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fecal incontinence, gastroparesis (causepersistent fullness and subsequent abdominalpain and vomiting), early satiety, bloating

Urogenital: Urinary retention or incontinence, bladder

urgency, bladder frequency, nocturia, enuresis,incomplete bladder voiding, impotence, loss ofejaculation, retrograde ejaculation, vaginaldryness

Thermoregulatory:

Hypothermia, hyperpyrexia

Secretomotor:

Anhidrosis or hypohydrosis (mainly in feet),hyperhidrosis (in feet/hands/head), gustatory

sweating, dryness of mouth/eyes, excessivesalivation

Pupillomotor:

Abnormalities of size (presents with blurredvision, glare in bright sunlight, difficulty infocusing, poor night vision)

Skin and joints:

Feeling of coldness, acrocyanosis, pallor,mottling or redness (vasomotor changes)

Loss of hair, nail thickening/ discolouration

Charcots joints: misshaped, crepitus, excessiverange of movement, pain

In general, some symptoms, such as those oforthostatic intolerance, are common in autonomicneuropathies, whereas other symptoms, such ascomplete anhidrosis, are rare as primary manifestation.OH is often the first recognized symptom and typicallyis the most disabling.

Most autonomic neuropathies have symptoms ofsympathetic as well as parasympathetic dysfunction.However, some neuropathies may have only sympathetic(pure adrenergic neuropathy) or parasympathetic (purecholinergic neuropathies like chronic idiopathicanhidrosis and Lambert-Eaton myasthenic syndrome(LEMS)) dysfunction.3

Many hereditary autonomic neuropathies,neuropathies seen in connective tissue diseases, leprosy,acquired immunodeficiency syndrome (AIDS),diphtheria, lyme disease, uremia, chronic inflammatorydemyelinating neuropathy (CIDP) and alcoholic

neuropathies have mild autonomic dysfunction, whichis usually clinically unimportant. While in neuropathiesassociated with diabetes, amyloidosis and in chronicparaneoplastic autonomic neuropathies, autonomicinvolvement is severe and clinically important. 3

Most autonomic neuropathies are chronic in natureand have insidious onset of symptoms. Someneuropathies, like acute pandysautonomia, GBS,

botulism, porphyria, drug-induced and toxic autonomicneuropathies, have acute to subacute onset of thesymptoms.3

Detailed family history may yield information about

possible inherited forms of autonomic neuropathy. Insome cases, involvement may be subtle in certain familymembers, thus escaping detection.

WHAT ARE THE SALIENT FEATURES OFVARIOUS AUTONOMIC NEUROPATHIES?Diabetic autonomic neuropathy : It typically presents

late in the course of diabetes and is generallyaccompanied by other features of distal sensorimotorpolyneuropathy. There is an increase in overall mortalityand sudden death in patients with diabetic autonomicneuropathy.2 Erectile failure is present in 30-75% of

diabetic men6 and can be the earliest symptom of diabeticautonomic neuropathy.2 Constipation and diabetic

Table 1 : Causes of autonomic neuropathies

I mmune -me diat ed Acute pandysautonomia

causes Gullain-Barre syndrome (GBS)

Paraneoplastic

Lambert-Eaton myasthenicsyndrome (LEMS)

Connective tissue diseases

Postural orthostatic tachycardiasyndrome (POTS)

Inflammatory bowel disorderrelated causes

Chronic inflammatory demyelinatingpolyneuropathy (CIDP)

Related to systemic Diabetic neuropathy

disease Acquired amyloid neuropathy

Uremic neuropathy

Hepatic disease- related causes

Infectious causes Botulism

Leprosy

Chaga's disease

Human immunodeficiency virusDiphtheria

Toxic causes Alcohol

Heavy metals

Organic solvents

Acrylamide

Hexacarbons

Drug induced Vincristine

Cisplatin

Taxols

Vacor

Amiodarone

Perhexiline

Pyridoxine

Hereditary Hereditary sensory and autonomicneuropathy (HSAN)

Fabry disease

Tangiers disease

Familial dysautonomia

Nutritional Vitamin B12 deficiency

Idiopathic Idiopathic distal small-fiberneuropathy Chronic idiopathic anhidrosis

Note: Modified from (3) and (4)


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gastroparesis are two important manifestations indiabetics, seen in 60%7 and 50%8 of the patientsrespectively.

Acute and subacute autonomic neuropathies : Autonomicdysfunction of various degrees has been reported in 65%

of patients of GBS admitted to the hospital.9

Seriouscardiac arrhythmias tend to be more frequent in GBSpatients with severe quadriparesis and respiratoryfailure.10

Acute pandysautonomia is characterized by the rapidonset of combined sympathetic and parasympatheticfailure without somatic and motor involvement,although reflexes are usually lost during the course ofthe illness. About half of the patients have autoantibodiesto ganglionic acetylcholine receptors, which may play apathogenic role.10 Only 40% of the patients recover fullyto premorbid status.2 Like GBS, this illness may present

as post/ parainfectious event3

and these patients mayhave mild sensory-motor signs and cyto-albuminological dissociation in cerebrospinal fluid.11

Because of these similarities, acute and subacutepandysautonomias are sometimes considered as GBS-variants.11 Acute dysautonomias can be restricted to thecholinergic system (acute cholinergic neuropathy).3

Dysautonomia is common in acute intermittentporphyria, and autonomic overactivity predominatesover autonomic failure, although both are present andoften coexistent.3

Botulism presents with the acute development of

cholinergic failure, ptosis, ophthalmoplegia, bulbarweakness and generalized neuromuscular paralysis.3

Dilated pupils, with poor response to light andaccommodation, are characteristic autonomic signs. Theillness begins with gastrointestinal manifestations.2

Typically, the symptoms begin 12-36 hours after theingestion of home-canned food contaminated byClostridium botulinum.3

Hereditary autonomic neuropathies : Hereditary sensoryautonomic neuropathy (HSAN) is a group ofneuropathies characterized by prominent sensory losswith autonomic features but without significant motor

involvement. Currently, these neuropathies are dividedinto five main groups (HSAN I-V). HSAN is distinctlyrare. Sensory loss in HSAN predisposes to unnoticed,recurrent trauma that may lead to neuropathic joints,nonhealing ulces, infections, and acral mutilations. Outof five types, HSAN I is the only autosomal dominantdisorder and it is the most common familial sensoryneuropathy.10 Autonomic manifestations are mostprominent in type III HSAN (Riley-Day syndrome orfamilial dysautonomia). The axon-reflex mediated,vasomotor response (the flare) after intradermalhistamine is absent in all HSAN.12

Fabrys disease is an X-linked recessive disorder. It ischaracterized by severe, paroxysmal pains in the hands

and feet, a truncal reddish-purple maculopapular rash,and angiectases of the skin and mucous membrane,together with the painful distal peripheral neuropathy,progressive renal disease, corneal opacities, andcerebrovascular accidents.2,10 Autonomic manifestations

include decreased sweat, saliva and tear production,impaired cutaneous flare response, and disorderedintestinal motility.2

Am yloi d neuropat hy : Autonomic dysfunctioncommonly accompanies the polyneuropathy of bothprimary (AL; associated with immunoglobulin lightchains) and hereditary (familial amyloidpolyneuropathy, autosomal dominant) amyloidosis.These patients have other systemic features includinghepatomegaly, macroglossia, cutaneous ecchymosis,cardiomyopathy, and nephrotic-range proteinuria.2,10

Paraneoplastic autonomic neuropathies : This occurs

frequently in association with anti-Hu antibodies. Theseantibodies are commonly found in patients with small-cell lung carcinoma, but can also occur in non-small celllung carcinoma and malignancies of gastrointestinaltract, prostate, breast, prostate, bladder, kidney, pancreas,testis, and ovary. Autonomic neuropathy can be the solemanifestation of an anti-Hu related paraneoplasticdisorder or part of general paraneoplastic syndrome.13,14

Autoantibodies specific for neuronal nicotinicacetylcholine receptors in the autonomic ganglia alsohave been found in patients with paraneoplasticautonomic neuropathy.10 Malignancies associated withthese antibodies include small-cell lung carcinoma,thymoma, bladder carcinoma, and rectal carcinoma.2

LEMS is an acquired presynaptic disorder ofneuromuscular transmission that cause weaknesssimilar to that of myasthenia gravis, cranial nerveabnormalities, depressed or absent reflexes, andautonomic changes like dry mouth and eyes, impotence,constipation, and bladder symptoms. Abnormalities arepredominantly restricted to parasympathetic nervoussystem. Majority of the cases are paraneoplastic.15,16

Miscellaneous : Acute, subacute and chronic autonomicdysfunctions can occur in settings of connective tissuediseases including systemic lupus erythematosus,scleroderma, mixed connective tissue disease andespecially, Sjogren syndrome.2,3

In leprous neuropathy, focal anhydrosis occurs inassociation with impaired pain and temperatureperception in the cooler parts of the body. These symptomsare the earliest neurological manifestations of leprosy.17

Of all cytotoxic agents, clinically evidentdysautonomia occurs most consistently with vincristine.The abnormalities generally reverse several months afterthe drug is stopped.18

Postural orthostatic tachycardia syndrome (POTS) is

characterized by symptomatic orthostatic intolerance(not OH) and an increase in heart rate to >120/min or


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(TST) and quantitative sudomotor axon reflex test(QSART).19,21 They respectively assess capacity toproduce sweat qualitatively and quantitatively.1

Quinirazine or Alizarine red is used as sweat indicatorpowder in TST.19

How to Investigatea Case of AutonomicNeuropathy?

Although clinical diagnosis is essential for diagnosingautonomic neuropathies, special studies can be helpfulin identifying a particular autonomic neuropathy. Inmost cases, the laboratory assists in identifyingsubclinical or subtle changes.

Various tests for laboratory assessment of autonomicneuropathy are enumerated in Table 3.

In pure autonomic neuropathies, because the involvedfibers are small myelinated and unmyelinated fibers,nerve conduction study can be normal. Plasma

catecholamine measurements have been used as anindex to separate postganglionic from preganglionicfailure. In a disorder where the lesion is preganglionic,resting supine NE is normal, but the response to thestanding will be reduced or absent. In a postganglioniclesion, the supine values would be reduced if the lesionis widespread.21 Measurements of plasma

Table 3 : Laboratory assessment of autonomic

neuropathy2

Chemi stry, hemat ology, and pathol ogy

Complete blood count and differential

Fasting blood glucose or glucose tolerance test

HIV testing

Immunoelectrophoresis of blood and urine

Plasma norepinephrine (supine and standing)

Porphyria investigations- urinary porphyrin concentration

Genetic testing for inherited neuropathies

Fat aspirate, rectal biopsy, or gingival biopsy for amyloid

Au t oant ibo dy assessment

Antinuclear antibody

Rheumatoid factor

Anti-Ro/SS-A, Anti-La/SS-BAntibodies to P/Q-type calcium channel

Antibodies to acetylcholine receptor

Paraneoplastic antibodies- anti-Hu, Purkinje-cell cytoplasmicantibodies type 2 etc.

Elect rophysio logical studies

Nerve conduction studies (including repetitive stimulation)

Qauntitative sensory testing

Table 4 : Symptomatic treatment of autonomic neuropathies2,3,22

Orthostatic hypotension -Plenty of fluids (up to 10 L/day)

-Adequate salt intake (up to 10 g/day)

-Mineralocorticoid: 9--fludrohydrocortisone (0.1-0.3 mg/day)

- receptor agonist: Midodrine (2.5 mg to 10 mg tds)Gastrointestinal dysfunction -Gastroparesis:

Control of blood sugars

Low fat content of diet

Prokinetics: Metochlopramide (10 mg p.o. 30 mins before meals)

Domperidone (10-20 mg qds)

Erythromycin (250 mg tds)

-Bowel Hypomotility:

Increased intake of high fiber diet with plenty of fluids

Stool softeners and osmotic laxative

-Bowel hypermotility:

Restriction of lactose and gluten

Cholestyramine, clonidine, somatostatin analogue, metronidazole

Genital dysfunction -Erectile failure:

PDE 5 inhibitors: Sildenafil (50 mg), Tadafil (20 mg) etc.Caution: ischemic heart disease, hypotension,significant OH, concomitant nitrates

Intracorporal injection of vasoactive substances e.g. papavarine and PGE

Transurethral delivery of vasoactive agents

Mechanical devices e.g. vacuum erection device, constricting rings

Penile prosthetic implants

-Vaginal lubricants & estrogen creams

Urinary tract dysfunction -Timed voiding schedules

-Bladder contraction increased by Crede maneuver

-Clean intermittent self catheterization (For impaired detrusor activity)

-Cholinergic agents: Bethanecol (10-30 mg tds) in detrusor areflexia

-Anticholinergic agents: Tolterodine tartrate (2 mg bid) for overactive bladder

Labile hypertension -Betablockers (propranolol)

and tachyarrhythmiashyperhydrosis -Anticholinergic Agents: trihexyphenidyl, glycopyrrolate

norepinephrine levels are low and do not rise on head-up tilt table testing in pandysautonomia.19 For evaluationof bladder dysfunction cystometrogram is required, while

ba ri um st udie s ar e us ef ul fo r gast ro in test in al


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