Edoardo Sessa

Brain-derived neurotrophic factor and TrkB receptor in experimental autoimmune encephalomyelitis and multiple sclerosis

The interaction between the immune and nervous systems can be both detrimental and beneficial. Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune demyelination that histologically and clinically mimics multiple sclerosis (MS). Myelin-reactive T cells produce and release brain-derived neurotrophic factor (BDNF) directly in the central nervous system, which stimulates tissue repair after traumatic injury. In EAE and MS, T cells in the vicinity of actively demyelinating lesions express BDNF, suggesting a neuroinflammatory reaction that is designed to limit brain damage and contribute to the repair process. Despite some evidence supporting MS therapies that enhance BDNF production by immune cells, no published reports have actually demonstrated that increased BDNF production can substantially ameliorate the clinical symptoms of MS. BDNF binds to a small subset of peripheral T cells that express TrkB, which is the BDNF receptor. This binding confers a partial resistance to apoptosis upon T cell activation, which could underlie the chronic nature of the inflammatory process. Here we will review the main aspects of BDNF and TrkB receptor involvement in neuroprotective autoimmunity in both EAE and MS. We will also discuss the latest findings with respect to the role of the BDNF/TrkB axis in regulating the survival of autoreactive T cells, with a focus on potential selectively immunomodulating strategies that may favor neuroprotection in MS.

Splanchnic ischemia and reperfusion injury is reduced by genetic or pharmacological inhibition of TNF-α

In the present study, we used TNF‐α receptor 1 knockout (TNF‐αR1KO) mice to evaluate a possible role of TNF‐α on the pathogenesis of ischemia and reperfusion injury of the multivisceral organs. Ischemia and reperfusion injury was induced in mice by clamping the superior mesenteric artery and the celiac artery for 30 min, followed thereafter by reperfusion. Sixty minutes after reperfusion, animals were killed for histological examination and biochemical studies. Injured wild‐type (WT) mice developed a significant increase of ileum TNF‐α levels, myeloperoxidase activity, and marked histological injury and apoptosis. Ischemia and reperfusion injury of the multivisceral organs was also associated with a significant mortality. Reperfused ileum sections from injured WT mice showed positive staining for P‐selectin, VCAM, ICAM‐1, and E‐selectin. The intensity and degree of P‐selectin, E‐selectin, VCAM, and ICAM‐1 were reduced markedly in tissue sections from injured TNF‐αR1KO mice. Ischemia and reperfusion‐injured TNF‐αR1KO mice also showed a significant reduction of neutrophil infiltration into the intestine, a reduction of apoptosis, an improved histological status of the intestine, and survival. In addition, we investigated the effect of Etanercept, a TNF‐α soluble receptor construct, on ischemia and reperfusion injury of the multivisceral organs. Etanercept (5 mg/kg administered i.p. 5 min prior to reperfusion) significantly reduced the inflammatory response and the ileum injury. Taken together, our results clearly demonstrate that TNF‐α plays an important role in the ischemia and reperfusion injury and put forward the hypothesis that modulation of TNF‐α expression may represent a novel and possible strategy.

Heavy Metals and Neurodegenerative Diseases: An Observational Study

In this study, we evaluated the levels of some of the most investigated metals (Cu, Se, Zn, Pb, and Hg) in the blood of patients affected by the most common chronic neurodegenerative diseases like Alzheimer’s disease (AD) and multiple sclerosis (MS), in order to better clarify their involvement. For the first time, we investigated a Sicilian population living in an area exposed to a potentially contaminated environment from dust and fumes of volcano Etna and consumer of a considerable quantity of fish in their diet, so that this represents a good cohort to demonstrate a possible link between metals levels and development of neurodegenerative disorders. More specifically, 15 patients affected by AD, 41 patients affected by MS, 23 healthy controls, and 10 healthy elderly controls were recruited and subjected to a venous blood sampling. Quantification of heavy metals was performed by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). This technique has allowed us to establish that there is a concomitance of heavy metal unbalance associated with AD more than in other neurodegenerative pathologies, such as MS. Also, we can assess that the concentration of these elements is independent from the diet, especially from occasional or habitual consumption of fruits and vegetables, prevalence in the diet of meat or fish, possible exposure to contaminated environment due both to the occupation and place of residence.

Quantitative Analysis of Pursuit Ocular Movements in Parkinson’s Disease by Using a Video-Based Eye Tracking System

The purpose of this study is to assess the efficacy and the tolerability of a new vision-based non-intrusive eye tracker in a population composed of normal controls and in patients affected by nonadvanced Parkinson’s disease (PD). PD patients characteristically have difficulty in sustaining repetitive motor actions. Previous studies showed a progressive bradykinesia and hypokinesia of pursuit ocular movements (POM) in advanced PD. We found that the values of POM were lower in PD patients than in normal controls (p < 0.001). In PD patients, the values correlated closely with Hoehn and Yahr stage and Unified Parkinson Disease Rating Scale motor subscore (p < 0.001, for both). Our data suggest that deficit in POM occurs also in nonadvanced PD patients and it is closely correlated with clinical scores. Thus, this vision-based system can be considered a new method to provide, noninvasively, measures of POM dysfunctions and can be used as reliable indices of disease severity in PD patients.

Heterogeneous seizure manifestations in Hypomelanosis of Ito: report of four new cases and review of the literature.

Hypomelanosis of Ito (HI) is a rare neuroectodermal disorder often associated with mental retardation and epilepsy. We report on four new HI patients presenting with heterogeneous seizure manifestations and we review the literature concerning epileptic seizures in HI. At one extreme, there are patients with generalized seizures well controlled by drug treatment, whereas at the opposite there are patients with severe, often pharmacoresistant, focal seizures. The genetic substrate for HI syndrome is not homogenous and only partially understood. Further researches are required to shed light on the pathogenesis of HI phenotypes.

Sertraline in the treatment of depressive disorders in patients with Parkinson's disease.

We studied 54 idiopathic Parkinson’s disease (PD) patients with depressive disorders (DD) to compare the efficacy and the effect of treatment with sertraline in the usual formulation and in the liquid oral concentrate (LOC) formulation. After 6 months of sertraline treatment, the Hamilton Depression Rating Scale and the Montgomery and Asberg Depression Rating Scale showed a decrement (p<0.001, for both formulations). Parkinson’s Disease Questionnaire scores improved (p<0.005 for usual formulation and p<0.001 for LOC formulation), as did Clinical Global Impression-Severity of Illness scale and Clinical Global Impression-Global Improvement scale scores (p=0.1, for both formulations). Mini Mental State Examination and Unified Parkinson’s Disease Rating Scale motor subscores did not change. These results suggest that sertraline LOC may also be a useful treatment for DD in PD patients, especially for those with swallowing problems, and have significant benefit for quality of life, without worsening of parkinsonian features.

Sativex in the Management of Multiple Sclerosis-Related Spasticity: Role of the Corticospinal Modulation

Sativex is an emergent treatment option for spasticity in patients affected by multiple sclerosis (MS). This oromucosal spray, acting as a partial agonist at cannabinoid receptors, may modulate the balance between excitatory and inhibitory neurotransmitters, leading to muscle relaxation that is in turn responsible for spasticity improvement. Nevertheless, since the clinical assessment may not be sensitive enough to detect spasticity changes, other more objective tools should be tested to better define the real drug effect. The aim of our study was to investigate the role of Sativex in improving spasticity and related symptomatology in MS patients by means of an extensive neurophysiological assessment of sensory-motor circuits. To this end, 30 MS patients underwent a complete clinical and neurophysiological examination, including the following electrophysiological parameters: motor threshold, motor evoked potentials amplitude, intracortical excitability, sensory-motor integration, and Hmax/Mmax ratio. The same assessment was applied before and after one month of continuous treatment. Our data showed an increase of intracortical inhibition, a significant reduction of spinal excitability, and an improvement in spasticity and associated symptoms. Thus, we can speculate that Sativex could be effective in reducing spasticity by means of a double effect on intracortical and spinal excitability.

Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis

OBJECTIVE The aim of our study was to better investigate the role of Sativex(®) in improving pain in multiple sclerosis (MS) patients by means of either clinical or neurophysiological assessment. SETTING Pain is a common symptom of MS, affecting up to 70% of patients. Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results. Clinical pain assessment in MS is very difficult, and more objective tools are necessary to better quantify this symptom and its potential response to the treatments. SUBJECTS AND METHODS We enrolled 20 MS patients (10 with and 10 without neuropathic pain), who underwent a specific clinical (such as visual analog scale) and neurophysiological assessment (by means of laser-evoked potentials and transcranial magnetic stimulation), before and after 4 weeks of Sativex administration. RESULTS One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life. Interestingly, such effects were paralleled by an increase of fronto-central γ-band oscillation and of pain-motor integration strength. CONCLUSIONS Our data suggest that Sativex may be effective in improving MS-related neuropathic pain, maybe through its action on specific cortical pathways.

Topiramate modulation of R3 nociceptive reflex in multiple sclerosis patients suffering paroxysmal symptoms

Sirs: Painful paroxysmal symptoms (PS) have been linked with multiple sclerosis (MS) ever since the earliest reports of the disease; they include trigeminal neuralgia, painful tonic spasms and dysesthetic or paresthetic symptoms [7, 14]. Topiramate (TPM) is a third generation, well-tolerated antiepileptic drug [13] found to be effective for refractory intercostal neuralgia [1] and trigeminal neuralgia in MS patients [15]. No neurophysiological evaluation of the effects of TPM on PS in MS has been performed. A close relationship has been found between the subjective sensation of pain, the R3 component of the blink reflex and the pain threshold on electrical stimulation of the supraorbital nerve [9–12]. Not all authors accept this reflex as a measure with which to evaluate pain [5]. However, no neurophysiological test regarding pain measurement is at present accepted by all authors. Previously, we studied this reflex in MS patients and found it to be a good tool for evaluating the nociceptive system in this disease without [3] and with [2] antiepileptic drug therapy. In order to reduce these limitations, we evaluated the effects of TPM on the nociceptive system of MS patients suffering PS, by means of the R3 component of the blink reflex associated with the Visual Analogue Scale (VAS) [4]. A study was performed on 13 clinically diagnosed [8] MS patients (Table 1), 5 males, 8 females (mean age 37.2 years), with Expanded Disability Status Scale (EDSS) score [6] between 1.5 and 7.0 (mean 4,2). All were suffering PS with VAS ≥ 6: 4 had trigeminal neuralgia, 5 painful tonic spasms, and 4 dysesthetic-paresthetic symptoms. All were being followed up as outpatients at the MS Ambulatory of Study and Treatment Center for Long-Stay Neurological Patients (of the Chair of Neurophysiopathology, University of Messina). None of the patients were in relapse at the time of the study, nor had they experienced a relapse for at least one month, nor had they been treated with any drugs for at least one month. R3 reflex and the VAS were performed at TPM therapy onset day (before the first administration) and after 12 weeks’ treatment, all at the same hour. TPM was administered twice daily. The initial dose was 50 mg/day. The daily dose was increased by 50 mg each week until the optimal one was achieved (good response: VAS ≤ 3, no severe and persistent, > 24 hours, side effects). Prior to the R3 reflex recording, the patients were informed about the procedure of the test in order to obtain their maximum collaboration. They were asked to lie supine on a bed in a quiet room with their eyes closed and to relax. The room temperature was maintained between 22–24°C. The skin surface was cleaned carefully prior to application of the surface electrodes, which were tightly fixed to the skin with electrolytic gel. The skin temperature was maintained at 32–34°C. The right supraorbital nerve was transcutaneously stimulated by surface electrodes. The cathode was placed over the supraorbital notch on the right; the anode was placed 2 cm higher and rotated laterally at an oblique angle to avoid spread of current to the controlateral supraorbital nerve. Stimulation consisted of a 300 Hz train of rectangular pulses, 20 ms train duration (6 stimuli), 0.1 ms LETTER TO THE EDITORS

Neuropsychological findings in patients with Unverricht–Lundborg disease

The aims of this study were to clarify if patients with Unverricht-Lundborg disease (ULD) have adequate cognitive functioning and to delineate their neuropsychological profile. We evaluated 20 patients with ULD and 20 healthy, matched controls. Mean age of the patients was 35 years, and mean duration of disease, 22 years. Patients underwent a neuropsychological battery exploring intelligence, executive functions, visuospatial and verbal memory, depression, and anxiety. Eleven of 20 subjects with ULD had mild to moderate cognitive impairment. Compared with controls, patients with ULD had lower scores on all short-term memory and executive function tasks. Linear regression analysis disclosed significant associations between impaired performance on some memory tests and duration of disease and between severity of myoclonus and performance on most executive function tests. In conclusion, most patients with ULD seem to be impaired with respect to cognitive abilities. Longitudinal prospective studies are needed to confirm and further expand our findings.