Journal ofNeurology, Neurosurgery, and Psychiatry 1992;55:16-19

Bilateral striatal necrosis, dystonia andoptic atrophy in two siblings

V Leuzzi, E Bertini, A M De Negri, M Gallucci, B Garavaglia

AbstractTwo siblings developed a neurologicaldisorder in the first decade characterisedby generalised dystonia, hypokinesia,and subacute visual loss. CT and serialMRI examinations showed bilaterallesions of the striatum, mainly in theputamen. The classification of thesepatients is discussed in relation toinfantile bilateral striatal necrosis(IBSN), Leigh's disease, and Leber'soptic neuropathy. The literature shows aclinical and aetiopathogenetic overlapbetween these syndromes. In our casesparental consanguinity and the in-volvement of a single generation suggesta new clinical condition with autosomalrecessive transmission.

With the development of non-invasive diag-nostic techniques, there has been an increase inreported cases of a progressive dystonic syn-drome beginning in childhood and associatedwith selective lesions of the basal ganglia.'2Improvement of CNS investigations hasbrought new criteria for the differential diag-nosis between idiopathic and secondary dys-tonias.3 We report two siblings with dystonia,hypokinesia, symmetrical striatal necrosis, andvisual failure. These cases, together with otherspreviously reported,4 may represent a newclinical entity.

Istituto diNeuropsichiatriaInfantile, Universita"La Sapienza", RomaV LeuzziOspedale "BambinoGesu9", RomaE BertiniClinica Oculistica,UniversitA "LaSapienza", RomaAM De NegriIstituto di Radiologia,Universita de L'AquilaM GallucciIstituto Neurologico"Besta", MilanoB GaravagliaCorrespondence to:Dr Leuzzi, Istituto diNeuropsichiatria Infantile,Via dei Sabelli, 108. 00185Roma, Italy.Received 10 September 1990and in final revised form1 March 1991.Accepted 8 March 1991

PatientsThe parents were first cousins. The paternalgrandfather had suffered from left hemiparesis,which started at the age of 8 years during anunspecified exanthematic illness. The couplehad four children, and the two patients were theproduct of the second and third pregnancyrespectively (the latter was a dizygotic twinpregnancy).

Case IThis 20 year old woman had had a normal birthand development. At the age of 6 years shecontracted measles. Four days after exanth-ematic eruption she had transient (a fewseconds) amaurosis which disappeared spon-taneously without further effects. Six monthslater she experienced a painless rapid bilateraldeterioration in visual acuity. At the age of 7she began to invert and plantar flex the left footwith dorsiflexion of the big toe when walking;dystonia then slowly progressed to involve herleft arm. At the age of 10, she underwent leftAchilles tendon and extensor hallucis longus

tendon lengthening procedures. At the age of1 1, the left dystonic hemiparesis worsened: thehip and the knee were flexed, the foot wasequinovarus, the toes plantar flexed. The armexhibited athetoid postures and movements.Both optic discs were pale. Visual acuity wascorrectable to VR 1/10, VL 10/10. A CT scanshowed an area of low attenuation in the rightputamen and in the head of the right caudatenucleus with slight enlargement of thehomolateral ventricle.The patient was re-examined in April 1987 at

the age of 18. In addition to dystonic posturesand movements of the left limbs, there wasdistinct generalised hypokinesia and bradykin-esia. Both arms presented high frequency distalpostural tremor; there was a plastic rigidity oflimbs and tendon reflexes of the left leg wereweak. The left kneecap was dislocated upwardbecause of the shortening of the rectus femoris,which showed regular, almost rhythmical (2-3 Hz), myoclonic jerks either in the restingcondition or during leg movement. She had anexternal squint. Ophthalmoscopy revealed abilateral optic atrophy; the vessels wereunusually tortuous. On examination, the visualacuity was correctable to VR 3/50,VL 2/10; thestudy of visual fields (Goldmann) showed anabsolute centrocaecal scotoma with a small areaofnormal central vision on the right eye and anabsolute centrocaecal scotoma, multiple abso-lute paracentral, and peripheral scotomas onthe left eye. The right pupil was larger than theleft, but light and near reflexes were normal.Visual evoked responses to flash stimuli showednormal voltage and latency; no cortical respon-ses were evoked by patterned stimuli. Brain CTand MRI scans showed bilateral putaminallesions and involvement ofthe head ofthe rightcaudate nucleus (fig 1). Fasting resting bloodlactate concentration was normal, but bloodpyruvate and alanine concentrations wereelevated (8-8 mg/l, normal range 3-6-5-9 mg/l,and 1061-3 uM/1, normal range 273-449 ,uM/l,respectively). She was re-examined in October1989. Visual acuity had worsened, and shecomplained of episodes of sudden transientamaurosis for about 10 minutes several times aday. Neurological, neuro-ophthalmological,and neuroradiological (MRI) examinationswere unchanged. Her mental functionremained unaffected.

Case 2This 11 year old boy had been born preterm(eight months, weight 2550 g) after an uncom-plicated twin pregnancy and delivery. Growthand development were normal until the age of 7

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Bilateral striatal necrosis, dystonia and optic atrophy in two siblings

Figure 1 MRIexamination of case I aged18years:left-Ti-weighted (IR1800/400) axial sequence;both putamina (arrows)and head of right caudatusnucleus (curved arrow)show hypointense signal;head of left caudatus andanterior third of leftputamen are normallyrepresented; right-Ti-weighted (SE 350/30)coronal scan; arrowsindicate bilateralinvolvement ofputamina.

years and 10 months, when his parents noticedthat his right arm irregularly adopted bizarrepostures (extension and adduction of the arm,pronation of the forearm and hand). Despiteabnormal postures, the child could performskilful movements (such as writing). When 9years old, he developed an increasingly severerigidity of the left leg which disturbed walking.The homolateral upper limb was flexed with aclenched fist. He became anorexic and asthenic.On examination (in April 1987), at the age of9 years and 5 months, he was a pale boy withnormal somatic growth, poor muscle develop-ment, and dystonic movements and postures ofthe limbs (left more than right). The mostconsiderable neurological disorders of thearms, however, were hypokinesia and brady-kinesia, which were the cause ofclumsiness andinadequacy in intentional skilled movements.There was plastic rigidity and mild weakness(left more than right). Tendon reflexes werebrisk and polyphasic with bilateral Babinski'ssigns. Speech was quiet, slow, monotonous,and somewhat slurred. Sensation was intact.Mental function remained unaffected.Both optic discs showed temporal pallor, and

the retinal vessels were narrowed. On examina-tion, the visual acuity was correctable to VR 5/10, VL 8/10; perimetry showed a distinctconcentric constriction of visual fields and en-hanced blind spot. Colour vision was impairedin the red-green region (Ishihara test). Non-sustained horizontal nystagmus to the rightwas present. Visual evoked responses to flashstimuli showed normal voltage and latency;pattem reversal VEPs showed low amplitude,delayed P2 component (140 ms) in 01, and anormal response in 02. A brain CT scan andMRI examination showed bilateral selectivelesions of the putamina (fig 2). His fastingresting blood lactate concentration was normal,but on four separate occasions the bloodpyruvate concentration was elevated one and ahalf to three times the normal values. Pyruvateoxidation and respiratory chain function of

cultured fibroblasts were normal. Histo-chemical and ultrastructural studies of leftdeltoid muscle biopsy specimens showed noabnormalities.The patient was re-examined when 10 years

old. He walked with more difficulty. Intentionalmovements of the arms were slow and clumsy;his speech was slurred and writing muchslower. There was generalised muscularhypotrophy and weakness. Visual acuity wascorrectable to VR 4/10, VL 6/10. A secondbrain MRI examination was unchanged. Heunderwent clinical assessments every sixmonths until June 1990. Neurological, neuro-ophthalmological, and neuroradiological(MRI) examinations revealed no change fromhis previous state. He had no intellectualimpairment or learning difficulties. His somaticdevelopment, however, was arrested (heightbelow 10% and weight below 3%).The analysis of mitochondrial DNA

obtained by PCR-amplification on total DNAfrom muscle specimens showed a normal SfaNI digestion of the 316 bp PCR product, thatincludes the nt 11778 mutation associated withLeber's hereditary optic neuropathy5 (Dr CGellera, Istituto Neurologico "Besta" Milano).In both patients values were normal for thefollowing analyses: standard blood and urinarystudies, VDRL, serum copper and caerulo-plasmin, 24 hour urinary copper, serum lipid,serum protein electrophoresis, plasma andurinary aminoacid chromatography, urinarymucopolysaccharides, urinary organic acids,urinary arylsulfatase-A, and an assay of lyso-somal enzymes in white blood cells and fibro-blasts in case 2. EMG and nerve conductionstudies, EEG, BAEP, SEP, ERG, and slit lampexamination for Kayser-Fleischer ring werealso normal. The twin of case 2 has beensurveyed for four years. He is an intelligent,normal child with no motor or neuro-ophthal-mological disability. Three brain MRI examin-ations performed at intervals of six monthsgave normal results.

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Leuzzi, Bertini, De Negri, Gallucci, Garavaglia

Figure 2 MRIexamination of case 2 aged10 years. Selectiveinvolvement of bothputamina (arrows),appear hypointense inTi-weighted(IR 1800/400) (left) andhyperintense inT2-weighted (SE1800/120) sequence(right). Caudate nucleiand anterior portion ofright putamen shownormal signal intensity.

DiscussionThe two siblings reported here show anuncommon clinical disorder characterised bydystonic movements and postures associatedwith generalised hypokinesia, subacute visualloss ofvarying degrees, and bilateral and selec-tive lesions of the striatum detected byneuroradiological techniques (CT and MRI).Mental deterioration was absent. We suggestthat three clinico-pathological conditionsshould be considered; infantile bilateral striatalnecrosis (IBSN), Leigh's disease, and Leber'soptic neuropathy (LHON). With the term ofinfantile bilateral striatal necrosis, Friede6defined a group ofinfantile encephalopathies inwhich the main pathological finding wasbilateral, symmetrical, spongy degeneration ofputamina, caudate nuclei, and, less commonly,pallidum. Modern imaging techniques such asbrain CT and MRI can detect basal gangliaabnormalities.7 Though they cannot substituteneuropathological examination, they do enablenew cases of IBSN to be observed in vivo, andserial studies can assess the evolution of thedisease.

Cases reviewed by Friede, as well as thosemore recently described,4"" are clinicallyheterogeneous. Age at onset varies frominfancy to adulthood; some cases present aprogressive disorder, others an acute or sub-acute neurological disorder, sometimes pre-ceded by an acute febrile illness. Clinicalfeatures, with various combinations, includedystonia, hyperkinesia, spasticity, bilateraloptic atrophy, abnormal eye movements,seizures, mental retardation or mentaldeterioration, disturbed behaviour, and failureto thrive. The disorder has a poor prognosis:death usually occurs, but at intervals from a fewweeks to some years after onset of symptoms.Cases with complete or partial remission,however, have also been reported.'0 Allpreviously reported familial cases were in onegeneration or the same sibship,4 1' 1417 suggest-

ing autosomal recessive transmission. Thefamily described by Bargeton-Farkas et al'5is the only published example of parentalconsanguinity we know of.

Confining the discussion to slowly progres-sive cases, those described by Miyoshi et al'6and Pebenito et al" differ from ours in thatmental retardation was prominent in the for-mer and visual function was unaffected in all.Both clinical and neuroradiological findings ofour patients are similar to the clinical observa-tions of Marsden et al,4 who described sevenpatients in two families. The patients exhibiteda slowly progressive generalised dystonic syn-drome, which was variably associated withsubacute visual loss and striking bilateral sym-metrical lucencies on CT, particularly affectingthe putamen. The patients showed no obviousmental deterioration. In one case the visualdeficit was isolated and in another a diagnosis ofLeigh's disease was suggested. Symmetricalareas of low attenuation in the basal ganglia onCT scan, dystonic movements, optic atrophy,and increase of blood pyruvate and alanine areoften observed in patients with Leigh's dis-ease.'"2' This constitutes a heterogeneousgroup of disorders associated with a distur-bance in mitochondrial energy metabolism.'8The clinical features are variable and arerelated to the multiplicity and site of theneuropathological lesions.'822 The coexistenceofmultiple neurological deficits is also found inlate onset cases which usually progress moreslowly.2324 Recently, Van Erven et al2 reportedthree sporadic patients with a slowly progres-sive condition like Leigh's disease in whichhypokinesia and rigidity were the mostprominent neurological disorders. Neverthe-less, other signs and symptoms in these casessuggest the multi-systemic aspect typical ofLeigh's disease: deterioration during inter-current infections followed by a slow recovery,exercise intolerance, poor somatic growth,abrupt changes in respiratory and cardiac rates,

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Bilateral striatal necrosis, dystonia and optic atrophy in two siblings

strabismus, nystagmus, dysarthria, ataxia,tremor, and dysmetria.

Neuroradiological data derived from MRI,particularly ifserial studies are performed, offera valuable tool for differentiating in vivo selec-tive lesions of the striate nuclei, as in IBSN,from the multifocal involvement of the brainseen in Leigh's disease.2"29 In the absence of aneuropathological report, we believe thatLeigh's disease is unlikely in our patients as nodamage was present outside the striatum (asdetected repeatedly by CT and MRI) and noclinical signs of brainstem, cerebellar, andperipheral nerve involvement were ever noted.Moreover, we did not find any pyruvate oxida-tion defects and respiratory chain abnor-malities in fibroblasts of case 2.

In our patients, subacute painless visualfailure suggests the diagnosis of Leber's opticneuropathy (LHON). This is a maternallyinherited form of optic nerve atrophyassociated with neurological and psychiatricsymptoms in a high percentage ofcases, both inaffected patients and in their collaterals.3' Afew reports exist in which LHON is associatedwith IBSN. Novotny et al32 studied a singlelarge pedigree (79 members in five generations)of patients affected by Leber's disease. Eightmembers had neuroretinopathy, 14 had aprogressive, generalised dystonia attributed tostriatal degeneration, but only one had bothdisorders. In six out of 14 neurologically affec-ted patients CT examination demonstratedlow-density in the putamen as the earliestfinding. Caudate nuclei were affected later, andone subject had low density lesions in thecentromedian nucleus region of both thalami.Recently, Wallace et al5 and Singh et al"identified amitochondrialDNA point mutation(at nt 11778) that correlated with Leber'sdisease in nine out of 11 tested pedigrees. Theauthors did not find the same mutation,however, in cases ofLHON plus IBSN, whichmay be the result ofthe presence ofa mixture ofmutant and normal mitochondrial DNAsequences (heteroplasmy).3Our two patients were not seen in the acute

phase of the optic neuropathy, when theperipapillary microangiopathy gives a patho-gnomonic appearance of Leber's disease.35 Theclinical picture, some ophthalmoscopic findings(arterioral attenuation and persistence oftortuous vessels in case 1), and visual fielddeficits may suggest this disease. Although therestriction-fragment-length polymorphismnegativity after digestion of mitochondrialDNA with Sfa NI enzyme might accord withthe hypothesis of different genetic origins ofclassical LHON and LHON associated withIBSN, the parental consanguinity and theapparent involvement of a single generationsuggest a new clinical condition with anautosomal recessive transmission.

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