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Epilepsy potassium channel conductance,10 sug- ...... gesting that its mechanism of action dif- fers from other antiepileptic drugs. Lev- etiracetam also has a specific A new antiepileptic drug stereoselective binding site in the CNS,1 and cannot be displaced from this site by S D Shorvon, K van Rijckevorsel other classic anticonvulsant drugs (car- ...... bamazepine, phenytoin, valproate, phe- nobarbital), although ethosuximide does Levetiracetam, a pyrrolidone recently licensed as an show binding affinity. The extent of the antiepileptic efficacy in the audiogenic antiepileptic drug seizure model in mice was found to be correlated with the affinity for the bind- ecently a new antiepileptic drug, tonic seizures induced by maximal elec- ing site of a series of S-homologues of levetiracetam (LEV), was approved troshock or clonic seizures induced by levetiracetam. Levetiracetam has no for the add on treatment of partial pentylenetetrazol (PTZ) stimulation in binding to membranes outside of the R 2–4 epilepsy, both in the United States and in the classic rodent models. It however CNS. Europe. This is of potential importance, has very marked protection against because this drug is from a class not pre- seizures in audiogenic mice, mice kin- CLINICAL PHARMACOKINETICS viously used in epilepsy, although pira- dled with corneal electroshock or PTZ, The pharmacokinetic properties of lev- cetam, a compound with a structure and amygdaloid kindled rats. It protects etiracetam have been studied in healthy similar to that of levetiracetam, is useful against spontaneous spike and wave dis- adult volunteers, patients with epilepsy, in myoclonus. Both drugs are pyrro- charges in the GAERS model and in and special populations, including paedi- lidone derivatives, a class of drugs of pilocarpine or kainic acid induced focal atric and elderly patients and patients interest for both psychotropic and noo- seizures in rats.245 The dose dependent with renal or hepatic insufficiency. Lev- tropic applications and potentially as ability of levetiracetam to inhibit the etiracetam is rapidly and almost com- neuroprotectants. Levetiracetam (avail- development of kindling suggests a pletely absorbed after oral administra- able under the registered trademark of R potential antiepileptogenic effect as tion of doses ranging from 250 mg to UCB S.A., Keppra ) is the S-enantiomer 6 α well. Levetiracetam is the most effective 5000 mg, with peak plasma concentra- of -ethyl-2-oxo-1-pyrrolidine aceta- of any of the pyrrolidone drugs in these tions achieved in about 1 hour and mide (fig 1). Homologues sharing the S epilepsy models. Its R-enantiomer has steady state concentrations achieved in configuration include a range of other no antiepileptic activity. 48 hours. Absolute oral bioavailability is compounds, some of which also have The dose at which toxic effects on the nearly 100%. When taken with food, the antiepileptic action.1 The range and rotarod test are produced is much higher extent of absorption is not affected, extent of the compounds’ activity in than the effective antiseizure dose in although the rate of absorption may be experimental models of epilepsy and both the GAERS model and the corneally slowed. Levetiracetam is not significantly other conditions varies considerably kindled mice. The safety margin of bound to plasma proteins (<10%), and with minor changes to chemical struc- levetiracetam in these models is much its volume of distribution is about 0.6 ture, but the full extent of the range of greater than for other drugs. In acute l/kg, similar to the volume of distribution properties of these drugs in humans has of intracellular and extracellular water. not been explored. This article reviews and chronic toxicity studies in animals, levetiracetam shows generally low toxic- In addition, levetiracetam exhibits lin- http://jnnp.bmj.com/ the experimental and clinical data relat- ear, dose proportional, kinetics, with low ing to the antiepileptic action of levetira- ity. Oral doses up to 5000 mg/kg acutely (maximum tested dose) are not lethal in intrasubject and intersubject variability, cetam. 11 mice and rats. Levetiracetam has not dis- and a half life of 6 to 8 hours. Levetira- cetam does not undergo hepatic metabo- EXPERIMENTAL STUDIES played any teratogenic, mutagenic, or carcinogenic properties. lism, nor does it induce or inhibit Levetiracetam shows an unusual profile 12 The mechanism of action of levetira- cytochrome P-450 enzymes. Levetira- of antiepileptic activity in experimental cetam is to a limited extent metabolised animal models of partial and generalised cetam (or indeed the other -acetam

(by hydrolysis) by a serine esterase on September 24, 2021 by guest. Protected copyright. epilepsy.2 Unlike other antiepileptic drugs) is not clearly understood, and it does not seem to involve any conven- enzyme in blood and other tissues and drugs, levetiracetam has no effect on excreted through the kidneys un- tional modulation of the three main changed or as inactive metabolites.11 mechanisms relevant for the action of Renal clearance of levetiracetam is classic antiepileptic drugs.7 The drug directly proportional to creatinine clear- does not bind to receptors associated ance. Clearance of levetiracetam is sig- with excitatory or inhibitory neurotrans- nificantly reduced in patients with se- mitters (for example, γ-aminobutyric O vere hepatic impairment and N acid (GABA), glutamate, glycine, adeno- concomitant renal impairment (hepato- sine), has no effect on sodium or T-type CH3CH2 renal syndrome). No differences are seen calcium channel function, and does not in patients with mild to moderate affect GABA transaminase or glutamic C hepatic impairment. In studies with eld- acid decarboxylase (GAD) activity or erly patients, the elimination half life of second messenger systems (cyclic ad- levetiracetam is prolonged to 10 to 11 CONH2 enosine monophosphate, protein kinase 2 H C). By contrast, it has recently been reported that levetiracetam reduces high ...... Figure 1 Levetiracetam is a pyrrolidone voltage activated Ca2+ currents,8 reverses derivative and is chemically designated Abbreviations: LEV, levetiracetam; PTZ, (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide. It inhibition of GABA and glycine gated pentylenetetrazol; GABA, γ-aminobutyric acid; has a molecular weight of 170.21 and currents induced by negative allosteric GAD, glutamic acid decarboxylase; SUDEP, 9 molecular formula of C8H14N2O2. modulators, and effects voltage gated sudden and unexplained death in epilepsy

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Table 1 Pooled responder rates for those patients who completed titration and were evaluated on a stable dose (evaluation period), and for all patients randomised (the intent to treat population) during the complete treatment period

Intent to treat population, total treatment period titration Evaluation period on stable dose included

Levetiracetam Levetiracetam

Placebo 1000 mg/day 2000 mg/day 3000 mg/day Placebo 1000 mg/day 2000 mg/day 3000 mg/day (n=301) (n=195) (n=95) (n=269) (n=312) (n=204) (n=106) (n=282)

>50% responder rate 12.6 27.7 31.6 41.3 9.4 28.6 35.2 39.5 >75% responder rate 3.3 11.8 16.8 22.3 2.6 10.8 16.2 22.4 Seizure freedom* 0.6 3.9 2.1 8.2 0.3 2.9 2.8 6.0

*Seizure-free during the analysed period (evaluation period or total treatment period). hours and is likely attributable to the age 32.5 for patients receiving levetiracetam 69 patients (71%) who were selected for related decline in renal function. After compared with 7 for patients receiving the monotherapy phase were success- single oral dose administration of 20 placebo (p<0.001). The responder rate fully down titrated, and 36 of 69 (52%) mg/kg levetiracetam in children between (the proportion of patients experiencing completed the monotherapy phase. The 6 and 12 years old, total body clearance a 50% or greater reduction in seizure fre- median percentage reduction compared was about 30% to 40% higher than in quency compared with baseline) during with baseline was 73.8% (p=0.037), the adults, and the half life was roughly 6 the evaluation period was 27.7% (54/ 50% responder rate was 59.2% (29/49), hours.13 195), 31.6% (30/95), and 41.3% (111/ and nine patients (18.4%) remained sei- Because it does not undergo hepatic 269) for patients receiving 1000, 2000, zure free during monotherapy. metabolism and is not significantly and 3000 mg/day respectively, compared protein bound, levetiracetam has a very with 12.6% (38/301) of patients who Long term efficacy studies low potential for pharmacokinetic inter- received placebo (fig 2; p>0.001, all Long term analysis of results from the 12 actions. Findings from studies in vitro, doses versus placebo). The percentage of 1422 patients with epilepsy from the first 14–16 clinical trials in patients, and specific patients experiencing a 75% or greater day of exposure to levetiracetam or 17 18 studies with digoxin, phenytoin, war- reduction in seizures was 11.8% (23/ placebo in phase I, II, or III studies show farin, valproic acid, and oral 195), 16.8% (16/95), and 22.3% (60/269) estimated retention rates (Kaplan-Meier 11 contraceptives support this assertion. of patients receiving 1000 mg, 2000 mg, analysis) of about 60% after 1 year and 3000 mg of levetiracetam respec- (number of patients at risk=826), 44% CLINICAL ANTIEPILEPTIC EFFECT tively, compared with 3.3% (10/301) of after 2 years (number of patients at Add on therapy in partial epilepsy placebo treated patients (p<0.001, all risk=489), and 32% after 4 years The efficacy of levetiracetam as add on doses versus placebo). In addition, 5.7% (number of patients at risk=175), for up therapy has been assessed in three (32/559) of patients treated with leveti- to 8 years (number of patients at prospective, double blind, placebo con- 19 racetam became seizure free, compared risk=1). Twenty six per cent of patients trolled trials in patients with refractory with 0.6% (2/301) in the placebo group withdrew due to reasons inherent to epilepsy. The studies were powered for 14–16 (p<0.001). A statistically significant re- clinical trials, 16% due to adverse events parallel group comparison. Doses of duction in seizure frequency for all and 18% due to lack of efficacy. Of the levetiracetam evaluated in these trials http://jnnp.bmj.com/ patients with a baseline evaluation included 1000, 2000, and 3000 mg/day different subtypes of partial seizures (n=1321), 548 (41.5%) had>50% and given in twice daily regimens. A total of (simple partial, complex partial, and sec- 355/1321 (26.9%) had 75% reduction in 904 patients with refractory partial sei- ondarily generalised seizures) was found > seizure frequency compared with base- zures, with or without secondary gener- with levetiracetam treatment (fig 3). alisation, who were not controlled de- line during the last 6 months of therapy. spite being on a stable dose regimen of Monotherapy Of the 1422 patients, 183 (12.9%) were one to a maximum of two marketed One of the efficacy trials was extended seizure free for at least 6 months, and into a levetiracetam responder selected 109 (7.7%) were seizure free for at least 1 antiepileptic drugs, participated in these 16 on September 24, 2021 by guest. Protected copyright. trials. Patients were evaluated after 12 or monotherapy phase. Forty nine of the year. The efficacy of levetiracetam was 14 weeks, and seizure frequency during maintained over time. Sixty six (5%) of the evaluation period was compared the patients were successfully converted with a baseline period of 8 or 12 weeks. + + >– 50% reduction to monotherapy. + >– 75% reduction Demographic characteristics across 50 Seizure free studies were comparable for sex, age, p < 0.05 40 p < 0.001 race, and other baseline assessments. – Placebo (n = 301) LEV (n = 559) Responder rate and seizure count analy- 30 41 80 ses were based on the patients who com- p < 0.05 69 32 70 p < 0.001 pleted titration and entered the stable 20 28 60 dose evaluation period (n=860). In Patients (%) 22 50 10 17 43 13 12 36 addition, the responder rates were also 40 33 analysed for the total randomised popu- 0 3 0.6 4 2 8 30 23 20 lation during the treatment period (the 17 10 Placebo LEV LEV LEV 10 7 intent to treat population; n=904). The (n = 301) (n = 95) 0 data from both analyses are presented in 1000(n mg/day = 195) 2000 mg/day 3000(n mg/day = 269) All partial Simple Complex Secondary table 1. Treatment partial partial generalised At all doses evaluated in these studies, Median % reduction from baseline Seizure type Figure 2 Pooled efficacy results showing levetiracetam was significantly more the responder rates during the evaluation Figure 3 Pooled efficacy results showing effective than placebo. The median per- period at three different doses, and on the median % reduction from baseline in centage reduction from baseline was placebo. LEV=levetiracetam. partial seizure subtypes; LEV=levetiracetam.

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Other seizure types The range of effectiveness of levetira- Table 2 Adverse events (%) according to FDA and EMEA standards cetam in human epilepsy has not yet Adverse reaction* (FDA) Undesirable effects† (EMEA) been fully explored, but there are some Levetiracetam Levetiracetam indications that the drug will be useful (n=769) Placebo (n=439) (n=672) Placebo (n=351) in a wider range of seizure types and syndromes.20 Preliminary open studies of Somnolence 15 8 12 9 Asthenia 15 9 7 3 levetiracetam in patients with general- Dizziness 9 4 14 8 ised tonic clonic, absence, and myoclonic Infection 13 8 — — seizures have been very encouraging, as they have in the multiple seizure types of *Adverse reaction: any event reported during clinical trial; FDA, Food and Drug Administration; the Lennox-Gastaut syndrome. The drug †undesirable effect: all adverse events at least possibly related to the study drug; EMEA=European Medicinal Evaluation Agency. also has a dramatic effect on Note: Adverse reactions and undesirable effects are derived from three efficacy and one safety, photosensitivity,21 and there is pilot data double blind placebo controlled trials. Patient numbers differ because the FDA included the suggesting potential effectiveness in re- crossover part of the study in the analysis, and these patients were counted twice. fractory juvenile myoclonic epilepsy.22

SIDE EFFECTS Throughout the entire clinical develop- stereospecificity of levetiracetam and the One of the striking aspects of the clinical ment programme, there were 22 deaths of diversity of properties of related com- trial programme of levetiracetam was patients with epilepsy receiving levetira- pounds are intriguing.1 The fact that the the low rate and mild nature of the cetam (crude mortality rate 0.91 per 100 different pyrrolidone derivatives have reported side effects. The incidence of patient-years). Eight were sudden and such different properties encourages our the most common adverse reactions (the unexplained death in epilepsy (SUDEP) view that the full range of actions of lev- FDA term) and the most common unde- in the levetiracetam group (3.54 per 100 etiracetam has not been fully explored. sirable effects (the European Medicinal person years) versus one in the placebo Its usefulness in a wide range of seizure Evaluation Agency term) derived from group (6.58 per 100 person years). The types has been suggested in open label three efficacy trials and one safety difference was not significant. studies and would indicate further clini- placebo controlled, double blind trial are Safety data regarding laboratory and cal investigation, and studies in non- shown in table 2.14–16 The side effects were physical examinations have been ob- epilepsy indications such as myoclonus, primarily related to the CNS. Somno- tained from 3347 patients exposed to lev- migraine, neuropathic pain, bipolar dis- lence, asthenia, and dizziness were most etiracetam (adults with epilepsy, n=1393; ease, and other areas could be worth- commonly reported. In the pooled analy- children, n=29; patients with other dis- while. As an antiepileptic drug, it has a sis, there was no evidence of a dose eases, n=1558; healthy volunteers, preclinical profile which is unlike any dependent relation within the recom- n=367), for a total of 2421 patient-years. other marketed antiepileptic drug, fa- mended dose range of 1000 to 3000 Overall, physical and neurological exami- vourable pharmacokinetics, good effi- mg/day. Patients receiving levetiracetam nations were unremarkable in patients cacy, and an excellent safety profile (at also reported a slightly higher incidence treated with the drug. Minor but statisti- least at this stage of experience), and of symptoms of upper respiratory infec- cally significant decreases were found in also a broad spectrum potential. For all tion, which was not associated with leu- mean values of the red blood cell count, these reasons, it is already likely to kopenia or dose reduction. The pro- haemoglobin, and packed cell volume, but become an important addition to the portion of patients who discontinued there were no significant changes in other range of medications which are currently http://jnnp.bmj.com/ treatment prematurely or required a laboratory parameters. available for epilepsy. dose reduction because of an adverse event was not significantly different between levetiracetam and placebo DOSING RECOMMENDATIONS ACKNOWLEDGEMENTS groups (15.0% v 11.6%). Adverse events The recommended dosing regimen for Professor Shorvon has received hospitality and that led to withdrawal in patients treated levetiracetam as add on therapy is twice speaker’s honoraria from UCB and was the with levetiracetam included somnolence daily doses of 500 mg to 1500 mg, for a author of the clinical expert report submitted (4.4%), convulsion (3.0%), dizziness total daily dosage of between 1000 mg to the European Medicine Evaluation Agency on September 24, 2021 by guest. Protected copyright. (1.4%), asthenia (1.3%), and headache and 3000 mg. Higher doses have been on Levetiracetam. Professor van Rijckevorsel has received consultant’s honoraria from UCB (1.0%). A greater percentage of patients studied, but with little evidence of added and has participated in the analysis of data for from the placebo groups discontinued effectiveness. The initial starting dose of the redaction of the clinical expert report because of convulsion (3.4%) and rash 1000 mg/day has been shown to be clini- submitted to the European Medicine Evalua- (1.1%). A worsening of seizure, defined cally effective, but if sufficient seizure tion Agency on Levetiracetam. as an increase in seizure frequency of control is not obtained, doses can be J Neurol Neurosurg Psychiatry 2002;72:426– >25%, was significantly lower in pa- increased up to 3000 mg/day. In patients 428 tients treated with levetiracetam com- with renal impairment, doses should be pared with placebo (levetiracetam, adjusted downwards in accordance with ...... 14.2%; placebo, 25.6%; p<0.001). During creatinine clearance.23 24 At present, suffi- Authors’ affiliations long term treatment, only 225 (16%) of cient data are not available to recom- S D Shorvon, Institute of Neurology, University the 1422 patients withdrew because of mend treatment with levetiracetam dur- College London, Queen Square, London, an adverse event.19 ing pregnancy. In patients withdrawn WC1N 3BG, UK and National Hospital for During long term treatment, there was from levetiracetam, a gradual tapering of Neurology and Neurosurgery London, UK, and a slightly higher incidence of psychiatric 1000 mg every 1 to 2 weeks has been the National Neuroscience Institute, Singapore K Van Rijckevorsel, Centre Neurologique side effects recorded than in the placebo successful and has not resulted in with- William Lennox, Université Catholique de controlled phase and these included irri- drawal seizures. Louvain, Ottignies-Louvain La Neuve, Belgium tability, aggression, anger and hostility, and hallucinations. It would be wise to The introduction of a new antiepilep- Correspondence to: Professor S Shorvon, Institute of Neurology, University College monitor patients for these side effects tic from a novel class of drug is an inter- London, Queen Square, London, WC1N 3BG, especially if prone to psychiatric disorders. esting development. The remarkable UK; [email protected]

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REFERENCES 9 Rigo J-M, Nguyen L, Belachew S, et al. antiepileptic agent levetiracetam does not 1 Shorvon SD, Pyrrolidone derivatives. Lancet Levetiracetam: novel modulation of ionotropic alter digoxin pharmacokinetics and 41 2001;200:1885–1892. inhibitory receptors. Epilepsia 2000; (suppl pharmacodynamics in healthy volunteers. 7):35. Epilepsy Res 2001;46:93–9. 2 Klitgaard H, Matagne A, Gobert J, et al. 10 Madeja M, Margineanou D, Klitgaard H. 18 Browne TR, Szabo GK, Leppik IE, et al. Evidence for a unique profile of levetiracetam Effect of levetiracetam on voltage-gated, Absence of pharmacokinetic drug interaction in rodent models of seizures and epilepsy. Eur potassium channels: a novel anti-epileptic of levetiracetam with phenytoin in patients J Pharmacol 1998;353:191–206. mechanism? Epilepsia 2001;42(suppl 2):19. with epilepsy determined by new technique. J Gower AJ 3 , Noyer M, Verloes R, et al. ucb 11 Patsalos PN. Pharmacokinetic profile of Clin Pharmacol 2000;40:590–5. L059, a novel anti-convulsant drug: levetiracetam: towards ideal characteristics. 19 Krakow K, Walker M, Otoul C, et al. pharmacological profile in animals. Eur J Pharmacol Ther 2000;85:77–85. Long-term continuation of levetiracetam in Pharmacol 1992;222:193–203. 12 Nicolas JM, Collart P, Gerin B, et al. In vitro patients with refractory epilepsy. Neurology 4 Löscher W, Hönack D. Profile of ucb L059, a evaluation of potential drug interactions with 2001;56:1772–4. novel anticonvulsant drug, in models of partial levetiracetam, a new antiepileptic agent. Drug 20 Betts T, Waegemans T, Crawford P. A and generalised epilepsy in mice and rats. Eur Metab Dispos 1999;27:250–4. multicentre, double-blind, randomized parallel J Pharmacol 1993;232:147–58. 13 Pellock JM, Glauser TA, Bebin EM, et al. group study to evaluate the tolerability and 5 Gower AJ, Hirsch E, Boehrer A, et al. Effects Pharmacokinetic study of levetiracetam in efficacy of two oral doses of levetiracetam, of levetiracetam, a novel antiepileptic drug, children. Epilepsia 2002 (in press). 2000 mg daily and 4000 mg daily, without on convulsant activity in two genetic rat 14 Cereghino JJ, Biton V, Abou-Khalil B, et al. titration in patients with refractory epilepsy. models of epilepsy. Epilepsy Res Levetiracetam for partial seizures. Results of a Seizure 2000;9:80–7. 1995;22:207–13. double-blind, randomized clinical trial. 21 Kasteleijn-Nolst Trenité DGA, Marescaux 6 Löscher W, Hönack D, Rundfeldt C. Neurology 2000;55:236–42. C, Stodieck S, et al. Photosensitive epilepsy: a Antiepileptogenic effects of the novel 15 Shorvon SD, Löwenthal A, Janz D, et al. model to study the effects of antiepileptic anticonvulsant levetiracetam (ucb L059) in the Multicenter double-blind, randomized, drugs. Evaluation of the piracetam analogue, kindling model of temporal lobe epilepsy. J placebo-controlled trial of levetiracetam as levetiracetam. Epilepsy Res 1996;25:225–30. Pharmacol Exp Ther 1998;284:474–9. add-on therapy in patients with refractory 22 Smith K, Betts T, Pritchett L. Levetiracetam, a 7 Zona C, Niespodziany I, Marchetti C, et al. partial seizures. Epilepsia 2000;41:1179–86. promising option for the treatment of juvenile Levetiracetam does not modulate neuronal 16 Ben-Menachem E, Falter U. Efficacy and myoclonic epilepsy. Epilepsia voltage-gated Na+ and T-type Ca2+ currents. tolerability of levetiracetam 3000 mg/d in 2000;41(suppl):39. Seizure 2001;10:279–86. patients with refractory partial onset seizures: 23 KeppraTM levetiracetam 250, 500, 750 mg 8 Niespodziany I, Klitgaard H, Margineanu a multicenter, double-blind responder-selected tablets. Prescribing information. Brussels, D-G. Levetiracetam inhibits the study evaluating monotherapy. Epilepsia Belgium: UCB Pharma, 2000. higher-voltage-activated Ca++ current in 2000;41:1276–83. 24 KeppraTM (250 mg, 500 mg, 1000 mg). pyramidal neurons of rat hippocampal slices. 17 Levy RH, Ragueneau-Majlessi I, Baltes E. Summary of product characteristics. Brussels, Neurosci Lett 2001;306:5–8. Repeated administration of the novel Belgium: UCB SA, June 2000.

EDITORIAL COMMENTARIES reduction in antisaccade errors associ- ated with risperidone treatment is not Schizophrenia simply the result of practice effects...... Given that many of the claims for beneficial effects of atypical antipsy- chotic medications on cognition are Improved antisaccade performance based on less robust methods,5 this is a considerable contribution. However, it in schizophrenia with risperidone should be noted that the groups studied by Burke and Reveley were small and it is S B Hutton important that their findings are repli- ...... cated and extended in a larger sample. http://jnnp.bmj.com/ Atypical treatment improves cognitive function J Neurol Neurosurg Psychiatry 2002;72:429–430 everal recent studies have suggested dorsolateral prefrontal cortex and are par- that atypical antipsychotic medica- ticularly impaired in schizophrenia. The ...... tions such as risperidone can amel- author’s findings support suggestions that Author’s affiliations S S B Hutton, Department of Experimental iorate certain cognitive deficits associ- oculomotor paradigms may prove to be a Psychology, University of Sussex, Falmer, ated with schizophrenia.1 Such findings particularly sensitive tool for evaluating the Brighton BN1 9QG, UK on September 24, 2021 by guest. Protected copyright. have important implications, as cogni- neurocognitive effects of antipsychotic tive impairment is a significant predictor medications.3 Correspondence to: Dr S B Hutton; [email protected] of both social and occupational function- Recently, increased antisaccade errors ing in schizophrenia. In this issue, Burke have been reported in the first degree REFERENCES and Reveley (pp 449–454)2 show that relatives of patients with schizophrenia, 1 Meltzer HY, McGurk SR. The effects of patients treated with the atypical antip- leading to the suggestion that saccadic clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr sychotic risperidone make fewer antisac- disinhibition may be a useful marker of Bull 1999;25:233–55. 4 cade errors than when they are treated genetic vulnerability to the disorder. The 2 Burke JG, Reveley, MA. Improved with conventional antipsychotic drugs. findings of Burke and Reveley suggest antisaccade performance with risperidone in schizophrenia. J Neurol Neurosurg Psychiatry The antisaccade task has a number of that saccadic disinhibition may reflect 2002;72:449–54. advantages over more traditional neuro- “state” as well as “trait” factors. This has 3 Hutton SB, Cuthbert I, Mutsatsa S, et al.The psychological indices of cognitive function important implications for the utility of effects of typical and atypical neuroleptics on in schizophrenia: it is quick to administer, antisaccade error rate as a biological neuropsychological and oculomotor function in first-episode schizophrenia. Schizophr Res the instructions are simple to comprehend, marker for schizophrenia and merits 2000;41:40. and performance can be measured objec- further investigation. 4 Curtis CE, Calkins ME, Grove WM, et al. tively and accurately. Furthermore, antisac- By using a counterbalanced crossover Saccadic disinhibition in patients with acute and remitted schizophrenia and their cade errors (reflexive saccades towards a design, in which one group of patients first-degree biological relatives. Am J sudden onset target, instead of away from switched from typical antipsychotics to Psychiatry 2001;158:100–6. it) are thought to reflect dysfunctional risperidone and another group switched 5 Harvey PD, Keefe RSE. Studies of cognitive change in patients with schizophrenia inhibitory control processes. Such in the opposite direction, Burke and following novel antipsychotic treatment. Am J processes are generally associated with the Reveley were able to show that the Psychiatry 2001;158:176–84.

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Cervical dystonia results, it is impossible to give a conclu- ...... sive answer to this question. For the time being clinicians may be best advised to use the following landmarks for their Respective potencies of Botox and dosing decisions when treating patients with dystonia. Firstly, the equivalence ratio of Dysport to Botox should not be Dysport: a double blind, randomised, greater than 3:1 according to the majority of available comparative clinical studies. crossover study in cervical dystonia Secondly, for cervical dystonia, the indi- cation studied by Ranoux et al, a double W Poewe blind dose ranging study has shown that ...... Dysport doses needed for a satisfactory Clinically appropriate conversion factor may be less than three response are greater than 250 units and that doses greater than 500 units are associated with clear increases in adverse he issue of apparently different Fifty four patients with cervical dysto- event frequency and severity. potencies of the two available for- nia and a satisfactory response to two J Neurol Neurosurg Psychiatry 2002;72:430 Tmulations of botulinum toxin type consecutive injections of Botox at the A—Dysport and Botox—has continued same dose into identical muscles received ...... to perplex clinicians for more than a three successive treatments of either their Author’s affiliation decade. Empirically chosen doses ex- usually effective dose of Botox or three or W Poewe, Universitätsklinik für Neurologie, β pressed in mouse units in different series four times that dose of Dysport. Treat- Universität Innsbruck, Anichstra e 35, A-6020 Innsbruck, Austria and different indications reported in the ments were given in randomised order literature seemed to differ by factors of using identical volumes of injection and Conflict of interest: WP has been reimbursed by 12 muscle patterns. The effect size as assessed Allergen Inc, the manufacturer of Botox and three to six. To date only two ran- IPSEN, the manufacturer of Dysport, for speaking domised controlled studies have tried to by changes in Tsui scores and Toronto at conferences or educational courses. His answer the question of what the correct Western spasmodic torticollis rating scale department has also received grants from both. conversion factor yielding bioequiva- (TWSTRS) pain scores was significantly Correspondence to: Dr W Poewe; lence should be. One was conducted in greater with both Dysport treatments and [email protected] previously untreated patients with duration of effect was also longer. Three- blepharospasm or hemifacial spasm and fold or fourfold doses of Dysport produced REFERENCES 1 Durif F. Clinical bioequivalence of the current found a bioequivalence ratio of Botox to similar effect sizes but duration tended to commercial preparations of botulinum toxin. Dysport of 1:4 with duration of effect as be increased with the fourfold dose. Side Eur J Neurol 1995;2:17–8. the primary outcome variable.3 The effects were significantly more frequent 2 Marion MH, Sheehy M, Sangla S, et al. Dose standardisation of botulinum toxin. J Neurol second comparative trial randomly as- with both Dysport doses than with Botox Neurosurg Psychiatry 1995;59:102–3. signed patients with cervical dystonia but again not significantly different be- 3 Sampaio C, Ferreira JJ, Simoes F, et al. DYSBOT: a single-blind, randomized parallel previously treated with Botox to receive tween the two Dysport doses (17.6% of study to determine whether any differences either their clinically defined individual patients treated with Botox, and 33% and can be detected in the efficacy and tolerability dose of Botox or three times that dose as 36% of patients treated with Dysport 1:3 of two formulations of botulinum toxin type 4 A—Dysport and Botox—assuming a ratio of Dysport units and found similar effect and 1:4, respectively). 4:1. Mov Disord 1997;12:1013–8. size, duration of effect, and rates of In summary, the authors suggest that 4 Odergren T, Hjaltason H, Kaakkola S, et al. A double blind, randomised, parallel group http://jnnp.bmj.com/ adverse events. In the paper by Ranoux et even lower conversion ratios be used than study to investigate the dose equivalence of al (this issue pp 459–462)5 of this issue, 3:1 for Dysport to Botox. Should it then Dysport and Botox in the treatment of cervical results of another double blind ran- be 1:2.5 or even 1:2? If so, should we be dystonia. J Neurol Neurosurg Psychiatry 1998;64:6–12. domised study comparing efficacy and using lower doses of Dysport or higher 5 Ranoux D, Gury C, Fondarai J, et al; safety of the type A preparations seem to doses of Botox to achieve this? With only Respective potencies of Botox and Dysport: a double blind, randomised, cross over study in suggest that the clinically appropriate three randomised trials available differ- cervical dystonia. J Neurol Neurosurg conversion factor may be less than three. ing in design, target population, and Psychiatry 2002;72:459–62. on September 24, 2021 by guest. Protected copyright.

Rehabilitation the intensity of physical training after ...... middle cerebral artery stroke brought about improvements in the recovery dur- ing the first 6 months. When the addi- Intensity of rehabilitation: some tional training was focused on the upper limb improvements in dexterity were answers and more questions? observed; when the lower limb was targeted walking ability and Barthel ac- P Langhorne tivities of daily living (ADL) scores im- ...... proved. In their follow up paper (Kwakkel et al this issue pp 473–479)2 they address No benefits to intensive rehabilitation in the long term the question of whether these benefits continue in the longer term. This follow or many years rehabilitation re- enhanced by rehabilitation interven- up paper indicates that there were no sig- searchers have pondered whether tions, in particular by increasing the nificant differences between the treat- Fthe observed recovery of patients intensity of rehabilitation input. A care- ment groups at one year after random- from stroke occurs at the optimum natu- fully conducted randomised trial by isation, an observation that appears to ral recovery rate or may be further Kwakkel et al1 indicated that increasing confirm previous similar trials.34

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Why did the early benefits of intensive months showed the largest subsequent ...... training disappear at a later stage? The changes (including both improvement Author’s affiliation first possibility is that there were differ- and deterioration) in impairments and P Langhorne, Academic Section of Geriatric ences in treatment after the intervention disability. This observation is probably Medicine, 3rd Floor, Centre Block, Royal Infirmary, Glasgow G4 0SF, UK period ended but this appears unlikely. not an artefact of the measures used and None of the patient groups received does indicate that there is potentially a Correspondence to: Dr P Langhorne; much rehabilitation input after six subgroup of patients in whom increased [email protected] months. The second possibility is that therapy could be targeted at a later stage. REFERENCES the treatment group suffered a decline in The main message appears to be that 1 Kwakkel G, Wagenaar RC, Twisk JWR, et al. function after their intensive treatment increasing the intensity of upper and Intensity of leg and arm training after primary lower limb training for selected patients middle-cerebral-artery stroke: a randomised was removed. This also appears unlikely, trial. Lancet 1999;354:191–6. as it is not supported by the longitudinal after a stroke can speed up recovery but 2 Kwakkel G, Kollen BJ, Wagenaar RC. Long data. A third possibility is that the the longer term effects are uncertain. It term effects of intensity of upper and lower limb training after stroke: a randomised trial. J control group continued to improve until remains to be established whether we Neurol Nurosurg Psychiatry 2002;72:473–9. their function matched that of the inter- can identify patients who are exceptions 3 Sivenius J, Pyorala K, Heinonen OP, et al. to this general rule and would benefit The significance of intensity of rehabilitation vention groups. On balance, this seems after stroke. Stroke 1985;16:928–31. the most compelling explanation. from later intervention to optimise their 4 Sunderland A, Fletcher D, Bradley L, et al. An additional observation was that recovery. Enhanced physical therapy for arm function after stroke: a one year follow up study. J patients who were noted to have made J Neurol Neurosurg Psychiatry Neurol Neurosurg Psychiatry an incomplete functional recovery at 6 2002;72:430–431 1994;57:856–8.

Headache and hypertension medication treatment. A similar effect ...... was observed in women with migraine. Their study is relevant because it is a cross sectional study of a large unse- Headache and hypertension: refuting lected population. Hypertension is more common in men but women have a the myth higher incidence of headaches. Both women (10 698) and men (11 987) D Friedman participated in HUNT-1 and HUNT-2 ...... (Nord-Trøndelag Health Survey), sup- porting the conclusions in both sexes. Why does the hypertension headache myth persist? Generalisation of the results was ad- dressed by the authors in other reports.4 atients often tell their physicians, “I The Physicians’ Health Study prospec- Race and geographic region contribute to know when my blood pressure is tively examined 22 701 American male variations in the prevalence of headache http://jnnp.bmj.com/ Phigh because I get a headache”. The physicians aged 40–84 years, who were and hypertension. Participants in the relation of headache to hypertension has randomly assigned to receive daily aspi- HUNT studies were a homogeneous been debated in the medical literature rin, β carotene, both agents, or placebo.2 white population. Thus, the applicability for almost a century. Janeway observed it Analysis of various risk factors for of the results to other populations, such in a large clinical study of hypertensive cerebrovascular disease found no differ- as African Americans, who have a higher patients (systolic blood pressure ence in the percentage of patients with a prevalence of hypertension, is uncertain. 1 > 160 mm Hg) in 1913. He described history of hypertension between the J Neurol Neurosurg Psychiatry 2002;72:431 the “typical” hypertensive headache as migraine and the non-migraine groups. on September 24, 2021 by guest. Protected copyright. non-migrainous, present upon awaken- Additionally, no difference in risk factors ...... ing and resolving during the morning. was found between physicians with However, his illustrative case histories non-migrainous headaches and those Authors’ affiliations D Friedman, Department of Neurology, are somewhat misleading because they with no headaches. University Hospital, 750 E Adams Street, all had malignant hypertension and The paper by Hagen et al (this issue Syracuse, New York 13210, USA systolic pressures > 230 mm Hg. Addi- pp 463–466)3 lends definitive clarity to the tionally, one patient was likely in analge- issue. In their prospective study spanning Correspondence to: Dr D Friedman; [email protected] sic rebound. 13 years of 22 685 adults in Nord- There are several reasons why the Trøndelag County, Norway, patients’ blood REFERENCES “hypertension headache” misperception pressure was measured interictally and 1 Janeway TC. A clinical study of hypertensive persists: hypertension may be an epiphe- they provided information regarding cardiovascular disease. Arch Intern Med nomenon of acute pain, headache is asso- headaches and the use of pain relieving 1913;12:755–98. ciated with hypertensive encephalopathy medications. Patients were subdivided 2 Buring JE, Hebert P, Romero J, et al. Migraine and subsequent risk of stroke in the as a manifestation of increased intracra- into those with migrainous and those Physicians’ Health Study. Arch Neurol nial pressure, and headache is a side effect with non-migrainous headache based on 1995;52:129–34. of some antihypertensive treatments. modified International Headache Society 3 Hagen K, Strovmer LJ, Vatten L, et al. Blood pressure and risk of headache: a prospective Conversely, many of the antihypertensive criteria for migraine. Contrary to popular study of 22 685 adults in Norway. J Neurol medications are also effective for head- belief, high systolic blood pressure at Neurosurg Psychiatry 2002;72:463–6. ache prevention, so the risk of concurrent baseline was associated with low 4 Hagen K, Zwart JA, Vatten L, et al. Prevalence of migraine and non-migrainous headache may be low unless the influence headache prevalence 11 years later. This headache: head-HUNT, a large population of treatment is considered. was not related to antihypertensive study. Cephalalgia 2000;30:900–6.

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Author’s reply thunderclap headaches (without subarach- CORRESPONDENCE The strongest risk factor for haemorrhagic noid haemorrhage) are more likely to harbour transformation of cerebral infarction in pa- aneurysms due to primary or drug induced Radiology of stroke tients not treated with any antithrombotic or abnormalities of vessel tone. thrombolytic drug is simply having an exten- Dr Dodick reviews cases where thunderclap The optimum time frame for imaging embolic sive large infarct. It so happens that cardio- headache was associated with unruptured infarcts for stigmata of haemorrhagic trans- aneurysms, without cerebral arterial vasocon- genic cerebral embolism often results in large formation should have merited discussion striction, and where thunderclap headache cerebral infarcts (because thrombi arising under the heading “special clinical was associated with vasoconstriction, without 1 from the heart are often large and block a circumstances”, not least because of conflict- unruptured aneurysms. It should be noted largish vessel). Thus, there is an association ing evidence about the benefits versus risks that unruptured aneurysms have been associ- between cardiogenic cerebral embolism and of early anticoagulation in the context of ated with vasoconstriction, without thunder- haemorrhagic transformation. This associ- unpredictable evolution of embolic infarcts clap headache.5 This point is emphasised by ation may be exaggerated by administering with or without anticoagulant treatment. In a an additional, hitherto unpublished case antithrombotic or anticoagulant or thrombo- study comprising 30 patients with cardio- (courtesy Dr C Miller Fisher) of severe lytic therapy to these patients. Unfortunately, genic cerebral embolism, three patients with cerebral vasoconstriction, stroke, and death an initially non-haemorrhagic cerebral inf- it is difficult to draw conclusions on the risks associated with two unruptured and asymp- arct, visualised by computed tomography and benefits of anticoagulant treatment from tomatic intracerebral aneurysms without within 12 hours of stroke onset, showed non-randomised studies. The complete data thunderclap headache. The patient, a 65 year asymptomatic haemorrhagic transformation from the international stroke trial (20 000 woman, was admitted in January 1977 with in the absence of anticoagulant treatment patients) clearly show that heparin started probable Guillain-Barré syndrome. The hospi- 2–8 days later. One other patient in this sub- within the first 48 hours of stroke and contin- tal course was notable for episodic hyper- group did, however, develop sudden worsen- ued for the first 14 days may reduce the risk of tension (maximum blood pressure 200/ ing of hemiparesis despite having initially recurrent ischaemic stroke but at the risk of 100 mm Hg). On day 4, she developed cortical presented with a small infarct.2 Among 1457 increasing haemorrhagic stroke and death, 1 blindness, abulia, aphasia, and right hemiple- patients anticoagulated with unfractionated and as a result there is no net benefit. When to gia. Computed tomography showed infarc- heparin in the presence of embolic cerebral start or continue anticoagulant treatment tions in both occipital lobes and a parasagittal infarct associated with atrial fibrillation, after stroke in the small proportion of patients meningioma. A selective cerebral arteriogram haemorrhagic transformation (within 14 with a clear cardiac source of embolism is a showed aneurysms in the anterior communi- days) was significantly commoner decision that needs to be made in light of each cating and left middle cerebral artery, severe (p < 0.0001) than in their non-heparinised patient’s risk factors and continues to be a attenuation of proximal intracranial arteries, counterparts.3 Ischaemic stroke recurred thorny problem. However, the benefits of aspi- and “sausaging” of distal arteries. After with a 4.9% frequency in the latter subgroup rin (while less effective) are still worthwhile returning from the arteriogram the patient (comprising 1612 patients) during that time with less risk of haemorrhagic transformation. became obtunded, then deteriorated clini- frame, and this complication was signifi- There is no easy answer to this problem. cally, and died on day 13. A necropsy showed cantly less common (p = 0.001) in their anti- J M Wardlaw cerebral oedema with bilateral temporal lobe 3 coagulated counterparts. Anti-coagulation Department of Clinical Nurosciences, Western herniations, infarctions in the inferior cer- in the presence of haemorrhagic transforma- General Hospital, Crewe Road, Edinburgh ebellum and both occipital and frontal lobes, a tion has been advocated as being without risk EH4 2XU, UK parasagittal meningioma, and two unrup- on the basis of the outcome in 12 patients so Reference tured aneurysms (a 5 × 5 mm anterior com- 4 × treated, but the caveat is that, in another 1 International Stroke Trial Collaborative municating aneurysm and a 10 7 mm left study also involving patients with embolic Group. The international stroke trial (IST): a middle cerebral artery aneurysm). There was stroke, the subsequent development of haem- randomised trial of aspirin, subcutaneous no evidence for arterial inflammation. Lym- orrhagic transformation in 5 of 231 patients heparin, both, or neither among 19435 phocytic infiltration was present in the sciatic anticoagulated with heparin was associated patients with acute ischaemic stroke. nerves, consistent with infectious polyneuri- with significant clinical deterioration.5 It is International Stroke Trial Collaborative Group. tis. As stated in the review article,1 it is 349 this unpredictability in the consequences and Lancet 1997; :1569–81. difficult to account for any mechanism tempo of haemorrhagic transformation and whereby the aneurysms may have precipi- in the impact of early anticoagulation on this Thunderclap headache, reversible tated the vasoconstriction. phenomenon that causes anxiety among cerebral arterial vasoconstriction, A B Singhal clinicians at all levels of experience. and unruptured aneurysms Stroke Service, VBK-802, Massachusetts General O M P Jolobe Hospital, Boston, MA 02114, USA; In his comprehensive review of thunderclap [email protected] 1 Department of Adult Medicine, Tameside General headache, Dr Dodick discusses two patients References Hospital, Fountain Street, Ashton-under-Lyne with the triad of thunderclap headache, OL6 9RW, UK 1 Dodick DW. Thunderclap headache. J Neurol cerebral arterial vasoconstriction, and unrup- Neurosurg Psychiatry 2002;72:6–11. References tured cerebral aneurysms. We recently re- 2 Singhal AB, Caviness VS, Begleiter AF, et al. 1 Wardlaw JM. Radiology of stroke. J Neurol ported on two very similar patients, in whom Cerebral vasoconstriction and stroke after use Neurosurg Psychiatry 2001;70(suppl the symptoms developed shortly after expo- of serotonergic drugs. Neurology 1):i7–11. sure to commonly used serotonin enhancing 2002;58:130–3. 2 Cerebral Embolism Study Group. drugs.2 The interrelation between thunderclap 3 Singhal AB, Koroshetz W, Caplan LR. Immediate anticoagulation of embolic stroke: headache, cerebral arterial vasoconstriction, Cerebral vasoconstriction syndromes. In: Bogousslavsky J, Caplan LR, eds. Uncommon brain hemorrhage and management options. and unruptured aneurysms is not clear, and in 15 causes of stroke. Cambridge: Cambridge Stroke 1984; :779–89. these four patients the aneurysms may well 3 Saxena R, Lewis S, Berge E, et al, for the University Press, 2001:114–23. International Stroke Trial Collaborative Group. have been incidental findings. However, it is 4 McEvoy AW, Kitchen ND, Thomas DGT. Risk of early death and recurrent stroke and interesting that, in addition to segmental Intracerebral hemorrhage caused by drug effect of heparin in 3169 patients with acute vasoconstriction, cerebral angiograms in pa- abuse. Lancet 1998;351:1029. ischaemic stroke and atrial fibrillation in the tients with the Call-Fleming and some other 5 Friedman P, Gass H, Magidson M. Vasospasm international stroke trial. Stroke vasoconstriction syndromes3 can have areas of with an unruptured and unoperated aneurysm. Surg Neurol 1983;19:21–5. 2001;32:2333–7. vasodilatation beyond the normal diameter of 4 Pessin MS, Estol CJ, Lafranchise F, et al. the artery. Moreover, patients with stroke Safety of anticoagulation after hemorrhagic associated with the use of vasoconstrictive Author’s reply infarction. Neurology 1993;43:1298–303. 5 Chamorro A, Vila N, Ascaso C, et al. drugs such as cocaine and “ecstasy” are I would like to thank Dr Singhal for his inter- Heparin in acute stroke with atrial fibrillation: known to have an unusually high number of est and thoughtful insights concerning the 4 1 clinical relevance of very early treatment. Arch aneurysms. It is conceivable that patients review article on thunderclap headache. I Neurol 1999;56:1098–102. who develop cerebral vasoconstriction or will address his comments in order.

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Firstly, I had already read with great interest 3 Armstrong FS, Hayes GJ. Segmental cerebral opposed to “homoplasmy”, where only one the recent article from Dr Singhal et al2 arterial constriction associated with type is present. It is hypothesised that pheno- regarding three patients with thunderclap pheochromocytoma. J Neurosurg typic expression of mtDNA pathology may headache, reversible vasospasm, and ischaemic 1961;18:843–6. occur when heteroplasmy within an organ Trommer BL stroke possibly secondary to exposure to sero- 4 , Homer D, Mikhael MA. Cerebral vasospasm and eclampsia. Stroke reaches a certain level. This concept is known tonergic medications. He also correctly points 1988;19:326–9. as the “threshold effect”. The severity of the out that the unruptured aneurysms found in 5 Margolis MT, Newton TH. Methamphetamine phenotype is thought to correlate with the some patients with thunderclap headache and (“speed”) arteritis. Neuroradiology degree of heteroplasmy in different tissues. reversible vasospasm are possibly incidental—a 1971;2:179–82. Interestingly, both syndromes, MELAS and point that I made in the review article. On the 6 Kaye BR, Fainstat H. Cerebral vasculitis MIDD, can be found in a single pedigree with basis of the association with unruptured aneu- associated with cocaine abuse. JAMA the A3243G mutation. The A3243G mutation rysms or exposure to sympathomimetic and 1984;258:2104–6. is also associated with Kearns-Sayre syn- serotonergic medications in some patients with 7 Tang-Wai DF, Phan TG, Wijdicks EFM. Hypertensive encephalopathy presenting with drome. Assuming that all patients with the thunderclap headache and vasospasm, he raises A3243G mutation have the MELAS syndrome the provocative and interesting possibility that thunderclap headache. Headache 2001;41:198–200. leads to an incorrect diagnosis, with signifi- patients who develop thunderclap headache cant implications for patient counselling. A (without subarachnoid haemorrhage) are more diagnosis of MELAS implies that the patient likely to harbour aneurysms due to primary or Cochlear implantation in a has developed stroke-like episodes or en- drug induced abnormalities in vessel tone. profoundly deaf patient with cephalopathy. There are certainly cases of thunderclap As more people with SNHL become geno- headache with reversible vasospasm that have MELAS syndrome typed and the identification of the true preva- occurred shortly after exposure to sympatho- In response to the article “Cochlear implanta- lence of mitochondrial SNHL becomes more mimetic medications such as cocaine or tion in a profoundly deaf patient with MELAS obvious, a database of already successfully amphetamines, as well as during hyperadren- syndrome” (mitochondrial myopathy, en- treated patients by cochlear implantation will ergic metabolic states such as eclampsia and 3–6 cephalopathy, lactic acidosis, and stroke-like be useful for quantitative analyses of perform- hypertensive crisis. Most of the patients 1 episodes), we feel concerned that this patient described in the literature, however, did not ances of these patients with cochlear im- may have a different diagnosis. This woman harbour intracranial aneurysms, and prospec- plants. Here also, the correct label must be who received a cochlear implant is described tive longitudinal studies of patients with non- assigned to patients. as having the MELAS syndrome, in both the aneurysmal thunderclap have not found an More information on mitochondrial SNHL increased risk of subarachnoid haemorrhage. title and the text, when perhaps she has the can be obtained on the Hereditary Hearing Ideally, a longer prospective study of patients less severe maternally inherited diabetes mel- loss Homepage on http://www.uia.ac.be/ with thunderclap headache with cerebrovas- litus with deafness (MIDD) syndrome. dnalab/hhh/. She has the A3243G point mitochondrial cular imaging or careful assessment of a large A R Sinnathuray, V Raut, J G Toner group of patients with unruptured aneurysms DNA (mtDNA) mutation associated with (such as the international unruptured aneu- insulin dependent diabetes mellitus, congeni- Department of Otolaryngology, Belfast City Hospital, Belfast, UK ryms study) for a history of thunderclap tal cataracts, short stature, leg weakness, headache would be required to address the fatigue, and sensorineural hearing loss A Magee hypothesis raised by Dr Singhal. (SNHL), with no encephalopathy or strokes. The age of onset of SNHL was 22 years, with a Department of Medical Genetics, Queen’s Dr Singhal also suggests that unruptured University, Belfast at the Belfast City Hospital aneurysms may present with vasospasm in the slow deterioration to right profound SNHL at absence of a thunderclap headache. The case the age of 29 years, and bilateral profound Correspondence to: Mr J G Toner, Director, (courtesy of C Miller Fisher) that he uses to illus- SNHL and tinnitus at the age of 30 years. Regional Cochlear Implant Centre, Belfast City trate this point is a very interesting one. While it Caloric testing and computed tomography of Hospital, Lisburn Road, Belfast BT9 7AB, Northern is certainly possible that the unruptured aneu- her temporal bones were both normal. Her Ireland, UK; [email protected] rysms in this case may have given rise to the mother suffered from diabetes, glaucoma, and vasospasm, I believe the vasospasm in this 65 a lesser degree of SNHL, and a sister has pro- References year old woman with Guillian-Barré syndrome found SNHL and mental retardation. 1 Hill D, Wintersgill S, Stott L, et al. Cochlear was more likely related to the severe labile MELAS is a multisystem disorder with a implantation in a profoundly deaf patient with hypertension—a result of dysautonomia fre- wide variety of possible clinical features. MELAS syndrome. J Neurol Neurosurg Psychiatry 2001;71:281. quently seen in this disease. As alluded to earlier, Among these multiple features, the diagnostic 2 2 Hirano M, Ricci E, Koenigsberger MR, et al. vasospasm has been well described in patients criteria for MELAS are as follows : Melas: an original case and clinical criteria with acute hypertensive crises such as phaeo- • Stroke-like episodes before age 40 years; for diagnosis. Neuromuscul Disord chromocytoma, eclampsia, and hypertensive en- 1992;2:125–35. cephalopathy. Hypertensive encephalopathy with • Encephalopathy (seizures, dementia, or both); 3 DiMauro S. MELAS (mitochondrial posterior leucoencephalopathy syndrome (PLES) • Mitochondrial myopathy (lactic acidosis, encephalomyopathy, lactic acidosis, and was recently described in a patient with thunder- ragged red muscle fibres, or both); stroke-like episodes; myopathy, clap headache,7 and I have just submitted a simi- mitochondrial-encephalopathy-lactic lar case for publication in a young woman who • Two of the following three: normal early acidosis-stroke). In: GeneReviews at psychomotor development, recurrent head- GeneTests-Gene Clinics: Medical Genetics also had reversible vasospasm in the setting of a Information Resource [database online]. hypertensive crisis and PLES. In fact, it is possible ache, recurrent vomiting. Now these clinical findings can be con- Copyright, University of Washington, Seattle. that in many cases of drug induced cerebral 1997–2001. 26 February 2001. vasospasm, the effect on vascular tone and firmed with a positive molecular genetic test http://www.genetests.org. 3 calibre may reflect the effect of these sympatho- for mtDNA mutations. The A3243G mutation 4 Oshima T, Ueda N, Ikeda K, et al. Bilateral mimetic drugs on arterial blood pressure in addi- in the mitochondrial tRNALeu(UUR) gene, MTTL1, sensorineural hearing loss associated with the tion to a direct vasoconstrictive effect of the causes MELAS and is responsible for MELAS point mutation in mitochondrial genome. drugs. Indeed, it would have been of notable in approximately 80% of patients. Laryngoscope 1996;106:43–8. interest to know the arterial blood pressure in the MIDD has a narrower phenotype of bilat- 5 Remes AM, Majamaa K, Herva R, et al. Adult-onset diabetes mellitus and neurosensory patients he described with reversible vasospasm eral, progressive, symmetrical SNHL, gener- ally preceding diabetes mellitus (ranging hearing loss in maternal relatives of MELAS and stroke in patients exposed to serotonergic patients in a family with the tRNA(Leu(UUR)) medications, since the magnetic resonance imag- from abnormal glucose tolerance to insulin mutation. Neurology 1993;43:1015–20. ing abnormalities in his patients are very similar dependent diabetes mellitus) and occurs in adulthood, on a background of maternal to the changes seen in patients with PLES. Author’s reply D W Dodick inheritance. Sporadic occurrence has been noted.4 It is associated with short stature and We are grateful to Dr Sinnathuray and Department of Neurology, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, Arizona can be expressed as type 1-like or type 2-like colleagues for their very useful comments on 5 85259, USA; [email protected] diabetes. The A3243G transition mutation the precise diagnosis of our patient’s condi- References has been identified as the cause of MIDD in tion. We agree entirely with the comment that 60% of cases. the A3243G mutation also occurs in mater- 1 Dodick DW. Thunderclap headache. J Neurol Neurosurg Psychiatry 2002;72:6–11. In patients with mtDNA disease, affected nally inherited diabetes mellitus with deaf- 2 Singhal AB, Caviness VS, Begleiter AF, et al. cells and tissues tend to harbour mixtures of ness (MIDD). In our patient the original diag- Cerebral vasoconstriction and stroke after use of mutant and wildtype mtDNA in different pro- nosis was made by a clinical geneticist in 1994 serotonergic drugs. Neurology 2002;58:130–3. portions. This is called “heteroplasmy”, as and therefore, in a rapidly changing field,

www.jnnp.com 98 PostScript greater precision in diagnosis might have resolved. From a didactic point of view, and to been possible with a further genetics consul- allow the reader to learn more about the tation at a later date. We should point out that anatomical substrate of this rather catastrophic this article was originally submitted in No- outcome in patients with bilateral PVP,the MRI vember 2000 and this, also, may have contrib- scans should have been shown in this impor- uted to the diagnosis of MELAS syndrome tant paper. I invite Merello et al to publish rather than MIDD syndrome. We are most relevant axial and coronal postoperative brain grateful to Dr Sinnathuray and colleagues for MRI scans of these three patients in their their useful comments. answer to this letter, showing the locations of J Graham the bilateral posteroventral GPi lesions that were responsible for the reported “corticobul- UCL Cochlear Implant Unit, Royal National Throat, Nose & Ear Hospital, 330–332 Gray’s Inn Road, bar syndrome and psychic akinesia.” London WC1X 8DA, UK M I Hariz Department of Neurosurgery, University Hospital, Bilateral lesions restricted to the 901 85 Umeå, Sweden; posteroventral pallidum are [email protected] References unlikely to provoke corticobulbar 1 Merello M, Starkstein S, Nouzeilles MI, et al. syndrome and psychic akinesia Bilateral pallidotomy for treatment of Parkinson’s disease induced corticobulbar Merello et al reported a randomised study syndrome and psychic akinesia avoidable by comparing bilateral simultaneous postero- globus pallidus lesion combined with ventral pallidotomy (PVP) with a combination contralateral stimulation. J Neurol Neurosurg of unilateral PVP and contralateral pallidal Psychiatry 2001;71:611–14. stimulation.1 After having included three 2 Scott R,GregoryR,HinesN,et al. patients in each group, the study had to be Neuropsychological, neurological and aborted because of the severe complications functional outcome following pallidotomy for encountered in the patients who had had Parkinson’s disease. A consecutive series of bilateral pallidotomy. eight simultaneous bilateral and twelve unilateral procedures. Brain This interesting paper raises some serious 1998;121:659–75. concerns. 3 Schuurman PR, de Bie RM, Speelman JD, et First, the three patients who had bilateral al. Bilateral posteroventral pallidotomy in PVP had a mean age of 67 years and those advanced Parkinson’s disease in three who had PVP and contralateral pallidal patients. Move Disord 1997;12:752–5. stimulation had a mean age of 55 years. This 4 Counihan TJ, Shinobu LA, Eskandar EN, et difference in age is said to be non-significant. al. Outcomes following staged bilateral As there are only three patients in each group pallidotomy in advanced Parkinson’s disease. 56 it would perhaps have been more appropriate Neurology 2001; :799–802. 5 Intemann PM, Masterman D, Subramanian I, to have given the ages of the individual et al. Staged bilateral pallidotomy for patients rather than the means. treatment of Parkinson disease. J Neurosurg Second, at three months after surgery, the 2001;94:437–44. patients who had bilateral PVP showed dete- rioration in parts I (mood) and II (activity of Author’s reply daily living) of the unified Parkinson’s disease rating scale (UPDRS). The subscores of gait We greatly appreciate the publication of the and postural instability worsened signifi- letter from Professor Hariz, which gives us cantly. The patients showed deterioration in occasion to provide more information about depression and apathy scores, and it was not our paper and confirm the dangerous effect of possible to perform neuropsychological evalu- simultaneous bilateral lesions within the GPi. ation after surgery. The patients required feed- We all know how limited the literature is on ing tube, their gait freezing deteriorated, and negative results of surgical procedures and they had no benefit from increased levodopa how important they are. Surgery for Parkin- doses. They suffered from severe loss of initia- son’s disease is an extremely useful tool in a tive and motivation. In my opinion, even certain subgroups of patients, but it is not though bilateral pallidotomy may increase the entirely risk-free and unfortunately many of risks of complications,2–5 the disastrous out- the side effects seen at the bedside are poorly Figure 1 Axial MRI scans with three month come of the three patients described in Merel- represented in published reports. old bilateral pallidal lesion performed in the lo’s paper poses serious questions as to the On the basis of unpublished descriptions by patients who underwent bilateral ablative exact location of the lesions. I believe that in many neurosurgeons, bilateral procedures are procedures. order to provoke the severe corticobulbar syn- performed by placing a normal lesion on one drome and “psychic akinesia” described, the side, involving as much as possible of the motor akinesia was only present in simultaneous bilat- pallidal lesions must have encroached on the portion of the GPi, followed by a smaller erally lesioned cases. internal capsule bilaterally, and also have contralateral lesion. An excellent point arises We are sure that Hariz must have already included antero-dorso-medial parts of the GPi. from the concern expressed by Hariz: should read a recent review by Laplane and Dubois,2 The authors wrote that “brain MRI three both lesions be the same size? Perhaps staged which clearly describes the psychic akinesia months after surgery showed that all nine asymmetric lesions could provide an alterna- syndrome as a result of bilateral basal ganglia lesions and the three electrodes were located tive, but this was not the case in our report; we lesions, providing deep insight into the entirely within the GPi. Coordinates of the made simultaneous lesions which both in- non-motor roles of the basal ganglia, such as lesion/lead as well as lesion volumes were not volved as much as possible of the motor portion behavioural activation, cognitive processing, significantly different between the groups.” The of the GPi, and our conclusions should not be affectivity, and conscious awareness, with authors concluded: “Our present findings argue extended to other surgical contexts. which we fully agree. against the possibility that lesion inaccuracy is As requested, we provide MRIs of our cases responsible for the unacceptable rate of side (fig 1) and fully agree that lesion placement is M Merello effects of bilateral procedures as targets were crucial, as Hariz is well aware, given his reported Movement Disorders Section, Raul Carrea Institute confirmed by microrecording, lesions checked outcome of five of 13 patients (that is, almost for Neurological Research, FLENI, Buenos Aires, by MRI and the same criteria were followed 40%) who subsequently required seven further Argentina; either for lesioned or stimulated patients.” procedures, presumably because of initial lesion [email protected] It is indeed very fortunate that the authors misplacement.1 Whatever the importance of References did perform the postoperative MRI at three descriptive photography, we believe it was more 1 Hariz M, Bergenheim T. A 10-years follow-up months after surgery—that is, when the surgi- important that non-significant statistical differ- review of patients who underwent Laksell’s cal oedema that would disturb the interpret- ences were found in lesion/stimulation place- posteroventral pallidotomy for Parkinson’s ation of the lesion location had completely ment between the groups, and clinical psychic disease. J Neurosurg 2001;95:552–8.

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2 Laplane D, Dubois B. Auto-activation deficit: clinical presentation and stroke aetiologies Channelopathies of the nervous a basal ganglia related syndrome. Move are less successful. Except for coverage of car- system Disord 2001;16:810–14. diac investigations and prothrombotic states, these chapters are rather brief and general, Edited by M R Rose and RC Griggs (Pp 347, and serve only as introductions to the subjects £60.00). Published by Butterworth Heine- BOOK REVIEWS discussed. In the non-management chapters, mann, Oxford, 2001. ISBN 0-7506-4507-5 the authors seek to cover the waterfront and Ischemic cerebrovascular at least mention most things neophytes and Over the past few years there has been an non-stroke experts would want to look up. explosion of knowledge regarding a group of disease These non-management chapters are covered diseases that have become known as the much better and in much more detail in other channelopathies. Like many new chapters of By Harold P Adams, Vladimir Hachinski, and texts. The presentations are practical and are medical discovery it always seems obvious in John W Norris (Pp 575, £95.00). Published time locked to trials and results of treatment. retrospect. After all, ion channels are one of by Oxford University Press, New York, 2001. There is little theoretical background or the most critical structures for normal neural ISBN 01951-328-90 detailed discussions of anatomy, pathology, activity. This cascade of new knowledge has and pathophysiology. The attempt to cover all now firmly established that dysfunction of The most recent book in the very successful topics means that some are very scantily con- both ligand gated and voltage gated ion chan- “black book” Contemporary neurology series from sidered. The sections on vertebral artery nels may cause human diseases. The dysfunc- Oxford University Press is a monograph on disease, cerebellar infarction, and lacunar in- tion either may be caused by autoimmune brain ischaemia. The book is written by three farction are extremely brief. Many of the non- attack, such as myasthenia gravis, or may be experienced and well respected North Ameri- atherosclerotic conditions and cardioembolic the result of mutations in ion channel genes, can authors—Adams from the United States sources are mentioned only in brief pithy such as the skeletal muscle channelopathies. and Hachinski and Norris from Canada. The paragraphs. Non-stroke experts would derive In the main, channelopathies are disorders of present monograph is a successor to a the barest information from the text but can excitable tissues and the nervous system is of previous book entitled The acute stroke by look up references. Unfortunately, most refer- course particularly affected. Hachinski and Norris published 16 years ago. ences are only to journal articles; references to It is therefore timely that Channelopathies of There are now many books on stroke and on monographs and review of topics considered the nervous system should be published to brain ischaemia. While reading this present scantily would also have been helpful. provide a snap shot of current knowledge in endeavour, I continued to ponder the role of This book will be most useful to non- this area. The editors state that their aim is “to this monograph among the already burgeon- neurologists and non-stroke specialists who inform both clinicians and neuroscientists as ing library of books. Whom is it aimed at? have the responsibility of managing patients to the state of the art of neurological Who will profit most by its content? When, with acute brain ischaemia acutely in emer- channelopathies, both clinically and scientifi- why, and how will readers use this book? gency rooms and in hospitals. It serves as an cally”. I think this has been achieved through The text can be conveniently divided into excellent reference source concerning a wide the contributions of 34 recognized authorities four parts. The initial portion consists of four variety of topics related to brain ischaemia, in various subfields of neurological chan- chapters: an introductory general chapter fol- which are considered in more detail elsewhere. nelopathies. lowed by single survey chapters on epidemiol- The foreword is particularly informative ogy, clinical presentation of ischaemic and Louis Caplan and sets the scene very well for what is to fol- transient ischaemic strokes, and imaging and low. In the preface the editors acknowledge laboratory evaluation of these patients. The The behavioral neurology of that the ultimate importance of channelopa- second portion of the book consists of five thies and of ion channel dysfunction remains descriptive chapters: four concern different white matter to be determined. It is certainly true that all stroke aetiologies—atherosclerotic diseases, the channelopathies defined to date are non-atherosclerotic vasculopathies, cardiac Edited by Christopher M Filley (Pp 267, relatively rare diseases. However, there is of sources of embolism, and prothrombotic £43.50). Published by Oxford University course enormous expectation that ion chan- states; the fifth chapter considers ischaemic Press, New York, 2001. ISBN 0-19-513561-X nel dysfunction will be important in the most strokes in the young. The final five chapters common paroxysmal disorders: epilepsy and discuss management: medical therapy, surgi- This is a single author review and is a small migraine. This remains unproved. cal therapy, acute management of patients book of 279 pages. It is divided into three parts, The layout of the book is logical and gener- with ischaemic stroke, and hospital manage- the first covering the normal function, develop- ally user friendly. Each chapter stands more or ment and rehabilitation. The management ment, and imaging of white matter. The second less alone and as expected for a multiauthor section, although consisting of only five chap- and largest covers diseases affecting white text the styles vary. The book is divided into ters, makes up 245 pages, nearly half of the matter. While the range of conditions covered is eight main parts: basic science, assessment of 575 pages of the book. comprehensive, each condition receives from a channel function (in vitro and in vivo), The book has some attractive features that short paragraph to a couple of pages. While the channel gene expression, genetic and acquired make it very user friendly. It is well organised. material in the first two sections therefore neuromuscular channel disorders, central There is a detailed outline at the beginning of focuses on white matter, these sections do not nervous system disorders, toxin induced chan- the book and at the beginning of each chapter. provide any information that would not be nel disorders, and potential channel disorders. Furthermore, there are clear bold subhead- readily accessible in standard neurological Recent genetic discoveries indicate that proxi- ings and a detailed index. These features texts. The third section deals specifically with mal myotonic myopathy and Schwartz-Jampel make it quite easy to locate desired infor- the cognitive and neurobehavioural aspects of have in fact both bitten the dust as potential mation. Tables are sprinkled amply through- white matter disease. An overview of the channelopathies! I found the chapters on the out and the tables succinctly summarise key cognitive changes that may be seen is provided central nervous system disorders especially points. The book is very heavily referenced along with further discussion of individual readable although already out of date in what and the references are up to date. There are syndromes but again the information provided is such a rapidly expanding area. ample figures that illustrate well the main on each syndrome is brief. Similar comments This is one of the first texts on this subject disorders and the main diagnostic tools. A apply to the following section on psychiatric and I can recommend it to interested neurolo- unique feature is the inclusion of clear syndromes. Readers consulting the book for gists and neuroscientists. diagrams and figures of echocardiograms. advice on any aspect of management will be Michael Hanna Cardiac investigations are not usually covered disappointed; this is scarcely mentioned at all. nearly as well in monographs about stroke. Another common issue, the selection of appro- The best and most useful portion of the priate scales and tests for the assessment of Disorders of voluntary muscle, book is the section on management of cognitive loss, is also striking by its absence. 7th edn patients with ischaemic stroke. This was the It is difficult to see where this book will fit core of the predecessor of this book. Treatment in; the first two sections would be better cov- ered elsewhere. The final section provides Edited by G Karpati, D Hilton-Jones, and R C discussions are practical, detailed, evidence Griggs (Pp 775, £140.00). Published by based, and up to date. The chapter on more unusual material but even so this is brief, somewhat theoretical, and devoid of Cambridge University Press, Cambridge, management of patients with acute ischaemic 2001. ISBN 0-521-65062-3 stroke is especially well done and will be quite information on diagnosis or management. It useful for non-neurologists and non-stroke may be useful as an introductory monograph It is estimated that at least one in 500 people neurologists who lead stroke treatment in for people in training entering the field. will be affected by specific genetic or other hospitals and stroke units. The chapters on John Bowler lifelong neuromuscular disorders. Inevitably

www.jnnp.com 100 PostScript this figure is likely to be a significant underes- Several of the dystrophies, congenital my- documents on an enormous variety of issues timate because of inadequate case ascertain- opathies, and, of course, the inflammatory including diagnostic criteria and treatment of ment, as well as our limited ability to identify myopathies are covered in some detail, each in most disorders an old age psychiatrist is likely what is likely to be another large number of as separate sections. These are, generally speak- to encounter, service standards, and legal and yet unrecognised muscle disorders. Into the ing, up to date and provide, in particular, a ethical issues. Some of the more interesting, latter group may fall patients who complain of good account of the recent advances in the and important, areas are genetic testing for muscle weakness, fatigue, or aching in whom molecular genetics, particularly of the dystro- Alzheimer’s disease, advice on capacity and no specific abnormality can yet be identified. phies. The section on mitochondrial disorders decision making, electronic tagging, advice on Thus, muscle diseases constitute an important is also comprehensive and provides a useful bathing persons with dementia, and use of area of clinical activity and such patients are algorithm for assessment of patients with music therapy. Many governmental publica- seen by neurologists, rheumatologists, gen- possible mitochondrial disease. It is the tions are summarised into a page or so, eral physicians, and a variety of other special- section on the inflammatory myopathies that including “Forget-me-not”, the National ists. Thus, an up to date, comprehensive, and will probably be most used by generalists, Service framework for older people, “No accessible textbook is extremely valuable for including both neurologists and rheumatolo- secrets”, “The way to go home”, “The coming the generalist, as well as for those with a spe- gists. The section written by Dalakas and Kar- of age”, and other essential reading. I also cific interest in muscle disorders. pati is excellent and provides a comprehensive recommend the introduction, which has a This book has become a standard text for overview of the clinical, morphological, aetio- balanced overview about how guidelines are myologists and neurologists alike ever since logical, and therapeutic aspects of these constructed, their use, and their shortcomings its first publication in 1964. It has been disorders. In particular, the discussion of the (including legal issues). If I have one sugges- through several editions and this most recent involvement of muscle in other inflammatory tion for the second edition, it is that there be a one has been supervised by three leading disorders is helpful. My only suggestion might brief critical appraisal of each guideline, myologists. It is divided into four sections have been an algorithm to help guide clini- although the authors do provide a template covering the scientific basis of muscle disease, cians in the treatment of these disorders. for the reader to do this. methods of investigation, clinical features of Genetic counselling in muscle diseases has The same stable have produced another muscle disorders, and, finally, the principles now become a critically important area. excellent compendium, Assessment scales in old for their management. This therefore provides Therefore, the chapter by Bushby is very wel- age psychiatry by Burns et al (1999), that must a comprehensive review of the foundations of come. This sets out clearly the approach that have saved countless hours of researchers’ neuromuscular diseases. The list of contribut- clinicians should take to achieving a diagnosis time and is in my view an essential compan- ing authors is impressive. There are several and to counselling patients and relatives with ion to anyone undertaking research in the outstanding contributions. I will mention the various types of inherited muscle disease. discipline. Clinical guidelines in old age psychiatry only a few of these. I imagine that this section in particular will has a broader audience and is likely to prove Skeletal muscle biochemistry is often an find its way in some easily accessible form just as valuable. area where even myologists begin to feel into the clinic drawer. James Warner uncertain. There have been several important Finally, the last chapter deals with practical recent advances in this area, particularly in management issues in patients with muscle understanding the relation between bio- disease. This is clearly a very important area Mood and anxiety disorders in chemical defects and clinical manifestations. for patients who sadly often progress inexora- children and adolescents: a The section on skeletal muscle biochemistry bly and require an increasing degree of help psychopharmacological approach by John Land is exceptional and provides a from carers and the medical profession as clear and succinct view of the important areas each year passes. This is one of the most of skeletal muscle chemistry, including the important areas for managing patients with By David Nutt, Caroline Bell, Christine effects of exercise and training. This section muscle disease and it is pleasing that this has Masterson, and Clare Short (Pp 110, complements the chapter on metabolic my- been covered in some detail. £19.95). Published by Martin Dunitz Publish- opathies, which provides a detailed account of Where do the faults lie? In reality,none of my ers, London, 2001. ISBN 1-85317-924-8 muscle biochemistry and how it may result in criticisms are anything but quibbles. Some of human disease. Inevitably some of the sec- the sections seem a little superficial but Anxiety disorders are among the more com- tions are brief but this is balanced by a good inevitably this must reflect the constraint of mon psychiatric disorders of childhood, and range of references. The two sections taken chapter size in what must be intended to be a adolescent depression is being increasingly together should prove a significant help to single volume text. There are of course other recognised in clinical practice. In contrast with those having to deal with patients who texts with which this will have to compete. the popularity of psychotropic medication in present with metabolic abnormalities of mus- Both Myology by Engel and Franzini-Armstrong the treatment of adults with anxiety and cle. and Neuromuscular disorders by Katirji et al are depressive disorders, it is comparatively rare The morphological examination of muscle also excellent texts covering a similar range of for this to be prescribed in childhood. This is disease lies at the centre of the evaluation of topics. Needless to say, these are all pretty hefty partly because of the efficacy of alternative patients with myopathies. The section by tomes and the reader will have to select which psychotherapeutic techniques but is also Sewry and Dubowitz provides an excellent of these suits him or her best. The latest Disor- determined by the paucity of supportive background review of this area, as well as a ders of voluntary muscle must rank alongside the research for psychotropic drugs until recently. comprehensive analysis of morphological ab- other top texts in this area. This is now changing rapidly and evidence normalities in muscle disease. Inevitably the Anthony Schapira is emerging for the efficacy of selective sero- contribution has had to be condensed but this tonin reuptake inhibitors for both anxiety and section should provide a rapid and easy guide depressive disorders of childhood. to those who may not necessarily be experts Clinical guidelines in old age This book is timely in outlining the current in muscle morphology. psychiatry state of knowledge on these disorders from a The clinical evaluation of the patient with psychopharmacological perspective and in symptoms of muscle disease is critical to By A Burns, T Dening, and B Lawlor (Pp 208, aiming to give clinicians practical advice on achieving an accurate diagnosis. Generally, £29.95). Published by Martin Dunitz, London, the use of medication in this age group. It diseases of muscle have only a limited range 2002. ISBN 1-84184-0297 draws on knowledge—mainly from the adult of clinical expression and it is often the subtle literature—on underlying neurobiological features that give a guide to diagnosis or an Do we really need a book on clinical guidelines processes. It gives an overview of neurotrans- appropriate plan of investigation. Muscle pain for old age psychiatry? Read this book and I mitters involved, the mechanisms of action, is probably one of the most frequent com- think you will agree with me the answer is and side effect profiles of various drugs avail- plaints and, as intimated above, investigation yes! I suspect many clinicians, like myself, able. The research evidence is reviewed and of many of these patients is negative, al- have an innate dislike of guidelines. They are practical advice is given on the use of though this does not, of course, exclude their perceived as constraining clinical freedom, are medication. Families are becoming better having an underlying muscle disorder. A care- generally (inevitably) reductionist in their informed about different child psychiatric ful approach to patients with myalgia is criti- approach, and may be used as a stick with treatments and they may be expected to be cal. Thus, it is helpful for this topic to have which to beat us. Furthermore, the prov- offered treatment choices and their evidence been covered in some detail in this section. enance of some guidelines is dubious but once base. This book will be helpful to clinicians Moreover, the painful muscle syndromes are published they garner a mantle of authority when considering the indications and con- specifically covered by Lane, and this detailed that is difficult to neutralise. traindications of medication as part of clinical analysis of the various causes of this symptom This excellent book summarises 129 guide- interventions. is also particularly helpful. lines, statements, official reports, and policy Elena Garralda

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Neurological eponyms predominantly the spinal arachnoid, it also unclear to him. The book is beautifully covers important cranial subdivisions of the produced and pleasant to hold in the hand. Edited by Peter J Koehler, George W Bruyn, condition, in addition to associated conditions Ramón y Cajal’s work is as central to neuro- and John M S Pearce (Pp 386, £39.50). Pub- such as syringomyelia. There is an interesting logical research today as it was century ago. lished by Oxford University Press, New York, section on questionable causes of arachnoidi- The translators and publishers deserve our 2000. ISBN 0-19-513366-8 tis, which are very relevant because the previ- gratitude for bringing this essential work to a ously predominant causes—namely, injection new generation of readers. I enjoyed this book. It is one to delve into W I McDonald rather than to read formally. It appears to of foreign materials into the intrathecal com- have had a rather long gestation since the partment of the spine for diagnostic and introduction is dated September 1999. The therapeutic purposes—are no longer used or Clinical evaluation and book is separated into five sections though at are regarded with circumspection. The final management of spasticity times the inclusion of a particular chapter in a sections relate to the thorny question of diag- particular section seems somewhat arbitrary. nosis, which is extremely difficult, and to the Edited by David A Gelber and Douglas R Jef- The editors have aimed for a uniformity of limited treatment options available. Arach- fery (Pp 385, US$125.00). Published by approach in which a brief historical survey is noiditis is a condition that would be better Humana Press, Totowa, 2002. ISBN followed by a resume of the original descrip- prevented than treated. Unfortunately, the 0-89603-636-7 tion and then a setting of that description in a prognosis remains bleak for these patients but the management strategies in dealing with This is a useful and interesting book. It is modern context. Inevitably the quality and increasingly recognised that several treatment interest of the contributions vary consider- multiple concerns faced by such patients are well described. The senior author is to be con- strategies can be beneficial in the manage- ably. The chapters are well illustrated with ment of spasticity, particularly using more both portraits of the person and, where gratulated on producing a single volume, based on some eight thousand references, and recent drugs such as tizanidine and botuli- relevant, illustrations from original descrip- num toxin. The book is a comprehensive tions. In general the editing has been thor- his undoubted unique experience of dealing with hundreds of such cases, which is a review of the subject. No important topics are ough though curiously the chapter on missed, although the length and thorough- Creutzfeldt-Jakob disease ends with a para- unique contribution to our body of knowl- edge. ness of the chapters do vary to a significant graph covering data that had been previously degree. discussed in the middle of the text. Some It is salutary reading for some of the more senior members of our profession and will The book opens with a brief chapter on the authors chose not to question the appropri- physiology and pharmacology of spasticity. ateness of the attribution of a particular syn- provide guidance to the younger members. It is a useful book for anyone treating patients Although the book is targeted towards a clini- drome or sign to a particular person; others do cal audience, and as such is a practical so sometimes amusingly as, for example, in with this awful affliction and it can provide guidance to those involved in dealing with textbook, it is a pity that this opening chapter the chapter by Bruyn and William Gooddy on is so brief with regard to the neurophysiology Horner’s syndrome. There is little to quibble patient complaints or litigation. The book pro- vides both philosophical and scientific view- of spasticity. An understanding of the under- with in terms of the attributions, though why lying principles is important for logical treat- on earth cluster headache is entitled Horton’s points. J Van Dellen ment. Alex Dromerick produces a good chap- syndrome is not entirely clear to this reviewer. ter covering the clinical features of spasticity Although Horton himself had the temerity to and a brief resume of complications. This is suggest that the specific type of headache he Texture of the nervous system of followed by an excellent chapter on the described in 1939 had not been described man and the vertebrates, measurement of spasticity by David Good, adequately in the literature, he clearly had not which I found to be one of the most useful read Wilfred Harris’s contributions published volume II summaries of this field that I have read for in Neuritis and neuralgia in 1926 and later in some time. My major disappointment in the The facial neuralgias in 1937. Harris described By Santiago Ramón y Cajal. Translated and book is the brevity of the following chapter on virtually all the characteristic features of clus- edited by Pedro Pasik and Tauba Pasik (Pp physical and occupational approaches. The ter headache including distribution, periodic- 667, US$150.00). Published by Springer involvement of a neurological physiotherapist ity, duration, frequency, presence of conjuncti- Verlag, Wien, 2000. ISBN 3-211-83201-7 in the management of spasticity is vital and val injection and lacrimation, the sometimes while this chapter is thorough it is too brief associated Horner’s syndrome, and the re- This is the second of three projected volumes and fails to do justice to the key involvement sponse to subcutaneous ergotamine. So much that present for the first time in English one of of a physiotherapist in the spasticity team. for a headache that had not been described the great classics of microscopical anatomy: This defect is partially overcome with an adequately in the literature. Santiago Ramón y Cajal’s Texture of the nervous excellent subsequent chapter on orthotic My only concern about this book is that the system, which first appeared in Spanish in management, which is a very clear and useful publishers, who seem now to be publishing as 1904. The Texture and Sherrington’s integrative overview of an increasingly complex subject. frequently from New York as from Oxford, action of the nervous system, which appeared in The standard pharmacological interventions seem to have acquired a taste for American 1906, are the two fundamental works from (baclofen, tizanidine, dantrolene, and the spelling. Perhaps they need a visit down the which modern neurological science grew. benzodiazepines) are thoroughly covered in road at Oxford to the OED. Hitherto, the Texture was available only in the the ensuing chapters with an additional brief David Perkin original Spanish and in the somewhat en- chapter on alternative pharmacological thera- larged French edition of 1911, reprinted in pies. Nerve blocks, botulinum toxin, and Arachnoiditis: the silent 1952. intrathecal medications are adequately cov- epidemic This new edition is important, not only ered. The chapter by Mary Keenan and Patrick because it makes Ramón y Cajal’s contribu- McDaid on orthopaedic interventions for the Edited by J Antonio Aldrete (Pp 339, tion widely accessible, but also because the management of limb deformities in spasticity US$110.00). Published by Futuremed Publish- translators have gone back to the original is the best chapter on this subject I have ever ers, Denver, and the Arachnoiditis Foundation illustrations, which are preserved in the read and certainly should be compulsory Inc, Seaside, 2000. ISBN 968-7860-56-1 Museum of the Instituto Cajal in Madrid. The reading for the physician who may need to high quality of the paper compared with that refer to surgical colleagues for the manage- This book provides a comprehensive analysis, of earlier editions means that much detail is ment of complex and drug resistant spasticity. and comments on a condition we hope will be now visible that was formerly obscure. This is The problem with these early chapters is significantly reduced in incidence with new well shown by comparing the section of the that they lack an overall strategic approach to imaging modalities. It provides an extensive medulla and cerebellum in figure 238 in the the patient with spasticity. The editors have bibliography providing reference on the views present volume with figure 78 in volume II of tried to correct this problem with the last four expressed, the likely multifactorial aetiologi- the French edition: the beautiful cellular chapters in the book, which give individual cal factors responsible for the development of detail is simply not visible in the latter. views of the management of spasticity in chil- a very disabling combination of signs and Modern investigators are further in the dren with cerebral palsy and in adults with symptoms, and management strategies. The debt of the translators for having provided multiple sclerosis, traumatic brain injury, and earlier chapters provide a historical perspec- (and almost always checked) the full refer- spinal cord injury. These are useful chapters tive together with relevant anatomical, patho- ences cited by Cajal, correcting errors that had that bring the rest of the book together, logical, and physiological information, which escaped his attention, and annotating the text although there is some rather unavoidable will be useful to the reader while reading the sparingly but helpfully when modern re- repetition. A few illustrative case histories later chapters. Although the book discusses search had clarified issues that remained might have been useful in this section.

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Overall this is a thorough, reasonably com- paraneoplastic and non-cancer related au- prognostic index (derived from multivariate prehensive, well referenced, and up to date toantibodies, as well as possible pathogenic regerssion coefficients, mean values of co- textbook, which can be recommended to the mechanisms, are up to date and clear. A chap- variables, and number of embolic signals) by multidisciplinary spasticity team and is a use- ter on the ontogeny of skeletal muscle cells, double exponential function. ful reference for any neurologist. although well written, is out of place in this Michael Barnes text. The book is well edited and illustrated and the references are thorough. The focus of Autoantibodies in neurological the text is weighted towards disorders of the diseases peripheral nervous system, likely reflecting the more extensive literature on these disor- 1.0 ders. Clinicians and basic investigators in 0.9 Edited by Angela Vincent and Gianvito neurology and immunology will find this 0.8 Martino (Pp 160, US$64.00). Published by book an excellent resource. 0.7 Springer-Verlag Italia, Milan, 2002. ISBN Joseph Dalmau 0.6 88-470-0119-6 0.5 0.4 Antineuronal antibodies were initially de- 0.3 scribed 40 years ago and since then many CORRECTIONS TIA and stroke 0.2 autoantibodies have been discovered and 0.1 0.0 characterised. Despite this, there is a limited 0 10 20 30 40 50 60 70 number of texts devoted to the subject of Goertler M, Blaser T, Krueger S, et al. Cessation Predicted probability of recurrent Persisting embolic signals (n/h) autoantibodies in neurological diseases. Even of embolic signs after antithrombotic preven- less common are books that describe autoan- tion is related to reduced risk of recurrent tibodies and clinical-immunological associa- arterioembolic transient ischaemic attack and tions in a manner useful to both clinicians stroke. J Neurol Neurosurg Psychiatry 2002;72: and investigators. This book fills the void. 338–42. Although the title evokes a laundry list of Single exponential function was errone- antibodies this edition offers an even balance ously used for the calculation of figure 2. The Shorvon SD, van Rijckevorsel K. A new between clinical descriptions, immunological correct figure 2 is reproduced below, which antiepileptic drug. J Neurol Neurosurg Psychiatry mechanisms, and therapeutic implications. shows the predicted probability of recurrent 2002;72:426–9. An error has been noted in The inevitable overlap of topics in a multiau- TIA and stroke as calculated from the rows 1–3 of columns 3 and 4 in table 2. The thored book is kept to minimum. An introduc- cumulative underlying hazard and the correct table appears here. tory chapter on techniques used for measur- ing and evaluating the pathogenic role of autoantibodies will be useful for clinicians not directly involved in laboratory research. Sub- Table 2 Adverse events (%) according to FDA and EMEA standards. sequent chapters comprehensively cover dis- orders of the neuromuscular junction and Adverse reaction* (FDA) Undesirable effects† (EMEA) peripheral nerve and less extensively disor- Levetiracetam Placebo Levetiracetam Placebo ders of the central nervous system associated (n=769) (n=439) (n=672) (n=351) either with autoantibodies or with other evidence of autoimmunity. Among the latter Somnolence 15 8 14 8 are chapters on autoantibodies and epilepsy Asthenia 15 9 12 9 and vasculitis of the central nervous system, Dizziness 9 4 7 3 topics rarely encountered in other texts. Two Infection 13 8 — — chapters on autoimmunity and pregnancy, particularly in association with myasthenia *Adverse reaction: any event reported during clinical trial; FDA, Food and Drug Administration; gravis, nicely discuss the effects of immunity †undesirable effect: all adverse events at least possibly related to the study drug; EMEA, European on the embryo and newborn. With the excep- Medicinal Evaluation Agency. tion of disorders associated with antibodies to Note: Adverse reactions and undesirable effects are derived from three efficacy and one safety, double blind placebo controlled trials. Patient numbers differ because the FDA included the gangliosides that are not discussed, descrip- crossover part of the study in the analysis, and some of these patients were counted twice. tions of most of the recently described

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