Too Hot, Too Cold, Too High, Too Low - Blame it on Dysautonomia!
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1 Too Hot, Too Cold, Too High, Too Low - Blame it on Dysautonomia! MitoAction Webcast 6-May, 2011 Richard G. Boles, M.D. Medical Genetics Childrens Hospital Los Angeles Associate Professor of Pediatrics Keck School of Medicine at USC
2 Maternal Inheritance of Functional Disorders Cancer Dyslexia Bipolar, Migraine Colitis Colitis Seizures, CVS, Migraine, Bipolar, Anxiety GERD, Migraine, Depression, Seizures, Hearing loss Bipolar Migraine CVS Migraine Seizures Muscle Weakness Depression ASD/VSD CRPS CRPS SIDS Migraine Migraine Abdominal GERD Migraine CP Preemie Muscle CVS migraine Seizures Migraine Depression Blind weakness Hypoglycemia Ptosis Reyes syndrome Failure to thrive Many of these conditions involve abnormal autonomic nervous system activity, and can be thought of as dysautonomias.
3 Gardner Boles 2006 depression The functional symptoms tinnitus migraine fibromyalgia elephant cyclic vomiting complex regional pain syndrome functional abdominal pain irritable bowel syndrome interstitial cystitis restless legs syndrome The elephant is lying down due to chronic fatigue
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5 The Autonomic Nervous System Turns On and Off the Fight or Flight Response Sympathetic Nervous System On switch tiger stalking Parasympathetic Nervous System Off switch tiger gone
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8 Case Report 15-year-old girl with cyclic vomiting syndrome, constipation and chronic fatigue During vomiting episodes and viral infections she is unable to read. Eye examinations are normal by two ophthalmologists. The school is alleging psychiatric disease or malingering. She is more comfortable wearing a hat, even indoors, and wears a hat to the clinic visit.
9 Autonomic Nervous System - The Eye Sympathetic Nervous System On switch tiger stalking Pupils dilate for better peripheral vision Lens focuses on distance Parasympathetic Nervous System Off switch tiger gone Pupils constrict to focus vision on central object Lens focuses on near
10 Autonomic Nervous System - The Eye Sympathetic Nervous System On switch tiger stalking Pupils dilate for better peripheral vision causing photophobia; she is uncomfortable outdoors in the sunlight or under florescent lights. Wearing a hat is adaptive, so are sunglasses. Lens focuses on distance making it difficult to read. The solution is reading glasses during illnesses. Parasympathetic Nervous System Off switch tiger gone Pupils constrict to focus vision on central object Lens focuses on near
11 Autonomic Nervous System - Blood Vessels Postural orthostatic tachycardia syndrome Color changes/rash: flushed, pallor, mottled, circles under eyes Heat and cold intolerance Pain syndromes migraine/abdominal migraine complex regional pain syndrome
12 Case Report 14-year-old boy with mild dysautonomic symptoms, including chronic pain syndromes. Sister and multiple matrilineal relatives have functional/dysautonomic-related symptoms/ conditions Presented with sudden episodes of loss of consciousness with pallor. Episodes are preceded by nausea and dizziness.
13 Autonomic Nervous System - Blood Vessels Postural orthostatic tachycardia syndrome Dizziness, blackouts Often precipitated by standing up More common in adolescents First-line treatment is increased fluids and salt Can be dramatic and appear as seizure May require medication
14 Complex Regional Pain Syndrome-I: Symptoms: allodynia, painful, edematous, cold, purple, unable to stand or walk
15 Complex Regional Pain Syndrome-I: Treatment: exercise/pt do not immobilize IVF D10+lytes amitriptyline coenzyme Q10
16 Autonomic Nervous System - The Heart Fast (tachycardia) and slow (bradycardia) heart rates are very common in mito disease. In adults, heart attacks are not uncommon, but rare in children. Usually, there was a trigger (Imitrex, surgery) or no mito-care. Chest pain in mito kids is almost always GERD, and occasionally costochondritis. Syncope is usually due to dysautonomia. Cardiac birth defects are likely increased.
17 Autonomic Nervous System - Secretory Glands Sweat glands Salivary glands Lacrimal (tear) glands Mammary (milk) glands Reproductive system glands Digestive system glands
18 Autonomic Nervous System - The Gut Sympathetic Nervous System On switch tiger stalking Blood flow increases to brain and muscle, for quick thinking and the power to act. Blood flow decreases to the gut, this is no time for digestion. Parasympathetic Nervous System Off switch tiger gone Blood flow increases to the gut allowing for digestion.
19 Autonomic Nervous System - The Gut Sympathetic Nervous System On switch tiger stalking Blood flow increases to brain and muscle, for quick thinking and the power to act. Blood flow decreases to the gut, this is no time for digestion. Parasympathetic Nervous System Off switch tiger gone Blood flow increases to the gut allowing for digestion. Thus, indigestion caused by decreased gut dysmotility is common in sympathetic-driven conditions precipitated in part by mitochondrial dysfunction.
20 Dysmotility = bad movement Abnormal rate Fast: dumping, diarrhea Slow: bloating, constipation Direction GERD Vomiting Failure (very poor motility) Pyloric stenosis Malabsorption Pseudoobstruction
21 Mito-dysmotility Often occurs at different levels in the same child Intermittent Very common in mito disease Delayed gastric emptying X X X Malabsorption Gastroesophageal reflux X Irritable bowel Occurs in many different mito disorders Another example of mito disease preferentially affecting the high-energy demand tissues of muscle and nerve: The GI tract is composed of muscle, and synchronized by nerves.
22 Level of Dysmotility: Esophagus Gastroesophageal Reflux Disease GERD High prevalence: Very common in the general population. Nearly universal in mito Clinical presentations: quite varied: Heartburn, abdominal pain Chronic nausea Chronic sinusitis, allergy Cough, asthma Failure-to-thrive Malaise, fatigue
23 Level of Dysmotility: Esophagus Gastroesophageal Reflux Disease GERD Diagnosis: Scans (nuclear medicine, upper GI) Tubes (ph probe, endoscopy) Response to empirical treatment Treatment: Mechanical (angle bed) Diet thicken feeds small, frequent meals/snacks low-fat heart-healthy diet Antacids Acid blockers (Zantac) Proton pump inhibitors (Prilosec OTC, Protonex, Aciphex, Nexium) Prognosis: Usually intermittent, worse in babies and elderly
24 Level of Dysmotility: Esophagus Gastroesophageal Reflux Disease GERD Diagnosis: Scans (nuclear medicine, upper GI) Tubes (ph probe, endoscopy) Response to empirical treatment Treatment: Mechanical (angle bed) Diet thicken feeds small, frequent meals/snacks low-fat heart-healthy diet Antacids Acid blockers (Zantac) Proton pump inhibitors (Prilosec OTC, Protonex, Aciphex, Nexium) Prognosis: Usually intermittent, worse in babies and elderly
25 Level of Dysmotility: Stomach Delayed Gastric Emptying Intermediate prevalence Causes Stomach failure (gastroparesis) Outlet obstruction (pyloric stenosis) Clinical presentations: Abdominal pain Bloating Chronic nausea Early satiety Failure-to-thrive
26 Level of Dysmotility: Stomach Delayed Gastric Emptying Diagnosis: Imaging (nuclear medicine, upper GI) Tubes (ph probe, endoscopy) Response to empirical treatment Treatment: Diet small, frequent meals/snacks low-fat heart-healthy diet liquid/pureed diet Medications - prokinetic drugs (Reglan) Surgery pyloroplasty bypass stomach (J-tube or G-J-tube) Prognosis: Intermittent or progressive
27 Level of Dysmotility: Stomach Delayed Gastric Emptying Diagnosis: Imaging (nuclear medicine, upper GI) Tubes (ph probe, endoscopy) Response to empirical treatment Treatment: Diet small, frequent meals/snacks low-fat heart-healthy diet liquid/pureed diet Medications - prokinetic drugs (Reglan) Surgery pyloroplasty bypass stomach (J-tube or G-J-tube) Prognosis: Intermittent or progressive
28 Level of Dysmotility: Small Intestine Malabsorption Low prevalence Clinical presentations: Diarrhea Failure-to-thrive Metabolic decompensation (fasting-invoked)
29 Level of Dysmotility: Small Intestine Malabsorption Diagnosis: Imaging (nuclear medicine, upper GI) Tubes (ph probe, endoscopy, colonoscopy) Capsule Motility studies Treatment: Diet small, frequent meals/snacks low-fat heart-healthy diet liquid/pureed diet elemental diet Medications antibiotics (small intestine bacterial overgrowth = SIBO) probiotics Parental nutrition ( TPN ) Prognosis: Often progressive, SIBO is treatable
30 Level of Dysmotility: Small Intestine Malabsorption Diagnosis: Imaging (nuclear medicine, upper GI) Tubes (ph probe, endoscopy, colonoscopy) Capsule Motility studies Treatment: Diet small, frequent meals/snacks low-fat heart-healthy diet liquid/pureed diet elemental diet Medications antibiotics (small intestine bacterial overgrowth = SIBO) probiotics Parental nutrition ( TPN ) Prognosis: Often progressive, SIBO is treatable
31 Level of Dysmotility: Large Intestine Irritable Bowel High prevalence: Very common in the general population. Nearly universal in mito Clinical presentations: Constipation Diarrhea Alternating constipation and diarrhea Abdominal pain (usually relieved by BM) Distension/bloating Vomiting Failure-to-thrive Metabolic decompensation (fasting-invoked)
32 Level of Dysmotility: Large Intestine Irritable Bowel Diagnosis: Imaging (x-ray for stool) Tubes (colonoscopy) Motility studies Treatment: Diet low-fat heart-healthy diet prune juice, etc. Medications Polyethylene glycol (MiraLax, GoLytely) Milk of magnesia Amitiza Mechanical (enemas) Prognosis: Usually intermittent, serious cases can progress to pseudoobstruction
33 Level of Dysmotility: Large Intestine Irritable Bowel Diagnosis: Imaging (x-ray for stool) Tubes (colonoscopy) Motility studies Treatment: Diet low-fat heart-healthy diet prune juice, etc. Medications Polyethylene glycol (MiraLax, GoLytely) Milk of magnesia Amitiza Mechanical (enemas) Prognosis: Usually intermittent, serious cases can progress to pseudoobstruction
34 Diagnosis Clinical intermittent, multiple functional symptoms Increased symptoms with illness, fasting Maternal inheritance Urine organic acids, ketosis Other biochemical testing mtdna sequencing Ruling out other possible diagnoses Response to mitochondrial-targeted therapies
35 Six Questions Predict Mitochondrial Function Gardner and Boles, Bio Psycho Soc Med 2008 My heart sometimes beats hard or irregularly for no real reason. (Somatic Anxiety, item 34, p = 0.003). I often have aches in my shoulders and in the back of my neck. (Muscular Tension, item 4, p = 0.031). My body often feels stiff and tense. (Muscular Tension, item 33, p = 0.031). I think I must economize my energy. (Psychasthenia, item 40, p = 0.015). In order to get something done I have to spend more energy than most others. (Psychasthenia, item 53, p = 0.031). I feel easily pressured when I am urged to speed up. (Psychasthenia, item 93, p = 0.014). 13/14 subjects with ATP production rates below the normal range answered at least two of those six items as Applies Completely, compared to only 1/7 subjects with ATP production rates within our control range (chisquare P = ).
36 Therapy: General Principles Combine mitochondrial-directed treatment together with symptom-directed treatment. Mitochondrial-directed treatment is to: Decrease energy demand Increase energy supply
37 Therapy: Agents Lifestyle Changes: Fasting avoidance 3+3 diet Special caution during viral illnesses, may need IV fluid Hydration Exercise in moderation Cofactors: Co-enzyme Q10 L-carnitine Riboflavin Creatine Antioxidants (vitamins C and E) Medications: Psychtropics (amitriptyline) PPIs (Prilosec) PEG (Miralax)
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