The aim of this study was to characterize the expression in skin nerves of native (n-syn) and misfolded or phosphorylated (p-syn) α-synucleins in pure autonomic failure (PAF) and idiopathic Parkinson disease (IPD). We studied 30 patients, including 16 well-characterized IPD, 14 patients fulfilling PAF diagnostic criteria, and 15 age-matched controls. Subjects underwent skin biopsy from cervical, thigh and leg sites to study small nerve fibers and intraneural n-syn and p-syn. PAF and IPD both showed a skin denervation, more severely expressed in patients with higher p-syn load. N-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not found in controls, but it was disclosed in all PAF and IPD patients with different skin innervation. In addition, abnormal α-syn deposits were found in all analysed skin samples in PAF, but in 49% of samples only with higher positivity rate in the cervical site in IPD. In conclusion: (1) intraneural p-syn was a reliable in vivo marker of PAF and IPD; (2) neuritic p-syn inclusions differed in PAF and IPD, suggesting a different underlying pathogenesis; (3) searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF, but it is critical in IPD.

The object of this study is to investigate whether: (1) phosphorylated α-synuclein (p-syn) deposits in peripheral nerves might represent a useful biomarker in dementia Lewy Body (DLB) helping to differentiate DLB from other forms of dementia; (2) small fiber neuropathy (SFN) may be part of DLB pathological picture contributing to autonomic dysfunctions. 20 well-characterized DLB patients (11 of them complaining autonomic symptoms particularly orthostatic hypotension) were studied together with 23 patients with dementia of different pathogenesis (Dementia without synuclein- DWS) including 13 patients fulfilling diagnostic criteria for Alzheimer’s disease, 6 with Frontotemporal Dementia and 4 with vascular dementia. Twenty-five age-matched healthy subjects served as controls. Subjects underwent: nerve conduction velocities from the leg to evaluate large nerve fibers; skin biopsy from proximal (i.e. cervical) and distal (i.e. thigh and distal leg) sites to study small nerve fibers and deposits of phosphorylated α-synuclein, considered the pathological form of α-synuclein. P-syn was not found in any skin sample in DWS patients and controls but it was found in all DLB patients with a proximal-distal gradient with all patients positive in the cervical site. Patients complaining of autonomic symptoms showed higher widespread positivity of analyzed skin samples than patients without autonomic symptoms. Furthermore DLB patients showed a length-dependent SFN particularly important in patients complaining autonomic symptoms. Conclusions: (1) p-syn in peripheral nerves is a sensitive biomarker for DLB diagnosis helping to differentiate DLB from other forms of dementia; (2) SFN was part of DLB pathological picture contributing to induce autonomic symptoms.

Conflicting data have been reported on resting autonomic tone in narcolepsy with cataplexy (NC) including both reduced or increased sympathetic activity. To settle this important point we measured muscle nerve sympathetic activity (MSNA) and cardiovascular activities in NC patients during wakefulness. We studied 19 NC untreated patients and 19 sex-age matched controls. Subjects underwent resting microneurographic recording of MSNA from peroneal nerve and heart rate (HR) whereas blood pressure (BP) was measured with a sphygmomanometer after the end of microneurographic recording. The awake state was continuously monitored by an ambulatory polygraphic recorder. NC patients displayed significantly lower resting MSNA, HR and BP values than controls. Pearson regression analysis showed a significant correlation between CSF hypocretin-1 level and MSNA or HR whereas no correlation was found with BP; however patients with virtually absent hypocretin-1 displayed lower BP than patients with the highest hypocretin-1 value. (1) NC patients displayed decreased resting MSNA, HR and BP during wakefulness lowering their cardiovascular risk profile; (2) a positive correlation supported a direct effect of CSF hypocretin-1 deficiency on MSNA or HR regulation; (3) although hypocretin-1 was not correlated with BP, patients with absent hypocretin-1 had lower BP.

This study aimed to test whether peripheral α-synuclein staining might be useful for pure autonomic failure (PAF) diagnosis helping to differentiate degenerative from acquired peripheral autonomic neuropathy. We studied 21 patients with chronic peripheral autonomic neuropathy. Twelve patients showed a specific cause of neuropathy (acquired autonomic neuropathy – AAN) whereas nine had no specific acquired causes fulfilling the diagnostic criteria for PAF. Fifteen matched healthy subjects served as controls. Subjects underwent skin biopsy from thigh and leg to study skin innervation and phosphorylated α-synuclein deposits in the peripheral axons. Somatic and autonomic skin innervations were significantly decreased in peripheral autonomic neuropathy patients compared to controls. No differences were found between AAN and PAF. The deposits of α-synuclein were not found in controls but served to distinguish acquired from degenerative autonomic peripheral neuropathy: all pure autonomic failure patients showed α-synuclein deposits in the postganglionic sympathetic adrenergic and cholinergic nerve fibers which were absent in acquired autonomic neuropathy patients. Our study demonstrated that a search for neuritic inclusions of phosphorylated α-synuclein in the skin sympathetic nerve fibers could provide a sensitive in vivo biomarker for degenerative peripheral autonomic neuropathy and may shed more light on the PAF pathogenesis.

2021 Background: The role of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) in elderly pts with GBM remains unclear. We therefore evaluated the efficacy of this approach in pts >70 years in the context of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in neuro-oncology. Methods: The criteria for selecting pts enrolled in the PERNO study were: age >70 years; PS 0-3; histologically confirmed GBM; postoperative radiotherapy after surgery; residence in the Emilia Romagna region. Data were collected prospectively. Results: Pts accrual, started on January 1 2009, was closed, as planned, on December 31 2010. In the pts enrolled (n=53), median overall survival (mOS) was 11.1 months (95% CI: 8.8 - 13.5); survival rates at 1-, 2- and 3-years were 41.5% (95% CI: 28.2 – 54.8%), 15.2% (95% CI: 4.8 – 25.6%) and 6.1% (95%CI: 0 – 15.9%), respectively. Twenty-eight pts received RT/TMZ, and 25 pts RT alone. mOS was 11.6 months (95% CI: 8.6 – 14.6) following RT/TMZ and 9.3 months (95% CI: 8.1 – 10.6) following RT alone. mOS for pts with MGMT methylated status (n = 17) was 13.5 months (95% CI: 7.7 – 19.2), being 17.2 months (95% CI: 11.5 - 22.9) in those treated with RT/TMZ (n = 6) and 8.8 months (95% CI: 2 – 15.6) in those treated with RT alone (n = 11, p = 0.09). Elderly pts with MGMT unmethylated status (n = 25) had a mOS of 8.5 months (95% CI: 6 – 11, p = 0.014), being 8.5 months (95% CI: 2.3 – 14.7) in pts treated with RT/TMZ (n =10), and 8 months (95% CI: 3 – 12.9) in those treated with RT (n = 15, p = 0.55). Conclusions: RT/TMZ appears to be more effective in prolonging the mOS of elderly pts in those with MGMT methylation status (17.2 vs 8.5 months), and seem to perform better than TMZ alone, for which mOS was 9.7 months in the Nordic phase III trial. These findings underline the value of the ongoing randomized EORTC 26062-22061/NCIC CE.6 phase III comparing RT/TMZ with short course RT alone.

BACKGROUND AND PURPOSE:Optic nerve involvement is frequent in mitochondrial disease, and retinal abnormalities are described in Parkinson's disease (PD). METHODS:We evaluated retinal nerve fiber layer (RNFL) thickness by optical coherence tomography in 43 patients with PD and in 86 age-matched controls. We considered separately the eyes ipsilateral and contralateral to the most affected body side in patients with PD. ancova analysis, Pearson test, and multiple regression analysis were used (P < 0.05). RESULTS:Patients with PD showed significantly thinner temporal RNFL thickness compared to controls (P = 0.004), more evident in the eye contralateral to the most affected body side. Average RNFL thickness significantly correlated with age in both controls and patients with PD (P-values ranging from 0.001 to 0.019), whereas in patients with PD RNFL thickness did not correlate with clinical variables. CONCLUSIONS:Our study reveals a loss of retinal nerve fibers in the temporal quadrant in PD, which is typically susceptible in mitochondrial optic neuropathies.

OBJECTIVES:Ross syndrome (RS) is a rare degenerative disorder characterized by tonic pupil, areflexia and anhydrosis. The underlying lesion affects postganglionic skin sympathetic nerve fibers whereas the postganglionic muscle sympathetic branch is thought to be spared. Microneurography explores both skin and muscle peripheral sympathetic branches and it does not usually detect peripheral sympathetic outflow in either branch in chronic autonomic failure syndromes. The aim of this study was to record sympathetic activity by microneurography for the first time in RS patients to confirm the selective involvement of skin sympathetic nerve activity (SSNA) with spared muscle sympathetic nerve activity (MSNA). METHODS:We studied seven patients (49 ± 14 years, four males) with a typical clinical picture and skin biopsy findings. Patients underwent cardiovascular reflexes and microneurography from the peroneal nerve (anhydrotic skin) to record MSNA, SSNA and the corresponding organ effector responses (skin sympathetic response-SSR and skin vasomotor response-SVR) in the same innervation field. The absence of sympathetic bursts was established after exploring at least three different corresponding nerve fascicles. Twenty age-matched healthy subjects served as controls. RESULTS:RS patients complained of diffuse anhydrosis and they showed tonic pupil and areflexia. Cardiovascular reflexes were normal. All patients displayed absent SSNA, SSR and SVR whereas MSNA was always recorded showing normal characteristics. CONCLUSION:Microneurographic study of sympathetic activity from affected skin confirmed the selective involvement of skin sympathetic activity with spared muscle sympathetic activity and it may represent the neurophysiological hallmark of the disease. SIGNIFICANCE:Microneurography together with clinical and skin biopsy findings may contribute to RS diagnosis. Our data also suggest that autonomic damage in RS does not involve cardiovascular activity.

We aimed to compare apparent steady-state oral clearance (CL/F) of the antiepileptic drug levetiracetam (LEV) in elderly (66–80 years, n = 105) and very elderly (81–96 years, n = 70) vs nonelderly (30–65 years, n = 97) patients with epilepsy. Median weight-normalized CL/F (mL min−1 kg−1) decreased from 1.23 (nonelderly) to 0.83 (elderly) and 0.59 (very elderly) (p < 0.001). LEV CL/F significantly declines with aging, elderly and very elderly patients requiring an about 30% and 50% lower dose, respectively, compared to nonelderly adults to achieve a given LEV plasma concentration.

Despite the burden of chronic daily headache (CDH), general practitioners' (GPs) ability to recognize it is unknown. This work is a sub-study of a population-based study investigating GPs' knowledge on their CDH patients. Patients diagnosed with CDH through the screening questionnaire were interviewed by their GPs who indicated if subjects were known as patients suffering from CDH with medication overuse (MO), CDH without MO, episodic headache (EH) or non-headache sufferers. Our study showed that 64.37 % of CDH sufferers are misdiagnosed by their GPs. However, overusers are better known to GPs.

Background Pure autonomic failure (PAF) and multiple system atrophy (MSA) are both characterised by chronic dysautonomia although presenting different disability and prognosis. Skin autonomic function evaluation by indirect tests has revealed conflicting results in these disorders. Here, the authors report the first direct analysis of skin sympathetic fibres including structure and function in PAF and MSA to ascertain different underlying autonomic lesion sites which may help differentiate between the two conditions.Methods The authors studied eight patients with probable MSA (mean age 60 +/- 5 years) and nine patients fulfilling diagnostic criteria for PAF (64 +/- 8 years). They underwent head-up tilt test (HUTT), extensive microneurographic search for muscle and skin sympathetic nerve activities from peroneal nerve and punch skin biopsies from finger, thigh and leg to evaluate cholinergic and adrenergic autonomic dermal annexes innervation graded by a semiquantitative score presenting a high level of reliability.Results MSA and PAF patients presented a comparable neurogenic orthostatic hypotension during HUTT and high failure rate of microneurographic trials to record sympathetic nerve activity, suggesting a similar extent of chronic dysautonomia. In contrast, they presented different skin autonomic innervation in the immunofluorescence analysis. MSA patients showed a generally preserved skin autonomic innervation with a significantly higher score than PAF patients showing a marked postganglionic sympathetic denervation. In MSA patients with a long disease duration, morphological abnormalities and/or a slightly decreased autonomic score could be found in the leg reflecting a mild postganglionic involvement.Conclusion Autonomic innervation study of skin annexes is a reliable method which may help differentiate MSA from PAF.

Objective: Agrypnia Excitata (AE) is characterized by autonomic over-activity and cardiovascular fluctuations but direct evidence of sympathoexcitation is lacking. AE is a common feature of acquired (i.e. Morvan's syndrome - MS) and genetic (i.e. fatal familial insomnia - FFI) conditions where a dysfunction of the thalamo-limbic system has been Suggested. The aim of this study is to report the first microneurographic recordings of sympathetic activity in acquired and genetic AE to investigate the pattern of sympathetic activation.Methods: We describe two patients presenting acquired AE (MS) as demonstrated by elevated serum antibody levels to voltage-gated potassium channels and one patient with genetically confirmed FFI. Patients and fifteen sex and age-matched healthy controls underwent microneurography from peroneal nerve to assess muscle sympathetic nerve activity (MSNA) and heart rate (HR).Results: Mean level of resting awake MSNA and HR was significantly increased inpatients compared to controls. Patients presented a similar pattern of MSNA with a normal cardiac rhythmicity and a very high burst incidence expressed in approximately each cardiac beat.Conclusions: Acquired and genetic AE presented a resting awake sympathetic over-activity.Significance: AE patients may develop high blood pressure and/or cardiovascular instability potentially increasing the morbility/mortality of the underlying disorders. (C) 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.