Regional hippocampal atrophy in multiple sclerosis.

Gray matter brain structures, including deep nuclei and the cerebral cortex, are affected significantly and early in the course of multiple sclerosis and these changes may not be directly related to demyelinating white matter lesions. The hippocampus is an archicortical structure that is critical for memory functions and is especially sensitive to multiple insults including inflammation. We used high-resolution MR imaging at 3.0 T to measure hippocampal volumes in relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients and controls. We found that both groups of MS patients had hippocampal atrophy and that this volume loss was in excess of global brain atrophy. Subregional analysis revealed selective volume loss in the cornu ammonis (CA) 1 region of the hippocampus in RRMS with further worsening of CA1 loss and extension into other CA regions in SPMS. Hippocampal atrophy was not correlated with T2-lesion volumes, and right and left hippocampi were affected equally. Volume loss in the hippocampus and subregions was correlated with worsening performance on word-list learning, a task requiring memory encoding, but not with performance on the Paced Auditory Serial Addition Task (PASAT), a test of information processing speed. Our findings provide evidence for selective and progressive hippocampal atrophy in MS localized initially to the CA1 subregion that is associated with deficits in memory encoding and retrieval. The underlying histopathological substrate for this selective, symmetric and disproportionate regional hippocampal vulnerability remains speculative at this time. Further understanding of this process could provide targets for therapeutic interventions including neuroprotective treatments.

A longitudinal fMRI study of the paced auditory serial addition task.

The paced auditory serial addition task (PASAT) is a test of working memory and attention that is frequently abnormal in MS and is used serially to assess cognitive dysfunction as part of the MS Functional Composite in clinical trials. Previous studies using functional MRI (fMRI) during PASAT performance have shown significant differences in activation patterns between healthy controls and MS patients matched for performance, but serial fMRI measures have not been reported. A confound is that learning effects are common with repeated PASAT testing, diminishing over successive trials. After measuring PASAT performance weekly for four weeks in 10 healthy controls to eliminate practice effects, we assessed brain activity using fMRI at baseline and after six months to determine the reproducibility of activation patterns in healthy controls during PASAT performance. Results showed that scores improved during the first three testing trials and stabilized subsequently. Brain activation during PASAT performance was seen in left frontal and parietal regions consistent with previous reports. After a six-month interval, PASAT performance and fMRI activity were stable, suggesting that serial fMRI during PASAT performance could be used as an outcome measure in trials assessing cognitive decline in clinical populations once practice effects are eliminated.

Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis.

BACKGROUND: Although patients with multiple sclerosis (MS) are advised to stop interferon (IFN) beta-1a therapy before becoming pregnant, some patients become pregnant while on treatment. METHODS: We examined individual patient data from eight clinical trials with IFNbeta-1a. RESULTS: Of 3,361 women in the studies, 69 pregnancies were reported, of which 41 were patients receiving (or who had stopped receiving within 2 weeks prior to conception) IFNbeta-1a (in utero exposure group), 22 were patients who discontinued IFNbeta-1a treatment more than 2 weeks before conception (previous exposure group), and six were patients receiving placebo. The 41 in utero exposure pregnancies resulted in 20 healthy full-term infants, one healthy premature infant, nine induced abortions, eight spontaneous abortions, one fetal death, and one congenital anomaly (hydrocephalus). One patient was lost to follow-up. The 22 previous exposure pregnancies resulted in 20 full-term healthy infants, one healthy premature infant, and one birth-related congenital anomaly (Erb palsy). CONCLUSIONS: The majority (21/31) of pregnancies that had the potential to go to full term produced healthy infants. The rate of spontaneous abortion was higher, but not significantly so, in the in utero exposure group compared to general population estimates. Until more exposure data become available, patients remain advised to stop IFNbeta therapy before becoming pregnant.

Multiple sclerosis gender issues: clinical practices of women neurologists.

Substantially more women than men develop multiple sclerosis (MS), but information about the effects of MS and gender-specific issues such as pregnancy, breastfeeding, menstruation and hormone use is lacking. A survey study of neurologists' practice patterns was undertaken to elicit information about gender-specific topics and the use of disease-modifying MS therapies (DMT) including the interferons and glatiramer acetate (GA). A total of 147 surveys were returned. Half of respondents require patients to discontinue DMT during pregnancy, while 35% encourage discontinuation. Among those who allow patients to continue therapy, half consider GA to be safer during pregnancy than the interferons. Nearly 86% of respondents do not use DMT in patients who are breastfeeding. Among the 11% who actually prescribe during breastfeeding, most recommend GA. Neurologists generally leave the decision to breastfeed up to patients, and most refer patients to obstetrician/gynaecologists for counselling about contraception or hormone replacement therapy. The survey results described here provide insight into how neurologists manage reproductive health issues among women with MS.

Event-related potential correlates of early processing in normal aging.

Auditory event-related potentials were recorded from normal elderly and young adult subjects during simple reaction time and discrimination conditions. In both response conditions, the stimuli were randomly presented, as in an auditory "oddball" paradigm. It was found that NA, an index of early information processing, was significantly delayed in the elderly. Although the latency of N1 was not significantly different between the groups, the latencies of N2 and P3 were significantly longer for the aged subjects. The amplitudes of N1, NA1, NA2 and N2 showed no group differences. The raw amplitude of P3 showed a group difference in topography: Pz was greater than Fz for the young group, but not for the aged. When the amplitudes of NA1, NA2, and P3 were scaled, however, the topography of these components showed no significant group differences. These findings suggest that the age-related slowing of later ERP components and behavior may be partially accounted for by delays in early attention dependent perceptual processes, as indexed by NA.

Endogenous event-related potentials as indices of dementia in multiple sclerosis patients.

Auditory event-related potentials (ERPs) were recorded in a "double oddball" paradigm requiring an easy and a hard pitch discrimination from multiple sclerosis (MS) patients with and without dementia, and a group of age and sex matched normal subjects. Cognitive function was assessed by a short battery of neuropsychologic (NP) tests, and the two groups of MS patients were selected on the basis of substantial non-overlapping degrees of cognitive deficit in the demented as compared to the non-demented group. The N100, P200 and P300 ERP components were longer in latency in the demented patients, and the N100-P300 interval was prolonged as well, compared to the non-demented patients, whose ERP latencies did not differ from those of the normal subjects. Increased P300 latency was associated with poorer performance on the NP tests, especially those sensitive to impairment of learning and retrieval from memory. The reaction times of both patient groups were prolonged as compared to the controls, whereas the accuracy of the demented patients was significantly poorer than that of the non-demented patients.

High-dose oral baclofen: experience in patients with multiple sclerosis.

We reviewed a 10% random sample of charts from an outpatient clinic for multiple sclerosis to determine the frequency with which baclofen was prescribed for spasticity in high doses (greater than 80 mg/d). About 20% of patients had taken high-dose baclofen, and 15% were still receiving a high dose. Taking a high dose was not associated with discontinuing treatment.

The utility of visual evoked potentials using hemifield stimulation and several check sizes in the evaluation of suspected multiple sclerosis.

One hundred and eleven patients with suspected multiple sclerosis (64 possible, 47 probable) and 16 with a definite diagnosis of MS were evaluated with pattern-reversal visual evoked potentials (VEPs), employing monocular full-field checks subtending 7', 14' and 28' of visual angle, and right and left hemifield 28' checks. Thirty-seven patients (29%) had a completely normal study. Sixty-six patients (52%) had abnormal responses to full-field 28' checks, and in 13 (10%) of these, additional abnormalities were found in one or more of the other test conditions, which indicated the presence of an additional site of dysfunction in the visual pathway. Twenty-four patients (19%) with 'normal' full-field 28' responses had abnormalities in one or more of the other test conditions; these included prolonged latency to small size (7' and 14') full-field checks, abnormal responses in homonymous hemifields, and abnormal responses limited to a hemifield of one eye. Thus, the use of several check sizes and hemifield stimulation not only increases the sensitivity of VEPs in the evaluation of patients with suspected demyelinating disease, but enhances the capability of the VEP to demonstrate more than one area of visual system impairment.

Trimodal evoked potentials compared with magnetic resonance imaging in the diagnosis of multiple sclerosis.

Twenty-three patients with the clinical diagnosis of possible multiple sclerosis (MS) were tested with magnetic resonance imaging (MRI) and trimodal evoked potentials. Fourteen patients showed abnormalities on both MRI scans and at least one evoked potential modality (65%). Four patients had normal MRI scans but at least one abnormality on evoked potential testing (17%). One patient had normal triple evoked potentials with an abnormal MRI result. Four patients had normal results on both MRI and triple evoked potential testing; two of these patients were later found to have immunologic abnormalities in the cerebrospinal fluid consistent with the diagnosis of MS. Combined evoked potential testing was found to have a higher sensitivity than MRI in confirming a diagnosis of MS. Three patients with the clinical diagnosis of definite MS were also tested. All these patients showed abnormalities on evoked potential testing, although one patient had a normal MRI result. Of all 26 patients who were studied, 17 showed abnormal MRI results and 21 showed at least one abnormality on evoked potential testing.

Multiple sclerosis. Current concepts in management.

Multiple sclerosis is a chronic, often progressive disease of the central nervous system which can produce visual, sensory, motor, and genitourinary dysfunction. Although there is no cure, many disabling symptoms can be ameliorated. Baclofen is the treatment of choice for spasticity and is usually given in doses of 30 to 80 mg/day, although higher doses may be used. Bladder symptoms in multiple sclerosis generally fall into the categories of failure to store, failure to empty, and mixed types. Most patients can be managed after obtaining a urine culture and sensitivity and post-voiding residual. A variety of anticholinergic agents plus intermittent self-catheterisation is usually the most effective treatment for bladder dysfunction. Prevention of infection is accomplished by urinary acidifiers or low-dose antibiotics. There is no evidence that long term use of corticosteroids has a beneficial effect on the outcome of multiple sclerosis, although they appear to be useful in hastening the recovery time from an acute exacerbation. There are a number of experimental therapeutic agents which are used to modulate the immune response, which may prove to be of use in slowing or arresting the progression of multiple sclerosis.

Radioisotope studies of neurogenic bladder in multiple sclerosis.

Urinary dysfunction is a frequent and often serious manifestation of multiple sclerosis. If ignored, urinary tract pathology can cause disabling symptoms and life-threatening complications. Symptomatic relief and preventative measures are available once the underlying neurogenic pathology has been identified. The conceptualization of the categories "Failure to Store," "Failure to Empty," or "Combined" provide practical diagnostic and treatment catagories. One important diagnostic test to help define treatment parameters is the radioisotope renal/residual urine study.

Field testing of a minimal record of disability in multiple sclerosis: the United States and Canada.

The IFMSS Minimal Record of Disability (MRD) in Multiple Sclerosis was field tested at eight medical centers in the U.S. and Canada. The goals were to conduct a qualitative and quantitative evaluation of the MRD. Assessment were completed on 249 patients with definite MS by neurologists and allied health professionals. Effective administration required some study and practice. Refinement of some unclear wording and awkward format will improve ease of administration. The MRD fit well into clinic routines and was accepted by staff and patients. Scoring presented few problems and these were related to overlap among the MRD scales, poor wording, and content not appropriate to MS. Quantitative evaluation of the MRD indicated that Incapacity Status primarily reflects disability in mobility and self-care when used as a composite score. Heterogeneity of content in Incapacity Status suggests that summed scores be used cautiously. Both Incapacity and Environmental Status had high levels of reliability and high correlations with established measures of impairment in MS. Inter-rater agreement of the ISS and ESS were also high. Once some necessary revisions are made, the MRD should be well on its way to achieving the IFMSS goal of developing a brief, reliable, valid, and appropriate instrument acceptable to a wide variety of workers in MS.