J Neurol Neurosurg Psychiatry - BMJ

LETTERS

Emotion processing in theminimally conscious stateAs a newly described condition distinct fromcoma or the vegetative state, minimallyconscious state (MCS) is characterised by athreshold level of consciousness, and diag-nostic criteria have recently been proposed.1

In MCS, cognitively mediated behaviour occursinconsistently, but is reproducible or sustainedenough to be differentiated from reflexivebehaviour. It is clinically essential to distin-guish this condition from persistent vegetativestate (PVS), due to a potentially more favour-able outcome.1 So far, whether patients inMCS can process emotion is unknown.

Cortical processing has been described inPVS using auditory and visual functionalparadigms with positron emission tomogra-phy.2 3 However, to date hardly any func-tional imaging studies are available inpatients in MCS.4 We used fMRI to assessbrain activity induced by an emotionalstimulus in a patient in MCS.

A 17 year old man was riding his bicyclewhen he was hit by a train. The accidentresulted in head trauma and immediatecoma, progressing to MCS over the courseof 4 months, when he was admitted to ourinstitution. This research protocol wasapproved by the Institutional EthicsCommittee. At the time of the fMRI study,5 months after the accident, the patientlocalised noxious stimuli, had spontaneouseye opening, detectable sleep/wake cycles,sustained visual fixation, and contingentsmiling, thus meeting criteria for MCS. Astructural MRI study showed mild corticalatrophy and dilated ventricles. Auditoryevoked potentials showed decreased conduc-tion velocities at brainstem level. The patientincreased his level of awareness 2.5 monthsafter the functional study was conducted.Auditory evoked potentials after recoverywere within normal range, while MRIshowed much less ventricle dilatation. Sixmonths after recovering full consciousness,he was able to chat normally and feedhimself. Currently we are retesting thepatient with the same paradigm.

Non-familiar voice v silence and mother’svoice v non-familiar voice recognition weretested in an fMRI block design with 30 sec-onds per epoch. The patient listened to his

mother reading a story, followed 30 secondslater by an age matched voice reading thesame story, for 30 seconds with silence epochsin between. Blood oxygen level dependentimages were acquired using a T2 weighted gra-dient echo planar sequence on a GeneralElectric Signa CVI, 1.5T system with real timeimage processing of multislice and multi-phase images during patient stimulation andrest periods. The Medx 3.4 Sensor System wasused to carry out fMRI post-processing, includ-ing motion correction and Gaussian smooth-ing. An uncorrected significance thresholdof P,0.001 was used because amygdalaand insula activation was expected, owingto emotional voice processing. Activated clus-ters were localised following co-registrationwith an anatomical T1-IR volume.

Subtraction of the phrases read by the agematched voice from silence was the controlexperiment, showing a significant focus ofactivation in the transverse and superiortemporal gyri, which spread to the planumtemporale; more anterior activation wasfound in the superior (right) and inferior(left) insula (fig 1A). The subtraction of themother’s phrases from the age matched voicedisclosed a strong activation of the amygdalaand insula spreading to the inferior frontalgyrus; there was also weaker activation of thetransverse temporal gyrus, temporal opercu-lum, and planum temporale (fig 1B,C).Activation was lower on the right hemispherein both comparisons, non-familiar voice vsilence and familiar voice v non-familiar.

To the best of our knowledge, our resultsprovide for the first time anatomical evidencefor the response of an MCS patient to afamiliar voice, in which both amygdala andinsula appear to play a major role.

The activation pattern of the controlexperiment agrees with previous studies.5

Our results showed that the mother’s voiceactivates the extended amygdala, an emo-tionally related structure, and a directlyconnected area such as the insula, perhapsacting jointly as limbic integration cortex.Although residual cerebral activity wasunequivocal in our case, representing frag-mentary cognitive processing, it should notbe assumed that it depicts a fully integratedsystem required for normal levels of aware-ness; however, our findings highlight thelegal and ethical implications of carelessbedside chatter. Whether functional imagingrepresents a reliable method to evaluateneural processing in MCS patients, in whom

cognitive output is extremely difficult toassess, remains to be seen.

T Bekinschtein, J Niklison, L Sigman, F ManesCognitive Neurology Section, Institute for Neurological

Research (FLENI), Buenos Aires, Argentina

R Leiguarda, F ManesDepartment of Neurology, Institute for Neurological

Research (FLENI), Buenos Aires, Argentina

J ArmonyDepartment of Experimental Psychology, McGill

University, Montreal, Canada

A OwenMRC-CBU, Cambridge, UK

S CarpintieroFunctional Neuroimaging Laboratory, Institute for

Neurological Research (FLENI), Buenos Aires,Argentina

L Olmos, F ManesRehabilitation Institute (FLENI), Buenos Aires,

Argentina

Correspondence to: Dr F Manes, Cognitive NeurologySection, Institute for Neurological Research (FLENI),

Montaneses 2325 (C1428AQK). Buenos Aires,Argentina; [email protected]

doi: 10.1136/jnnp.2003.034876

References

1 Giacino JT, Ashwal S, Childs N, et al. Theminimally conscious state: definition anddiagnostic criteria. Neurology 2002;58:349–53.

2 de Jong BM, Willemsen AT, Paans AM. Regionalcerebral blood flow changes related to affectivespeech presentation in persistent vegetative state.Clin Neurol Neurosurg 1997;99:213–16.

3 Menon DK, Owen AM, Williams EJ, et al. Corticalprocessing in persistent vegetative state. WolfsonBrain Imaging Centre Team. Lancet1998;352:200.

4 Boly M, Faymonville ME, Peigneux P, et al.Auditory processing in severely brain injuredpatients: differences between the minimallyconscious state and the persistent vegetative state.Arch Neurol 2004;61:233–8.

5 Laureys S, Faymonville ME, Degueldre C, et al.Auditory processing in the vegetative state. Brain2000;123:1589–601.

Figure 1 Brain areas of activation produced by non-familiar voice subtracted from silence in coronal view (control experiment, A). Brain areas ofactivation produced by mother’s voice subtracted from non-familiar voice in coronal view (B), and in axial view (C)

Received 22 December 2003Revised 12 February 2004

Accepted 13 February 2004

This work was supported by the Institute forNeurological Research, FLENI.

Competing interests: none declared

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Neurosyphilis presenting withgummatous oculomotor nerve palsyAlthough epidemiological studies suggestthat the incidence of primary syphilis isrising,1 neurosyphilis remains an uncommonmanifestation of Treponema pallidum infec-tion. In addition, the MRI appearances of thistreatable neurological condition are not wellknown. Many patients with neurosyphilis areasymptomatic, but manifestations includesubacute basal meningitis, a meningovascu-lar syndrome of small deep cerebral andcranial nerve infarctions, chronic gummatousinflammation with focal intracranial masslesions, chronic comportmental dementia ofgeneral paresis, and chronic sensory-ataxicmyelopathy of tabes dorsalis. We report acase in which a meningeal form of neuro-syphilis presented with rapid evolution of apupil-involving oculomotor nerve palsy tohighlight the clinical, CSF, and MRI featuresand good response to treatment.

Case reportThe patient was a 54 year old right handedhomosexual man with a history of syphilis ofunknown stage, treated with penicillin 25years previously. He was well until 6 weeksprior to evaluation when he sustained minorhead trauma in an automobile accident,followed by intermittent headaches, fatigue,photophobia, and anorexia. Four days beforeadmission he developed worsening and per-sistent drooping of the right eyelid anddouble vision. On examination, his mentalstatus was remarkable only for psychomotorslowing. The right pupil was round butenlarged at 6 mm and sluggishly constrictedto 5 mm with direct and consensual lightstimulation as well as near vision. The leftpupil was round and 4 mm and constrictedbriskly to 2 mm to light. The right eye showedmoderate ptosis of the upper lid, and theglobe was deviated laterally in primary gazewith markedly impaired adduction and ele-vation. In the left eye, ptosis was absent andocular motility was normal. Other cranialnerve, sensory, motor, and reflex functionsand gait were normal with the exception of aslight decrease in vibration and positionsense in the feet. There were no signs ofmeningeal irritation. Head computed tomo-graphy (CT) and CT angiography revealedneither blood in the subarachnoid space norevidence of intracranial aneurysm. MRI ofthe head (fig 1) showed a spheroid contrast-enhancing lesion at the root of the rightoculomotor nerve, which extended towardsthe cavernous sinus. Incidentally noted wereright cerebellar and right frontal develop-mental venous anomalies. CSF examinationrevealed normal opening pressure at lumbarpuncture, 344 white blood cells (WBCs) (95%lymphocytes), 14 red blood cells (RBCs),protein of 167 mg%, and glucose of 39mg%. CSF Venereal Disease ResearchLaboratory test (VDRL) was positive at 1:8whereas serum Rapid Plasma Reagin (RPR)was positive at 1:64. HIV testing was nega-tive. Treatment with intravenous penicillin G(4 million Units every 6 hours) was adminis-tered for 2 weeks. By treatment day 4, theadduction and elevation of the right eyewere improving. At 1 month follow up, mildfatigue persisted. There was trace right ptosis.Elevation and adduction of the right eye hadimproved to nearly normal, but the pupilremained 6 mm and sluggishly responsive tolight. Repeat CSF examination showed seven

WBCs (97% lymphocytes), protein of 86mg%, and glucose of 71 mg%. CSF VDRLand serum RPR titres were unchanged. At 6months, no additional improvement in oculo-motor nerve functions was seen but fatiguehad subsided. Repeat MRI 7 months afterhospital admission showed complete resolu-tion of the oculomotor nerve abnormality.

DiscussionNeurosyphilis is known to cause oculomotornerve palsies either in the meningovascularphase, due to small vessel vasculitis withresultant nerve infarction,2 or in granuloma-tous basal meningitis, due to inflammation ofthe nerve or its investiture; however, theliterature on syphilitic mass lesions aroundthe oculomotor nerve is sparse. Vogl et al3

reported a case of oculomotor nerve palsyassociated with MR findings similar to oursthat also resolved with penicillin treatment.Standaert et al4 described an enhancingpenicillin-responsive lesion based in theinterpeduncular cistern that compressed theventral midbrain. The oculomotor nervelesion in our patient was isointense toadjacent brain on T1 and T2 MR sequences,with brisk enhancement after intravenousinjection of gadolinium contrast. We believethe lesion was a manifestation of meningealsyphilis in the form of an oculomotor nervegumma. A gumma is a focally accentuated,exuberant granulomatous response of themeninges, typically with sparse treponemalorganisms. Nonetheless, treatment of the under-lying infection quiets the inflammatory processand can, as in our patient, lead to significantreversal of neurological deficit. We add our

case to the growing literature on MR correlatesof neurosyphilis and encourage a search forneurosyphilis when an unexplained masslesion is present in the basal subarachnoidspace. Neurosyphilis, albeit rare, still deservesinclusion among eminently treatable causes ofa rapidly developing oculomotor nerve palsy.

W W Seeley, N VennaUCSF Memory and Aging Center, PO Box 1207, San

Francisco, CA 94143-1207, USA

Correspondence to: W W Seeley, UCSF Memory andAging Center, PO Box 1207, San Francisco, CA

94143-1207, USA; [email protected]

doi: 10.1136/jnnp.2003.025932

References

1 Stephenson J. Syphilis outbreak sparks concerns.JAMA 2003;289(8):974.

2 Holmes MD, Brant-Zawakzki MN, Simon RP.Clinical features of meningovascular syphilis.Neurology 1984;34:553–6.

3 Vogl T, Dresel S, Lochmuller H, et al. Third cranialnerve palsy caused by gummatous neurosyphilis:MR findings. Am J Neuroradiol1993;14(6):1329–31.

4 Standaert DG, Galetta SL, Atlas SW. Meningo-vascular syphilis with a gumma of the midbrain.J Clin Neuroophthalmol 1991;11(3):139–43.

High dose cyclophosphamide forsevere refractory myasthenia gravisMyasthenia gravis (MG) exemplifies auto-immune disease. Most patients require immuno-modulating treatment, including steroids,chemotherapy, or intravenous immunoglo-bulin (Ig), in addition to anticholinesterase

Figure 1 Head MRI showing the 8 mm (antero-posterior) 66 mm (left to right) 66 mm (rostro-caudal) tapering spheroid lesion at the base of the right midbrain, tracing the course of theoculomotor nerve forward into the cavernous sinus (panels A–F). The lesion is isointense to adjacentbrain on T1 and T2 sequences (panels A and B) and enhances on a T1 sequence after gadoliniumcontrast (panel C). Pre-treatment (D–F) and post-treatment (G–I) coronal images demonstratecomplete resolution at 7 months.

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treatment. Drachman et al1 published thebeneficial effects of high dose cyclophosph-amide in three patients with severe refractorymyasthenia. We recount our experience ofthree myasthenic patients treated in a similarway.

Materials and methodsAll patients participated in studies approvedby the Drexel University College of Medicineand signed informed consent. These threepatients with severe (class IVb) refractoryMG includes all patients treated. Pati-ents received cyclophosphamide 50 mg/kg(adjusted ideal body weight)/day over fourconsecutive days. Patients received antibac-terial, antiviral, and antifungal prophylaxis.Haemorrhagic cystitis prophylaxis includedMesna and forced diuresis. Packed red cellsand platelets were transfused to maintainhaemoglobin >8.5 g/dL and platelets >10 6109/L, respectively. Patients received filgras-tim (G-CSF) (5 mg/kg/day) starting day 10until their absolute neutrophil count (ANC)reached 10 6109/L for two consecutive days.

ResultsPatient 1 was diagnosed with seronegativeMG at 30 years of age by a positive tensilontest and a decremental response on repetitivestimulation. Initial treatment included pyr-idostigine and plasmapheresis, but worseningsymptoms prompted thymectomies at 12 and18 months later. Her thymic pathologyrevealed thymic hyperplasia. Additionaltreatment with only transient responsesincluded low dose oral cyclophosphamide,intravenous Ig, azathioprine, methylpredni-solone, and continued pyridostigine withplasmapheresis. She required 27 intubationsbetween initial diagnosis and immunoabla-tive treatment at 41 years of age.

Patient 2, previously reported, sufferedfrom both seronegative MG and chronicinflammatory demyelinating polyneuropathy(CIDP).2 He presented at 47 years of age withfluctuating double vision, ptosis, dysphagia,arm weakness, and breathing difficulties. Test-ing revealed a decremental response on repe-titive stimulation. Pyridostigine was initiated.Thymectomy revealed a 75 g lipoma. HisMG resulted in two intubations. After

thymectomy, to control symptoms, predni-sone (25–40 mg daily) was required. At 54years of age, CIDP was diagnosed. Despitesteroids (plasmapheresis, intravenous Ig, aza-thioprine, and pyridostigmine) he continuedwith symptoms of double vision, dyspho-nia, and dysphasia with a continued decre-mental response to repetitive stimulation.At 56 years of age, he underwent high dosecyclophosphamide without stem cell rescue.

Patient 3 was diagnosed with antibodypositive MG at 12 years of age, initiallytreated with pyridostigine. She received herfirst thymectomy at age 18 years and conti-nued on pyridostigine and occasional steroids.By 36 years of age, she was steroid depen-dent. Between ages 38 and 41 years sherequired 11 intubations and only transi-ently responded to intravenous Ig andplasmapheresis. A second thymectomy wasperformed at age 39 and cyclosporine (CsA)was initiated. She continued on prednisone25 mg qod, scheduled intravenous Ig every3–4 weeks, and intermittent plasmapheresis.The CsA and Cellcept were maintained butpoorly tolerated. At 41 years of age, sheunderwent high dose cyclophosphamide with-out stem cell rescue.

Treatment coursePatient 1 had 13 days of neutropenia,required three units of packed red cells andthree platelet transfusions. Patient 2 had 9days of neutropenia, required two units ofpacked red cells, and three platelet transfu-sions. Patient 3 had 11 days of neutropenia,required five units of packed red cells, andtwo platelet transfusions. Patients 1 and 3experienced MG flares requiring intravenousIg and plasmapheresis, but neither requiredintubation.

Neurological follow upPatient 1, intubated 27 times before treat-ment, required a single intubation during 48months of follow up. To control less severeexacerbations, during the first 40 monthsafter immunoablative treatment, oral cyclo-phosphamide was necessary. She continuesscheduled plasmapheresis and pyridostigmine.No other immunomodulatory medicationsare prescribed.

Patient 2 had myasthenic symptoms ofdysphagia and diplopia. Seven months aftertreatment pyridostigmine was stopped andafter 12 months prednisone was stopped.Twenty five months after treatment, his MGis in full remission.

Patient 3 experienced five flares at 1, 6, 11,19, and 30 weeks following treatment. Theexacerbations at 1, 6, and 11 weeks requiredintravenous Ig and steroids; exacerbations at1, 19, and 30 weeks required plasmapheresis.Her last exacerbation necessitated intubation.Between exacerbations her functional abilityconsistently improved. She stopped steroidsat 50 weeks. At 52 weeks, a slow pyridosti-gine taper began. Her serum AChr levels didnot correlate with disease activity during thefollow up periods.

DiscussionThe patients discussed have all suffered fromsevere refractory MG, which requires multi-ple intubations. All underwent thymectomy:patients 1 and 3 repeat thymectomies. Patient2 had an early and sustained response totreatment. Patients 1 and 3 had multipleexacerbations. As this treatment targets IgGproduction, exacerbations following treatmentare expected. Patient 1, who required 27 intu-bations before treatment and only once since,and who has in the past 6 months stoppedoral cyclophosphamide, may yet to enjoy themaximum benefit of this treatment. Patient3, one year after treatment, has an improvingactivity level. The intervals between exacer-bations are increasing: 5, 8, and 11 weeks.It is 26 weeks since her last exacerbation.

Recently, Drachman et al1 published asingle institution case series of three patientswith refractory MG who were also treatedwith high dose cyclophosphamide. In thisseries, one patient had AChR antibodynegative MuSK antibody positive myasthe-nia. Their mean disease duration was 10.3(range: 3–15) years; one required intubationand median follow up was 24 (range: 7–40)months. In comparison, in the three patientsdescribed here, two had antibody negativemyasthenia and the mean disease durationwas 16.3 (range: 9–29) years. All requiredmultiple intubations: 27, 2, and 11, and ourmedian follow up is 25 (range: 13–48)months. During follow up, patient 3’s serumAChr levels remained detectable and did notcorrelate with her clinical course. Drachmanet al reported a decline in antibody levels intheir patients treated in a similar way,although AChr antibody titres and MuSKantibodies persisted in their patients evenafter 2 years.1 This suggests that long termremissions in MG may be possible evenwithout achieving complete immunoabla-tion. High dose cyclophosphamide has thepotential to significantly reduce symptomsand increase life quality among people withMG refractory compared to conventionaltreatment. Long term follow up is necessaryto evaluate the duration effect and time tomaximum benefit. High dose cyclophosph-amide treatment warrants further study as atreatment for severe refractory MG.

D E GladstoneStony Brook University, Health Sciences Center,

Division of Oncology, New York, USA

T H Brannagan IIIWeill Medical College of Cornell University, New

York, USA

R J Schwartzman, A A Prestrud, I BrodskyDrexelUniversityCollege ofMedicine, Philadelphia, USA

Table 1 Patient characteristics before high dose cyclophosphamide treatment

Age/sex Patient 1 41/female Patient 2 56/male Patient 3 41/female

Duration of MG (y) 11 9 29MG severity class IVb IVb IVbAChr antibody Undetectable Undetectable DetectablePrevious treatmentPyridostigine X X XThymectomy(ies) 2 1 2iv Ig (no ofinfusions)

1 1 62

Prednisone 10–100 mg qd, duration 3years

40–100 mg qd,duration 7 years

10–60 mg qd,duration 4 years

Plasmapheresis(no. of procedures)

217 14 16

Azathioprine 50 mg/d, duration 7 monthslimited by nausea/vomiting

200 mg qd, duration 2months limited bynausea/vomiting

50–150 mg qd,duration 15 months

Oralcyclophosphamide

100 mg qd, 28 months

Cyclosporine 50–125 mg bid,duration 39 months

Cellcept 250–500 mg qd,duration 7 months

MG, myasthenia gravis; iv, intravenous; Ig, immunoglobulin; qd, four times daily; bid, twice daily


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Correspondence to: Dr D E Gladstone, Stony BrookUniversity, Health Sciences Center, Division of

Oncology, T17-080, Stony Brook, NY 11794, USA;[email protected]

doi: 10.1136/jnnp.2003.019232

References

1 Drachman DB, Jones RJ, Brodsky RA. Treatmentof refractory myasthenia: ‘‘rebooting’’ with high-dose cyclophosphamide. Ann Neuro2003;53(1):29–34.

2 Brannagan TH III, Pradhan A, Heiman-Patterson T, et al. High-dose cyclophosphamidewithout stem-cell rescue for refractory CIDP.Neurology 2002;58(12):1856–8.

Acute head drop after cervicalhyperflexion injuryHead drop is familiar to neurologists, but notwidely appreciated by neurosurgeons. Thereare multiple causes of this condition1 inwhich the patient is unable to hold theirhead up because of weakness of the neckextensor musculature. It predominantly resultsfrom primary muscle pathologies in the neckextensor muscles, with occasional evidencesupporting a neurogenic aetiology.1 2 I des-cribe three patients in whom acute head dropclosely followed cervical hyperflexion injury,and suggest that the cause is bilateral tractionneurapraxia of one or more cervical dorsal rami.

Patient A was an 84 year old man whoenjoyed excellent health prior to fallingbackwards, striking his occiput on a walland sustaining forced flexion of the cervicalspine. He complained of posterior cervicalpain but, when seen in casualty for closure ofan occipital laceration, was found to beneurologically intact. Cervical x rays showedonly degenerative disease in the mid-lowercervical spine and loss of lordosis. Over 2weeks the pain in his neck resolved, but hebecame aware of a difficulty holding his headup as the day progressed and, later, of achingin his neck extensor muscles. He was referredto neurosurgery as a possible case of delayedinstability. Cervical x rays demonstrated 5˚offorward angulation at C4/C5, which did notchange with neck flexion, but were otherwiseunchanged. He remained neurologicallyintact but, fearing progression of the angula-tion and development of neural injury,posterior segmental fixation at C4/5 with aHartshill rectangle and sublaminar wiringwas advised. Surgery was remarkable only forthe absence of significant ligamentous injuryor abnormal mobility. Unfortunately, hishead ptosis recurred after 2 months. x Raysshowed that the sublaminar wires at C5 had‘‘cheese-wired’’ through the bone and allowedrecurrence of angulation. He remainedneurologically intact. After some discussion,he submitted to extended fixation fromC3–C7, producing good alignment, albeitwith restricted neck movements. However,he had ongoing problems with neck painbecause of prominence of the metalworkdue to profound atrophy of the paraspinalmuscles. Three months later, he againdeveloped head drop because of ‘‘cheese-wiring’’, and the Hartshill rectangle waseroding through the skin, necessitating athird procedure to remove it. At this stage,a muscle biopsy was performed showingend-stage atrophy and fibrosis although nocomment could be made as to aetiology. Thepatient declined further investigation or sur-gery and was managed in a Philadelphia collarin the long term. Despite all the above, the

malalignment at C4/5 never progressed, nordid any neurological deficits develop.

Patient B was a fit 72 year old man whosustained a flexion/extension whiplash injuryduring a road traffic accident (RTA). Incasualty, he had minor neck pain but wasneurologically intact and had cervical x raysshowing only minor degenerative changesand loss of lordosis. He was managed withanalgesics and a rigid collar. Ten days later hereturned to casualty complaining of aching inhis neck and progressive difficulty in holdingup his head throughout the day. Neurologicalexamination remained normal. Cervical x raysshowed angulation into 7˚of flexion at C5/6,but were otherwise unchanged. He wasreferred to neurosurgery and at review wasstrikingly reminiscent of patient A. He had tohold his chin up with a hand to look ahead,had pain in the back of his neck, whichdeveloped over the day unless he used hiscollar, and was neurologically normal,including in the cervical dermatomes.Magnetic resonance imaging (MRI) of hisneck revealed normal soft tissue anatomy. Aneurological opinion confirmed the normalexamination, other than head ptosis. Therewas no evidence of inflammatory, auto-immune, or endocrine disease clinically orbiochemically, the Tensilon test was negative,and serum creatine kinase was normal. Therewere no features of Parkinson’s diseaseor amyotrophic lateral sclerosis (ALS).Electroneuromyography (EMG) studies ofthe neck muscles performed 3 weeks afterinjury were normal in the ventral muscles,but there were typical features of acutepartial denervation in the neck extensorsbilaterally, particularly in a band in the mid-to-low cervical spine with more normalEMGs above and below this. However,electrophysiological examination of the limbswas abnormal also and consistent with anasymptomatic peripheral neuropathy. Thepatient declined muscle or nerve biopsy.

In view of patient A’s course and theevidence in patient B of acute denervationthat might recover, patient B was managedexpectantly. Physiotherapy was used tomaintain range of neck movement andencourage use of the neck extensor muscles.He was given a Philadelphia collar, whichwas worn by day once he became aware ofhead ptosis. With this regime he recovered tonormal over 4 months, including recovery ofthe spinal alignment at C5/6, and thePhiladelphia collar was withdrawn. Therehas been no recurrence of head ptosis.

Patient C, a 54 year old man, was similar topatient B. He suffered a whiplash injury in anRTA and developed head ptosis and angula-tion at C5/6 on cervical x rays 2 weeks later.Investigation and management mirroredpatient B. He also had focal abnormality ofhis neck extensor muscle EMG, which sug-gests partial denervation, but otherwise wasnormal clinically, biochemically, and electro-physiologically. We did not suggest muscle ornerve biopsy as it was clear he would bemanaged conservatively. With physiotherapyand external bracing, patient C made a com-plete recovery in 2 months, including recov-ery of spinal alignment at C5/6. There was norecurrence of head ptosis at last contact.

Although there are reports of head drop inconditions predominantly affecting neuralrather than muscular elements,3 Umapathiet al1 cite Braun et al,4 who treat refractorytorticollis by section of multiple cervicaldorsal rami without generating significantfunctional deficits, as evidence that focal

denervation of neck extensor muscles isunlikely to cause head ptosis. This surgicaldenervation, however, is unilateral and thedenervated muscles are also likely to begrossly abnormal because of secondarychanges resulting from the underlying con-dition. The cat neck extensor muscle biventercervicis (analogous to human semispinaliscapitis) has tendinous inscriptions definingserially arranged compartments, each receiv-ing segmental innervation from a cervicaldorsal ramus. The muscle only generates usefultension if all compartments are co-stimulated;unstimulated compartments act as weak springsin series and dissipate tension within themuscle.5 There is some evidence for similararchitecture in human neck extensors: theyreceive innervation from several cervicaldorsal rami6 and have tendinous inscriptionsproducing several at least partially serialcompartments.7 Denervation of one compart-ment bilaterally would produce significantweakness and fatigability in such compart-mentalised muscles. Additionally, the deepermuscles only traverse one motion segmentand are innervated by one posterior primaryramus. Segmental denervation of either typeof muscle would lead to angulation at amotion segment, limited in degree by intactjoints, ligaments, and disc space.

Whiplash injury can cause neurapraxia ofcranial nerve XI,8 XII,9 and branches of thecervical plexus,10 and there are other reportsof traction neuropathies in the neck.11 12 Inthe present cases, the close temporal relation-ship of the head drop to a forced flexioninjury and the EMG findings suggestingacute denervation of neck extensor musclesare consistent with a neurogenic mechanism.Although dystonia of neck flexor muscles canproduce head drop, these patients couldeasily lift their chins and there was noevidence of ventral muscle hypertonia onclinical examination. In addition, in patientsB and C, there were normal EMG findings inthe ventral neck muscles but abnormalfindings in the neck extensors.

Neurapraxia of dorsal primary rami wouldbe expected to recover in time, as happenedin patients B and C. Equally, muscle tearingwould recover in time, but it is inconceivablethat sufficient fibres would have been torn toproduce head drop without also producingsoft tissue abnormalities on MRI scanning.This is not the case. Only two of the caseswere investigated to exclude primary neuro-muscular disorders. These were excluded inpatient C. Although patient B had evidence ofa pre-existing peripheral neuropathy, thismay simply have made him more prone totraction neurapraxia after whiplash and hiseventual recovery is consistent with theproposed mechanism.

It is unclear why this syndrome has notbeen described before. Perhaps most whi-plash injuries produce insufficient neura-praxia to provoke head drop unless patientfactors adversely affect the transmission offorces to the nerves or their susceptibility toinjury. In non-predisposed individuals, suffi-ciently severe injuries might instead producefractures/dislocations, whose managementmasks signs of a concomitant neurapraxia.Lesser injuries might produce mild headdrop, which is either not recognised orrecovers quickly and never requires secondaryreferral. Furthermore, although motor defi-cits may be rare after whiplash, sensorysymptoms may be common, presenting asthe patient’s symptoms in a case of ‘‘typical’’whiplash syndrome. There is support for this


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notion from reports of symptomatic reliefafter cervical nerve blocks in cases of ‘‘thirdoccipital nerve headache’’ and other post-whiplash syndromes.13 14

Finally, Umapathi et al1 suggest thatcervical spinal fusion might be useful inoptimising head position for patients withhead drop. I would caution against thisapproach, given our experience with patientA, although alternative fixation methods,such as lateral mass plating, with carefulattention paid to achieving bony fusion,might be appropriate on occasion if conser-vative measures have failed.

AcknowledgementsI would like to acknowledge the contribution of theneurophysiologists involved in these cases, particu-larly Dr Roger Cull, Consultant Neurophysiologist,Department of Clinical Neurosciences, WesternGeneral Hospital, Edinburgh, UK.

R F PriceDepartment of Neurosurgery, Royal Adelaide

Hospital, North Terrace, Adelaide SA5000, Australia;[email protected]

doi: 10.1136/jnnp.2003.006429

References

1 Umapathi T, Chaudhry V, Cornblath D, et al.Head drop and camptocormia. J NeurolNeurosurg Psychiatry 2002;73:1–7.

2 Chaouat D, Belange G. Dropped head syndrome.Three case reports. Rev Rhum Engl Ed1999;66:430–3.

3 Hoffman D, Gutmann L. The dropped head syn-drome with chronic inflammatory demyelinatingpolyneuropathy. Muscle Nerve 1994;17:808–10.

4 Braun V, Mayer M, Antoniadis G, et al.Reconstruction of the spinal accessory nerve withan anastomosis to the dorsal C3 branch: technicalnote. Neurosurgery 1996;38:208–10.

5 Price RF. The use of Succinylcholine in theidentification and characterisation of afferentaxons from tandem muscle spindles. PhD Thesis,Edinburgh University, 1991.

6 Bogduk N. The clinical anatomy of the cervicaldorsal rami. Spine 1982;7:319–30.

7 Kamibayashi LK, Richmond FJ. Morphometry ofhuman neck muscles. Spine 1998;23:1314–23.

8 Bodack MP, Tunkel RS, Marini SG, et al. Spinalaccessory nerve palsy as a cause of pain afterwhiplash injury. J Pain Symptom Manage1998;15:321–8.

9 Clavier E, Thiebolt J, Hannequin D, et al. Cervico-occipital injury and bilateral paralysis of cranialnerve XII. Apropos of a case. J Radiol1986;67:3235–35.

10 Tosi L, Zanetta G. Trapezius muscle atrophy afterwhiplash injury: accessory nerve injury or cervicalplexus injury? J Neurol Neurosurg Psychiatry1991;54:561.

11 Narakas AO. Injuries of the brachial plexus andneighbouring peripheral nerves in vertebralfractures and other trauma of the cervical spine.Orthopade 1987;16:81–6.

12 Ginsburg GM, Bassett GS. Hypoglossal nerveinjury caused by halo-suspension traction. A casereport. Spine 1998;23:1490–3.

13 Lord SM, Barnsley L, Wallis BJ, et al. Third occipitalnerve headache: a prevalence study. J NeurolNeurosurg Psychiatry 1994;57:1187–90.

14 Bovin G, Berg R, Dale LG. Cervicogenicheadache: anaesthetic blockade of cervicalnerves (C2–C5) and facet joint (C2/C3). Pain1992;49:315–20.

Acute disseminatedencephalomyelitis temporallyassociated with CampylobactergastroenteritisThe association of Campylobacter infection andGuillain-Barre syndrome is well recognised.

We report a case of acute disseminatedencephalomyelitis (ADEM) temporally asso-ciated with Campylobacter gastroenteritis in apreviously fit man. A MedLine search usingthe keywords ‘‘ADEM’’, ‘‘demyelination’’,and ‘‘campylobacter’’ revealed no previousreports of ADEM associated with Campy-lobacter infection in isolation.

A 24 year old man presented to his generalpractitioner with a 4 day history of non-bloody diarrhoea associated with fevers andsweats. His past medical history was unre-markable. He drank 6 units of alcohol perweek and smoked only occasionally. Hisgeneral practitioner prescribed loperamidefor symptomatic relief. Campylobacter specieswas later isolated from stool samples. By day5 of his illness, his diarrhoea had settled andhe had become constipated. However, heremained febrile and developed nausea andvomiting. His general practitioner prescribederythromycin but he tolerated only two dosesbecause of nausea.

Fourteen days into the illness he wasadmitted to hospital complaining of headache,fever, and sweats. Examination revealed a tem-perature of 38.4 C, pulse of 65 beats/min andnormal blood pressure. Rectal examinationrevealed hard stool. There were no focal neuro-logical signs. His haemoglobin was15.3 g/dl,leukocyte count was 13.36109/l (87.1% neutro-phils) and C-reactive protein was 12.8 mg/l.Two days after admission (day 16 of illness),his family reported a change in his persona-lity and he complained of slurring of speech,intermittent diplopia, and difficulty in walk-ing. Examination revealed mild dysarthria, leftsided facial weakness, mild left pyramidal limbweakness, and decreased sensation in the leftleg. Tendon reflexes were brisk but plantarresponses were flexor. His gait was ataxic.Cranial CT scan showed no significant abnor-malities. Lumbar puncture revealed an open-ing pressure of 160 mm CSF, total cell count of34/mm3 with a white cell count of 20/mm3

(100% lymphocytes), total protein of 541 mg/l,glucose of 3.2 mmol/l, and negative oligoclo-nal banding. No organisms were seen andPCR was negative for enteroviruses andherpes virus. An EEG showed mild excessof generalised slow wave activity. CranialMRI scan was performed on a 1.5 TSiemens magnetic system. T2 weightedimaging of the brain showed multiple highsignal foci in the supra- and infra-tentorialcompartments involving the cortex, whitematter, and deep grey matter. One lesionin the right peri-trigonal white matter showedslight enhancement following intravenousgadolinium diethylene-triaminopenta-aceticacid (gadolinium DTPA) injection (fig 1).The abnormalities were consistent with ADEM.

The patient was initially treated withaciclovir 10 mg/kg three times daily, ampi-cillin 2 g four times daily and ciprofloxacin500 mg twice daily, but was subsequentlygiven intravenous methylprednisolone 1 gdaily for 3 days after the diagnosis ofADEM was made. Aciclovir and ampicillinwere discontinued when the negative labora-tory results were available but ciprofloxacinwas continued for 7 days. One day aftertreatment with methylprednisolone henoticed an improvement in his speech andgait, and after 7 days of starting treatment hehad no ataxia and was discharged home. Heappeared to have made a full recovery whenhe was reviewed at 6 weeks and has sinceremained asymptomatic.

ADEM is an acute monophasic immunemediated inflammatory demyelinating

disease of the central nervous system. It isan uncommon but a serious condition withmortality rates estimated between 10–30%.1

In the majority of cases, the conditiondevelops after systemic viral infections mostcommonly measles, mumps, rubella, influ-enza A and B, herpes simplex, Epstein-Barrvirus, varicella, and vaccinia.2 It has also beenreported following bacterial infections withMycoplasma pneumoniae, Chlamydia, Legionella,and Streptococcus, or following immunisationsfor rabies, diphtheria/tetanus/pertussis, small-pox, measles and Japanese B encephalitis.2

The pathogenesis of ADEM remains poorlyunderstood. However, the evidence suggeststhat activated T cells, which recognise aminoacid sequences shared between microbialepitopes and myelin antigens, attack centralnervous system structures alone or in synergywith antibodies.3 Viral or bacterial super-antigens could likewise trigger autoactive Tcells with similar results.

The diagnosis of ADEM is usually madeclinically with the aid of MRI scanning,lumbar puncture finding and electrophysiol-ogy studies. MRI scanning reveals multipleareas of increased signal on T2 weightedimages in the white matter throughout thecentral nervous system, most being located inthe subcortical white matter of both hemi-spheres, which are often quite extensive andenhance with contrast. CSF findings includemononuclear pleocytosis and mild proteinelevation. There are few data available onevidence based treatment regimens, buttreatment is usually instituted with high doseglucocorticoids. Plasmapheresis and intra-venous immunoglobulin have also been used.

Campylobacter gastroenteritis is the mostcommon cause of acute gastroenteritis in theUK, accounting for over 56 000 cases in 2000.Its incidence has risen progressively over thepast 2 decades. In the majority of cases, theillness self terminates within a few days withno long term consequences. It is estimatedthat approximately 1/1000 reported campylo-bacteriosis cases leads to Guillain-Barresyndrome, and around 33% of Guillain-Barre syndrome cases in the western worldmay be triggered by campylobacteriosis.Huber et al reported a case of combinedADEM and acute motor axonal neuropathyfollowing Campylobacter jejuni infection andhepatitis A immunisation.4 Cranial MRIscanning showed a slight enhancement inthe left cerebral peduncle that disappearedwhen the study was repeated a week later.Nasralla et al reported a case of postinfectiousencephalomyelitis in a young child followingCampylobacter jejuni enteritis.5 Cranial MRIscanning showed a combination of predomi-nant grey matter involvement with concomi-tant focal areas of subcortical white matterlesions with no parenchymal enhancement,which the authors felt to be different fromthe pattern of signal abnormalities seen inpatients with ADEM. The MRI abnormalitiesin our case were in keeping with ADEMalthough, as with the case reported by Huberet al, the amount of enhancement was mini-mal, indicating that the majority of the lesionswere not acute.6 The paucity of reportedcases of ADEM following Campylobacter infec-tion is surprising given the strong associationbetween Campylobacter jejuni infection andGuillain-Barre syndrome and the pathogen-esis of the latter. In these cases, Campylobacterjejuni induces humeral and cellular immuneresponses due to molecular mimicry betweenspecific lipopolysaccaride epitopes on theinfecting agent and target epitopes on the


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surface components of the peripheral nerves,resulting is myelin destruction and axonaldegeneration.7 Furthermore, patients withADEM often have peripheral nervous systeminvolvement and there have been occasionalcases of ADEM associated with Guillain-Barre syndrome. Our patient did not haveany clinical features suggestive of peripheralnervous system involvement. However, nerveconduction studies were not performed and adegree of sub-clinical neuropathy cannottherefore be excluded.

We describe the first identifiable case ofADEM temporally associated with Campy-lobacter gastroenteritis alone. Our patientmade an excellent recovery associated withtherapy with high dose methylprednisolone.

AcknowledgementsWe are most grateful to Dr D Connolly for reviewingthe MRI imaging.

D Orr, M W McKendrickDepartment of Infection and Tropical Medicine,

Royal Hallamshire Hospital,Sheffield, UK

B SharrackDepartment of Neurology, Royal Hallamshire

Hospital, Sheffield, UK

doi: 10.1136/jnnp.2003.013433

References

1 Kennard C, Swash M. Acute viral encephalitis.Its diagnosis and outcome. Brain1981;104:129–48.

2 Tselis AC, Lisak RP. Acute disseminatedencephalomyelitis. In: Antel J, Birnbaum G,Hartung HP, eds. Clinical neuroimmunology.Boston: Blackwell Science, 1998;116–47.

3 Hartung HP, Crossman RI. ADEM: distinct diseaseor part of the MS spectrum? Neurology2001;56:1257–60.

4 Huber S, Kappos L, Fuhr P, et al. Combinedacute disseminated encephalomyelitis and acutemotor axonal neuropathy after vaccination forhepatitis A and infection with Campylobaccterjejuni. J Neurol 1999;246:1204–6.

5 Nasralla CA, Pay N, Goodpasture HC, et al.Postinfectious encephalopathy in a child followingCampylobacter jejuni enteritis. Am J Neuroradiol1993;14:444–8.

6 Singh S, Alexander M, Korah IP. Acutedisseminated encephalomyelitis: MRimaging features. Am J Roentgenol1999;173:1101–7.

7 Hughes RA, Hadden RD, Gregson NA,et al. Pathogenesis of Guillain-Barresyndrome. J Neuroimmunol 1999;100:74–97.

Figure 1 Axial T2 weighted image showing supra- and infra-tentorial high signals in both hemispheres, and coronal T1 weighted images showingperi-trigonal white matter lesions with slight enhancement following intravenous gadolinium DTPA injection in keeping with ADEM.

Competing interests: none declared

Received 26 February 2003Revised 14 July 2003

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CORRESPONDENCE

Evidence for an associationbetween the CSF HVA:5-HIAAratio and aggressiveness infrontotemporal dementia but notin Alzheimer’s diseaseIn their recent paper, Soderstrom et al1

confirmed their preliminary data suggestingthat the CSF HVA:5-HIAA ratio was asso-ciated with psychopathic traits and, inparticular, violent and aggressive behaviourwith childhood onset and adult expression.These findings might indeed reflect changeddopaminergic activity, possibly as a resultof serotonergic dysregulation. We hypothe-sise that their findings might be applicable toother brain disorders characterised by specificbehavioural disturbances, including aggres-sion and agitation. Indeed, since severalstudies have found associations betweenaltered serotonergic neurotransmission andaggression in persons with dementia,2 3 wecould propose that the CSF HVA:5-HIAAratio might be associated with aggression inpersons with dementia as well. To test thishypothesis, we performed an interim analysison 102 out of 302 patients who were includedin a prospective and longitudinal study onneurochemical and genetic correlates ofbehavioural and psychological signs andsymptoms of dementia (BPSD). The datapresented further support a general applica-tion of the interesting findings of Soderstromet al.1

Patients with various neurodegenerativeforms of dementia were included in thisprospective study, and were followed up bymeans of a neuropsychological and beha-vioural assessment every six months. In anycase of death, brain autopsy was performedfor neurochemical analysis as well as forneuropathological confirmation of the clin-ical diagnosis. All subjects and their care-givers gave informed consent to participationin the study, which was approved by the localethics committee.At baseline, behaviour was assessed by

means of a battery of behavioural assessmentscales which included the BehaviouralPathology in Alzheimer’s Disease RatingScale (Behave-AD) and the Cohen-MansfieldAgitation Inventory (CMAI). Lumbar punc-ture was performed between 9 and 10 amfollowing overnight bed rest and fasting. Thefirst 11 ml of CSF were collected in severalpolypropylene vials that were immediatelyfrozen in liquid nitrogen and stored at 280 C.Neurochemical analysis was carried out onthe CSF fraction containing 6–7.5 ml bymeansof high performance liquid chromatographyand electrochemical detection according to amodification of a recently described method.4

Routine investigation of the CSF includedcell count, total protein and glucose analy-sis, and agar gel electrophoresis of proteins.For this interim analysis, HVA and 5-HIIA

levels were determined in the CSF of 13 par-ticipants with frontotemporal lobe dementia(FTD) and 89 participants with probableAlzheimer’s disease (AD). Spearman Rank

Order was used for correlation analysisbetween the CSF HVA:5-HIAA ratio andBPSD, applying SigmaStat Software (SPSSScience, Erkrath, Germany).In the AD patient group, no significant

correlations were found between the CSFHVA:5-HIAA ratio and Behave-AD clusters,total and global scores, or CMAI clusters(aggressive, physically non-aggressive, andverbally agitated behaviours) and totalscores. In persons with FTD, however, theCSF HVA:5-HIAA ratio correlated signifi-cantly with the Behave-AD aggressivenesscluster score (r = 0.586; p = 0.033) andwith the CMAI verbally agitated behaviourcluster score (r = 0.564; p = 0.041). Despitesmall sample sizes, effects of treatments wereruled out by comparing the CSF levels of HVA(t test: p = 0.691), 5-HIAA (p = 0.370), andthe CSF HVA:5-HIAA ratio (p = 0.157)between six untreated subjects with FTDand seven subjects with FTD who werereceiving atypical antipsychotics.Our preliminary results revealed an asso-

ciation between aggression and the CSFHVA:5-HIAA ratio in participants with FTDbut not in those with AD. More refinedneurochemical analyses, including the deter-mination of all catecholamines and serotoninin an extended population of FTD patients,are scheduled. These will allow furthertesting of the hypothesis that altered seroto-nergic modulation of dopaminergic neuro-transmission leads to BPSD and in particularto aggression. Meanwhile, our findings sug-gest that the association between the CSFHVA:5-HIAA ratio and aggression asobserved by Soderstrom et al 1 is not limitedto violent and aggressive behaviour with child-hood onset and adult expression, but mayindicate an underlying pathophysiologicalmechanism that may be common to aggres-sive symptomatology in other brain disorders,such as frontotemporal lobe dementia.

S Engelborghs, E Vloeberghs, K Maertens,B Marescau, P P De Deyn

Laboratory of Neurochemistry and Behaviour, Born-Bunge Foundation, University of Antwerp, Belgium

S Engelborghs, P P De DeynDepartment of Neurology, Middelheim General

Hospital, Antwerp, Belgium

Correspondence to: Professor P P De Deyn;[email protected]

References

1 Soderstrom H, Blennow K, Sjodin A-K, et al.New evidence for an association betweenthe CSF HVA:5-HIAA ratio and psychopathictraits. J Neurol Neurosurg Psychiatry2003;74:918–21.

2 Lai MKP, Tsang SWY, Francis PT, et al. Reduced5-HT1A receptor binding in the temporal cortexcorrelates with aggressive behavior in Alzheimerdisease. Brain Res 2003;974:82–7.

3 Sukonick DL, Pollock BG, Sweet RA, et al. The5-HTTPR*S/*L polymorphism and aggressivebehavior in Alzheimer disease. Arch Neurol2001;58:1425–8.

4 Engelborghs S, Marescau B, De Deyn PP. Aminoacids and biogenic amines in cerebrospinal fluidof patients with Parkinson’s disease. NeurochemRes 2003;28:1145–50.

Extensive radiculopathy: anotherfalse localising sign inintracranial hypertensionWe read with interest the review by Larner1

on false localising signs. Among the variousfalse localising signs described in patientswith intracranial hypertension (ICHT), radi-culopathy is an important manifestationwhich is probably under recognised. Manyauthors have documented subtle features ofradiculopathy in patients with isolated intra-cranial hypertension (IIH). The usual mani-festations of radiculopathy in these caseswere acral paraesthesias,2 and backache andradicular pain.3 4 Rarely, motor deficits due toradiculopathy caused by ICHT have beendescribed.5 6

Obeid et al reported two patients withextensive radiculopathy due to ICHT5; oneindividual had IIH and the other had cerebralsinus venous thrombosis. Both persons hadpapilloedema, marked visual impairment, andflaccid areflexic quadriparesis with normalMRI of brain, brainstem, and cervical spinalcord. The electrophysiological findings wereconsistent with radiculopathy. Both indivi-duals initially received intravenous immunoglo-bulin for Guillain–Barre syndrome, withoutbenefit, but they responded well to lumbo-peritoneal shunting. We also encounteredtwo such cases with angiographically pro-ven cerebral venous sinus thrombosis.6

The most likely mechanism at the basis ofradiculopathy appears to be similar to that ofother cranial neuropathies in ICHT—that is,mechanical compression of nerve roots, dueto elevated CSF pressure distending thesubarachnoid space. Documented enlargementof spinal subarachnoid space and distendedroot pouches in a patient with radicularpain and areflexia due to IIH supports thisview.3 Radiculopathy secondary to ICHT hasbeen reported almost exclusively in patientswith IIH or cerebral venous sinus thrombosis.Other causes of ICHT may not induce a

diffuse increase in pressure in both intracra-nial and intraspinal compartments, and areunlikely to manifest as radiculopathy. Theconstellation of flaccid-areflexic quadriplegiaand papilloedema may be misdiagnosed asGuillain–Barre syndrome with papilloedema.5

Careful analysis of the evolution of symp-toms, estimation of CSF pressure, and appro-priate vascular imaging should help tocorrectly identify the cause of ICHT.

A Moosa, M A Joy, A KumarDepartment of Neurology, Amrita Institute of MedicalSciences and Research Center, Cochin, Kerala, India

Correspondence to: Dr N V A Moosa;[email protected]

References

1 Larner AJ. False localising signs. J NeurolNeurosurg Psychiatry 2003;74:415–18.

2 Round R, Keane JR. The minor symptoms ofincreased intracranial pressure: 101 patients withbenign intracranial hypertension. Neurology1988;38:1461–4.

3 Bortoluzzi M, Di Lauro L, Marini G. Benignintracranial hypertension with spinal andradicular pain. J Neurosurg 1982;57:833–6.


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4 Santinelli R, Tolone C, Toraldo R, et al. Familialidiopathic intracranial hypertension with spinaland radicular pain. Arch Neurol 1998;55:854–6.

5 Obeid T, Awada A, Mousali Y, et al. Extensiveradiculopathy: a manifestation of intracranialhypertension. Eur J Neurol 2000;7:549–53.

6 Moosa A, Kishore A, Gupta AK, et al. Blindness,ophthalmoplegia and extensive radiculopathy- anunusual clinical syndrome in intracranial sino-venous thrombosis. Neurol India (in press).

Role of entacapone in laterParkinson’s disease not yetestablishedThe study by Brooks and Sagar,1 along with anumber of previous others, demonstratesbenefit for the catechol-O-methyltransferase(COMT) inhibitor entacapone when com-pared with placebo in Parkinson’s disease(PD). However, this is insufficient evidence tojustify the authors’ conclusion that ‘‘itappears logical to employ levodopa combinedwith entacapone routinely’’. The importantissue is not whether entacapone is moreefficacious than placebo, but whether it ismore or less clinically effective and costeffective than the other available treatmentsfor patients with PD that is no longeradequately controlled by levodopa alone.Other available agents—including dopamineagonists and monoamine oxidase type B(MAOB) inhibitors—have also shown effi-cacy when compared with placebo. The paperwould have benefited from a balanced discus-sion of the merits of entacapone comparedwith these other available treatment options.Such a discussion is likely to have been

inconclusive, however, as there is a dearth ofreliable evidence on the best treatment forPD, at any stage of the disease, since very fewtrials directly comparing active treatmentshave been undertaken.2 Companies are reluc-tant to undertake such trials, as it is not intheir commercial interests to risk studies thatmight show their product to be inferior tothat of a competitor. For this reason, inde-pendently funded trials—such as the currentPD MED trial in the UK3—should be sup-ported to provide the reliable evidence oncomparative efficacy needed to enable clin-icians to make informed treatment decisions.Analysis, presentation and interpretation ofthe results of independent studies are alsolikely to be more objective than those of com-mercial studies. The potential for bias in com-mercial trials has recently been highlightedby systematic reviews and journal editors—for example ‘‘systematic bias favours pro-ducts which are made by the companyfunding the research’’4 and ‘‘scientific studiescan be manipulated in many ways to giveresults favourable to companies’’.5

There are problems with the trial reportedby Brooks and Sagar, and these are commonto many PD trials, which are generally of poormethodological quality.2 In a progressivecondition such as PD, it is important toevaluate the long term effects of treatment,and six months follow up is inadequate. Theoutcome measures used should reflect theimpact of treatment on the patients’ ownperception of their functioning and quality oflife, not that of clinicians as with the UnifiedParkinson’s Disease Rating Scale (UPDRS). Itis unclear how well the data obtained fromon-off diaries correlates with global quality oflife. True intention to treat (ITT) analysis wasnot performed, since patients who withdrewfrom treatment were excluded from theanalysis—ITT analysis requires such patients

to be followed up and included in theanalysis according to the arm to which theywere allocated even if they have withdrawnfrom allocated therapy.6 Nearly 50% morepatients (24.1% v 16.5%) dropped out of theentacapone arm than from the placebo armand, in progressive diseases such as PD,dropout bias tends to favour the activetreatment.7 Thus, although COMT inhibitorsare welcome additions to the treatmentoptions in PD, large, rigorously conductedcomparative trials, assessing the long termimpact on patient-rated measures of overallquality of life, are still needed to define theirrole in routine clinical practice.

K Wheatley, N Ives, R GrayUniversity of Birmingham Clinical Trials Unit,University of Birmingham, Birmingham, UK

C ClarkeCity Hospital, Birmingham, UK

Correspondence to: Professor K Wheatley,Birmingham Clinical Trials Unit, University ofBirmingham, Park Grange, 1 Somerset Road,

Edgbaston, Birmingham B15 2RR, UK;[email protected]

References

1 Brooks DJ, Sagar H, the UK-Irish EntacaponeStudy Group. Entacapone is beneficial in bothfluctuating and non-fluctuating patients withParkinson’s disease: a randomised, placebocontrolled, double blind six month study. J NeurolNeurosurg Psychiatry 2003;74:1071–9.

2 Wheatley K, Stowe RL, Clarke CE, et al.Evaluating drug treatments for Parkinson’sdisease: how good are the trials? BMJ2002;324:1508–11.

3 PD MED: A phase III Parkinson’s disease trial.www.pdmed.bham.ac.uk (accessed 17 March2004).

4 Lexchin J, Bero LA, Djulbegovic B, et al.Pharmaceutical industry sponsorship andresearch outcome and quality: systematic review.BMJ 2003;326:1167–70.

5 Smith R. Medical journals and pharmaceuticalcompanies: uneasy bedfellows. BMJ2003;326:1202–5.

6 Collins R, Peto R, Gray R, et al. Large-scalerandomized evidence: trials and overviews. In:Weatherall D, Ledingham JGG, Warrell DA, eds.Oxford Textbook of Medicine, Volume 1. London:Oxford University Press, 1996:21–32.

7 Gray R, Stowe RL, Hills RK, et al. Non-randomdrop-out bias: intention to treat or intention tocheat? [Abstract] Control Clin Trials2001;22:38S–39S.

Portal-systemic shunts,manganese, and parkinsonismI read with interest the article by Yoshikawaand colleagues.1 The authors reported thecase of a 44 year old woman with hereditaryhaemorrhagic telangiectasia (Rendu-Osler-Weber disease) involving the liver, who hadraised serum concentrations of manganese,hyperintense areas in the basal ganglia onT1 weighted magnetic resonance images,and levodopa unresponsive parkinsonism.Naturally, I agree that the parkinsonism inthis case is most probably related to portal-systemic (portal-venous) shunts. There are,however, two points that deserve clarification.

First, it is not entirely clear whether theirfig 2 (left panel) shows portal-systemic orarteriovenous shunts. The authors say thatthe figure shows a selective angiogram of thesuperior mesenteric artery. If that were thecase, there should not be a ‘‘feeding artery’’involved in the intrahepatic shunts (as theystate in the legend to fig 2). Instead, thefigure would show the portal vein and portal-systemic shunts (that is, portal phase of theangiogram). If, on the other hand, thecatheter were in the coeliac artery (as theymention in the text), then the figure wouldprobably correspond to the arterial phase ofthe angiogram and show a feeding artery (thehepatic artery) and arteriovenous (not portal-systemic) shunts. Interestingly, there is evi-dence to suggest that both types of shuntmay be necessary for the development ofneurological complications in the presence ofan intact (or mostly preserved) hepaticparenchyma.2 Thus excessive quantities ofpotentially toxic substances (for example,ammonia, manganese) passing directly fromthe gut to the systemic circulation throughportal-systemic shunts could be rapidlycleared by a normal liver as long as thehepatic arterial blood flow is adequate.Second, Yoshikawa and colleagues claim

that the parkinsonism of their patient wasinduced by manganese. While this is areasonable working hypothesis, the authorsprovide no direct evidence supporting such astatement. The fact that serum manganesewas raised does not necessarily imply thatmanganese played a key role in the patho-genesis of parkinsonism. Indeed, their patientlacked various clinical features often seen incases of manganese induced parkinsonism3

(for example, cock walk and propensity to fallbackwards).Levodopa unresponsive parkinsonism is a

well known manifestation of chronic non-Wilsonian hepatocerebral degeneration.4

Although blood concentrations of ammoniawere within the normal range in the casereported by Yoshikawa and colleagues, thepossibility of transient abnormal increases ofammonia occurring particularly after mealswas not investigated.

R de la Fuente-FernandezDivision of Neurology, Hospital A Marcide, EstradaSan Pedro-Catabois s/n, 15405 Ferrol, A Coruna,

Spain

Correspondence to: Dr Raul de la Fuente-Fernandez,[email protected]

References

1 Yoshikawa K, Matsumoto M, Hamanaka M,et al. A case of manganese induced parkinsonismin hereditary haemorrhagic telangiectasia.J Neurol Neurosurg Psychiatry2003;74:1312–14.

2 Yilmaz S, Kirimlioglu V, Katz D, et al. An attemptto decrease ammonia levels after portacavalanastomosis in dogs: hepatic periarterialneurectomy. Dig Dis Sci 2002;47:1943–52.

3 Calne DB, Chu NS, Huang CC, et al. Manganismand idiopathic parkinsonism: similarities anddifferences. Neurology 1994;44:1583–6.

4 Adams RD, Victor M, Ropper AH. Principles ofneurology, 6th ed. New York: McGraw-Hill,1997.

Authors’ replyWe are pleased to have an opportunity tocomment on the important issues raised byDr de la Fuente-Fernandez regarding a caseof hereditary haemorrhagic telangiectasia

Competing interests: We are investigators in the PDMED trial and thus have a vested interest in obtainingobjective evidence on the best treatment for PD. CChas received honoraria for lectures, consultancy fees,and travel expenses from the manufacturers of manyof the drugs discussed.

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with parkinsonism. Raised serum manganesecombined with the abnormal findings incranial magnetic resonance imaging andabdominal angiography were the rationalefor our conclusion that the parkinsonism inour patient was induced by manganese thathad accumulated because of portal-systemicshunting.About the angiogram: the angiogram of the

superior mesenteric artery presented in ourmanuscript showed a dilated feeding artery, adense mottled hepatogram, and early fillingof the hepatic vein. These findings con-cerned the arterial phase. The intrahepaticarteriovenous shunts were definite diagnosticevidence of hereditary haemorrhagic telan-giectasia but not of portal-systemic shunts.We therefore agree with Dr de la Fuente-Fernandez that we should have presentedanother angiogram in the portal phaseshowing a hypoplastic portal vein withabnormal vessels between the mesentericand inferior vena cava to confirm theportal-systemic shunt.About the parkinsonism: after the failure

of treatment by levodopa, we took othermeasures to relieve the parkinsonism; forexample, we persuaded the patient to avoidmanganese-rich foods such as blueberries.Fortunately, her serum manganese graduallydecreased below the normal upper limitduring the next six months, and her neuro-logical symptoms became less prominent.Alleviation of parkinsonism in inverse pro-portion to serum manganese concentrationssuggests that the parkinsonism in this casemay have been caused by manganese accu-mulation, and that the patient was in theearly stage of manganese intoxication inwhich neurological symptoms were incom-plete and partially reversible.About transient hyperammonaemia: we

searched for cases of hyperammonaemiarelated parkinsonism, and finally found acase with portal-systemic encephalopathyand parkinsonism which disappeared aftertreatment of the portal-systemic shunting.1

The mechanism of parkinsonism in thatcase is certainly open to debate, as hyper-ammonaemia is generally thought to causedisturbance of consciousness or negativemyoclonus rather than parkinsonism. We donot deny the possibility that our patient mayhave had a transient increase in serumammonia, though it seems unlikely whenthere had never been a disturbance ofconsciousness.

K Yoshikawa, M NakagawaDepartment of Neurology, Research Institute for

Neurological Diseases and Geriatrics, KyotoPrefectural University of Medicine, 465 Kawaramachi-

hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan

Correspondence to: Dr K Yoshikawa,[email protected]

Reference

1 Federico P, Zochodne DW. Reversibleparkinsonism and hyperammonaemia associatedwith portal vein thrombosis. Acta Neurol Scand2001;103:198–200.

Intraventricular assessment ofpreoperative electrographicrecordingsThe paper by Song et al1 describes theplacement of intraventricular arrays withendoscopic assistance for preoperative

electrographic recordings for epilepsy sur-gery. The 4.2 mm external diameter rigidendoscope was introduced up to the temporalostium from where the arrays were advanceduntil a point of resistance was felt.In our paper2 we reported the use of a

1.2 mm outer diameter semirigid endoscopeto explore the contents of the ventricles priorto electrode placement, with direct visualassessment of the final electrode position,which helped us obtain appropriate pre-resection electrographic recordings. Perhapsit would be more convenient to use semirigidendoscopes or slim fibrescopes to fullyvisualise the ventricle as well as flexiblearrays to avoid electrode displacement result-ing in unintentional cerebral lesions.

O H JimenezDept Neurosurgery, Hospital General ‘‘Dr. Miguel

Silva’’, Secretarıa de, Salud de Michoacan, Mexico

N NagoreDept Neurosurgery, Universidad Michoacana de SanNicolas de Hidago, Morelia, Michoacan, CP 58000,

Mexico

Correspondence to: Dr O Jimenez,[email protected]

References

1 Song JK, Abou-Khalil B, Konrad PE.Intraventricular monitoring for temporal lobeepilepsy: report on technique and initial results ineight patients. J Neurol Neurosurg Psychiatry2003;74:561–5.

2 Jimenez O, Leal R, Nagore N. Minimally invasiveelectrodiagnostic monitoring in epilepsy surgery.Br J Neurosurg 2002;16:498–500.

Parkinsonism and persistentvegetative state after head injuryMatsuda et al recently reported three patientswith a persistent vegetative state (PVS) aftersevere head injury who, after recovering fromprolonged disturbance of consciousness, pre-sented parkinsonian features (mainly rigidityand hypokinesia) which improved afterlevodopa treatment.1 MRI studies showedlesions in the dorsolateral midbrain andcerebral peduncles suggesting axonal injuryinvolving the dopaminergic system (substan-tia nigra and ventral tegmental area). Similarobservations were made in a series of 125patients with severe vegetative state follow-ing head injury (survival time 1–10 years).Nineteen of 49 patients surviving in fullydeveloped or mild recovery stages of PVSinitially presented with severe to moderate,mainly symmetrical, parkinsonian symptoms(amimia, rigidity, hypokinesia, convergencedisorders). Following levodopa treatment, 11patients showed incomplete and four fullimprovement of both the PVS and parkinson-ism, while four patients showed completerecovery from both syndromes. However, in15 patients—despite good recovery from theinitial PVS and other neurological symptoms(spasticity, frontal and cerebellar symptoms),and long term levodopa treatment—a prog-ressive parkinsonian syndrome (rigidity,hypokinesia) developed; in six patients thiswas associated with unilateral or bilateral rest-ing tremor. In MRI studies done in 34 patients,32 showed unilateral or bilateral lesions in themidbrain involving both the dorsolateral teg-mentum and the cerebral peduncles.2

Neuropathological studies were underta-ken in 32 patients surviving without essentialimprovement of the PVS for at least two

months after head injury. Parkinsoniansyndromes were severe in seven, moderatein five, and mild in four.3 In addition to olderhaemorrhages or necroses in the striatum(n=6), globus pallidus and thalamus(n=8), all brains revealed multiple lesionsin the rostral brain stem with unilateral orbilateral focal lesions in the substantia nigra,vascular lesions in the lateral and dorsolateralmidbrain in seven, and symmetrical post-anoxic cellular depletion and gliosis or uni-lateral necroses in the substantia nigra in onecase each. In nine cases, there was a goodcorrelation between the severity of clinicalparkinsonian signs and the severity andextent of nigral lesions; three patientsshowed severe parkinsonian signs associatedwith only mild nigral damage, but there wassevere bilateral damage to the globus pallidusin two. In four patients the expression ofclinical parkinsonian signs was more severethan the anatomical lesions, in particular thedamage to the substantia nigra. The distribu-tion pattern of the brain stem lesionscorrelated with the sequelae of transtentorh-inal shifting caused by increased intracranialpressure; direct or ‘‘primary’’ traumaticlesions to the oral brain stem usually causeacute death, as seen in two young men withrupture of the diencephalon and acutehaemorrhage into the substantia nigra ormidbrain following severe and acute fatalhead injuries. However, in rare patients withlong survival following head injury, symme-trical necrosis of the substantia nigra withouta clinical parkinsonian syndrome has beenreported.4

The clinical phenotype of post-traumaticparkinsonism often resembles that in post-encephalitic parkinsonism, both showingakinesia, rigidity, hypomimia, rare tremor, andoptomotor and vegetative disorders. Both thelesion pattern and the therapeutic efficacy oflong term levodopa treatment suggest adysfunction of the striato-nigral dopaminergicsystem which, however, may show progressivedecompensation in some patients with longlasting PVS after severe head injury.

K A JellingerInstitute of Clinical Neurobiology, Kenyongasse 18,

A-1070 Vienna, Austria

Correspondence to: Dr Kurt A Jellinger,[email protected]

REFERENCES

1 Matsuda W, Matsumura A, Komatsu Y, et al.Awakenings from persistent vegetative state:report of three cases with parkinsonism and brainstem lesions on MRI. J Neurol NeurosurgPsychiatry 2003;74:1571–3.

2 Kothbauer P, Gerstenbrand G, Jellinger K.Concerning the question of posttraumaticparkinsonian syndromes. Meeting of the AustrianParkinsonian Society, Vienna, 1977. Roche-Fortbildungs-Service, 1977:1–6.

3 Jellinger K, Seitelberger F. Protractedposttraumatic encephalopathy. Pathology,pathogenesis, and clinical implications. J NeurolSci 1970;104:51–94.

4 Huhn B, Jakob H. Traumatic brain stem lesionswith long-term survival. Contribution to thepathology of substantia nigra and the pontinesyndrome. Nervenarzt 1970;41:326–34.

Authors’ replyWe greatly appreciate the thoughtful com-ments offered by Dr Jellinger, and his interestin our report of three cases in a persistentvegetative state (PVS) after severe head

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injury, who recovered from a prolongeddisturbance of consciousness after they weregiven levodopa.1

Jellinger et al reports that in cases ofprolonged post-traumatic coma the brainsshowed multiple lesions of primary andsecondary traumatic origin and that thehighest incidence of lesions was found inthe rostral brain stem. These were consideredto be almost exclusively of secondary origin,resulting from cerebral and peripheral circu-latory disorders, post-traumatic oedema, andincreased intracranial pressure. Primary(direct) traumatic lesions to the rostral brainstem usually cause acute death.2 In contrastto this report, the brain stem injuries in ourcases suggested by MRI may have been theprimary traumatic lesions. All these casesshowed high intensity lesions in the dorso-lateral midbrain on T2 weighted MRI.1 Thesefindings implied that the midbrain wasinjured by tentorial compression induced bytranslatory and rotatory acceleration whenthe cranium was struck in its sagittal axis, orby posterolateral damage. MRI findings,particularly in the acute stage, are useful forevaluating primary brain damage.3 4

Furthermore, another distinctive feature ofour cases was that the anatomical distribu-tion of the lesions was not multifocal but waslocalised in the cerebral peduncle or thedorsolateral midbrain, implying diffuse axo-nal injury involving the substantia nigra orthe ventral tegmental area.1 The neuroradio-logical findings, the clinical features of extra-pyramidal dysfunction, and the efficacy oflevodopa treatment all strongly suggest thatthe dopaminergic pathways were selectivelydamaged and caused defects in the nigro-striatal, mesocortical, or mesolimbic system.As Dr Jellinger indicates, progressive

decompensation in levodopa treatment is aconsiderable problem. However, not all ourpatients have required permanent medica-tion; an example is case 1 in our report,1

whose recovery was sustained even after thelevodopa treatment was discontinued. Somepatients may need levodopa only as a triggeragent at the start of treatment to interruptthe vicious cycle of exhaustion of neuro-transmitter. However, discriminating whichcases fall into this category is very difficultand withdrawal of medication involves ethi-cal problems.In recent neuropathological and neuro-

radiological studies on PVS after traumaticbrain injury,4–6 the most common structuralabnormalities were diffuse axonal injuryinvolving the corpus callosum, the dorsolat-eral aspect of the rostral brain stem,5 and thethalamus.6 Although the clinical features willvary in such cases, a take-home messagewhich we learned from our three cases is thatin any group of patients with PVS after severehead injury there may be some whosedopaminergic systems may have been selec-tively damaged; such individuals may res-pond to levodopa treatment. It is necessary toaccumulate a great deal more clinical experi-ence and data to elucidate the pathogenesisand pathophysiological mechanism of post-traumatic PVS. We respect Dr Jellinger’scareful observations and descriptions of hiscases of prolonged post-traumatic coma, andlook forward to further views from him onthis topic.

W Matsuda, Y KomatsuDepartment of Neurosurgery, Tsukuba Medical Centre

Hospital, 1-3-1 Amakubo, Tsukuba, Ibaraki 305-0005, Japan

A Matsumura, K YanakaDepartment of Neurosurgery, Institute of Clinical

Medicine, University of Tsukuba, 1-1-1 Tennodai,Tsukuba, Ibaraki 305-8575, Japan

Correspondence to: Dr Wakoto Matsuda,[email protected]

References

1 Matsuda W, Matsumura A, Komatsu Y, et al.Awakenings from persistent vegetative state:report of three cases with parkinsonism and brainstem lesions on MRI. J Neurol NeurosurgPsychiatry 2003;74:1571–3.

2 Jellinger K, Seitelberger F. Protracted post-traumatic encephalopathy. Pathology,pathogenesis, and clinical implications. J NeurolSci 1970;104:51–94.

3 Matsumura A, Mitsui I, Ayuzawa S, et al.Prediction of reversibility of the brain stemdysfunction in head injury patients. In:Nakamura N, ed. Recent advances inneurotraumatology. Tokyo: Springer-Verlag,1993:192–5.

4 Matsumura A, Meguro K, Shibata Y, et al.Persistent vegetative state [letter]. J Neurosurg1998;89:895–6.

5 Kampfl A, Franz G, Franz A, et al. The persistentvegetative state after closed head injury: clinicaland magnetic resonance imaging findings in 42patients. J Neurosurg 1998;88:809–16.

6 Adams JH, Graham DI, Jennett B. Theneuropathology of the vegetative state after anacute brain insult. Brain 2000;123:1327–38.

Each article is summarised in half a page orso under the headings introduction (or back-ground), methods, results, and conclusion.This is followed by a brief editorial comment,often interesting and pithy. At least some ofthis signed editorial comment is derived ver-batim, or with only minor paraphrasing, fromeditorial comment in the journal originallypublishing the chosen paper.1 So whose opin-ion are you really reading in the yearbook?Although interestingly informative outside

one’s subspecialty, one does need to ask whe-ther the concept of a single volume yearbookisn’t becoming submerged by the sheer volumeof potentially eligible papers published eachyear. And, although this 2003 yearbook arrivedon my desk in December 2003, it predomi-nantly covers papers published in 2001, withsome from early 2002, and an occasionalhangover from 2000. So, it isn’t that up todate. I guess libraries will buy it, partly out ofhabit. But for individuals, £74 is a steep pricefor neurological coffee table reading.

M Donaghy

Reference1 Donaghy M. Assessing the risk of drug-induced

neurological disorders: statins and neuropathy.Neurol 2002;58:1321–2.

Catatonia: a clinician’s guide todiagnosis and treatment

Max Fink, Michael Alan Taylor. Cambridge:Cambridge University Press 2003, pp 210,£50.00 (hardback). ISBN 0-521-82226-2.

This nicely produced book reviews one ofthe historically most interesting, but clini-cally still very important, disorders of neuro-psychiatry. Catatonia, described by Kahlbaumin the latter half of the 19th century, washijacked by Kraepelin to be incorporatedinto his concept of dementia praecox, andalmost disappeared from the literature inthe first half of the 20th century, being finallyeclipsed by the introduction of effective psy-chotropic drugs thereafter. But, as Fink andTaylor explore here, catatonia as a diagnosisis still a diagnostic challenge, with causes farbeyond schizophrenia and a syndrome witheffective treatment, notably, but not exclu-sively electroconvulsive therapy (ECT).For those interested in the cerebral basis

of psychiatry, a condition with the mainpresenting signs of mutism, immobility,negativism, posturing, stereotypy, and echo-phenomena cannot fail to attract attention,and the many faces of catatonia (title,chapter 3) are an olla podrida of neuro-psychiatry. It is refreshing to find reference toLeonhard’s work and the cycloid psychoses ina text from American authors, who arethoroughly appreciative of the Europeanliterature on their subject, and shyly criticalof DSM-IV. Their overall conclusions areclear. Catatonia is a common stable syn-drome, neuroleptic malignant syndrome ismalignant catatonia, catatonia is not usuallyassociated with schizophrenia, and it is asyndrome of motor dysregulation with a goodprognosis—if identified and treated early.This book is a pleasure to read, but shouldbe on the imperative reading list for allpsychiatric trainees to inform them aboutthe history of their discipline, the importanceof neuropsychiatry, and how to write clearly.

M R Trimble

BOOK REVIEWS

Year book of neurology andneurosurgery 2003

Edited by Scott R Gibbs and Ashok Verma.Published by Mosby, Philadelphia, 2003,pp 337, £73.99 (hardback). ISBN 0-323-02058-5

Every year, countless journals publish myriadneurology and neurosurgery papers. There isimmense attraction in the notion of a singlevolume yearbook that selects and commentsupon the best. So, how well does the Yearbookof neurology and neurosurgery succeed ininforming about significant advances inknowledge outside my own subspecialty areafor 2003? The editors draw their selectionfrom a survey of 500 journals, with some-thing from most of those with big impact.Thirty seven associate editors assisted byreviewing the various subspecialty areas; ofthese all except 11 come from North America,of whom 9 are neurosurgeons rather thanneurologists, an intriguing imbalance.Papers selected cover every conceivable

subspecialty, and sometimes the inconceivable.New gene mutations abound, illuminatingcase histories are provided, we learn thatthe visual cortex is hyper-excitable inmigraineurs, and about informed consentin neurosurgery, and we are treated topictures of new cranial remodelling devicesfor treating craniosynostosis. To provide acritical review of such a diversity of subjectmatter would be an impossibility. All onecan do is to congratulate the editors for high-lighting a selection of topics that opensone’s eyes to the dazzling diversity of ourspecialty. Nevertheless, you would not goto a yearbook for a comprehensive reviewof developments in a particular subspeci-alty. Therefore, this is essentially armchairreading, and none the less useful for that.

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New Oxford textbook of psychiatry,vols 1 and 2

M G Gelder, Jaun Lopez-Ibor Jr, Nancy CAndreasen, eds. Oxford: Oxford UniversityPress 2003, pp 2432, £125.00. ISBN 0-19-852810-8

The New Oxford textbook is the latest andlargest from the Oxford textbook of psychiatry’sstable. The book was originally published in2000 and has recently appeared in paperback.This is the best modern British textbook ofpsychiatry. It is over 2000 pages long andcomes in two stout volumes. The interna-tional editorship is led by Michael Gelder,Emeritus Professor of Psychiatry at Oxford,with Spanish (Jaun Lopez-Ibor) and American(Nancy Andreasen) co-editors. The book isinevitably based on a myriad of individualcontributions although the choice of contri-butor and standard of editing is exemplary.The first volume covers general issues and

the scientific basis of psychiatry, includ-ing a number of reviews of neurobiology.Interestingly, psychodynamic contributionshave a separate section. The remainder ofthe first volume is taken up with coverage ofthe clinical syndromes of adult psychiatry,including substantial coverage of dementia.The second volume includes review of

special topics with a number of articles onaspects of the psychiatry and medical condi-tions. This includes a useful chapter onneurological disease by Maria Ron, and onepilepsy by Brian Toone. The remaining partof the second volume addresses the psychia-tric subspecialties as well as having a substan-tial section on psychiatric treatments, bothpharmacological and non-pharmacological.This text is my personal first choice when I

encounter a problem in the clinic that I wantto look up—and I am rarely disappointed bywhat it says. This is a Rolls Royce of atextbook. There is a tendency to think ofbooks as large as this one (particularly at aprice of £125 even for the paperback) assuitable only for libraries. This would be amistake. Despite its size and price this book’saccessibility and comprehensiveness shouldmake it the first choice as a postgraduatehandbook, not only for psychiatrists but forneurologists and neurosurgeons too.

M Sharpe

The parallel brain: the cognitiveneuroscience of the corpus callosum

Eran Zaidel, Marco Iacoboni. Massachusetts:The MIT Press, 2003, pp 576, £61.95. ISBN 0-262-24044-0

Roger Sperry’s research on the cognitiveabilities of split-brain patients followingcallosal section is a landmark in the studyof brain–behaviour relationships. His studiesfirmly established the role of the corpuscallosum in inter-hemispheric informationtransfer. What have we learned more recentlyabout the role of the corpus callosum incognition? In this book Eran Zaidel (origin-ally one of Sperry’s students) and neurologistMarco Iacoboni present 22 chapters based ona 1996 NATO Advanced Science Institute thatattempt to answer this question. The centralfocus is on the classic problem of whyreaction time to respond to a light flashedin either visual field differs according towhether the ipsilateral or contralateral hand

is used to respond (known as thePoffenberger effect, after the psychologistwho described it in 1912). This is thoughtto reflect callosal information transferbetween the hemispheres; the book usesanatomical, physiological, and behaviouralperspectives to address the question of whatinformation is transferred and how thetransfer might take place. Many chaptersare accompanied by commentaries and edi-torial comment, giving a flavour of thedebates and controversies in the field.Perhaps reflecting the long interval betweenthe original conference and this book, morerecent studies that use functional neuro-imaging techniques to investigate callosalfunction are relatively poorly represented.However, there is still much of interest inthis otherwise comprehensive volume. Thechapters generally have a basic scientific focus,but chapters on multiple sclerosis, dyslexiaand alexia, schizophrenia, and attention deficithyperactivity disorder also contain muchthat will interest the practicing clinician.

G Rees

Magnetic resonance imaging instroke

Stephen Davis, Marc Fisher, Steven Warach,eds. Cambridge: Cambridge University Press2003, pp 266, £80.00. ISBN 0-521-80683-6

This book does much more than its titlewould suggest. Although mainly concernedwith magnetic resonance imaging (MRI) instroke, the text actually covers single photonemission computed tomography (SPECT) andpositron emission tomography (PET) imagingas well and containing one of the bestchapters ever written on computed tomogra-phy (CT) in stroke. The approach and contentreflect the predominance of neurologistsamong the editors and authors, with only afew radiologists, and is really aimed atneurologists and stroke physicians.The scene is set in the first chapter with a

discussion of the limitations of clinicaldiagnosis of stroke and the specific role thatimaging can play in diagnosing the type andcause of stroke. There is a superb chapter onCT in acute stroke, which exemplifies howthe role of imaging in any diagnostic processshould be evaluated. Separately, there is achapter on CT evaluation of cerebral bloodflow, a useful and practical introduction toMRI, discussion of conventional structuralMR techniques such as T2, FLAIR, andgradient echo sequences, and a section onMR angiography. Much of the rest of thebook (about half of it) is given over todiffusion and perfusion MRI, including itsevaluation in animal models, concepts ofidentifying the ischaemic penumbra, evalua-tion of transient ischaemic attacks, selectionof patients for new therapies and drugdevelopment trials, and finally a chapter onMR spectroscopy and a (very short) chapteron functional MR after stroke.Although written by MR enthusiasts, the

text is tempered with some discussion of thedrawbacks of MR, such as poorer patientaccessibility (compared with CT) and pro-blems of metallic foreign bodies. It alsomakes the point that, despite the hugeinterest in MR diffusion and perfusionimaging, the precise thresholds of definingirreversibly damaged tissue and tissue at riskare yet to be determined. Some aspects of

stroke MRI are not dealt with in much detail,for example classification or interpretation ofwhite matter lesions (frequently found instroke patients), or the identification andinterpretation of microhaemorrhages on MRand how they might influence decisionsregarding stroke treatment, or on usingdiffusion imaging to identify lesions inpatients with milder strokes or at later timeintervals after acute stroke (that is, notjust the first few hours). There is very littleon practical issues (perhaps reflecting theneurology rather than the radiologyapproach) such as how one assesses a strokepatient who is unable to speak prior to MR tomake sure that it is safe for the patient to gointo the magnet, and how one manages thepatient while in the magnet with respect tofactors such as oxygenation.Some of the authors express personal views

that not all readers will agree with. Forexample, in the chapter on assessment of atransient ischemic attack (TIA), the authorssuggest that the definition of a TIA shouldbe changed to one based on the presenceor absence of certain imaging features.Although this clearly represents a personalopinion expressed by the authors, my objec-tion to changing a classification that is sofundamental to stroke epidemiology andclinical practice is that only those with accessto an MR scanner with diffusion imagingwould be able to correctly diagnose a TIAusing this new classification. Not only that,but the diagnosis of TIA might be dependenton the ability of the local radiologist orclinician to spot subtle features of recentischaemia on diffusion, and on the timing ofscanning after symptom onset.I found it a little disappointing that a

proportion of the perfusion images were pre-sented in black and white when this is onetechnique which really requires colour displayfor proper interpretation and appreciation.In summary, this is a useful textbook,

particularly for neurologists or stroke physi-cians who need to understand more aboutimaging and its role in patient characterisa-tion, decision making, and assessment oftreatments in acute stroke. It’s not just aboutMR and everybody with an interest in strokeshould read the chapter on clinical efficacy ofCT in acute cerebral ischaemia. At just over250 pages it is easily digestible and yet also auseful reference. At £80.00 I think comparedwith other books on MR and on stroke itrepresents good value for money.

J M Wardlaw

Cortex and mind: unifying cognition

Joaquin M Fuster. Oxford: Oxford UniversityPress 2003, pp 284, £47.95. ISBN 0-19-514752-9

Joaquin Fuster is a distinguished Americanneuroscientist whose work has explored theneurophysiology of cognition, largely inanimals, but with the ultimate goal of under-standing how the humanmind is implementedin the brain. His own research has focusedparticularly on the neuronal basis of workingmemory, revealing ‘‘memory’’ cells in theprefrontal cortex that help to retain the infor-mation an animalmust ‘‘keep inmind’’ if it is toact appropriately after a delay—like the positionof a covered well containing food. Theseprefrontal memory cells are a key componentof an extensive cortical network required tomaintainworkingmemory, which also involves

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posterior brain regions closer to the sensorycortices, with a more traditional role in repre-senting our surroundings.Cortex and mind ranges far beyond the

confines of Fuster’s own experimental work.Its ambition is to describe how our keycognitive abilities—perception, memory, atten-tion, language, and intelligence—emerge fromthe widely distributed cortical networks, orcognits in Fuster’s terminology, which, hebelieves, represent the entirety of our knowl-edge. Fuster’s interesting position is thatinterwoven and sometimes identical networksare involved in each of these cognitive func-tions, which are therefore far less well localisedand less distinct than much of our contem-porary quasi-phrenological thinking suggests:no cognitive function has a fully dedicatedcortical area or network; conversely, a corticalnetwork or representation is at the dispositionof any and all functions.This view has a good deal of appeal;

perception is in part the reactivation ofmemory, attention is expressed in the chan-ging content of perception, language andintelligence emerge from the categories thatperceptual memory creates…and yet otherobservations, like the role of the medialtemporal lobes in acquiring declarative mem-ories, or of the fusiform gyrus in faceperception or inferior parietal lobe in spatialawareness, seem to call for a more finelydifferentiated theory of cortical function thanFuster’s general line of argument suggests.Fuster’s main thesis condemns him to

repeat himself at times as he works throughthe roster of our cognitive functions, and hetends to a rather abstract style. But there ismuch fascinating information to be foundhere—I particularly enjoyed the closingchapters on language and intelligence—andanyone who is used to locating corticalfunctions on colourful scans will find causefor thought in these pages.

A Zeman

The bard on the brain—understanding the mind through theart of Shakespeare and the scienceof brain imaging

Paul M Matthews, Jeffrey McQuain. New York:The Dana Press 2003, pp 222, £24.50. ISBN0-9723830-2-6

One of the great challenges of popular sciencewriting is to convey a coherent and consistentimpression of scientific ideas while avoidingconfusing, specialist terminology. The mostuseful tools for this task are metaphor andpictures. The Dana Press, publisher for theCharles A Dana Foundation, has as itsmandate ‘‘the provision of information aboutthe personal and public benefits of brainresearch’’. With The bard on the brain, theyhave chosen to use the voice of WilliamShakespeare, the master craftsman ofmetaphor, to introduce the areas of humancognition that have attracted the most atten-tion in recent functional imaging research.The logic behind this approach is that, asthe authors explain, ‘‘Shakespeare’s geniusderives from his keen insight into the humanmind’’ and that, in functional imaging,‘‘brain scientists finally have the means toaddress questions that Shakespeare so elo-quently put forward four centuries ago’’.The book is a play in seven acts, each of

which tackles a different field of research in

cognitive neuroscience, including perception,language, the inner world of memory andemotions, and the breakdown of the mind incertain neuropsychiatric disorders. Withinthese acts, each scene examines a particularfeature of the mind and illustrates howShakespeare dissected and explored it in hisown laboratory—the theatre. The scene openswith a quotation from a chosen play and abrief synopsis of the plot before moving on todiscuss the hard neuroscience underlying thiscognitive phenomenon as revealed by thelatest neuroimaging techniques. For example,in discussing the role of the frontal lobes inattention shifting and the planning of beha-viour, the example is chosen of Prince Hal,the wayward, youthful heir of Henry IV whopurposely turns from the influence of SirJohn Falstaff and his frivolous drinkingcompanions in order to develop the resolveand strength of character which will laterserve him well as King Henry V. This trans-formation is compared with the case ofPhineas Gage, the 19th century rail workerwho survived a dramatic penetrating injuryto his cranium but consequently displayed aremarkable alteration in his personality.Recent computed tomography reconstructionsof Gage’s skull by Hannah and AntonioDamasio have clearly delineated the passageof the three foot tamping iron through thefrontal cortex—the area ‘‘responsible for thefunctioning of what we call a moral sense’’.The concept is an entertaining one and the

authors have worked hard to bring it to life.The target audience presumably consists ofpeople with no specialist knowledge of eitherShakespeare or neurology and, if this is so,the reader will find plenty to hold his or herinterest. The rich neuroscientific tableauranges from Chomsky and language to thefunctional imaging of hallucinatory experi-ence in schizophrenia, while the bite-sizedchunks of Shakespeare successfully conveythe bard’s penetrating insight into the humanpsyche. The suggestion is that scientists, too,need to step outside the laboratory to findinspiration for their hypotheses. Lavish illus-tration with functional magnetic reson-ance imaging (fMRI), positron emissiontomography, and single photon emissioncomputerised tomography images, alongsidenumerous performance photos from wellknown theatre companies, give the book anenticing, coffee table appeal.However, the book suffers from the con-

tortions undergone in order to link theShakespearian poetry to the scientific project.Take, for example, the use of Macbeth’sgrasping at an illusory dagger to introduce adiscussion of the cerebellar control of com-plex motor acts, or the soliloquy fromHamlet’s murderous uncle, Claudius, whichbegins ‘‘O, my offence is rank, it smells toheaven’’ as a cue to show fMRI pictures of‘‘areas of the brain that become active withsmell’’. In addition, the simplistic, ratherthan simplified, portrayal of functional ima-ging is coupled with brain images that areoften unlabelled and poorly explained, givingthe impression of a gaudy backdrop used todistract from an empty plot. The inherentdanger in this approach is that, instead offacilitating public understanding of neuro-science, an aura of charmed infallibility iscreated. A brief mention of some of thelimitations of functional imaging techniqueswould have helped to avoid this pitfall.On balance, where this book succeeds, it

does so due to the infectious enthusiasm ofthe authors. The tortuous metaphors and

fancy pictures do not help much. Dialoguebetween science and literature has come along way since CP Snow gave his famousRede Lecture on the two cultures in 1950.Non-scientists are devouring popular sciencebooks—perhaps scientists need to reciprocatethe attention. The Bard on the brain couldcertainly be instrumental in encouraging usto get to the theatre more often.

C Butler

Parkinson’s disease, diagnosis &clinical management

Stewart A Factor, William J Weiner. New York:Demos Medical Publishers 2002, pp 716,$175.00. ISBN 1-888-799-50-1.

This multi-authored tome on Parkinson’sdisease (PD) admirably captures the com-plexity and diversity of the many clinicalchallenges and scientific problems that sur-round this common neurodegenerative dis-order. Contributions over 58 chaptersembrace an international body of expertise,with a pronounced north American empha-sis, and range from discussing the earlyhistory of the condition to a welcome sectionon social issues, with in depth attention paidto the clinical presentation, including psychol-ogical features, structural and chemicalpathology, theories of aetiopathogenesis,drug, surgical, and other treatments, andatypical and familial forms of parkinson-ism. The text is generously referenced andwell-illustrated with black and white fig-ures. There are impressive chapters on thecontribution of MPTP to our understandingof PD, genetic and environmental factors,and the drug classes employed in treat-ment as well as the complications oftreatment, including dyskinesia and motorfluctuations. Proper attention is given tothe management of psychosis and cognitivedecline, with discussion of the relationshipof these features in PD to dementia withLewy bodies and Alzheimer type pathology.Future avenues of treatment, includingneuroprotection and gene therapy, are alsocovered in this near encyclopaedic compen-dium, which is highly recommended for allthose who treat patients with PD inneurology, geriatrics, and old age psychia-try departments, as well as research scien-tists in the field, and it should be requiredreading for all neurological trainees.

R Pearce

Principles and practices ofemergency neurology—handbookfor emergency physicians

S M Shah, K M Kelly. Oxford: OxfordUniversity Press, 2003, pp 454, £40.00,(paperback). ISBN 0521009804

This is a handbook based on an earlier largerbook, Emergency neurology: principles and prac-tice, in response to enquiries from emergencymedicine residents about whether a hand-book, based on this main text, would beavailable. This is the result. Whether it isjustified in calling itself a handbook is hardto say. The area covers three of my hands(small!). It runs to over 400 pages withapproximately 50 authors. It covers neuro-logical examination and neurodiagnostic

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testing, common neurological presentations,for example headache and weakness, specificneurological conditions, for example mul-tiple sclerosis and cerebrovascular disease,neurological trauma, paediatric neurologicalemergencies, pregnancy related neurologicalemergencies, neurotoxicology, and brain death.So, it attempts a comprehensive coverage.The editors consider it to be symptom

based, although this is not always achieved.It has many tables, good illustrations, andmanagement of algorithms with ‘‘pearls andpit falls’’ at the end of every chapter.The neurological examination is done

poorly, particularly the cranial nerves. Thisneeds to be done with pictures of the lesions,their causes, and the anatomy, based aroundthe common emergency presentations inA&E. Although British neurologists woulddisagree with some of the advice given, mostof the text is reliable and clear. (For instance,in the chapter on myasthenia gravis, it states‘‘useful gauges include pulse oximetry, peakexpiratory flow and PCO2 measurement’’,which are all poor gauges of impending ven-tilatory failure and vital capacity is the mostimportant measurement in this respect.)The most disappointing feature is that the

chapters are not adequately focused onemergency conditions. The chapter on move-ment disorders covers virtually the wholespectrum of chronic movement disorderswithout specifically concentrating on thecommon acute presentations, such as druginduced dystonia with oculogyric crisis andhemiballismus, which are likely to come toA&E. Unfortunately the editors and authorshave failed to produce a sufficiently conciseaccount of emergency conditions to makethis book really useful. It needs to be muchbriefer and appropriately focused to achieveits aim and it would be better as a pocketbook, similar to the edition of the Oxford text ofmedicine, which seems to occupy the pocketsof most medical students! If only we couldachieve the same for the pockets of medicalSHOs in emergency neurology, things mightimprove!

D E Bateman

Duchenne muscular dystrophy, 3rdedn

Alan E H Emery, Francesco Muntoni. Oxford:Oxford University Press, 2003, pp 280, £79.50(hardback). ISBN 0-19-851531-6

Quite simply, this monograph is essentialreading for anybody involved with thisdevastating condition, and indeed for thoseinvolved with any form of muscular dystro-phy, whether in the clinic or in the labora-tory. Duchenne muscular dystrophy (DMD)is the archetypal dystrophy. It is because theclinical course is so stereotyped that it wasthe first of the dystrophies to be definedclearly, over a century ago. The historicaljourney from the first clinical descriptions toour present state of knowledge forms the coreof this book, with side branches relevant tothe identification of other specific forms ofdystrophy, particularly the limb girdle dys-trophies. The nihilist may suggest that all ofthis knowledge has as yet failed to find acure, but for the clinicians intimatelyinvolved with these patients we can now domore than ever to provide an improvedquality of life. There is of course great hopethat ‘‘genetic engineering’’ will lead to a cure,but patients and their families cannot live on

hope alone and Professors Emery andMuntoni have elegantly summarised presentmanagement options.The second edition was published in 1986,

a matter of months before the identificationof the gene involved in the disease processand its protein product dystrophin. Within afew years it became apparent that dystrophinand dystrophin associated proteins have afundamental role in various forms of mus-cular dystrophy, and for a while it looked as ifthere might be a common mechanism ofmembrane fragility due to dysfunction ofthese membrane associated proteins. Thenabnormal cytosolic proteins were found insome forms of limb girdle dystrophy and itbecame clear that there was no simple singledisease mechanism. Despite that, alteredfunction of membrane proteins is clearly offundamental importance in many dystro-phies and Muntoni has been at the forefrontof recent discoveries relating to alteredglycosylation of the membrane proteina-dystroglycan in various forms of congenitaland adult onset limb girdle dystrophies.There is no need to describe the individual

chapters in detail. In brief, the monographcovers the history of the disease (Emery beinga noted medical historian), clinical features,differential diagnosis, molecular pathology,pathogenesis, genetic counselling, and man-agement. Emery is retired from clinicalpractice but the clinical setting is kept up todate by his being joined by Muntoni for thistimely third edition.All those involved in the management of

DMD will find something of value in thisbook. Some patients and families may alsowant to dip into it. Those interested in thehistory of medicine, and the evolution ofmodern genetic and molecular techniques,will find it a fascinating story.Let us hope that a fourth edition, detailing

the successes of genetic engineering, will notbe too far off, but in the meantime there ismuch that can be done to alleviate theconsequences of this truly awful condition.

D Hilton-Jones

Mental and behavioral dysfunctionin movement disorders

Marc-Andre Bedard, Yves Agid, SylvainChouinard, Stanley Fahn, Amos D Korczyn,Paul Lesperance. New Jersey: Humana Press2003, pp 543, $185.00 (hardback). ISBN 1-58829-119-7

It was not long ago that the basal gangliawere confidently asserted to have no influ-ence on cognition, and to have only motorfunctions. This was the province of neurol-ogy, and the concept that they might beinvolved in disordered behaviour other thanthat referred to as movement disorders wasan anathema to generations of neurologists.As Goetz notes, in the introduction to this

nicely produced book, this view ignored overa 100 years’ of clinical observation, and muchsubsequent work, theoretical, clinical, neuro-chemical, and neuroanatomical, all of whichunderline the central role of the basal gangliastructures in regulating behaviour, in itswidest sense, and hence the associationbetween movement disorders and cognitiveand behavioural dysfunction.The openers in this text are with neuro-

anatomy and neurochemistry, rightly so sincethe impact of the discovery of dopamine and

the unveiling of the new neuroanatomy ofthe limbic forebrain,have fundamentally alteredthe way we think about the brain and itsfunctions, and should profoundly influencedclinical thinking. A chapter on the cerebellumis also included in the opening section.The book then contains chapters on two

main themes, cognition in movement dis-orders, including the long controversial areaof links with dementia, and the neuro-psychiatry of movement disorders. The maindiseases discussed are the obvious epon-ymous ones of Parkinson’s, Huntington’s,and Gilles de la Tourette, as well as cortico-basal degeneration. There are some curiousomissions, Wilson’s disease, Sydenham’schorea, and supranuclear palsy, amongothers. The cognitive problems embrace suchtopics as speech disorders and apraxias, andinclude chapters on animal models as well asclinical research.The section on neuropsychiatric aspects is

laid out rather differently and less system-atically. A chapter on mood disorders and thepallidum, another on depression and thebasal ganglia, another on psychosis and mooddisorders in Huntington’s disease, some dis-ease orientated, others anatomically based.Nevertheless, the individual chapters are, forthe most part, well written, and included arecontributions on REM sleep behaviour disor-der, psychogenic movement disorders, andobsessive compulsive disorder. A separatesection is devoted to quality of life studies.The book is a timely reminder of the

growth of interest in and the clinical impor-tance of neuropsychiatry, and quite somespace in the text is given to treatment andmanagement issues. No longer can the basalganglia simply be viewed as structures sub-serving motor function, they represent drivesand affects which are re-represented corti-cally and which propel our very being.

M Trimble

CORRECTIONS

doi: 10.1136/jnnp.2003.029074corr1

In the review by Rockwood in the May issueof JNNP (K Rockwood. Size of the treatmenteffect on cognition of cholinesterase inhibi-tion in Alzheimer’s disease. J Neurol NeurosurgPsychiatry 2004;75:677–85) there is an incor-rect entry on the x axis each of the tables infigure 1. The sixth entry should read 0.25,instead of 0.5. The corrected table can beviewed at http://www.jnnp.bmjjournals.com/cgi/content/full/75/5/677/DC1

doi: 10.1136/jnnp.2003.034876corr1

The authorship list of the letter entitledemotion process in the minimally consciousstate, by Bekinsctein et al (JNNP May2004;75:788), was incorrectly printed as TBekinschtein, J Niklison, L Sigman, F Manes,R Leiguarda, J Armony, A Owen, SCarpintiero, and L Olmos. However, thecorrect order is as follows: T Bekinschtein, RLeiguarda, J Armony, A Owen, S Carpintiero,J Niklison, L Olmos, L Sigman, F Manes.

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