JStroke Cerebrouasc Dis 1991;1:37-48 © 1991 Demos Publications

Potentiation of Rehabilitation: Medication Effects on the Recovery of Function After Brain Injury and Stroke Mark A. Dietz, M.D., and Fletcher H. McDowell, M.D.

In neurologic rehabilitation nothing is currently in clinical use that is effective in restoring lost neurologic function. This paper presents an overview of the various medicines that have been studied for their potential to facilitate recovery after brain injury. Early studies of acetylcholine and anticholinesterase drugs were reported favorably, but subsequent experience with them has not substantiated the initial enthusiasm. In the last two decades, data from work on rodents and cats suggest that certain drugs may facilitate or impede neurologic recovery after brain injury. Human studies on the effects of d-amphetamine and related compounds are sparse, and, although provocative, several problems make the results controversial. Data from studies in the laboratory suggest that clinicians may be impeding clinical outcome in stroke patients with some frequently used poststroke medications. A table lists (with references) the drugs that may impede recovery or reinstate deficits and drugs that may accelerate recovery. Key Words: Brain injury-Stroke rehabilitation-Functional recovery-Medications.

"Rehabilitation" in the true meaning of the wordrestoring something to its previous condition-has not as yet been possible following stroke. For patients with stroke and physical disability, rehabilitation, as it is now practiced, involves teaching the patient how to become as independent as possible despite continuing physical impairment. In neurologic rehabilitation, nothing is currently in clinicaluse that is effective in restoring lost neurologic function. For the past 70 years, investigators have studied numerous medications for their potential to facilitate recovery after brain injury. Studies on medications that may impede recovery have been just as essential, since many of these compounds are commonly prescribed in the population most at risk for stroke (26). This paper is a brief overview of the various mediFrom the Burke Rehabilitation Center, White Plains, NY, U.S.A. Address correspondence and reprint requests to Dr. F.H. McDowell at Burke Rehabilitation Center, 785Mamaroneck Avenue, White Plains, NY 10605, U.S.A.

cines studied, effects they have, and possible explanations for these effects.

Early Studies on Recovery of Function The earliest literature, summarized by Ward and Kennard (59), comes from France in the 1920-30s. Working under the theory that stimulation of the nervous system promotes recovery, French investigators used acetylcholine, as it was believed to act as a central nervous system (eNS) stimulant. Various case reports described recovery from hemiplegia, blindness, and aphasia with acetylcholine. In 1934, Sciclounoff (52) published results of a controlled series of 221 hemiplegic patients; 70 were treated with acetylcholine chlorohydrate (0.1-0.3 grains/day subcutaneously) and 151 with the "usual" treatment, presumptively physical therapy alone. His results were rather dramatic. Patients receiving acetylcholine had twice the chance of improvement and three times the chance for "cure" compared to controls. The risk of death was halved with acetylcholine treat-

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M. A. DIETZ AND F. H. McDOWELL

ment. Scic1ounoff found that younger patients and those started on the drug early after stroke had a better outcome. Sciclounoff's study was not blinded, and the criteria for grouping the patients into "conservative treatment" and "acetylcholine treatment" and the degree of their initial functional deficits are not described. These results suggest that medical treatment to accelerate recovery from stroke may be worth pursuing. In 1943, Ward and Kennard (59) studied the effect of carbaminol choline, an acetylcholine agonist with nicotinic and muscarinic properties, on the motor recovery of brain-lesioned monkeys. Monkeys treated with combinations of carbaminol choline, strychnine, and thiamine recovered more from motor deficits caused by lesions of Brodmann's areas 4 and 6 than untreated controls. Thisimprovement, most pronounced with carbaminol choline, still occurred if treatment was delayed for weeks after the injury and lasted for at least 3 months after completing treatment. These results are questionable because of the small sample size. A total of 14 monkeys was used for at least 11 different therapeutic combinations. The investigators did not evaluate results blinded, and the evaluation of test animals was done by subjective description of their cage activity. Soviet investigators continued research of cholinergic mechanisms with the use of anticholinesterase drugs. The Russian literature, reviewed by Luria in 1968 (40), suggests anticholinesterase therapy, through increasing the amount of available acetylcholine, overcomes, or "deblocks," inhibited neuronal pathways. Luria describes several Russian reports on the use of physostigmine, neostigmine, and dibazol (a Soviet anticholinesterase), in which patients with brain injury either from trauma or stroke, showed functional recovery when given these drugs. Some patients showed improvement when the drug was given years after injury, while others showed immediate and permanent recovery after a single dose. Other Russian reports described improvements in patients with deficits of sensation, speech, gnosls, and praxis. Luria and his group reported on their use of neostigmine (l-ml injection of 1:1000 or 1:2000 dilution) in brain-injured patients with paresis and paralysis (40). Patients with injuries in the premotor area, who could not perform "delicate dynamic coordination" tasks returned to more normal function within 25 min after an injection of neostigmine, with the improvement persisting for at least 20 h. Luria summarized 25 years of Soviet experience by stating: (a) anticholinesterase drugs may help restore function after brain injury, probably through "de38

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inhibiting" depressed preserved parts of the brain, (b) other pharmacologic agents, such as caffeine, vitamin B12, and glutamic acid may have similar functions, (c) improvement seen with these drugs is not as dramatic if the "patient does not receive his proper attention at the height of the action of the drug," and (d) treatment should be started soon after injury has occurred (days rather than months). This body of literature is difficult to obtain, and Luria does not provide details from which his conclusions are drawn. Another criticism of some of the above studies is that neostigmine and carbaminol do not cross the blood-brain barrier (BBB) (54). Although this is true in normal subjects, patients with brain injury including those with stroke, have, for a time, a defective BBB (51). The passage of water, electrolytes, and macromolecules across the BBB in patients with stroke is well known. This increased permeability is temporary, lasting for days to weeks. This would not explain the dramatic improvements Luria described in patients years after their strokes. Much of the early literature on cholinergic mechanisms is flawed by design, but the data provide a background for the theories and knowledge from which much of more recent research is based. The first study suggesting that the noradrenergic system may playa role in motor recovery was published in 1946. Maling and Acheson (42) were testing the effect of d-amphetamine (d-AMP) on muscular coordination in low-decerebrate and spinal cats. Unexpectedly, they found that d-AMP (10 mg/kg intra_ peritoneally) restored the righting response in these animals. Initially, these animals showed signs of intoxication: increased respirations, pilomotor erection widening of palpebral fissures, dilation of pupils, and salivation'.About 1~ min a~er the d~se, and peaking at 30-40 mm, the animals displayed righting and other postural activity that was absent without treatment which lasted up to 3 h. ' In 1950, Macht (41) described the same righting response using AMP in decerebrate cats from 3 to 52 days after surgery. These responses were also restored temporarily in hemi-decorticatc animals 5-8 months later and in totally decorticate animals studied up to 38 days later.

Introduction to Recent Animal Studies in Functional Recovery In the 1970s,the number of experiments with brain_ injured animals treated with amphetamine increaSed dramatically. Better study designs, and the use of cOn_ trol groups and blinded observers, make the results of these investigations more interpretable than earlier

MEDICATION EFFECTS ON FUNCTION RECOVERY

reports. Part of the impetus for this research came from the finding that ischemic brain injury and cerebral infarction affect the metabolism of eNS catecholamines (47), and these changes spontaneously improve over 3-6 weeks. Since 1970, animal studies have utilized rodents and cats. These models are less than satisfactory in predicting functional outcome in humans. In the rodent model, some of the techniques used to create deficits produce few observable effects, whereas others produce more significant hemiplegia. Allcompletely and spontaneously resolve over several weeks. The cat stroke model more closely approximates the human model, but deficits from cortical ablation will also spontaneously resolve, but over months. The older, less well-controlled studies of cortical lesions in monkeys described patterns of recovery much more closely approaching a useful model for humans.

Rodent Data Studies in the mid·1970s demonstrated recovery of a septal rage syndrome (SRS) in lesioned rats treated with dopamine agonists (43). Rats that have bilateral lesions of the septal nuclei show a stereotypic rage response consisting of explosive reactivity to any stimulus, manifested by biting, attack, fleeing, increased muscle tone, and muricide. Without treatment, this response resolves over 4 months, with most of the recovery occurring during days 20-120. Rats treated with a single intraperitoneal injection of t-dopa, apomorphine, piribedil (a dopamine agonist), or AMP show more rapid recovery from SRS compared with those receiving a saline (SAL) injection . Blinded investigators observed that recovery occurred most rapidly (over the first 5 days) with large doses of t-dopa (100 mglkg) and apomorphine (20 mg/kg), and somewhat less rapidly with piribedil and AMP. The recovery for each was permanent with a single injection. Animals were not believed to be intoxicated or sedated, since other cage behaviors remained the same. This experiment demonstrated that the catecholinergic system can be manipulated pharmacologically to hasten neurologic recovery. Other investigators used sensorimotor (SM) cortical ablation in rats to create contralateral impaired motor function, tested by having the animal traverse a narrow beam. In one study (15), before surgery, all animals could cross the beam without difficulty. Immediately after ablation, no animals were able to cross the same beam. Without any treatment (or with an intraperitoneal saline injection), difficulty in beam walkingdeclined and returned to normal in 2-4 weeks (Table 1). Ratsgiven a single intraperitoneal injection

Table 1.

Results of unilateral cortical ablation in rats on Q varietyof treatments Results

Treatment after ablation Untreated (controls) Single dose of AMP Single dose AMP with immediate confinement Single dose of HAL Single dose of AMP

+ HAL

Recovery of task in 2-4 weeks More rapid recovery than controls Recovery same as control Recovery worse than controls Recovery worse than controls

AMP, amphetamine; HAL, haloperidol.

of AMP (2 or 4 mglkg) and given hourly beam-walking tests while intoxicated showed more rapid recovery in this task, sometimes as quickly as in the first hour after injection. This improvement lasted beyond the period of intoxication and drug activity. Rats confined to small cages during the period of AMP intoxication showed none of this improvement with the same doses of drug, suggesting that AMP and task experience were both important in hastening recovery. During these same experiments, some of the rats were given a single intraperitoneal injection of haloperidol (HAL) (0.4 mg/kg), Some received the injection with a dose of AMP; others received HAL alone. Both groups displayed retarded recovery periods compared to SAL controls. Those that received HAL alone had the most delayed recovery. Complete recovery eventually occurred in all animals. The fact that a catecholaminergic stimulant can hasten recovery, and a catecholaminergic blocker can retard recovery, lent support that these mechanisms may be crucial to the recovery phenomenon. To further define the nonspecific stimulation effect of AMP, Boyeson and Feeney (2) used cortical ablation to produce motor deficits in rats and 24 h later gave a single intraventricular infusion of either norepinephrine (NE) or dopamine (DA). Only rats infused with NE showed acceleration of recovery. Weaver et al. (61) provided further differentiation of the receptors responsible for motor recovery. Rats trained in a beam-walking task were given a unilateral 8M cortical ablation. Twenty-four hours after surgery, the rats were given a single intraperitoneal injection of prazosin (4 mglkg), yohimbine (10 mg/kg) (an alpha-2-adrenergic blocker that also enhances the release of NE), propranolol (10 mglkg), or methoxamine (1, 4, or 8 mg/kg) (an alpha-adrenergic stimu-

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M A. DI£1Z AND F. 11. McDOWELL

Table 2. Results of unilateral motor cortical ablation

studies in cats on a variety of different treatments Treatmentafter ablation Untreated (controls) Singledose of AMP Multiple doses of AMP Multiple doses,with confinement after each

Results Recovery over 10-60 days Immediateacceleration of recovery Greater acceleration of recovery compared to single dose No recoveryuntil day 4, then accelerated

AMP, amphetamine. lant). Beam-walking testing done over the next 15 days showed that the alpha-adrenergic blocker (prazosin) retarded recovery, yohimbine showed a trend toward enhancement of recovery, and propranolol and methoxamine had no effect. It was believed that, although methoxamine is an alpha-adrenergic stimulant, the short half-life may have prevented any beneficial effect. After these animals fully recovered (30 days), they were given single injections of propranolol, prazosin, clonidine (0.4 mglkg), or phenoxybenzamine (10 mglkg). The three alpha-adrenergic blockers reinstated deficits, whereas propranolol had no effect. A further study showed this to be a dosedependent effect (53). A similar experiment using idazoxan, a selective alpha-2 antagonist, demonstrated that the recoveryfacilitation effect of AMP was blocked by the drug (56). Recently, Goldstein and Davis (24) found similar results in cortically injured rats treated with clonidine. It was noted specifically that no rat showed signs of sedation following drug administration.

Cat Data Study protocols similar to the above rodent studies were devised to test motor recovery in cortically injured cats. In a study by Hovda and Feeney (29), cats had unilateral cortical ablation leaving the animal with a hemiplegia lasting for at least 10 days but impeding beam-walking ability for at least 60 days. They were then divided into groups, given injections, and then tested/trained for beam-walking 1, 2, 3, and 6 h after each injection for up to 60 days. Study groups received: (a) SAL on days 10, 14, 18, and 22, (b) a single dose of AMP (5 mg/kg i.p.) on day 10, (c) multiple doses of AMP on days 10, 14, 18, an~ 22,.or (~) the same as group 3 but with no tests during intoxication . Results (Table 2) showed an immediate and 40 JSTROKE CEREBROVASC DIS, VOL 1, NO.1, 1991

enduring acceleration of motor recovery with AMP, with the rate of recovery more rapid with four injections instead of one. Cats with no testing during intoxication (task experience) showed no difference in the rate of recovery compared to SAL controls until the fourth injection (day 22), when their rate of recovery dramatically increased, surpassing the SAL controls. In cats fully recovered from this type of injury (3-8 months postsurgery), a single dose of phenoxybenzamine reinstated the hemiplegia for up to 4 days (31). It was noted that normal control cats given the same dose showed "no effect . . . except to make them drowsy:' The investigators felt this was nota soporific effect, since pentobarbital also produced sedation in both groups. It is not stated how the degree of sedation compared to that during phenoxybenzamine intoxication. Pentobarbital did not reinstate hemiparesis in the injured group. Haloperidol, given at this late stage in recovery, had little effect on any of the animals. Functions other than those of the motor system can also be affected by catecholaminergic manipulation in the cat model. Cats that have bilateral cortical ablation of areas 17, 18, and 19 have a total and permanent loss of depth perception but a rapid return of visual acuity (11,34). Depth perception can readily be tested in cats through the use of a "visual cliff" (46). This apparatus consists of a start box containing the animal, which is elevated 16 ern above a sheet of glass covering two shelves covered with a black-and-white grid pattern. Under the glass, the shelves individua[, ly can be adjusted to different heights. Normally, a cat stepping out of the box will place his lead paw on the shallow side without error. Using this model, Feeney and Hovda (18) investi_ gated visual depth perception recovery in cats when treated with AMP after ablation. Animals were tested on the visual cliff 4 days after surgery and shOwed random placement of the lead paw. They were then divided into groups receiving (a) AMP (5 mglkg Lp.) on days 10,14,18, and 22,with postdose training done 1,2,3, and 6 h after each dose; (b) SAL, but treated the same otherwise as group 1; or (c) AMP on days 10, 14, 18, 22, 26, 30, and 45, but placed in darkness for 24 h after each injection. The investigators discovered that cats receiving AMP with postdose training shOwed a dramatic improvement in depth perception within 6 h after the first dose and returned to a normal baselin by day 26 (Table 3). The cats that received SAL e AMP with no postdose training showed no recove Or of depth perception. The remarkable recovery Se ry in the first group was a permanent change, since t~n animals performed faultlessly 60 days later. To d.... e ern,

MEDICATION EFFECTS ON FUNCTION RECOVERY

Table 3. Results of bilateral visualcortex ablation studies in cats on a variety of treatments Treatment after ablation Untreated (controls) Multiple doses of AMP (starting on day 10) Multiple AMP + darkness during intoxication (starting on day 10) AMP + HAL (day 10) AMP starting day 90

Results Permanent loss of depth perception Accelerated and permanent recovery of depth perception Same as controls

Same as controls Same as controls

AMP, amphetamine; HAL, haloperidol.

onstrate that this improved performance was due to a return of depth perception, the investigator covered one eye of each cat and noted that each animal's performance dropped to that expected by chance again. When three of the unrecovered control animals were given a dose of AMP and postdose training at 90 days, no recovery in depth perception was seen. In another study (30), postsurgical animals given AMP (5 mg/kg) and HAL (0.4 mglkg) showed no improvement in depth perception, with performances the same as SAL controls.

Anatomic Localization ofAreas Responsible for Facilitation of Recovery Since the primary source of NE in the brain is the locus ceruleus (LC) (10), investigators turned their efforts here to localize and characterize the site and mechanisms responsible for the effects observed. The LC is known to have diffuse noradrenergic projections throughoutthe cortex (8,10),and it may be an essential component of the activating system in such functions as cortical arousal and in the induction of paradoxical sleep (10). If focalinjury causes a depression of function in areas other than the primarily injured area, perhaps the LC, when stimulated, reactivates (or "arouses") these areas. Evidence for this was provided by Feeney et al (19). After unilateral SM cortical ablation, rats were given a single injection of either SAL,HAL,or AMP. Twentyfour hours after this injection, they received an injection of 14C-2-deoxyglucose, a compound used to measure cerebral metabolism. Forty-five minutes later, the animals were sacrificed. Brains from SAL controls showed widespread depression of glucose utilization, whereas AMP-treated animals showed a

reversal of this depression. Haloperidol blocked this reversing effect. Histochemical support of the above findings was also supplied by Feeney at a1. (19). Rats given ipsilateral lesions of the LC were injected with a histochemical stain for the oxidative enzyme alpha-glycerophosphate dehydrogenase (alpha-GPDH), which is used to map cortical depression. If a rat is given a cortical injury and injected with alpha-GPDH, a generalized paling of the cortex will be seen with the stain (13). Cortically lesioned animals treated with AMP showed no paling (i.e., no generalized cortical suppression) in two of three animals. Lesioned animals given AMP and haldol, or apomorphine, showed "no prevention of paling." In 1984, Boyeson and Feeney (2) studied rats, pretrained on beam-walking and given unilateral SM lesions. Twenty-four hours after cortical ablation, the rats received either a single dose of AMP (2 mglkg) or SAL On days 2, 6, or 18, the LC and cerebellum were assayed for levels of NEand its metabolite 3-methoxy4-hydroxyphenylglycoI. SAL-treated rats on day 2 showed depressed NE turnover compared to controls with unilateral caudate nucleus lesions, while AMPtreated animals had higher NE turnover rates. It is unclear why controls were given caudate nucleus lesions instead of SM cortical lesions, since the authors do not comment on this. The AMP-treated rats also showed improvement on the motor task by day 2. No differences were seen between groups on day 6. By day 18, NE turnover in the cerebellum of AMP-treated rats was eight times that of the SALcontrols. No mention is made of differences in the LC. Further research done by Boyeson and Feeney (2) showed that removal of the left cerebellar cortex in rats caused deficits that were not affected by AMP, SAL, or HAL In the few rats that did recover, phenoxybenzamine and propranolol did not reinstate deficits. Although the authors conclude that these data suggest the cerebellum is critical to recovery of beamwalking ability, by creating a model with a different lesion than prior SM ablations, comparison to previous models is difficult. A combined cortical ablation and contralateral cerebellum ablation model perhaps may have proved more useful. Krobert et al. (35) provided further evidence of the role of the LC in facilitating motor recovery. Rats had lesions of the ipsilateral LC and motor cortex. One grou p was given both lesions simultaneously; the cortex was lesioned 1 week after the LC lesion in the second group and 2 weeks after in the third. All were given an injection of NE in the contralateral cerebellar hemisphere 24 h after the cortical lesion. All animals demonstrated facilitation of recovery (Table 4),

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M. A. DIm AND r. II. McDOWELL Table 4. Results of lesioning locus ceruleus and motor

cortex atvarious times in tire rodent model

Ablations 1. LC + MCor simultaneously 2. LC then MCor lesion 1-2 weeks later 3. Same as 2, then opposite LC lesion after recovery

Results after NE injection Into cerebellum after MCor lesion

Acceleration of recovery Greater acceleration of recovery Reinstatement of hemiparesis

LC, locus ceruleus; MCor, motor cortex; NE. norepinephrine.

but only the two groups in which the cortex was lesioned 1-2 weeks after the LC was there"a remarkable jump in functional recovery." In recovered animals, a lesion in the contralateral LC reinstated the hemiparesis. The authors concluded that these data suggest that"a behavioral supersensitivity had developed in the contralateral cerebellum" when a week or more lapsed between lesions. They also reasoned that the opposite LC assumed functions normally handled by the damaged ipsilateral LC.

ConclusiOtlS from Animal Data Rodent and cat data suggest that certain drugs may facilitate or impede neurologic recovery after brain injury. This effect is seen in the motor, visual, sensory, and limbic systems. Motor recovery has been studied in the greatest depth. Research indicates that facilitation of motor recovery is mediated by NE, and, more specifical1y, through alpha-z-adrenerglc receptors. Furthermore, histo-and biochemical evidence suggests widespread depression of cerebral function after a focal cortical injury, and that the LC may act to "reactivate" depressed, but functional, areas of the brain. Paralleling the functional status of the animal, this depression is reversed with AMP unless the ipsilateral LCis lesioned. The cerebellum may also playa role In this phenomenon, since cortical injury and AMP affect NE and its metabolites at this remote site.

Human Studies Despite the large body of animal data on noradrenerglc reinstatement of function after cortical injury, very little human data have been collected. There are U

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some human data to support the theory of diffuse cortical diaschisis after unilateral hemispheric injury. Lagreze et 011. (36) describe the phenomenon in six ~oststroke patients, as measured by inhalation of 8F-f1uromethaneand positron emission tomography. The effect was found to be secondary to contralateral reduction in cerebral blood flow. One recent study (57) described the effect oft-dopa and physostigmine on neurologic functioning of 38 comatose patients with severe head injury. Patients were at least 4 weeks postinjury and had shown few signs of improvement. Assessment was made with the Glasgow Coma Scale. Patients were given either t-dopa, in the form of Madopar (200 mg t-dopa, 50 mg bezerazide, up to four times a day) or physostigmine (1-1.5 mg tv. or three doses of 1 mg i.m.-the frequency of injections was not given), or a combination of both. In the group of patients selected, there was a tendency for improvement before the initiation of treatment. The degree of improvement increased in both motor and verbal scores while on treatment. In 29 of the trials, patients showed no improvement in the 2 weeks prior to the study. Nineteen (66%) of these improved while given treatment (4 with physostigmine, 11 with t-dopa, and 4 both treatments). In 18 of the patients, cerebrospinal fluid homovaniUic acid levels significantly increased during treatment with t-dopa, The investigators found that increased severity of head trauma tended to predict poorer response to the medications. They also recommended that t-dopa be continued for 2-3 weeks after an opti. mal score is obtained. Physostigmine was found to permanently improve verbal scores in a few patients after a single dose. Others needed intramuscular maintenance therapy for lasting benefit. Although this study supports previous findings of improved function with dopaminergic and cholinergic medica. tions, the study was unblinded, not placebo-controUed. and there was no comparison to the clinical course of similar, but untreated, patients. Clinical data on the effects of AMP and related com. pounds in brain-injured patients are also sparse. In 1975, Kaplitz (33) observed the effect of methyl_ phenidate on a withdrawn, apathetic hospitalized geriatric population. Patients received methylpheni. date (10 mg p.o, b.i.d.) or placebo over 6 weeks and were scored by blinded observers in categories SUch as mental status, global evaluation, target-sympt0tn response, and ward behavior. Patients Who receiVed methylphenidate improved significantly across all categories compared to placebo-treated patients. N side effects were seen. 0 In a study not blinded or placebo-eontrolled, Clark and Mankikar (9) treated inpatient geriatric patients

MEDICATION EFFECTS ON FUNCTIONRECOVERY

who failed to respond to rehabilitation with d-AMP to improve motivation. Twenty-eight of the 88 were patients with stroke. d-AMP was given for 3 weeks in increasing dosage as tolerated (2.5-10 mg p.o. b.i.d.). A total of 48 patients showed improved scores in mobility, self-care, and motivation; 28 of these were able to be discharged because of their improved status. No mention is made of the number of patients with stroke who improved. There was a correlation between diminished effectiveness of the drug and increasing age. Twenty-three patients had to be withdrawn from the study because of side effects,primarily psychiatric in nature. Upper and Tuckman (39) described a 25-year-old patient, 16 months post head trauma, admitted to a psychiatric hospital because of bouts of confusion, suicidal behavior, depression, paranoid thoughts, and violence. He was placed on d-AMP 5 mg p.o. b.i.d, which was gradually increased to 15 mg p.o. b.i.d, over 5 days. Over the next 5 days, the patient markedly improved, becoming more oriented, less confused, and with more appropriate behavior. Eighteen days after being on AMP (and receiving 30 mg/day for at least 13 days), the patient was abruptly switched to placebo, with return of all previous symptoms within 1 day. Despite further adjustments in dosage of the drug, the clinicians were unable to obtain the initial success again. Later in the patient's clinical course, amitriptyline 300 mg/day was added to the AMP (30 mg/day), and, again, temporary clearing of thought was observed over the next several weeks. The only human study attempting to duplicate laboratory AMP studies was done by Crisostomo et a1. (12). The study by design was good: randomized, prospective, and double-blinded. All patients had hemiplegia with onset within 10 days of entrance into the study, Patients were excluded with severe intractable hypertension, heart disease, concurrent use of monoamine oxidase inhibitors, or evidence of prior stroke or current hemorrhage. Patients were assessed with the motor function subcategory of the Fugl-Meyer Scale (21), which isa cumulative numerical scoring system for grading physical performance of stroke patients. Motor scores were obtained on days 1and 2. Following the second examination, patients were given a single oral dose of either 10 mg AMP or placebo. Within 3 h of the dose, patients had at least 45 min of physical therapy of their weakened side. On day 3, final scoring was made. Eight patients were included in the study; four received placebo, the others AMP. Patients tolerated AMP well. Of the four patients who received AMP, patients 1 and 2 improved by at least 14 points on the motor scale, patient 3 had a four-point increase, and

patient 4 had a three-point increase. None of the placebo-treated patients showed more than a twopoint improvement. Although these findings are provocative, several problems make the results controversial. First, the small number of patients inherently makes differences difficult to interpret. Second, since "no significant difference" was found between the first and second baseline motor scores, Crisostomo averaged these, and this calculated value was compared to the score from day 3. If data from all 3 days were listed, trends for spontaneous improvement would have been seen more readily. Also, in the placebo group, two of the patients had worse scores (one with a flaccid hemiplegia) than the lowest score of the AMP-treated group. A third patient had normal use of his arm on the affected side, but the leg was markedly plegic. From the start, the placebo group had more profound deficits than the AMP-treated group. Although this study attempted to show AMP-induced functional improvement, additional studies will be needed to decide if true differences exist.

Effect of Other Compounds on Functional Recovery Animal Data

The work of early investigators with cholinergic medications has already demonstrated that functional recovery may be influenced by chemicals other than NE. Recent rodent studies demonstrate that gammaamino butyric acid (GABA)infused into injured brain may affect recovery as well. In a study by Brailowsky and Knight (6), young and old rats were taught to traverse a narrow beam. All were able to learn this skill, although the older rats were slower and more cautious. Afterwards, osmotic minipumps were implanted into the skulls of the animals. The cannula for drug infusion was implanted into the left somatomotor cortex corresponding to the hindlimb area. All pumps were filled with, and released, tiny amounts of either GABAor SALfor 7 days. Observers were blinded to the substance being infused. Initially,all animals demonstrated bilateral motor deficits, secondary to the injury from implanting the pump and cannula. Over the next 2 days, these deficits cleared in all animals receiving SAL. Animals receiving GABAgradually recovered, but it took up to 5 days in young rats and 2 weeks in older rats. The older group never attained its presurgical motor scores, even after GABA infusion had stopped. In a further study (4), the investigators gave similar GABA-treated animals a dose of HAL 3 weeks after

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pump implantation. Re-emergence of motor deficits appeared in all GADA-treated rats, lasting up to 24 h in younger animals and 72 h in older animals. The SAL-treated controls were not given HAL. As would be expected, nonoperated controls showed no lateralizing signs with HAL. Although these studies suggest that GADA may playa role in neurologic recovery, they do not convincingly prove that the retarding effect seen in GADA-treated animals was not secondary to sedation or other mechanisms that may have decreased spontaneous motor activity. Because of the relationship ofbenzodiazepines and the GABAergic system, Schallert et at. (50) studied the effect these drugs have on the recovery of function after brain injury. In their study, a rat model was devised in which the somatosensory system was tested. When rats are lesioned in the somatosensory cortex, their response to bilateral forelimb tactile stimulation is withdrawal of the ipsilateral paw, instead of a normal symmetrical response. Recovery occurs over a week, as the response becomes symmetrical again. After rats were lesioned in this manner, half received diazepam (5 mglkg) three times per day for 3 days followed by twice per day for the next 19 days. The other half received no drug. Testing was done before the morning dose (16 hours after the last injection of the previous day). Their results showed that all rats display severe asymmetry on the first postsurgery day. Dyday 8, all but one (of eight) control rats had a symmetrical response, and this one recovered by day 22. None of the diazepam-treated rats showed recovery over the 22 days. They noted that none of the diazepam-treated animals appeared sedated and actually reacted to the stimulus slightly faster than control rats. No diazepam was given beyond day 22, yet 3 months after being lesioned, there was no further recovery of response. A smaller group of animals was lesioned in a similar way, but the drug was not given for 3 weeks (when full recovery had occurred). The course of diazepam over the next 22 days failed to reinstate asymmetry in these animals. Anticonvulsants, a commonly used class ofdrugs in the poststroke period, have been studied with similar models. The effect of phenytoin and phenobarbital on motor recovery was first studied in 1945 by Watson and Kennard (60) in monkeys with motor cortex lesions. Using only one monkey in each treatment category, they observed the effects of phenobarbital, phenytoin, and carbaminol with atropine in various combinations. The authors concluded that (a) phenobarbital produced a marked delay and extentofrecovery in doses that had no observable sedative effect (although one clearly was sedated, and the dose had 44

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to be lowered) and (b) Oilantin does not cause a delay in motor recovery, but, when given with carbaminol, it prevented the enhanced recovery seen with carbaminol alone. As with other older studies on this subject, the small numbers, inadequate follow-up, subjective, unblinded observers, and lack of proper controls makes this study difficult to interpret. In 1986, the problem was reapproached, when Brailowsky et at. (5) studied phenytoin and its effect on recovery from hemiplegia in the rat. The rats were first trained and tested on a beam-walking task and sensory tasks involving orientation to or withdrawal from stimulation of an extremity. They were pretested with 50 mglkg of intraperitoneal phenytoin, which caused no change in motor/sensory skills. The investigators then implanted a cannula into the motor cortex on one side, which was connected to a minipump containing either SAL or GABA. The cannula created a motor deficit in aUanimals; however, those infused with GABA showed more marked hemiplegia than those without GABA. This technique was used instead of cortical ablation to permit the evaluation of phenytoin "at different levels of hemiplegic severity without introducing the complications associated with varying lesion size." AUanimals received either phenytoin solvent or phenytoin (SO mglkg) on days 1,3,4, and 5 with motor/sensory functions tested before and 30 min after injection by blinded observers. The GABA-treated group demonstrated a transient worsening of motor function between days 3 and 5 (during OPH administration), whereas the SAL-treat_ ed group showed no changes. When aUof the animals were give OPH (50 mg/kg) 14 days after surgery, no significant lateraIizing effects were seen. As with the benzodiazepine-treated animals, it is difficult to say how much of the transient worsening seen was actual_ ly from sedation or other factors.

Human Data The implications of the above animal studies ar large. Might clinicians be impeding clinical outcorne from stroke or brain injury with certain frequent} e used poststroke medications? y Human data are sparse. Meyer et at. (45) describ the results of a study of 15 patients with stroke treat d with intracarotid infusion of phenoxybenzamine a e d propranolol, in hopes ofreducing elevated extracel~ lar levels of neurotransmitters released after br ~­ . . n' d' OlIn injury. Patients were stu led a mean of 13 days aft onset of cerebral ischemia (range, 1-38 days) er . monitoring techni, and . Iu de d imvasrve eva Iua tion InC Ue s with multiple catheter insertions into the cer qb " e rOll transverse SInUS, supenor vena cava, internal carotid,

MEDICATION EFFECTS ON FUNCTION RECOVERY

Table 5. Summary of medications used in brain

injury trials Drugs that may impede recovery or reinstate deficits Haloperidol (4,15,30) Prazosin (61) Clonidine (24,61) Phenoxybenzamine (31, 45,61) GABA (4,6,27) Benzodiazepines (50) Phenytoin (5,60) Phenobarbital (60) Idazoxan (61)

Drugs that may accelerate

recovery Amphetamine (7,12,14,15, 16,17,18,23,25,29,32,39, 42,43,44,49) Norepinephrine (2,3) Caffeine (1) Phentermine (28) Phenylpropanolamine (20) GMt-ganliosides (48,49) Yohimbine (61) Carbaminol choline (59) ACh chlorohydrate (52) Neostigmine (40) Physostigmine (40,57) COP-choline (55) t-Dopa (43,57) Apomorphine (16,43)

and brachial arteries, and, by way of a lumbar puncture, a catheter into the subarachnoid space. Data obtained from the study were primarily physiologic; however, a statement is made that there was a "slight transient worsening of the existing neurologic deficit" in four patients. Clinical criteria for this worsening is not described. Although other authors cite this report as evidence that phenoxybenzamine may worsen neurologic deficits (19,20), the complicated methods used and minimal clinical descriptions give this conclusion little support. Therefore, despite suggestion in animal data that certain drugs may be detrimental to stroke recovery, especially when given during the acute postictal period, no human studies have convincingly demonstrated this. A summary of medications that may affect functional outcome in animal and human models is shown in Table 5.

Models for the Mechanisms of Recovery In some situations after brain injury, motor/visual ability may be intact (or partially intact), but access to these memories is not. There is some evidence to support this theory. In one study (37), rats were trained to choose the lighter of two exits in an apparatus and then subjected to ablation of the posterior portion of the dorsal pallial cortex. After surgery,

there was no recoIlection of the learned response, but these animals relearned the response at a rate similar to preoperative values. Further studies helped determine whether this was because that memory was truly gone or the retrieval of the memory was defective. When rats were trained in a similar task, and then subjected to posterior neocortical ablation, the group receiving 1 mglkg of racemic AMP relearned the task at a quicker rate than those that did not (7). This dosage had no effect on the learning rate of the same task in nontraumatized controls. In a similarly designed experiment (38), but with use of a black-white discriminative task, one postablation group of rats was retrained to respond to the same preoperative response, the second group to the reverse response. Immediately after surgery, neither group could make the correct response; however, with training, the group retrained to the same presurgical task learned more quickly than the second group. This suggests that memories are present and may facilitate or interfere with postsurgery learning of particular tasks. Meyer and Beattie (44) studied rats with bilateral ablation of the dorsal pallial cortex on a two-way shuttle-avoidance task. Untreated postablation rats are unable to learn this task (28). Rats treated initially with AMP or SAL performed poorly during the first 300 trials (30 trials/day over 10 days), although there was an initial modest increase in correct avoidance behavior in the AMP-treated group that was not maintained. The following 300 trials were preceded by daily injections of d-AMP. An immediate dramatic improvement was seen in these trials, which disappeared after AMP was discontinued. If AMP was slowly tapered during this training period, the animals were able to maintain some degree of improvement after AMP was stopped, although this level was not as high as with AMP. Meyer and Beattie feel that this offers evidence that the training taught the animals something, but they were unable to retrieve this relearned material until AMP facilitated its retrieval. The authors state, "amphetamines have much more powerful effects upon remembering than they have upon processes of learning." They feel that "once (memory engrams) are established, (they) are exceptionally hard to get rid of." Drugs like AMP combined with task experience facilitate retrieval of these functions. If the substrate for the function itself is damaged, however, recovery will not occur, even with facilitation. The beneficial results seen in studies of d-AMP and methylphenidate in the geriatric population suggest that some of these effects may be related to increased motivation, and hence, accelerated learning. This may play some part in the acceleration of recovery but

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M A. DIE:TZ AND F. II. McDOWEll

docs not explain, for Instance, the tasting improvement in depth perception seen in cats. Denervation superscnsitivity may also be a factor in the effect seen. This, however, would depend on the size and location of the lesion, since the postsynaptic receptors must remain Intact (or the e((cct to occur. With this theory, it is difficult to rectify why a single dose may provide lasting benefit. Acceleration of axonal sprouting milY also have a role In this process, although rat hippocampi studies show that new sprouting takes 10-15 days to become functional (62). Finally, the idea of diaschisis, or "remote functional depression," must be considered. This theory was Introduced by von Monakowin 1914 (58),whostated that the focally Injured brain has depression of function beyond the area of Injury. Over time, these nondamaged areas recover (rom "shock" and regain their function, whereas the area of primary damage does not recover. This theory fell out of favor after being challenged as a circular argument. Uninjured remote areas "shutdown" initially, and then over time "restart." The only way of deciding which areas were injured were those that regained function. The theory hasrecently regained credibility, now that techniques are being used to map out physical, as well as functional, injury,

Trends for Further Research Glick and Zimmerberg (22) discussed factors affecting the outcome of brain lesion studies, and these are quite applicable to human research done on the subject. Lesion size and location are critical in outcome studies of brain injury. Animal studies can control the extent and location of an injury much more so than the wide variety oflesions seen in a stroke popuJation. Other factors such as postinjury interval to treatment, dose-response curves, and drug scheduling all playa role in outcome. Also, brain-injured subjects may respond to a drug in a different way than normal controls, and drug sensitivity in the same individual may change over time. These drugs may also have a more persistent effect secondary to a damaged BBB. An of these factors will need to be considered in devising protocols and in interpreting data from these studies. What do the animal models teach us for devising new study protocols? Ukely,a multiple dose regimen of AMP (or other drug) will be most beneficial Also, postdose experience (l.e, physical, occupational, speech, and cognitive therapies) is likely to be a crudal clement. There is a critical period after the ictus that medicines will need to be given to obtain any 46

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benefit, Currently, we have no way of knowing what that period is in humans. Investigators will need to avoid the use of certain drugs during these trials, such as certain antihypertensives, anticonvulsants, and benzodiazepines, so that confounding factors are minimized. More bothersome, and possibly the limiting factor in these studies, is the fact that benefit was seen repeatedly only from intoxicating doses in animal models. The lO-mg dose used by Crisostomo may not be sufficient to induce the desired effect. Higher doses in the geriatric population will likely not only be intolerable secondary to side effects, but downright dangerous. By limiting studies to patients without risk factors for AMP, a large proportion of the stroke population will be eliminated. Less toxic drugs such as caffeine (1), phentermine (28), and phenyl. propanolamine (20) have been shown to induce f'C6 covery in rodent and cat models, although not as effectivelyas AMP. Perhaps these are better drugs to study in this population. Finally, further research is needed not only with adrenergic compounds but also with cholinergic drugs, anticholinesterases, dopamine, and other compounds with possible beneficial effects such as GMt-ganglioside (48,49) and cytidine5'-diphosphochoJine (CPD-choline) (55). The need for the investigation of potentially detrimental drugs in the poststroke period is just as crucial. as demonstrated by the striking delay of recovery in animals with these compounds, and the scarcity of human data on the subject Despite encouraging findings in animal models. there have been few convincing data to support accelerated functional recovery in humans to this date. Feeney and Sutton (20) state: ''We think it unwise to simply dismiss the observations of so many investiga. tors as incorrect, when they independently described similar results." Until blinded, controlled studies with adequate patient numbers arc conducted, some skepticism must remain, but certainly the investigations must continue.

References 1. Bogen JE, Suzuki M, Campbell B. Paw contact placin in the hypothalamiccat given caffeine. 1Ntllrobiol1975~

6:125-7. • 2. Boyeson MG, Feeney OM. The role of norepinephrin~ in recovery (rom brain injury (abstr). Soc Nwrosci 198". 10:68. • 3. Boyeson MG, Krobert KA, Hughes JM. Norepinephrine infusions into the cerebellum facilitate recovery Irom sensorimotor cortex injury in the rat (abstr), Soc Nturosd 1986;12:1120. 4. Brailowsky 5, Knight RT, Blood I