Abnormal sweating patterns associated with itching, burning and tingling of the skin indicate possible underlying small-fibre neuropathy.

BACKGROUND: Itching, burning, numbness and tingling of the skin are frequent reasons for dermatology consultation. We hypothesized that these sensations may be attributable to a small-fibre neuropathy. Sweating, which is mediated by small nerve fibres, may be a surrogate marker of small-fibre neuropathy. OBJECTIVES: To investigate the results of thermoregulatory sweat testing (TST), which depicts and estimates whole-body sweating, in patients with itching, burning, numbness and tingling sensations. METHODS: We retrospectively reviewed the medical records of 227 patients with itching, burning, numbness and tingling sensations involving the skin who were seen at our institution during 2008 and also underwent TST. RESULTS: The mean age of the cohort was 54 years (range 3-89), and 58% were female. In all, 149 patients (66%) had abnormal TST results; in 119 (80%) of these patients the areas of anhidrosis on TST corresponded to their symptomatic areas. For each symptom analysed separately, the area of anhidrosis correlated with the area of symptoms in most patients. CONCLUSIONS: Patients with burning, itching, numbness and tingling have abnormal sweating patterns and often do not sweat in the symptomatic areas. These novel findings suggest that a small-fibre neuropathy may underlie many cutaneous symptoms and that the neuropathy can be estimated using TST.

Results of computer-assisted sensory evaluation in 41 patients with erythromelalgia.

BACKGROUND: Erythromelalgia is a rare disorder characterized by the clinical syndrome of burning pain, warmth and redness of the limbs. Neurological abnormalities (both large- and small-fibre neuropathy) are common. There have been few published reports on the sensory status of patients with erythromelalgia. AIM: To investigate the results of quantitative sensation testing in erythromelalgia using computer-assisted sensory evaluation, including vibratory detection threshold, cool detection threshold and heat-pain threshold (HPT). METHODS: Patients who underwent dermatological or neurological evaluation of suspected erythromelalgia at our institution and received a final diagnosis of erythromelalgia were identified from a master diagnosis index covering the period January 1994 to June 2008. A retrospective chart review was performed. Main outcome measures were sensory abnormalities (e.g. pain, burning sensation, tingling) in response to heat, cooling and vibration during computer-assisted sensory testing. RESULTS: In total, 41 patients with erythromelalgia were enrolled in the study and underwent computer-assisted sensory evaluation. Of these, 34 patients (82.9%) had abnormal results. The commonest abnormality was isolated HPT: 11 patients (26.8%) had heat hypoalgesia and 18 (43.9%) had heat hyperalgesia, whereas only 2 (4.9%) of the healthy control patients had hyperalgesia on testing. CONCLUSIONS: Multiple sensory modalities were found to be abnormal in patients with erythromelalgia, with the commonest clinical abnormality being isolated heat-pain abnormality. These findings lend support to the notion that neuropathy underlies the clinical diagnosis of erythromelalgia. Future studies will explore the nature of the relationship between these sensory abnormalities and the clinical features of erythromelalgia.

Autonomic dysfunction in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVES: Autonomic deficits in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have not been adequately quantitated. The Composite Autonomic Severity Score (CASS) is a validated instrument for laboratory quantitation of autonomic failure derived from standard autonomic reflex tests. We characterized dysautonomia in CIDP using CASS. METHODS: Autonomic function was retrospectively analyzed in 47 patients meeting CIDP criteria. CASS ranges from 0 (normal) to 10 (pandysautonomia), reflecting summation of sudomotor (0-3), cardiovagal (0-3), and adrenergic (0-4) subscores. Severity of neurologic deficits was measured with Neuropathy Impairment Score (NIS). Degree of small fiber involvement was assessed with quantitative sensation testing. Thermoregulatory sweat test (TST) was available in 8 patients. RESULTS: Patients (25 men) were middle-aged (45.0 ± 14.9 years) with longstanding CIDP (3.5 ± 4.3 years) of moderate severity (NIS, 46.5 ± 32.7). Autonomic symptoms were uncommon, mainly gastrointestinal (9/47; 19%) and genitourinary (8/47; 17%). Autonomic deficits (CASS ≥1) were frequent (22/47; 47%) but very mild (CASS, 0.8 ± 0.9; CASS ≤3, all cases). Deficits were predominantly sudomotor (16/47; 34%) and cardiovagal (10/47; 21%) with relative adrenergic sparing (4/47; 9%). TST was abnormal in 5 of 8 patients (anhidrosis range, 2%-59%). Sudomotor impairment was predominantly distal and postganglionic. Somatic deficits (disease duration, severity, small fiber deficits) did not predict presence of autonomic deficits. CONCLUSION: Our data characterize the autonomic involvement in classic CIDP as mild, cholinergic, and predominantly sudomotor mainly as a result of lesions at the distal postganglionic axon. Extensive or severe autonomic involvement (CASS ≥4) in suspected CIDP should raise concern for an alternative diagnosis.

Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting.

BACKGROUND: Despite the relatively high prevalence of gastroparesis and functional dyspepsia, the aetiology and pathophysiology of these disorders remain incompletely understood. Similarly, the diagnostic and treatment options for these two disorders are relatively limited despite recent advances in our understanding of both disorders. PURPOSE: This manuscript reviews the advances in the understanding of the epidemiology, pathophysiology, diagnosis, and treatment of gastroparesis and functional dyspepsia as discussed at a recent conference sponsored by the American Gastroenterological Association (AGA) and the American Neurogastroenterology and Motility Society (ANMS). Particular focus is placed on discussing unmet needs and areas for future research.

Sudomotor dysfunction in autoimmune autonomic ganglionopathy.

BACKGROUND: Autoimmune autonomic ganglionopathy is characterized by impairment of multiple autonomic domains of which sudomotor function is among the most common. Many patients with this disorder have difficulties with thermoregulation and anhidrosis. Our objective was to characterize the distribution and severity of sudomotor dysfunction in this disorder. METHODS: Sudomotor function was analyzed in a cohort of 21 patients with ganglionic alpha3 nicotinic acetylcholine receptor (nAChR) antibody positive autoimmune autonomic ganglionopathy. Standard measurements of sudomotor function were used including the Thermoregulatory Sweat Test and Quantitative Sudomotor Axon Reflex Test. RESULTS: The clinical presentation in all patients was characterized by widespread sudomotor dysfunction. Sudomotor impairment was predominantly postganglionic in 17 of the 21 patients studied. Higher ganglionic alpha3 nAChR antibody levels resulted in progressive postganglionic predominant dysfunction (postganglionic, r = 0.637, p = 0.002; mixed ganglionic, r = 0.709, p < 0.001). The pattern of anhidrosis on Thermoregulatory Sweat Testing was consistent with a ganglionopathy in the majority of patients (14 of 21) and a distal pattern in a minority of patients (8 of 21). These patterns of anhidrosis coupled with increasing postganglionic dysfunction in a proximal to distal pattern (foot > distal leg > proximal leg > forearm) indicate lesions at both the ganglia and distal axon of the postganglionic sudomotor sympathetic neuron. CONCLUSIONS: Our data characterize the unique sudomotor dysfunction in autoimmune autonomic ganglionopathy as widespread, predominantly postganglionic, and a result of lesions at both the ganglia and distal axon. This study provides important support to the hypothesis that this disorder represents a ganglionic neuropathy.

Dopamine cell loss in the periaqueductal gray in multiple system atrophy and Lewy body dementia.

BACKGROUND: Experimental studies indicate that dopaminergic neurons in the ventral periaqueductal gray matter (PAG) are involved in maintenance of wakefulness. Excessive daytime sleepiness (EDS) is a common manifestation of multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) but involvement of these neurons has not yet been explored. METHODS: We sought to determine whether there is loss of dopaminergic neurons in the ventral PAG in MSA and DLB. We studied the midbrain obtained at autopsy from 12 patients (9 male, 3 female, age 61 +/- 3) with neuropathologically confirmed MSA, 12 patients (11 male, 1 female, age 79 +/- 4) with diagnosis of DLB and limbic or neocortical Lewy body disease, and 12 controls (7 male, 5 female, ages 67 +/- 4). Fifty-micron sections were immunostained for tyrosine hydroxylase (TH) or alpha-synuclein and costained with thionin. Cell counts were performed every 400 mum throughout the ventral PAG using stereologic techniques. RESULTS: Compared to the total estimated cell numbers in controls (21,488 +/- 8,324 cells), there was marked loss of TH neurons in the ventral PAG in both MSA (11,727 +/- 5,984; p < 0.01) and DLB (5,163 +/- 1,926; p < 0.001) cases. Cell loss was more marked in DLB than in MSA. There were characteristic alpha-synuclein inclusions in the ventral PAG in both MSA and DLB. CONCLUSIONS: There is loss of putative wake-active ventral periaqueductal gray matter dopaminergic neurons in both multiple system atrophy and dementia with Lewy bodies, which may contribute to excessive daytime sleepiness in these conditions.

Efficacy of immunotherapy in seropositive and seronegative putative autoimmune autonomic ganglionopathy.

OBJECTIVE: To evaluate the efficacy of immunotherapy in the treatment of patients with seropositive and seronegative putative autoimmune autonomic ganglionopathy (AAG) using validated autonomic function tests and instruments. BACKGROUND: AAG is an immune-mediated disorder characterized by prominent and selective involvement of autonomic nerve fibers or ganglia. Treatment with i.v. immunoglobulin (IVIg) or plasma exchange (PE) has been reported to be effective in single case reports. METHODS: We studied six patients, four with seropositive and two with seronegative putative AAG, who underwent autonomic function tests and completed two validated questionnaires, to assess autonomic symptoms before and after immunomodulatory treatment. Patients were treated with standard doses of IVIg, PE, or immunosuppressants in a specific sequential therapy protocol depending on clinical response. RESULTS: Of the six patients (all women, mean ages 49.3 +/- 10.6 years), four patients were ganglionic (alpha3) AChR autoantibody positive and two were autoantibody negative. All patients showed clinical improvement after treatment. Sudomotor function assessed by quantitative sudomotor axon reflex test and thermoregulatory sweat test improved in four patients after treatment. CONCLUSIONS: Immunomodulatory treatment can be effective in both seropositive and seronegative putative autoimmune autonomic ganglionopathy. Plasma exchange or combined therapy with immunosuppressive agents should be considered in patients who do not benefit from i.v. immunoglobulin alone.

Second consensus statement on the diagnosis of multiple system atrophy.

BACKGROUND: A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here. METHODS: Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology. RESULTS: The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality. CONCLUSIONS: These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.

Mesopontine cholinergic neuron involvement in Lewy body dementia and multiple system atrophy.

BACKGROUND: The pedunculopontine (PPT) and laterodorsal (LDT) tegmental nuclei are involved in control of REM sleep and thalamocortical arousal. REM sleep behavior disorder (RBD) is a feature of multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), which is also associated with visual hallucinations and cognitive fluctuations. We sought to determine the degree of PPT/LDT involvement in DLB compared to MSA. METHODS: We counted the cholinergic neurons in the PPT and LDT in 13 patients with neuropathologically confirmed DLB, 11 patients with MSA, and 11 control cases. Five patients with DLB and eight patients with MSA had history or polysomnographic evidence of RBD. Ten patients with DLB and no patient with MSA had history of visual hallucinations or cognitive fluctuations. RESULTS: There was a significant loss of PPT and LDT neurons in both DLB and MSA. Cell loss in both the PPT and LDT was more severe in MSA than in DLB. The number of cells/section for the PPT were 148 +/- 21 in controls, 54 +/- 10 in DLB (p < 0.001), and 20 +/- 3 in MSA (p < 0.001), and for the LDT, 112 +/- 16 in controls, 49 +/- 8 in DLB (p < 0.01), and 16 +/- 2 in MSA (p < 0.001). Severity of neuronal loss in MSA or DLB did not relate to the presence or absence of history of RBD. CONCLUSIONS: Loss of cholinergic pedunculopontine tegmental nuclei/laterodorsal tegmental nuclei neurons occurs in both dementia with Lewy bodies and multiple system atrophy but is probably not the primary mechanism of REM sleep behavior disorder in these disorders.

Rostral raphe involvement in Lewy body dementia and multiple system atrophy.

Depression is a feature of both Lewy body disorders and multiple system atrophy (MSA). Since serotonergic neurons of the rostral raphe have been implicated in depression, we sought to determine whether there is a differential involvement of these neurons in cases with clinically diagnosed dementia with Lewy bodies (DLB) or MSA. We studied the brainstem obtained at autopsy from fourteen patients with diagnosis of DLB and pathological limbic or neocortical stage Lewy body disease, 13 patients with clinical and neuropathological diagnosis of MSA, and 12 controls with no history of neurologic disease. The clinical features of these patients were analyzed retrospectively by reviewing their medical records. Serial sections were immunostained for tryptophan hydroxylase (TrOH) and alpha-synuclein and cell counts were performed in the dorsal raphe (DR), median raphe (MR) and medullary raphe nuclei. There was loss of serotonergic cells in both the DR and MR in DLB compared to control cases: For the DR, the number of cells/section were 53 +/- 6 in DLB versus 159 +/- 13 (P < 0.001) respectively, and for the MR 70 +/- 11 in DLB versus 173 +/- 23 (P < 0.001) respectively. In contrast, these cells were relatively preserved in MSA. The caudal raphe groups were affected both in MSA and in DLB. There is a differential involvement of raphe neurons in DLB and MSA. Although loss of rostral raphe neurons may contribute to depression in DLB, this appears to be less likely in MSA. Factors other than the neurochemical phenotype determine neuronal vulnerability in MSA.

Autoimmune autonomic ganglionopathy: IgG effects on ganglionic acetylcholine receptor current.

BACKGROUND: Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated form of diffuse autonomic failure. Many patients have serum antibodies that bind to the ganglionic acetylcholine receptors (AChRs) that mediate fast synaptic transmission in autonomic ganglia. Previous clinical studies and observations in animal models suggest that AAG is an antibody-mediated neurologic disorder. METHODS: Using whole-cell patch clamp techniques, we recorded ganglionic AChR currents in cultured human IMR-32 cells and examined the effects of bath application of IgG derived from patients with AAG. RESULTS: IgG from seven patients with AAG all produced a progressive decline in whole-cell ganglionic AChR current, whereas IgG from control subjects had no effect. The effect was abolished at low temperature. Fab antibody fragments had no effect unless a secondary antibody was added concurrently. IgG from one patient also produced a more immediate reduction of ganglionic AChR current. CONCLUSIONS: The characteristics of antibody-mediated inhibition of ganglionic acetylcholine receptor (AChR) current are consistent with modulation and blocking of the membrane AChR, analogous to the effects of muscle AChR antibodies in myasthenia gravis. Our observations demonstrate that antibodies in patients with autoimmune autonomic ganglionopathy (AAG) cause physiologic changes in ganglionic AChR function and confirm that AAG is an antibody-mediated disorder.

Calf venous compliance in multiple system atrophy.

In multiple system atrophy (MSA), increased venous compliance with excessive venous pooling is assumed to be a major contributor to orthostatic hypotension (OH); however, venous compliance has never been assessed in MSA patients. We evaluated the severity and distribution of adrenergic, cardiovagal, and sudomotor failure in 11 patients with probable MSA, 14 age- and sex-matched control subjects, and 8 patients with Parkinson's disease (PD) but not OH. Calf venous compliance, venous filling, and capillary filtration were measured using calf plethysmography. The response to the directly acting alpha-adrenergic stimulation (10 mg midodrine) on calf venous compliance was additionally evaluated. Contrary to our hypothesis, pressure-volume curves in the legs of MSA patients were flatter than in PD patients (P < 0.05) or controls (P < 0.001); this indicated reduced calf venous compliance in MSA. The MSA group had reduced venous filling compared with control (P < 0.001) or PD subjects (P < 0.001) but had a normal capillary filtration rate (P = 0.73). Direct alpha-adrenergic stimulation resulted in a slight but significant reduction of calf venous compliance in controls (P = 0.001) and PD subjects (P < 0.001) but not in the MSA group. The compliance change in MSA significantly regressed with autonomic failure (composite autonomic severity scale, r(2) = 0.56) but not with parkinsonism (Unified MSA Rating Scale, r(2) = 0.12). Our data indicate that MSA patients with chronic OH have reduced, rather than increased, venous compliance in the lower leg. We postulate that chronic venous distension that is associated with OH results in structural remodeling of veins, leading to reduced compliance, a change which may protect patients against orthostatic stress.

The burden of inpatient neurologic disease in two Ethiopian hospitals.

OBJECTIVES: To define the burden of inpatient neurologic disease seen in Ethiopian teaching hospitals. METHODS: We reviewed records of all medical inpatients admitted over a 6-month period to two teaching hospitals, one with and one without neurologists. RESULTS: Neurologic cases made up 18.0% and 24.7% of all medical admissions. The mortality rates were 21.8% and 34.7%. Noninfectious diseases were 36.7% and 31.7% of neurologic cases, but unknown etiologies made up 42.2% and 29.0% of all cases. Of total cases, only 42.9% and 24.1% had at least a high level of diagnostic certainty. CONCLUSIONS: Patients with neurologic disease make up a substantial minority of medical inpatients in Ethiopia. Noninfectious neurologic disease is at least as common as infectious neurologic disease. Reaching a well-defined final diagnosis occurs in only a minority of cases. Areas for improving the mortality rate include improving the barriers to diagnostic certainty and increasing treatment options for Ethiopian patients.

Involvement of vagal autonomic nuclei in multiple system atrophy and Lewy body disease.

BACKGROUND: Multiple system atrophy (MSA) and Lewy body disorders (LBDs) are associated with impaired control of gastrointestinal and cardiac functions. The dorsal vagal nucleus (DMV) innervates enteric neurons, whereas the ventrolateral nucleus ambiguus (NAmb) innervates the heart. The relationship between DMV and NAmb involvement and the gastrointestinal or cardiovagal manifestations in MSA and LBD is unclear. METHODS: The authors counted the cholinergic neurons in the DMV and NAmb in 15 cases of neuropathologically confirmed MSA, 14 of LBD (4 brainstem, 3 limbic, and 7 neocortical), and 12 control cases. All MSA and 8 of the 14 LBD cases had gastrointestinal symptoms; 8 of 12 MSA and 1 of 4 LBD cases had laboratory evidence of cardiovagal failure; 5 of the MSA and no LBD cases had laryngeal stridor. RESULTS: There was loss of cholinergic DMV neurons in all MSA and LBD cases. The degree of DMV cell loss was similar in LBD patient with or without gastrointestinal symptoms. In MSA but not in LBD cases, there was neuronal loss in the ventrolateral NAmb, with lower counts in patients with cardiovagal failure. CONCLUSIONS: There is comparable involvement of the dorsal vagal nucleus (DMV) in multiple system atrophy (MSA) and different stages of Lewy body disorders (LBDs). The relationship of DMV involvement and gastrointestinal symptoms is uncertain. Loss of neurons in the ventrolateral nucleus ambiguus may explain the more consistent cardiovagal failure in MSA than in LBD.

The North American Multiple System Atrophy Study Group.

The North American Multiple System Atrophy Study Group involves investigators in 12 US medical centers funded by a grant from the National Institutes of Health. The objectives are to examine the environmental and genetic risk factors for MSA; elucidate pathogenic mechanisms underlying the disorder; and refine evaluations used for assessment. During its first year, the group enrolled 87 patients, implemented four cores, and initiated four scientific projects. Most patients among the 87 had parkinsonian features, which frequently began asymmetrically and remained asymmetrical; one-third responded to levodopa and many developed levodopa complications; almost two-thirds of the patients had cerebellar dysfunction, of these 90% had ataxia; urinary incontinence occurred commonly, and sleep disorders affected most. The investigators studied the effects of oxidative and nitrative stress upon the formation of alpha-synuclein inclusions; generated transgenic models of alpha-synuclein accumulation that recapitulate several behavioral and neuropathological features of MSA; and compared the severity of the autonomic features of MSA, Parkinson's disease and dementia with Lewy bodies.

Autonomic dysfunction in dementia with Lewy bodies.

OBJECTIVE: To assess autonomic function in patients with dementia with Lewy bodies (DLB). METHODS: The authors compared data from 20 DLB patients evaluated from 1995 to 2000 to 20 age-matched multiple system atrophy (MSA) and Parkinson disease (PD) patients evaluated from 1999 to 2002. Analysis of variance, Fisher exact test, and Student t-test were applied to compare disease characteristics, autonomic symptoms, and function tests on the Composite Autonomic Scoring Scale (CASS) and Thermoregulatory Sweat Test (TST). RESULTS: In DLB, mean age at onset of autonomic symptoms was 70.3 +/- 8.9 years. Orthostatic symptoms were common and orthostatic hypotension occurred in 10/20 DLB, 17/20 MSA, and 1/20 PD patients (p = 0.023, 0.003). CASS-sudomotor for DLB, MSA, and PD were 1.6 +/- 1.2, 2.5 +/- 0.7, and 0.9 +/- 0.8 (p < 0.00001). CASS-cardiovagal were 1.4 +/- 0.9, 2.1 +/- 0.8, and 0.7 +/- 0.6 (p < 0.00001). CASS-adrenergic function were 2.4 +/- 1.2, 3.5 +/- 0.9, and 0.5 +/- 0.6 (p < 0.00001). Total CASS were 5.2 +/- 2.0, 8.1 +/- 1.3, and 2.2 +/- 1.2 (p < 0.00001). The most common pattern of TST in DLB was distal anhidrosis. Mean duration of follow-up was 3.0 +/- 1.8 years. Six patients needed medication to maintain blood pressure and five had good response. CONCLUSIONS: Autonomic dysfunction is frequent in dementia with Lewy bodies and the severity is intermediate between that of multiple system atrophy and Parkinson disease.

Autonomic peripheral neuropathies: clinical presentation, diagnosis, and treatment.

This brief review was written with the intention of familiarizing the reader with autonomic peripheral neuropathies. We have discussed what we think are the main presenting symptoms of these conditions, briefly outlining some specific autonomic neuropathies. We then provide a general guideline to evaluation and diagnosis by using both widely available, as well as more sophisticated, techniques. Finally, we have addressed management. Whenever possible, specific treatment of underlying disorders leads to the best outcome However, for many autonomic neuropathies, no cure is available, although symptomatic management can effectively improve patients" quality of life.