Autonomic Nervous System

AUTONOMIC NERVOUS SYSTEM

Hatem S. Shehata, M.DProfessor of Neurology – Cairo University

February, 27, 2017

‘Autonomic' implies a certain degree of independence that is exercised under control of a higher power

___ John Langley, 1898

INTRODUCTION

¢ ANS is a part of PNS that regulates involuntary body functions and activities (heart, smooth muscles and glands)

¢ Two parts:� Visceral motor� Visceral sensory

¢ Limited origin __ Wide distribution:� One PRE-ganglionic __ 8 – 9 POST-ganglionic (up to > 30)

INTRODUCTION (CONT’D)

Autonomic integration centers

Visceralsensorydivision

(afferent)

Visceralreceptors

Stimulus

Sympatheticdivision(efferent)

Parasympatheticdivision

(efferent)

Autonomic effects(cardiac, smooth muscles, glands, skin)

Response



(afferent)

Visceralreceptors

Stimulus



(efferent)


Response




(afferent)

Visceralreceptors

Stimulus



(efferent)


Response

Opposing but Integrating



¢ Anatomical difference between:_ MOTOR “visceral” [involuntary] (ANS) ---- And;_ MOTOR “somatic” [voluntary]


autonomic

somatic

Note: the autonomic ganglion is motor

1 2 3

thin myelinated chains of 2 motor neuronsorigin

???????FROMCOMETHEYHEREW

Parasympathetic(craniosacral)

Sympathetic(thoracolumbar)

No skin / No adrenal gland

Cranial nerves(III,VII, IX and X)

S2-S4(Nervi ergentis)

Acetylcholine at end organ and ganglionicsynapse: “cholinergic

D1 – L3

CENTRAL INTEGRATION – AFFERENTPATHWAYS – EFFERENT PATHWAYS

¢ Central autonomic network: � Cerebral cortex (the insular and medial prefrontal regions), � Limbic system (amygdala, stria terminalis), hypothalamus,

� Brainstem centers (periaqueductal gray, parabrachial pons, nucleus of the tractus solitarius, and intermediate reticular zone of the medulla)

¢ The afferent pathways: � Receptors reside the viscera (mechanical, chemical, or thermal

stimuli)

� Along somatic and autonomic nerves ----- dorsal root ------spinal cord ///// Cranial nerves ------- Brainstem

� Impulses initiate local, segmental, or rostral reflexes

EEFERENT PATHWAYS

¢ Sympathetic system descends to the intermediolateraland intermediomedial cells in the thoracolumbarregions of the spine (TI - L2-3) , from where the neurons originate in the lateral horns of gray matter (thoracolumbar outflow)

¢ While; the parasympathetic system exits the central nervous system primarily with cranial nerves III, VII, IX, and X, and sacral spinal roots S2-4 (Craniosacral)

TWO EFFERENT “MOTOR” NEURONS

Lateral Horn of spinal cord

1. Preganglionic neuron (in brain or cord) 2. Gangionic neuron (cell body in ganglion

outside CNS)

¢ Ganglia are either:� Lateral ganglia: paravertebral “pair of ganglia for each segment”,

except in cervical “only three pairs” [sympathetic]� Collateral ganglia: prevertebral – around the origin of blood vessel;

as in superior mesenteric, inferior mesenteric, superior hypogastric, and celiac [both sympathetic and parasympathetic].

� Terminal ganglia: in organ [parasympathetic EXCEPT !!!! ].

PRE - GANGLIONIC POST - GANGLIONIC• Thin myelinated [B-fibers].

• Sympathetic: from spinal cord – anterior root – enter the white rami communicans to join a ganglion – short – cholinergic

• Parasympathetic: long peripheral projections – ganglia (end organs) –cholinergic

• Unmyelinated [C-fibers].

• Sympathetic: after relay in lateral ganglia – gray rami communicans

• Parasympathetic: short –cholinergic – muscarinic

BASICALLY

Anterior root

White rami comm

Gray rami comm

Dorsal root

DRG

Terminal ganglia, vagus

OPPOSING; YET, INTEGRATING SYSTEMS

SYMPATHETIC PARASYMPATHETIC

ORIGIN Thoraco-Lumbar Cranio-Sacral

OUTPUT Wider distributionLimited: no parasympathetic to ventricles, skin, sweat glands, spleen, and adrenal medulla.

FUNCTION Catabolic.VC except coronaries.Viscid [trophic] glandular secretion.

Anabolic.VD except coronaries.Secretomotor.Contract walls, relax sphincters.

THE FOUR CRANIAL PARASYMPATHETIC GANGLIA

Inferior division (nerve to I.O)

Green = parasympatheticRed = sympatheticBlue = sensory

Ciliary Ganglion

FACIAL NERVEOrigin: from special nucleus in the pontine tegmentum, dorso-medial to the facial nucleus (superior salivatory nucleus)

SSN

Vidian Nerve synapse

lacrimalgland

Submandibularganglion

Submandibular glandSublingual gland

GLOSSOPHARYNGEAL NERVEOrigin: (inferior salivatory nucleus)

ISN

Auriculotemporal N

Parotid

SUBMANDIBULAR GANGLION

SSN

Preganglionic

SympatheticNo relay

ECA

OTIC GANGLION

Interrupted lines: parasympatheticContinuous lines: sympatheticRed lines: motor

PARASYMPATHETIC (CONT’D)¢ Cranial outflow

� III - pupils constrict� VII - tears, nasal mucus, saliva� IX – parotid salivary gland� X (Vagus n) – visceral organs of thorax & abdomen:

¢ Stimulates digestive glands¢ Increases motility of smooth muscle of digestive tract¢ Decreases heart rate¢ Causes bronchial constriction

¢ Sacral outflow (S2-4): pelvic splanchnic nerves� Supply 2nd half of large intestine� Supply all the pelvic (genitourinary) organs

SYMPATHETIC NERVOUS SYSTEM“FIGHT, FLIGHT OR FRIGHT”

¢ Lead to every part of the body (unlike parasymp.) � Easy to remember that when nervous, you sweat; when afraid,

hair stands on end; when excited blood pressure rises (vasoconstriction): these sympathetic only

� Also causes: dry mouth, pupils to dilate, increased heart & respiratory rates to increase O2 to skeletal muscles, and liver to release glucose

¢ Norepinephrine is neurotransmitter released by most postganglionic fibers (acetylcholine in preganglionic): “adrenergic”

SYMPATHETIC NERVOUS SYSTEM (CONT’D)

SYMPATHETIC OUTFLOW¢ Cervical Ganglia (Superior, Middle, and Inferior):

� ICA: 2 long ciliary: __ Dilator Pupillae, Mullers muscles, VC.� ECA: Sudomotor

¢ Stellate(Inferior Cervical and Upper 2 Thoracic): UL¢ Upper 4 thoracic:

� Heart: increase HR, coronaries VD.� Lung: bronchodilatation, pulmonary VC.

¢ D 5 – 10: Abdominal (Greater splancnic): Coeliac� Liver: Glucogenolysis (++ Glu).� Spleen: Contracted (++ Hct).� Suprarenal: (++ NE 20%, EP 80%).� GIT: contract wall, relax sphincter.

¢ D 11 – 12; L 1, 2, 3: Lesser Splanchnic: Inferior mesenteric� Retension of urine and stool.� Ejaculation: contracted Vas.� Shrinkage of penis: VC.

ECEPTORSRDRENERGICA(1) alpha: peripheral V.C(2) beta-1: increase HR (3) beta-2: relaxation of smooth

muscle located in the peripheral vessels, bronchi, GIT, and genitourinary (GU) organs

THERMOREGULATION

¢ Central integration: preoptic and anterior hypothalamus (thermosensitive neurons)� When temperature is below the set-point ----------- heat

generation ---------- (shivering and cutaneous V.C and piloerection)

� When body temperature exceeds it --------------- sudomotoractivity stimulates sweating (evaporative heat loss) and precludes cutaneous V.C and piloerection

¢ Factors affecting thermoregulation: activities, sleep-wake cycles, hormonal cycles and fluid balance

¢ Thermoregulation is mainly sympathetic -------sudomotor postganglionic are cholinergic

CARDIAC AND VASCULAR REGULATION

¢ CVS function is controlled by a negative-feedback

¢ ++ BP and C.OP ----------------- ++ Afferent pathway ----------------Reflexly (-) sympathetic activity &/or (+) parasympathetic activity (and vice versa)

¢ Afferent pathways:- Arterial baroreceptors in carotid sinus and aortic arch

Glossopharyngeal and vagus N- Cardiac mechanoreceptors (mechanical deformation of the cardiac chambers)

Vagus N- Pulmonary stretch receptors (sensitive to lung volumes)

Vagus N

PUPILLARY REGULATION

¢ Central integration: dorsal midbrain and E-W nucleus

¢ Afferent: along the optic nerve¢ Sympathetic:

� Preganglionic (C8-T2) via the superior cervical ganglion� Postganglionic: along carotid artery to cavernous sinus -----

-------- V Cr.N ------------ orbit� Action: pupillary dilation and involves Mueller's muscle of

the upper lid.¢ Parasympathetic:

� From the III Cr.N and ciliary ganglion� Action: pupillary constrictor and the ciliary muscle for

accommodation

HORNER SYNDROME

¢ Etiology: (unknown in 35-40%) of cases.¢ Central (first order neuron) Horner’s: Hypothalamic,

brainstem and spinal cord lesions as stroke (lateral medullarysyndrome), M.S, SOL, and syrinx (syringomyelia or syringobulbia).

¢ Preganglionic (second order neuron): Thoracic outlet (cervical rib, subclavian artery aneurysm), mediastinal tumors, Pancoast's tumor, and neck (thyroid malignancies)

¢ Postganglionic (third order neuron): Superior cervical ganglion lesions (trauma, neck dissection) , lesions of ICA (neck, skull base, cavernous sinus and parasellar regions)

¢ Other causes include cluster headaches.¢ In children, trauma (birth trauma or neck trauma) is the most

common cause of Horner’s syndrome

¢ Eyelids: patients have a mild (less than 2 mm) upper lid ptosis and inverse ptosis of the lower lid which produces a decreased palpebral aperture compared to the fellow eye.

¢ Pupils: Patients have anisocoria (miotic affected eye). The smaller pupil takes a longer time to dilate when a bright source of light is moved away from the eye. This phenomenon is called dilation lag.

¢ Iris heterochromia. In children with congenital Horner’s.

¢ Other signs of sympathetic denervation include ipsilateralconjunctival injection, changes in accommodation and lower intraocular pressure.

HORNER SYNDROME

EGULATIONRENITOURINARYG¢ Afferent: along autonomic and somatic pathways¢ Sympathetic:

� T11-L2 – Inferior mesenteric – Superior hypogastricganglia, and Hypogastric nerves

� Ejaculation in males� Bladder wall inhibition, detrusor muscle and internal

sphincter contraction¢ Parasympathetic:

� S2-S4 and pelvic nerves� Erections in males� Bladder wall contraction, detrusor and internal sphincter

relaxation¢ The external sphincters innervated by pudendal N

(somatic)

GASTROINTESTINAL REGULATION

¢ Central integration: mainly in nucleus of the tractussolitarius and the nucleus ambiguus

¢ Sympathetic:� Thoracolumbar, celiac, superior mesenteric and inferior

mesenteric ganglia, and the splanchnic, hypogastric, and colonic nerves

� It relaxes wall and contracts esophageal sphincters and internal rectal sphincter

¢ Parasympathetic: � From vagus nerve (esophagus, stomach, small intestines,

and proximal colon)� From S2 to S4 (distal colon and internal anal sphincter)� It stimulates motility and relax the internal rectal

sphincter.¢ The external sphincters: Pudendal N (somatic)

TESTS FOR AUTONOMIC FUNCTIONS

¢ Pretesting preparation

¢ Stop alcohol, caffeine, and nicotine for 3 hours (preferably 12 h)

¢ Stop anticholinergics (eg, antidepressants and antihistamines), adrenergic antagonist (eg, beta blockers), sympatho/parasympathomimetic, and fluid-altering druds (eg, diuretics or fludrocortisone)

¢ Patients should be relaxed during and before the test. Compressive elastic stockings should be removed.

CARDIOVASCULAR TESTS

¢ Head-up tilt table testing¢ Beat-to-beat BP measure using photoplethysmographic

devices [similar to intra-arterial invasive]

¢ Upon changing from a recumbent to upright position on a tilt table: 1/3 shift of venous return to peripheral compartment decreased cardiac filling pressures and stroke volume (40%) decreases afferent from the sensory baroreceptorsdecrease para-sympathetic then increase sympathetic increase HR. Overall, COP drops 20%, and blood pressure is largely maintained

¢ Then, the sympathetically mediated increase in peripheral resistance VAGAL RESPONSE -- HR

¢ Cardiovascular responses to standing and 30:15 ratio¢ Instruction. Subject lies quietly for 3 minutes, then

stands up (within 5 seconds) and remains motionless for 2 minutes

¢ Using automatic ECG analysis

¢ In normal individuals, immediate increase HR (by 5 – 30 bpm), which is MAXIMUM at 15 seconds after standing (around the 15th beat), then it SLOWS down to near-supine rate by approximately 30 seconds (around the 30th beat)

¢ The “30:15 ratio” is calculated by dividing length of longest R-R interval at beat 30 after standing by length of shortest R-R at beat 15 after standingNormally: “30:15 ratio” is abnormal if less than: 1.03

¢ OSH: a fall in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg when a person assumes a standing position

RESPIRATORY SINUS ARRHYTHMIA

¢ Sinus arrhythmia = Variation of HR with respiration¢ Inspiration +++ HR; and Expiration ---- HR

¢ Determinants of HR fluctuations with respiratory activity: � Neural coupling. From the respiratory centre to vagal efferent

neurons resulting in vagal inhibition with inspiration� Arterial baroreceptor-mediated HR responses to BP

changes that occur during the respiratory cycle� Bainbridge reflex: increase HR results from increase central

venous volume thro baroreceptos� Hering-Breuer reflex: ++ stretch receptor in the lung and chest

wall provoked by inspiration +++ HR

¢ However, HR variation during normal breathing is often minimal ___ Dependent on the frequency and depth of respiration ___ MAXIMUM ++ HR at RR (5-10 breath/min)

HEART RATE RESPONSE TO DEEP BREATHING (HRDB). VALSALVA MANEUVER AND VALSALVA RATIO

¢ In this manoeuvre the subject takes a deep inspiration and then attempts to expire forcefully while closing glottis and/or nose, and mouth [increases intrathoracic and intra-abdominal pressures]

¢ The subject can expire forcefully into manometer or a disposable syringe connected to the mercury column with airway pressure of 40 mmHg

¢ Forced expiration is maintained for 10 to 15 seconds

VALSALVA MANEUVER

Phase I: Transient BP /// HR ______ [ intrathoracic pressure ______ mechanical squeeze of the great vessels]

Phase II:Early component: venous return , which results in stroke volume and BP /// HR

Late component: BP recovers to baseline due to peripheral vascular resistance from sympathetically mediated V.C

Phase III: (STRAIN RELEASE). Transient BP (decrease previously increased intrathoracic pressure) /// HR Phase IV: (OVERSHOOT) __ BP // HR (barorecptors mediated)

The Valsalva ratio:Ratio of maximal HR (phase II) to minimal HR (phase IV) ___ OR ___ Ratio of longest R-R interval (phase IV) to the shortest of phase II ... A ratio of 1.5 or greater is normal

BLOOD PRESSURE RESPONSE TESTS

¢ Blood pressure response to sustained handgrip� Maintain grip at 30% maximal activity for up to 5

minutes BP and HR [decrease parasympathetic and increases sympathetic activity]. The diastolic blood pressure should >15 mm Hg

¢ Blood pressure response to mental stress� As arithmetic or even sudden noise sympathetic

outflow, which BP and HR

¢ Blood pressure response to cold water immersion� Submerging hand in ice water BP

Afferent: somatic ///,Efferent: sympathetic.(lacks sensitivity)

TESTS OF SWEATING

¢ Quantitative sudomotor axon reflex test (QSART) :

� Most sensitive test of distal small fiber neuropathy� It involves iontophoresis of A.Ch onto the skin to stimulate

sympathetic C-fibers in the sweat glands� Patient is covered by alizarin in the four tested areas

(FA/F/DL/PL):this powder turns from orange to purple when moisted

� Offenders for the test: CRPS, atopic dermatitis and anticholinergic drugs

¢ Thermoregulatory sweat test (TST)� Patient is placed in a warming cabinet to provoke sweating.

The sweating pattern is then assessed by alizarin powder dusted over the body

¢ Sympathetic skin response test (reliable)� Stimulus. Electrical stimulation

� Recording. Surface electrodes on hand or foot � Response. Slow wave due to activation of the sudomotor

sympathetic efferent fibers

� Monitor. Amplitude or Latency of the response. SSR is considered abnormal if no significant responses are detected

� The potentials in the hands have larger amplitudes and shorter latencies than those in the feet

� The latency is about 1.5 seconds in the hand and about 2 seconds in the foot

PLASMA CATECHOLAMINE LEVELS

¢ Plasma norepinephrine levels approximately double with the upright posture (initiation of vasopressorresponses, which are sympathetic and adrenergic)� In preganglionic sympathetic disorders such as MSA

“resting supine norepinephrine level is normal but fail to rise when at standing because of the lack the preganglionic drive”

� In postganglionic sympathetic disorders, such as progressive autonomic failure, resting supine norepinephrinelevels are low and fail to rise when at standing

TESTS OF PUPILLARY REGULATION

¢ Sympathetic denervation (Horner’s):� Topical Cocaine test. It blocks reuptake of (NE), so will dilate

pupil with intact sympathetic innervation. After instillation of two drops of 10% cocaine, the normal pupil dilates more than the Horner's pupil

� Topical Apraclonidine (alternate to cocaine). It is an alpha adrenergic agonist. 0.5% causes pupillary dilation in the Horner's pupil (1 – 4.5 mm) > normal (0.5 mm) due to denervation supersensitivity

� Topical Hydroxyamphetamine is used to differentiate pre and postganglioninc Horner's.It releases (NE) from adrenergic nerve endings causing pupillary dilation. Instilling 1% HAP drops dilation of both pupils indicate PREGANGLIONIC .. If the smaller pupil fails to dilate it indicates POSTGANGLIONIC

READ IT PLEASE …….

TESTS OF GIT / GENITOURINARY

¢ Tests of GIT autonomic regulation� Manometry is placed in different sites of GIT to localize sites of

stasis� EMG of rectal sphincter. Abnormal in MSA, due to

degeneration of the Onuf nucleus in the sacral spinal cord

¢ Tests of genitourinary autonomic regulation¢ Electrophysiologic:

� Bulbocavernosus reflexes

� Sensory conduction in the dorsal nerve of the penis

� Pudendal sensory-evoked potentials

� Motor latencies of the pudendal nerve

DYSAUTONOMIA-PANOFANIFESTATIONSM¢ Eyes:

� Pupilary paralysis: blurring of vision, sensitivity to light and loss of accommodation (difficulty with focusing)

� Impaired tears.� (+/-): loss of spino-ciliary reflex, ptosis, conjunctival injection

(Horner’s).

¢ Face: � Flushing or pallor.� Impaired sudomotor: anhydrosis, or hyperhidrosis.

¢ Mouth: � Dry mouth.� Absent tongue papillae.

¢ CVS:� OSH: (associated with postprandial state, exercise, or

temperature-induced exacerbation of hypotension). Often, this is the first recognized symptom.

� Arrhythmias and even chest pain and shortness of breath. � Presyncope and light-headedness: micturition and defecation

may induce presyncope.

¢ PVD:Due to loss of vasomotor tone:

¢ Patchy blotching.¢ Ulcerations, and trophic changes/brittle nails/loss of hair.¢ Acropathies [tends to increase at night]

DYSAUTONOMIA-PANOFANIFESTATIONSM

¢ GIT: bowel stasis (gastroparesis, bloating, ileus)� Altered sense of taste, early satiety, pain and vomiting.� Hyposalivation, dysphagia, may be increase motility and

incontinence.� Constipation, bacterial overgrowth, with resulting diarrhea.

¢ Genito-urinary:� Bladder: [hesitancy/nocturia/urgency/incontinence].� ED (parasympathetic) and loss of ejaculation (sympathetic),

+/- female sexual dysfunction.

¢ Sweating: anhidrosis (hypohidrosis): hyperpyrexia. Hypothermia (inability to vasoconstrict to prevent heat loss)

¢ Fatigue….SIADH.


¢ General examination:� Vital signs� Skin an m.m changes: leprosy, Lyme’s, diphtheria� Angiokeratoma of trunk, CRF, strokes: Fabry’s� Dry eyes and mouth (Sjögren),� Liver, renal and cardiac disease: amyloidosis. � Metabolic diseases� Hepatomegaly, caput medusae, parotid hypertrophy,

Dupuytren contracture: alcoholism� Detailed F.H; HSAN� HIV

¢ Neurological examination: � Pupils� Tendon areflexia


PERIPHERAL CAUSES OF DYSAUTONOMIA

¢ Immune-mediated causes� Acute pandysautonomia: up to 50% associated with

positive “autonomic ganglionic Ach-R antibody”� Postural orthostatic tachycardia syndrome (POTS):

young female, excess sinus tachycardia and near-syncope

� Lambert-Eaton myasthenic syndrome (LEMS): antibodies present against presynaptic V-G Ca2+ channels (P/Q-type). Dysautonomia is severe in 20% of patients. In 50% of cases, LEMS is associated with a neoplasm, most commonly SCC of the lung

� Holmes-Adie syndrome: tonic pupil(s) with tendon areflexia +/- autonomic neuropathy and OSH …Ross syndrome: related syndrome + segmental anhidrosis

¢ Immune-related (Cont’d):� Guillain Barré syndrome, CIDP� Paraneoplastic: autonomic neuropathy:

- anti-Hu antibodies in 23% of patients, or autoantibodies against neuronal cytoplasmic proteins and against Purkinje cell cytoplasm (PCA-2) - there is autoimmune destruction of autonomic postganglionic neurons

� RA, SLE, Systemic sclerosis, Sjögren syndrome, Mixed connective tissue disease, Autoimmune thyroiditis (Low, 1997)

� Anti–CRMP-5 (collapsin response mediator protein-5) antibody syndrome and Anti-M-phase phosphoprotein-1 (anti-MPPI) antibody syndrome (Yu, 2001)

� IBS: acute autonomic and sensory neuropathy

¢ Infectious causes� Chagas disease: Trypanosoma cruzi (parasympathetic >

sympathetic) � Human immunodeficiency virus: in late – terminal stages � Leprosy __ Diphtheria __ Lyme disease

¢ Toxic causes� Amiodarone __ Alcohol __ Acrylamide� Botulism: due to prevented release of A.Ch from presynaptic

terminus � Cisplatin __ Carboplatin __ Gemcitabine� Vincristine __ Vinorelbine� Suramin� Taxol __ Thallium poisoning � Pyridoxine intoxication __ Perhexiline

¢ Idiopathic causes� Idiopathic distal small-fiber neuropathy (Holland, 1998,

Stewart, 1992) � Chronic idiopathic anhidrosis (Low, 1997)

¢ Hereditary causes� HSAN (5 types)� Fabry disease: X-linked recessive __ mutations in the

gene for alpha-galactosidase --- Neuropathy is due to accumulation of glycolipids. Attacks are triggered by changes in temperature or exercise. Nerve pathology demonstrates loss of both small myelinated and unmyelinated fibers

� Tangiers disease (Low, 1997) � Mitochondrial neurogastrointestinal

encephalomyopathy (MNGIE)

HSANSignsCharacteristic

SymptomsOnsetMode of InheritanceHSAN

Low sensory AP amplitude

Ulceration of the feet (especially soles)2nd decade

AD, point mutations (9q22.1-9q22.3)

Type I

Loss of myelinated and unmyelinated fibers

Pansensory loss (UL, LL, trunk and forehead); early ulcers

CongenitalARType II, Morvandisease

Absence of unmyelinated with normal myelinated fibers

Pallor in infancy, irregular BP and; Difficulties in swallowing

Childhood, (Ashkenazi Jews)

AR, 9q31Type III, Riley-Day syndrome (familial dysautonomia)

Loss of myelinated and small unmyelinated fibers

Widespread anhidrosis, lost sense of pain, MR.Congenital

AR, 1q21-1q22 (Gene defect in tyrosine kinasereceptor A)

Type IV

Not applicablePain insensitivity and preservation of other sensory modalities

CongenitalARType V

CAUSES RELATED TO SYSTEMIC DISEASES

¢ Diabetic autonomic neuropathies ¢ Acquired amyloid neuropathies:

� Ig (kappa or lambda) light chains (associated with multiple myeloma)� Another form occurs with dialysis, (beta2-microglobulin) deposits� N.B: Familial Amyloid Neuropathy: mutation in transthyretin gene

--- or rarely gelsolin gene which produces a protein important in cytoskeletal actin

¢ Uremic neuropathy¢ Alcoholic neuropathy¢ Subacute combined degeneration: B12 and alcohol¢ Hepatic diseases: especially primary biliary cirrhosis

(autonomic neuropathy in 48%) – reversible following liver transplant

¢ Celiac Disease

DYSAUTONOMIAOFCAUSESENTRALC¢ Sarcoidosis (why ??)

¢ Other central lesional patholohy

¢ PD, Parkinson plus, MSA

¢ DLB

¢ Prion diseases

¢ Some SCA (as MJS)

AUTONOMICSYMPTOMS

QUESTIONNAIRE(LOW, 1993)

ANAGEMENTM¢ Sympathomimetic agents: in OSH, if simple

measures yield no improvement (???) . ¢ Midodrine (ProAmatine): it is a prodrug metabolized

to desglymidodrine, a selective alpha1-agonist;causes vasoconstriction. � Dose: 2.5 – 15 mg/d� Contraindication. Cardiac disease, urine retention,

pheochromocytoma¢ Fludrocortisone (Florinef):

� Dose: 0.1 – 0.2 mg/d

MANAGEMENT (CONT’D)

¢ Anticholinergic agents -- These agents are useful in cases of difficult bladder emptying.

¢ Oxybutynin (Ditropan):� Dose: adults: 5 mg PO tid, in pediatric: 2.5 mg tid� Pregnancy (B) - Usually safe but benefits must outweigh the

risks. ¢ Tolterodine tartrate (Detrol) -- Competitive muscarinic

receptor antagonist, differs from other anticholinergic types because of selectivity for urinary bladder over salivary glands� Adult Dose: 2 mg PO bid

)D’ONT(CANAGEMENTM¢ Cholinergic: ¢ Bethanechol hydrochloride (Duvoid, Urecholine) -- Used for

selective stimulation of the bladder to produce contraction to initiate micturition and empty bladder. Rarely used (GIT) � 10-50 mg PO tid/qid� Contraindicated: peptic ulcer disease, COPD, bradycardia

¢ Phosphodiesterase inhibitors (Sildenafil), it inactivates cGMP, allowing attenuation of the vasodilatory effect of NO.

¢ Vasopressin analogues -- Oral or nasal spray agents acting to prevent nocturnal urinary production. � Desmopressin acetate (DDAVP) -- Vasopressin analogue without

effect on V1 receptors responsible for vasopressin-induced vasoconstriction. Acts on V2 receptors at renal tubuli, increasing cellular permeability of collecting ducts, responsible for antidiureticeffect

Healthcare

Autonomic Nervous System