Verapamil-induced changes in central conduction in patients with multiple sclerosis.

The electrophysiological characteristics of demyelinated axons are sensitive to changes in plasma calcium concentration. This study investigated the effect of verapamil, a calcium antagonist drug, on brainstem auditory, visual, and somatosensory evoked potentials in multiple sclerosis patients. Eight clinically stable patients with abnormal visual and/or brainstem auditory evoked potentials and four normal volunteers were studied. During intravenous infusions of verapamil (mean plasma concentration = 130.0 +/- 56.4 ng/ml), the latencies of peaks III and V were shortened (p less than 0.05) in multiple sclerosis patients with abnormally prolonged BAEPs. The I-III (delta = 0.08 ms), III-V (delta = 0.46 ms), and I-V (delta = 0.53 ms) interpeak intervals, and the P100 latency (delta = 10.15 ms) of the visual evoked potential were similarly affected in these patients. In contrast, normal evoked potentials of both multiple sclerosis patients and control subjects were not altered compared to baseline recordings obtained 24 hours earlier. Intravenous verapamil, therefore, alters the BAEPs and VEPs of some multiple sclerosis patients with demyelinated auditory and visual pathways by shortening pathologically prolonged latencies toward normal. The present study suggests pharmacological manipulation of calcium-dependent processes, possibly at the level of the demyelinated axon, can acutely facilitate central conduction of electrical impulses in some patients with clinically stable multiple sclerosis.     

Sensitivity of laser-evoked potentials versus somatosensory evoked potentials in patients with multiple sclerosis.

OBJECTIVE: Somatosensory evoked potentials (SEPs) play a less important role in the diagnosis of multiple sclerosis (MS) than visually evoked potentials. Since standard SEPs only reflect the dorsal column function, we now investigated spinothalamic tract function in patients with MS using laser-evoked potentials (LEPs). METHODS: LEPs to thulium laser stimuli (3ms, 540 mJ, 5mm diameter) were recorded from 3 midline positions (Fz, Cz, Pz) in 20 patients with MS, and 6 patients with possible but unconfirmed MS. Peak latencies and peak-to-peak amplitude of the vertex potential negativity (N2) and positivity (P2) were evaluated and compared with normative values from 22 healthy control subjects. Median and tibial nerve SEPs were recorded with standard methods. Depending on the results of sensory testing, two skin areas (both hands, both feet, or one hand and foot of the same body side) were assessed in each patient. RESULTS: In group comparisons, LEPs in patients with MS were significantly delayed and reduced in amplitude compared with healthy subjects (P<0.001) or patients with suspected but unconfirmed MS (P<0.05). In intraindividual comparisons within the patients with MS, LEP amplitude was significantly lower (P<0.01) and latencies were significantly longer (N2: P<0.01; P2: P<0.05) for a clinically hypoalgesic skin area than an unaffected control area. On a single case basis, LEPs were abnormal in 12 (60%) and SEPs in 8 (40%) of the patients with MS; combined analysis of LEPs and SEPs raised sensitivity to 75% (15 patients). LEPs were also abnormal for 7 skin areas with clinically normal nociception and thermal sensitivity, indicating subclinical lesions. Standard SEPs detected subclinical lesions in 5 areas with normal tactile sensitivity. CONCLUSIONS: In patients with multiple sclerosis, spinothalamic tract function and LEPs were impaired more often than dorsal column function and SEPs. LEPs also detected subclinical lesions. Combined assessment of LEPs and SEPs can help to document dissemination of demyelinating CNS lesions and thus contribute to the diagnosis of multiple sclerosis.     

Cortical somatosensory magnetic responses in multiple sclerosis.

Somatosensory evoked magnetic fields (SEFs) to contralateral median and ulnar nerve stimulation were analyzed in 10 patients with multiple sclerosis and in 8 healthy controls. SEFs were recorded with a 24-channel SQUID gradiometer over both hemispheres. Seven patients showed abnormally large-amplitude SEF deflections at 60-80 msec; 5 of them had multiple lesions around lateral ventricles in magnetic resonance imaging. In 2 patients with plaques at the level of 3rd and 4th ventricles and medulla, the 30 msec responses were enlarged. The equivalent sources of 20 msec and 30-80 msec responses were in the primary hand sensorimotor cortex both in patients and in control subjects. The results suggest that early and middle-latency SEFs reflect parallel processing of somatosensory input. Recording of middle-latency evoked responses, electric or magnetic, may give additional information about the somatosensory function in multiple sclerosis.     

Hypothalamic lesions in multiple sclerosis.

Demyelinating lesions of fiber bundles in and adjacent to the hypothalamus (i.e. the fornix. anterior commissure, internal capsule, and optic system) may be the basis for autonomic and endocrine alterations in multiple sclerosis (MS) patients. Therefore we investigated the presence and immunological activity of lesions in hypothalamic fiber bundles of 17 MS patients and 14 controls. In the MS group, 16 of 17 patients showed demyelinated lesions. The incidence of active lesions was high (60%) and outnumbered chronic inactive lesions in the internal capsule (p = 0.005). In 4 of 17 MS patients, axonal damage was observed and in 3 of 17 MS patients grey matter lesions were apparent. Duration of MS was inversely related to the active hypothalamic MS lesion score (r = -0.72, p = 0.001). Since comparison of hypothalamic lesions with MS lesions in other areas of the brain in the same patients (n = 7) showed a great similarity both as stage and appearance was concerned, this negative relation in all likelihood reflects the clinical consequences of high disease activity throughout the whole brain. In controls no demyelinating lesions were seen but in 11 control cases HLA expression was observed that was lower than that present in MS patients (p = 0.02). In the median eminence region that lacks a blood-brain barrier, all controls showed a strong HLA expression around the blood vessels. We conclude that systematic pathological investigation of the hypothalamus in MS patients reveals an unexpected high incidence of active lesions that may impact on hypothalamic functioning.     

Electrophysiological and clinical correlates of corpus callosum atrophy in patients with multiple sclerosis

Abstract

Multiple sclerosis (MS) is an idiopathic inflammatory demyelinating disorder of the central nervous system (CNS) characterized by demyelination and axonal degeneration. Corpus callosum (CC) is commonly involved during the disease process leading to atrophy (93%). Currently, there are no established markers of disease progression and the interplay of processes leading to brain atrophy in MS remains unknown. The primary aim of this study was to assess the frequency of CC atrophy in MS patients. Furthermore, the relationship between expanded disability status scale (EDSS) and transcranial magnetic stimulation (TMS) evoked motor potentials (MEP) were assessed to capture disease effects by independent parameters. Seventy-nine MS patients and 50 controls were included and their CC volumes were assessed. Out of 79 patients, 31 patients (39·2%) had CC atrophy. The distribution of EDSS scores among the group with CC atrophy [13 (32%) patients with EDSS 0–2; 11 (58%) patients with EDSS 2–4; 19 (24%) patients with EDSS ≥4] was not statistically significant (p>0·05). MEP latency was abnormal in 34 (43%) patients, 67 (85%) patients had abnormal MEP amplitude and CMCT was abnormal in 32 (41%) patients. The relation between EDSS and MEP was statistically significant among the patient population including the subgroup of patients with CC atrophy (p<0.05). Our results lacked to provide an association between disability and CC atrophy, but there was a correlation between CC atrophy and TMS evoked motor potentials. Early evolution of axonal degeneration and brain atrophy should be considered in terms of follow-up measures to provide long-term efficiency impacting disability, progression and brain atrophy.     

Immunological time-course of gadolinium-enhancing MRI lesions in patients with multiple sclerosis

In multiple sclerosis (MS) gadolinium (Gd)-enhanced MRI activity correlates weakly with immunological markers of disease activity. We, therefore, tested the hypothesis that the poor correlation could be partly explained by the temporal profile of Gd enhancement. We measured urinary neopterin:creatinine ratios (neopt.:creat.(urine)) in 5 patients with active MS undergoing weekly Gd-enhanced MRI studies of the brain. The neopt.:creat.(urine) associated with new Gd-enhancing lesions (<8 days) was significantly higher than the ratio not associated with new Gd-enhancing lesions [mean(geometric) neopt.: creat.(urine) = 413 micromol/mol (range = 207-521) vs. 250 micromol/mol (range = 132-492), p = 0.03]. Pro-inflammatory immunological markers, which are probably produced early on in the life cycle of an active MS lesion, should preferably be correlated with newly enhancing lesions (<8 days). Failure to do this may explain the poor and unpredictable correlations between immunological markers and Gd-enhanced MRI activity, which cannot be accurately aged in cross-sectional and serial monthly MRI studies.     

Morphometric analysis of axons in the minute multiple sclerosis lesions and shadow plaques in patients with multiple sclerosis

The objective of the present study was to quantitatively detect axons in the minute multiple sclerosis (MS) lesions and in shadow plaques, taking into consideration the relapsing-remitting(R-R) and secondary progressive(SP) stages of MS. The brain tissue of 12 patients deceased due to MS was investigated. An image-computerized analysis was made for measurements of axons. Based on the findings we concluded that damage to axons appears in both the minute MS lesions and in shadow plaques. Demyelination and ineffective (too late or too slow) remyelination seemed to be very important factors in axonal damage. Irreversible damage to axons may appear in both the secondary progressive and relapsing-remitting stages of MS, causing permanent neurological deficits, irrespective of the duration of the disease.     

Correlation of somatosensory evoked potentials and long loop reflexes in patients with multiple sclerosis

Based on the results of somatosensory evoked potentials (SEPs) and long loop reflexes (LLRs) obtained from the 50 upper limbs of 25 normal controls by stimulating the median nerve, four regions were set up in a latency correlation diagram between N20 and LLR, which were assumed to mainly represent the afferent and the efferent functions, respectively. Seventy upper limbs of patients with multiple sclerosis, differently marked according to the presence or absence of pyramidal sign and/or impaired vibration sense, were plotted on the diagram. The regions to which the patient belonged turned out to be reasonably compatible with the neurological status of the patient. Simultaneous measurements of SEPs and LLRs are therefore useful to evaluate the afferent and efferent pathways in the central nervous system.     

Effect of raising body temperature on visual and somatosensory evoked potentials in patients with multiple sclerosis.

The effects of raising body temperature on the visual (VEP) and somatosensory (SEP) evoked potentials were observed in normal subjects and in patients with multiple sclerosis. The amplitude of the VEP was significantly reduced to the same degree after heating in normal subjects and in patients with multiple sclerosis but there was no effect on the latency of the potential. Changes in amplitude could not be related to reduction in acuity. In contrast, the cervical SEP was greatly disorganised after heating in many patients with multiple sclerosis while the only effect in normal subjects was to reduce the latency by increasing peripheral conduction velocity. These results suggest that heat caused conduction block in demyelinated axons in the sensory pathways of the cervical spinal cord.     

Cortical somatosensory magnetic responses in multiple sclerosis

Somatosenosor evoked magnetic fields (SEFs) to contralateral medium and ulnnar nerve stimulation were analyzed in 10 patients with multiple sclerosis and in 8 healthy controls. SEFs were recorded with a 24-channel SQUID gradiometer over both hemispheres. Seven patients' showed abnormally large-amplitude SEF deflections at 60–80 msec; 5 of them had multiple lesions around lateral ventricles in magnetic resonance imaging. In 2 patients with plaques at the level of 3rd and 4th ventricles and medulla, the 30 msce response were enlarged. The equivalent sources of 20 msec and 30–80 msec responses were in the primary hand sensorimotor cortex both in patients and in control subjects. The results suggest that early and middle-latency SEFs reflect parallel processing of somatosensory input. Recording of middle-latency evoekd responses, electric or magnetic, may give additional information about the somatosensory function in multiple sclerosis.     

Visual and somatosensory evoked cortical potentials in multiple sclerosis.

The diagnostic value of the pattern reversal evoked cortical potential (VEP) and the somatosensory evoked cortical potential (SEP) has been compared in 50 patients with established or suspected multiple sclerosis. A prolonged latency of VEP was found in 96% of definite cases of multiple sclerosis, 58% of probable cases, and 20% of possible cases. A prolonged latency of SEP by stimulation of median or peroneal nerves or both was found in 86% of definite cases of multiple sclerosis, 83% of probable cases, and 50% of possibe cases. When combining the results of all three tests the diagnostic yield increased to 100%, 92%, and 50%, respectively.     

Anxiety in patients with multiple sclerosis.

Anxiety disorders are quite common, and frequently overlooked, in patients with Multiple Sclerosis (MS). This is often due to the difficulty differentiating anxiety from personality correlates or reactive tendencies in patients with neurologic disease. This chapter offers the consulting psychiatrist guidelines for providing psychological support to patients with MS at various stages of their disease. DSM-IV-based differential diagnosis, psychotherapeutic techniques, behavioral interventions, and pharmacological support (including the newer alternative therapies) are reviewed. The physical, functional, and symbolic losses caused by this chronic and progressive disease are considered in the broader context of individual patients' lives. Particular attention has been given to specific pharmacological treatment of steroid-induced anxiety. This is essential knowledge for the consulting psychiatrist. The overlap between depressive symptoms, manic symptoms and cognitive changes in MS patients is reviewed with special emphasis on the structural correlates. Current neuro-imaging techniques, including emerging technologies such as gadolinium enhancement, single photon emission computed tomography and brain electrical mapping (BEAM), now provide a far more accurate view of brain damage in MS. This permits diagnosis of the disease much earlier, and is also beginning to show correlation between neuropsychiatric clinical findings, and the nature and location of demyelinating plaques in the brains of MS patients. This chapter seeks to clearly define the associations between anxiety disorders and cerebral involvement in MS patients, suggesting that common neurological and biochemical mechanisms are more extensive than generally suspected. It is hoped that this information will aid clinicians in more accurately diagnosing and effectively treating anxiety in MS patients.     

Somatosensory evoked responses and central afferent conduction times in patients with multiple sclerosis.

Evoked responses following median nerve stimulation were recorded from Erb's point, the cervical spine and the scalp and afferent conduction times between each recording point were determined in 44 patients with multiple sclerosis. A prolonged central conduction time was frequently the only finding in MS patients, particularly in the early stages of the disease. Changes in central conduction time thus seem to be more sensitive than changes either in response latencies or response morphology.     

Memory performance in multiple sclerosis patients correlates with central brain atrophy

OBJECTIVE: To assess whole brain and central brain atrophy as well as their differential relation to memory, cognitive performance, fatigue, depression and quality of life in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A 3D flow compensated gradient recalled T1-weighted MRI was acquired in 45 RRMS patients. An automated analysis tool was used to calculate brain parenchymal fraction (BPF) and ventricular brain fraction (VF). All patients were assessed with neuropsychological tests focusing on memory and self-rating scales for depression, fatigue and quality of life. Age corrected partial correlations between brain atrophy, motor performance, psychological scales and test scores were calculated. RESULTS: BPF correlated moderately (0.3 < or = r < 0.5) with duration of symptoms and disease, the Expanded Disability Status Scale (EDSS), the upper extremity motor performance, and with mental aspects of quality of life. VF correlated moderately with EDSS, upper and lower extremity motor performance and memory functions. Neither BPF nor VF correlated with fatigue and depression. Results of several cognitive tests correlated moderately with depression and fatigue, the Paced Auditory Serial Addition Test (PASAT) showing the largest correlation. CONCLUSIONS: Memory performance shows a correlation with relative ventricular size in RRMS patients, indicating the strategic location of the ventricle system along the structures of the limbic system and its vulnerability in MS. The PASAT and several other cognitive tests show moderate correlations with depression and fatigue, arguing for an inter relation between the cognitive functioning and the emotional state of patients. However, this relation is independent of measurable brain atrophy.     

Electrophysiological patterns of oropharyngeal swallowing in multiple sclerosis

ObjectiveWe performed an electrophysiological study of swallowing (EPSS) in multiple sclerosis (MS) to describe oropharyngeal swallowing abnormalities and to analyze their correlations with dysphagia and with overall neurological impairment.MethodsNeurological examinations were quantified using the Kurtzke Functional Systems and the Expanded Disability Status Scale (EDSS). Dysphagia was evaluated using the Dysphagia in Multiple Sclerosis (DYMUS) questionnaire, while fiberoptic endoscopic evaluation of swallowing (FEES) was used to establish the degree of aspiration and penetration, graded using the penetration–aspiration scale (PAS). The EPSS measured the duration of suprahyoid/submental muscle EMG activity (SHEMG-D), the duration of the laryngeal–pharyngeal mechanogram (LPM-D), and the duration of the pause in cricopharyngeal muscle EMG activity (CPEMG-PD); it also measured the interval between onset of the suprahyoid/submental muscle EMG activity (SHEMG) and onset of the laryngeal–pharyngeal mechanogram (I-SHEMG-LPM).Results92% of patients showed at least one electrophysiological abnormality. I-SHEMG-LPM correlated positively with the DYMUS questionnaire. I-SHEMG-LPM, SHEMG-D, and DYMUS correlated positively with the PAS. Moderate to severe bladder sphincter dysfunction was associated with a significant reduction, or absence, of CPEMG-PD.ConclusionEPSS improves our understanding of the pathophysiology of dysphagia in MS.SignificanceThis investigation could be useful in MS patients with swallowing abnormalities.     

Tumour-like lesions in multiple sclerosis

The presence of tumefactive lesions on magnetic resonance imaging (MRI) in multiple sclerosis (MS) patients can cause diagnostic difficulties. It requires differential diagnosis between tumefactive demyelinating lesion (TDL) and the coexistence of neoplasm; it also implies further management. The precise assessment of such lesions at the first clinical manifestation of the disease is particularly important. We present three cases of MS presenting with tumour-like lesions of the brain. Based on serial MRI studies, stereotactic biopsy and the response to treatment with corticosteroids, the diagnosis of TDL was established in every case.