Skin α-synuclein deposits differ in clinical variants of synucleinopathy: an in vivo study.

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. IN CONCLUSION: 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.

A novel presenilin 1 L166H mutation in a pseudo-sporadic case of early-onset Alzheimer's disease.

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.

Cavernous angiomas of the spinal district: surgical treatment of 11 patients.

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.

Intraoperative monitoring of spinal cord SEPs during microsurgical DREZotomy (MDT) for pain, spasticity and hyperactive bladder.

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.

Effects of long term vigabatrin on somatosensory evoked potentials in epileptic patients.

1. Vigabatrin has proved to be a very effective antiepileptic in clinical trials, with excellent long term tolerability. 2. The purpose of this study was to test the central nervous system (CNS) safety of the drug during long term clinical use, due to the existence of species-dependent intramyelinic oedema in animal toxicology studies. 3. Somatosensory evoked potentials were recorded repeatedly over a mean period of 11 months, in 54 adult patients with refractory epilepsy who received vigabatrin as add-on therapy to their current antiepileptic regime. 4. There was no suggestion throughout the study that vigabatrin could lead to a prolongation of neuronal conduction times within the CNS pathways. 5. The results are consistent with previous studies of somatosensory, visual and brainstem auditory evoked potentials in patients. In view of the results observed in the dog, where increases in central latencies of somatosensory evoked potentials were clearly apparent, these data provide strong reassurance about the neurological safety of vigabatrin in the treatment of epileptic patients.

Effects of long-term vigabatrin on somatosensory-evoked potentials in epileptic patients.

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.

Facilitation of quadriceps motoneurones by group I afferents from pretibial flexors in man. 1. Possible interneuronal pathway.

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).

Facilitation of quadriceps motoneurones by group I afferents from pretibial flexors in man. 2. Changes occurring during voluntary contraction.

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.

Extreme somatosensory evoked potentials (ESEPs) elicited by tapping of hands or feet in children: a somatosensory cerebral evoked potentials study.

Six children with tactile-evoked spikes in the EEG, also defined as extreme somatosensory evoked potentials (ESEPs), underwent an SEPs study in order to define the characteristics of such evoked potentials. Short-latency SEPs showed normal mean latency and amplitude values. Mid- or long-latency SEPs of abnormally high amplitude were recorded after stimulation of one or more extremities. Such extreme responses which showed the same reactivity proper to normal long-latency SEPs could be considered to correspond to the evoked spikes in the EEG.