Signs Of Demyelination Research Articles

Cuprizone short-term exposure: Astrocytic IL-6 activation and behavioral changes relevant to psychosis

A growing body of evidence suggests the involvement of inflammatory processes in the pathophysiology of schizophrenia. Four- to 8-week exposure to cuprizone, a copper chelator, causes robust demyelination and has been used to build a model for multiple sclerosis. In contrast, we report here the effects of 1-week cuprizone exposure in mice. This short-term cuprizone exposure elicits behavioral changes that include augmented responsiveness to methamphetamine and phencyclidine, as well as impaired working memory. The cellular effects of 1-week cuprizone exposure differ substantially from the longer-term exposure; perturbation of astrocytes and microglia is induced without any sign of demyelination. Furthermore, the proinflammatory cytokine interleukin-6 was significantly up-regulated in glial fibrillary acidic protein (GFAP)-positive cells. We propose that this cuprizone short-term exposure may offer a model to study some aspects of biology relevant to schizophrenia and related conditions.

Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease

Krabbe disease is a devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. A significant subset of the infantile form of the disease is due to missense mutations that result in aberrant protein production. The currently used mouse model, twitcher, has a nonsense mutation not found in Krabbe patients, although it is similar to the human 30 kb deletion in abrogating GALC expression. Here, we identify a spontaneous mutation in GALC, GALCtwi-5J, that precisely matches the E130K missense mutation in patients with infantile Krabbe disease. GALCtwi-5J homozygotes show loss of enzymatic activity despite normal levels of precursor protein, and manifest a more severe phenotype than twitcher, with half the life span. Although neuropathological hallmarks such as gliosis, globoid cells and psychosine accumulation are present throughout the nervous system, the CNS does not manifest significant demyelination. In contrast, the PNS is severely hypomyelinated and lacks large diameter axons, suggesting primary dysmyelination, rather than a demyelinating process. Our data indicate that early demise is due to mechanisms other than myelin loss and support an important role for neuroinflammation in Krabbe disease progression. Furthermore, our results argue against a causative relationship between psychosine accumulation, white matter loss and gliosis.

Cerebral demyelination in children with collagenous colitis

Collagenous colitis (CC) is a form of microscopic colitis characterized by the presence of inflammatory infiltrate and subepithelial deposition of collagen in the colon and it is a rare condition with a predominant prevalence in the adult population. Only few cases have been reported in children. We report two children with the CC with concomitant neurological manifestations. Both cases demonstrated variable neurological symptoms clinically and significant cerebral demyelination. In both patients, the gastrointestinal manifestations drastically improved with a short course of prednisolone. However, the neurological symptoms were persistent and progressive. To the best of our knowledge, similar association has not been reported in children.

Abbreviated exposure to cuprizone is sufficient to induce demyelination and oligodendrocyte loss

Cuprizone intoxication is one of several animal models used to study demyelination and remyelination. Early treatment protocols exposed mice to cuprizone for 6 weeks to induce demyelination; however, more recent reports have varied exposure times from 4 to 5 weeks. The goal of this study was to determine the minimal exposure of cuprizone in C57BL/6 mice that would induce a pathology of robust demyelination and gliosis similar to that described for a 5- or 6-week treatment. We found that an abbreviated insult of only 2 weeks of exposure to cuprizone induced significant demyelination 3 weeks later (5-week time point) but was somewhat variable. Three weeks of exposure to cuprizone produced extensive demyelination by week 5, equivalent to that observed with 5 weeks of exposure. The depletion of mature oligodendrocytes, as well as microglia and astrocyte accumulation, showed trends similar to those with 5-week exposure to cuprizone. Once mature oligodendrocytes are perturbed after a 3-week treatment, the progression to demyelination occurs without requiring further exposure. Furthermore, the early removal of cuprizone did not accelerate remyelination, suggesting that other sequences of events must follow before repair can occur. Thus, a short, "hit and run" CNS insult triggers a cascade of events leading to demyelination 2-3 weeks later.

Antibodies to Gliomedin Cause Peripheral Demyelinating Neuropathy and the Dismantling of the Nodes of Ranvier

Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are conditions that affect peripheral nerves. The mechanisms that underlie demyelination in these neuropathies are unknown. Recently, we demonstrated that the node of Ranvier is the primary site of the immune attack in patients with GBS and CIDP. In particular, GBS patients have antibodies against gliomedin and neurofascin, two adhesion molecules that play a crucial role in the formation of nodes of Ranvier. We demonstrate that immunity toward gliomedin, but not neurofascin, induced a progressive neuropathy in Lewis rats characterized by conduction defects and demyelination in spinal nerves. The clinical symptoms closely followed the titers of anti-gliomedin IgG and were associated with an important deposition of IgG at nodes. Furthermore, passive transfer of antigliomedin IgG induced a severe demyelinating condition and conduction loss. In both active and passive models, the immune attack at nodes occasioned the loss of the nodal clusters for gliomedin, neurofascin-186, and voltage-gated sodium channels. These results indicate that primary immune reaction against gliomedin, a peripheral nervous system adhesion molecule, can be responsible for the initiation or progression of the demyelinating form of GBS. Furthermore, these autoantibodies affect saltatory propagation by dismantling nodal organization and sodium channel clusters. Antibodies reactive against nodal adhesion molecules thus likely participate in the pathologic process of GBS and CIDP.

Nonequivalence of Classical MHC Class I Loci in Ability to Direct Effective Antiviral Immunity

Structural diversity in the peptide binding sites of the redundant classical MHC antigen presenting molecules is strongly selected in humans and mice. Although the encoded antigen presenting molecules overlap in antigen presenting function, differences in polymorphism at the MHC I A, B and C loci in humans and higher primates indicate these loci are not functionally equivalent. The structural basis of these differences is not known. We hypothesize that classical class I loci differ in their ability to direct effective immunity against intracellular pathogens. Using a picornavirus infection model and chimeric H-2 transgenes, we examined locus specific functional determinants distinguishing the ability of class I sister genes to direct effective anti viral immunity. Whereas, parental FVB and transgenic FVB mice expressing the H-2Kb gene are highly susceptible to persisting Theiler's virus infection within the CNS and subsequent demyelination, mice expressing the Db transgene clear the virus and are protected from demyelination. Remarkably, animals expressing a chimeric transgene, comprised primarily of Kb but encoding the peptide binding domain of Db, develop a robust anti viral CTL response yet fail to clear virus and develop significant demyelination. Differences in expression of the chimeric Kbα1α2Db gene (low) and Db (high) in the CNS of infected mice mirror expression levels of their endogenous H-2q counterparts in FVB mice. These findings demonstrate that locus specific elements other than those specifying peptide binding and T cell receptor interaction can determine ability to clear virus infection. This finding provides a basis for understanding locus-specific differences in MHC polymorphism, characterized best in human populations.

Thoracic Outlet Syndrome—Postural Type: Ultrasound Imaging of Pectoralis Minor and Brachial Plexus Abnormalities

Thoracic outlet syndrome (TOS) is a controversial diagnosis that sometimes is referred to as disputed or nonspecific neurogenic TOS because diagnostic test results typically are negative or inconclusive [1-10]. A review of the pathomechanics and associated dysfuncional body habitus suggests that use of the term “postural TOS” is more appropriate for this ommon type of presentation [10]. Postural TOS is thus recommended in cases without bjectifiable neurologic or vascular abnormality. In contrast, the less-common type of TOS nvolves compromise of the neurovascular bundle (NVB), which includes the brachial lexus (BP), the axillary or subclavian artery, and the axillary or subclavian vein [1-8,10]. Compression in all types of TOS may occur superiorly at the interscalene space, the costoclavicular space, or beneath the pectoralis minor muscle (PMM). The PMM location is recognized as a common and important site of compression in both the postural and nonpostural types of TOS [1-3,9-13]. The findings on an electrodiagnostic examination (EDX) typically are normal in patients with postural TOS because there is no axonal damage and no significant conduction block or demyelination [1,8,10]. Results of blood-flow studies usually are normal as well, and although they may reveal mild vascular compromise during stress maneuvers [1,2], this finding may not be clinically significant because it also can be seen in asymptomatic persons [1,7-9]. In addition, it is important to consider differential diagnoses and rule out the following conditions: cervical radiculopathy, peripheral nerve entrapment (median or ulnar), peripheral polyneuropathy, cervical cord lesion, or superior sulcus (Pancoast) tumor. The EDX may reveal the first 3 categories, but cervical magnetic resonance imaging (MRI) and a chest radiograph will be needed if the other conditions are considered. Neuromuscular ultrasound (NMUS) is a new imaging modality for examining nerve structures within the thoracic outlet area [14,15]. NMUS has unique applications for the postural type of TOS; as some researchers have noted, “evaluation of proximal nerves is often problematic when using electrodiagnostic techniques and may be more easily studied with ultrasound” [16]. My experience with this type of postural TOS [1,2,9,12,17,18] suggests that the PMM is contributory, and NMUS now appears to support these prior clinical impressions. Palpation of increased tension and trigger points in the PMM, combined with shoulder protraction, suggests that the PMM has shortened. The hypothesis herein is that the effects of a tight PMM can be observed to affect the NVB and explain the symptoms. The goal of this article is to present and analyze imaging findings in patients with TOS who were examined with NMUS while in neutral and stress positions, while monitoring for symptoms.

Clinical and electrophysiological characteristics of neuropathy associated with Tangier disease

Tangier disease (TD) (OMIM#205400) is a rare autosomal recessive disorder resulting from mutations in the ABCA1 gene, leading to decreased levels of plasma high-density lipoproteins (HDL). Peripheral neuropathy is a common finding in this disease, and may present as relapsing/remitting mono/polyneuropathies or as syringomyelia-like neuropathy. We retrospectively analyzed four patients, and report here their clinical, biological, electrophysiological, imaging, and genetic findings. Three patients had a typical pseudosyringomyelic neuropathy including facial diplegia, but asymmetrical onset was observed in one patient who had first been misdiagnosed with Lewis-Sumner syndrome. Electrophysiological pattern was heterogeneous, showing both signs of demyelination and axonal degeneration. Truncating mutations of the ABCA1 gene, including two previously undescribed mutations, were constantly found. Atypical symptom onset and demyelinating features on electrophysiological examination can be misleading in case of pseudosyringomyelic neuropathy. These reports illustrate two different neurological phenotypes in TD, namely the pseudosyringomyelic type and the Lewis-Sumner-like type, and advocate for a systematic assessment of lipid profile including HDL cholesterol in demyelinating neuropathies.

Sporadic diffuse leucoencephalopathy with axonal spheroids: report of a profuse and rapid cortical–spinal degeneration

Diffuse leucoencephalopathy with axonal spheroids (DLS) is a rare disease affecting the white matter leading to dementia and progressive motor impairment. The neuropathological hallmark includes axonal swelling and spheroids as well as myelin loss. We report a case of a 46-year-old man with memory deficit and behavioral changes followed by a rapid cognitive decline and pyramidal syndrome. Head magnetic resonance imaging showed cortical atrophy of the brain and symmetric corticospinal tract involvement. He died 4 years after the first symptoms. Autopsy was performed and the brain revealed cortical and corpus callosum atrophy, a grayish granular appearance of the white matter and ventricular enlargement. Myelin stains showed a significant demyelination of the centrum ovale and corticospinal tract. Such degeneration was accompanied by axonal loss, axonal swelling, and numerous spheroids. There was no pigment overload or inflammation. We discuss this new DLS case with bilateral, severe, and rapid cortical-spinal involvement.

Local Anesthetic Schwann Cell Toxicity Is Time and Concentration Dependent

Peripheral nerve blocks with local anesthetics (LAs) are commonly performed to provide surgical anesthesia or postoperative analgesia. Nerve injury resulting in persistent numbness or weakness is a potentially serious complication. Local anesthetics have previously been shown to damage neuronal and Schwann cells via several mechanisms. We sought to test the hypothesis that LAs are toxic to Schwann cells and that the degree of toxicity is directly related to the concentration of LA and duration of exposure. Intraneural injection of LAs has been shown to produce nerve injury. We sought to test the hypothesis that a prolonged extraneural infusion of LA can also produce injury. Schwann cells cultured from neonatal rat sciatic nerves were incubated with LAs at different concentrations (10, 100, 500, and 1000 μM), and each concentration was assessed for toxicity after 4, 24, 48 and 72 hours of exposure. Local anesthetics tested were lidocaine, mepivacaine, chloroprocaine, ropivacaine, and bupivacaine. Cell death was assessed by lactate dehydrogenase release measured by optical density.In a separate experiment, a microcatheter was placed along the sciatic nerves of Sprague-Dawley rats. Rats were randomly assigned to receive either 0.9% saline (n = 8) or bupivacaine (0.5%, n = 4; 0.75%, n = 4) via the perineural catheters for 72 hours. The rats were then killed, and their nerves sectioned and stained for analysis. Sections were stained for myelin and with an antimacrophage (CD68) antibody. None of the LAs tested produced significant Schwann cell death at very low concentrations (10 μM, or 0.0003%) even after prolonged exposure. With prolonged exposure (48 or 72 hrs) to high concentrations (1000 μM, or 0.03%), all of the LAs tested produced significant Schwann cell death (increased lactate dehydrogenase release relative to control as measured by optical density, 0.384-0.974; all P values < 0.001). Only bupivacaine produced significant cell death (0.482, P < 0.001) after prolonged exposure to low concentrations (100 μM, or 0.003%). At intermediate concentrations (500 μM, or 0.015%), cell death was more widespread with bupivacaine (0.768, P < 0.001) and ropivacaine (0.675, P < 0.001) than the other agents (0.204-0.368; all P values < 0.001). Prolonged extraneural exposure of rat sciatic nerves to bupivacaine caused significant demyelination and infiltration of nerves with inflammatory cells. Local anesthetics induce Schwann cell death in a time- and concentration-dependent manner. Bupivacaine and ropivacaine have greater toxicity at intermediate concentrations, and prolonged exposure to bupivacaine produces significant toxicity even at low concentrations. Brief exposure to high concentrations of bupivacaine damages Schwann cells. Prolonged extraneural infusion of bupivacaine results in nerve injury.

Falta de integridad de la sustancia blanca en la depresión bipolar como posible marcador estructural de la enfermedad

Background Diffusion tensor imaging allows the study of integrity of white matter (WM) tracts. Literature suggests that WM integrity could be altered in bipolar disorder. Heterogeneity of brain imaging methods, the studied samples, and drug treatments make localization, nature, and severity of the WM abnormalities unclear. Methods We applied tract-based spatial statistics of diffusion tensor imaging measures to compare fractional anisotropy (FA), mean, and radial diffusivity of the WM skeleton in a group of 40 consecutively admitted inpatients affected by a major depressive episode without psychotic features with a diagnosis of bipolar disorder type I and 21 unrelated healthy volunteers from the general population. Results Compared with control subjects, patients showed lower FA in the genu of the corpus callosum and in anterior and right superior-posterior corona radiata and higher values of radial diffusivity in WM tracts of splenium, genu and body of corpus callosum, right mid-dorsal part of the cingulum bundle, left anterior and bilateral superior and posterior corona radiata, bilateral superior longitudinal fasciculus, and right posterior thalamic radiation. Patients had no brain areas with higher FA or lower diffusivity values than control subjects. Conclusions Reduced FA with increased mean and radial diffusivity suggests significant demyelination and/or dysmyelination without axonal loss. Comparing our findings with other observations in homogeneous samples of euthymic and manic patients, it can be hypothesized that changes in measures of WM integrity might parallel illness phases of bipolar illness.

Peripheral Neuropathy in Patients with Systemic Lupus Erythematosus

In patients with systemic lupus erythematosus (SLE), to determine 1) the prevalence and clinical features of peripheral neuropathies (PN) and whether they were SLE related, 2) whether there are associations between other SLE features and PN. Patients who met the American College of Rheumatology case definition criteria for SLE peripheral neuropsychiatric syndromes were selected from the University of Toronto Lupus Clinic database. Demographic data and SLE-related clinical and laboratory data were extracted. Health-related quality of life was assessed using the mental and physical component summary score of the SF-36 questionnaire. In a nested case-control study, SLE patients with PN were matched by disease duration and compared with those without PN. Of 1533 patients in the database, 207 (14%) had PN. Of these, 40% were non-SLE-related. Polyneuropathy was diagnosed in 56%, mononeuritis multiplex in 9%, cranial neuropathy in 13%, and mononeuropathy in 11% of patients. Asymmetric presentation was most common (59%) and distal weakness occurred in 34%. Electrophysiologic studies indicated axonal neuropathy in 70% and signs of demyelination in 20% of patients. Compared with patients without PN, those with PN had significantly more central nervous system involvement, higher SLE-disease activity index 2000 and lower SF-36-PCS. The prevalence of PN is relatively high in SLE and occurs more frequently in patients with central nervous system involvement and high SLE-disease activity index. There is a predilection for asymmetric and lower extremities involvement, especially peroneal and sural nerves. This manifestation of the disease has a significant impact on the patient's quality of life.

Biocompatibility of Chronically Implanted Transverse Intrafascicular Multichannel Electrode (TIME) in the Rat Sciatic Nerve

The transverse intrafascicular multichannel electrode (TIME) is intended to be transversally implanted in the peripheral nerve and to selectively interface subsets of axons in different fascicles within the same nerve. Two versions of TIME (TIME-2, TIME-3) were designed and tested for biocompatibility and safety in the sciatic nerve of the rat. TIME-2 was implanted in two groups: one group had only an acute implant and the second group had chronic implantation for 2 months; a third group was also chronically implanted with the TIME-3 version, designed to avoid the mechanical traction produced by muscles motion. We evaluated the functional and morphological effects of either TIME-2 or TIME-3 implanted in the rat sciatic nerve for 2 months. The results of the study indicate that implantation of the TIME-2 and TIME-3 devices in the rat sciatic nerve did not cause significant axonal loss or demyelination, as evidenced by the functional and histological results. The results of this study indicate that the TIME-2 and TIME-3 designs are biocompatible and safe after chronic implantation in a small peripheral nerve, such as the rat sciatic nerve.

Central nervous system dysfunction in a mouse model of Fa2h deficiency

Fatty acid 2-hydroxylase (FA2H) is responsible for the synthesis of myelin galactolipids containing hydroxy fatty acid (hFA) as the N-acyl chain. Mutations in the FA2H gene cause leukodystrophy, spastic paraplegia, and neurodegeneration with brain iron accumulation. Using the Cre-lox system, we developed two types of mouse mutants, Fa2h(-/-) mice (Fa2h deleted in all cells by germline deletion) and Fa2h(flox/flox) Cnp1-Cre mice (Fa2h deleted only in oligodendrocytes and Schwann cells). We found significant demyelination, profound axonal loss, and abnormally enlarged axons in the CNS of Fa2h(-/-) mice at 12 months of age, while structure and function of peripheral nerves were largely unaffected. Fa2h(-/-) mice also exhibited histological and functional disruption in the cerebellum at 12 months of age. In a time course study, significant deterioration of cerebellar function was first detected at 7 months of age. Further behavioral assessments in water T-maze and Morris water maze tasks revealed significant deficits in spatial learning and memory at 4 months of age. These data suggest that various regions of the CNS are functionally compromised in young adult Fa2h(-/-) mice. The cerebellar deficits in 12-month-old Fa2h(flox/flox) Cnp1-Cre mice were indistinguishable from Fa2h(-/-) mice, indicating that these phenotypes likely stem from the lack of myelin hFA-galactolipids. In contrast, Fa2h(flox/flox) Cnp1-Cre mice did not show reduced performance in water maze tasks, indicating that oligodendrocytes are not involved in the learning and memory deficits found in Fa2h(-/-) mice. These findings provide the first evidence that FA2H has an important function outside of oligodendrocytes in the CNS.

Using diffusion tensor imaging and immunofluorescent assay to evaluate the pathology of multiple sclerosis

To determine the ability of the principal diffusion tensor imaging (DTI) indices to predict the underlying histopathology evaluated with immunofluorescent assay (IFA). Conventional T2 and 3D multishot-diffusion weighted echoplanar imaging (3D ms-DWEPI) was performed on a fixed, ex vivo human cervical spinal cord (CSC) from a patient with a history of multiple sclerosis (MS). In all, 170 regions of interest (ROIs) were selected within the white matter and categorized as a high intensity lesion (HIL), low intensity lesion (LIL), and normal-appearing white matter (NAWM). The longitudinal diffusivity (λl), radial diffusivity (λr), and fractional anisotropy (FA) were obtained from each ROI. The underlying histopathology was then evaluated using immunofluorescent assay with antibodies directed to myelin and neurofilament staining. The mean values for λl and λr were significantly elevated within HIL relative to NAWM and LIL. IFA analysis of HIL demonstrated significant demyelination, without significant if any axon loss. The FA values were significantly reduced in HIL and LILs. FA values were also reduced in lesions with increased λl and λr values relative to normal. Aberrant λl, λr, and FA relative to normal values are strong indicators of demyelination. DTI indices are not specific for axon loss. IFA analysis is a reliable method to demonstrate myelin and axon pathology within the ex vivo setting.

Corpus Callosum Microstructural Changes Correlate with Cognitive Dysfunction in Early Stages of Relapsing-Remitting Multiple Sclerosis: Axial and Radial Diffusivities Approach

The corpus callosum is the largest fiber bundle in the central nervous system and it takes part in several cognitive pathways. It can be affected by multiple sclerosis (MS) early in the disease. DTI is capable of infering the microstructural organization of the white matter. The vectorial analysis of the DTI offers the more specific indices of axial diffusivity (AD) and radial diffusivity (RD), which have shown to be useful to discriminate myelin damage from axon loss, respectively. This study presents DTI results (mean diffusivity (MD), fractional anisotropy (FA), RD, and AD) of 23 relapsing-remitting MS patients and its correlation with cognitive performance. There were 47.8% of cognitive impaired patients (MS CI). We found signs of demyelination, reflected by increased RD, and incipient axon loss, reflected by AD increase, which was slightly higher in the MS CI. The cognitive changes correlated with the DTI parameters, suggesting that loss of complexity in CC connections can impair neural conduction. Thus, cognitive impairment can be related to callosal disconnection, and DTI can be a promising tool to evaluate those changes.

Disruption of White Matter Integrity in Bipolar Depression as a Possible Structural Marker of Illness

Diffusion tensor imaging allows the study of integrity of white matter (WM) tracts. Literature suggests that WM integrity could be altered in bipolar disorder. Heterogeneity of brain imaging methods, the studied samples, and drug treatments make localization, nature, and severity of the WM abnormalities unclear. We applied tract-based spatial statistics of diffusion tensor imaging measures to compare fractional anisotropy (FA), mean, and radial diffusivity of the WM skeleton in a group of 40 consecutively admitted inpatients affected by a major depressive episode without psychotic features with a diagnosis of bipolar disorder type I and 21 unrelated healthy volunteers from the general population. Compared with control subjects, patients showed lower FA in the genu of the corpus callosum and in anterior and right superior-posterior corona radiata and higher values of radial diffusivity in WM tracts of splenium, genu and body of corpus callosum, right mid-dorsal part of the cingulum bundle, left anterior and bilateral superior and posterior corona radiata, bilateral superior longitudinal fasciculus, and right posterior thalamic radiation. Patients had no brain areas with higher FA or lower diffusivity values than control subjects. Reduced FA with increased mean and radial diffusivity suggests significant demyelination and/or dysmyelination without axonal loss. Comparing our findings with other observations in homogeneous samples of euthymic and manic patients, it can be hypothesized that changes in measures of WM integrity might parallel illness phases of bipolar illness.

Focal demyelination in Alzheimer’s disease and transgenic mouse models

We have investigated alterations in myelin associated with Abeta plaques, a major pathological hallmark of Alzheimer's disease (AD), in human tissue and relevant transgenic mice models. Using quantitative morphological techniques, we determined that fibrillar Abeta pathology in the grey matter of the neocortex was associated with focal demyelination in human presenilin-1 familial, sporadic and preclinical AD cases, as well as in two mouse transgenic models of AD, compared with age-matched control tissue. This demyelination was most pronounced at the core of Abeta plaques. Furthermore, we found a focal loss of oligodendrocytes in sporadic and preclinical AD cases associated with Abeta plaque cores. In human and transgenic mice alike, plaque-free neocortical regions showed no significant demyelination or oligodendrocyte loss compared with controls. Dystrophic neurites associated with the plaques were also demyelinated. We suggest that such plaque-associated focal demyelination of the cortical grey matter might impair cortical processing, and may also be associated with aberrant axonal sprouting that underlies dystrophic neurite formation.

A 45‐YEAR OLD MALE WITH LEFT‐SIDED HEMIHYPESTHESIA

A 45-year-old man presented with progressive brainstem and cerebellar dysfunction. Extensive immunological and radiological investigations were not able to differentiate between an intrinsic brain tumor and a demyelinating disease. Stereotactic biopsies of the brainstem were performed; the findings of abundant Rosenthal fibers, interjacent spindle-shaped and gemistocytic cells partially with dark and irregularly formed nuclei favored primarily the diagnosis of a malignant astrocytoma, although a demyelinating disease could not be definitely excluded. Facing the fulminant clinical course radio- and chemotherapy was initiated; however, the patient died of sepsis-associated multi-organ failure three and a half years after disease onset. Post mortem pathology finally revealed lesions with central amorphic necrosis surrounded by areas of significant demyelination, astrocytosis, microglia cells and macrophages typical for MS. Although criteria for establishing MS are well known, a correct diagnosis can be extremely challenging in small stereotactic specimens, where so-called pathological hallmarks are spared and unusual pathological findings are predominant.

Autonomic dysfunction in experimental allergic neuritis.

Beat-to-beat variation (R-R variation) in the electrocardiogram was studied in experimental allergic neuritis in the Sprague-Dawley rat. Reduced R-R variations were found in 2 of 10 animals, probably as a sign of autonomic dysfunction. The vagal nerves from these two animals, studied in vitro, showed disturbed conduction. In one animal prolonged conduction latencies to supramaximal electrical stimuli were found. Vagal nerves from controls and from animals without clinical symptoms showed normal conduction. Histologically, the vagal nerves from affected animals showed a slight inflammatory cell infiltration and signs of demyelination but there was no evidence of involvement of the brainstem vasomotor nuclei. Thus, we suggest that the autonomic dysfunction in experimental allergic neuritis, measured as reduced R-R variations, is caused by a peripheral vagal neuropathy.