J Neurol Neurosurg 1999;67:121–133 121 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from

normal latency and amplitude of P14 and left and right precentral and postcentral gyri N20 potentials without any late cortical com- and premotor cortices (figure, blue colour). LETTERS TO ponents. After remaining in a vegetative state This case report oVers an insight into the for 19 days the patient regained conscious- neural correlates of human consciousness (at THE EDITOR ness. Her sequelae consisted of a bilateral least, external awareness as it can be assessed spastic of upper and lower limbs. at the patient’s bedside). Given that global Neuropsychological testing 1 month after glucose utilisation levels remained essentially admission showed an attention deficit with the same, the recovery of consciousness moderate impairment of short term memory. seems related to a modification of the Cerebral during vegetative One year after the accident she showed a regional distribution of brain function rather state and after recovery to with altered fine motor function, than to the global resumption of cerebral consciousness most prominent on the right, a slurred metabolism. The main decreases in metabo- speech, and minor short term memory lism seen during the vegetative state but not One way to approach the study of conscious- disturbances. FDG-PET was performed dur- after recovery were found in parietal areas, ness is to explore lesional cases in which ing the vegetative state (day 15 after admis- including the precuneus. This is in agreement impairment of consciousness is the promi- sion) and after recovery to consciousness with postmortem findings in persistent veg- nent clinical sign. Vegetative state is such a (day 37). etative state, in which involvement of the condition wherein awareness is abolished The control population consisted of 48 association cortices is reported as a critical whereas arousal persists. It can be diagnosed drug free, healthy volunteers, aged from 18 to neuroanatomical substrate3 and with PET clinically soon after a brain and may be 76 years (mean: 42 (SD 21) years). studies in postanoxic syndrome, in which the reversible (as in the following case report) or The study was approved by the ethics parieto-occipital cortex showed the most progress to a persistent vegetative state or committee of the University of Liège. In- consistent impairment.4 The functions of death. The distinction between vegetative formed consent was obtained by the husband these areas are manifold: lateral parietal areas state and persistent vegetative state is that the of the patient and for all control subjects. Five are involved in spatial perception and atten- second is defined as a vegetative state that has to 10 mCi FDG was injected intravenously; tion, working memory, mental imagery, and continued or endured for at least 1 month.1 PET data were obtained on a Siemens CTI language, whereas the precuneus is activated We present a patient who developed a vegeta- 951 R 16/31 scanner in bidimensional mode. in episodic memory retrieval, modulation of tive state after carbon monoxide poisoning Arterial blood samples were drawn during the visual perception by mental imagery, and and in whom we had the opportunity to whole procedure and cerebral metabolic glu- attention.2 Our data point to a critical role for measure brain glucose metabolism distribu- cose rates (CMRGlu) were calculated for all these posterior associative cortices in the tion during the vegetative state and after subjects. PET data were analysed using SPM emergence of conscious experience. recovery to consciousness. Using [18F]fluoro- software (SPM96 version; Welcome Depart- deoxyglucose (FDG) PET and statistical ment of Cognitive , Institute of STEVEN LAUREYS parametric mapping (SPM) we compared Neurology, London, UK).2 The use of SPM CHRISTIAN LEMAIRE both patient’s sets to a normal control popu- to assess between subject (rather than within PIERRE MAQUET lation. Our findings oVer an insight into the subject) variability is unlikely to alter the rel- Cyclotron Research Centre, University of Liège, Sart neural correlates of “awareness”, pointing to evance of our results given their high degree Tilman, 4000 Liège, Belgium a critical role for posterior associative cortices of significance. Data from each subject were CHRISTOPHE PHILLIPS in consciousness. normalised to a standard stereotactic space Institute of Cognitive Neurology, University College A 40 year old right handed woman and then smoothed with a 16 mm full width London, Alexandra House, 17 Queens Square, London attempted suicide through CO intoxication half maximum isotropic kernel. The analysis WC1N3AR, England, UK and was found unconscious. She was treated identified brain regions where glucose me- GEORGE FRANCK with hyperbaric oxygen but evolved to a veg- tabolism was significantly lower in each Department of Neurology, CHU Liège Sart, Tilman etative state diagnosed according to the patient scan compared with the control B-35, 4000 Liège, Belgium following criteria:1 (1) spontaneous eye open- group. The resulting foci were characterised Correspondence to: Dr Pierre Maquet, Cyclotron ing without evidence of awareness of the in terms of peak height over the entire volume Research Centre (B30), University of Liège, Sart environment; (2) no evidence of reproducible analysed at a threshold of corrected p<0.05.2 Tilman, 4000 Liège, Belgium Telephone 0032 43 66 36 87; fax 0032 43 66 29 46; email voluntary behavioural responses to any During the vegetative state, average grey http://jnnp.bmj.com/ stimuli; (3) no evidence of language compre- matter glucose metabolism was 38% lower [email protected] hension or expression; (4) intermittent wake- than in controls (4.5 v 7.3 (SD 1.4) mg/100 fulness and behaviourally assessed sleep- g/min). No substantial change in mean 1 The Multi-Society Task Force on PVS. Medical wake cycles; (5) normal cardiorespiratory CMRGlu was found after recovery (4.7 aspects of the persistent vegetative state (1). N function and blood pressure control; (6) pre- mg/100 g/min). During the vegetative state, Engl J Med 1994;330:1499–508. served pupillary, oculocephalic, corneal, and significant regional CMRGlu decreases were 2 Frackowiak RSJ, Friston KJ, Frith CD, et al. vestibulo-ocular reflexes. Brain MRI per- found in the left and right superior parietal Human brain function. San Diego: Academic Press, 1997. formed 14 days after admission was normal. lobule; the left inferior parietal lobule; the 3 Kinney HC, Samuels MA. Neuropathology of Electroencephalography showeda6Hzbasal precuneus; the left superior occipital, supe- the persistent vegetative state: a review. J Neu- on September 28, 2021 by guest. Protected copyright. activity with more pronounced slowing on the rior and middle temporal gyri; and the ropathol Exp Neurol 1994;53:548–58. left parietal regions. Auditory evoked poten- premotor and postcentral and precentral cor- 4 De Volder AG, GoYnet AM, Bol A, et al. Brain glucose metabolism in postanoxic syndrome. tials were normal. Somaesthetic evoked tex (figure, yellow colour). After recovery, Positron emission tomographic study. Arch potentials of the median nerve showed metabolic impairment was confined to the Neurol 1990;47:197–204.

Localisation of voxels in which cerebral glucose metabolism was impaired during vegetative state (in yellow) and after recovery to consciousness (in blue), compared with the control population. SPM{Z} threshold was set at voxel level corrected p<0.05 and projected on the patient’s coregistered MRI, normalised to the stereotaxic space of Talairach. 122 Letters, Correspondence, Book reviews, Correction J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from

Electrical inexcitability of nerves and exons 7 and 8 of the telomeric SMN gene, all 1 The International SMA consortium. Meeting muscles in severe infantile spinal three siblings showed a large deletion in the report. Neuromusc Disord 1992;2:423–8. 2 Lefebvre S, Burglen L, Reboullet S, et al. Identi- muscular atrophy region that includes all alleles of the multi- fication and characterization of spinal muscu- copy markers Ag1-CA and C212, localised at lar atrophy-determining gene. Cell 1995;80: Spinal muscular atrophy (SMA) is one of the the 5' end of the two SMN gene copies. It has 155–65. 3 Zerres K, Wirth B, and Rudnik-Schoneborn S. most common fatal autosomal recessive been postulated that the severity of disease Spinal muscular atrophy-clinical and genetic disorders, characterised by progressive de- may be correlated to the extent of a deletion correlations. Neuromusc Disord 1997;7:202–7. generation of anterior horn cells. Before the involving the SMN gene and the multicopy 4 Korinthenberg R, Sauer M, Ketelsen UP, et al. markers.3–5 The infant in our report with Congenital axonal neuropathy caused by dele- advent of genetic testing, the diagnosis of tions in the spinal muscular atrophy region. SMA was based on clinical, histopathologi- SMA type I showed electrical inexcitability of Ann Neurol 1997;42:364–8. cal, and electrophysiological features. In motor nerves as well as the characteristic 5 Wirth B, Hahnen E, Morgan K, et al. Allelic 1992, the International SMA Consortium alteration of the SMN gene. association and deletions in autosomal reces- sive proximal spinal muscular atrophy: associ- defined diagnostic criteria of proximal SMA Although it has been known for some time ation of marker genotype with disease severity based on clinical findings.1 In SMA type I from histological studies that sensory systems and candidate cDNAs. Hum Mol Gen 1995;4: (severe; Werdnig-HoVmann disease), af- are involved in SMA, electrophysiological 1273–84. fected persons have onset of symptoms before sensory findings have been previously re- 6 months of age and are never able to sit ported only once.4 Sensory nerve conduction Acute overdosage and intoxication with without support. Electromyography demon- velocity was tested in an infant with severe strates denervation features. In early 1995, SMA and showed no recordable potential, carbidopa/levodopa can be detected in the candidate gene, the survival motor but the infant in our report also exhibited the subacute stage by measurement of neuron (SMN) gene, was identified, making universal absence of sensory potentials. In 3-o-methyldopa the confirmation of SMA by DNA analysis both cases, DNA analysis disclosed the 5q possible.2 deletion. It is unclear whether this finding Although the eVects of a chronic overdosage With the availability of a genetic test for represents a distinct entity or merely the with levodopa are well known, few cases of 12 SMA, many investigators are refining the severe end of classic Werdnig-HoVmann dis- acute intoxication have been described. A diagnostic criteria published by the Consor- ease. The diagnostic criteria produced by the particular problem in establishing a diagnosis tium. Studies involving hundreds of patients International SMA Consortium currently of levodopa overdosage is the relatively short 34 with proximal SMA have disclosed a subset of lists “abnormal sensory nerve action poten- half life in the circulation of levodopa. If patients who fulfill at least one exclusion cri- tials” as an exclusion criterion.1 Our finding there is a delay in bringing an acutely intoxi- terion defined by the Consortium.3 We iden- of absent sensory potentials in a 5q deletion cated patient to hospital, perhaps due to late tified an infant with severe SMA who fulfilled established case of SMA indicates further discovery, the blood concentration of levo- two exclusion criteria and also showed need for revision of the Consortium criteria. dopa could already be normal (correspond- inexcitability of all nerves as well as muscles. Studies involving large series of patients ing to the peak levodopa concentration in This report will further delineate the wide with SMA have identified cases of SMA Parkinson’s disease therapy) after 6–8 hours. range of phenotypes for this particular gene variants.3 These patients were diagnosed as Depending on the extent of the overdosage, mutation. infantile SMA by the presence of proximal the time could be even shorter. This report A 2945 g male infant was born at term. and atrophy, hypotonia, and evi- describes the clinical eVects and the plasma First fetal movements were noted at 13 weeks dence of neurogenic alterations in EMG and concentrations of levodopa and specific of gestation. Chorionic villus sampling at 10 muscle biopsy. In addition, these patients also metabolites over a period of 132.5 hours after weeks of gestation disclosed normal chromo- exhibited one of the exclusion criteria defined ingestion of 30 tablets of carbidopa/levodopa (50 mg/200 mg tablets). somes. Decreased fetal movement and poly- by the Consortium—for example, diaphrag- A 76 year old patient had a pre-existing hydramnios were noted at about 34 weeks of matic weakness, involvement of the CNS, or mild akinetic rigid Parkinson’s syndrome, gestation. At delivery, the infant was cyanotic arthrogryposis. Although these patients did which had been treated for the past 1.5 years with no respiratory eVort and was subse- not show the typical SMN deletion and were with 3×1 tablets of carbidopa/levodopa (50 quently intubated. On physical examination, therefore probably not linked to chromosome mg/200 mg) a day without a substantial the infant had no spontaneous movements. 5q, they could have had point mutations. The He opened his eyes with brief fixation but no response. The weight of the patient was 74

infant in our report showed no respiratory http://jnnp.bmj.com/ kg. A known chronic obstructive airway following. Tongue were eVort after birth, indicating diaphragmatic present. Other cranial nerves seemed intact. disease was treated with a home oxygen weakness. He did, however, possess the char- Mild flexion contractures of both elbows, appliance. At about 8.30 pm, the patient had acteristic SMN gene alterations. This finding knees, and ankles were noted. Tone was flac- attempted suicide by taking 30 tablets of suggests that diaphragmatic weakness should cid in both upper and lower limbs, and there carbidopa/levodopa. About 9.00 pm he ap- be reconsidered as an exclusion criterion by was no movement response to painful stimu- peared psychically altered, crying without the Consortium. lus. Deep tendon reflexes were absent. reason, anxious, and depressed. After about Brain MRI disclosed mild diVuse cortical Review of the literature disclosed no previ- 30 minutes he was increasingly inadequate, and deep atrophy. His EMG was severely ous reports of electrically inexcitable muscles agitated, and subeuphoric, and was experi- abnormal, with widespread fibrillations and in SMA. This phenomenon is known to occur encing visual hallucinations; he was restless, on September 28, 2021 by guest. Protected copyright. absent voluntary motor units except in the in a few other neuromuscular conditions such tossing and turning, and getting out of bed. genioglossus, where mildly neurogenic motor as periodic and critical illness He did not represent peak dose or units with decreased recruitment were seen. polyneuropathy. , as seen in the other extrapyramidal clinical features. At Stimulation of the median, ulnar, tibial, and infant in our report, are commonly seen in 10.00 pm he showed bilaterally maximally peroneal nerves with a maximal stimulus acute denervation and are thought to be dilated pupils. The muscle stretch reflexes resulted in no clinical or electrical response. caused by perturbation of the sarcolemmal were lively, there were no pyramidal tract The biceps brachii and rectus femoris membrane, rendering it unstable. One possi- signs, and he did not show any signs of muscles were electrically inexcitable by direct bility may be that the severe denervation in Parkinson’s syndrome or dyskinesia. Arterial needle stimulation. Median, ulnar, and sural SMA type I can result in abnormal function hypertonus and sinus tachycardia could be sensory potentials were not obtainable. DNA of the membrane to make it electrically inex- registered. testing showed a homozygous deletion of citable. Further electrophysiological studies After an empty box of Striaton (carbidopa/ exons 7 and 8 in the telomeric SMN gene, at the cellular level are required to delineate levodopa, 50 mg/200 mg) was found in the confirming the diagnosis of SMA. The infant this interesting finding. patient’s flat, 1 g of carbon was given by expired at 3 weeks of age, and the parents ALICE A KUO stomach tube after gastric lavage. Cranial CT declined postmortem examination. Department of Pediatrics was carried out before the diagnosis of Typical EMG studies in those with SMA intoxication had been made; it showed a pro- STEFAN-M PULST show fibrillations and fasciculations at rest DAWN S ELIASHIV nounced subcortical arteriosclerotic en- and an increased mean duration and ampli- CAMERON R ADAMS cephalopathy with reduced brain volume. tude of motor units. Motor nerve conduction Division of Neurophysiology, Cedars-Sinai Medical The patient was moved to the medical inten- velocities may be slowed but are usually nor- Center, Los Angeles, CA, USA sive care unit and observed for 24 hours. The mal. Korinthenberg et al reported inexcitabil- Correspondence to: Dr Cameron R Adams, De- ECG showed a P pulmonale, but no other ity of motor nerves in three siblings, each of partment of Neurophysiology, Cedars-Sinai Medi- unusual features. Echocardiography showed whom died from SMA before 1 month of cal Center, 8631 West Third Street, Room 1145, normal right and left ventricular function age.4 In addition to a homozygous deletion of East Tower, Los Angeles, CA 90048, USA. with suspicion of right ventricular hypertro- Letters, Correspondence, Book reviews, Correction 123 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from

70 000 Distribution into muscles rather then very marked. Progression over time of the metabolism may largely determine the in Huntington’s disease 60 000 plasma half life of levodopa and explain why can be monitored using the quantitative this was only slightly altered with overdose. neurological examination (QNE). This meas- 50 000 The measured peak concentration of 66 763 ure has three subscales, an eye movement ng/ml is about 30 times higher than the peak scale, a motor impairment scale (MIS) quan- 40 000 concentration to be expected after taking one tifying voluntary movement, and a

ng/ml 12 30 000 tablet of carbidopa/levodopa (50 mg/200 scale measuring involuntary movement. mg). It is apparent that the 30 tablets did not Pharmacological control of the symptoms 20 000 interfere with absorption or lead to a gastro- has been shown to be eVective with dopamine intestinal paralysis due to the high dose of antagonists,34but their use is limited because 10 000 levodopa; the relation between amount in- of the side eVects. Clinically the most gested and plasma concentration seems to be problematic of these are sedation, cognitive 0 linear, at least in this dose range. slowing, increased mobility problems, and 200 806040 100 140120 We conclude from these findings that in hypotension. The inability of traditional Time (h) cases of suspected levodopa intoxication dopamine antagonists to improve functional Time course of the measured concentrations of some hours previously, it could be important capacity, despite ameliorating chorea, is pos- levodopa (half filled circles) and to measure the concentration of 3-o- sibly due to suppression of voluntary motor 3-o-methyldopa (full circles) after an overdose of methyldopa, so as not to overlook an activity.45Tardive dyskinesia has occasionally levodopa (6000 mg). The peak of 3-OMD overdosage with levodopa, which may be due been reported in patients with Huntington’s appears after a delay, and the concentrationen to a suicide attempt. In addition to the diag- disease treated with these drugs.56The atypi- falls very slowly, corresponding to a half life in nostic uncertainty in relation to the immedi- plasma of 16.7 hours. cal antipsychotic clozapine has been shown to ate treatment of the patient, this would also be eVective in improving the movement have an eVect on further psychiatric and psy- disorder. However, in a double blind ran- phy. Blood was taken for the measurement of chological therapy. levodopa and metabolites 2.5 hours after domised trial of clozapine which included ingestion, and again after 9, 14.5, 34, and H J STUERENBURG patients who were already receiving tra- 132.5 hours. Using high performance liquid B G H SCHOSER ditional antipsychotic medication and a chromatography with electrochemical detec- Neurological Department, University Hospital group who had not received drug treatments Hamburg-Eppendorf, Hamburg, Germany tion, we measured the plasma concentrations for their movement disorder, chorea was of levodopa, 3-o-methyldopa, dihydroxyphe- Correspondence to: Dr Hans Joerg Stuerenburg, reduced in those who were antipsychotic nylacetic acid, homovanillic acid, noradren- Neurological Department, Universitètskranken- naive only and the authors concluded that haus Eppendorf Martinistrasse 52, 20246 Ham- aline, adrenaline, and dopamine. The time clozapine was of little additional benefit in burg, Germany. Telephone 0049 40 4717 4832; fax Huntington’s disease.7 Olanzapine is a new course of the concentrations of levodopa and 0049 40 4717 5086; email [email protected] 3-o-methyldopa are shown in the figure. hamburg.de atypical antipsychotic drug. It is a thienod- After 24 hours the patient was moved from ibenzodiazepine structurally very similar to the intensive care unit to a normal medical clozapine. Unlike clozapine it is not associ- 1 Hoehn MM, Rutledge CO. Acute overdose with ated with the potentially serious side eVect of ward. At this point no neuropsychiatric signs levodopa. Clinical and biochemical conse- of levodopa intoxication could be detected. quences. Neurology 1975;25:792–794. agranulocytosis and therefore frequent blood Clinically, the most prominent symtoms of 2 Sporer KA. Carbidopa-levodopa overdose. Am monitoring is not necessary. levodopa overdosage are confusion, agitation, J Emerg Med 1991;9:47–8. This report describes the progress of a man 3 Contin M, Riva R, Martinelli P, et al. Longitudi- sleeplessness, and excessive motor activity. nal monitoring of the levodopa concentration- who has Huntington’s disease. He developed The initial levodopa concentration in our eVect relationship in Parkinson’s disease. Neu- a marked movement disorder and was unable patient was 66 763 ng/ml, the concentrations rology 1994;44:1287–92. to tolerate both sulpiride and risperidone but 4 Bredberg E, Lennernas H, Paalzow L. Pharma- of DOPAC, homovanillic acid, noradren- cokinetics of levodopa and carbidopa in rats had symptomatic improvement when treated aline, adrenaline, and dopamine were raised following diVerent routes of administration. with olanzapine. 2.5 hours after ingestion and rapidly returned Pharm Res 1994;11:549–55. He is a man in his early 50s who had a con- to normal. A very noticeable feature of this 5 Korczyn AD, Keren O. The eVect of L-dopa on firmatory genetic test for Huntington’s dis-

pupillary diameter in mice. Experimentia 1982; http://jnnp.bmj.com/ case was the maximal bilateral mydriasis, with 38:481–2. ease in 1994, after the development of absent light reaction, at the time of the maxi- clinically obvious motor symptoms. It is likely mal intoxication with a 30-fold increase in that the onset of symptoms had occurred a plasma levodopa concentration. To our The use of olanzapine for movement few years previously as he had experienced knowledge, this association of a levodopa disorder in Huntington’s disease: a first diYculties in concentration and attention at intoxication with maximally dilated, light case report work, attributed at the time to stress, leading unresponsive pupils and without signs of dys- to the loss of employment. In addition his kinesia has not previously been reported. It Movement disorder is a prominent feature of family, watching family videos of a few years can be assumed that the eVect is caused by Huntington’s disease and consists of involun- earlier, thought that there was evidence of the peripheral conversion of levodopa into tary and voluntary components as well as early signs of his movement disorder. How- on September 28, 2021 by guest. Protected copyright. noradrenaline, which stimulates á-adrenergic associated bradykinesia. Pharmacological ever there was no known family history of receptors in the dilatator iridis. There is no treatment is problematic because of the side Huntington’s disease which might have led to indication from animal experiments of a spe- eVects of the drugs used, which may further an earlier diagnosis. By May 1995 his cific activation of dopamine receptors.5 The compromise cognitive functioning and mo- involuntary movements were becoming more arterial hypertonus measured initially can bility. Patients are often not subjectively noticeable, although control of voluntary also be attributed to the high systemic aware of their movements but can be consid- movement was good. A trial of sulpiride concentrations of noradrenaline, and the erably disabled by them and carers are often commencing at 200 mg twice daily and tachycardia to the raised concentrations of distressed and enquire about treatment op- increasing over 1 week to 800 mg daily was adrenaline and dopamine. As seen in the fig- tions. If drug treatment is considered it is undertaken with a subsequent decrease in the ure, the only indicator which can show a important to achieve the maximum improve- frequency and extent of involuntary move- levodopa intoxication in the subacute stage is ment in movements with the minimum of ment recorded in case notes; unfortunately the concentration of 3-o-methyldopa. The negative side eVects. This paper describes the the QNE was not repeated at this time. How- metabolite 3-o-methyldopa results from the eVect of olanzapine on movements when ever, the patient experienced a subjective o-methylation of levodopa, which explains the other treatment options had been ineVective slowing of his cognitive processes, concur- delayed peak of the 3-o-methyldopa concen- or limited by side eVects. rently became depressed, and decided to stop tration. The half-life of 3-o-methyldopa in Huntington’s disease is a hereditary pro- the treatment within 3 weeks. Paroxetine, a plasma was calculated at 16.7 hours in this gressive neurodegenerative disorder. It con- selective serotonin reuptake inhibitor antide- patient. On the other hand, the plasma half sists of a triad of symptoms comprising pressant, was started at a dose of 20 mg a day, life of levodopa was 111 minutes; this is motor, psychological, and cognitive abnor- which led to an improvement in his low slightly longer than normal, and can be malities. The motor component consists of mood. His involuntary movements continued explained by assuming a rate limited metabo- involuntary choreiform movements and in- to cause diYculties in his daily living. He was lism of levodopa when the substrate concen- creasing diYculties with voluntary move- unable to sit comfortably in a chair and when tration for the enzymes metabolising it is ment. The degree of the involuntary move- out he felt that he was disturbing others by raised. ments is variable but in some patients can be knocking into them. He agreed to a trial of 124 Letters, Correspondence, Book reviews, Correction J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from

14 HEATHER C DIPPLE MIS Department of Psychiatry, Leicestershire Mental Health Service Trust, Huntington’s Disease Service, 12 Chorea Mill Lodge, Mill Lane, Kegworth, Derby DE74 2EJ, UK. Telephone 0044 1509 670774. 10

8 1 Folstein SE, Jensen B, Leigh RJ, et al. The measurement of abnormal movements: meth- ods developed for Huntington’s disease. Neu- Score 6 robehav Toxicol Teratol 1983;5:605–9. 2 Folstein S. Huntington’s disease: a disorder of 4 families. Baltimore: John Hopkins University Press 1989. 3 Quinn N, Marsden CD. A double blind trial of 2 sulpiride in Huntington’s disease and tardive dyskinesia. J Neurol Neurosurg Psychiatry 1984; 0 47:844–7. 06/95 05/96 07/96 03/97 04/97 04/97 06/97 4 Girotti F, Carella F, Scigliano G, et al.EVect of neuroleptic treatment on involuntary move- Quantitative neurological examination scores showing the progress of the movement disorder. 06/95: ments and motor performances in Hunting- before trial sulpiride, no medication; 05/96: before risperidone, 20 mg paroxetine daily; 07/96: 1 mg ton’s Disease. J Neurol Neurosurg Psychiatry risperidone four times daily and 20 mg paroxetine daily; 03/97: before retrial sulpiride, 20 mg 1984;47:848–52. paroxetine daily; 04/97: 400 mg sulpiride in the mornings 600 mg at night and 20 mg paroxetine; 5 Schoulson I. Care of patients and families with Huntington’s disease. In: Marsden CD, Fahn, 04/97: before olanzapine, 140 mg lofepramine daily; 06/97: 5 mg olanzapine at night, 140 mg eds.Movement disorders. London: Buttersworth, lofepramine daily. 1982:277–90. 6 Schott K, Ried S, Stevens I, et al. Neurolepti- risperidone. This was started at a dose of 1mg tions considered enhance the quality of life of cally induced dystonia in Huntington’s disease: twice daily, increasing to a dose of 1mg four the patient and improve overall functioning. a case report. Eur Neurol 1989;29:39–40. times a day over a period of 2 weeks, stopped It may not always be in the best interests of 7 Bymaster FP,Calligaro DO, Falcone JF, et al. after a brief period. He developed hypoten- Radiorecptor binding profile of the atypical the patient to use drug treatments for the antipsychotic olanzapine. Neuropsychopharma- sion (blood pressure 100/60 mg Hg), com- movement disorder. In those patients who cology 1996;14:87–96. plaining of dizziness after the initial dose. His have severe movements, however, a trial of 8 van Vugt JP, Siesling S, Vergeer M, et al. Cloza- blood pressure remained stable, although pine versus placebo in Huntington’s disease: a treatment may be appropriate and continued double blind study. J Neurol Neurosurg Psychia- low, after this and as there was improvement if a clear benefit has been achieved. Neuro- try 1997;63:35–9. in his movements the drug was continued. logical monitoring and the patient’s own per- However, he decided to stop the risperidone ception of the eVect of the drug must be taken after 4 months because of his subjective into account. Transient hiccups after posteroventral experience of slowed thinking and occasional The mechanism by which olanzapine may pallidotomy for Parkinson’s disease dizziness. A repeated trial of sulpiride was have beneficial eVects is unclear. Olanzapine carried out in March 1997. Sulpiride was has been shown to have high aYnity for a Hiccup is defined as an abrupt intermittent, started at a dose of 200 mg twice a day and large number of receptors including D1, D2, involuntary, contraction of the diaphragmatic increased to a total daily dose of 1000 mg and external (inspiratory) intercostal mus- D4, 5HT2A, 5HT2C, 5 HT3, á-1- over 2 weeks. He was on sulpiride for 4 weeks adrenergic, histamine H1, and 5 muscarinic cles, with inhibition of expiratory intercostal with no improvement in his movements,so it receptors. This binding profile is similar to activity. This results in a sudden inspiration, was discontinued. The patient continued to abruptly opposed by closure of the glottis.1 clozapine, another atypical antipsychotic experience low mood and after the discon- Hiccup may result from various structural or drug, but substantially diVerent to the tinuation of sulpiride, his antidepressant drug functional disorders of the medulla, the aVer- conventional antipsychotic haloperidol.7 was changed to lofepramine commencing at ent or eVerent nerves to the respiratory mus- Preferential loss of D2 projection neurons 70 mg once a day and increasing after a few cles, and the gastrointestinal tract.23Newson which are involved in a feedback loop days to 140 mg daily. There were no changes Davis performed a study of hiccup with elec- noted in his movements during this change. normally active in the suppression of involun- trophysiological techniques and concluded tary movements is thought to be the patho- Although the patient was subjectively una- that hiccup is served by a supraspinal mech- http://jnnp.bmj.com/ physiological basis of chorea in patients with ware of the extent of his movements his eve- 8 anism distinct from that generating rhythmic ryday life continued to be aVected. The social Huntington’s disease. The D2 antagonist breathing.3 The principal site of interaction of venues he felt able to attend were becoming properties of olanzapine may explain its pos- the hiccup discharge with other descending more limited and activities he wanted to pur- sible benefits in the improvement of chorea. drives to the respiratory motoneuron is at the sue such as travelling abroad by air were However, the eVect at other receptors such as spinal level. Neurogenic hiccup is particularly problematic. A trial of olanzapine was then D4 may also be important, as D4 receptor associated with structural lesions of the instituted. He was started on 5 mg a day in density has been shown to be raised in Hunt- medulla oblongata. the morning. There was a marked improve- ington’s disease, therefore the D4/D2 ratio of Since 1994 we have performed 66 palli- activity may also be relevant. DiVerences in dotomies for Parkinson’s disease in 60 ment in his involuntary movements within 1 on September 28, 2021 by guest. Protected copyright. week but once again he experienced slowed binding profile across a range of receptors patients. So far, we have seen transient thinking. However, adjusting the time of may explain clinical diVerences in outcome hiccups in seven patients after the operation medication to the evening led to an improve- when comparing diVerent antipsychotic (table). Our target coordinates for the poster- ment in this. Six months later the improve- drugs. oventral globus pallidus at the border of the ment in his involuntary movements is main- This case report indicates that olanzapine medial and lateral segments are 2–3 mm tained. Serial quantitative neurological may be a useful addition to the treatments for anterior to the midcommissural point, 5 mm examination scores are illustrated in figure 1. movement disorder, for some patients, and below the intercommisural line, and 22 mm In the absence of a cure for Huntington’s controlled trials of its use in Huntington’s lateral to the midline of the third ventricle. disease, it is very important that any interven- disease would be welcome. Ventriculography was performed for target Patient characteristics

Ye a r s H and Y* UPDRS oV† Age at with staging prepallidotomy/ Pallidotomy Patient surgery Sex PD On/oV postpallidotomy side Transient side eVects Medication additional to levodopa 1 66 M 8 2/5 57/NP‡ R Slight facial paresis, swallowing Tryptizol, temazepam, alprazolam, problems, drooling apomorphine 2 43 F 7 2/2.5 22/7 L Slight Trihexifenidyl 3 49 M 15 2/3 55/15 L Facial paresis Pergolide, amantadine 4 50 M 12 2/2 45/22 L Slight dysarthria Selegeline, biperideen 5 53 M 14 2.5/4 69/36 R Facial paresis, hypophonia Pergolide, selegeline 6 55 M 13 2.5/3 48/27 L Facial paresis, aphasia Selegeline, biperideen 7 61 F 15 2.5/4 55/NP R Clozapine, temazepam, cisapride

*H and Y=Hoehn and Yahr; †UPDRS oV=unified Parkinson’s disease rating scale part 3 (motor examination), in a standardised oV state, 12 hours without antipar- kinson medication; ‡NP=not performed. Letters, Correspondence, Book reviews, Correction 125 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from localisation. Patients started with a short ment of the globus pallidus or pressure, due emotionalism is that most people do not schedule of corticosteroids (5 days) the night to oedema, on an adjacent structure like the make a distinction between emotionalism, before surgery. internal capsule or putamen. We could not and pathological crying and laughing. As a The hiccups started immediately after the find other reports of hiccups as an adverse result all disorders of emotionality after operation or the next day, were intermittent, event after functional stereotactic surgical are stereotyped as being related to and the bouts of hiccup of six patients, with a interventions, nor after lesions of other brain damage and therefore psychologically duration of hours, resolved within 3 days after aetiology involving the striatium.5 Based on meaningless. the procedure. One patient complained of our experience we hypothesise that the globus None the less, many patients with emotion- yawning more often and frequent bouts of pallidus or a neighbouring structure may be alism describe their crying as provoked by hiccup for 6 months. involved in a supramedullary system involved emotionally congruent experiences, which Five patients were men. All patients were in triggering hiccups. makes the tearfulness seem understandable.1 12 right handed. The mean age at surgery was RMADEBIE In two previous studies we have shown that 54 years and the mean duration of Parkin- J D SPEELMAN stroke patients with emotionalism have more son’s disease was 12 years. All patients were Department of Neurology symptoms of psychological disorder than do taking levodopa. In four patients the hiccups P R SCHUURMAN patients without emotionalism. In the present appeared after a left sided pallidotomy. D A BOSCH study, we explored further the psychological Patient 2 had a right sided thalamotomy 4 Department of , Academic Medical characteristics of stroke patients with emo- years before the pallidotomy. Patient 5 Center, University of Amsterdam, The Netherlands tionalism. Our aim was to determine whether underwent a left sided pallidotomy 10 Correspondence to: Dr RMAdeBie,Department they diVered from patients without emotion- months before the right sided pallidotomy of Neurology, Academic Medical Center, PO Box alism in their psychological reactions to which caused the hiccups. The pallidotomies 22700, 1100 DE Amsterdam, The Netherlands. stroke, or in the coping strategies they improved parkinsonism in the “oV” state Telephone 0031 20 566 3856; fax 0031 20 679 reported. (table), contralateral , and pain 1438; email [email protected] Post-traumatic stress disorder is also char- accompanying Parkinson’s disease. Six pa- acterised by recurrent episodes of intrusive tients had transient adverse events: four and uncontrollable emotion, and we were patients had a transient facial paresis postop- 1 Newson Davis J. An experimental study of hiccup. Brain 1970;93:851–72. therefore interested in whether patients with eratively and two a slight transient dysarthria 2 Howard RS. Persistent hiccups. British Medical emotionalism also experienced the intrusive (table). Two patients had choreatic move- Journal 1992;305:1237–8. thoughts typical of post-traumatic stress 3 Newson Davis J. Pathological interoseptive ments after the pallidotomy at the contralat- disorder. Because emotionalism is often eral side which resolved spontaneously within responses in respiratory muscles and the mech- anism of hiccup. In: Desmedt J, ed. New devel- described as uncontrollable, we were inter- 2 hours and is associated with a favourable opments in electromyography and clinical neuro- ested in the possibility that patients were 4 surgical outcome. physiology. Vol 3. Basel: Karger, 1973:751–60. more generally helpless, passive, or avoidant Postoperative MR scans were obtained in 4 Merrello M, Cammarota A, Betti O, et al.Invol- untary movements during thermolesion pre- in their responses to stroke. Again, because of the first six patients, and showed that in five dict a better outcome after microelectrode the reported uncontrollability of emotional- patients the lesions were located in the poste- guided posteroventral pallidotomy. J Neurol ism, we postulated that patients with emo- rior part of the globus pallidus pars externa Neurosurg Psychiatry 1997;63:210–13 5 Bathia KP, Marsden CD. The behavioral and tionalism would report a more external locus (GPe) and interna (figure). In patient 5 the motor consequences of focal lesions of the of control3 than those without emotionalism lesion was situated slightly more anterior in basal ganglia in man. Brain 1994;117:859–76. Participants were adults admitted to local the GPe and putamen. In patient 3 there was general hospitals after stroke, and were inter- a small separate lesion more dorsal, probably Psychological adjustment and self viewed within 1 month of admission. Exclu- an infarct. sions were due to poor physical health, cogni- We never encountered hiccups in 150 other reported coping in stroke survivors with tive impairment, communication diYculties, stereotactic procedures for Parkinson’s dis- and without emotionalism or lack of consent. Approval for the study was ease, such as thalamotomies or deep brain obtained from the local research ethics com- stimulation electrode implantation in the Emotionalism after stroke is common, occur- mittees. thalamus and therefore it is unlikely that ring in 10%–20% of a community sample.1 All participants completed a standardised medication or positive contrast medium ven- Psychological factors in its cause or mainte- measure of distress—the general health ques-

triculography with Iohexol evoked the hic- nance have not been studied; research has http://jnnp.bmj.com/ tionnaire, GHQ-124; a widely used measure cups. tended to concentrate instead on location of of intrusive thoughts of the sort encountered A possible cause for the transient hiccups the stroke lesion. We suspect that one reason in post-traumatic stress disorder—the impact could be the lesion in the ventral medial seg- for this neglect of psychological aspects of of events rating scale5; a measure of cognitive coping—the mental adjustment to stroke scale (O’Rourke S, Dennis M, MacHale S, Slattery J. The development of the mental adjustment to stroke scale: reliability, patient outcome and associations with mood and

social activity, manuscript in preparation); on September 28, 2021 by guest. Protected copyright. and a measure of beliefs about responsibility for recovery from illness—the recovery locus of control scale.3 All the measures are self report questionnaires. A total of 177 stroke patients were screened, of whom 112 were excluded. The 65 participants (29 men, 36 women) had a mean age of 71.8 years (range 43 to 88 years). Nineteen (29.2%) patients met our criterion for emotionalism,1 a rate similar to that found in other studies. Their scores on the study measures are compared with the scores of patients without emotionalism in the table. It might be that these associations with emotionalism were accounted for by the greater general levels of distress experienced by those with emotionalism. We therefore undertook analysis of covariance with GHQ- 12 and presence of emotionalism as the cov- ariates, and each of the other test items in turn as the independent variable. The results showed an association, after adjustment for Five months after left sided pallidotomy, MRI of patient 6: (A) transversal slice at the level of the GHQ-12 score, between emotionalism and anterior commisure and (B) 6 mm more ventral. the impact of events subscales intrusion 126 Letters, Correspondence, Book reviews, Correction J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from

Comparison of stroke survivors with and without emotionalism, assessed in hospital 1 month after “stiV limb syndrome” refers to the focal form stroke of SMS when one or more distal limbs are involved; two of their patients were also anti- No emotionalism Emotionalism (n=19) GAD antibody positive, but none were tested (n=45) Mean (SD) Mean (SD) for antibodies to amphiphysin or identified as GHQ- 12* 3.2 (2.4) 5.3 (3.5) having an underlying . We present a Recovery locus of control scale 33.2 (3.3) 34.2 (3.7) patient clinically consistent with the stiV limb Impact of events scale intrusion subscale** 2.9 (4.6) 9.2 (6.6) syndrome who was found to have autoanti- Impact of events scale avoidance subscale* 4.7 (4.6) 9.9 (6.1) body to GAD and breast cancer. MASS Fighting spirit subscale 49.1 (4.0) 48.8 (5.2) A 68 year old woman presented with a 1 MASS Anxious preoccupation subscale** 22.2 (2.8) 25.2 (4.0) MASS Fatalism subscale* 20.0 (1.9) 21.3 (2.2) month history of painful in her legs. MASS Avoidance subscale 1.7 (0.8) 1.9 (0.8) were associated with tactile stimuli MASS Helplessness/hopelessness subscale** 10.9 (2.5) 14.1 (3.5) and emotional upset. Within weeks, inversion began at the left and then right ankle, making MASS = Mental adjustment to stroke scale. ambulation diYcult. Her medical history was *p<0.05; **p<0.01, t tests. significant for Graves’ disease treated with thyroidectomy and radiation therapy, and (F=15.33, p<0.001), and avoidance should also explore the psychological factors hyperlipidaemia. She was a chronic smoker. (F=11.84, p=0.001); the mental adjustment which might contribute to its cause or to stroke scale subscales helplessness/ continuation. General examination was noteworthy for lymphadenopathy in the right axilla. Her hopelessness (F=11.7 1, p=0.00 1) and anx- mental status was worse during periods of ious preoccupation (F=8.05, p=0.006). The We thank those patients who participated in the lower extremity spasms, during which she associations with fatalism (F=14.79, study and the staV of local hospitals and the Leeds p=0.052) and avoidance (F=0.06, p=0.80) Stroke Database for their invaluable help. We also became anxious, diaphoretic, and tachy- on the mental adjustment to stroke scale were thank Dr Louise Dye for her statistical advice. This cardic. Cranial nerve and motor evaluations study was completed as part of work for the degree were unremarkable, but assessment of the left no longer significant after adjustment for of DClinPsychol at Leeds University (SE). GHQ-12 score. leg, due to painful spasms elicited by light This study confirms earlier work by show- STEVEN ECCLES touch, was diYcult. Inversion and plantar- ALLAN HOUSE ing that stroke survivors with emotionalism flexion were essentially fixed at the left ankle Division of Psychiatry and Behavioural Sciences in but could be overcome on the right. Deep have more other mood symptoms (here rated Relation to Medicine, University of Leeds, Leeds, UK by the GHQ-12) than do those without emo- tendon reflexes were 3+ in the upper and tionalism. It goes further however, in showing PETER KNAPP lower extermities, with sustained clonus at Stroke Outcome Study, Research School of Medicine, the right ankle. Sensory examination, with that they also have intrusive thoughts about Leeds, UK their stroke, of a sort similar to those reported the exception of hyperaesthesia in the distal by people with post-traumatic stress disorder. Correspondence to: Dr Allan House, Division of lower extremities, and coordination testing Psychiatry and Behavioural Sciences in Relation to This unpleasant remembering is probably were grossly normal. No hyperlordosis or Medicine, University of Leeds, 15 Hyde Terrace, was noted. Gait was limited due responsible for their higher ratings on anxious Leeds LS2 9LT, UK. preoccupation. It is compatible with our to ankle posturing. finding in a previous study2 that irritability is The laboratory evaluation was noteworthy associated with emotionalism, as irritability is 1 House A, Dennis M, Molneaux A, et al. for a CSF with increased IgG indices (2.5, Emotionalism after stroke BMJ 1989;298:991– a common response to threatening intrusive 4. 3.4; normal, 0.2–0.8) and oligoclonal bands memories of the sort encountered in post- 2 Calvert T, Knapp P, House A. Psychological (5, 5) but no pleocytosis. Serological testing traumatic stress disorder. It may not be that associations with emotionalism after stroke. J for anti-Hu, anti-Yo, and anti-Ri antibodies Neurol Neurosurg Psychiatry 1998;65:928–9 emotionalism is a direct manifestation of 3 Partridge C, Johnston M. Perceived control of was unremarkable, and the haemoglobin post-traumatic stress disorder, although that recovery from physical disability: measurement A1C was 6.6 (5.6–7.7)%. Skin biopsy at three condition has been described after stroke,6 and prediction. Br J Clin Psychol 1989;28:5359. sites on the patient’s leg showed diminished but the analogy raises the possibility that an 4 Goldberg D. General health questionnaire epidermal nerve fibre density and terminal (GHQ–12). In: Compendium of Health Psychol- abnormality in processing emotionally im- ogy Assessments. Windsor: NFER-Nelson, axonal swelling distally, consistent with a portant stimuli may be one of the causes of 1992. small fibre sensory neuropathy.6 The patient http://jnnp.bmj.com/ emotionalism. If correct it suggests possible 5 Horowitz MJ, Wilner N, Alvarez W. Impact of would not tolerate EMG. Magnetic reso- events scale as a measure of subjective stress. treatment strategies along the lines of those Psychosom Med 1979;41:209–18. nance images of the brain and the entire spi- used in post-traumatic stress disorder. 6 Sembi S, Tarrier N, O’Neill P, et al. Does post- nal cord were normal. Fine needle aspiration A corollary is our finding of increased feel- traumatic stress disorder occur after stroke: a of a soft tissue right axillary mass showed ings of helplessness and hopelessness, cou- preliminary study. International Journal of Geri- metastatic adenocarcinoma. On an open sur- atric Psychiatry 1998;13:315–22. pled with avoidance—at least as a cognitive gical procedure, infiltrating duct carcinoma coping strategy reported on one of our meas- of the breast was identified. Anti-GAD ures. Avoidant coping may perpetuate the Paraneoplastic stiV limb syndrome autoantibodies were positive by immunocyto- symptom of emotionalism, by preventing chemical assay and immunoprecipitation, but on September 28, 2021 by guest. Protected copyright. habituation to the social stimuli which StiV man syndrome (SMS) is a rare, severe antibodies to amphiphysin were not detected provoke it. Alternatively it may lead to a progressive motor disorder characterised by by immunocytochemistry, immunoprecipita- reduction in social support, exacerbating painful spasms, symmetric axial muscle tion, or western blotting (Dr P De Camilli, coexistent mood disturbance. Thus, it may be rigidity, and uncontrollable contractions Yale University). that avoidant coping is not an integral part of leading to distorted posturing. The disorder Ongoing therapy with clonazepam and a emotionalism, but rather that it is an has been associated with the autoantigens, trial of oral dexamethasone did not improve important maintaining factor. glutamic acid decarboxylase (GAD), and the lower extremity symptoms. The patient’s We predicted that patients with emotional- amphiphysin, which are cytoplasmic proteins ankle posturing continued a slow progression ism would have more “external” scores on the in neurons of the CNS. A large series of to marked inversion, with spontaneous exten- locus of control measure, reflecting their patients with SMS found that most have sion of hallucis longus. The patient died 18 sense of lack of personal control over crying. autoantibodies against GAD,1 whereas am- months after symptom onset. Gross necropsy They did not, perhaps because the emotional phiphysin is presumably the predominant attributed the cause of death to aspiration expression, although not apparently control- autoantigen in paraneoplastic SMS.2 Re- pneumonia. Neuropathological evaluation lable by internal resources, is none the less cently, Brown et al3 presented four patients showed a grossly normal brain and spinal perceived as having psychological meaning, with a stiV leg syndrome marked by progres- cord. Microscopically, the lumbar cord had so that responsibility for it it cannot readily be sive rigidity and spasms of the lower extremi- mild reactive gliosis in the anterior horns but devolved to others. ties. This group of patients tested negative for no evidence of inflammation. Sections of the Our study used a relatively weak between- anti-GAD antibody by immunoprecipitation frontal cortex, pons, and medulla showed groups design, the number of patients was and demonstrated distinct electrophysiologi- mild diVuse reactive astrocytosis. not large, and we cannot be sure that all con- cal features. By contrast, another report StiV man syndrome is increasingly recog- founders were dealt with. None the less, our described two patients with stiV leg syndrome nised as a heterogeneous disorder.7 Other results suggest that future research into emo- who tested positive for anti-GAD antibody.4 case reports have documented patients with tionalism could profitably concentrate not Finally, in presenting a group of 13 patients, “focal” disease involving either lower3–5 or just on seeking its biological correlates, but Barker et al5 proposed that the nomenclature upper extremity posturing,8 which contrast Letters, Correspondence, Book reviews, Correction 127 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from with the “diVuse” axial and subsequent 410 955 6626; fax 001 410 614 1008; email victim’s medical condition, as described in proximal muscle distribution of the classic [email protected] this report. The patient was a 52 year old disorder.9 Our patient diVers from those uraemic woman. The uraemia was of unde- reported with stiV leg syndrome in that an 1 Solimena M, Folli F, Aparisi R, et al. Autoanti- fined aetiology. Over the past 3 years she has occult malignancy was present. Unfortu- bodies to gaba-ergic neurons and pancreatic â received regular haemodialysis. One day both cells in stiV-man syndrome. N Engl J Med nately, we were unable to obtain electrophysi- 1990;322:1555–60. she and her husband, a healthy 55 year old ological studies for comparison. The search 2 Folli F, Solimena M, Cofiell R, et al. Autoanti- man, ate a fish soup. About 4 hours after the for a paraneoplastic process was based on the bodies to a 128-kd synaptic protein in three meal she developed a headache and a lingual women with the stiV-man syndrome and breast findings of axillary lymphadenopathy and an cancer. N Engl J Med 1993;328:546–51. and circumoral tingling sensation and numb- abnormal CSF. Our patient is only the second 3 Brown P, Rothwell JC, Marsden CD. The stiV ness at the distal parts of all four limbs. She reported patient with paraneoplastic SMS leg syndrome. J Neurol Neurosurg Psychiatry was dizzy and unsteady, had diYculty in associated with anti-GAD antibody; the other 1997;62:31–7. 4 Saiz A, Graus F, Valldeoriola F, et al.StiV-leg swallowing, and became very weak. She was had upper limb rigidity in the setting of breast syndrome: a focal form of stiV-man syndrome. taken to the emergency service and was cancer and additionally mounted an immune Ann Neurol 1998;43:400–3. placed on machine assisted ventilation as res- response to amphiphysin.8 5 Barker RA, Revesz T, Thom M, et al. Review of piratory distress and cyanosis developed. Her 23 patients aVected by the stiV man syndrome: Paraneoplastic processes can aVect any clinical subdivision into stiV trunk (man) husband remained asymptomatic throughout component of the nervous system and, occa- syndrome, stiV limb syndrome, and progressive this time. sionally, multiple levels, as in the syndrome of encephalomyelitis with rigidity. J Neurol Neuro- The patient’s condition kept on deteriorat- sensory neuronopathy-encephalomyelitis. Our surg Psychiatry 1998;65:633–40. 6 McCarthy BG, Hsieh S-T, Stocks A, et al. Cuta- ing, developing eventually into a comatous- patient’s findings were not entirely consistent neous innervation in sensory neuropathies: like state with no spontaneous or reflexive eye with criteria for classic SMS9 in that an evaluation by skin biopsy. Neurology 1995;45: opening or limb movement within 30 min- apparent and a small fibre 1848–55. utes of intubation. On neurological examina- 7 Kissel JT, Elble RJ. StiV-person syndrome: stiV neuropathy were identified—for example, opposition to a simple explanation. Neurology tion, the pupillary light reflex was absent and her dysautonomia (tachycardia and relative 1998;51:11–14. oculocephalic manoeuvre elicited no ocular hypertension) during spasms may have been 8 Rosin L, De Camilli P, Butler M, et al. Stiff-man movements. All four limbs were areflexic and a manifestation of involvement of small syndrome in a woman with breast cancer: an uncommon central nervous system paraneo- Babinski’s signs were absent. Brain CT and fibres. The role of autoantibodies in the plastic syndrome. Neurology 1998;50:94–8. laboratory studies of arterial blood gas (under pathogenesis of SMS and cancer is 9 Lorisch TR, Thorsteinsson G, Howard FM. assisted ventilation), electrolytes, liver func- unclear.278 Via its probable function in StiV-man syndrome updated. Mayo Clin Proc tion, blood glucose, and CSF study were 10 1989;64:629–36. endocytosis, amphiphysin has been postu- 10 David C, McPherson PS, Mundigl O, et al.A unremarkable. An examination of renal func- lated to play a part in the regulation of role of amphiphysin in synaptic vesicle endocy- tion indicated chronic renal insuYciency with growth factor internalisation; however, the tosis suggested by its binding to dynamin in mild azotaemia (urea nitrogen 70 mg/dl, cre- absence of an autoimmune response to this nerve terminals. Proc Natl Acad Sci USA 1996; 93:331–5. atinine 9.1 mg/dl). An EEG, recorded 18 autoantigen in our patient suggests that hours after the onset of symptoms when the other mechanisms of oncogenesis in SMS neurological condition was unchanged, exist. Given anecdotal evidence of improve- Tetrodotoxin intoxication in a uraemic showed posterior dominant alpha waves ment in paraneoplastic SMS after treating patient intermixing with trains of short duration, dif- the underlying malignancy,8 we suggest that fuse theta waves. When brief noxious stimuli all patients with SMS, diVuse or focal, be Tetrodotoxin intoxication results from ingest- were applied to the sternum, they were screened for occult cancer. ing puVer fish or other animals containing the replaced transiently by beta activities. The ISAAC E SILVERMAN toxin. Clinical presentation is mainly acute findings suggested that the profound neuro- Department of Neurology, Johns Hopkins University, motor weakness and respiratory paralysis. logical dysfunction might be peripheral in Baltimore, USA Death is common in the worst aVected origin. The patient was given a course of Correspondence to: Dr I E Silverman, Johns Hop- victims. Although the severity of the symp- haemodialysis according to the set schedule kins Hospital, Pathology 509, 600 North Wolfe toms generally depends on the amount of for uraemia at 21 hours after onset of the Street, Baltimore, MD 21287, USA. Telephone 001 toxin ingested, it may be influenced by the symptoms. Her condition improved dramati-

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Acroparaesthesia

Orolingual numbness on September 28, 2021 by guest. Protected copyright. Respiratory paralysis

Proximal weakness

Distal weakness

Bulbar weakness

Ophthalmoparesis and ptosis

Papillary areflexia

Depressed tendon reflex Changes in the symptoms of poisoning in relation to each course of haemodialysis. Scales in the vertical axis represent the arbitrary measurements of severity of each symptom; the numbers indicating day(s) after onset; ↓= haemodialysis). 128 Letters, Correspondence, Book reviews, Correction J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from cally within an hour. She could open her eyes amenable to haemodialysis. Traditionally, the and she communicated and answered ques- management of tetrodotoxin intoxication is Axonal tions correctly by blinking. Pupillary reflex mainly supportive, such as gastric lavage to Critical illness Guillain-Barré polyneuropathy recovered and voluntary eye movements were remove unabsorbed toxin and machine as- syndrome limited only at the extreme lateral gaze. Mus- sisted ventilation when respiration is severely cle power was grade 3 and 4 in the proximal aVected. We suggest that haemodialysis may and distal parts of the four limbs. Tendon be an eVective method in the treatment of reflexes were still absent. She was taken oV tetrodotoxin intoxication. mechanical ventilation the next day. Her MIN-YU LAN clinical condition continued to improve and SHUNG-LON LAI four limbs, occasional involvement of facial her symptoms subsided in a stepwise pattern, SHUN-SHENG CHEN muscles and frequent involvement of the in response to each course of haemodialysis Department of Neurology, Kaohsiung Medical College, muscles of respiration, the depression or (figure). When recalling, she could remember Kaohsiung City, Taiwan absence of deep tendon reflexes, and some certain events such as the recording of the DENG-FWU HWANG evidence of distal sensory impairment. EEG, but was “too weak to move” at that Department of Food Science, National Taiwan Ocean The first step by Bolton et al1 in determin- time. She regained her initial strength by the University, Keelung City, Taiwan ing exact aetiology was to diVerentiate critical time she was discharged on day 16. illness polyneuropathy from Guillain-Barré When analysing the remains of the cooked Correspondence to: Dr Shun-Sheng Chen, syndrome. In reviewing the patients with fish (identified as Yongeichthys nebulosus), tet- Department of Neurology, Kaohsiung Medical College Hospital, 100 Shih-Chung 1st Road, critical illness polyneuropathy and Guillain- rodotoxin was demonstrated by thin layer Barré syndrome who were studied in their chromatography, high performance liquid Kaohsiung City 807, Taiwan. Telephone 00886 7 3121101 ext 6771; fax 00886 7 3234237; email EMG laboratory, they found marked diVer- chromatography, and cellulose acetate mem- [email protected] ences between the two types of polyneuropa- brane electrophoresis. Toxicity was assayed thy. Patients with Guillain-Barré syndrome by using Institute of Cancer Research strain had greater slowing of the speed of impulse adult male mice and the toxicity score was 25 1 Hwang DF, Jeng SS. Bioassay of tetrodotoxin using ICR mouse strain. J Chinese Biochem Soc conduction, and, in the initial stages, abnor- mouse units (MU)/g in fish muscle (1 1991; :80–6. mal spontaneous activity in the muscle was 1 20 MU=0.178 µg in the ICR strain mouse). 2 Takata M, Moore JW, Kao CY, et al. Blockage of absent, indicative of a predominantly demy- Tetrodotoxin exerts its eVect through sodium conductance increase in lobster giant elinating polyneuropathy. The CSF was only axon by tarichatoxin (tetrodotoxin). JGen binding with and blocking the voltage de- mildly increased in patients with critical 2 Physiol 1966;49:977–88. pendent sodium channel. The voltage clamp 3 Brismar T, Tegnèr R. Experimental uremic neu- illness polyneuropathy, but it was much experiments showed that tetradotoxin dimin- ropathy. Part 2. Sodium permeability decrease increased in patients with Guillain-Barré ished the early sodium inward current and inactivation in potential clamped nerve fibers. J Neurol Sci 1984;65:37–45. syndrome. Comprehensive studies done at responsible for the depolarisation of excita- 4 Tani I. Toxicological studies of puVers in Japan. necropsy and nerve biopsies of patients with tory membrane. The gating properties of the Teikoku-Tosho (Tokyo) 1945:103. critical illness polyneuropathy showed the sodium channel, such as the activation and 5 Kao CY. Tetrodotoxin, and their presence of primary axonal degeneration of inactivation mechanism, are not altered— significance in the study of excitation phenom- ena. Pharmacol Rev 1966;18:997–1049. the motor and sensory fibres, mainly distally, that is, the sodium channel is not perma- with no evidence of inflammation.2 Zochodne nently damaged and its function recovers et al (including Bolton) therefore concluded when the bound toxin is released. In uraemia, Relation between critical illness that the two types of polyneuropathies most ion conductance through the sodium channel polyneuropathy and axonal probably are separate entities. is also impaired. Sodium permeability Guillain-Barré syndrome Guillain and colleagues enumerated the through excitatory membranes is reduced clinical and spinal fluid features of one form and small inward sodium current and re- The clinical entity critical illness polyneu- of acute flaccid paralysis without regard for duced action potential amplitudes are noted ropathy occurs almost exclusively in patients the underlying physiology or pathology. Clas- in experimental uraemic neuropathy.3 By in critical care units and has been character- sic pathological studies of Guillain-Barré contrast with the eVects of tetrodotoxin, ised as a complication of sepsis and multiple syndrome, however, have identified promi- uraemia changes the basic property of the organ failure.12 Critical illness polyneuropa- nent demyelination and inflammatory infil- sodium channel by an increased inactivation thy may be a common cause of the diYculty trates in the spinal roots and nerves. Guillain- http://jnnp.bmj.com/ and an impaired activation mechanism. The in weaning patients from the ventilator, Barré syndrome often has been considered to excitability of peripheral nerves will be more particularly those who show intractable be synonymous with the pathological desig- significantly depressed when these two condi- ventilator dependence. All the measures used nation of acute inflammatory demyelinating tions combine. The synergistic eVect of urae- to prevent or treat sepsis and multiple organ polyneuropathy, and physiological abnor- mia and tetrodotoxin is obvious in this failure are the main methods now used to malities consistent with demyelination have incident in which the patient and her deal with critical illness polyneuropathy. been taken as supportive evidence for the husband ingested roughly an equal amount of Knowledge of this type of polyneuropathy is diagnosis of Guillain-Barré syndrome. tetrodotoxin (about 200 µg, calculated from of help in making decisions about respirator Feasby et al (with Bolton)3 first called toxic score times the weight of ingested fish). techniques, nursing care, prognosis, and attention to patients who were clinically con- on September 28, 2021 by guest. Protected copyright. The amount is about 10% of the estimated overall management. Moreover, recognition sidered as having Guillain-Barré syndrome, lethal dose in humans—2200 µg/60 kg body of critical illness polyneuropathy indicates the but who were characterised electrophysi- weight4 (body weights of the patient and her need for physiotherapy, rehabilitation, and ologically as having early axonal degeneration husband were 54.5 and 62 kg respectively)— other supportive measures as the patient of the motor and sensory nerve fibres. The and caused no clinical evidence of poisoning recovers. Bolton et al1 have made an impor- evidence included a rapid fall in compound in the healthy person. It was of interest that tant positive contribution to the care of muscle action potentials and sensory nerve the CNS was relatively spared from the toxic- patients with critical illness polyneuropathy. action potentials, and no evidence of demyeli- ity as the EEG showed a posterior dominant, The actual aetiology, however, has yet to be nation. Such patients often had severe promptly reactive alpha rhythm and the determined. The pathogenesis needs to be paralysis and made a slow recovery, presum- patient retained consciousness when the clarified to treat patients more eVectively. ably reflecting the need to regenerate axons symptoms were at their most severe. Critical illness polyneuropathy invariably rather than remyelination. Pathological find- One of the most striking clinical features in occurs at the peak of critical illness and ings are consistent with axonal degeneration our patient was the response to haemodialy- sepsis, but in Guillain-Barré syndrome there without demyelination. Feasby et al3 termed sis. Despite the small amount of toxin is a brief period of recovery after a relatively this pattern axonal Guillain-Barré syndrome ingested, the dramatic improvement of her minor illness or inoculation. Except for and suggested that there is a fundamental clinical condition was most likely attributed diVerences in the predisposing causes, as diVerence in the underlying pathophysiology, to the rapid elimination of absorbed toxin in Bolton et al1 reported, it is diYcult to distin- resulting in primary axonal damage rather the course of haemodialysis, rather than guish critical illness polyneuropathy from than demyelination. GriYn et al4 then con- spontaneous recovery. The physical and Guillain-Barré syndrome on purely clinical firmed the existence of the acute motor- chemical properties of tetrodotoxin are also grounds. In both, polyneuropathy runs a sensory axonal neuropathy (AMSAN) pat- supportive to this hypothesis.5 It has a low monophasic course, the onset being relatively tern of Guillain-Barré syndrome described by 3 molecular weight (C11H17N3O8), is water solu- acute but with subsequent improvement in Feasby et al. ble, and is not significantly bound to protein most instances. The clinical features also are caused by the gram negative bac- —all these features are often found in toxins similar; evidence of muscle weakness in all terium Campylobacter jejuni, a leading cause Letters, Correspondence, Book reviews, Correction 129 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from of acute diarrhoea, commonly precedes the Repetitive transcranial magnetic Table Neuropsychological tests and PANSS development of Guillain-Barré syndrome.5 stimulation in the treatment of chronic scores There is a close association between axonal negative schizophrenia: a pilot study Guillain-Barré syndrome and antecedent C Test Mean (SD) infection.5 The antecedent infectious jejuni Recently, a new technology known as repeti- Block design Pre 49 (11.95) NS symptom was diarrhoea in three of five tive transcranial magnetic stimulation Post 50 (8.69) patients with axonal Guillain-Barré syn- (RTMS) has been developed.1 In 1994, the Trail making test Pre 38.3 (9.83) NS drome described by Feasby et al.3 Observa- use of magnetic stimulation in clinical A Post 42.6 (14.1) tions by GriYn et al4 confirmed that AMSAN psychiatry was suggested.2 Since then, it has Trail making test Pre 38.3 (4.5) NS follows C jejuni infection. Serum samples B Post 41 (10.03) been used in the study or treatment of Inmediate visual Pre 50.5 (4.82) NS from patients with axonal Guillain-Barré obsessive-compulsive disorder, conversion reproduction Post 54.8 (11.2) syndrome subsequent to C jejuni enteritis disorder, schizophrenia, and particularly, Delayed visual Pre 46.19 (8.23) p<0.05 often have IgG class autoantibodies to depression.3 reproduction Post 53.8 (12.64) gangliosides GM1, GM1b, GD1a, or Our pilot study aimed to assess the possible Inmediate verbal Pre 54 (7.46) NS paired GalNAc-GD1a in the acute phase of the adverse eVects of this treatment in chronic Post 59.5 (10.03) illness,6 and there is molecular mimicry schizophrenic patients with severe negative associates Delayed verbal Pre 8.8 (1.1) NS. between these gangliosides and the lipopoly- symptoms; to evaluate if direct RTMS of the paired Post 8.8 (1.17) saccharides of C jejuni isolates from patients prefrontal cortex might improve negative associates with Guillain-Barré syndrome.6 This ganglio- symptoms or cognitive impairments4 in pa- PANSS-PG Pre 37.67 (11.15) NS side mimicry may trigger high production of tients with chronic schizophrenia; and Post 36.5 (11.47) the IgG antiganglioside antibodies, and these thirdly, to note if RTMS might modify the PANSS-N Pre 31.67 (8.26) p<0.02 autoantibodies may cause motor nerve dys- deficit in prefrontal cortical activity, often Post 27.83 (8.47) PANSS-P Pre 16.83 (7.28) NS function in patients with GBS. referred to as hypofrontality, long established Post 15.33 /7.55) Interestingly, Hagensee et al7 reported a in schizophrenia,5 specially under conditions case of “C jejuni bacteremia and subsequent of task activation. Pre=pretreatment; Post=post-treatment; PANSS= Guillain-Barré syndrome” that occurred in a Six right handed patients with chronic positive and negative syndrome scale; PG=general patient with chronic graft versus host disease schizophrenia were identified at the outpa- psychopathology scale; N=negative scale; after allogenic bone marrow transplantation. tient psychiatric service of the Hospital Clínic P=positive scale. Because there was acute flaccid paralysis of Barcelona. There were two men and four associated with sepsis, some physicians might women (mean age 39). ses. All patients tolerated the RTMS well, have diagnosed critical illness polyneuropa- Exclusion criteria included alcohol or sub- with minimal side eVects (mild headache and thy. Conversely, the existence of this case stance abuse dependence disorder in the past tinnitus). strongly suggests that some diagnoses of 5 years, focal neurological findings, systemic Initial SPECT of one patient was reported critical illness polyneuropathy should actually neurological illness, taking cerebral metabolic to be normal, showing no evidence of hypo- be axonal Guillain-Barré syndrome or activator or vasodilator medications, electro- frontality. The remainder of the patients AMSAN. Our hypothesis of the nosological convulsive therapy within 6 months, and sig- showed hypofrontality on the initial neuroim- relation between critical illness polyneuropa- nificant abnormal findings on laboratory aging. The results after RTMS indicated no thy and axonal Guillain-Barré syndrome is examination. change in the hypofrontality. shown in the figure. Serum IgG antibodies All patients were taking neuroleptic drugs, Negative symptoms showed a general against GM1, GM1b, GD1a, or GalNAc- but a stable dose for at least 3 months was decrease for all patients (table). Significance GD1a could be used as immunological required. All patients were studied oV benzo- (p<0.02) was noted on the PANSS negative markers for axonal Guillain-Barré diazepines for at least 1 week before begin- symptoms subscale. These patients seemed syndrome.6 To examine the aetiology of criti- ning the treatment. During the RTMS, to be more sociable than when originally cal illness polyneuropathy and its nosological psychotropic medications were continued at seen. Nevertheless, clinical eVects of the relation to axonal Guillain-Barré syndrome, it the initial dosage. RTMS were subtle and diYcult to distinguish is necessary to investigate whether patients All patients were admitted to hospital. from those derived from the supportive envi- Inpatients underwent the UKU side eVects ronment of the psychiatric ward. with critical illness polyneuropathy have anti- 6 http://jnnp.bmj.com/ ganglioside antibodies during the acute phase scale, the positive and negative syndrome With regard to the neuropsychological bat- of the illness. scale (PANSS), and a neuropsychological tery, we found a general improvement in all battery, the day before beginning the treat- post-treatment scores (table), but only de- NOBUHIRO YUKI ment and at the end of the treatment. The layed visual memory achieved significance KOICHI HIRATA UKU scale was also administered after each (p<0.05). This feature might be basically Department of Neurology, session. explained by improvement of attention, Dokkyo University School of Medicine, Japan An equivalent neuropsychological battery specifically of the maintenance of attention, Correspondence to: Dr Nobuhiro Yuki, Depart- was used on both occasions, which consisted which allows the correct function of the ment of Neurology, Dokkyo University School of of the block design subtest of the Wechsler working memory. Thus, although there are Medicine, Kitakobayashi 880, Mibu, Shimotsuga, adult intelligence scale, the trail making tests methodological limitations regarding the on September 28, 2021 by guest. Protected copyright. Tochigi 321–0293, Japan. A and B, the FAS verbal fluency test, and two power of our conclusions, it is certain that subtests of the Wechsler memory scale (the there has been an improvement in the atten- visual memory reproduction and the verbal tional capability. 1 Bolton CF, Laverty DA, Brown JD, et al. Critically ill polyneuropathy. Electrophysiologi- paired associates subtests). We found that all patients (except one, who cal studies and diVerentiation from Guillain- A brain SPECT study was performed was always within the normal range) dimin- Barré syndrome. J Neurol Neurosurg Psychiatry using a rotating dual head gamma camera, ished their number of perseverative answers 1986;49:563–7. 2 Zochodne DW, Bolton CF, Wells GA, et al. fitted with high resolution fanbeam collima- and errors on WCST (items characteristically Critical illness polyneuropathy. A complication tors. Two 99mTc-HMPAO SPECT scans with altered in schizophrenia) after the RTMS. of sepsis and multiple organ failure. Brain cognitive activation, such as the Wisconsin However, significance was not achieved on 1987;110:819–42. card sorting test (WCST), were performed any WCST scores. 3 Feasby TE, Gilbert JJ, Brown WF, et al.An acute axonal form of Guillain-Barré polyneu- on each patient (24 hours before the Two patients who initially did not perform ropathy. Brain 1986;109:1115–26. beginning of the treatment and 24 hours after any categories on WCST, after the treatment, 4GriYn JW, Li CY, Ho TW, et al. Pathology of the last session). achieved one category, a possible indication motor-sensory axonal Guillain-Barré syn- RTMS was given with a Mag Pro magnetic of improvement of their abstract thinking. drome. Ann Neurol 1996;39:17–28. 5 Rees JH, Soudain SE, Gregson NA, et al. stimulator, 5 days a week, during 2 weeks, at This change leads us to consider a research Campylobacter jejuni infection and Guillain- a dosage of 20 Hz for 2 seconds, once per strategy previously reported, in which the Barré syndrome. N Engl J Med 1995;333: minute for 20 minutes at 80% motor thresh- WCST is used as a screening test for selecting 1374–9. old. The motor threshold was determined by schizophrenic patients. Those initially achiev- 6 Yuki N. Anti-ganglioside antibody and neu- ropathy. Review of our research. J Periph Nerv visualisation of finger movement. A butterfly ing low category scores would be compared Syst 1998;3:3–18. magnetic coil was placed tangential to the to higher category scorers in an eVort to 7 Hagensee ME, Benyunes M, Miller JA, et al. orbital area, on the C3 and C4 EEG point. identify a subgroup most likely to benefit Campylobacter jejuni bacteremia and Guillain- An important finding of this study was that from RTMS. Barré syndrome in a patient with GVHD after allogenic BMT. Bone Marrow Transplant 1994; RTMS may be given to stable schizophrenic Taking into account these mild improve- 13:349–51. patients without exacerbating their psycho- ments together, and the lack of changes in 130 Letters, Correspondence, Book reviews, Correction J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from hypofrontality after treatment, we are consid- the alien limb. Not believing that you are any attempt to explain this finding occurs in the ering extending the treatment course to 20 more in control of a limb is not likely to be a context of fear. It may be that our apprehen- sessions, each at 30 Hz for 1 second, at 90% pleasant experience. sion leads us to misinterpret innocent reflex- of motor threshold. It was also suggested that Those with seem to ive acts of our hands, such as scratching or other positions of the coil and other kinds of jump to extremely negative conclusions con- rubbing, as malevolently inspired. Plus it coils might give better results. cerning the intent of the limb. Typically, as in could be that our interpretation of spiteful The clinical change in our cohort after the the report of Ay et al, the common belief is possession in turn inspires the hand itself, RTMS could be attributed to both the treat- that the limb has deeply malevolent inten- only this is beyond our conscious awareness. ment and the supportive environment of the tions towards the victim. It may therefore be that we need to believe psychiatric ward, and even to enhance It is this aspect of alien hand syndrome that in our own and personal control over compliance to medication during hospital I suggest also needs incorporating into its our acts, because if we did not, we might find admission. We are aware that the small sam- neurological explanations, and which pro- the experience of our bodies acting as if we ple size and lack of controls compel a very vides a clue as to why our everyday merely came along for the ride, too frighten- careful interpretation of the results. experience of being in charge of our bodies, ing. Also, we may no longer believe that our Nevertheless, in the light of these, we suggest and so initiating all personal action, itself has bodies or its relevant parts belong to us. All further controlled studies of the eYcacy of a neurological basis. In other words, while the neurologists who have reported alien hand RTMS in negative symptoms of schizophre- brain is the seat of all our actions and experi- syndrome remark on how psychologically nia, not only as an add on technique but also ences, there is also a part of our nervous sys- disturbing the symptom is for the patient. as a sole therapeutic procedure. Research on tem which is responsible for our belief that we Psychiatrists would be interested in the RTMS also requires some controlled studies have free will over our behaviour. Patients parallels between alien hand syndrome and aimed to the complexity of the methodology with alien hand syndrome think that they are the “passivity phenomena” of schizophrenia, (dosage, duration, and localisation), as this no longer in control of a limb because the plus the fact that the two diseases may share 4 form of intervention may prove to be an eco- part of the brain that gives us the sensation of pathology, could go some nomical and convenient therapy in treating control over our bodies has been damaged. way to explaining why schizophrenic symp- several psychiatric disorders. When that happens, our limbs seem to act toms are frightening to the patient. So it E COHEN independently of us. seems we know that our limbs belong to us M BERNARDO Research2 conducted in the 1980s has because they obey us. When they seem to J MASANA found that the same electrical brain wave stop responding to our wills, we conclude that FJARRUFAT changes that characteristically precede all our limbs are no longer our own, and try to V NAVARRO limb movements, occur several 100 ms before fend them oV. Hence it would seem that one Department of Psychiatry we seem to consciously decide to move a of the prices we had to pay for conscious J VALLS-SOLÉ limb. If our conscious decision to act is awareness of ourselves to evolve as a function Department of Neurophysiology preceded by brain changes that anticipate of the brain, is the delusion that we are T BOGET action, then our “decision” to choose how to responsible for all our actions. If we had con- N BARRANTES behave or “freedom”, as in free will, is in fact scious awareness of ourselves, but no sense of S CATARINEU illusory. Our choices have in a sense been free will, our bodies would feel alien to us. M FONT decided beforehand by our brains. The philosophical importance of alien hand Department of Psychology Spence3 asserts that evidence such as this, syndrome is that it shows emphatically via F J LOMEÑA combined with phenomena such as alien neurology that it is possible to drive a wedge Department of Nuclear Medicine, hand syndrome, means that philosophers between consciousness and the experience of Institut d’ Investigacions Biomédiques August Pi i have to reconsider whether we have free will. free will. The brain had to develop the sensa- Sunyer, Hospital Clínic i Provincial. Universitat de tion of free will after developing conscious- He argues that these data suggest that our Barcelona, Spain ness, because being without the sensation of sense of agency is illusory and it follows that free will produces extremely negative emo- Correspondence to: Dr M Bernardo, Servicio de most of us share in common the useful delu- Psiquiatría, Hospital Clínic i Provincial, Villarroel tional experiences. So the fact that every case sion that we have free will. Patients with alien 170, 08036 Barcelona, Spain. Telephone 00343 so far reported of alien hand syndrome hand syndrome have lost this experience in 2275400, ext 2405; fax 00 343 2275477; email imputes negative intent to the alien limb [email protected] relation to a particular limb. There is a sense

might not be an incidental finding, but a core http://jnnp.bmj.com/ then that those who experience the syndrome aspect of the disorder. are closer to the reality of how much we are 1 Barker AT, Jalinous R, Freeston IL. Non- responsible for our actions than the rest of us. R PERSAUD invasive magnetic stimulation of the human This is because they have lost the function of The Maudsley Hospital, Croydon Mental Health motor cortex. Lancet 1985;i:1106–7. Services, Westways Rehabilitation Unit, 49 St James’s 2 George MS, Wassermann EM. Rapid-rate tran- the part of the brain that normally works to Road, West Croydon, Surrey CR9 2RR, UK. Telephone scranial magnetic stimulation and ECT. Con- make us think that we have conscious 0044 181 700 8512; fax 0044 181 700 8504; email vuls Ther 1994;10:251–4. freedom of will. They develop the experience, 3 Pascual-Leone A, Catala MD, Pascual-Leone [email protected] AP. Lateralized eVect of RTMS on the prefron- therefore, of becoming mere remote specta- tal cortex on mood. Neurology 1996;46:499– tors to the actions of their bodies.

502. on September 28, 2021 by guest. Protected copyright. Defenders of human “free will” argue what 1 Ay H, Buonanno FS, Price BH, et al. Sensory 4 Elliot R, Sahakian B. The neuropsychology of alien hand syndrome: case report and review of schizophrenia: relations with clinical and neu- happens before the brain itself decides to act is still unknown, and there may be a role for the literature. J Neurol Neursurg Psychiatry robiological dimensions. Psychol Med 1995;25: 1998;65:366–9. 581–94. our own autonomy there. But even these free 2 Libet B, Gleason CA, Wright EW. Time of con- 5 Wolkin A, Sanfilipo M, Wolf AP, et al. Negative will guardians concede the neurological scious intention to act in relations to onset of symptoms and hypofrontality in chronic research indicates that whatever happens cerebral activity: readiness-potential. Brain schizophrenia. Arch Gen Psychiatry 1992;49: 1983;106:623–42. 959–65. before the brain is roused, must occur below 3 Spence SA. Free will in the light of neuropsy- 6 Lingjaerde O, Ahlfors UG, Bech P, et al. The our conscious awareness. chiatry. Philosophy Psychol Psychiatry 1996;3: UKU side eVects scale. Acta Psychiatr Scand Yet in alien hand syndrome the patient 75–90. 1987;76(suppl 334):1–100. thinks that the hand has hostile motivations; 4 Crow TJ. Schizophrenia as a transcallosal misconnection syndrome. Schizophr Res 1998; it is invariably the case that the patient not 30:111–4. only thinks that the limb is “not self” but finds that the limb behaves towards the self in a destructive and aggressive manner. This The authors reply: CORRESPONDENCE could be explained by the suggestion that if We appreciate Persaud’s comments regarding we lose our conscious sense of voluntary con- the alien hand syndrome, “the perceived trol over our bodies, our minds have to come malevolence of the aVected limb towards its up with an explanation for the location of victim, and the question of whether with loss action of our movements. We decide that if of the conscious sense of voluntary control Sensory alien hand syndrome ourselves are not in control, then someone or over our bodies, our minds... decide that if something else must be; therefore, we no ourselves are not in control then someone or The case report by Ay et al1 of alien hand syn- longer have a sense of the limb belonging to something else must be”. We would oVer that drome and review of the literature neglected us. the value of our particular case is that it was the intriguing issue of why in every case so far Because to lose control over our bodies is due to a central deaVerentation—therefore reported the patient seems to be terrified of one of the most terrifying experiences, our the term “sensory alien hand syndrome”. As Letters, Correspondence, Book reviews, Correction 131 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from opposed to the idea that “we know our limbs 2 Heilman KM, Valenstein E, eds. Clinical neu- gions by seizure activity which then inter- belong to us because they obey us”, we know ropsychology 3rd ed. New York: Oxford Univer- rupts the sensory feedback loop to motor sity Press 1993:361. that our limbs belong to us because they pro- integration with inhibition of subcortical and vide us with sensory input that is recognised cortical areas.5 as self. Many patients with movement Vasomotor reactivity is exhausted in PETER W KAPLAN disorders or paralysis lose control of their transient ischaemic attacks with limb Johns Hopkins Bayview Medical Center, 4940 Eastern limbs but still have no diYculty in realising shaking Avenue, Baltimore, MD 21224, USA them as self. Indeed even in “phantom limb” there is sense of self due to central processes The article of Baumgartner and Baumgartner in the absence of a limb. Our patient, as do entitled “Vasomotor reactivity is exhausted in 1 Baumgartner RW, Baumgartner I. Vasomotor reactivity is exhausted in transient ischaemic others with anosognosia and primary abnor- transient ischaemic attacks with limb malities of central sensory systems, shows attacks with limb shaking. J Neurol Neurosurg shaking”1 provides interesting new infor- Psychiatry 1998;65:561–4. perhaps that it is central sensory processes mation regarding the nature of involuntary 2 Kaplan PW. Focal seizures resembling transient that are the key to identifying “self”. We ischemic attacks due to subclinical ischemia. limb movements contralateral to haemody- know our limbs not because they obey us but Cerebrovasc Dis 1993;3:241–3. namic failure from severe carotid artery because there is a pattern of sensory activa- 3 Lee H, Lerner A. Transient inhibitory seizures occlusive disease. The authors evoke an mimicking crescendo TIAs. Neurology 1990;40: tion that accompanies our own limb move- “exhausted cerebral vasoreactivity in the 165–6. ments. When this pattern never reaches 4 Tinuper P, Aguglia U, Laudadio S, et al. hemispheres opposite the involuntary limb specific cortical regions, then the limb is not Prolonged ictal paralysis: electroencephalo- movements”. In their report, involuntary graphic confirmation of its epileptic nature. perceived as self; called “amorphosynthesis” movements aVected only the limbs, and Clin Electroenceph 1987:18:12–14. by Denny-Brown and Banker.1 Self stimula- 5 Luders H, Lesser RP, Dinner DS, . The sec- displayed no tonic contraction, tonic-clonic et al tion by the centrally deaVerented limb in ondary sensory area in humans: evoked poten- jerking, or Jacksonian march and no epileptic “sensory” or “posterior” alien hand syn- tial and electrical stimulation studies. Ann Neurol 1985;18:177–84. drome, or kinaesthetic stimuli due to move- activity during or between the attacks. These ment of the limb as in the “anterior” or findings led the authors to strongly argue against seizures as the cause of limb shaking “motor” alien hand syndrome, is perceived as Baumgartner and Baumgartner reply: in these transient ischaemic events. due to another person or thing without criti- We are grateful for the response of Kaplan to In contradistinction, a 72 year old right cal questioning. This raises the most interest- our short report. We agree that somatic handed man was admitted to our hospital ing question of what brain region is deaVer- inhibitory seizures may mimick transient with a 3 month history of episodic weakness ented in the anterior alien hand syndrome ischaemic attacks (TIAs). Such TIAs are and numbness of the right arm. The patient where the sensory processing is intact. associated with negative symptoms such as then had six discrete stereotypic episodes of It is not our clinical experience nor the sensorimotor deficits and diYculty with right arm weakness and clumsiness that were conclusions based on published reports that speaking, EEG evidence of seizure activity, also associated with diYculty in speaking. all patients suVering with alien hand syn- and ceasing of the TIAs after the administra- Several episodes of dysarthria, numbness and drome are terrified by the eVected limb. In tion of an anticonvulsant drug.12Limb shak- weakness of the right arm and leg (MRC one author’s experience (BHP), two patients ing TIAs, however, diVer from TIAs related grade 4/5) were seen, unrelated to posture, with alien hand syndrome and related to inhibitory seizures in several ways. (1) some of which occurred when the patient was intermanual conflict were irritated by but not They are associated with positive phenomena supine. Most episodes were characterised by terrified by their opposing limbs simultane- (limb shaking), and the involuntary move- slight tremulousness and -like move- ously vying for a cigarette or book. Another ments do not aVect the facial muscles. (2) ments of the outstretched right arm. There patient was amused but rather indiVerent to Patients with attacks of shaking movements was a return to baseline functioning between his aVected left side. The most terrifying situ- of the limbs have no EEG evidence of epilep- events.2 Video/EEG monitoring, however, ation we have heard is when the patient iden- tic activity, and involuntary movements do showed low voltage spikes in the left central- tified his aVected left side as belonging to his not stop after administration of anticonvul- parietal head regions contralateral to the mother in law! A patient reported by sive therapy. (3) Although the patient pre- 2 facial twitching and the right arm and right Heilman’s group with persistent alien hand sented by Kaplan had a 95% stenosis of the leg weakness. Although ongoing clinical and syndrome referred to it as “my little sister”. left internal carotid artery, it is unclear EEG seizure activity stopped after 2 mg

Similar to our experience, they suggest that a whether haemodynamic failure was present http://jnnp.bmj.com/ intravenous lorazepam, they reoccurred after predisposing personality type may be neces- or not, because no studies evaluating the loading with phenytoin. Because angiography sary given that most patients with collosal haemodynamic reserve of the homolateral disclosed a greater than 95% stenosis of the infarcts or tumours do not emphasise this hemisphere were presented. This is in left internal carotid artery (while the patient complaint. accordance with the finding that the involun- was treated with phenytoin at a concentration Unlike our case of limited duration, the tary movements as well as the sensorimotor of 16.5 mg/l), the patient was anticoagulated persistence of alien hand syndrome seems deficits of Kaplans’ patient were not related with heparin, but episodes continued. It was dependent on mesial frontal dysfunction. to posture. (4) The pathogenesis is thought to only after a left carotid endarterectomy that These patients rarely deny that the aVected be due to disinhibition of subcortical control all episodes of weakness, tremulousness, and limb belongs to them. Instead, they under- mechanisms as a result of ischaemia. EEG epileptiform activity stopped. They on September 28, 2021 by guest. Protected copyright. stand it in terms of their “anarchic hand”. In our opinion, it is not clear whether the have not recurred over the past 5 years. Hence, although the initial syndrome may asterixis-like movements of the outstretched The literature includes several cases of result in disjointed and terrifying perceptions, right arm of Kaplan’s patient are due to epi- focal motor inhibitory seizures causing it seems that the brain quickly re-establishes leptic seizures, because unilateral asterixis of weakness.34 Although it is impossible to its control by presently unknown adaptive the outstretched arm has been reported with prove a negative, it could be argued that capacities. Furthermore, why it almost exclu- contralateral vascular lesions aVecting almost although no epileptiform or other evidence of sively involves the left body side in right all cerebral structures involved in motion seizure activity is present in a particular case, handed people remains unknown. Studying control including ischaemia in the territory of the abolition of ongoing clinical and EEG this syndrome in greater detail may yield the middle cerebral artery.3 additional insights into the pathophysiology evidence of inhibitory motor activity by RALF W BAUMGARTNER of denial and misidentification. intravenous diazepam argues in favour, at least in part, of an ictal contribution. The fact Department of Neurology, University Hospital of HAKAN AY that in virtually all reported cases, abnormal Zürich , Switzerland FERDINANDO S BUONANNO movements are more definitively resolved by IRIS BAUMGARTNER DEAN A LE carotid endarterectomy, argues for an under- Division of Angiology, University Hospital of Bern, WALTER J KOROSHETZ Switzerland Department of Neurology, Stroke Service, lying ischaemic aetiology that induces focal Massachusetts General Hospital, Harvard Medical seizures. There are few reports that clearly Correspondence to: Dr Ralf W Baumgartner, Neu- School, 32 Fruit Street, Boston MA 02114, USA delineate the interaction and association of rologische Klinik, Frauenklinikstrase 26, CH-8091 inhibitory focal motor seizures and transient Zürich, Switzerland. Telephone 0041 1 255 56 86; BRUCE H PRICE ischaemic attacks, as there are few sequential fax 0041 1 255 43 80; email Department of Neurology, McLean Hospital, 115 Mill [email protected] Street, Belmont MA 02178–9106, USA trials of antiseizure drugs or anticoagulation (under EEG monitoring) and finally carotid endarterectomy. Several authors support the 1 Denny-Brown D, Banker B. Amorphosynthesis 1 Kaplan PW. Focal seizures resembling transient from left parietal lesion. Arch Neurol Psychiatry concept of an inhibition of motor function in ischemic attacks due to subclinical ischemia. 1954;71:302. parietal and secondary somatosensory re- Cerebrovasc Dis 1993;3:241–3. 132 Letters, Correspondence, Book reviews, Correction J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from

2 Lee H, Lerner A. Transient inhibitory seizures of personal teaching slides from a successful increasingly available for the non-invasive mimicking crescendo TIAs. Neurology 1990;40: academic career all vouch for the provenance imaging of intracranial structures, particu- 165–6. 3 Melo TP, Bogousslavsky J. Specific neurologic and informative nature of the atlas. However larly the basal cerebral arteries. There are manifestations of stroke. In: Ginsberg MD, the place of such a book within a neurologist’s now four principal components to the Bogousslavsky J, eds. Cerebrovascular disease. library has to be questioned. There are a technique: B mode ultrasound which can be Pathophysiology, diagnosis, and management.Vol 2. Malden, MA: Blackwell Science, 1998:961– plethora of high quality textbooks devoted to used to image the brain parenchyma; colour 85. all aspects of , all well illus- coded Doppler which provides a colour trated and most in colour. They provide in image of the basal vessels; spectral analysis of depth analysis of all aspects of the disease and pulsed wave Doppler which is used to derive although their illustrations tend to be smaller blood flow velocities; and latterly “power” this is where I would choose to put my Doppler which is also used for vascular imag- money. It may be that the circulation of this ing following analysis of the amplitude rather BOOK REVIEWS book will be higher than expected as it is than the frequency of the reflected ultrasound likely to be a popular choice for some beam. In addition, echocontrast agents are pharmaceutical companies. now available which can increase the signal to NEIL ROBERTSON noise ratio and thus help overcome some of the detrimental acoustic eVects of the skull. Neurology for the MRCP Part II. By This volume of 400 pages and liberal DAVID SMITH. (Pp164, £15.99). Published by Calvarial and Dural Reconstruction. colour diagrams and prints is edited by three Arnold, London 1998. ISBN 034069175. Edited by SETTI R RENGACHARY and EDWARD C exponents of the technique. Thirty one chap- BENZEL. (Pp 200). Published by AANS, ters written by a further 20 contributors cover To the MRCP candidate neurology is one of Illinois 1998. ISBN 1-879284-63-4. topics from the history of transcranial ultra- the more daunting specialties. The unfamiliar sound, through the physics of Doppler ultra- nerve conduction study and the frankly mys- This monograph is the latest to be produced sound to potential clinical applications. The terious EEG can distress an otherwise well by the American Association of Neurological book is helpfully split into two sections with rounded senior house oYcer. Despite the fact Surgeons as part of its Neurosurgical Topics the theoretical aspects described in the first that much of neurology is commonly seen on series. It begins by tracing the history of cal- half and clinical aspects in the second. a general medical ward—, dementias varial reconstruction from ancient times. This is certainly a specialised book and will and so forth—the general perception is of an There follows a discussion of the diVerent really only appeal to those interested in, or unimaginable list of eponymous syndromes autologous donor sites and synthetic materi- wishing to develop, expertise in transcranial and obscure signs. Rather than dwell on the als currently available for repair of calvarial colour coded ultrasound. For such readers last, in this book Dr Smith tries to address the and facial defects. The merits, disadvantages, the technical chapters on instrumentation, commoner complaints as examination style and contraindications of each are considered. signal processing, echocontrast agents, har- questions each with a “simple clinical les- Dural substitutes are then dealt with in simi- monic imaging etc will certainly provide a son”. The “grey case” section, for instance, lar fashion. Specific problems, such as scalp complete understanding of the priciples includes questions on multiple sclerosis, reconstruction, the management of commi- behind the technique. I think that some of the cluster headache, and HSV encephalitis, nuted frontal sinus fractures, and reconstruc- errors made in the interpretation of vascular while broadening the topics to include tion of the anterior skull base are the subject ultrasound examinations are due to an postinfective demyelination, chronic hemi- of separate chapters. The final part of the incomplete understanding of the physics of crania, and acute haemorrhagic encephalo- book is devoted to craniosynostosis. A review Doppler ultrasound, hence the attention paid myelitis. There is, however, a tendency for the of current knowledge on pathogenesis is to this area is commendable. discussion after each question to be rather followed by a good account of some of the The clinical section covers the examination brief. A fuller explanation, with more allow- more common techniques used to treat single technique, normal reference values, the main ance for the reader’s ignorance, would have suture synostosis. Understandably, in a book categories of cerebrovascular disease, and been appreciated. The data interpretation of this type there is space only for an overview also contains chapters on areas which may be section is somewhat better, covering CSF, of the treatment and complications of multi- less immediately suitable for ultrasound EEG, and other data extremely well. Perhaps suture involvement, but the chapter provides study. For example, the findings in head a little too well; would an MRCP candidate well chosen references for further reading. trauma, tumours, psychiatric disorders, and http://jnnp.bmj.com/ really be expected to recognise the character- The reconstruction of traumatic and post- movement disorders are the subject of istic EEG of Creutzfeldt-Jakob disease? I surgical calvarial defects occupies the bulk of separate chapters. Although I have no prob- surely hope not. Finally, the slide tests are this volume, and is dealt with very eVectively. lem with enthusiasm for this technique a little disappointing. If anything, neurology lends Operative techniques and the relative merits pragmatism would not go amiss. A more bal- itself best to this section of the written exam- of various materials are covered in a clear and anced discussion of the limitations as well as ination but it is let down by the poor quality consise manner. By contrast, the section on potentials of the technique could have been of some of the images in this book. This is aural substitutes is a little disappointing applied. especially unfortunate, as other images in the because it does not provide the reader with As with any book with multiple authors same section are remarkably impressive. The there is some variation in style and overlap,

reasoned argument on how to select the most on September 28, 2021 by guest. Protected copyright. Sturge-Weber skull radiograph and central appropriate graft from the sometimes bewil- particularly in the introductions and conclu- pontine myelinolysis MRI are beautiful. In dering variety of autologous, synthetic, and sions of the chapters. Nevertheless, it is a summary, this is a creditable first edition. I xenograft materials which are available when comprehensive current review of transcranial look forward to the second. vascularised pericranial tissue is not an colour coded sonography. Although the option. reader must decide exactly how this tech- STEFAN MARCINIAK Craniosynostosis is a topic which is cov- nique fits into clinical practice the book will ered very well in standard paediatric neuro- certainly stimulate some ideas. An Atlas of Multiple Sclerosis. Edited by surgical texts and it is not worth buying this PETER MARTIN Charles M Poser. (Pp 134, £48.00/$85.00). book for that section alone. However, the Published by Parthenon Publishing, account of techniques for repair of calvarial defects is excellent and merits the inclusion of Spinal Cord Diseases-Diagnosis and Carnforth 1998. ISBN 1-85070-946-7. this text in a departmental library. Treatment. Edited by GORDON L ENGLER, This book, after a short introduction to some ROBERT MACFARLANE JONATHAN COLE, and W LOUIS MERTON. (Pp of the fundamental features of the disease 675, US$195). Published by Marcel Dekker, goes on to provide some 117 illustrations of Echoenhancers and Transcranial Color New York, 1998. ISBN 0-8247-9489-3. aspects of the disease from Cruveihier’s plates to histopathological specimens and also a Duplex Sonography. Edited by ULRICH This is volume 47 of a series entitled heavy leaning to imaging particularly mag- BOGDAHN, GEORG BECKER, and FELIX Neurological Disease and Therapy, series editor netic resonance scanning, as might be SCHLACHETZKI. (Pp 420). Published by W C Koller. This volume is edited by an expected. There is no doubting the aesthetic Blackwell Science, Oxford 1998. ISBN American surgeon and two British neuro- impact of this short book. In addition, the fact 0-632-04856-5. physiologists. Most of the 45 contributors are that these illustrations emanate from a well American or British, almost half of whom, established figure in the multiple sclerosis Transcranial colour duplex sonography is an including Dr Cole, are from Southampton. world and are likely to be a representative set ultrasound technique which is becoming The book begins with a pathophysiological Letters, Correspondence, Book reviews, Correction 133 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.67.1.121 on 1 July 1999. Downloaded from introduction setting the scene for the five Neurologic Disease in Women. Edited by If pushed to criticise, the indexing could be main disease sections covering develop- Peter Kaplan. (Pp 480 $150). Published by more complete and certain conditions con- mental/genetic disease, spinal injury, infec- Demos, New York 1998. ISBN sidered in more detail, in particular, paraneo- tion, tumour, and the eVect of neurological 1-888799-153. plastic conditions associated with breast and and systemic disease on the spinal cord. This gynaecological malignancies. However, that chapter covers a wide area from multiple This is the second time that I have been asked aside, I think this a rather special book and sclerosis to motor neuron disease to vascular to review a book on this topic. The first time not only a good addition to any neurological disease to metabolic diseases. Then follows a I approached the task with some scepticism— library but a useful purchase for anyone section on investigation considering imaging, were neurological diseases in women really so interested in female medical issues. neurophysiology, and urodynamics. Finally, diVerent from those in men that they GILLIAN HALL there is a miscellaneous section covering warranted their own text book? But I rapidly clinically important entities such as pain, became a convert to the cause, being The reader may be interested in the sexual problems, and terminal care associated reminded that there are issues specific to following: with spinal cord disease but also including a females that influence both disease, investiga- highly specialised chapter on the role of tion, and treatment (pregnancy, breast feed- omental transfer in spinal cord injury. ing, menopause, to name the most obvious) Neuro-Oncology for Nursing. Edited by This is an ambitious attempt at being com- and that not all neurological diseases attack DOUGLAS GUERRERO. (Pp 330, £24.50). prehensive. The editors themselves worry the sexes equally. There are also wider socio- Published by Whurr Publishers Ltd, London that the emphasis favours surgical conditions. economic and legal issues that play a part in 1998. ISBN 1-86156-087-7. Although this might be the case, many surgi- the complete disease picture which many of cal cases present to the neurologist or us neglect too often but which this book is rheumatologist, care for spinal disease often careful to address (see below). Leaving A Research Portfolio on Chronic falling between several specialties. Therefore, content aside for a moment, this is a Fatigue. Edited by ROBIN FOX. (Pp 72, it is of benefit to the clinician to have all beautifully presented book; clearly headed £14.95). Published by The Royal Society of aspects of spinal disease in one volume. The and with wide use of well constructed tables. Medicine Press Ltd, London 1998. ISBN 1 standard and style of the individual chapters It encourages one to read on. It seems up to 85315 367 2. varies, that on motor neuron disease being up date and well referenced. to date and topical, malignancies being The contributors (40 in total) are exclu- covered in depth. That on sexual problems sively American, and east coast American at associated with spinal cord disease is excel- that with only occasional forays westward. lent, particularly practical and a must for The text is divided into three sections. The both doctors dealing with spinal disease and first, entitled General Issues in Women includes for patients themselves who are often unin- an anatomical chapter considering the sex CORRECTION formed (our fault, not theirs). The chapter on diVerences of regional brain structure and decompression illness will be food for function. More novel for this type of text, it thought for many doctors who enjoy recrea- contains two thoughtful chapters considering tional diving, for although studies have not women’s health within the context of their yet shown adverse aVects on the quality of life lifestyles and women’s health and its relation Hanna PA, Jankovic J, Vincent A. in those who dive frequently but without with the law. This chapter considers issues incident, the evidence for cumulative neuro- Comparison of mouse bioassay and such as coercive approaches to preventing immunoprecipation assay for botuli- logical damage from neurophysiological, im- foetal harm, those relating to informed aging, and pathological studies is compelling. consent to medical treatment, and diYcult num toxin antibodies. J Neurol Neuro- The quality of illustration is high. Perhaps choices with neurological implications. The surg Psychiatry 1999;66:612–16. not surprisingly, this is particularly evident in law and the case examples are exclusively During the editorial process the de- the imaging section (where there is a rather American but the issues are universal. This scriptions of the histograms in figure 4 spectacular sagittal T2 weighted MRI of a opening section leaves no doubt that this is a intramedullary arteriovenous malformation). (p 614) were wrongly ascribed. The book that has taken female issues extremely corrected figure is reproduced below. In addition to imaging many of the chapters seriously. http://jnnp.bmj.com/ also make good use of schematic diagrams The second section looks at neurological and line drawings to enhance the text. diseases as they aVect females at diVerent life No response to test injection Drs Engler, Cole, and Merton end their Good response to test injection stages, from birth through menarche, preg- 20 preface by commenting that “Our main hope, nancy, and menopause, to the elderly woman. however, is that the chapters will read as a As well as considering genetic diseases that series of views on the spinal cord and its dis- strike at a particular age, these chapters ease, so that a surgeon may learn about consider the influence of changing physiology current practice as well as the wide range of and hormonal balance on neurological dis- 10 conditions aVecting the cord that are outside

ease. The third section is the most conven- on September 28, 2021 by guest. Protected copyright. the field of surgery”. While I agree that edu- tional. Each chapter considers a neurological Observations (n) cating surgeons is an admirable aim, I think disease representing these diseases with em- that the authors rather undersell themselves phasis on their eVect on women and there is, 0 and that this book’s main strength, as I have by necessity, some overlap between this and 0/1 2 3/4 said above, is that it will appeal to all the previous section. As a non-American, I Clinical response to BTX-A disciplines that deal with spinal cord disease, would feel more comfortable to believe that bringing together neurological, rheumato- Figure 4 Correlation of clinical response the high number of female patients with (grade 0 or 1 response indicates non-responders, logical, and surgical disease that is often cov- peripheral nerve secondary to physical ered in separate textbooks. grade 2 response indicates reduced response, and beatings, knife wounds, or gunshot wounds grade 3 or 4 are responders) with response to test GILLIAN HALL reflected the country of origin of this book! injections.