Peripheral Polyneuropathy Research Articles

Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family

Acute necrotizing encephalopathy (ANE) typically affects young, healthy children who develop rapid-onset severe encephalopathy triggered by viral infections. This disease is more commonly reported in Japan but occurs worldwide, although it remains under-recognized in Western countries. An autosomal dominant form, ANE1, was recently identified. We report the details of a 9-year-old Caucasian female who experienced recurrent ANE episodes at the ages of 9 months and 9 years. Brain magnetic resonance imaging findings were characteristic of ANE during both episodes, although more extensive in the recent episode, which resulted in severe neurological sequelae; influenza A was identified on bronchoalveolar lavage during this episode. Interestingly, there was evidence of peripheral polyneuropathy during the recent episode, which has not previously been described in sporadic ANE. Both the patient and her mother, who had also had postviral polyneuritis in the past, harbour a mutation in Ran-binding protein 2 (RANBP2); this occurred de novo in the mother and confers genetic susceptibility to ANE. Our case suggests that recurrent disease and/or an expanded clinical phenotype raises the possibility of ANE1; positive family history, although supportive, is not necessary as the mutation can occur de novo. Increased awareness may lead to earlier recognition and better treatment options.

Parasitic Infections in Solid Organ Transplant Recipients

Parasitic Infections in Solid Organ Transplant Recipients

Extensive cutaneous Mycobacterium abscessus infection due to contaminated insulin delivery system

A 48-year-old insulin-dependent diabetic woman presented with multiple lesions at her insulin injection sites. The lesions had gradually appeared and progressively enlarged over a 7-week period. Her background included 27 years of insulin-dependent diabetes mellitus, complicated by micro-vascular disease with early diabetic nephropathy, sensory peripheral polyneuropathy and grade 1 diabetic retinopathy. Diabetic management had been with a basal-bolus regimen of insulin, but with generally poor diabetic control (glycosylated haemoglobin of 10–11%). The lesions were only associated with her isophane insulin (delivered by a Novojet™ pen system) injection sites; her abdominal neutral insulin (Actrapid™) injection sites were unaffected. She denied any constitutional symptoms. Despite rotating her insulin injection sites, improving her injection site hygiene, and using clean insulin needles and canisters, new lesions continued to occur, and empiric oral antimicrobial therapy including flucloxacillin, erythromycin and amoxycillin/clavulanic acid had been ineffective. On examination she was afebrile and appeared well, however she had multiple erythematous, violaceous, non-tender plaques on the anterior aspect of her thighs (Figure 1). There was no associated lymphadenopathy, and her anterior abdominal wall insulin injection sites were unremarkable. Apart from signs of end-organ diabetic disease the remainder of her examination was normal. Figure 1. Left anterior thigh lesions at the infected insulin injection …

Guillain–Barré Syndrome During a Relapse of Ulcerative Colitis: A Case Report

To the Editor: A 59-year-old male patient was admitted to the hospital for bloody diarrhea and fever. He had a 5-year history of ulcerative colitis (UC) but he was in remission during the last 2 years, being treated with 5-aminosalicylate (5-ASA). Clinical examination demonstrated a well-nourished patient with a normal abdomen. He had mild iron deficiency anemia, the erythrocyte sedimentation rate (ESR) was normal, but C-reactive protein (CRP) was raised to 15.2 mg/L. His biochemical profile was within normal limits except for a slight decrease of the albumins. An abdominal ultrasound showed a slightly enlarged liver with mild steatosis and the presence of sludge in the gallbladder. Chest and abdominal x-ray were normal. Tumor markers (CEA, AFP, CA19-9, CA125, PSA) and thyroid hormones were within normal limits. Stool specimens did not reveal any ova or parasite and stool cultures including Clostridium difficile testing were negative. A colonoscopy showed a typical flare-up of UC with a moderately active chronic UC on histology. He was treated with intravenous (IV) prednisolone 25 mg twice daily and 5-ASA 1000 mg 3 times daily and as soon as clinical improvement was achieved he was discharged. Three days later he was readmitted with lower extremity weakness. On neurological examination the patient was fully consciousness. He had no deficit from cranial nerves. No speech or articulation disorders were detected. We observed neither meningial sign nor jaw reflex. There was a mild to moderate decrease in proximal muscle strength with normal tone. Superficial, vibration, and deep sensory modalities were apparently normal. Deep tendon reflexes of upper and lower extremities were reduced bilaterally. The muscle weakness of the lower extremities was more profound proximally than distally. A moderate impairment of deep sensation was observed, while superficial sensation was normal. There was a flexor plantar response. He was unable to stand or walk without aid. Therefore, he underwent neurophysiological and electromyographical studies. Electromyogram did not show any evidence of acute or chronic denervation in several muscles. However, electroneurogram (ENG) demonstrated a motor-sensory symmetrical demyelinating peripheral polyneuropathy. Cerebrospinal fluid was clear and colorless. Examination showed normal glucose up to 52 mg/dL and pathologically increased albumin up to 905 mg/L. As far as cells were concerned, 2/mm 3 lymphocytes were

Polineuropatia periférica em pacientes com lúpus eritematoso sistêmico juvenil

INTRODUCTION: Peripheral polyneuropathy is one of 19 neuropsychiatric syndromes seen in systemic lupus erythematosus, according to the classification criteria proposed by the American College of Rheumatology (ACR) for neuropsychiatric syndromes. However, this manifestation has not been reported very often, especially in patients with juvenile systemic lupus erythematosus (JSLE). PATIENTS AND METHODS: From 1983 to 2007, 5,079 patients were seen at the Pediatric Rheumatology Unit of the ICr-HC-FMUSP; 228 (4.5%) patients were diagnosed with JSLE according to the criteria of the ACR. Peripheral polyneuropathy was diagnosed according to the criteria for neuropsychiatric syndromes of the ACR. RESULTS: Five (2.2%) out of 228 patients with JSLE developed peripheral polyneuropathy and were described retrospectively. The diagnosis was confirmed by electroneuromyography, which showed the presence of distal peripheral polyneuropathy, sensorial and/or motor, involving all four limbs, in two patients, and the lower limbs, in three patients. Three of those patients were females, and peripheral neuropathy developed after the diagnosis of JSLE. The mean age of onset of the disease was 14 years, and the mean time between the onset of JSLE and the diagnosis of peripheral polyneuropathy was 23 months. The most common clinical presentations included muscular weakness and hyporeflexia. Antiphospholipid antibodies were present in all patients. Treatment consisted of corticosteroids in all patients, associated with intravenous cyclophosphamide in three patients. One patient evolved to functional disability and paresis of the lower limbs, requiring a wheelchair. One female patient died of severe sepsis. CONCLUSIONS: Peripheral polyneuropathy is a rare, severe, and occasionally incapacitating manifestation of JSLE, commonly associated with the presence of antiphospholipid antibodies.

Charcot’s arthropathy secondary to herpetic encephalitis sequelae: an unusual presentation

Neuropathic arthropathy (Charcot's arthropathy) is a progressive articular disease associated with a reduced sensorial and protector proprioceptive reflex. Its etiology includes many different conditions such as syringomyelia, traumatic lesion causing medullary deformity, spina bifida, diabetic neuropathy, leprosy neuropathy, neurofibromatosis, amyloid neuropathy, alcohol, and repetitive injection of hydrocortisone into joints, among others. However, the relationship between Charcot's arthropathy and herpetic encephalitis has not yet been described. Herpes encephalitis causes acute and chronic diseases of the peripheral or central nervous system. It can manifest as subacute encephalitis, recurrent meningitis, or myelitis. It can also resemble psychiatric syndromes, diplopia, sensory changes in the face and limbs, personality changes, frontal dysexecutive syndrome, stiff neck, subclinical alterations of the vestibular function, intracranial hypertension, convulsion, hemiparesis, and generally includes motor components, among others. On the other hand, pure peripheral sensory disturbance has not been described. In this article, we report the clinical case of a patient with Charcot's arthropathy secondary to pure peripheral sensory polyneuropathy as a consequence of progressive herpetic encephalitis sequelae. In this article, the authors report the first case of Charcot's arthropathy secondary to herpetic encephalitis.

Extreme efficacy of intravenous immunoglobulin therapy for severe burning pain in a patient with small fiber neuropathy associated with primary Sjögren’s syndrome

Neurological involvement occurs in approximately 20% of patients with primary Sjögren's syndrome. Although neurological symptoms can affect the peripheral nervous system and the central nervous system, the most frequent symptom is polyneuropathy. Small fiber neuropathy (SFN) is a form of painful peripheral polyneuropathy that is common in patients with diabetic neuropathy, but may also occur in toxic, infectious, or immune-mediated neuropathy. We show here a patient with Sjögren's syndrome who developed SFN and was treated with intravenous immunoglobulin (IVIG) therapy, which was immediately and extremely effective. Because of the efficacy of IVIG therapy, we propose that direct immune-mediated mechanisms may be involved in the pathogenesis of SFN complicated by Sjögren's syndrome.

Causative Factors, Epidemiology, and Follow‐up of Bilateral Vestibulopathy

Bilateral vestibulopathy (BV) is characterized by impaired or lost function of both peripheral labyrinths or of the eighth nerves. In a review of 255 patients (mean age +/- SD, 62 +/- 16 years) with BV diagnosed in the authors' dizziness unit between 1988 and 2005, 62% of the patients were male. Previous vertigo attacks had occurred in 36%, indicating a sequential manifestation. The definite cause of BV was determined in 24% and the probable cause in 25%. The most common causes were ototoxic aminoglycosides (13%), Ménière's disease (7%), and meningitis (5%). Strikingly, 25% exhibited cerebellar signs. Cerebellar dysfunction was associated with peripheral polyneuropathy in 32% compared with 18% in BV patients without cerebellar signs. In a follow-up study on 82 BV-patients (mean age at the time of diagnosis 56.3 +/- 17.6 years), the frequency and degree of recovery or worsening of vestibular function over time were determined. The patients were reexamined 51 +/- 6 months after the first examination. Electronystagmography with bithermal caloric irrigation was analyzed by measurement of the mean peak slow-phase velocity (SPV) of the induced nystagmus. Statistical analysis of the mean peak SPV revealed a nonsignificant worsening over time (initial mean peak SPV 3.0 +/- 3.5 degrees/s vs. 2.1 +/- 2.8 degrees/s). Only patients with BV due to meningitis exhibited an increasing, but nonsignificant SPV (1.0 +/- 1.4 degrees/s vs. 1.9 +/- 1.6 degrees/s). Forty-three percent of patients subjectively rated the course of their disease as stable, 28% as worsened, and 29% as improved.

Periphere Polyneuropathie und beidseitige Optikusneuropathie unter Behandlung einer chronischen Hepatitis C

A 54-year-old female patient with recently confirmed chronic hepatitis C, genotype Ib and positive HCV-RNA was admitted for interferon induction therapy. Physical examination findings were normal. Ultrasound examination of the abdomen revealed slightly compacted liver structure with otherwise no pathological findings. Laboratory results showed marginally increased GPT value at 46 U/l with HCV-RNA of 769,000 U/ml. All other laboratory results were within the reference range. There was no indication for autoantibodies. After one-week induction therapy with interferon-alpha (IFN-alpha2a) plus ribavirin and amantadine, maintenance therapy with pegylated interferon-alpha (PEG-IFN-alpha2a) plus ribavirin and amantadine was initiated. Complete virus elimination was achieved after two and a half months. Five months after onset of therapy, painful peripheral neuropathy of the limbs occured and after one more month, severe vision impairment with opticus neuropathy and bilateral papilledema developed. Simultaneously, peripheral polyneuropathy progressed with additional motoric deficits. Interferon therapy was terminated and the patient received high-dose corticosteroids which resulted in an improvement of neuropathic complaints. Eight months later, only discrete bilateral vision impairment with optic nerve atrophy remained. Side effects occurring with interferon-alpha therapy and pegylated interferon-alpha therapy are generally low and well tolerated. However, in individual cases - as in our patient - side effects including severe peripheral neuropathy and optic neuropathy have been observed. In these cases, interferon therapy must be terminated immediately as severe damage of nerves may result.

Endothelial dysfunction in children and adolescents with type 1 diabetes mellitus and its role in the development of diabetic peripheral polyneuropathy

Aim. To measure endothelial factors (nitric oxide (NOx) metabolites, endothelin-1 (ET-1), and basic fibroblast growth factor (bFGF)) in children and adolescentswith diabetes mellitus (DM) during development of diabetic peripheral polyneuropathy (DPNP). Materials and methods. A total of 130 children and adolescents with diabetes mellitus were examined. Duration of DM varied from 3 months to 14 years. Thecontrol group comprised 20 children and adolescents without DM or neurologic pathology. Subjective manifestations of DPNP were assessed based on thedata of a standardized Neuropathy Symptom Score (NSS) questionnaire. Neuropathy Disability Score (NDS) questionnaire was used to monitor objectivechanges of DPNP. NOx metabolites were detected with Griess reagent (Aldrich Chemical Co, USA). Serum ET-1 and bFGF were measured using solid-phaseimmunoenzyme assay (DRG, USA) and CYTIMMINE (USA) kits respectively. Results. All children and adolescents with DM1 had lower NOx and bFGF levels than controls. ET-1 level in DM patients was 3.5 times that in controls. DMpatients with DPNP had more pronounced endothelial dysfunction than DM patients without DPNP and control subjects. Patients with hyperproduction ofNOx had DM for more than 10 years and their total NDS score was significantly higher than in two other groups. Conclusion. Endothelial dysfunction in children and adolescents with type 1 diabetes mellitus progresses with the development of DPNP. Depletion of endothelialfunctional reserve is responsible for the unfavourable course of DPNP.

The value of contact heat evoked potentials for the early diagnosis of diabetic peripheral polyneuropathy

Objective To study the value of contact heat evoked potentials (CHEPs) for the early diagnosis of diabetic peripheral polyneuropathy. Methods Seventy-five diabetic patients were examined by conventional nerve conduction velocity studies and then divided into 2 groups: diabetics with normal nerve conduction and diabetics with abnormal nerve conduction. Thirty-three normal subjects were used as controls. Toronto Clinical Neuropathy Sco-ring System was used to evaluate the patients. CHEPs were recorded using different stimulation intensities at different temperatures. Results The peak latencies of 45℃ , 50℃, 53℃ in diabetics with normal nerve conduction group were longer than those in normal control group, with a significant difference between the 2 groups(P<0.05). The peak latencies of diabetics were positively related to Toronto scores. Conclusion CHEPs could detect the impair-ment of diabetic peripheral nerve and reveal the impairment earlier than conventional nerve conduction velocity exami-nation, The prolongation of peak latency in diabetics group was significantly and positively related to clinical condi-tion. Key words: Contact heat evoked potentials; Diabetes mellitus; Diabetic peripheral polyneuropathy

Hereditary neuropathy with liability to pressure palsies and amyotrophic lateral sclerosis

A 56-year-old male with recurrent painless focal neuropathies and a family history of peripheral neuropathy of unknown etiology presented with progressively worsening of impaired sensations and weakness in his lower extremities. His initial electrodiagnostic evaluation was suggestive of severe sensory and motor peripheral polyneuropathy. The genetic testing was performed for familial causes of peripheral neuropathy as there was a family history of peripheral neuropathy of unknown etiology. The patient was found to have 1.5-Mb deletion in the PMP22 gene which was confirmatory of hereditary neuropathy with liability to pressure palsies (HNPP). He developed progressive upper and lower extremity weakness, bulbar dysfunction and widespread fasciculations during the course of his illness. He was subsequently diagnosed with amyotrophic lateral sclerosis (ALS). This is the second reported case of HNPP associated with ALS. We discuss significant clinical and electrodiagnostic findings of this interesting case.

Sleep disturbances and occupational exposure to solvents

A solvent can be defined as "a liquid that has the ability to dissolve, suspend or extract other materials, without chemical change to the material or solvent". Numerous chemical or technical processes rely on these specific properties of organic solvents in industry. Occupational exposure to solvents is not rare and some activities may cause substantial exposure to these substances in the workforce. Short-term or acute exposures cause a prenarcotic syndrome, and long lasting exposure conditions have been associated with various neurological and neuropsychiatric disorders, e.g., anosmia, hearing loss, colour vision dysfunctions, peripheral polyneuropathy and depression, but most significantly with the gradual development of an irreversible toxic encephalopathy. For the last 3 decades reports and epidemiological studies have been published reporting sleep disturbances among other complaints, related to long-term exposure to these compounds. In addition, the question has been posed if solvents can be the cause of a sleep apnoea syndrome in exposed workers, or on the contrary, if these workers are misdiagnosed and 'common' sleep apnoea syndromes are the cause of their chronic symptoms of fatigue and memory and attentional disturbances.

Valor predictivo negativo del SPECT con Ioflupano 123I en los trastornos del movimiento

ObjectiveA non-degenerative etiology is supported by a normal SPI [normal SPECT with 123I-Ioflupane (SPI)] in a patient with movement disorders (MD). MethodA total of 196 SPIs were conducted during the period of 2004/05. Of these, 44 were selected in order to rule out degenerative MD (DMD), the results being normal in these patients. The clinical background of these patients were reviewed in a minimum period of 24 months (range 24-40), collecting the diagnoses reached by the neurology specialists. The SPI were evaluated using a consensus, according to subjective criteria and quantification. ResultsThirty-six of the 44 patients (81%) were identified at 2 years of having nondegenerative movement disorders: 18 as essential tremor, 5 as drug-induced disorder, 4 as vascular disease, 3 as peripheral polyneuropathy, 2 postural tremors, 1 writer's cramp, 1 psychogenic tremor, 1 intercranial hypertension and 1 fibromyalgia. The remaining 8 patients were diagnosed with Parkinson's disease in 5 cases, 1 corticobasal degeneration, 1 multisystemic atrophy and another degenerative Parkinsonism with unclear etiology. ConclusionThe SPI in our hospital has a lower negative predictive value than the data reported in the literature. The false negatives could be explained because most of our patients come from neurologist physicians who are not movement disorder experts. In addition, a small proportion of degenerative Parkinsonism could evolve with normal SPI.

B152 First Analysis of HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Doxorubicin, Dexamethasone (PAD) vs. VAD as Induction Treatment Prior to High-dose Melphalan (HDM) in Patients with Newly Diagnosed Multiple Myeloma (MM)

The randomized, open-label, phase III trial HOVON-65/GMMG-HD4 was designed to evaluate the efficacy of bortezomib prior to HDM for response and progression-free survival (PFS) in patients with newly diagnosed MM. The trial was performed in 75 referral centers in the Netherlands and Belgium (HOVON group) and Germany (GMMG group). Patients with Salmon & Durie (SD) stage II or III, age 18-65 years inclusive, were randomly assigned to 3 cycles of VAD (vincristine 0.4 mg, adriamycine 9 mg/m2 days 1-4, dexamethasone 40 mg days 1-4, 9-12, and 17-20) or PAD (bortezomib 1.3 mg/m2 days 1,4,8,11, adriamycine 9 mg/m2 days 1-4, dexamethasone 40 mg days 1-4, 9-12, and 17-20). No thrombosis prophylaxis was given. Stem cells were mobilized using the CAD regimen, including cyclophosphamide 1000 mg/m2 iv day 1, and G-CSF. After induction therapy, all patients were to receive 1 or 2 cycles of high-dose melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance with thalidomide 50 mg daily (VAD arm) or bortezomib, 1.3 mg/m2 once every 2 weeks (PAD arm) for 2 years. Between May 4, 2005 and May 16, 2008, 833 patients were randomized. After the trial was closed, we here report the planned interim analysis data on response after induction and HDM-1 of the initial 300 (150 per arm) randomized patients. The 2 randomization arms were equal for SD stage of disease, ISS stage, and distribution of chromosomal abnormalities. 137 patients (91%) completed PAD or 136 (91%) completed VAD and 132 patients (88%) in each arm completed HDM-1. Full dose bortezomib could be administered in 95% (PAD1), 89% (PAD2) and 85% (PAD3) of patients. Successful stem cell apheresis was achieved in all 137 PAD treated patients who received CAD mobilization . Peripheral polyneuropathy CTC grade 3-4 during PAD vs VAD was 16% vs 6%, while DVT/pulmonary embolism was diagnosed in 3% during VAD and 4% during PAD. Responses were assessed according to EBMT criteria including VGPR and nCR after PAD/VAD, after HDM-1 and best response on protocol treatment. Complete Response (CR/nCR), Very Good Partial Response (VGPR) and Partial Response (PR) in both arms were compared by logistic regression (table 1). Deletion of chromosome 13q or presence of t(4;14) did not have a significant impact on VGPR or (n)CR. We conclude that PAD induces significantly more PR+VGPR+(n)CR as compared with VAD, and that this effect is sustained after HDM-1.

Electromyographic and nerve conduction findings in a patient with neuromyotonia, normocalcemic tetany and small-cell lung cancer

A 57-year-old man with neuromyotonia and normocalcemic tetany as probable paraneoplastic symptoms of small-cell lung cancer was examined neurophysiologically. In EMG, spontaneous action potential generation was demonstrated in peripheral motor axons. There were also time-locked high-frequency discharges after some voluntarily activated motor unit potentials. After electrical stimulation of motor axons, the M-response as well as spinal F-response or H-reflex was often followed by a sequence of oscillating potentials which could last several hundred msec. There was no evident peripheral polyneuropathy. Tetany subsided when carbamazepine therapy was started. The only striking abnormality in extensive laboratory studies was an increase in the plasma noradrenaline value.

Severe ataxia with neuropathy in hereditary gelsolin amyloidosis

Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder caused by a G654A or G654T gelsolin mutation, reported from Europe, North America, and Japan. Principal clinical signs are corneal lattice dystrophy, cutis laxa and cranial neuropathy, often deleterious at advanced age. Peripheral neuropathy, if present, is usually mild. We report a 78- year old male Finnish patient who presented with ataxia and mainly sensory peripheral polyneuropathy (PNP) signs, causing severe disability and ambulation loss. Electrophysiological studies showed severe generalized chronic mainly axonal sensorimotor PNP with facial paralysis. In magnetic resonance imaging proximal lower limb and axial muscle atrophy with fatty degeneration as well as moderate spinal cord atrophy were seen. A G654A gelsolin mutation was demonstrated but no other possible causes of his disability were found. At age 79 he became bedridden and died of pulmonary embolism. Neuropathological examination revealed marked gelsolin amyloid deposition at vascular and connective tissue sites along the entire length of the peripheral nerves extending to the spinal nerve roots, associated with severe degeneration of nerve fibers and posterior columns. Our report shows that advanced AGel amyloidosis due to degeneration of central and distal sensory nerve projections results in deleterious ataxia with fatal outcome. Severe posterior column atrophy may reflect radicular AGel deposition, although even altered gelsolin - actin interactions in neural cells possibly contribute to neurodegeneration with successive ataxia in carriers of a G654A gelsolin mutation.

Negative Predictive Value of the SPECT with 123I Loflupane in movement disorders

Objective A non-degenerative etiology is supported by a normal SPI [normal SPECT with 123I-Ioflupane (SPI)] in a patient with movement disorders (MD). Method A total of 196 SPIs were conducted during the period of 2004/05. Of these, 44 were selected in order to rule out degenerative MD (DMD), the results being normal in these patients. The clinical background of these patients were reviewed in a minimum period of 24 months (range 24-40), collecting the diagnoses reached by the neurology specialists. The SPIs were evaluated using a consensus, according to subjective criteria and quantification. Results Thirty-six of the 44 patients (81%) were identified at 2 years of having nondegenerative movement disorders: 18 as essential tremor, 5 as drug-induced disorder, 4 as vascular disease, 3 as peripheral polyneuropathy, 2 postural tremors, 1 writer's cramp, 1 psychogenic tremor, 1 intercranial hypertension and 1 fibromyalgia. The remaining 8 patients were diagnosed with Parkinson's disease in 5 cases, 1 corticobasal degeneration, 1 multisystemic atrophy and another degenerative Parkinsonism with unclear etiology. Conclusion The SPI in our hospital has a lower negative predictive value than the data reported in the literature. The false negatives could be explained because most of our patients come from neurologist physicians who are not movement disorder experts. In addition, a small proportion of degenerative Parkinsonism could evolve with normal SPI.

A splice variant of GNB3 and peripheral polyneuropathy in type 1 diabetes.

Abnormalities in G protein-mediated signal transduction could be involved in the pathogenesis of diabetic polyneuropathy (DPN). Here we test whether the GNB3 C825T variant confers susceptibility to DPN in type 1 diabetes (T1D) mellitus. The C825T marker of GNB3 was genotyped in genomic DNA from blood isolated from a total of 213 Russian T1D patients 100 of whom had DPN. Compared to carriers of the wild-type genotype C/C, diabetic subjects with genotypes T/T had significantly increased risk to develop DPN (Odds Ratio (OR) of 4.4 (p = 0.001). The adjustment for confounders (age, sex, body mass index, cigarette smoking, and level of reduced glutathione) resulted in increase of the OR value up to 4.72 (p = 8.9 × 10-3). The further adjustment for hypertension abolished the association between the GNB3 C825T variant and DPN (OR = 1.95, p = 0.18). Non-complicated subjects homozygous for T/T showed decreased levels of reduced glutathione (T/T: 69 ± 19 vs. C/T: 74 ± 19 vs. C/C: 77 ± 17 μmol/l, p = 0.009). Compared to other GNB3 variants, carriers of the T/T genotype had elevated systolic blood pressure (SBP) in complicated (T/T: 115.8 ± 9.1 vs. C/T: 113.3 ± 8.2 vs. C/C: 109.5 ± 8.7 mm/Hg, p = 0.036) and non-complicated T1D patients (T/T: 118.1 ± 8.4 vs. C/T: 116.9 ± 7.9 vs. C/C: 112.1 ± 7.2 mm/Hg, p = 0.02). However, the significance of association between the C825T polymorphism was lost after adjustment for confounding risk factors. In conclusion, the 825T allele of GNB3 is likely to accelerate the development of DPN through primary effects to SBP and hypertension in subgroups of diabetic patients with impaired neurovascular function and advanced oxidative stress.

VAMP/ThaCyDex: Velcade® (Bortezomib), Adriamycin, Melphalan and Prednisone Alternating with Thalidomide, Cyclophosphamide and Dexametasone as a Salvage Regimen in Relapsed Multiple Myeloma Patients

Background: Bortezomib and Thalidomide have demonstrated to be effective in relapsed and refractory Multiple Myeloma (MM) patients, including those with adverse cytogenetics (CG). Moreover, Bortezomib and thalidomide-based combinations result attractive to improve efficacy, but toxicity could be increased. Based on this background, we have tested if an alternating regimen consisting on two highly effective schedules could overcome MM drug resistance without an increase in toxicity in relapsed/refractory MM patients.Patients and Methods: Treatment schedule consisted on 6 alternating cycles of VAMP (Bortezomib 1,3mg/msq IV days 1,4,8 and 11; Melphalan, 9mg/msq po, days 1–4; Prednisone 60mg/msq po, days 1–4; and conventional or liposomal Adriamycin 40 or 30mg/msq respectively on day 1 of a 28 day cycle) alternating with ThaCyDex (Thalidomide 200mg/d po day 1–28; Cyclophosphamide 50mg/d po, days 1–28; and Dexametasone 40mg/d po, days 1–4). After 6 cycles, responding patients, received the previous schedule, every other month as consolidation therapy.Results: From June 2007 until August 2008, 20 patients have been included, with a median age of 63 years (Range 48–81); 15 patients (75%) had previously received autologous stem cell transplantation. 6 patients (30%) had previously received Bortezomib-based therapy, and one patient (5%) had previously received IMID-based therapy. Efficacy and toxicity were evaluated on an intent-to-treat basis. After a median of 6 cycles, 20 patients were evaluable for response, 9 patients (42%) achieved immunofixation negative Complete Response (CR), 3 patients (16%) nCR, 9 patients (47%) partial response, which makes an ORR of 94,7%. In addition, 1 patient (5%) remained in stable disease and one patient died during induction therapy due to septic shock. Seven patients presented high risk cytogenetic abnormalities [t(4;14) and/or delRB], and CR was obtained in 3 of them (42%) plus one additional nCR in 1 patient (14%). Moreover, allogeneic stem cell transplantation was performed in two of these high risk patients, as they were effectively rescued by this salvage regimen. Two patients progressed during the consolidation treatment. Toxicity was manageable, being haematologic events the most frequently reported. 6 patients (30%) developed ≥G3 thrombocytopenia and 6 patients (30%) neutropenia. Infection ≥G3 occurred in 3 patients (16%). Despite the combination of two drugs with potential neurologic toxicity, the use of them in alternated schedule resulted in that only 3 patients (15%) developed Peripheral Polyneuropathy, none of them >G2.Conclusion: Preliminary results show that alternating VAMP/ThaCyDex is a highly effective salvage regimen in relapsed/refractory MM patients, including high risk subgroup with adverse cytogenetic abnomalities. Haematologic toxicity was the most frequent adverse event, while the incidence of Peripheral Polyneuropathy was low, despite the use of two neurotoxic drugs. This results indicate that the alternating approach allows the exposure to a large number of active drugs without increase in the toxicity. A second analysis will be performed in December 2008 and results will be updated.