Robert D. Fealey

Autoantibodies to Ganglionic Acetylcholine Receptors in Autoimmune Autonomic Neuropathies

BACKGROUND Idiopathic autonomic neuropathy is a severe, subacute disorder with a presumed autoimmune basis. It is indistinguishable from the subacute autonomic neuropathy that may accompany lung cancer or other tumors. Autoantibodies specific for nicotinic acetylcholine receptors in the autonomic ganglia are potentially pathogenic and may serve as serologic markers of various forms of autoimmune autonomic neuropathy. METHODS We tested serum from 157 patients with a variety of types of dysautonomia. Immunoprecipitation assays with iodine-125-labeled epibatidine and solubilized human neuroblastoma acetylcholine receptors were used to detect autoantibodies that bound to or blocked ganglionic receptors. RESULTS Ganglionic-receptor-binding antibodies were found in 19 of 46 patients with idiopathic or paraneoplastic autonomic neuropathy (41 percent), in 6 of 67 patients with postural tachycardia syndrome, idiopathic gastrointestinal dysmotility, or diabetic autonomic neuropathy (9 percent), and in none of 44 patients with other autonomic disorders. High levels of the binding antibodies correlated with more severe autonomic dysfunction (including the presence of tonic pupils). Levels of these antibodies decreased in patients who had clinical improvement. All seven patients with ganglionic-receptor-blocking antibodies had ganglionic-receptor-binding antibodies and had idiopathic or paraneoplastic autonomic neuropathy. CONCLUSIONS Seropositivity for antibodies that bind to or block ganglionic acetylcholine receptors identifies patients with various forms of autoimmune autonomic neuropathy and distinguishes these disorders from other types of dysautonomia. The positive correlation between high levels of ganglionic-receptor antibodies and the severity of autonomic dysfunction suggests that the antibodies have a pathogenic role in these types of neuropathy.

Thermoregulatory Sweating Abnormalities in Diabetes Mellitus

A properly performed thermoregulatory sweat test (TST) can be informative in patients with diabetic neuropathy. Of 51 patients suspected of having neuropathy on the basis of a clinical examination, 48 (94%) had unequivocal abnormalities on the TST. Pathologic loss of sweating occurred distally in 65%, segmentally in 25%, and only in isolated dermatomes in 25%; 78% of patients had a combination of two or more patterns. Global anhidrosis was noted in eight patients (16%), all of whom had profound autonomic neuropathy, and in the entire group, the percentage of body surface anhidrosis correlated with the degree of clinical dysautonomia (rank correlation coefficient = 0.77; P less than 0.01). Discrete zones of anhidrosis on the thorax and abdomen were noted in patients with painful diabetic radiculopathy, and they correlated highly with thoracic paraspinal muscle fibrillation potentials. Distal loss of sweating detected on the TST was always associated with a subnormal quantitative sudomotor axon reflex response or abnormal electromyographic findings, an indication of a distal axonal neuropathy. The TST provides reliable information about the distribution of diabetic neuropathic involvement and can be especially useful in the diagnosis of truncal radiculopathy and clinically significant autonomic neuropathy.

Neurologic manifestations in welders with pallidal MRI T1 hyperintensity

Background: Neurologic symptoms have been attributed to manganese fumes generated during welding. Increased T1 MRI signal in the basal ganglia is a biologic marker of manganese accumulation. Recent studies have associated welding and parkinsonism, but generally without MRI corroboration. Objective: To characterize the clinical and neuropsychological features of patients with MRI basal ganglia T1 hyperintensity, who were ultimately diagnosed with neurotoxicity from welding fumes. Methods: The medical records of welders referred to the Department of Neurology with neurologic problems and basal ganglia T1 hyperintensity were reviewed. Results: All eight patients were male career welders with increased T1 basal ganglia signal on MRI of the brain. Several different clinical syndromes were recognized: a parkinsonian syndrome (three patients), a syndrome of multifocal myoclonus and limited cognitive impairment (two patients), a mixed syndrome with vestibular–auditory dysfunction (two patients), and minor subjective cognitive impairment, anxiety, and sleep apnea (one patient). Neuropsychometric testing suggested subcortical or frontal involvement. Inadequate ventilation or lack of personal respiratory protection during welding was a common theme. Conclusions: Welding without proper protection was associated with syndromes of parkinsonism, multifocal myoclonus, mild cognitive impairment, and vestibular–auditory dysfunction. The MRI T1 hyperintensity in the basal ganglia suggests that these may have been caused by manganese neurotoxicity.

The spectrum of autoimmune autonomic neuropathies

We analyzed the clinical characteristics of 18 patients (13 female, 5 male) who had autoimmune autonomic neuropathy (AAN) and ganglionic acetylcholine receptor (AChR) autoantibodies. Mean age was 61.4 years (standard deviation, 12.0 years). Ten patients had subacute symptom onset, six with an antecedent event. Eight patients had chronic AAN, characterized by insidious symptom onset, without antecedent event, and gradual progression. A majority of patients with high antibody values (>1.00 nmol/L) had a combination of sicca complex (marked dry eyes and dry mouth), abnormal pupillary light response, upper gastrointestinal symptoms, and neurogenic bladder. Chronic AAN segregated into two subgroups. One subgroup (N = 4) had low antibody titer (0.09 ± 0.01 nmol/L) and a paucity of cholinergic symptoms. It was indistinguishable from pure autonomic failure. The other subgroup (N = 4) had high antibody titer (11.6 ± 2.08 nmol/L), sicca complex, abnormal pupils, and neurogenic bladder; three had severe upper gastrointestinal dysfunction. Higher antibody titers correlated with greater autonomic dysfunction and more frequent cholinergic dysautonomia. These observations expand the clinical spectrum of AAN to include chronic cases, some being indistinguishable from pure autonomic failure, and support the concept that ganglionic AChR antibodies are important diagnostically and pathophysiologically in acquired dysautonomia.Ann Neurol 2003;53:752–758

Hyperhidrosis: Evolving Therapies for a Well-Established Phenomenon

The socially embarrassing disorder of excessive sweating, or hyperhidrosis, and its treatment options are gaining widespread attention. In order of frequency, palmar-plantar, palmar-axillary, Isolated axillary, and cranlofacial hyperhidrosis are distinct disorders of sudomotor regulation. A common link among these disorders is an excessive, nonthermoregulatory sweat response often to emotional stimuli in body regions influenced by the anterior cingulate cortex as opposed to the thermoregulatory sweat response regulated by the preoptic-anterior hypothalamus. Diagnosis of these mechanistically ambiguous disorders is primarily from patient history and physical examination, whereas results of laboratory studies performed with indicator powder reveal the distribution and severity of resting hyperhidrosis and document the integrity of thermoregulatory sweating. Treatment options lie on a continuum based on the severity of hyperhidrosis and the risks and benefits of therapy. In general, therapy begins with antiperspirants or anticholinergics. Iontophoresis is available for palmar-plantar and axillary hyperhidrosis. Botulinum toxin type A or local excision/curettage is effective for isolated axillary hyperhidrosis not responsive to topical application of aluminum chloride. Endoscopic thoracic sympathectomy may be used for severe cases of palmar-plantar and palmar-axillary hyperhidrosis. No sole therapy of choice has emerged for craniofacial sweating. The long-term sequelae of hyperhidrosis and its treatment also are discussed.

Detection of small-fiber neuropathy by sudomotor testing

The symptoms of burning sensation affecting the feet, thought to be due to a distal small‐fiber neuropathy (DSFN) affecting somatic unmyelinated fibers, are usually accompanied by vasomotor or sudomotor changes suggestive of involvement of autonomic fibers. We therefore examined the relationship between pattern of anhidrosis and DSFN and its etiology, comparing patients with “pure” DSFN (with normal nerve conduction) to those with clinical DSFN (minor conduction abnormalities). We reviewed 125 cases with a clinical phenotype of DSFN. These patients had distal burning discomfort, variable sensory deficits, and intact motor function. All had undergone assessment with thermoregulatory sweat test (TST), autonomic reflex screen (ARS), and nerve conduction studies and electromyography (NCS/EMG). TST showed a distal pattern of anhidrosis in 74%. The quantitative sudomotor axon reflex test (QSART) was abnormal in 74%, with 80% of those having a length‐dependent pattern of anhidrosis/hypohidrosis. In total, 93% of patients had a distal pattern of abnormality on QSART or TST. The Composite Autonomic Severity Score (CASS) was used to quantify the severity and distribution of autonomic deficits: 98% had CASS abnormality (sudomotor, 98%; adrenergic, 43%; cardiovagal, 35%). EMG was normal or showed unrelated abnormalities in 75%. The most common etiologies of DSFN were idiopathic (73%), presumed hereditary (18%), and diabetes (10%). Sudomotor examination is thus a highly sensitive detection tool in DSFN. Autonomic involvement is mainly distal, and additionally may involve adrenergic and the long cardiovagal fibers. Muscle Nerve, 2006

Idiopathic autonomic neuropathy Clinical, neurophysiologie, and follow‐up studies on 27 patients

We evaluated the natural history, electrophysiologic characteristics, spectrum of autonomic involvement, pathology, and laboratory features in 27 patients with idiopathic autonomic neuropathy who were followed up for a mean of 32 months. The typical features of idiopathic autonomic neuropathy include the absence of an associated disease, frequent history of preceding infection, and acute or subacute onset with a monophasic course. The spectrum of autonomic involvement ranges from panautonomic to selective adrenergic or cholinergic failure. There is infrequent involvement of somatic nerve fibers as assessed by routine nerve conduction studies. Pathologic features include the presence of a small inflammatory mononuclear cell infiltrate in the epineurium. Recovery tends to be gradual and frequently incomplete. The acute onset, frequent antecedent viral infection, selectivity of involvement by fiber type and autonomic level, and presence of perivascular mononuclear cell infiltration suggest that the underlying mechanism is likely to be immune-mediated. These observations may justify plasma exchange or other immunosuppressive modalities as early therapeutic intervention in patients with progressive disability.

Prospective Evaluation of Clinical Characteristics of Orthostatic Hypotension

OBJECTIVE To undertake a prospective study of the clinical characteristics of orthostatic intolerant patients referred to the Mayo Autonomic Reflex Laboratory with suspected orthostatic hypotension (OH). DESIGN Autonomic function tests were performed to quantify the severity of sudomotor, adrenergic, and cardiovagal failure and generate a composite autonomic symptom score (CASS). CASS was related to a symptom score, which was derived from the frequency of orthostatic intolerance and syncope and the standing time until occurrence of symptoms. RESULTS Three groups were defined by their response to a tilt study: group I, 90 patients with symptomatic OH, mean age, 63.6 years; group II, 60 patients who had symptoms without OH, mean age, 48.9 years; and group III, 5 patients with asymptomatic OH, mean age, 68.0 years. Group I had a significantly higher CASS (P < 0.001) than did those without OH. Further analysis was done on the 90 patients in group I. The most common symptoms were lightheadedness, weakness, impaired cognition, visual blurring, tremulousness, and vertigo. The most common aggravating factors were prolonged standing, exercise, warming, and eating. Most patients (75%) could stand for less than 5 minutes before symptoms occurred. Symptoms regressed significantly with CASS but not with the tilt grade. CONCLUSION Patients with generalized autonomic failure have a recognizable pattern of symptoms and aggravating factors that relate, albeit imperfectly, to the severity of autonomic failure.

Ganglionic Acetylcholine Receptor Autoantibody: Oncological, Neurological, and Serological Accompaniments

OBJECTIVE To describe the clinical utility of the nicotinic ganglionic acetylcholine receptor (alpha3-AChR) autoantibody as a marker of neurological autoimmunity and cancer. DESIGN Case-control study. SETTING Mayo Clinic, Rochester, Minnesota. PATIENTS A total of 15,000 patients seen at Mayo Clinic (2005-2007) and evaluated on a service basis for paraneoplastic neurological autoimmunity for whom clinical information was obtained retrospectively by medical record review as well as 457 neurologically asymptomatic patients or control subjects of whom 173 were healthy, 245 had lung cancer, and 39 had systemic lupus erythematosus or Sjögren syndrome. OUTCOME MEASURES Neurological, oncological, and serological associations of alpha3-AChR autoantibody seropositivity. RESULTS Of 15,000 patients tested on a service basis, 1% were seropositive (median, 0.12 nmol/L; range, 0.03-18.8 nmol/L; normal, < or =0.02 nmol/L), 55% were male, and the median age was 65 years. Cancer was found (new or by history) in 24 of 78 patients evaluated for cancer while at Mayo Clinic (30%); 43% had adenocarcinoma (more patients had breast cancer than prostate, lung, and gastrointestinal cancers; each of the latter groups had about the same number of patients). Of 12 patients with high antibody values (> or =1.00 nmol/L), 83% had pandysautonomia. Of 85 patients with medium antibody values (0.10-0.99 nmol/L), neurological presentations were more diverse and included peripheral neuropathies (36%), dysautonomia (20%, usually limited), and encephalopathy (13%). Of 58 patients with low antibody values (0.03-0.09 nmol/L), 54% had a nonautoimmune neurological disorder or no neurological disorder. Of 245 control patients with lung cancer, 7.8% were seropositive. Only 1 of 212 control patients without cancer (0.5%) was seropositive (P < .001). CONCLUSION The detection of alpha3-AChR autoantibody aids the diagnosis of neurological autoimmunity and cancer.

Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure.

OBJECTIVE To report preliminary results of a prospective ongoing study of multiple system atrophy (MSA) and Parkinson disease (PD), with a large subset of patients with PD with autonomic failure (25%), to evaluate autonomic indices that distinguish MSA from PD. METHODS We used consensus criteria, detailed autonomic studies (Composite Autonomic Symptom Scale, Composite Autonomic Scoring Scale, thermoregulatory sweat test, and plasma catecholamines), and functional scales (Unified MSA Rating Scale [UMSARS] I-IV and Hoehn-Yahr grading) on a prospective, repeated, and ongoing basis. RESULTS We report the results of a study on 52 patients with MSA (mean [SD], age, 61.1 [7.8] years; body mass index (calculated as weight in kilograms divided by height in meters squared), 27.2 [4.6]; Hoehn-Yahr grade, 3.2 [0.9]; UMSARS I score, 21.5 [7.4]; and UMSARS II score, 22.7 [9.0]) and 29 patients with PD, including PD with autonomic failure (mean [SD], age, 66.0 [8.1] years; body mass index, 26.6 [5.5]; Hoehn-Yahr grade, 2.2 [0.8]; UMSARS I score, 10.4 [6.1]; and UMSARS II score, 13.0 [5.9]). Autonomic indices were highly significantly more abnormal in MSA than PD (P < .001) for the Composite Autonomic Scoring Scale (5.9 [1.9] vs 3.3 [2.3], respectively), Composite Autonomic Symptom Scale (54.4 [21.8] vs 24.7 [20.5], respectively), and thermoregulatory sweat test (percentage anhidrosis, 57.4% [35.2%] vs 9.9% [17.7%], respectively). These differences were sustained and greater at 1-year follow-up, indicating a greater rate of progression of dysautonomia in MSA than PD. CONCLUSIONS The severity, distribution, and pattern of autonomic deficits at study entry will distinguish MSA from PD, and MSA from PD with autonomic failure. These differences continue and are increased at follow-up. Our ongoing conclusion is that autonomic function tests can separate MSA from PD. Autonomic indices support the notion that the primary lesion in PD is ganglionic and postganglionic, while MSA is preganglionic.