Type 1 interferon signature and cytotoxic T lymphocyte activation targeted against sweat ducts in inflammatory acquired idiopathic generalized anhidrosis.

BACKGROUND: Acquired idiopathic generalized anhidrosis (AIGA) leads to heat intolerance due to the loss or reduction in thermoregulatory sweating over an extensive area of the body. The pathomechanism of AIGA is still unclear but is believed to be autoimmune. OBJECTIVES: We investigated the clinical and pathological features of inflammatory AIGA (InfAIGA) and noninflammatory AIGA (non-InfAIGA) within the skin. METHODS: We compared anhidrotic and normohidrotic skin samples from 30 patients with InfAIGA and non-InfAIGA, as well as skin samples of melanocytic nevus as a negative control. We conducted morphometric analysis and immunohistochemical analysis of cell types and expression of inflammatory molecules (TIA1, CXCR3 and MxA). MxA expression was used as a proxy for type 1 interferon activity. RESULTS: We found that tissue samples from patients with InfAIGA exhibited inflammation within the sweat duct and atrophy of the sweat coil, whereas patients with non-InfAIGA exhibited only atrophy of the sweat coil. Cytotoxic T lymphocyte infiltration and MxA expression were only observed in the sweat ducts of patients with InfAIGA. CONCLUSIONS: InfAIGA is associated with increased sweat duct inflammation and sweat coil atrophy, whereas non-InfAIGA is only associated with sweat coil atrophy. These data suggest that inflammation leads to epithelial destruction of sweat ducts associated with the sweat coil atrophy and subsequent loss of function. Non-InfAIGA may be regarded as a postinflammatory state of InfAIGA. These observations indicate the contribution of both type 1 and type 2 interferons to sweat gland injury. The mechanism involved is similar to the pathomechanism of alopecia areata (AA).

Degranulation and shrinkage of dark cells in eccrine glands and elevated serum carcinoembryonic antigen in patients with acquired idiopathic generalized anhidrosis.

BACKGROUND: Acquired idiopathic generalized anhidrosis (AIGA) is characterized by anhidrosis/hypohidrosis without other autonomic and neurological dysfunctions. Pathologically, AIGA is considered to usually present no significant morphological alterations in eccrine glands, the secretory portion which consists of clear cells, dark cells, and myoepithelial cells. AIGA patients recently have been reported to show high serum concentrations of carcinoembryonic antigen (CEA). OBJECTIVE: Our aim is to reveal morphological abnormalities of dark cells and investigate their relationship with serum CEA. METHODS: We performed comparative analysis of eccrine glands between sweat-preserved and non-sweating skin in four AIGA patients. Serum CEA concentrations in 22 cases with AIGA were measured with healthy volunteers. Furthermore, we semiquantitatively investigated dermcidin, FoxA1 and CEA expression in eccrine glands of 12 cases with AIGA and 5 cases with non-AIGA. RESULTS: Marked degranulation and shrinkage of dark cells consistently occurred in AIGA. Furthermore, high serum CEA concentrations were found in 14 of 22 AIGA patients (over 60%), but serum CEA levels were not correlated with CEA expression in eccrine glands. Dermcidin expression in dark cells apparently decreased in AIGA patients, severely in those with high serum CEA and moderately in those with low serum CEA, while well-preserved expression was found in non-AIGA subjects. CONCLUSION: Our study suggests morphological damage and molecular dysregulation of dark cells, leading to impairment of their functions in AIGA patients. Severely damaged dark cells correspond to high serum CEA. Accordingly, these pathological changes in eccrine dark cells may be involved in anhidrosis/hypohidrosis of AIGA.

Preserved autonomic function in patients with POEMS syndrome.

AIM: We systematically performed autonomic testing on patients with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome (POEMS) to determine whether autonomic function is preserved in such patients. METHODS: We studied 17 POEMS patients, 17 diabetic neuropathy (DN) patients and 17 age-matched normal subjects. Blood pressure responses to the head-up tilt test and heart rate variability were used to evaluate cardiovascular autonomic function. Sweat responses and cutaneous vasoconstriction to several stimuli were recorded via the finger tips to estimate cutaneous sympathetic function. In addition, motor nerve conduction studies were performed. RESULTS: Although the results of the autonomic testing were normal in POEMS patients, motor disability was severe, and motor nerve conduction studies provided evidence of extensive axonal loss. The DN patients showed significantly impaired autonomic responses despite mild motor dysfunction. CONCLUSIONS: Autonomic function was normal in POEMS patients, indicating the preservation of autonomic fibers and selective involvement of large fibers.

Reduced perfusion in the anterior cingulate cortex of patients with pure autonomic failure: an 123I-IMP SPECT study.

BACKGROUND: Pure autonomic failure (PAF) is a selective peripheral disorder in which Lewy bodies form within the autonomic ganglia. Patients with this disorder usually have no central lesions; however, chronic autonomic failure may secondarily affect the central nervous system. This study evaluated brain perfusion in patients with PAF by using N-isopropyl-p-(123)I iodoamphetamine ((123)I-IMP) single photon emission computed tomography (SPECT). METHODS: Six patients with PAF (all men; mean (SD) age 68+/-5 years) who had experienced autonomic symptoms for more than 5 years and six age-matched healthy control subjects (all men; mean (SD) age 67+/-5 years) were included in this study. The regions of interest (ROI) on spacially normalized (123)I-IMP SPECT images were automatically computed for both groups. RESULTS: Perfusion of the dorsal anterior cingulate cortex was decreased in the PAF group compared with the healthy control group (0.93 vs 1.01; p<0.001). In the other brain regions measured, there was no significant difference in regional perfusion between the two groups. CONCLUSIONS: The dorsal anterior cingulate cortex is poorly perfused and may be functionally altered in patients with PAF. The reduced perfusion in such individuals may be a secondary change that results from chronic autonomic failure.

Sudomotor, skin vasomotor, and cardiovascular reflexes in 3 clinical forms of Lewy body disease.

OBJECTIVE: To elucidate the differences among dementia with Lewy bodies (DLB), Parkinson disease with dementia (PDD), and Parkinson disease without dementia (PD), with respect to the involvement of the autonomic nervous system, we clinically investigated the cutaneous and cardiovascular autonomic functions in patients with Lewy body disease. METHODS: We studied 36 patients with Lewy body disorders, including 12 patients with DLB (age, 75.4 +/- 5.9 years), 12 patients with PDD (71.0 +/- 6.8 years), and 12 patients with PD (70.9 +/- 4.2 years), and 12 healthy control subjects (69.9 +/- 5.3 years). Sympathetic sweat response (SSwR) and skin vasomotor reflex (SkVR) on the palm were recorded to estimate the cutaneous sympathetic function, and the head-up tilt test was performed and coefficient of variation of R-R intervals (CV(R-R)) was studied to estimate the cardiovascular function. RESULTS: The patients with DLB, patients with PDD, and patients with PD showed severely reduced SSwR amplitudes, significantly lower than that in the controls. The mean SkVR amplitudes in the patients with DLB and patients with PDD were significantly lower than that in the controls, but not in the patients with PD. The mean decreases in the systolic blood pressure during the head-up tilt test in the patients with DLB and patients with PDD were less than that in the controls. The mean CV(R-R) value was significantly lower in the patients with DLB. CONCLUSION: Sudomotor function on the palm may be severely affected in Lewy body disorders, while skin vasomotor function and the cardiovascular system may be more severely affected in dementia with Lewy bodies and Parkinson disease with dementia than in Parkinson disease.

Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET.

OBJECTIVE: To characterize brain cholinergic deficits in Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB). METHODS: Participants included 18 patients with PD, 21 patients with PDD/DLB, and 26 healthy controls. The PD group consisted of nine patients with early PD, each with a disease duration of less than 3 years, five of whom were de novo PD patients, and nine patients with advanced PD, each with a disease duration greater than or equal to 3 years. The PDD/DLB group consisted of 10 patients with PDD and 11 patients with DLB. All subjects underwent PET scans with N-[11C]-methyl-4-piperidyl acetate to measure brain acetylcholinesterase (AChE) activity. Brain AChE activity levels were estimated voxel-by-voxel in a three-compartment analysis using the arterial input function, and compared among our subject groups through both voxel-based analysis using the statistical parametric mapping software SPM5 and volume-of-interest analysis. RESULTS: Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = -12%) (false discovery rate-corrected p value <0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = -27%) (p < 0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced. CONCLUSIONS: Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies.

Clinical and brain MR imaging features focusing on the brain stem and cerebellum in patients with myoclonic epilepsy with ragged-red fibers due to mitochondrial A8344G mutation.

SUMMARY: We report 3 patients with myoclonic epilepsy with ragged-red fibers (MERRF) diagnosed by mitochondrial A8344G mutation. Cerebellar ataxia was the first symptom in all patients. Conventional brain MR imaging showed atrophy of the superior cerebellar peduncles and the cerebellum in all patients and brain stem atrophy in 2 patients. In diffusion tensor analysis, fractional anisotropy of the superior cerebellar peduncles was mildly decreased in 1 patient. There was a discrepancy between clinical disabilities (severe) and radiologic abnormalities (mild). This discrepancy and atrophy of the superior cerebellar peduncles and the cerebellum may be important findings suggesting a diagnosis of MERRF.

Skin vasomotor reflex responses in two contrasting groups of autonomic failure: multiple system atrophy and pure autonomic failure.

BACKGROUND & AIM: A variety of stimuli such as deep inspiration, isometric exercise and mental arithmetic, result in a transient vasoconstriction,mediated by sympathetic efferent nerves, in the skin of the fingers and toes of healthy controls (Skin Vasomotor Reflex: SkVR). Multiple system atrophy (MSA) and pure autonomic failure (PAF) provide contrasting models of autonomic failure. In MSA the lesion is central and preganglionic, whilst in PAF the lesion site is peripheral and postganglionic. We evaluated the SkVR in response to various stimuli in MSA and PAF, to determine differences in skin vasomotor involvement between these two patient groups. METHODS: 25 subjects (10 MSA, 7 PAF, 8 healthy controls) were studied. Baseline recordings of skin blood flow were obtained with a laser Doppler probe on the left index finger pulp and forearm. The subject then underwent a variety of stimuli with rest periods in between to reestablish baseline SkBF. These stimuli were: single deep inspiration (inspiratory gasp); mental arithmetic; bilateral leg elevation and cutaneous cold. RESULTS: Healthy control subjects demonstrated marked SkVRs on the finger pulp to each of the stimuli of a magnitude similar to those seen in previous studies, but no SkVRs on the forearm. In MSA SkVRs to inspiratory gasp on the finger pulp were reduced relative to controls. In PAF SkVRs were reduced relative to controls or MSA. The magnitude of SkVR response to gasp and cutaneous cold in PAF was significantly less than in healthy controls. In addition, the magnitude of the response in PAF was significantly less than in MSA for inspiratory gasp. CONCLUSIONS: PAF showed a decreased SkVR response to all 4 stimuli, the response being significantly less than controls (for inspiratory gasp and cutaneous cold) or MSA (cutaneous cold inspiratory gasp). The decreased responses in PAF may reflect the extensive postganglionic sympathetic denervation seen in this group. The measurement of SkVR may therefore provide a non-invasive aid to the differentiation of MSA and PAF.

Heat-provoked skin vasodilatation in innervated and denervated trunk dermatomes in human spinal cord injury.

STUDY DESIGN: Cross-sectional, observational, controlled study. OBJECTIVE: High spinal cord injury (SCI) results in disruption of sympathetic vasomotor control. Vasodilatation as a response to local heating is a biphasic mechanism: the first phase (neurogenic) is mediated by the axon-reflex and is modulated by activity of sympathetic nerves. Our objective was to determine whether the response to heat provocation in trunk dermatomes may provide a measure of vasomotor sympathetic function in SCI. SETTING: National Spinal Injuries Centre, Stoke Mandeville Hospital, Buckinghamshire, UK; Autonomic Unit, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Neurovascular Medicine Unit, Imperial College London at St Mary's Hospital, UK. SUBJECTS: A total of 30 subjects were studied; 18 had chronic complete SCI (level C6-T11) and 12 were healthy controls. METHODS: Recordings of skin blood flow (SkBF) were obtained with thermostatic laser Doppler probes placed in the upper trunk (at C4) and lower trunk (T10 or T12) dermatomes. RESULTS: SkBF at baseline (SkBF(bas)) and SkBF at the first peak of vasodilatation (SkBF(max)) showed no significant differences between SCI and controls either in upper or lower trunk dermatomes. However, the ratio of SkBF(max)/SkBF(bas) was significantly different in lower trunk dermatomes in SCI at C6-T5 level (7.5+/-3.5 PU) compared to SCI at T6-T11 level (3.5+/-1.5 PU) (P < 0.01). CONCLUSION: Measurement of SkBF in response to local heating may provide a safe, noninvasive method to assess integrity of sympathetic spinal pathways to the local vasculature. This may aid the classification of the SCI lesions, as the autonomic component currently is not included in the accepted American Spinal Injury Association scoring.

Impaired circadian rhythm of gastric myoelectrical activity in patients with multiple system atrophy.

In order to evaluate gastric motility and its circadian rhythm in patients with multiple system atrophy (MSA) and healthy control subjects, we measured gastric myoelectrical activity (GMA) for 24 hours using a cutaneous electrogastrogram (EGG) recorder in 14 MSA patients and 9 age-matched controls. We analyzed six 10-minute segments of EGG before and after each meal and two 20-minute EGG segments during sleep; three parameters were used for the analysis: dominant frequency (DF), instability coefficient of dominant frequency (ICDF), and dominant power (DP). DF increased during daytime and decreased during sleep in the control, while this circadian variation was blunted in the patients with MSA. The average DF of the eight segments in the MSA patients did not differ from that of the control. Both MSA patients and control subjects did not show the circadian variation of ICDF and DP. The average ICDF of the eight segments in the patients with MSA was significantly decreased when compared with that of the control (p < 0.01). No differences were observed in DP between the two groups. This study indicates that the healthy subjects appear to have a circadian rhythm of DF, and the patients with MSA appear to have impaired circadian rhythm of DF and decreased ICDF possibly due to the degeneration of the central autonomic neurons.

Lower urinary tract function in dementia of Lewy body type.

OBJECTIVE: Dementia of Lewy body (DLB) type is the second commonest degenerative cause of dementia and autonomic dysfunction has been recognised in DLB. Lower urinary tract (LUT) function in DLB has not been fully delineated. We investigated LUT function in DLB by evaluating clinical and urodynamic data. METHODS: We examined 11 patients (eight men, three women; age range 65-81; disease duration 2-14 years) with probable DLB. Urodynamic studies consisted of: measurement of postvoid residual in all patients, uroflowmetry in five, and electromyography (EMG) cystometry in seven. RESULTS: All patients had symptoms of LUT: urinary incontinence (urgency type/functional type due to dementia and immobility/both urgency and stress type in 7/2/1 patients, respectively); night-time frequency; urgency; and daytime frequency and voiding difficulty. Seven had postvoid residuals, and three had residual urine volume >100 ml. Decreased urinary flow was seen in all five and detrusor overactivity in 5/7 patients who underwent flowmetry and EMG cystometry, respectively. Low compliance detrusor (storage phase, n = 2; with bethanechol supersensitivity), an underactive detrusor (n = 4), an acontractile detrusor (n = 1), and detrusor-sphincter dyssynergia (voiding phase) (n = 1) were also seen; 2/3 patients who underwent motor unit potential analysis had neurogenic changes. CONCLUSION: LUT dysfunction is a common feature in DLB, not only due to dementia and immobility, but also to central and peripheral types of somato-autonomic dysfunction.

Post-micturitional hypotension in patients with multiple system atrophy.

BACKGROUND: Patients with multiple system atrophy (MSA) occasionally have episodes of syncope or pre-syncope after micturition. OBJECTIVE: To clarify the mechanism of these episodes by investigating the haemodynamic changes associated with micturition. METHODS: 25 patients with probable MSA and 16 age matched normal controls were studied. Continuous records of blood pressure and heart rate were made during water cystometry, along with the Valsalva manoeuvre, head up tilt testing, measurement of plasma noradrenaline, and calculation of coefficient of variance of RR intervals. RESULTS: Compared with normal controls, MSA patients had a lower baseline blood pressure, smaller blood pressure and heart rate increases during bladder filling, and an abnormal fall in blood pressure for a longer duration after voiding, resulting in significantly lower blood pressure than at baseline (mean systolic blood pressure reduction -15.2 mm Hg), and hypotension compared with control blood pressure (-29.0 mm Hg). The blood pressure fall was greater in patients with micturition syncope/pre-syncope than in those without. It was also greater in patients with abdominal straining resulting from difficulty in voiding. Other cardiovascular indices did not correlate with the fall in blood pressure. CONCLUSIONS: Hypotension after voiding in MSA patients may result from generalised autonomic dysfunction and abnormal abdominal straining, resulting in micturition syncope.

Requirement of the Caenorhabditis elegans RapGEF pxf-1 and rap-1 for epithelial integrity.

The Rap-pathway has been implicated in various cellular processes but its exact physiological function remains poorly defined. Here we show that the Caenorhabditis elegans homologue of the mammalian guanine nucleotide exchange factors PDZ-GEFs, PXF-1, specifically activates Rap1 and Rap2. Green fluorescent protein (GFP) reporter constructs demonstrate that sites of pxf-1 expression include the hypodermis and gut. Particularly striking is the oscillating expression of pxf-1 in the pharynx during the four larval molts. Deletion of the catalytic domain from pxf-1 leads to hypodermal defects, resulting in lethality. The cuticle secreted by pxf-1 mutants is disorganized and can often not be shed during molting. At later stages, hypodermal degeneration is seen and animals that reach adulthood frequently die with a burst vulva phenotype. Importantly, disruption of rap-1 leads to a similar, but less severe phenotype, which is enhanced by the simultaneous removal of rap-2. In addition, the lethal phenotype of pxf-1 can be rescued by expression of an activated version of rap-1. Together these results demonstrate that the pxf-1/rap pathway in C. elegans is required for maintenance of epithelial integrity, in which it probably functions in polarized secretion.

PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations.

The authors performed linkage analysis in 39 families with autosomal recessive early-onset PD (AR-EOPD) negative for parkin and DJ-1 mutations. Eight families including three Japanese, two Taiwanese, one Turkish, one Israeli, and one Philippine showed evidence of linkage with PARK6 with multipoint log of the odds (lod) score of 9.88 at D1S2732. The results indicate worldwide distribution of PARK6-linked parkinsonism.

Primary Sjogren's syndrome presenting with generalized autonomic failure.

A 64 year-old woman developed Raynaud's phenomenon and dry eyes/mouth. Laboratory examination revealed positive Schirmer's test, rheumatoid factor and anti-nuclear antibody, and lymphocytic sialoadenitis on salivary gland biopsy. These features strongly suggested the diagnosis of primary Sjogren's syndrome. Three years later, she gradually developed generalized autonomic failure without apparent sensory neuropathy on nerve conduction study. She had systolic pressure fall of 51 mmHg on head-up tilt test, cardiovascular supersensitivity to diluted norepinephrine infusion, cardiac denervation in [123I]-MIBG scintigraphy, impaired R-R variability, decreased sweating and prolonged colonic transit time. Autoimmune autonomic ganglionopathy was mostly responsible for her autonomic failure.