Differential involvement of A-delta and A-beta fibres in neuropathic pain related to carpal tunnel syndrome

Carpal tunnel syndrome (CTS), a common entrapment neuropathy involving the median nerve at the wrist, frequently manifests with neuropathic pain. We sought information on pain mechanisms in CTS.We studied 70 patients with a diagnosis of CTS (117 CTS hands). We used the DN4 questionnaire to select patients with neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to assess the intensity of the various qualities of neuropathic pain. All patients underwent a standard nerve conduction study (NCS) to assess the function of non-nociceptive Aβ-fibres, and the cutaneous silent period (CSP) after stimulation of the IIIrd and Vth digits, to assess the function of nociceptive Aδ-fibres. In 40 patients (75 CTS hands) we also recorded laser-evoked potentials (LEPs) in response to stimuli delivered to the median nerve territory and mediated by nociceptive Aδ-fibres. We sought possible correlations between neurophysiological data and the various qualities of neuropathic pain as assessed by the NPSI.We found that the median nerve sensory conduction velocity correlated with paroxysmal pain and abnormal sensations, whereas LEP amplitude correlated with spontaneous constant pain.Our findings suggest that whereas paroxysmal pain and abnormal sensations reflect demyelination of non-nociceptive Aβ-fibres, spontaneous constant pain arises from damage to nociceptive Aδ-fibres.     

Ovarian hormones and cortical excitability. An rTMS study in humans.

OBJECTIVE: Ovarian steroids influence neural excitability. Using repetitive transcranial magnetic stimulation (rTMS) we investigated changes in cortical excitability during the menstrual cycle. METHODS: Eight women underwent rTMS on Days 1 and 14 of the menstrual cycle. As a control group, 8 age-matched men were also tested twice, with a 14-day interval between the two experimental sessions. Repetitive magnetic pulses were delivered in trains of 10 stimuli (5 Hz frequency and 120% of the motor threshold calculated at rest) to the left motor area of the first dorsal interosseous muscle. RESULTS: In women, the motor evoked potential (MEP) size did not increase on Day 1, but it increased progressively during the train on Day 14. The duration of the silent period progressively lengthened during the train on both days. In men the MEP increased in size, and the silent period lengthened to a similar extent on both days. CONCLUSIONS: In women, hormone changes related to the menstrual cycle alter cortical excitability. SIGNIFICANCE: Low estrogen levels probably reduce cortical excitability because their diminished action on sodium channels reduces recruitment of excitatory interneurons during rTMS thus abolishing the MEP facilitation.     

Physiological characterization of human muscle acetylcholine receptors from ALS patients

Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons leading to muscle paralysis. Research in transgenic mice suggests that the muscle actively contributes to the disease onset, but such studies are difficult to pursue in humans and in vitro models would represent a good starting point. In this work we show that tiny amounts of muscle from ALS or from control denervated muscle, obtained by needle biopsy, are amenable to functional characterization by two different technical approaches: "microtransplantation" of muscle membranes into Xenopus oocytes and culture of myogenic satellite cells. Acetylcholine (ACh)-evoked currents and unitary events were characterized in oocytes and multinucleated myotubes. We found that ALS acetylcholine receptors (AChRs) retain their native physiological characteristics, being activated by ACh and nicotine and blocked by α-bungarotoxin (α-BuTX), d-tubocurarine (dTC), and galantamine. The reversal potential of ACh-evoked currents and the unitary channel behavior were also typical of normal muscle AChRs. Interestingly, in oocytes injected with muscle membranes derived from ALS patients, the AChRs showed a significant decrease in ACh affinity, compared with denervated controls. Finally, riluzole, the only drug currently used against ALS, reduced, in a dose-dependent manner, the ACh-evoked currents, indicating that its action remains to be fully characterized. The two methods described here will be important tools for elucidating the role of muscle in ALS pathogenesis and for developing drugs to counter the effects of this disease.     

Repetitive Deep Transcranial Magnetic Stimulation Improves Verbal Fluency and Written Language in a Patient with Primary Progressive Aphasia-Logopenic Variant (LPPA)

BackgroundTo date, no therapies are available for the logopenic variant of primary progressive aphasia (LPPA). Even though deep repetitive transcranial magnetic stimulation (rTMS) may improve cognitive functions in some neurodegenerative disorders, no previous studies investigated its effects in patients with LPPA.ObjectiveOur aim was to investigate the effects on cognitive function of high frequency rTMS (hf-rTMS) delivered over the left dorso-lateral prefrontal cortex (DLPFC) through a coil designed for deep rTMS, compared to a SHAM stimulation, in a right-handed patient with LPPA.MethodsThe patient presented a progressive language impairment (phonological errors in speech and naming, impaired single word retrieval and sentences repetition) and predominant left perisylvian atrophy and hypoperfusion. He received four stimulation cycles (two REAL and two SHAM) each of whom lasted 20 min for 5 consecutive days. Patient's performances in frontal, visuo-spatial and linguistic tasks were evaluated before and after each stimulation session. Test scores after REAL were compared with those obtained at baseline and after SHAM.ResultsWe found a temporary and highly significant improvement in the linguistic skills (both oral and written tasks) but not in the other cognitive domains tested, after REAL, but not SHAM stimulations.DiscussionHf-rTMS delivered over the DLPFC could improve language in LPPA by enhancing long-term potentiation and synaptic plasticity within the stimulated and interconnected areas involved in language network. Our findings might prompt future researches into the feasibility and efficacy of deep hf-rTMS as a therapeutic tool in progressive aphasia syndromes and other neurodegenerative disorders.     

Targeting EGFR in non-small-cell lung cancer: lessons, experiences, strategies

Cancer is a genetic disease and this concept is now widely exploited by both scientists and clinicians to design new targeted molecules. Indeed many data have already allowed us to ameliorate not only our knowledge about cancer onset, but also about patients treatment. Correlation between mutations in cancer alleles and drug response is a key point to identify drugs that match the genetic profile of each individual tumors. On the other hand, experience derived from inhibition of tyrosine kinase receptors has pointed out that targeted treatment is really successful only in a small subset of tumors. The latter are eventually addicted to those genetic alterations which are responsible for receptors activation and for the continued expression of their signalling. Overall these observations provide a strong rationale for a molecular-based diagnosis and patients selection for targeted therapies. This review analyses the current state of the art of molecularly-tailored pharmacological approach to lung cancer, one of the biggest killers among human solid tumors. Main relevance is addressed to genetic lesions activating the EGFR pathway transducers, focusing on their role as markers of targeted drug response.     

Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons that leads to progressive paralysis of skeletal muscle. Studies of ALS have revealed defects in expression of acetylcholine receptors (AChRs) in skeletal muscle that occur even in the absence of motor neuron anomalies. The endocannabinoid palmitoylethanolamide (PEA) modified the clinical conditions in one ALS patient, improving muscle force and respiratory efficacy. By microtransplanting muscle membranes from selected ALS patients into Xenopus oocytes, we show that PEA reduces the desensitization of acetylcholine-evoked currents after repetitive neurotransmitter application (i.e., rundown). The same effect was observed using muscle samples from denervated (non-ALS) control patients. The expression of human recombinant α1β1γδ (γ-AChRs) and α1β1εδ AChRs (ε-AChRs) in Xenopus oocytes revealed that PEA selectively affected the rundown of ACh currents in ε-AChRs. A clear up-regulation of the α1 subunit in muscle from ALS patients compared with that from non-ALS patients was found by quantitative PCR, but no differential expression was found for other subunits. Clinically, ALS patients treated with PEA showed a lower decrease in their forced vital capacity (FVC) over time as compared with untreated ALS patients, suggesting that PEA can enhance pulmonary function in ALS. In the present work, data were collected from a cohort of 76 ALS patients and 17 denervated patients. Our results strengthen the evidence for the role of skeletal muscle in ALS pathogenesis and pave the way for the development of new drugs to hamper the clinical effects of the disease.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease marked by the degeneration of motor neurons. It leads to progressive paralysis ending with the death of the patient 3–5 y after diagnosis. Although most ALS cases are sporadic, about 10% are familial and are linked to monogenic mutations in different genes such as the gene for superoxide dismutase 1 (SOD1), genes encoding RNA-binding proteins such as TARDBP and FUS, or the noncoding region of the poorly characterized C9ORF72 gene (1). These mutations have been used to develop mammalian animal models that mimic some of the symptomatology and to investigate some of the molecular mechanisms of the disease. In mice, as well as in patients, the first observed disease event is the destruction of the neuromuscular junction (NMJ) (2). Studies have uncovered defects in the skeletal muscle that occur even in the absence of motor neuron anomalies, supporting the “dying-back” hypothesis in which distal motor endplate degeneration plays a key role in the progression of the disease (2–4). NMJs of ALS patients consistently show electrophysiological properties distinctly different from those of patients with pure denervation (5, 6). Using muscle biopsies from sporadic ALS patients, we previously characterized the nicotinic acetylcholine currents resulting from the activation of functional acetylcholine receptors (AChRs) (5). Upon denervation, receptors formed by the α1β1γδ (γ-AChR) instead of the α1β1εδ (ε-AChR) subunits appear widely distributed over the entire sarcolemma (7, 8). In ALS patients, in whom muscle denervation and abnormal reinnervation are pathological hallmarks of the disease, both γ- and ε-AChRs are present. In addition, we showed that riluzole, the only approved drug available against ALS, may affect AChR function in ALS muscle (6). These findings strengthen the hypothesis that pathogenic events target the NMJ directly and suggest that its protection could be a useful therapeutic strategy.The cannabinoid system, consisting of cannabinoid (CB) receptors, endocannabinoids (eCBs), and enzymes involved in the synthesis and degradation of these eCBs, has been shown to be a key player in ALS etiology (9, 10). The eCB-related molecule palmitoylethanolamide (PEA) induces anti-inflammatory effects through the PPARα receptor without binding to CB receptors and consequently without side effects (11, 12). Notably, PEA was able to improve pulmonary function and clinical conditions in a single case of ALS (13). Here, taking advantage of the microtransplantation technique by which cell membranes isolated from human muscle are injected into Xenopus oocytes (14), we investigated whether PEA can modulate AChR currents using voltage-clamp intracellular recordings in oocytes transplanted with membranes from ALS muscle. We measured the composition of AChR subunits in ALS muscle compared with non-ALS denervated muscle by quantitative PCR (qPCR) analysis. In addition, we studied the effect of PEA in a cohort of ALS patients to determine whether this compound can improve the clinical characteristics of patients, with particular attention to muscle force and respiratory capacity.     

Urodynamic and neurophysiological evaluation in Parkinson's disease and multiple system atrophy.

AIMS: To determine whether Parkinson's disease and multiple system atrophy each has a distinct pattern of micturition abnormalities and whether a urodynamic evaluation could be useful in the differential diagnosis between the two diseases. METHODS: Sixty two patients (30 with Parkinson's disease and 32 with multiple system atrophy) underwent a complete urodynamic evaluation and neurophysiological testing. RESULTS: Of the parkinsonian patients 36.6% had normal micturition findings with normal bladder sensitivity; 26.7% had delayed or incomplete pelvic floor relaxation; 26.7% had hyperreflexia with vesicosphincteric synergy; and 10% had hyperreflexia with vesicosphincteric synergy associated with incomplete pelvic floor relaxation. Parkinsonian patients with a normal urodynamic pattern had significantly less severe disease and a shorter duration of disease in years than those who had abnormal patterns. Patients with hyperreflexia had significantly higher severity of disease. All the patients with multiple system atrophy had hyperreflexia with synergy. Two urodynamic patterns were identified: hyperreflexia with vesicosphincteric synergy (90.6% of patients), and hyperreflexia with vesicosphincteric synergy and incomplete pelvic floor relaxation (in 9.4%). Hyperreflexia with synergy correlated neither with the severity nor with the duration of disease. Sphincter EMG analysis showed that all the parkinsonian patients had normal sphincter EMG whereas 24 of the 32 patients with multiple system atrophy had neurogenic signs. CONCLUSIONS: Urodynamic evaluation and sphincter EMG are both useful tests in the differential diagnosis between Parkinson's disease and multiple system atrophy. Urodynamic findings may be abnormal before patients with multiple system atrophy reach an advanced stage of the disease. Recordings of EMGs from perineal muscles become abnormal as the disease progresses in multiple system atrophy but not in Parkinson's disease.