Inpharma 1327 - 2 Mar 2002

Adjuvant therapy in stroke rehabilitation– Cameron Johnston –

Given that only 2–3% of patients with acute stroke in the US are treated with antithrombolytic therapy – it maybe as high as 5–6% per cent in some teaching centres – it is an unfortunate reality that most patients emerge fromthe experience with at least some degree of deficit. This means that a significant part of the recovery from strokewill take place in the rehabilitation setting. At the annual meeting of the American Stroke Association [SanAntonio, US; February 2002], stem cells, growth factors, amphetamines and even a drug used to treat Down’ssyndrome were all offered as potential adjuvants that could be used to aid rehabilitation of the stroke patient.However, whether these agents are truly useful is not clear from the data that were presented.

Dr Seth Finklestein, an associate professor of human umbilical cord blood cells will survive, migrate,neurology at Harvard Medical School, Boston, US, said and improve functional recovery when injected into thethat part of the brain’s recovery process involves an brains of mice in which a stroke has been induced.endogenous pool of stem cells and precursor, or Conflicting medicationsprogenitor cells within the brain, particularly in the Because the management of acute stroke is ansubventricular zone. When the brain is injured, the ‘infinitely complex’ process, and frequently involvesprogenitor cells proliferate and migrate to the site of caregivers in more than one department at a hospital, orinjury where some of them differentiate into neurons even in more than one institution, it is not uncommonand neuroglia. Basic fibroblast growth factor (bFGF) is a for stroke patients to receive conflicting medications,protein synthesised by cells which has been shown to said Dr Larry Goldstein from Duke University Medicalenhance the proliferation of those stem cells on the School, Durham, US. 1ipsilateral side of the infarct. With these two points in As for the use of amphetamines in the rehabilitationmind, the question was raised as to whether either setting, he said, this is a case where there simply is notprogenitor/stem cells or growth factors could be used as enough conclusive evidence to justify their use –exogenous sources to stimulate ‘re-wiring’ within the although it is difficult to say that they should not bebrain. used, either. Much of the present rationale for usingbFGF, neural stem cells enhance recovery amphetamines comes from a trial done in 1988 that

In a rat model, involving a cortical infarction in the involved a small number of patients who were treatedsuperficial striata, it was shown that bFGF administered with a single dose of methylphenidate 10mg.2 The drugwithin 4 hours of the onset of the infarct could decrease initially appeared to be beneficial, although this benefitinfarct volume, Dr Finklestein explained. However, if the wore off with time. Nonetheless, the use ofgrowth factor was administered intracisternally 1 day amphetamines became fairly common for strokeafter the onset of the infarct, the infarct itself would not patients, and remains so in many settings, a fact that Drbe smaller, but functional recovery of the affected limbs, Goldstein calls ‘a terrible extrapolation of very limitedand neural sprouting on both sides of the brain appeared data’.to be enhanced. Since then, two subsequent studies investigating

Neural stem cells also appear to have an effect in methylphenidate have failed to show any benefit whenenhancing post-stroke recovery, at least in animals. In a the drug was used as adjuvant therapy.3 Two otherstudy in which mice (n = 10 per treatment group) were studies did demonstrate some benefit, although theadministered cultured mouse neural cells (1MU) sample sizes were small, and according to Dr Goldstein,intracerebrally, or bFGF (0.5µg) injected directly into the the benefit did not stand up under ANOVA repeated-cisterna magna, or a combination of the two, a measurement testing.4, 5 ‘The same data analyzednoticeable, though nonsignificant improvement was differently means we have to be very careful not to jumpseen in a number of functional parameters. Although on them just because a paper reports a statisticallythere was some spontaneous recovery in the fore-limb significant benefit from looking at the data in one way’,and hind-limb placing tests, recovery was even greater he said.among mice treated with either neural stem cells or ‘Smart drugs’ also controversialgrowth factor. The mice given combination therapy Also controversial in rehabilitation therapy are so-showed even greater improvement. Similarly, on a called ‘smart drugs’, or nootropic agents such asspontaneous limb-use test, the combination therapy piracetam, that have been reported to enhance certainenhanced recovery, while the individual adjuvants did brain functions including learning and memory.not. On the body-swing test, the groups of animals that Piracetam is a cyclic derivative of γ-aminobutyric acid,received growth factor alone, or combination therapy which has been used for years, with a great deal ofshowed a beneficial effect. controversy, in the treatment of children with Down’sAlthough these results are highly preliminary, Dr syndrome.Finklestein said that they are reproducible. However, he Dr Wolf-Dieter Heiss from the University of Cologne,said that he could not explain the mechanism of action. Germany, said that 70 000 new cases of aphasia are‘We don’t know what happens to the stem cells, where caused by stroke each year in Germany. These resolvethey go and what they turned into. We can show that spontaneously in approximately 28% of patients, 10%they have an effect. Now we’re trying to show what the show no change, and 60% are left with some deficit.mechanism might be’, he said. Dr Finklestein added that These patients represent an important segment of thehuman umbilical cord cells are also being used population who could benefit from adjuvant therapy, heexperimentally, and though he was unable to discuss commented. In a study conducted by Dr Heiss anddata from his studies at ViaCell Inc., where he is also an colleagues in Cologne, 24 patients with mild-to-investigator, he said it has been demonstrated that IV

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Adjuvant therapy in stroke rehabilitation – continuedmoderate aphasia were randomised to receive lot can change between the bench and the bedside.piracetam 2400 mg twice daily or placebo, in addition to Amphetamines appear to work in some studies, but notspeech therapy, over a period of 6 weeks.5 Those who in others; at least they are inexpensive, and do notreceived piracetam fared significantly better than those appear to be overtly harmful. Piracetam, too, is awho received placebo. The data also showed a product that may or may not be beneficial. It is beingsignificantly greater increase in activation in the brain of sold without prescription by mail-order drugthose patients who received piracetam, compared with warehouses, and for that reason, it may be unlikely thatthose who received placebo, and an improvement in 6 any drug company will choose to fund any randomised,language function tests among piracetam recipients, placebo-controlled clinical trials in support of its morecompared with 3 in the placebo group. A 2001 Cochrane widespread use.study has also examined speech and language Unless there is a significant breakthrough in the nearrehabilitation with pharmacotherapy and concluded that future with stem cell and growth factor technologies,piracetam was the only agent with any beneficial effect, adjuvant therapy appears to be a questionableDr Heiss said. therapeutic option in the stroke rehabilitation setting.

1. Goldstein LB. Stroke recovery. Reply. Neurology 46: 1187-1188, Apr 1996.Conclusion2. Huber W, et al. Piracetam as an adjuvant to language therapy for aphasia: aWhile adjuvant therapy is clearly justified for stroke randomized double-blind placebo-controlled pilot study. Archives of Physical

Medicine and Rehabilitation 78: 245-250, Mar 1997.patients in the rehabilitation setting, the questions raised3. Walker-Batson D, et al. A double-blind, placebo-controlled study of the use ofin presentations at the Stroke meeting suggest that

amphetamine in the treatment of aphasia. Stroke 32: 2093-2098, Sep 2001.much still needs to be done to improve the efficacy of 4. Walker-Batson D, et al. Amphetamine paired with physical therapy accelerates

motor recovery after stroke: further evidence. Stroke 26: 2254-2259, Dec 1995.existing agents – or to find more efficacious agents5. Kessler J, et al. Piracetam improves activated blood flow and facilitatesaltogether. rehabilitation of poststroke aphasic patients. Stroke 31: 2112-2116, Sep 2000.

Stem cell technology might be attractive, but is still at 800888172

the animal modelling stage – and, as any investigatorwho has ever studied neuroprotective agents knows, a

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