1129 EDITORIALS Treatment for stroke? Outcome after an ischaemic stroke is related to the volume of infarction measured by computed tomographic (CT) scanning.1 If a treatment achieved the modest aim of reducing this volume by even 20 %, a substantial amount of disability would be prevented. This is the ultimate goal of researchers seeking to unravel the pathophysiology of cerebral infarction. Hopes for salvaging ischaemic brain after cerebral artery occlusion depend on the perception of cerebral infarction as a process rather than an event. In studies of cerebral blood flow and metabolism in cerebrovascular disease, notably with positron emission tomography (PET), a series of compensatory mechanisms follow reduction of cerebral perfusion pressure.2 Initially vasodilatation (demonstrable as focally increased cerebral blood volume) prevents any fall in cerebral blood flow. Areas of brain with exhausted vascular reserves may be recognised by nuclear medicine methods that are not dependent on PET technology--eg, single photon emission tomography. Other isotopic methods that measure mean cerebral transit time depend on still more widely available equipment and may be more applicable in clinical trials.3 3 Even when the cerebrovascular reserve is exhausted and cerebral blood flow falls, adequate energy supplies may be provided by increased oxygen extraction, maintaining the cerebral metabolic rate for oxygen until further falls of cerebral perfusion pressure overcome homoeostatic mechanisms and the ischaemic process begins. Our understanding of cerebral ischaemia is founded on the concept of ischaemic thresholds and the "ischaemic penumbra" developed by Astrup and colleagues.4 At various levels of cerebral blood flow below 20 ml/100 g per min a hierarchy of functional disruption starts. First there is failure of neuronal electrical (and therefore clinical) function; at flows below 15 ml/ 100 g per min there is progressive failure of the energy-dependent ionic pumps that maintain the internal milieu of the neurons; and below 10 ml/100 g per min there is a dramatic flux of ions across the neuronal membrane and a cascade of destructive events leading to irreversible cell death. Oxygen deficiency via ischaemia prevents oxidative phosphorylation, which curtails ATP production, thereby impairing ion or neurotransmitter transport across cell membranes and protein biosynthesis. ATP poverty is especially destructive in its effects on the intricate control over calcium ion entry and distribution within cells.’ The uncontrolled calcium entry into neurons and their mitochondria associated with homoeostatic failure activates destructive lipases, proteases, and endonucleases. During this calcium- triggered cascade, highly reactive free-radical species (atoms or molecules with an unpaired electron in their outer orbit) are released, probably contributing to ischaemic damages If there is supply of glucose to ischaemic brain, some ATP can be produced by anaerobic metabolism, but this process generates hydrions. Acidosis exacerbates the ischaemic process, including free-radical generation. Hydrogen ion extrusion via a Na + !H antiporter is one regulator of intracellular pH, but consequent entry of sodium ions exacerbates cell swelling if it is accompanied by failure of the energy-dependent sodium pumps. Hydrogen ion entry into neurons probably also displaces calcium from intracellular binding sites, further enhancing cellular damage. The role of the excitatory neurotransmitter glutamate in the ischaemic process excited much interest after the observation that in ischaemia there is an increase in extracellular glutamate. This increase may be caused by inappropriate entry of calcium into presynaptic terminals, probably with impairment of the ATP-requiring reuptake of glutamate into neurons and astrocytes. On the postsynaptic membrane are three main subtypes of glutamate receptor, activated selectively by N-methyl-D- aspartate (NMDA), kainate (K), and quisqualate (Q), respectively. The K and Q receptors operate a conductance channel for monovalent ions that allows Na to enter in exchange for K +. The NMDA receptor operates a Ca + channel which is blocked by Mag+ in a voltage-dependent manner. This receptor is also subject to inhibitory modulation by glycine. Depolarisation of the neuron allows calcium entry via the NMDA gated channel and amplifies the ischaemic cascade. Neurons that are especially sensitive to ischaemia--eg, the cornu Ammonis 1 pyramidal cells of the hippocampus-have a high density of glutamate receptors. If the cause of ischaemic stroke is cerebral arterial occlusion, why not open up the vessel, either surgically or with thrombolysis? Unfortunately this
Transcript
1129
EDITORIALS
Treatment for stroke?
Outcome after an ischaemic stroke is related to thevolume of infarction measured by computedtomographic (CT) scanning.1 If a treatment achievedthe modest aim of reducing this volume by even 20 %,a substantial amount of disability would be prevented.This is the ultimate goal of researchers seeking tounravel the pathophysiology of cerebral infarction.Hopes for salvaging ischaemic brain after cerebral
artery occlusion depend on the perception of cerebralinfarction as a process rather than an event. In studiesof cerebral blood flow and metabolism incerebrovascular disease, notably with positronemission tomography (PET), a series of
compensatory mechanisms follow reduction ofcerebral perfusion pressure.2 Initially vasodilatation(demonstrable as focally increased cerebral bloodvolume) prevents any fall in cerebral blood flow. Areasof brain with exhausted vascular reserves may be
recognised by nuclear medicine methods that are notdependent on PET technology--eg, single photonemission tomography. Other isotopic methods thatmeasure mean cerebral transit time depend on stillmore widely available equipment and may be moreapplicable in clinical trials.3 3 Even when thecerebrovascular reserve is exhausted and cerebralblood flow falls, adequate energy supplies may beprovided by increased oxygen extraction, maintainingthe cerebral metabolic rate for oxygen until furtherfalls of cerebral perfusion pressure overcome
homoeostatic mechanisms and the ischaemic processbegins.Our understanding of cerebral ischaemia is founded
on the concept of ischaemic thresholds and the"ischaemic penumbra" developed by Astrup andcolleagues.4 At various levels of cerebral blood flow
below 20 ml/100 g per min a hierarchy of functionaldisruption starts. First there is failure of neuronalelectrical (and therefore clinical) function; at flowsbelow 15 ml/ 100 g per min there is progressive failureof the energy-dependent ionic pumps that maintainthe internal milieu of the neurons; and below 10
ml/100 g per min there is a dramatic flux of ions acrossthe neuronal membrane and a cascade of destructiveevents leading to irreversible cell death.Oxygen deficiency via ischaemia prevents oxidative
phosphorylation, which curtails ATP production,thereby impairing ion or neurotransmitter transportacross cell membranes and protein biosynthesis. ATPpoverty is especially destructive in its effects on theintricate control over calcium ion entry anddistribution within cells.’ The uncontrolled calcium
entry into neurons and their mitochondria associatedwith homoeostatic failure activates destructive lipases,proteases, and endonucleases. During this calcium-triggered cascade, highly reactive free-radical species(atoms or molecules with an unpaired electron in theirouter orbit) are released, probably contributing toischaemic damages If there is supply of glucose toischaemic brain, some ATP can be produced byanaerobic metabolism, but this process generateshydrions. Acidosis exacerbates the ischaemic process,including free-radical generation. Hydrogen ionextrusion via a Na + !H antiporter is one regulator ofintracellular pH, but consequent entry of sodium ionsexacerbates cell swelling if it is accompanied by failureof the energy-dependent sodium pumps. Hydrogenion entry into neurons probably also displaces calciumfrom intracellular binding sites, further enhancingcellular damage.The role of the excitatory neurotransmitter
glutamate in the ischaemic process excited muchinterest after the observation that in ischaemia there isan increase in extracellular glutamate. This increasemay be caused by inappropriate entry of calcium intopresynaptic terminals, probably with impairment ofthe ATP-requiring reuptake of glutamate intoneurons and astrocytes. On the postsynapticmembrane are three main subtypes of glutamatereceptor, activated selectively by N-methyl-D-aspartate (NMDA), kainate (K), and quisqualate (Q),respectively. The K and Q receptors operate a
conductance channel for monovalent ions that allowsNa to enter in exchange for K +. The NMDA
receptor operates a Ca + channel which is blocked byMag+ in a voltage-dependent manner. This receptoris also subject to inhibitory modulation by glycine.Depolarisation of the neuron allows calcium entry viathe NMDA gated channel and amplifies the ischaemiccascade. Neurons that are especially sensitive to
ischaemia--eg, the cornu Ammonis 1 pyramidal cellsof the hippocampus-have a high density of glutamatereceptors.
If the cause of ischaemic stroke is cerebral arterial
occlusion, why not open up the vessel, either
surgically or with thrombolysis? Unfortunately this
1130
may cause haemorrhagic transformation of blandinfarctions in which the vascular endothelium is made
leaky by ischaemia. Furthermore, after ischaemia ofsome duration, swelling and local thrombosisactivated during the ischaemic cascade may preventreflow.8 Opening up vessels--eg, with the
thrombolytic agent human tissue-type plasminogenactivator-might help if patients are at the criticalstage of cerebrovascular reserve exhaustion before theischaemic process has started. Ischaemic brain mayneed additional protective therapy before blood flow isrestored; restoration occurs spontaneously in manyarterial occlusions.9How much time is there to salvage ischaemic brain
before cell death becomes inevitable? Some braintissue in the territory of an occluded artery mayreceive enough blood via anastomotic channels tomaintain flow above the level of complete ionic pumpfailure but below that required for electrical function.This is the ischaemic penumbra. Experimentalevidence suggests that metabolic failure may occur ifthis precarious flow is not reversed within 3-4 hours. 10The central zone of the arterial territory is denselyischaemic and infarction will occur within 60 minutes,probably before therapy could be initiated. At theedge of the territory (probably more patchily than theexpression penumbra suggests) tissue may be
salvageable. Therapeutic intervention needs to be wellorganised since it is unusual for patients with stroke tobe assessed in hospital within 6 hours, althoughFieschi et al9 have shown that this is possible.Are there any agents that might halt the ischaemic
process before infarction becomes inevitable? Amongthe possibilities are. NMDA receptor blockers,calcium ion channel blockers such as nimodipine,other calcium overload blockers such as
flunarizine, and free radical scavenging agents (eg,21-aminosteroids). Non-competitive NMDA
antagonists such as MK-801 reduce the size ofischaemic lesions in laboratory animals with middlecerebral artery occlusion. Trials of NMDA
antagonists in stroke will be organised if side-effectscan be overcome." Results of small trials with
nimodipine in cerebral infarction have been
encouraging. 12Various simple aspects of treatment help to reduce
the size of cerebral infarction after stroke. Lacticacidosis in the ischaemic penumbra can be diminishedby maintaining normal blood glucose concentrations.There is clinical evidence that hyperglycaemia mayincrease the size of cerebral infarction and impairoutcome." Most experimental evidence suggests thathyperglycaemia increases the size of cerebral
infarction, although there is some confusion relating inpart to the type of ischaemia studied. In end-arteryocclusion the osmotic effects of hyperglycaemia(reducing cerebral swelling) may outweigh the adverseeffects of lactic acidosis. In ischaemic areas that are still
partly supplied by anastomotic circulation, the lacticacidosis produced by hyperglycaemia worsens the
infarction, outweighing any osmotic advantage. 14There is evidence from work on a rat forebrainischaemia model that insulin infusion to maintain lownormal glucose levels protects brain function.15J6
Blood pressure is usually high after an ischaemicstroke but falls during the first weeks In theischaemic penumbra, pressure-flow autoregulationfails and flow is related linearly to pressure, so it is wiseto leave the blood pressure high. However, more workis required to examine the behaviour of blood pressureafter stroke and the effects of its manipulation. If theblood pressure is low through hypovolaemia, it can berestored by colloid replacement. Colloids may alsoconfer some rheological benefit, improving bloodviscosity (and therefore flow at low shear rates) in theischaemic penumbra, although trials of haemodilutiontherapy have been disappointing.18What of the swelling of ischaemic brain which
further jeopardises flow in the ischaemic penumbra?Ischaemic oedema is a complex mixture of cytotoxicoedema (part of the ischaemic cascade) and vasogenicoedema from loss of integrity of the blood brainbarrier at endothelial tight junctions. That the
vasogenic component of ischaemic oedema is pressuredriven but peaks later than cytotoxic oedema may beimportant for early blood pressure management.Trials of hyperosmolar agents have in general beendisappointing, though one study of glycerol suggestedsome effect on survival. 19 Steroids, even in high doses,seem to have no beneficial effect20 and may haveadverse effects upon ischaemic neurons.21
All therapies for stroke care require careful yetprompt assessment of patients. Many countries willhave to improve their systems of stroke care
considerably if the potential of any of these newtherapies is to be fulfilled.
1. Allen CMC. Predicting outcome after acute stroke: role of computedtomography. Lancet 1985; ii: 464-65.
2. Powers WJ, Press GA, Grubb RL, et al. The effect of hemodynamicallysignificant carotid artery disease on the hemodynamic status of thecerebral circulation. Ann Intern Med 1987; 106: 27-35.
3. Gibbs JM, Wise RJS, Leenders KL, Jones T. Evaluation of cerebralperfusion reserve in patients with carotid artery occlusion. Lancet 1984;i: 310-14.
4. Astrup J, Siesjo BK, Symon L. The state of penumbra in the ischemicbrain: viable and lethal threshold in cerebral ischemia. Stroke 1981; 12:723-25.
5. Siesjö BK, Bengtsson F. Calcium fluxes, calcium antagonists and calciumrelated pathology in brain ischemia, hypoglycemia and spreadingdepression: a unifying hypothesis. J Cereb Flow Metab 1989; 9: 127-40.
6. Schmidley JW. Free radicals in central nervous system ischemia. Stroke1990; 25: 7-12.
7. Rothman SM, Olney JW. Glutamate and the pathophysiology ofhypoxic-ischemic brain damage. Ann Neurol 1986; 19: 105-11.
8. Hossman KA. Haemodynamics of post-ischemic reperfusion of thebrain. In: Weinstein PR, Faden AI, eds. Protection of the brain fromischemia. Baltimore: Williams & Wilkins, 1990: 21-36.
9. Fieschi C, Agentino C, Lenzi GL et al. Clinical and instrumentalevaluation of patients with ischaemic stroke within the first six hours.J Neurol Sci 1989; 91: 311-22.
10. Collins RC, Dobkin BH, Choi DW. Selective vulnerability of the brainnew insights into the pathophysiology of stroke. Ann Inter Med 1988;110: 992-1000.
11. Albers GW, Golderg MP, Choi DW. N-methyl-D-aspartate antagonists:ready for clinical trial in brain ischemia? Ann Neurol 1989; 25: 398-403.
12. Gelmers HJ, Gorter K, de Weerdt CJ, Wiezer HJ. A controlled trial ofnimodipine in acute ischemic stroke. N Engl J Med 1988; 318: 203-07
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13. Pulsinelli WA, Levy DE, Sigsbee B, et al. Increased damage after strokein patients with hyperglycemia with or without established diabetesmellitus. Am J Med 1983; 74: 540-44.
14. Ginberg MD. Glycolytic metabolism in brain ischemia. In: WeinsteinPR, Faden AI, eds. Protection of the brain from ischemia. Baltimore:Williams & Wilkins, 1990: 21-36.
necessary for linear growth; the hormone continues tobe secreted in adult life but for what purpose isunclear. GH secretion is pulsatile but decreases withage-integrated GH levels are 30% lower after the ageof 55 than they are during the third decade. Thisdecline in GH is matched by a decline in circulatinglevels of insulin-like growth factor 1 (IGF-1), whichmediates many of the actions of GH.1
Is this decline in GH and IGF-1 important inhuman ageing? Ageing is associated with a decrease inmetabolic rate and changes in body composition--eg,decrease in muscle mass, relative increase in adiposetissue, and decrease in skin thickness. Exercise
performance declines. GH deficiency in early lifeleads to some of these changes.2 Thus lean body massand skin thickness are decreased and adipose tissuemass is increased in GH-deficient children; bodycomposition returns towards normal with GH
therapy.Studies of GH replacement in adults with GH
deficiency have provided information on the
physiological role of the hormone once linear growthis complete. GH was replaced by daily subcutaneousinjection at doses of 0-07 units/kg body weight or2 units/m2 in patients with either isolated GH
deficiency or GH deficiency as one of the componentsof hypopituitarism.-"-6 As in GH-treated children,therapy in adults resulted in an increase in lean bodymass and a decrease in adipose tissue mass. Total bodyweight was unchanged. Waist: hip ratio decreased.Muscle volume assessed by computed tomographyincreased, isometric muscle strength improved, andexercise capacity on a cycle ergometer increased.Resting metabolic rate rose, as would be expectedfrom the increase in muscle mass. Bone mineraldensity has been reported to increase after GH
therapy for 12 months in one study, although nosignificant change was observed after 6 months’treatment in another.8
These beneficial effects of GH in GH-deficientadults and the fact that secretion of the hormonedeclines with normal ageing aroused hopes that GHsupplementation might reverse some of the effects ofold age. Short-term experiments in elderly patientsshowed that GH led to a positive nitrogen balance andan increase in circulating concentrations of
osteocalcin, a marker of bone synthesis. In the firstmajor trial of supplementation in normal elderlypeople,1O GH at a daily dose of 0-03 mg/kgsubcutaneously three times weekly for 6 months toindividuals with initially low IGF-1 concentrationsresulted in circulating IGF-1 values in the youngadult normal range. Lean body mass increased by 9%,adipose tissue decreased by 14%, and there was asmall (7%) though statistically insignificant increasein skin thickness. Bone density of the lumbarvertebrae increased by 1-6%.These effects of GH supplementation will
undoubtedly stimulate more studies of its role inelderly people. Nevertheless, it is as well to rememberthat low GH levels are a feature of and not the cause ofhuman ageing. Young adults with GH deficiency arenot the same as old people. Complications of GHsupplementation in adult life remain to be clarified.Short-term side-effects of existing replacementregimens in GH-deficient adults include ankle
oedema, arthralgia, hypertension, and carpal tunnelsyndrome. Lower doses or a slow increase in dosagemay help to lessen these complications. The thriceweekly regimen used in normal elderly people seemedto be free of short-term side-effects, but data onlong-term effects will require years to accrue.The relation between GH status and vascular
disease is complex. Long-term hypopituitarism isassociated with an increased risk of death from
premature vascular disease, to which GH deficiencymay be a contributory factor.11 Increased serum
triglyceride and cholesterol and an increase inwaist: hip ratio, which occur in GH deficiency, are riskfactors for vascular disease. GH replacement maytherefore be beneficial and serum cholesteroldecreases with GH replacement in deficient adults.However, over-treatment may be harmful.
Acromegaly is associated with hypertension,cardiomyopathy, and a four-fold increased risk ofpremature death from vascular disease."," Fornormal elderly people, optimum treatment regimensand doses and means of monitoring therapy (totalcirculating IGF-1 concentrations are far from
perfect), and even the best injection sites are
unknown.
The possibility that GH treatment may increase therisk of cancer also needs long-term investigation.IGF-1 has mitogenic properties in addition to its
stimulatory effects on growth. Patients with
hypopituitarism have a lower than average risk ofdeath from cancer (although deaths overall are raised),whereas acromegaly in both men and women isassociated with an increased risk of malignant
