Dysautonomia: Experience from a Large Single Center

Transcription

1 Dysautonomia: Experience from a Large Single Center David S. Cannom, M.D. Clinical Professor of Medicine UCLA School of Medicine Good Samaritan Hospital/Cedars Sinai Heart Institute September 13, 2018

2 Venous system disease Abnormalities of the venous system, called dysautonomias, share symptoms of lightheadedness or fainting, unstable blood pressure, and an abnormal heart rate. Symptoms develop most commonly. in young women during puberty and affect 1 to 3 million teenagers Symptoms vary markedly from being an annoyance to forcing complete bedrest for years

3 Understanding Dysautonomia No agreement on definitions of disease states Very little understanding of basic mechanisms Very few descriptive large clinical series Few natural history studies No randomized treatment trials except many pacing therapy trials for vasovagal syncope (not helpful) plus a florinef trial and recent droxydopa (Northera) trial for BP support (very helpful) Little interest among cardiologists, industry or NHLBI

4 Three major categories of dysautonomia Vasovagal episode: simple faint Orthostatic hypotension Postural Orthostatic Tachycardia Syndrome (POTS) Straight forward Complicated

5 LACA dysautonomic patients: 410 followed 9/18 Vasovagal syncope 34% Orthostatic hypotension 10% Mild POTS 27% Disabling POTS 29% Population 77% female 85 patients on waiting list to be seen

6 How Did This Happen? Our practice is large and is willing to see these patients Los Angeles basin has 11 million people No regional university centers have any interest or competence in managing these pts Closest referral center is Stanford or Mayo Clinic I cared for a complicated ULCA anesthesiologist who wrote a book on her cure We were on every website

7 Typical POTS patient MM is a 32 yo patient first seen in December, She had been in good health until February, 2014, when she had a severe allergic rx to naicin. She developed dyspnea, presyncope and dizziness with changes in position. Her pulse increased to 140 bpm with minimal exertion. Long term monitoring correlated her dyspnea with a rapid pulse. Thyroid normal. She was started on a beta blocker with prompt resolution of her tachycardia. She gained 30 lbs and was changed to ivabradine. Doing nicely and is now seen every year.

8 Heart rate and blood pressure with upright tilt in postural tachycardia syndrome Circulation 2013;127:

9 Criteria for the Postural Tachycardia Syndrome Heart rate increases >30 bpm from supine to standing (10 min) Symptoms worsen with standing and improve with recumbence Symptoms present for >6 mo Absence of overt causes of orthostatic symptoms or tachycardia (eg, active bleeding, acute dehydration, medications) First described in 1994 Circulation 2013;127:

10 Causation of POTS Recent studies in humans have shown there is actual damage to the ANS which reduces contraction of the venous system with resultant blood pooling in the abdomen & legs In some patients antibodies to the nerves themselves have been demonstrated. Also an inflammatory process is suspected: some 50% of our pts presented after a serious infection esp Lyme disease or EBV Four patients presented after a serious rx to a vaccine: others have had neck & head trauma

11 Heart Rhythm Society, 2015

12 Heart Rhythm Society, 2015

13 Ivabradine A newly available agent which competively inhibits the potassium channel in the sinus node (so called funny channel ) and slows the sinus rate Physician can increase dose over a narrow range until desired effect achieved (2.5 to 10 mg bid) Few if any side effects unlike beta blockers Approved for treatment of heart failure pts Must fail a trail of BB before it can be used

14 The Complicated POTS Patient

15 Case Report: seen 8/16 KL: 34 yo female in good health until a complicated oopherectomy 10 years earlier: early sx were presyncopal spells, tunnel vision and a racing pulse when standing up. Episodes initially once per month and increased to several times a week. GI symptoms of nausea and constipation diagnosed as due to gastroparesis in Nausea and cramping caused by dairy, lactose, tomatoes, onions, garlic, eggplant, bananas, avocado, and alcohol: all of these also cause skin rashes. Has H/O asthma (MAST cell disease) Musculoskeletal pain involving neck, back, knees, and hands: associated with elevated ANA Sicca syndrome with red mouth and eyes: also developed Hashimoto s disease Migraines twice per week, temperature instability and trouble sleeping No physical activity because of fatigue and palpitations Lives with mother: cannot work BP 112/84 lying with pulse of 68; standing 94/70 with pulse of 138

16 Case Report: seen 8/16 No workup for autonomic disease until we saw her Tilt test: Phase 1 BP 104/66 pulse 75-90: with Isuprel BP went from 100/63 to 54/30 Zio Patch: sinus tachycardia to 145 bpm at rest MAST Cell workup: 2.3 DINR 11B-Prostaglandin pg/mg (nl <5205): random histamine <1.5 Clinical diagnosis of Ehlers-Danlo made: TFTs hypothyroid MRI brain unremarkable Now taking:» Midodrine 5 mg bid» Zantac 160 mg bid» Zyrtec 10 mg/d» NaCl 3 gms per day» Synthroid 125 mcg/day BP standing 118/76, no dizziness, GI sx better following low histamine diet, started pilates

17 Who are these patients and what do they have to do with simple POTS? These patients represent the majority of our dysautonomic population Patients typically have the Tricky Triad of EDS, MAST cell disease, and POTS POTS itself may be a secondary phenomenon Associated abnormalities have nothing to do with simple definition of POTS (although even the Mayo Clinic does not make this distinction)

18 Additional Clinical Problems Gastroparesis Multiple allergies to environmental factors and foods Skin rashes and hives Migraine headaches Ehlers Danlo Syndrome Anxiety and depression Impaired sleep Extreme fatigue, brain fog and poor nutrition cause inability to work or go to school

19 Characteristics and Ancillary Test Results of Patients with POTS Mean ±SD age (y) Female Male Total Feature Mean ± SD symptom duration (y) Female Male Total MayoClinProc 2007;82(3): Finding 30.8 ± ± ± ± ± ± 4.9 No. (%) of pts (N=152) 132 (86.8) 20 (13.2) 152 (100) 128 (86.5) 20 (13.5) 148 (97.4) Mean ± SD heart rate increase to head-up tilt (b/min) 44.2 ± (100) Mean ± SD TST percent anhidrosis 8.2 ± (51.3) Median supine norepinephrine level (pg/ml) (IQR) No. with supine norepinephrine level > 100 pg/ml ( ) 8 98 (64.5) 98 (8.2)

20 History Remote history of orthostatic intolerance or syncope Yes No Unknown Total Family history of orthostatic intolerance Yes No Unknown Total Symptom onset Acute (<1 mo) Subacute (1-3 mo) Insidious (>3 mo) Unknown Total History of receding illness Yes Preceding illness type Viral, gastrointestinal Viral, upper respiratory tract Viral, unspecified Postoperative Total No Total Characteristics and Ancillary Test Results of Patients with POTS No. (%) of Pts (N=152) 63 (41.4) 77 (50.7) 12 (7.9) 152 (100) 19 (12.5) 71 (46.7) 62 (40.8) 152 (100) 19 (12.5) 21 (13.8) 9 (5.9) 103 (67.8) 152 (100) 42 (27.6) 5 (11.9) 6 (14.3) 27 (64.3) 4 (9.5) 42 (100) 109 (71.7) 151 (99.3) MayoClinProc 2007;82(3):

21 Symptoms MayoClinProc 2007;82(3): Orthostatic and Nonorthostatic Symptoms in Patients with POTS (cont) Nonorthostatic Bloating Nausea Vomiting Abdominal pain Constipation Diarrhea Bladder dysfunction Pupillary dysfunction Generalized associated Fatigue Sleep disturbance Migraine headache Myofascial pain Neuropathic pain No. (%) of Pts (n=152) 36 (23.7) 59 (38.8) 13 (8.6) 23 (15.1) 23 (15.1) 27 (17.8) 14 (9.2) 5 (3.3) 73 (48.0) 48 (31.6) 42 (27.6) 24 (15.8) 3 (2.0)

22 Symptoms Orthostatic and Nonorthostatic Symptoms in Patients with POTS Orthostatic Light-headedness or dizziness Presyncope Weakness Palpitations Tremulousness Shortness of breath Chest pain Loss of sweating Hyperhidrosis Exacerbation by heat Exacerbation by exercise Exacerbation by meals Exacerbation associated with menses No. (%) of Pts (n=152) 118 (77.6) 92 (60.5) 76 (50.0) 114 (75.0) 57 (37.5) 42 (27.6) 37 (24.3) 8 (5.3) 14 (9.2) 81 (53.3) 81 (53.3) 36 (23.7) 22 (14.5) MayoClinProc 2007;82(3):

23 Mast Cell Activation Disease Mast cells are the major effector cells of allergic reactions and can secrete over 100 mediators by which they influence other cells. They can act as innate immune cells and regulate inflammation. Widely distributed in the body. NEJM 2015;373:163-72

24 MAST Cell Symptoms Episodic, even daily, presence of red rash over neck, arms, trunk: very pruritic and associated with anxiety Provoked by foods high in histamine GI sx common including IBS, diarrhea nausea and vomiting Seems associated with fatigue, memory problems and brain fog: a marker of a disabled patient Prominent musculoskeletal pain can lead to opioid addiction

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27 Clinically Relevant Mediators Released from Mast Cells and Putative Effects Treatment includes H1 and H2 receptor antagonists such as loratadine (H1 blocker) and ranitidine (H2 blocker) plus cromolyn a GI inhibitor of mast cell absorption. Ketotifen has more potent blocking effects of mast cell activation. NEJM 2015;373:163-72

28 Treatment of complicated POTs patient Begin with attention to pulse rate and BP: Midodrine for BP support, BB or ivabradine for pulse Look for evidence of mast cell activity and treat if any possibility this is present Obtain referrals for migraines, rheumatologic disease, pain management Obtain help for gastroparesis: very difficult Encourage physical activity Psychologic support important

29 Histamine-Rich & Histamine-Releasing Foods Aged cheese Chocolate Olives Sour cream Anchovies Citrus fruits Papaya Sour milk Apricots Dates Peanuts Soy Sauce Artificial dyes Eggplant Pepperoni Spinach Artificial preservatives Fits Pickles Strawberries Avocados Goat cheese Pineapple Tomatoes Bacon Hotdogs Prunes Tuna Bananas Kefir Raisins Vinegar Beer Kombucha Raspberries Walnuts Buttermilk Mackerel Sardines Wheat germ Cashews Mahi-mahi Sauerkraut Wine Champagne Milk Smoked fish Yogurt

30 Etiology of POTS and its variability of symptoms in different patients is not well understood. Common clinical observation is that a viral or bacterial infection preceded the onset of POTS in prior 6 months Recent studies from the Mayo Clinic, Oklahoma City VA Hospital, and Lund University measured circulating antibodies in POTS patients, VVS patients and normal patients and showed differences between these three groups Auto antibody-mediated alpha 1 adrenergic receptor blockade blunts the normal adrenergic response to upright posture at the level of the peripheral vascular receptor Elevated basal serum tryptase associated with increased genetpsab1 in some EDS,MCAD & POTS pts (Nat Genet 2016) We have twp pts whom have benefited from plasmapharesis (UCI) Randomized trials are necessary: would IVIG be useful in treating these patients? (Need the NIH)

31 JAMA April 2018

32 Effects of Serum Immunoglobulin G (IgG) from Subjects with POTS, WS, and Control on Activation of Angiotensin II Type 1 Receptor (AT1R) in AT1R-trasfected Chinese Hamster Ovary Cells A AT1R activity (% baseline) POTS (n=17) WS (n=6) Control (n=10) B AT1R activity (% baseline) POTS (n=17) ** ** WS (n=6) ** p<0.01 Control (n=10) JAMA April 2018

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34 Treatment of the sick POTs patient Has to be an integrated multidisciplinary approach with experienced physicians -- neurologists, psychiatrists, rheumatologists, allergists, geneticists -- willing to see patients Dedicated office staff imperative Support groups of great help Need basic science guidance to help on the role of mast cell disease Need trials to see how much of a role underlying inflammatory and/or autoimmune disease plays

35 Less obvious challenges in RX Many pts are chronically ill and don t expect to improve: altered family dynamics with parents Great reliance on internet and popular POTS websites: much doctor shopping Many consultants will not see these patients: psychiatrists of little help Use of opioids is excessive and pain management a major problem

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38 Histamine-Rich & Histamine-Releasing Foods Aged cheese Chocolate Olives Sour cream Anchovies Citrus fruits Papaya Sour milk Apricots Dates Peanuts Soy Sauce Artificial dyes Eggplant Pepperoni Spinach Artificial preservatives Fits Pickles Strawberries Avocados Goat cheese Pineapple Tomatoes Bacon Hotdogs Prunes Tuna Bananas Kefir Raisins Vinegar Beer Kombucha Raspberries Walnuts Buttermilk Mackerel Sardines Wheat germ Cashews Mahi-mahi Sauerkraut Wine Champagne Milk Smoked fish Yogurt

39 European Heart Journal 2009;30:

40 Neurocardiogenic Syncope (Vasovagal) During head up tilt in normals there is gravity displacement of blood downward with pooling in the legs with increase in HR and vasoconstriction. In the syncope patient there is marked decrease in cardiac blood volume compared to nonsyncopal patient. Excessive venous pooling with upright posture causes central hypovolemia and an abrupt fall in venous return to the heart.

41 Incidence Rates of Syncope Rate per 1000 Person-Years Progress in Cardiovascular Diseases 2013;55: Age Group (yr)

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43 Treatment of dysautonomia Little progress has been made in treating underlying causes: empiric trials of an immunoglobulin IVIg and other autoimmune therapies show mixed results Most efforts intended to keep the BP and pulse rate as normal as possible with medication There is increasing evidence that dysautonomia activates histamine in the blood stream. Correcting this abnormality has led to cures in our experience

44 Treatment of Vasovagal Syncope Avoid inciting causes esp known triggers and heat Chief concern is head injury and/or bone fracture Hydration and adequate salt intake In cases of repetitive syncope consider need for blood pressure support with midodrine Pacemakers effective in recurrent syncope with injury

45 Orthostatic hypotension Most frequently in patients > 50 years: after standing patients experience significant drop in BP of 20 to 80 mm Hg with severe CNS symptoms and/or syncope Usually have severe underlying hypertension on treatment Typically have associated neurological disease eg Parkinson s

46 77 yo female with orthostatic hypotension 1990s: Began having syncopal spells, some with warning and some not. Had workup at the University of South Carolina where a tilt test, coronary angiogram and EPS were all normal. BP 140/75 (no orthostasis) 2005: Reveal device implanted: PAF 2006: Moved to California and LACA. Having 2-3 episodes of syncope per week despite midodrine 20 mg tid and florinef 0.1 mg/d. Typically no prodrome. Dual chamber ppm implanted 11/06: syncope caused tibial fibular fracture: syncopal spells increased. 40 mm of orthostasis first noted. Tilt test done and BP went from 129/77 to 77/48 after 14 minutes. Pulse 54 (no syncope)

47 77 yo female (cont.) 8/14: CVA with left hemiparesis: neg CT scan brain. Diagnosis of Parkinson s BP 170/80 supine falling to 80/60 upright 2015: 14 episodes of syncope a month despite midodrine 30 mg tid, florinef 0.1 mg bid, Losarten 50 mg/d, Keppra 500 mg bid. 70 mmhg of orthostasis 2015: started Northera 300 mg tid which stabilized BP. 2/16: Fractured hip after a fall. Also 2 nd CVA with left hemiparesis 1/17: No syncope in 9 months on Northera 300 mg tid. Zyrtec 20 mg/dm, Zantac 150 mg bid, flecainide 100 mg bid, hydralazine 25 mg q 6 hours, clonidine 0.1 mg q 6 hours prn for BP over 180, ASA 81 mg/d. Lives alone in Ventura. Does not drive. Internet for shopping. Has motorized scooter at home,

48 Treating orthostatic hypotension Uniformly elderly patients with significant supine hypertension and mm Hg of orthostasis Need to balance enough midodrine to prevent syncope while lowering systolic hypertension to avoid a stroke: sometimes only a little midodrine is needed if systolic BP is normal By far the most difficult dysautonomics to treat Most have either early or advanced Parkinson s

49 Etiology of POTS and its variability of symptoms in different patients is not well understood. Common clinical observation is that a viral or bacterial infection preceded the onset of POTS in prior 6 months Recent studies from the Mayo Clinic, Oklahoma City VA Hospital, and Lund University that measured circulating antibodies in POTS patients, VVS patients and normals are beginning to show the differences between these groups The findings in these studies were that autoantibody-mediated alpha 1 adrenergic receptor blockade blunts the normal adrenergic response to upright posture at the level of the peripheral vascular receptor. In orthostatic hypotension patients, autoantibodies directed toward the beta 2 adrenergic receptor and the M3 muscarinic receptor were found in 6 patients and help explain the hypotensive response Further studies are necessary: would IVIG be useful in treating these patients?....

50 Postural Tachycardia Syndrome 50% of patients with POTS have a restricted autonomic neuropathy of small and distal postganglionic nerve fibers predominantly of the feet and toes Impaired sympathetic tone reduces venoconstriction leading to venous pooling in the lower limbs and splanchnic beds. This neuropathic reality requires a high cardiac output to compensate for reduced splanchnic and peripheral resistance. Abnormal tissues in dependent blood vessels of patients with Ehler-Danlos syndrome can cause excessive venous pooling. Blood volume is reduced in 70% of patients Hyperadrenergic POTS is associated with systolic BP increase of >10 mmhg while standing upright and plasma norepinephrine levels of >600 pg/ml.