Foot drop of central origin: a misleading alteration of nerve conduction study

We present a case of foot drop of central origin in a 45-year-old woman who was diagnosed a malignant brain tumor in the motor area. Extensive neurophysiological assessment with nerve conduction study and electromyography (EMG) was performed during the diagnostic process and showed abnormalities which challenged us towards a comprehensive clinical and neurophysiological evaluation

Transcranial magnetic stimulation as a new tool to control pain perception.

Treatment for chronic pain is frequently unsuccessful or characterized by side-effects. The high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has been suggested in the management of refractory chronic pain. Various studies have shown that HF-rTMS sessions of long-duration applied at primary motor cortex induce pain relief through mechanisms of plastic changes. Efficacy of rTMS mostly depends on stimulation parameters, but this aspect requires better characterization. A rationale to target other cortical areas exists. Current data are promising, but a careful analysis of stimulation settings and maintenance treatment design are need

Central Sensitization in the Bladder Pain Syndrome

Introduction: Nociceptive hyper-excitability and Central Sensitization (CS), have been identified as responsible for maintaining pain in several chronic neuropathic pain conditions, among which Bladder pain syndrome (BPS). Aim of the present study was to evaluate in patients with BPS the correlation between CS and the following items pain duration, the number of other CS related diseases, the number of tried treatments for pain and of diagnostic investigations before the proper diagnosis and to identify the cut-off value of the pain delays for predicting the worsening of sensitization. Method: Fifty-eight consecutively BPS outpatients were recruited from 2014 to 2016. They were submitted to Central Sensitization Inventory (CSI), Overactive Bladder Questionnaire (OAB-8v) and visual analogic scale (VAS) for pain. We used a descriptive analysis (mean, standard deviation, range) and Spearman and Kendall test coefficient as correlation index. One-way ANOVA test was used for the comparison between groups. P-value less than 0.05 were required for statistical significance. We used receiver operating characteristic (ROC) curve analysis to retrospectively analyze the association between the years of the disease and pathological values o of CSI. Results: The patients were observed after 13.1 + 11.0 years by the onset of The CSI score was 69.7+15.8. Resulting significantly lower in patients with BPS onset in the last year the correlation between CSI and the disease duration was significant. The number of previous investigations was 3.7 + 2.8while the number of previous treatments for chronic pain was 5.9 + 3.1, resulting significantly related to CSI score. The OAB-8v was 21 + 7.5 (range 2-34). The worsening of the symptoms related to the overactive bladder at OAB-8v was related to a greater CS. After 1,5 years of the onset of the pain the CS show a progressive worsening. The mean number of other diseases (fibromyalgia, irritable bowel syndrome, anxiety or depression, migraine, neck injury, Panic Disorder Attack, chronic fatigue syndrome, temporomandibular joint syndrome, restless leg syndrome, multiple chemical sensitivities) associated to CS was 2.8+1.9. The correlation between the number of diseases associated to CS and the years of disease resulted significant. Conclusion: Patients with long lasting pelvic pain show high levels of CS, and other central sensitivity syndromes (CSS) together to worsening of overactive bladder symptoms, and increasing number of used drugs. The delay of diagnosis is related to a greater sensitization process

Dysphagia in amyotrophic lateral sclerosis: impact on patient behavior, diet adaptation, and riluzole management

This retrospective study aimed to investigate the clinical features associated with deteriorated swallow in amyotrophic lateral sclerosis (ALS) patients with spinal and bulbar onset, describe the modification of diet and liquid intake, and assess the impact of dysphagia on the use of riluzole. One hundred forty-five patients were observed periodically every 3-6 months. They underwent routinely fiberoptic endoscopic evaluation of swallowing (FEES) and spirometry; dysphagia severity was classified according to the Penetration Aspiration Scale and the Pooling score (P-score) integrated with other parameters such as sensation, collaboration, and age (P-SCA score). During a mean follow-up period of about 2 years, the percentage of ALS patients suffering from dysphagia increased to 85 (rising from 35 to 73% in patients with spinal onset and from 95 to 98% in those with bulbar onset). Also, 8% of patients with dysphagia by FEES did not perceive the disorder. The frequency of normal and semi-solid diets decreased over time, while that of pureed diets and percutaneous endoscopic gastrostomy (PEG) prescription increased. Forty-four percent of dysphagic patients refused thickeners or PEG. A significant difference was observed in the mortality rate between patients untreated with riluzole and patients treated with riluzole oral suspension (p < 0.05). Disease duration mainly impacted on the frequency of dysphagia in spinal onset patients, appearing very early in those with bulbar onset. Riluzole oral suspension would allow the safe administration in dysphagic ALS patients to avoid tablet crushing and consequent dispersion in food, common practices that are inconsistent with the safe and effective use of the drug

The Compound Muscle Action Potential as Neurophysiological Marker for Amyotrophic Lateral Sclerosis.

Objectives: To definite the peripheral nervous involvement in ALS through the repeated use of the compound motor action potential (CMAP) to test the progression of disease, to determine different change of phrenic CMAP and forced vital capacity (FVC) in spinal and bulbar onset, and to establish clinical and neurophysiological features of patients with poor prognosis. Material & Methods: CMAP from phrenic, ulnar, and medial plantar nerves, Medical Research Council (MRC) score, revised ALS functional rating scale (ALSFRS-R) and FVC were evaluated in 117 ALS patients every three months in one year-period. Results: Bulbar onset patients had lower FVC but similar amplitude of phrenic CMAP at baseline compared to spinal onset patients. The patients with poor prognosis had lower phrenic CMAP and FVC at baseline. CMAP values, when compared to the rate found in the previous visit, reduced significantly in both poor and good prognosis groups during the entire follow-up period, while the FVC reduced significantly only in the first three months. Conclusions: CMAP is a reproducible sensitive marker for motor neurons loss and collateral reinnervation in ALS also in a short period of time. The changes in CMAP, MRC, FVC and ALSFRS-R score resulted correlated, but CMAP is the only parameter with the advantage to demonstrate objectively the progression of disease in both patients with poor and good prognosis for the entire period of follow-up. It should be used as clinical outcome of ALS in clinical trials, taking advantage of its objectivity and selectivity for peripheral nervous system study

Parkinson's disease: autoimmunity and neuroinflammation

Parkinson's disease is a neurodegenerative disease that causes the death of dopaminergic neurons in the substantia nigra. The resulting dopamine deficiency in the basal ganglia leads to a movement disorder that is characterized by classical parkinsonian motor symptoms. Parkinson's disease is recognized as the most common neurodegenerative disorder after Alzheimer's disease. PD ethiopathogenesis remains to be elucidated and has been connected to genetic, environmental and immunologic conditions. The past decade has provided evidence for a significant role of the immune system in PD pathogenesis, either through inflammation or an autoimmune response. Several autoantibodies directed at antigens associated with PD pathogenesis have been identified in PD patients. This immune activation may be the cause of, rather than a response to, the observed neuronal loss. Parkinsonian motor symptoms include bradykinesia, muscular rigidity and resting tremor. The non-motor features include olfactory dysfunction, cognitive impairment, psychiatric symptoms and autonomic dysfunction. Microscopically, the specific degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are brain deposits containing a substantial amount of α-synuclein, have been recognized. The progression of Parkinson's disease is characterized by a worsening of motor features; however, as the disease progresses, there is an emergence of complications related to long-term symptomatic treatment. The available therapies for Parkinson's disease only treat the symptoms of the disease. A major goal of Parkinson's disease research is the development of disease-modifying drugs that slow or stop the neurodegenerative process. Drugs that enhance the intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay treatment for motor symptoms. Immunomodulatory therapeutic strategies aiming to attenuate PD neurodegeneration have become an attractive option and warrant further investigation

Glutamate-mediated blood-brain barrier opening. implications for neuroprotection and drug delivery

The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. SIGNIFICANCE STATEMENT: In this study, we reveal a new mechanism that governs blood-brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders

RNA Interference and Neuromuscular Diseases: A Focus on Hereditary Transthyretin Amyloidosis

: Neuromuscular diseases are severe disorders affecting the peripheral nervous system, usually driving to death in a limited time. Many new drugs, through RNA-interference technology, are revolutionizing the prognosis and quality of life for these patients. Nevertheless, given the increased life expectancy, some new issues and phenotypes are expected to be revealed. In the transthyretin-mediated hereditary amyloidosis (ATTR-v, "v" for "variant"), the RNA interference was demonstrated to effectively reduce the hepatic synthesis of transthyretin, with a significant increase in disease progression in terms of polyneuropathy and cardiomyopathy. The increased life expectancy could promote the involvement of organs where the extra-hepatic transthyretin is deposited, such as the brain and eye, which are probably not targeted by the available treatments. All these issues are discussed in this editorial

Laryngeal sensitivity in patients with amyotrophic lateral sclerosis

Recent studies have shown the involvement of the sensory nervous system in patients with amyotrophic lateral sclerosis (ALS). The aim of our study was to investigate the correlation between the laryngeal sensitivity deficit and the type of ALS onset (bulbar or spinal) in a large series of 114 consecutive ALS patients. Participants were subdivided into two groups, bulbar and spinal ALS, according to the clinical onset of disease and submitted to a clinical and instrumental evaluation of swallowing, including a fiber-optic endoscopic evaluation of swallowing with sensory testing. Dysphagia severity was scored using the Penetration–Aspiration Scale (PAS) and the Pooling score (P-score). In addition, three patients with laryngeal sensitivity deficit were submitted to a laryngeal biopsy to assess the status of the sensory innervation. All patients showed a normal glottal closure during phonation and volitional cough. Fifty-six subjects (49%), 14 spinal- and 42 bulbar-onset ALS, showed dysphagia at the first clinical observation (PAS score >1; P-score >5). Dysphagia resulted more frequently in bulbar-onset ALS (P < 0.01). Thirty-eight (33%) patients had a sensory deficit of the larynx. The sensory deficit of the larynx was significantly more frequent in bulbar-onset ALS (P < 0.01). The sensory deficit of the larynx among dysphagic patients was also significantly more frequent in bulbar-onset ALS (P = 0.02). Several abnormalities were found in all three subjects who underwent a laryngeal biopsy: in one patient, no intraepidermal fiber was found; in the other two, the fibers showed morphological changes. Our observations are important to consider for assessment and management of dysphagia in patients with AL