Demyelination in vivo by Guillain-Barré syndrome and other human serum

Serum from patients with acute inflammatory polyneuropathy (the Guillain-Barré syndrome, GBS) demyelinates peripheral nerves in vivo more intensely than control human serum. To clarify the processes leading to demyelination we injected rat sciatic nerves with serum from GBS and control subjects in the presence of complement and examined the sequential morphologic changes over 7 days. One day after injection, five of six GBS sera but none of seven control sera caused vesicular demyelination; 3-5 days after injection both GBS and control sera produced macrophage-mediated demyelination. These observations suggest that GBS serum can initiate acute myelin injury through a humoral mechanism that is disease associated. This response appears to be distinct from delayed cell-mediated serum-induced demyelination that is not disease specific.     

Early relapse risk after a first CNS inflammatory demyelination episode: examining international consensus definitions

The International Pediatric Multiple Sclerosis Study Group (IPMS) has recently proposed consensus definitions for paediatric multiple sclerosis (MS) and related disorders. The term 'acute disseminated encephalomyelitis' (ADEM) has been used previously to describe any monophasic episode of disseminated demyelination. The study group now propose that ADEM must be multifocal, polysymptomatic, and include encephalopathy (as an essential requirement). An alternative diagnosis for a first acute inflammatory event is 'clinically isolated syndrome' (CIS). A CIS event may be either monofocal (such as isolated optic neuritis) or multifocal, but cannot include encephalopathy. As with adults, children with two or more discrete demyelinating events separated in time and space meet criteria for MS. In children with MS, the demyelination events must not meet ADEM criteria. To test the usefulness of these new criteria, a new cohort of 40 patients (18 males, 22 females; mean age 8 y [SD 4 y 4 mo]) with central nervous system (CNS) demyelination were studied. Using IPMS definitions, the presenting diagnosis was ADEM in 12 patients and CIS in 28 patients. At presentation, patients with CIS were more likely to have intrathecal synthesis of oligoclonal bands and fulfil KIDMUS MS magnetic resonance imaging criteria, compared with patients with ADEM (p<0.025). Patients were followed-up for a mean of 2 years 2 months. Only one of 12 patients with ADEM went on to develop MS during the study period, whereas 13 of 28 patients with CIS relapsed and fulfilled a diagnosis of MS (p<0.025). The new diagnostic criteria for ADEM may be criticized for being overly restrictive (particularly with encephalopathy being an essential criterion), and it is suspected that many practising physicians will be of the opinion that these new criteria will underdiagnose ADEM, and overdiagnose MS at the expense of multiphasic ADEM. However, it is hoped that these new criteria may improve prognostic specificity and provide uniformity to future paediatric CNS demyelination research.     

Neurocognitive outcome after acute disseminated encephalomyelitis

Cognitive dysfunction has been demonstrated in multiple sclerosis but has not been extensively studied after acute disseminated encephalomyelitis (ADEM). Because ADEM often presents with widespread demyelination, which may not completely resolve, these patients may be at risk for persistent cognitive dysfunction. The study objective was to explore the profile and severity of neurocognitive sequelae in pediatric ADEM. Children aged 6-15 years diagnosed with ADEM were invited to participate in a structured neurologic assessment, neuropsychological evaluation, and a follow-up magnetic resonance imaging. Nine of 15 children diagnosed with ADEM met the age criteria and six participated in the study. The mean age at presentation was 7.7 years; the mean duration of follow-up was 3.5 years. As a group, these children with prior ADEM performed within the average range on cognitive testing. However, a variety of mild cognitive deficits were demonstrated in each of the children, even in those whose magnetic resonance imaging studies had completely normalized. Four children demonstrated a cognitive profile of relatively poorer visuospatial/visuomotor function. The cognitive deficits observed in these children are similar but less severe than those previously reported in adults and children with multiple sclerosis, which may reflect the monophasic nature of ADEM, compared with the chronic, recurrent demyelination characteristic of multiple sclerosis.     

Fulminant form of acute disseminated encephalomyelitis: successful treatment with hypothermia.

We described herein a case of the fulminant form of acute disseminated encephalomyelitis (ADEM) that developed after mycoplasma pneumonia. A 28-year-old man who presented with fever, headache, and writing difficulty was admitted to our hospital in August 1997. He developed hernia on the 3rd hospital day. Surgical decompression and intravenous prednisolone failed to halt his progressive deterioration. We introduced systemic hypothermia and he has shown marked recovery; despite having Broca's type aphasia, he could comprehend spoken language and communicate with others by gesture. Head MRI demonstrated diffuse high signals over the white matter on fluid attenuated inversion recovery (FLAIR) images, which suggested extensive demyelination. The clinical course, imaging studies and presence of polymorphonuclear dominant leucocytosis in the blood and CSF in the patient are somewhat similar to findings in acute hemorrhagic leukoencephalitis, however, the result of a brain biopsy was inconclusive. The fulminant form of ADEM is usually fatal. Treatments such as corticosteroids, intravenous immunoglobulin, and surgical decompression have been performed to improve the prognosis. Our case results indicate that hypothermia, which suppresses both brain edema and immune response, may be included in the repertoire of treatment for the fulminant form of ADEM.     

Imaging of acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is a monophasic demyelinating disease of the central nervous system typically affecting the gray and the white matter of the brain and spinal cord in multiple locations. In the acute stages, ADEM is characterized histologically by perivenous edema, demyelination, and infiltration with macrophages and lymphocytes, with relative axonal sparing, whereas the late course of the disease is characterized by perivascular gliosis.     

MRI and proton MR spectroscopy in acute disseminated encephalomyelitis

Introduction Acute disseminated encephalomyelitis (ADEM) is one of a group of demyelinating disorders of the central nervous system (CNS). It is said to be attributed to an overshooting immunologic response following an infection or vaccination. The clinical course and type of manifestation is heterogeneous. The early application of corticosteroids has been shown to be beneficial to outcome; thus, an early diagnosis is highly desirable.Methods The potential diagnostic value of advanced MR techniques such as proton MR spectroscopy and diffusion-weighted imaging (DWI) was investigated in two paediatric patients with ADEM, one of whom had a remitting and relapsing clinical course and presented with additional cranial nerve involvement. Proton MR spectroscopy revealed typical signs of acute demyelination, such as increased macromolecules, not found in other forms of non-necrotising pathology.Conclusion The addition of proton MR spectroscopy and DWI adds to the diagnostic power of MRI in the setting of post-infectious demyelinating disorders of the CNS or ADEM and may obviate the need for biopsy.     

Electrophysiological studies in the Guillain–Barré syndrome: Distinguishing subtypes by published criteria

Guillain–Barré syndrome (GBS) is recognized clinically by the presence of acute, rapidly progressive weakness, areflexia, and albuminocytological dissociation in cerebrospinal fluid. Although GBS was initially considered to be primarily an acute inflammatory demyelinating polyneuropathy (AIDP), several other subtypes have been recognized: acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN), and Fisher syndrome (FS). Because each of these subtypes may have an independent immunopathogenesis and, therefore, may require selective treatments in the future, recognition of these subtypes is important. When using nerve conductions to classify the subtypes, the most easily and confidently identified subtype is AIDP. Therefore, most electrodiagnostic criteria have attempted to identify demyelination in this acute setting, in which physiology is constantly changing. In a single well-defined GBS population, we compared the various published criteria for demyelination in GBS. We reviewed charts of 43 patients with GBS between 1991 and 1996. Applying six available criteria sets, the number of patients categorized as having AIDP ranged from 21% to 72%. Until investigators can agree on a single set of criteria, considerable variability will continue to exist when identifying cases of AIDP. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1275–1279, 1998.     

Physiologic-pathologic correlation in Guillain-Barré syndrome in children

OBJECTIVE: To correlate electrophysiologic patterns with sural nerve pathology in children with Guillain-Barré syndrome (GBS). BACKGROUND: Based on electrophysiologic and pathologic observations, GBS has been divided into demyelinating and axonal subtypes. The acute motor axonal neuropathy (AMAN) involves predominantly motor nerve fibers with a physiologic pattern suggesting axonal damage, whereas the acute inflammatory demyelinating polyneuropathy (AIDP) involves both motor and sensory nerve fibers with a physiologic pattern suggesting demyelination. In this study, we sought to confirm these observations by correlating sural nerve pathology with electrophysiologic findings in GBS patients. METHODS: Biopsies of sural nerve from 29 of 50 prospectively studied GBS patients were obtained. Nerves were examined by light and electron microscopy, and with immunocytochemistry for macrophages, lymphocytes, and complement activation products. RESULTS: Sural nerves from AMAN patients were normal or had only a few (0.1% to 0.7%) degenerating fibers without lymphocytic infiltration or complement activation. One patient with reduced sural sensory nerve action potential classified as acute motor sensory axonal neuropathy (AMSAN) had many degenerating fibers (2.3%) in the sural nerve. All three AIDP patients displayed active demyelination, and in two patients, lymphocytic infiltration and complement activation products were observed on the abaxonal Schwann cell surface. CONCLUSION: Classification of Guillain-Barré syndrome subtypes based on motor conduction studies correlates closely with pathologic changes seen in sural nerve. In acute motor axonal neuropathy cases, the sural nerve is almost completely spared pathologically. In acute inflammatory demyelinating polyneuropathy cases, macrophage-mediated demyelination and lymphocytic infiltration are common in the biopsies of sural nerves.     

Humoral mechanisms in immune neuropathies.

Antibody and complement are implicated in the pathogenesis of a number of human, primarily demyelinating neuropathies. The ability of serum and purified, primarily IgM, antibodies to mediate demyelination was demonstrated in both in vitro and in vivo model systems. Complement activation to produce channel-forming terminal complement complexes, C5b-8 and C5b-9, was required for demyelination in vitro. Antibodies implicated in the demyelination of peripheral nerve of GBS patients and patients with monoclonal gammopathy-associated neuropathy bind carbohydrate epitopes on various neutral or acidic glycolipids and glycoproteins of peripheral nerve. In acute monophasic GBS, antibodies of multiple specificities may be induced to different infectious agents. These Ab, following penetration of a damaged blood-nerve barrier, are proposed to bind determinants of human peripheral nerve and participate in demyelination of nerve through activation of complement. These antibodies correlate with the clinical course, the generation of complement activation products, and the response to plasmapheresis. The mechanism by which the blood-nerve barrier is broken in GBS and other inflammatory demyelinating neuropathies and the extent of the role of the cellular immune system remain to be determined. Recent experiments demonstrated that T cells, antibody, and complement could synergistically contribute to central nervous system demyelination in naive rats. A similar synergism would be an attractive hypothesis for demyelination in the peripheral nervous system.     

Acute disseminated encephalomyelitis in children: clinical features and HLA-DR linkage

This study includes 90 children (41 female and 49 male) in the age range of 2-16 years with acute disseminated encephalomyelitis (ADEM). Thirty-three patients developed ADEM following rubella infection, 26 children following varicella infection, 20 suspected viral aetiology ADEM and 11 multiphasic disseminated encephalomyelitis (MDEM). All patients had neurological, routine laboratory and viral serology study with an enzyme-linked immunosorbent assay. Brain and/or spinal cord magnetic resonance imaging (MRI) were performed in 14 children. A follow-up study was in 1-5 years. Typing of DRB1 gene HLA class II was performed in 38 patients. We established that the varicella and rubella groups had preferential patterns. Rubella ADEM is characterized by acute explosive onset, seizures, coma and moderate pyramidal signs, whereas varicella infection is characterized by cerebella ataxia and mild pyramidal dysfunction. The suspected viral aetiology ADEM was characterized by polisymptomatic presentation. MDEM was characterized by older age of patients (11.6 +/- 2.8 years), more severe and prolonged local neurological symptoms, including myelitis symptoms and marked extrapyramidal signs, with distinct demyelination in MRIs. As a whole, ADEM is associated with DRB1*01 and DRB1*017(03) in the Russian population. Thus, ADEM is a separate autoimmune condition with a specific mechanism due to the type of genetic immunoregulatory base and specificity of viral trigger.     

Acute axonal form of Guillain–Barré syndrome in a multiple sclerosis patient: chance association or linked disorders?

Multiple sclerosis (MS) is characterized by inflammation, demyelination and gliosis, involving the central nervous system (CNS) and commonly sparing the peripheral nervous system (PNS). Coexistence of CNS and PNS chronic demyelination has been rarely demonstrated in chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) and in MS, but the occurrence of acute polyradiculoneuropathy in a patient with MS is even more unusual. We describe the case of a woman with relapsing-remitting MS who presented with an acute severe tetraparesis. Cerebrospinal fluid (CSF) examination together with neurophysiological data and sural nerve biopsy study demonstrated an axonal form of Guillain-Barré Syndrome (GBS). It remains unresolved if the association of an axonal form of GBS and MS is fortuitous or, on the contrary, is indicative of the coexistence in some individuals of common pathogenetic mechanisms.     

Guillain-Barré syndrome after brachial plexus trauma: case report

The Guilllain-Barré syndrome (GBS) is an acute predominantly demyelinating polyneuropathy. In many cases GBS is preceding by infection, immunization, surgery or trauma. Although there are a few reports of GBS after head trauma, there is no report of this syndrome after brachial plexus injury. We report on a 51 years-old man who presented GBS fifteen days after a brachial plexus trauma. The polineuropathy resolved completely in a few weeks. We believe that GBS was triggered by the trauma that evoked an immune mediated disorder producing inflammation and demyelination of the peripheral nerves.     

Tau protein concentrations in the cerebrospinal fluid of children with acute disseminated encephalomyelitis

Background: Acute disseminated encephalomyelitis (ADEM) is clinically characterized by the acute onset of neurological symptoms after a viral infection or immunization, and is thought to represent an autoimmune disease directed against myelin. Tau protein is a phosphorylated microtubule-associated protein, primarily located in neuronal axons. Increased levels of tau protein in cerebrospinal fluid (CSF) are found in various pathological conditions. Methods: We used tau protein as a marker of axonal damage and examined its concentration in the CSF of 27 children with ADEM. Results: CSF tau protein concentration in children with ADEM was significantly higher than that in the CSF of control subjects (P = 0.008). There were no significant differences in CSF tau protein concentrations in the ADEM patients with and without encephalopathy. The CSF tau protein concentration in patients with partial lesion resolution in follow-up brain MRI was significantly higher than in patients with complete lesion resolution (P = 0.014). Conclusions: In conclusion, we demonstrated that CSF tau protein concentration was significantly increased in ADEM patients. Our findings suggest that axonal damage may occur in addition to demyelination in children with ADEM.     

A-waves in Guillain-Barré syndrome: correlation with electrophysiological subtypes and antiganglioside antibodies

ObjectiveTo investigate the relationship of A-waves with conventional electrophysiological subtypes of Guillain–Barré syndrome (GBS), as well as with anti-ganglioside antibodies.MethodsThe subjects consisted of 30 GBS patients who were classified into acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy, and unclassified based on the results of nerve conduction studies. “Abundant A-waves” were defined for the upper-limb nerves (median and ulnar nerves) using receiver–operator characteristic curves. The presence or absence of IgG anti-ganglioside antibodies was also noted.ResultsAbundant A-waves at weeks 3–6 from onset were observed in 64% of the 14 AIDP patients and 0% of 16 non-AIDP patients, and in 60% of 15 antibody-negative patients and 0% of 15 antibody-positive patients. In the earlier period, this relationship was less clear. The correlation between the conventional electrophysiological subtypes and antibodies was present, but was much weaker.ConclusionsAbundant A-waves in GBS after the acute phase were strongly associated with demyelination that was not mediated by antiganglioside antibodies, possibly through the mechanism of proximal re-excitation induced by electrical inhomogeneities due to segmental demyelination.SignificanceAbundant A-waves are promising as a novel reliable marker of demyelination.     

An uncommon illness with a rare presentation: neurosurgical management of ADEM with tumefactive demyelination in children

Purpose  

This study determined the statewide incidence and prevalence of acute disseminated encephalomyelitis (ADEM) and examined the course of three pediatric patients treated for tumefactive demyelination (TD) at the Blair E. Batson Children’s Hospital.     

An antibody to VacA of Helicobacter pylori in cerebrospinal fluid from patients with Guillain-Barre syndrome

OBJECTIVE: To detect antibodies to recombinant vacuolating cytotoxin (r-VacA) of Helicobacter pylori in cerebrospinal fluid (CSF) from patients with Guillain-Barre syndrome (GBS). METHODS: CSF samples from 13 patients with GBS (electrophysiologically classified as eight acute inflammatory demyelinating polyradiculoneuropathy (AIDP), four acute motor axonal neuropathy (AMAN), and one unexcitable nerve conduction) and eight disease control patients were studied. The r-VacA protein was separated by SDS/PAGE, and Western blot analysis was carried out. RESULTS: Six of the 13 patients with GBS had a specific IgG antibody to VacA of H pylori, which was confirmed by absorption experiments using r-VacA. Every patient with positive CSF anti-r-VacA IgG had AIDP. CONCLUSION: The sequence homology previously found between VacA and human (Na(+)+K(+))-ATPase A subunit suggests that antibodies to VacA involve ion channels in abaxonal Schwann cell plasmalemma resulting in demyelination in some patients with GBS.     

In vivo demyelinating activity of sera from patients with Guillain-Barré syndrome

The in vivo demyelinating capacity of sera from 27 patients with Guillain-Barré syndrome (GBS) and 47 other individuals was studied by intraneural injection into rat sciatic nerves. The morphological features of the nerves in cross section taken just proximal to the site of needle insertion was assessed 48 hours after injection and the extent of demyelination was quantitated. All 27 GBS serum samples were obtained in the first three weeks of clinical disease. Of these, 11 (41%) produced demyelination. Demyelinative activity of GBS sera correlated only with severity of clinical disease (p<0.01). The extent of demyelination after intraneural injection of human sera was less intense on average than that produced by sera from animals with experimental allergic neuritis. Three of 40 (7.5%) sera obtained from normal subjects and patients with other neurological diseases also caused in vivo demyelination, although the activity was weaker and occurred less often than with GBS serum.     

Guillain-Barré syndrome: An update

Guillain-Barré syndrome (GBS) is an acute polyneuropathy consisting of different subtypes. Acute inflammatory demyelinating polyradiculoneuropathy, the classic demyelinating form of GBS, accounts for 90% of all GBS cases in the Western world. Acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN) are axonal forms of GBS that are more prevalent in Asia, South and Central America, often preceded by infection by Campylobacter jejuni. AMAN and AMSAN may be mediated by specific anti-ganglioside antibodies that inhibit transient sodium ion (Na⁺) channels. The efficacy of plasmapheresis and intravenous immunoglobulin has been established in large international randomised trials, with corticosteroids proven ineffective. Although axonal demyelination is an established pathophysiological process in GBS, the rapid improvement of clinical deficits with treatment is consistent with Na⁺ channel blockade by antibodies or other circulating factors, such as cytokines. This review provides an update on the epidemiology, clinical features, diagnosis, pathogenesis and treatment of GBS.     

Encephalomyelitis-associated antimyelin autoreactivity induced by streptococcal exotoxins

OBJECTIVE: After implicating Streptococcus pyogenes as causing acute disseminated encephalomyelitis (ADEM) in a child, we wanted to prove that in vivo activation of autoreactive T lymphocytes by superantigens of this Streptococcus contributed to the dramatic demyelination. BACKGROUND: ADEM is a demyelinating disorder of the CNS sharing many similarities with MS. Demyelination in MS is considered to be the result of an autoimmune process mediated by autoreactive T lymphocytes with specificity for myelin antigens. METHODS: Phenotypic analysis and proliferation assays on blood monocytes, as well as isolation of myelin basic protein (MBP)-reactive T-cell lines/clones; and TCR repertorium analysis by PCR-ELISA and cytokine production. RESULTS: 1) The blood T-cell receptor (TCR) repertoire was compatible with in vivo expansion induced by S. pyogenes exotoxins. 2) TCR expression analysis indicated clonal expansion of CD8+ MBP-reactive T cells, suggesting in vivo activation. MBP-reactive T cells showed crossreactivity to S. pyogenes supernatant and exotoxins. 3) Cytokine mRNA quantification of the mononuclear cells revealed a Th2-biased profile. CONCLUSION: In vivo exposure to S. pyogenes may have induced activation of pathogenic myelin reactive T cells, contributing to the dramatic inflammatory demyelination.     

儿童MOG抗体阳性的中枢神经系统脱髓鞘病变12例临床特点分析

目的探讨髓鞘少突胶质细胞糖蛋白(MOG)抗体阳性的儿童中枢神经系统脱髓鞘病变的临床特点。方法回顾性分析2016年1月至2018年12月广东三九脑科医院神经内科收治的12例儿童MOG抗体阳性的中枢神经系统脱髓鞘病患者的临床症状、影像学特点、实验室检查、预后及随诊情况。结果 12例患者中男4例,女8例,起病年龄5~10岁,平均(8.0±3.1)岁。首发症状以意识水平下降、癫痫大发作等急性播散性脑脊髓膜炎(ADEM)样症状最多见(8例,8/12),其次为视力下降(5例,5/12),其中1例以ADEM样症状和视力下降同时起病。另有3例以ADEM样症状首发,起病后1周左右出现视力下降。12例患者行头颅MRI检查,11例(11/12)可见颅内异常病灶,以皮层下白质(10例,10/11)、脑干(7例,7/11)、丘脑(6例,6/11)、视神经(5例,5/11)受累为主,小脑(4例,4/11)、胼胝体(1例,1/11)亦可受累。9例患者行全脊髓MRI检查,5例(5/9)有异常病灶,均累及颈髓(5例,5/5),3例(3/5)累及胸髓,累及胸髓的病灶均为>3个椎体节段的长节段脊髓受累。12例患者行血清MOG抗体检测,11例(11/12)阳性,另1例(1/12)血清抗体阴性而脑脊液抗体阳性;8例患者行脑脊液MOG抗体检测,3例(3/8)阳性。所有患者经糖皮质激素及免疫球蛋白治疗,预后均良好,3例患者出现复发。结论MOG抗体相关的儿童中枢神经系统脱髓鞘病变以ADEM、视神经脊髓炎谱系疾病(NMOSD)最常见,往往以意识水平下降、癫痫大发作或视力下降起病,其预后相对较好,糖皮质激素治疗对缓解临床症状及预防复发有重要作用。