1. Hasan Abdallah, MD Children’s Heart Institute
Dysautonomias
Hasan Abdallah, MD
Children’s Heart Institute

2. Dysautonomias
Definition:
altered autonomic function

3. History
Galen(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 glands
Abel 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.

4. Scope of the Problem
Up to 1% of teenagers are debilitated with chronic fatigue.
Autonomic dysfunction is identified in around 50% patients with CFS

5. Autonomic Nervous System ( ANS) ANATOMY AND PHYSIOLOGY
Sympathetic (thoracolumbar)
Parasympathetic (craniosacral)
Enteric
The ANS is largely involuntary motor/ effector system.
The CAN (Central Autonomic Network)
Maintains integral relationships with visceral sensory neurons via afferent
input from the vagus nerve and relays transmission
through 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)

7. ANS
Complex 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

8. Embryologic Development
Development of the ANS is intimately related to the
development of the sensory nervous system;
both have their embryonic origins in the multipotential neural
crest cells. These cells migrate and eventually evolve into
sensory and autonomic ganglia as well as the adrenal
chromaffin cells.
Their differentiation and commitment
to function in the mature nervous system is incumbent
on exposure to growth factors released by structures
along the migratory route and then within the target
tissue.

10. Fuctional 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

11. orthostatic intolerance
Humans absolutely require a functionally
intact sympathetic nervous system to tolerate the “nonemergency”
behavior of simply standing up. This explains
why orthostatic intolerance constitutes a cardinal clinical
manifestation of sympathetic neurocirculatory failure

12. Autonomic 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

13. RAR = rapidly adapting receptor;
SAR = slowly adapting receptor.

14. Orthostatic 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

16. Symptoms Associated With ANS Disorders
System
Dysfunction
Symptom
Ophthalmologic
Alacrima
Dry Eye
Nonreactive/sluggish pupils
Dark/light intolerance
Ptosis
Strabismus
Anisocoria
Severe myopia
Sudomotor
Altered sweating
Hypohidrosis or hyperhidrosis
Urologic)
Delayed bladder emptying
Nocturnal enuresis GI
Dysmotility
Gasto perisis

17. Gastrointestinal Symptoms
Nausea
Early satiety,
Abdominal cramping after meals,
Frequent diarrhea or constipation (or alternating bouts of both),

18. Genitourinary Symptoms
May include
Urinary incontinence
Urinary frequency and urgency
Urinary retention.
Erectile dysfunction
Decreased libido and inability to achieve orgasm
Menstrual Disturanances

19. POTS-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 orthostatic
hypotension.
Symptoms of orthostatic intolerance are those due to brain hypoperfusion and sympathetic overaction.

20. POTS-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 be
produced in control subjects given sufficient provocation. The underlying cause of
orthostatic hyperpnea remains obscure, but postural stimulation appears to be necessary, and
Abnoraml interactions between carotid baroreceptor and chemoreceptors are probably the root cause.

21. Acrocyanosis The distribution
of color change does not mimic the distribution of discoloration
in Raynaud phenomenon, which is confined to the
hand and foot. Rather, as shown in Figure 1, there is more
widespread extension, especially in dependent extremities with
a mottled appearance comprising islands of pink skin with
normal cutaneous blood flow interspersed among prevailing
cyanosis with decreased cutaneous blood flow.

22. Tachycardia of POTS could represent absolute
Blood Volume
Tachycardia of POTS could represent absolute
hypovolemia. This has been demonstrated in some patients
with POTS41 and may relate to defective denervation of the
kidneys and associated hyporeninemic hypoaldosteronism.
42,43 A reflex response to fluid shifts results in the
circulatory insufficiency observed in patients.44
More recent
data indicate that hypovolemia tends to be modest and may
not by itself explain orthostatic intolerance in these patients.45
Nevertheless, decreased blood volume further impairs venous
return and is at least a contributing factor:
All compensatory
mechanisms for orthostasis depend on circulatory volume
adequacy and all will ultimately fail during sufficiently severe
hypovolemia.
Conversely, repletion of blood volume is often
helpful in orthostatic intolerance of whatever cause because it
invariably enhances postural venous return., although effects unrelated to blood
volume may play a role. Although a primary disturbance in
blood volume (or renal volume regulation) has been proposed
for some cases of POTS,47-49 volume loading may improve
patient well-being nonspecifically as well.

23. physical forces comprise a primary
Muscle Pump
physical forces comprise a primary
defense against lower extremity pooling in human beings in
the form of the ‘‘skeletal muscle pump’’ in which contractions
of leg and gluteal muscles increase interstitial pressure and
propel sequestered venous blood back to the heart.
Skeletal
muscle may also be involved in neurogenic compensation
through chemoreceptors and through local control
mechanisms.
Recent data indicate that while the muscle
pump is normal in most patients with POTS, the muscle
pump is defective in a subset of patients with POTS who also
have decreased resting peripheral blood flow unrelated to
exercise capability but exacerbated by bed rest.

24. Neurovascular Compensation
Neurovascular compensation limits dependent blood
pooling. This includes rapid peripheral arterial vasoconstriction
limiting flow to the extremities and splanchnic vascular
bed while promoting passive venous emptying.53 Active
venoconstriction occurs in the splanchnic circulation,54 but
there is little evidence for venous beds other than splanchnic
contributing to active orthostatic venoconstriction; rather,
recent data suggest that other veins and venules contribute to
venous return by passive elastic recoil during arterial
vasoconstriction.55,56
A useful way to view vascular control systems is to view
them as long distance or local control systems.

25. ‘‘Long Distance’’ Vascular Control

26. ‘‘Local’’ Vascular Control
compensatory response to orthostasis
arising from local vasoactive responses are often less well
appreciated. 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 neurogenic
mechanisms such as the axon reflex,73 and neurogenic
inflammation (CGRP, substance P),74,75 especially within
the cutaneous and enteric circulations. Local responses
contribute to classic myogenic, metabolic, and venoarteriolar
flow control, which may be important compensatory
mechanisms during

27. physiologic variants of POTS
distinguished on the basis of measurements of peripheral
blood flow and peripheral arterial resistance in association with
characteristic changes in regional circulations:

28. Classification
Hyperadrenergic states
Autonomic neuropathy involving antiganglionic antibodies
Absolute hypovolemia
Redistributive form of hypovolemia(central thoracic blood volume is reduced in the upright position, even though overall blood volume is normal)

29. Impedance Plethysmography (IPG)

31. Normal-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 tilt
Normal peripheral resistance supine and enhanced peripheral resistance upright..
Intact graded reflex-mediated compensatory Intense peripheral vasoconstriction
No generalized sympathetic failure.
Severe degree of gravitational dependent acrocyanosis due to stagnant hypoxia
Probable Mechanisms:
Selective splanchnic denervation
intact autonomic splanchnic activity confounded by local vasoactive substances e.g.
Vasoactive intestinal polypeptide (VIP), substance P, or nitric oxide.

32. Low-flow POTS (Uniform Hypovolemia & Reduced blood flow in multiple regional circulations )
intense peripheral vasoconstriction and low resting cardiac output while supine and decreased blood volume
Pallor, extensive supine and upright acrocyanosis, cool skin and extremities,
Tachycardia while supine and graded tilt.
Defective skeletal muscle pump common
Decreased blood flow most notable in the dependent parts of the body
splanchnic blood flow does not change during tilt
Abnormal Hyperemic blood flow indicating endothelial dysfunction and abnormal local blood flow regulation.
Fluid Infusions usually helpful

33. High-flow POTS (Lower body vasodilation)
Increased cardiac index
Increased peripheral blood flow,
Decreased peripheral resistance in the lower extremities and pelvic segment,
Unchanged peripheral blood flow during orthostatic stress
May be related to a long tract neuropathy and high cardiac output is caused by inadequate peripheral vasoconstriction supine and upright.
Patients typically are acy
anotic, warm to touch with extensive filtration, resulting in dependent edema.
patients are peripherally
vasodilated and mildly tachycardic when supine and have
relatively increased blood volume, reduced total peripheral
resistance, and high resting cardiac output compared with
healthy control subjects.1
Defective Peripheral vasoconstriction
during orthostasis remains defective, leading to excess blood
delivery to the lower limbs with enhanced microvascular
filtration and edema formation.63 Acrocyanosis does not often
occur. Persistent upright vasodilation
responds to vasoconstrictor
therapy with midodrine or similar agents. Often such
patients have illness after a viral infection. A perip

34. POTS-ONSET, EPIDEMIOLOGY, AND NATURAL HISTORY
Onset often
follows an infectious disease
Patients often
slowly improve after the initial infectious illness, only to
become ill again spontaneously or during an intercurrent
infection.
1 Approximately 75% to 80% of patients are women
ranging in age from 14 to 50 years22
POTS is relatively
uncommon in preadolescent children and may have a distinct
pathophysiology in the very young. The illness may follow a remitting and
relapsing clinical course, often enduring for years, but seems in
many instances self-limited.

35. Symptoms of orthostatic intolerance
Lightheadedness
Headache
Fatigue
Neurocognitive/sleep disorders
Exercise intolerance
Weakness
Hyperpnea/dyspnea
Tremulousness
Nausea/abdominal pain
Sweating
Anxiety/palpitations

36. Pathophysiologic Mechanisms (not mutually exclusive) include
Peripheral Autonomic Denervation
Hypovolemia
venous pooling,
β-receptor supersensitivity
Impairment of brain stem regulation.
Secondary
Prolonged deconditioning
Psychological factors
Poor Nutrition status

37. Physiological 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.

38. Is 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 deconditioning
Barbara E. U. Burkhardt, MD, Phil R. Fischer, MD, et al- (J Pediatr 2011;158:15-9)

39. Deconditioning 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

40. POTS Vs. Non POTS Significantly higher resting HR
Delay in HR RECOVERY 5 minutes after exercise
Significantly lower stroke volume with increasing exercise work load.

41. Medow and Stewart22 described
a pathophysiological model with 3 groups of patients
with POTS—so-called ‘‘low-flow’’, ‘‘normal-flow’’, and
‘‘high-flow’’ POTS—admitting that this distinction may
not be clinically relevant yet

42. HR recovery after exercise shows higher HR in
patients with POTS and deconditioned subjects.

43. rapid eye movement (REM)-behavioral sleep disturbances
Sleep Disorders
Insomnia
Fragmented Sleep
rapid eye movement (REM)-behavioral sleep disturbances

44. Dysautonomia
Range from transient episodes in otherwise healthy people to progressive neurodegenerative diseases;
from conditions in which altered
autonomic function plays a primary pathophysiologic
role to those in which it worsens an independent pathologic
state

45. Orthostatic 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 standing
Results from:
Intravascular Depletion
Prolonged bedridden state and Deconditioning.
Autonomic failure-sympathetic Neurocirculatory Failure

46. Chronic 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.

47. Mechanisms of Herbal Remedies
Release Norepinephrine: Ma-Huang Yohimbe Bark

48. Peroneal Muscle Sympathetic Activity
In normal patients Peroneal Muscle Sympathetic Activity approximately doubles during orthostatic stress, with an approximate doubling of the plasma norepinephrine concentration

49. Deficiency of Membrane Norepinephrine Transporter

50. Hyper Noradrenergic Essential Hypertension
Increased cardiac and renal spillover of norepinephrine
increased rates of efferent sympathetic nerve firing in the outflow to the skeletal muscle vasculature The sympathetic
Mechanism:
Activation originates within the CNS and mediated via noradrenergic projections from the brainstem to the forebrain
Chronic sympathetic cardiac stimulation and peripheral vasoconstriction;
Increased renin secretion and tubular reabsorption of sodium
Present in about 40% of young patients with untreated essential
hypertension

51. Increased sympathetic and Adrenomedullary Outflows
Panic Disorder
Increased sympathetic and Adrenomedullary Outflows
Wilkinson 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:

52. Congestive Heart Failure

53. CHRONIC 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 Throat
Tender Lymphadenopathy,
Myalgia,
Arthralgia
Headache
Unrefreshing sleep,
Postexertional malaise

54. CFS Women are affected about 3 times more than men Prevelance:10 to
200 to 250/ persons in US

55. CFS Loss of heart rate variability consistent with vagal withdrawal,
increased blood pressure variability consistent
with enhanced modulation of sympathetic tone, and impaired baroreflex.
Stewart JM, Gewitz MH, Weldon A. Orthostatic intolerancein adolescent chronic fatigue syndrome. Pediatrics. 1999;103:

56. In a recent placebo-controlled
clinical trial of this therapeutic approach (86), 100 patients
with CFS who had positive results on tilt-table testing took
escalating doses of placebo or fludrocortisone for 9 weeks.
Symptoms improved in 10% of the placebo recipients and
in 14% of patients receiving fludrocortisone—a statistically
nonsignificant difference. The ability to tolerate tilt also
did not improve, and there was no correlation between the
tilt-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 fatigue
syndrome: a randomized controlled trial. JAMA. 2001;285:52-9. [PMID: ]
TREATMENT
One of the most important aspects of treatment of
patients with dysautonomia is careful education of patients

57. TREATMENT
1.Education of patients and caregivers 2. Identify situations that may precipitate or worsen symptoms 3.

58. Non pharmacological Management
Orthostatic intolerance
Increase salt and fluid intake
Head of bed elevated 4-5 inches
Lower body resistance isometric training exercises
Smaller low fat, low carb, high protein frequent meals
Plan Excersice activities to occur later in the day
Avoid morning Hot bath or showers
Secretomotor symptoms
Artificial tears
Over-the-counter oral mucous membrane moisturizers
Punctal plugging or cauterization
Sudomotor symptoms
External cooling devices
Avoidance of warm/hot environments if heat intolerance
Use of antiperspirants (Drysol) for excessive sweating

59. Adequate Fluid intake Fluid intake > 3L/day
Sodium Intake ,000 mg/Day
Avoid Caffeine intake
Fluid intake log
Elevate 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

60. Exercise & Reconditioning
Maximize lower body and abdominal tone to improve venous return
Start with recumbent exercises
Encourage:
Repetitively standing on tiptoes
Frequently Contract calf muscles and perform knee bends.
Formal rehabilitation and Exercise program

61. POTS-Pharmacological Treatment
Midodrine 2.5–15 mg TID
Pyridostigmine.15–60 mg TID or SR 180 mg daily
Beta Blockers ( Acetabutalol, Betaxalol metoprolol, nadolol, propranolol)
Fludrocortisone 0.1–0.2 mg daily or every other day
Selective serotonin reuptake inhibitors (SSRIs)
Erythropoietin 2000–10,000 units subcutaneously,
weekly, titrated to hematocrit of 55%

62. Midodrin 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 have
some control of their doses so that on days when they
are more symptomatic and their orthostatic blood pressure
drop is more severe, they may take a higher dose of
the medication.

63. Pyridostigmine (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.

64. Autoimmune Autonomic Neuropathy
Plasmapheresis Infusion of intravenous immunoglobulin (IVIg) Oral immunosuppressive medications for long-term therapy

65. Acute 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 IV
Methylprednisolone
Chronic Anhidrosis:

66. Localized: subcutaneous injections of botulinum
Hyperhidrosis-RX
Localized: subcutaneous injections of botulinum
toxin to denervate sweat glands.1
Generalized Hyperhidrosis: medications with strong anticholinergic side effect, such as amitriptyline or glycopyrrolate.
Topical treatments for
excessive sweating include aluminum chloride (the active
ingredient in antiperspirants) and topical compounded
cream formulations of glycopyrrolate.

67. Secretomotor Abnormalities-RX
Xerophthalmia: Chronic, severe dry eye has a risk of development of corneal abnormalities and should be treated aggressively.
Punctal plugging
Artificial tears and cyclosporine eye drops locally,
fish oil oral supplements.
Xerostomia:
over-the-counter agents to control symptoms of dry
mouth; pyridostigmine in refractory cases.

68. Multiple system Atrophy (Shy-Drager syndrome)

69. Norepinephrine Transporter Protein Deficiency
Another recent autonomic condition producing a complex
form of POTS is the.
Reported in only a single family.
Specific genetic defect in
norepinephrine transporter protein deficiency64 exerting both
central and peripheral effects on vascular regulation.65 Despite
its rarity, the illness has furnished an ideal monogenetic model
for autonomic illness, and appropriate animal knock-out
models have been constructed and investigated.66

70. Noradrenergic projections
Broadly distributed throughout the CNS and PNS
Play important modulatory roles in
attention, pain perception, learning, memory, and autonomic function
originate from a small population of brainstem nuclei, the noradrenergic cell groups
The 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) transporter
Regulate 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 as
desipramine and reboxetine and for drugs of abuse
including 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 clearance
has been associated with depression (Klimek et al., 1997)
and with several heart and vascular system diseases including
orthostatic intolerance (Jacob et al., 1999).

72. Hereditary Sensory and Autonomic Neuropathies (HSANs)
Genetic Errors affecting a specific aspect of small fiber neurodevelopment
Variable 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)

73. RX: Clonidine to control vomiting and the dysautonomic crisis, FD
Affected 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 parasympathetic
Hypoactive Corneal and tendon reflexes,
Diminished taste appreciation due to absence of lingual fungiform papillae
Vibratory sensory loss and impaired coordination with age
Absence of tears(alacrima) with emotional crying
Poor oral coordination and hypotonia are and frequent GER and aspiration
Protracted episodes of nausea and vomiting triggered by emotional or physicalstress
Frequent erythematous skin blotching and hyperhidrosis
Extreme hypertension and sever postural hypotension without compensatory tachycardia
Relative insensitivity to hypoxemia
RX: Clonidine to control vomiting and the dysautonomic crisis,
Fludrocortisone and midodrine to mange Hypotension.

74. probably secondary to impaired thoracolumbar sympathetic outflow.
CIPA/HSAN type IV
Anhidrosis causes episodic fevers and extreme hyperpyrexia that is usually the earliest
probably secondary to impaired thoracolumbar sympathetic
outflow.
thick and calloused appearance of the skin with
lichenification of palms, dystrophic nails, and areas of
hypotrichosis on the scalp.38
Miosis due parasympathetic
dysfunction,
mild postural hypotension.
The insensitivity to pain is profound and can result in
self-mutilation, autoamputation, and corneal scarring