Christian Lettieri

Paroxysmal itch caused by gain-of-function Nav1.7 mutation

Summary A novel clinical syndrome is described, characterized by paroxysmal itch and ensuing burning pain triggered by warmth and spicy food associated with a gain‐of‐function Nav1.7 variant. ABSTRACT Itch is a common experience. It can occur in the course of systemic diseases and can be a manifestation of allergies or a consequence of diseases affecting the somatosensory pathway. We describe a kindred characterized by paroxysmal itch caused by a variant in SCN9A gene encoding for the Nav1.7 sodium channel. Patients underwent clinical and somatosensory profile assessment by quantitative sensory testing, nerve conduction study, autonomic cardiovascular reflex, and sympathetic skin response examination, skin biopsy with quantification of intraepidermal nerve fiber density, and SCN9A mutational analysis. The index patient, her mother, and a sister presented with a stereotypical clinical picture characterized by paroxysmal itch attacks involving the shoulders, upper back, and upper limbs, followed by transient burning pain, and triggered by environmental warmth, hot drinks, and spicy food. Somatosensory profile assessment demonstrated a remarkably identical pattern of increased cold and pain thresholds and paradoxical heat sensation. Autonomic tests were negative, whereas skin biopsy revealed decreased intraepidermal nerve fiber density in 2 of the 3 patients. All affected members harbored the 2215A>G I739V substitution in exon 13 of SCN9A gene. Pregabalin treatment reduced itch intensity and attack frequency in all patients. The co‐segregation of the I739V variant in the affected members of the family provides evidence, for the first time, that paroxysmal itch can be related to a mutation in sodium channel gene.

Brain Interstitial Nociceptin/Orphanin FQ Levels are Elevated in Parkinson's Disease

Expression and release of nociceptin/orphanin FQ (N/OFQ) are elevated in the substantia nigra reticulata of 6‐hydroxydopamine‐hemilesioned rats, suggesting a pathogenic role for N/OFQ in Parkinsons disease. In this study, we investigated whether elevation of N/OFQ expression in 6‐hydroxydopamine‐hemilesioned rats selectively occurs in substantia nigra and whether hypomotility following acute haloperidol administration is accompanied by a rise in nigral N/OFQ levels. Moreover, to prove a link between N/OFQ and idiopathic Parkinsons disease in humans, we measured N/OFQ levels in the cerebrospinal fluid of parkinsonian patients undergoing surgery for deep brain stimulation. In situ hybridization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (compacta +160%, reticulata +105%) and subthalamic nucleus (+45%), as well as reduction in caudate putamen (−20%). No change was observed in globus pallidus, nucleus accumbens, thalamus, and motor cortex. Microdialysis coupled to the bar test allowed to demonstrate that acute administration of haloperidol (0.8 and 3 mg/kg) increased nigral N/OFQ levels (maximally of +47% and +53%, respectively) in parallel with akinesia. A correlation with preclinical studies was found by analyzing N/OFQ levels in humans. Indeed, N/OFQ levels were found to be ∼3.5‐fold elevated in the cerebrospinal fluid of parkinsonian patients (148 fmol/ml) compared with nonparkinsonian neurologic controls (41 fmol/ml). These data represent the first clinical evidence linking N/OFQ to idiopathic Parkinsons disease in humans. They strengthen the pathogenic role of N/OFQ in the modulation of parkinsonism across species and provide a rationale for developing N/OFQ receptor antagonists as antiparkinsonian drugs.

Surgery for insular low-grade glioma: predictors of postoperative seizure outcome.

OBJECT Although a number of recent studies on the surgical treatment of insular low-grade glioma (LGG) have demonstrated that aggressive resection leads to increased overall patient survival and decreased malignant progression, less attention has been given to the results with respect to tumor-related epilepsy. The aim of this investigation was to evaluate the impact of volumetric, histological, and intraoperative neurophysiological factors on seizure outcome in patients with insular LGG. METHODS The authors evaluated predictors of seizure outcome with special emphasis on both the extent of tumor resection (EOR) and the tumors infiltrative pattern quantified by computing the difference between the preoperative T2- and T1-weighted MR images (ΔVT2T1) in 52 patients with preoperative drug-resistant epilepsy. RESULTS The 12-month postoperative seizure outcome (Engel class) was as follows: seizure free (Class I), 67.31%; rare seizures (Class II), 7.69%; meaningful seizure improvement (Class III), 15.38%; and no improvement or worsening (Class IV), 9.62%. Poor seizure control was more common in patients with a longer preoperative seizure history (p < 0.002) and higher frequency of seizures (p = 0.008). Better seizure control was achieved in cases with EOR ≥ 90% (p < 0.001) and ΔVT2T1 < 30 cm(3) (p < 0.001). In the final model, ΔVT2T1 proved to be the strongest independent predictor of seizure outcome in insular LGG patients (p < 0.0001). CONCLUSIONS No or little postoperative seizure improvement occurs mainly in cases with a prevalent infiltrative tumor growth pattern, expressed by high ΔVT2T1 values, which consequently reflects a smaller EOR.

Clinical outcome of deep brain stimulation for dystonia: constant-current or constant-voltage stimulation? A non-randomized study.

Bilateral globus pallidus deep brain stimulation (GPi‐DBS) represents an effective and relatively safe therapy for different forms of refractory dystonia. The aim of this study was to assess, retrospectively, the effect of two different stimulation settings during GPi‐DBS in 22 patients affected by primary generalized or multi‐segmental dystonia.

Botulinum neurotoxin serotype D is poorly effective in humans: An in vivo electrophysiological study

OBJECTIVE Botulinum neurotoxins act on nerve endings and block neurotransmitter release. Their potency is due to their enzymatic activity and high affinity binding to neurons. Botulinum toxin type A is used in the treatment of human diseases characterized by hyperactivity of peripheral cholinergic nerve terminals, but some patients are or become resistant to it. This can be overcome by using other botulinum toxins, and studies have been performed with different toxin serotypes. Botulinum neurotoxin type D has never been tested in humans in vivo, and, therefore, we investigated the action of this toxin in mouse and human muscles. METHODS Botulinum toxin type D potency was determined on mouse hemidiaphragm and on rat neuronal cultures. From these experiments, doses to be injected in human volunteers were decided. The compound muscle action potential of toxin-injected Extensor Digitorum Brevis muscle was measured at different times points after injection in human volunteers. RESULTS Botulinum toxin type D is poorly effective in inducing human skeletal muscle paralysis. CONCLUSIONS Botulinum toxin type D is very potent in mice and almost ineffective in humans in vivo. SIGNIFICANCE The results shed new light on the mechanism of toxin type D binding to the neuronal surface receptors.

Switching from constant voltage to constant current in deep brain stimulation: A multicenter experience of mixed implants for movement disorders

For many years deep brain stimulation (DBS) devices relied only on voltage‐controlled stimulation (CV), but recently current‐controlled devices have been developed and approved for new implants as well as for replacement of CV devices after battery drain. Constant‐current (CC) stimulation has been demonstrated to be effective in new implanted parkinsonian and dystonic patients, but the effect of switching to CC therapy in patients chronically stimulated with CV implantable pulse generators (IPGs) has not been assessed. This report shows the results of a consecutive retrospective data collection performed at five Italian centers before and after replacement of constant‐voltage with constant‐current DBS devices, in order to verify the clinical efficacy and safety of this procedure.

Microsubthalamotomy improves sleep in patients affected by advanced Parkinson's disease.

BACKGROUND Deep brain stimulation of the subthalamic nucleus (STN-DBS) improves sleep in patients affected by Parkinsons disease (PD). Since microsubthalamotomy (mSTN) shows positive effects on motor symptoms, it could improve sleep in PD patients. Our goals were: to assess the effects of mSTN on sleep in patients affected by advanced PD; and to look for a correlation between sleep and motor features after the neurosurgical procedure. METHODS Fifteen patients who underwent bilateral STN-DBS were enrolled. Subjective sleep evaluation was assessed using the Parkinsons Disease Sleep Scale (PDSS). Data on sleep schedule and presence of restless legs syndrome (RLS) were obtained. Objective sleep features were investigated by polysomnography (PSG). To evaluate the mSTN effect, we compared motor state and sleep features before and after the neurosurgical procedure, before the programmable pulse generator was switched on. RESULTS mSTN had beneficial effects on motor state and sleep features. After the surgery, the mean total PDSS score increased from 84.0±25.2 to 115.2±16.6 (P<0.001). PD patients reported longer total sleep time duration, decreased daytime sleepiness, and improvement in RLS symptoms. PSG data showed an increase in total sleep time and sleep efficiency with a decrease in wakefulness after sleep onset and arousal index. No correlation between motor improvements and sleep features modifications was observed after mSTN. CONCLUSIONS mSTN improves sleep quality and ameliorates several sleep complaints, as well as motor symptoms, in advanced PD patients who have undergone STN-DBS.

Levodopa/carbidopa intestinal gel (LCIG) therapy for advanced Parkinson's Disease: An early toxic effect for small nerve fibers?

Introduction: Peripheral neuropathy related to levodopa/carbidopa intestinal gel (LCIG) therapy for advanced Parkinson disease (PD) is under investigation and is debated in the literature. The purpose of the study was to detect whether small nerve fibers are damaged during LCIG infusion. Methods: Five advanced PD patients were enrolled prior to starting LCIG infusion. Six PD patients on oral levodopa (LD) treatment and 6 PD patients naïve to LD were also enrolled. Clinical examination, the Quantitative Sensory Testing battery testing, nerve conduction studies, and intraepidermal nerve fiber density examinations were collected at baseline and at 3, 6, and 12 months after LCIG infusion was started in the study cohort. Results: After 3, 6, and 12 months, severe skin denervation and increased thermal thresholds were observed in the LCIG group. Conclusions: Significant damage to small nerve fibers was detected in PD patients soon after LCIG infusion had started, suggesting careful monitoring of small fiber impairment during LCIG is needed. Muscle Nerve, 2016 Muscle Nerve 54: 970–972, 2016

Unusual Parsonage-Turner syndrome with relapses and bilateral simultaneous anterior interosseous neuropathy.

We report an unusual case of Parsonage–Turner syndrome with relapses and simultaneous bilateral anterior interosseous neuropathy (AIN). A 66-year-old man, after a typical right brachial amyotrophic neuralgia few months previously, underwent surgery for left carpal tunnel syndrome. The day following surgery, wrist aching and bilateral weakness, even if prevalent on the right side, on thumb and index finger flexion appeared. Neurophysiology was consistent with bilateral AIN neuropathy and serology revealed anti-nucleus antibody positivity. Association of relapses with bilateral acute AIN involvement in the subject with autoantibody detection can suggest an immunological pathogenesis.

Second Surgery in Insular Low-Grade Gliomas

Background. Given the technical difficulties, a limited number of works have been published on insular gliomas surgery and risk factors for tumor recurrence (TR) are poorly documented. Objective. The aim of the study was to determine TR in adult patients with initial diagnosis of insular Low-Grade Gliomas (LGGs) that subsequently underwent second surgery. Methods. A consecutive series of 53 patients with insular LGGs was retrospectively reviewed; 23 patients had two operations for TR. Results. At the time of second surgery, almost half of the patients had experienced progression into high-grade gliomas (HGGs). Univariate analysis showed that TR is influenced by the following: extent of resection (EOR) (P < 0.002), ΔVT2T1 value (P < 0.001), histological diagnosis of oligodendroglioma (P = 0.017), and mutation of IDH1 (P = 0.022). The multivariate analysis showed that EOR at first surgery was the independent predictor for TR (P < 0.001). Conclusions. In patients with insular LGG the EOR at first surgery represents the major predictive factor for TR. At time of TR, more than 50% of cases had progressed in HGG, raising the question of the oncological management after the first surgery.