HYPERTROPHY OF SPINAL ROOTS IN CHRONIC INFLAMMATORY DEMYELINATING NEUROPATHY

We have demonstrated in the SH-SY5Y human neuroblastoma cell line that the antineoplastic drug paclitaxel induces apoptosis associated with the phosphorylation of c-raf and Bcl-2, thus causing Bcl-2 inactivation. In addition, we have observed the cleavage of caspase 7 and PARP, and the involvement of JNK/SAPK cascade.
In this study, we investigated the possible anti-apoptotic effect of resveratrol on paclitaxel-induced apoptosis. Resveratrol is a natural antioxidant occurring in grapes and wine that as been shown to have anticancer and anti-inflammatory effects. Studies on the effect(s) of resveratrol on nervous cells are very few and limited to testing its ability in preventing oxidative stress in rat pheocromocytoma PC12 cells. However, the biological and pharmacological properties of resveratrol suggest that this natural compound might act on neuronal cells with a mode of action that is different from the antioxidant ones. To confirm this hypothesis, we studied the possible antagonist effect(s) of resveratrol on paclitaxel-induced apoptosis pathways.
Our results indicate that the simultaneous treatment of 50M resveratrol and 1M paclitaxel induces a significant reduction of the percentage of apoptotic cells in comparison with 1M paclitaxel alone. Furthermore, we have demonstrated that resveratrol treatment determines a significant reduction of the phosphorylation of c-raf and Bcl-2 and a partial reduction of cleavage of caspase 7 and PARP. Finally, we observed an evident reduction of activation of JNK/SAPK in the presence of resveratrol. On the contrary, resveratrol does not affect the tubulin polymerization induced by paclitaxel.
In conclusion, our results suggest that resveratrol is able to partially antagonize a nonoxidative stress apoptotic stimulus by influencing the typical signal pathways involved in apoptosis.     

UNMYELINATED NERVE FIBER DEGENERATION IN CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive disorder, is characterized by insensitivity to pain, self-mutilating behaviour, anhidrosis and recurrent hyperpyrexia. It is a hereditary sensory and autonomic neuropathy, also classified as HSAN, due to a defect of the receptor for nerve growth factor. CIPA is the first human genetic disorder caused by a defect in the neurotrophin signal transduction system. This is the first clinical report of CIPA patients characterized on molecular grounds. The clinical phenotypes of our patients show that CIPA is characterized by a multisystem involvement besides the nervous system, including bone fracture with slow healing, immunologic abnormalities, such as low response to specific stimuli, chronic inflammatory state ending in systemic amyloidosis. The molecular characterization allows a better understanding of most of the clinical features.     

C5b-9 TERMINAL COMPLEX ACTIVATION IN CHRONIC INFLAMMATORY DEMYELINATING NEUROPATHY

Aim of the Study : Amplify neurological balance in patients with recent vertebral spinal cord disease to establish the extension and gravity of damage on anterior horn cells, motor and sensory roots and the presence of entrapment neuropathies.
Materials and Methods: Fourteen consecutive patients (13 males and 1 female), mean age: 42.9 years (range 24–65), an interval of time from lesion>1 and < 3 months with cervical lesions in nine cases and lumbosacral lesions in five cases. Central and peripheral nervous system and/or systemic diseases preceding trauma were excluded. Besides neurological evaluations and vertebral NMR/CT, standard EMG were performed: motor (M) and sensory (S) nerve conductions (NC), F-wave study, and extensive muscular needle study differentiated in relation to cervical or lumbosacral side of lesion.
Results: In cervical traumas 5 subjects showed complete medullar transversal lesion (C8-T1 in 4 cases, C7 in 1 case) and 4 subjects incomplete lesion. EMG data: show amplitude CMAP in 5 subjects, MNC reduction in 4 patients, F-Wave absence in 1 case. Normal SNC in 7 cases. No observed relation between gravity of clinical palsy and EMG alterations. At needle examination frequently presence of alterations often also over and under clinical level spinal cord lesion. In lumbar trauma we verified 3 cases with complete medullar palsy and 2 cases cauda equina syndrome as clinical aspects. EMG data: extreme MNC alterations in 2 of 3 cases with medullar palsy (normal in 1 case). In 2 cases with cauda equina syndrome we observed strict concordance between clinical and EMG aspects.
Conclusions: EMG can usefully propose as systematically associated investigation in patients with post-traumatic spinal cord diseases in order to define the localization and the gravity of neurological lesion and the contribution of lower motor neuron lesion to clinical palsy.     

AUTOMIC FAILURE AND NORMAL PRESSURE HYDROCEPHALUS IN A PATIENT WITH CHRONIC DEMYELINATING INFLAMMATORY NEUROPATHY

We described a male child of two years and three months affected by assial hypotonia, psicomotor retardation, muscular distal hypotrophy with hyporeflexia, dystonic movements and deafness. He was born from non-consanguineous parents by spontaneous caesarian twin delivery at 38 weeks. His sister is healthy. He came to our observation at 16 months of age. Screenings for metabolic diseases and CSF neurotransmitters and lactate were normal, whereas the serum lactate was mildly increased. Brain MRI showed delayed myelination, with the normal lactate at the spectroscopic study. EEG showed interemispheric asymmetry with epileptic discharges. EMG showed a neurogenic pattern. Molecular DNA analysis for Spinal Muscular Atrophy was negative. Muscle biopsy showed neurogenic injury and an absence of ragged red fibers; enzymatic assay showed a severe deficiency of Complex I (2.8 nmol/min/mg protein, n.v. 17–33) and a mild deficiency of Pyruvate Dehydrogenase (PDHC=0.47 nmol/min/mg protein, n.v.0.8-2).
The clinical features of patients with a dysfunction in mitochondrial metabolic pathways are variable. A PDHC deficiency leads to a graduated spectrum of neurological involvement starting from severe forms with death in the neonatal period, Leigh disease and carbohydrate-induced episodic ataxia. The most common features associated with a PDHC defect are delayed development and hypotonia. Patients with Complex I deficiency show a variable phenotype from fatal infantile encephalomyopathy to adult-onset myopathy; neurodegenerative disorders are also described: Parkinson's disease, dystonia and Leber's optic neuropathy. A combined PHDC and Complex I deficiency is rarely reported. We can make the hypothesis that a defect of a single enzyme (Complex I) can play a role on the other enzyme deficiency. The presence of a primitive PHDC and Complex I deficiency is unlikely be hypothesized since the parents are not consanguineous and a double genetic defect is improbable.     

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP) ASSOCIATED WITH MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Up to now four patients with acute, purely motor, demyelinating neuropathy and conduction blocks have been described. Three cases had Campylobacter Jejuni (CJ) enteritis. In two ab anti-GM1 were detected, along with ab anti-GalNAc-GD1a in one. Two men (41 and 20 years old) developed weakness respectively ten days after enteritis and rubella. Examination showed in both proximal and distal weakness in all limbs with no sensory loss. Tendon reflexes were normal in the first patient, and brisk in the second. CSF proteins were increased. Serological tests did not support a recent CJ infection. High titres of IgG anti-GD1a and IgM anti-GM1 were found in the first patient. Electrophysiological examination showed, since the first days after onset, partial motor conduction block in ulnar nerves of the first patient and in eight motor nerves of the second patient. Sensory conductions were normal even across the sites of conduction block. Four plasmaphereses were performed. In the first patient conduction blocks gradually improved to disappear in 3 weeks without excessive temporal dispersion of proximal motor responses. In the second patient conduction blocks disappeared in 8–16 weeks with development of excessive temporal dispersion in 4  /  8 nerves.
We deem that acute motor neuropathy with conduction block is a GBS variant in which only motor fibers are involved with early conduction block in intermediate nerve segments. Our electrophysiological findings indicate that conduction block may be of the "anaesthetic type" followed by fast recovery or may progress to de-remyelination with a slower course.     

INFLAMMATORY DEMYELINATING NEUROPATHY IN C57BL/KaLwRij MICE

Neuropathies associated with monoclonal gammopathy (MG) in humans have been extensively studied in the past few years, but experimental models have proved difficult to create. C57BL mice are prone to develop benign MG and it has been reported that some of these mice with benign IgG MG present an inflammatory demyelinating neuropathy (IDN). In order to verify such findings, the serum and the sciatic nerve of the first group of 28 C57BL/KaLwRij mice were examined: none of 10 mice with normal serum showed ultrastructural abnormalities in the sciatic nerve, while lesions of IDN were present in three out of 10 mice with benign IgG MD, in two out of seven with benign IgM MG, and in a mouse with Waldenström–like lymphoma. The second group of animals was studied in the same way; it was composed of seven C57BL mice with transplanted multiple myeloma, and six C57BL mice with Morbus Waldenstrom–like lymphoma. In none of these animals, which were younger than those of the first group, was any lesion of IDN observed.     

NEUROPHYSIOLOGICAL DETERMINATION OF THE CARPAL TUNNEL SYNDROME IN PATIENTS WITH CHRONIC DEMYELINATING POLYNEUROPATHY

Clerici R., De Riz M., Corrà B., Baron P.L., Scarpini E., Conti G., Scarlato G.
Department of Neurological Sciences, Univ. of Milan, IRCCS Ospedale Maggiore, Milano
The specific spinal cord lesion caused by vitamin B12 deficiency is known as subacute combined degeneration (SCD). This is a rare cause of demyelination of the dorsal and lateral columns of spinal cord and even more rarely of peripheral nerves, optic nerve and brain.
We report a case of SCD in a vegetarian 55-year-old fe- male who presented with 6 weeks history of gradually progressive paresthesia involving thoracoabdominal skin below C5 dermatome and both lower limbs and postural instability due to a mild impairment of deep sensation. Hematological tests revealed abnormal Medium Corpuscular Volume (MCV) without anaemia and low vitamin B12 levels. The cause of this deficiency was secondary to atrophic gastritis. A spinal cord MRI demonstrated two T2-weighted hyperintense signal alterations (C1-C3 and C3-C4). She was treated with parenteral vitamin B12 supplements and experienced gradual improvement in her clinical symptoms. Repeat MRI of cervical spinal cord after 5 months showed a relevant decrease in the areas of abnormal signal. In other documented cases reported in literature, there was a precocious clinical improvement, while the MRI lesions recovered with a delay. However, it is essential to recognize SCD among the different demyelinating diseases and treat it as soon as possible.     

DISCRIMINATION OF ELEVATED IMMUNOGLOBULIN CONCENTRATIONS IN CSF DUE TO INFLAMMATORY REACTION OF THE CENTRAL NERVOUS SYSTEM AND BLOOD-BRAIN-BARRIER DYSFUNCTION

Inflammatory reactions of the central nervous system (CNS) are diagnosed by the determination of elevated immunoglobulin concentrations in cerebrospinal fluid (CSF) due to local production of immunoglobulins. However, unspecific disturbances of the blood-brain-barrier (BBB) can also cause an increase of CSF immunoglobulin concentration as a result of filtration from blood serum. The methods described here attempt a more precise characterization of immunoglobulins in CSF and to define that portion of CSF immunoglobulin derived from the CNS. Albumin and the immunoglobulin fractions IgG, IgA and IgM are determined in serum and CSF. The ratio of albumin in serum and CSF is taken as an indicator of BBB function. By the determination of quotients an overproportional immunoglobulin elevation in CSF as expression of an inflammatory reaction of the CNS can be detected. Methodological problems and the definition of normal ranges are discussed.     

CHRONIC RELAPSING EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS IN THE GUINEA-PIG: IN-VITRO ANALYSIS OF MENINGEAL INFLAMMATORY CELLS

Inflammatory cells from the meninges of guinea-pigs with chronic relapsing experimental allergic encephalomyelitis (CREAE) have been isolated and compared to a similar cell population obtained from guinea-pigs with acute EAE. A mean of 6.2 x 10(6) cells were recovered from the brains of animals with CREAE while a similar number of cells (8.0 x 10(6)) was obtained from animals with acute EAE. Only 5.3% of the cells from animals with CREAE were found to be phagocytic in contrast with 28% of the cells obtained from animals with acute EAE. The meningeal inflammatory cells from guinea-pigs with CREAE did not respond, in the lymphocyte transformation test, to specific antigens or to mitogen. Peritoneal exudate cells (PECs) from these animals did, however, proliferate in the presence of tuberculin and of mitogen, but not with the brain antigen myelin basic protein (MBP). In contrast, the meningeal inflammatory cells from animals with acute EAE did respond to mitogen and PECs from the same animals responded to both the specific antigens and to the mitogen. The meningeal inflammatory cells and PECs from the guinea-pigs with CREAE did, however, behave in a similar manner to similar cell populations obtained from guinea-pigs fully protected against clinical signs of acute EAE.     

OBJECTIVE ASSESSMENT OF MUSCLE STRENGTH IN CHROIIIC RELAPSING DYSIMMUNE POLYRADICULONEUROPATHY

Chronic, relapsing dysimmune polyradiculoneuropathy is an uncommon disease which occasionally affects children. The relapsing-remitting and/or progressive symptoms may be refractory to treatment. Regular, objective assessment of muscle strength, visually displayed, facilitates knowledge of the natural history of the disease and predicts response to treatment, and thus optimum planning for treatment. Myometry, discussed in this report, appears to be an objective and useful technique for this purpose, as illustrated in two teenage girls with this disease.     

CHANGES IN SERUM IMMUNOGLOBULIN LEVELS DURING PHENYTOIN TREATMENT of EPILEPSY

Immunoglobulin concentrations were determined by radial immunodiffusion in sera from 15 epileptic patients before and during phenytoin therapy. Three reaction patterns were recorded: Two patients developed IgA deficiency (<0.05 mg/ml) during the first 3–4 months of treatment. Both patients also had a decrease in serum IgG and IgM, but no significant fall or increase in serum IgE. the IgA deficiency state was apparently reversible, since normalization of serum levels occurred after withdrawal of phenytoin. Five patients developed a 35–80 per cent reduction in serum IgA. In these patients, the decline in serum levels of IgG and IgM was inconsistent. Eight patients showed no significant fluctuations in serum immunoglobulins during phenytoin treatment. When a fall in serum IgA occurred, it did not correspond to a fall in serum or in red cell folate. Mean serum IgG was lower (9.37 mg/ml) in epileptic patients who had taken phenytoin for < 1 year and had a low IgA, than in patients who had taken phenytoin for 10 years or more (11.50 mg/ml).     

DIAZEPAM: INTRAVENOUS INFUSION IN the TREATMENT of STATUS EPILEPTICUS

As the anticonvulsant plasma level of diazepam (DZP) after intravenous injection is maintained only for a short period, it is profitable to administer DZP as an intravenous infusion. It has, however, been claimed that DZP cannot be mixed with dextrose injection as DZP would precipitate. As this is in contrast to our clinical experience we added DZP of various brands to dextrose injections. A precipitate was in fact found in dextrose injections containing Valium® and Stesolid®, whereas Diazepam A.L.® was only slightly cloudy. the concentration of DZP was, however, the same in all the samples and corresponded to the calculated concentration. the precipitate in the solutions with Valium® and Stesohid® which did not pass the filter must therefore be due to additives, most probably benzoates. On the basis of these findings and our clinical experience of this mode of administration we recommend the infusion method as one of the most effective in the acute treatment of status epilepticus.     

MAINTENANCE TREATMENT OF CHRONIC SCHIZOPHRENIA WITH NEUROLEPTIC DRUGS

The difficulties for the short-stay doctor of managing the drug treatment of long-stay schizophrenic patients are discussed. Some principles to follow are suggested. The results of following these principles for 7 years are analysed. Only 74 out of a population of 475 chronic schizophrenics had been considered suitable for trial without drugs. Only five of these still remained off drugs. The relapses of the other 69 patients occurred after an average of about 4 1/2 months. Possible reasons for the widely different results of drug withdrawl trials are suggested.     

尼莫地平和丹参联合用药治疗外伤性脑血管痉挛的临床研究

目的:通过对60例外伤性脑血管痉挛的病人随机分为两组进行前瞻性对照研究,实验组为尼莫地平和丹参联合用药组,对照组为尼莫地平单独用药组,评价两种治疗方法的疗效。方法：实验组,30例病人发病后第三天始口服国产尼莫地平片剂40mg,每日3次,连续用药14～21天,从第三天开始同时静滴国产丹参注射液16mL,每日1次,连续用药14～21天。对照组：30例病人单独使用尼莫地干片剂,剂量、用药途径及用药时间与实验组相同。结果：脑功能恢复率,实验组为93．33％,对照组为73．33％,P＜0．05。结论：尼莫地平和丹参联合用药的疗效要优于单独用尼莫地平。     

DEMONSTRATION OF OLIGOCLONAL IMMUNOGLOBULIN G IN GUILLAIN-BARRÉ SYNDROME

Elevated concentrations in CSF of the immunoglobulins G, A, and M, when expressed as a percentage of the total protein concentration of CSF, were demonstrated during the initial phase of the course of the disease in a patient with Guillain-Barre syndrome (GBS). A slight elevation of the relative concentrations of IgG and IGM in CSF were also registered later in the course of the disease, at the time when the patient's neurological symptoms were in regression. Multiple discrete IgG bands were demonstrated by agarose electrophoresis in serum and in CSF during the first 2 weeks after onset of the neurological symptoms, and also after week 2 and still during week 12 after onset. The finding of transient oligoclonal IgG in a parient with GBS may suggest stimulation with e.g. viral antigen.     

E-CADHERIN AND β-CATENIN COMPLEX IN ANIMAL MODELS OF HEREDITARY DEMYELINATING PERIPHERAL NEUROPATHY

E‐cadherin, a major adhesive glycoprotein in Schwann cells (Fannon et al., 1995), is localized at the paranode, at Schmidt‐Lanterman incisures in the peripheral nerve along with β‐catenin, and associated with adherens‐type junctions. To investigate the functional role of E‐cadherin/β‐catenin complex in Schwann cells biology, we studied expression and localization of E‐cadherin and β‐catenin complex in sciatic nerve from normal mice and from animal model of hereditary demyelinating peripheral neuropathy. We found that E‐cadherin mRNA and proteins levels are regulated in normal mouse sciatic nerve during development like other myelin proteins. Furthermore, E‐cadherin expression in regenerating nerve is mediated by axonal/SC interaction. On the contrary, β‐catenin mRNA and protein levels did not change during development and following nerve lesion. Moreover, E‐cadherin/β‐catenin complex localization is altered in P0 knockout mice (P0‐/‐). In fact, E‐cadherin was diffusely distributed throughout the fibers in an unusual beaded pattern of staining, and β‐catenin was found in the perinuclear region of P0 ‐/‐ Schwann cells. Furthermore, E‐cadherin/β‐catenin complex localization is altered in peripheral nerve from other model of primary demielination where myelin compaction is lacking, such as Trembler‐J mice, while it is normally localized in Trembler mice, where demyelination is less severe and compaction is preserved. In conclusion, it appears that the process that leads to a restricted localization of E‐cadherin at the paranodal region is highly regulated and is disrupted in the peripheral nerve lacking compaction. Therefore, compaction contributes to the process of reorganization of the Schwann cells membrane during myelination and formation of a mature paranode. Altered E‐cadherin/β‐catenin complex localization, associated with absence of adherens junctions lead to changes in the structure of the paranodal region with important consequences on the molecular architecture of the Node of Ranvier, which lead to an altered transmission of impulses along axons, having important consequences in the pathogenesis of hereditary demyelinating peripheral neuropathy.