 mm Hg or a decrease in diastolic pressure of at least 10 mm Hg within 3 minutes of standingResults from:Intravascular DepletionProlonged bedridden state and Deconditioning.Autonomic failure-sympathetic Neurocirculatory Failure
46Chronic Autonomic Failure Secondary (Most Common) :Diabetes, amyloidosis, or multiple myeloma),Toxic agents (e.g. Alcohol),Medications ( antidepressant, antipsychotic, antihypertensive, or antineoplastic).Primary:Pure Autonomic Failure (PAF) : Orthostatic Hypotension without symptoms or signs of central neurodegeneration.Multiple System Atrophy (MSA): Autonomic failure and progressive central neurodegeneration,Subtypes: Parkinsonian, Cerebellar, and Mixed forms.
47Mechanisms of Herbal Remedies Release Norepinephrine: Ma-Huang Yohimbe Bark
48Peroneal Muscle Sympathetic Activity In normal patients Peroneal Muscle Sympathetic Activity approximately doubles during orthostatic stress, with an approximate doubling of the plasma norepinephrine concentration
49Deficiency of Membrane Norepinephrine Transporter
50Hyper Noradrenergic Essential Hypertension Increased cardiac and renal spillover of norepinephrineincreased rates of efferent sympathetic nerve firing in the outflow to the skeletal muscle vasculature The sympatheticMechanism:Activation originates within the CNS and mediated via noradrenergic projections from the brainstem to the forebrainChronic sympathetic cardiac stimulation and peripheral vasoconstriction;Increased renin secretion and tubular reabsorption of sodiumPresent in about 40% of young patients with untreated essentialhypertension
51Increased sympathetic and Adrenomedullary Outflows Panic DisorderIncreased sympathetic and Adrenomedullary OutflowsWilkinson DJ, et al. Sympathetic activity in patients with panic disorder at rest,under laboratory mental stress, and during panic attacks. Arch Gen Psychiatry.1998;55:
53CHRONIC FATIGUE SYNDROME (CFS) New, unexplained fatigue that lasts for at least 6 months, is not relieved by rest, and has no clear cause.Associated with 4 or more new symptoms:Memory or concentration problems,Sore ThroatTender Lymphadenopathy,Myalgia,ArthralgiaHeadacheUnrefreshing sleep,Postexertional malaise
54CFS Women are affected about 3 times more than men Prevelance:10 to 200 to 250/ persons in US
55CFS Loss of heart rate variability consistent with vagal withdrawal, increased blood pressure variability consistentwith enhanced modulation of sympathetic tone, and impaired baroreflex.Stewart JM, Gewitz MH, Weldon A. Orthostatic intolerancein adolescent chronic fatigue syndrome. Pediatrics. 1999;103:
56In a recent placebo-controlled clinical trial of this therapeutic approach (86), 100 patientswith CFS who had positive results on tilt-table testing tookescalating doses of placebo or fludrocortisone for 9 weeks.Symptoms improved in 10% of the placebo recipients andin 14% of patients receiving fludrocortisone—a statisticallynonsignificant difference. The ability to tolerate tilt alsodid not improve, and there was no correlation between thetilt-table test measures and any of the self-rating categories.Rowe PC, Calkins H, DeBusk K, McKenzie R, Anand R, Sharma G, et al.Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatiguesyndrome: a randomized controlled trial. JAMA. 2001;285:52-9. [PMID:]TREATMENTOne of the most important aspects of treatment ofpatients with dysautonomia is careful education of patients
57TREATMENT1.Education of patients and caregivers 2. Identify situations that may precipitate or worsen symptoms 3.
58Non pharmacological Management Orthostatic intoleranceIncrease salt and fluid intakeHead of bed elevated 4-5 inchesLower body resistance isometric training exercisesSmaller low fat, low carb, high protein frequent mealsPlan Excersice activities to occur later in the dayAvoid morning Hot bath or showersSecretomotor symptomsArtificial tearsOver-the-counter oral mucous membrane moisturizersPunctal plugging or cauterizationSudomotor symptomsExternal cooling devicesAvoidance of warm/hot environments if heat intoleranceUse of antiperspirants (Drysol) for excessive sweating
59Adequate Fluid intake Fluid intake > 3L/day Sodium Intake ,000 mg/DayAvoid Caffeine intakeFluid intake logElevate head of the bed frame to 4 inches above horizontal, by placing cinder blocks under bed frame and not by using pillows.24-hour urinary sodium excretion should be greater than 150 mEq per 24 hrs.Total Urinary output > 2.5 L/24 hrs
60Exercise & Reconditioning Maximize lower body and abdominal tone to improve venous returnStart with recumbent exercisesEncourage:Repetitively standing on tiptoesFrequently Contract calf muscles and perform knee bends.Formal rehabilitation and Exercise program
61POTS-Pharmacological Treatment Midodrine 2.5–15 mg TIDPyridostigmine.15–60 mg TID or SR 180 mg dailyBeta Blockers ( Acetabutalol, Betaxalol metoprolol, nadolol, propranolol)Fludrocortisone 0.1–0.2 mg daily or every other daySelective serotonin reuptake inhibitors (SSRIs)Erythropoietin 2000–10,000 units subcutaneously,weekly, titrated to hematocrit of 55%
62Midodrin Peripherally acting a-adrenergic receptor agonist , only Duration of action: Up to 4 hours. It is typically used at. Side effects: scalp tingling and ‘‘goose bumps’’due to piloerection at the skin surface,supine hypertension,and urinary retention.Generally, patients may havesome control of their doses so that on days when theyare more symptomatic and their orthostatic blood pressuredrop is more severe, they may take a higher dose ofthe medication.
63Pyridostigmine (Mestinon) Acetylcholinesterase inhibitor:Potentiales acetylcholine neurotransmission at peripheral autonomic ganglia, thereby increasing peripheral vasoconstriction via sympathetic nerve fiber transmission.Increases vagal cardiac input.The most common side effects: increased salivation, sweating, and increased gastrointestinal motility.Rarely patients may experience muscle fasciculations.
64Autoimmune Autonomic Neuropathy Plasmapheresis Infusion of intravenous immunoglobulin (IVIg) Oral immunosuppressive medications for long-term therapy
65Acute idiopathic Anhidrosis or Hypohidrosis:, May be a form of limited autonomic neuropathy,skin biopsy: Lymphocytic infiltration around sweat glands and ducts.RX: Short course oral prednisone or IVMethylprednisoloneChronic Anhidrosis:
66Localized: subcutaneous injections of botulinum Hyperhidrosis-RXLocalized: subcutaneous injections of botulinumtoxin to denervate sweat glands.1Generalized Hyperhidrosis: medications with strong anticholinergic side effect, such as amitriptyline or glycopyrrolate.Topical treatments forexcessive sweating include aluminum chloride (the activeingredient in antiperspirants) and topical compoundedcream formulations of glycopyrrolate.
67Secretomotor Abnormalities-RX Xerophthalmia: Chronic, severe dry eye has a risk of development of corneal abnormalities and should be treated aggressively.Punctal pluggingArtificial tears and cyclosporine eye drops locally,fish oil oral supplements.Xerostomia:over-the-counter agents to control symptoms of drymouth; pyridostigmine in refractory cases.
69Norepinephrine Transporter Protein Deficiency Another recent autonomic condition producing a complexform of POTS is the.Reported in only a single family.Specific genetic defect innorepinephrine transporter protein deficiency64 exerting bothcentral and peripheral effects on vascular regulation.65 Despiteits rarity, the illness has furnished an ideal monogenetic modelfor autonomic illness, and appropriate animal knock-outmodels have been constructed and investigated.66
70Noradrenergic projections Broadly distributed throughout the CNS and PNSPlay important modulatory roles inattention, pain perception, learning, memory, and autonomic functionoriginate from a small population of brainstem nuclei, the noradrenergic cell groupsThe largest of these groups is the locus coeruleus (LC), which projects widely to the cortex, amygdala,olfactory bulb, hippocampus, septum, hypothalamus,brainstem nuclei, and spinal cord
71(NE) transporterRegulate the duration of NE neurotransmission by removal of the NE from the extracellular space.80–90% of released NE may be recaptured and re released,NETs are important targets of antidepressants such asdesipramine and reboxetine and for drugs of abuseincluding cocaine and amphetamine (Ritz et al., 1990;Pacholczyk et al., 1991; Chen and Reith, 1994; Wall et al.,1995; Tatsumi et al., 1997).Loss of NETs or NE clearancehas been associated with depression (Klimek et al., 1997)and with several heart and vascular system diseases includingorthostatic intolerance (Jacob et al., 1999).
72Hereditary Sensory and Autonomic Neuropathies (HSANs) Genetic Errors affecting a specific aspect of small fiber neurodevelopmentVariable phenotypic expression(HSAN type I), AD, presenting in the second decade of life,(HSAN type III)=Familial Dysautonomia &III) AR, present at birth.(HSAN type IV) congenital insensitivity to pain with anhidrosis (CIPA)
73RX: Clonidine to control vomiting and the dysautonomic crisis, FDAffected gene IKBKAP that aids in expression of various neurotransmitters .Inadequate development, and limited survival, of sensory and autonomic neurons.the sympathetic neurons are more exetnsively affected than the parasympatheticHypoactive Corneal and tendon reflexes,Diminished taste appreciation due to absence of lingual fungiform papillaeVibratory sensory loss and impaired coordination with ageAbsence of tears(alacrima) with emotional cryingPoor oral coordination and hypotonia are and frequent GER and aspirationProtracted episodes of nausea and vomiting triggered by emotional or physicalstressFrequent erythematous skin blotching and hyperhidrosisExtreme hypertension and sever postural hypotension without compensatory tachycardiaRelative insensitivity to hypoxemiaRX: Clonidine to control vomiting and the dysautonomic crisis,Fludrocortisone and midodrine to mange Hypotension.
74probably secondary to impaired thoracolumbar sympathetic outflow. CIPA/HSAN type IVAnhidrosis causes episodic fevers and extreme hyperpyrexia that is usually the earliestprobably secondary to impaired thoracolumbar sympatheticoutflow.thick and calloused appearance of the skin withlichenification of palms, dystrophic nails, and areas ofhypotrichosis on the scalp.38Miosis due parasympatheticdysfunction,mild postural hypotension.The insensitivity to pain is profound and can result inself-mutilation, autoamputation, and corneal scarring