Pain-Related Vertex Evoked Potentials. Comparison of Surface Electrical to Heat Stimulation.

INTRODUCTION: Demonstration of nociceptive fiber abnormality is important for diagnosing neuropathic pain and small fiber neuropathies. This is usually assessed by brief heat pulses using lasers, contact heat, or special electrodes. We hypothesized that pain-related evoked potentials to conventional surface electrical stimulation (PREPse) can index Aδ afferences despite tactile Aß fibers coactivation. PREPse may be more readily used clinically than contact heat evoked potentials (CHEPS). METHODS: Twenty-eight healthy subjects. Vertex (Cz-A1/A2) recordings. Electrical stimulation of middle finger and second toe with conventional ring, and forearm/leg skin with cup, electrodes. Contact heat stimulation to forearm and leg. Compression ischemic nerve blockade. RESULTS: PREPse peripheral velocities were within the midrange of Aδ fibers. N1-P1 amplitude increased with pain numerical rating scale graded (0-10) electrical stimulation (n = 25) and decreased with increasing stimulation frequency. Amplitudes were unchanged by different presentation orders of four stimulation intensities. PREPse N1 (∼130 milliseconds) and N2 (∼345 milliseconds) peaks were approximately 40 milliseconds earlier than that with CHEPS. PREPse and CHEPS N1-N2 interpeak latency (∼207 milliseconds) were similar. PREPse became unrecordable with nerve blockade of Aδ fibers. CONCLUSIONS: PREPse earlier N1 and N2 peaks, and similar interpeak N1-N2 latencies and central conduction velocities, or synaptic delays, to CHEPS are consistent with direct stimulation of Aδ fibers. The relation of vertex PREPse amplitude and pain, or the differential effects of frequency stimulation, is similar to pain-related evoked potential to laser, special electrodes, or contact heat stimulation. The relationship to Aδ was validated by conduction velocity and nerve block. Clinical utility of PREPse compared with CHEPS needs validation in somatosensory pathways lesions.

Analysis of muscle magnetic resonance imaging of a large cohort of patient with VCP-mediated disease reveals characteristic features useful for diagnosis.

BACKGROUND: The diagnosis of patients with mutations in the VCP gene can be complicated due to their broad phenotypic spectrum including myopathy, motor neuron disease and peripheral neuropathy. Muscle MRI guides the diagnosis in neuromuscular diseases (NMDs); however, comprehensive muscle MRI features for VCP patients have not been reported so far. METHODS: We collected muscle MRIs of 80 of the 255 patients who participated in the "VCP International Study" and reviewed the T1-weighted (T1w) and short tau inversion recovery (STIR) sequences. We identified a series of potential diagnostic MRI based characteristics useful for the diagnosis of VCP disease and validated them in 1089 MRIs from patients with other genetically confirmed NMDs. RESULTS: Fat replacement of at least one muscle was identified in all symptomatic patients. The most common finding was the existence of patchy areas of fat replacement. Although there was a wide variability of muscles affected, we observed a common pattern characterized by the involvement of periscapular, paraspinal, gluteal and quadriceps muscles. STIR signal was enhanced in 67% of the patients, either in the muscle itself or in the surrounding fascia. We identified 10 diagnostic characteristics based on the pattern identified that allowed us to distinguish VCP disease from other neuromuscular diseases with high accuracy. CONCLUSIONS: Patients with mutations in the VCP gene had common features on muscle MRI that are helpful for diagnosis purposes, including the presence of patchy fat replacement and a prominent involvement of the periscapular, paraspinal, abdominal and thigh muscles.

Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population.

Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy.

Novel autosomal dominant TPM3 mutation causes a combined congenital fibre type disproportion-cap disease histological pattern.

Tropomyosin 3 (TPM3) gene mutations associate with autosomal dominant and recessive nemaline myopathy 1 (NEM1), congenital fiber type disproportion myopathy (CFTD) and cap myopathy (CAPM1), and a combination of caps and nemaline bodies. We report on a 47-year-old man with polyglobulia, restricted vital capacity and mild apnea hypopnea syndrome, requiring noninvasive ventilation. Physical assessment revealed bilateral ptosis and facial paresis, with high arched palate and retrognathia; global hypotonia and diffuse axial weakness, including neck and upper and lower limb girdle and foot dorsiflexion weakness. Whole body MRI showed a diffuse fatty replacement with an unspecific pattern. A 122 gene NGS neuromuscular disorders panel revealed the heterozygous VUS c.709G>A (p.Glu237Lys) on exon 8 of TMP3. A deltoid muscle biopsy showed a novel histological pattern combining fiber type disproportion and caps. Our findings support the pathogenicity of the novel TPM3 variant and widen the phenotypic gamut of TMP3-related congenital myopathy.

Review of techniques useful for the assessment of sensory small fiber neuropathies: Report from an IFCN expert group.

Nerve conduction studies (NCS) are an essential aspect of the assessment of patients with peripheral neuropathies. However, conventional NCS do not reflect activation of small afferent fibers, including Aδ and C fibers. A definitive gold standard for laboratory evaluation of these fibers is still needed and therefore, clinical evaluation remains fundamental in patients with small fiber neuropathies (SFN). Several clinical and research techniques have been developed for the assessment of small fiber function, such as (i) microneurography, (ii) laser evoked potentials, (iii) contact heat evoked potentials, (iv) pain-related electrically evoked potentials, (v) quantitative thermal sensory testing, (vi) skin biopsy-intraepidermal nerve fiber density and (vii) corneal confocal microscopy. The first five are physiological techniques, while the last two are morphological. They all have advantages and limitations, but the combined use of an appropriate selection of each of them would lead to gathering invaluable information for the diagnosis of SFN. In this review, we present an update on techniques available for the study of small afferent fibers and their clinical applicability. A summary of the anatomy and important physiological aspects of these pathways, and the clinical manifestations of their dysfunction is also included, in order to have a minimal common background.

La brucelosis en el diagnóstico diferencial de las meningitis asépticas: a propósito de un caso

Aseptic meningitis represents a diagnostic challenge for the clinician. Cytological and chemical parameters are key in the differential diagnosis. Hypoglycorrhachia is a strong predictor of a bacterial origin for aseptic meningitis. We report a 44-year-old male with a history of recurrent febrile headaches admitted with fever and delirium. The initial cerebrospinal fluid (CSF) analysis showed low glucose levels. Magnetic resonance imaging did not show abnormalities. The patient was discharged but was admitted again three weeks later with fever, headache and a stiff neck. The CSF was inflammatory with low glucose levels. Serology for brucellosis was positive. The patient was treated with ceftriaxone and rifampicin with a good clinical response.

Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice.

BACKGROUND: Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus. METHODS: Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated. RESULTS: Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer. CONCLUSIONS: Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.

[Aseptic meningitis caused by brucellosis. Report of one case]. / La brucelosis en el diagnóstico diferencial de las meningitis asépticas: a propósito de un caso.

Aseptic meningitis represents a diagnostic challenge for the clinician. Cytological and chemical parameters are key in the differential diagnosis. Hypoglycorrhachia is a strong predictor of a bacterial origin for aseptic meningitis. We report a 44-year-old male with a history of recurrent febrile headaches admitted with fever and delirium. The initial cerebrospinal fluid (CSF) analysis showed low glucose levels. Magnetic resonance imaging did not show abnormalities. The patient was discharged but was admitted again three weeks later with fever, headache and a stiff neck. The CSF was inflammatory with low glucose levels. Serology for brucellosis was positive. The patient was treated with ceftriaxone and rifampicin with a good clinical response.

Spinal cord infarction with ipsilateral segmental neuropathic pain and flaccid paralysis. A functional role for human afferent ventral root small sensory fibres.

This paper illustrates the cases of two patients with an acute onset of right brachial neuropathic pain, flaccid paralysis and contralateral thermal and thermal pain hypoesthesia, without posterior column impairment nor pyramidal signs below the segmental lesion. MRI showed right sided spinal cord infarction, in the anterior spinal artery territory between C1 and C5 in one patient and between C3 and C7 in the other. Contact Heat Evoked Potentials and Quantitative Thermal Sensory testing are consistent with contralateral, but not ipsilateral, spinothalamic tract involvement. Electromyographic results established ipsilateral segmental denervation and somatosensory evoked responses were consistent with dorsal column sparing. Unilateral anterior cervical spinal cord infarction may present with acute ipsilateral segmental neuropathic pain, lower motor neurone-type weakness, contralateral thermoanalgesia and no pyramidal signs. The ipsilateral pain provides novel evidence that in some instances, ventral roots can play a role in nociception in humans. The infarcted territory may result from occlusion of a sulcal commissural artery or a number of more proximal vessels (including a single or duplicated anterior spinal artery, vertebral arteries or feeding radicular arteries).

Characterization of diabetic neuropathy progression in a mouse model of type 2 diabetes mellitus.

Diabetes mellitus (DM) is one of most common chronic diseases with an increasing incidence in most countries. Diabetic neuropathy (DN) is one of the earliest and main complications of diabetic patients, which is characterized by progressive, distal-to-proximal degeneration of peripheral nerves. The cellular and molecular mechanisms that trigger DN are highly complex, heterogeneous and not completely known. Animal models have constituted a valuable tool for understanding diabetes pathophysiology; however, the temporal course of DN progression in animal models of type 2 diabetes (T2DM) is not completely understood. In this work, we characterized the onset and progression of DN in BKS diabetic (db/db) mice, including the main functional and histological features observed in the human disease. We demonstrated that diabetic animals display progressive sensory loss and electrophysiological impairments in the early-to-mid phases of the disease. Furthermore, we detected an early decrease in intraepidermal nerve fiber (IENF) density in 18-week-old diabetic mice, which is highly associated with sensory loss and constitutes a reliable marker of DN. Other common histological parameters of DN - like Schwann cells apoptosis and infiltration of CD3+ cells in the sciatic nerve - were altered in mid-to-late phases of the disease. Our results support the general consensus that DN evolves from initial functional to late structural changes. This work aimed to characterize the progression of DN in a reliable animal model sharing the main human disease features, which is necessary to assess new therapies for this complex disease. Finally, we also aimed to identify an effective temporal window where these potential treatments could be successfully applied.

Congenital Myasthenic Syndrome due to DOK7 mutations in a family from Chile.

Congenital myasthenic syndromes (CMS) are neuromuscular transmission disorders caused by mutations in genes encoding neuromuscular junction proteins. A 61-year-old female and her older sister showed bilateral ptosis, facial and proximal limb weakness, and scoliosis since childhood. Another female sibling had milder signs, while other family members were asymptomatic. Facial nerve repetitive stimulation in the proband showed decrement of muscle responses. Single fiber EMG revealed increased jitter and blocking. Muscle biopsy showed type 2-fiber atrophy, without tubular aggregates. Mutational analysis in the three affected siblings revealed two compound heterozygous mutations in DOK7: c.1457delC, that predicts p.Pro486Argfs*13 and truncates the protein C-terminal domain, and c.473G>A, that predicts p.Arg158Gln and disruption of the dok7-MuSK interaction in the phosphotyrosine binding (PTB) domain. Unaffected family members carried only one or neither mutation. Discussion: Two of the affected sisters showed marked improvement with salbutamol treatment, which illustrates the benefits of a correct diagnosis and treatment of DOK7-CMS.

Paraneoplastic cerebellar degeneration in a patient with a primary fallopian tube adenocarcinoma. A case report and brief review.

We describe a 65-year-old woman with subacute cerebellar syndrome expressed as severe ataxia, and the presence of anti Purkinje cell antibodies (Anti-Yo). A small adnexal mass was only evident on PET CT with the pathological feature of fallopian tube adenocarcinoma. Anti-Yo antibodies have been strongly associated with paraneoplastic cerebellar degeneration, and nearly always associated to ovarian adenocarcinomas. Few cases have been reported in which this paraneoplastic syndrome has been related to fallopian tube adenocarcinoma. In this report, we discuss this association and its relation with fallopian tube and ovarian carcinoma.

ALS-linked protein disulfide isomerase variants cause motor dysfunction.

Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease.

Cerebral and Cutaneous Involvements of Xanthoma Disseminatum Successfully Treated with an Interleukin-1 Receptor Antagonist: A Case Report and Minireview.

A young male presented with panhypopituitarism (including diabetes insipidus) and temporal lobe epilepsy. A histology specimen of cutaneous papules was diagnostic of non-Langerhans histiocytosis. The diagnosis of xanthoma granulomata was considered based on the clinical and brain MRI findings. Brain lesions significantly worsened over time despite radiotherapy until anakinra induced a complete clinical and radiological remission of all active lesions. Although a single case, the outcome of this patient with xanthoma disseminatum treated with an interleukin-1 receptor antagonist opens and strengthens new and recent physiopathogenic and treatment perspectives for the otherwise difficult-to-treat non-Langerhans cell histiocytosis. Similar results with anakinra have been observed in patients with Erdheim-Chester disease and in multicentric reticulohistiocytosis.

Toward an objective measure of functional disability in dysferlinopathy.

INTRODUCTION: Understanding the natural history of dysferlinopathy is essential to design and quantify novel therapeutic protocols. Our aim in this study was to assess, clinically and functionally, a cohort of patients with dysferlinopathy, using validated scales. METHODS: Thirty-one patients with genetically confirmed dysferlinopathy were assessed using the motor function measure (MFM), Modified Rankin Scale (MRS), Muscle Research Council (MRC) scale, serum creatine kinase (CK) assessment, baseline spirometry data, and echocardiographic and electrophysiologic studies. RESULTS: MFM and MRC scores showed a significant negative correlation with disease duration and inverse correlation with MRS, but not with onset age, clinical phenotype, or CK levels. Percent forced vital capacity (%FVC) correlated negatively with disease duration and onset age. Eight known pathogenic mutations were identified recurrently, 4 of which accounted for 79% of the total. CONCLUSIONS: The results suggest that MFM is a reliable outcome measure that may be useful for longitudinal follow-up in dysferlinopathy. Recurrent mutations suggest a founder effect in the Chilean population.

Resection of cervical ependymoma.

Intramedullary ependymomas are surgically curable tumors. However, their surgical resection poses several challenges. In this intraoperative video we illustrate the main steps for the surgical resection of a cervical intramedullary ependymoma. These critical steps include: adequate exposure of the entire length of the tumor; use of the intraoperative ultrasound; identification of the posterior median sulcus and separation of the posterior columns; Identification of the plane between the spinal cord and the tumor; mobilization and debulking of the tumor and disconnection of the vascular supply (usually from small anterior spinal artery branches). Following these basic steps a complete resection can be safely achieved in many cases. The video can be found here: http://youtu.be/QMYXC_F4O4U.

Actividad espontánea de nociceptores cutáneos en pacientes con neuropatía de fibras delgadas / Spontaneous activity of cutaneous nociceptors in patients with painful polyneuropathy. Report of three patients

Background: Painful polyneuropathy may result from selective impairment of small diameter nerve fibers, while tactile and motor functions are preserved. In these patients clinical and electrophysiological assessment is usually unrevealing. We report three patients with a pure painful polyneuropathy. One of them had neurogenic pruritus additionally. Quantitative sensory analysis disclosed a slight warm hypoesthesia (3/3) and paradoxical hot sensation (2/3) in the feet. Intraneural recordings from the peroneal nerve demonstrated abnormal spontaneous activity in 8 of 17 nociceptive afferents. One of them displayed double firing reflecting impulse multiplication. These results support the notion that patients with pain or pruritus with a distal distribution similar to a polyneuropathy, could have small diameter afferent fiber damage, despite normal function of large diameter fibers.