Transcript Dysautonomias - Children`s Heart Institute

Dysautonomias
Hasan Abdallah, MD
Children’s Heart Institute
Dysautonomias
• Definition:
altered autonomic
function
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.
Scope of the Problem
• Up to 1% of teenagers are debilitated with
chronic fatigue.
• Autonomic dysfunction is identified in
around 50% patients with CFS
Autonomic Nervous System ( ANS)
ANATOMY AND PHYSIOLOGY
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Sympathetic (thoracolumbar)
Parasympathetic (craniosacral)
Enteric
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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.
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Autonomic Outflow Discharge: Occur independently, partially regulated
and integrated by the central autonomic network (CAN)
ANS
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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
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
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to function in the mature nervous system is
incumbent
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on exposure to growth factors released by
structures
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along the migratory route and then within the
target
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tissue.
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
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
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
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RAR = rapidly adapting receptor;
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SAR = slowly adapting receptor
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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
Symptoms Associated With ANS
Disorders
System
Dysfunction
Symptom
Ophthalmologic
Alacrima
Dry Eye
Nonreactive/sluggish
pupils
Dark/light intolerance
Ptosis
Strabismus
Anisocoria
Severe myopia
Altered sweating
Hypohidrosis or
hyperhidrosis
Urologic)
Delayed bladder emptying
Nocturnal enuresis
GI
Dysmotility
Gasto perisis
Sudomotor
Gastrointestinal Symptoms
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Nausea
Early satiety,
Abdominal cramping after meals,
Frequent diarrhea or constipation (or
alternating bouts of both),
Genitourinary Symptoms
• May include
Urinary incontinence
Urinary frequency and urgency
Urinary retention.
Erectile dysfunction
Decreased libido and inability to achieve
orgasm
Menstrual Disturanances
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.
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.
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.
Blood Volume
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Tachycardia of POTS could represent absolute
hypovolemia. This has been demonstrated in some patients
with POTS and may relate to defective denervation of the
kidneys and associated hyporeninemic hypoaldosteronism.
A reflex response to fluid shifts results in the
circulatory insufficiency observed in patients.
More recent
data indicate that hypovolemia tends to be modest and may
not by itself explain orthostatic intolerance in these patients.
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, volume loading may improve
patient well-being nonspecifically as well.
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Muscle Pump
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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.
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. Active
• venoconstriction occurs in the splanchnic circulation, 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.
• A useful way to view vascular control systems is to view
• them as long distance or local control systems.
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‘‘Long Distance’’ Vascular Control
‘‘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) metabolites (adenosine,
• Ca , CO , H ions, lactate) autacoids (histamine,
• bradykinin, 5-HT, PAF, prostaglandins), local neurogenic
• mechanisms such as the axon reflex, and neurogenic
• inflammation (CGRP, substance P), 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
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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:
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)
Impedance
Plethysmography
(IPG)
Normal-flow POTS
(Pool in splanchnic circulation due to increased splanchnic blood flow)
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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..
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Intact graded reflex-mediated compensatory Intense peripheral vasoconstriction
No generalized sympathetic failure.
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Severe degree of gravitational dependent acrocyanosis due to stagnant
hypoxia
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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.
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Low-flow POTS
(Uniform Hypovolemia & Reduced blood flow in multiple
regional circulations )
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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.
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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
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Abnormal Hyperemic blood flow indicating endothelial dysfunction and abnormal local blood flow
regulation.
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Fluid Infusions usually helpful
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.
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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.
Peripheral vasoconstriction
during orthostasis remains defective, leading to excess blood
delivery to the lower limbs with enhanced microvascular
filtration and edema formation. 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
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POTS-ONSET, EPIDEMIOLOGY, AND NATURAL
HISTORY
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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.
Approximately 75% to 80% of patients are women
ranging in age from 14 to 50 years
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.
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Symptoms of orthostatic intolerance
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Lightheadedness
Headache
Fatigue
Neurocognitive/sleep disorders
Exercise intolerance
Weakness
Hyperpnea/dyspnea
Tremulousness
Nausea/abdominal pain
Sweating
Anxiety/palpitations
Pathophysiologic Mechanisms (not
mutually exclusive) include
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Peripheral Autonomic Denervation
Hypovolemia
venous pooling,
β-receptor supersensitivity
Impairment of brain stem regulation.
Secondary
• Prolonged deconditioning
• Psychological factors
• Poor Nutrition status
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.
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)
Deconditioning Definition:
• Peak V 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
O2
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.
• Medow and Stewart described
• a pathophysiological model with 3 groups
of patients
• with POTS—so-called ‘‘low-flow’’, ‘‘normalflow’’, and
• ‘‘high-flow’’ POTS—admitting that this
distinction may
• not be clinically relevant yet
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HR recovery after
exercise shows
higher HR in
patients with POTS
and deconditioned
subjects.
Sleep Disorders
• Insomnia
• Fragmented Sleep
• rapid eye movement (REM)-behavioral
sleep disturbances
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
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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
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.
Mechanisms of Herbal Remedies
Release Norepinephrine:
Ma-Huang
Yohimbe Bark
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
Deficiency of Membrane Norepinephrine
Transporter
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
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;55:511-20.
Congestive Heart Failure
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
CFS
• Women are affected about 3 times more
than men
Prevelance:10 to
200 to 250/100 000 persons in US
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:
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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
TREATMENT
in 14% of patients
fludrocortisone—a
statistically
Onereceiving
of the most
important aspects
of
nonsignificant difference.
The ability to tolerate tilt also
treatment of
did not improve,
and there
no correlation
between the
patients
withwas
dysautonomia
is careful
tilt-table test measures
any of the self-rating categories.
educationand
of patients
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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:
11150109]
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TREATMENT
1.Education of patients and caregivers
2. Identify situations that may precipitate or
worsen symptoms
3.
Non pharmacological Management
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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
Adequate Fluid intake
Fluid intake > 3L/day
Sodium Intake 4000-10,000 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
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
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%
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Midodrin
• Peripherally acting a-adrenergic
• receptor agonist , only
• Duration of action: Up to 4 hours
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. 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.
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.
Autoimmune Autonomic Neuropathy
Plasmapheresis
Infusion of intravenous immunoglobulin
(IVIg)
Oral immunosuppressive medications for
long-term therapy
Hypohidrosis
• 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:
Hyperhidrosis-RX
• Localized: subcutaneous injections of botulinum
toxin to denervate sweat glands.
Generalized Hyperhidrosis: medications with strong
anticholinergic side effect, such as amitriptyline or
glycopyrrolate.
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Topical treatments for
• excessive sweating include aluminum chloride (the
active
• ingredient in antiperspirants) and topical compounded
• cream formulations of glycopyrrolate.
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.
Multiple system
Atrophy (Shy-Drager syndrome)
Norepinephrine Transporter Protein
Deficiency
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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 deficiency exerting both
central and peripheral effects on vascular regulation. 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.
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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
(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).
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)
FD
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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
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RX: Clonidine to control vomiting and the dysautonomic crisis,
Fludrocortisone and midodrine to mange Hypotension.
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.
• Miosis due parasympathetic
• dysfunction,
• mild postural hypotension.
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• The insensitivity to pain is profound and can result in
• self-mutilation, autoamputation, and corneal scarring