Update Article
Approach to a Case of Autonomic Peripheral Neuropathy
D Chowdhury*, N Patel**

Abstract
Autonomic neuropathy is the term used to describe autonomic disturbances resulting from diseases of theperipheral autonomic nervous system. This is a group of disorders in which the small, lightly myelinated andunmyelinated autonomic nerve fibers are selectively targeted. Most often, autonomic neuropathies occur inconjunction with a somatic neuropathy (i.e. with motor weakness and/or sensory loss), but they can occur inisolation. Causes of autonomic neuropathies are immune-mediated, paraneoplastic, infectious, toxic anddrug-induced, hereditary, nutritional and idiopathic. Amongst all, diabetes mellitus is the most commoncause. Autonomic features, which involve the cardiovascular, gastrointestinal, urogenital, sudomotor, andpupillomotor systems, occur in varying combination in these disorders. Orthostatic hypotension is often thefirst recognized and most disabling symptom. Noninvasive, well-validated clinical tests of autonomicfunctions along with a host of laboratory tests are of immense value to diagnose the presence and to demonstratethe distribution of autonomic failure. Treatment aims to treat specific cause of the autonomic neuropathy (ifpossible) and to control symptoms of autonomic dysfunction. Present review attempts to outline clinicalapproach to a case of autonomic peripheral neuropathy. ©

INTRODUCTION
Rapid adjustments in vital physiologic mechanismscritical to survival are accomplished by theautonomic nervous system (ANS). From anatomicalpoint of view, ANS is divided into two parts:parasympathetic (craniosacral) and sympathetic(thoracolumbar). Disorders of the ANS may result fromcentral nervous system (CNS) or peripheral nervoussystem (PNS) causes. Peripheral neuropathies are themost common cause of chronic autonomic insufficiency.1Autonomic nerve fibers are the small, lightly myelinated(type B, preganglionic fibers) and unmyelinated (type C,postganglionic fibers). These fibers are affected in mostsymmetrical peripheral neuropathies. This involvementis mild or subclinical in many cases. However, in a groupof peripheral neuropathies, autonomic fibers arepredominantly involved.2 Autonomic neuropathy is theterm used to describe autonomic disturbances resultingfrom diseases of the peripheral autonomic nervoussystem.3 Present review attempts to outline clinicalapproach to a case of autonomic peripheral neuropathy.The review is presented in the form of questions, whicha clinician is likely to ask when confronted with a caseof autonomic neuropathy.
*Associate Professor; **Senior Resident, Department of Neurology, GB Pant Hospital, New Delhi 110 002.
What are The Causes of Autonomic Peripheral Neuropathy?
Various causes of autonomic neuropathies areenumerated in Table 1. Diabetes mellitus is the mostcommon cause of autonomic neuropathy.2
How do Autonomic Neuropathy Manifest Clinically?
The autonomic nervous system (ANS) modulatesnumerous body functions, and therefore, dysfunction ofthis system can manifest with numerous clinicalphenotypes. Most often, they occur in conjunction witha somatic neuropathy (i.e. with motor weakness and/orsensory loss) as in Gullain-Barre syndrome (GBS), butthey can occur in isolation (as in pandysautonomia).
Various autonomic abnormalities seen in a case ofautonomic neuropathy are as follows:5


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 alcoholicneuropathies 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 aboutpossible inherited forms of autonomic neuropathy. Insome cases, involvement may be subtle in certain familymembers, thus escaping detection.
WHAT ARE THE SALIENT FEATURES OF VARIOUS AUTONOMIC NEUROPATHIES?
Diabetic autonomic neuropathy : It typically presentslate 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% ofdiabetic men6 and can be the earliest symptom of diabeticautonomic neuropathy.2 Constipation and diabetic 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 presentas post/ parainfectious event3 and these patients mayhave mild sensory-motor signs and cyto-albuminological dissociation in cerebrospinal fluid.11Because 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 ofcholinergic failure, ptosis, ophthalmoplegia, bulbarweakness and generalized neuromuscular paralysis.3Dilated pupils, with poor response to light andaccommodation, are characteristic autonomic signs. Theillness begins with gastrointestinal manifestations.2Typically, 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 motorinvolvement. 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
Fabry’s 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 manifestationsinclude decreased sweat, saliva and tear production,impaired cutaneous flare response, and disorderedintestinal motility.2
Amyloid neuropathy : 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 occursfrequently 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.13,14Autoantibodies 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) ischaracterized by symptomatic orthostatic intolerance(not OH) and an increase in heart rate to >120/min or by 30/min with standing, most commonly in youngadult women.1
WHAT ARE THE IMPORTANT POINTS/ TESTS FOR CLINICAL EXAMINATION OF AUTONOMIC NEUROPATHY?
Examination of skin, mucous membrane, nails andjoints may indicate presence of autonomic dysfunction.Careful general examination may also give clue to theetiology. For example, characteristic skin changes areobserved in leprosy and angiokeratoma of the trunk issuggestive of Fabry’s disease. Occurrence of arthritisand rash can suggest a connective tissue disorder.Pupillary examination may reveal Argyl-Robertsonpupil, Horner’s syndrome or tonic pupils. Detailedneurological evaluation with special emphasis on motorand sensory system examination is important to detectassociated somatic peripheral neuropathy. Presence ofpyramidal, extrapyramidal, or cerebellar signs indicatea separate neurological disorder of the autonomicnervous system like multisystem atrophy or Parkinson’s disease.
Noninvasive, well-validated clinical tests ofautonomic functions are very useful and widely used.These tests are of immense value to diagnose the presenceand to demonstrate the distribution of autonomic failure.19 These tests are summarized in Table 2.
A combination of these tests is usually requiredbecause certain ones are sensitive to sympatheticdysfunction and others to parasympatheticdysfunction.20 No food, coffee, or nicotine is permittedfor 3 hours before the tests. Medications affecting ANSare stopped for five half-lives.19
Measurement of lying, sitting and orthostatic bloodpressure to detect a postural decrease is one of thesimplest bedside clinical tests of autonomic function.Sustained drops in systolic (>20 mm Hg) or diastolic(>10 mm Hg) BP after standing for at least 2 min that arenot associated with an increase in pulse rate of >15 beatsper minute suggest autonomic deficit. In nonneurogeniccause of OH (e.g. hypovolemia), the BP drop isaccompanied by a compensatory increase in heart rateof > 15 beats per minute.1 Cold pressure test and isometricexercise test have not been well validated clinically.20
Electrocardiography can be used to monitor heart ratewhile examiner observes respiratory rhythm todetermine if normal respiratory variations are present.Beat-to-beat BP and pulse monitoring is required torecord changes in these parameters during Valsalvamaneuver. Sympathetic skin response (SSR) can be donein electrophysiology laboratory. Special laboratoryequipments are required for thermoregulatory sweat test (TST) and quantitative sudomotor axon reflex test(QSART).19,21 They respectively assess capacity toproduce sweat qualitatively and quantitatively.1Quinirazine or Alizarine red is used as sweat indicatorpowder in TST.19
How to Investigate a Case of Autonomic Neuropathy?
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. Plasmacatecholamine 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 norepinephrine levels are low and do not rise on head-up tilt table testing in pandysautonomia.19 For evaluationof bladder dysfunction cystometrogram is required, whilebarium studies are useful for gastrointestinal dysfunction.20 Nocturnal penile tumescence can berecorded in sleep laboratory.20

How to Treat a Patient with Autonomic Neuropathy?
Treatment aims to treat specific cause of the autonomicneuropathy (if possible) and to control symptoms ofautonomic dysfunction. Adequate control of blood sugaris very important in diabetic neuropathy. Steroids andintravenous immunoglobulins are helpful in immune-mediated neuropathies. Immediate withdrawal ofoffending drug or toxin is necessary. As most of theautonomic neuropathies are not completely reversible,symptomatic management holds very important placein these cases. It is summarized in Table 4.

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