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PubMed2002

Tuberous sclerosis complex: a review of neurological aspects.

Tuberous sclerosis complex is characterized by hamartomatous lesions involving skin, brain, kidneys, eyes and heart. Pathologically, tuberous sclerosis is a disorder of cell migration, proliferation and differentiation. Cell lineage and cell migration disorders in the developing cortex of tuberous sclerosis complex patients might produce very different neurological phenotypes including epilepsy, cognitive impairment and autism. Cortical tubers constitute the hallmark of the disease and are pathognomonic of cerebral tuberous sclerosis. Epilepsy is the most common neurological feature, occurring in 96% of patients. Seizures often begin in the first months of life and are frequently severe and intractable. The treatment of seizures has recently benefited from the advent of the new anti-epileptic drugs. Selected drug-resistant patients with tuberous sclerosis complex could be considered for surgical treatment. Clear localization of the most active epileptogenic focus and the zone of the cortical abnormality may lead to tuberectomy and improved seizure control in selective drug-resistant patients. The finding of multiple areas of cerebral involvement should not automatically preclude epilepsy surgery in a child with intractable seizures and a well defined seizure origin.

Anticonvulsants↗
PubMed2003

Glatiramer acetate treatment in patients with childhood and juvenile onset multiple sclerosis.

BACKGROUND: Recent data indicate that in multiple sclerosis disease onset before the age of 16 is more common than previously assumed. However, current therapeutic options are limited to the treatment of acute attacks in these patients. Glatiramer acetate has been successfully applied in adults with relapsing-remitting multiple sclerosis, but there are no data available about the use of glatiramer acetate in childhood and juvenile onset multiple sclerosis. METHODS: Seven patients with relapsing-remitting multiple sclerosis and disease onset between 9 and 16 years of age were treated with daily subcutaneous injection of 20 mg glatiramer acetate (Copaxone). Patients were followed for 24 months. Treatment was initiated in all patients before the age of 18. RESULTS: The use of glatiramer acetate in our cohort of early onset multiple sclerosis patients was safe and well tolerated. Two out of seven patients remained relapse-free during the two year period. Clinical disability as measured by the EDSS remained stable in three out of seven patients. CONCLUSION: Due to the small number of patients the efficacy of the treatment has to be interpreted with caution. However, there might be a more pronounced treatment benefit in patients with low disability at treatment initiation and early treatment onset.

Adjuvants, Immunologic↗
PubMed1995

[Psychoses in multiple sclerosis--a reevaluation].

With the aim of reaching a new classification of psychoses with multiple sclerosis we reviewed the twentieth century literature for observations with regard to the subject, as well as 688 medical records of our patients, looking for the occurrence of paranoid and hallucinatory psychoses in the course of multiple sclerosis. Special attention was paid to the occurrence of cycloid psychoses. With multiple sclerosis, psychoses on the whole--but cycloid psychoses in particular--occur more frequently than in the general population. Women are affected just as frequently as men. Cycloid psychoses occur earlier in the course of the multiple sclerosis than the other psychoses; here, hallucinations occur with a higher frequency. Similar as in the case of HIV-infection, multiple sclerosis can act as a trigger of a cycloid psychosis. The results of our study indicate that men and women experience this disease as similarly threatening. A shortcoming of critical faculties based on the organic disease is an additional factor that favours the outbreak of such a psychosis.

Adult↗
PubMed1978

Cellular immunity in Guamanians with amyotrophic lateral sclerosis and Parkinsonism-dementia.

To test the hypothesis that host resistance factors may be abnormal in Guamanians in whom amyotrophic lateral sclerosis and Parkinsonism-dementia develop, cellular immunity was evaluated in both diseases and compared to that of Guamanians with other nervous-system diseases, normal adult Guamanians and non-Guamanians with amyotrophic lateral sclerosis and Parkinsonism. Diminished responses to skin-test antigens, lymphopenia, diminished per cent and total T cells and, less frequently, decreased mitogen responses were seen in Guamanian patients with amytorophic lateral sclerosis and Parkinsonism-dementia but not in the other patient or normal groups. Guamanian patients with amyotrophic lateral sclerosis and diminished cellular immunity had an increased frequency of HLA-Bw35 (P less than 0.005) and shorter mean duration of disease (P less than 0.05) than those with normal cellular immunity. In Parkinsonism dementia diminished cellular immunity was less strongly associated with HLA-BW35 (P less than 0.05) and was not associated with differences in duration of disease. Normal Guamanians and those with other nervous-system diseases showed no association of diminished cellular immunity with HLA-Bw35. The association appeared disease-related, with onset concomitant with the neurologic expression of Guamanian amyotrophic lateral sclerosis and Parkinsonism-dementia.

Adult↗
PubMed1984

Inhibition of terminal axonal sprouting by serum from patients with amyotrophic lateral sclerosis.

To investigate the pathogenesis of amyotrophic lateral sclerosis, we compared the effect of serum from patients with this disease on the regenerative sprouting of terminal axons in botulinum-treated mouse gluteus muscle with the effects of serum from controls and from patients with diabetic peripheral neuropathy. Serum from 9 of 19 patients with the sporadic form of amyotrophic lateral sclerosis and from 2 of 6 patients with the familial form caused a reduction in the proportion of sprouting terminal axons, as compared with that found in muscles treated with serum from controls or diabetic patients. Immunoglobulin from patients with amyotrophic lateral sclerosis, when tested on immunoblots, recognized a 56-kilodalton protein secreted by denervated rat diaphragm muscle; rabbit antiserum raised against this protein also suppressed terminal axonal sprouting. Thus, we have detected an antibody in the serum of patients with amyotrophic lateral sclerosis that inhibits sprouting of neurons and subsequent reinnervation of skeletal muscle. Whether this antibody is of primary pathogenic importance or represents a secondary response to neuromuscular destruction is not known. In either case, serum from patients with amyotrophic lateral sclerosis may provide reagents for studies of the trophic communications between muscle and motor neurons.

Adult↗
PubMed1987

Selective loss of the suppressor-inducer T-cell subset in progressive multiple sclerosis. Analysis with anti-2H4 monoclonal antibody.

The T4+ lymphocyte population includes a subset that induces suppressor T lymphocytes (T8+ cells) and can be distinguished by dual-color fluorescence analysis with anti-2H4 and anti-T4 monoclonal antibodies. To investigate the possible role of these cells in multiple sclerosis, we used anti-2H4 antibody to characterize peripheral-blood lymphocyte subsets in 63 patients with multiple sclerosis that was progressive, stable, or acute (relapsing-remitting). Twenty-three of 37 patients with progressive multiple sclerosis had a selective decrease in the number and percentage of peripheral-blood T cells that induce suppressor cells (T4+2H4+ cells), whereas only 3 of 16 patients with stable disease and 2 of 10 patients in the midst of an acute attack had a significant decrease. These selective decreases of circulating T4+2H4+ cells occurred in only 1 of 34 patient controls with other neurologic diseases and in 2 of 50 healthy controls (P less than 0.0001 by Fisher's exact test). The absolute number of T4+2H4+ cells and the percentage of reactivity in the populations studied were 187 +/- 28 per cubic millimeter and 8.3 +/- 1 percent in patients with progressive multiple sclerosis; 353 +/- 60 per cubic millimeter and 14.5 +/- 2 percent in patients with stable disease; 368 +/- 72 and 14.6 +/- 2.1 percent in patients with acute disease; 402 +/- 64 and 15.6 +/- 2 percent in controls with other neurologic diseases; and 519 +/- 44 and 19.7 +/- 1 percent in healthy controls. Functional studies using a pokeweed mitogen-driven IgG assay demonstrated a correlation between decreased numbers of T4+2H4+ cells and increased production of IgG in vitro. Family studies showed that the 2H4 antigen was not part of an inherited polymorphic antigenic determinant. Our results suggest that in progressive multiple sclerosis decreases in inducers of suppressor T cells may permit the activation of cells reactive with elements of the central nervous system.

Adult↗
PubMed1992

Serum antibodies to L-type calcium channels in patients with amyotrophic lateral sclerosis.

BACKGROUND AND METHODS: Sporadic amyotrophic lateral sclerosis is a chronic, progressive degenerative disease of the motor neurons of the spinal cord and motor cortex. The cause is unknown. Recent electrophysiologic studies in animals indicate that immunoglobulins from patients with this disease alter presynaptic voltage-dependent calcium currents and calcium-dependent release of neurotransmitters. To determine whether similar interactions might be identified biochemically, we used an enzyme-linked immunosorbent assay (ELISA) to detect the reaction of serum IgG with purified complexes of L-type voltage-gated calcium channels from rabbit skeletal muscle. The results from patients with amyotrophic lateral sclerosis were compared with those obtained from patients with other types of motor neuron disease, patients with autoimmune and non-autoimmune neurologic diseases, and normal subjects. RESULTS: Serum samples from 36 of 48 patients with sporadic amyotrophic lateral sclerosis (75 percent) contained IgG that reacted with L-type calcium-channel protein, and serum reactivity on ELISA correlated with the rate of disease progression (Spearman rank-correlation coefficient, 0.62). Reactive serum was present in only 1 of 25 normal subjects and 1 of 35 control patients with no motor neuron disease. Antibodies to L-type voltage-gated calcium channels were identified in 6 of 9 patients with Lambert-Eaton syndrome, and in 3 of 15 patients with Guillain-Barré syndrome. CONCLUSIONS: Antibodies to L-type voltage-gated calcium channels are present in the serum of patients with amyotrophic lateral sclerosis, and antibody titers correlate with the rate of disease progression. Together with previous data, these results suggest a role for autoimmune mechanisms in the pathogenesis of sporadic amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗
PubMed1978

Components in multiple sclerosis cerebrospinal fluid that are detected by radioimmunoassay for myelin basic protein.

Components in cerebrospinal fluid that are antigenically related to myelin basic protein have been identified by a technique described recently [Barbarese, E., Braun, P. E. & Carson, J. H. (1977) Proc. Natl. Acad. Sci. USA 74, 3360-3364] involving separating the cerebrospinal fluid proteins by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and measuring the individual components by radioimmunoassay for myelin basic protein. Samples of cerebrospinal fluid from 48 different patients (23 with definite multiple sclerosis, 4 with suspected multiple sclerosis, and 21 with other neurological diseases) were examined by this technique. The results indicate that cerebrospinal fluid can contain at least three separate components that are detected by radioimmunoassay for myelin basic protein. On the basis of their apparent molecular weights, the three components were identified as follows: component I, intact myelin basic protein; component II, proteolytic fragments of myelin basic protein; and component III, a protein of unknown origin with an apparent molecular weight of 50,000. Most samples of cerebrospinal fluid (45 of 48) from patients with multiple sclerosis and from patients with other neurological diseases contained components I and II. Component III was detected in all of the samples from patients with definite multiple sclerosis, in three of four samples from patients with suspected multiple sclerosis, and in none of the samples from patients with other neurological diseases. Some implications of these findings are discussed.

Humans↗
PubMed2002

Optic neuritis in multiple sclerosis.

PURPOSE: To review the clinical features, natural history, potential pathogenic mechanisms, differential diagnosis, and management of optic neuritis in multiple sclerosis. METHODS: Relevant literature regarding optic neuritis in multiple sclerosis from 1970 to the present was reviewed. RESULTS: Optic neuritis is an acute inflammatory optic neuropathy. It is the most common type of optic neuropathy causing acute visual loss in young adults (peak age at 30-40 years), especially among women. Patients usually present with an acute reduction of visual acuity, orbital pain exacerbated by eye movements, dyschromatopsia, and an afferent papillary defect, with or without swelling of the optic nerve head. Visual field testing most often reveals central defects, but others, such as centrocecal, can also occur. Magnetic resonance image (MRI) scanning of the brain should be undertaken in all cases of acute optic neuritis for diagnostic and prognostic purposes. The brain lesions of multiple sclerosis are commonly seen as T2 ovoid high-signal white matter lesions on MRI scans of the brain located in perivenular regions perpendicular to ventricles with variable enhancement. For atypical presentations of optic neuritis, additional laboratory tests, such as cerebrospinal fluid analysis, serologic tests, and visual evoked potentials, prove to be useful in the diagnosis and subsequent management of the patient. The recommended treatment for optic neuritis is intravenous steroids, as shown in the Optic Neuritis Treatment Trial (ONTT). CONCLUSION: Optic neuritis is often the initial presentation of multiple sclerosis. Recent advances in the understanding of the immune basis for multiple sclerosis has led to earlier and more effective treatment of this disease.

Brain↗
PubMed2001

Health status and quality of life of people with multiple sclerosis.

PURPOSE: The aim of this study was to ascertain the health status and quality of life of a community based cohort of people with multiple sclerosis. METHOD: A postal questionnaire with self-completed measures of impairment, disability, physical dependency and quality of life was sent to a random sample of 203 people with multiple sclerosis from a population register. The sample was stratified according to five disease courses. The population register is of the prevalent population of 760 people with multiple sclerosis resident in the Leeds Health Authority. The register used multiple sources of ascertainment and is prospectively maintained with new incident cases. RESULTS: The estimated mean age of people with multiple sclerosis is 46 years (SE: 0.85), and mean duration of disease is 14.4 years (SE: 0.69). Almost four in five (78 %) are female, and one in six (17%) live alone. Impairments of balance, vision and memory are common and in all cases there is little difference in the frequency between disease course groups. In contrast, impairments of bladder and bowel are more common in those with a progressive disease course. Disability is more common in those with a progressive disease course but all scores on the SF36 Physical Function scale are low and demonstrate the disabling consequences of the disease, irrespective of disease course. These consequences must contribute to the fact that over two-thirds (68 %) were not employed at the time of the survey. Quality of life does not differ across disease course groups, but rather varies by age and duration. CONCLUSIONS: People with multiple sclerosis experience a range of impairments and disabilities. Those with progressive disease courses experience greater levels of impairment and disability than other groups. There is not a straightforward exchange between health status and quality of life. A measure of subjective quality of life may reflect adjustment to disease, such that, for example, the longer the duration, the older the individual, the more likely the person will report a relatively good quality of life.

Female↗
PubMed2005

Polygenic effects and cigarette smoking account for a portion of the familial aggregation of nuclear sclerosis.

Cataract is the most common cause of blindness worldwide. Nuclear cataract, an advanced stage of nuclear sclerosis, is the most common type of age-related cataract. The authors assessed data from 2,089 persons within 620 extended pedigrees who participated in the 1988-1990 Beaver Dam Eye Study in Wisconsin to determine whether the observed familial aggregation of nuclear sclerosis could be explained by inheritance of a major gene. Familial correlations were examined and segregation analyses were performed on nuclear sclerosis measurements adjusted for age, sex, and pack-years of cigarette smoking. There was modest correlation among close family members after adjustment for age, sex, and pack-years of cigarette smoking: 0.084 between parents and offspring, and 0.198 between sibling pairs. Although results do not support involvement of a single major locus in the etiology of nuclear sclerosis, models that allowed for familial correlation, attributable in part to polygenic effects, did provide a better fit to the observed data than models without a polygenic effect. This finding suggests that several genes of modest effect may influence development of nuclear lens opacity, possibly in conjunction with environmental factors. Cigarette smoking was an important covariate in these analyses. Overall, results highlight the complex etiology of nuclear sclerosis.

Adult↗
PubMed1993

The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. A 5-year follow-up study.

A 5-year follow-up study was performed on 89 patients who had undergone brain magnetic resonance imaging (MRI) at presentation with an acute clinically isolated syndrome of the optic nerves, brainstem or spinal cord of a type suggestive of multiple sclerosis. At presentation, MRI was abnormal, revealing one or more asymptomatic cerebral white matter lesions in 57 (64%), and was normal in 32 (36%). At follow-up, progression to clinically definite multiple sclerosis had occurred in 37 out of 57 (65%) with an abnormal MRI and one out of 32 (3%) with normal MRI. Human leucocyte antigen (HLA) typing was performed in 70 patients and cerebrospinal fluid (CSF) was examined at presentation in 36. The presence of HLA-DR2 antigen or cerebrospinal fluid oligoclonal IgG bands were both associated with a significantly increased risk of progression to multiple sclerosis, but MRI was much more powerful in predicting outcome. The presence of four or more MRI lesions at presentation was associated with a higher rate of progression to multiple sclerosis, more frequent development of moderate or severe disabilities and a greater number of new MRI lesions at follow-up. The results indicate that brain MRI at presentation with a clinically isolated syndrome suggestive of multiple sclerosis is a powerful predictor of the clinical course over the next 5 years. This observation, combined with an ability to detect other sometimes treatable disorders which can also cause such syndromes, suggests that MRI is the investigation of choice in evaluating this group of patients.

Adolescent↗
PubMed1994

Event-related brain potential evidence for a verbal working memory deficit in multiple sclerosis.

Memory deficits are frequently identified in patients with multiple sclerosis. Both working (short-term) and long-term memory appear affected, particularly on free-recall tasks. The focus of our study was to examine neurophysiological correlates of working memory processes and to identify the specific components responsible for the working memory deficits reported in multiple sclerosis. Event-related brain potentials (ERPs) were recorded from the scalp of mildly afflicted multiple sclerosis patients and their matched normal controls during the performance of phonological and visuo-spatial working memory tasks. Neuropsychological test, behavioural performance and ERP data all indicated that verbal working memory is especially susceptible to impairment by multiple sclerosis, while visuospatial working memory is less susceptible. The pattern of results further indicated that the verbal working memory dysfunction in multiple sclerosis is at least partially due to impairment in the phonological loop, a rehearsal mechanism for retaining verbal information in working memory.

Adult↗
PubMed1994

Increased expression of high affinity IL-2 receptors and beta-adrenoceptors on peripheral blood mononuclear cells is associated with clinical and MRI activity in multiple sclerosis.

Enhanced expression of beta-adrenoceptor densities on peripheral blood mononuclear cells (PBMCs) in progressive multiple sclerosis patients has been observed in a number of independent studies. A link between increased number of beta-adrenoceptors and inflammatory disease has been further indicated by studies in rheumatoid arthritis and relapsing-remitting multiple sclerosis patients. In a serial monthly assessment of relapsing-remitting multiple sclerosis patients, we have demonstrated that increased beta-adrenoceptors on PBMCs correlate with the expression of high affinity interleukin-2 receptors (IL-2Rs) and disease activity as determined by clinical and MRI findings. Magnetic resonance imaging activity was strongly correlated with IL-2R expression and it appears to be a sensitive marker of PBMC immunoactivation in multiple sclerosis. In vitro studies showed that beta-agonist stimulation of PBMCs reduces the IL-2R expression and suppresses cell proliferation following mitogenic stimulation. This observation may indicate a recovery role for the enhanced beta-adrenoceptor expression in multiple sclerosis. However, its therapeutic importance remains to be tested by appropriate trials using either beta-agonists or agents activating the second messenger system, c-AMP, in lymphocytes.

Adult↗
PubMed1997

The progress of cognitive decline in multiple sclerosis. A controlled 3-year follow-up.

The purpose of this study was to illustrate how cognitive functioning evolves over time in patients with multiple sclerosis. We followed the evolution of cognitive performances in two clinically and demographically similar multiple sclerosis groups, the 'cognitively preserved' (n = 20) and the 'cognitively mildly deteriorated' (n = 22), and in healthy controls (n = 34). We conducted the follow-up examination using the Mild Deterioration Battery, the Mini-Mental State Examination, and a set of additional neuropsychological measures after an interval of 3 years. The drop-out rate in our study was only 5%. The 'cognitively preserved' multiple sclerosis group showed substantial neuropsychological stability by performing as well as the controls both at baseline and at follow-up. By contrast, the initially 'cognitively mildly deteriorated' group demonstrated progressive cognitive decline on many neuropsychological tests. The intermediate-length screening battery, the Mild Deterioration Battery, was sensitive to this decline, whereas the briefer Mini-Mental State Examination was not. The progressive cognitive decline could not be predicted from other disease variables. The study demonstrated that intact cognitive functioning in multiple sclerosis may remain stable, whereas incipient cognitive decline seems to be widespread and progressive in nature. Thus, progressive cognitive deterioration should be considered as one of the characteristics of multiple sclerosis.

Adult↗
PubMed1997

Sensitivity of contrast enhanced MRI in multiple sclerosis. Effects of gadolinium dose, magnetization transfer contrast and delayed imaging.

Although clinical end points remain the definitive measure of therapeutic efficacy in multiple sclerosis, more sensitive markers of disease activity are required to screen potential disease-modifying agents. The use of gadolinium contrast-media in MRI studies increases both the reliability and sensitivity of detecting active lesions in multiple sclerosis. We studied three potential methods for further improving sensitivity; the use of 0.3 mmol/kg (triple dose) gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA), magnetization transfer (MT) contrast imaging and the introduction of a delay between contrast-medium injection and imaging. Fifty patients were studied (seven with benign, 14 with relapsing-remitting, 10 with secondary progressive, 16 with primary progressive and three with transitional multiple sclerosis). Imaging was performed on two occasions, 24-72 h apart, with triple- and single-dose Gd-DTPA. Pairs of contrast-enhanced T 1-weighted studies, with and without MT, were obtained at three different times, i.e. within early (0-20 min), short-delay (20-40 min) and long-delay (40-60 min) time-windows. Nineteen patients did not have the full complement of studies. Seven patients suffered minor self-limiting adverse events possibly related to triple-dose Gd-DTPA. Overall, triple-dose Gd-DTPA resulted in a 75% increase in the number of enhancing lesions detected compared with the single dose (P < 0.002). The use of MT or delay alone did not significantly increase the sensitivity of either single- or triple-dose studies. The combination of MT and short delay increased the number of enhancing lesions detected with single-dose Gd-DTPA by 47% (P < 0.05) and with triple-dose Gd-DTPA by 27% (P < 0.01). Detection was not significantly further improved by a long delay. The most sensitive modality was MT imaging with a long delay following triple-dose Gd-DTPA, resulting in the detection of 126% more enhancing lesions than in standard single-dose imaging (P < 0.05). This applies to all subgroups except for primary progressive multiple sclerosis, in which none of these methods alone or in combination improved the sensitivity. We conclude that for relapsing-remitting and secondary progressive multiple sclerosis, the combination of triple-dose Gd-DTPA and delayed MT imaging more than doubles the sensitivity to contrast-enhancing lesions.

Adult↗
PubMed1999

Infratentorial atrophy on magnetic resonance imaging and disability in multiple sclerosis.

Loss of tissue volume in the central nervous system may provide an index of fixed neurological dysfunction in multiple sclerosis. Recent magnetic resonance studies have shown a modest relationship between clinical disability rating scores and transverse sectional area of the cervical spinal cord. To explore further the relationship between atrophy and disability in multiple sclerosis, we estimated the volumes of infratentorial structures from MRIs in a cross-sectional study of 41 patients, 21 with relapsing-remitting multiple sclerosis and 20 with secondary progressive multiple sclerosis. We used the Cavalieri method of modern design stereology with point counting to estimate the volume of brainstem, cerebellum and upper cervical spinal cord from three-dimensional MRIs acquired with an MPRAGE (Magnetization-prepared Rapid Acquisition Gradient Echo) sequence. The volume of the upper (C1-C3) cervical spinal cord was significantly correlated with a composite spinal cord score derived from the appropriate Functional Scale scores of the Expanded Disability Status Scale (r = -0.50, P < 0.01). The cerebellar (r = 0.49, P < 0.01) and brainstem (r = 0.34, P < 0.05) volumes correlated with the Scripp's Neurological Disability Rating Scale scores. The upper cervical cord volumes (r = -0.39, P < 0.01), but not the brainstem or cerebellar volumes, were significantly associated with disease duration. MRI-estimated structural volumes may provide a simple index of axonal and/or myelin loss, the presumed pathological substrates of irreversible impairment and disability in multiple sclerosis.

Activities of Daily Living↗
PubMed2000

Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation.

Damage to axons is taken as a key factor of disability in multiple sclerosis, but its pathogenesis is largely unknown. Axonal injury is believed to occur as a consequence of demyelination and was recently shown to be a feature even of the early disease stages. The present study was aimed at characterizing the association of axonal injury and histopathological hallmarks of multiple sclerosis such as demyelination, cellular infiltration and expression of inflammatory mediators. Therefore, axon reduction and signs of acute axonal damage were quantified in early lesion development of chronic multiple sclerosis and correlated with demyelinating activity and inflammation. Patients with secondary progressive multiple sclerosis revealed the most pronounced axonal injury, whereas primary progressive multiple sclerosis patients surprisingly showed relatively little acute axonal injury. Acute axonal damage, as defined by the accumulation of amyloid precursor protein (APP), was found to occur not only in active demyelinating but also in remyelinating and inactive demyelinated lesions with a large inter-individual variability. Only few remyelinating lesions were adjacent to areas of active demyelination. In this minority of lesions, axonal damage may have originated from the neighbourhood. APP expression in damaged axons correlated with the number of macrophages and CD8-positive T lymphocytes within the lesions, but not with the expression of tumour necrosis factor-alpha (TNF-alpha) or inducible nitric oxide synthase (iNOS). Axonal injury is therefore, at least in part, independent of demyelinating activity, and its pathogenesis may be different from demyelination. This has major implications for therapeutic strategies, which aim at preventing both demyelination and axonal loss.

Adolescent↗