EDITORIAL 617 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.039982 on 15 April 2005. Downloaded from

EDITORIAL than in western white populations, but ...... this remains to be clarified. Only 6% of all particles (even the smallest) injected into the carotid in an experi- What causes lacunar ? mental model ended up in the lenticu- lostriate arteries, the rest going to the J M Wardlaw cortical arteries or their cortical branches.9 Studies that suggested stron- ...... ger associations between lacunar stroke and emboli cited carotid stenoses as mild as 25%16 or cardiac abnormalities not clearly associated with quarter of all ischaemic type of ischaemic stroke. Finally, some (for example, left ventricular hypertro- (a fifth of all strokes) are lacunar classifications, such as the Trial of Org phy),13 or they had no, or an inappropri- type.1 Lacunar infarcts are small 10172 in Acute Stroke Treatment ate control group. It would certainly be A 8 infarcts (2–20 mm in diameter) in the (TOAST) method actually use risk useful to be able to infer the likely deep cerebral white matter, basal gang- factors (such as embolic sources or underlying mechanism of lacunar lia, or , presumed to result from the ) to determine the stroke ischaemic stroke (that is, to identify occlusion of a single small perforating type, thus potentially biasing studies of the 10–15% of embolic/stenotic versus supplying the subcortical areas of differences in risk factors. Hence, inad- other intrinsic small vessel strokes) the .2 Although a recognised stroke vertent misdiagnosis of lacunar as cor- from the appearance of the brain lesion, subtype for over 50 years, the cause tical stroke, and vice versa, the paucity as that might help target effective of lacunar ischaemic stroke,2 and whe- of pathological material, and bias in secondary prevention regimens, but ther it is different to cortical ischae- some clinical classification systems may much more work is required to see mic stroke, remains under debate.34 have confounded previous pathology, whether different patterns actually Furthermore, lacunar stroke is not prognosis, and risk factor studies. exist, before determining how closely benign; 30% of patients are left depen- these relate to the underlying mechan- dent,5 and scant long term data suggest ism. IS THE CAUSE OF LACUNAR that up to 25% of patients have a second Hypertension and are said to DIFFERENT FROM CORTICAL stroke within 5 years.6 Therefore, the be strongly associated with lacunar ? prevention and treatment of this com- ISCHAEMIC STROKE ischaemic stroke. However, in studies The lacunar hypothesis supports the mon stroke subtype may be less than using risk factor free ischaemic stroke concept that lacunar ischaemic stroke ideal. subtype definitions, there was only a is due to an intrinsic cerebral small copyright. marginal excess of hypertension with arteriolar abnormality,2 in contrast to lacunar versus non-lacunar infarction PROBLEMS IN THE STUDY OF cortical ischaemic stroke, which is com- (RR 1.11; 95% CI 1.04 to 1.19) and no monly due to embolism from the heart LACUNAR STROKE difference for diabetes (RR 0.95; 95% CI Several factors have hampered the study or large arteries. Although some studies 0.83 to 1.09).10 Nor was there clear of lacunar stroke. Firstly, few patients suggest that many lacunar strokes are evidence of any association between die from lacunar stroke; if they do, caused by emboli, and while it is smoking, prior transient ischaemic death may occur long after the stroke, perfectly possible for a small embolus attack, excess alcohol consumption, or making autopsy material scant and to enter and occlude a lenticulostriate raised cholesterol in lacunar compared difficult to interpret, and the small artery,9 a systematic review of risk with non-lacunar infarction.10 cerebral vessels require meticulous dis- factors including only studies using

section. Studies of risk factors and subtype definitions for ischaemic stroke http://jnnp.bmj.com/ causation have predominantly used a free of risk factors found that atrial IS THERE OTHER EVIDENCE OF A clinical diagnosis of stroke type, prob- fibrillation and carotid were DIFFERENT MECHANISM IN ably resulting in some misclassification. associated more with non-lacunar than LACUNAR ISCHAEMIC STROKE? Although lacunar infarcts are associated lacunar infarction (relative risk (RR) of After lacunar ischaemic stroke, a recur- with specific neurological syndromes, lacunar versus non-lacunar infarction: rence is more likely to be lacunar then and most patients with a clinical lacu- 0.51, 95% confidence cortical; 47% of recurrences after a nar syndrome have a small deep sub- interval (CI) 0.42 to 0.62; ipsilateral lacunar stroke were lacunar compared

cortical infarct on brain imaging (if carotid stenosis 0.35, 95% CI 0.28 to with 15% of recurrences after a non- on September 23, 2021 by guest. Protected visible), 10–20% actually have a recent 0.44).10 Indeed, common causes of large lacunar stroke).19 If lacunar and cortical small cortical infarct in a location that artery (cortical) infarction, such as ischaemic strokes were due to the same explains their stroke presentation.7 emboli from the large arteries or mechanisms, then recurrent strokes Similarly, 10–20% of patients with a heart,11–13 or intracranial large artery would be equally likely to be cortical clinical mild cortical stroke actually atheromatous stenoses,12 appear un- after a lacunar stroke as lacunar, which have a recent relevant lacunar infarct likely to cause more than 10–15% of appears not to be the case. on imaging.7 Epidemiologically, these lacunar strokes.14–17 Perhaps lacunar Lacunar ischaemic stroke also appears patients behave more like the lesion infarcts due to emboli or middle cerebral to be more closely associated with white type on imaging than the clinical syn- artery stenoses are recognisable by being matter lesions (WMLs) than does cor- drome of the lesion they actually have.7 larger than non-embolic/stenotic tical ischaemic stroke. WMLs are abnor- Many studies have used an inappropri- lacunes,12 18 possibly because the embo- mal areas of hypodensity (on computed ate control group; age matched normal lus/stenosis occluded the origin of tomography scans) or hyperintensity controls can only indicate whether or several lenticulostriate arterioles simul- (on T2 weighted magnetic resonance not a particular risk factor is associated taneously. There is a suggestion that imaging (MRI)) in the deep hemi- with stroke, whereas identification of lacunar stroke secondary to middle spheric and periventricular white matter associations specific to lacunar stroke cerebral artery stenosis may be more and brain stem.20 They are in turn requires a control group with a different common in south Asian populations associated with cognitive decline,21 and

www.jnnp.com 618 EDITORIAL J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.039982 on 15 April 2005. Downloaded from increased risk of future stroke, particu- weak (RR 1.11; 95% CI 1.04 to 1.19).10 with microhaemorrhages (small blood larly lacunar type.22 WMLs also progress Thickened vessels may narrow or leaks).27 rapidly after lacunar stroke.23 After occlude the lumen, leading to ischae- Is there other evidence of endothelial lacunar stroke, 15–20% develop demen- mia, but relatively few truly occluded failure? Patients with isolated lacunar tia (more than might reasonably be vessels have been seen pathologi- infarction, or lacunar infarction plus attributed to the amount of brain cally.29 30 Thickened vessel walls may be WMLs, have elevated systemic plasma damage caused by a lacunar stiff and impair autoregulation, and markers of endothelial activation infarct).62124 After lacunar ischaemic indeed patients with WMLs may have (plasma intercellular adhesion molecule stroke, new ‘‘silent lacunar infarcts’’ impaired autoregulation.34 Some studies 1, thrombomodulin, and tissue factor occur on follow up imaging.25 found reduced cerebral blood flow pathway inhibitor) compared with age Asymptomatic small deep white matter (CBF) in patients with WMLs,35 but matched normal controls.43 However, in infarcts, in addition to the symptomatic others did not.36 CBF is difficult to the absence of non-lacunar controls, lesion, have been seen on MR diffusion quantify: ‘‘reduced’’ CBF may be arte- it is unclear if these patterns are specific imaging at presentation with lacunar factual,37 or simply the consequence of a to lacunar stroke. Several studies ischaemic stroke.26 The imaging appear- reduction in normal tissue to supply. have identified retinal microvascular ance of these asymptomatic lacunar None of this explains what starts the abnormalities that were associated with infarcts suggests that they are slightly vessel abnormality, only the features or increased risk of stroke, cognitive older than the presenting lesion. behaviour of the vessels and the possible impairment, and white matter lesions. Cerebral microhaemorrhages, which mechanisms for damaging the brain, Those most closely related to these are tiny, apparently asymptomatic once the abnormality is established. cerebral abnormalities (microaneur- bleeds (or ‘‘leaks’’) in the brain are also ysms, retinal haemorrhages, and soft associated with lacunar stroke and exudates) were most commonly seen WMLs.27 These observations suggest IF NOT OCCLUSION AND when there was breakdown of the that most lacunar strokes are the clini- ISCHAEMIA, THEN WHAT? blood–retinal barrier.45 Unfortunately cally focal manifestation of what is The underlying abnormal lenticulostri- most of these studies did not examine actually a diffuse abnormality of the ate artery can be seen in about 10% of stroke subtypes, so more work is small cerebral arterioles, which, if lacunar infarcts on detailed MRI scans.38 required. extensive enough, can also manifest Although this appearance could be an clinically as cognitive decline and intra-luminal thrombus (a small arter- SUMMARY dementia.28 iolar ‘‘hyperdense middle cerebral artery sign’’ equivalent), other features suggest The mechanism underlying, and the that blood products had passed into the long term consequences of, lacunar WHAT IS THE CEREBRAL SMALL ischaemic stroke, the cause of a quarter vessel wall and . The ? of all ischaemic strokes, are poorly copyright. VESSEL ABNORMALITY infarcts appear to be around, rather Detailed pathology studies in the 1950s understood, but are not benign. than at the end of the abnormal identified abnormal small deep perfor- Evidence supports the hypothesis that, segment. Lesions that resemble an ating (lenticulostriate) arteries resulting in most lacunar strokes, the vascular ‘‘incomplete’’ lacunar infarct (perivas- in lacunar infarcts,29 termed segmental abnormality is pathologically diffuse, cular oedema related lesions) at arterial wall disorganisation (since even if the clinical manifestations are autopsy39 suggest that the ‘‘infarct’’ called lipohyalinosis or fibrinoid necro- focal, and result from small vessel was actually due to oedema fluid leak- sis). In lipohyalinosis, the vessel wall endothelial damage, subtle increase in ing from the arteriole and damaging appears thickened, with focal dilation, blood–brain barrier permeability, and and eventually leads to disintegration of adjacent tissue. leakage of substances toxic to the brain the wall with an infarct around it. This Increased ‘‘leakage’’ of intravenously into the perivascular tissue. As originally injected MR contrast agent across the

arteriolar abnormality remains the most proposed in the lacunar hypothesis, only http://jnnp.bmj.com/ commonly described defect to date.30 31 blood–brain barrier have been found on a small proportion of lacunar stroke However, there is debate about the detailed MR imaging in patients with appears to result from artery to artery or 40 pathology and its relationship to symp- WMLs. There are numerous other cardiogenic emboli or intracranial large toms; many studies did not ascertain examples in a rather scattered literature artery stenoses. These latter embolic/ that the lesion seen at autopsy was pointing to ‘‘leaky’’ small arterioles stenotic lesions may be recognisable by symptomatic, some studied multiple predisposing to WMLs and lacunar their size (being larger). small ‘‘holes’’ in the brain regardless of ischaemic stroke, of which the following It might be questioned how this are but a few. Extravasated plasma symptoms, and many lesions came from presumably gradual process could pro- on September 23, 2021 by guest. Protected few patients.32 Lipohyalinosis is found in proteins have been found at autopsy in duce a sudden lacunar infarct. In fact, areas of the brain corresponding with WMLs in patients with ischaemic cere- lacunar stroke symptoms (more than 41 WMLs on imaging.33 brovascular disease in life. Discrete other stroke subtypes) not uncommonly The nature of the intrinsic arteriolar areas of extravasated plasma proteins progress after onset.44 Perhaps the inter- abnormality remains unresolved. It may have been seen around small cerebral stitial fluid composition eventually be microatheroma, poor cerebral blood arterioles in hypertensive primates.42 reaches a critically abnormal point flow, or vasospasm. It is difficult to see These combined observations suggest where the axons cease to transmit why would affect the small that the initiating step for most lacunar signals, or the vessel wall thickening arterioles when there is a lack of ischaemic stroke and WMLs may be narrows the lumen and reduces blood association with the better understood failure of the arteriolar endothelium flow, or fails to allow nutrients out and large artery atheroma in lacunar infarc- (that is, the blood–brain barrier) allow- waste products of metabolism back into tion,10 14 Vasospasm, inducible in animal ing extravasation of blood components the circulation. This diffuse endothelial models with extreme hypertension, into the vessel wall, and consequently failure might also account for additional causes fibrinoid necrosis, but the asso- vessel wall, perivascular neuronal, and asymptomatic lacunar infarcts observed ciation of lacunar infarction with any glial cell damage.28 39 41 42 This would at presentation with,26 or during follow excess of hypertension (more than other explain the features described histo- up after,25 a symptomatic lacunar infarct types of ischaemic stroke) in patients is logically,29 31 32 and the association with no underlying embolic source.

www.jnnp.com EDITORIAL 619 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.039982 on 15 April 2005. Downloaded from

These asymptomatic lesions, gradually Received 11 November 2004 23 Samuelsson M, Lindell D, Olsson G-B. multiplying, could be the source of the In revised form 29 November 2004 Lacunar infarcts: A 1-year clinical and MRI Accepted 1 December 2004 follow-up study. Cerebrovasc Dis WMLs. Neurones can switch off sud- 1994;4:265–72. denly, even when the underlying pro- Competing interests: none declared 24 Voisin T, Rous de Feneyrols AR, Pavy Le Traon A, et al. Cognitive impairment after first lacunar cess is gradual; for example, neurones stroke: clinical features and risk factors. switch off electrical activity (manifest as REFERENCES Cerebrovasc Dis 2002;13(suppl 3):297. a stroke) as cerebral blood flow falls 25 O’Sullivan M, Rich PM, Barrick TR, et al. Frequency of subclinical lacunar infarcts in below about 25 ml/100 g brain/min, 1 Sudlow CLM, Warlow CP. Comparable studies of ischemic leukoaraiosis and cerebral autosomal thus the fall in blood flow may have been the incidence of stroke and its pathological types. dominant arteriopathy with subcortical infarcts gradual but the symptoms are sudden. Results from an international collaboration. Stroke and leukoencephalopathy. Am J Neuroradiol 1997;28:491–9. 2003;24:1348–54. An important target for new thera- 2 Bamford JM, Warlow CP. Evolution and testing of 26 Chowdhury D, Wardlaw JM, Dennis MS. Are peutic approaches to prevent or treat a the lacunar hypothesis. Stroke 1988;19:1074. multiple lacunar infarctions caused by embolic common form of ischaemic stroke and 3 Futrell N. Lacunar infarction. Embolism is the key. mechanisms? J Neurol Neurosurg Psychiatry cognitive decline may have been over- Stroke 2004;35:1778–9. 2004;75. In press. 4 Norrving B. Lacunar infarction. Embolism is the 27 Kato H, Izumiyama M, Izumiyama K, et al. looked. It is important to understand key: Against. Stroke 2004;35:1779–80. Silent cerebral microbleeds on T2*-weighted this process better, not simply in order 5 Bamford J, Sandercock P, Dennis M, et al. MRI: correlation with stroke subtype, stroke to reduce the burden of lacunar stroke, Classification and natural history of clinically recurrence, and leukoaraiosis. Stroke identifiable subtypes of . Lancet 2002;33:1536–40. but because the same mechanism may 1991;337:1521–6. 28 Wardlaw JM, Sandercock PA, Dennis MS, et al. also underlie WMLs and consequent 6 Samuelsson M, Soderfeldt B, Olsson GB. Is breakdown of the blood-brain barrier cognitive decline to dementia. Lacunar Functional outcome in patients with lacunar responsible for lacunar stroke, leukoaraiosis, and infarction. Stroke 1996;27:842–6. dementia? Stroke 2003;34:806–12. ischaemic stroke has for too long been 7 Mead GE, Lewis S, Wardlaw JM, et al. Should 29 Fisher CM. Lacunes: Small, deep cerebral infarcts. simply lumped together with other computed tomography appearance of lacunar 1965;15:774–84. stroke subtypes; while it is likely that stroke influence patient management? J Neurol 30 Arboix A, Marti-Vilalta JL. Estudio de los infartos Neurosurg Psychiatry 1999;67:682–4. lacunares a partir del analisis de las principales many older stroke patients will share 8 Adams HP Jr, Bendixen BH, Kappelle LJ, et al. series anatomopatologicas de la literatura. Rev common vascular risk factors, this ten- Classification of subtype of acute ischemic Neurol 1998;26:365–7. dency has hindered understanding of stroke. Definitions for use in a multicenter 31 Lammie GA. Pathology of small vessel stroke. Br clinical trial. TOAST. Trial of Org 10172 Med Bull 2000;56:296–306. what appears to be an importantly in Acute Stroke Treatment. Stroke 32 Fisher CM. The arterial lesions underlying different stroke subtype that may 1993;24:35–41. lacunes. Acta Neuropath 1969;12:1–15. require different acute treatment and 9 Macdonald RL, Kowalczuk A, Johns L. Emboli 33 Pantoni L. Pathophysiology of age-related enter penetrating arteries of monkey brain in cerebral white matter changes. Cerebrovasc Dis prevention. For example, the association relation to their size. Stroke 1995;26:1247–51. 2002;13(suppl 2):7–10. with microhaemorrhages, a possible risk 10 Jackson C, Sudlow C. Are lacunar strokes really 34 Bakker SLM, de Leeuw F-E, de Groot JC, et al. factor for intracerebral haemorrhage, is different? A systematic review of differences in Cerebral vasomotor reactivity and cerebral white worrying, and may increase the risk of risk factor profiles between lacunar and non- matter lesions in the elderly. Neurology lacunar infarcts. Stroke 2004. In press. 1999;52:578–83. copyright. haemorrhage complicating anti-throm- 11 Adachi T, Kobayashi S, Yamaguchi S, et al. MRI 35 O’Sullivan M, Lythgoe DJ, Pereira AC, et al. botic drug treatment compared with findings of small subcortical ‘‘lacunar-like’’ Patterns of cerebral blood flow reduction in their use in cortical ischaemic stroke. infarction resulting from large vessel disease. patients with ischemic leukoaraiosis. Neurology J Neurol 2002;247:280–5. 2002;59:321–6. Further studies, using detailed, accu- 12 Baumgartner RW, Sidler C, Mosso M, et al. 36 Yao H, Yuzuriha T, Fukuda K, et al. Cerebral rate, and unbiased patient classification, Ischemic lacunar stroke in patients with and blood flow in nondemented elderly subjects with are needed to examine risk factors for without potential mechanism other than small- extensive deep white matter lesions on magnetic artery disease. Stroke 2003;34:653–9. resonance imaging. J Stroke Cerebrovasc Dis lacunar stroke including blood–brain 13 Kazui S, Levi CR, Jones EF, et al. Lacunar stroke: 2000;9:172–5. barrier function (now possible with Transoesophageal echocardiographic factors 37 Blamire A, Styles P. Does contrast based detailed MRI),40 how to identify those influencing long-term prognosis. Cerebrovasc Dis perfusion imaging give the right answer in 2001;12:325–30. pathological tissue? A Monte Carlo simulation lacunar strokes that are due to embo- 14 Mead GE, Lewis SC, Wardlaw JM, et al. Severe study. Proc Intl Soc Mag Reson Med lism, and clarify long term outcomes. ipsilateral carotid stenosis and middle cerebral 2001;9:1586. Study of small arteriolar abnormalities artery disease in lacunar ischaemic stroke: 38 Wardlaw JM, Dennis MS, Warlow CP, et al. http://jnnp.bmj.com/ innocent bystanders? J Neurol Imaging appearance of the symptomatic in other vascular beds (for example the 2002;249:266–71. perforating artery in patients with lacunar retina, where the arterioles can be 15 Ay H, Oliveira-Filho J, Buonanno FS, et al. infarction: occlusion or other vascular pathology? directly observed) and systemic endo- Diffusion-weighted imaging identifies a subset of Ann Neurol 2001;50:208–15. lacunar infarction associated with embolic source. 39 Lammie GA, Brannan F, Wardlaw JM. thelial abnormalities will help both Stroke 1999;30:2644–50. Incomplete lacunar infarction (type 1b lacunes). in understanding the mechanisms of 16 Uehara T, Tabuchi M, Mori E. Occlusive lesions of Acta Neuropath 1998;96:163–71. lacunar ischaemic stroke and in identify- carotid and intracranial arteries in patients with 40 Starr JM, Wardlaw J, Ferguson K, et al. ing diagnostic and prognostic markers. symptomatic lacunar infarction. Evaluation by MR Increased blood-brain barrier permeability in angiography. Clin Neurol 1997;37:796–801. type II diabetes demonstrated by gadolinium on September 23, 2021 by guest. Protected 17 Tejada J, Diez-Tejedor E, Hernandez- magnetic resonance imaging. JNNP Echebarria L, et al. Does a relationship exist 2003;74:70–6. ACKNOWLEDGEMENTS between carotid stenosis and lacunar infarction? 41 Tomimoto H, Akiguchi I, Suenaga T, et al. Stroke 2003;34:1404–11. I would like to acknowledge the many people Alterations of the blood-brain barrier and glial 18 de Jong G, Kessels F, Lodder J. Two types of cells in white matter lesions in cerebrovascular who have discussed with me the possible lacunar infarcts: further arguments from a study and Alzheimer’s disease patients. Stroke mechanisms of lacunar ischaemic stroke or on prognosis. Stroke 2002;33:2072–6. 1996;27:2069–74. authored some of the supporting papers, in 19 Jackson C, Sudlow C. Risks of death and 42 Kemper TL, Blatt GJ, Killiany RJ, et al. particular Professor C Warlow, Professor M recurrent vascular events after lacunar and non- Neuropathology of progressive cognitive Dennis, Dr C Sudlow, Dr A Lammie, Dr J lacunar ischaemic stroke (LACI and non-LACI) – a decline in chronically hypertensive rhesus Bamford, Professor P Sandercock, Dr P systematic review of follow-up studies. monkeys. Acta Neuropathol (Berl) Cerebrovasc Dis 2004;17(suppl 5):52. 2001;101:145–53. Armitage, and Dr G Mead. 20 Inzitari D. Leukoaraiosis. An independent risk 43 Hassan A, Hunt BJ, O’Sullivan M, et al. Markers J Neurol Neurosurg Psychiatry factor for stroke? Stroke 2003;34:2071. of endothelial dysfunction in lacunar infarction 2005;76:617–619. 21 Schmidt R, Enzinger C, Ropele S, et al. and ischaemic leukoaraiosis. Brain Progression of cerebral white matter lesions: 6- 2003;126:424–32. doi: 10.1136/jnnp.2004.039982 year results of the Austrian Stroke Prevention 44 Nakamura K, Saku Y, Ibayashi S, et al. Study. Lancet 2003;361:2046–8. Progressive motor deficits in lacunar infarction. Correspondence to: Dr J M Wardlaw, Division 22 Kuller LH, Longstreth WT Jr, Arnold AM, et al. Neurology 1999;52:29–33. of Clinical Neurosciences, Western General White matter hyperintensity on cranial magnetic 45 Wong TY. Is retinal photography useful in the Hospital, Crewe Rd, Edinburgh EH4 2XU UK; resonance imaging. A predictor of stroke. Stroke measurement of stroke risk? Lancet Neurol [email protected] 2004;35:1821–3. 2004;3:179–83.

www.jnnp.com 620 EDITORIAL COMMENTARY J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.039982 on 15 April 2005. Downloaded from

Huntington’s disease sufficient participants and generate ...... resources for such trials? Shorter trials that require fewer patients would clearly be preferable. The statistical answer Imaging Huntington’s disease (HD) would be: let us reduce end point variability. – imagine HD trials! Enter the paper by Kipps et al 5 (this issue, pp 650–5), about imaging the H P H Kremer structural disease progression in precli- nical disease. Using a novel approach to ...... statistical imaging, called tensor based morphometry, they were able to demon- Tensor based morphometry strate over a period of two years a progressive regional grey matter loss in he true and ultimate aim of research the past and ongoing neuroprotection 17 presymptomatic Huntington muta- in Huntington’s disease (HD) is to trials in HD have studied compounds tion carriers compared with 13 mutation Tarrest the progressive neurodegen- derived from this hypothetic excitotoxi- negative controls. In contrast, clinical eration and thus the debilitating clinical city. measurements failed to pick up any and functional deterioration—or so it But these trials have faced one major deterioration. If this result can be seems to those involved in the clinical problem. All of them have used serial confirmed by others, imaging would care of the unfortunate individuals clinical or functional assessments of become a powerful tool in neuroprotec- affected by it. Two major clinical chal- symptomatic patients as the primary tion trials. Imagine an intervention trial lenges confront us: to retard, or better, outcome measure. Despite their demon- in which 40 patients are randomised to abolish disease progression in symp- strated robustness, linearity, and rele- and followed for two years, with, as the tomatic individuals; and to prevent vance, the intrinsic variability of clinical major measurements, an MRI scan at phenoconversion in presymptomatic outcome measures in treated cohorts baseline and at the end of the trial. individuals. has been large. As a result, phase II and Although such measurements would Huntington’s disease is considered to III neuroprotection trials have typically have to be considered surrogate end be rare, but extrapolation of its esti- included relatively large numbers of points, they would nevertheless assume mated prevalence—in western countries symptomatic patients who were fol- a crucial role in the selection of com- 5 to 10 per 100 000—yields for the lowed for several years. Thus a North pounds to undergo the final test of current 25 countries of the European American trial which studied the effects clinical efficacy: a randomised con- Union (with 455 million people in 2004) of remacemide and coenzyme Q (CoQ) trolled clinical trial with 1000 patients a total number of between 22 500 and against placebo in a 262 factorial design enrolled and followed for 30 months, copyright. 45 000 clinically affected patients in enrolled 347 patients and followed them with clinical outcome as the primary various stages of the disease. The for 30 months. The study failed to show end point. We could certainly start number of presymptomatic mutation any benefits of the treatment, although planning a ‘‘primary prevention’’ trial carriers is much higher. Recent a trend towards an effect of CoQ has 4 aimed at postponing (or abolishing?) advances in our understanding of the been suggested. Based upon this study, the onset of the disease. molecular pathobiology have raised calculations predicted that a sufficiently hopes that rational treatments may be powered CoQ trial would require more J Neurol Neurosurg Psychiatry 2005;76:620. near. Huntington’s disease is caused by than 1000 patients to be followed for at doi: 10.1136/jnnp.2004.056267 an expanded CAG triplet repeat in exon least two years. The European EHDI trial Correspondence to: Dr H P H Kremer, 1 of the huntingtin gene, and this that studies the effects of riluzole on Department of Neurology 326, PO Box 9101, 6500 HB Nijmegen, Netherlands; h.kremer@ mutation is expressed and translated disease progression in a 1:2 randomisa- http://jnnp.bmj.com/ into an expanded polyglutamine tion design enrolled 560 patients who neuro.umcn.nl sequence in about half of all huntingtin were followed for 37 months. Results of Competing interests: none declared protein molecules that are produced in this trial are pending. Previous inter- the body cells. The physiological func- ventions which studied baclofen, idebe- tions of the protein are still unknown. none, vitamin E, and lamotrigine REFERENCES But many details of huntingtin interac- included 100 patients or fewer, but all 1 Bates G. Huntingtin aggregation and toxicity in tions, cleavage, conformational changes, of them turned out to be clearly under- Huntington’s disease. Lancet 2003;361:1642–44. aggregation, and proteasomal break- powered. The lesson: Huntington trials 2 Steffan JS, Bodai L, Pallos J, et al. Histone on September 23, 2021 by guest. Protected down have been clarified in the past need large numbers of participating deacetylase inhibitors arrest polyglutamine- decade.1 Based upon these mechanistic patients, to be followed for years. dependent neurodegeneration in Drosophila. Nature 2001;413:739–43. models, various potential drugs have If we were to conduct 10 such 3 Heiser V, Engemann S, Brocker W, et al. been proposed. In fact, efficacy of such European protection trials simulta- Identification of benzothiazoles as potential proposals has been demonstrated in neously, about a quarter of all the polyglutamine aggregation inhibitors of Huntington’s disease by using an automated filter simple cellular or more complex animal patients in the 25 EU countries would retardation assay. Proc Natl Acad Sci USA 2 models, such as transgenic flies or mice. have to be enrolled and followed for 2002;99(suppl 4):16400–6. Another approach has been the large many years. If we were to conduct 4 Huntington Study Group. A randomized, scale screening of promising compounds an intervention in presymptomatic placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 3 in simple systems ; and even older patients, the difficulties would be 2001;57:397–404. hypotheses regarding the causes of compounded because of the very long 5 Kipps CM, Duggins AJ, Mahant N, et al. neurodegeneration, such as excitotoxi- follow up times required to demonstrate Progression of structural neuropathology in preclinical Huntington’s disease: a tensor based city, have yielded proposals for neuro- phenoconversion. The logistics issue morphometry study. J Neurol Neurosurg protective treatments. In fact, most of then becomes: how can we persuade Psychiatry 2005;76:650–5.

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Weight bearing asymmetry non-paretic side than in controls. Since ...... the changes in the reaction forces were observed early after vestibular sti- mulation (320–500 ms), the authors Weight bearing asymmetry in standing assumed that this initial response was likely to be purely vestibular in origin. hemiparetic patients Marsden et al also found that the degree of asymmetry induced by galvanic sti- DPe´rennou mulation was correlated with the degree of corticospinal damage induced by ...... transcranial magnetic stimulation. They concluded that MCA stroke may MCA stroke may disrupt corticobulbar projection to disrupt corticobulbar projection to output pathways involved in the vestibular control of balance brainstem output pathways which are involved in the vestibular control of ostural disorders are a primary strategy to prevent contralesional fall- balance. They suggested that stroke is disability after stroke.1 They lead ing.1 associated with a lateralised deficit in the motor output stage of vestibular to loss of autonomy and expose In a very elegant experimental study P processing rather than in the sensory or patients to a high risk of falling. We published in this issue (pp 670–8), spatial processing stages. must bear in mind that following a total Marsden et al propose a new approach Postural rehabilitation must be anterior circulation infarct, the median to the problem of postural instability in guided by a better understanding of time to recover the ability to stand for standing hemiparetic patients. Using the postural disorders displayed by 10 s is 44 days (25th–75th percentile: the measurement of forces and move- 2 patients. There is no doubt that the 38–57 days) . Retraining the patient to ments elicited by galvanic and transcra- paper by Marsden et al contributes to stand is therefore a primary goal in post nial electrical stimulation, they have this knowledge. This new insight on the stroke rehabilitation, especially follow- explored the possibility of asymmetric postural instability of standing stroke ing hemisphere strokes. vestibulo-spinal excitability in chronic patients must now be confirmed and Three main patterns characterise middle cerebral artery (MCA) stroke integrated with knowledge of the many the standing posture of hemiparetic patients, in patients with isolated corti- other alterations and deficiencies which patients1: i) an increase in centre of cospinal tract lesions, and in normal are involved in postural disorders gravity displacement, which reflects subjects. Patients and subjects were caused by hemisphere strokes. postural instability and results from required to stand barefoot on two orthopaedic, sensorimotor, and cogni- separate force plates with equal weight J Neurol Neurosurg Psychiatry 2005;76:621. copyright. tive impairments; ii) the presence of a on both legs and with eyes closed. One doi: 10.1136/jnnp.2004.050468 small area of stability beyond which the advantageous feature of galvanic vestib- Correspondence to: D Pe´rennou, Service de centre of gravity cannot move without ular stimulation is that it is possible to Re´e´ducation Neurologique et INSERM ERIT exposing the patient to a loss of balance evoke a bilateral response by stimulat- M-207, Centre Hospitalo-Universitaire de (this results either from an inability to ing vestibular afferents on one side Re´e´ducation, 23 rue Gaffarel, 21034 Dijon control a stressed equilibrium system or only,45 which means any asymmetries cedex, France; [email protected] from impaired co-ordination between that may exist in the response pattern Competing interests: none declared posture and movement); and iii) weight can be identified. It also offers an bearing asymmetry, with more weight opportunity to decide whether asymme- REFERENCES on the non-paretic leg. Unstable stand- try arises from an abnormality in the 1 Pe´rennou DA, Bronstein AM. Balance disorders ing posture, although a major target in processing of sensory information and vertigo after stroke: assessment and http://jnnp.bmj.com/ stroke rehabilitation, is still poorly (altered response in both legs for a rehabilitation. In: Bogousslavsky J, Barnes M, understood. Weakness certainly plays a lateralised deficit of sensory informa- Dobkin B, eds. Recovery after stroke. Cambridge: Cambridge University Press, role, as do cognitive disorders observed tion) or an abnormality in the motor 2005, pp 320–98. in patients with lesions of the right control of one side of the body (altered 2 Smith MT, Baer GD. Achievement of simple hemisphere.3 These cognitive disorders response in one leg and not the other mobility milestones after stroke. Arch Phys Med Rehabil 1999;80:442–7. result in distortion of the coordinates irrespective of which ear is stimulated). 3 Rode G, Tiliket C, Charlopain P, et al. Postural used to distribute loading over the two The main finding of the Marsden et al asymmetry reduction by vestibular caloric stimulation in left hemiparetic patients. legs while standing. Since some patients study was abnormal interleg response on September 23, 2021 by guest. Protected Scand J Rehabil Med 1998;30:9–14. align their erect posture to a biological asymmetry to galvanic vestibular stimu- 4 Marsden JF, Playford ED, Day BL. The vestibular vertical contralesionally tilted, it has lation in stroke patients only, the control of balance after stroke. J Neurol also been suggested that the shift amplitude of the response being higher Neurosurg Psychiatry 2005;76:670–8. 5 Fitzpatrick RC, Day BL. Probing the human in the center of gravity towards the on the non-paretic side than on the vestibular system with galvanic stimulation. J Appl ipsilesional leg might be a compensatory paretic side, and higher on the Physiol 2004;96:2301–16.

www.jnnp.com 622 EDITORIAL COMMENTARY J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.039982 on 15 April 2005. Downloaded from

Guillain–Barre´syndrome ultrastructurally by Griffin and collea- ...... gues. The authors also identified a small number of patients who were unable to walk six months after the illness but all Prognosis in the acute motor axonal of whom continued to improve until they could walk independently in sub- form of Guillain–Barre´ syndrome sequent years. It is possible that several different C M Gabriel pathophysiological processes exist in AMAN to explain the dichotomous ...... recovery patterns: reversible distal nerve failure at motor terminals or conduction Prognosis in axonal Guillain–Barre´syndrome block at nodes of Ranvier in association with rapid recovery, and Wallerian primary axonal form of Guillain– Schwann cell membrane, and subse- degeneration requiring axonal regrowth Barre´ syndrome was first quent degeneration of both Schwann which may continue over many months described by Feasby and collea- cell cytoplasm and axon. and years. In AIDP, conventionally A1 gues in 1986. Initial indications were It has become clear in more recent considered a demyelinating condition, that this had a worse prognosis than years that although AMAN progresses severe lesions may result in axonal demyelinating forms of the disease and more rapidly to nadir, recovery times for degeneration as well as myelin destruc- it was suggested that recovery might AMAN and acute inflammatory demye- tion, and a similar distinction depen- require axonal regeneration along the linating polyradiculoneuropathy (AIDP) dent on disease severity may occur in entire length of the nerve fibre. In the are similar, and that in fact some AMAN. Certainly there is no unifying intervening years it has become appar- patients with AMAN recover more hypothesis to date, but it is encouraging ent that recovery from acute motor quickly,5 especially if their illness is that all forms seem to be potentially axonal neuropathy (AMAN) may actu- preceded by Haemophilus influenzae. reversible. ally be either rapid or slow. This is Clinically, those who recover more J Neurol Neurosurg Psychiatry 2005;76:622. confirmed in a paper by Hiraga and rapidly are equally weak at the peak of doi: 10.1136/jnnp.2004.055376 colleagues (this issue, pp 719–22),2 and in their illness, though they are more likely addition they observed that in patients to retain their tendon reflexes than Correspondence to: Dr C M Gabriel, St Mary’s Hospital, Praed Street, London W2 1NY, UK; with slow recovery, clinical improve- those with AIDP. [email protected] ment to independent ambulation may Rapid recovery in AMAN in the Competing interests: none declared

continue for more than four years. current study was defined as an copyright. In the early 1990s, AMAN was char- improvement of two or more Guillain– acterised in northern China as a rapidly Barre´syndrome disability scale grades REFERENCES ascending tetraparesis with Wallerian- in the first four weeks e.g. from bed- 1 Feasby TE, Gilbert JJ, Brown WF, et al. An acute like degeneration of motor fibres at bound to independent ambulation, axonal form of Guillain–Barre´polyneuropathy. necropsy.3 This syndrome is most which occurred in 27% of the AMAN Brain 1986;109:1115–26. common in Japan and northern group. Such improvement would be 2 Hiraga A, Mori M, Ogawara K, et al. Recovery patterns and long term prognosis for axonal China, occurs uncommonly in Western incompatible with the primary pathol- Guillain–Barre´syndrome. J Neurol Neurosurg countries, and is associated with ogy being Wallerian degeneration. Other Psychiatry 2005;76:719–22. Campylobacter jejuni (in 60–70%), explanations might be degeneration 3 McKhann GM, Cornblath DR, Griffin JW, et al. Acute motor axonal neuropathy: a frequent cause Haemophilus influenzae (in 10–20%), and restricted to the distal motor nerve of acute flaccid paralysis in China. Ann Neurol, antiganglioside antibodies. Detailed terminal where regeneration could 1993 Apr, 33:333–42. ultrastructural study4 showed that the occur quickly, immune mediated con- 4 Griffin JW, Li CY, Macko C, et al. Early nodal http://jnnp.bmj.com/ changes in the acute motor axonal neuropathy earliest changes were of myelin disrup- duction block at the axonal membrane, pattern of the Guillain–Barre´syndrome. tion at nodes of Ranvier, followed by or complement mediated damage to J Neurocytol 1996;25:33–51. macrophage extrusion into the periax- perisynaptic Schwann cells. This may 5 Kuwabara S, Mori M, Ogawara K, et al. Indicators of rapid clinical recovery in Guillain– onal space at the paranode, with separa- imply additional pathological mechan- Barre´syndrome. J Neurol Neurosurg Psychiatry tion of the axon from the adjacent isms distinct from those described 2001;70:560–2. on September 23, 2021 by guest. Protected

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