Brain

Hughes, T. A. T.

doi: 10.1093/brain/awf263pmid: N/A

Duysens, J.

doi: 10.1093/brain/awf261pmid: 12429588

Willison, Hugh J.; Yuki, Nobuhiro

doi: 10.1093/brain/awf272pmid: 12429589

This review charts the progress of anti‐glycolipid antibodies in neuropathy, from their original discovery 20 years ago in immunoglobulin M paraproteinaemic neuropathy through to current discoveries mapping their relationship to subtypes of Guillain–Barré syndrome. Antibodies to >20 different glycolipids have now been associated with a wide range of clinically identifiable acute and chronic neuropathy syndromes. Particular progress has been achieved in understanding the link between acute motor axonal neuropathy and antibodies to GM1, GD1a, GM1b and GalNAc‐GD1a, and between the cranial, bulbar and sensory variants of GBS and antibodies to the disialylated gangliosides GQ1b, GT1a, GD1b and GD3. In addition to clinical and serological studies, the origins and measurement of anti‐glycolipid antibodies and their relationships to similar carbohydrate structures on infectious organisms, particularly Campylobacter jejuni , are discussed in the context of a molecular mimicry hypothesis. The structure and nomenclature of relevant glycolipids are outlined, along with information on their localization in nerve, and the influence this has on clinical phenotypes. Major advances have been made in animal modelling of anti‐glycolipid antibody‐associated diseases, both in vitro and in vivo. This has advanced our understanding of the role of anti‐GQ1b antibodies in Miller Fisher syndrome with particular respect to the motor nerve terminal as a potential site of injury, and led to the creation of rabbit models of anti‐GD1b and anti‐GM1 antibody‐mediated sensory and motor neuropathy, respectively. With such information in place, it will now be possible to determine the precise mechanisms by which antibodies injure the different compartments of peripheral nerve and establish how a range of immunomodulating therapies, including current treatments, exert their therapeutic effects. Despite these very significant advances, considerable gaps in our knowledge persist, and it is likely that other pathogenic pathways operate in inflammatory neuropathy that are unrelated to glycolipid antibodies, although these are outside the scope of this review.

Dietz, Volker; Müller, Roland; Colombo, Gery

doi: 10.1093/brain/awf273pmid: 12429590

The aim of this study was to differentiate the effects of body load and joint movements on the leg muscle activation pattern during assisted locomotion in spinal man. Stepping movements were induced by a driven gait orthosis (DGO) on a treadmill in patients with complete para‐/tetraplegia and, for comparison, in healthy subjects. All subjects were unloaded by 70% of their body weight. EMG of upper and lower leg muscles and joint movements of the DGO of both legs were recorded. In the patients, normal stepping movements and those mainly restricted to the hips (blocked knees) were associated with a pattern of leg muscle EMG activity that corresponded to that of the healthy subjects, but the amplitude was smaller. Locomotor movements restricted to imposed ankle joint movements were followed by no, or only focal EMG responses in the stretched muscles. Unilateral locomotion in the patients was associated with a normal pattern of leg muscle EMG activity restricted to the moving side, while in the healthy subjects a bilateral activation occurred. This indicates that interlimb coordination depends on a supraspinal input. During locomotion with 100% body unloading in healthy subjects and patients, no EMG activity was present. Thus, it can be concluded that afferent input from hip joints, in combination with that from load receptors, plays a crucial role in the generation of locomotor activity in the isolated human spinal cord. This is in line with observations from infant stepping experiments and experiments in cats. Afferent feedback from knee and ankle joints may be involved largely in the control of focal movements.

Picconi, Barbara; Pisani, Antonio; Centonze, Diego; Battaglia, Giuseppe; Storto, Marianna; Nicoletti, Ferdinando; Bernardi, Giorgio; Calabresi, Paolo

doi: 10.1093/brain/awf269pmid: 12429591

Excessive activation of ionotropic glutamate receptors in the striatum contributes to the pathophysiology of motor symptoms in Parkinson’s disease. Metabotropic glutamate (mGlu) receptors regulate striatal excitatory synaptic transmission, and adaptive changes in their function might occur following dopaminergic denervation and chronic levodopa‐treatment (L‐DOPA). Corticostriatal glutamatergic transmission was examined in striatal slices obtained from rats unilaterally denervated with the dopaminergic neurotoxin, 6‐hydroxy dopamine (6‐OHDA), and from denervated rats chronically treated with L‐DOPA plus benserazide (25 + 6.25 mg/kg, intraperitoneally, twice daily for 21 days). Selective agonists of mGlu2 and ‐3 receptor subtypes (compounds LY379268 and (2S,2′R,3′R)‐2‐(2′,3′‐( 3 H)‐dicarboxycyclopropyl)glycine (( 3 H)DCG‐IV)) exhibited a much greater potency in depressing excitatory transmission and corticostriatal synapses in slices prepared from 6‐OHDA‐lesioned animals. Dopaminergic denervation affected neither the ability of L‐(+)‐2‐amino‐4‐phosphonobutyric acid (L‐AP4; a selective agonist of mGlu4, ‐6, ‐7 and ‐8 receptors) to inhibit corticostriatal transmission, nor the ability of (S)‐3,5‐dihydroxyphenylglycine (3,5‐DHPG; a selective agonist of mGlu1 and ‐5 receptors) to potentiate responses mediated by N ‐methyl‐ d ‐aspartate (NMDA) receptor activation in striatal neurones. The increased responsiveness to mGlu2/3 receptor agonists was no longer detected in slices from 6‐OHDA‐lesioned animals chronically treated with L‐DOPA. 6‐OHDA‐induced denervation also led to an increased expression of striatal mGlu2/3 receptor proteins and to a >2‐fold increase in the maximal density ( B max ) of ( 3 H)DCG‐IV binding sites. These increases were again reversed by chronic treatment with L‐DOPA. No changes in the expression of mGlu4 receptors or the α i1 and α i2 subunits of the G i proteins were induced by any of the treatments. We suggest that an enhanced sensitivity of pre‐synaptic inhibitory mGlu2/3 receptors might represent an adaptive change triggered by dopaminergic denervation, which can be reversed by L‐DOPA treatment.

Reddy, H.; Narayanan, S.; Woolrich, M.; Mitsumori, T.; Lapierre, Y.; Arnold, D. L.; Matthews, P. M.

doi: 10.1093/brain/awf283pmid: 12429592

Previous work has demonstrated potentially adaptive cortical plasticity that increases with brain injury in patients with multiple sclerosis. However, animal studies showing use‐dependent changes in motor cortex organization suggest that functional changes also may occur in response to disability. We therefore wished to test whether brain injury and disability lead to distinguishable patterns of activation with hand movement in patients with multiple sclerosis. By employing a passive as well as an active movement task, we also wished to test whether these changes were independent of voluntary recruitment and thus more likely to reflect true functional reorganization. Fourteen patients (Extended Disability Status Score (EDSS) 0–7.5) with relapsing–remitting multiple sclerosis were selected on the basis of pathology load and hand functional impairment for three study groups: group 1, low diffuse central brain injury (DCBI) as assessed from relative N‐acetylaspartate concentration (a marker of axonal integrity) and normal hand function ( n = 6); group 2, greater DCBI and normal hand function ( n = 4); and group 3, greater DCBI and impaired hand function ( n = 4). Functional MRI (fMRI) was used to map brain activation with a four‐finger and both one‐finger passive and active flexion–extension movement tasks for the three groups. Considering all the patients, we found increased activity in ipsilateral premotor and ipsilateral motor cortex (IMC) and in the ipsilateral inferior parietal lobule with increasing global disability (as assessed from the EDSS score). These changes appear to define true functional reorganization, as fMRI activations in IMC ( r = 0.87, P < 0.001) and in the contralateral motor cortex ( r = 0.67, P < 0.007) were highly correlated between active and passive single finger movements. We attempted to disambiguate any distinct effects of disability and brain injury by direct contrasts between patients differing predominantly in one or the other. To make these contrasts as powerful as possible, we used impairment of finger tapping as a measure of disability specific to the hand tested. A direct contrast of patients matched for DCBI, but differing in hand disability (group 3 – group 2) showed greater bilateral primary and secondary somatosensory cortex activation with greater disability alone. A contrast matched for hand disability, but differing in DCBI (group 2 – group 1) showed a different pattern of changes with relative ipsilateral premotor cortex and bilateral supplementary motor area activity. We conclude that the pattern of brain activity with finger movements changes both with increasing DCBI and with hand disability in patients with multiple sclerosis, and that these changes are distinct. Those related directly to disability may reflect responses to altered patterns of use. As injury‐ and disability‐related activation changes are found even with passive finger movements, they may reflect true brain reorganization.

Mayo, Isabel; Arribas, Joaquín; Villoslada, Pablo; Alvarez DoForno, Rita; Rodríguez‐Vilariño, Susana; Montalban, Xavier; de Sagarra, María Rosa; Castaño, José G.

doi: 10.1093/brain/awf274pmid: 12429593

Multiple sclerosis seems to be an autoimmune disease of unknown aetiology affecting the white matter of the CNS. It is generally accepted that the autoimmune response is directed against specific components of myelin. We show here that proteasome, a ubiquitous protease complex composed of 14 different subunits, is a target for autoantibodies (IgG and IgM classes) present in the serum (66%, 73 out of 110) and in the CSF (61%, 16 out of 26) of patients with multiple sclerosis. Using recombinant proteasomal subunits we demonstrate the presence of specific autoantibodies against subunits C2, C8, C9 and C5 in multiple sclerosis patients. Recombinant C2 constructs allow us to localize an immunodominant autoepitope recognized by the sera of multiple sclerosis patients within the C‐terminal of C2 proteasomal subunit (251‐DEPAEKADEPMEH‐263). In addition, two constructs of the recombinant proteasomal subunits C2 and C8 were also used to study the proliferation of peripheral blood mononuclear cells from multiple sclerosis patients; 12 out of 30 (40%) multiple sclerosis patients show positive proliferation with one or both of these recombinant subunits. The high prevalence of anti‐proteasome autoantibodies in multiple sclerosis sera compared with sera from patients with other chronic inflammatory conditions: systemic lupus erythematosus (35%, 35 out of 100), primary Sjogren’s syndrome (16%, 5 out of 31), vasculitis (0 out of 20), sarcoidosis (7%, 1 out of 13) and Behcet’s disease (19%, 4 out of 21) suggest that humoral autoreactivity to proteasome could be a useful test in multiple sclerosis patients that may be of help in the diagnosis and/or progression of this chronic inflammatory disease. Finally, these results suggest that some global abnormality in B and/or T cell function is also involved in the chronic inflammatory response observed in multiple sclerosis patients, as it is frequently observed in other human organ‐specific autoimmune diseases.

Nabbout, Rima; Prud’homme, Jean‐François; Herman, Alexandra; Feingold, Josué; Brice, Alexis; Dulac, Olivier; LeGuern, Eric

doi: 10.1093/brain/awf281pmid: 12429594

Febrile seizures (FS) syndromes exhibit major clinical and genetic heterogeneity. We report a clinical and genetic study of three families with simple FS segregating as an autosomal dominant (AD) trait with high penetrance. All affected members presented a homogeneous phenotype of simple FS. The FS ceased before the age of 5 years. Among the 29 affected family members, only one patient presented two afebrile seizures, and none of the others developed concomitant or subsequent epilepsy. The phenotype differs from that previously reported in families presenting FS or generalized epilepsy with febrile seizures plus (GEFS+). After exclusion of already known loci for FS and GEFS+, we performed a genome‐wide scan in the largest family. It led to the identification of a new locus on chromosome 6q22–q24 spanning 6.4 cM between D6S1620 and D6S975 . For one of the other two families, the trait also segregated with this locus, but linkage studies could not restrict the candidate region further. The absence of linkage in the third family supports genetic heterogeneity of the AD form of pure simple FS. Sequence analysis excluded the implication of five candidate genes (A kinase anchoring protein 18 (AKAP18), syntaxin 7, putative neurotransmitter receptor (PNR), G protein receptor 57 (GPR57) and G protein receptor 58 (GPR58)) in the interval based on function. The locus mapping to 6q22–q24 seems to be the first identified locus responsible for pure simple FS, the most frequent form of FS. Studies are ongoing to identify the gene.

Houlden, Henry; Smith, Stephen; de Carvalho, Mamede; Blake, Julian; Mathias, Christopher; Wood, Nicholas W.; Reilly, Mary M.

doi: 10.1093/brain/awf270pmid: 12429595

Triple A (Allgrove) syndrome is characterized by achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. Affected individuals have between two and four of these relatively common clinical problems; hence the diagnosis is often difficult in all but the classical presentation. The inheritance is autosomal recessive, and most cases of triple A have no family history. Using genetic linkage analysis in a small number of families, a locus on chromosome 12q13 was identified. The triple A gene was identified recently at this locus and called ALADIN (alacrima, achalasia, adrenal insufficiency neurologic disorder). Mutations in this gene were reported in families from North Africa and Europe. The majority of mutations were homozygous. We have identified 20 families with between two and four of the clinical features associated with the triple A syndrome. Sequencing of the triple A gene revealed five families that had a total of nine compound heterozygous mutations, and one Portuguese family (previously published) had two homozygous mutations; these changes were spread throughout the triple A gene in exons 1, 2, 7, 8, 10, 11, 12, 13 and 16, and the poly(A) tract. Those bearing mutations had the classical triple A syndrome of achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. We identified a spectrum of associated neurological abnormalities in these cases, including pupil and cranial nerve abnormalities, frequent optic atrophy, autonomic neuropathy and upper and lower motor neurone signs including distal motor neuropathy and amyotrophy with severe selective ulnar nerve involvement. In these families, we have made genotype–phenotype correlations. Mutations in the triple A gene are thus an important cause of this clinically heterogeneous syndrome, and sequencing represents an important diagnostic investigation. Identifying further mutations and defining their phenotype along with functional protein analysis will help to characterize this neuroendocrine gene.

Lux, S.; Kurthen, M.; Helmstaedter, C.; Hartje, W.; Reuber, M. ; Elger, C. E.

doi: 10.1093/brain/awf276pmid: 12429596

Using ictal neuropsychological testing in pre‐surgical patients with focal epilepsies, we examined the localizing value of the constituent functions of consciousness as opposed to ‘conscious behaviour’ as a unitary variable. ‘Conscious behaviour’ was defined in terms of awareness and responsiveness. The constituent functions of consciousness examined included the orientation to the examiner, intentional behaviour demonstrated by expressive or receptive speech, and postictal memory. Frequency and patterns of impairment of constituent functions and ‘conscious behaviour’ were assessed. To achieve this, pre‐surgical video‐EEG ( n = 40) or video‐electrocorticography recordings ( n = 76) of ictal neuropsychological assessments were reviewed retrospectively. Patients were divided into groups with frontal ( n = 29), right temporal ( n = 21), left temporal ( n = 38) and bitemporal ( n = 28) seizure activity. Consciousness was most commonly impaired in patients with bitemporal and left temporal seizure activity. There were different patterns of impairment of the assessed constituent functions in the four groups: patients with frontal seizure activity showed loss of orientation behaviour and expressive speech whereas patients with left temporal seizure activity had impairments of memory, expressive and receptive speech. Patients with seizure activity limited to the right temporal lobe rarely exhibited ictal impairment of any of the assessed functions. In contrast, patients with bitemporal seizure activity showed impairment of all examined functions. Hence, normal functioning of the left temporal lobe or both temporal lobes is necessary for the preservation of all constituent aspects of consciousness. The localizing value of patterns of impairment of constituent functions is superior to that of ‘consciousness’ as a whole.