Transcript Autonomic Dysfunction - Internal Medicine of Northern Virginia

Samuel Shor, MD, FACP
Associate Clinical Professor
George Washington University
Health Care Sciences
Internal Medicine of Northern Virginia
1860 Town Center Drive #230
Reston, Virginia 20190
703 709-1119
www.INTMEDNOVA.com
July 7, 2015
Samuel Shor, MD, FACP
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Define this often perceived “black
box” VERY common
phenomenon-with practical
considerations
Systems impacted
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Emphasis on cardiovascular
manifestations
Management-in a hopefully
“usable” “take home” approach
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Clinical manifestations of dysfunction-overview
Anatomy/Physiology-BRIEF Overview
Potential etiologies
Systems impacted
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Briefly: GI/GU
emphasis on cardiovascular system
Management
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“While we are not constantly aware of the
activity of the autonomic nervous
system as we are of unusual sensory
and motor events, the normal
functioning of the autonomic nervous
system day and night, from heart beat
to heart beat, plays a largely
unconscious but vital role in our
livelihood. It is not surprising,
therefore, that autonomic
abnormalities, though they are usually
more difficult to recognize than a
severe pain, a sensory loss or paralysis
of a limb, may be even more
important in impairing the quality and
even jeopardizing the continuation of
life.”*
*Dr. David R Streeten, The National Dysautonomia Research Foundation (NDRF): www.ndrf.org
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Symptom
Frequency
Postural hypotension
94%
Lightheadedness, fainting, dimness of vision,
weakness, unsteady gait, slurred speech
Urinary dysfunction
65%
Frequency, nocturia, urgency, stress incontinence
Sexual dysfunction
51%
Impotence, loss of libido, dry or retrograde
ejaculation
Bowel dysfunction
30%
Intermittent diarrhea, nocturnal diarrhea, rectal
Decreased sweating
11%
Data derived from: Thomas JE, Schirger A. Idiopathic orthostatic hypotension. Arch Neural 1970;22:289–93.
Copyright © 1990 Butterworth Publishers
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Sympathetic:

Responsible for mediating energy expenditure
 For example, "fight or flight" response, including an increase
in heart rates and respiratory rates, shunting blood from the
extremities to core organs

Anatomy
 Originating in the thoracic and lumbar regions of the spinal
cord
 Norepinephrine-released as the neurotransmitter for the
sympathetic nervous system
 Adrenal Medulla
 norepinephrine
 epinephrine- by attaching a methyl group
 [note: Adrenal cortex which surrounds the medulla and secretes
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Samuel Shor, MD, FACP
cortisol]
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Alpha 1 Receptors
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Vascular smooth muscle postsynaptic neurons
 Vasoconstriction
 [note: agonist: proamatine vs antagonist: prazosin]

Myocardium
 Positive Inotrope
 Negative Chronotrope
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Alpha 2 Receptors

Peripheral Alpha 2 Receptors
 Vascular Smooth Muscle (mixed effect)
 Modulates large vessel tone
 Arteriolar and venous vasoconstriction
 Opposes alpha 1 receptor vasoconstriction
 Inhibits Norepinephrine release
 Decreases adrenergic activity

Central Alpha 2 Receptors (CNS)
 Peripheral vasodilatation [note: agonist: clonidine]
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Beta receptors-stimulated by epinephrine
 ß1 adrenergic receptors-cardiostimulation
 ß2 adrenergic receptors-bronchodilatation and
vasodilatation.
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Parasympathetic
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Responsible for energy conservation and
restoration.
Anatomy: originating in the brainstem and the lower
part of the spinal cord and vagus nerve
Function:
 Cardiovascular System:
 slower heart rates, increased peripheral vascular flow,
blood flow to all cells, liver and kidneys, and venous return
to the heart.
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Parasympathetic

Function:
 GI
 mediates gut function, peristalsis, resting states after meals
and at night, digestion and nutrient storage
 GU
 coordination of bladder function
 Miscellaneous
 Sweating abnormalities
 Sluggish papillary reaction-with night vision and
accommodation issues
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Homeostasis: balance between both divisions
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The general action of each of the branches of the
ANS is to oppose the other. As one branch begins to
work the other branch begins to return it to
baseline. Consequently, persistently elevated tone in
one branch can result in a persistently depressed
tone in the other.
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The parasympathetic nervous system can
change faster than the sympathetic nervous
system.
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As the sympathetic starts to mediate a stress
response the parasympathetic immediately begins to
counter it.
Conceptually:
 If the parasympathetic is not faster than the
sympathetic, then any stress response could send the
heart into tachycardia and onto ventricular fibrillation
before the parasympathetic could act to prevent it.
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Since the parasympathetic is faster to respond, it is
usually the branch that is first to indicate changes
in health status.
Although clinically, sympathetic dysfunction
produces the most striking symptoms
Note: these abnormalities are INDEPENDENT of
any cardiac dysfunction which may or may not be
coexisting. USUALLY cardiac function is normal.
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It is my contention that the majority of causes
of autonomic dysfunction are in some way
related to LBC [Lyme Borrelia Complex]
Those causes NOT likely related to this
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Can generally dismissed because of their clinical
manifestations and/or infrequency
Should be considered in relation to the underlying
LBC and either avoided [eg. Drugs] or concomitantly
be treated [eg. Diabetes]
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Primary “idiopathic”*
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Infectious
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Adrenal insufficiency*
Diabetes Mellitus
Drug
Toxin
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Lyme disease
Syphilis
HIV
Endocrine
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Pure autonomic failure *
Multiple system atrophy*
Parkinsons Disease*
Multiple Sclerosis*
Arsenic
mercury
Renal Failure
Age
Miscellaneous
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Potassium depletion
Chronic Fatigue Syndrome*
Guillain Barre Syndrome*
Acute Intermittent Porphyria
Amyloid
*potentially actually due to occult or actually diagnosed Lyme disease
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Active neurotropic invasion by spirochete
and/or associated infections
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Resultant tissue inflammation/dysfunction
Microbe neurotoxins
Systemic cytokine response to the above, with
subsequent noxious influence
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Assuming that LBC is at least in part, if not entirely the cause:
Ruling out clinically
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Consider evaluation/management of:
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Adrenal insufficiency
Toxin/heavy metal
Avoidance
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Syphilis
Diabetes Mellitus
Renal Failure
Drugs
Potassium depletion
Rare:
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Acute Intermittent Porphyria
Amyloid
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Drugs:
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Alcohol
Alpha blockers [eg. for prostatism]
Tricyclics [eg. for fibromyalgia]
l-dopa [eg for restless leg syndrome]
Phenothiazines [eg as antiemetics]
Barbiturates [eg. with headache analgesics]
Zanaflex [tizanidine] alpha 2 agonist
Diuretics
Nitrates
MAO inhibitors
Alpha-methyldopa
Bethanidine
Dibenzyline
Pronestyl
Guanabenz
Quinidine
Guanadryl
Guanethedine
Trimethaphan
Isoniazid
Reserpine
Vincristine
Caveat-caution with concomitant use
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Brief:
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Emphasis
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Gastrointestinal
Genitourinary
Cardiovascular
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HypOactivity:

Oral/upper GI
 paralysis or partial paralysis of tongue, gag reflex, esophagus, stomach
and nearby organs

Lower GI
 small and/or large instestine “ileus,” intestinal “spasms,” megacolon,
encopresis and rectal muscle cramping “proctalgia fugax.”
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Hyperactivity-hypermotility of gut associated with diarrhea
Note: secondary nonautonomic issues:
 bacterial overgrowth
 Also nonautonomic control:
 Intrinsic enteric neurons
 multiple neuropeptides-local and systemic
 Striated motor innervation-such as external anal sphincter
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Primary clinical manifestations:
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Urinary frequency, urgency, hesitation
Note: the bladder also has conscious intervention via striated
motor innervation
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Limited options
Treatment of presumed underlying etiologies
[majority of cases will be LBC]
Nonspecific:
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Symptomatic
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Alpha lipoic acid
Eg. Antispasmodics, antiemetics, etc
Miscellaneous issues
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Eg. Bacterial overgrowth-consider Xifaxin, probiotics
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Symptom
Frequency
Postural hypotension
94%
Lightheadedness, fainting, dimness of vision,
weakness, unsteady gait, slurred speech
Urinary dysfunction
65%
Frequency, nocturia, urgency, stress incontinence
Sexual dysfunction
51%
Impotence, loss of libido, dry or retrograde
ejaculation
Bowel dysfunction
30%
Intermittent diarrhea, nocturnal diarrhea, rectal
Decreased sweating
11%
Data derived from: Thomas JE, Schirger A. Idiopathic orthostatic hypotension. Arch Neural 1970;22:289–93.
Copyright © 1990 Butterworth Publishers
July 7, 2015
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Sympathetic dysfunction
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Hypotension/Sympathetic withdrawal [usually
symptomatic]
 Normal response to hypotension
 Baroreflex mechanisms regulate systemic blood pressure by increasing heart
rate and vascular resistance
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Baroreceptor dysfunction-either hypo or hyperstimulated
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usually symptomatic, from most to least severe dysfunction [left to right]

Caveats:
 Sympathetic Withdrawal generates relative
hypotension
 The parasympathetic nervous system can change faster
than the sympathetic nervous system.
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NMS or NMH-Neurally mediated syncope/hypotension
[bradycardia] aka vasodepressant syncope or vasovagal
syncope-parasympathetic hypersensitivity
POTS-postural orthostatic tachycardic syndrome
[tachycardia]-loss of parasympathetic tone, allowing for a hyper
compensatory tachyardia response
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OH-orthostatic hypotension [normal heart rate]
 Neither vagal effects or sympathetic compensatory
mechanism in play
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Hypertension [usually asymptomatic]
 Labile
 Sustained
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Timing
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Immediate to 1.0min: ~500-1000cc blood shifting to
lower abdomen/extremities venous capacitance
20-30min: loss of plasma volume [~14% in the order of a
unit of blood]
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Compensatory increases
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Sympathetics
Renin/angiotensin/aldosterone
Adrenal-cortisol
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Special considerations
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Impact of eating: in susceptible individuals, post
prandial blood pressure may drop as much as
40mmHg
Hyperventilation-even associated with exercise or
pain, by dropping CO2 can exacerbate hypotension
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Orthostatic:
Lightheadedness to presyncope to frank syncope
 Malaise
 Palpitations
 Shortness of breath
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Caveats
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Most of the diagnosis will be done by obtaining
orthostatic VS, which should be done at EVERY visit
Assuming already diagnosis of Lyme and/or related
tick born infection, that may be enough for the
mildly characterized individual
For the more severe/recalcitrant
 Consider ANSAR testing [most people DON’T have to
undergo tilt table testing]
 Salivary adrenal testing
 Echo to r/o structural/hemodynamic issues
 Post chelation heavy metal analysis
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ANSAR Testing
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Heart Rate Variability
(HRV)-http://www.ans-hrv.com/
Procedure [~15minutes]
 Rest-baseline “balance”
 Deep breathing [stimulating
parasympathetics]
 Valsalva [stimulating
sympathetics]
 Stand [stimulating both]
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Goals-symptomatic relief
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Treat the patient, not the number
Less is better
Expectations
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Variable from profound response to minimal
intervention to persistent symptoms in the setting of
maximal intervention
Often with some residua, even in the setting of
inactive underlying infection
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Caveats
Intervention usually provides a MORE pronounced
therapeutic effect in orthostatic blood pressure than
supine.
 HOWEVER, there usually is some concomitant increase
in supine blood pressure that needs to anticipated.
 Home BP monitoring:

 Stand in AM [anticipated LOW daily blood pressure]
 Supine HS [anticipated HIGH daily blood pressure]
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OCCASIONALLY the supine increases in blood pressure
will actually paradoxically warrant additional
antihypertensives.
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High Salt Diet/tablets [eg. Thermatabs]
Compression stocks
Proamatine [midodrine]
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Florinef WITH potassium replacement
SNRIs
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Alpha Lipoic Acid
Endocrine issues: Adrenal dysfunction
Miscellaneous
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Effexor/Cymbalta/?Pristiq
Beta blockers
Nonspecific
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Side effects[paresthesias/bladder outlet issues]
Psychostimulants
Pyridostigmine bromide (Mestinon)
DDAVP
Other issues/conditions eg heavy metals, diabetes
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o
High Salt Diet/tablets [such as thermatabs]
o Mechanism of action
o Osmotic fluid retention
o Perhaps JUST diet is enough. Otherwise start with one
thermatab daily and increase to need/tolerance, up to
THREE THREE times daily
o Side effects
o usually simply edema
o Dyspepsia/nausea
o Occasionally headaches
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o
Proamatine [Midodrine]
o Mechanism of action
o Alpha agonist
o Side effects
o Paresthesias “tingling of the scalp”
o Dyspepsia/nausea
o Occasionally urinary outlet issues
o More “physiologic” than florinef
o Dosing:
o Start slowly at 2.5mg once in or in am and lunch. Push to
need/tolerance [PDR “recommended dose 10mg tid”]
o Personal experience with as high as 10mg ONE and 1/2 tablets at
~0600, 0800, 1000, 1200, 1400 and 1600; IF going out in the evening
take ONE at 1800
o Caveat-start low and move slow Back off if having hypertension,
particularly supine hs and/or side effects
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o
Florinef [fludrocortisone]
o Mechanism of action
o Sodium retention driving osmotic fluid retention
o With concomitant potassium lowering
o Dosing-0.1mg ½ daily, up to perhaps FOUR tablets daily. But
usually limited to side effects, perhaps BP overshoot.
o
Side effects
o Hypokalemia-should generally empirically START KCl
replacement with initiation and/or increases in dose
o usually simply edema
o Dyspepsia/nausea
o Occasionally headaches
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o
SNRIs [Selective Norepinephrine Reuptake Inhibitors]o
o
Primarily Effexor and secondarily Cymbalta, ?Pristiq
Mechanism of action
o Vasoconstrictor and central effects of norepinephrine
o
Dosing of Venlafaxine
o Usually 37.5mg one daily, occasionally 25mg ½ tab daily
o Up to 300mg/day
o
Side effects
o Possible agitation because of potential stimulatory effects
o Withdrawal issues
o
Added benefits, potential Rx of comorbidities
o Mood disorders
o Fibromyalgia and neuropathic pain
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Beta blockers Alpha/beta blocker-Coreg [carvedilol] CR vs generic
 alpha-1 adrenergic antagonist
 Selective beta blockers Toprol [Lopressor]/Tenormin[atenolol]
 Note issues of 24hr efficacy

Clonidine [central alpha 2 agonist]
 useful for hs supine HTN
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CCB
 Diltiazem/verapamil
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o
Compression Stockings [Jobst or Medistrumpf]
o Generally BELOW the knee 20-30mmHg
o Can go as high as 30-40mmHg, but more uncomfortable
o Above the knee only are helpful if used with garters and generally not practical
o Mechanism of action
o Improving venous return from mechanical compression
o
Side effects
o Uncomfortable
o Particularly at higher pressures and if with hyperanalgesias issues and in warm
weather
o unsightly
o
Caveats
o Don’t want to use these chronically because of the tendency to contribute to
muscle atrophy, but rather on an as needed basis. For example if anticipating
activities that will require to be upright for a more prolonged period of time.
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Endocrine
Hypothalamic/pituitary/adrenal dysfunction
 Mechanisms
 Direct infectious invasion/dysfunction at any level
 “chronic stress” leading to inability to compensate and
“adrenal fatigue”
 Supplementation
 Herbals-eg. Cordryceps, Nutramedix Adrenal Support, etc
 Cortef [hydrocortisone] 12-15mg/m2//day generally 2/3
upon awakening and 1/3 later in the day
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Alpha Lipoic Acid
•Over the counter
•Dosing
•Initially 100mg/day
•Up to 600mg twice daily
•Caution with potential hypotension
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o
o
Psychostimulants [eg. Adderall,Ritalin,etc]
Cautions:
o Exacerbation of tachycardia in POTS
o Drug interactions, particularly with several SSRIs [eg
prozac, zoloft]-risk for “serotonin syndrome”
o Risk, albeit small of delusional behavior
o
Added benefits
o Stimulants helpful in subset of patients with fatigue
and cognitive impairment/ADD like qualities
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Pyridostigmine bromide (Mestinon)- NOT often used
acetylcholinesterase inhibitors, resulting in a lower heart rate
 Indications
 myasthenia gravis,
 Exposure to certain nerve gases
Therapeutic benefit for a small group of individuals primarily
with POTS, mainly by increasing the amount of parasympathetic
tone in the autonomic nervous system.
Doses of 30-60mg 1-2 times daily
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POTS
Try to stabilize the orthostatic drop prior to choosing an
agent to slow the HR, which may improve with this
intervention.
 Invariably will need an agent to slow HR

 Beta blockers
 Preferentially Coreg [Carvedilol] better tolerated, particularly
if associated with parasympathetic excess.
 Secondarily Toprol [Metoprolol] [particularly if risk for
reactive airways
 Clonidine
 CCB-Diltiazem/Verapamil-not as well tolerated b/o gut
related dysauotonomic issues particularly as relates to
constipation with verapamil
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OI with resting supine HTN
This can represent a particular challenge
 Will particularly need antihypertensive management
when anticipate being supine ie in general hs
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Common issues
Characterize and prioritize intervention
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Less is better
Judicious use of life style and pharmacologic
intervention
Perhaps not so enigmatic a “black box?”
To download a copy of this presentation, go to: www.INTMEDNOVA.com
July 7, 2015
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