EDITORIAL 281 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.72.3.281 on 1 March 2002. Downloaded from

New psychotropic drugs limbic cortex.12 Of all the newer drugs, ...... is the only one that seems not to bind to the core of the nucleus accumbens. Relevance of new psychotropic drugs Other relevant mechanisms might include a high affinity for muscarinic M1 for the neurologist receptors of some agents (for example, clozapine, ), that make them A E Hensiek, M R Trimble potent drugs. It has been argued that the simultaneous blockade ...... of D2 and M1 receptors by these drugs may be much more effective in prevent- Clinicians can now select psychotropic agents from a wide ing parkinsonism than non- choice simultaneous blockade.9 Several atypical drugs he discovery of neuroleptic and anti- considered a second line . Pa- also have a higher affinity for cortical drugs about 50 years ago tients treated with clozapine initially (5-HT) receptors rather than marked a breakthrough in pharma- need weekly blood count screening, striatal D2 receptors. The blockade of T 5-HT receptors could explain the lack of cotherapeutics, which has revolutionised which is reduced to fortnightly after 18 the therapy of many neuropsychiatric weeks and then to monthly after 1 year parkinsonian side effects, as neuroleptic conditions. The efficacy of the early and of satisfactory blood results. All patients induced catalepsy can be reduced by then standard agents in alleviating de- on clozapine have to be registered with serotonin antagonists such as pressive and psychotic symptoms and the Clozaril Patient Monitoring Service.4 or or by lesions of serot- onin nuclei. Reduced serotonin moder- preventing their reoccurrence has been Other disadvantages of clozapine include ates the reduction in func- established in numerous trials, but other its propensity to cause worsening confu- sion due to anticholinergic properties,5 tion, resulting from blockade of D2 factors limit their utility. These include 13 6 receptors. It seems, however, that an at the facts that not all patients respond to and its potential to induce . Sei- least 10-fold greater affinity for 5-HT treatment, and that they tend to often zures are seen with clozapine in up to 5% than for D2 receptors is required to have an unacceptable incidence of side of patients with doses of 600 mg or more, but even on lower doses EEG changes achieve this effect (as with clozapine or effects, many of which are neurological 9 may be noted. Generalised tonic-clonic ). in nature—such as parkinsonism, dysto- A strong affinity to the D4 nia, , and seizures. and myoclonic seizures are the most fre- quent reported. has been proposed to be rel- In an effort to match improved thera- evant in the atypical action of some new peutic efficiency with a better side effect The new generation of antipsychotic drugs includes those that have a similar antipsychotic drugs, in particular clozap- profile, various new and ine. The therapeutic dose of clozapine antipsychotic drugs have recently been receptor profile as clozapine, such as olanzapine and , and others, correlates well with its dissociation con- developed. These are becoming widely stant at D4, and clozapine has a higher used and their introduction may have such as risperidone. The term “atypical” relates to their low affinity for D4 rather than D2. The D4 important consequences for neurological propensity to cause extrapyramidal side receptor belongs to the D2 receptor fam- practice. effects, and they have minimal effects on ily and it has been suggested that it may serum concentrations.7 The be a relevant receptor for mediating ANTIPSYCHOTIC DRUGS antipsychotic action.14 D4 receptors seem mechanism of this “atypicality” seems to http://jnnp.bmj.com/ According to the dopamine hypothesis relate to different receptor profiles—that to be restricted to the limbic region, for , limbic D2 receptor is, broader receptor profiles or more which could account for the reduced blockade is essential for a drug to have likelihood of clozapine to produce ex- 1 selective binding. antipsychotic activity. Classic neurolep- Several mechanisms have been pro- trapyramidal side effects.15 drugs, such as , antagonise posed. Many mixed atypical compounds act dopamine D2 receptors and their clinical Some drugs oc- on various other receptors—for example, efficacy correlates with inhibitory activ- cupy lower levels of D2 receptors (for , sigma, or recep- ity at these receptor subtypes. Haloperi- example, 20%–50% for clozapine) than tors. In addition they influence GABA on October 2, 2021 by guest. Protected copyright. dol leads to parkinsonism in 15%-45% of the classic antipsychotic drugs, which and including neuro- 2 treated schizophrenic patients. occupy between 80% and 90%.8 This effect tensin, metencephalin, and cholecystoki- The development of clozapine with is dose dependent and it has been nin. Even though several hypotheses for properties differing from traditional proposed that it may be partly due to a potentially important role of these neuroleptic agents has heralded the era rapid displacement of these agents from actions have been proposed, the rel- of “atypical” antipsychotic drugs which the receptors by endogenous dopamine— evance in terms of therapeutic and are claimed to have improved tolerability that is, they are more loosely bound.9 The adverse effects of treatment is not and effectiveness compared with con- D2 receptor occupancy of olanzapine and known. ventional neuroleptic drugs. The effec- risperidone is similar to traditional neu- Despite their common features, each tiveness of clozapine in treating patients roleptic drugs at clinically used doses. of the atypical antipsychotic drugs has a with schizophrenia refractory to other Newer antipsychotic agents generally different relative affinity for the various medications,3 coupled with a low inci- have a lower affinity for striatal D2 receptors, which accounts for their indi- dence of extrapyramidal side effects, has receptors and some preferentially vidual properties. Table 1 summarises been attributed to a unique receptor pro- bind to limbic rather than striatal D2 the receptor profiles of haloperidol and file and marked a major advance in psy- receptors (for example, clozapine, various atypical antipsychotic agents. chopharmacotherapy. However, therapy amisulpiride).10 11 A possible explanation Table 2 shows results of animal stud- with clozapine is limited by its potential for this phenomenon would be that ies, which have measured the potential for serious adverse effects, in particular higher output of endogenous dopamine of different antipsychotic drugs to gener- the induction of in in the displaces more D2 bound ate catalepsy and their effect on condi- 1%–2% of patients and it is therefore drug, compared with low output in the tioned avoidance, which is sensitive for

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Table 1 Receptor binding profiles of antipsychotic drugs16*

Affinity for receptor (Ki (nmol/l))

Drug D1 D2 D4 α1 α2 H1 5-HT2a 5-HT2c M

Haloperidol 25 1 5 46 360 >1000 78 >1000 570 Clozapine 85 126 97861281.0 Risperidone 75 37231550.626>1000 Olanzapine 31 112 27 19 228 7 4 11 2.1 Quetiapine 455 160 NA 7 87 11 220 615 56

*Information from premarketing trials and product monograph. D1, D2, D4 , dopamine receptors; α1, α2, adrenergic receptors; M, muscarinergic receptor; 5-HT2a, 5-HT2c, serotonin receptors ; H, Histamine receptors. predicting ratios for activities against Amisulpiride, which is a recently ment of in Parkinson’s disease. extrapyramidal side effects.16 licensed analogue, differs from All published trials have been positive, other agents in that it exhibits selective suggesting good antipsychotic activity Clinical trials concerning the rate of affinity for D2 and D3 receptors and is without worsening of parkinsonism. occurrence of drug induced movement devoid of affinity for other dopamine Clozapine seems to ameliorate psychosis disorders of different new antipsychotic receptor subtypes, serotinergic or cholin- in Parkinson’s disease at much lower agents have been difficult to interpret ergic receptors.11 The incidence of ex- dosages than those required for and compare, because often patients trapyramidal side effects is dose depend- schizophrenia.22 23 It has been suggested have been on conventional antipsychotic ent but lower compared with that clozapine may also have a beneficial 2 drugs until shortly before entering a conventional antipsychotic drugs. Data effect on other behavioural symptoms of trial. Clozapine has been most exten- on comparison with other newer agents Parkinson’s disease—for example, sleep sively studied and several reports indi- are limited. disturbance, , and depression. In cate that it improves or halts progression addition there have been reports of a of tardive dyskinesia, chronic , Because of their lesser potential to 17 beneficial effect of clozapine on parkin- and drug induced parkinsonism. There produce parkinsonism, atypical neu- sonian .24 have been no reports of cases of tardive roleptic drugs have not only gained Reports on the use of risperidone in dyskinesia in patients who have only growing importance in the therapy of treatment of dopaminergic psychosis taken clozapine, but no other antipsy- schizophrenia, but have also taken on a have been slightly conflicting. Even chotic drug. central role in the management of though some trials show a beneficial Reports on the use of risperidone for dopaminergic psychosis in extrapyrami- effect on relieving psychotic symptoms, patients with tardive dyskinesia are dal disorders such as Parkinson’s disease this has often been associated with a unclear, some suggesting induction and or related conditions such as Lewy body worsening of others suppression. Parkinsonism and . Psychotic symptoms occur as 25 akathisia have been reported to occur a complication of drug therapy in about or confusion. Similar to reports on non- after risperidone18 and it seems to cause one fifth of patients with Parkinson’s parkinsonian patients, the effect of olan- more extrapyramidal side effects than disease21 and commonly in Lewy body zapine in treating dopaminergic psycho- clozapine. The pharmacological profile of dementia. Although it may be possible in sis seems to lie between that of clozapine and risperidone. Whereas olanzapine

risperidone differs from clozapine, in some patients to reduce antiparkinso- http://jnnp.bmj.com/ that risperidone has a much higher nian therapy, this usually makes parkin- seems to be effective in treating psycho- affinity for D2 receptors and less anti- sonism worse and may not be well toler- sis in parkinsonian patients, there have properties. ated. In this situation the use of atypical been some reports of worsening in motor Olanzapine has a similar pharmaco- neuroleptic drugs is indicated. function.26 Others, however, report no logical profile to clozapine; however, it The benefits and limitations of differ- change of extrapyramidal symptoms.27 has a slightly higher affinity to D2 and ent atypical neuroleptic drugs in Data on the use of quetiapine in Parkin- 5-HT receptors. The potential of olanzap- dopaminergic psychosis correspond to son’s disease are limited, although sev- eral studies have shown improvement of ine to cause extrapyramidal side effects what would be expected from data of on October 2, 2021 by guest. Protected copyright. is probably intermediate between clozap- extrapyramidal symptoms in non- psychosis without worsening of ine and risperidone.19 Quetiapine, which parkinsonian patients. Clozapine, which parkinsonism.28 29 There are only limited has low D2 and also low 5-HT affinity, seems to have least extrapyramidal side data available on the use of causes few, if any extrapyramidal side effects in non-parkinsonian patients, has in patients with extrapyramidal disor- effects.20 been most extensively studied for treat- ders.

Table 2 Effect of antpsychotic drugs in behavioural models of extrapyramidal syndrome

Effect on conditioned avoidance in Drug rats (ED50 (mg/kg)) Catalepsy scores in rats (ED50 (mg/kg))

Haloperidol 0.28 0.74 Clozapine 33.5 >8 Risperidone 1.3 4.3 Olanzapine 5.6 23 Quetiapine 108 (80 mg quetiapine produces 37.9 s catalepsy compared with 36.5 s for 4 mg haloperidol and 9.5 s for 80 mg clozapine)

Reproduced from Kerwin and Taylor 1996.16

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Table 3 Side effects associated with action on different receptors

Receptor system Effects

Blockade of α1 adrenergic receptors Postural , reflex Stimulation of serotonin 5-HT1 receptors Antidepressant, anxiolytic effect, hypophagia Stimulation of serotonin 5-HT2 receptors , , agitation Stimulation of serotonin 5-HT3 receptors Gastrointestinal effects Blockade of M1 receptors Dry mouth, confusion, tachycardia Urinary retention Blockade of H1 histamine receptors Sedation, weight gain

ANTIDEPRESSANT DRUGS factors. More recent studies reported rates and 5-HT3 receptor subtypes.43 The SSRIs The development of antidepressant of less than 1% for patients with no risk can also provoke extrapyramidal disor- drugs represents another important ad- factors on therapeutic doses.37 38 The risk ders including akathisia and dystonias.44 vance in . The life- of seizures with TCAs is dose related and The latest generation of antidepres- time rates for major depression are rises with increased plasma concentra- sant drugs has been developed to derive between 3% and 19%30—a number that is tions. Reviews of patients who have taken their therapeutic benefits from tailor- probably higher for patients with neuro- overdoses of TCAs report seizures in made action on specific receptors, as a 39 logical disease (for example, 25%-60% in 3%–8%. basis for efficacy with better patients with medically intractable epi- Selective serotonin reuptake inhibi- tolerability.45 lepsy31). The original monoamine hy- tors (SSRIs), which were introduced in is a highly selective nor- potheses suggested that depression is the late 1980s are chemically unrelated reuptake inhibitor (NARI) due to deficiency of one or another of to and and have a with a low affinity to histamine, cholin- more selective effect on the reuptake of α three monoamines—namely serotonin, 40 ergic, dopaminergic, and 1-adrenergic 32 33 serotonin. The currently available noradrenaline, and/or dopamine, and receptors. It has minimal interaction preparations are , fluoxetine, it has stood the test of time. with the serotinergic system, which fluvoxamine, , and . The almost unsurpassed efficacy of mediates side effects such as nausea or Citalopram is the most selective of the antidepressant drugs (TCAs) is sexual dysfunction.46 Reboxetine has SSRIs, and it inhibits serotonin reuptake probably the result of their non-selective 3000 times more than noradrenaline been shown to be as equally effective as interaction with these () reuptake and 22 000 and more effective than neurotransmitters. However, their action 41 fluoxetine in treating severe times more than dopamine. The SSRIs 47 on these and other transmitter systems are now the most widely prescribed anti- depression, but is better tolerated com- (for example, cholinergic, ) depressant drugs. They are better toler- pared with first generation antidepres- produces a wide range of clinically ated, safer in overdose, and have a lower sant drugs. relevant side effects, including cardio- risk compared with tricyclic is a serotonin- toxicity and the occurrence of spontane- drugs.42 However, there are some case noradrenaline reuptake inhibitor (SNRI), 34 ous seizures. This is relevant for any reports of patients without predisposing similar to first generation antidepressant patient in whom the factors, who have had seizures on thera- drugs. It does not, however, interact with may be reduced. The exact neurotrans- peutic doses of SSRIs. Additional side adrenergic, histaminergic, or cholinergic

mitter mechanisms underlying the pro- effects include anxiety, sleep distur- receptors, avoiding the side effects associ- http://jnnp.bmj.com/ convulsant effect are unclear.35 bance, sexual dysfunction, and gastro- ated with activity on these receptor Early studies reported seizures in 3% to intestinal disturbance, which have been systems.48 Several studies have indicated 4% of patients receiving TCAs,36 however attributed to the action of increased at least equal and occasionally superior many of these patients had predisposing serotonin concentrations on the 5-H-2 effectiveness of venlafaxine compared

Table 4 Receptor profile57 and epileptogenic potential of antidepressant drugs on October 2, 2021 by guest. Protected copyright. Drug Action on receptor : Seizures/epilepsy H1 M1 NA 5-HT1 5-HT2 5-HT3 Imipramine −−++++0.1–4%37–39 In overdose36: 3.8–8% Paroxetine65 66 000+++Prolonged seizures during ECT58: In overdose59: no seizures in 15 patients with maximum dose 850 mg Sertraline67 000+++Rarereportsofseizures secondary to SIADH60 In overdose: no seizures in 40 patients up to 8000 mg61 000+++<0.1%34* Citalopram000+++Noworsening of epilepsy in 16 patients62 In overdose63:100–1.9 g : 18% seizures 1.9 g:49% Reboxetine 0 0/− +0000.13%46* Venlafaxine00++++0.18%* In overdose64:Seizures in dosages over 1000 mg 000+−+ No seizures in premarketing trials, since then rare reports of convulsions* Mirtazepine − 0++−−<0.1%54*

*Information from premarketing trials and product monograph. 0, no or negligible effect; +, stimulation,; −, blockade; Hl, histamine; Ml, muscarine; NA, noradrenaline; 5-HT1, 5-HT2, 5-HT3, serotonin receptors.

www.jnnp.com 284 EDITORIAL J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.72.3.281 on 1 March 2002. Downloaded from with other antidepressant drugs (imi- 2 Barnes TRE, McPhillips MA. Novel other akinetic-rigid syndromes. J Clin pramine, fluoxetine).49 , extrapyramidal side effects Psychiatry 1995;12:556–9. and tardive dyskinesia. Int Clin 26 Molho ES, Factor SA. Worsening of motor Nefazodone is a serotonin antagonist/ Psychopharmacol 1998;13(suppl 3):S49–57. features of parkinsonism with olanzapine. reuptake inhibitor (SARI), the most 3 Kane J, Honigfed G, Singer J, et al. Mov Disord 1999;14:1014–16. potent action of which is blockade of Clozapine for the treatment-resistant 27 Wolters EC, Jansen EN, Tuynman-Qua HG, schizophrenia. A double-blind comparison et al. Olanzapine in the treatment of 5-HT2 postsynaptic receptors leading to with . Arch Gen Psychiatry dopaminergic psychosis in patients with a dual mechanism of action on the 1988;45:189–96. Parkinson’s disease. 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vCJD cases of vCJD have been homozygous for ...... at codon 129 of the prion protein gene. One important variable in all estimates of vCJD numbers is the year Variant Creutzfeldt-Jakob disease cases first appeared. The paper by Hillier at al2 provides important support to the R G Will hypothesis that vCJD is a new disease which really did first appear in the mid- ...... 1990s. How new is new? J Neurol Neurosurg Psychiatry 2002;72:285–286

f variant Creutzfeldt-Jakob disease phenotype of vCJD is relatively distinct ...... (vCJD) is caused by bovine spongi- from sporadic CJD and also fairly con- 10 Authors’ affiliations Iform encephalopathy (BSE) it must be sistent between cases. The implication R G Will, National CJD Surveillance Unit, a new disease, as human exposure to the is that it is likely that cases of vCJD are Edinburgh University (Old Pharmacy Building), BSE agent is unlikely to have happened being identified in life by neurologists Western General Hospital, Crewe Road, much before 1983.1 The study by Hillier et and, assuming notification to the sur- Edinburgh EH4 2XU, UK; [email protected] 2 al (this issue, pp 304–309) adds signifi- veillance system, that the figures on REFERENCES cantly to the evidence supporting the numbers of cases of vCJD are accurate. 1 Anderson RM, Donnelly CA, Ferguson NM, hypothesis that vCJD really is a new dis- There is a separate surveillance system et al. Transmission dynamics and ease, with the caveat that the study una- for vCJD in children,11 which has led to epidemiology of BSE in British cattle. Nature http://jnnp.bmj.com/ voidably had incomplete follow up data. the identification of six cases of vCJD 1996;382:779–88. 2 Hillier CEM, Salmon RL, Neal JW, Hilton DA. No previously unrecognised cases of where the patient’s age was less than 16 Possible underascertainment of variant vCJD were found in a systematic retro- years at onset of symptoms. The diagno- Creutzfeldt-Jakob disease: a systematic study. spective study in Wales, which included sis of vCJD has been confirmed in a J Neurol Neurosurg Psychiatry 12 2002;72:304–9. review and restaining of available neu- patient aged 74 years, significantly 3 Majeed A, Lehmann P, Kirby L, et al. Extent of ropathological tissue. A similar study extending the age range and raising misclassification of death from based on death certificates in England questions about the efficiency of surveil- Creutzfeldt-Jakob disease in England 1979–96: retrospective examination of and Wales between 1979 and 1996 also lance in elderly people. Accuracy of data

clinical records. BMJ 2000;320:145–7. on October 2, 2021 by guest. Protected copyright. failed to identify missed cases of vCJD3 on the numbers of cases of vCJD is criti- 4 Venters GA. New variant Creutzfeldt-Jakob and no case with a similar neuropatho- cal to public health planning and to both disease: the epidemic that never was. BMJ 2001;323:858–61. logical phenotype to vCJD has been short term and long range forecasts of 5 Almond J, Pattison J. Human BSE. Nature identified in any country despite exten- the future of the vCJD epidemic. 1997;389:437–8. sive review of archival neuropathology Analyses of short term trends in vCJD 6 Collinge J. Variant Creutzfeldt-Jakob disease. 13 Lancet 1999;354:317–23. tissues. Although there are still have been published and currently 7 Will RG, Ironside JW, Zeidler M, et al. A new 4 doubters, informed opinion supports indicate an approximate doubling in the variant of Creutzfeldt-Jakob disease in the UK. the view that vCJD really is a new number of cases of vCJD in the United Lancet 1996;347:921–5. disease.56 It is important to recognise Kingdom every 3 years. Longer term pre- 8 Warlow CP. Ethical barriers to research into diseases of the human brain. Advances in that the availability of stored brain sam- dictions of vCJD numbers have been Clinical Neuroscience and rehabilitation ples was critical to the identification of more controversial with a wide range of 2001;1:10–3. vCJD7 and to the study of Hillier et al2. future scenarios varying between a total 9 Grand round. Creutzfeldt-Jakob disease in a 14 young woman. Lancet 1996;347:945–8. Defending medical activities deemed by of just over 200 cases, a few thousand 10 Will RG, Zeidler M, Stewart GE, et al. some to be ethically controversial is cases15 and over 130 000 cases.16 This Diagnosis of new variant Creutzfeldt-Jakob essential both for research and informed variation reflects the many uncertainties disease. Ann Neurol 2000;47:575–82. 8 11 Verity CM, Nicoll A, Will RG, et al. Variant clinical practice. about BSE and vCJD, including the Creutzfeldt-Jakob disease in UK children: a Although the clinical features of the extent of human exposure to BSE, the national surveillance study. Lancet first three cases of vCJD were judged to level of the species barrier between 2000;356:1224–7. 12 Lorains JW, Henry C, Agbumu DA, et al. be “well within the recognised diagnos- bovine and human, and variations in Variant Creutzfeldt-Jakob disease in an elderly tic spectrum for CJD”,9 the neurological host susceptibility—to date all tested patient. Lancet 2001;357:1339–40.

www.jnnp.com 286 EDITORIAL COMMENTARY J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.72.3.281 on 1 March 2002. Downloaded from

13 Andrews NJ, Farrington CP, Cousens SN, et time based on age characteristics of vCJD in Creutzfeldt-Jakob disease epidemic. Science al. Incidence of variant Creutzfeldt-Jakob the . Science 2001;294:1729–31. disease in the UK. Lancet 2000;356:481–2. 2001;294:1726–8. 16 Ghani AC, Ferguson NM, Donnelly CA, et al. 14 Valleron A-J, Boelle P-Y, Will R, et al. 15 Huillard d’Aignaux JN, Cousens SN, Smith Predicted vCJD mortality in Great Britain. Estimation of epidemic size and incubation PG. Predictability of the UK variant Nature 2000;406:583–4.

Dystonia made an important contribution by ...... determining that, if actively sought, dys- tonia may be one of the most common clinical features of MSA. The authors do Dystonia in multiple system atrophy note that some doubt was cast on the dystonic nature of antecollis in MSA in a D E Riley recent report attributing the forward ...... flexion of the neck to myopathy in extensor muscles.5 Dystonia is often encountered in untreated MSA The report of Boesch et al helps flesh out our knowledge regarding the clinical repertoire of MSA. It also extends previ- n this issue (pp 300–303) Boesch et al untreated patients with MSA. Antecollis ous descriptions of the response of report on their experience with dysto- accounted for most of the dystonia patients with MSA to levodopa. It is a nia in multiple system atrophy encountered in these patients, with focal I 1 welcome addition to our expanding body (MSA). They correctly point out the limb dystonias comprising the rest. Of of knowledge on the clinical differential relative neglect of dystonia in previous note, disease related focal limb dystonia diagnosis of parkinsonism. clinical descriptions of patients with improved on levodopa in five of five MSA. In 1986, Adams declared that dys- patients. Over 80% of patients with a J Neurol Neurosurg Psychiatry 2002;72:286 tonia was “not part of the clinical predominantly parkinsonian presenta- tableau” of striatonigral degeneration,2 a tion (MSA-P) enjoyed a moderate to ...... quarter of a century after he described excellent response to levodopa initially, Author’s affiliations the disease. (Striatonigral degeneration although this was unsustained in most. D E Riley, Department of Neurology, University corresponds to the MSA-P designation, Almost half of those responsive to Hospitals of Cleveland and Case Western Reserve University School of Medicine, 11100 carried by the bulk of the patients of levodopa developed drug induced Euclid Avenue, Cleveland, Ohio 44106, USA; Boesch et al, of current diagnostic classi- cranial-cervical dystonia. Their facial [email protected] fications of MSA). Even when discussion predilection and their dystonic character, focused on the motor problems caused regardless of distribution, seem to distin- REFERENCES 3 by MSA, dystonia was not mentioned. guish the drug induced dyskinesias of 1 Boesch SM, Wenning GK, Ransmayr G, et al. These influential writings have led us to MSA from those seen in Parkinson’s dis- Dystonia in moultiple system atrophy. J Neurol Neurosurg Psychiatry 2002;72:300–3. discount the likelihood of MSA causing a ease. 2 Adams RD, Salam-Adams M. Striatonigral combination of dystonia and parkinson- Boesch et al do not comment on the degeneration. In: Vinken PJ, Bruyn GW, ism in favour of other diagnoses, such as discrepancy between the high prevalence Klawans HL, eds. Extrapyramidal disorders. Parkinson’s disease or corticobasal de- of dystonia in their series and the low Amsterdam: Elsevier, 1986:205–12. 3 Quinn NP, Marsden CD. The motor disorder generation. occurrence rates in prior studies. Un- of multiple system atrophy. J Neurol Neurosurg Psychiatry 1993;56:1239–42. Much as in Parkinson’s disease, dysto- doubtedly the observational meticulosity http://jnnp.bmj.com/ nia may be a direct manifestation of of the authors of this prospective study 4 Wenning GK, Tison F, Ben Shlomo Y, et al. Multiple system atrophy: a review of 203 MSA or the result of treatment with played a major role. It is also likely that pathologically proven cases. Mov Disord dopaminergic agents. The highest previ- focal dystonia is overshadowed in most 1997;12:133–47. ously recorded prevalence of dystonia in patients by parkinsonism, cerebellar 5 Askmark H, Eeg-Olofsson K, Johansson A, et 4 al. Parkinsonism and neck extensor myopathy: MSA was 12%. In the current report, deficits, or corticospinal tract impair- a new syndrome or coincidental findings? dystonia was documented in 46% of ment. Nevertheless, Boesch et al have Arch Neurol 2001;58:232–7. on October 2, 2021 by guest. Protected copyright.

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