MRI and visual-evoked potentials in partners of multiple sclerosis patients

Hawkes CH, Chawda S, Derakshani S, Muhammed N, Visentin E, Boniface D. MRI and visual‐evoked potentials in partners of multiple sclerosis patients.
Acta Neurol Scand: 2012: 125: 424–430.
© 2011 John Wiley & Sons A/S. Objective – Some epidemiological evidence, particularly concerning the role of Epstein Barr Virus implies that multiple sclerosis (MS) may be transmissible and if correct, this might be revealed by increased prevalence of MS in cohabiting partners. Methods – We addressed this problem by neurological assessment, visual‐evoked potentials (VEP) and magnetic resonance imaging (MRI) in 112 partners of patients with MS in comparison to a control group of 93 individuals with clinically non‐significant head or neck pain and in comparison to UK prevalence. Results – We found one instance of conjugal definite MS. Including this case, VEP were abnormal in five instances with either significant delay (n = 3) or increased interocular latency difference (IOLD) (n = 2) in partners of MS patients thus raising the possibility of subclinical optic nerve demyelination. The mean absolute value of IOLD in partners was greater than the value in controls (P = 0.033). There were no significant differences in MRI findings between the two groups. Conclusion – The finding of one conjugal pair and abnormal VEP in a further four MS partners could have several explanations. It is compatible with the concept of a transmissible agent, although our observations could be due to several biases as well as the play of chance alone.     

Visual evoked potentials in normal subjects and patients with multiple sclerosis

Visual evoked potentials (VEPs) by checkerboard pattern-reversal stimulation were recorded in 70 subjects aged 10–69 years and in 100 patients with definite, probable or possible multiple sclerosis (MS). Longer latencies and smaller amplitudes of the major positive component were found in male subjects, in old subjects and when the amplifier's band-pass was narrowed. Subjects 10–14 years old had longer latencies and higher amplitudes than mature adults. Based on findings in the normal material, the following three criteria were used in evaluating the recordings from patients: the latency, the side difference in latencies and the ratio of amplitudes between the two sides of the major positive component with various limits for the two sexes and different age groups.
The incidence of abnormal recordings was 85% for all the patients, 100% in 50 patients with definite, 70% in 50 patients with probable or possible MS, 73% in patients who had a history of spinal symptoms only, 98% if they had and 74% if they had not experienced optic neuritis. The incidence of abnormal findings increased with increasing duration of symptoms. All patients with visual acuity below 0.67 had abnormal VEPs.
The high incidence of abnormal recordings confirmed the value of the test in establishing the diagnosis, and suggested that the use of different normative values for sex and age may increase the diagnostic yield without increasing the number of false positive findings.     

Evaluation of visual pathways in multiple sclerosis. I. After-images compared to visual evoked potentials

The value of flight of colours (FOC), i.e. the succession of coloured afterimages following light stimulation, in diagnosing and following visual impairment was evaluated in 65 patients with multiple sclerosis (MS). Previous optimistic reports of the use of a pocket flashlight (PFL) method could not be confirmed, and are ascribed to inadequate methods. An electronic flashlight (EFL) method developed by us, proved a significantly better diagnostic tool (61% abnormal versus 18% abnormal). The EFL method was diagnostically less sensitive than pattern reversal visual evoked potential (PR-VEP) (80% abnormal). It did, however, add to PR-VEP by diagnosing 16 eyes with normal PR-VEP latency. The EFL method reflected the degree of degenerative changes in the central visual pathways and may be of value in following the disease activity in MS. The potential of the EFL method may be further improved by proposed modifications.     

Motor evoked potentials in multiple sclerosis patients without walking limitation: amplitude vs. conduction time abnormalities

We used Motor Evoked Potentials (MEPs), elicited by transcranial magnetic stimulation, for assessing a motor pathways dysfunction in a selected group of Multiple Sclerosis (MS) patients, without limitation in walking. We selected 32 Relapsing Remitting MS patients, in remission phase, with EDSS ≤ 3.5 and 20 healthy individuals with similar height and age distribution. We measured the following MEP parameters: motor thresholds; central motor conduction time (CMCT); amplitude and area, both expressed as MEP/CMAP ratio. Patients were divided into two groups according to the EDSS score: non-disabled group (ND; EDSS 0–1.5) and disabled group (D; EDSS 2–3.5). Mean average MEP values were significantly different in the patients compared with the controls. Even in MS patients with no or minor neurological signs (ND group), MEP parameters showed differences from controls and furthermore all MEP parameters were significantly different in the D group compared with the ND group. The 75% of the patients had an amplitude or area alteration; this percentage was significantly higher than the percentage of patients with a CMCT alteration (56.2%). In addition, CMCT increase was always associated with reduced amplitude and area, but amplitude and area alterations were present also in patients with normal CMCT. In early stages of MS, the higher percentage shown in alteration of MEP amplitudes and areas as opposed to CMCTs has not previously been highlighted in the literature. Independently of its pathogenesis (demyelination or axonal loss), the amplitude or area decrease should be considered in clinical trials and in follow-up studies, as a marker of the motor pathways dysfunction, at least as much as CMCT increase. Received in revised form: 3 April 2006     

Detection of brainstem lesions in multiple sclerosis: comparison of brainstem auditory evoked potentials with nuclear magnetic resonance imaging

Topographical information provided by brainstem auditory evoked potentials (BAEPs) was investigated in 43 patients by comparison with cerebral nuclear magnetic resonance imaging (NMR). Lesions in the region of the brainstem auditory pathways were demonstrated by BAEPs in 44.2%, and in 39.5% by NMR. As regards brainstem levels, in 15/21 (71.4%) with abnormal findings at least one lesion was verified by NMR-matched BAEP results. The study confirms the topographical information provided by the BAEPs on the different levels of the brainstem, but not the assumption that generation of the BAEPs is predominantly ipsilateral. BAEPs retain their importance for the detection of disseminated lesions in the diagnosis of multiple sclerosis (MS) in the era of expensive imaging methods.     

Multiple sclerosis: incorporation of results of laboratory techniques in the diagnosis

In a retrospective study of 100 multiple sclerosis patients we compared the diagnostic classification according to the Schumacher/Rose criteria and the newest criteria, proposed by Poser et al. It is clear that by incorporating the results of laboratory investigations in the diagnostic criteria a firm diagnosis of multiple sclerosis can be reached more often and at an earlier stage of the disease. Evaluating abnormal laboratory findings, we found that it was possible to detect more than 90% of diagnostically important findings, i.e. findings effecting a change in diagnostic classification (from possible multiple sclerosis to probable or definite, from probable to definite), using only two of the laboratory tests: cerebrospinal fluid analysis and visual evoked response. Because the results of laboratory tests contributing to diagnostic classification are not specific for multiple sclerosis, the importance of evaluating the complete differential diagnosis of diseases that can be confused with multiple sclerosis is stressed.     

Cognition in relapsing-remitting multiple sclerosis: a multichannel event-related potential (P300) study

Auditory event-related potentials (AERP) were elicited in 47 patients with relapsing-remitting (RR) multiple sclerosis (MS) and 24 age-matched controls. MS patients had significantly prolonged N2 and P3 latencies as well as low P3 amplitude compared with controls. Seven of them exceeded 3 standard deviations from the control mean values. The observed N2 and P3 alterations are associated with the patients' disability status as it is defined by the Kurtzke expanded disability status scale (EDSS), but are not related to the duration of the disease. A possible cognitive decline as reflected in the observed AERP components alterations in MS patients is subsequently discussed.     

Central motor conduction as a measure of disease progression in early multiple sclerosis

We monitored disease progression in 27 patients with clinically or laboratory-supported definite multiple sclerosis by means of clinical assessments [expanded disability status scale (EDSS), and the neurologic rating scale (NRS)] repeated at 6 month intervals for 2 years. Each clinical assessment was accompanied by evoked potentials (EP; visual, brain stem auditory, and somatosensory evoked potentials), motor evoked potentials elicited by magnetic stimulation, and magnetic resonance imaging of the brain and brain stem. Central conduction indices were calculated for each central pathway. According to the EDSS 18 patients deteriorated, eight were unchanged and one improved. The central motor conduction index (CMCI) was the only conduction parameter which correlated significantly with both EDSS and NRS at baseline [rho=0.51 (EDSS); -0.65 (NRS)], at final investigation, and when individual changes from baseline to final investigation were addressed (rho=0.38; -0.38). Individual deteriorations or improvements of the CMCI during the 2 years correlated with changes in both EDSS and NRS (rho = 0.51; -0.38). The MRI parameters did not correlate with the clinical scores. The concordance between MRI and CMCI in detection of disease activity was 63%. We conclude that the CMCI stands out as an objective, accurate and easily obtained outcome parameter.     

The value of brain stem auditory, visual and somatosensory evoked potentials and blink reflexes in the diagnosis of multiple sclerosis

Cervical and cortical somatosensory evoked potentials (SEP) following electrical stimulation of the median nerve and blink reflexes (BR) following electrical stimulation of the supraorbital nerve were recorded in 30 normal subjects aged 20–49 years. Subjects aged 40–49 had longer SEP latencies than subjects aged 20–39 years.
A total of 29 slightly affected patients with multiple sclerosis (MS) aged 26–49 years, including four patients without clinical signs (suspected MS) and 19 patients with signs indicating only one lesion (possible MS) were examined by low-rate random-stimulated brain stem auditory (BAEP), checkerboard pattern-reversal visual evoked potentials (VEP), SEP and BR. Abnormal recordings by at least one of the examinations were found in all but three patients, and by all four tests in five patients.
In patients with definite or probable MS, demonstration of clinically recognized or subclinical lesions was of minor diagnostic value, in contrast to the importance such findings had in patients with suspected or possible MS. Silent lesions were shown by at least one of the tests in the four suspected and in 13 of the possible MS patients, so these 17 patients could be transferred to a more certain diagnostic category. This reclassification was most often due to the BAEP recording.
In patients with spinal signs, the combination of BAEP and VEP recording was sufficiently efficient. In patients with optic neuritis a combination of BAEP and SEP was preferred. No abnormal recordings were found in 15 normal subjects examined by all four tests.     

The latency distribution of motor evoked potentials in patients with multiple sclerosis

Objective

To compare the individual latency distributions of motor evoked potentials (MEP) in patients with multiple sclerosis (MS) to the previously reported results in healthy subjects (Firmin et al., 2011).

Methods

We applied the previously reported method to measure the distribution of MEP latencies to 16 patients with MS. The method is based on transcranial magnetic stimulation and consists of a combination of the triple stimulation technique with a method originally developed to measure conduction velocity distributions in peripheral nerves.

Results

MEP latency distributions in MS typically showed two peaks. The individual MEP latency distributions were significantly wider in patients with MS than in healthy subjects. The mean triple stimulation delay extension at the 75% quantile, a proxy for MEP latency distribution width, was 7.3 ms in healthy subjects and 10.7 ms in patients with MS.

Conclusions

In patients with MS, slow portions of the central motor pathway contribute more to the MEP than in healthy subjects. The bimodal distribution found in healthy subjects is preserved in MS.

Significance

Our method to measure the distribution of MEP latencies is suitable to detect alterations in the relative contribution of corticospinal tract portions with long MEP latencies to motor conduction.     

The hot bath test in multiple sclerosis: comparison with visual evoked responses and oligoclonal bands

We studied 50 patients with definite, probable, and possible multiple sclerosis (MS), prospectively (20 patients) and retrospectively (30 patients), to determine the value of the hot bath test for diagnosing MS and to compare it to visual evoked responses and oligoclonal bands. The hot bath test was abnormal in 8 of the 23 patients with definite MS (35%), and 4 of the 27 patients with probable or possible MS (15%). Only one patient with an abnormal hot bath test did not also have other evidence of definite multiple sclerosis. Our results suggest that the hot bath test seldom adds diagnostic information, especially when tests for evoked responses and oligoclonal bands are available.     

Tests of autonomic dysfunction in patients with multiple sclerosis

Autonomic dysfunction is frequent in patients with multiple sclerosis (MS). The sympathetic skin response (SSR) and the R-R interval variation (RRIV) are simple electrophysiologic tests for the assessment of central and peripheral autonomic disturbances. Both tests were performed in 60 patients with clinically definite MS and 30 controls. The SSR was recorded simultaneously from both upper and both lower limbs. In all volunteers normal responses were recorded from the four limbs, but 39 patients (65%) showed abnormal responses in at least one limb. The reduction in amplitude of the response was correlated with patients' EDSS. In individual limbs, the SSR amplitude correlated with weakness, spasticity and cerebellar dysfunction, but was not sufficiently related to the deep sensory loss. The RRIV was abnormal in 48 MS patients (80%), as compared to the controls, but showed no significant relationship either to the EDSS or to the SSR. The sensitivity of SSR and RRIV is high and comparable with that of visual and somatosensory evoked potentials.     

Motor evoked potentials in a mouse model of chronic multiple sclerosis

We tested cortical motor evoked potentials (cMEPs) as a quantitative marker for in vivo monitoring of corticospinal tract damage in a murine multiple sclerosis model (experimental autoimmune encephalomyelitis, EAE). The cMEPs, previously standardized in naive C57BL/6 developing and adult mice, were studied longitudinally in adult EAE mice. Central conduction times (CCTs) increased significantly shortly before the earliest clinical signs developed (10 days postimmunization, dpi), with peak delay in acute EAE (20-40 dpi). In clinically stable disease (80 dpi), CCTs did not increase further, but cMEP amplitude declined progressively, with complete loss in >80% of mice at 120 dpi. Increase in CCT correlated with presence of inflammatory infiltrates and demyelination in acute EAE, whereas small or absent cMEPs were associated with continuing axonal damage in clinically-stabilized disease and beyond (>80 dpi). These results demonstrate that cMEPs are a useful method for monitoring corticospinal tract function in chronic-progressive EAE, and provide insight into the pathological substrate of the condition.     

Primary progressive multiple sclerosis: clinical and paraclinical characteristics with application of the new diagnostic criteria

The aim of our study was to analyse clinical and paraclinical characteristics of patients with multiple sclerosis (MS) with previous diagnosis of primary-progressive (PP) MS according to the Poser's criteria and further investigate if they fulfil the McDonald's diagnostic criteria for this disorder. A total of 561 MS patients were registered in the database at the Institute of Neurology, Belgrade, from 1 January 1997 to 31 December 2000 and 63 of them (11.2%) with previous diagnosis of PPMS were analysed retrospectively. Male/female ratio was 1.3:1 and mean age at onset 33.2 years. Most frequent at onset were pyramidal (in 73% of patients) and sensory symptoms (in 41% of patients); 74.6% of patients had greater than or equal to nine brain magnetic resonance imaging (MRI) lesions. Intrathecal oligoclonal immunoglobulin G (IgG) was detected in 96.7% and prolonged visual evoked potentials (VEP) P100 latency in 82.4% of patients. Of the total study group of 561 patients, 10.2% fulfilled the recently recommended McDonald's diagnostic criteria for the diagnosis of PPMS. Our findings further support the significance of the brain/spinal cord MRI, cerebrospinal fluid and VEP findings for precise diagnostic assessment in patients with suspected PP form of MS.     

Multiple sclerosis: modulation of apoptosis susceptibility by glatiramer acetate

OBJECTIVES: We investigated whether therapy of multiple sclerosis (MS) with glatiramer acetate (GA) involves the modulation of programmed cell death (apoptosis) in disease-relevant T-helper lymphocytes. MATERIAL AND METHODS: Blood was drawn from 15 relapsing-remitting MS patients both before (baseline) as well as 6, 12, and 18 weeks after GA therapy and from 15 healthy controls. Detection of apoptosis was performed in response to in vitro stimulation with GA, myelin basic protein or medium alone. RESULTS: T-helper lymphocytes from untreated MS patients displayed an overall increased apoptosis susceptibility in vitro, compared to controls. During subsequent GA therapy, apoptosis vulnerability of these T cells in MS patients significantly declined under the initial baseline before treatment, and was finally equal in treated patients and controls. GA itself had no direct apoptosis-modulatory properties in vitro. CONCLUSION: Our findings indicate that therapy of multiple sclerosis with glatiramer acetate presumably involves the compensation of altered apoptosis in T-helper lymphocytes.     

T cell vaccination in multiple sclerosis: results of a preliminary study

Myelin basic protein (MBP)-reactive T cells are potentially involved in the pathogenesis of multiple sclerosis (MS), and can be depleted by subcutaneous inoculations with irradiated autologous MBP-reactive T cells (T cell vaccination). This preliminary open label study was undertaken to evaluate whether depletion of MBP-reactive T cells would be clinically beneficial to patients with MS. Fifty-four patients with relapsing-remitting (RR) MS (n=28) or secondary progressive (SP) MS (n=26) were immunized with irradiated autologous MBP-reactive T cells and monitored for changes in rate of relapse, expanded disability scale score (EDSS) and MRI lesion activity over a period of 24 months. Depletion of MBP-reactive T cells correlated with a reduction (40 %) in rate of relapse in RR-MS patients as compared with the pre-treatment rate in the same cohort. However, the reduction in EDSS was minimal in RR-MS patients while the EDSS was slightly increased in SP-MS patients over a period of 24 months. Serial semi-quantitative MRI examinations suggest stabilization in lesion activity as compared with baseline MRI. The findings suggest some potential clinical benefit of T cell vaccination in MS and encourage further investigations to evaluate the treatment efficacy of T cell vaccination in controlled trials. Received: 27 November 2000, Received in revised form: 10 May 2001, Accepted: 11 June 2001     

Multiple sclerosis in India: a case-control study of environmental exposures

Objectives – To compare the rate of prior environmental exposures between Indian multiple sclerosis (MS) patients and controls in order to identify potential disease triggering factors. Material and methods – A standard self-administered questionnaire regarding prior exposures was presented to 56 Indian MS patients and 147 other neural disease and healthy controls at two large medical centers in India. Results – The rate of prior foreign travel, surgeries, blood transfusions, clinical chicken pox and mumps infections and exposure to cats and farm animals was not significantly different between MS patients and controls. However, clinical measles infection and dog exposure occurred significantly more often in the MS patients. Conclusion – These findings are consistent with but do not prove an association between prior measles infection, dog exposure and MS.