BRAIN INJURY,

1992, VOL. 6, NO. 1, 1-14

Review Advances in neuropharmacolog~cal rehabilitation for brain dysfunction N A T H A N D. ZASLER Brain Inj Downloaded from informahealthcare.com by University of Sydney on 12/31/14 For personal use only.

Medical College of Virgmia, Virgmia Commonwealth University, USA

(Received 6 October 1990; accepted 1 December 1990) The use of pharmacologcal agents as rehabilitative tools following brain injury remains to some degree both a science and an art. Recent work in the area of the neural sciences has shed new light on the workings of basic CNS neurochemical systems and the use of pharmacologic agents in altering central neurophysiologic processes. The major central neurochemical systems are reviewed both anatomically and physiologdly. An overview is provided of basic neuropharmacologic agents by class. Lastly, some of the newer neuropharmacological options for treatment of post-acute brain injury deficits are examined.

Introduction The basic tenet of positively affecting neurological outcome and functional status after brain injury through the use of pharmacological agents is by no means new [l, 21. Nevertheless, most rehabilitation professionals have historically relied almost exclusively on non-pharmacological modalities to address sequelae following traumatic and non-traumatic brain injury. Physiatrists have lately become more comfortable at managing both the pharmacological and the more traditional non-pharmacological rehabilitative aspects of care of individuals following brain injury. Until recently, there was little o r no evidence that medications could make a difference in either the rate of plateau of neurological or functional recovery following brain injury. There is now good evidence that many acute, sub-acute and chronic neurological and functional sequelae resulting from brain injury can be lessened and potentially even abated through the thoughtful and appropriate use ofpharmacological agents [3,4]. This paper provides an overview of neuropharmacological management of brain injury with primary emphasis on the post-acute period. Selected basic neurochemical systems and commonly utilized classes of neuropharmacological agents are reviewed prior to a discussion of present treatment options for a variety of specific clinical entities.

Basic neurochemical systems Although there is believed to be a cornucopia of putative neurotransmitters in the mammahan central nervous system (CNS), most that have been identified can be grouped Address correspondence to: Dr N. D. Zasler, Brain Injury Rehabilitation Services, Department of Rehabilitation Medicine, Medical College of Virginia, P.O. Box 677, Richmond, VA 23298, USA. 0269-9052/92 $3.00 0 1992 Taylor 81 Francis Ltd.

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into four main categories: acetylcholine, monoamines, peptides and amino acids. The number of putative neurotransmitters now exceeds forty, most of which are thought to be small peptides. Neurotransmitters are chemicals that are released from the nerve terminal (pre-synaptic neuron) as the result of changes in membrane potential generated by the arrival of an action potential. The process of ‘normal’ neuronal function relies greatly on appropriate synthesis and release from the pre-synaptic neuron, successful crossing of the synaptic cleft, binding to the post-synaptic receptors, and termination of reccptor stimulation by either removal or degradation. Cholinergic neurons (nerves that release acetylcholine) are distributed throughout a variety of areas in the central nervous system including the ventral forebrain, upper brainstem and striatal interneurons [5, 6, 71. There are two major sub-classcs of cholinergic receptors: nicotinic and muscarinic. Functionally, choiincrgic systems have been theorized to play a role in learning/memory processes, motor control, stress, affective disorders and arousal [8]. Monoaminergc systems tend to have long-branched ascending and descending axons and are mainly associated with the more diffuse neural pathways in the CNS; their cell bodies are typically in small groups of neurons, primarily located in the brainstem. Whereas noradrenaline, adrenaline and dopamine are chemically classified as catecholamines, serotonin is an indoieamine. Dopaininergic projections are typically divided into three categories based on length: long, short and ultra-short. The long tracts emanate from the substantia nigra (nigrostriatal tract) and the ventral tegmentum (mesolimbic/mcsocortical tracts). The intermediate length systems include the tubero-infundibular system, the incerto-hypothalamic neurons and the medullary periventricular group. Ultra-short systems are found in the retina and olfactory bulb [5. 7, 81. I t is presently theorized that there are several subtypes of dopaminergic receptors. D, receptors are believed to be linked to stimulation of the enzyme adenylate cyclase, whereas D2 receptors are not linked or negatively linked with adenylate cyclasc. A D, autoreceptor has also been proposed [6,7,9]. I t should be noted that the exact interrelationship between D, and D2receptors remains unclear; however, it is theorized that activation of both receptors is necessary for full expression of dopaminergically mediated motor behaviours [lo, 1 I]. Functionally, dopaminergc systems have been theorized to be involved with behaviour, motor control, hypothalamic function and arousal [8]. Noradrenergc cell bodies in the C N S are found in the locus ceruleus and lateral tegmental nuclei, all in the pons and medulla. Noradrenergc axons innervate multiple structures, both caudally and rostrally, including the forebrain, medulla, spinal cord and cerebellum. Adrenergc cell bodies are found in the dorsal and lateral tegmentum in the lower brainstem and innervate limbic as well as spinal structures [ 5 , 7, 81. Noradrenergc and adrenergc systems act at both alpha receptors (alpha 1 and alpha 2) and beta receptors (beta 1 and beta 2) [9]. Functionally, central noradrenergic pathways have been postulated to be involved with sleep/wake cycle regulation, learning and memory, anxiety-nociception, bchavioural vigilance and affective disturbance. There is little known about the functional role of adrenergx systems within the C N S [ 8 ] . Serotonergc cell bodics are also confined to the brainstem, mostly within the raphe nuclei. These axons project into the forebrain, cerebellum and spinal cord [ 5 , 7, 81. Multiple subtypes of CNS serotonergc receptors have been identified [9]. Functionally, scrotonergic systems have been theorized to be involved with arousal, sleep/wake cycle regulation, mood and emotion including aggression, feeding, thermoregulation, ataxia and wxual bchaviour IS], Pcptidergc neurons have recently been the focus of intense research with regard to their potential role as putative neurotransmitters. In recent years, the opioid peptides and

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their precursors have probably received the most attention of all the neuropeptides secondary to their role in stress and pain mediation within the CNS. These neurochemical systems, including beta-endorphins, enkephalins and dynorphins, have their cell bodies in deeper, more primitive regions of the brain such as the limbic system, reticular formation, medulla and hypothalamus [5, 7, 81. There are at least three subtypes of opiate receptors that have been proposed; specifically, mu, delta and kappa receptors [ 6, 91. Other CNS peptides which have been postulated to have a neurotransmitter or neuromodulator role include: substance P, vasopressin, oxytocin, somatostatin, and thyrotropin-releasing hormone to name just a few. The exact roles for all of the peptidergic substances have not been fully clarified [5-71. Amino acids are thought to be the most common of all putative neurotransmitters. Some of the more common amino acid neurotransmitters are gamma-aminobutyric acid (GABA) and glycine (both inhibitory), as well as glutamate and aspartate (both excitatory). GABA, which serves as an inhibitory neurotransmitter, is concentrated in Purkinje cells within the cerebellar cortex and in the striatum. GABA A receptors are postsynaptic, whereas GABA B receptors occur on presynaptic autonomic and central nerve terminals [6, 71. Functionally, gabaminergic systems have been theorized to be involved with the control of spinal reflexes, movement, anxiety states and epilepsy [8]. It was long assumed, in accordance with Dale’s principle, that one neuron secreted one neurotransmitter at all its terminals. However, we now know that there are several examples of neurons that contain and secrete more than one biologically active substance. In the CNS this most often takes the form of mixed monoamine and peptide neurons. The exact biological significance of this phenomenon is unclear, but is at present an active area of research given the obvious clinical treatment implications.

Overview of pharmacological agents by class Many pharmacological agents exist which may have potential utility in altering function following brain injury. Much of what is known regarding pharmacological rehabilitation of this patient population is based on theories derived from work done at the basic science level with animal models or from individual clinical experience. The peer-reviewed scientific literature, as it presently stands, does not provide much useful information regarding well-controlled, methodologically sound, prospective research data regarding this topic. Nevertheless, clinicians should be aware of the major pharmacological agents in each neurotransmitter class in order to better grasp how they may have an effect, positive or otherwise, on neurological recovery and functional capabilities following brain injury. Additionally, rehabilitation professionals should be familiar with the major side-effects of these drugs. Although drug interactions, precautions and contraindications must also be considered, these topics are beyond the scope of this paper. The reader is referred to the Physicians Desk Reference or an equivalent source [12] for this information.

Catecholaminergic agonists The major drugs in this class include L-dopa, amantadine, bromocriptine, pergolide, lisuride and some of the more ‘classic’ stimulant drugs such as dextroamphetamine, methylphenidate and pemoline. The ‘classic’ dopamine agonist has historically been levodopa (L-dopa). A combination formulation of L-dopa and carbidopa is also available. The use of the combination drug minimizes peripheral (non-CNS) side-effects of the drug and increases the amount available for CNS incorporation. L-dopa has its action pre-synaptically and is agonistic at

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both the D , and DZreceptor sites [13]. Side-effects are numerous, but the more frequent ones include dyshnesias, various bradykinetic episodes (ix. ‘on-off phenomena), psychiatric disturbances, gastrointestinal disturbances (nausea, vomiting, anorexia and slowing of gastric motility), as well as orthostatic hypotension [ 121. Carbidopa-levodopa is available in ratios of 1 : 10 (100 mg r-dopa to 10 mg carbidopa) and 1 : 4 (100 mg L-dopa to 25 mg carbidopa). Most patients with clear clinical evidence of dopaminergic deficiency will respond to a 1 : 10 ratio provided that the daily dosage of carbidopa is 70 mg or more. When the 1 : 4 ratio is used, the usual starting dose is 1 tablet 3 times a day, increasing by 1 tablet every 2 days up to a maximum dosage of 6 tablets daily. If the 1 : 10 ratio is used, the usual starting dose is 1 tablet 3 - 4 times per day, increasing by 1 tablet every 2 days, to a maximum of 8 tablets daily [12, 141. In addition to carbidopa, other enzyme inhibitors such as benserazide and r-deprenyl (a monoamine oxidase type B inhibitor) have been used in conjunction with L-dopa in an attempt to increase therapeutic efficacy 131. Amantadine hydrochloride has been utilized clinically as an antiviral agent, as well as an anti-Parkinsonian agent. Its exact mechanism of action is still not fully elucidated; however, it has been theorized to have a pre-synaptic action, as well as a possible post-synaptic action [13, 151. Some authors have speculated that amantadine may also increase central cholinergic and gabaminergc activity [16, 171. Therapy can be initiated at between 50 and 100 mg/day and increased to a maximum of 400 mg/day. Since the drug is not metabolized and is excreted unchanged in the urine, dosage adjustments must be mdde when there is concurrent decreased renal function, such as in the elderly or in patients with renal disease. Peripheral side-effects include but are not limited to peripheral oedema, lightheadedness, orthostatic hypotension, hot and dry skin, rash and livedo reticularis. Livedo reticularis is a discoloration of the skin which occurs in a reddish-blue to purple blotchy pattern. The reaction tends to occur after at least 1 month of treatment and it may occur more commonly at higher does. Livedo reticularis is totally benign and the medication does not need to be discontinued unless the cosmetic aspects outweigh the therapeutic benefit 113, 141. Central side-effects which are more commonly seen in the geriatric population include conbsion and hallucinations. It is also this author’s experience that Amantadine may lower seizure threshold even when given in ‘therapeutic’ doses. Due to the ‘indirect’ mechanism of action of L-dopa, researchers have pursued and developed several direct dopamine-receptor stimulating agents all of which happened to be of the ergot-alkaloid class. These direct agents include bromocriptine, lisuride and pergotide. Both bromocriptine and lisuride are antagonistic at the D, receptor and agonistic a t the D, receptor. Pergolide, on the other hand, is agonistic at both the D, and D, receptor sites. Bromocriptine mesylate tends to produce fewer problems with dyskinesias, but more problems with mental side-effects, orthostasis and neusea than L-dopa [ 131. Clinical results have demonstrated a triphasic response to bromocriptine, with dopamine agonism occumng only in the mid-range doses [14]. Dosing should start with a test does of 1.25 mg and, if tolerated, the patient can begin at a dose of 2.5 mg daily, increasing to a 3-4 times a day dose fairly quickly. Once at 10 mg/day, the dose can be increased every 4 days by 2.5 mg. Typically, clinical experience has chctated that doses higher than 60 mg/day are unnecessary in patients with acquired brain injury. As a point of interest, the manufacturer has not established safety limits for dosages greater than 100 mg/day 1121. Pergolide and lisuride are relatively new agents in this country and there is little or no literature on their utility in the pharmacologcal rehabilitation of the individual with brain injury. It should be noted that pergolide is an extremely potent dopamine agonist and only very small doses are required. In this author’s limited

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experience with pergolide, most patients with brain injury are unable to tolerate the drug secondry to sedation. Lisuride is also extremely potent and therapeutic effects are typically seen with daily doses ranging from 4 to 10 mg/day [13]. Most of the ergot alkaloids also have concomitant central serotonergic receptor agonism whch might explain the high incidence of mental status changes with this class of dopamine agonists. The classic ‘psychostimulant’ drugs include dextroamphetamine, methylphenidate, pemoline and, to a lesser extent, activating tricyclic antidepressants. These agents have typically been theorized to have mixed dopaminergic and noradrenergic agonist activity. Dextroamphetamine has been theorized to produce noradrenergic agonism via bloclung of the re-uptake mechanism for norepinephrine (noradrenalme). In higher doses, it is also dopaminergic via a similar mechanism of dopamine re-uptake blockade [7]. Dosing of dextroamphetamine should be initiated at 4 mg one or twice daily. The maximum recommended dose of dextroamphetamine is 60 mg/day [12], however, there are few or no data addressing dosing limits in individuals following brain injury. To avoid problems with insomnia, the last dose of medication should be given at least 6 hours before sleep. There is some evidence that ‘pulsed’ dosing of noradrenergic agonists via standard formulations, rather than extended release dosing, may be preferential with regard to the resultant psychostimulant effects. Generally, adults are fairly sensitive to psychostimulant therapy, particularly so after brain injury. Relative or absolute ‘toxicity’ may be manifested by anxiety, dysphoria, increased irritability, cardiovascular symptoms, headache, palilalia, sterotypical thoughts, cognitive impairment, hallucinations, insomnia, and motor disorders including dyslunesias, tics and worsening of spasticity [12, 181. Methylphenidate hydrochloride is a mixed dopaminergic-noradrenergic agonist whose pharmacological action is similar to amphetamines. The main sites of action appear to be the cerebral cortex and subcortical structures such as the thalamus. Dosing typically should be initiated at 5 mg twice a day and titrated up to a maximum dose of 60 mg/day. An extended release formulation is also available. The adverse effects of this drug are analogous to those of dextroamphetamine. Pemoline is an oxazolidinone derivative stimulant with pharmacological actions qualrtatively similar to dextroamphetamine and methylphenidate. Evidence suggests that pemoline may have its stimulatory effect via dopaminergic mechanisms. The drug is typically dosed initially at 37.5 mg daily as a morning dose, with increases of 18.75 mg made weekly as appropriate. The effective dose typically ranges from 56.25 mg/day to 75 mg/day. The most frequently encountered adverse effects include insomnia and anorexia, both being dose related.

Serotonergic agonists The major drugs in this class include trazodone hydrochloride, fluoxetine, buspirone and L-tryptophan. Trazodone hydrochloride is a triazolopyridine derivative that selectively inhibits serotonin uptake. Initial dosing should begin at low doses (50-150 mg), typically at bedtime with food. The dose should be on the lower end of the dosing range in geriatric patients secondary to more common side-effects such as sedation and orthostatic hypotension. The dose may be increased by 50 mg/day every 3-4 days, to a maximum of approximately 400 mg/day. If closely monitored, as in an inpatient setting, the maximum dose may be as high as 5 mg/kg/day. Fluoxetine is also a serotonin re-uptake inhibitor, but it tends to be more activating than other serotonergic drugs like trazodone. Initial dosing should be 20 mg/day given as a morning dose. Doses above 20 mg/day should be given on a twice a day schedule, with a maximum daily dose of no more than 80 mg. The

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N.D. ZasIer major reported side-effects include headache, nausea, nervousness and insomnia [ 19, 201. Buspirone is a novel benzodiazepine anxiolytic which is theorized to work through its serotonergc agonist activity at the 5-HT' receptor 112, 191. It should also be noted that this medication is pre-synaptically antagonistic at the D2 dopaminergic receptor [21, 211. The medication should be initiated at a dose of 10-15 mg/day in 2-3 divided doses and increased by 5mg every 2 3 days over 4-6 weeks to a maximum of 60 mg/day based on patient response and tolerance 112, 221. The main side-effects with buspirone are dizziness, headache, nervousness and lightheadedness [23]. L-tryptophan is a serotonergic precursor which has recently received much attention secondary to the incidence of eosinophilic myalga syndrome. This syndrome has been purportedly traced to a bad batch of this phannacologcal agent produced in Japan [24]. Its use remains barred for the present by thc Federal Drug Administration. Newer serotonergic uptake inhibiting drugs, which may prove of utility from a neurophannacologcal rehabilitative standpoint, include citalopram, fluvoxamine, paroxetine and sertraline. They are still under clinical investigation [25].

Opioid untapnists The two most commonly used opioid antagonists are naloxone and naltrexone, the latter b a n g preferred secondary to its oral route of administration and prolonged mode of action. Dosing typically starts low, with a 12.5 - 25 mg daily dose with titration up to 150 mg/day, with an average daily dose of 50 mg [12]. Exact dosing schedules and upper limits have not been well established in traumatic brain injury. The major side-effects relate to gastrointestinal complaints and hepatocellular injury. Gahamineyic agunirtr

A variety of pharmacological agents which are commonly used in the general rehabilitation setting fall into this category. I t should be noted, however, that only a few o f them can be recornmended for use in the patient with concomitant brain injury. Classic anti-spasticity agents such as Valium and baclofen are gabaminergc agents, GABA A and GABA l3, respectively. Many of the presently available anticonvulsant agents are also ga baminergic; specifically, valproate, barbiturates and benzodiazepines. Other commonly utilized anticonvulsants such as phenytoin and carbamazepine are felt to mediate their anticotivuisant effect through other neurochemical systems "261. From a clinical standpoint, many gabaminergic agents tend to be too sedating in the brain-injured patient, with concomitant suppression of cognitive processes. The use of these agents in the sub-acute and chronic phases following brain injury should be examined carefully given their potential side-effects 141. Valproic acid is typically dosed at 15 rng/kg per day. Dosages may be increased by 5-10 mg/kg per day at weekly intervals until clinical efficacy is achieved or adverse side-effects prevent further increases. Due to potential adverse gastrointestinal side-effects, it is recommended to administer the drug in two or more divided dosages. The maximum daily recommended dose is 60 mg/kg 1121. Side-effects are generally dose dependent.

Cholineyic ugunists Although vanous agents fall under this category, most o f them have fairly limited utility secondary to their lack of CNS specificity, poor ability to penetrate the CNS, short half-life and side-effect profile. Various drugs including direct agonists, acetylcholine precursors and acetylcholinesterase inhibitors have been utilized in an

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attempt to provide ‘cholinergic stimulation’ following brain injury. Newer drugs such as tetrahydro-9-aminoacridine (THA) may hold better promise than more standard drugs such as physostigmine.

Review of treatment options for specific clinical deficits

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Appetite dysregulation Alterations in appetite are not uncommon in patients with brain injury. The hyperphagic patient or ‘bulemic-type’ must be contrasted with the hypophagic or ‘anorectic-type’. Presumptive central neurochemical and neurophysiological mechanisms responsible for alterations in appetite regulation form the basis of drug treatment for these functional sequelae (271. The present consensus based on animal as well as human studies suggests that serotonergic agonists (trazodone, fluoxetine and fenfluramine), opioid antagonists (naltrexone) and possibly corticotropin releasing factor (CRF) may all inhibit feeding behaviour [28. 291. Central serotonergic antagonists such as cyproheptadine can be utilized when there are problems with anorexia/hypophagia [28]. The drug fenfluramine should probably not be prescribed until further studies examining its potential neurotoxic effects have been completed.

Ataxia Various forms of brain injury can result in cerebellar atoxia including trauma, stroke, tumour, degenerative conditions, and inherited ataxias such as Friedreich’s ataxia. Several authors have reported that the serotonergic precursor L-tryptophan can significantly improve cerebellar ataxia due to a variety of primary aetiologies [28, 30-321. Oral thyrotropin-releasing hormone also appears to be a promising agent [32, 331. Other agents that have been utilized with some success include propranolol, gamma-vinyl GABA, acetazolamide and phthalazinol [32]. Peterson and colleagues have reported good success with amantadine for Friedreich’s ataxia presumptively through either a dopaminergic or more likely a gabaminergic mechanism [16].

Autonomic dysregulation One of the most challenging clinical conditions to treat following severe CNS injury is that of autonomic dysregulation with associated symptoms of hyperthermia [34], diaphoresis, tachycardia and tachypnoea. There have been numerous neurochemical systems thought to be involved with central control of temperature regulation, but relatively speaking hypothalamic dopaminergic systems seemingly play a very significant role [35, 361. Hyperpyrexia following brain injury has been successfully treated at a central level with dopaminergic agonists [37, 381. Dantrolene sodium has also been utilized to help decrease peripheral systemic effects such as rigidity commonly associated with this condition.

Hemi-ina ttentiodneglect Ascending dopaminergic pathways have been experimentally implicated in mediation of attentional processes including hemi-spatial neglect. Two small studles have demonstrated a potential utility of dopamine agonists; specifically, bromocriptine in the treatment of

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neglect secondary to cerebrovascular accident [39] and traumatic brain injury [37].Both studies utilized an ABA paradigm and demonstrated significant differences in testing performance as well as hnctional capabilities while patients were receiving dopamine agonist pharmacotherapy. Further prospective studies are obviously warranted based on the encouraging results of these two studies.

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M o v e m e n t disorders A variety of movement disorders have been treated with some success following brain injury. These include dystonia, tremors, parkinsonism, tics, akathisia, myocionus, and dyslunesias such as chorea, ballismus and athetosis. Dystonia, whether focal, segmental or generalized, has been treated with a variety of agents but generally with mixed results. Dopaminergic agonists and antagonists, anticholinergcs, baclofen, benzodiazepines and carbamazepine have all been utilized in the treatment of this class of movement disorders (40, 411. Tremors are typically of the postural and/or kinetic type following traumatic brain injury, whereas resting tremors are typically seen with non-traumatic degenerative cerebral disorders resulting in dopaminergic deficiency. Pharmacological treatment tends to work better for non-traumatically induced tremor than for tremor resulting from trauma. A variety of drugs have been utilized, including beta-adrenergic blocking agents, benzodiazepines, dopaminergc agents, valproic acid and anticholinegics [42-44). Isoniazid has been used for treating cerebellar tremor related to multiple sclerosis [45]. O n e must always consider drug-induced tremor as a result ofiatrogenic prescription and/or patient use ofnicotine [46]. Parkinsonism, when a result of trauma, can generally be treated fairly well with pharmacologcal intervention. Numerous authors have reported parkinsonian-like symptoms following diffuse brain injury such as bradykinesia, dysarthria, decreased facial expression and rigidity [47-503. Drugs that have been shown to be effective for ‘post-traumatic parkinsonism’ include dopaminergc agonists and to a lesser extent anticholinergics [48]. Tics are a rare consequence of acquired brain injury [40,41]. The drugs used to treat tics include gabaminergic agonists, dopamine antagonists and, to a lesser extent, noradrenergc drugs such as clonidine [41]. Akathlsia has been reported following brain injury and is thought to be associated in animal models with a relative dopaminergic deficiency in the prefiontal area (511. Successful treatment of akathisia after brain injury with bromocnptine has been reported [52]. Other drugs that have been utilized but with fairly limited success include benzodiazepines and beta-adrenergic blockers [53]. Myoclonus is a common sequela of severe hypoxic ischaemic brain injury, but can also be seen after non-hypoxemic brain injury. Cortical myoclonus must be differentiated from epilepsy partialis continua [54]. A variety of drugs including benzodiazepines (clonazepam), semtonergic agonists such as trazodone and L-tryptophan valproic acid, primidone and piracetam have all been reported effective [55-571. Dyskinesias can occur in a variety of conditions and be manifested as ballismus, chorea o r athetosis. These types of movement disorders can result fiom thalamic and/or striatal injury as a result of trauma. Typically, the drugs that have shown some utility for dyskinesias associated with traumatic brain injury include dopaminergc antagonists, as well as a variety of anticonvulsants including carbamazepine, phenobarbital, valproic acid and phenytoin (40, 58-60]. It should be noted that certain dyskinesias may actually be atypical presentations of post-traumatic epilepsy.

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Neurogenic heterotopic ossijication

The only pharmacological therapies at present available to minimize the extent of morbidity associated with neurogenic heterotopic ossification following brain injury involve the use of etidronate disodium [61] and non-steroidal anti-inflammatory agents (NSAIDs). Didronel presumptively works by interfering with biological calcification; specifically, impairing the calcification of osteoid. When there is still an acute phase to the condition, NSAIDs have been advocated to decrease the suspected inflammatory component of this pathologcal process. Didronel therapy is typically initiated at 20 mg/kg and the dose is subsequently Iowered afier several weeks to months to 10 mg/kg. There are no well-controlled, prospectively sound trials examining the use of this agent in ‘homogeneous’ brain injury populations; therefore, many, if not all, of the recommendations are based on the spinal cord injury literature. The main side-effect of the medication involves gastrointestinal complaints in the form of diarrhoea and nausea. Seizure disorders

At the present time, most neurosurgeons in the USA use either phenytoin or phenobarbital for early management of seizures and/or seizure prophylaxis, due to the fact that these medications can be administered parenterally (by intravenous route in the acute care setting). It is still quite unclear as to the exact utility of prophylactic anticonvulsant agents in the prevention versus suppression of late post-traumatic seizures [62-64]. There is now a trend within the field of brain injury rehabilitation to advocate for the utilization in the post-acute setting of specific anticonvulsants following brain injury (traumatic or non-traumatic); specifically, carbamazepine and valproic acid [65-671. In general, carbamazepine should be a first-line agent for treatment of partial seizures, whether simple or complex. O n the other hand, valproic acid should be the agent of choice for multi-focal epilepsy and generalized tonic-clonic seizures. It should be noted that valproic acid has been reported to be associated with encephalopathy and alterations in consciousness most likely secondary to hyperammonaemia [68-701. Obviously, side-effects of the various anticonvulsant medications must be taken into consideration, particularly with patients with altered levels of consciousness and/or significant cognitive impairment. Various studies have demonstrated significant negative effects on cognitive function secondary to phenytoin and phenobarbital [71-731. There is a recent study questioning this general consensus opinion [74], bringing to light the need for further research in this area. A variety of newer agents such as oxcarbazepine, flunarizine, lamotrigine and others are presently being studied in an attempt to develop more effective drugs with fewer cognitive and systemic side-effects [75]. Speech-language disorders

A number of different medications have been used successfully for a variety of speech-language disorders in patients with brain dysfunction. Bromocriptine has been reported to improve speech dysfunction in patients with diffuse brain injury following trauma, with dosages ranging from 20 to 40 mg/day [76]. Another series of studies demonstrated the efficacy of bromocriptine in the treatment of dysphasia; specifically, the

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transcortical niotor variant [77,781. Animal studies have yielded some support for the role of dopaminergc pathways in both spontaneous and reflex swallowing [79, 801, leading to human studies supporting the potential efficacy of DA agonist therapy for dysphagia following brain injury utilizing L-dopa/carbidopa [81]. Parkinsonian hypokinetic dysarthria has been treated with low dose clonazepam (0.25 - 0.5 mg/day); the presumptive mechanism for its efficacy being striatal gabaminergic agonism [82].Lastly, a case o f post-traumatic adult onset stuttering responsive to anticonvulsant treatment has been reported, suggesting that ictal speech disorders should always be considered in this patient population [83].

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Srsiral dy+nctiorr It is not uncommon for persons to have problems in the area of sexuality following brain injury. One of the most common complaints is alteration in libido [ l , 841. Hyposexuality can be treated pharmacologcally with a number of different agents, including activating antidepressants, yohimbine (a noradrenergic agonist), dopamine agonists and hormonal supplementation [ 85-88]. Hypersexuality, on the other hand, is a relatively rare clinical condition which is more difficult to broach from a pharmacotherapeutic standpoint. Hornional agents, specifically medroxyprogesterone acetate, have been utilized to ‘chemically castrate’ individuals with severe hypersexuality problems [89-921. For patients who have bi-temporal involvement and associated hypersexuality, as seen in the Kluver-Bucy syndrome, carbamazepine is generally considered to the treatment of choice 1931. Other agents that may hold potential utility for treatment of the hypersexual patient following brain injury include serotonergc agonists, gabaminergc agonists and opioid agonists [94].There are obviously significant ethical and medicolegal ramifications to the utilization of agents affecting sexual drive in this population.

Conclusions It is obviously o f great import for rehabilitation professionals treating individuals with brain injury to appreciate the potential benefits of pharmacotherapeutic interventions, if we are to truly maximize neurological and functional outcome. It is critical, therefore, to have a good understanding of CNS neurochemical systems, both anatomically and physiologically, as well as basic pharmacologcal issues prior to instituting any type of pharmacolopal therapies in this patient population.

Acknowledgements This work was partly supported by Grants #H133B80029 and #G0087C219 from the National Institute on Disability and Rehabilitation Research, United States Department of Education.

References 1. CHAVAW, J. A.: Kble des causes occasioncllcs dam Ic di-t6miinisme du ramolissemcnt cerCbral (reflections thkrapeutiques a Ic propos). Pratique ntidicalefranpise, 7: 285-295, 1928. 2. SCICLOUNOFF,F.: L’acetylcholine dans le traitcment dc I’ictus hemipltgique, Presse midicak, 42: 1110, 1934.

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