Autonomic Disorders: Overview

Home , Autonomic dysreflexia, Familial dysautonomia

Autonomic Disorders: overview

Paola Sandroni, MD, PhD

1 What is the Autonomic Nervous System?

• It is an efferent system that controls visceral function

• It include the • sympathetic • parasympathetic, • enteric nervous system

• Autonomic outputs are triggered in response to two main type of inputs: • sensory inputs from visceral or somatic receptors • inputs from areas of the brain involved in homeostasis, emotion, and stress responses • In general: • the sympathetic system controls patterns of response involving several effectors • the parasympathetic system mediates visceral reflexes triggered by local afferents • the enteric nervous system control gut function relatively independently from other inputs

2 What are the Functions of the Autonomic Nervous System?

• The sympathetic output is critical for • maintenance of arterial blood pressure • regulation of local blood flow • thermoregulation • responses to stress (including metabolic, emotional stress, and exercise)

• The parasympathetic output is critical for • Pupil response to light • Salivation and lacrimation • Beat-to-beat control of the heart rate • Motility of the esophagus and stomach • Micturition • Erectile function

• The enteric nervous system is critical for • Motility and secretion in the gut • Defecation

3 Basic Sympathetic Pathways

Cranial organs

Enteric ganglia (ENS)

Acetylcholine Norepinephrine

Thoracic and Abdominal organs

Skeletal muscle Blood T1 vessel

Sympathetic Skin (intermediolateral cell column)

L2 Paravertebral Sweat sympathetic Prevertebral gland ganglia Sympathetic ganglia

Adrenal medulla Pelvic organs

4 Basic Parasympathetic Pathways

Cranial organs Local ganglia

Enteric ganglia (ENS)

Acetylcholine Acetylcholine or NO/VIP

III

Cranial VII parasympathetic IX Thoracic and Abdominal X organs

Sacral parasympathetic S2/S3

Pelvic organs

5 Summary: Sympathetic and Parasympathetic Effects Target Sympathetic Parasympathetic

Dilatation (NE/ ) Constriction (ACh/ M ) Pupil 1 3

Salivary gland Variable Stimulation (Ach/M3)

Heart Stimulation (NE/1) Inhibition (Ach/M2)

Vessels Constriction (NE/1) Dilation (NO) Dilatation (NO) Dilatation (Epi /)

Sweat gland Stimulation (ACh/M3)

Bronchi Relaxation (Epi /) Constriction (ACh/ M3)

GI tract motility Inhibition (NE/2,  ) Stimulation (ACh/ M3) Inhibition (NO) GI secretion Stimulation (NO, VIP) Bladder detrusor Inhibition (NE/ ) Stimulation (ACh/ M3) neck Contraction (NE/ ) 1 Relaxation (NO)

Sexual organs Ejaculation (NE/1) Erection (NO)

6 Central Autonomic network Level-Specific Function Behavioral Arousal Anterior Cingulate Interoceptive awareness cortex Emotion Insular cortex Stress responses Homeostasis Amygdala Hypothalamus Integration of autonomic function with arousal Periaqueductal gray and pain modulation, Barrington nucleus Dorsal motor Parabrachial nucleus nucleus of the vagus

-Tonic control of blood pressure Nucleus of the -Respiratory rhythms solitary tract -Autonomic reflexes (NTS) RVLM Nucleus - circulation, ambiguus - respiration Ventrolater Medullary al raphe - micturition medulla CVLM - gastrointestinal

Intermediolateral cell column Segmental sympathetic and sacral (micturition, defecation, erection) Sacral parasympathetic reflexes nucleus Onuf nucleus

7 Introduction

 Symptoms referable to autonomic dysfunction are relatively common  Cause may be primary autonomic nervous pathology or secondary to other medical and/or environmental factors

8 Symptoms

 Orthostatic hypotension and reduced orthostatic tolerance may manifest with non-specific symptoms such as weakness, dizziness, “brain fog” etc.  Neurogenic bladder: urgency, incomplete emptying, incontinence  Gastrointestinal dysmotility: gastroparesis, constipation  Impaired production of sweat, tears, saliva  Erectile dysfunction

9 Approach

 Focus on reversible causes: hypovolemia, malnutrition, deconditioning, weight loss, DRUGS!  Look for evidence of systemic disease  Then focus on CNS/PNS

10 Autonomic Neuropathies: Definitions and Overview Autonomic neuropathies are defined as peripheral neuropathies with selective or predominant involvement of autonomic fibers

Large myelinated fibers: Motor, sensory (position, touch)

Small myelinated fibers: Sensory (pain, temperature)

Unmyelinated fibers: Sensory (pain, temperature) and autonomic

11 Acute Autonomic Neuropathies A. Autoimmune autonomic ganglionopathy B. Acute cholinergic neuropathy C. Acute paraneoplastic autonomic neuropathy D. Guillain-Barre syndrome with autonomic failure E. Acute neurogenic POTS E. Botulism F. Porphyria G. Drug induced acute autonomic neuropathies Cisplatin, Vincristine, Vacor, Amiodarone, Perhexiline, Paclitaxel H. Toxic acute autonomic neuropathies Heavy metals, Organic solvents, Acrylamide, Hexacarbons I. Morvan’s Syndrome

12 Chronic Autonomic Neuropathies

A. Distal Sympathetic Neuropathies B. Pure Cholinergic Neuropathies - Lambert-Eaton myasthenic syndrome (LEMS) - Adies syndrome - Chagas' disease C. Pure Adrenergic Neuropathy D. Combined Sympathetic and Parasympathetic Failure (autonomic dysfunction clinically important) - Amyloid neuropathy (AL, TTR, gelsolin) - Diabetic autonomic neuropathy - Familial dysautonomia E. Combined Sympathetic and Parasympathetic Failure (autonomic dysfunction clinically not main feature) - Hereditary neuropathies (HSAN I, HSMN, Friedreich’s ataxia, adrenomyeloneuropathy, Fabry’s) - Others (CTD, infectious, metabolic, nutritional, immune-mediated))

13 Amyloid neuropathy • Amyloid - Misfolded proteins (with glycosaminoglycans) - Normal alpha-helical configuration forms a beta-pleated sheet configuration in the extracellular space of tissues and organs - Stains selectively with - Congo red - Methyl violet - Immuno-stains - Polarized light => “apple-green” birefringence

14 Primary (AL) amyloidosis

 Most common form of amyloidosis in the Western world  1275 to 3200 cases annually in the U.S.  Plasma cell proliferative disorder  Clonal population of bone marrow cells produces kappa or lambda monoclonal immunoglobulin light chains or light-chain fragments  Symptoms typically appear in the 6th or 7th decade.  Usually present with weight loss and fatigue  Peripheral neuropathy – may be presenting feature or an incidental finding  Autonomic involvement of the cardiovascular, gastrointestinal and urogenital systems in 65% of patients with peripheral neuropathy  Other symptoms: macroglossia, ecchymosis, hepatomegaly

15 Primary (AL) amyloidosis

 Median survival ranges from 13-35 months  3 year survival of 38-50 %  Prognosis for patients with autonomic neuropathy and cardiac disease esp. heart failure is considerably worse  Treatment  High dose chemotherapy with autologous stem cell transplantation in carefully selected patients improves survival  Rx protocols include dexamethasone, cytoxan, melphalan, bortezomib, lenalidomide, and thalidomide in varying combinations

Muchtar E, Buadi FK, Dispenzieri A, Gertz MA. Immunoglobulin Light-Chain Amyloidosis: From Basics to New Developments in Diagnosis, Prognosis and Therapy. Acta Haematol 2016;135:172-190. Mahmood et al. Update on treatment of light chain amyloidosis. Haematologica. 2014; 99: 209–221.

16 Familial amyloid polyneuropathy (FAP)

 Autosomal dominantly inherited diseases  The amyloid precursor is a mutant protein  Mutant transthyretin (TTR) most common cause (~ 100 documented mutations)  Also, mutations in genes encoding for apolipoprotein-A1 and A2, fibrinogen Aα, lysozyme and gelsolin

17 World distribution of familial amyloidotic polyneuropathy

From Ando: Arch Neurol 62;2005:1057–1062

18 Familial amyloid polyneuropathy  Transthyretin amyloidosis  Typically presents in the 3rd to 5th decade  Prominent dysautonomia  Painful sensorimotor neuropathy  Carpal tunnel syndrome  Vitreous opacities,  Enteropathy, nephropathy and cardiomyopathy

 Death occurs 5-15 years after the appearance of symptoms  Most mutated amyloidogenic TTR is secreted by liver  Orthotopic liver transplant is current Rx “surgical gene therapy” (Significantly decreases circulating, mutated TTR, improves neurophysiologic measures, and survival: ~ 80% 5 year survival)

TTR Amyloidosis Treatment

 TTR stabilizing strategies  Diflunisal  Repurposed non-steroidal TTR stabilizer  Tafamidis meglumine  Novel, small molecule stabilizer of TTR  Exhibits non-cooperative binding to the two thyroxine binding sites on the native tetrameric form of TTR preventing dissociation into monomers

 Experimental therapies  Gene silencing – siRNA and anti-sense oligonucleotides  Reduce deposition  Antibody mediated clearance

Freeman R, Barroso F. Recent advances in familial amyloid polyneuropathy. Current opinion in neurology 2015;28:494-499.

21 Diabetic Autonomic Neuropathy

 Diabetes mellitus  World wide prevalence estimated to increase from 171 million in 2000 to 366 million in 2030 http://www.who.int/diabetes/facts/world_figures/en/index.html

 Diabetes peripheral neuropathy  Newly diagnosed diabetics - 7.5% after 25 years ~ 50%  Cross-sectional data 55% in T1DM and 54% in T2DM Pirart J, Diabetes Care 1978; 1: 168-188 Dyck et al. Neurology. 1993;43:817-824

22 Effect of Autonomic Failure on Prognosis (Astrup et al 2006). Primary endpoint = Mortality or Major vascular event

 A: Nephropathy group  N=197

 B: Norm- albuminuria group  N=191

23 Cardiovascular autonomic neuropathy

 The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration.  Established risk factors for CAN are glycemic control in type 1 and a combination of hypertension, dyslipidemia, obesity and glycemic control in type 2 diabetes.  CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy.

24 Treatment induced neuropathy A reversible painful autonomic neuropathy

 “Insulin neuritis” first reported in 1933  Recent reports have described treatment induced neuropathy in individuals with type 1 and type 2 diabetes  Treated with oral hypoglycemic agents or with insulin.  Pre-treatment glycosylated hemoglobin (A1C) is typically high  Glycemic control is usually rapid

Caravati, CM. Insulin neuritis: a case report. Va Med Monthly. 1933; 59:745-746. Gibbons, C and Freeman, R. Treatment induced neuropathy. Annals of Neurology 2010

25 Treatment induced neuropathy

 Autonomic 18 symptoms, tests, 16 IENFD and pain 14 tend to improve 12 over time A1C 10 8

4  Greater 10

improvements 8

were seen after 18 6

months in type 1 4

vs. type 2 diabetic Pain Scores subjects 2 0

-30 -20 -10 0 10 20 30 40 Months

Caravati, CM. Insulin neuritis: a case report. Va Med Monthly. 1933; 59:745-746. Gibbons, C and Freeman, R. Treatment induced neuropathy. Annals of Neurology 2010; 67: 534-541.

26 Autonomic Symptoms

Drop in A1C over 3 months 2-2.9 3-3.9 4-4.9 5-5.9 ≥6

Syncope

Orthostatic Intolerance Sexual Symptoms Sudomotor symptoms Nausea

Gastroparesis

Gibbons, C and Freeman, R. Treatment induced neuropathy: an acute, iatrogenic complication of diabetes. Brain. Brain (2015) 138: 43-52

27 AAG – Clinical characteristics

• Typically young/middle-aged, previously healthy individuals • Severe autonomic failure (pandysautonomia) with peak severity within days (acute) to weeks (subacute) • Female:male = 2:1 • Course usually monophasic with slow spontaneous recovery • Antecedent viral syndrome (59%), immunization, minor surgical procedure - upper respiratory infection - gastroenteritis - no specific infectious agent (HSV, EBV, Coxsackie) • 1/3 complete, 2/3 incomplete recovery (Erectile dysfunction and sweat loss last to recover)

Young et al.,1964; Suarez et al., 1994; Vernino et al., 2000; Klein et al., 2003; Rakocevic et al., 2003

28 AAG - Antibodies • Transgenic mice homozygous for null mutations in the 3 gene of the ganglionic nAChR • lack ganglionic AChR: premature death due to severe autonomic failure • IgG antibody against ganglionic nAChR found in patients with AAG • Antibodies with specific binding to ganglionic nAChR present in 50% of AAG • low titers found in paraneopl. Syndromes • LEMS, other (thymoma, SCLC) • Isolated GI dysmotility (10%) • Isolated sicca, chronic idiopathic anhydrosis

Xu et al., 1999; Vernino et al., 2000, Vernino et al., 2004; Sandroni et al., 2004

29 AAG – Antibodies • Serum levels of ganglionic AB correlate with severity of autonomic dysfunction (between subjects) => higher AB levels = more severe and widespread autonomic failure

Vernino et al., 2000; Klein et al., 2003

30 AAG - Treatment • Immunomodulatory therapy (case reports) - IVIG - Plasma exchange - Steroids and azathioprine - Rituximab, mycophenolate mofetil

• Symptomatic treatment - Midodrine, Fludrocortisone, sodium chloride, Jobst, etc. for OH - Laxatives, feeding tube, catheterization, etc. - Pyridostigmine

Smit et al, 1995; Heafield et al., 1996; Mericle et al., 1997; Schroeder et al., 2005

31 Other immune-mediated neuropathies

 Parainfectious  Associated with GBS/AIDP  Paraneoplastic (anti-Hu most common: 30% have autonomic abn.; P/Q Ca-ch, NMDA, K-ch., CRMP-5, PCA-2 also can cause AN)  Associated with other autoimmune disorders (Sjögren, SLE, celiac etc.)

32 Hereditary autonomic neuropathies

 HSAN I-V  Fabry’s disease  Tangier’s disease  Navajo Indian neuropathy (loss of sweating, sensory loss, weakness, loss of reflexes, liver and corneal involvement…)  Triple A (Allgrove) s.: achalasia, adrenal insuff., alacrima (and other autonomic abnormalities)  Multiple endocrine neoplasia type 2b (adrenal involvement)

33 Toxic autonomic neuropaties

 Organ solvent  Acrylamide  Vacor  Heavy metals  Marine toxins  Iatrogenic

34 Focal autonomic disorders

 Autonomic cephalalgias  Hyper/hypohidrosis  Focal  Acral  Associated with pain syndromes like CRPS (aka, RSD), erythromelalgia (due to small fiber dysfunction)

35 Hyperhidrosis

36 Erythromelalgia

37 Myelopathies • Spinal Cord Injuries • Incidence: 23 per million. US: 4.0 per 100,000 • Prevalence: Roughly 300K/300M or 0.1%, 100 per 100,000. • Level (National SCI Stats 2012) • Complete tetraplegia 16% • Incomplete tetraplegia 40% • Complete paraplegia 22% • Incomplete paraplegia 22% • Autonomic dysreflexia: may occur in 50% of those above T6 • Perhaps 30 per 100k (no published number)

Lee 2013

38 Autonomic Dysfunction Two spinal levels to consider

• > T6: Orthostatic Hypotension • Splanchnic circulation innervation • At risk for autonomic dysreflexia

• > S1: Upper motor bladder/bowel • Lower motor neuron at conus

39 Autonomic Dysreflexia • Sudden rise in BP from a stimulus below cord lesion • Distended bowel or bladder, UTI, etc. • Abscess, in-grown toenail, rib fracture (most frequently missed) • Head Symptoms: • Throbbing headache • No correlation between the magnitude of the hypertensive response and the headache (Teasell 2000) • Head tingling • Nasal congestion • Pupillary dilation • Sweating and flushing above the lesion

40 Wallin, Macefield et al, Exp Physiol 2013

41 Autonomic Dysreflexia: Pathophysiology

 Upper Cord: Loss of descending inhibition  Lower Cord: Nociceptive C-fiber afferents sprouting into the spinal cord, produce aberrant connections  Glutamate mediated  End-organ: Vascular Hypersensitivity

42 Autonomic Dysreflexia Management

 Prevention is best  Need to lower BP promptly  Understand etiology  US bladder, bowel, gallbladder  X-ray spine and lower extremities  May need tagged WBC scan  Symptomatic treatment using pathophysiologic principles: clonidine, baclofen, tizanidine

43 Central Autonomic Disorders

 Hypothalamic lesion  Serotonin, opioid  Spinal cord injury (SCI) neuroleptic, illicit drug  Synucleinopathies (MSA, syndromes PAF, PD)  Paraneoplastic syndromes (rare)

44 Synucleinopathies  MSA  Parkinsonism (MSA-P) or Cerebellar ataxia (MSA-C)  Autonomic failure  Diffuse Lewy body disease:  Dementia, parkinsonism, hallucinations, REM sleep behavior disorder, autonomic dysfunction less severe than MSA  Parkinson disease:  Autonomic involvement is least severe. Can have some dementia. Best response to levodopa of all.  Pure autonomic failure (Bradbury-Eggleston syndrome):  Selective autonomic failure

45 α-synucleinopathies

Lewy body Glial cytoplasmic inclusions

46 Consensus criteria (Gilman et al., 2008): Clinical domains, features and criteria used in the diagnosis of MSA.

A sporadic, progressive, adult-onset (>30) disease characterized by:

 Autonomic failure:  Cerebellar dysfunction:  Orthostatic fall in blood pressure (by  1. Gait ataxia 30 mm Hg systolic or 15 mm Hg  2. Ataxic dysarthria diastolic) or urinary incontinence  3. Limb ataxia (persistent, involuntary partial or  4. Cerebellar oculomotor total bladder emptying, dysfunction accompanied by erectile dysfunction in men) or both. Definite MSA:  Parkinsonism, poorly L-DOPA Widespread, abundant alpha-synuclein responsive glial inclusions and neurodeg.  1. Bradykinesia changes  2. Rigidity Probable MSA:  3. Postural instability (not caused by AF and P or C primary visual, vestibular, cerebellar, or proprioceptive dysfunction) Possible MSA:  4. Tremor (postural, resting or P or C and at least 1 feature of AF and at both) least 1 of additional features

47 HUT: MSA (note resting HTN)

48 Thermoregulatory Sweat Test

Alizarin red indicator powder clearly delineates sweating (purple) and anhidrotic (orange) areas. The digitized body image is used to calculate the percentage of anhidrosis (TST%) The oral (core) temp rise vs time is used to compute the Slope value Above: TST in patient with complete mid thoracic SCI

49 TST Digital Photos: MSA patient

50 MSA treatment

 Symptomatic only  L-DOPA therapy: transient, partial response; may worsen OH  Anti-OH therapy  Treat neurogenic bladder and bowel  Tracheostomy to prevent death during sleep  Manage RBD  Physiotherapy, nutritional status (feeding tube), speech therapy, occupational therapy

51 Orthostatic Hypotension Management: As Simple as ABC  Abdominal binder  Bolus treatment (2 x 8oz glasses of water)  Bed up (head of bed elevated 4 inches)  Countermaneuvers. Physical countermaneuver raise standing BP  Drugs  Midodrine  Fluodrocortisone  Pyridostigmine  Droxidopa  Education (recognize subtle symptoms and orthostatic stressors)  Fluids and salt

Modified from: Figueroa et al 2010

52 Treatment of Supine Hypertension

 Reduce fludrocortisone  Head of bed up  Dietary including alcohol timing  Drugs  Losartan 50 mg at night  Hydralazine 25 mg  Nifedipine 10 mg  nitroglycerin patch 0.1mg/h

53 Dysfunctional syndromes

 Postural tachycardia syndrome  Irritable bowel and functional dyspepsia  Interstitial cystitis  Chronic fatigue

 They often coexist

54 Orthostatic Intolerance

 Reduced capacity to tolerate erect posture due to:

 Postural Tachycardia syndrome (POTS)

 Orthostatic hypotension

 Syncope

55 Orthostatic Disorder overlap

Orthostatic Syncope intolerance POTS

56 Definitions

 Reduced capacity to tolerate erect posture due to:  Orthostatic intolerance (OI): HR increment > 30 bpm (>40 in children/teenagers)+ Symptoms of cerebral hypoperfusion ± Symptoms of sympathetic activation  Postural tachycardia s. (POTS): Symptoms + Ortho. HR > 120 bpm (>130 in childresn/teenagers)  POTS almost always have multiple other somatic symptoms. It can be disabling or severely affecting quality of life  Syncope: unless recurrent, usually not disabling and generally monosymptomatic

57 220 150

Heart Rate 180 100

HR(bpm)

Systolic BP

140 50 BP (mmHg)BP

100 0 Diastolic BP

60 -50 0 200 400 600 800 1000 Time (sec)

58 POTS: Clinical Features

 Sx of presumed cerebral hypoperfusion

 LH, dizziness

 Sx of sympathetic activation

 Tachycardia, tremulousness, chest pain

 GI sx are present in 2/3 of patients

 Heat intolerance and sicca sx variably present

 Fatigue

 Sleep problems

 Anxiety/hypervigilance

 “Brain fog”

 Mast cells activation

59 Conditions that may be contributing to POTS symptoms…  Ehlers-Danlos syndrome = 33%  Confirmed autoimmune diseases = 20%  Hashimoto’s thyroiditis  Sjogren’s syndrome  Celiac disease  Lupus  Mast cell activation disorders = ~20% ?  Genetics/epigenetics = % unknown  Anxiety/hypervigilance = high %  Deconditioning = high %

60 Subtypes?

 Neurogenic

 Hyperadrenergic

 Hypovolemic

 Central dysregulation

61 What People Think About Subtypes

Neuropathic Hypovolemic

POTS

Hyperadrenergic Central

What Subtypes Really Are

Neuropathic Hypovolemic

Hyperadrenergic Central

Key to management of dysfunctional syndromes

 Empower patients  Education!  Use non- +/-pharmacologic strategies:  Lifestyle modifications  Exercise  Dual effect agents (modulating anxiety/vasomotor symptoms, pain etc.)