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gical evaluation for epilepsy surgery. Antiepi- signal over the right lateral temporal neocor- leptic drugs were withdrawn to facilitate tex and contralateral basal ganglion. An LETTERS TO seizure recording. A diagnosis of temporal interictal cerebral SPECT study was repeated lobe epilepsy was based on analysis of the at 4 weeks after postictal psychosis which THE EDITOR electroclinical events and, if applicable, post- showed a complete resolution of hyperper- operative outcome after anterior temporal fusion signal in the right temporal lobe and lobectomy. Psychosis was diagnosed accord- basal ganglia. Anterior temporal lobectomy ing to the fourth edition of the diagnostics was performed and she became seizure free and statistical manual of mental disorders after surgery. Postictal psychosis related regional (DSM-IV) criteria of brief psychotic disorders Patient 2 was a 44 year old man with cerebral hyperperfusion without marked stressor. HMPAO-SPECT was intractable complex partial seizures since the performed during the psychotic period, age of 30. His seizures were intractable to Postictal psychosis is a known complication which ranged from 2–4 days after the last sei- multiple antiepileptic drugs. Brain MRI of complex partial seizure in particular zure. Interictal cerebral SPECT, brain MRI, showed left hippocampal sclerosis. Interictal temporal lobe epilepsy. It usually runs a and a Wada test were performed as part of cerebral SPECT showed a relative hypoper- benign and self limiting course. A postictal presurgical evaluation. fusion area over the left hemisphere. Interic- phenomenon with focal cerebral hypofunc- Patient 1 was a 34 year old Chinese woman tal surface EEG was non-lateralising but ictal tion (similar to Todd’s palsy), rather than with complex partial seizures since the age of EEG disclosed a right hemispheric onset. On ongoing seizure activity, has been 18. Her seizure control was suboptimal on a withdrawal of antiepileptic drugs, seven postulated.12 Surface EEG is either normal combination of antiepileptic drugs. Brain complex partial seizures with secondary gen- or showing non-specific slow waves.3 Hence, MRI showed a small hippocampus on the eralised tonic clonic seizures were recorded antipsychotic medications are prescribed right. Interictal EEG showed bilateral tempo- within a period of 72 hours. His usual instead of antiepileptic drugs. Until recently, ral sharp waves and ictal recordings con- antiepileptic drugs were then restarted. the pathogenic mechanisms have remained firmed a right temporal epileptogenic focus. Thirty hours after his last secondary general- unknown. In this communication, we report A Wada test confirmed right hippocampal ised tonic-clonic seizure; he began to develop on two patients with postictal psychosis, dur- memory dysfunction. Six hours after her last emotional lability, talking nonsense, restless- ing which a cerebral SPECT study showed a secondary generalised tonic-clonic seizure ness, auditory hallucination, persecutory hyperperfusion signal over the right temporal after video-EEG telemetry, she began to delusion, and delusion of superstition. Cer- lobe and contralateral basal ganglion. As develop emotional lability, talking nonsense, ebral SPECT study, performed 2 days later hyperperfusion in ictal cerebral SPECT is motor restlessness, and auditory hallucina- while his psychotic features persisted, closely linked to epileptic activities,4 our find- tion. A cerebral SPECT study was performed showed two relative hyperperfused areas over ings support a contrary explanation for at day 4 after her last seizure. Her psychotic the right temporal neocortex and contralat- postictal psychosis. features persisted although she was taking eral basal ganglion in addition to the original Prolonged video-EEG telemetry study was antipsychotic medication (pimozide). Cer- hypoperfused area over the left hemisphere. performed in patients who underwent presur- ebral SPECT showed a clear hyperperfusion An antipsychotic agent (thioridazine) was http://jnnp.bmj.com/ on October 1, 2021 by guest. Protected copyright.

Interictal SPECT and SPECT performed during postictal psychosis. (Top) A SPECT study of patient 1 showing areas of relative hyperperfusion over the right temporal neocortex (red arrows) and the left basal ganglia (blue and yellow arrows) during postictal psychosis. (Bottom) SPECT study of patient2 showing areas of hyperperfusion over the right temporal neocortex and the left basal ganglia. Arrows indicate areas of hyperperfusion. J Neurol Neurosurg Psychiatry 2000;68:100–126 101 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from started after the cerebral SPECT. His with cerebral SPECT or PET may enhance tion of their disease. There was no drug psychotic symptoms resolved 2 weeks later our understanding on the mechanism of pos- history before bleeding. Control specimens with full recovery. tictal psychosis. from two right gyri recti and one cerebellar Cerebral SPECT performed during the G C Y FONG tonsil were obtained, respectively, from op- interictal period (IP) and during postictal K Y FONG erations for ruptured aneurysms of the ante- psychosis (PP) were analysed visually and W MAK rior communicating artery or for Arnold areas of hyperperfusion were identified. K L TSANG Chiari disease. Quantitaive data at regions of interest (ROIs) K H CHAN Immunohistochemical evaluations were were measured on coronal and axial slides R T F CHEUNG performed on 5 µm thick cryostat sections containing basal ganglia (BG), mesial (MT), SLHO using a protocol reported previously.5 Owing and lateral (LT) temporal lobe structures. Division of Neurology, University Department of to the limited amount of available material, Asymmetry index (ASI) was calculated as Medicine, The University of Hong Kong only in a few cases was some fresh tissue ((ROI focus−ROI contralateral)/ROI WYHO retained to allow western blots. Distribution focus+ROI contralateral))×200%. We set an Department of Nuclear Medicine, Queen Mary of FN and TN isoforms was investigated arbitrary change of ASI >100% to be signifi- Hospital, Hong Kong using three monoclonal antibodies (mAbs) or cant. As there were only two patients, statisti- Correspondence to: Dr GCYFong,Department two Ab fragments, obtained by phage display cal testing was not performed. of Medicine, Queen Mary Hospital, Pokfulam Road, technology, respectively. These Abs, prepared Both patients showed postictal psychosis Hong Kong email cyfong.medicine @graduate.hku.hk in our laboratory, were found to work on fresh and had a regional increase in rCBF over the frozen material. According to the previous right temporal neocortex and the left basal characterisations the BC-1 mAb and the 1 Savard G, Andermann F, Olivier A, et al. Postic- ganglion compared with their interictal study tal psychosis after partial complex seizures: a TN-11 Ab fragments are specific for isoforms (figure). Quantitative analysis for patient 1 multiple case study. Epilepsia 1991;32:225–31. occurring almost exclusively in fetal tissues showed changes of ASI during IP and PP 2 Morell F. Memory loss as a Todd’s paresis. and in tumours, with the recognised TN iso- Epilpesia 1980;21:185. over right MT was +75% (-6.64476 to 3 Kanner AM, Stagno S, Kotagal P, et al. Postictal form being typically associated with anaplas- -1.65289); over the right LT was +1167.8% psychiatric events during prolonged video- tic gliomas (table). (1.07527 to 12.55764); and over the left BG electro-encephalographic monitoring studies. Control sections were processed identically was +206.8% (-2.07373 to 2.21574). Quan- Arch Neurol 1996;53:258–63. to the other specimens, but the primary 4 Ho SS, Berkovic SF, Newton MR, et al. Parietal titative analysis for patient 2 showed changes lobe epilepsy: clinical features and seizure antibody was substituted with a specific of ASI during IP and PP over right MT was localization by ictal SPECT. Neurology 1994; immunoglobulin of recombinant antibodies. −3.8% (13.14217 to 12.64158); over right 44:2277–84. The antibodies were blocked using the specific LT was +178.6% (10.4696 to 18.70027); 5 Toone B. Psychoses and epilepsy. In: Reynolds antigens. The antigens were recombinant pro- EH, Trimble MR, eds. Epilepsy and psychiatry. and over left BG was +155.9% (−5.85556 to London: Churchill Livingstone, 1981:113–7. tein containing the epitope produced in E Coli. 3.27522). For the mAb BC-1 we used the recombinant Postictal psychosis is a distinct clinical protein containing the type-III repeats 7B-8–9. event associated with temporal lobe epilepsy.1 Oncofetal matrix glycoproteins in For the mAb IST-4 we used the recombinant The diagnosis of postictal psychosis requires cerebral arteriovenous malformations protein containing the type-III repeats 2–8. a close temporal relation between bouts of and neighbouring vessels For the recombinant antibodies TN-11 and complex partial seizures and the onset of psy- TN-12 the recombinant type-III repeat C and chosis. The psychosis usually develops after a Cerebral arteriovenous malformations the recombinant fragment containing the cluster of complex partial seizures precipi- (AVMs) are thought to be congenital lesions EGF-like repeats were used, respectively. tated by abrupt withdrawal of antiepileptic exhibiting features of either mature vascular All 10 AVMs were found to contain large drugs.1 The cluster occurs in patients with walls or embryonal anastomotic plexuses. It is amounts of FN and TN, as shown by intense poor drug compliance or during video EEG generally assumed that changes in size are immunostaining with the use of the IST-9 / telemetry studies when antiepileptic drugs dependent on enlargement of the venous IST-4 mAbs and the TN-12 Ab fragment. are withdrawn purposefully. The clinical compartment, organisation in the setting of The staining was localised either in the course of postictal psychosis is usually benign microhaemorrhages, and gliosis. However, endothelium or the subendothelial layer. A and predictable.15In our patients, the recent findings are consistent with the positive response was found in several artery- duration of psychotic disturbances lasted hypothesis of ongoing angiogenesis.12 like vessels and in a few vessels with thinner from 10 to 14 days, which is in keeping with Previous research from this laboratory walls using the mAb BC-1. Staining with the

the good prognosis. Antipsychotic drugs, disclosed that peculiar isoforms of fibronectin TN-11 Ab fragment showed occurrence of http://jnnp.bmj.com/ such as haloperidol and fluphenazin are usu- (FN) and tenascin (TN) typically occur in type III repeat C TN isoform in the inner ally prescribed.1 fetal and neoplastic tissues.3–5 These isoforms layers of the vascular components of the The underlying mechanism of postictal are a blend of structurally diVerent glycopro- nidus, irrespective of their morphology. psychosis is unknown. Postictal cerebral teins that result from alternative splicing of the Six out of the 10 examined specimens were hypofunction has been postulated as an ana- primary transcript and are mainly expressed found to contain portions of cerebral tissue logue to Todd’s paralysis after seizure.12 in the extracellular matrix. Their expression is surrounding the angiomatous nidus. In all However, the presence of increased rCBF undetectable in normal adult tissues, with the these cases the wall of several vessels during postictal psychosis, may suggest an exception of the vessels in the regenerating exhibited intense staining with the use of the alternative explanation as ictal SPECT has endometrium. To gain further insight into the TN-11 Ab fragment. Using the BC-1 mAb been shown to be highly sensitive and specific pathobiology of the AVMs the present report some of these vessels exhibited some staining on October 1, 2021 by guest. Protected copyright. in demonstrating seizure foci.4 sought to ascertain whether these lesions also (figure). In the control specimens (brain and To conclude, our results are contradictory express oncofetal FN and TN isoforms. cerebellum) both the FN isoform containing to the hypofunction theory of Todd’s paraly- Tissue samples were obtained after neuro- the ED-B sequence (ED-B+FN), and the sis in postictal psychosis. We think that these surgical excisions of ruptured AVMs. All 10 type III repeat C TN isoform were absent, hyperperfusion areas are responsible for the patients had experienced an intracerebral despite the widespread distribution of total postictal psychosis. Further serial studies haemorrhage as the first clinical manifesta- FN and TN in the vascular walls.

Characterisation of the employed Abs and distribution of the recognized isoforms.

Anti-FN mAbs45 Anti-TN Ab fragments3

IST-4 IST-9 BC-1 TN-12 TN-11

Recognised isoforms Total FN Isoforms containing Isoform containing the ED-B Total TN Type III repeat C Isoform the ED-A sequence sequence Distribution of the isoform (s) Widespread Widespread Absent in adult tissues (with the Widespread Absent in adult tissues exception of the regenerating Present in fetal tissues endometrium) Present in the vascular wall and the Absent in several types of matrix of fetal tissues and tumours malignancies Present in the vascular wall of anaplastic gliomas 102 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

2 Rothbart D, Awad IA, Jiyon L, et al. Expression of angiogenic factors and structural proteins in central nervous system vascular malforma- tions. Neurosurgery 1996;38:915–25. 3 Carnemolla B, Castellani P, Borsi L, et al. Iden- tification of a glioblastoma associated tn-c iso- form by a high aYnity recombinant antibody. Am J Pathol 1999;154:1345–52. 4 Carnemolla B, Leprini A, Allemanni G, et al. The Inclusion of type III repeat ED-B in the fibronectin molecule generates conformational modifications that unmask a cryptic sequence. J Biol Chem 1992;267:24689–92. 5 Castellani P, Viale G, Dorcaratto A, et al. The fibronectin isoform containing the ED-B on- cofetal domain: a marker of angiogenesis. Int J Cancer 1994;59:612–18.

Hashimoto’s encephalopathy presenting as “myxoedematous madness”

The neuropsychiatric sequelae of hypo- thyroidism range from lethargy and mental slowing to the florid psychotic illness referred to as “myxoedematous madness”. The last condition is characterised by frank hypo- thyroidism accompanied by psychosis, and may respond completely to thyroxine.1 More recently described is a syndrome of subacute encephalopathy, associated with high titres of thyroid autoantibodies, raised CSF protein, EEG abnormalities, and perfusion deficits in the presence of normal structural neuro- 2–4 Immunostaining with the TN-11 Ab fragment or the BC-1 mAb shows the presence of the type III imaging. In most cases, the encephalopathy repeat C TN-(A) and ED-B+ FN-(B) isoforms in angiomatous vessels. These isoforms are also occurs without any gross change in circulat- present in the wall of vessels of the cerebral tissue adjacent to the angiomatous nidus (TN: C; FN: D). ing concentrations of thyroid hormones, sug- Bar=10 µm. gesting that an inflammatory process is responsible for the cerebral dysfunction. In Previous findings showed that ED-B+FN The presence of angiogenic features in the absence of pathological data, the evidence presents with conformational modifications in AVMs might result from maintenance of pro- for a specific pathogenetic mechanism is its central part and results from deregulation of liferating and remodelling potentials, or from largely circumstantial: a small vessel vasculitis FN pre-mRNA.4 The distribution of this a specific response to haemodynamic stress in and immune complex deposition have both isoform was found to be highly restricted in vascular structures subjected to increased been suggested.34 normal adult tissues. By contrast, ED-B+ FN blood flow and pressure. Occurrence of these Although none of the published cases of exhibited widespread distribution in the vascu- features also in vessels lying in areas periph- Hashimoto’s encephalopathy has described lature of fetal tissues, including brain, and of eral to the nidus might be related to psychosis as a primary feature, it is possible several types of malignancies. It was therefore recruitment of the neighbouring vasculature, that “myxoedematous madness”, a condition regarded as a marker of angiogenesis.5 possibly dependent on focal ischaemia in the first described in detail by Asher in 19491 lies Similarly, the type III repeat C TN setting of arteriovenous shunting.12However, in a range of encephalopathic phenomena isoform, recognised by the Ab fragment the presence in apparently normal vascula- mediated by autoimmune mechanisms. This TN-11, was found to occur in the vascular ture of molecules typically occurring in fetal suggestion would certainly be consistent with walls of anaplastic gliomas. Northern blot tissues and malignancies indicate that cer- the range of clinical presentations of other http://jnnp.bmj.com/ analysis showed that the mRNA of this ebral AVMs may not be static lesions. Further autoimmune cerebral vasculitides.5 As au- isoform was undetectable in normal tissues studies are needed to ascertain whether this toimmune thyroiditis is the commonest cause and some malignancies, but was present in phenomenon results merely from haemody- of thyroid failure in this country,6 it is likely to large amounts in fetal tissues, including namic stress or actually reflects an intrinsic have been present in at least some of Asher’s brain, and in glioblastomas3 growth potential. Should this second be the original 14 cases. Although most had florid Recent advances in the pathology of cerebral case, current therapeutic strategies would myxoedematous features at psychiatric pres- AVMs suggest that these lesions might not be possibly require revision. entation, this may simply reflect the diYculty static. Tyrosine kinase, an endothelial cell spe- This study was partially supported by the of diagnosing subclinical thyroid disease cific receptor upregulated in glioblastomas, National Research Council (CNR), AIRC before rapid laboratory assays became widely was found to be highly expressed in both and the Ministry of University and Scientific available. Many features of the present case, on October 1, 2021 by guest. Protected copyright. AVMs and in the vessels of cerebral tissue bor- Research (MURST). We thank Sergio De- however, favoured an endocrine rather than dering the malformations, by contrast with the seri, EE, for his technical help and Mr. Tho- an inflammatory mechanism, suggesting that down regulation occurring in the vasculature mas Wiley for manuscript revision. the condition of “myxoedematous madness”, of the normal brain.1The pattern of distribu- though rare, remains a valid diagnostic entity. tion of structural proteins was consistent with ANTONIO PAU A 63 year old market stallholder without A DORCARATTO the hypothesis of diVuse activation of angio- GLVIALE medical or psychiatric history was brought to genesis, without specific relation to individual DISCATDepartement of Surgery, Division of a local psychiatric hospital by the police. His 2 vessel types. Neurosurgery, University of Genoa Medical School, S business had been in decline for several Furthermore, use of the cell proliferation Martino Hospital, Pad 2, Largo Rosanna Benzi 10, months, and his family had noticed uncharac- marker MIB-1 showed endothelial prolifera- 16132 Genova, Italy teristic emotional lability. In the weeks tion in arterioles, venules, and capillaries of P CASTELLANI preceding admission he had experienced the cerebral tissue neighbouring AVMs.1 A SIRI delusions and hallucinations, and exhibited The present findings indicate that a L ZARDI uncharacteristic behaviour. He had reported particular FN isoform, mainly expressed by Laboratory of Cell Biology National Cancer Institute, a vision of the crucifixion, and hearing the the vasculature of fetal and tumorous tissues, Genoa, Italy voice of his dead mother. He claimed that his as well as a TN isoform typically detected in Correspondence to: Dr A Pau house was occupied by the devil, drove the walls of vessels in anaplastic gliomas, also around aimlessly in his car, and appeared occur in AVMs and in vessels of adjacent cer- constantly fearful and withdrawn. On the day ebral tissue, but that both isoforms are absent 1 Hatva E, Jääskeläinen J, Hirvonen H, et al.Tie of admission he had made a bonfire in the in normal brain. This evidence provides endothelial cell-specific receptor tyrosine ki- garden and burned his wife’s clothes, family nase is upregulated in the vasculature of arter- further support to the hypothesis of ongoing ovenous malformations. J Neuropathol Exp photographs, furniture, and business papers. angiogenesis in and around these lesions. Neurol 1996;55:1124–33. When his wife and son tried to intervene he J Neurol Neurosurg Psychiatry 2000;68:100–126 103 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

Table 1 Laboratory and neuropsychological results at presentation (A) and at 12 month follow up (B) P J DE VRIES N HUNT Laboratory (units) A B University of Cambridge Department of Psychiatry, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK Full blood count Normal Normal A CRAWFORD Erythocyte sedimentation rate 12 6 J R HODGES Urea and electrolytes Normal Normal MRC Cognition and Brain Sciences Unit, 15 Chaucer Liver function tests Normal Normal Antinuclear antibody Negative Negative Road, Cambridge CB2 2EF,UK B12 and folate Normal Not tested K BALAN VDRL Negative Not tested Department of Nuclear Medicine, Addenbrooke’s Thyroid stimulating hormone (mU/l) 58.4 0.87 Hospital, Cambridge CB2 2QQ, UK Free T4 (pmol/l) 7.4 Not tested Correspondence to: Dr P Garrard, University of Antithyroid microsomal antibody titres 1:25600 1:1600 Cambridge Neurology Unit, Box 165, Adden- Psychometric (normal/predicted range): Folstein MMSE (>24) 25/30 25 brooke’s Hospital, Cambridge CB2 2QQ, UK NART IQ 10th percentile 18th percentile email [email protected] WAIS-R (verbal) 13th percentile Not tested WAIS-R (performance) 27th percentile Not tested 1 Asher R. Myxoedematous madness. BMJ FAS verbal fluency (>30) 25 23 1949;555–62. Cognitive estimates test (<6) 10 11 2 Thrush DC, Boddie HG. Episodic encepha- Graded naming test (>15) 10/30 16/30 lopathy associated with thyroid disorders. J Digit span forwards (>5) 7 6 Neurol Neurosurg Psychiatry 1974;37:696–700. Rey-Osterreith complex figure (copy) (36) 25.5 24 3 Shaw PJ, Walls TJ, Newman PK, et al. Rey-Osterreith complex figure (recall) ( 30%) Not tested 75% Hashimoto’s encephalopathy: a steroid respon- sive disorder associated with high anti-thyroid antibody titers: report of 5 cases. Neurology 1991;41:228–33. 4 Forchetti CM, Katsamakis G, Garron DC. became aggressive and threatened them with fered minimally, if at all, from the first exam- Autoimmune thyroiditis and a rapidly progres- a saw. The general practitioner was called and ination. sive dementia: global hypoperfusion on suspected either an acute psychosis or a In summary, therefore, this patient pre- SPECT scanning suggests a possible mech- severe depressive illness. Police assistance was sented in clear consciousness with a first anism. Neurology 1997;49:623–6. 5 Scolding NJ, Jayne DR, Zajicek J, et al. Cerebral requested because of the patient’s continuing episode of acute psychosis, and evidence of vasculitis: recognition, diagnosis and manage- violent behaviour. subtle executive and linguistic neuro- ment. QJMed1997;90:61–73. On admission he was unkempt but coop- psychological disturbance, on the background 6 Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. 1996; :99–107. erative and apparently euthymic. He denied of gradual behavioural and aVective change. N Engl J Med 335 depression, but displayed no insight into the He was profoundly hypothyroid due to an irregularity of his behaviour. No psychotic autoimmune thyroiditis, but there was no Alien hand sign in Creutzfeldt-Jakob features were seen, although during the clinical evidence of thyroid failure other than disease admission he consistently rationalised all the abnormal mental state. The psychiatric reported psychotic phenomena. He was component of his illness recovered fully, and The clinical picture of Creutzfeldt-Jakob dis- aggressive towards staV and made repeated the antithyroid microsomal antibody titre fell ease (CJD) includes various movement disor- attempts to abscond. General physical exam- markedly after thyroxine replacement, al- ders such as myoclonus, parkinsonism, ination was unremarkable. Neurological ex- though his mild neuropsychological deficits hemiballism, and dystonia. We report on a amination was normal except for spoken remained unchanged. Corticosteroids were patient with CJD who manifested the alien language, which was fluent and grammatical, not used at any stage. hand sign. We suggest that CJD should be but contained word finding pauses, circum- The response to thyroxine does not, in included in the diVerential diagnosis of locutions, and occasional semantic errors itself, imply that the cerebral illness had an diseases which present with an alien hand. (for example, “I just want to get my feet back endocrine origin; a recent report described a Creutztfeldt-Jakob disease, one of the on the table”). Formal neuropsychological patient with a subacute encephalopathic human prion diseases, is characterised by testing, and a screen of laboratory tests for illness and compensated hypothyroidism in rapidly progressive mental and motor reversible causes of encephalopathy, were the presence of increased antimicrosomal deterioration.1 Involuntary movements occur performed on admission, and results are pre- antibodies, all of which responded to thyrox- in above 90% of the patients in the course of sented below (column A). Attention is drawn ine replacement alone.4 In that case, however, the disease, the most common being http://jnnp.bmj.com/ to his mild naming deficit, and poor both EEG and SPECT were abnormal, the myoclonus.1 Other movement disorders performance on the Rey figure, which was SPECT showing multiple areas of severely range from tremor to chorea, athetosis, due to planning rather than visuospatial reduced perfusion, which normalised with dystonia, and hemiballism.1 We report on a errors, suggesting a predominantly “dysex- treatment. By contrast, in the present case the patient with CJD who presented with an alien ecutive” pattern. CT and EEG were both EEG was normal and the SPECT abnormal- hand. normal, and SPECT disclosed widespread ity was marginal and changed little, if at all, Alien hand is a rare and striking phenom- but mild cortical hypoperfusion. Trifluop- with treatment. The evidence for a significant enon defined as “a patient’s failure to recog- erazine (2 mg twice daily) was started on vasculitic component to the illness is, there- nise the action of one of his hands as his own”.2 admission, and thyroxine (75 µg once daily) fore, unconvincing. One of the patient’s hands acts as a stranger to on October 1, 2021 by guest. Protected copyright. added 1 week later. His mental state and The mild and relatively circumscribed the body and is uncooperative. Thus, there is behaviour stabilised, leading to discharge neuropsychological deficits coupled with loss of feeling of ownership but not loss of sen- after 2 months. florid psychotic phenomena, also contrast sation in the aVected hand. Originally de- At 6 month follow up the patient had with the profound global disturbance of cog- scribed in callosal tumours,3 the aetiology of stopped neuroleptic drugs, but continued nition usually associated with Hashimoto’s alien hand also includes surgical callosotomy,4 taking thyroxine. He reported feeling “back encephalopathy.3 This distinction suggests infarction of the medial frontal cortex, occipi- to normal”, had bought a new house, and was that microvascular disruption and thyroid totemporal lobe, and thalamus,15 infection,6 working as a part time shop assistant. He still hormone depletion may emphasise diVerent and corticobasal degeneration.57 had subtle word finding diYculties, and was aspects of the clinical range in Hashimoto’s A 70 year old, right handed Jewish man referred to the regional memory clinic for encephalopathy. Although the present case born in Argentina, living in Israel for the past further evaluation, which took place 6 would support Asher’s conclusion that the 20 years, was admitted to the Neurology months later. Behavioural assessment showed psychiatric features of Hashimoto’s encepha- Department. Until a month before his persisting deficits in delayed recall of verbal litis typically respond to thyroid replacement, admission, he was apparently healthy and material, verbal fluency, and visuospatial it additionally suggests that subtle neuro- helped in the accounting oYce of the village function. Formal psychometric testing, blood psychological deficits may be apparent even where he lived. His neurological illness had tests, and SPECT were repeated, 1 year after in the absence of obvious cerebral perfusion presented insidiously during the past month the original examinations. Laboratory and deficits, and that these may not be fully with unsteadiness of gait and frequent falls. neuropsychological results are presented in reversible. He also manifested behavioural changes, the table. It is of note that, whereas his nam- P GARRARD became aggressive, and had visual hallucina- ing ability had improved, performance on J R HODGES tions, perceiving insects and mice moving frontal executive tasks remained impaired. University of Cambridge Neurology unit, through his visual field. Often, he expressed The appearance of the follow up SPECT dif- Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK his fear from seeing that the “ceiling was 104 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from falling over him”. His wife mentioned bizarre, The literature seems to describe distinct 6 Berger JR, Concha M. Progressive multifocal useless movements of his left hand which forms of alien hand. All share the occurrence leukoencephalopathy: the evolution of a disease once considered rare. Journal of Neurovirology were present from the beginning of the of involuntary movements contrary to the 1995;1:5–18. disease. patient’s stated intent, but the types of move- 7 Riley DE, Lang AE, Lewis A, et al. Cortical- On admission, he was awake, brady- ment diVer. In the callosal form, there are basal ganglionic degeneration. Neurology 1990; phrenic, and partially collaborative. His con- purposeful movements of the non-dominant 40:1203–12. 9 8 MacGowan DJL, Delanty N, Petito F, et al. Iso- versation was often disrupted by hallucina- hand. In the frontal form, there is grasping lated myoclonic alien hand as the sole presen- tions. The aVect was sad and he had partial and utilisation behaviour of the dominant tation of pathologically established Creutzfeldt- insight for his mental dysfunction. He was hand.9 In the corticobasal degeneration, there Jakob disease: a report of two patients. J Neurol are aimless movements of either hand.57 Neurosurg Psychiatry 1997;63:404–7. disoriented for time, place, and situation. He 9 Feinberg TE, Schindler RJ, Gilson Flanagan N, could understand speech and was able to fol- When a consequence of tumorous or vascular et al. Two alien hand syndromes. Neurology 9 low oral instructions involving two consecu- pathology, alien hands can perform complex 1992;42:19–24. tive components. Naming was preserved. acts such as trying to tear clothes or undoing 10 Barclay CL, Bergeron C, Lang AE. Arm levita- buttons. The description by MacGowan et al8 tion in progressive supranuclear palsy. Neurol- Prominent dysgraphia and dyscalculia were ogy 1999;52:879–82. noticed. Immediate recall and short term has characteristics of the callosal form (espe- memory were severely disturbed, whereas cially in patient 2). However, our case long term memory, especially for personal life suggests that the alien hand sign in CJD may Recurrent peripheral neuropathy in a events, was relatively spared. Abstract think- appear in a diVerent type, performing less girl with celiac disease ing was severely aVected. Bimanual move- complex movements which resemble those reported by Riley et al in corticobasal The involvement of the peripheral nervous ments, such as clapping, were extremely diY- 7 cult. degeneration. These authors described the system (PNS) in children with celiac disease alien limb as “ involuntarily rising and touch- The cranial nerves were normal as were is particularly rare. Furthermore, in both ing the mouth and eyes” (patient 1). The ocular fundi. The motor examination showed children and adults with celiac disease, patient thought that she “was powerless to normal force. Deep reflexes were symmetric neurological complications are chronic and stop this movement” and when directed to 1 and plantar responses were flexor. The right progressive. stop responded that “she can’t”. Another arm had a dystonic posture. His gait was We report on a 12 year old girl aVected by patient’s left arm was at times “elevated in ataxic on a wide base. celiac disease, who on two separate occasions front of him”, while he was “unaware of this presented with an acute peripheral neurologi- At times, the left arm would spontaneously situation until his attention was called to it” rise in front of the patient during speaking or cal syndrome after accidental reintroduction (patient 10). of gluten in her diet. while using his right hand. He was unaware of Another related phenomenon coined as these movements until they were brought to This patient was born uneventfully to “arm levitation” was reported in progressive healthy non-consanguineous parents with no his attention. When questioned about their supranuclear palsy. In these patients the arm purpose, the patient denied that they were family history of neurological or metabolic involuntarily raised and performed semi- diseases. At the age of 6 months she was voluntary. No grasping of either hand or foot 10 purposeful movements. diagnosed as having celiac disease according was found. The patient had no cortical One common denominator between CJD, sensory loss. to the European Society of Paediatric Gastro- corticobasal degeneration, and progressive enterology and Nutrition (ESPGAN) crite- The laboratory data including blood chem- multifocal leukoencephalopathy,6 in which an istry, haematology, and sedimentation rate ria. Since then she was on a strict gluten free alien hand sign has also been described, is diet and was asymptomatic until the age of 10 were normal, as were folic acid, vitamin B12 multifocality. In corticobasal degeneration, it concentrations, and thyroid function.Vene- years when severe diarrhoea, vomiting, and was proposed that more than one site is abdominal pain manifested 6 days after the real disease research laboratory and HIV tests a ected or that a “release” phenomenon V intake of corn flakes erroneously thought to were negative. The cerebrospinal fluid had occurs accounting for the aetiology of alien be gluten free. No previous infections had normal content. Brain CT showed mild hand.7 In CJD, bilateral cortical damage to been noticed. One week after the onset of cerebral atrophy. An EEG showed severe dif- motor areas might be the origin of their sub- these symptoms she experienced acute weak- fuse slowing at admission. Within a week, sequent isolation and disconnection. ness and pins and needles sensation confined repeated EEGs showed triphasic waves with a We suggest that CJD should be added to to her legs. At that time her parents stopped periodic pattern of 1- 1.5 Hz. the diVerential diagnosis of diseases present- her intake of corn flakes on the suspicion that During the next 2 weeks, the patient devel- ing with an alien hand with or without myo- these were responsible for the symptoms. oped myoclonic jerks. Severe dysphasia and clonus. http://jnnp.bmj.com/ Despite this, symptoms worsened during the cognitive decline were accompanied by con- next 2 days, confining her to bed. fusion and aggression. He became grossly We are indebted to Professor Eran Zardel, Depart- At hospital admission, she was alert and ataxic, and unable to walk and perform any of ment of Physiology, University of California, Los mentally stable. Results of general physical Angeles, USA. his daily activities even with help. Transferred examination were unremarkable. Neurologi- to a chronic care hospital, he died few weeks R INZELBERG cal examination disclosed symmetric, pre- later. Postmortem examination was not al- P NISIPEANU dominantly distal, weakness of the legs; the S C BLUMEN lowed. knee jerks and ankle reflexes were depressed; This short fatal neurological disease mani- R L CARASSO Department of Neurology, Hillel YaVe Medical Center, plantar reflexes were flexor. Distal stocking fested by fulminant dementia, myoclonic on October 1, 2021 by guest. Protected copyright. Hadera, Israel glove decreased in pin prick and temperature jerks, and extrapyramidal and cerebellar dys- with sparing of propioception and light function was strongly suggestive of CJD. The Correspondence to: Dr Dr R Inzelberg, Depart- ment of Neurology, Hillel YaVe Medical touch. Coordination tests were normal. periodic EEG pattern reinforced this diagno- Center, Hadera, 38100, Israel Laboratory investigations showed a white sis. Our patient’s alien hand was part of the email [email protected] cell count of 9300/mm3. The results of the otherwise characteristic clinical picture of following investigations were within the CJD, but it occurred early in the disease normal limits: haemogram, erythrocyte sedi- 1 Brown P, Gibbs CJ, Rodgers-Johnson P, et al. course when no myoclonic jerks were Human spongiform encephalopathy: the Na- mentation rate, serum urea, nitrogen, electro- present. We are aware of only one report of tional Institutes of Health series of 300 cases of lytes, creatinine, glucose, transaminase, bi- alien hand in CJD. MacGowan et al8 experimentally transmitted disease. Ann Neurol lirubin, immunoglobulins (Igs), lead, iron, described two patients with CJD with a 1994;35:513–29. 2 Levine DN. The alien hand. In: Joseph AB, copper, urinalysis, urinary porphyrin, folic myoclonic alien hand syndrome. In one Young RR, eds. Movement disorders in neurology acid, and vitamins A, B1,B6,B12, and E. Anti- patient the left arm “was noted to have and neuropsychiatry. Oxford: Blackwell, 1999: bodies to Campylobacter jejuni, neurotropic spontaneous movements which appeared 645–9. antivirus antibodies, specific and non-specific 3 Brion S, Jedynak CP. Troubles du transfert purposeful...wandered out of her view”. In interhemispherique. A propos de trois observa- organ autoantibodies, IgA and IgG antiglia- the second, the alien limb performed com- tions de tumeurs du corps calleux. Le signe de din antibodies (AGAs), IgA antiendomesium plex actions such as unbuttoning her blouse la main etrangere. Rev Neurol 1972;126:257– antibodies (EMAs), and IgA antireticulum 66. and removing a hair pin. Although our 4 Bogen JE. The callosal syndromes. In: Heilman antibodies (ARA), assayed by enzyme linked patient had no myoclonus or pyramidal signs KM, Valenstein E, eds. Clinical neuropsychology. immunoadsorbent assay (ELISA) and im- when the alien hand appeared, in their 2nd ed. New York: Oxford University Press, munofluorescence (IF) were also negative. patients it was associated with spontaneous 1985:295–338. Lumbar puncture was not performed. Anti- 5 Doody RS, Jankovic J. The alien hand and or stimulus sensitive myoclonus, spastic related signs. J Neurol Neurosurg Psychiatry bodies against gangliosides GM1 and GQ1b, hemiparesis, and cortical sensory loss. 1992;55:806–10. myelin associated glycoprotein and myelin J Neurol Neurosurg Psychiatry 2000;68:100–126 105 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

Electrophysiological study suggestive in both episodes of an acute demyelinating peripheral neuropathy SALVATORE MUSUMECI confined to the lower limbs. Values were within normal limits in the upper limbs Department of Paediatrics, University of Sassari, Sassari, Italy 1st Episode 2nd Episode AGATA POLIZZI

L L L L Neurosciences Group, Institute of Molecular Medicine, Peroneal R Tibial R Peroneal R Tibial R Department of Clinical Neurology, University of Oxford, Oxford, UK MCV (ms) 26 27 22 24 24 28 20 23 Correspondence to: Dr Agata Polizzi, Division of DL (ms) 7.3 8.0 7.2 8.8 Paediatric Neurology, Department of Paediatrics, 7.5 8.4 7.0 9.0 University of Catania, Viale A Doria 6, 95125 F wave latency (ms) 70 72 83 84 Catania, Italy email: [email protected] CMAP (µV) 3 2.7 L L Sural R Sural R 1 Cooke WT, Thomas Smith W. Neurological SCV (ms) 38 40 disorders associated with adult coeliac disease. 42 41 Brain 1966;89:683–722 AMP (µV) 16.2 17.4 2 Gobbi G, Bouquet F, Greco L, et al. Coeliac 16.8 18 disease, epilepsy and cerebral calcifications. Lancet 1992;340:439–43 MVC=motor conduction velocity; DL=distal latency; CMAP=compound motor action potential; 3 Papadatou B, Di Capua M, Gambarara M, et al. SCV=sensory conduction velocity; AMP=amplitude; L=left; R=right. Nervous system involvement in paediatric coe- liac patients. In: Mearin ML, Mulder CJJ, eds. Coeliac disease. Dordrecht: Kluwer Academic, basic protein were not tested. Nerve conduc- in fact, neurological complications of celiac 1991:199–203. tion studies were consistent with a predomi- disease are rarely encountered and are mostly 4 Simonati A, Battistella PA, Guariso G, et al. nately motor demyelinating peripheral neu- confined to the CNS2: to the best of our Coeliac disease associated with peripheral neu- ropathy in a child: a case report. Neuropediatrics ropathy (table). Her symptoms improved knowledge, there are only two previously 1998;29:155–8 spontaneously and she was discharged home reported cases of PNS involvement in children 5 Bottaro G, Sciacca A, Failla P, et al. Antigliadin after 2 weeks. For 2 years she was asympto- with celiac disease. In both cases, however, antibodies in the various stages of coeliac disease in children. Pediatr Med Chir 1988;10: matic on a gluten free diet. these were chronic axonal polyneuropathies 409–13 At the age of 12 she presented acutely with presenting during a gluten free diet.34 severe abdominal pain 8 days after a weekly In both episodes in the present case neuro- intake of bread meant to be gluten free. Two physiology was strongly supportive of a Frontal release signs in older people weeks later, due to persisting gastrointestinal demyelinating peripheral neuropathy, which with peripheral vascular disease symptoms, her parents excluded the bread is most commonly attributed to a direct from her diet. After 2 further weeks, while the immune mediated attack to the myelin. By A growing body of research examining abdominal pain was gradually improving, she contrast, wallerian and axonal degeneration neurological aspects of clinically “silent” cer- had a new episode of acute weakness in the may be caused by vasculitis, and nutritional, ebrovascular disease suggests that neurologi- lower limbs and sensory abnormalities in- metabolic, and toxic factors. cal signs indicative of generalised organic cluding burning paraesthesiae. On neurologi- An autoimmune pathogenesis in associ- brain damage may occur in the absence of cal examination the legs showed marked ation with strong evidence of a genetic completed stroke.1 These soft signs include diminution in muscle power; absent deep susceptibility has been proposed for celiac primitive reflexes (frontal release signs), rep- tendon reflexes, and a reduction in pain and disease. Although it is well established that resenting an anatomical and functional deaf- temperature; light touch, perception of posi- AGA, EMA, and ARA are reliable indicators ferentation of cortical from subcortical struc- tion, and vibration were preserved. Walking of sensitisation to gluten at least at the time of tures. Primitive reflexes are known to occur in was impaired and the patient was bedridden. diagnosis, in the clinical practice at follow up, a wide variety of dementias, including Otherwise the examination was normal. during a gluten challenge, pathological values Alzheimer’s disease2 and vascular dementia.3 A haemogram showed white cell counts of of these antibodies may not be detected.5 In It is likely that the presence of undetected 9700/mm3. Laboratory investigations were the present case the time course of the disease cerebrovascular disease accompanying pe- within normal values as in the past. IgA and might be suggestive of an antibody mediated ripheral vascular disease is underestimated, IgG AGA, IgA EMA, and IgA ARA assayed response. However, we could not detect as peripheral vascular disease is known to be by ELISA and IF were again negative. Nerve pathological concentrations of AGA, EMA, a risk factor for transient ischaemic attacks. A conduction studies confirmed the presence of or ARA antibodies either during the course of study assessing 373 older patients with a predominantly motor demyelinating neu- the disease or at follow up. peripheral vascular disease found that 72 of http://jnnp.bmj.com/ ropathy (table). The parents refused consent It is known that in celiac disease many the 144 patients who had not experienced a for a lumbar puncture or nerve biopsy. immunological perturbations can occur out- transient ischaemic attack or stroke were Over the next 2 weeks her neurological dis- side the gastrointestinal tract. Crossing of the found to have a degree of carotid stenosis of abilities spontaneously improved until full antigens through a damaged small intestinal between 60% and 99%.4 recovery was complete. After 4 weeks, AGA, mucosa, deposition of immune complexes in In the present study, the prevalence of EMA, and ARA were still negative. target organs, a reduction in immune surveil- primitive reflexes was examined in older peo- On her most recent admission, 1 year after lance, mechanism of molecular mimicry, and ple with peripheral vascular disease and a the onset of her first neurological symptoms, activated T cell response may contribute to non-vascular control group. Independent she is still on a strict gluten free diet and has the pathogenesis of the diseases associated predictors of these reflexes were also exam- on October 1, 2021 by guest. Protected copyright. no residual symptoms or signs. with celiac disease. Direct toxic eVects of ined in peripheral vascular disease. Both The natural history of celiac disease is well gliadin and vitamin deficiency are other pos- groups were drawn from the same geographi- known and the typical celiac enteropathy is sible pathogenic mechanisms of damage to cal area. All were interviewed and examined often associated with several other disorders. the nervous system. Although we ruled out a outside hospital by myself. Interviewees were However, as celiac disease is a relatively com- vitamin deficiency it is still questionable community residents from the catchment mon and lifelong condition, it is likely that whether a toxic neuropathy can be the case. area of an inner city London teaching hospi- some of these associations may occur by In conclusion, this case shows two major tal. chance. issues: an acute polyneuropathy can be a Twenty five consecutive non-amputees on This patient, who was diagnosed as having complication of celiac disease in childhood the waiting list for femoropopliteal bypass frank celiac disease at the age of 6 months, and its benign course could help in the operation were compared with 25 postopera- experienced two episodes of acute peripheral understanding of the underlying pathogenic tive patients who had undergone elective hip neuropathy, at the age of 10 and 12 years, mechanisms. or knee replacement and a period of inpatient respectively. Two major pieces of evidence rehabilitation. All participants were aged 65 strongly support the assumption of a gluten We are grateful to Professor Angela Vincent and over at the time of interview. Patients derived disease: (1) the episodes occurred on (Oxford) for her helpful suggestions in reviewing the with peripheral vascular disease all had clini- manuscript. both occasions when gluten was accidentally cal and Doppler proved evidence of periph- reintroduced in the diet; and (2) the response AGATA POLIZZI eral ischaemia. Controls were interviewed to a gluten free diet was reasonably rapid, MARIA FINOCCHIARO between 6 months and 1 year after their ENRICO PARANO occurring within weeks. PIERO PAVONE operation. Both groups had no history of The present case, however, diVers clinically Division of Paediatric Neurology, Department of stroke or transient ischaemic attack. from those with neurological involvement pre- Paediatrics, University of Catania A more detailed description of instruments viously reported. In the paediatric age group, Catania, Italy is provided elsewhere.1 All subjects were 106 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

Table 1 Primitive reflexes in patients with peripheral vascular disease (n=25) and controls (n=25)

Hand grasp Foot grasp Glabellar Palmomental Paratonia Rooting Snout Sucking (tactile) Sucking (visual)

U 274.0 312.5 199.5 287.5 287.0 235.5 287.5 261.0 287.5 pValue 0.15 1.0 0.001* 0.15 0.29 0.01* 0.44 0.08 0.30

*Higher mean score in people with peripheral vascular disease. examined using a rating scale for the Small numbers of patients, which may also 5 years earlier. The angioplasty was compli- examination of frontal release signs (FRSS), have obscured other significant findings cated by the occurrence of a seizure, thought with nine operationally defined items, each between the two groups, limit the present to be related to dye injection, and phenytoin on a seven point semiquantitative scale. The study. However, there is some evidence that had been prescribed for a short time thereaf- nine reflexes were paratonia and palmomen- clinically relevant cerebrovascular disease ter. There was a remote history of heavy alco- tal, hand grasp, foot grasp, glabellar, rooting, may accompany peripheral vascular disease hol use, but he had been abstinent for several snout, and visual/tactile sucking reflexes. and that concomitant disruption of frontal/ years. His father had had a stroke at the age of Neuropsychological measures included the subcortical brain function may not present 65. assessment of frontal lobe function (trailmak- with hard neurological signs. As it is possible Six months earlier the patient had also col- ing tests A and B, behavioural dyscontrol that silent brain infarction was present in lapsed at home and been taken to hospital scale, and the controlled word association patients with peripheral vascular disease, fur- with a left hemiplegia. Brain CT at that time test) and generalised cognitive impairment ther studies incorporating brain imaging are was normal, as were carotid Doppler studies (CAMCOG). Depression was assessed using required before there can be a clearer under- and an echocardiogram. During that admis- the Hamilton rating scale for depression, 15 standing of the relation between peripheral sion to hospital, several generalised seizure- item geriatric depression scale, and diagnos- and central vascular pathology. like episodes were seen, some with retained tic criteria for DSM IV major depressive dis- consciousness, and he had again been started order. Family history of depression, wish to I thank Dr Robert Howard for supervision of this on phenytoin therapy. A follow up outpatient die, and suicidal ideation within the past year study and Professor Stephen Jackson and Mr Paul brain MRI was normal and it was concluded were also recorded, as were blood pressure Baskerville for allowing me to interview patients that the hemiplegia was non-organic in under their care. The study was carried out as part and a checklist for chronic physical illness. of a University of London MD thesis. origin. He was described to have made a Total FRSS scores and scores on FRSS gradual, near complete, recovery from this subscales were compared between groups RAHUL RAO first hemiplegic episode and was scheduled using the Mann-Whitney test for inde- Department of Old Age Psychiatry, Maudsley Hospital for an imminent return to work at the time of U and Institute of Psychiatry, London pendent samples. In the peripheral vascular his relapse. disease group, a correlation matrix for total Correspondence to: Dr Rahul Rao, Department of On transfer to this hospital the patient was Old Age Psychiatry, Guy’s, King’s, and St Thomas FRSS score against DSMIV depression, Medical School, Job Ward, Thomas Guy House, alert, oriented, and cooperative. Although up CAMCOG score, behavioural dyscontrol Guy’s Hospital, St Thomas Street, London SE1 to date on current aVairs and able to describe scale score, verbal fluency score (total 9RT, UK email [email protected] the investigations performed at the transfer- number of words beginning with F, A, and S) ring hospital, he scored only 23/30 on a mini and trailmaking test times was examined mental state examination, with absent three 1 Rao R, Jackson S, Howard R. Primitive reflexes using the Spearman correlation coeYcient, in cerebrovascular disease: a community study word recall, impaired registration, and poor controlling for age, sex, blood pressure, and of older people with stroke and carotid stenosis. copying of a two dimensional line drawing. chronic physical illness. Behavioural dyscon- International Journal of Geriatric Psychiatry (in Further bedside neuropsychological testing press). trol scale scores, trailmaking A/B test times, 2 Burns A, Jacoby R, Levy R. Neurological signs showed other findings indicative of construc- and verbal fluency scores were first converted in Alzheimer’s disease. Age Ageing 1991;20:45– tional apraxia and left hemineglect. Specifi- into binary variables according to whether 51. cally, when asked to draw a clock with the they were at/above or below the median value 3 Vreeling FW, Houx PJ, Jolles J, et al. Primitive time at 10 minutes to 2 o’clock, all the num- reflexes in Alzheimer’s disease and vascular for the group. CAMCOG score was divided dementia. Journal of Geriatric Psychiatry and bers, and the clockhands, were placed on the into subjects scoring 69 or above or less than Neurology 1995;8:111–17. right hand side of the clock outline (figure A). 69. Those associations with a two tailed 4 Alexandrova NA, Gibson WC, Norris JW, et al. Copying of three dimensional line drawings Carotid artery stenosis in peripheral vascular http://jnnp.bmj.com/ significance of 0.1 or less were then entered disease. J Vasc Surg 1996;23:645–9. was also significantly impaired (figure B). into a linear regression equation using the 5 Phillips NA, Mate-Kole CC, Kirby RL. Neuro- When asked to bisect a line, however, the stepwise method. psychological function in peripheral vascular patient did so only minimally to the right of Patients with peripheral vascular disease disease amputee patients. Arch Phys Med Reha- the midpoint (58% of the distance from the bil 1993;74:1309–14. had a higher mean score on the frontal release 6 Phillips NA, Mate-Kole C. Cognitive deficits in left side). signs scale than controls (5.8 (SD 4.6) v 1.7 peripheral vascular disease. A comparison of Cranial nerve examination suggested an (SD 1.9)) (Mann-Whitney U=144.500, mild stroke patients and normal control incongruent and inconsistent left hemianop- subjects. Stroke 1997;28:777–84. Z=−3.33, two tailed p=001), as well as on sia to confrontation testing but was otherwise glabellar and rooting reflexes (table). Only normal, including bilaterally symmetric op- one variable (trailmaking B test time) was Factitious clock drawing and tokinetic nystagmus. Motor examination on October 1, 2021 by guest. Protected copyright. entered into the equation; this accounted for constructional apraxia showed paralysis of the left arm and leg, with 23% of the variance in FRSS score (B=4.6, bilaterally symmetric bulk, tone, and deep 95% confidence interval (95% CI) (B) A 45 year old man presented witha1day tendon reflexes. The plantar response was 1.3–8.0, p=0.01). history of headache, possible seizures, and flexor bilaterally. Sensory examination In peripheral vascular disease, there is lim- left sided weakness. On the day of presenta- showed decreased pinprick and absent light ited information available concerning the tion the patient’s wife had twice found him, touch, joint position sense, and vibration intellectual and neurological sequelae of inexplicably, on the floor. After the second sense on the entire left side. There was also coexisting cerebrovascular disease. Phillips et such episode she brought him to hospital for impaired perception of a tuning fork’s al found greater impairment in psychomotor evaluation. Examination disclosed a com- vibration on the left side of the forehead, with speed and abstract reasoning in patients with plete left hemiplegia and hemianaesthesia, a distinct demarcation in the midline. The peripheral vascular disease than age/sex although muscle tone was documented to be rest of the physical examination was unre- matched controls, with less significant diVer- normal and the plantar responses downgoing markable. ences between the groups in verbal fluency, bilaterally. Brain CT was normal and routine Brain CT and MRI, CSF examination, and concentration, abstract thought, perception, blood examination was unremarkable. There routine EEG were normal. Routine haemato- and constructional skills.5 Another study by were no further seizure-like episodes and logical and metabolic analyses plus erythro- the same group found poorer performance in the patient was transferred to this hospital cyte sedimentation rate, serum lactate, pro- patients with peripheral vascular disease than 10 days later, hemiplegia unchanged, for thrombin time/partial thromboplastin time, controls on visual memory, trailmaking B possible angiography and further investiga- fasting serum glucose, HbA1c, serum Ig sur- test, and visuospatial skills. Patients with tions. vey, and thyroid stimulating hormone were all peripheral vascular disease were also equally He was an exsmoker with hypercholestero- within normal limits. A hypercoagulability impaired in these areas compared with a laemia and peripheral vascular disease which profile was negative. A lipid profile showed matched group of stroke patients.6 had been treated by a left femoral angioplasty mild hyperlipidaemia with increased low J Neurol Neurosurg Psychiatry 2000;68:100–126 107 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

AB patient’s willingness to undergo medical investigations, including video monitoring. It is unclear how or when the patient acquired the information needed to mimic a constructional apraxia. Previous bedside neuropsychological evaluations may have served to familiarise him with the format of such testing, acting as an impetus to research the issue of stroke and focal brain deficits (which might also have occurred after his father’s stroke), much in the same way he is now researching conversion disorder, thereby discovering what expected answers should look like. Despite repeated questioning, how- ever, no evidence could be gathered from the patient to support this speculation. I KHAN IFAYAZ Division of Neurology J RIDGLEY Division of Neuropsychology (A) Asked to: “put all the numbers on a clock and make the time ten to two”. (B) Patient’s copies (at right) of three dimensional line drawings. Top:common constructional distortion of cube. Bottom: R WENNBERG unusual mirror image representation of house. Department of Medicine, Division of Neurology, The Toronto Hospital, University of Toronto, Toronto, ON, density lipoprotein (3.92 mmol/l) and triglyc- oV work and was receiving disability funding. Canada erides (4.30 mmol/l) and low high density He walked with a limp favouring his left side Correspondence to: Dr R Wennberg, EC8–022, lipoprotein (0.73 mmol/l). Serum phenytoin and complained of persistent decreased The Toronto Hospital, 399 Bathurst Street, To- concentration was therapeutic at 74 µmol/l. sensation on the left side. Forced choice sen- ronto, Ontario, Canada M5T 2S8. Telephone 001 An ECG was normal. sory testing of finger and arm movement on 416 603 5402; fax 001 416 603 5768. Ophthalmological consultation and formal the left3 demonstrated performance to be visual field testing demonstrated a concentri- worse than chance (68% wrong choices). 1 Bernard L, Houston W, Natoli L. Malingering cally constricted field of mild degree in the Motor bulk, tone, and reflexes were symmet- on neuropsychological memory tests: potential right eye and tunnel vision in the left eye. ric and plantar responses downgoing. He objective indicators. J Clin Psychol 1993;49:45– The patient consented to overnight video- 53. drew a clock normally at the 1 year follow up. 2 Prigatano G, Amin K. Digit memory test: EEG monitoring and was seen on multiple The clinical and laboratory findings de- unequivocal cerebral dysfunction and sus- occasions to move his left arm and/or leg in a scribed above indicate beyond any doubt the pected malingering. J Clin Exp Neuropsychol normal fashion, at one point using the left non-organic nature of this patient’s left 1993;15:537–46. arm to readjust his bed covers shortly after 3 Pankratz L, Binder L, Wilcox L. Evaluation of hemiplegia/hemianaesthesia. His seizure-like an exaggerated somatosensory deficit with arousal from sleep, before glancing briefly at episodes at presentation are presumed to symptom validity testing. Arch Neurol 1987;44: the video camera and completing the task have been non-epileptic in origin (as had 798. 4 Strub R, Black W. Constructional ability. In: with his right arm. The prolonged EEG was been suspected during his previous admission normal. Strub R, Black W. The mental status examination to hospital) although this cannot be defini- in neurology. Philadelphia: FA Davis, 1985: A formal neuropsychological assessment tively proved. 101–23. performed in hospital documented impaired The inability to copy line drawings or to 5 American Psychiatric Association. Diagnostic attention, concentration, and working and statistical manual of mental disorders. 4th ed, draw a clock is, from a neurologist’s perspec- revised Washington: American Psychiatric memory, as well as several atypical calcula- . tive, typically associated with parietal lobe Association, 1994. tion and spelling errors, the second involving dysfunction, usually of the non-dominant unusual “near miss” letter substitutions or hemisphere, especially if associated with left reversals (for example, “anixety”, “excecu- 4 Anosognosia and mania associated with hemispatial neglect. To our knowledge, this http://jnnp.bmj.com/ tive”). The formal testing identified no right thalamic haemorrhage is the first reported case of factitious clock consistent evidence of visuospatial deficits or constructional apraxia. The findings were drawing and constructional apraxia. Bedside Both anosognosia and secondary mania are interpreted as inconsistent with the patient’s mental status testing also demonstrated the associated with right hemispheric lesions. more common simulated deficits of impaired history but the possibility of a factitious aeti- 1 These two non-dominant syndromes, how- ology was not specifically addressed—that is, attention and absent three word recall. In ever, are rarely described as occurring tests designed to detect malingering during retrospect, the severe neglect on clock together. We present a patient with a right neuropsychological testing12were not admin- drawing was perhaps “too good to be true”, thalamic haemorrhage giving rise to pro- istered by the examiner, who had not been especially in the light of the near normal line found denial of hemiplegia and elated mood. informed at the time of consultation of the bisection demonstrated on the same day. The This case suggests mechanisms for the on October 1, 2021 by guest. Protected copyright. presumptive neurological diagnosis of malin- mirror image distortion of the house was also common production of mania and anosogno- gering or factitious disorder. very unusual and, furthermore, the mirror sia. No further investigations were performed reversal itself is evidence of lack of clinical A 53 year old, right handed, black man, and the patient was transferred via the origi- neglect. The distortion of the cube, however, with a history of alcohol misuse and depend- nal hospital to a rehabilitation facility and could easily be misinterpreted as evidence of ence and untreated hypertension, was subsequently discharged to home. Con- organic constructional impairment if seen in brought to the emergency room a few hours fronted with the findings of the video the absence of the other relevent clinical and after developing an intense headache and left monitoring the patient appeared sanguine laboratory information. sided numbness and weakness. and accepting of the evidence that he should During follow up, the patient admitted to On admission he was described as “bellig- be able to move his left side. Six months later feeling tremendous occupation related erent,” “agitated,” and “confused.” Blood he was ambulatory but otherwise not signifi- stresses, and described how he had come to pressure was 240/160. Neurological exam- cantly improved. He had been assessed by a both fear and detest his job. Given the clear ination disclosed left lower facial droop, psychiatrist but had refused psychiatric fol- benefit to the patient of removal from his decreased left corneal and gag reflexes, and low up, electing instead to be followed up by work environment, the relapse of his symp- left hemiparesis with dense sensory deficits. a psychologist. He understood his diagnosis tomatology just as he was scheduled for With increasing obtundation, the patient was to be “conversion disorder” and reported that return to work after his first non-organic transferred to the intensive care unit and he was actively collecting information on the hemiplegic episode, and the intentionality intubated. Brain MRI showed a large, right subject via the internet. required to feign poor clock drawing and sided, hyperacute thalamic bleed with mass Outpatient brain SPECT and visual and constructional apraxia, there is much to sup- eVect and oedema. The patient was extu- somatosensory evoked potentials performed port a diagnosis of malingering.5 bated 2 days later and 4 days after the stroke 1 year after discharge demonstrated no hemi- Nevertheless, classification as a factitious dis- he was described as being drowsy and spheric abnormalities. The patient remained order is at least as justifiable in view of the inattentive, but was able to answer questions 108 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from appropriately. Neurological examination impaired. He was able to correctly recognise phenomena) on the basis of euphoria. showed contralateral gaze preference, supra- and produce facial emotional information. Moreover, Starkstein et al,7 finding that simi- nuclear vertical gaze palsy, diYculty converg- Simple attention was intact, but attentional lar frequencies and severities of major and ing, left sided flaccid hemiparesis, and dense, control (backward span and mental control) minor depression were present in patients left sided hemianaesthesia. Deep tendon was impaired. Visuomotor tracking was slow with and without anosognosia, suggest that a reflexes were absent on the left and Babinski’s and he had significant problems with concep- particular mood state may not necessarily reflex was present on the left. In addition, tual shifting (both auditory and visual). Lan- influence insight. visual extinction and neglect were present. guage processing diYculties included very Several explanations have been proposed At the time of onset of right sided weakness poor reading ability, impaired confrontation to explain the phenomenon of anosognosia.89 the patient insisted that he was “fine,” and an naming, and impaired performance on a ver- All the models invoke dysfunction of the cer- ambulance was called over his objections. bal task of fluency and initiation. Auditory ebral cortex, especially the parietal cortex. It After being extubated, the patient acknowl- comprehension was mildly impaired. Vo- is interesting that in this case functional MRI edged that he had had a stroke, but, despite cabulary scored formally in the borderline failed to demonstrate decreased CBV in the his hemiparesis, insisted that he was ready to impaired range, as did abstract verbal reason- parietal lobe. go home and go back to work. His belief in his ing. On tests of praxis he demonstrated a ten- In summary, we present a case of mania ability to walk led to near falls, and he was dency to use the hand as object. Memory accompanying anosognosia in a patient with a moved to a room nearer to the nurses’ station performances were relatively intact. His right thalamic haemorrhage. The coexistence for closer observation. He told the nurses that initial recall of two paragraphs scored for- of mania and anosognosia may be more com- someone else’s arm was in his bed. On one mally within the low average range and after a mon than previously appreciated. The associ- occasion, holding up his left arm with his 30 minute delay, he was able to recall most of ation with anosognosia implies that the right, he told the nurse to, “take it away; it the information initially encoded, scoring mechanisms implicated in the pathogenesis keeps scratching me.” That the left arm formally within the average range. of secondary mania may be similar to those of “smelled funny” was another reason he Structural brain MRI on admission to the anosognosia. The absence of evidence of wanted the nurses to take it away. emergency room showed a large right tha- abnormal parietal, temporal, or frontal lobe Four weeks after the stroke he first lamic hemorrhage with mass eVect and function by functional MRI in this case is acknowledged that his left arm belonged to oedema, with oedema extending into the cer- intriguing. him. He spontaneously recalled believing ebral peduncle with internal susceptibility ELIZABETH LIEBSON otherwise. By this time he had a moderate consistent with deoxyhaemoglobin. Also Department of Psychiatry, Tufts, New England hemiplegia and recognised “a little weak- present was increased T2 signal bilaterally in Medical Center, 750 Washington Street, Box 1007, ness,” but continued to insist that he was well frontal areas consistent with ischaemic Boston, MA 02111, USA. Telephone 001 617 636 and able to return to work. By the 6th week changes. Brain CT 30 days after stroke 1633; email [email protected] after stroke the patient more consistently showed, in addition to the thalamic lesion, acknowledged that he was weak on the left moderate cerebellar atrophy and mild to 1 Bech P, Kastrup M, Rafaelsen OJ. Mini- side of his body. A request for disabled hous- moderate prominence of the frontal cortical compendium of rating scales for states of anxi- ety, depression, mania, schizophrenia, with ing “so that I won’t be a burden to my family” sulci compatible with cerebral atrophy. corresponding DSM-III syndromes: mania seemed to indicate an appreciation of his Structural MRI performed 44 days after scale. Acta Psychiatr Scand 1986;73(suppl impairment, but this insight was fleeting; the stroke showeda2cmright thalamic hae- 236):29–31. within an hour of making such statements the matoma. Functional MRI2 performed the 2 Belliveau J. Functional cerebral imaging by sus- ceptibility contrast NMR. Magn Reson Med patient might insist that after a week’s same day demonstrateda2cmarea of absent 1990;14:538–546. exercise he would be ready to return to work. cerebral blood volume at the posterior 3 Babinski J. Contribution a l’etude des troubles His awareness of his hemiplegia fluctuated margin of the right thalamus without any evi- mentaux dans l’hemeplegie organique cereb- rale. Rev Neurol 1914;22:845–8. for 8 weeks after stroke before becoming dence of decreased cerebral blood volume 4 Joltrain E. Un nouveau cas d’anosognosie. Rev fixed, but remained shallow after 12 weeks; he within the right parietal, frontal, or temporal Neurol 1924:638–40. no longer planned to return to work and cortex. 5 Weinstein EA, Kahn RL. The syndrome of ano- sognosia. Arch Neurol Psychiatry 1950;64:772– applied for social security disability insurance This is a case of anosognosia of hemiplegia 91. “because they say I’m disabled.” and mania co-occurring in a patient with a 6 Cutting J. Study of anosognosia. J Neurol Neuro- The patient’s mood was remarkably cheer- large right thalamic haemorrhage. Although surg Psychiatry 1978;41:548–55. ful and optimistic. A week after the stroke he anosognosia and mania are not generally 7 Starkstein SE, FedoroV JP, Price TR, et al. Ano- sognosia in patients with cerebrovascular was noted to praise extravagantly the hospital thought of as occurring together, when lesions: a study of causative factors. Stroke food, and the nurses found him “talkative.” Babinski3 introduced the term anosognosia 1992;23:1446–53. http://jnnp.bmj.com/ When he arrived on our ward 11 days after he used as one of his examples a case in which 8 Ellis SJ, Small M. Denial of illness in stroke. Stroke 1993;24:757–9. the stroke he was flirtatious with female staV the patient, though not confused, was “a little 9 Heilman KM. Anosognosia: possible neuro- and boasted of having fathered 64 children. overexcited,” and in a later paper he pre- psychological mechanisms. In: Prigatano GP, His girlfriend was surprised when he kissed sented a case4 in which there was “a certain Schacter DL, eds. Awareness of deficit after brain her in front of the staV because he had never injury. New York: Oxford University Press, agitation, which expresses itself by exagger- 1991:53–62. publicly displayed aVection before. He re- ated loquacity, a decrease in attention, and a ported excellent energy and expansively tendency to erotic ideas.” Weinstein and invited all of the staV to his home for thanks- Kahn5 noted that euphoria was common in Epileptic cardiac asystole giving. Sleep was not disrupted or reduced patients with anosognosia. Moreover, al- on October 1, 2021 by guest. Protected copyright. and he had a good appetite. When beginning though Cutting6 emphasised that apathy is A patient is reported on with habitual to acknowledge his left sided weakness, he the mood more usually associated with episodes of collapse and loss of consciousness remained blissfully unconcerned. He scored anosognosia, 10% of his patients with ano- associated with EEG evidence of focal 31 points on a mania rating scale,1 which was sognosia were described as having “euphoric epileptiform discharges. Simultaneous ECG well in the manic range. The mania resolved mood.” recordings disclosed 25 seconds of cardiac gradually over a 10 week period after stroke. Right sided thalamic lesions are known to ventricular asystole occurring 24 seconds Other than alcoholism, the patient had no produce both anosognosia and mania, but the after the onset of electrical seizure activity. history of psychiatric illness and there was no relation of each to the pathology is unclear. After changes to antiepileptic medication and family history of psychiatric illness. The Only some of the patients with right hemi- the insertion of a permanent cardiac pace- patient had not seen an physician in many spheric lesions are manic or agnosic. These maker he has had no further episodes. In years. Visual acuity was found to be reduced two syndromes may be related to dysfunction cases of epileptic cardiac dysrhythmia, iso- to 20/800 in both eyes on the basis of hyper- of diVerent neural networks and only occur lated EEG or ECG recording may prove tensive retinopathy. together when a disease process aVects both insuYcient and prolonged simultaneous Evaluation 1 month after stroke showed networks. EEG/ECG monitoring may be required. many deficits and a few strengths. Inattention Another possibility is that these syndromes Cardiac arrhythmias subsequent to epilep- to the left hemispace was marked. By 2 are aetiologically related. Could anosognosia tic seizures have been recognised for more months after stroke he no longer extinguished be a manifestation of mania? Although it is than 90 years. They provoke diagnostic to double simultaneous stimulation, but, easy to conceive how elevated mood might confusion and may be a mechanism of although he could see to the left, was still facilitate anosognosia of hemiplegia (or other sudden unexplained death in epilepsy. missing targets in his left visual hemifield. types of anosognosia), it is diYcult to explain Whereas sinus tachycardia was noted to Visual integration, both with and without the the presence of denial of ownership and accompany more than 90% of epileptic requirement of construction, was severely dislike of the left arm (other anosognosic seizures, isolated bradycardia was seen much J Neurol Neurosurg Psychiatry 2000;68:100–126 109 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

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Time : 07:05:21 16 Channel ictal EEG (eight channels illustrated with ECG) showing electrographic seizure onset and subsequent bradycardia and asystole. less commonly (only 1 of 74 seizures typically the asystolic periods in documented asystole of 25 seconds duration demonstrated recorded).1 A review in 1996 of the “ictal cases are in the region of 5–10 seconds.2 by prolonged simultaneous EEG/ECG moni- bradycardia syndrome” showed only 15 Shorter duration asystole may not compro- toring which responded well to pacemaker documented cases in the literature of either mise cerebral function suYciently to cause insertion. bradycardia or asystole associated with loss of consciousness. Implantation of a A previously well 34 year old right handed seizures.2 Most patients had temporal lobe cardiac pacemaker is advocated but does not builder was referred witha1yearhistory of seizures. The longest duration of asystole ensure that lapses of consciousness are elimi- fortnightly episodes of loss of consciousness. previously reported is in a 17 year old man nated if these are directly related to the There was no associated warning, aura, chest with temporal lobe epilepsy who sustained a seizure rather than to the secondary asystole. pain, or palpitations and the patient was only 22 second pause in cardiac output. More We report on a patient with epileptic cardiac aware of the episode once consciousness was 110 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from restored and he found himself lying on the neous EEG and ECG recordings were (PMP-22) gene.1 HNPP typically presents floor. On recovery there was no confusion, acquired, ictal arrhythmias occurred in 52% recurrent pressure palsies of peripheral drowsiness, dysphasia, or diuresis. Often, of seizures, the commonest being irregular nerves, such as the axillary, median, radial, however, he sustained soft tissue injuries to abrupt changes in heart rate, (both accelera- ulnar, or peroneal nerves, at common entrap- his face and scalp. tion and deceleration) occurring towards the ment sites. Respiratory muscle weakness has Witnesses reported that the patient would, end of the period of EEG abnormality.1 not been previously reported in HNPP. We without warning, suddenly collapse to the Interictally, patients with epilepsy seem no describe a patient with HNPP in whom ground where he would remain unrousable, more likely than age and sex matched healthy respiratory failure and proximal muscle inaccessible, and motionless for 90 to 120 subjects to experience arrhythmias although weakness were prominent features. seconds. On two occasions he appeared con- in one study patients with epilepsy had a The patient started to have dyspnoea on fused and disorientated immediately before a faster ventricular rate and a longer QT inter- exertion at the age of 44. At the age of 47, he collapse. During the period of unconscious- val than control subjects.3 noticed a slowly progressive weakness of the ness he would demonstrate no involuntary It has been hypothesised that there is later- pelvic girdle and lower limbs. At the age of movements, orofacial automatisms, or cyano- alisation with respect to central autonomic 57, he experienced diYculty in going up sis but he would become pale and “ashen” cardiac control with an increase in heart rate stairs. However, he was almost independent while staring straight ahead with a glazed seen after an intracarotid injection of amo- in daily life At the age of 60, he was admitted look. On resolution of the episode his colour barbital and inactivation of the left hemi- to Narita Red Cross Hospital as an emer- sphere and a decrease in heart rate on right would return to normal and within 2 minutes gency patient with a coma due to CO2 narco- hemispheric inactivation. Experimental he would have fully recovered. Unusually sis (PCO2 117.6, PO2 64.0). Responding to during one reported episode of unconscious- stimulation of the rostral posterior insular mechanical ventilatory support, he com- ness he was seen to briefly extend the fingers cortex in anaesthetised rats has been shown pletely recovered consciousness within a day. of both hands. to induce tachycardia and more caudal region His respiratory condition in the daytime 4 He was admitted to his local hospital and stimulation to cause bradycardia. Addition- improved to that previously. However, he CT, MRI, interictal EEG, and 24 hour ECG ally, prolonged stimulation resulted in ven- needed mechanical ventilation during sleep were normal. No episodes were witnessed tricular ectopics, heart block, QT prolonga- because of nocturnal hypoventilation. while he was an inpatient but they were tion, and death. In presurgical temporal The patient had no history of diabetes thought to be epileptic in origin and therefore lobectomy patients stimulation of the left mellitus, pulmonary disease, or other medical he was started on phenytoin, with no benefit. insular cortex (particularly posteriorly) pro- problems. There was no familial history of Carbamazepine was added, again with mini- duced bradycardia and a depressor response neurological disorder, including entrapment mal eVect. significantly more often than tachycardia and neuropathies. After a few months, he noted 5 The patient was then referred to the a pressor eVect. It was suggested that an epi- that in his teens he had experienced some Epilepsy Assessment Centre of The National leptic discharge in the insular cortex may episodes of right peroneal and right axillary Society for Epilepsy and National Hospital result in cardiac arrhythmias. nerve palsies which resolved themselves over for Neurology and Neurosurgery for further Recurrent episodes of loss of consciousness a few months. investigation and management. are a common clinical problem. An accurate In a neurological examination, the patient’s Cardiovascular and neurological examina- diagnosis relies principally on the patient’s mental state and cranial nerves were normal. tion was normal, as were MRI and routine and witnesses’ accounts of events. Further Evidence of muscular atrophy and lumbar interictal EEG. Sixteen channel ambulatory investigations are frequently required which lordosis was found. The muscular atrophy EEG using an Oxford Instruments digital are often normal unless an episode is was prominent in the shoulder girdle, inter- EEG receiver was performed continuously for captured during monitoring. Recording costal muscles, paravertebral muscles, and 340 hours before an episode was captured. solely the EEG or the ECG may result in pelvic girdle, and moderate atrophy was Interictally rare spikes were seen over the right erroneous conclusions being drawn and present in all four limbs (figure). There was insuYcient or inappropriate therapy being frontocentrotemporal region during sleep. The moderate weakness of the shoulder and pelvic instituted. Distinction between a primary onset of the episode was not witnessed and the girdle and mild weakness of the distal limbs. cardiac arrhythmia and a secondary central patient was found lying on the floor, regaining The thorax showed poor respiratory move- arrhythmia is possible only with simultaneous consciousness at about 07:06. The event EEG ment, and the patient showed paradoxical EEG/ECG recordings. showed a short run of bilateral semirhythmic movement of the abdomen in the supine 2–3 Hz activity at 07:04:34 (figure A), persist- FERGUS J RUGG-GUNN position. Tendon reflexes were hypoactive in ing for 8 seconds before being obscured by JOHN S DUNCAN all limbs. The patient’s sensations of touch muscle and movement artefact. Twenty four SHELAGH J M SMITH and pain were mildly impaired in the four http://jnnp.bmj.com/ seconds after the first EEG change, at Epilepsy Research Group, University Department of distal limbs. His position sensation was Clinical Neurology, Institute of Neurology, The 07:04:58, the ECG changed from sinus National Hospital for Neurology and Neurosurgery, normal. His vital capacity was 1.9 l (55% of rhythm at 90 bpm to a brief period of sinus Queen Square, London WC1N 3BG, UK the normal mean) in the sitting position, but bradycardia, followed by a period of asystole Correspondence to: Professor John S Duncan, 1.3 l (38%) in the supine position. The with only very occasional ventricular com- National Society for Epilepsy, Chalfont St Peter, percentage of forced expiratory volume in 1 plexes lasting 25–30 seconds (figure B). After a Gerrards Cross, Bucks SL9 0RJ, UK second was normal (99%). Chest radio- few seconds of bradycardia then tachycardia, email [email protected] graphy at inspiration and expiration showed sinus rhythm was restored. Throughout the poor movement of the diaphragm but no episode the QT interval on the ECG remained 1 Blumhardt LD, Smith PEM, Owen L. Electro- abnormality in the lung field. Routine on October 1, 2021 by guest. Protected copyright. within normal limits. The EEG became visible cardiographic accompaniments of temporal haematological and serological studies gave again 16 seconds into the asystolic period, at lobe epileptic seizures. Lancet 1986;i:1052–5. normal results. No monoclonal or polyclonal which time it was dominated by diVuse low 2 Reeves AL, Nollet KE, Klass DW, et al. The ictal proteins were detected. IgG and IgM anti- bradycardia syndrome. Epilepsia 1996;37:983–7. amplitude slow activity at <1–2 Hz which per- 3 Drake M, Reider C, Kay A. Electrocardiography bodies to gangliosides GM1 and GD1b were sisted for 10 seconds (figure C). This was fol- in epileptic patients without cardiac symptoms. negative. Analysis of CSF showed 1 lowed by marked attenuation of the EEG Seizure 1993;2:63–5. lymphocyte/mm3 and 25 mg/dl protein. 4 Oppenheimer SM, Hachinski VC, Cechetto activity over the next 10 seconds before large DF. Cardiac chronotropic organization of the Motor nerve conduction studies showed pro- amplitude generalised rhythmic <1Hz activity rat insular cortex. Society of Neurosciences longed distal latencies in the right median became apparent. DiVuse theta activity was Abstracts 1989;15:595. (8.8 m/s (normal value in our laboratory seen for a further 15 seconds before the EEG 5 Oppenheimer S, Gelb A, Girvin J, et al. Cardio- vascular eVect of human insular cortex stimu- <4.6)) and ulnar (6.2 ms (normal<3.6)) returned to its resting state. lation. Neurology 1992;42:1727–32. nerves, and moderate decreased conduction A VVI permanent pacemaker was inserted. velocities in the right median (40 m/s The phenytoin was withdrawn and replaced (normal>45)), ulnar (45 m/s (normal>49)), by lamotrigine. Carbamazepine was left Respiratory insuYciency in a patient tibial (35 m/s (normal>38)), and peroneal unchanged. The patient was discharged, his with hereditary neuropathy with (29 m/s (normal>41)) nerves. There were medication left unaltered, and at follow up 9 liability to pressure palsy moderate decreases in the amplitude of com- months later reported no further episodes. pound action potentials in all the nerves Cardiac dysrhythmias are an uncommon Hereditary neuropathy with liability to pres- tested, and an amplitude reduction of 50% but serious consequence of partial seizures. sure palsies (HNPP) is an autosomal domi- was detected across the cubital tunnel of the Our case is unusual because of the duration nant disorder, the molecular basis of which is right ulnar nerve. Minimum F wave latencies of the asystole. In a series of 26 patients with a 1.5 mb deletion in chromosome 17p11.2 were prolonged in all the nerves tested. The 74 temporal lobe seizures in which simulta- including the peripheral myelin protein-22 latency in the right phrenic nerve was slightly J Neurol Neurosurg Psychiatry 2000;68:100–126 111 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

General muscle atrophies, which are most prominent in the trunk are shown. A tracheotomy was performed for nocturnal hypoventilation because the patient required mechanical respiratory support during the night. delayed (8.7 ms (normal<8.0)). Sensory presence of tomacula, and genetic analysis MASATO ASAHINA nerve conduction studies showed a reduced confirmed a diagnosis of HNPP. However, SATOSHI KUWABARA amplitude of sensory nerve action potentials the patient’s dominant clinical features— TAKAMICHI HATTORI and conduction slowing in all the nerves respiratory failure and proximal muscle Department of Neurology, School of Medicine, tested. Electromyography carried out in the weakness—were atypical for HNPP. Al- Chiba University, 1–8–1 Inohana, Chuo-ku, Chiba 260–8670, Japan supraspinatus, deltoid, biceps, flexor carpi though respiratory muscle weakness has been ulnaris, brachioradialis, quadriceps femoris, reported in hereditary motor and sensory MASATO ASAHINA biceps femoris, tibialis anterior, and gastroc- neuropathy (HMSN),2–4 there has been no KAORU KATAYAMA nemius muscles showed polyphasic motor report of respiratory insuYciency associated Department of Neurology, Narita Red Cross Hospital, 90–1 Iida-cho, Narita-shi, Chiba 286–0041, Japan unit potentials of long duration, but denerva- with HNPP to our knowledge. tion potentials were rare. A left sural nerve The weakness of the truncal muscles, Correspondence to: Dr Masato Asahina, 1–8–1 http://jnnp.bmj.com/ Inohana, Chuo-ku, Chiba-shi, Chiba 260–8670, biopsy showed scattered tomaculous thicken- including the respiratory accessory muscle, is Japan. Telephone 0081 43 222 7171 ext 5414; fax ing of the myelin sheath and some abnor- a possible cause of respiratory failure in our 0081 43 226 2160; mally thin axonal myelin sheaths. The density patient. On the other hand, he had experi- email: [email protected] of myelinated fibres was reduced (5726/mm2). enced hypoventilation in the supine posture A gene analysis disclosed a 53% gene dose of and paradoxical movement of the abdomen, 2 1 Chance PF, Alderson MK, Lepping KA, et al. PMP-22 related to normal controls, using which suggested diaphragmatic weakness. DNA deletion associated with hereditary neu- Southern blots of DNA digested with EcoRI. Also, chest radiography showed poor move- ropathy with liability to pressure palsies. Cell Given the possibility of superimposing ment of the diaphragm. Although the prolon- 1993;72:143–51 2 Eichacker PQ, Spiro A, Sherman M, et al. Res- demyelinating neuropathy, especially chronic gation of distal latency in the phrenic nerve piratory muscle dysfunction in hereditary on October 1, 2021 by guest. Protected copyright. inflammatory demyelinating polyneuropathy, was mild considering the severity of respira- motor sensory neuropathy, type I. Arch Intern oral prednisolone (60 mg/day) was given for 1 tory failure, assessment of axonal loss is not Med 1988;148:1739–40. 3 Hardie R, Harding AE, Hirsch N, et al. month. However, the patient’s clinical condi- possible with phrenic nerve stimulation. In Diaphragmatic weakness in hereditary motor tion did not respond to this treatment. fact, phrenic nerve latency is not necessarily and sensory neuropathy. J Neurol Neurosurg Pulmonary dysfunction and proximal muscle associated with pulmonary dysfunction in Psychiatry 1990;53:348–50. weakness were almost steady during the next HMSN.4 4 Carter GT, Kilmer DD, Bonekat HW, et al. Evaluation of phrenic nerve and pulmonary 3 years. DiVuse proximal weakness in our patient is function in hereditary motor and sensory neu- We examined the patient’s elder sister (64 an uncommon finding as for HNPP.Mancardi ropathy. Muscle Nerve 1992;15:459–62. years old), elder brother (62 years old), and et al5 reported on three patients with progres- 5 Mancardi GL, Mandich P, Nassani S, et al. Pro- gressive sensory-motor polyneuropathy with younger sister (58 years old), although they sive sensory-motor polyneuropathy associated tomaculous changes is associated to 17p11.2 had no neurological complaints. All of them with 17p11.2 deletion, and the initial symptom deletion. J Neurol Sci 1995;131:30–4. had experienced generalised hyporeflexia or of one patient was proximal weakness in one areflexia but no weakness or sensory loss, and arm. We propose that our patient represents a nerve conduction studies showed moderate clinical phenotypic variability among HNPP.It Spinal accessory neuropathy and conduction slowing with accentuation at the may be necessary to pay attention to respira- internal jugular thrombosis after common entrapment sites, suggesting demy- tory function in HNPP. carotid endarterectomy elinating neuropathy. Our patient recalled experiencing recur- Spinal accessory neuropathy is a rare compli- rent episodes of transit entrapment monone- We thank Dr T Yamamoto from the University of cation of carotid endarterectomy (CEA).1 uropathies, and the familial occurrence of Occupational and Environmental Health for the Internal jugular venous thrombosis after gene analysis and Mr T Nagase from Chiba Univer- asymptomatic entrapment neuropathy was sity for his technical help with the sural nerve CEA has also been reported rarely, but is detected by nerve conduction studies. The biopsy. likely more common; as internal jugular 112 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from venous thrombosis is often asymptomatic, or other possibilities. As in our patient, high Ischaemic stroke in a sportsman who presents with non-specific pain, it is probably carotid dissection and retraction have been consumed MaHuang extract and 2 unrecognised in many cases. Concurrent reported to precede spinal accessory creatine monohydrate for body building ipsilateral spinal accessory neuropathy and neuropathy.14 internal jugular venous thrombosis after CEA The spinal accessory nerve courses along We report the first case of extensive cerebral is expected to be rare, and this is underscored the internal jugular vein and near the internal infarct in a young sportsman consuming high by the lack of published cases. Despite this carotid artery, typically well above the carotid doses of MaHuang extract and creatine apparent rarity, a common pathogenetic bifurcation. It stands to reason that a high monohydrate. This should alert the sport mechanism for postoperative spinal accessory incision and retraction resulting from a high community to possible serious adverse effects neuropathy and internal jugular venous carotid bifurcation would place the nerve at of energy supplements. thrombosis may well be present, at least in risk. Whether this realisation may lead to any A 33 year old man had a severe aphasia on some cases, which may lead to the considera- technical modification to decrease the risk of awakening in the morning of 23 January tion of the possibility of both when either is spinal accessory neuropathy in those with a 1999. He did not complain of headache or of discovered. high bifurcation is unclear. other symptoms. He was referred to our We report on a patient who developed right From our search, internal jugular venous department on 26 January 1999. He had a spinal accessory neuropathy and internal thrombosis after CEA has been reported in Wernicke aphasia with a slight right sided jugular venous thrombosis after right CEA. only one case.2 As Southcott noted, face and arm weakness and a right Babinski A 59 year old man underwent right CEA et al retraction of the internal jugular during CEA sign. His blood pressure was 140/60 and his for possibly symptomatic stenosis. Angio- pulse 54 per minute. Brain CT showed signs graphy had shown 90% stenosis of the right may cause complete occlusion, leading to thrombosis from venous stasis or endothelial of extensive left middle cerebral artery internal carotid. The operation was done infarct. Cervical ultrasound duplex scanning injury. Other causes of internal jugular under general anaesthesia. The carotid bifur- and cerebral angiography were normal. Cer- venous thrombosis include jugular cannula- cation was unusually distal, necessitating a ebral CSF examination was normal. There tion, blunt cervical trauma, and a hyperco- long dissection and high retraction. No was no coagulopathy. D-dimeres were within agulable state. Internal jugular venous throm- immediate postoperative complications were the normal range (360 ng/ml, normal <500 evident. The next day, the patient complained bosis may occur within a week after neck ng/ml). Creatinine was in the normal range of mild pain at the operative site, but he did dissection, often with recanalisation after sev- 5 (102 µmol/litre). Transoesophageal echo- not notice any weakness. The pain spread eral months. cardiography and ECG were also normal into his right shoulder within several days; at The presence of induration about the inci- except for a patent foramen ovale. that time, he also noted diYculty raising his sion site and a palpable supraclavicular cord The patient had no vascular risk factors, in right arm. His symptoms worsened further a in our patient led us to suspect venous particular no tobacco use, and he was few weeks later. The symptoms persisted, and thrombosis. Internal jugular venous throm- perfectly fit until his stroke. He was a sports- he presented for neurological evaluation 4 bosis may often be asymptomatic. Potential man with 2 hours daily intensive training for months after CEA. At that time, he had some symptoms of internal jugular venous throm- body building. He was working as a baggage induration along the incision site and a bosis include headache, dysphagia, and ante- handler in an international airline company. palpable cord within the right supraclavicular rolateral neck pain, tenderness, and swelling. During a recent journey to Miami, Florida, fossa. There was moderate atrophy of the In addition to perivenous induration, fever he bought tablets of “energy pills” in a shop- right sternocleidomastoid and trapezius, with and leukocytosis may occur.2 ping store to enhance his athletic perform- right shoulder drooping and minor right Common pathogenetic mechanisms for ances. The first drug contained MaHuang scapular winging. Right arm abduction pro- spinal accessory neuropathy and internal extract (corresponding to 20 mg ephedra duced more prominent scapular winging and jugular venous thrombosis may include intra- alkaloids), 200 mg caVeine, 100 mg was limited to 90 degrees due to pain and operative traction, haematoma, and postop- L-carnitine, and 200 µg chromium per two weakness. Electrodiagnostic studies were erative inflammation and scarring. capsules. The second drug contained 6000 consistent with partial right accessory neu- Although the onset of either spinal acces- mg creatine monohydrate, 1000 mg taurine, ropathy with minor denervation of the right sory neuropathy or internal jugular venous 100 mg inosine, and 5 mg coenzyme Q10 per trapezius. Cervical ultrasonography and MRI thrombosis in our patient cannot be deter- scoop. He consumed 40–60 mg ephedra demonstrated right internal jugular venous mined precisely, it is likely that both devel- alkaloids, 400–600 mg caVeine, and 6000 mg thrombosis. The patient was treated with a oped at about the same time. The delayed creatine monohydrate daily for about 6 weeks shoulder support, analgesics, and low dose before his stroke.

worsening of spinal accessory neuropathy in http://jnnp.bmj.com/ aspirin. There was no significant clinical Although a paradoxical embolism through this case suggests postoperative scarring or change 1 year after CEA. Repeat electrodiag- a patent foramen ovale in this patient cannot nostic studies were consistent with severe inflammation. The lack of improvement after be ruled out as he recently returned from a chronic right spinal accessory neuropathy, a year, as in some other cases of spinal acces- transatlantic air flight, there was no deep and repeat ultrasonography showed persist- sory neuropathy after CEA, implies consider- venous thrombosis and D-dimeres were nor- ent right internal jugular venous thrombosis. able axonal injury, but does not clarify the mal. However, ephedrine has an indirect Spinal accessory neuropathy was first manner of injury. sympathomimetic action and is responsible 3 reported as a complication of CEA in 1982. GEORGE WOODWARD for arteriolar vasoconstriction in addition to Since then, there have been several case RAM VENKATESH other catecholaminergic eVects. Both ischae- reports and small series.14 A 1996 review of Department of Neurology, University of Kansas, and mic and haemorrhagic stroke associated with on October 1, 2021 by guest. Protected copyright. reports of cranial neuropathy after CEA Neurology Section, VA Eastern Kansas Health Care ephedrine use have been reported.1–3 Acute disclosed only one patient with spinal acces- System, VA,USA myocardial infarction and acute psychosis 1 sory neuropathy in over 3000 cases. Al- Correspondence to: Dr George Woodward, Neu- have also been reported after taking ephe- though the authors did not include several rology Section (111), VA Medical Centre, Leaven- drine and other sympathomimetic drugs.3 other reports34 which, taken together, may worth, Kansas 66048, USA. Telephone 001 913 Ephedrine and its metabolites are natural seem to suggest a somewhat higher incidence, 682 2000 extension 2441; fax 001 913 758 4225. products that are used in non-prescription the overall small number of reported cases in medicines for multiple uses. MaHuang ex- proportion to the hundreds of thousands of tract, which contains ephedrine, is used CEAs that have been done worldwide 1 Yagnik PM, Chong PST. Spinal accessory nerve among young sportsmen and sportswomen as suggests that clinically significant spinal injury: a complication of carotid endarterec- an energy supplement in non-prescription accessory neuropathy is a rare complication. tomy. Muscle Nerve 1996;19:907–9. tablets in some countries. 2 Southcott AJ, Sandhu A, Ferguson LJ, et al. Minor or transient spinal accessory neu- Internal jugular vein thrombosis following Although no cardiovascular side eVects ropathy after CEA may be more frequent. carotid endarterectomy. Aust N Z J Surg 1994; have been reported with the use of creatine The cause of spinal accessory neuropathy 64:60–2. monohydrate, this compound, used in associ- after CEA is usually not well established, but 3 Sarala PK. Accessory nerve palsy: an uncom- ation with other drugs as energy supplement mon etiology. Arch Phys Med Rehabil 1982;63: intraoperative nerve stretching or compres- 445–6. may have deleterious side eVects. This may sion from retraction is most often invoked.4 4 Sweeney PJ, Wilbourn AJ. Spinal accessory be particularly true when used at high doses Delayed onset (after 3 weeks) has been noted (11th) nerve palsy following carotid endarter- in combination with sympathomimetic drugs in some; for these patients, postoperative ectomy. Neurology 1992;42:674–5. as in our patient. Renal dysfunction has also inflammation and scarring seem more likely 5 Quraishi HA, Wax MK, Granke K, et al. been reported after oral creatine Internal jugular vein thrombosis after func- 4 causes. Spinal accessory nerve transection or tional and selective neck dissection. Arch supplements. Our patient had a slight ischaemia/infarction (arterial or venous) are Otolaryngol Head Neck Surg 1997;123:969–73. increase in creatinine concentration although J Neurol Neurosurg Psychiatry 2000;68:100–126 113 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from it remained in the normal range. Whether the with slight elevation of the left shoulder. The coactivation. The patient barely noted the use of high doses of caVeine can enhance the facial movement disorder was clearly diVer- dyskinesias. Audiometry showed a hearing cardiovascular eVect of ephedrine remains a ent from hemifacial spasm. There were no threshold at 30 Db on the left side and lack of possibility as stroke after taking a combina- tonic or clonic synchronous contractions of stapedius reflex on the left side. Oculoves- tion of caVeine and amphetamine has been facial muscles and no signs of involuntary tibular response to caloric stimulation was reported.5 Drug addiction in sportsmen and sports- women is becoming a major concern in our societies, involving both professionals and amateurs. As energy supplements, thought to enhance performance, are easily available in some countries without the need of medical prescription, everybody should be aware that these so called “benign” drugs may have major adverse eVects. This first case report of an extensive cerebral infarct in a young sportsman con- suming high doses of MaHuang extract and creatine monohydrate should alert the sport community to this possible adverse eVects of energy supplements, particularly when used in multiple combination. K VAHEDI V DOMIGO P AMARENCO M-G BOUSSER Service de Neurologie, Hôpital Lariboisière, Paris, France Correspondence to: Dr K Vahedi, Service de Neu- rologie, Hôpital Lariboisière, 2 Rue A Paré, 75010 Paris, France email [email protected]

1 Stoessl AJ, Young GB, Feasby TE. Intracerebral hemorrhage and angiographic beading follow- ing ingestion of catecholaminergics. Stroke 1985;16:734–6. 2 Yin PA. Ephedrine-induced intracerebral hem- orrhage and central nervous system vasculitis. Stroke 1990;21:1641. 3 Bruno A, Nolte KB, Chapin J. Stroke associated with ephedrine use. Neurology 1993;43:1313– 6. 4 GreenhaV P. Renal dysfunction accompanying oral creatine supplements. Lancet 1998;352: 213–4. 5 Lambrecht GL, Malbrain ML, Chew SL, et al. Intranasal caVeine and amphetamine causing stroke. Acta Neurol Belg 1993;93:146–9.

Petroclival meningioma as a cause of ipsilateral cervicofacial dyskinesias http://jnnp.bmj.com/ Hyperkinetic movement disorders of facial and neck muscles such as blepharospasm, hemifacial spasm, facial myokimia, and cervi- cal dystonia have rarely been associated with unilateral brainstem or posterior fossa pathologies. We report a case of unilateral cervicofacial dyskinesias due to an ipsilateral petroclival meningioma.

A 32 year old left handed woman com- on October 1, 2021 by guest. Protected copyright. plained about left sided facial dysaesthesia of the upper quadrant of her face for 1 year. In addition she had intermittent ipsilateral headache. A left sided facial palsy and hypo- geusia developed. When progressive hearing loss and persistent ipsilateral tinnitus oc- curred she sought medical advice. She was referred to our department for further treatment after a large tumour in the left cer- ebellopontine angle had been demonstrated by MRI. On admission, the left corneal reflex was absent. There was marked hypoaesthesia of the first two divisions of the left trigeminal nerve and a mild left facial palsy. There was also hypogeusia of the left half of the tongue. Speech was slightly dysarthric. During exam- ination dystonic and choreic movements of the left facial muscles were seen. The (A) Axial T2 weighted SE MR images of a 32 year old woman with left sided cervicofacial dyskinesias dystonic grimacing increased when the pa- show a large left petroclival meningioma compressing the brainstem. (B) Coronal inversion recovery MR tient was being observed. There were also scans demonstrate marked displacement and distorsion of the brainstem due to the petroclival intermittent jerky dystonic head movements meningioma. (C) Gadolinium enhanced axial T1 weighted SE MR scans 3 months postoperativly show with turning of the head to the left, associated complete removal of the tumour and normalisation of the displacement of the brain stem. 114 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from decreased on the left side. Furthermore, there Correspondence to: Dr J K Krauss, Department of was mild left dysdiadochokinesia. Neurosurgery, University Hospital, Klinikeem Neurography of the facial nerve was Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 normal on both sides. Needle myography of Mannheim, Germany email [email protected] the left frontalis and orbiculari oculis did not show signs of denervation. An MRI study showed a large gadolinium 1 Singer C, Schatz N, Bowen B, et al. Asymmetric enhancing tumour within the left cerebello- predominantly ipsilateral blepharospasm and contralateral parkinsonism in an elderly patient pontine angle extending to the cavum Meck- with a right mesencephalic cyst. Mov Disord eli with marked displacement of the brain- 1998;13:135–9. stem to the contralateral side (figure A and 2 Sprik C, Wirtschafter JD. Hemifacial spasm due to intracranial tumor. Ophthalmology 1988;95: B). Cerebral angiography showed a discrete 1042–5. blush of the tumour as typically seen in men- 3 Krauss JK, Wakhloo AK, Scheremet R, et al. ingiomas. The tumour was totally removed Facial myokimia and spastic paretic facial con- by a combined transpetrosal supratentorial tracture as the result of anaplastic pontocer- ebellar glioma. Neurosurgery 1993;32:1031–4. and infratentorial presigmoidal approach. 4 Krauss JK, Seeger W, Jankovic J. Cervical dysto- The postoperative course was uneventful and nia associated with tumors of the posterior there were no new deficits. The facial palsy fossa. Mov Disord 1997;12:443–7. 5 Tolosa E, Montserrat L, Bayes A. Blink reflex improved slightly as well as the trigeminal studies in focal dystonias: enhanced excitability hypoaesthesia. Audiometry remained un- of brainstem interneurons in cranial dystonia changed. Postoperative imaging showed no and spasmodic torticollis. Mov Disord 1988;3: residual tumour and the displacement of the 61–9. Axial T1 weighted image after contrast brain stem within the posterior fossa had administration showing multiple focal lesions in the periventricular white matter and left resolved (figure C). Marked improvement of Acute multifocal cerebral white matter centrum semiovalis exhibiting thick annular the left sided craniofacial dyskinesias oc- lesions during transfer factor therapy enhancement. curred during the next weeks. The postoperative improvement of the dys- Transfer factor is an active substance of muscle, and antineutrophil cytoplasmic anti- tonic and choreic grimacing and the cervical unknown structure present in dialysable leu- bodies, lupus anticoaugulants, cryoglobulins, dystonia indicates a causal association between cocyte extract which is assumed to transfer immune complexes, complement fractions, the petroclival meningioma and the segmental cell mediated immunity in an antigen specific and neoplastic markers. hyperkinetic movement disorder. Such a rela- fashion.1 The mechanisms of action of trans- Serological investigations showed IgG but tion is supported also by the absence of a fam- fer factor are still far from clear; in vitro dia- not IgM against cytomegalovirus (CMV), ily history of movement disorders and the lysable leucocyte extract increases macro- Herpes simplex, Varicella zoster, Epstein-Barr absence of previous exposure to neuroleptic phage activation and interleukin (IL) 1 viruses, and Toxoplasma gondii; the Paul Bun- medication. Hyperkinetic movement disorders production and enhances leucocyte chemo- nel reaction, anti-HIV, and the markers of due to tumours of the brainstem or of the pos- taxis and natural killer function. Transfer fac- hepatitis virus B and C infection were terior fossa have been reported only rarely. tor has been reported to stimulate the cell negative. Asymmetric blepharospasm was recently mediated antigen specific response in patients Cell, protein, and glucose concentrations found in a patient with an ipsilateral mesen- with various infections1; therefore, treatment in CSF were normal. No oligoclonal bands or 1 cephalic cyst. Hemifacial spasm was seen in with transfer factor has been suggested in antibody against CMV, Herpes simplex, Vari- patients with acoustic neurinomas, meningi- patients with selective deficits in cell medi- cella zoster, Epstein-Barr virus, Coxsackie, omas, and epidermoid tumours of the cerebel- ated immunity such as in some refractory 2 Adenovirus, Enterovirus or Borrelia burgdorferi lopontine angle. Acoustic neurinomas and neoplasms and chronic infections. Moreover, were present. Polymerase chain reaction anaplastic pontocerebellar glioma can be asso- it has been used in the treatment of uveitis.2 search for Herpes simplex 1 and 2, Varicella ciated with facial myokymia and spastic paretic Administration of dialysable leucocyte ex- , CMV,Epstein- Barr virus, and JC virus 3 zoster facial contracture. Also, cervical dystonia due tract has seemed to be free of hypersensitivity, in the CSF was negative. to tumours of the cerebellopontine angle have long lasting side eVects, or complications, Brain MRI showed several extensive asym- 4 been reported recently. except for transitory hyperpyrexia.1 metric lesions in the subcortical and periven- The pathophysiological mechanisms re- We report on a patient in whom multiple tricular cerebral white matter, some of which sponsible for dystonic movement disorders cerebral white matter lesions developed after exerted a mass eVect on the nearby CSF http://jnnp.bmj.com/ caused by structural or functional lesions of taking dialysable leucocyte extract orally for spaces. All lesions exhibited thick ring-like the brainstem are not fully understood. The uveitis. A 28 year old man was admitted to enhancement after intravenous contrast ad- possibility of denervation supersensitivity of hospital because of headache, mental confu- ministration (figure). The brain stem, cer- cranial nerve nuclei has been proposed previ- sion, and right hemiparesis. He had had ebellum, and cervical spinal cord were ously. Alternatively, enhanced excitability of recurrent bilateral uveitis from the age of 12 spared. brainstem interneurons has been suggested. to 14 with residual cataract of the right eye. In The patient had a progressive spontaneous This pathophysiological mechanism is sup- January 1995 retinal vasculitis was diagnosed remission of symptoms and signs. The ported by the findings of blink reflex studies at fundoscopy and in July 1995 he started neurological examination 20 days after onset in patients with blepharospasm, spasmodic oral transfer factor as dialysable leucocyte showed slightly increased deep tendon re- on October 1, 2021 by guest. Protected copyright. dysphonia, and cervical dystonia. Tolosa et al extract twice a week. He complained of gen- flexes on the right side and was normal 40 found significantly less inhibition of the test eralised weakness after the second dose and days later; all laboratory analyses were stimulus polysynaptic late response and the referring symptoms developed after the normal except for antistreptolysin titres (265 marked enhancement of the recovery curve of third dose. UI/ml). Two MR scans at 1 and 4 months the late response under such conditions com- Neurological examination on admission after onset showed progressive reduction of 5 pared with the response in healthy subjects. showed mental confusion and severe right the extension of cerebral white matter lesions, Our case provides further evidence that spastic hemiparesis with right Babinski’s sign. which did not show contrast enhancement. A functional impairment by compression and No fever or meningismus were present. final MR scan 20 months after onset showed distortion of the brain stem may cause hyper- Laboratory examinations on admission further regression of lesions without contrast kinetic cervicofacial movement disorders. It showed a slight increase in total serum enhancement but a new large lesion in the left is important to know that such movement protein (8.4 g/l, normal 6.0–8.0 g/l, although occipital white matter, which showed moder- disorders are accessible to surgical treatment the serum protein fraction was normal), ate contrast enhancement. At present, after 5 of the underlying pathology. Therefore, pa- antistreptolysin titres (355 UI/ml, normal years, the patient is in a good state of health tients with cranial or cervical dystonia or <200 UI/ml), and anticardiolipin IgG (30 and neurological examination and laboratory choreic dyskinesia should undergo MR imag- UI/ml, normal< 12 UI/ml). Negative results tests are normal. ing to rule out a surgically treatable cause. were obtained for routine tests and serum The close temporal relation between as- THOMAS POHLE immunoglobulins, venereal disease research sumption of dialysable leucocyte extract JOACHIM K KRAUSS laboratory test, erythrocyte sedimentation therapy and appearance of cerebral white Department of Neurosurgery, Inselspital, University of rate, fibrinogenaemia, C reactive protein, matter lesions in our patient supports the Berne, Berne, Switzerland rheumatoid factor, Waaler-Rose, protein possibility that the association of the two JEAN-MARC BURGUNDER electrophoresis, antinuclear, anti-DNA, an- events might not be casual. Despite the Department of Neurology timitochondrial, anti-ENA, anti-smooth absence of biopsy, we reasonably excluded J Neurol Neurosurg Psychiatry 2000;68:100–126 115 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from the diagnosis of vasculitis or neuro-Behçet’s Correspondence to: Dr Francesco Giuseppe Fo- Fahr’s disease1—whether idiopathic or associ- disease although in the absence of biopsy. In schi, Semeiotica Medica, Dipartimento di Medicina ated with hypoparathyroidism—previously fact, the clinical, laboratory, and MRI find- Interna, Epatologia e Cardioangiologia, Università been associated with this handicap. We present ings were not typical and a low titre of degli Studi di Bologna, Policlinico Sant’Orsola, via the case of a 24 year old man with Asperger’s G Massarentin°9, 40138 Bologna, Italy. Telephone anticardiolipin antibodies is found in 2% of 0039 51 308943; fax 0039 51 308966; email: syndrome, primary hypoparathyroidism, and 3 healthy subjects. [email protected] multifocal brain calcifications. The occurrence at diVerent time of focal According to medical history, the patient’s cerebral white matter lesions highly supports mother had received weekly injections of 1 Fudenberg HH, Fudenberg HH. Transfer the diagnosis of multiple sclerosis, but some factor: past, present and future. Annu Rev Depoprovera during pregnancy. A single clinical and laboratory findings in the our Pharmacol Toxicol 1989;29:475–516. child born after a normal term delivery, he patient are not typical for this condition. 2 Abramson A, Khan A, Tate GW, et al. Immuno- underwent surgery for an inguinal hernia at 3 competence of transfer factor therapy in Mental confusion is not common at the onset uveitis. Br J Ophthalmol 1980;64:332–8. weeks. Developmental milestones were only of multiple sclerosis whereas it is often found 3 Lockshin MD. Answers to the antiphospholipid moderately delayed. At 9 months, he rolled in acute disseminated encephalitis.4 In addi- antibody-syndrome? N Engl J Med 1995;332: instead of crawling. He walked at 15 months, tion, CSF without oligoclonal banding argues 1025–7. spoke at 2 years with poor articulation, and 4 Kesselring J, Miller DH, Robb SA, et al. Acute against a diagnosis of multiple sclerosis, disseminated encephalomyelitis. Brain 1990; still speaks in short, unelaborated sentences. whereas it is commonly found in acute 113:291–302. His social and language development lagged 4 5 Khan S, Yaqub BA, Poser CM, et al. Multipha- in grade school and he occasionally got into disseminated encephalitis. On the other sic disseminated encephalomyelitis presenting hand the possibility that acute disseminated alterning hemiplegia. J Neurol Neurosurg Psy- fights. In late adolescence, antisocial behav- encephalitis may recur has been accepted5 chiatry 1995;58:467–70. iour took the form of shoplifting and repeated and on the basis of the patient’s clinical 6 Illowsky Karp B, Yang JC, Khorsand M, et al. long distance calls to pornographic hot lines. Multiple cerebral lesions complicating therapy picture and CSF, we favoured such a diagno- with interleukin-2. Neurology 1996;47:417–24. As an adult, his social adaptation remains sis. poor: he currently lives with his mother and The pathogenic mechanisms underlying works irregularly as a dishwasher in a restau- the triggering, development, and duration of Fahr’s disease and Asperger’s syndrome rant. He is indiVerent, isolated, and resists multiple sclerosis and acute disseminated in a patient with primary hypo- novelty. He enjoys repetitive and solitary encephalitis are still far from clear despite the parathyroidism activities such as slot machine games and progress made in unravelling them. Some playing the piano. findings suggest that acute disseminated Abnormal calcium phosphate metabolism has Neurological examination showed bilateral encephalitis and multiple sclerosis lie at the not previously been associated with Asperger’s hyperreflexia, mild imprecision of fine finger two poles of an autoimmune range, in which syndrome, a form of pervasive developmental movements, dysgraphaesthesia on sensory autoantigen reactivity is only temporary and disorder. Nor have symmetric calcifications of testing, and a manneristic gripping direct against a single antigen in acute the basal ganglia, dentate nuclei and cortex, or handshake. There were no extrapyramidal disseminated encephalitis and multiple anti- gens in multiple sclerosis. Although the hypothesis that dialysable leucocyte extract had triggered an autoim- mune disorder in our patient cannot be proved, our finding is in line with the report of multiple cerebral lesions after therapy with IL-2 in patients with malignancies or HIV infections.6 On the other hand, the fact that acute dis- seminated encephalitis is often correlated with the administration of foreign proteins, such as during vaccinations or viral infections4 led us to postulate in this patient a cell mediated immunological mechanism.

Therefore, an immunological cross reaction http://jnnp.bmj.com/ between viral antigens (or other foreign material contained in vaccines) and various parts of the nervous system resulting in acute disseminated encephalitis might have oc- curred. As already noted, dialysable leucocyte extract contains a multitude of immunos- timulating or potentially activating sub- stances so it is impossible to pinpoint which one could have been responsible for the demyelinating eVect seen in our patient. This on October 1, 2021 by guest. Protected copyright. notwithstanding, our finding indicates that neurological surveillance is worthy in patients assuming dialysable leucocyte extract therapy. FRANCESCO G FOSCHI LORENZO MARSIGLI MAURO BERNARDI Semeiotica Medica, Dipartimento di Medicina Interna, Epatologia e Cardioangiologia, Università di Bologna, Italy FABRIZIO SALVI Dipartimento di Scienze Neurologiche, Ospedale Bellaria, Bologna, Italy MARIO MASCALCHI Cattedra di Radiologia, Università di Pisa, Italy GIOVANNI GASBARRINI Cattedra di Medicina Interna, Università Cattolica del Sacro Cuore, Roma, Italy GIUSEPPE F STEFANINI Divisione di Medicina Interna, Ospedale di Faenza Brain CT,axial section: dense calcific deposits in the basal ganglia, thalamus,and orbitofrontal cortex (Ravenna), Italy consistent with Fahr’s disease. 116 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from symptoms. His IQ score was in the low range ute to repetitive and ritualistic activities. (WAIS-C=85 at the age of 13; Barbeau- Additionally, developmental lesions of the Pinard=82 at the age of 17). He also basal ganglia and cerebellum may contribute presented an impairment on the Tower of to the abnormalities of sensory attention, London test, which measures executive func- procedural learning, and motor intention in tion, and in a task assessing the understand- this patient. ing of other people’s intentions. These two The finding that the clinical picture of findings are reliably present in pervasive autism can be found in a wide range of medi- developmental disorders, in this IQ range. In cal conditions giving rise to organic brain addition, his performance on the Tower of dysfunction is not new, but the relation Toronto test disclosed impaired performance between these conditions and autism are in procedural learning. Psychiatric assess- often considered meaningless.3 By contrast, ment showed scores above the cut oV for this case, similarly to some others45 suggests autism according to the autism diagnostic that dysfunction in key brain circuits may interview (ADI),2 a standardised interview result in behavioural and cognitive abnor- that requires specific training and those malities currently indistinguishable from administering it to have a 0.90 reliability with idiopathic pervasive developmental disorder. other researchers. The subject was positive This case also suggests that careful biological for the diagnosis of autism, being above cut assessment of this group of patients may dis- oV values in the three relevant areas of com- close focal brain lesions associated with iden- munication, social interactions, restricted tifiable cognitive deficits. Could these clinical interests, and repetitive behaviours. coincidences be instructive for a neurodevel- Nevertheless, he did not present delay in lan- opmental model of autism? guage acquisition or morphological atypicali- E STIP Preoperative sagittal T1 weighted MRI of the ties in language development, which corre- N BLACK cervical spine with gadolinium enhancement. A sponds to DSM-IV criteria for Asperger’s J M EKOÉ retro-odontoid and extradural mass displacing syndrome. L MOTTRON the spinal cord is seen at the craniovertebral junction. Brain CT showed dense calcium deposits Hopital LH Lafontaine, Départment de Psychiatrie, Université de Montréal, 7331, rue Hochelaga, in the basal ganglia, thalamus, cerebellar 99 Montréal (Québec) H1N 3V2, Canada scan with Tc was unremarkable. Magnetic dentate nucleus, and orbitofrontal cortex, resonance imaging showed a retro-odontoid consistent with Fahr’s disease (figure). Correspondence to: Dr Emmanuel Stip, Centre de Recherche Fernand Séguin, Hopital LH Lafontaine, extradural mass that was homogeneous and SPECT showed increased activity in basal Départment de Psychiatrie, Université de Montréal, isointense on T1 weighted signal, demon- ganglia relative to the cerebral cortex. A fine 7331, rue Hochelaga, Montréal (Québec) H1N 3V2, strated no enhancement after intravenous banded karyotype was normal. Serum cal- Canada. email [email protected] gadolinium contrast, and was compressing cium was 1.55 mM/l (normal 2.15–2.55 the upper cervical spinal cord (figure). The mM/l), phosphate 1.69 mM/l (normal 0.70– 1 Fahr T. Idiopatische Verkalkung der Hirngefas- laboratory tests were normal, confirming the 1.5 mM/l). Ionised calcium was 0.80 mM/l at se.Zentrabl Allg Pathol 1930–1931;50:129. absence of rheumatoid arthritis, metabolic pH 7.4 (normal 1.19–1.34 mM/l); urinary 2 Le Couteur A, Rutter M, Lord C, et al. Autism disease, or gout. Surgical removal via a tran- calcium was 0.8 mM (normal 2.5–6.3 mM). diagnostic interview: a standardized soral approach with a minimal bony resection investigator-based instrument. J Autism Dev Serum parathyroid hormone was below 0.6 Disord 1989;19:363–87. was direct and provided suYcient space to (normal 1.0–6.55 µM/l), and a nuclear scan 3 Minshew N, Sweeney JA, Bauman ML. Neuro- obtain spinal cord decompression. It was fol- of the parathyroid glands showed an absence logical aspects of autism. In: DJ Cohen, FR lowed by a posterior C1-C2 fusion. Macro- Volkmar, eds. Handbook of autism and pervasive of activity. With a combination of vitamin developmental disorders . New York: John Wiley scopically, the lesion had no capsule and D3-calcium supplementation and cognitive- 1997:344–69. resembled a hypertrophic ligamentum fla- behavioural therapy, serum calcium, and 4 Mottron L, Mineau S, Décarie JC, et al. Visual vum. Microscopically, it was non- phosphate concentrations normalised and his agnosia with temporo-occipital brain lesions in inflammatory, hypocellular, and ligamentary an autistic child: a case study. Dev Med Child behaviour improved marginally. Neurol 1997;39:699–705. pieces found within the mass appeared Asperger’s syndrome is a subtype of perva- 5 Jambaqué I, Mottron L, Ponsot G, et al. Autism fibrous and almost disintegrated. The patient sive developmental disorder of unknown and visual agnosia in a child with right occipi- regained normal neurological function. Over

tal lobectomy. J Neurol Neurosurg Psychiatry http://jnnp.bmj.com/ aetiology. Evidence for involvement of spe- 1998;65:555–60. a 3 year follow up period there was no recur- cific brain regions in pervasive developmental rence. disorder are scarce and inconclusive.3 Al- We focus attention on hypertrophic atlan- though the temporo-occipital region is the Hypertrophic atlantoaxial ligaments: an toaxial ligamentary disease as a degenerative most often involved in pervasive developmen- unusual cause of compression of the disease that must be considered within the tal disorders45 abnormal functioning of the upper spinal cord possible causes of high spinal cord compres- frontal lobes is also suspected from replicated sion. findings of executive function deficits and The craniovertebral junction can be aVected ALEJANDRA TERESA RABADAN from occasional findings of frontal hypome- by several pseudotumorous masses extradur- Department of Neurosurgery, Instituto de tabolism or abnormal macroscopic brain ally located, such as rheumatoid panus, Investigaciones Medicas “Alfredo Lanari”, Facultad de on October 1, 2021 by guest. Protected copyright. morphology.3 Abnormal cell counts and mor- hypertrophic non-union of odontoid fracture, Medicina, Universidad de Buenos Aires, and Equipo de phology in the cerebellar hemispheres have post-traumatic cicatrix, synovial cysts, tumor- Neurocirugía de Buenos Aires, Argentina also been reported, but the relation of these ous calcium pyrophosphate dihydrate crystal GUSTAVO SEVLEVER findings to autism is controversial.3 deposition, tophaceous gout, calcification of Department of Pathology, Clinica Bazterrica, Buenos Fahr’s disease consists of symmetric calci- the posterior longitudinal ligament, synovial Aires, and Equipo de Neurocirugía de Buenos Aires, fications, located mainly in the basal fore- disease-like pigmented villonodular synovitis, Argentina brain and cerebellum, which are of various and synovial chondromatosis.1–5 Hypertrophy Correspondence to: Dr Alejandra T Rabadan, Bill- aetiologies. Cognitive and behavioural abnor- of the atlantoaxial ligaments as a conse- inghurst 1976 PB, 1425 Buenos Aires, Argentina. malities may be present when calcifications quence of degenerative disease was recently Telephone 0054 1 902 4417;fax 0054 1 903 occur early in development. A fortuitous recognised as an individual entity. Only five 8928;email rabadan @ movi.com.ar association between pervasive developmental previous cases have been published.1 We add disorder and hypercalcaemia, given the pau- another case to the short series available in 1 Crockard HA, Sett P, Geddes JF, et al. Damaged city of published cases, is plausible in the pre- the literature, emphasising that as the cause ligaments at the craniovertebral junction pre- senting as an extradural tumour: a diVerential sented patient. Nevertheless, our case of the spinal cord compression is amenable to diagnosis in the elderly. J Neurol Neurosurg Psy- suggests that abnormal phospho-calcium surgical removal, symptomatic patients chiatry 1991;54:817–21. metabolism could produce an autistic syn- should be diagnosed and treated without 2 Pare MC, Currier BL, Ebersold MJ. Resolution of traumatic hypertrophic periodontoid cicatrix drome when brain calcifications cause spe- delay. after posterior cervical fusion: case report. cific neuropsychological deficits, due to their A 66 year old woman presented with a Neurosurgery 1995;337:531–4. localisation. For example, errors of social rapid development of progressive spastic 3 ShaVrey CI, Muñoz EL, Sutton CL, et al. judgement may be related to calcifications of tetraparesis and an unremarkable medical Tumoral calcium pyrophosphate dihydrate deposition disease mimicking a cervical spine the orbitofrontal cortex, whereas dysfunction history. There was no osteolysis or instability neoplasm: case report. Neurosurgery 1995;37: of frontal-basal ganglia circuits may contrib- on plain cervical radiography and CT.A bone 335–9. J Neurol Neurosurg Psychiatry 2000;68:100–126 117 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

4 Sze G, Brant-Zawadzki MN, Wilson CB, et al. sity lesion at the dorsolateral midbrain in The MR images in our case showed a dis- Pseudotumour of the craniovertebral junction addition to the previous lesion (figure). crete lesion at the left dorsolateral midbrain. associated with chronic subluxation: MR imag- ing studies. Radiology 1986;161:391–4. Brain MRI, taken 3 days later, demon- Topographical study at this lower midbrain 5 Tihanski DP. Unilateral hypertrophy of the cer- strated an intraparenchymal lesion, at the level showed that the lateral and ventral vical ligamentum flavum presenting as pseudo- surface of the left dorsolateral midbrain in spinothalamic and ventral trigeminothalamic tumor. 1986; :5368. N Y State J Med 86 high intensity on a T2 weighted image. The tracts pass at the surface of this level by high intensity lesion corresponding to hae- carrying a superficial somatofacial sensory Selective hemihypaesthesia due to tentorial matoma on CT was seen in the ambient cis- input.3 The lesion shown in our MR images coup injury against dorsolateral midbrain: tern (figure). Taking both CT scans and MRI seemed to be localised to these tracts. The potential cause of sensory impairment into consideration, this case was diagnosed as medial leminiscus for the deep sensation and after closed head injury traumatic midbrain contusion. lateral leminiscus and nucleus of inferior col- The loss of pain and temperature sensation liculus associated with hearing function run A 63 year old woman who fell oV her bicycle improved gradually and the patient was ventral and dorsal to these tracts, respec- had a left temporal region head injury with discharged 2 weeks later. tively; which were seemingly spared in our 3 evidence of initial loss of consciousness of 5 T2 weighted images 1 month later showed patient. The topographical anatomy seemed minutes and scalp excoriation of that area. a more localised lesion in the same area. The to correspond to the neurological manifesta- On arrival at our hospital 30 minutes later she coronal slices showed a high intensity lesion tions of our patient. was alert and oriented. Cranial nerve func- at the level of lower midbrain coinciding with The mechanism of midbrain injury in our tions, including extraocular motion and hear- the tentorium level, disclosed as a low line patient was speculated to be due to tentorial ing function, were preserved. Pain and between the occipital lobe and the cerebellar coup injury based on MR images. The temperature sensations of the right side, hemisphere (figure). location of contusion was at the lower dorso- including her face, showed a 70% decrease The neurological deficits almost disap- lateral midbrain, coinciding with the tentorial compared with the left side; however, position peared 6 months later. edge level. Initiation of injury was the surface and vibration sensations were normal. Other Somatosensory impairment including pain of the midbrain; however, due to the proxim- neurological examinations, including motor is one of the most common complaints among ity of the tentorial edge to the midbrain on function, coordination, and deep tendon patients with craniocervical injury. Responsi- the injured side, tentorial contact to the mid- reflex, were normal. The patient’s only com- ble lesions for sensory impairment, detectable brain supposedly occurred more readily. plaints were left temporal headache and right by neuroimaging studies, almost always ac- Brain MRI findings support the anatomical hemihypaesthesia. company associated neurological deficits.12To features of this tentorial coup injury. This Brain CT on admission showed a discrete our knowledge, a selective injury at the injury is not rare in patients with severe head and linear high density at the left ambient spinothalamic or trigeminothalamic tracts due injury, accompanied by other intracranial cistern without other intracranial lesions. On to closed head injury has not been highlighted lesions, and is often caused by lateral the next day CT showed an obscure low den- in the neurological literature. displacement of the brain stem relative to the tentorium. It is influenced by congenital vari- ation in the size and shape of the tentorial incisura.12The brain stem of the patient with a narrow incisura is more vulnerable to the direct contusive eVects than that of a patient with a wider incisura. Therefore, even in minor head injury, this mechanism may occur in patients preconditioned with narrow tento- rial incisura, which may have been the case in our patient. The concept of tentorial coup injury against the midbrain is not new.4 It usually accompanies various degrees of conscious disturbance and other long tract signs, sensory deficits as well as cerebellar and

cranial nerve palsy due to the midbrain http://jnnp.bmj.com/ lesion or other associated intracranial lesions.1245The clinical manifestation of our patient may represent one of the mildest forms of the midbrain contusion. Therefore, when we see a patient with post-traumatic sensory deficit, the possibility of this tento- rial injury should be kept in mind even in minor head injury.

NAOKATSU SAEKI on October 1, 2021 by guest. Protected copyright. YOSHINORI HIGUCHI Departments of Neurological Surgery, Chiba University, School of Medicine, Chiba, Japan KENRO SUNAMI Kawatetsu Chiba Hospital, Japan AKIRA YAMAURA Departments of Neurological Surgery, Chiba University, School of Medicine, Chiba, Japan Correspondence to: Dr Naokatsu Saeki, Depart- ment of Neurological Surgery, Chiba University, School of Medicine, 1–8–1 Inohana, Chuoh-ku Chiba-shi, Chiba Japan 260–8670 email [email protected] (A) CT on admission showed a discrete and linear high density at the left ambient cistern. (B) Axial T2 weighted image taken 3 days later showed an intraparenchymal lesion, at the left posterolateral midbrain in high intensity. (arrow) The margin was rather obscure. The high and low intensity lesion 1 Gean AD. Imaging of head trauma. New York: corresponding to haematoma on CT was seen in the ambient cistern in the axial image. (arrow head) Raven, 1994:215. Taking both CT scans and MRI, this case was diagnosed as traumatic midbrain contusion. (C) An 2 Saeki N, Yamaura A, Sunami K. Brain stem contusion due to tentorial coup injury: case axial T2 weighted image 1 month later demonstrated a more discrete lesion at the dorsolateral report and pathomechanical analysis from nor- midbrain tegmentum (arrow). (D) A coronal image showed a discrete high intensity lesion at the level mal cadavers. Br J Neurosurg 1998;12:151–5. of the lower midbrain (arrow) coinciding with the level of the tentorium, which was shown in low line 3 DeArmond SJ, Fusco MM, Dewey MM. Struc- between the occipital lobe and cerebellar hemisphere. The distance between the tentorial margin and ture of the human brain. 2nd ed. New York brain stem was shorter on the injured side. :Oxford University Press, 1976:84–8. 118 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

4 Lindenberg R. Significance of the tentorium in Correspondence to: Dr Dirk Deleu, College of quence of introducing from these 36 non- head injury from the blunt forces. Clin Medicine, PO Box 35, Sultan Qaboos University, selected patients a hypothetical single case Neurosurg 1964;12:129–42. Al-Khod, Muscat-123, Sultanate of Oman that had a family history of tuberous sclerosis 5 Miller N, Newman N. Walsh and Hoyt’s clinical email [email protected] neuro-ophthamology, 5th ed. Vol 1. Baltimore: complex and a subependymal nodule which Williams and Wilkins, 1998:1227–34. enhanced with gadolinium. The eVect would 1 Miyagi Y, Shima F, Ishido K, Yasutakeet. be to remove the stated statistical significance Tremor induced by toluene misuse successfully (using Fisher’s exact tests) between the treated by a Vim thalamotomy. J Neurol Neuro- surg Psychiatry 1999;66:794–6. outcome and both of these explanatory vari- 2 Stengard K, Tham R, O’Connor WT, et al. ables. Acute toluene exposure increases extracellular Identifying the risk factors that can tell us CORRESPONDENCE GABA in the cerebellum of rat: a microdialysis study. Pharmacol Toxicol 1993;15:327–34. which subependymal lesions will become 3 Bjornaes S, Naalsund LU. Biochemical changes invasive is important. As subependymal nod- in diVerent brain areas after toluene inhalation. ules and SEGAs seem to be histologically Toxicology 1988;49:367–74. identical it is unlikely that pathologists will 4 Campanella G, Filla A, De Falco F, et al. Fried- reich’s ataxia in the south of Italy: a clinical and provide an answer. The study of Nabbout et Toluene induced postural tremor biochemical survey of 23 patients. Can J Neurol al suggests some new hypotheses and reiter- Sci 1980;7:351–7. ates some others. However, the definitive We read with interest the article by Miyagi et 5 Deleu D, Hanssens Y. Cerebellar dysfunction in answer will not be provided by studies of 1 chronic toluene abuse: beneficial response to al and comment on the medical treatment of amantadine hydrochloride. J Toxicol Clin Toxicol selected samples but by follow up of a popu- toluene induced tremor. Microdialysis experi- (in press). lation based sample of patients with tuberous ments in rats have shown that inhalation of 6 Deutch AY, Elsworth JD, Roth RH, et al. sclerosis complex. In the absence of such a toluene increases extracellular -aminobutyric 3-Acetylpyridine results in degeneration of the ã extrapyramidal and cerebellar motor systems: study we would be cautious about imple- acid (GABA) concentrations within the cer- loss of dorsolateral striatal dopamine innerva- menting screening programmes based on ebellar cortex2 which probably explains why tion. Brain Res 1990;527:96–102. what may be misleading criteria. GABA agonists including benzodiazepines (for example, clonazepam) are not very eVec- FINBAR J K O’CALLAGHAN ANDREW LUX tive in toluene induced tremor and ataxia. Rat Early diagnosis of subependymal giant cell astrocytoma in children with JOHN OSBORNE experiments also showed a 50% reduction in Bath Unit for Research in Paediatrics, Royal United 3 brain catecholaminergic neurons. Degenera- tuberous sclerosis Hospital, Bath BA1 3NG, United Kingdom tion of certain cerebellar pathways is probably Nabbout 1 have attempted to identify the Correspondence to: Dr Finbar J K O’Callaghan, responsible for the loss of this dopaminergic et al Bath Unit for Research in Paediatrics, Royal United innervation.4 Dopamine agonists could there- risk factors for the progression of subependy- Hospital, Bath BA1 3NG, United Kingdom fore be of potential interest in the treatment of mal nodules into giant cell astrocytomas toluene induced tremor. This hypothesis was (SEGAs) in tuberous sclerosis complex. In 1 Nabout R, Santos M, Rolland Y, . Early explored in a recently described case,5 which attempting to develop screening strategies et al that avoid iatrogenic morbidity, patient in- diagnosis of subependymal giant cell astrocy- showed remarkable clinical and iconographic toma in children with tuberous sclerosis. J similarities with that described by Miyagi et convenience, and excess cost, it is essential Neurol Neurosurg Psychiatry 1999;66:370–5. al1:(a) long history of chronic toluene inhala- that the natural history of these lesions in the tion, ( ) marked postural tremor, ( ) progres- general population of patients with tuberous b c Atypical form of amyotrophic lateral sive worsening of the symptoms despite absti- sclerosis complex be understood well. nence from inhalant misuse, and (d) mild We think that there are two problems with sclerosis: a new term to define a cerebral atrophy and marked low signal inten- this study that should make the physician cau- previously well known form of ALS sity in globus pallidi, thalami, red nuclei, and tious about accepting the factors identified by Nabbout et al as a basis for a screening We read with interest the article by Sasaki et substantia nigrae on T2 weighted MRI. As 1 our patient’s tremor was progressive, medical programme. The first is that this study was al concerning the atypical form of amyo- treatment with a dopamine agonist was performed in a population that had been trophic lateral sclerosis (ALS). The pattern of referred to a tertiary medical centre, and then muscular atrophy in these patients di ered considered. One particular agent (amanta- V had been further selected by virtue of having from that of typical ALS in that severe muscle dine) caught our attention because it had had at least 3 years tertiary centre follow up involvement was confined to the upper limbs, proved successful in the treatment of postural and needing two MR scans of the head. The predominantly the proximal portion and tremor and ataxias of heredodegenerative dis- http://jnnp.bmj.com/ prevalence of astrocytomas and risk factors, shoulder girdle, sparing the face and the legs orders in which the dentatorubro-olivary sys- and hence the positive predictive value of any until late in the disease’s course or until the tem is aVected. In addition, there is evidence screening test in a general population of terminal stage. that catecholaminergic pathways are also patients with tuberous sclerosis complex is Over the past few years, we have noticed a involved in this type of ataxias, supported by likely to be diVerent from those described in growing interest in the renaming of this clini- low concentrations of these neurotransmitters the highly selected group studied in this paper. cal form of ALS, which has its origins and in the CSF of patients with heredodegenera- The second point is that the authors have predomination in the proximal muscles and tive ataxias.6 In our patient, amantadine made a potentially misleading decision to upper limbs and little or no eVect of either a hydrochloride (100 mg twice daily) abolished exclude more than half their study sample bulbar nature or in the lower limbs.

postural tremor and ataxia completely over a 3 2 on October 1, 2021 by guest. Protected copyright. because they do not have lesions close to the Thus Hu et al coined the term flail arm month period. foramen of Monroe. It is not certain that all syndrome, to describe a subgroup of patients Subsequently, the treatment was discontin- SEGAs arise from lesions close to the aVected by ALS that predominantly showed ued, which resulted in relapse of the tremor foramen. They may arise in the fourth ventri- signs of lower motor neuron disease in the and ataxia. He was rechallenged to amanta- cle. Furthermore, the late presentation of upper limbs, without significant functional dine, which progressively oVered him the many lesions in the lateral ventricles has, in involvement of other regions on clinical pres- same clinical improvement as in the first 3 the past, precluded accurate determination of entation. This subgroup of patients was clini- months. After 3 years the treatment was dis- their point of origin. The study selects 24 of cally characterised by the display of progres- continued without any sign of relapse. 60 patients who had met their entry criteria sive atrophy and weakness aVecting the Although this finding needs confirmation, but does not state how many of the excluded proximal muscles in the upper limb muscles amantadine treatment could form a new 36 patients had no subependymal nodules or in a more or less symmetric manner. approach in the medical treatment for nodules that were not “near the foramen of Recently, along these lines, Katz et al3 toluene induced tremor and ataxia. Intracta- Monroe”. Indeed no definition is given for described a series of patients aVected by an ble cases would then justify a more aggressive what constitutes proximity to the foramen. adult onset motor neuron disorder restricted approach such as ventrointermedius tha- The authors were apparently not blinded at to the upper limbs, with severe proximal and lamotomy. the point when they selected which patients varying degrees of distal involvement, calling DIRK DELEU had lesions near to the foramen and therefore it amyotrophic brachial diplegia syndrome. Departments of Clinical Pharmacology and Neurology, there is an obvious issue of potential selection Other terms used in the past to refer to this College of Medicine, Sultan Qaboos University, bias. form of ALS have been dangling arm PO Box 35, Al Khod, Muscat-123, The consequence of excluding these pa- syndrome, suspended form, orangutan sign, Sultanate of Oman tients may have been that false significance is dead arm sign, bibrachial palsy, rizomelic YOLANDE HANSSENS given to their results. The data they present amyotrohy, and the idea of naming it a Drug Information Services, Hospital Pharmacy are fragile. Consider, for example, the conse- distinctive phenotype of a neurogenic J Neurol Neurosurg Psychiatry 2000;68:100–126 119 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

“man-in-the-barrel” syndrome has even been Correspondence to: Correspondence to: Dr Josep 1 Sasaki S, lwata M. Atypical form of amyotrophic suggested. Gamez, Servicio de Neurologia, Hospital Gral, lateral sclerosis. J Neurol Neurosurg Psychiatry Universitari Vall d‘Hebron, Passeig Vall d’Hebron 1999;66:581–5. Probably all these terms used to define this 2 Keegan JJ. The cause of dissociated motor loss variation of ALS are synonyms for an older, 119–135, 08035 Barcelona, Spain. email: [email protected] in the upper extremity with cervical well known condition, the scapulohumeral spondylosis: a case report. J Neurosurg 1965;23: form, or the chronic anterior poliomyelitis 528–36. 3 Sasaki S, lwata M. Motor neuron disease with reported by Vulpian in 1886 and known in 1 Sasaki S, Iwata M. Atypical form of amyotrophic predominantly upper extremity involvement: a Franco-German literature as Vulpian- lateral sclerosis. J Neurol Neurosurg Psychiatry clinicopathological study. Acta Neuropathol (in Bernhardt’s form of ALS. 1999;66:581–5. press). 2 Hu MTM, Ellis CM, Al-Chalabri A, et al. Flail At certain stages of the disease’s clinical arm syndrome: a distinctive variant of amyo- course, it is probably diYcult to diVerentiate trophic lateral sclerosis. J Neurol Neurosurg Psy- Isolated dysarthria it from progressive muscular atrophy (PMA). chiatry 1998;65:950–1. Some authors have said that PMA with late 3 Katz JS, Bryan WW, Andersson PB, et al. The syndrome of amyotrophic brachial diplegia. We read with interest the article by Urban et onset scapulohumeral distribution (over 45 Neurology 1999;52(suppl 2):A83–4. al. Using transcranial magnetic stimulation, years of age) generally leads to ALS as a mat- 4 Erbslöh F. DiVerentialdiagnose der StoVwech- the authors demonstrated electrophysiologi- ter of course.4 selerkrankungen des Zentralnervensystems (Degenerationen). In: Bodechtel G, ed. DiVer- cal evidence for a central monoparesis of the Be that as it may, the truth is that this entialdiagnose neurologischer Krankheitsbilder. tongue in patients with isolated dysarthria atypical form of amyotrophic lateral sclerosis 2nd ed. Stuttgart: Georg Thieme Verlag, 1963: from stroke.1 As in their patients transcranial behaves diVerently from typical ALS. The 690–1. 5 Wilkinson M. Motor neuron disease and magnetic stimulation induced absent or comparative study with the rest of the ALS cervical spondylosis. In: Norris FH, Kurland L, delayed corticolingual responses at the group supplied important clinical findings, eds. Motor neuron disease: research on amyo- tongue, the authors ascribed isolated dysar- such as little or no functional impairment of trophic lateral sclerosis and related disorders. Vol II. New York: Grune and Stration, 1968:130–4. thria to interruption of the corticolingual the bulbar muscles or legs. Hu et al also made pathways. On the whole, these results seem four important statistical discoveries. plausible, but we would like to comment on (1) The prevalence of this form of ALS Sasaki replies: the underlying mechanism of isolated dysar- constituted 10% of the ALS group as a whole We thank Gamez et al for their interest in our thria. (n=395). (2) The age of onset of this form article concerning the atypical form of amyo- As in the case of isolated dysarthria was similar to the rest of ALS. (3) There was trophic lateral sclerosis (ALS).1 reported by Urban et al, all of our patients a clear predominance among men (the male/ Over many years, several researchers have with isolated dysarthria had lacunar infarc- female ratio was 9:1 in this form, compared recognised this peculiar distribution of mus- tions involving the internal capsule and with 1.5:1 in the total ALS group). (4) There cle atrophy in clinical practice. The clinical corona radiata.2 Measurement of cerebral was a longer median survival (a median manifestations consist of the muscular atro- blood flow with IMP-SPECT in these survival of 57 months compared with 39 phy confined to the shoulder girdle and the patients disclosed frontal cortical hypoper- months in the ALS group). arms (proximally dominant), absence of deep fusion, particularly in the anterior opercular Some of these patients have a long ALS tendon reflex in the arms,almost normal deep and medial frontal regions. Anterior opercu- clinical course, in that they usually preserve tendon reflex in the legs, and subluxation of lar lesions produce facio-pharyngo-glosso- ambulatory ability, albeit with gait disorders, the shoulder joints. Some patients progress to masticatory paresis (anterior opercular syn- for more than 5 years after the onset of symp- bulbar involvement. As Gamez et al cite, drome), and damage to the medial frontal toms many terms have been coined to describe this regions, including the supplementary motor On a personal level, we also note two find- peculiar pattern of the muscular atrophy such area, causes speech expression disorders. ings characteristic of these patients. In the as dangling arm, orang utan sign, dead arm White matter lesions can disrupt aVerent and initial stages of the illness, there is no eVect on sign, suspended form, flail arm syndrome, eVerent fibre connections with cerebral lan- the diaphragm and the respiratory muscle amyotrophic brachial diplegia syndrome, guage areas, resulting in dysfunction of these failure occurs much later than in the typical bibrachial palsy and man-in-the-barrel syn- cortices.3 Therefore, we postulated that iso- form of ALS. This can be seen in the follow drome. Some researchers classified into a lated dysarthria results from interruption of up of the results obtained in the respiratory category of motor neuron disease (ALS or corticosubcortical networks indispensable for function tests (FVC, PImax, and PEmax). spinal progressive muscular atrophy). How- speech output, involving the thalamocortical We do not know the reason for either the ever, others could not exclude the possible and corticostriatal fibres as well as the characteristic distribution of weakness or cause of cervical diseases such as dissociated corticobulbar fibres. In fact, lacunar infarc- muscle atrophy. A meticulous study shows motor loss in the upper extremity.2 In fact, tions around the internal capsule-corona http://jnnp.bmj.com/ that there is an atrophy of the deltoideus these patients had cervical abnomalities such radiata are likely to undercut these ascending (especially in the pars spinata) and a loss of as cervical spondylosis and ossification of and descending projections.45 strength in the external rotation of the shoul- posterior longitudinal ligament disclosed by To assess corticopontocerebellar tract der (infraespinatus, supraespinatus, and teres cervical radiography, MRI, or myelography. function, Urban et al investigated cerebellar minor). As a consequence, the upper limbs By contrast with clinical awareness of this blood flow in patients with isolated dysarthria adopt a characteristic position, with the peculiar pattern of muscular atrophy, no using HMPAO-SPECT. The authors con- shoulders slumped, and the arms, forearms, pathological confirmation had been made cluded that the corticopontocerebellar tract is and hands in pronation. until we first reported necropsy cases in our preserved in isolated dysarthria because of no The atrophy and weakness of the in- articles.13 Now, these patients with their evidence for cerebellar diaschisis on SPECT. on October 1, 2021 by guest. Protected copyright. fraespinatus and the supraespinatus, that act peculiar pattern of muscular atrophy are con- Their SPECT findings on cerebellar blood as an active ligament in scapulohumeral sidered to be ALS or a subtype of ALS. In my flow were similar to our results. However, we articulation, would explain the presence of private opinion, “dangling arm syndrome” or wonder whether cerebral cortical blood flow subluxation of the shoulder joints in these “dead arm sign” seems to be the most was preserved in their patients, because our patients. suitable term depicting this type of motor SPECT study suggested frontal cortical dys- Finally, we are in complete agreement that neuron disease. function as an underlying mechanism of iso- the coexistence of cervical spondylosis and I agree with Hu et al reporting four impor- lated dysarthria. Lingual paresis was clinically ALS can cause diYculty in diagnosis. The tant statistical discoveries in this form of evident in three of seven patients reported by problem lies in the fact that cervical spondy- ALS: the prevalence percentage of 10% of the Urban et al and in two of 12 by us. This indi- losis is a common condition. It is found in whole ALS group, the similar age onset to the cates that isolated dysarthria originates in 83.5% of men and 80.7% of women over the rest of ALS, a predominance among men (the incoordination of multiple organs necessary age of 55. The faster progressive deteriora- male/female ratio was 3:1 in our study), and a for articulation as well as a lingual monopare- tion of the symptoms, the appearance of bul- longer median survival. It is clinically impor- sis. Although interruption of the corticolin- bar signs, and the absence of sensory tant to give wider publicity to the existence of gual pathways is a likely cause of isolated dys- symptoms and signs would favour the diag- this atypical form of ALS to avoid unneces- arthria, it should be borne in mind that nosis of ALS.5 sary surgical intervention for cervical abnor- damage to other descending and ascending malities. projections may contribute to isolated dysar- JOSEP GAMEZ thria. CARLOS CERVERA SHOICHI SASAKI AGUSTIN CODINA Department of Neurology, Neurological Institute, Tokyo BUNGO OKUDA Servicio de Neurologia, Hospital Gral, Universitari Women’s Institute, Tokyo Women’s Medical College, HISAO TACHIBANA Vall d‘Hebron, Passeig Vall d’Hebron 119–135, 08035 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Division of Neurology, Fifth Department of Internal Barcelona, Spain Japan Medicine, Hyogo College of Medicine, Nishinomiya 120 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from

1 Urban PP, Wicht S, Hopf HC, et al. Isolated lation with a dyskinesia rating scale, had a 2 Abbruzzese G, Buccolieri A, Marchese R, et al. dysarthria due to extracerebellar lacunar more advanced stage of the disease possibly Intracortical inhibition and facilitation are stroke: a central monoparesis of the tongue. J abnormal in Huntington’s disease: a paired Neurol Neurosurg Psychiatry 1999;66:495–501. with coexisting dystonia or rigidity. These magnetic stimulation study. Neurosci Lett 1997; 2 Okuda B, Kawabata K, Tachibana H, et al. Cer- assertions deserve some comments. 228:87–90. ebral blood flow in pure dysarthria: role of The mean disease duration of our nine 3 Thompson PD, Berardelli A, Rothwell JC, et al. frontal cortical hypoperfusion. Stroke 1999;30: patients with Huntington’s disease was 6.2 The coexistence of bradykinesia and chorea in 109–13. Huntington’s disease and its implication for 3 Okuda B, Tanaka H, Tachibana H, et al. (4.1) years which is actually shorter than the theories of basal ganglia control of movement. Cerebral blood flow in subcortical global duration of the six patients reported by Brain 1988;111:223–44 aphasia: perisylvian cortical hypoperfusion as a Hanajima et al (8.3 (5.9) years). Most of our 4 Harper PS. Huntington’s disease. London: Saun- crucial role. 1994; :1495–9. Stroke 25 patients could be considered in an early stage ders, 1991:37–80. 4 Ozaki I, Baba M, Narita S, et al. Pure dysarthria 5 Berardelli A, Noth J, Thompson PD, et al. due to anterior internal capsule and/or corona of the disease, according to the Unified Pathophysiology of chorea and bradykinesia in radiata infarction: a report of five cases. J Neu- Huntington’s disease rating scale, and none Huntington’s disease. Mov Disord 1999;14: rol Neurosurg Psychiatry 1986;49:1435–7. 398–403. 5 Rousseaux M, Lesoin F, Quint S. Unilateral presented dystonia, rigidity, or any other additional movement disorder. In this re- 6 Abbruzzese G, Assini A, Buccolieri A, et al. pseudobulbar syndrome with limited cap- Comparison of intracortical inhibition and sulothalamic infarction. Eur Neurol 1987:27: gard, however, it should be pointed out that facilitation in distal and proximal arm muscles 227–30. bradykinesia is often associated with chorea in humans. J Physiol 1999;514:895–903. in patients with Huntington’s disease3 and 7 Ziemann U, Winter M, Reimers CD, et al. Impaired motor cortex inhibition in patients Urban et al reply: may even precede the appearance of choreic with amyotrophic lateral sclerosis. Evidence dyskinesias.4 Chorea itself is often reduced in Okuda et al draw attention to their article on from paired transcranial magnetic stimulation. the more advanced Huntington’s disease Neurology 1997;49:1292–8. pure dysarthria in Stroke1 which we read with stages.4 It is unlikely, therefore, that any neu- much interest. They refer to 12 patients with rophysiological approach can test purely pure dysarthria, 11 of whom showed multiple chorea even in the early Huntington’s disease The authors reply: bilateral infarctions involving the internal stages. In addition, diVerent mechanisms are We are very grateful for the response of capsule and corona radiata. The main diVer- involved in Huntington’s disease and other Abbruzzese et al to our paper. We completely ence to our series of seven patients is the choreas as suggested by the lack of impair- agree with their opinions. multiple involvement of the brain. We think 12 ment of somatosensory evoked responses The discrepancy between the two studies that single lesions as collected by us2 are more and long latency stretch reflexes in the may not be mainly due to the diVerent stage appropriate to correlate lesion topography second.5 of the disease between the two groups of with impaired function. The findings of We were not really surprised at the results patients. Although the duration of the disease Okuda et al are in line with our conclusion is one factor to judge the disease stage, the of Hanajima et al as we do share their opinion that interruption of the corticolingual path- severity of the disease (stage of the disease) is way is crucial in the pathogenesis of dysar- that patients with Huntington’s disease may be characterised by large individual diVer- also positively correlated with CAG repeat thria of extracerebellar origin. Obviously, number. impairment of the corticolingual tract of one ences in the involvement of motor cortical areas. Actually, three patients in our study We may have to take CAG repeat number hemisphere by a single small lesion is an into consideration in comparisons. Unfortu- adequate condition for dysarthria. The pa- showed an amount of intracortical inhibition within the confidence limits of the control nately, however, we have no way to do such tients of Okuda et al had more severe vascular population. We also think that the impair- comparisons between these two studies. We disorder of the brain than our patients as can could say, at least, that the intracortical inhi- be concluded from the multiple infarctions. ment of intracortical inhibition is likely to develop during the disease progression as we bition was normal even at the same stage of Thus, the bilateral frontal cortical hypoper- the disease as that of the patients of Abbruzz- fusion as disclosed by SPECT in the series of did not find any change in four patients, two of them already reported,2 with positive DNA ese et al, if studied with our method. Okuda et al may be due to infarction in other testing but completely asymptomatic. We also consider that methodological dif- parts of the brain compared with the lesion ferences are very important in paired mag- causing pure dysarthria. The discrepancies between the two studies are more likely to be explained, at least in netic stimulation. The results strongly depend P P URBAN part, by some methodological diVerences. on the intensities of both a conditioning and a S WICHT For instance, the amplitude of the control test stimulus. Especially, the intensity of the H CH HOPF response was larger in our set (approximately conditioning stimulus is critical. We have no Department of Neurology, University of Maine, 1.0 mV compared with 0.3 mV in the study of diYculty in showing normal inhibition, but Langenbeckstrasse 1, D55101 Mainz, Germany have much diYculty in showing reduced or

Hanajima et al). This may induce a diVerent http://jnnp.bmj.com/ S FLEISCHER sensitivity of the test, and the amount of absent inhibition because of such marked Department of Communication Disorders intracortical inhibition in our normal con- dependence of the results on the intensities of trols is greater (see also6) than in the study of stimuli. Therefore, we used several intensities O NICKEL of the conditioning stimulus before we Department of Nuclear Medicine Hanajima et al. 3 When interpreting the results of studies confirmed inhibition in studies of patients. with paired transcranial magnetic stimulation We used an intensity of 5% less than the active 1 Okuda B, Kawabata K, Tachibana H, et al. Cer- pathophysiologically it should be kept in threshold as a conditioning stimulus in our ebral blood flow in pure dysarthria: role of study of chorea.2 We did not need to change frontal cortical hypoperfusion. Stroke mind that similar changes of intracortical 1999;30:109–13. inhibition have been shown in patients with the intensity of the conditioning stimulus 2 Urban PP, Wicht S, Hopf HC, et al. Isolated various movement disorders (focal dystonia, because we always obtained a normal inhibi- on October 1, 2021 by guest. Protected copyright. dysarthria due to extracerebellar lacunar tion with this intensity. We consider that this is stroke: a central monoparesis of the tongue. J myoclonus, parkinsonism, restless legs syn- Neurol Neurosurg Psychiatry 1999;66:495–501. drome, Tourette’s disorder), but also in very important. If using a suprathreshold diVerent diseases such as amyotrophic lateral (active threshold) conditioning stimulus, a sclerosis.7 We think, therefore, that the facilitatory eVect must often superimpose on Motor cortical excitability in impairment of intracortical inhibition cannot the intracortical inhibition. This makes the Huntington’s disease be regarded as the marker of a specific patho- interpretation diYcult. Was the intensity of physiological mechanism, but is likely to 80% of the resting threshold always below the We read with great interest the paper of active threshold in their patients? In our 1 reflect a non-specific imbalance of inhibitory Hanajima et al reporting that intracortical and facilitatory circuits within the motor experience, 80% of the resting threshold was inhibition of the motor cortex is normal in cortex. sometimes above the active threshold. These patients with chorea of various origins. At factors must be considered in interpreting the variance with these results we previously G ABBRUZZESE results of paired magnetic stimulation. 2 found a reduced intracortical inhibition in a R MARCHESE Such a methodological problem is inherent group of patients with genetically confirmed in human studies because we have no direct C TROMPETTO Huntington’s disease. Hanajima suggest way of detecting the threshold of the motor et al Department of Neurological Sciences and Vision, that the discrepancies between the two stud- Movement Disorders Clinic, University of Genoa, cortex. Our two results must be true. We may ies might be due to diVerences in patient Via De Toni 5, I—16132 Genova, Italy have two completely diVerent interpretations selection as they included patients with early of these results. (1) The intracortical inhibi- stage Huntington’s disease to “study the tion is normal in Huntington’s disease. pathophysiology of chorea unaVected by 1 Hanajima R, Ugawa Y, Terao Y, et al. Intracorti- Abbruzzese showed the reduced inhibi- cal inhibition of the motor cortex is normal in et al other disorders movement.” They postulated chorea. J Neurol Neurosurg Psychiatry tion because they used a high intensity condi- that our cases, because of the reported corre- 1999;66:783–6 tioning stimulus with which the degree of the J Neurol Neurosurg Psychiatry 2000;68:100–126 121 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from intracotical inhibition is often decreased even realistic assumption that CVR1 is equal to by a sum of intracranial pressure (ICP) and in normal subjects. The 80% of the threshold about half of CVR0 it follows for CCP2: the tension in the arterial walls: for relaxed muscles must correspond to CCP2=0.5ABP+0.5CCP CCP=ICP+active tension of arterial walls diVerent values relative to the threshold for With decreasing CVR1/CVR0 ratios, Aaslid3 proposed the mathematical formula active muscles in patients from that in normal CCP2 becomes more and more dependent taken for calculations: subjects. (2) The intracortical inhibition is on ABP and independent of CCP. In any CCP1=ABPs-ABPpp/FVpp×FVs= disturbed in Huntington’s disease. This slight case, without exact knowledge of the CVR1/ ABP−ABPpp/FVpp×FV abnormality could be detected with their CVR0 ratio, equation 4 is useless for a valid (where ABP and FV are mean values of method but not with ours because their CCP calculation. arterial pressure and MCA flow velocity, method has better sensitivity in detecting an The second criticism concerns the correla- ABPs and FVs are systolic values, ABPpp and abnormality than ours. Whichever is true, the tion of the calculated CCP2 values with mean FVpp are peak to peak amplitudes ). A intracortical inhibition must be normal or ABP found by the authors (r=0.5; p<0.05). graphical interpretation of this formula has slightly disturbed in Huntington’s disease. According to the original idea of Burton,3 been given in1 in fig 1. CCP1 is an x intercept CCP represents a certain mean ABP value point of linear regression between subsequent R HANAJIMA below which small vessels begin to collapse. Y UGAWA systolic and diastolic values recorded within 6 CCP should, therefore, be a constant value Department of Neurology, Division of Neuroscience, second intervals of flow velocity (along y axis) Graduate School of Medicine, University of Tokyo, independent of the actual ABP. On the other and arterial pressure (along x axis). 7–3–1 Hongo, Bunkyo-ku, Tokyo 113–8655, Japan hand, this significant correlation can be In fact, the formula proposed by Michel et explained by our equation 5, again indicating al4 is very similar. The only diVerence is that the missing physiological basis of the CCP 1 Abbruzzese G, Buccolieri A, Marchese R, et al. instead of the original waveforms of FV and Intracortical inhibition and facilitation are concept of the authors. ABP, first (fundamental) harmonic compo- abnormal in Huntington’s disease: a paired Thirdly, it seems doubtful that CCP could nents were taken for the same graphical magnetic stimulation study. Neurosci Lett be estimated using pressure and flow values construction—that is: 1997;228:87–90. from ABP ranges clearly above CCP and flow 2 Hanajima R, Ugawa T, Terao Y, et al. Intracorti- CCP2=ABP−A1/F1×FV cal inhibition of the motor cortex is normal in values clearly above zero flow, respectively. As In our paper1 we confirmed empirically chorea. J Neurol Neurosurg Psychiatry 1999;66: long as small vessels do not collapse that both CCP1 and CCP2 produced the 783–6. (ABP>CCP) it is not possible to decide 3 Hanajima R, Ugawa Y, Terao Y, et al. Ipsilateral same values in a group of patients after head cortico-cortical inhibition of the motor cortex whether their actual wall tension is deter- injury, therefore the mathematical considera- in various neurological disorders. J Neurol Sci mined more by transmural pressure or by tion of Diehl (equations 1–5) must contain an 1996;140:109–16. active vasoconstriction. However, the relative error! contribution of both eVects is critical for the First of all we cannot see how equation (1) limit of CCP. from Diehl’s letter can be derived from any of Critical closing pressure: a valid Finally, I would be interested in the authors’ concept? our formulae. Everyone who has tried to plot explanation of negative diastolic flow values as momentary values from ABP pulse waveform seen in Doppler spectra of arteries with a high 1 against momentary values of FV waveform Czosnyka et al recently published a study vascular resistance (peripheral arteries, middle investigating the clinical significance of critical knows that it never plots a straight line (as cerebral artery during strong hypocapnea). In equation (1) implies). In between two closing pressure (CCP) estimates in patients the case of ABPd

Therefore, equation 2 changes to http://jnnp.bmj.com/ Definition of CVR0 as FV/(ABP-CCP) is FV(t) = (ABP(t)−CCP)/CVR (1) FV=(ABP-ICP)/CVR0 (6) completely artificial and lacks a physiological At the time of systolic and diastolic and equation 5 to pressure values (ABPs, ABPd), respectively, it basis. It is rather taken from the geometrical CCP2=ABP(1−CVR1/CVR0)+CVR1/ 1 follows that systolic and diastolic FV (FVs, CVR0×ICP (7) interpretation of figure 1 in . In our material FVd) should be equal to (ABPs−CCP)/CVR Equation 7 explains well the positive corre- equivalent of parameter CVR0 (as defined by and (ABPd−CCP)/CVR, respectively. How- lations found between CCP2 and ABP and Diehl) is 1.007 (SD 031) and CVR1 0.972 ever, it is a well known fact that the vascular between CCP2 and ICP, respectively, with- (SD 0.29), the diVerence between them was resistance valid for the static pressure/flow out assuming a connection between CCP2 not statistically significant. Therefore, the connection (CVR0, concerning mean pres- and Burton’s concept of “critical closing suggestion that the CVR1/CVR0 ratio is 0.5 sures and flows) is diVerent from and is in pressure”.3 is not correct. Real CVR0 should be calcu- on October 1, 2021 by guest. Protected copyright. general much higher than resistances deter- lated as (ABP−ICP)/FV. We fully agree that mining dynamic pressure/flow relations ROLF R DIEHL equation (5) proposed by Diehl is “useless for (CVR1) as in the case of pulsatile pressures.2 Department of Neurology, Krupp Hospital, valid CCP calculation”. We have not used it Therefore, equation 1 cannot be applied to Alfried-Krupp-Straâe, 45117 Essen, Germany and have never suggested anyone could do so. describe dynamic flow. This can best be illus- The second criticism was that our CCP trated using the frequency domain approach 1 Czosnyka M, Smielewski P, Piechnik S, et al. positively correlated with ABP. (ABP=mean pressure; FV=mean flow veloc- Critical closing pressure in cerebrovascular cir- It should not be a surprise. When ABP ity; A1=amplitude of the pulsatile pressure culation. J Neurol Neurosurg Psychiatry 1999; decreases, vasodilatation occurs and arterial 66:606–11. wave; F1=amplitude of the pulsatile flow 2 Milnor WR. Hemodynamics. Baltimore: Wil- wall tension decreases. Therefore presuming wave): liams and Wilkins, 1989. ICP was constant, CCP should decrease. A FV=(ABP−CCP)/CVR0 (2) 3 Burton AC. On the physical equilibrium of the rather weak (though significant) correlation small blood vessels. Am J Physiol 1951;27:319– F1=A1/CVR1 (3) 29. suggests that not all of our patients were Inserting equations 2 and 3 into the pressure reactive or ICP was not always con- frequency domain equation for CCP2 of the stant. authors Czosnyka et al reply: The final issue concerning negative flow CCP2=ABP-A1/F1×FV (4) We thank Diehl very much for the interesting velocity is a trap Diehl has prepared for him- leads to letter provoking some mathematical consid- self. We never suggested that any factor inter- CCP2=ABP−CVR1/CVR0×(ABP−CCP) erations about cerebral haemodynamics. pretable as cerebrovascular resistance (CVR0 =ABP(1−CVR1/CVR0)+CVR1/ We need to emphasise that our primary or CVR1) should be involved in the concept of CVR0×CCP (5) intention1 was to investigate Burton’s hypoth- critical closing pressure. From the definition, Obviously, CCP2 is only in the case of esis in patients with head injury2 that critical closure is a strongly non-linear phenomenon, CVR1=CVR0 equal to CCP.Under the more closing pressure (CCP) may be represented therefore applying linear theory here is very 122 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from risky. How risky—we can see from Diehl’s let- nection is somatotopically segregated, so that 5 Guridi J, Herrero MT, Luquin MR, et al. ter. Cerebrovascular resistance certainly never fibres from the supplementary motor area Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis. Brain increases to infinity, only after death. project to the most medial portion and fibres 1996;119:1717–27. We fully agree with the considerations from the primary and premotor areas termi- 6 Limousin P, Pollak P, HoVmann D, et al. regarding equations (6) and (7). CCP can be nate in the lateral region of the subthalamic Abnormal involuntary movements induced by understood as a combination of ABP and ICP nucleus.10 All this heterogenity may have subthalamic nucleus stimulation in parkinso- nian patients. Mov Disord 1996;11:231–5. with coeYcients describing properties of the pathophysiological relevance, one aspect of 7 Guridi J, Obeso JA. The role of the subthalamic cerebrovascular bed. Whether it simplifies our which could be the findings in the patient nucleus in the origin of hemiballism and knowledge—we personally find it doubtful. reported by Figueiras-Mendez et al.8 How- parkinsonism: new surgical perspectives. Adv Finally, we are truly obliged to Diehl for an ever, before the findings of this case may be Neurol 1997;74:235–47. 8 Figueiras-Mendez R, Marín F, Molina JA, et al. opportunity to have this interesting discus- used to sustain a new hypothesis on the role Subthalamic nucleus stimulation improves sion. of the subthalamic nucleus in the origin of directly levodopa-induced dyskinesias in Par- levodopa induced dyskinesias, there is a cru- kinson’s disease. J Neurol Neurosurg Psychiatry MAREK CZOSNYKA cial issue to resolve—namely, the location of 1999;66:549–50. PIOTR SMIELEWSKI 9 Mitchell IJ, Jackson A, Sambrook MA, et al. The the tip of the stimulation electrodes. STEFAN PIECHNIK role of the subthalamic nucleus in experimental There are several points leading us to chorea. Evidence from 2-deoxiglucose meta- Academic Neurosurgical Unit, Box 167, Addenbrooke’s bolic mapping and horseradish peroxidase Hospital, Cambridge CB2 2QQ, UK question the actual site of action of the elec- trode: (1) Stimulation of the subthalamic tracing studies. Brain 1989;112:1533–48. Correspondence to: Dr Marek Czosnyka 10 Nambu A, Takada M, Inase M, et al. Dual nucleus in Parkinson’s disease has been asso- email [email protected] somatotopical representations in the primate ciated with the production of dyskinesias only subthalamic nucleus: evidence for ordered but relieved by reduction in levodopa intake.6 reversed body-map transformations from the primary motor cortex and the supplementary 1 Czosnyka M, Smielewski P, Piechnik S, et al. Moreover, Benabid et al who pioneered this Critical closing pressure in cerebrovascular cir- motor area. J Neurosci 1996;16:2671–83. culation. J Neurol Neurosurg Psychiatry technique, consider the induction of dyskine- 1999;66:606–12. sias by high frequency stimulation of the sub- 2 Burton AC. On the physical equilibrium of the thalamic nucleus as a good indicator of a very Figueiras-Méndez et al reply: small blood vessels. Am J Physiol 1951;164: positive response. (2) Fibres travelling to the 319–29. We thank Obeso et al for their comments 3 Aaslid R. Cerebral hemodynamics. In: Newell thalamus from the globus pallidum internum regarding our recent report.1 In summary, DW, Aaslid R, eds. Transcranial Doppler. New are placed dorsocaudally to the subthalamic they raised some interesting points which York: Raven Press, 1992:49–55. nucleus and could be blocked by high need further clarification. 4 Michel E, Hillebrand S, von Twickel J, et al. Frequency dependence of cerebrovascular im- frequency stimulation. (3) When the record- Recognition of the electrical activity of the pedance in preterm neonates: a diVerent view ing electrode goes into a region caudally to subthalamic nucleus was based on the follow- on critical closing pressure. J Cereb Blood Flow the subthalamic nucleus in sagittal planes 11 ing criteria: (a) high frequency discharge (25 Metab 1997;17:1127–31. mm or less, neuronal activity is characterised Hz or higher) within the nucleus23;(b) a tonic by action potentials of large amplitudes (regular), phasic (irregular) or a rhythmic pat- High frequency stimulation of the (0.5–1 mV) with low background activity, tern of discharge2;(c) response to voluntary/ tonically firing neurons, and absent sensori- 24 subthalamic nucleus and levodopa passive movements. When rhythmic dis- motor responses (“driving”). All these char- induced dyskinesias in Parkinson’s charges were recorded irregular passive acteristics seemed to be present in the patient manipulations were performed or the patients disease discussed here. Neuronal activity in the asked to moved the limbs irregularly; (d) sensorimotor region of the subthalamic response to tremor activity. Positive cells were Reduction in the neuronal activity of the sub- nucleus is diVerent from the above but on thalamic nucleus leading to diminished exci- so considered based on the correlated activity occasions the distinction may not be easy. with the EMG and the accelerometer re- tation of the globus pallidum internum is Accordingly, it is very important to docu- associated with chorea-ballism in monkeys.1 corded simultaneously. Artificial manual stop- ment in more detail the findings in the case of ping by one experimenter (confirmed by Levodopa induced dyskinesias are currently Figueiras-Mendez .8 Ideally we would like 2 et al visual inspection, silence in the EMG, and thought to share a similar pathophysiology to see the trajectory and length of the diVer- but recent findings also suggest that abnor- stoppage in the oscillating accelerometer) ent recording tracks, the eVects of micros- and/or spontaneous arrest in the tremor mal patterns of neuronal firing in the globus timulation, and the postsurgery MRI with 3 modified the firing frequency and discharge pallidum internum may be as relevant. Data measurements of the location of the tip of the from both parkinsonian monkeys and pattern or rhythmic cells corroborating the electrodes. If, as assumed, the subthalamic tremor nature of the cells; (e) the activity of http://jnnp.bmj.com/ patients with Parkinson’s disease submitted nucleus was indeed correctly targeted in this 45 the cells above the subthalamic nucleus in the to lesion or functional blockade of the sub- patient, the pathophysiology of the basal gan- thalamic nucleus6 are in keeping with such a thalamus and zona incerta with proper glia will need to be revisited. 2 general principle, but the threshold to induce characteristics ;(f) a change in the back- dyskinesias in the parkinsonian state is higher J A OBESO ground basal noise when entering the subtha- than in intact animals.7 The case recently G LINAZASORO lamic nucleus. A higher activity is observed2; described by Figueiras-Mendez 8 is J GURIDI (g) the contrary is observed when leaving the et al E RAMOS extremely interesting as it suggests that func- nucleus. A lower background noise level; (h) Centro de Neurologia y Neurocirugia Funcional, the activity of substantia nigra pars reticulata tional inhibition of the subthalamic nucleus Clinica Quiron, San Sebastian, Spain by high frequency stimulation blockades cells when further lowering the microelec- on October 1, 2021 by guest. Protected copyright. levodopa induced dyskinesias. This is clearly J A OBESO tode. These cells discharge at high frequency M C RODRIGUEZ-OROZ at regular intervals as identified in patients2 at odds with the current pathophsyiological Hospiten, Tenerife, Spain model of the basal ganglia.9 Thus, the finding and primates.5 All these points were fulfilled of Figueiras-Mendez et al 8 rises the intrigu- J GURIDI by the patient reported. ing possibility that dyskinesias depend or are Hospital de Navarra, Pamplona, Spain Considering the questions in the letter by mediated by neuronal firing in a given region Correspondence to: Correspondence to: Professor Obeso et al, we make the following com- of the subthalamic nucleus, which was J A Obeso, 30 Cizur Artea, Cizur Mayor, 31180 ments: (a) Action potentials of large ampli- blocked by high frequency stimulation. Navarra, Spain. tude are easily recognised from the rest of the Measurement of aVerent synaptic activity by recording cells, and are not very common. 1 Hamada I, DeLong MR. Excititoxic acid lesions the technique of 2-deoxylucose (2-DG) of the primate subthalamic nucleus result in The recordings shown in the article have uptake showed an increment in the subtha- transient dyskinesias in the contralateral limbs. amplitudes less than 0.3 mV and could not be lamic nucleus (compatible with increased J Neurophysiol 1992;68:1850–8. considered large amplitude potentials. We inhibition from the globus pallidum exter- 2 Crossman AR. A hypothesis on the pathophysi- start to record activity from 3 mm before ological mechanism that underlie levodopa or num), particularly in the ventromedial tip of dopamine agonist-induced dyskinesia in Par- entering the subthalamic nucleus, traverse the nucleus.9 This contrasts with the findings kinson’s disease: implications for future the length of the subthalamic nucleus, and go in monkeys with chorea induced by pharma- strategies in treatment. Mov Disord 1990;5: further down several mm to encounter 100–8. cological blockade of the globus pallidum 3 Obeso JA, Rodriguez MC, DeLong MR. Basal substantia nigra pars reticulata cells. Changes externum, in which 2-DG uptake was maxi- ganglia pathophysiology. A critical review. Adv in the background activity are clearly recog- mal in the dorsolateral portion of the subtha- Neurol 1997;74:3–18. nised and are higher when entering the lamic nucleus, where the sensorimotor region 4 Bergman H, Wichmann T, DeLong MR. subthalamic nucleus. Enough cells are re- 10 Reversal of experimental parkinsonism by lies. A recent anatomical study also showed lesions of the subthalamic nucleus. Science corded along the tracks experimented so as to that the cortical-subthalamic nucleus con- 1990;249:1436–8. recognise a large amplitude potential. The J Neurol Neurosurg Psychiatry 2000;68:100–126 123 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from low background activity found in our record- Nitric oxide in acute ischaemic stroke wide variety of pharmacological agents that ings is only due to the better signal-to-noise may have favourable eVects on endothelial ratio of the electrodes used. “Good recording The pivotal role of nitric oxide (NO) in NOS as stroke preventive therapy. Rather, it electrodes” depend on many variables such as cerebral ischaemia has been elegantly high- is focused on the possible ways of inhibiting tip size, tip profile, insulation material, lighted in the recent editorial by O’Mahony neuronal NOS and inducible NOS mediated impedance, manufacture, etc.6 The signal-to- and Kendall.1 Although studies of neuropro- nitric oxide release after the event of acute noise ratio of the cells in question has the tective agents have been largely disappoint- stroke. At present, there is no information same ratio as the subthalamic nucleus cell ing, pharmacological manipulation of NO indicating that acute administration of statins shown by Hutchinson et al.2 may represent a novel means of protecting the in animal models of ischaemic stroke is neu- (b) In our report, cells discharged tonically, brain from ischaemic insult. One area not roprotective. Their point about statins and but also other cells fired phasically, well discussed in this editorial is the neuroprotec- endothelial NOS is interesting, but not diVerentiated by a profuse burst activity and tive eVect of 3-hydroxy-3methylglutaryl relevant to neuroprotective therapy in acute identified by statistical means (autocorrela- coenzyme A reductase inhibitors or “statins” stroke. tion and interval histograms). in cerebral ischaemia. Preliminary studies (c) Motor responses and tremorgenic cells have shown that statins modulate brain nitric DENIS O’MAHONY in line with the above mentioned criteria were oxide synthase (NOS) isoform activity in a Clinical Investigation Unit, Queen Elizabeth Hospital, found along the trajectory of the electrode. neuroprotective manner. Data from a murine Edgbaston, Birmingham B15 2TH, UK Unfortunately, this point was not mentioned model of ischaemic stroke demonstrate that in the paper. It would surely have changed the prophylactic statin therapy reduces infarct opinion of Obeso et al. size by about 30%, and improves neurologi- Considering the mentioned patient, a total cal outcome in normocholesterolaemic of eight neurons were recognised as belong- animals.2 In this investigation, statin therapy ing to the subthalamic nucleus in the right directly up regulated endothelial NOS in the BOOK REVIEWS hemisphere, with a mean frequency of 74 Hz brain without altering expression of neuronal (range 38–109 Hz). Four of them responded NOS. Recent findings also suggest that statin to passive and/or voluntary movements and therapy influences the activity of inducible one was considered tremorgenic. The stimu- NOS. Lovastatin has been shown to inhibit lating electrode was placed in laterality 11. cytokine mediated upregulation of inducible Immunological and Inflammatory Disorders Of One track was performed. In the left NOS and production of NO in rat astrocytes . Edited by NEIL hemisphere, two tracks were performed. One and macrophages,3 and this inhibition may the Central Nervous System track was dismissed by the poor responding represent a novel means of suppressing SCOLDING. (Pp264, £45.00). Published by activity of the cells recorded. In the other inflammatory responses that accompany is- Butterworth Heinemann, Oxford, 1999. ISBN track, nine neurons were recorded in the sub- chaemia. Most interestingly, these prelimi- 0-7506-2357-8. thalamic nucleus (always following the above nary findings suggest that statin therapy may mentioned criteria) with a mean of 69 Hz modify the friendly and unfriendly faces of That neuroimmunology has come of age is (range 17–98 Hz). Five cells responded to brain NO in a synergistically neuroprotective demonstrated by the profusion of volumes passive and/or voluntary movements. One of manner. These and other vascular eVects4 of published on the subject in recent years. This them was also positive to tremor. The stimu- statins in cerebral ischaemia are potentially of volume focuses on the central nervous lating electrode was placed in laterality 12. great importance in human neuroprotection system, and aims to satisfy the curiosity of The eVect of the stimulating electrode is and ongoing studies such as the The both the clinician faced with a diagnostic always tested in the surgery before cementing Prospective Study of Pravastatin in the conundrum and the experimental immunolo- it and, only when the symptoms are consid- Elderly at Risk (PROSPER) study5 will help gist inquiring into the clinical relevance of his ered of unquestionable benefit it is left in the clarify their role in human cerebrovascular findings. At first sight it seems improbable chosen place. The final position of the disease. that both of these goals might be achieved in electrodes, assessed by ventriculography, was CARL J VAUGHAN one volume; this book however, succeeds as follows: (a) posteroanterior: 1.5 mm Division of Cardiology, Department of Medicine, Weill admirably in what it sets out to do, as much as behind the mean point of intercommisural Medical College of Cornell University, The New York th a result of its literary style as its content. line, (b) height: 6–6.5 mm below the Presbyterian Hospital, Starr 4, 525 E. 68 Street, New York, New York 10021, USA The intrusive authorial voice fell into disfa- intercommissural line, and (c) lateral: 12 mm vour in literary circles around the turn of the NORMAN DELANTY for the right hemisphere, and 11.5 mm for the century because it was thought that calling http://jnnp.bmj.com/ left hemisphere. Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA attention to the act of narrating might detract ROBERTO FIGUEIRAS-MÉNDEZ from realistic illusion, so reducing the emo- Correspondence to: Dr Carl J Vaughan FERNANDO MARÍN-ZARZA tional intensity of what was being represented. email [email protected] JOSÉ ANTONIO MOLINA It is a device much favoured by postmodern FÉLIX JAVIER JIMÉNEZ-JIMÉNEZ writers, who expose the nuts and bolts of their MIGUEL ORTÍ-PAREJA 1 O’Mahony D, Kendall MJ. Nitic oxide in acute fictional constructs. The intrusive medical CARLOS MAGARIÑOS ischaemic stroke: a target for neuroprotection. MIGUEL ANGEL LÓPEZ-PINO J Neurol Neurosurg Psychiatry 1999;67:1–3. author never dropped out of fashion, although 2 Endres M, Laufs U, Huang Z, et al. Stroke in these days of evidence based prejudice, VICENTE MARTÍNEZ protection by 3-hydroxy-3-methylglutaryl authorial omniscience might be considered on October 1, 2021 by guest. Protected copyright. Correspondence to: Correspondence to: Dr F (HMG)-CoA reductase inhibitors mediated by Jiménez-Jiménez, C/Corregidor, Jose de Pasamonte endothelial nitric oxide synthase. Proc Natl suspect. The authors of this volume are intru- 24 3°D, E 28030 Madrid, Spain Acad Sci 1998;95:8880–5. sive in a guiding conversational manner that 3 Pahan K, Sheikh FG, Namboodiri AMS, et al. makes this book by far the most readable of Lovastatin and phenylacetate inhibit the induc- 1 Figueiras-Méndez R, Marín-Zarza F, Molina tion of nitric oxide synthase and cytokines in the neuroimmunological texts. JA, et al. Subthalamic nucleus stimulation rat primary astrocytes, microglia, and macro- The book opens with a highly accessible improves directly levodopa-induced dyskine- phages. J Clin Invest 1997;100:2671–9. chapter on immune responses in the nervous sias in Parkinson’s disease. J Neurol Neurosurg 4 Delanty N, Vaughan CJ. Vascular eVects of stat- system. There follows a chapter that inte- Psychiatry 1999;66:549–50. ins in stroke. Stroke 1997;28:2315–20. 2 Hutchinson WD, Allan RJ, Opitz H, et al. Neu- 5 Gaw A, Shepherd J, Blauw GL, et al. Pravastatin grates the neurobiology of multiple sclerosis rophysiological identification of the subtha- in the prevention of cerebrovascular disease with contemporary issues of aetiology, cell lamic nucleus in surgery for Parkinson’s and its consequences in the elderly-the PROS- injury, and repair. Next, a chapter on inflam- disease. Ann Neurol 1998;44:622–8. PER design [abstract]. Stroke 1999;30:251A. 3 Benabid AL, Pollak P, Benazzouz A, et al. matory demyelinating diseases examines syn- Grenoble guidelines for deep brain stimula- dromes of isolated demyelination, acute tion. First European Symposium on Stimula- O’Mahony replies: disseminated encephalomyelitis and allied tion in Parkinson’s disease. 1998. 4 Limousin P, Pollak P, Benazzouz A, et al.EVect The comments of Vaughan and Delanty draw conditions, and some of the syndromes of of parkinsonian and symptoms of bilateral sub- attention to the evidence that statin therapy demyelination that are now accepted as part thalamic nucleus stimulation. Lancet 1995;345: up regulates endothelial NOS without aVect- of the range of multiple sclerosis. The 91–5. 5 Magariños-Ascone C, Buño W, García-Aaustt ing neuronal NOS. Their contention is that chapters on demyelinating disease are drawn E. Activity in substantia nigra neurons related statin therapy may be neuroprotective. Stat- to a close by a discussion of existing and to a simple learned movement. Exp Brain Res ins may indeed prevent strokes and reduce experimental therapies for multiple sclerosis. 1992;88:283–91. infarct size when given as prophylactic The book continues with chapters on para- 6 Lemon R, Prochazka AS. In: Smith R, ed. IBRO Handbook series: method in neuroscience.New therapy in at risk persons. However, our edi- neoplastic disorders of the CNS, stiV man York: Wiley, 1985:71–98. torial article was not intended to discuss the syndrome, neurological complications of 124 J Neurol Neurosurg Psychiatry 2000;68:100–126 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from connective tissue disorders, organ specific Neurologic Complications in Organ Stroke and Alzheimer’s Disease. Edited autoimmunity, sarcoidosis, and cerebral vas- Transplant Recipients. Edited by ELCO F M by DIDIER LEYS, FLORENCE PASQUIER, and PHILIP culitis. WIJDICKS (Blue Books of Practical SCHELTENS. (Current Issues in Neuro- Each chapter is an appropriate length and Neurology). (Pp 248, £70.00). Published By degenerative Diseases Volume 9). (Pp 225). well referenced; the wood is always clearly Butterworth Heinemann, Oxford, 1999. Published by Holland Academic Graphics, visible between the trees. This book is ISBN 0 7506 7066 5. The Hague, 1998. ISBN 90-5560-061-9. suYciently readable and small to be recom- mended as holiday reading. Its only drawback Organ transplantation, once medical exotica, Volume nine of the Current Issues in Neurode- is that in making erudition so readily is now almost routine. In the United generative Diseases series examines the inter- available, one risks being outshined yet again Kingdom each year are performed cadaveric play between cerebrovascular disease and by one’s registrar. organ transplants of about 1800 kidneys (in dementia, particularly Alzheimer’s disease. addition to 160 live kidney donors), 700 Two hundred pages of what are essentially 20 JON SUSSMAN livers, and 450 heart/lungs (UK Transplant brief review articles comprise this text, sadly Support Service Authority). The basic surgi- without any illustrations. Ploughing through Alzheimer’s Disease—From Basic cal techniques were established at the begin- the introduction to each chapter there is a ning of the century in canine models. Trans- certain sense of deja vu, although on the Research to Clinical Applications. Edited lation of these experiments to humans positive side each contribution is extremely by HERMANN J GERTZ and THOMAS ARENDT. awaited safe and eVective immunosuppres- well referenced. (Pp315, US$99.00). Published by sion. Until the 1960s, the only forms of The book is divided into five sections cov- Springer-Verlag, Wien, 1998. ISBN immunosuppression were radiation (total ering the historical concepts of vascular and 3-211-83113-4. body or total lymphoid) and non-selective Alzheimer’s dementias, the arguments for a chemical reagents (benzene and toluene). pure vascular dementia, the role of As Alzheimer’s disease becomes of increasing Then the antiproliferative drug Alzheimer’s disease in the genesis of demen- importance to society, basic science research 6-mercaptopurine (6-MP) was introduced, tia after stroke, the contribution of white in this field needs to provide the building shortly followed by a derivative, azathioprine, matter changes on neuroimaging to demen- blocks for both therapeutic interventions and with improved oral bioavailability. Combined tia, and finally a short section examining accurate diagnosis. This publication is a with corticosteroids, these allowed the first practical questions such as the management collection of papers presented at an inter- human solid organ transplants to be per- of stroke in patients with dementia. national Alzheimer’s disease research meet- formed: in 1963 the first lung transplant in Although common conditions in their own right, stroke and Alzheimer’s disease do ing in Leipzig in 1997. This conference aimed Mississippi and liver transplant in Colorado. Then in 1967 Christian Barnard captured the seem to cross paths more often than would to bring together both clinical and basic world’s imagination with the first heart trans- be expected by chance alone, and more often science disciplines and this is reflected in the plant. His technique has been modified than can be explained by the presence of papers selected for this book. There are 31 slightly since, but the increasing success of amyloid angiopathy and recurrent lobar papers included, covering topics from early organ transplantation rests mainly on im- haemorrhages. Perhaps common genetic symptomatology and cognitive features to proved immunosuppression with drugs that factors are responsible and here the APoE immunobiology and theoretical neuronal selectively suppress lymphocytes by inhibit- alleles are discussed. The comprehensive treatment strategies. The contributors to this ing lymphokine generation (cyclosporin A, section on deep white matter lesions seeks to book are some of the most authoritative in tacrolimus), signal transduction (sirolimus, explain the connection further—and con- their field, predominantly based in Europe. leflunomide), or diVerentiation (15- vinces the reader that there is still a lot which Covering all aspects of Alzheimer’s disease deoxyspergualin) pathways. As a result, over is not well understood. It is in this section research from the correct diagnosis to basic the last 10 years in the United Kingdom, the particularly that illustrations are greatly science approaches of treatment is ambitious 1 year survival of grafts has improved from missed. Brief mention is made of other con- for such a compact book (315 pages), and 80% to 90% (kidney), 55% to 75% (liver), ditions which may produce white matter although the editors succeed in collecting an and 70% to 90% (heart/lung). changes and dementia such as CADASIL, interesting series of papers around these Wijdicks estimates that 10% of transplan- cerebral lupus, and the primary antiphos- themes, they make no claims to be compre- tation patients have a significant neurological pholipid syndrome. hensive in their scope. The papers included complication, the three most common being Some typographical errors and mistransla- tions detract a little further from a book range from original research reports to neurotoxicity of immunosuppressive drugs, http://jnnp.bmj.com/ seizures, and failure to awaken. Yet this is the which seems unlikely to appeal to most neu- reviews of the current literature. The review first text devoted to the neurological aspects rologists, although it will no doubt be a papers are generally excellent, concise, clear, of organ transplantation. It is therefore a source of reference to those working in the well referenced, and illustrated—for example, timely subject for another title in the excellent field of cognitive disorders, particularly vas- there are excellent reviews of Alzheimer’s dis- Blue Books Of Practical Neurology series. cular dementias. ease with vascular pathology (Pasquier et al), Twenty authors contribute (one Dutch, one and Lewy body disease (McKeith et al), great Swiss, the rest American) to four chapters on PETER MARTIN updates on neuropathology (Jellinger and the transplant procedures themselves fol- Bancher, Braak et al), and several worthy lowed by 10 chapters on neurological compli-

Healing Stories—Narrative in Psychiatry on October 1, 2021 by guest. Protected copyright. reviews of treatment strategies for cations of transplantation including failure to and Psychotherapy. Edited by GLENN Alzheimer’s disease including NSAIDS awaken, and psychiatric, neuromuscular and ROBERTS AND JEREMY HOLMES. (Pp 226, (Möller), antioxidants, and radical scavengers demyelinating complications. Especially use- £47.50). Published by Oxford University, (Rösler et al). I found the review by Reisburg ful to the neurologist without much experi- et al on ontogenic models in the understand- ence of transplantation are the comprehen- Oxford, 1999 ISBN 0-19-262827-5. ing of the management of Alzheimer’s disease sive chapters on immunosuppressive drugs Evolutionary biologists would probably tell particularly interesting. However, the papers and the opportunistic infections associated us that the enchantment of stories is due to of original research are of more limited inter- with them (most commonly Listeria monocy- togenes, Aspergillus fumigatus, and Cryptococcus survival having been dependent on the est to the general reader. Although, as passing of oral culture from one generation to mentioned, the quality of illustrations is neoformans). The peripheral nerve and plexus injuries associated with transplantation are the next. Information put in narrative form good, there is some variability in the defini- painstakingly described; astonishingly a sig- not only delights, but is easily recalled. tion of abbreviations and occasional lapses nificant ulnar neuropathy occurs in up to Stories also construct meaning by interweav- into other European languages. 40% of kidney transplants. The Cincinnati ing observation, inference, motive, and con- Certainly, I think this book would be of Transplant Tumour Registry has recorded sequence in a fashion that informs future value for investigators interested in the information on 10 813 cancers arising de novo action. Our experience of the world is neuropathology, immunopathology, and mo- in organ allograft recipients worldwide and constructed around such narratives. They lecular biology of Alzheimer’s disease. It here are presented the data in the 300 of these define us as individuals, family members, would make an excellent addition to libraries with CNS involvement. This is one for the professionals, and cultural groups. as a reference text for many researchers of shelves of any neurologist involved in organ This book is a series of essays on varied interests. transplantation. psychotherapy, psychiatry, and also medicine that sees the awareness and use of narrative in CLARE GALTON ALASDAIR COLES clinical practice as a construct that can both J Neurol Neurosurg Psychiatry 2000;68:100–126 125 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.1.100 on 1 January 2000. Downloaded from deliver eVective care as well as act as a concep- Childhood Epilepsies and Brain relevant topics—for example, refractory tual bridge between the diVerent disciplines. Development. Edited by ASTRID NEHLIG, schizophrenia or the diYcult panic patient. One of the great pleasures of being a doctor JACQUES MOTTE, SOLOMON L MOSHE, and The emphasis is very much on pharmacologi- has always been listening to patient’s stories, cal management. PERRINE PLOUIN. (Pp 311, £59.00). Published but the editors of this book fear that this essen- The second half of the book is more of a by John Libbey, London, 1999. ISBN 0– tial art can be overtaken by dull scientific mixed bag, both in terms of the areas covered pragmatism. Roberts, in the most outstanding 86196–578–7. and the quality of the chapters. Two excellent chapter, writes a lucid and well reasoned chapters covering all aspects of the assessment account of the need to search for and maintain Childhood Epilepsies and Brain Development is and management of anorexia nervosa and narrative meaning in treating psychosis. This the fruit of a symposium held in 1997 to try chronic fatigue are followed by a thorough avoids the dehumanising eVect to both pa- and bridge the chasm between those working review of the pharmacological management of tients and professionals of identifying individu- in the clinic or at the bedside and those in the substance misuse. Then come two weak als by their illness as in schizophrenics. Every laboratory. Both groups must collaborate and chapters on behavioural disturbances in old psychiatric library should buy this book for this communicate to improve the management of age and the violent patient in the community. paper alone, which should be required reading children (and older patients) with epilepsy. This last chapter will be of particular interest for all psychiatric trainees. The book is essentially a collection of to community psychiatrists but is not one that The rest of this book is of variable quality. monographs of heterogeneous content and I would recommend because some aspects of There is a rather prosaic essay on gender style and the result, perhaps not surprisingly, the practical management of violence are issues, and there is repetition in various chap- is that some of the component parts are bet- missing—for example, a documented risk- ters concerning attachment theory, a useful ter than the sum. The clinically oriented sec- benefit analysis, good failsafe communication, but over worked paradigm. However, there tion will clearly be of particular interest to or deciding when to detain. One of the last are two very fine accounts of narrative in psy- those who treat children and their families. chapters is a very good account of the chotherapy by James Phillips and Jeremy The chapters on infantile spasms and management of hyperactivity in childhood, Holmes. Lennox-Gastaut syndrome are informative with good practical advice on the use of meth- and provide some new but speculative DUNCAN MCLEAN ylphenidate. insights into the pathogenesis of spasms. Apart from the chapters on chronic fatigue However, it was surprising that severe myo- and the treatment of tardive dyskinesia there Women and Epilepsy.ByTIM BETTS and clonic epilepsy of infancy did not merit a spe- is little in this book which is of immediate PAM CRAWFORD. (Pp 84, gratis from the cific chapter in view of the unique electro- interest to neurologists. However general British Epilepsy Association). Published by clinical evolution and natural history of this psychiatrists wishing to improve their pre- Martin Dunitz, London, 1998. ISBN syndrome. The crucial issue of the cognitive scribing skills will find this book useful. and behavioural sequelae of early and fre- SIMON FLEMINGER 1-85317-680-X. quent seizures on the immature brain, which is probably of most concern to both clinicians In a small accessible and easily digestible and families, is succinctly addressed in two volume, the authors address a clinically impor- The Bethlem and Maudsley NHS Trust chapters—although a clear and consistent tant field. Faced with slim evidence on which Prescribing Guidelines 1999. Edited by cause and eVect relation remains to be estab- to base clinical recommendations, they ac- DAVID TAYLOR, DENISE MCCONNELL, HARRY lished. The chapters covering basic neuro- knowledge that their very useful management MCCONNELL, KATHRYN ABEL, and ROBERT physiology, neuropharmacology, and neu- advice “has often had to be based on practical KERWIN. (Pp190, £14.95). Published by ropathology, are erudite and fascinating but clinical experience rather than the results of at times are barely comprehensible. Further Martin Dunitz, London, 1999. ISBN clinical trials or formal research . . .” This dis- work is needed, including answering the fun- 1-85317-835-7. claimer seems to have allowed them to mix damental question—why does the first sei- evidence and opinion, limit references, and The Maudsley prescribing guidelines are zure occur—before the clinician and basic confuse the reader regarding the level of produced each year for a local readership, but scientist are able to talk the same language— evidence. A pity, as the authors, with special this, the fifth edition, is the first to go public. for the benefit of the patient with epilepsy. expertise in this important area, have made a The authors and principal contributors, a The concept of Childhood Epilepsies and good start in putting together diVerent aspects mixture of pharmacists and psychiatrists with Brain Development is innovative and com- of the care of the woman with epilepsy in a an interest and background in clinical mendable and although some of the mono- practical book that is of direct interest and rel- psychopharmacology, are to be compli- graphs are interesting and informative, the evance to neurologists, obstetricians, general mented on producing a guide of manageable http://jnnp.bmj.com/ overall impression is that the individual parts practitioners, nurse specialists, and trainees. size and ready accessibility. (the chapters) are better than the whole (the Moving on from the general to the particu- The book is divided into sections dealing book). The lack of an index is a strange omis- lar, the text, although expansive in parts, with the treatment of broad groups of clinical sion, perhaps reflecting a prolonged editorial glosses over some important points. Exam- disorders—for example, psychosis—special atypical absence, and although this militates ples include ( ) which oral vitamin K prepa- patient populations—for example, elderly a against it becoming a well thumbed reference rations are considered safe in pregnancy people, with further sections on the manage- text, the book is an erudite addition to the (phytomenadione), ( )diVerential eYcacy of ment of emergencies and the adverse eVects of b mossy fibre-like sprouting of the epileptologi- various antiepileptic drugs in diVerent syn- psychotropic drugs. Much of the information cal literature. dromes versus side eVect and teratogenicity is laid out in tabular form. It could become an on October 1, 2021 by guest. Protected copyright. profile, (c) more information on the limita- RICHARD E APPLETON indispensable resource for a busy on call sen- tion of available evidence to support the ior house oYcer (the dimensions would fit statement “no monotherapy human abnor- comfortably into the pocket of a clinical white mality reported” with certain new antiepilep- DiYcult Clinical Problems in coat, were they still to be worn) but more sen- tic drugs in pregnancy, (d) the need to Psychiatry. Edited by MALCOLM LADER and ior clinicians will find plenty of use for it in the consider osteoporosis prevention well before DIETER NABER. (Pp 246, £39.95). Published clinic. It does not aim at great erudition, but the menopause (and not only with enzyme by Martin Dunitz, London, 1999. ISBN provides a useful list of references. inducing drugs such as valproate has also 1-85317-550-1. There are a few cavils. The section on been implicated), (e) discussion of differences treatment of anxiety is skimpy (one and a half (and available formulations) between syn- DiYcult clinical problems in psychiatry come pages) compared with say the treatment of thetic and natural progesterone, (f) stages of in many forms. Diagnosis often causes aVective illness (22 pages) or psychosis (16 pregnancy when various malformations are diYculty, particularly in cases which demand pages). The brevity is only partly explained detectable on scanning, and (g) time to some assessment of the role of physical illness by the undeveloped state of that particular closure of the neural tube (diVerent from the in symptom formation. Perhaps for most psy- area of psychopharmacology. Sections on 21-56 days they quote as the “most sensitive chiatrists practising in community settings contraindications to and indications for lum- time of the fetus to the induction of risk assessment comes high on their list of bar puncture and indications for EEG seem malformations by exogenous agents.”). concerns. to have been displaced from some other Despite these comments (made with an eye Unsurprisingly, given the psychopharma- primer for busy junior doctors. There is no on the next edition) I would recommend this cological expertise of the editors, this book is index. book to all those involved in the care of particularly interested in treatment resist- These quibbles apart, prescribing guide- women with epilepsy. ance. The first 6 chapters give excellent lines can be wholeheartedly recommended. LINA NASHEF reviews of the management of clinically BRIAN TOONE