Safety and feasibility of autologous bone marrow cellular therapy in relapsing-progressive multiple sclerosis.

In this phase I study, we assessed the safety and feasibility of intravenous, autologous bone marrow (BM) cell therapy, without immunosuppressive preconditioning, in six patients with clinically definite, relapsing-progressive multiple sclerosis (MS). Assessment of efficacy was a secondary objective and employed clinical disability rating scales, multimodal evoked potential (MMEP) recordings, and magnetic resonance imaging (MRI) scans. Cells were harvested, filtered and infused intravenously in a day-case procedure that was well tolerated by patients and was not associated with any serious adverse events (AEs). Over a period of 12 months after the therapy, clinical disability scores showed either no change (Extended Disability Status Score, EDSS) or improvement (MS impact scale-29, MSIS-29), and MMEPs showed neurophysiological improvement. MRI scans did not show any significant changes over a post-therapy period of 3 months. The lack of serious adverse effects and the suggestion of a beneficial effect in this small sample of patients with progressive disease justify conducting a larger phase II/III study to make a fuller assessment of the efficacy of mobilization of autologous BM in patients with MS.

Effect of 902 MHz mobile phone transmission on cognitive function in children.

We examine whether a standard mobile exposure at 902 MHz has a significant effect on cognitive function in 18 children 10-12 years of age. These were in a single group in which each child was given a single training session and then three test sessions in a randomized, three-way crossover design, using the cognitive drug research (CDR) cognitive assessment system. Exposures were 0, 0.025, or 0.25 W from a standard Nokia 3110 mobile phone handset mounted on a plastic headset in normal use position. The results of testing showed that the baseline (0 W) performance for the reaction time measurements was considerably slower than for the comparable measures in adult. There was a tendency for reaction time to be shorter during exposure to radiation than in the sham (baseline) condition, an effect that was most marked for simple reaction time. However, no effects reached statistical significance after Bonferroni correction. Therefore, we conclude that this study on 18 children did not replicate our earlier finding in adults that exposure to microwave radiation was associated with a reduction in reaction time. It should be noted that the present study investigated the effects of radiation from a GSM handset, whereas in our previous study the effect on reaction time was observed only with a more powerful analogue handset.

Hearing preservation and facial nerve function in vestibular schwannoma surgery.

The objective of this study was the assessment of hearing preservation in vestibular schwannoma surgery. This study reports a prospective cohort of 40 patients with clinically useful hearing from a consecutive series of 191 patients with unilateral vestibular schwannoma. The patients were managed in a tertiary centre by a combined team of Neurosurgeon, Otologist and Neuro-monitoring Scientist via a neuro-oto-surgical-retrosigmoid approach. Pure tone speech audiometry was conducted preoperatively and 6 months to 9 years following surgery. Using the AA0-HNS classification, useful hearing, i.e. grades A, B and C, was preserved in 47.5% of patients. Thirty-eight per cent achieved grade A or B. Using appropriate surgical and monitoring techniques, it is possible to preserve useful hearing in approximately 50% of patients following removal of a vestibular schwannoma via the retro-sigmoid approach.

Effect of propofol anaesthesia on the event-related potential mismatch negativity and the auditory-evoked potential N1.

BACKGROUND: Studies on the effects of anaesthesia on event-related potentials and long latency auditory-evoked potentials (AEP) are sparse. Both provide information on cortical processing and may have potential as monitors of awareness. We studied the effect of propofol on the event-related potential mismatch negativity (MMN) and the long-latency AEP NI. METHODS: Twenty-one patients received 1 microgram ml-1 stepped increases in the target concentration of propofol using Diprifusor until a maximum of 6 micrograms ml-1 was achieved or the patient had lost consciousness. Neurophysiological responses (MMN and N1) and the patients' level of consciousness were recorded before the administration of propofol and at a target effector site concentration of propofol of 1, 2, 3, 4, and 6 micrograms ml-1. Grand average evoked potentials were computed at baseline, before the administration of propofol (A); at the highest propofol concentration at which each patient was responsive (B); and at the concentration of propofol at which the patient became unconscious (C). RESULTS: Patients lost consciousness at different target concentrations of propofol, all being unresponsive by 4 micrograms ml-1. The response to the deviant stimuli used to elicit duration-shift MMN was significantly more negative than to the standard stimuli at A (mean difference 2.58 microV, P = 0.0011) but this difference was virtually abolished at point B, before the patients lost consciousness (mean difference 0.63 microV, P = ns). The amplitude of N1 evoked by standard stimuli was negative compared with electrical baseline at both point A (mean amplitude -3.81 microV, P < 0.001) and at point B (mean amplitude -2.2 microV, P = 0.002), but was no longer significantly different to baseline at point C (mean amplitude 0.51 microV, P = ns). The change in the mean amplitude of N1 from last awake (point B) to first unconscious (point C) was also significant (mean difference in amplitude 1.69 microV, P = 0.02). CONCLUSIONS: MMN is unlikely to be a clinically useful tool to detect awareness in surgical patients. In contrast, the loss of N1 may identify the transition from consciousness to unconsciousness and deserves further study.

Visual search in Alzheimer's disease: a deficiency in processing conjunctions of features.

Human vision often needs to encode multiple characteristics of many elements of the visual field, for example their lightness and orientation. The paradigm of visual search allows a quantitative assessment of the function of the underlying mechanisms. It measures the ability to detect a target element among a set of distractor elements. We asked whether Alzheimer's disease (AD) patients are particularly affected in one type of search, where the target is defined by a conjunction of features (orientation and lightness) and where performance depends on some shifting of attention. Two non-conjunction control conditions were employed. The first was a pre-attentive, single-feature, "pop-out" task, detecting a vertical target among horizontal distractors. The second was a single-feature, partly attentive task in which the target element was slightly larger than the distractors-a "size" task. This was chosen to have a similar level of attentional load as the conjunction task (for the control group), but lacked the conjunction of two features. In an experiment, 15 AD patients were compared to age-matched controls. The results suggested that AD patients have a particular impairment in the conjunction task but not in the single-feature size or pre-attentive tasks. This may imply that AD particularly affects those mechanisms which compare across more than one feature type, and spares the other systems and is not therefore simply an 'attention-related' impairment. Additionally, these findings show a double dissociation with previous data on visual search in Parkinson's disease (PD), suggesting a different effect of these diseases on the visual pathway.

Age-related changes in the preattentional detection of visual change.

The ability to detect changes in the environment which occur outside the focus of current awareness is essential if the individual is to be able to divert attention to biologically salient stimuli. The preattentional mechanism underlying the automatic detection of stimulus change in the auditory modality has been extensively studied by recording an event-related potential known as the mismatch negativity. Recently a homologous response from the visual cortex has also been described. Ageing has been shown to affect the efficiency of preattentional processing in the auditory modality, a factor which may contribute to cognitive changes in the elderly. It is unclear whether a similar effect occurs in the visual system. To investigate this issue the visual mismatch negativity was recorded from 12 older adults and 24 younger adults. Whereas the younger adults displayed a robust visual MMN, that evoked in the older adults was significantly reduced in amplitude. The results are indicative of age-related deficits in automatic visual processing.

Referred sensations following stroke.

Referred sensations are recognized as phenomena experienced after amputation of a limb and have been used as proof of the consequences of changes in somatosensory body part representation in the adult brain. Such changes may accompany interruption of afferent sensory projections after subcortical stroke. This report describes some misplaced localization to touch in a subject 15 months after cerebral haemorrhage involving the posterior limb of the right internal capsule and lateral thalamus. The results revealed the occurrence of referred sensations, indicating some scrambling of the somatosensory representation of the affected limbs. While many stimuli were localized correctly, there were a number of stimuli applied to the hand and foot that were referred to more proximal limb segments. Stimuli to the upper arm were sometimes felt in more distal parts of the limb. Stimuli to the face were localized to the arm and not the hand. With the aim of determining consistency of findings, testing of the upper limb was carried out on four separate occasions. The subject had less referred sensations in each test, possibly indicating some change in his somatosensory representation that occurred with experience.

Consultants workload due to alcohol related conditions in acute medical receiving gastroenterology and endocrinology.

A four-week survey was performed into the incidence of alcohol related problems in the acute medical receiving unit, and the prevalence of alcohol related cases in a ward shared between two gastroenterologists and an endocrinologist. Alcohol related conditions were the commonest reason for acute admission (19%). Gastroenterologists, in contrast to their colleagues have a substantial workload related to alcohol, especially chronic liver disease. These patients have longer lengths of stay with higher morbidity and mortality than those without alcohol related conditions. The reason for these differences and the implications for service planning are discussed.

The pupillary light reflex in aging and Alzheimer's disease.

The pupillary light reflex is reported to be reduced in amplitude in Alzheimer's disease (AD). The purpose of this study was to determine whether this effect is measurable under conditions typical of clinical rather than laboratory settings. A head-mounted infra-red videopupillometer was used to measure the amplitude of pupillary constriction in 12 patients with probable AD, 12 healthy age-matched older adults and 12 young adults. The constriction to the onset of bright light relative to the resting amplitude was significantly reduced in AD compared with both control groups. This result is consistent with an acetylcholine-related deficit in AD and supports the findings of Prettyman et al. and Fotiou et al. The impairment is likely to be caused by degeneration in relays in the midbrain but cholinergic deficits in the peripheral parasympathetic pathway cannot be excluded. The variation in pupillary response between individuals may preclude its use for diagnostic purposes. However, if the changes in pupillary response in AD are related to change in neurotransmitter status, then the value of such a technique may be in its use in providing an objective, non-invasive monitor of physiological abnormality with which to follow disease progression and treatment efficacy.

Coma outcome prediction using event-related potentials: P(3) and mismatch negativity.

The prediction of the outcome from coma is of considerable importance to the patients, their relatives and attendant medical staff, and yet current clinical methods lack sensitivity and specificity. Objective investigations can enhance the accuracy of such predictions and are an important adjuvant when reaching decisions to continue or terminate life support. Of the neurophysiological methods available, electroencephalography and short-latency somatosensory evoked potentials have proved the most useful in the clinical setting. These tests are good predictors of an adverse outcome; however, they tell us only about the ongoing cerebral activity and integrity of the primary somatosensory pathways, respectively. The presence of long-latency event-related potentials has been shown to be a useful predictor of a favourable neurological outcome, and thus their use complements other neurophysiological techniques. Their potential application in clinical practice is reviewed.

Intraoperative monitoring during surgery for acoustic neuroma: benefits of an extratympanic intrameatal electrode.

OBJECTIVES: To assess the utility of an extratympanic intrameatal electrode for intraoperative monitoring during acoustic neuroma and other cerebellopontine angle tumour surgery and to define the neurophysiological and surgical factors which influence hearing preservation. METHODS: Twenty two patients, 18 with acoustic neuromas and four with other cerebellopontine angle tumours, underwent intraoperative monitoring during tumour excision. The extratympanic intrameatal electrode (IME) was used to record the electrocochleogram (ECoG) and surface electrodes to record the brainstem auditory evoked response (ABR). RESULTS: The compound action potential (CAP) of the ECoG was two and a half times greater in amplitude than wave I of the ABR and was easily monitored. Virtually instant information was available as minimal averaging was required. Continuous monitoring was possible from the commencement of anaesthesia to skin closure. The IME was easy to place, non-invasive, and did not interfere with the operative field. Operative procedures which affected CAP or wave V latency or amplitude were drilling around the internal auditory meatus, tumour dissection, nerve section, and brainstem and cerebellar retraction. Hearing was achieved in 59% of patients. CONCLUSIONS: The IME had significant benefits in comparison with other methods of monitoring. The technique provided information beneficial to preservation of hearing.

Quantitative electroencephalographic evaluation of non-fatal and fatal traumatic coma.

Diffuse axonal injury (DAI) is an important cause of morbidity and mortality after traumatic brain injury (TBI), and its severity is therefore a major determinant of outcome. There have been suggestions that the extent of DAI may be reflected in quantitative measures of cerebral function, including the electroencephalogram (EEG) and brain-stem auditory evoked potentials (BAEPs). It has therefore been proposed that these quantitative methods of analysis may provide objective predictors of outcome following TBI. We prospectively investigated the relationship between quantitative EEG and BAEP measures and outcome, in 60 comatose patients (47 male and 13 female; age range 1-80 years, mean 36.4) after severe, closed head injury (post-resuscitation Glasgow Coma Scale (GCS) of 8). The Spearman correlation coefficients (rs) have been calculated for quantitative EEG measures (mean regional power and interhemispheric coherence) and BAEPs with patient outcome on the Glasgow Outcome and Disability Rating Scales at 6 months and 1 year. The measures most significantly correlated with outcome (P < 0.001) are over the left hemisphere, beta activity power (amplitude squared) in the fronto-central and centro-temporal regions, and alpha activity power in the centro-temporal region. We found no correlation between interhemispheric coherence (a statistical measure of cross-correlation in the frequency domain) and outcome at either 6 months or 1 year post-injury. In 10 fatalities, we examined the relationship between interhemispheric EEG coherence prior to deaths and the histopathological severity of DAI, in concordant regions. The only significant correlation between DAI and interhemispheric coherence is seen in the alpha band at the temporo-occipital site (rs = -0.79, P = 0.007). Our data indicate that there is regional information in EEG power spectra over the left hemisphere, which could be used in prognostic predictions for patients in coma after severe TBI. We were unable to demonstrate a correlation between interhemispheric coherence and outcome, or any clear and consistent evidence of a relationship between interhemispheric coherence and the severity of DAI.

The effects of visual cortex lesions on the perception of rotated shapes.

Monkeys with inferior temporal cortex lesions cannot discriminate between different shapes (e.g., + vs. O) but can discriminate between shapes that differ only in orientation (e.g., 6 vs 9). Lesions of the parietal cortex, on the other hand, impair the discrimination of rotated shapes but spare the ability to discriminate between different shapes. A similar dissociation is found between some visual agnosics who can match but not identify rotated views of objects and other patients who can identify and discriminate objects only if the view is conventional; any change in orientation disrupts performance. In this paper we argue that two mechanisms may be available for the perception of rotated shapes. Which mechanism is used depends on the degree of rotation. It is suggested that the different effects of parietal and temporal lesions reflect the relative contributions of the two areas to the task and disrupt different stages of the two strategies used. A framework for the cortical processing of rotated shapes in the non-human primate is presented.

Event-related potentials--neurophysiological tools for predicting emergence and early outcome from traumatic coma.

OBJECTIVE: To determine the prognostic value of multimodal evoked potentials (EPs) and event-related (ERPs) potentials in coma (Glasgow Coma Score <8), after severe traumatic brain injury (TBI). DESIGN: Prospective, longitudinal study of neurophysiological responses recorded during traumatic coma. SETTING: Intensive Care Unit, Frenchay Hospital, Bristol, UK. PARTICIPANTS: Fifty-four comatose TBI patients (age range 1-80 years, mean 36.4). METHODS: Neurophysiological responses were recorded from 11 scalp electrodes with earlobe reference. Conduction times were measured for brainstem auditory, flash visual and somatosensory, short-latency EPs. Peak latencies and amplitudes were determined for long-latency components of visual and auditory ERPs, generated by passive "oddball" paradigms. These neurophysiological and various clinical parameters were correlated with patient outcome using Pearson's coefficient. MAIN OUTCOME MEASURE: Three month Glasgow Outcome Scale (GOS). RESULTS AND CONCLUSION: Highly significant (P <0.001) correlations exist between long-latency ERP components and 3-month outcome. Short-latency EPs, brainstem (wave I-V) and somatosensory conduction times also correlate significantly with the GOS (P <0.01). Of the clinical measurements, pupillary response patterns, APACHE II and Glasgow Coma Scores (GCS) correlate significantly with outcome, as do the retrospective measures of duration of coma and post-traumatic amnesia (PTA) in survivors. Unfortunately, due to variance of long-latency responses, even in controls, absolute values cannot be relied upon as prognosticators. The presence of "mismatch negativity" predicted the return of consciousness (89.7% sensitivity and 100% specificity) and preceded changes in GCS. Its latency was the single best indicator of 90-day outcome from coma (r = -0.641).

Functional outcome in patients after excision of extracanalicular acoustic neuromas using the suboccipital approach.

An audit of surgery for acoustic neuroma was carried out to determine the frequency and nature of postoperative symptoms and their impact upon the patient's quality of life and vocation. Fifty-six patients were interviewed between 6 months and 5 years (mean 26 months) after surgical excision of an acoustic neuroma. The objective surgical results in these patients are good, with normal or near normal functional preservation rates of 80% for the facial nerve (House-Brackmann grade I/II), and 27.3% for a previously functioning acoustic nerve. Despite this there was no significant overall reduction in the reported occurrence of balance problems, tinnitus, headache and other neurological sequelae of the tumour after surgical excision. In 20% of the patients persistent symptoms, including deafness and facial weakness, had prevented the resumption of former social activities. As a result of these symptoms 8.6% of the patients were certified medically unfit for work, but of those employed preoperatively over 70% had returned to their jobs. The success of neuro-otological surgical management of acoustic neuroma is offset by some degree of chronic morbidity. Our patients expressed the need to know whether their symptoms would resolve, but were often too afraid to ask. Patients can be reassured that the majority resume their former social and vocational activities, but should be advised that some symptoms can persist or occur de novo after surgery. Our data suggest that early intervention would reduce the incidence of these troublesome sequelae.

The electrophysiological basis of colour processing in macaques with V4 lesions.

Monkeys with lesions of visual area V4 have deficits in colour constancy, but are able to discriminate hues and segment the spectrum in a categorical manner. To investigate the nature of the processing mechanisms subserving the spared functions we recorded occipital visual evoked potentials (VEPs) of normal monkeys and monkeys with bilateral lesions of area V4. The stimuli used to elicit the potentials were chromatic and achromatic gratings of low spatial frequency. The waveforms from the two groups of animals were similar in all respects. VEPs for the onset of a chromatic grating were negative-going, indicative of the activity of sustained units, as opposed to those elicited by offset or reversal of the grating which were positive-going. The amplitude of the chromatic, 12.5 Hz reversal VEP went through a minimum at isoluminance, in accord with low temporal resolution of colour processing. The VEP waveforms were identical in character from three weeks to approximately four years post-operatively. These data indicate that chromatic processing in areas V1 and V2 is normal after V4 lesions and, together with the behavioural evidence, that these areas are sufficient for some basic aspects of colour perception.

The effects of V4 lesions on the visual abilities of macaques: hue discrimination and colour constancy.

Monkeys with lesions of cortical visual area V4 were compared with unoperated monkeys in three experiments. In Expt. 1 they were tested for the reacquisition of a pre-operatively learned hue discrimination task. In Expt. 2, as a test of colour constancy, the monkeys were required to perform previously overlearned colour discrimination tasks when the amounts of red, green and blue light in the illuminant were changed. In Expt. 3 the animals were compared on the post-operative acquisition of hue, greyness and saturation discrimination tasks. The results of Expt. 1 showed that monkeys with V4 lesions can regain their pre-operative levels of performance on hue discrimination tasks. Expt. 2 showed that monkeys with V4 lesions have a colour constancy deficit. Expt. 3 reinforced the finding that the animals with V4 lesions could learn to perform fine hue discriminations but that their final, asymptotic performance was not as reliable as that of normal animals. The wavelength discrimination data are discussed within the context of recent electrophysiological findings that V4 is involved in selective attention to visual stimuli and the constancy data are interpreted as evidence that V4 is important for defining colour constancy thresholds but not for constructing the perceptual categories underlying constant colour perception.