Infiltrative peripheral neuropathy of acute monoblastic leukemia during hematologic remission

A 38-year-old woman with acute monoblastic leukemia developed severe continuous pain in the left arm while she was in hematologic remission following both systemic and intrathecal chemotherapy. A nerve conduction study (NCS) showed marked decrease of amplitude in the left ulnar nerve, consistent with infiltration of leukemic cells. The pain in the arm was reduced by irradiation to the left brachial plexus, but right facial nerve palsy occurred. No improvement was achieved by systemic and intrathecal chemotherapy plus irradiation to the whole brain and right parotid. After sometime, she complained of pains in the legs and right foot drop. NCS showed amplitude decrease in bilateral peroneal nerve. Throughout the course, bone marrow remained in complete remission, and no signs of meningeal leukemia were obtained. A treatment with high dose Ara-C appeared to be effective for the pain in the legs. The foot drop, however, persisted and peripheral neuropathy progressed even after high dose Ara-C therapy. Peripheral nerve involvement in acute leukemia appears to be rare, and even more so in case of hematologic remission. The blood-nerve barrier may allow some malignant cells to escape from cytotoxic agents. Therefore, irradiation or high dose Ara-C therapy would seem to be rational approaches to the problem.     

Nociceptor hyper-responsiveness during vincristine-induced painful peripheral neuropathy in the rat

Neuropathic pain accompanies peripheral nerve injury after a wide variety of insults including metabolic disorders, traumatic nerve injury, and neurotoxic drugs. Chemotherapy-induced neuropathic pain, caused by drugs such as vincristine and taxol, occurs in cancer patients who receive these drugs as antineoplastic agents. Although a variety of remediations have been attempted, the absence of knowledge concerning mechanisms of chemotherapy-induced neuropathic pain has hindered the development of treatment strategies. Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy in humans and mechanical hyperalgesia in rats. To test the hypothesis that alterations in C-fiber nociceptor function occur during vincristine-induced painful peripheral neuropathy, we performed in vivo extracellular recordings of single neurons from the saphenous nerve of vincristine-treated rats. Forty-one percent of C-fiber nociceptors were significantly hyper-responsive to suprathreshold mechanical stimulation. As a population, these mechanically hyper-responsive nociceptors also had significantly greater responses to suprathreshold heat stimulation; however, heat hyper-responsiveness was found only in a subset of these nociceptors and was never detected in the absence of mechanical hyper-responsiveness. In addition, mean conduction velocities of A-fibers and C-fibers in vincristine-treated rats were significantly slowed. Mean heat and mechanical activation thresholds of C-fiber nociceptors, their distribution among subclasses, and the percentage of spontaneously active neurons in vincristine-treated rats were not statistically different from controls. Vincristine does not, therefore, cause generalized impairment of C-fiber nociceptor function but rather specifically interferes with mechanisms underlying responsiveness to suprathreshold stimuli. Furthermore, vincristine-induced nociceptor hyper-responsiveness may involve alterations specifically in mechanotransduction in some nociceptors and alterations in general cellular adaptation mechanisms in others.     

Human xenomitochondrial cybrids. Cellular models of mitochondrial complex I deficiency

The subunits forming the mitochondrial oxidative phosphorylation system are coded by both nuclear and mitochondrial genes. Recently, we attempted to introduce mtDNA from non-human apes into a human cell line lacking mtDNA (rho degrees), and succeeded in producing human-common chimpanzee, human-pigmy chimpanzee, and human-gorilla xenomitochondrial cybrids (HXC). Here, we present a comprehensive characterization of oxidative phosphorylation function in these cells. Mitochondrial complexes II, III, IV, and V had activities indistinguishable from parental human or non-human primate cells. In contrast, a complex I deficiency was observed in all HXC. Kinetic studies of complex I using decylubiquinone or NADH as limiting substrates showed that the Vmax was decreased in HXC by approximately 40%, and the Km for the NADH was significantly increased (3-fold, p < 0.001). Rotenone inhibition studies of intact cell respiration and pyruvate-malate oxidation in permeabilized cells showed that 3 nM rotenone produced a mild effect in control cells (0-10% inhibition) but produced a marked inhibition of HXC respiration (50-75%). Immunoblotting analyses of three subunits of complex I (ND1, 75 and 49 kDa) showed that their relative amounts were not significantly altered in HXC cells. These results establish HXC as cellular models of complex I deficiency in humans and underscore the importance of nuclear and mitochondrial genomes co-evolution in optimizing oxidative phosphorylation function.     

Anesthesia for a child with complex I respiratory chain enzyme deficiency

Computed tomography (CT) excretory urography was performed in five adult female dogs after intravenous injection of a bolus of four different doses of water-soluble iodinated contrast medium (100, 200, 400, and 800 mgI/kg). CT images centered over the urinary bladder were performed before injection and 1, 3, 5, 7, 9, 11, 15, 20, 25, 30, 40, 50, and 60 minutes after injection. Opacification of both ureters was evaluated by measuring maximum CT number of individual ureters at each time. Time opacification curves were generated for each dose. Best opacification of the ureters was obtained with 400 and 800 mgI/kg, with a constant peak at 3 minutes and durable opacification for 1 hour. Insufficient opacification was obtained with lower dose of 100 and 200 mgI/kg.     

Cryoglobulinemic peripheral neuropathy: neurophysiologic evaluation in twenty-two patients

The aim of this study was to evaluate the frequency and degree of peripheral neuropathy in 22 consecutive patients with mixed cryoglobulinemia, whether symptom-free or with subjective neurological symptoms. Electrophysiological investigations were carried out and a biopsy of the sural nerve was performed in six patients. Peripheral neuropathy of the lower limbs was demonstrated, which was mostly sensory and light or moderate in 86% of cases (19 patients). F-Wave and H-reflex recordings were found to be the most reliable methods; in 77% of cases, they were abnormal (17 patients). Using somatosensory evoked potentials, we were able to exclude simultaneous central nervous system involvement in 10 patients.     

Infantile familial cardiomyopathy due to mitochondrial complex I and IV associated deficiency

Two brothers, aged 27 and 20 months, born from consanguineous healthy parents, presented with cardiomyopathy, lactic acidosis and carnitine abnormalities in serum and muscle, without clinical evidence of muscle involvement. The histochemical reaction for cytochrome c oxidase (COX) activity was negative in all muscle fibres, although the holoenzyme and subunits were present at a normal level, as shown by immunocytochemistry. The COX activity was, respectively, 5 and 25% of control values, in muscle biopsies. Partial deficiency of complex IV was confirmed in fresh isolated muscle mitochondria from patient 2 and was associated with a defect of complex I. Patient 1 died at age 3 yr 6 months. Partial improvement of cardiomyopathy in patient 2 was obtained under carnitine therapy, but seizures occurred and CT scan and magnetic resonance imaging (MRI) revealed thalamic hypodensity. Thus, the disorder appears to be progressive despite the clinical stabilization of the cardiomyopathy. This further demonstrates the complexity and clinical heterogeneity of combined respiratory chain complex deficiencies.     

Modulation of peripheral blood lymphocyte subsets during methylprednisolone pulse therapy

We determined fluctuations in circulating lymphocyte subsets induced by methylprednisolone pulse therapy (MPT) and the continuous administration of prednisolone (PSL) in 17 patients with autoimmune or systemic rheumatic disease. Two-color flow cytometry, using monoclonal antibodies to various lymphocyte subsets, was performed to identify a possible association between the clinical efficacy of treatment and modulative effects on each subset. Both MPT and continuous oral PSL showed suppressive effects on most of the lymphocyte subsets: CD4+, CD45RA or CD45RA+CD4+, CD8+, CD11b.CD8+, CD5+ B, and CD57+ or CD57 CD16+ cells. Modulation of lymphocyte subsets were more profound with MPT than with continuous oral PSL. The results are relevant to the different degrees of immuno-suppression effected by the two treatment modalities. We found that the number of CD45RA.CD4+ cells after MPT treatment correlated with the clinical efficacy of the treatment: the less CD45RA.CD4+ cell numbers decreased after MPT treatment, the greater was the clinical efficacy of the treatment. The results probably are associated with a rapid recovery of the subset after MPT treatment in the responders. Thus, the sequential monitoring of circulating lymphocyte subsets is useful in predicting the clinical effects of MPT treatment.     

Absence of peripheral neuropathy in long-term lead-exposed subjects

The safety of a blood lead concentration of 70 microgram/100 ml as a hygienic border value with regard to development of lead neuropathy was tested in 95 employees, who had been exposed occupationally to lead for more than 9 years. The blood lead concentration was slightly above the border value in nine subjects, while the erythrocyte-Zn-protoporphyrin concentration was significantly elevated in 81 subjects, indicating an abnormal accumulation of metabolically active lead. None of the group showed clinical evidence of peripheral neuropathy, and the vibratory perception thresholds as well as motor conduction data from the median, radial, and common peroneal nerves were normal, as compared with an age-matched control group of 21 non-exposed normal subjects. The amplitude ratio between proximally and distally evoked muscle action potentials was normal in all lead-exposed subjects. These findings suggest that lead-exposed subjects are well protected against peripheral lead neuropathy, when blood lead levels are kept below the hygienic border value.     

Fatal vascular leak syndrome with extensive hemorrhage, peripheral neuropathy and reactive erythrophagocytosis: an unusual complication of recombinant IL-3 therapy

A 39-year-old patient with severe aplastic anemia (AA), resistant to therapy, received recombinant human IL-3 (rhIL-3) on a phase I/II trial. During treatment she developed disseminated skin lesions, suggestive of vasculitis, and severe progressive peripheral neuropathy culminating in complete paralysis. She died 25 days after beginning treatment from profuse bleeding. On autopsy, evidence of vascular leaks with widespread bleeding and extensive hemorrhagic involvement of peripheral nerves was found. An additional feature was massive reactive erythrophagocytosis in lymph nodes, spleen and bone marrow. The coincidence between rhIL-3 administration and the dramatic events suggest a causal relation. As a possible pathogenic mechanism, an rhIL-3 induced excessive stimulation of macrophages and production of secondary cytokines such as tumor necrosis factor (TNF) is suggested. TNF is considered as a major factor in the development of both a vascular leak and reactive erythrophagocytosis. This case report can be regarded as an example of the possible unusual pathologic phenomena we may expect to see in the near future with increasing use of growth factors.     

Advances in the genetics of peripheral neuropathy in childhood

Pneumocystis carinii pneumonia (PCP) occurs commonly in immunocompromised patients. Sulfamethoxazole-trimethoprim (SMX-TMP) is effective prophylaxis, although PCP may still occur despite apparently adequate use. We report three cases of PCP which highlight some of the pitfalls of prophylaxis.     

p75 neurotrophin receptor induction and macrophage infiltration in peripheral nerve during experimental diabetic neuropathy: possible relevance on regeneration

In this study we examined the expression of the neurotrophin receptor p75 (p75NTR) and the activation of macrophages in the sciatic nerve of rats at different time points after the induction of diabetes with streptozotocin (STZ). Northern blot and immunocytochemical analysis showed that p75NTR was not detectable in the sciatic nerve by Week 2 after STZ treatment. At this time, single nerve fiber immunostaining using ED1 monoclonal antibody revealed that active macrophages were infiltrating the endoneurium, which had a normal morphological aspect. By Weeks 5 and 15 p75NTR mRNA and protein were induced in the endoneurium of diabetic animals. Immunocytochemical analysis of teased single nerve fibers showed that p75NTR protein was distributed uniformly along isolated fibers with no pathological evidence of axonal degeneration or myelin disruption. At this time, cells of the phagocyte lineage had already disappeared from the nerve. These data show that during experimental diabetic neuropathy, the endoneurial induction of p75NTR is localized along isolated nerve fibers showing no morphological alterations, and in time, follows the recruitment of active macrophages in the nerve, suggesting that these cells, directly or through their products, can influence p75NTR induction. This process might play an important role in STZ diabetic neuropathy, as a response to decreased levels of neurotrophins such as NGF and promoting nerve regeneration in the early phases of the disease.     

Hereditary thermosensitive neuropathy: an autosomal dominant disorder of the peripheral nervous system

We report the clinical and electrophysiologic characteristics of eight patients (four men and four women) with a hereditary neuropathy with probable thermosensitivity (HTN) of autosomal dominant inheritance. Patients presented reversible episodes of ascending muscle weakness, paresthesiae, and areflexia apparently triggered by an elevation of body temperature over 38.5 degrees C. Mean age at onset was 13 +/- 12 (SD; range 6 to 43). Four patients had suffered up to five attacks. EMG and pathologic findings were compatible with a reversible demyelinating neuropathy such as Guillain-Barré syndrome. We excluded loci causing other hereditary demyelinating neuropathies, such as Charcot-Marie-Tooth disease type I (CMT type I) and hereditary neuropathy with liability to pressure palsies (HNPP), by linkage analysis; thus, HTN is not allelic to either CMT type I or to HNPP.     

Decompression sickness presenting as forearm swelling and peripheral neuropathy: a case report

Bleeding stomal varices is a rare complication of portal hypertension. We report the case of a cirrhotic patient, with a history of colonic adenocarcinoma, who had recurrent bleeding stomal varices. Treatment with transjugular intrahepatic portosystemic shunt and stomal varice embolization was performed because failure of medical treatment of portal hypertension and sclerotherapy. Twenty six months later only one stomal hemorrhage was noted. This suggests that transjugular intrahepatic portosystemic shunt and stomal varice embolization is effective in case of recurrent bleeding of stomal varices.     

Evidence of peripheral axonal neuropathy in primary restless legs syndrome

The aim of this study was to assess the risk and prognostic factors of gut perforation after orthotopic liver transplantation in children with biliary, atresia using univariate and stepwise regression analysis. Among 51 pediatric recipients who underwent transplantation because of biliary atresia after failure of portoenterostomy, 10 patients (20%) had 19 episodes of gut perforations after 14 transplantations. The median delay between transplantation and perforation was 13 days. These perforations were treated either by suture (n = 21) or ostomy (n = 11). The study of preoperative and perioperative variables showed that children with gut perforation were in surgery for a significantly longer period of time including a longer period of receiving hepatectomy and undergoing portal venous clamp. These children also needed large amounts of blood transfused during hepatectomy. After transplantation there was no difference regarding total steroid doses and early occurrence of cytomegalovirus disease between the two groups. Stepwise regression analysis identified three factors associated with the occurrence of gut perforation: duration of transplant operation, posttransplant intra-abdominal bleeding requiring reoperation, and early portal vein thrombosis. During the postoperative course, severe fungal infections were significantly more frequent in the gut perforation group. The 3-year patient survival rate was 70% in the group with gut perforation and was not different from the group without perforation (80%). This study shows that children with previous portoenterostomy carry a high risk of developing gut perforation after liver transplantation. This is especially true for those patients with the most difficult hepatectomies, which are responsible for the iatrogenic injury of the bowel. Other risk factors pointed out in this study were splanchnic congestion in case of prolonged portal venous clamp time or early portal vein thrombosis and repeated trauma of the bowel caused by reoperations. On the other hand, other well known risk factors, such as steroid therapy and viral diseases, were not involved in the occurrence of gut perforations in this study. Besides emergent surgical treatment, this type of complication requires aggressive therapy against fungal infections.     

The therapy of peripheral obstructive arteriopathies: rational bases

The authors underline the relations among the anatomical lesion progression, the appearance of the clinical signs (claudicatio) of tissue ischaemia and the thromboembolic event in vascular districts like myocardium and brain, at high morbidity and mortality risk. They widely state the pathogenetic mechanism of the atherosclerotic arterial disease and the compensative mechanisms that may prevent the ischaemic effects of the vascular obstruction. It has been considered the importance of the hemorheologic changes and their influence on the development of the ischaemic syndrome. The therapeutic choice in relation to physiopathologic and hemorheologic events in the peripheral obstructive arterial disease is considered.     

Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy

AIMS: This series analyses the results of conservative surgery for large lower pole breast cancers by lumpectomy associated with a bilateral remodelling mammoplasty, in order to avoid residual deformities. METHODS: This retrospective study concerns 50 patients with a lower pole breast cancer treated between 1986 and 1996 by lumpectomy, mammoplasty and irradiation. The contralateral breast was immediately made symmetrical in all cases. The mean tumour size was 32.5 mm. RESULTS: The mean weight of the lumpectomy specimen was 270 g. Resection margins were tumour-free in 90% of cases. The main complication observed was delayed healing, thus postponing post-operative treatment in 6.5% of cases. The median follow-up was 48 months. The 5-year actuarial ipsilateral local recurrence rate was 7% and 5-year actuarial metastasis-free and overall survival rates were 81 and 97%, respectively. Cosmesis was satisfactory in 85% of patients. We observed better results when radiotherapy was performed after rather than prior to surgery (92 vs. 67%: NS). CONCLUSIONS: Performing a bilateral mammoplasty at the time of initial surgery for large breast cancers situated in the lower quadrants of the breast facilitates larger lumpectomies with good cosmetic results.