544 Letters to the Editor

mum.-

Figure 1 Brain CT showing a low densityarea involving the frontal right lobe.

attainement (phonological and semanticword fluency, sentence construction test);verbal memory (Rey's 15 word memorytest); visual memory (immediate visualmemory test); and abstract thinking (simpleanalogies, Raven's coloured progressivematrices). The overall cognitive perfor-mance was measured by the mental deterio-ration battery5 which takes into accountresults obtained on eight tests: phonologicalword fluency, sentence construction, shortterm recall, delayed recall, immediate visualmemory, simple copy, copy with landmarks,and Raven's coloured matrices. The globalcognitive performance was normal. Asexpected, of the individual cognitive tasks,only the simple copy and copy with land-marks were abnormal.The most intersting findings were made

assessing his ability to play the piano andwrite music. The patient was requested toplay what he saw on one page of unfamiliarmusic using both hands. Next, he wasinstructed to search for and cross out all the

notes previously played, with a pencil in hisright hand and without a time limit. Thesheet of music was placed with respect tothe midline of his body and this placementwas held constant across all the differenttasks. Almost without exception, the patientaccurately played all notes on both sides ofthe page, using the entire keyboard and allpedals appropriately. Despite this good per-formance, when asked to cross out the noteshe had just played, he cancelled the notes onthe right side of the page and neglected 75%of those on the left side. Moreover, when heattempted to write a new musical theme or a

simple scale, he again omitted the left side ofthe page (fig 2). To better understand thepatient's awareness of the notes on the leftside of the page, the patient was requestedto sing the musical pieces before playingthem. Again, when singing he did notneglect words or notes on the left side.

Unilateral visuospatial neglect syndromeis characterised by a broad range of presen-tations that may be apparent only duringspecific situations or when performing dif-ferent tasks. More commonly, it is not an"all or none phenomenon", such that sepa-rate tests may not identify the neglect syn-drome in all patients.4 Additionally, singledeficits are not always evident with the same

aspect and extent during different tasks.6According to other authors,7 patients with

non-dominant right lobe injury may beunable to focus their attention on singlecomponents on the left side of a global fig-ure, yet they may have a well structuratedglobal perception. These patients have animplicit awareness of stimuli that are notseparately perceived and identified. Ourpatient's neglect was particularly evidentwhen focal attention was concentrated onsingle elements of a more complex presenta-tion. As shown by his capacity to play thepiano and to sing music, our patient couldhave a global perception of the music but hewas clearly unable to shift his attention onsingle notes. The modularity of music per-ception and reproduction has previously

X =~~,,

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Figure 2 The patient's attempts to write a musical scale (top) and to draft a composition. Bothseries were begun from the centre of the page. The left hand side was systematically ignored.

been shown.8 Indeed, it has been suggestedthat musical competence might be shifted tothe left hemisphere in persons with highermusical education.9 Perhaps, our patient'sneglect was similar to that of a patientrecently described by Marshall and Halligan:"He can perceive the whole forest, but onlyhalf the trees".'0 Interestingly, whereas thepatient described by Marshall and Halliganshowed both parietal and frontal lesions, CTof our patient showed only a frontal infarc-tion, which may represent the real culprit inthis syndrome.

FRANCESCO LANDIGIUSEPPE ZUCCALAALBERTO COCCHI

ROBERTO BERNABEIALESSIA TAFANI

PIERUGO CARBONINInstitute of Internal Medicine and Geriatrics,Catholic University ofSacred Heart,

Rome, ItalyCorrespondence to: Dr Francesco Landi, Depart-ment of Geriatrics, Catholic University of SacredHeart, Largo A Gemelli 8, 00168, Rome, Italy.

1 Marshall JC, Halligan PW. Imagine only thehalf of it. Nature 1993;364:193-4.

2 Marshall JC, Halligan PW. Blindsight andinsight in visuo-spatial neglect. Nature 1988;336:766-7.

3 Heilman KM, Watson R, Valenstein E.Neglect and related disorders. In: HeilmanKM, Watson R, eds. Clinical neuropsychology.3rd ed. New York: Oxford University Press,1993.

4 Cermak SA, Lin K. Assessment of unilateralneglect in individuals with right cerebralvascular accident. Topics in GeriatricRehabilitation 1994;10:42-55.5 Caltagirone C, Gainotti G, Masullo C, MiceliG. Validity of some neuropsychological testsin the assessment of mental deterioration.Acta Psychiatr Scand 1979;60:50-6.

6 Herman EW. Spatial neglect: new issues andtheir implications for occupational therapypractice. Am J Occup Ther 1992;46:207-16.7 Halligan PW, Marshall JC. Toward a princi-pled explanation of unilateral neglect.Cognitive Neuropsychology 1994;- 1: 167-206.

8 Basso A, Capitani E. Spared musical abilitiesin a conductor with global aphasia and ideo-motor apraxia. J Neurol Neurosurg Psychiatry1985;48:407-12.

9 Bever T, Chiarello R. Cerebral dominance inmusicians and non-musicians. Science 1974;185:357-9.

10 Marshall JC, Halligan PW. Seeing the forestbut only half the trees? Nature 1995;373:521-3.

Two unusual clinical presentations ofthe mitochondrial DNA A3243G pointmutation in adult neurological practice

The most often identified mitochondrialtRNA gene point mutation is at position3243 (A to G) in the mitochondrial transferRNA gene for leucine (UUR). It was origi-nally described in association with themitochondrial encephalomyopathy, lacticacidosis, and stroke-like episodes (MELAS)phenotype, but is increasingly recognised tooccur in association with other phenotypes.Disease associated with this point mutationpresents in childhood or early adult life inthe vast majority of cases and there are oftenother affected family members in the matri-lineal line.'-3 In this report we describe twopatients presenting with unusual phenotypesover the age of 50 years without any familyhistory. We highlight the importance of con-sidering mitochondrial disease associatedwith this mutation in this age group andshow that it may have important investiga-tive and prognostic implications.

Patient 1 was a right handed 51 year oldman who presented with a three day historyof progressive difficulty using his left side,and left sided inattention. A year previouslyhe had presented with a noctural seizure and

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Letters to the Editor

a few days later developed fluent dysphasiaover the course of a day. Brain CT at thattime was reported as showing a left temper-oparietal infarction. His speech had recov-ered completely but residual mild cognitivedifficulties had been noted by his family.Normal investigations at that time includedtransthoracic echocardiography, carotidDoppler imaging, autoimmune screen, andthrombophilia screen. There was no familyhistory of stroke or other neurological dis-ease.

Neurological examination showed leftsided neglect. He had a non-dominant pari-etal lobe syndrome. He showed pronounceddressing apraxia, left sided astereognosis,dysgraphaesthesia, left/right disorientationand was disoriented in the ward environ-ment. He persistently held his left arm in anextended elevated posture. Muscle powerwas normal throughout. General and cardio-vascular examination were normal.

Brain MRI was abnormal (figure). The T2axial scan showed extensive abnormal signalinvolving the cortex and white matter of theright parietal and temporal lobes. Theaffected gyri were swollen with sulcal efface-ment and mild ventricular compression. Theright occipital lobe was also involved to alesser degree. Intra-arterial angiographyshowed an area of neovascularisation in theright parietal lobe supplied predominantly bysmall new vessels arising from the distal rightpericallosal artery. The MRI appearenceshad initially raised the possibility of a spaceoccupying lesion; however the presence ofneovascularisation on angiography suggestedthat the abnormality seen was primarilyinfarction although not conforming to a sin-gle vascular territory. This combination ofMRI and angiographic appearences was sug-gestive of a MELAS type lesion and a musclebiopsy was therefore undertaken. This wasdiagnostic of a mitochondrial myopathyshowing ragged red fibres and fibres demon-strating both increased and absentcytochrome c oxidase (COX) staining.Analysis of mtDNA extracted from muscleshowed 87% A3243G point mutation.Resting serum lactate was normal. Thepatient was managed conservatively andmade a good functional recovery.

Axial T2 weighted image of brain ofpatient 1

illustrating areas of increased signal in the righttemperoparietal and occipital regions.

Patient 2 was a 69 year old man who hada two year history of progressive generalisedmuscle wasting, weight loss, and decreasingexercise tolerance. He gave a six month his-tory of slurring dysarthria. He had previ-ously been fit and well and had been anactive sportsman. He had a brother who haddeveloped epilepsy as a boy and had insulintreated diabetes mellitus. There was noother family history of neurological disease.

Neurological examination showed pro-nounced generalised muscle wasting. Eyemovements were normal but he had a slightright ptosis. There was a mild bulbar slur-ring dysarthria and mild weakness of neckflexion. He had global proximal and distallimb weakness MRC grade 4. He was are-flexic. There were occasional fasiculations.

Creatine phosphokinase was persistentlymildly increased at three times the upperlimit of normal. Electrophysiological studiesshowed normal sensory studies and conduc-tion velocities. There was no evidence ofconduction block. Needle EMG was consis-tent with widespread denervation and rein-nervation showing positive sharp waves,spontaneous fasciculations, and giant motorunit potentials in all four limbs. The pro-gressive muscular atrophy variant of motorneuron disease was considered but in viewof the absence of any upper motor neuronsigns a muscle biopsy was performed. Thisshowed charcteristic features of a mitochon-drial myopathy. There were many raggedred fibres and there were fibres showingincreased and absent staining with the COXstain. ATPase staining showed fibre group-ing consistent with denervation and reinner-vation. Analysis of mtDNA extracted fromblood and muscle showed the A3243G pointmutation (5% in blood and 56% in muscle).This mutation was not detected in hisbrother's blood. The patients resting lactatewas twice the upper limit of normal. He wastreated with ubiquinone and subjectivelyfeels better although objectively examinationnine months later showed no change in hislimb weakness but evidence of an earlyexternal ophthalmoplegia. His resting serumlactate remains increased.

Although the mitochondrial encephalo-myopathies are a group of disorders whichhave the common theme of disordered respi-ratory chain function they are recognised tobe clinically and biochemically heteroge-neous.4 This has made classification diffi-cult. The discovery of primary mutations ofmtDNA initially suggested that that theremay be genotype-phenotype correlations.5However, it is increasingly apparent that thesame genotype can be associated with arange of phenotypes which are separate.This seems to be especially the case for dis-ease associated with the A3243G pointmutation. This mutation was originallydescribed in association with the MELASphenotype which has been defined byHirano and colleagues6 using the following"invariant' criteria: (1) multiple stroke-likeepisodes before the age of 40 years, (2)encephalopathy characterised by seizures, ordementia, or both, and (3) lactic acidosis orragged red fibres, or both. They suggest thatthe diagnosis may be considered secure ifthere are at least two of the following: nor-mal early development, recurrent headache,or recurrent vomiting. However, only abouthalf the patients harbouring the A3243Gpoint mutation exhibit the MELAS pheno-type in most series.' 2 The other phenotypesdescribed include chronic progressive oph-thalmoplegia, other encephalopathic ill-

nesses without stroke, diabetes mellitusalone, and with deafness and, rarely, myopa-thy alone.' I In the vast majority of reportedcases disease onset is in childhood or youngadult life. Hammans et al reported three outof 20 probands harbouring the A3243Gmutation presenting over the age of 50. Twoof these had progressive external ophthalo-moplegia, an easily recognisable mitochon-drial disease phenotype.' Ciafaloni et alreported that one of 21 typical MEIAS(A3243G) cases presented at the age of 50years.2 Moraes et al reported that none oftheir 16 cases with atypical A3243G pheno-types presented over the age of 42.3

Although patient 1 reported here has radi-ological features consistent with the MELASsyndrome7 the clinical presentation is quitedifferent from that of typical MELAS casesand he does not meet the "invariant' criteriaproposed by Hirano et al.6 It is well recog-nised that the A3243G mutation should belooked for in cases of young atypical strokebut the patients illustrated here indicate thatit should be considered as a cause of strokein older patients, particularly if the clinicalevolution and radiological features are atypi-cal. The findings of mild fibre type groupingand electrophysiological changes consistentwith denervation and reinnervation inpatient 2 suggest that the A3243G mutationmay be causing anterior horn cell dysfunc-tion in this patient.The patients reported here further high-

light the phenotypic variation associatedwith the A3243G point mutation and indi-cate the importance of considering mito-chondrial disease associated with thismutation in this age group. Both of thesepatients were sporadic with no other familymembers exhibiting more typical A3243Gassociated phenotypes. In patient 1 a brainbiopsy had been considered before the cor-rect diagnosis was achieved, whereas inpatient 2 the prognosis for his mitochondrialmyopathy is likely to be better than that ofthe progressive muscular atrophy variant ofmotor neuron disease. The selection ofwhich patients to investigate over the age of50 years, who do not have classic mitochon-drial phenotypes, remains difficult due tothe wide range of potential presenting symp-toms. However, in younger patients withboth complex combinations of CNS symp-toms with or without muscle weakness orwith purely peripheral neuromuscular symp-toms a mitochondrial disorder should enterinto the differential diagnosis. The highestyielding investigation remains muscle biopsyfor histochemistry, mitochondrial DNAanalysis, and biochemical respiratory chainanalysis.8The precise explanation for the pro-

nounced phenotypic diversity associatedwith the A3243G mutation remainsunknown. Additional intragenic mutationswhich modulate the consequence of themutation have recently been suggested' butthere are other possibilities. It does not seemto be solely a reflection of the mutation loadand its tissue distribution.' Further study ofsuch late onset patients who seem to be ableto tolerate the presence of the mutation formany years before manifesting disease mayhelp to elucidate the origins of this diversity.

MG HANNAJR VAUGHANPA SILBURNPTG DAVIS

RCD GREENHALLDepartment of Clinical Neurology.

MV SQUIERDepartment ofNeuropathology

KR MILLS

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546 Letters to the Editor

Department ofNeurophysiologyS RENOWDEN

Department ofNeuroradiology, Radcliffe Infirmary,Oxford, UKA SELLAR

DNA Laboratory, Churchill Hospital. Oxford, UK

Correspondence to: Dr MG Hanna, Departmentof Clinical Neurology, Institute of Neurology,Queen Square, London WC1N 3BG, UK.

1 Hammans SR, Sweeney MG, Hanna MG,Brockington M, Morgan-Hughes JA,Harding AE. The mitochondrial DNA trans-fer RNAL'U(UUR) A->G(3243) mutation: a clinicaland genetic study. Brain 1995;118:721-34.

2 Ciafaloni E, Ricci E, Shanske S, et al. MELAS:clinical features, biochemistry, and moleculargenetics. Ann Neurol 1992;31:391-398.

3 Moraes CT, Ciacci F, Silvestri G, et al.Atypical clinical presentations associatedwith the MELAS mutation at position 3243of human mitochondrial DNA. NeuromuscDisord 1993;3:43-50.

4 Morgan-Hughes JA. Mitochondrial diseases.In: Engel AG, Franzini-Armstrong C, eds.Myology. New York: McGraw Hill 1995:1610-60.

5 Goto Y, Nonaka I, Horai S. A mutation in thetRNA Leu(UUR) gene associated with theMELAS subgroup of mitochondrialencephalomyopathies. Nature 1990;348:651-3.

6 Hirano M, Ricci E, Koenigsberger MR, et al.MELAS: an original case and clinical criteriafor diagnosis. Neuromusc Disord 1992;2:125-35.

7 Rosen I, Phillips S, Enzmann D. Magnetic res-onance imaging in MELAS syndrome.Neuroradiology 1990;32: 168-71.

8 Jackson MJ, Schaefer JA, Johnson MA, et al.Presentation and clinical investigation ofmitochondrial respiratory chain disease: Astudy of 51 patients. Brain 1995;118:339-57.

MATTERSARISING

Brain and spinal cord MRI in motorneuron disease

We read with interest the article by Thorpeet al I raising the question of the importanceof MRI alterations as prognostic factors inmotor neuron disease. In a retrospectivestudy at our institute, we also found signalabnormalities in MRI along the pyramidaltracts in 11 of 16 patients affected by amy-otrophic lateral sclerosis.2 In all of them,symmetric hyperintensity in T2 weightedimages were recognisable at the level of thecorona radiata, in the internal capsule andthe cerebral peduncles; in two of these casessignal changes were also present in the pons.When the patients with and without MRIabnormalities were compared, we failed tofind prognostic factors. Age, spinal or bulbaronset, disease severity as assessed by theNorris scale,3 time interval between onset ofdisease and MRI investigation, duration ofdisease (time interval between onset anddeath or study closure) did not differbetween the two groups of patients.Conversely, MRI signal abnormalities wereassociated with more pronounced uppermotor neuron signs. Thus in our experience,alterations in MRI do not have a prognosticvalue but they simply reflect the severity ofpyramidal tract degeneration. As Thorpe etal suggested,' abnormalities of MRI may behelpful in early diagnosis of motor neurondisease. However, this has to be confirmedin further studies, as neuropathologicalexaminations have shown great variability in

the expression of the involvement of thepyramidal tracts even in the typical cases.4

D TESTAF CARELLA

Division ofNeurology,National Neurological Institute "C Besta ",

Milan, ItalyCorrespondence to: Dr D Testa, Divisione diNeurologia, Istituto Nazionale Neurologico "CBesta", V Celoria 11, 20133, Milano, Italy.

1 Thorpe JW, Moseley IF, Hawkes CH,MacManus DG, McDonald WI, Miller DH.Brain and spinal cord MRI in motor neurondisease. J Neurol Neurosurg Psychiatry 1996;6:314-7.

2 Carella F, Grisoli M, Savoiardo M, Testa D.Magnetic resonance signal abnormalitiesalong the pyramidal tracts in amyotrophiclateral sclerosis. Ital J Neurol Sci 1995;16:511-5.

3 Norris FH Jr, Calanchini PR, Fallat RJ,Panchari S, Jewett B. The administration ofguanidine in amyotrophic lateral sclerosis.Neurology 1974;24:721-8.

4 Bronwell B, Oppenheimer DR, Hughes JT.The central nervous system in motor neurondisease. J7 Neurol Neurosurg Psychiatry 1970;33:338-57.

NOTICE

Announcement from the BritishNeuropsychiatry Association: 1997summer meeting

The 1997 summer meeting of the BNPAwill be held jointly with the AmericanNeuropsychiatry Association on 20-22July at Robinson College, Cambridge,UK. It will include half day sessionson frontosubcortical circuits and emotion/reward/violence, and the presentation ofshort scientific papers, posters, and singlecase videos by members. The winner of the1997 BNPA Prize will be announced. Twoprizes of £200 each will be given to the bestpaper/poster presentations by junior mem-bers. The AGM of the BNPA will be heldon 21 July.

For further details of this meeting pleasecontact Suzanne Miller, 44 Roan Street,London SEIO 9JT. Telephone 0181 8582699; fax 0181 853 4416; e-mailwight@compuserve.com.

For details of membership of the BNPA, whichis open to psychiatrists, psychologists, neurolo-gists, and those in related fields, please contactDr J7onathan Bird, Secretary BNPA, BurdenNeurological Hospital, Stoke Lane, Stapleton,Bristol BSI 6 IQT.

BOOKREVIEWS

All titles reviewed here are available fromthe BMJ Bookshop, PO Box 295, LondonWC1H 9TE. Prices include postage in theUnited Kingdom and for members of theBritish Forces Overseas, but overseascustomers should add £2 per item forpostage and packing. Payment can be made

by cheque in sterling drawn on a UnitedKingdom bank, or by credit card(Mastercard, Visa or American Express)stating card number, expiry date, and yourfull name.

Pituitary Adenomas. Edited by A MLANDOLT, M L VANCE and P L REILLY. (Pp656; £125-00.) Published by ChurchillLivingstone, Edinburgh. 1996. ISBN0443051348.

I very much enjoyed reviewing this bookwhich has been edited by three neurosur-geons, from Europe, the United States andAustralia. It is a very complete text whichcovers everything that you wanted to knowabout pituitary adenomas and would previ-ously have had to search widely for contem-porary answers. The editors have succeededin commissioning a wide range of expertopinion covering all related specialist areas.The chapters have been logically arrangedand there are many high quality illustrationsincluding colour plates of histological slides.This is essential to achieve adequate clarityfor interpretation by the non-expert reader.Inevitably there is some repetition, but insome ways this is no bad thing as the chap-ters can be read in isolation.As a surgeon I was particularly interested

in the chapters covering radiology, microsurgical anatomy, the history of pituitarysurgery and current surgical techniques. Thecontemporary surgeon largely operates viathe transnasal transphenoidal approach withminimal morbidity and high rates of cure.These remarkable achievements rely verymuch on sophisticated pre and per operativeimaging techniques and the use of the oper-ating microscope. Following an excellentand detailed account of the trans-sphenoidalapproach there are further chapters on surgi-cal results and prognosis for the variouspituitary adenomas.

Following on from surgical considerationsare excellent and very readable chapters cov-ering the medical treatment of the differentendocrinopathies associated with pituitarytumours. I particularly enjoyed the chapterson the different radiotherapeutic approachesto pituitary tumours. I have never been cer-tain about which patients can safety bespared the potential long term morbidity ofthis treatment. Although optic neuropathy,brain necrosis and vascular injury are themost feared complications, hypopituitarismrequiring hormonal replacement therapyeventually develops in a large proportion ofpatients after fractionated radiotherapy. Itseems increasingly clear that despite full hor-mone replacement therapy many patientswith iatrogenic hypopituitarism have areduced quality of life.The clinical features, diagnosis, and man-

agement of pituitary apoplexy are covered ina single chapter. This gives sound advice tothe non-specialist neurosurgeon who may becalled upon to deal with these cases whenthey present as emergencies. I would concurwith the view that the beneficial effects onneurological, visual, and endocrine functionsare sound reasons for early surgical interven-tion by the transphenoidal approach. Theimproved prognosis of pituitary apoplexythat has been achieved by contemporarymanagement is amply illustrated by the factthat all 12 patients in the first publishedseries of apoplexy were diagnosed atnecropsy.

Overall I think that this is an excellent

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