eMedicine Specialties > Neurology > Neuromuscular Diseases

Autonomic Neuropathy: Differential Diagnoses & Workup

Author: Steven D Arbogast, DO, Fellow, Neuromuscular Medicine, University Hospitals Case Medical Center, Cleveland
Coauthor(s): J Douglas Miles, MD, PhD, Clinical Instructor of Neuromuscular Medicine, Case Western Reserve University School of Medicine; Bashar Katirji, MD, FACP, Director, Neuromuscular Center and EMG Laboratory, The Neurological Institute, University Hospitals Case Medical Center; Professor of Neurology, Case Western Reserve University School of Medicine
Contributor Information and Disclosures

Updated: Jun 25, 2009

Differential Diagnoses

Aromatic L-amino acid decarboxylase deficiency
Pure Autonomic Failure
Autonomic dysreflexia syndrome in spinal injuries.
Surgical sympathectomy
Dopamine beta-hydroxylase deficiency
Syphilis (tabes dorsalis)
Multiple System Atrophy
Vagotomy
Parkinson Disease
Parkinson-Plus Syndromes
Progressive Supranuclear Palsy

Workup

Laboratory Studies

Initial laboratory evaluation should include a complete blood count, basic metabolic panel, liver function testing, and immunoelectrophoresis. More specific testing should be based on the patient’s history of other medical conditions.

Special situations
Based upon the findings after the above evaluation and clinical situation, more specific tests may be considered.

  • Blood tests may be considered based upon the clinical history and findings on autonomic testing.
    • Oral glucose tolerance test to evaluate for diabetes mellitus, if an initial serum glucose level is normal or nondiagnostic.
    • Testing for SS-A and SS-B if there is concerns for Sjögren syndrome (Sicca syndrome).
    • Anti-ganglionic acetylcholine receptor (AChR) autoantibodies if the onset was acute to subacute in nature.
    • Specific genetic tests for the familial forms of dysautonomia can be ordered.
    • Specific tests for infections, inflammatory, autoimmune, and paraneoplastic causes can be ordered based upon the history and physical examination.
    • Measurement of basal plasma norepinephrine levels can be useful in specific forms of autonomic neuropathy. In pandysautonomia, basal norepinephrine levels are low and do not rise on head-up tilt table testing. Following an overnight supine position, low norepinephrine levels can be found in patients with POTS.
    • A history of neuropathy, mental status changes, and abdominal pain should prompt the physician to evaluate the patient for acute intermittent porphyria. In cases of suspected porphyria, high levels of porphobilinogen and delta-aminolevulinic acid can be found in urine during acute episodes.
  • Evaluation of cerebrospinal fluid (CSF) via lumbar puncture can be useful in specific cases.
    • In pandysautonomia, CSF protein is elevated, as is CSF enolase, which may indicate damage to the dorsal root ganglia.
    • In HIV or AIDS, the CSF may demonstrate an elevated protein as well as pleocytosis.
    • Paraneoplastic varieties of autonomic neuropathies also tend to show an inflammatory picture in the CSF. However, abnormal CSF protein is not specific for autoimmune, inflammatory, or infectious causes of autonomic neuropathy.

Imaging Studies

  • SPECT and PET scanning may identify cardiac sympathetic dysfunction in both type I and type II diabetes mellitus.
  • The pattern of sympathetic disturbances tends to be heterogeneous, with denervation affecting mainly the posterior myocardial region, whereas focal hyperinnervation can be observed of the proximal segment.

Procedures

Autonomic testing

Autonomic testing using the following methods should be performed to assess the severity and parts of the autonomic nervous system that are involved. These tests have also recently been recommended (Level B) by the American Academy of Neurology for evaluation of patients with distal symmetric polyneuropathy.48

  • Tilt table testing to test adrenergic vasomotor function and cardiac sympathetic function.
  • Cardiac response to deep breathing and R-R interval to evaluate cardiovagal functions.
  • Cardiac response to Valsalva maneuvers to test parasympathetic innervation to the heart.
  • Quantitative Sudomotor Axon Reflex Testing (QSART) to evaluate the postganglionic segment of the thermoregulatory pathway. Four regions are tested: forearm, proximal leg, distal leg, and dorsum of the foot. Electrical stimulation (iontophoresis) is applied to the skin, and the volume of sweat produced can be measured.

Nerve conductions studies and electromyography
Findings on nerve conduction studies (NCS) and electromyography (EMG) can be normal in pure autonomic neuropathies because the involved fibers are small myelinated and unmyelinated fibers, which cannot be assessed with NCS or EMG.

  • In autonomic neuropathies with concomitant sensory neuropathy, absence of sensory potentials may occur.
  • In autonomic neuropathies with concomitant sensorimotor neuropathy, marked loss of motor and sensory potentials is noted.
  • In cases of suspected neuromuscular transmission defect, such as with botulism or LEMS, a typical electrophysiologic pattern of low-amplitude compound muscle action potentials increasing with high-frequency repetitive stimulation is characteristic of a presynaptic neuromuscular defect.
Specialized studies
  • In Sjögren syndrome, results of the Schirmer test with a rose-Bengal eye stain, as well as lip biopsy to identify chronic sialoadenitis, can be diagnostic.
  • Postprandial blood pressures: An abnormal result would be to measure a drop in systolic blood pressure of >20 mm Hg approximately 15-20 minutes after a meal.
  • Other uncommon bedside stimuli that can be used to assess for a rise in blood pressure during continuous blood pressure monitoring include isometric exercise (sustained hand grip for 3 min), a cold pressor test (immersion of a hand in ice water for 90 s), and mental arithmetic (with serial-7 or serial-17 subtraction), all of which stimulate sympathetic outflow and elevate blood pressure in healthy patients.
  • Multiple daily blood pressures to examine for diurnal fluctuation: A difference of <15 mm Hg with either systolic or diastolic blood pressure between daytime (awake) values and nighttime (sleeping) values could indicate presence of autonomic neuropathy (Foss, 2001).49
  • Skin or nerve biopsy (see histology findings) may be performed if clinically indicated.
  • Specific autonomic tests that are being performed at some institutions include the following:
    • The thermoregulatory sweat test (TST) complements the quantitative sudomotor axon reflex test (QSART)9 and is used to assess thermoregulatory pathways.7 The patient is covered with alizarin red powder, which, when moist, changes from orange to purple. The patient's temperature is then raised above core temperature, and photography is performed to map for areas of color change, revealing areas of anhidrosis/hypohidrosis where color did not change.50 The TST and QSART can both be useful in idiopathic anhidrosis. A lack of color changes with the TST is essentially diagnostic for postganglionic sudomotor dysfunction.
    • Sympathetic skin responses (SSR) can be assessed with routine EMG equipment. This test can be used to identify indirect evidence of sweat production via measurement of changes in skin conductance on the palm/sole in response to an electrical stimulus. The stimulation of an afferent somatic branch with SSRs gives an assessment of potential adrenergic sweat production. Brief electrical stimuli are administered at intermittent intervals and a response is measured from the hands or the feet, representing a change in skin resistance due to sweating.
    • Quantitative sensory testing (QST) can be helpful in autonomic disorders with sensory neuropathy.9 QST permits comparison of sensory thresholds by using vibration and temperature perception to assess both large and small-fiber modalities. These patients typically have impaired thresholds for heat and pain51 , but vibration and cool sensitivity may be normal.
    • Pupillometry measure changes in papillary response and is being investigated at some institutions as a potential marker for autonomic neuropathy.52
    • Quantitative direct and indirect test of sudomotor function (QDIRT) involves making a silicone impression of a patient's skin while sweating is induced by acetylcholine iontophoresis. The presence of sweat droplets can be quantified in the silicone cast53 , providing a marker of sudomotor function.
  • Vascular studies are occasionally useful in assessing autonomic neuropathy.
    • Adrenergic function can be assessed by measuring skin blood flow, transcutaneous oxygenation, and skin temperature.
    • Doppler probes can be used for blood flow measurements.
    • Infrared thermometry and telethermography can be used to measure skin temperature.
    • Assessment of skin temperature can be useful in patients with small-fiber neuropathy.
  • Urological studies
    • Urodynamic studies may be used to examine the lower urinary tract function.54
    • Measurements include urine flow rate, residual volume, cystometry during filling and voiding, urethral pressure profile measurements, and pelvic floor neurophysiology.
    • An important measure in assessment of a neurogenic bladder is the postmicturition residual volume; this can be measured invasively by urethral catheterization after voiding, but it can also be measured noninvasively with ultrasonography.
  • Gastrointestinal studies
    • Videofluoroscopy is useful in assessment of swallowing in the presence of oropharyngeal dysphagia.
    • A barium swallow study, meal, and follow-through study are helpful in suspected upper gastrointestinal disorders, though endoscopic assessment provides the opportunity for biopsy in particular situations, as well as better visualization.
    • Esophageal manometry may be of value in disorders of motility and esophagogastric function.
    • Gastric motility may be assessed by using radioisotope methods and scintigraphic scanning.
    • In cases of small-bowel disorders suspected to be neurologic in nature, manometry may be of value in discriminating myopathic from neuropathic disorders. Large-bowel dysfunction can be assessed via measurement of transit time.47
    • Esophageal manometry and gastric emptying scintigraphy can also be useful in patients with possible autonomic neuropathy and dysphagia.
      • Diabetic patients with symptoms of esophageal dysmotility have insufficient lower esophageal sphincter relaxation and a higher percentage of simultaneous waves detected, while diabetic patients with cardiovascular autonomic neuropathy have greater pathological simultaneous contractions.55
      • Esophageal dysmotility and delayed gastric emptying may occur in up to 50% of diabetic patients. In particular, reports of abdominal fullness predicted delayed gastric emptying.56

Histologic Findings

Biopsy findings

Sural nerve biopsy is occasionally diagnostic for types of autonomic neuropathy. In inherited autonomic neuropathies, a selective loss of particular fiber types can indicate the diagnosis. In autoimmune or infectious mediated forms of autonomic neuropathy, small perivascular infiltrates may be visible. In amyloidosis, characteristic Congo red staining indicates the presence of eosinophilic, extracellular, amorphous material surrounding perineurial and endoneurial vessels and within sympathetic ganglia and vagal nerves.

Epidermal skin biopsy can be used in the diagnosis of small-fiber neuropathies.57 This technique is less invasive than nerve biopsy. In autonomic neuropathies, autonomic fibers are deeper than the epidermal level; therefore, deeper biopsy is required to assess the fibers innervating sweat glands and piloerector muscles. In general, autonomic neuropathies of greater severity are associated with reduced epidermal fiber densities.58

As distal endings are primarily involved in distal axonopathy forms of neuropathy, skin biopsy may be more sensitive than sural nerve biopsy to detect early abnormalities.59 Skin biopsy is also useful in congenital causes of autonomic neuropathy, as in congenital insensitivity to pain with anhidrosis (CIPA), where a lack of nerve fibers in the epidermis and only a few hypotrophic and uninnervated sweat glands are found in the dermis.60

Immunologic findings
Patients with autoimmune autonomic neuropathy can have antiganglionic acetylcholine receptor (AChR) autoantibodies.61 Patients with high antibody values (>1.00 nmol/L) tend to have a constellation of sicca complex (marked dry eyes and dry mouth), abnormal pupillary light responses, upper gastrointestinal symptoms, and neurogenic bladder. Higher antibody titers correlate with greater autonomic dysfunction as well as increased frequency of cholinergic dysautonomia.

Patients with POTS may also demonstrate presence of ganglionic receptors.16

In specific disorders, testing for the presence of autoantibodies can help determine a diagnosis. Antinuclear antibodies and antibodies to Sjögren syndrome antigens A and B (SSA and SSB) are seen in several connective tissue disorders. Antibodies against voltage-gated calcium channels (VGCC) are associated with LEMS. 

Staging

The combination of tilt table testing, cardiac responses to deep breathing and the Valsalva maneuver, and QSART comprise the composite autonomic scoring scale (CASS), which may be used to assess the severity of autonomic dysfunction. The CASS is reliable and useful for monitoring clinical progression with an autonomic neuropathy. The CASS is a 10-point scale; 4 points are allotted for adrenergic and 3 points each for sudomotor and cardiovagal failure. Scores are normalized for age and sex. Patients with a score of less than 4 on the CASS have mild autonomic failure; a score of 4-6 suggests moderate autonomic failure; and a score of 7-10 implies severe failure.62

The TST can be useful in monitoring progression of idiopathic anhidrosis and Sjögren syndrome where prominent anhidrosis/hypohidrosis occurs.

More on Autonomic Neuropathy

Overview: Autonomic Neuropathy
Differential Diagnoses & Workup: Autonomic Neuropathy
Treatment & Medication: Autonomic Neuropathy
Follow-up: Autonomic Neuropathy
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

syndrome of acute pandysautonomia, postural orthostatic tachycardia syndrome, POTS, Guillain-Barré syndrome, GBS, acute inflammatory demyelinating polyneuropathy, AIDP, Lambert-Eaton myasthenic syndrome, LEMS, Holmes-Adie syndrome, idiopathic distal small-fiber neuropathy, human immunodeficiency virus, HIV, Chagas disease, Chagas' disease, botulism, chronic idiopathic anhidrosis, familial amyloid polyneuropathy, FAP, diabetes mellitus, uremic neuropathy, hepatic disease, vitamin B-12 deficiency, paraneoplastic autonomic neuropathy, Sjögren syndrome, acute intermittent porphyria, variegate porphyria, hereditary sensory autonomic neuropathy, HSAN, Fabry disease, autonomic dysreflexia, AD, acquired immunodeficiency syndrome, AIDS, autonomic nervous system, ANS, autonomic reflex screen, ARS, composite autonomic scoring scale, CASS, collapsin response–mediator family, CRMP-5, cerebrospinal fluid, CSF, vasopressin, DDAVP, electromyography, EMG, inhibitor of k-light polypeptide gene enhancer inB-cells, IKBKAP, mitochondrial neurogastrointestinal encephalomyopathy, MNGIE, M-phase phosphoprotein-1, MPPI, multiple system atrophy, MSA, nerve conduction studies, NCS, progressive autonomic failure, PAF, primary biliary cirrhosis, PBC, Purkinje cell cytoplasmic antibody-2, PCA-2, Parkinson disease, PD, positron emission tomography, PET, peripheral nervous system, PNS, quantitative sudomotor axon reflex test, QSART, quantitative sensory testing, QST, single-photon emission computed tomography, SPECT, serine palmitoyltransferase, SPT, sympathetic skin responses, SSR, selective serotonin reuptake inhibitor, SSRI, thermoregulatory sweat test, TST

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Contributor Information and Disclosures

Author

Steven D Arbogast, DO, Fellow, Neuromuscular Medicine, University Hospitals Case Medical Center, Cleveland
Steven D Arbogast, DO is a member of the following medical societies: American Academy of Neurology and American Osteopathic Association
Disclosure: Nothing to disclose.

Coauthor(s)

J Douglas Miles, MD, PhD, Clinical Instructor of Neuromuscular Medicine, Case Western Reserve University School of Medicine
J Douglas Miles, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Medical Association, and Society for Neuroscience
Disclosure: Nothing to disclose.

Bashar Katirji, MD, FACP, Director, Neuromuscular Center and EMG Laboratory, The Neurological Institute, University Hospitals Case Medical Center; Professor of Neurology, Case Western Reserve University School of Medicine
Bashar Katirji, MD, FACP is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Physicians, and American Neurological Association
Disclosure: Nothing to disclose.

Medical Editor

Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center
Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
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