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These processes can affect the sym- pathetic, parasympathetic, and enteric arms of the nervous system or a combination of systems and thus can present with a large variety of symptoms (Box 8.1). Orthostatic hypotension (OH) is usually a more severe and often late finding that many physicians consider the primary manifestation of symptomatic autonomic dysfunction. Dysautonomia results from numerous disease states with diverse pathogenic mechanisms, many of which have only symptomatic treatment available. This chapter will discuss immune-mediated (Box 8.2) or probable immune-mediated forms of autonomic dysfunction that have proven or supportive evidence for more effective forms of treatment. Examples include Guillain–Barré syndrome, primary immune-mediated autonomic neuropathies, paraneoplastic syndromes, and rheumatologic diseases such as Sjögren syn- drome and systemic lupus erythematosus. These conditions are important to bear in mind when evaluating a patient with any form of autonomic dysfunction because early recognition of some disease states may lead to preventative treatment prior to significant nerve or neuronal injury or early detection of an underlying malignancy. 8 Immune-mediated autonomic neuropathies Louis H. Weimer and Mill Etienne Gastrointestinal: Constipation, diarrhea, postprandial bloating, fullness, nausea, vomiting, postprandial dizziness, sweating or orthostatic hypotension Genitourinary: Urinary retention, incomplete emptying, incontinence, frequency Orthostatic: Lightheadedness, weakness, fatigue, cognitive changes, visual disturbances, vertigo, anxiety, palpitations, pallor, nausea, syncope – exacerbated by prolonged standing, post-exercise, meals, warm environment, early morning, prolonged recumbency, physical countermaneuvers, speed of postural change, and medication effects Secretomotor: Dry eyes and mouth, need for natural tears, frequent sips of water Sexual: Erectile dysfunction, ejaculatory dysfunction, retrograde ejaculation into bladder Sudomotor: Reduction or loss of sweating (distally in polyneuropathies), excessive, paroxysmal, or inappropriate sweating, mixed pattern of distal loss and excessive proximal sweating, heat intolerance Vasomotor: Distal color changes, change in skin appearance, persistently cold extremities, Raynaud’s phenomenon, loss of skin wrinkling in water, heat intolerance, indoor gloves Visual: Blurred vision, sensitivity to light/glare, reduced night vision Other: Unexplained syncope Box 8.1 Autonomic review of systems. NICP_C08 04/05/2007 12:26PM Page 139 140 LOUIS H. WEIMER AND MILL ETIENNE Autonomic testing Many common autonomic symptoms, other than overt symptomatic orthostatic hypotension, are some- what nonspecific. A combination of symptoms or exclusion of other causes is often needed before auto- nomic causes are suspected. More objective evidence to assess the validity, severity, and progress of disor- ders is frequently useful and desirable. Conventional nerve conduction studies and electromyography are often performed but frequently are of limited direct diagnostic benefit because many autonomic condi- tions spare or minimally involve somatic sensory and motor nerve fibers. Other conditions have clear somatic neuropathy but unclear degree of autonomic impairment. For this purpose there are numerous reliable noninvasive techniques available. Dedicated autonomic testing laboratories exist in most large and medium size cities in the United States and in many cities in Europe, Japan, and Australia. Unlike motor and sensory nerve conduction studies most techniques do not directly record autonomic nerve fiber activity. Instead testing involves induction of physiologic perturbations followed by the evaluation of the responses of complex overlapping reflex loops via the measurement of end-organ function. Although many systems are potentially testable, the func- tions deemed most reproducible, reliable, and most commonly evaluated are cardiovagal (parasym- pathetic), adrenergic vasoconstriction (sympathetic), and sudomotor function. Noninvasive measures of cardiovascular para- sympathetic function involve the analysis of heart rate variability and the degree of sinus arrhythmia. The most common triggers are cyclic deep breathing, Valsalva maneuver, and active standing. Cardiovas- cular sympathetic function measures most commonly assess the blood pressure response to physiological stimuli, usually active standing or standardized head- up tilt. The beat-to-beat blood pressure response to Valsalva is another widely used method and many show changes prior to orthostatic challenge. Pro- longed tilt-table testing, with or without pharmaco- logical provocation, has become an important tool in the investigation of a predisposition to neurally mediated syncope (Freeman, 2006). Tilt studies are also useful in the evaluation of autonomic failure. Although limited testing can be performed with conventional equipment and at the bedside, a bat- tery of tests conducted in a dedicated laboratory is most desirable and dependable (Box 8.3). Formal laboratory testing can establish subclinical auto- nomic involvement, determine additional affected components not detected by bedside examination, grade disease severity, chart the clinical course, and assist in monitoring therapeutic response. Most physicians are familiar with and accustomed to performing the bedside examinations of para- sympathetic and sympathetic function mentioned in Box 8.3 and described elsewhere in greater detail (Low, 2003); however, tests of sympathetic cho- linergic function are not commonly measured or considered by many physicians. For that reason, these tests are briefly outlined in more detail, but are generally less available than other tests discussed earlier. The quantitative sudomotor action reflex test (QSART) tests postganglionic sudomotor function. It is performed by iontophoresing acetylcholine (ACh) Acute autonomic and sensory neuropathy Acute autonomic neuropathy (acute pandysautonomia) Acute cholinergic pandysautonomia Enteric neuronopathy Guillain–Barré syndrome Holmes–Adie syndrome Hyperexcitability syndromes (Isaacs syndrome, Morvan syndrome) Lambert–Eaton myasthenic syndrome (LEMS) Orthostatic intolerance (postural orthostatic tachycardia syndrome (POTS)) – some forms Other paraneoplastic syndromes (e.g. Anti-Hu, -CV2, -PCA-2, -CRMP-5) Rheumatologic diseases (e.g. rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, mixed connective tissue disease) Box 8.2 Immune-mediated autonomic neuropathies. NICP_C08 04/05/2007 12:26PM Page 140 Immune-mediated autonomic neuropathies 141 diluted in deionized water onto an isolated patch of skin. The ACh binds to muscarinic receptors on the eccrine sweat glands as well as nicotinic receptors on the postganglionic sudomotor axon. Retrograde impulses are generated that trigger an evoked sweat response from an adjacent but separate site and then recorded using a sudrometer; the test is sensitive, specific, and reproducibile (Hilz and Dutsch, 2006). The areas of QSART territories and actual induced sudomotor axon reflex sweating appear to be of similar size in human skin and vary according to site (Schlereth et al., 2005). QSART has also been shown to correlate well with epidermal nerve fiber density in small fiber painful neuropathy studies (Novak et al., 2001; Periquet et al., 1999). A device is commer- cially available and used in numerous centers as well as in clinical trials (Q-Sweat; WR Medical, Stillwell, MN). Silastic skin imprinting uses methods similar to the QSART to stimulate sweat production and measures sweat output by visualizing and quantify- ing sweat droplets by examining plastic or silicone which is allowed to harden over the treated area and subsequently transilluminated under a dissecting microscope or with video camera projection (Ravits, 1997). Although the silastic skin imprinting likely has similar sensitivity to QSART, it is not widely available (Hilz and Dutsch, 2006). The thermoregulatory sweat test (TST) evaluates both central and peripheral sudomotor function. A moisture-sensitive indicator powder, usually alizarin red, is dusted over the patient’s entire anterior skin surface. The patient is placed in a sweat chamber with temperature between 45–50 °C. As the patient is heated, the sweat changes the powder color and the areas of anhidrosis are visualized and quantified (Hilz and Dutsch, 2006). Although the TST is an excellent measure of both central and peripheral sudomotor function, it is only available at a few centers across the country. The sympathetic skin response (SSR) is the most commonly performed sudomotor test and is recorded with routine elec- tromyography (EMG) equipment. The SSR is best recorded from the palms of the hands and soles of the feet, with the reference electrodes on the dorsum of the hands and feet. Responses can be evoked by various types of stimulation, such as electrical, star- tle, cough, or inspiratory gasp stimuli. The response is variable and tends to habituate with repeated triggers; moreover there is no clear consensus regard- ing abnormal responses or uniform testing methods. Although the test is easy to perform, it is probably the least sensitive and reproducible of these techniques and has the most technical constraints including interpretation (Etienne and Weimer, 2006; Hilz and Dutsch, 2006). Microneurography is one special technique that directly records bursts of efferent muscle sympathetic nerve activity (MSNA) and is probably the best and most direct measure of sympathetic activity. How- ever, because this test is somewhat invasive, tech- nically difficult, and time consuming it is primarily used for research purposes and is not a routine clinical test. MSNA, usually recorded from the per- oneal nerve, is measured from a recording electrode inserted into a single nerve fascicle and through numerous calculations, sympathetic nerve activity can be measured (Hilz and Dutsch, 2006). There is a multitude of additional investigational tools that can be used to evaluate autonomic func- tion such as for evaluation of pupillary function, gastric and intestinal motility, bladder function, and others used by certain laboratories. Cardiovagal (Parasympathetic function) Heart rate response to deep breathing (HRDB) Heart rate response to Valsalva maneuver Heart rate response to standing (30:15 ratio) Adrenergic (Sympathetic function) Blood pressure response to Valsalva maneuver Blood pressure response to standing or passive tilt Blood pressure response to exercise, handgrip, and pharmacologic agents Sudomotor (Sympathetic cholinergic function) Quantitative sudomotor action reflex test (QSART) (Q-Sweat) Thermoregulatory sweat test Silastic skin imprinting (sweat imprint methods) Sympathetic skin response Box 8.3 Most common and best-accepted autonomic battery measures. NICP_C08 04/05/2007 12:26PM Page 141 [...]... examination raise a suspicion for LEMS (Lennon, 1997) Additional AChR antibody tests include modulating and blocking antibodies AchR-modulating antibodies bind to external segments of the AChR, cross-linking them on the cell surface and triggering their degradation They are positive in approximately 86% of MG patients and only 3–4% of AChR-binding antibody negative patients (Howard et al., 1987) AchR-blocking... unexplained subacute autonomic neuropathy In addition to anti-Hu (ANNA-1) and ganglionic AChR antibodies, the syndrome is associated with other antibodies including antibodies against Purkinje cell cytoplasmic type-2 (PCA-2), CV-2, and collapsin response-mediator protein (CRMP-5) The evidence suggests considerable overlap of paraneoplastic antibodies, which often coexist but predict an underlying malignancy... exacerbating condition with autonomic failure Epoetin alpha (Epogen) increases hematocrit, reduces symptoms, and elevates systolic pressure an average of 10 to 15 mm Hg (Biaggioni et al., 1994) Other drugs of potential but less consistent benefit include indomethacin, somatostatin analogs, caffeine, ergot alkaloids, and nocturnal desmopressin L-threo-3, 4-dihydroxyphenylserine is used in the rare but distinctive... 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Sidell, A.D 1 960 The Guillain–Barré syndrome, the need for exact diagnostic criteria N Engl J Med, 262 , 964 – 9 Pan, C.L., Tseng, T.J., Lin, Y.H., Chiang, M.C., Lin, W.M and Hsieh, S.T 2003 Cutaneous innervation in Guillain–Barré syndrome: Pathology and clinical correlations Brain, 1 26( 2), 3 86 97 151 Pardi, D.S., Miller, S.M., Miller, D.L et al 2002 Paraneoplastic dysmotility: Loss of interstitial cells... thymoma In TFH, lymphoid follicules and germinal centers form at the corticomedullary junction This architecture brings AChR-bearing myoid cells into intimate contact with antigen-presenting cells, the major histocompatibility complex (MHC)-II positive interdigitating cells The myasthenic thymus has all the cellular components required for autoantibody production: MHC-II positive antigen-presenting cells,... 1 969 ; Young et al., 1975) Small in ammatory mononuclear cell in ltrates have been seen in epineurial sural nerve biopsies with concomitant decreases in small myelinated and unmyelinated fibers, supporting the immune-mediated disease basis (Suarez et al., 1994) Vernino and Lennon developed an assay to detect serum antibodies against the ganglionic nicotinic acetylcholine receptor (AChR) after suspecting... reversal with recombinant erythropoietin Ann Intern Med, 121, 181– 6 Boukhris, S., Magy, L., Li, Y., Debras, C and Vallat, J.M 2005 Autonomic nervous system involvement in chronic in ammatory demyelinating polyneuropathy Revue Neurol (Paris), 161 , 1228–31 Camdessanche, J.P., Antoine, J.C., Honnorat, J et al 2002 Paraneoplastic peripheral neuropathy associated with anti-Hu antibodies A clinical and electrophysiological... 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