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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 May 24, 2017 Samuel Shor, MD, FACP 1 Define this often perceived “black box” VERY common phenomenon-with practical considerations Systems impacted Emphasis on cardiovascular manifestations Management-in a hopefully “usable” “take home” approach May 24, 2017 Samuel Shor, MD, FACP 2 Clinical manifestations of dysfunction-overview Anatomy/Physiology-BRIEF Overview Potential etiologies Systems impacted Briefly: GI/GU emphasis on cardiovascular system Management May 24, 2017 Samuel Shor, MD, FACP 3 “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 May 24, 2017 Samuel Shor, MD, FACP 4 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 May 24, 2017 Samuel Shor, MD, FACP 5 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 May 24, 2017 Samuel Shor, MD, FACP cortisol] 6 May 24, 2017 Samuel Shor, MD, FACP 7 Alpha 1 Receptors Vascular smooth muscle postsynaptic neurons Vasoconstriction [note: agonist: proamatine vs antagonist: prazosin] Myocardium Positive Inotrope Negative Chronotrope 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] May 24, 2017 Samuel Shor, MD, FACP 8 Beta receptors-stimulated by epinephrine ß1 adrenergic receptors-cardiostimulation ß2 adrenergic receptors-bronchodilatation and vasodilatation. May 24, 2017 Samuel Shor, MD, FACP 9 Parasympathetic 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. May 24, 2017 Samuel Shor, MD, FACP 10 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 May 24, 2017 Samuel Shor, MD, FACP 11 Homeostasis: balance between both divisions 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. May 24, 2017 Samuel Shor, MD, FACP 12 The parasympathetic nervous system can change faster than the sympathetic nervous system. 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. May 24, 2017 Samuel Shor, MD, FACP 13 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. May 24, 2017 Samuel Shor, MD, FACP 14 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 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] May 24, 2017 Samuel Shor, MD, FACP 15 Primary “idiopathic”* Infectious Adrenal insufficiency* Diabetes Mellitus Drug Toxin Lyme disease Syphilis HIV Endocrine Pure autonomic failure * Multiple system atrophy* Parkinsons Disease* Multiple Sclerosis* Arsenic mercury Renal Failure Age Miscellaneous Potassium depletion Chronic Fatigue Syndrome* Guillain Barre Syndrome* Acute Intermittent Porphyria Amyloid *potentially actually due to occult or actually diagnosed Lyme disease May 24, 2017 Samuel Shor, MD, FACP 16 Active neurotropic invasion by spirochete and/or associated infections Resultant tissue inflammation/dysfunction Microbe neurotoxins Systemic cytokine response to the above, with subsequent noxious influence May 24, 2017 Samuel Shor, MD, FACP 17 Assuming that LBC is at least in part, if not entirely the cause: Ruling out clinically Consider evaluation/management of: Adrenal insufficiency Toxin/heavy metal Avoidance Syphilis Diabetes Mellitus Renal Failure Drugs Potassium depletion Rare: Acute Intermittent Porphyria Amyloid May 24, 2017 Samuel Shor, MD, FACP 18 Drugs: 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 May 24, 2017 Samuel Shor, MD, FACP 19 Brief: Emphasis May 24, 2017 Gastrointestinal Genitourinary Cardiovascular Samuel Shor, MD, FACP 20 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.” 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 May 24, 2017 Samuel Shor, MD, FACP 21 Primary clinical manifestations: Urinary frequency, urgency, hesitation Note: the bladder also has conscious intervention via striated motor innervation May 24, 2017 Samuel Shor, MD, FACP 22 Limited options Treatment of presumed underlying etiologies [majority of cases will be LBC] Nonspecific: Symptomatic Alpha lipoic acid Eg. Antispasmodics, antiemetics, etc Miscellaneous issues Eg. Bacterial overgrowth-consider Xifaxin, probiotics May 24, 2017 Samuel Shor, MD, FACP 23 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 May 24, 2017 Samuel Shor, MD, FACP 24 Sympathetic dysfunction Hypotension/Sympathetic withdrawal [usually symptomatic] Normal response to hypotension Baroreflex mechanisms regulate systemic blood pressure by increasing heart rate and vascular resistance May 24, 2017 Baroreceptor dysfunction-either hypo or hyperstimulated Samuel Shor, MD, FACP 25 May 24, 2017 Samuel Shor, MD, FACP 26 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. May 24, 2017 Samuel Shor, MD, FACP 27 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 OH-orthostatic hypotension [normal heart rate] Neither vagal effects or sympathetic compensatory mechanism in play May 24, 2017 Samuel Shor, MD, FACP 28 Hypertension [usually asymptomatic] Labile Sustained May 24, 2017 Samuel Shor, MD, FACP 29 May 24, 2017 Samuel Shor, MD, FACP 30 Timing 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] Compensatory increases Sympathetics Renin/angiotensin/aldosterone Adrenal-cortisol May 24, 2017 Samuel Shor, MD, FACP 31 Special considerations 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 May 24, 2017 Samuel Shor, MD, FACP 32 Orthostatic: Lightheadedness to presyncope to frank syncope Malaise Palpitations Shortness of breath May 24, 2017 Samuel Shor, MD, FACP 33 Caveats 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 May 24, 2017 Samuel Shor, MD, FACP 34 ANSAR Testing Heart Rate Variability (HRV)-http://www.ans-hrv.com/ Procedure [~15minutes] Rest-baseline “balance” Deep breathing [stimulating parasympathetics] Valsalva [stimulating sympathetics] Stand [stimulating both] May 24, 2017 Samuel Shor, MD, FACP 35 May 24, 2017 Samuel Shor, MD, FACP 36 Goals-symptomatic relief Treat the patient, not the number Less is better Expectations 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 May 24, 2017 Samuel Shor, MD, FACP 37 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] OCCASIONALLY the supine increases in blood pressure will actually paradoxically warrant additional antihypertensives. May 24, 2017 Samuel Shor, MD, FACP 38 High Salt Diet/tablets [eg. Thermatabs] Compression stocks Proamatine [midodrine] Florinef WITH potassium replacement SNRIs Alpha Lipoic Acid Endocrine issues: Adrenal dysfunction Miscellaneous Effexor/Cymbalta/?Pristiq Beta blockers Nonspecific Side effects[paresthesias/bladder outlet issues] Psychostimulants Pyridostigmine bromide (Mestinon) DDAVP Other issues/conditions eg heavy metals, diabetes May 24, 2017 Samuel Shor, MD, FACP 39 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 May 24, 2017 Samuel Shor, MD, FACP 40 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 May 24, 2017 Samuel Shor, MD, FACP 41 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 May 24, 2017 Samuel Shor, MD, FACP 42 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 May 24, 2017 Samuel Shor, MD, FACP 43 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 CCB Diltiazem/verapamil May 24, 2017 Samuel Shor, MD, FACP 44 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. May 24, 2017 Samuel Shor, MD, FACP 45 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 May 24, 2017 Samuel Shor, MD, FACP 46 Alpha Lipoic Acid •Over the counter •Dosing •Initially 100mg/day •Up to 600mg twice daily •Caution with potential hypotension May 24, 2017 Samuel Shor, MD, FACP 47 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 May 24, 2017 Samuel Shor, MD, FACP 48 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 May 24, 2017 Samuel Shor, MD, FACP 49 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 May 24, 2017 Samuel Shor, MD, FACP 50 OI with resting supine HTN This can represent a particular challenge Will particularly need antihypertensive management when anticipate being supine ie in general hs May 24, 2017 Samuel Shor, MD, FACP 51 Common issues Characterize and prioritize intervention 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 May 24, 2017 Samuel Shor, MD, FACP 52