We aimed to characterize in vivo α-synuclein (α-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify ...the clinical variability. We studied multiple skin nerve α-syn deposits in 44 patients with synucleinopathy: 15 idiopathic Parkinson's disease (IPD), 12 dementia with Lewy Bodies (DLB), 5 pure autonomic failure (PAF) and 12 multiple system atrophy (MSA). Ten healthy subjects were used as controls. Antibodies against native α-syn, C-terminal α-syn epitopes such as phosphorylation at serine 129 (p-syn) and to conformation-specific for α-syn mature amyloid fibrils (syn-F1) were used. We found that p-syn showed the highest sensitivity and specificity in disclosing skin α-syn deposits. In MSA abnormal deposits were only found in somatic fibers mainly at distal sites differently from PAF, IPD and DLB displaying α-syn deposits in autonomic fibers mainly at proximal sites. PAF and DLB showed the highest p-syn load with a widespread involvement of autonomic skin nerve fibers.
1) p-syn in skin nerves was the optimal marker for the in vivo diagnosis of synucleinopathies; 2) the localization and load differences of aggregates may help to identify specific diagnostic traits and support a different pathogenesis among synucleinopathies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Sudden unexpected death in epilepsy (SUDEP) represents the main cause of death in patients with refractory epilepsy. A number of mechanisms have been proposed, including seizure-induced asystolia. We ...report two new patients with ictal asystolia revealed by long-term video-EEG monitoring. Case 1. A 76 year-old male with 1 year history of sudden falls to the ground associated with loss of consciousness, pallor and sweating, sometimes preceded by an olfactory hallucination. EEG: left temporal spikes. MRI: cerebral vascular changes. Case 2. A 55 year-old male with a 10 year history of focal seizures characterized by epigastric aura and loss of contact, more recently followed by sudden falls to the ground with pallor and stiffening. EEG: left temporal spikes. MRI: left temporal dysplasia. The video-EEG monitoring allowed to capture a number of seizures originating from the left temporal lobe and associated with ictal asystolia lasting for 10–20 s, with a corresponding syncope-like EEG picture. Focal seizures complicated by ictal asystolia may be suspected on clinical grounds by the appearance of syncope-like events preceded by typical epileptic auras. Long-term video-EEG recording is the gold standard to detect these events which may require pacemaker implantation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Cavernous angiomas, also called cavernous malformations or cavernomas, are vascular hamartomas accounting for 3-16% of all angiomatous lesions of the spinal district. Although histologically ...identical, these vascular anomalies may exhibit different clinical behavior and radiological features, depending on their location, hinting at different managements and therapeutic approaches. The authors report 11 cases of symptomatic spinal cavernous angiomas diagnosed and surgically treated over the past 18 years. Age of patients ranged from 15-75 years; males outnumbered females. Three patients had vertebral cavernous malformations, secondarily invading the epidural space; two had pure epidural lesions; two patients had intradural extramedullary lesions, and four intramedullary lesions. Surgical removal was completely achieved in four patients with intramedullary lesions, in two with subdural extramedullary lesions, and in one with a pure epidural lesion. Subtotal excision of another one epidural and three vertebral cavernous angiomas was followed by radiotherapy. There was no morbidity related to surgery; the mean follow-up was 2 years. The outcome was excellent in two cases, good in six, and unchanged in the other three. The authors discuss the different modalities of treatment of these vascular lesions variously placed along the spine.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Intraneural misfolded α-synuclein (syn) characterized different synucleinopathies such as pure autonomic failure (PAF), idiopathic Parkinson disease (IPD) and dementia with Lewy Bodies (DLB). The aim ...of this study is to characterize by immunofluorescence the skin intraneural α-synuclein (syn) deposits in PAF, IPD and DLB to ascertain conformation-specific differences which may justify a different clinical phenotype.
We identified a total of 21 skin intraneural abnormal syn deposits in PAF (3 patients), 22 in IPD (8 patients) and 40 in DLB (7 patients). Ten healthy subjects were used controls. Skin biopsy was performed on proximal (C7 paravertebral) and distal (thigh and leg) sites. To characterize abnormal syn deposits we used primary antibodies against native α-synuclein (NAC) and against C-terminal α-synuclein epitopes involved in post-translational modifications such as phosphorylation at serine 129 (pS129) and tyrosine 125 (pY125), nitrate α-synuclein at tyr125-133 (nY125-133) and advanced glycation end products (AGEs). Furthermore, the mature amyloid α-synuclein fibrils were characterized by using a non-commercial antibody (Syn-F) and ubiquitin deposits were identified by a specific antibody (UBI).
Antibody raised against pS129 disclosed abnormal skin nerves syn deposits in all patients and never in the control group. Abnormal pS129 syn deposits were often (80–90% of all analysed deposits) stained by the antibody recognizing a fibril conformation, seldom (around 40%) by native antibodies and very occasionally by antibodies against nY125-133. Furthermore, abnormal syn deposits were not stained by antibodies against pY125, AGEs and UBI. The immunofluorescence characterization of abnormal syn deposits showed similar findings in IPD, PAF and DLB although in these latter abnormal deposits were quantitatively higher than in IPD.
Phosphorylation at serine 129 was the most sensitive and specific epitope to identify skin nerves abnormal syn deposits for the in vivo diagnosis of synucleinopathies; (2) skin syn neuritis showed no relevant immunofluorescence differences in PAF, IPD and DLB suggesting a similar conformation among different clinical phenotypes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We report a 44-year-old woman presenting at 33 years with memory loss, followed by progressive dementia. Her family history was negative for dominant genetic disorders at high penetrance. Analysis of ...presenilin-1 gene revealed a missense mutation at codon 166, leading to the substitution from leucine to histidine. The mutation occurs in the third transmembrane domain of presenilin-1, at the position of two different mutations previously described, associated with an atypical phenotype. The present case has two implications: (1) mutations of presenilin-1 have to be searched also in apparently sporadic cases of dementia beginning in the third decade of life; (2) as yet unidentified factors, besides the gamma-secretase complex, influence the phenotype of presenilin-1 mutations.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The neuronal pathway of the facilitation of quadriceps (Q) motoneurones (MNs) evoked by stimulation of the common peroneal nerve (CPN) has been reinvestigated using both the post-stimulus time ...histogram (PSTH) method for measurement of the firing probability of individual units and the H reflex technique. It has been found that Ia (and to an unknown extent Ib) afferents from pretibial flexors - but not from peroneal muscles - are responsible for this excitation. The central latency of the CPN-induced excitation of Q MNs was estimated to be 3-3.7 ms longer than that of their monosynaptic Ia excitation. To further investigate the neuronal pathway of the CPN-induced excitation the spatial facilitation technique was used, the effects on the Q H reflex of two conditioning stimuli (applied to the CPN and the femoral nerve - FN) being compared when applied separately and together. When the two conditioning volleys were timed to reach the spinal cord simultaneously the facilitation of the H reflex on combined stimulation was larger than the algebraic sum of the effects by separate stimuli in 40% of the cases. It is argued that this additional facilitation reflects summation at a premotoneuronal level and it is concluded that non-monosynaptic Ia excitation of Q MNs from Q and pretibial flexors is, at least partly, mediated through a common pathway. In those individual units in which stimulation of the FN and/or the CPN evoked a non-monosynaptic Ia excitation, this excitation was reduced on combined stimulation of the two nerves. It is argued that this reflects inhibition of the interneurones mediating the excitation, i.e. consists in a disfacilitation of the MNs. It is suggested that the non-monosynaptic (homonymous and heteronymous) Ia excitation of Q MNs in man (and the inhibition of this excitation) is mediated through a system of neurones similar to the system recently described in the cat by Edgley and Jankowska (1987).
Since 1972, MDT has been performed in 234 patients with chronic pain, 140 with hyperspasticity and 12 with hyperactive neurogenic bladder. In the last 64 patients, the evoked electrospinogram has ...been recorded intraoperatively from the surface of the spinal cord, to monitor the electrophysiological effects produced by the surgical lesioning, not only on the conduction of lemniscal fibers when entering the dorsal column, but also on the postsynaptic responses of the dorsal horn cells. The decrease in amplitude of the latter responses (N13 or N22) was well correlated with (1) the depth and the width of the DREZ lesion, and (2) the number of spinal segments operated on. In most cases, amplitude was reduced in the order of 2/3, which was considered the best value.
The facilitation of the quadriceps (Q) H reflex evoked by stimulation of group I afferents from pretibial flexors exhibits biphasic changes during Q voluntary contraction. At short conditioning-test ...intervals the facilitation is increased, whereas it is decreased at longer intervals and/or at high conditioning stimulus intensities and/or when the contraction strength is increased. The spatial facilitation at a premotoneuronal level observed at rest on combined stimulation - common peroneal nerve (CPN) and femoral nerve (FN) - regularly disappeared during contraction. It is argued that the increase in facilitation at the onset of the weakest Q contraction reflects a descending facilitation of the interneurones mediating the CPN-induced excitation to Q MNs. An occlusion of descending and peripheral excitation in these interneurones can easily account for the depression of the facilitation when the conditioning stimulus intensity and/or the strength of the contraction is increased. However, occlusion cannot explain all the results and inhibition of the neurones mediating excitation of MNs, i.e. disfacilitation of the MNs, probably contributes to the decrease in facilitation observed during contraction.
Vigabatrin (gamma vinyl GABA, GVG) has been shown to be an effective antiepileptic agent. GVG specifically and irreversibly inhibits GABA-transaminase (GABA-T). Long-term animal toxicology studies ...have demonstrated that GVG can induce nonprogressive, reversible intramyelinic edema in central white matter tracts. The response to GVG varies among species, with rodents being the most dramatic and monkeys showing an equivocal effect even at high doses. The response in dogs is marked and measurable. The detection of these subtle findings requires the use of sophisticated technology. Evoked potentials are becoming reliable and sensitive tools in clinical neurology. This study, involving 54 patients for 11 months, was undertaken to assess the effect and safety of GVG in humans with refractory epilepsy. No data from this investigation indicate prolongation of neuronal conduction time in CNS pathways, suggesting that this agent is safe in humans.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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