Safety of apnea testing for the diagnosis of brain death: a comprehensive study on neuromonitoring data and blood gas analysis.

BACKGROUND AND PURPOSE: Here, we studied the safety of apnea testing (AT) for the determination of brain death with regard to intracranial pressure (ICP), cerebral perfusion and arterial blood gas parameters. We hypothesized that ICP only increases when cerebral perfusion pressure (CPP) remains positive during AT. METHODS: A total of 34 patients who fulfilled brain death criteria were identified by chart review (2009-2017). We analysed ICP, CPP and mean arterial pressure (MAP) prior to AT, during AT and after AT, as well as arterial pH, paCO2 , paO2 and arterial O2 saturation at the start and end of AT. RESULTS: Intracranial pressure was 87.9 ± 17.7 mmHg (mean ± SD) prior to AT, 89.9 ± 17.2 mmHg during AT and 86.4 ± 15.2 mmHg after AT (P = 0.9). CPP was -6.9 ± 12.8 mmHg prior to AT, -7.1 ± 13.7 mmHg during AT and -8.6 ± 13.0 mmHg after AT (P = 0.98), respectively. MAP was 82.9 ± 14.6 mmHg prior to AT, 84.7 ± 13.9 mmHg during AT and 79.7 ± 9.6 mmHg after AT (P = 0.57), respectively. A total of 10 patients had positive CPP (8.6 ± 4.3 mmHg), but ICP did not increase during AT. Arterial pH decreased from 7.43 ± 0.06 to 7.22 ± 0.06 (P < 0.05), paCO2 increased from 38.6 ± 4.2 to 69.6 ± 8.0 mmHg (P < 0.05), paO2 decreased from 416.3 ± 113.4 to 289.2 ± 146.5 mmHg (P < 0.05), and O2 saturation was stable at 99.8 ± 0.4% and 98.2 ± 3.2% (P = 0.39). CONCLUSIONS: Apnea testing had no detrimental effect on ICP, CPP, MAP or oxygenation, regardless of the presence of an initially positive CPP. The lack of further ICP elevations is presumably explained by critical closing pressures above individual CPP levels during AT.

Long-Term Effects of Serial Anodal tDCS on Motion Perception in Subjects with Occipital Stroke Measured in the Unaffected Visual Hemifield.

Transcranial direct current stimulation (tDCS) is a novel neuromodulatory tool that has seen early transition to clinical trials, although the high variability of these findings necessitates further studies in clinically relevant populations. The majority of evidence into effects of repeated tDCS is based on research in the human motor system, but it is unclear whether the long-term effects of serial tDCS are motor-specific or transferable to other brain areas. This study aimed to examine whether serial anodal tDCS over the visual cortex can exogenously induce long-term neuroplastic changes in the visual cortex. However, when the visual cortex is affected by a cortical lesion, up-regulated endogenous neuroplastic adaptation processes may alter the susceptibility to tDCS. To this end, motion perception was investigated in the unaffected hemifield of subjects with unilateral visual cortex lesions. Twelve subjects with occipital ischemic lesions participated in a within-subject, sham-controlled, double-blind study. MRI-registered sham or anodal tDCS (1.5 mA, 20 min) was applied on five consecutive days over the visual cortex. Motion perception was tested before and after stimulation sessions and at 14- and 28-day follow-up. After a 16-day interval an identical study block with the other stimulation condition (anodal or sham tDCS) followed. Serial anodal tDCS over the visual cortex resulted in an improvement in motion perception, a function attributed to MT/V5. This effect was still measurable at 14- and 28-day follow-up measurements. Thus, this may represent evidence for long-term tDCS-induced plasticity and has implications for the design of studies examining the time course of tDCS effects in both the visual and motor systems.

An initial transient-state and reliable measures of corticospinal excitability in TMS studies.

OBJECTIVE: The objective of this study was to determine if an initial transient state influences the acquisition of reliable estimates of corticospinal excitability in transcranial magnetic stimulation (TMS) studies. Whereas muscle evoked potential (MEP) amplitudes are an important index of cortical excitability, these are severely limited by sweep-to-sweep variability. Interesting in this context is the experimental observation that the first MEP amplitudes might be much larger than subsequent responses [Brasil-Neto JP, Cohen LG, Hallet M. Central fatigue as revealed by postexercise decrement of motor evoked potentials. Muscle Nerve 1994;17:713-9]. This led to the hypothesis that an initial transient-state of increased excitability affects MEP amplitude derived estimates of corticospinal excitability. METHODS: To address this issue we acquired repeated measures of single pulse MEP amplitudes over the primary motor cortex with and without navigated brain stimulation (NBS) and with various TMS-coils. Importantly, NBS allows for the sweep-to-sweep differentiation of physical and physiological variability. RESULTS: We found a significant decline in estimates of corticospinal excitability and a transition from log-Normal to Normal distributed state, after which reliable measures (British Standards Institute) could be acquired. CONCLUSIONS: We argue that an initial transient state of physiological origin influences measures of corticospinal excitability. SIGNIFICANCE: This has important implications for investigations of cortical excitability. For example, it could reduce variability over studies and within small group comparisons.

Effects of GABA(A) and GABA(B) agonists on interhemispheric inhibition in man.

OBJECTIVE: Animal studies on neurotransmitter systems that mediate interhemispheric inhibition (IHI) suggest that, (i) callosal transmission is regulated by presynaptic GABA(B) receptors, and (ii) GABA(A)-ergic neurones mediate early IHI, whereas GABA(B)-ergic neurones mediate later IHI. In humans the mechanism is unclear. Interactions between cortical inhibitory circuits suggest a postsynaptic GABA(B)-ergic mechanism. We will here test this hypothesis. METHODS: Short-latency IHI (s-IHI) and long-latency IHI (l-IHI) were evaluated using the paired pulse paradigm before and under medication with (i) a GABA(B)-agonist (baclofen) in 17 subjects, and (ii) a GABA(A)-agonist (midazolam) in 10 subjects participating twice. RESULTS: Baclofen did not significantly enhance s-IHI. L-IHI between 20 and 50ms was significantly strengthened, and obtained also at ISIs between 100 and 200ms. Midazolam had no effect on s-IHI, whereas l-IHI was attenuated. CONCLUSIONS: Our results support the hypothesis, that l-IHI in humans is mediated by postsynaptic GABA(B) receptors. GABA(A)-ergic medication resulted in attenuation of l-IHI. Regarding s-IHI, our results are inconclusive and require further investigation. SIGNIFICANCE: This is the first human study evaluating the effect of baclofen on IHI, indicating that l-IHI is mediated by GABA(B)-ergic neurones. Because interhemispheric interaction is now also been used as a therapeutic approach, understanding the underlying neurotransmitter systems will be increasingly relevant.

[Central and peripheral deafferent pain: therapy with repetitive transcranial magnetic stimulation]. / Zentrale und periphere Deafferenzierungsschmerzen: Therapie mit der repetitiven transkraniellen Magnetstimulation?

BACKGROUND: This study evaluates the effects of repeated sessions of low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex on central and phantom limb pain. METHODS: Twenty seven patients with central (n=13) and phantom limb (n=14) pain participated in a blind, randomised placebo-controlled study comparing the effect of 1-Hz and 5-Hz rTMS with sham stimulation. Each treatment block consisted of a 5-day baseline phase, a 5-day therapy phase, and an 18-day washout phase. In the therapy phase, 500 stimuli were applied in the particular frequency at about the same time on each day. RESULTS: A reduction in pain immediately after stimulation was observed in all therapy groups. This effect was similar for all treatment conditions, including sham stimulation. No significant long-term effects of rTMS on pain intensity or mood were observed. CONCLUSION: At present, rTMS can not be recommended as a standard therapy for central and phantom limb pain.

Transcranial magnetic and electrical stimulation compared: does TES activate intracortical neuronal circuits?

OBJECTIVE: To determine whether, and under which conditions, transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) can activate similar neuronal structures of the human motor cortex, as indicated by electromyographic recordings. METHODS: Focal TMS was performed on three subjects inducing a postero-anterior directed current (p-a), TES with postero-anteriorly (p-a) and latero-medially (l-m) oriented electrodes. We analyzed the onset latencies and amplitudes (single-pulse) and intracortical inhibition and excitation (paired-pulse). RESULTS: TMS p-a and TES p-a produced muscle responses with the same onset latency, while TES l-m led to 1.4-1.9 ms shorter latencies. Paired-pulse TMS p-a and TES p-a induced inhibition at short inter-stimulus intervals (ISI) (maximum: 2-3 ms) and facilitation at longer ISIs (maximum: 10 ms). No inhibition but a strong facilitation was obtained from paired-pulse TES l-m (ISIs 1-5 ms). CONCLUSIONS: Our findings support the hypothesis, that current direction is the most relevant factor in determining the mode of activation for both TMS and TES: TMS p-a and TES p-a are likely to activate the corticospinal neurons indirectly. In contrast, TES l-m may preferentially activate the corticospinal fibres directly, distant of the neuronal body. SIGNIFICANCE: TES is a suitable tool to induce intracortical inhibition and excitation.

Modulation of motor cortex excitability by pallidal stimulation in patients with severe dystonia.

OBJECTIVE: To study the influence of continuous high-frequency electrical stimulation with electrodes implanted in the globus pallidus internus (GPi) on motor cortex excitability in nine patients with dystonia. METHODS: Short-term effects related to switching off and on the deep brain stimulator were investigated >3 months after electrode implantation. Activation of motor cortical excitatory and inhibitory neurons was examined with transcranial magnetic stimulation (TMS) by analysis of electromyographic activity in the hand muscles. Parameters of corticospinally mediated excitatory motor responses included latency, threshold, and response sizes with increasing stimulus intensities (stimulus-response curves). Other measures of motor cortex excitability comprised the duration of the contralateral silent period and intracortical inhibition and facilitation in a paired-pulse paradigm. RESULTS: Switching off GPi stimulation led to a decrease of motor cortex excitability, as reflected by an increase in motor thresholds (GPi stimulation on 37.5 +/- 6.1%, mean +/- SD; GPi stimulation off for 15 to 120 minutes, 40.5 +/- 6.7% of maximum stimulator output), and reduced the size of contralateral responses in the stimulus-response curves established for relaxed muscles. The changes were reversible within minutes after switching on GPi stimulation. They were associated with mild changes of dystonia. By contrast, measures of intracortical inhibition were not altered by switching off GPi stimulation. Spinal excitability did not change as assessed by H-reflex. CONCLUSION: GPi stimulation influences motor cortex excitability by a rapid modulation of thalamocortical outputs.

In vivo assessment of human visual system connectivity with transcranial electrical stimulation during functional magnetic resonance imaging.

Functional magnetic resonance imaging (fMRI) was used to investigate local and distant cerebral activation induced by transcranial electrical stimulation in order to noninvasively map functional connectivity in the human visual system. Stimulation with lateromedially directed currents and the anode 4.5 cm dorsally to the inion over the right visual cortex induced phosphenes extending into the contralateral lower quadrant of the visual field. fMRI showed a focal hemodynamic response underneath the anode in extrastriate cortex and distant coactivation in subcortical (lateral geniculate nucleus), cortical visual (striate and extrastriate), and visuomotor areas (frontal and supplementary eye fields). This pattern of activation resembles a network of presumably interconnected visual and visuomotor areas. Analysis of activation sites supplies new information about cerebral correlates of phosphenes and shows that the cortical region underneath the cranial stimulation site is not necessarily the origin of behavioral and/or perceptual effects of transcranial stimulation. We conclude that combining transcranial electrical stimulation of neural tissue with simultaneous fMRI offers the possibility to study noninvasively cerebral connectivity in the human brain.

Unusual spontaneous and training induced visual field recovery in a patient with a gunshot lesion.

Over a period of more than 3 years, changes in visual and neuropsychological functions were examined in a patient with a visual field defect caused by a cerebral gunshot lesion. Initially, the patient had been completely blind, but after 6 months of spontaneous recovery, he showed a homonymous bilateral lower quadrantanopia and impairment of higher visual functions. Unexpectedly, recovery still continued after the first 6 months. This process was documented in detail by visual field examinations using high resolution perimetry. When visual field size had stabilised almost 16 months after the lesion, further improvement could be achieved by visual restitution training. The duration and extent of spontaneous recovery were unusual. In spontaneous as well as in training induced recovery, progress was mainly seen in partially defective areas (areas of residual vision) along the visual field border. Thus, it is speculated that modulation of perceptual thresholds in transition zones of visual field defects contributes to spontaneous and training induced recovery.

Behavioural relevance modulates access to spatial working memory in humans.

Neurophysiological studies in monkeys suggest selective representation of behaviourally relevant information in working memory. So far, no behavioural evidence for this has been reported for humans. Here, we investigated the role of behavioural relevance for access to human visuospatial working memory by using delayed oculomotor response tasks. Subjects were presented two successive visual cues in different and unpredictable locations while fixating on a central fixation point. After a delay, an unpredictable auditory signal (one beep or two beeps) sounded and the central fixation point was turned off, initiating the oculomotor response (i.e. memory-guided saccade) phase. Two groups of 10 subjects each were studied in two conditions: in the 'relevant' condition, subjects were instructed to memorize both visual cues and to move the eyes to the remembered position of the first cue (one beep) or the second cue (two beeps). The same stimuli were used in the 'irrelevant' condition, but subjects were instructed to memorize and move the eyes to the position of the first cue only, regardless of the second cue and the auditory signal. In the 'relevant' condition, we found a significant increase in errors of memory-guided saccades to the first cue, when the second cue was located between central fixation point and first cue. This spatially selective interference effect disappeared in the 'irrelevant' condition, despite identical stimuli. On a behavioural level, these results show for the first time the significance of behavioural relevance for access to human spatial working memory. These findings complement recent single-neuron studies in monkeys, showing that the neuronal substrates of working memory selectively represent behaviourally relevant perceptual information.

Involvement of the human frontal eye field and multiple parietal areas in covert visual selection during conjunction search.

Searching for a target object in a cluttered visual scene requires active visual attention if the target differs from distractors not by elementary visual features but rather by a feature conjunction. We used functional magnetic resonance imaging (fMRI) in human subjects to investigate the functional neuroanatomy of attentional mechanisms employed during conjunction search. In the experimental condition, subjects searched for a target defined by a conjunction of colour and orientation. In the baseline condition, subjects searched for a uniquely coloured target, regardless of its orientation. Eye movement recordings outside the scanner verified subjects' ability to maintain fixation during search. Reaction times indicated that the experimental condition was attentionally more demanding than the baseline condition. Differential activations between conditions were therefore ascribed to top-down modulation of neural activity. The frontal eye field, the ventral precentral sulcus and the following posterior parietal regions were consistently activated: (i) the postcentral sulcus; (ii) the posterior; and (iii) the anterior part of the intraparietal sulcus; and (iv) the junction of the intraparietal with the transverse occipital sulcus. Parietal regions were spatially distinct and displayed differential amplitudes of signal increase with a maximal amplitude in the posterior intraparietal sulcus. Less consistent activation was found in the lateral fusiform gyrus. These results suggest an involvement of the human frontal eye field in covert visual selection of potential targets during search. These results also provide evidence for a subdivision of posterior parietal cortex in multiple areas participating in covert visual selection, with a major contribution of the posterior intraparietal sulcus.

Saccadic suppression induces focal hypooxygenation in the occipital cortex.

This study investigated how a decrease in neuronal activity affects cerebral blood oxygenation employing a paradigm of acoustically triggered saccades in complete darkness. Known from behavioral evidence as saccadic suppression, electrophysiologically it has been shown in monkeys that during saccades an attenuation of activity occurs in visual cortex neurons (Duffy and Burchfiel, 1975). In study A, using blood oxygen level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI), the authors observed signal intensity decreases bilaterally at the occipital pole during the performance of saccades at 2 Hz. In study B.1, the authors directly measured changes in deoxyhemoglobin [deoxy-Hb] and oxyhemoglobin [oxy-Hb] concentration in the occipital cortex with near-infrared spectroscopy (NIRS). Whereas a rise in [deoxy-Hb] during the performance of saccades occurred, there was a drop in [oxy-Hb]. In a second NIRS study (B.2), subjects performed saccades at different rates (1.6, 2.0, and 2.3 Hz). Here the authors found the increase in deoxy-Hb and the decrease of oxy-Hb to be dependent on the frequency of the saccades. In summary, the authors observed a focal hypooxygenation in the human visual cortex dependent on the saccade-frequency in an acoustically triggered saccades paradigm. This could be interpreted as evidence that corresponding to the focal hyperoxygenation observed in functional brain activation, caused by an excessive increase in cerebral blood flow (CBF) over the increase in CMRO2 during decreased neuronal activity CBF, is more reduced than oxygen delivery.

Long-term reorganization of motor cortex outputs after arm amputation.

OBJECTIVE: To investigate the reorganization of the corticospinal system long after arm amputation at different levels. METHODS: Focal transcranial magnetic stimulation (TMS) was performed in 15 patients 21 to 65 years after arm amputation at the level of the forearm, upper arm, or shoulder. Cortically elicited electromyographic responses were investigated in muscles immediately proximal to the stump. TMS was performed on a skull surface grid overlying the motor cortex. The response threshold, number of effective stimulation sites, and the sum of the amplitudes elicited at these sites were evaluated for slightly contracted muscles. RESULTS: Seven of eight patients with forearm amputation had larger stimulation effects in the biceps supplied by the motor cortex contralateral to amputation, as indicated by variable patterns of lowered response thresholds, increased response amplitudes, or increased numbers of effective stimulation sites. In seven patients with a more proximal amputation, the motor responses were investigated in the deltoid and trapezoid muscle. In only two of them, the motor cortex contralateral to amputation showed an increased excitability. Three patients presented with a higher excitability of the motor cortex contralateral to the intact arm and two with a balanced type of excitability. CONCLUSION: Reorganization of the motor system can be present more than 20 years after amputation. Furthermore, differential patterns of reorganized corticospinal output were found for different stump muscles, which might be due to varying amounts of ipsilateral corticospinal projections.

Spatial memory deficits in patients with lesions affecting the medial temporal neocortex.

Lesion studies in monkeys suggest that neocortical subregions of the medial temporal lobe (MTL) carry memory functions independent of the hippocampal formation. The present study investigates possible differential contributions of MTL subregions to spatial memory in humans. Eye movements toward remembered spatial cues (memory-guided saccades) with unpredictably varied memorization delays of up to 30 seconds were recorded in patients with postsurgical lesions of the right MTL, either restricted to the hippocampal formation (n = 3) or including the adjacent neocortex (n = 5) and in 10 controls. Although saccadic targeting errors of patients with selective hippocampal lesions did not differ from controls, saccadic targeting errors of patients with additional neocortical involvement showed a significant and contralaterally pronounced increase at memorization delays above 20 seconds. We conclude that the human medial temporal neocortex carries spatial memory functions independent of the hippocampal formation and distinct from spatial short-term memory.

Cortical fMRI activation produced by attentive tracking of moving targets.

Attention can be used to keep track of moving items, particularly when there are multiple targets of interest that cannot all be followed with eye movements. Functional magnetic resonance imaging (fMRI) was used to investigate cortical regions involved in attentive tracking. Cortical flattening techniques facilitated within-subject comparisons of activation produced by attentive tracking, visual motion, discrete attention shifts, and eye movements. In the main task, subjects viewed a display of nine green "bouncing balls" and used attention to mentally track a subset of them while fixating. At the start of each attentive-tracking condition, several target balls (e.g., 3/9) turned red for 2 s and then reverted to green. Subjects then used attention to keep track of the previously indicated targets, which were otherwise indistinguishable from the nontargets. Attentive-tracking conditions alternated with passive viewing of the same display when no targets had been indicated. Subjects were pretested with an eye-movement monitor to ensure they could perform the task accurately while fixating. For seven subjects, functional activation was superimposed on each individual's cortically unfolded surface. Comparisons between attentive tracking and passive viewing revealed bilateral activation in parietal cortex (intraparietal sulcus, postcentral sulcus, superior parietal lobule, and precuneus), frontal cortex (frontal eye fields and precentral sulcus), and the MT complex (including motion-selective areas MT and MST). Attentional enhancement was absent in early visual areas and weak in the MT complex. However, in parietal and frontal areas, the signal change produced by the moving stimuli was more than doubled when items were tracked attentively. Comparisons between attentive tracking and attention shifting revealed essentially identical activation patterns that differed only in the magnitude of activation. This suggests that parietal cortex is involved not only in discrete shifts of attention between objects at different spatial locations but also in continuous "attentional pursuit" of moving objects. Attentive-tracking activation patterns were also similar, though not identical, to those produced by eye movements. Taken together, these results suggest that attentive tracking is mediated by a network of areas that includes parietal and frontal regions responsible for attention shifts and eye movements and the MT complex, thought to be responsible for motion perception. These results are consistent with theoretical models of attentive tracking as an attentional process that assigns spatial tags to targets and registers changes in their position, generating a high-level percept of apparent motion.

Effects of repetitive transcranial magnetic stimulation over dorsolateral prefrontal and posterior parietal cortex on memory-guided saccades.

We investigated the role of the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal cortex (PPC) in a visuospatial delayed-response task in humans. Repetitive transcranial magnetic stimulation (20 Hz, 0.5 s) was used to interfere temporarily with cortical activity in the DLPFC and PPC during the delay period. Omnidirectional memory-guided saccades with a 3-s delay were used as a quantifiable motor response to a visuospatial cue. The question addressed was whether repetitive transcranial magnetic stimulation (rTMS) over the DLPFC or PPC during the sensory of memory phase affects accuracy of memory-guided saccades. Stimulation over the primary motor cortex served as control. Stimulation over the DLPFC significantly impaired accuracy of memory-guided saccades in amplitude and direction. Stimulation over the PPC impaired accuracy of memory-guided saccades only when applied within the sensory phase (50 ms after cue offset), but not during the memory phase (500 ms after cue offset). These results provide further evidence for a parieto-frontal network controlling performance of visuospatial delayed-response tasks in humans. It can be concluded that within this network the DLPFC is mainly concerned with the mnemonic representation and the PPC with the sensory representation of spatially defined perceptual information.

Spontaneous eye movements during visual imagery reflect the content of the visual scene.

In nine naïve subjects eye movements were recorded while subjects viewed and visualized four irregularly-checkered diagrams. Scanpaths, defined as repetitive sequences of fixations and saccades were found during visual imagery and viewing. Positions of fixations were distributed according to the spatial arrangement of subfeatures in the diagrams. For a particular imagined diagrammatic picture, eye movements were closely correlated with the eye movements recorded while viewing the same picture. Thus eye movements during imagery are not random but reflect the content of the visualized scene. The question is discussed whether scanpath eye movements play a significant functional role in the process of visual imagery.

[Repetitive transcranial magnetic stimulation. Possibilities, limits and safety aspects]. / Repetitive transkranielle Magnetstimulation. Möglichkeiten, Grenzen und Sicherheitsaspekte.

Repetitive magnetic stimulation (rTMS) is a non-invasive, painless method to induce transient activation in circumscript regions of the human cortex. In contrast to TMS with single pulses rTMS allows a more effective stimulation of association cortex and temporary interference with the proper functioning of stimulated areas. Possible applications for examination of the functional anatomy of language lateralisation, memory functions and visual perception are discussed. Possible therapeutic for movement disorders and depression are discussed. On the basis of theoretical considerations and current experience rTMS induced epileptogenic effects are discussed and safety recommendations are given.

Functional magnetic resonance imaging shows localized brain activation during serial transcranial stimulation in man.

Area and depth penetration of transcranial stimulation methods such as transcranial electrical stimulation (TES) are poorly defined. We investigated the feasibility of a simultaneous TES and fMRI measurement. The aim was to compare the signal intensity changes measured using BOLD fMRI during sequential finger movement with the signal response during artificial transcranial stimulation. Tes induced contralateral finger contractions and in T2* weighted images a transient signal increase was observed in the area underlying the electrodes. Compared with the signal obtained during sequential finger movements, the area activated by TES was more localized, signal amplitude, was smaller and there was no post-stimulus undershoot. These data indicate that TES induces a local blood flow increase associated with a drop in the concentration of deoxyhaemoglobin.

Graft-versus-host-disease prophylaxis for matched unrelated donor bone marrow transplantation: comparison between cyclosporine-methotrexate and cyclosporine-methotrexate-methylprednisolone.

We performed a sequential study comparing two regimens, cyclosporine-methotrexate (CsA-MTX) and cyclosporine-methotrexate-methylprednisolone (CsA-MTX-MP) for graft-versus-host disease (GVHD) prophylaxis in patients undergoing matched unrelated donor bone marrow transplantation (MUD BMT). Study end-points were the development of GVHD, various infectious complications and survival. Twenty nine patients with malignant hematologic disease without HLA-compatible family donors were treated between May 1990 and November 1993. All donors were volunteers from the National Marrow Donor Program (NMDP) serologically HLA-A-A, B and DR identical. MLC reactivity and high resolution DR DNA typing were not used to exclude donors. Sixteen patients received CsA-MTX and 13 patients received CsA-MTX-MP. CsA and MTX doses were the same in both groups: CsA 1.5 mg/kg i.v. over 2h every 12h beginning the day prior to transplant (day-1) and MTX 10 mg/m2 i.v. bolus on days +1, +3 and +6 with leucovorin on days +2, +4 and +7. MP was administered at a dose of 0.25 mg/kg i.v. every 12h beginning on day +7 and increased to 0.5 mg/kg on day +14. Beginning on day +35 MP and CsA were tapered 5% per week with targeted discontinuation at 6 months. Both groups were comparable for primary disease, preparative regimen, recipient age (median 33 VS 33 years), donor age (median 39 vs 39.5 years), donor-recipient sex, donor ABO mismatch and serologic CMV positivity. All patients received similar supportive care.(ABSTRACT TRUNCATED AT 250 WORDS)