fMRI study of episodic memory in relapsing-remitting MS: correlation with T2 lesion volume.

OBJECTIVE: To determine whether memory loss in patients with multiple sclerosis (MS) results from faulty encoding or retrieval, we correlated extent of T2-weighted lesion involvement with brain activation patterns on fMRI scans obtained while patients performed a verbal episodic memory task. METHODS: We performed a neurologic examination, neuropsychological testing, and an event-related fMRI scan on 36 patients with relapsing-remitting MS. In addition, we obtained T2-weighted structural MRI scans to measure lesion volume. We performed a regression analysis to examine the association between lesion volume and regional brain activation. RESULTS: Increasing lesion volume correlated with increasing magnitude of brain activation, primarily in the left frontal and parietal association cortices. Significant correlations of function with lesion volume were primarily observed during the memory retrieval phase of the task. CONCLUSIONS: These results extend previous fMRI studies in multiple sclerosis (MS) by demonstrating an association between greater disease burden and increased neural recruitment during episodic memory. In addition, the stronger correlations observed between lesion volume and brain activation during retrieval than encoding would suggest that retrieval processes are more affected by MS-related cerebral pathology.

Progressive polyradiculoneuropathy in diabetes: correlation of variables and clinical outcome after immunotherapy.

OBJECTIVE: To quantify the progression of diabetic polyradiculoneuropathy-a condition in which immune factors have been implicated-after immunotherapy. METHODS: The study evaluated 15 consecutive patients with this condition. All patients were older than 40. Four had type I diabetes and six were women. The duration of pre-existing diabetes varied from 2 to 20 years. The clinical presentation was dominated by painful progressive motor weakness, with or without exacerbation of sensory symptoms. The weakness involved all limbs, but was often asymmetric. RESULTS: Electrophysiological testing showed a predominantly axonal polyneuropathy, with more recent denervating polyradiculopathy. Analysis of CSF showed increased protein in 14 and oligoclonal bands in five. Quantitative autonomic tests showed abnormalities in all patients. Sural nerve biopsy was performed in 14 patients; all showed fibre loss and segmental demyelination, four had occasional onion bulbs, and 10 showed various inflammatory infiltrates. After immunomodulating therapy, there was no further deterioration and clinical improvement occurred in all patients. Sweat responses, cardiovascular reflexes, and sural nerve fibre density correlated best with functional outcome. There was no significant difference between plasmapheresis and intravenous gammaglobulin. CONCLUSION: Immunotherapy may improve this condition, but only certain variables correlate with rapid therapeutic response.

Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation.

Multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis are immune-mediated diseases that are responsive to suppression or modulation of the immune system. For patients with severe disease, immunosuppression may be intensified to the point of myelosuppression or hematopoietic ablation. Hematopoiesis and immunity may then be rapidly reconstituted by reinfusion of CD34(+) progenitor cells. In 10 patients with these autoimmune diseases, autologous hematopoietic stem cells were collected from bone marrow or mobilized from peripheral blood with either granulocyte colony-stimulating factor (G-CSF) or cyclophosphamide and G-CSF. Stem cells were enriched ex vivo using CD34(+) selection and reinfused after either myelosuppressive conditioning with cyclophosphamide (200 mg/kg), methylprednisolone (4 g) and antithymocyte globulin (ATG; 90 mg/kg) or myeloablative conditioning with total body irradiation (1,200 cGy), methylprednisolone (4 g), and cyclophosphamide (120 mg/kg). Six patients with multiple sclerosis, 2 with systemic lupus erythematosus, and 2 with rheumatoid arthritis have undergone hematopoietic stem cell transplantation. Mean time to engraftment of an absolute neutrophil count greater than 500/microL (0.5 x 10(9)/L) and a nontransfused platelet count greater than 20,000/microL (20 x 10(9)/L) occurred on day 10 and 14, respectively. Regimen-related nonhematopoietic toxicity was minimal. All patients improved and/or had stabilization of disease with a follow-up of 5 to 17 months (median, 11 months). We conclude that intense immunosuppressive conditioning and autologous T-cell-depleted hematopoietic transplantation was safely used to treat these 10 patients with severe autoimmune disease. Although durability of response is as yet unknown, all patients have demonstrated stabilization or improvement.

T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: report on the first three patients.

Multiple sclerosis (MS) is a disease of the central nervous system characterized by immune-mediated destruction of myelin. In patients with progressive deterioration, we have intensified immunosuppression to the point of myeloablation. Subsequently, a new hematopoietic and immune system is generated by infusion of CD34-positive hematopoietic stem cells (HSC). Three patients with clinical MS and a decline of their Kurtzke extended disability status scale (EDSS) by 1.5 points over the 12 months preceding enrollment and a Kurtzke EDSS of 8.0 at the time of enrollment were treated with hematopoietic stem cell (HSC) transplantation using a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg), methylprednisolone (4 g) and total body irradiation (1200 cGy). Reconstitution of hematopoiesis was achieved with CD34-enriched stem cells. The average time of follow-up is 8 months (range 6-10 months). Despite withdrawal of all immunosuppressive medications, functional improvements have occurred in all three patients. We conclude that T cell-depleted hematopoietic stem cell transplantation can be performed safely in patients with severe and debilitating multiple sclerosis. Stem cell transplantation has resulted in modest neurologic improvements for the first time since onset of progressive disease although no significant changes in EDSS or NRS scales are evident at this time.

Executive functions in multiple sclerosis: an analysis of temporal ordering, semantic encoding, and planning abilities.

Previous studies have consistently demonstrated impairments in conceptual reasoning and set-shifting abilities in patients with multiple sclerosis (MS). Other executive functions have been less frequently examined. We compared 44 MS patients and 48 demographically matched controls on a temporal-ordering and semantic-encoding task and on a test of planning (Tower of Hanoi). Compared with controls, MS patients experienced deficient semantic encoding and planning but unimpaired temporal-order memory. For both tasks, post hoc analyses indicated that chronic-progressive MS patients contributed most to the group differences. A combination of poor planning and slowed information-processing speed was hypothesized to have contributed to MS patients' impaired Tower of Hanoi performance. Further research is needed to explore the possible relationship between semantic-encoding and planning deficits in MS and social and occupational disabilities.

Relationship between frontal lobe lesions and Wisconsin Card Sorting Test performance in patients with multiple sclerosis.

Conceptual reasoning deficits are common in patients with multiple sclerosis (MS) and are typically associated with focal lesions involving the frontal lobes. In this study, we predicted that MS patients with frontal white matter lesions (MS-F) would be more impaired on a standard conceptual reasoning task (Wisconsin Card Sorting Test; WCST) than patients with minimal frontal lesions (MS-NF), even if the total cerebral lesion area (TLA), measured from MRI, was equivalent across groups. We subdivided 43 definite MS patients into three groups based on MRI findings: seven in the MS-F group (mean TLA = 41.4 cm2) and seven in the MS-NF group (mean TLA = 50.0 cm2); 29 MS patients served as a low lesion burden control group (MS-C; mean TLA = 6.4 cm2). The groups did not differ with regard to demographic and illness characteristics. Although the three subgroups obtained comparable scores on a measure of global cognitive functioning (verbal intelligence), the MS-F group achieved significantly fewer categories and made more total errors on the WCST than did the MS-NF and MS-C groups. The MS-F group made significantly more perseverative responses than the MS-C group and nonsignificantly more than the MS-NF group. These results suggest that the pattern of cognitive decline in MS is a function of the location of demyelinating lesions within the cerebral hemispheric white matter. Finally, we supplement the group study results with a case report of an MS patient who was studied serially with MRI and cognitive testing.

[Stress and changes in immune response in elderly subjects]. / Estrés y alteraciones de la reacción inmunitaria en sujetos de la tercera edad.

The evaluation of different aspects of the immune response in stress in the aged was the objective of our study, that was done with 96 persons of the third age. They were divided in different age groups since 60 years old. No significative differences in the concentrations of immunoglobulin A,G and M were found. Important disorders were detected in a spontaneous rosette.

The differential projection of two cytoarchitectonic subregions of the inferior parietal lobule of macaque upon the deep layers of the superior colliculus.

Parietotectal projections were studied in the macaque monkey in experiments designed to compare the distribution of fibers originating in two cytoarchitecturally distinct regions within the inferior parietal lobule: the inferior bank of the intraparietal sulcus (area POa of Seltzer and Pandya, '80) and the adjoining part of area PG (von Bonin and Bailey, '47) on the convexity of the hemisphere, here called PGc. A dense fiber projection from POa to the intermediate and deep layers of the superior colliculus was observed by both anterograde autoradiographic and anterograde horseradish peroxidase methods. In contrast, only faint labeling was seen in the superior colliculus following injections of tritiated amino acids into area PGc on the convexity. In a second set of experiments, injections of horseradish peroxidase were placed in the intermediate and deep layers of the superior colliculus so that the cells of origin of the parietotectal projections could be identified. Many retrogradely labeled neurons were observed in POa, whereas very few labeled neurons were present in any other subdivision of the inferior parietal lobule or in the superior parietal lobule. These findings demonstrate that area POa has a prominent direct efferent projection to a major premotor region of the brainstem oculomotor system and suggest that by virtue of its parietotectal connection, this sulcal subdivision may have functional properties not shared with other subdivisions of the inferior parietal lobule.