Severe Sensory Neuropathy Research Articles

Dystonin-A3 upregulation is responsible for maintenance of tubulin acetylation in a less severe dystonia musculorum mouse model for hereditary sensory and autonomic neuropathy type VI.

Hereditary sensory and autonomic neuropathy type VI (HSAN-VI) is a recessive human disease that arises from mutations in the dystonin gene (DST; also known as Bullous pemphigoid antigen 1 gene). A milder form of HSAN-VI was recently described, resulting from loss of a single dystonin isoform (DST-A2). Similarly, mutations in the mouse dystonin gene (Dst) result in severe sensory neuropathy, dystonia musculorum (Dstdt). Two Dstdt alleles, Dstdt-Tg4 and Dstdt-27J, differ in the severity of disease. The less severe Dstdt-Tg4 mice have disrupted expression of Dst-A1 and -A2 isoforms, while the more severe Dstdt-27J allele affects Dst-A1, -A2 and -A3 isoforms. As dystonin is a cytoskeletal-linker protein, we evaluated microtubule network integrity within sensory neurons from Dstdt-Tg4 and Dstdt-27J mice. There is a significant reduction in tubulin acetylation in Dstdt-27J indicative of microtubule instability and severe microtubule disorganization within sensory axons. However, Dstdt-Tg4 mice have no change in tubulin acetylation, and microtubule organization was only mildly impaired. Thus, microtubule instability is not central to initiation of Dstdt pathogenesis, though it may contribute to disease severity. Maintenance of microtubule stability in Dstdt-Tg4 dorsal root ganglia could be attributed to an upregulation in Dst-A3 expression as a compensation for the absence of Dst-A1 and -A2 in Dstdt-Tg4 sensory neurons. Indeed, knockdown of Dst-A3 in these neurons resulted in a decrease in tubulin acetylation. These findings shed light on the possible compensatory role of dystonin isoforms within HSAN-VI, which might explain the heterogeneity in symptoms within the reported forms of the disease.

VOICE trial: Final results from multicenter phaseII study of assessment of clinical efficiency and safety in capecitabine plus intermittent oxaliplatin together with bevacizumab as first-line therapy for patients with advanced colorectal cancer.

740 Background: The FOLFOX with bevacizumab (B-mab) has been established as a standard first-line therapy for metastatic colorectal cancer (mCRC), and OPTIMOX1 study suggested that stop and go strategy for oxaliplatin reduced peripheral sensory neuropathy. The CapeOx is one of the standard treatments for mCRC that has been proven to be as effective as the FOLFOX regimen. Thus we accessed the efficacy and safety of the combination of intermittent CapeOx + B-mab as a first-line therapy in patients with mCRC in this trial. Methods: Eligibility criteria included ECOG PS: 0–1, No Peripheral neuropathy ( < Grade 1). Patients received CapeOX (oxaliplatin 130mg/m2, capecitabine 2000mg/m2 + B-mab 7.5mg/kg) q3 weeks for 5 cycles, maintenance without oxaliplatin for 5 cycles, and reintroduction CapeOX + B-mab for 5 cycles until progression. Primary endpoint was Progression Free Survival (PFS). Results: Between March 2011 and August 2013, 55 pts were enrolled. Baseline characteristics were median age of 67 years (range, 20–83); PS 0/1 (49/6 pts); male/female (33/22 pts), colon/rectum (28/27pts) and metastatic lesion liver/lung/lymph nodes (32/18/21 pts). A total of 47 pts were evaluated as Par Protocol Set population. 38 pts moved from initial CapeOX to maintenance Capecitabine. 20 pts moved to CapeOx reintroduction. Median PFS was 14.7months (95%CI, 8.6–19.5) and Median TTF was 12.3 months (95%CI, 10.3–14.3). Best overall response rate was 48.0%. Oxaliplatin reintroduction rate was 57.4%. Main grade 3/4 toxicity were: neutropenia (1 pt), anemia (1 pt), peripheral neuropathy (1 pt), allergic reaction of oxaliplatin (1 pt), deep vein thrombosis (1 pt), nausea (1 pt), hand-foot syndrome (1 pt), and hypertension (1 pt). Conclusions: This study met its primary endpoint PFS. CapeOx intermittent oxaliplatin indicated to reduce incidence of severe neutropenia and peripheral sensory neuropathy. The results suggested that our treatment strategy was well tolerate and effective for first line therapy in mCRC, and maintenance duration for 5 cycles, was reasonable. Clinical trial information: UMIN000005732.

Patient-tailored FOLFIRINOX in the first-line treatment of patients (pts) with advanced pancreatic cancer (PC).

499 Background: FOLFIRINOX is an effective reference regimen in the 1st line treatment of advanced PC, despite its high level of toxicity. We report recent data from pts treated with this regimen at Paul Brousse university hospital. Methods: From January to December 2016, 37 pts with advanced PC received patient-tailored FOLFIRINOX as 1st line intent to treat chemotherapy. The first 1 to 3 courses were administered without irinotecan if initial serum bilirubin was ≥ 1.5 x upper limit of normal. Oxaliplatin was stopped for severe sensory neuropathy. Initial dose reductions were made according to pt profile (e.g., age, comorbidity) and later due to toxicity. The treatment was continued until surgery or disease progression. Endpoints were time to progression (TTP), overall survival (OS), objective response rate (ORR) and secondary complete resection (R0R1). Results: There were 22 male (59%) and 15 female pts (41%) aged 44 to 81 years (median: 64). They had locally-advanced (18 pts, 49%) and metastatic PC (19 pts, 51%). PC was head, body, tail located in 24 (65%), 8 (22%) and 5 pts (14%) respectively. Biliary stent was placed in 22 pts (59%). Pts had a performance status (PS) of 0 (60%) or 1 (40%). Median treatment duration was 20 weeks for oxaliplatin, 22 weeks for irinotecan, 23 weeks for 5FU. At the cut-off on April 27th 2017, protocol was ongoing for 11 pts (30%). Median number of cycles was 9 (2-20). Median dose intensity was 29 mg/m2/w for oxaliplatin, 57 mg/m2/w for irinotecan and 886 mg/m2/w for 5FU. We observed 4 CR (11%), 12 PR (32%), 12 SD (32%) and 5 PD (14%). Four pts were not evaluable. ORR was 43%, disease control rate 75%, 11 pts (30%) underwent R0R1 resection. After a median follow-up of 8 months (1 - 16), median TTP and OS were not reached. TTP was associated with body location (HR = 3.5 [95% CL, 1.1-11.0], p = 0.033) and disease stage (HR = 10.5 [2.2-49.5], p = 0.003), a trend was observed with biliary stent placement (HR = 0.4 [0.1-1.1], p = 0.067). Conclusions: Modified FOLFIRINOX with patient-tailored dose adaptations seems to offer better results in pts with advanced PC compared with classic FOLFIRINOX. This strategy deserves prospective evaluation to further improve clinical outcomes in the management of advanced PC.

Susceptibility of different mouse strains to oxaliplatin peripheral neurotoxicity: Phenotypic and genotypic insights.

Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co-morbidities, cancer stage, demographics and treatment schedule, patients develop oxaliplatin-induced peripheral neurotoxicity with remarkably different severity. This suggests individual genetic variability, which might be used to glean the mechanistic insights into oxaliplatin neurotoxicity. We characterized the susceptibility of different mice strains to oxaliplatin neurotoxicity investigating the phenotypic features of neuropathy and gene expression profiles in dorsal root ganglia of six genetically different mice strains (Balb-c, C57BL6, DBA/2J, AJ, FVB and CD1) exposed to the same oxaliplatin schedule. Differential gene expression in dorsal root ganglia from each mice strain were assayed using a genome-wide expression analysis and selected genes were validated by RT-PCR analysis. The demonstration of consistent differences in the phenotypic response to oxaliplatin across different strains is interesting to allow the selection of the appropriate strain based on the pre-defined read-out parameters. Further investigation of the correlation between gene expression changes and oxaliplatin-induced neurotoxicity phenotype in each strain will be useful to deeper investigate the molecular mechanisms of oxaliplatin neurotoxicity.

Clinical, pathological and functional characterization of riboflavin-responsive neuropathy.

Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.

P 43 A novel deletion in two exons of the SH3TC2 gene with mutation in the DPYD gene in Charcot-Marie-Tooth disease type 4C

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive demyelinating neuropathy associated with SH3TC2 mutations. More than 60 variants including nonsense, frameshift, and splice site variants have been reported in families of different ethnic origins as well as in sporadic patients. CMT4C is clinically characterised by early onset neuropathy, cranial nerve involvement and spine deformities. We present a family from Kuwait with a novel deletion of exons 13 and 14 in the SH3TC2 gene combined with a novel homozygous mutation in the DPYD gene. The 40 year-old male patient had foot deformities in infancy and delayed walking after the age of two. He first required walking aids when ten years old and became wheelchair-bound since the age of 18. He had progressive hearing loss over five years. Walking difficulties and wheelchair-dependency were reported in his father as well as a cousin of his mother while there were no symptoms reported in his own siblings and child. Clinical examination showed hypoacusis requiring the use of hearing aids, marked widespread symmetric muscular atrophies with weakness, and areflexia. He could walk a few steps with bilateral support. He had sensory neuropathy with skin atrophy and loss of hair on the lower legs. Spinal examination and X-ray showed slight hyperkyphosis of the thoracic spine but no signs of kyphoscoliosis. Electrophysiological studies showed severe motor and sensory neuropathy with very low amplitudes, markedly prolonged distal motor latencies and very slow motor nerve conduction velocities in the ulnar nerve. Needle electromyography detected fibrillations, positive sharp waves and complex repetitive discharges. High resolution sonography of the median nerve at the wrist showed a few enlarged fascicles with only moderately raised cross sectional area. Creatin kinase levels were constantly and significantly raised. Genetic testing revealed a homozygous large deletion in the SH3TC2 gene comprising exons 13 and 14 that had not been described before. Furthermore a second homozygous novel mutation (c.680+1G>T;p.?) was found in the DPYD gene. The same combination in heterozygous form was detected in the asymptomatic eight year old daughter. This newly described family with CMT4C broadens the spectrum of genetic causes and underlines the clinical variability of phenotypes as the absence of scoliosis does not exclude mutations in the SH3TC2 gene even in patients with severe disabling Azzedine et al., 2006 , Azzedine et al., 2016 , Varley et al., 2015 , Inherited Peripheral Neuropathies Mutation Database, 2016 .

Poster 291: Severe Sensory Neuropathy vs Sensory Ganglionopathy in a Patient with Sjogren’s Syndrome: A Case Report

PM&RVolume 9, Issue 9S1 p. S224-S224 Neurological Rehabilitation Poster Hall: Case Report Poster 291: Severe Sensory Neuropathy vs Sensory Ganglionopathy in a Patient with Sjogren's Syndrome: A Case Report Brennan Boettcher DO, Brennan Boettcher DO Mayo Clinic, Rochester, MN, United StatesSearch for more papers by this authorTerin Euerle MD, Terin Euerle MD Mayo Clinic, Rochester, MN, United StatesSearch for more papers by this authorSarah E. Berini MD, Sarah E. Berini MD Mayo Clinic, Rochester, MN, United StatesSearch for more papers by this author Brennan Boettcher DO, Brennan Boettcher DO Mayo Clinic, Rochester, MN, United StatesSearch for more papers by this authorTerin Euerle MD, Terin Euerle MD Mayo Clinic, Rochester, MN, United StatesSearch for more papers by this authorSarah E. Berini MD, Sarah E. Berini MD Mayo Clinic, Rochester, MN, United StatesSearch for more papers by this author First published: 19 September 2017 https://doi.org/10.1016/j.pmrj.2017.08.231Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume9, Issue9S12017 AAPM&R Annual Assembly AbstractsSeptember 2017Pages S224-S224 RelatedInformation

Identification and functional characterization of two missense mutations in NDRG1 associated with Charcot-Marie-Tooth disease type 4D.

Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal-recessive demyelinating form of CMT characterized by a severe distal motor and sensory neuropathy. NDRG1 is the causative gene for CMT4D. To date, only four mutations in NDRG1 -c.442C>T (p.Arg148*), c.739delC (p.His247Thrfs*74), c.538-1G>A, and duplication of exons 6-8-have been described in CMT4D patients. Here, using targeted next-generation sequencing examination, we identified for the first time two homozygous missense variants in NDRG1, c.437T>C (p.Leu146Pro) and c.701G>A (p.Arg234Gln), in two Chinese CMT families with consanguineous histories. Further functional studies were performed to characterize the biological effects of these variants. Cell culture transfection studies showed that mutant NDRG1 carrying p.Leu146Pro, p.Arg148*, or p.Arg234Gln variant degraded faster than wild-type NDRG1, resulting in lower protein levels. Live cell confocal microscopy and coimmunoprecipitation analysis indicated that these variants did not disrupt the interaction between NDRG1 and Rab4a protein. However, NDRG1-knockdown cells expressing mutant NDRG1 displayed enlarged Rab4a-positive compartments. Moreover, mutant NDRG1 could not enhance the uptake of DiI-LDL or increase the fraction of low-density lipoprotein receptor on the cell surface. Taken together, our study described two missense mutations in NDRG1 and emphasized the important role of NDRG1 in intracellular protein trafficking.

Clinical spectrum of Castleman disease-associated neuropathy.

To define the peripheral neuropathy phenotypes associated with Castleman disease. We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study.

Acro-osteolysis.

Acro-osteolysis is an osteolysis of the distal phalanges of the hands and feet and can affect the terminal tuft or the shaft of the distal phalanx (transverse or band acro-osteolysis). It is often associated with distal digital ischemia, digital calcinosis, or severe sensory neuropathy. Acro-osteolysis has been associated with a heterogeneous group of disorders, including occupational activities, infections, rheumatic disorders (systemic sclerosis, psoriatic arthritis), endocrinopathies, genetic disorders, and lysosomal storage disorders. Plain radiography is the gold standard for the detection of acro-osteolysis.

Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCε-dependent activation of TRPV1

Severe painful sensory neuropathy often occurs during paclitaxel chemotherapy. Since paclitaxel can activate mast cell and basophils, whereas quercetin, a polyphenolic flavonoid contained in various plants, which can specifically inhibit histamine release as a mast cell stabilizer. In this study we explore whether quercetin could ameliorate paclitaxel-induced neuropathic pain and elucidated the underlying mechanisms. Quercetin inhibition on histamine release was validated in vitro by detecting histamine release from rat basophilic leukemia (RBL-2H3) cells stimulated with paclitaxel (10 μmol/L). In the in vivo experiments, rats and mice received quercetin (20, 40 mg·kg(-1)·d(-1)) for 40 and 12 d, respectively. Meanwhile, the animals were injected with paclitaxel (2 mg/kg, ip) four times on d 1, 3, 5 and 7. Heat hyperalgesia and mechanical allodynia were evaluated at the different time points. The animals were euthanized and spinal cords and dorsal root ganglions were harvested for analyzing PKCε and TRPV1 expression levels. The plasma histamine levels were assessed in rats on d 31. Pretreatment with quercetin (3, 10, 30 μmol/L) dose-dependently inhibited excessive histamine release from paclitaxel-stimulated RBL-2H3 cells in vitro, and quercetin administration significantly suppressed the high plasma histamine levels in paclitaxel-treated rats. Quercetin administration dose-dependently raised the thresholds for heat hyperalgesia and mechanical allodynia in paclitaxel-treated rats and mice. Furthermore, quercetin administration dose-dependently suppressed the increased expression levels of PKCε and TRPV1 in the spinal cords and DRGs of paclitaxel-treated rats and mice. Moreover, quercetin administration may inhibited the translocation of PKCε from the cytoplasm to the membrane in the spinal cord and DRG of paclitaxel-treated rats. Our results reveal the underlying mechanisms of paclitaxel-induced peripheral neuropathy and demonstrate the therapeutic potential of quercetin for treating this side effect.

ID 55 – Sensory neuropathy in children presenting with Behr syndrome due to OPA1 mutations

Behr syndrome is a complex genetic disorder occurring in children. It associates optic nerve atrophy and spinocerebellar degeneration (ataxia, pyramidal signs), some patients also presenting with peripheral neuropathy. Transmission is generally autosomal recessive and in some cases is related to mutation in OPA1 , a gene encoding a dynamin-related GTPase. 4 children (age 3–14 y-o) with severe visual loss and balance impairment due to OPA1 gene mutations underwent electrodiagnostic (EDX) examination. They presented with early visual loss, mixed cerebellar and proprioceptive ataxia. Some also had pyramidal signs. Compound heterozygous OPA1 mutations were found in all cases. EDX examination demonstrated a severe sensory neuropathy with absent sensory potentials or dramatic decrease of the amplitude, in contrast with normal motor nerve conduction parameters and needle EMG. To date, compound heterozygosity for OPA1 has been proven in only three patients from two unrelated families and neuropathy was not specifically assessed. This is therefore the first report demonstrating the occurrence of severe sensory neuropathy in such cases. Peripheral neuropathy sometimes represents a useful help in the diagnosis of a neurological or metabolic disease occurring in children. The search for sensory neuropathy in children with optic atrophy can be helpful in orientating the genetic diagnosis.

Painful small fiber neuropathy with gastroparesis: A new phenotype with a novel mutation in the SCN10A gene

Gain-of-function mutations in the SCN10A gene (encoding the Nav1.8 voltage gated sodium channel) have been reported in a small number of patients. All presented with predominantly painful sensory neuropathy, congruent with the expression of Nav1.8 in nociceptive sensory neurons of the dorsal root ganglion. Only a few had mild autonomic symptoms, including dry eyes and mouth, orthostatic dizziness, palpitations, diarrhea and constipation. The underlying mechanism of the autonomic symptoms in these patients is unclear. We describe a 37-year-old woman with severe progressive gastroparesis and diffuse painful small fiber sensory neuropathy that started at age 32. Due to the severe dysphagia she could not ingest solid food, and lost eight kilograms. The gastroparesis was documented by esophageal manometry and gastric scintigraphy. The neuropathic pain started distally and then intensified and spread to most body areas. The patient harbored a novel heterozygous mutation: c.G4915A:p.D1639N in the SCN10A gene. To the best of our knowledge, this is the first description of such a phenotype due to a Nav1.8 mutation. Thus, our study expands the clinical spectrum of Nav1.8 associated disorders, and suggests that mutations in this sodium channel should be considered in patients with gastrointestinal motility dysfunction and painful neuropathy.

Severe sensory neuropathy in patients with adult-onset multiple acyl-CoA dehydrogenase deficiency

Multiple Acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation. Most patients with late-onset MADD are clinically characterized by lipid storage myopathy with dramatic responsiveness to riboflavin treatment. Abnormalities of peripheral neuropathy have rarely been reported in patients with late-onset MADD. We describe six patients who presented with proximal limb weakness and loss of sensation in the distal limbs. Muscle biopsy revealed typical myopathological patterns of lipid storage myopathy and blood acylcarnitine profiles showed a combined elevation of multiple acylcarnitines supporting the diagnosis of MADD. However, nerve conduction investigations and sural nerve biopsies in these patients indicated severe axonal sensory neuropathy. Causative ETFDH gene mutations were found in all six cases. No other causative gene mutations were identified in mitochondrial DNA and genes associated with hereditary neuropathies through next-generation-sequencing panel. Late-onset patients with ETFDH mutations can present with proximal muscle weakness and distal sensory neuropathy, which might be a new phenotypic variation, but the precise underlying pathogenesis remains to be elucidated.

Generalized pruritus preceding paraneoplastic neuropathy

Paraneoplastic syndromes are a group of rare disorders involving non-metastatic systemic effects accompanying malignancies, and occur remotely from the tumor itself. Chronic pruritus lasting more than 6weeks can be from paraneoplastic origin. A 65-year-old woman was admitted for generalized pruritus lasting for 1month, despite treatment with prednisolone, levocetirizine and hydroxyzine. General examination was normal. Biological data and gastroscopy were normal. One month later, the patient was readmitted for worsening of her pruritus and walking impairment, revealing a severe sensory neuropathy. Blood anti-Hu antibodies returned positive at a level of 400 (normal <100). Bronchoscopy and bronchial biopsies revealed small-cell lung carcinoma. To our knowledge, the association of generalized pruritus and paraneoplastic neuropathy has been rarely reported. Our observation raises the question of a pathophysiological continuum between pruritus and neuropathy in a paraneoplastic context.

Neurolymphomatosis in patient with Adult T-cell leukaemia/lymphoma (ATLL)

Neurolymphomatosis is a rare manifestation of lymphoma characterized by infiltration of the peripheral nerves, leading to neuropathy. Although recent imaging studies such as PET study make it possible to diagnose neurolymphomatosis in the patient with lymphoma, the histochemical studies on a case with neurolymphomatosis by ATLL are still rare. We here report a patient presenting neurolymphomatosis of ATLL diagnosed by a histochemical study of biopsied sural nerve. A 74-year-old man presented a skin rush of left hand and was diagnosed with smoldering ATLL. A physical examination revealed slight weakness of the muscle of the extremities and sensory deficits with painful paresthesia. F-18 fluorodeoxy-glucose positron emission tomography (FDG-PET) demonstrated a cervical lesion at cervical lymph node but not a nerve root lesion suggesting neurolymphomatosis. The histochemical study of biopsied skin showed the CD4, CD8, and CD25 triple-positive cells in epidermal Pautrier microabscesses. Normal structure of lymph node was not seen in lymph node and was replaced with fatty tissue. Medium-sized atypical lymphocytic cells were scatterly noted with small lymphocytes. Those atypical lymphocytic cells had hyperchromatic pleomorphic nuclei and prominent nucleoli. While nerve conduction study revealed severe sensory dominant peripheral neuropathy, the density of myelinatied fibers was relatively preserved in biopsied sural nerve. The Histological examination showed a number of atypical lymphocytes broadly infiltrating perineurial connective tissue and subperineurium. The patient was treated with intravenous injection of methylpredonisolone. Although the treatment effects on the pain of the extremities and motor ability of the upper extremities just for short period after the treatment, sensory and motor symptoms progressed worse. A histological study of peripheral nerve is still useful for a diagnosis of neurolymphomatosis.

P138. Acute onset and reversibility of triphasic waves in the EEG correlating with hypercapnia

Triphasic waves are commonly seen in the EEG of patients with encephalopathy. Although typically associated with metabolic encephalopathy or post-hypoxic damage, they are unspecific in respect of the etiology of brain dysfunction. Here, we present a case report of acute-onset triphasic waves induced by hypercapnia. We report on a 27-year-old male with severe sensory and motor neuropathy, tetraparesis, ataxia, dysarthria, and cognitive impairment of yet unknown etiology since the age of 14 years. The patient was referred to our hospital and admitted to the EEG monitoring unit for differential diagnosis of recurrent episodes of loss of consciousness. At time of admission, a borderline oxygen saturation (SatO2) of around 80% was recorded, attributable to his chronic neuromuscular disease. During the first evening after admission, SatO2 repeatedly dropped below 80%. Oxygen insufflation was initiated by the doctor-on-call and the patient’s vigilance was repeatedly tested throughout the night. At a routine check, the patient was found stuporous. Blood gas analysis showed carbon dioxide partial pressure (pCO2) of 85.6 mmHg and oxygen partial pressure (pO2) of 75.6 mmHg. Emergency bag-valve mask ventilation was started, the patient was intubated, and transferred to the intensive care unit. After several days, the patient was extubated without any new-onset neurological deficit. Polysomnography revealed alveolar hypoventilation, and non-invasive assisted bilevel ventilation treatment was initiated before the patient was discharged home. Upon post hoc review, the EEG during the night after admission showed normal sleep patterns which were replaced by triphasic waves just about 10 min before the patient was found to be stuporous. Upon bag-valve-mask ventilation, the triphasic waves disappeared within 2–3 min, and the EEG showed a normal awake state prior to sedation intubation. This case demonstrates that hypercapnia may induce acute-onset triphasic waves in the EEG which are readily reversible within minutes after assisted ventilation. Moreover, this case illustrates the danger of oxygen insufflation in patients with chronic alveolar hypoventilation. We conclude that our patient suffered from chronic alveolar hypoventilation due to severe neuropathy which resulted in chronic moderate hypercapnia, with respiration triggered by hypoxia alone. When receiving oxygen insufflation, hypoxia-induced respiration failed leading to central hypopnea, acute pCO2 increase and stupor.

Familial Amyloid Polyneuropathy treatment with Tafamidis – evaluation of one- and two-year treatment in Porto, Portugal

Transthyretin (TTR) related Familial Amyloid Polyneuropathy presents as a severe sensory, motor and autonomic neuropathy. Tafamidis, an oral drug that stabilizes TTR preventing amyloid deposition, was recently introduced in Europe to delay neuropathy progression in ambulatory patients.

524P - Voice Trial-Results from a Multicenter Phase Ii Study of Assessment of Clinical Efficacy and Safety in Capecitabine Plus Intermittent Oxaliplatin Together with Bevacizumab As the First-Line Therapy for the Patients with Advanced Colorectal Cancer

ABSTRACT Aim: The FOLFOX with bevacizumab regimen has been established as a standard first-line therapy for metastatic colorectal cancer (mCRC), and the OPTIMOX1 study suggested that a stop and go strategy for oxaliplatin reduced peripheral sensory neuropathy. We had already evaluated the efficacy of OPTIMOX1 plus bevacizumab in patients (pts) with mCRC (CRAFT study, Tezuka et al, Invest New Drugs 2013). CapeOx is one of the standard treatments for mCRC that has been proven to be as effective as the FOLFOX regimen. Thus we assessed the efficacy and safety of the combination of intermittent CapeOx + Bevacizumab as a first-line therapy in patients with mCRC in this trial. Methods: Eligibility criteria included ECOG PS: 0–1, no peripheral neuropathy ( Results: Between March 2011 and August 2013, 55 pts were enrolled. Baseline characteristics were median age of 67 years (range, 20–83); PS 0/1 (49/6 pts); male/female(33/22 pts), colon/rectum (28/27pts) and metastatic lesion liver/lung/lymph nodes (32/18/21 pts). A total of 47 pts were evaluated as Par Protocol Set population. 38 pts moved from initial CapeOX to maintenance capecitabine. 20 pts moved to CapeOx reintroduction. Median PFS was 12.4 months (95%CI, 7.7–17.1) and Median TTF was 8.3 months (95%CI, 4.5–12.1). Best overall response rate was 50.9%. Median capecitabine courses were 5 cycles (range 1–5). Oxaliplatin reintroduction rate was 52%. The causes of reintroduction failure were disease progression (3 pts), successful liver resection (2 pts), peripheral sensory neuropathy grade 2 (1 pt). Main grade 3/4 toxicities: neutropenia, anemia, peripheral neuropathy, hand-foot syndrome, and hypertension in 1 patient. Conclusions: This study met its primary endpoint PFS. It was longer than the CRAFT study. CapeOx with intermittent oxaliplatin is indicated to reduce incidence of severe neutropenia and peripheral sensory neuropathy. The results suggested that our treatment strategy was well tolerated and effective for first-line therapy in mCRC, and maintenance of duration for 5 cycles was reasonable. Disclosure: All authors have declared no conflicts of interest.

Case Scenario: Postoperative Brachial Plexopathy Associated with Infraclavicular Brachial Plexus Blockade

Case Scenario: Postoperative Brachial Plexopathy Associated with Infraclavicular Brachial Plexus Blockade