Writer's cramp--a focal dystonia: etiology, diagnosis, and treatment

The complaint of hand cramps is common among patients who consult the neurologist or the hand surgeon. Classic writer's cramp is best characterized as a focal dystonia, and electromyographic studies reveal a characteristic pattern of cocontraction of the agonist and antagonist muscles of the forearm and hand. Although the outcome of treatment in the past has been unsatisfying, recent experience with new pharmacologic therapy, such as injections of botulinum toxin, has produced promising results. Further experience and improvement in this area will likely increase the therapeutic success in the treatment of writer's cramp and other focal dystonias.     

From writer's cramp to butcher's spasms: a case of interprofessional dystonia

INTRODUCTION: Occupational or professional dystonia is a focal motor dystonic disorder which affect motor programs necessaries for the exercise of the patient's profession. Clinical case. A patient with writer's cramp in the childhood presented at the age of 22 years a new dystonia, which we name 'butcher's spasm', giving rise to a laboral incapacity. Neurological exam was normal except for right arm distal (writer's cramp) and proximal dystonias (butcher's cramp), with intentional tremor in the upper extremities. We classified, after complementary exams, the disease as idiopathic. CONCLUSIONS: Idiopathic focal dystonias can progress to segmentary or multifocal dystonias, and, in exceptional cases as ours, can interfere with two different professional activities.     

A primate genesis model of focal dystonia and repetitive strain injury: I. Learning-induced dedifferentiation of the representation of the hand in the primary somatosensory cortex in adult monkeys

In this study we tested a neuroplasticity/learning origins hypothesis for repetitive strain injuries (RSIs), including occupationally induced focal dystonia. Repetitive movements produced in a specific form and in an appropriate behavioral context cause a degradation of the sensory feedback information controlling fine motor movements, resulting in the "learned" genesis of RSIs. Two adult New World owl monkeys were trained at a behavioral task that required them to maintain an attended grasp on a hand grip that repetitively and rapidly (20 msec) opened and closed over short distances. The monkeys completed 300 behavioral trials per day (1,100 to 3,000 movement events) with an accuracy of 80 to 90%. A movement control disorder was recorded in both monkeys. Training was continued until the performance accuracy dropped to below 50%. We subsequently conducted an electrophysiologic mapping study of the representations of the hand within the primary somatosensory (SI) cortical zone. The hand representation in the true primary somatosensory cortical field, SI area 3b, was found to be markedly degraded in these monkeys, as characterized by (1) a dedifferentiation of cortical representations of the skin of the hand manifested by receptive fields that were 10 to 20 times larger than normal, (2) the emergence of many receptive fields that covered the entire glabrous surface of individual digits or that extended across the surfaces of two or more digits, (3) a breakdown of the normally sharply segregated area 3b representations of volar glabrous and dorsal hairy skin of the hand, and (4) a breakdown of the local shifted-overlap receptive field topography of area 3b, with many digital receptive fields overlapping the fields of neurons sampled in cortical penetrations up to more than four times farther apart than normal. Thus, rapid, repetitive, highly stereotypic movements applied in a learning context can actively degrade cortical representations of sensory information guiding fine motor hand movements. This cortical plasticity/learning-based dedifferentiation of sensory feedback information from the hand contributes to the genesis of occupationally derived repetitive strain injuries, including focal dystonia of the hand. Successful treatment of patients with RSI will plausibly require learning-based restoration of differentiated representations of sensory feedback information from the hand.     

Management of acute extrapyramidal effects induced by antipsychotic drugs

The management of acute extrapyramidal effects (EPEs) induced by antipsychotic drugs is reviewed. EPEs associated with antipsychotics include acute dystonias, pseudoparkinsonism, and akathisia. Acute dystonias consist of abnormal muscle spasms and postures and usually occur three to five days after antipsychotic therapy begins or the dosage is increased. Acute dystonias should be treated with anticholinergic medications or benzodiazepines. Antipsychotic-induced pseudoparkinsonism has the same clinical appearance as idiopathic parkinsonism. Symptoms generally appear within the first three months. Pseudoparkinsonism is managed by lowering the anti-psychotic dosage or by adding an anticholinergic agent or a mantadine; switching to a low-potency agent or an atypical antipsychotic may also help. Akathisia is characterized by subjective feelings of restlessness and anxiety and objective signs of motor activity, such as inability to sit still. This EPE appears days to weeks after antipsychotic exposure begins and can be difficult to manage. If reduction of the antipsychotic dosage or a switch to a less potent antipsychotic is not practical or effective, an anticholinergic, beta-blocker, or benzodiazepine may be added. Lipophilic beta-blockers, especially propranolol and metoprolol, appear to be the most effective treatments. Anticholinergic agents are commonly given to prevent acute dystonias, especially in high-risk patients, but long-term prophylaxis is controversial. Atypical antipsychotics may have less potential to induce EPEs. Options in the management of antipsychotic-associated EPEs include using the lowest effective dosage of antipsychotic, treating the reactions with medications, and changing the antipsychotic to one with less potential for inducing EPEs.     

Botulinum toxin for neurological disorders in a movement disorders clinic in Singapore

AIM OF STUDY: This study was done to examine the usefulness of botulinum toxin A injections in treating various neurological disorders such as hemifacial spasm, blepharospasm, focal dystonia and task-specific dystonia. METHODS: This was a prospective, open-labelled trial of patients seen in a Movement Disorders Clinic with dyskinesias potentially treatable with botulinum toxin. All patients were assessed before and after injections using clinical rating scales, and those with focal and task-specific dystonias were also recorded on videotape. RESULTS: There were 102 patients with hemifacial spasm, 3 with blepharospasm, 13 with neck dystonia, 6 with writer's cramp, I with musician's cramp, and I with jaw dystonia. All patients with hemifacial spasm and blepharospasm obtained good results, while 77% of those with cervical dystonia received substantial benefit. Only half of those with writer's cramp improved. Hemifacial spasm seems more prevalent in Singapore compared with Western populations. CONCLUSION: Injections of botulinum toxin are useful in treating the various neurological disorders studied. This is an advancement in the treatment of these dyskinesias which respond poorly to oral medications.     

Occlusive arterial disease of the hand due to repetitive blunt trauma: a review with illustrative cases

OBJECTIVE: to increase clinical awareness of the role of repetitive blunt trauma, often occupational, in the development of occlusive arterial disease of the hand. STUDY DESIGN: illustrative cases are presented to emphasize the varied etiology and clinical features of occlusive arterial disease of the hand resulting from repetitive blunt trauma and an historical review of the literature is presented. RESULTS: Occlusive arterial disease of the hand due to repetitive blunt trauma is a common but often preventable disorder. The superficial location of many of the arteries of the hands and digits plus their close proximity to the bones of the hand makes them uniquely susceptible to injury from repetitive blunt trauma. An ever increasing number of occupations and leisure activities have been causally related to occlusive arterial disease of the hand. The diagnosis of occupational occlusive arterial disease due to blunt trauma is suggested by eliciting a history of repetitive blunt trauma to the hand in a patient with symptoms and/or signs of digital ischemia. The dominant hand is most commonly involved, but the non-dominant hand or both hands are affected in certain occupations. Possible predisposing or aggravating factors include tobacco use and working in a cold environment. The diagnosis of occlusive arterial disease confined to the hand or digits is confirmed by non-invasive studies in the vascular laboratory and demonstrated by arteriography. Conservative measures and protection of the hand from further trauma is sufficient for most patients, with surgical therapy being reserved for patients refractory to medical therapy or those with more severe ischemia. CONCLUSION: occlusive arterial disease of the hand may be more common than formerly thought and is often preventable by the proper use of hand tools or instruments and hand protection. This is another type of occlusive arterial disease in which tobacco may be a predisposing or aggravating factor.     

Brainstem substrates of sensory information processing and adaptive behavior

Emerging clinical and experimental data suggest that the brainstem may be an important part of the functional matrix from which normal mental development and behavior evolve. Although the brainstem has not been a focal point in considering etiologies of mental retardation nor even in analyses of adaptive behavior, information processing within both the brainstem sensory nuclei and adjacent reticular formation may indeed be one of the most critical and relevant areas for such investigations. Data are summarized from several ongoing experiments which are designed to explore the capacity of the brainstem to encode sensory, especially acoustic, stimuli and to modulate the resultant sensory information so as to produce a "learned" response. Such data indicate that in the absence of forebrain or even midbrain structures, a simple conditioned response can be supported by the brainstem. The reticular neuropil is considered particularly important to this response acquisition and is conceptualized as a structure which can receive and transmit acoustic information with retention of specific stimulus coding. It is further suggested that independent associative and reflex functions of the reticular formation may be highly significant in neonatal behavior but, with the development of descending influences from higher centers during maturation, these functions may become largely masked. In order to develop a temporal frame of reference for brainstem structures potentially involved in sensory information processing and learning phenomena "time constants of response plasticity" are being established for different levels of the brainstem system.     

Alteration of digital representations in somatosensory cortex in focal hand dystonia

Focal hand dystonia involves a loss of motor control of one or more digits; it is associated with the repetitive, synchronous movements of the digits made by musicians over periods of many years. Magnetic source imaging revealed that there is a smaller distance (fusion) between the representations of the digits in somatosensory cortex for the affected hand of dystonic musicians than for the hands of non-musician control subjects. The data suggest that use-dependent susceptibility to digital representation fusion in cortex may be involved in the etiology of focal dystonia. A successful therapy for the condition has been developed based on this consideration.     

Olfactory stimuli provoke diffuse esophageal spasm: reversal by ipratropium bromide

Diffuse esophageal spasm (DES) is a motor disorder of the esophageal smooth muscle characterized by multiple spontaneous contractions and by swallow-induced contractions that are of simultaneous onset, large amplitude, long duration, and repetitive occurrence. Although the pathogenesis of DES is unknown, provocative studies with cholinergic stimulation, esophageal balloon distention, or acid instillation have suggested involvement of both sensory and motor mechanisms. This report describes a patient with DES who would predictably become symptomatic with dysphagia and chest pain upon inhalation of perfume or other strong odors. Using esophageal scintigraphy to quantitate and analyze esophageal transit in this patient, we report for the first time that olfactory stimulation triggers episodes of DES and that such phenomena are mediated through the vagus nerve, because they can be ameliorated by the administration of ipratropium bromide. These observations suggest a new (sensory) pathway for the induction of DES and raise the intriguing possibility that inhaled anticholinergics may have a therapeutic role in the management of spastic esophageal motility disorders.     

The role of mast cells in mucosal permeability changes during ischemia-reperfusion injury of the small intestine

The ipsilateral primary motor cortex (M1) plays a role in voluntary movement. In our studies, we used repetitive transcranial magnetic stimulation (rTMS) to study the effects of transient disruption of the ipsilateral M1 on the performance of finger sequences in right-handed normal subjects. Stimulation of the M1 ipsilateral to the movement induced timing errors in both simple and complex sequences performed with either hand, but with complex sequences, the effects were more pronounced with the left-sided stimulation. Recent studies in both animals and humans have confirmed the traditional view that ipsilateral projections from M1 to the upper limb are mainly directed to truncal and proximal muscles, with little evidence for direct connections to distal muscles. The ipsilateral motor pathway appears to be an important mechanism for functional recovery after focal brain injury during infancy, but its role in functional recovery for older children and adults has not yet been clearly demonstrated. There is increasing evidence from studies using different methodologies such as rTMS, functional imaging and movement-related cortical potentials, that M1 is involved in ipsilateral hand movements, with greater involvement in more complex tasks and the left hemisphere playing a greater role than the right.     

A focal zone of thalamic plasticity

In this study, sensory maps in the thalamus were investigated by examining their volume and shape. We determined the forelimb representation in adult rats after the removal of hindlimb input by nucleus gracilis lesions. Three-dimensional reconstructions of thalamic sensory maps were obtained from a grid of electrode penetrations. We found that the volume of the shoulder sensory map contracted >50% at an acute time interval (n = 6), followed by a robust volumetric sensory map expansion of 25% at 1 week (n = 8) and 1 month (n = 8) after lesion relative to controls (n = 8). The topology of the volumetric increase was scrutinized by slicing functional maps in the coronal, sagittal, and horizontal planes. The equivalence of such slices from each animal was established by virtue of their distance from either a functional or neuroanatomical landmark. Surprisingly, all of the volumetric increase unequivocally occurred in a circumscribed coronal slice 300 micron thick. This focal zone was located toward the rostral pole of the thalamic tactile relay, the ventroposterolateral nucleus. Analysis in the sagittal plane revealed that, unexpectedly, the shoulder map volume expanded by superimposing its representation on that of the forepaw, via an advancement of the shoulder representation by 0.6 mm medially. We propose a "hot spot" hypothesis in which focal zones of plasticity may not be specific to the thalamus but may have manifestations elsewhere in the nervous system, such as the cerebral cortex or dorsal column nuclei.     

BCL-2: the pendulum of the cell fate

The influence of suprathreshold electrical stimulation of the extensor and flexor carpi radialis muscles on biomechanical and functional movement parameters is compared with the effect of a standardized active repetitive training of hand and fingers. Twelve patients suffering from ischaemic lesions in the territory of the middle cerebral artery participated in the study, which was conducted using a multiple baseline design. Following a baseline phase that lasted between one and three weeks all patients received electrical muscle stimulation for 20 minutes twice daily. In a third phase the repetitive training of hand and fingers was conducted for 20 minutes twice daily. Both interventions were applied in addition to conventional occupational therapy and physiotherapy. With the exception of spasticity in hand and finger flexors, repetitive electrical muscle stimulation does not improve biomechanical or functional motor parameters of the centrally paretic hand and arm. The repetitive motor training, however, is appropriate to improve biomechanical and functional movement parameters significantly. Apart from a possible effect on the muscle cell itself, the electrical muscle stimulation is thought to represent a mainly sensory, i.e. proprioceptive, and cutaneous intervention, whereas the active motor training is characterized by a continuous sensorimotor coupling within motor centres of the brain. The underlying neurophysiological mechanisms as well as basic principles concerning the role of afferent input for motor learning and recovery are discussed.     

Crossed and direct effects of digital nerves stimulation on motor evoked potential: a study with magnetic brain stimulation

We studied the influence of contralateral and ipsilateral cutaneous digital nerve stimulation on motor evoked potentials (MEPs) elicited in hand muscles by transcranial magnetic stimulation (TMS). We tested the effect of different magnetic stimulus intensities on MEPs recorded from the thenar eminence (TE) muscles of the right hand while an electrical conditioning stimulus was delivered to the second finger of the same hand with an intensity four times above the sensory threshold. Amplitude decrement of conditioned MEPs as a function of magnetic stimulus intensity was observed. The lowest TMS stimulus intensity produced the largest decrease in conditioned MEPs. Moreover, we investigated the effects of ipsilateral and contralateral electrical digital stimulation on MEPs elicited in the right TE and biceps muscle using an intensity 10% above the threshold. Marked MEP inhibition in TE muscles following both ipsilateral and contralateral digital stimulation is the main finding of this study. The decrease in conditioned MEP amplitude to ipsilateral stimulation reached a level of 50% of unconditioned MEP amplitude with the circular coil and 30% with the focal coil. The amplitude of conditioned MEPs to contralateral digital stimulation showed a decrease of 60% with the circular coil and more than 50% with the focal coil. The onset of the inhibitory effect of contralateral stimulation using the focal coil occurred at a mean of 15 ms later than that of ipsilateral stimulation. No MEP inhibition was observed when recording from proximal muscles. Ipsilateral and contralateral digital stimulation had no effect on F wave at appropriate interstimulus intervals, where the main MEP suppression was noted. We stress the importance of selecting an appropriate test stimulus intensity to evaluate MEP inhibition by digital nerves stimulation. Spinal and cortical sites of sensorimotor integration are adduced to explain the direct and crossed MEP inhibition following digital nerves stimulation.     

A critique of the application of sensory integration therapy to children with learning disabilities

Sensory integration (SI) therapy is a controversial--though popular--treatment for the remediation of motor and academic problems. It has been applied primarily to children with learning disabilities, under the assumption that such children (or at least a subgroup of them) have problems in sensory integration to which some or all of their learning difficulties can be ascribed. The present article critically examines the related issues of whether children with learning disabilities differentially exhibit concomitant problems in sensory integration, and whether such children are helped in any way by means specific to SI therapy. An overview of theoretical contentions and empirical findings pertaining to the first issue is presented, followed by a detailed review of recent studies in the SI therapy research literature, in an effort to resolve the second issue. Results of this critique raise serious doubts as to the validity or utility of SI therapy as an appropriate, indicated treatment for the clinical population in question--and, by extension, for any other groups diagnosed as having "sensory integrative dysfunction." It is concluded that the current fund of research findings may well be sufficient to declare SI therapy not merely an unproven, but a demonstrably ineffective, primary or adjunctive remedial treatment for learning disabilities and other disorders.     

Implicit short-lived motor representations of space in brain damaged and healthy subjects

This article reviews experimental evidence for a specific sensorimotor function which can be dissociated from higher level representations of space. It attempts to delineate this function on the basis of results obtained by psychophysical experiments performed with brain damaged and healthy subjects. Eye and hand movement control exhibit automatic features, such that they are incompatible with conscious control. In addition, they rely on a reference frame different from the one used by conscious perception. Neuropsychological cases provide a strong support for this specific motor representation of space, which can be spared in patients with lesions of primary sensory systems who have lost conscious perception of visual, tactile or proprioceptive stimuli. Observation of these patients also showed that their motor behavior can be "attracted" by a goal only under specific conditions, that is, when the response is immediate and when no cognitive representation of this goal is elaborated at the same time. Beyond the issue of the dissociation between an implicit motor representation and more cognitive processing of spatial information, the issue of the interaction between these two systems is thus a matter of interest. It is suggested that the conscious, cognitive representation of a stimulus can contaminate or override the short-lived motor representation, but no reciprocal influence seem to occur. The interaction observed in patients can also be investigated in normals. The literature provides examples of interaction between sensorimotor and cognitive framing of space, which confirm that immediate action is not mediated by the same system as delayed action, and that elaborating a categorial representation of the action goal prevents the expression of the short-lived sensorimotor representation. It is concluded that action can be controlled by a sensory system which is specialized for on-line processing of relevant goal characteristics. The temporal constraints of this system are such that it can affect the action before a full sensory analysis of this goal has been completed. The performance obtained on the basis of this spatial sensory processing suggests that short-lived motor representations may rather be considered as real "presentation" of the action world, which share its metric properties.     

Reliability among neurologists in the severity assessment of blepharospasm and oromandibular dystonia: a multicenter study

The reliability of a scale of 0 to 4 (where 0 is normal) in rating the severity of blepharospasm (BS) and oromandibular dystonia (OMD) was evaluated by the concordance among six neurologists from different neurological institutions. As expressed by k index, interobserver agreement was moderate either for BS or for OMD according to the Landis classification. Neurologists showed different rating attitude toward BS and OMD. In fact, the category analysis showed that raters were inclined to overestimate BS and to underestimate OMD. The familiarity with dystonia influenced reliability more than the length of professional experience in neurology. In fact, when examiners were subdivided into subgroups (each of three raters) according to the former criteria, the level of interobserver agreement increased significantly. Almost perfect agreement was obtained in intrarater comparisons. These results may be of value with regard to the conduct of multicenter epidemiologic and clinical studies on focal dystonias.     

Increased acute and chronic mitotic activity in rat laryngeal muscles after botulinum toxin injection

OBJECTIVES: To characterize the acute and chronic cellular effects of botulinum toxin (BT) injection into rat laryngeal muscles. A complete characterization of these effects is important because patients with focal dystonias of the head and neck are commonly treated with BT injection. Further, potential muscular changes in the larynx must be carefully delineated owing to the critical phonatory and airway protective functions of these muscles. STUDY DESIGN: The acute and chronic cellular effects of BT injection were studied using 5'-bromo 2'-deoxyuridine (BrdU) following single and repeated BT injection into rat laryngeal muscles. BrdU is incorporated into mitotically active nuclei such that changes in cell proliferative behavior following BT injection can be monitored. RESULTS: Increased mitotic activity was detected in the tissue samples studied following BT injection. Differences in the times of the peak distribution of BrdU-labeled cells in each laryngeal muscle were observed. This may be related to the diffusion effects of BT. Prolonged muscle fiber changes, including splitting, were also observed as the result of repeated BT injection. CONCLUSIONS: The results of this study suggest that BT may induce a proliferative response in muscle tissue.     

Median and ulnar nerve conduction studies among workers: normative values

To determine normative values for nerve conduction studies among workers, we selected a subset of 326 workers from 955 subjects who participated in medical surveys in the workplace. The reference cohort was composed exclusively of active workers, in contrast to the typical convenience samples. Nerve conduction measures included bilateral median and ulnar sensory amplitude and latency (onset and peak). Workers with upper extremity symptoms, medical conditions that could adversely affect peripheral nerve function, low hand temperature, or highly repetitive jobs were excluded from the "normal" cohort. Linear regression models explained between 21% and 51% of the variance in nerve function, with covariates of age, sex, hand temperature, and anthropometric factors. The most robust models were fitted for sensory amplitudes in the median and ulnar nerves for dominant and nondominant hands. The median-ulnar difference was least sensitive to adjustment, indicating it is the best measure to use if corrections are not made to account for relevant covariates. A key point was that the magnitude of variance increased with age and anthropometric factors. These findings provide strong evidence that to improve diagnostic accuracy, electrodiagnostic testing should control for relevant covariates, particularly age, sex, hand temperature, and anthropometric factors.     

Origin and evolution of sleep: roles of vision and endothermy

The origin of both sleep and memory appears to be closely associated with the evolution of mechanisms of enhancement and maintenance of synaptic efficacy. After the origin of activity-dependent synaptic plasticity, whereby single activations of synapses led to short-term efficacy enhancements, lengthy maintenance of the enhancements probably was achieved by repetitive activations ("dynamic stabilization"). These are thought to have occurred either in the course of frequent functional use, or to have been induced spontaneously within the brain to maintain synaptic efficacies in circuits that were in infrequent use. The latter repetitive activations are referred to as 'non-utilitarian' dynamic stabilization. With the evolution of increasing repertories and complexities of behavioral and sensory capabilities-with vision usually being the vastly preeminent sense-brain complexity increased markedly. Accompanying the greater complexity, needs for storage and maintenance of hereditary and experimental information (memories) also increased greatly. It is suggested that these increases led to conflicts between sensory input processing during restful waking and concomitant 'non-utilitarian' dynamic stabilization of infrequently used memory circuits. The selective pressure for the origin of primitive sleep may have been a need to achieve greater depression of central processing of sensory inputs-largely complex visual information-than occurs during restful waking. The electrical activities of the brain during sleep (aside from those that subserve autonomic activities) may function largely to maintain sleep and to dynamically stabilize infrequently used circuitry encoding memories. Sleep may not have been the only evolutionary adaptation to conflicts between dynamic stabilization and sensory input processing. In some ectothermic vertebrates, sleep may have been postponed or rendered unnecessary by a more readily effected means of resolution of the conflicts, namely, extensive retinal processing of visual information during restful waking. By this means, processing of visual information in central regions of the brain may have been maintained at a sufficiently low level to allow adequate concomitant dynamic stabilization. As endothermy evolved, the skeletal muscle hypotonia of primitive sleep may have become insufficient to prevent sleep-disrupting skeletal muscle contractions during 'non-utilitarian' dynamic stabilization of motor circuitry at the accompanying higher body temperatures and metabolic rates. Selection against such disruption during dynamic stabilization of motor circuitry may have led to the inhibition of skeletal muscle tone during a portion of primitive sleep, the portion designated as "rapid-eye-movement sleep." Many marine mammals that are active almost continuously engage only in unihemispheric non-rapid-eye-movement sleep. They apparently do not require rapid-eye-movement sleep and accompanying 'non-utilitarian' dynamic stabilization of motor circuitry because this circuitry is in virtually continuous use. Studies of hibernation by arctic ground squirrels suggest that each hour of sleep stabilizes brain synapses for as long as four hours.     

Cardiac allograft vasculopathy: a review

Cardiac allograft vasculopathy (CAV) remains a troublesome long-term complication of heart transplantation. It is manifested by a unique and unusually accelerated form of coronary disease affecting both intramural and epicardial coronary arteries and veins.CAV is characterized by vascular injury induced by a variety of noxious stimuli, including the immune system response to the allograft, ischemia-reperfusion injury, viral infection, immunosuppressive drugs, and classic risk factors such as hyperlipidemia, insulin resistance, and hypertension. The obstructive vascular lesions are thought to progress through repetitive endothelial injury followed by repair response. The role of major histocompatibility complex donor-recipient differences in the pathogenesis of CAV has not yet been completely elucidated. Intracoronary ultrasound studies reveal a dual morphology with donor-transmitted or de novo focal, noncircumferential plaques in proximal segments and/or a diffuse, concentric pattern observed in distal segments. A lack of correlation between microvascular and epicardial vessel disease suggests discordant manifestations and progression of CAV. Apoptosis and loss of functional vascular remodeling have to be considered as important mediators of clinically relevant CAV. Strategies for blocking T-cell costimulation and expression of adhesion molecules may help prevent chronic rejection in clinical transplantation. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and antiproliferative drugs may slow progression of CAV by various effects. Methods to augment endogenous nitric oxide bioavailability as well as newer immunosuppressive regimens may be protective. Balloon angioplasty has a limited role in the treatment of focal lesions. Experiences with coronary stenting, coronary artery bypass grafting, and transmyocardial laser revascularization are limited. Retransplantation has a worse outcome than initial transplantation.