Acute Demyelinating Research Articles

Pediatric central nervous system inflammatory demyelination: acute disseminated encephalomyelitis, clinically isolated syndromes, neuromyelitis optica, and multiple sclerosis

We review the recent consensus definitions for acute disseminated encephalomyelitis,clinically isolated syndromes, neuromyelitis optica, and multiple sclerosis (MS) in children. We also discuss the importance of clinically defined consistency, the need for biomarker-based patient delineation, the likelihood of subsequent MS diagnosis following acute demyelination, and current therapeutic options. Studies of children after a first episode of demyelination have identified disease onset in adolescence, intrathecal oligoclonal bands and optic neuritis as associated with a higher MS risk, whereas prepubertal onset, presence of polyfocal features with encephalopathy, and transverse myelitis have been associated with a lower risk of subsequent MS. The relapsing-remitting form of MS accounts for over 96% of all MS in children. Neuromyelitis optica appears to be a distinct clinical and biological entity for which neuromyelitis optica IgG provides a high degree of specificity. Neuroimaging plays a key role in the diagnosis of acute demyelination, and serial imaging can provide evidence of lesion dissemination in time that can confirm a diagnosis of MS even in the absence of clinical relapse. Although clinical definitions, increased awareness, and MRI have contributed to the increasing identification of acute demyelination and MS in children, challenges remain in predicting MS risk. Identification of reliable biomarkers or application of more advanced neuroimaging techniques would serve as invaluable tools to distinguish monophasic demyelination from the first attack of MS.

Lack of TIMP-1 increases severity of experimental autoimmune encephalomyelitis: Effects of darbepoetin alfa on TIMP-1 null and wild-type mice

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are both characterized by the infiltration of myelin-reactive T cells that trigger oligodendrocyte death associated with axonal loss and neurodegeneration in the CNS. Proteolysis of the cerebral vascular extracellular matrix (ECM) resulting in blood-brain barrier (BBB) breakdown is thought to facilitate infiltration of autoreactive T cells in both of these demyelinating disorders. Increased matrix metalloprotease (MMP) activity coupled with reduced levels of tissue inhibitor of metalloproteases (TIMPs) contribute to a loss of BBB integrity. Erythropoietin induces expression of TIMP-1 in endothelial cells suggesting this property may account in part for its ability to maintain BBB integrity and efficacy in a preliminary clinical MS trial. Consistent with this hypothesis, we report here that administration of the erythropoietin analogue darbepoetin alfa at a low dose that did not elevate hematocrit reduced EAE severity in female C57BL/6 mice when administered following the onset of clinical signs. The protective effects of darbepoetin alfa were associated with an increase in the number of astrocytes expressing TIMP-1 in the brain and spinal cord. In keeping with a central role for TIMP-1 in this autoimmune model of acute demyelination, TIMP-1 null mice displayed a more severe EAE phenotype than wild-type littermates. Interestingly, we observed a lack of effect of darbepoetin alfa on EAE severity in TIMP-1 null mice. These findings indicate that TIMP-1 deficiency both enhances disease severity and attenuates the beneficial effects of low dose darbepoetin alfa in a mouse model of EAE.

Cuprizone demyelination of the corpus callosum in mice correlates with altered social interaction and impaired bilateral sensorimotor coordination.

For studies of remyelination in demyelinating diseases, the cuprizone model of CC (corpus callosum) demyelination has experimental advantages that include overall size, proximity to neural stem cells of the subventricular zone, and correlation with a lesion predilection site in multiple sclerosis. In addition, cuprizone treatment can be ended to allow more direct analysis of remyelination than with viral or autoimmune models. However, CC demyelination lacks a useful functional correlate in rodents for longitudinal analysis throughout the course of demyelination and remyelination. In the present study, we tested two distinct behavioural measurements in mice fed 0.2% cuprizone. Running on a ‘complex' wheel with varied rung intervals requires integration between cerebral hemispheres for rapid bilateral sensorimotor coordination. Maximum running velocity on the ‘complex' wheel decreased during acute (6 week) and chronic (12 week) cuprizone demyelination. Running velocity on the complex wheel distinguished treated (for 6 weeks) from non-treated mice, even after a 6-week recovery period for spontaneous remyelination. A second behavioural assessment was a resident–intruder test of social interaction. The frequency of interactive behaviours increased among resident mice after acute or chronic demyelination. Differences in both sensorimotor coordination and social interaction correlated with demonstrated CC demyelination. The wheel assay is applicable for longitudinal studies. The resident–intruder assay provides a complementary assessment of a distinct modality at a specific time point. These behavioural measurements are sufficiently robust for small cohorts as a non-invasive assessment of demyelination to facilitate analysis of subsequent remyelination. These measurements may also identify CC involvement in other mouse models of central nervous system injuries and disorders.

Alcohol abuse and acute behavioural disturbances in a 24-year-old patient

MBD was named after two Italian pathologists who described acute demyelination of the corpus callosum at necropsy in 3 South-Italian male red-wine drinkers. Etiology is unknown. The main pathological features range from demyelination with preserved axon structure, to extensive necrosis with cystic formation and microbleedings. Clinical features are highly variable and include reduced consciousness, unsteady gait, behavioural disturbances, motor defects, seizures and, rarely, interhemispheric disconnection syndromes. Most of these can be seen in much more frequent alcohol-related disorders like Wernicke’s encephalopathy or central pontine myelinolysis, which may not have distinct ocular findings. Recent brain-imaging methods, particularly MRI, disclosed highly specific lesion patterns which, combined with the clinical features, were used to divide MBD in 2 subtypes: type A, characterized by consciousness impairment, extensive T2-weighted hyperintense swelling of the corpus callosum, and bad prognosis; and type B, characterized by behavioural and gait disturbances, restricted ‘‘sandwich-like” T2-weighted hyperintense lesions in the corpus callosum genu or splenium, and a better outcome. MRI also assumes a pivotal role in distinguishing MBD from other diseases, as the lesions affect the central layers of the corpus callosum and

Chronic toxic demyelination in the central nervous system leads to axonal damage despite remyelination

The majority of multiple sclerosis lesions fail to remyelinate after chronic demyelinating episodes resulting in neurologic disability. In the current study, chronic demyelination was investigated by using the cuprizone model, a toxic demyelination model. C57BL/6 mice were administered a 0.2% cuprizone diet up to 16 weeks to induce chronic demyelination. For comparison, another group was maintained only for 6 weeks on cuprizone to model acute demyelination. Both groups were analysed regarding the remyelination process after withdrawal of the toxin. Reexpression of myelin proteins after chronic demyelination was reduced by a factor of two as judged by LFB and myelin protein stainings compared to acute demyelination after 2 weeks on remyelination. During chronic demyelination mature oligodendrocytes (Nogo-A positive cells) were severely depleted by 90% compared to age matched controls. Nevertheless, extensive remyelination occurred after withdrawal of cuprizone and was nearly complete after 12 weeks. There was only minimal acute axonal damage as judged by APP staining, with the course of APP positive axons correlating with macrophage/microglia accumulation. Chronic axonal damage detected by SMI-32 positive staining was only seen after chronic demyelination and was still observable during the whole remyelination period. These data suggest that two pattern of axonal injury occur in the cuprizone model.

1H MR Spectroscopy of inflammation, infection, and ischemia of the brain

Different pathologic patterns in multiple sclerosis (MS) are reflected by alterations of metabolites in 1H MR spectroscopy of the brain. Elevated choline (Cho), lactate (Lac), lipids, and macromolecules are reliable markers for acute demyelination regardless of the clinical entity (also in acute disseminated encephalomyelitis). N-Acetyl-aspartate (NAA) is a suitable marker for neuronal integrity. It is reduced in acute MS lesions and in normal-appearing white matter, even distant to acute and chronic lesions. Recovery from reduced NAA levels to subnormal values during remyelination and varying time courses of NAA in normal-appearing white matter during relapsing remitting disease indicate the value of this spectroscopic marker for monitoring activity and recovery. Inositol (Ins) is increased in chronic MS lesions being a marker for astrocytic gliosis. In viral disease, Cho and Ins are always increased, whereas a reduction of NAA mostly reflects an advanced or a deteriorated clinical state. In bacterial brain abscesses, numerous amino acids, lipids, and Lac can be elevated. In ischemia, especially the Lac/NAA, comparison with perfusion and diffusion-weighted imaging seems to be a new measure for areas of metabolic need and may help to better characterise the penumbra of the stroke and the final infarct size.

Type I interferon receptor signalling is induced during demyelination while its function for myelin damage and repair is redundant

The type I interferons, interferon-beta and alpha (IFN-β, IFN-α), are widely used for the treatment of autoimmune demyelination in the central nervous system (CNS). Their effects on de- and remyelination through the broadly expressed type I IFN receptor (IFNAR), however, are highly speculative. In order to elucidate the role of endogenous type I interferons for myelin damage and recovery we induced toxic demyelination in the absence of IFNAR1. We demonstrate that IFNAR signalling was induced during acute demyelination since the cytokine IFN-β as well as the IFN-dependent genes IRF7, ISG15 and UBP43 were strongly upregulated. Myelin damage, astrocytic and microglia response, however, were not significantly reduced in the absence of IFNAR1. Furthermore, motor skills of IFNAR1-deficient animals during non-immune demyelination were unaltered. Finally, myelin recovery was found to be independent from endogenous IFNAR signalling, indicating a redundant role of this receptor for non-inflammatory myelin damage and repair.

Clinical and Diagnostic Features of Delayed Hypoxic Leukoencephalopathy

Clinical and Diagnostic Features of Delayed Hypoxic Leukoencephalopathy

Case of fulminant‐SSPE associated with measles genotype D7 from India: An autopsy study

Subacute sclerosing panencephalitis (SSPE), a post-measles progressive neurological disorder is still common in India because of indifferent vaccination compliance. However, the acute fulminant form of SSPE is extremely rare. An unusual case of fulminant SSPE in an 18-year-old man from south India with an ultra-short course of 19 days presenting with hemiparesis in absence of myoclonus and progressive cognitive decline, is reported. MRI showed frontal and parieto-occipital demyelination extending to nuclear areas. Antimeasles antibodies were demonstrable in CSF and serum with oligoclonal bands in CSF despite normal CSF protein and cell count. At autopsy, unlike classical SSPE, oligodendroglia containing measles viral antigen was sparse despite florid necrotizing leukoencephalitis with acute demyelination. Measles virus was isolated from the brain with hypermutation in M gene confirming the diagnosis. Phylogenetic analysis of the viral genotype indicated that it belonged to D7 genotype which is considered rare in India.

A simple, inexpensive and easily reproducible model of spinal cord injury in mice: Morphological and functional assessment

Spinal cord injury (SCI) causes motor and sensory deficits that impair functional performance, and significantly impacts life expectancy and quality. Animal models provide a good opportunity to test therapeutic strategies in vivo. C57BL/6 mice were subjected to laminectomy at T9 and compression with a vascular clip (30 g force, 1 min). Two groups were analyzed: injured group (SCI, n = 33) and laminectomy only (Sham, n = 15). Locomotor behavior (Basso mouse scale—BMS and global mobility) was assessed weekly. Morphological analyses were performed by LM and EM. The Sham group did not show any morphofunctional alteration. All SCI animals showed flaccid paralysis 24 h after injury, with subsequent improvement. The BMS score of the SCI group improved until the intermediate phase (2.037 ± 1.198); the Sham animals maintained the highest BMS score (8.981 ± 0.056), p < 0.001 during the entire time. The locomotor speed was slower in the SCI animals (5.581 ± 0.871) than in the Sham animals (15.80 ± 1.166), p < 0.001. Morphological analysis of the SCI group showed, in the acute phase, edema, hemorrhage, multiple cavities, fiber degeneration, cell death and demyelination. In the chronic phase we observed glial scarring, neuron death, and remyelination of spared axons by oligodendrocytes and Schwann cells. In conclusion, we established a simple, reliable, and inexpensive clip compression model in mice, with functional and morphological reproducibility and good validity. The availability of producing reliable injuries with appropriate outcome measures represents great potential for studies involving cellular mechanisms of primary injury and repair after traumatic SCI.

Acute Combined Central and Peripheral Nervous System Demyelination in Children

Reports of acute combined central and peripheral nervous system acquired inflammatory demyelination are rare in children. This study aimed to (1) define the clinical features and prognoses of patients with this entity; and (2) compare these patients with children presenting isolated acute central or peripheral nervous system demyelination. A retrospective chart review of 523 children with central or peripheral nervous system demyelination hospitalized between 1993-2006 was undertaken. Among these, 93 fulfilled criteria (clinical features and positive magnetic resonance imaging or electromyography/nerve conduction studies) for either acute central (n = 37; 39.8%) or peripheral (n = 43; 46%) nervous system demyelination, or a combination of the two (n = 13; 14%). Significant differences between groups were evident for age (median, 10 versus 7 versus 11 years, respectively; P = 0.047), admission to pediatric intensive care unit (8% versus 30% versus 58%, respectively; P = 0.001), length of hospital stay (median, 8 versus 9 versus 29 days, respectively; P < 0.001), treatment with steroids (52% versus 7% versus 75%, respectively; P < 0.001) and immunoglobulins (11% versus 81% versus 75%, respectively; P < 0.001), and poor evolution (3% versus 12% versus 54%, respectively; P = 0.002). This entity in children is not rare, and has a poorer outcome than isolated central or peripheral nervous system demyelination. Assessment is needed for a better understanding of risk factors, etiologies, management, and prognosis.

Into the looking glass

Acquired demyelination of the CNS may occur as a monophasic illness or may be the harbinger of multiple sclerosis (MS). In adults, internuclear ophthalmoplegia, partial transverse myelitis, and optic neuritis are prototypic clinical presentations with a high likelihood of further demyelination leading to a diagnosis of MS. CSF oligoclonal bands are detected in over 95% of adult patients with MS when tested using high quality isoelectric focusing techniques.1 MRI evidence of clinically silent lesions is the most robust predictor of a future diagnosis of MS, with over 80% of such individuals developing clinical MS relapses within 2 years.2 Clinical or paraclinical features predictive of a future diagnosis of MS following an initial demyelinating event in children are less well understood. In this issue of Neurology ®, Neuteboom et al.3 review 117 children diagnosed with acute demyelination from 11 neuropediatric centers in the Netherlands. Over a mean period of observation of 54 months (median 43 months, range 5 to 201 …

Acute hemorrhagic demyelination in a murine model of multiple sclerosis

Acute hemorrhagic leukoencephalomyelitis (AHLE) is a rare neurological condition characterized by the development of acute hemorrhagic demyelination and high mortality. The pathomechanism of AHLE, as well as potential therapeutic approaches, have remained elusive due to the lack of suitable animal models. We report the first murine model of AHLE using a variation of the Theiler's Murine Encephalitis Virus (TMEV) MS model. During acute TMEV infection, C57BL/6 mice do not normally undergo demyelination. However, when 7 day TMEV infected C57BL/6 mice are intravenously administered the immunodominant CD8 T cell peptide, VP2121–130, animals develop characteristics of human AHLE based on pathologic, MRI and clinical features including microhemorrhages, increased blood-brain barrier permeability, and demyelination. The animals also develop severe disability as assessed using the rotarod assay. This study demonstrates the development of hemorrhagic demyelination in TMEV infected C57BL/6 mice within 24 hours of inducing this condition through intravenous administration of CD8 T cell restricted peptide. This study is also the first demonstration of rapid demyelination in a TMEV resistant non-demyelinating strain without transgenic alterations or pharmacologically induced immunosuppression.

Simultaneous Guillain-Barré Syndrome and Acute Disseminated Encephalomyelitis in the Pediatric Population

Few cases of simultaneous acute demyelination of the peripheral and central nervous systems are reported. Four patients diagnosed as having Guillain-Barré syndrome and acute disseminated encephalomyelitis during the same hospitalization are described herein. Two patients manifest an atypical form of Guillain-Barré syndrome, with magnetic resonance imaging of the head showing acute disseminated encephalomyelitis. A third patient has acute disseminated encephalomyelitis and develops Guillain-Barré syndrome during his hospitalization. A fourth patient demonstrates transverse myelitis that evolves into Guillain-Barré syndrome, with demyelination seen on brain magnetic resonance imaging. All patients are treated with intravenous immunoglobulins or corticosteroids. Three patients have a favorable outcome; 1 patient has a chronic inflammatory demyelinating polyradiculoneuropathy. Guillain-Barré syndrome and acute disseminated encephalomyelitis can occur simultaneously in the pediatric population. This may be explained by a shared epitope between peripheral and central nervous system myelin. Further research is necessary to better describe this entity and its prognosis.

6 4 Integrin and Dystroglycan Cooperate to Stabilize the Myelin Sheath

Schwann cells integrate signals deriving from the axon and the basal lamina to myelinate peripheral nerves. Integrin alpha6beta4 is a laminin receptor synthesized by Schwann cells and displayed apposed to the basal lamina. alpha6beta4 integrin expression in Schwann cells is induced by axons at the onset of myelination, and rises in adulthood. The beta4 chain has a uniquely long cytoplasmic domain that interacts with intermediate filaments such as dystonin, important in peripheral myelination. Furthermore, alpha6beta4 integrin binds peripheral myelin protein 22, whose alteration causes the most common demyelinating hereditary neuropathy. All these data suggest a role for alpha6beta4 integrin in peripheral nerve myelination. Here we show that ablating alpha6beta4 integrin specifically in Schwann cells of transgenic mice does not affect peripheral nerve development, myelin formation, maturation, or regeneration. However, consistent with maximal expression in adult nerves, alpha6beta4 integrin-null myelin is more prone to abnormal folding with aging. When the laminin receptor dystroglycan is also ablated, major folding abnormalities occur, associated with acute demyelination in some peripheral nervous system districts. These data indicate that, similar to its role in skin, alpha6beta4 integrin confers stability to myelin in peripheral nerves.

MO39 Acute combined central and peripheral nervous system demyelination in children

MO39 Acute combined central and peripheral nervous system demyelination in children

1H MR spectroscopy of inflammation, infection and ischemia of the brain

Different pathologic patterns in multiple sclerosis (MS) are reflected by alterations of metabolites in 1H MR spectroscopy of the brain. Elevated choline (Cho), lactate (Lac), lipids and macromolecules are reliable markers for acute demyelination regardless of the clinical entity (also in acute disseminated encephalomyelitis). N-acetyl-aspartate (NAA) is a suitable marker for neuronal integrity. It is reduced in acute MS lesions and in normal appearing white matter, even distant to acute and chronic-lesions. Recovery from reduced NAA levels to subnormal values during remyelination, and varying time courses of NAA in normal appearing white matter during relapsing remitting disease indicate the value of this spectroscopic marker for monitoring activity and recovery. Inositol (Ins) is increased in chronic MS lesions being a marker for astrocytic gliosis. In viral disease, Cho and Ins are always increased, whereas a reduction of NAA mostly reflects an advanced or a detoriated clinical state. In bacterial brain abscesses, numerous amino acids, lipids and Lac can be elevated. In ischemia, especially the Lac/NAA in comparison with perfusion and diffusion weighted imaging seems to be a new measure for areas of metabolic need, and may help to better characterise the penumbra of the stroke and the final infarct size.

Guillain-Barre Syndrome

Guillain-Barre syndrome (GBS) is caused by an inflammatory polyradiculoneuropathy, which most commonly results from acute demyelination produced by a CD4 T-cell mediated response against myelin proteins. Axonal forms have also been recognized. Molecular mimicry between components of the bacterial wall of Campylobacter jejuni and gangliocytes in the membranes of peripheral axons may be responsible for some cases of axonal GBS. Immune therapy with plasma exchange or intravenous immunoglobulin is the standard of care for the treatment of patients with acute GBS. This review summarizes available information regarding the pathophysiology, clinical manifestations, therapeutic consid- erations, and prognosis of this disorder. inducing GBS as a complication. Sporadic cases of GBS can occur after surgeries, in patients with cancer, after transplan- tations, and in patients with HIV infection (11). The rather paradoxical occurrence of GBS, an autoimmune condition, in patients with immune depression is likely explained by a dysregulation of the mechanisms modulating immune re- sponses.

Acute Inflammatory Demyelinating Polyneuropathy and a Unilateral Babinski/Plantar Reflex

Acquired acute demyelinating peripheral polyneuropathy (AADP) is a general classification of pathologies that could affect secondary the peripheral nervous system. They are characterized by an autoimmune process directed towards myelin. Clinically they are characterized by progressive weakness and mild sensory changes. Acute inflammatory demyelinating polyneuropathy often is referred to as Guillain-Barré syndrome (GBS). GBS is the major cause of acute nontraumatic paralysis in healthy people and it is caused by autoimmune response to viral agents (influenza, coxsackie, Epstein-Barr virus, or cytomegalovirus) or bacterial infective organisms (Campylobacter jejuni, Mycoplasma pneumoniae). A detailed history, with symptoms of progressive usually bilateral weakness, hyporeflexia, with a typical demyelinating EMG pattern supports the diagnosis. Progressive affection of respiratory muscles and autonomic instability coupled with a protracted and unpredictable recovery normally results in the need for ICU management. We present a case report of a patient with a typical GBS presentation but with a unilateral upgoing plantar reflex (Babinski sign). A unifying diagnosis was made and based on a literature search in Pubmed appears to be the first described case of its kind.

Gadofluorine M-enhanced magnetic resonance nerve imaging: Comparison between acute inflammatory and chronic degenerative demyelination in rats

Nerve imaging by magnetic resonance imaging (MRI) is an emerging tool for the diagnostic work-up of patients with PNS disorders. We have recently shown that the experimental MR contrast agent gadofluorine M (Gf, Bayer Schering Pharma AG, Berlin) accumulates in nerves undergoing Wallerian degeneration and in areas of acute focal demyelination allowing in-vivo assessment of nerve pathology. The exact pathomechanism underlying Gf accumulation in peripheral nerve disorders is unknown so far. In the present study we compared nerve signal alterations on T2-w and Gf-enhanced T1-w MRI in two different models of acute inflammatory and chronic degenerative demyelination: experimental autoimmune neuritis (EAN) induced by immunization with PNS myelin and experimental Charcot–Marie-Tooth (CMT) disease in rats overexpressing the myelin protein PMP22. During the acute stage of inflammation and demyelination, strong Gf enhancement on T1-w MRI was seen in nerve roots and peripheral nerves in EAN, which resolved with completed remyelination. Similarly, Gf accumulation was seen in CMT rats during early stages with active demyelination at 6 weeks while at chronic stages (9 months) Gf enhancement decreased despite numerous demyelinated axons and onion bulb formation. At all disease stages no signal alterations were seen on T2-w MRI. In conclusion, our data show that the novel MR contrast agent Gf, but not Gadolinium (Gd)–DTPA, facilitates detection of ongoing demyelination by MR neurography independent from the underlying pathology. It appears that the extent of Gf enhancement depends on the acuity of demyelination and is probably related to a transient disturbance of the blood–nerve barrier. Clinical development of Gf may help to further improve the sensitivity of nerve lesion assessment by MRI in patients with peripheral neuropathies.