http://www.unicog.org/publications/DehaeneChangeux_ReviewConsciousness_Neuron2011.pdf

Experimental and Theoretical Approaches to Conscious Processing

Summary Multiple sclerosis (MS) is a progressive disease of the CNS that is characterised by widespread lesions in the brain and spinal cord. MS results in motor, cognitive, and neuropsychiatric symptoms, all of which can occur independently of one another. The common cognitive symptoms include deficits in complex attention, efficiency of information processing, executive functioning, processing speed, and long-term memory. These deficits detrimentally affect many aspects of daily life, such as the ability to run a household, participate fully in society, and maintain employment—factors that can all affect the overall quality of life of the patient. The increased use of neuroimaging techniques in patients with MS has advanced our understanding of structural and functional changes in the brain that are characteristic of this disease, although much remains to be learned. Moreover, examination of efforts to treat the cognitive deficits in MS is still in the early stages.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(08)70259-X.pdf

Cognitive impairment in multiple sclerosis

Multiple sclerosis is characterized morphologically by the key features demyelination, inflammation, gliosis and axonal damage. In recent years, it has become more evident that axonal damage is the major morphological substrate of permanent clinical disability. In our study, we investigated the occurrence of acute axonal damage determined by immunocytochemistry for amyloid precursor protein (APP) which is produced in neurones and accumulates at sites of recent axon transection or damage. The numbers of APP-positive axons in multiple sclerosis lesions were correlated with the disease duration and course. Most APP-positive axons were detected within the first year after disease onset, but acute axonal damage was also detected to a minor degree in lesions of patients with a disease duration of 10 years and more. This effect was not due to the lack of active demyelinating lesions in the chronic disease stage. Late remyelinated lesions (so-called shadow plaques) did not show signs of axon destruction. The number of inflammatory cells showed a decrease over time similar to that of the number of APP-positive axons. There was a significant correlation between the extent of axon damage and the numbers of CD8-positive cytotoxic T cells and macrophages/microglia. Our results indicate that a putative axon-protective treatment should start as early as possible and include strategies preventing T cell/macrophage-mediated axon destruction and leading to remyelination of axons.

Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time.

Primary erythermalgia is a rare autosomal dominant disease characterised by intermittent burning pain with redness and heat in the extremities. A previous study established the linkage of primary erythermalgia to a 7.94 cM interval on chromosome 2q, but the causative gene was not identified. We performed linkage analysis in a Chinese family with primary erythermalgia, and screened the mutations in the two candidate genes, SCN9A and GCA, in the family and a sporadic patient. Linkage analysis yielded a maximum lod score of 2.11 for both markers D2S2370 and D2S2330. Based on critical recombination events in two patients in the family, we further limited the genetic region to 5.98 cM between D2S2370 and D2S2345. We then identified two missense mutations in SCN9A in the family (T2573A) and the sporadic patient (T2543C). Our data suggest that mutations in SCN9A cause primary erythermalgia. SCN9A, encoding a voltage-gated sodium channel alpha subunit predominantly expressed in sensory and sympathetic neurones, may play an important role in nociception and vasomotor regulation.

https://jmg.bmj.com/content/jmedgenet/41/3/171.full.pdf

Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia

The use of magnetic resonance imaging as a surrogate outcome measure in clinical trials, or even as a prognosticator in the assessment of the natural evolution, assumes a close relationship between extent and rate of development of magnetic resonance imaging abnormalities with the clinical status and rate of development of disability. While it may seem obvious that patients who develop new lesions are worse off than those without new lesions, the association between clinical findings and radiological extent of involvement is generally poor. In this review, various confounders are discussed, including inappropriate clinical rating, lack of histopathological specificity (especially for axonal loss), neglect of spinal cord involvement, underestimation of damage to the normal appearing brain tissue (both white and gray matter), and masking effects of cortical adaptation. It is concluded that much progression has been made in magnetic resonance techniques so that the clinico-radiological dissociation has indeed proved to be a paradox. Thus, the relevance of normal appearing brain tissue damage, residual brain volume, spinal cord damage and cerebral plasticity had to be reiterated. The increased awareness of the subtle interplay between these dimensions should be kept in mind when magnetic resonance is used as a surrogate outcome measure. This corroborates with conventional wisdom that one should not rely on a single magnetic resonance measure, but take full advantage of the fact that magnetic resonance is able to provide multidimensional information.

The clinico-radiological paradox in multiple sclerosis revisited.

Inborn errors of metabolism (IEMs) may present in adolescence or adulthood as a psychiatric disorder. In some instances, an IEM is suspected because of informative family history or because psychiatric symptoms form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs. However, in some cases, psychiatric signs may be apparently isolated. We propose a schematic classification of IEMs into three groups according to the type of psychiatric signs at onset. Group 1 represents emergencies, in which disorders can present with acute and recurrent attacks of confusion, sometimes misdiagnosed as acute psychosis. Diseases in this group include urea cycle defects, homocysteine remethylation defects and porphyrias. Group 2 includes diseases with chronic psychiatric symptoms arising in adolescence or adulthood. Catatonia, visual hallucinations, and aggravation with treatments are often observed. This group includes homocystinurias, Wilson disease, adrenoleukodystrophy and some lysosomal disorders. Group 3 is characterized by mild mental retardation and late-onset behavioural or personality changes. This includes homocystinurias, cerebrotendinous xanthomatosis, nonketotic hyperglycinaemia, monoamine oxidase A deficiency, succinic semialdehyde dehydrogenase deficiency, creatine transporter deficiency, and α and β mannosidosis. Because specific treatments should be more effective at the ‘psychiatric stage’ before the occurrence of irreversible neurological lesions, clinicians should be aware of atypical psychiatric symptoms or subtle organic signs that are suggestive of an IEM. Here we present an overview of IEMs potentially revealed by psychiatric problems in adolescence or adulthood and provide a diagnostic strategy to guide metabolic investigations.

/pdf/psychiatric-manifestations-revealing-inborn-errors-of-4xe8fh42qw.pdf

Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults

Objectives To determine if callosal atrophy and interhemispheric dysfunction can be detected in the early stages of relapsing-remitting multiple sclerosis (MS) and to evaluate their progression in relation to the disability and evolution of lesions seen on magnetic resonance imaging during a 5-year period. Methods We compared 30 patients who had clinically definite early-onset replasing-remitting MS and mild disability with control subjects. Regional and segmental callosal size and extent of white matter abnormalities on magnetic resonance imaging, as well as performance on tasks exploring interhemispheric transfer of motor, auditory, and sensory information were assessed. Patients with MS were evaluated at baseline and after 5 years. Physical disability was determined at both times using the Expanded Disability Status Scale score. Results Patients with MS were seen with significant callosal atrophy and functional impairment of interhemispheric transfer at baseline that worsened during the 5-year study. A significant correlation was found between the magnitude of disability and the severity of morphological and functional callosal involvement at baseline. This association persisted at year 5. Baseline clinical characteristics such as age and prestudy relapse rate were unrelated to callosal size or interhemispheric performance. However, the number of baseline T2-weighted lesions was correlated with callosal involvement and this relation persisted at year 5. Conclusion Patients who had relapsing-remitting MS in the early stages of the disease and mild disability had significant callosal involvement that progressed over time. The relationship between disability, T2-weighted lesions load, and degree of morphological and functional callosal impairment confirm the potential value of using callosal dysfunction as a surrogate marker of disease progression in MS.

https://jamanetwork.com/journals/jamaneurology/articlepdf/778319/noc00065.pdf

A longitudinal study of callosal atrophy and interhemispheric dysfunction in relapsing-remitting multiple sclerosis.

• To investigate functional and anatomical features of callosal involvement in multiple sclerosis (MS), performances of 90 patients with definite MS and 25 matched normal control subjects were compared on three tasks exploring interhemispheric transfer of auditory, sensory, and motor information: a verbal dichotic listening task, a crossed tactile finger localization task, and an alternate finger tapping task. Each patient also underwent a magnetic resonance imaging (MRI) scan (1) to appreciate the extent of whitematter changes by a semiquantitative evaluation of hemispheric brain MRI hyperintensities and (2) to measure the degree of total and regional callosal atrophy using an automatized method of partition of the midsagittal callosal area. Interhemispheric transfer and/or integration was impaired in patients with MS for all modalities explored and proportional to both degree of callosal atrophy and diffusion of white-matter lesions. Moreover, in good agreement with data obtained from partial commissurotomy studies, performance on each functional task was predominantly associated with atrophy of one part of the callosum, namely left-ear dichotic suppression with the posterior callosal region, alternate finger tapping with the anterior region, and cross-localization with midanterior and posterior regions. Finally, a subgroup of patients without MRI white-matter hyperintensities also showed significant impairment of callosal function and relative atrophy of the callosum. These findings suggest the potential clinical value of callosal involvement in MS and the usefulness of MS as a model of interhemispheric disconnection.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=neur&articleId=592570&pdfFileName=archneur_50_10_018.pdf

Functional and magnetic resonance imaging correlates of callosal involvement in multiple sclerosis.

Objectives: To characterize the clinical, biological, and neuroradiological findings in Sneddon syndrome; to correlate magnetic resonance imaging abnormalities with disability, presence of hypertension and other vascular risk factors, presence of heart valvulopathy on echography, and titer of antiphospholipid antibodies; and to compare these findings in antiphospholipid-positive and antiphospholipid-negative patients. Design: Retrospective review of the records of 32 consecutive patients with livedo reticularis and neurological events, followed up in our institution between January 1991 and August 1995. Patients: Twenty-six patients (20 women and 6 men) who had at least 1 cerebral ischemic arterial event associated with generalized and pathological livedo reticularis. Results: The age at the first cerebral ischemic event ranged from 22 to 58 years. Motor deficit was the most frequent sign (found in 73% of cases). Disability was found in 50%, systemic hypertension in 65%, heart valvulopathy in 61%, and antiphospholipid antibodies in 42% of cases. Patients were classified in 6 groups according to magnetic resonance imaging findings. No correlation was found between the presence of hypertension or other vascular risk factors, valvulopathy, antiphospholipids, and magnetic resonance imaging abnormalities. There was no significant difference between antiphospholipid-positive and antiphospholipid-negative patients except for the presence of antinuclear antibodies. There was a significant correlation between the extent of magnetic resonance imaging abnormalities and disability. Conclusion: The severity of the disease seems to be correlated with magnetic resonance imaging aspects, but not to the presence of antiphospholipid antibodies. Magnetic resonance imaging may help to understand the natural course of the cerebral involvement of the disease.

Olivier Lyon-Caen

Papers

Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults

A longitudinal study of callosal atrophy and interhemispheric dysfunction in relapsing-remitting multiple sclerosis.

Functional and magnetic resonance imaging correlates of callosal involvement in multiple sclerosis.

The natural course of cerebral lesions in Sneddon syndrome.

Paramyotonia congenita: genotype to phenotype correlations in two families and report of a new mutation in the sodium channel gene