Journal of Neurology, Neurosurgery, and Psychiatry 199 1;54:624-626

Mid-brain pathology of Wilson's disease: MRIanalysis of three cases

Seiji Hitoshi, Makoto Iwata, Kohki Yoshikawa

AbstractMRI scans were obtained from threepatients with Wilson's disease, all ofwhom showed rigidity and dysarthria;two also showed tremor and dystonia.Two had been treated with D-peni-cillamine for seven and 14 years,respectively and their neurologicalabnormalities had improved, but thethird patient had not been treated. T2-weighted MRI of the mid-brain in allthree revealed the characteristic "face ofthe giant panda" sign, consisting of highsignal intensity in the tegmentum exceptfor red nucleus, preservation of signalintensity of the lateral portion of thepars reticulata of the substantia nigraand hypo-intensity of the superiorcolliculus. The clinical significance ofthese MRI abnormalities is discussed.

MRI provides more detailed anatomical infor-mation than CT of the brain especially of thestructure of the basal ganglia and brain-stem.It also provides biochemical information onthe distribution of heavy metal in the brainsubstance; MRI is clearly a useful method forassessing heavy metal storage disease. In Wil-son's disease, emphasis has hitherto been laidon lesions of the lenticular nucleus andthalamus, and atrophy of the cerebral andcerebellar cortex. In this paper three cases ofWilson's disease are reported and their MRIanalysed, particularly abnormalities of thebrain stem.

Faculty ofMedicine,University of Tokyo,Tokyo, JapanDepartment ofNeurology, Institute ofBrain ResearchS HitoshiM IwataDepartment ofRadiologyK YoshikawaCorrespondence to:Dr Hitoshi, 7-3-1 Hongo,Bunkyo-ku, Tokyo, 113JapanReceived 3 July 1990and in revised form30 October 1990.Accepted 15 November 1990

Case reportsCase 1 was a 39 year old male who haddeveloped sialorrhoea and dysarthria at theage of 17 years, and showed severe intentiontremor in the upper extremities by the age of21. The diagnosis of Wilson's disease was

made when he was 25, and he had since beentreated with D-penicillamine. His symptomshad improved and he exhibited only minimalrigidity and dysarthria.

Case 2 was a 23 year old female who hadfirst noticed finger tremor and dysarthria whenshe was 11 years old. A diagnosis of Wilson'sdisease was made at the age of 16, and she hadbeen treated with D-penicillamine. Onexamination a resting tremor was found in theleft upper and both lower extremities, andrigidity, dysarthria and a mild dystonic pos-ture were also seen.

Case 3 was a 17 year old male who firstexhibited sialorrhoea and dysarthria when hewas nine years old. Neurological examination

at the age of 17 revealed dysarthria, fingertremor, rigidity and a dystonic posture, andthe diagnosis of Wilson's disease was made.He had received no treatment.A 40 year old male and a 21 year old female,

both free from neurological abnormalities,were used as controls for MRI brain scanning.

Method and resultsImages were obtained with a SiemensMagnetom scanner with a superconductingmagnet of 1 5 Tesla field strength, spin echoTI-weighted (TR = 500 ms, TE = 17 ms)and T2-weighted (TR = 3000 ms, TE =90 ms). Proton density images were alsoobtained by the long spin echo method(TR = 3000 ms, TE = 22 ms).Atrophy of the mid-brain and pontine teg-

mentum was present in all three patients. Thecerebral and cerebellar cortex and the medullaoblongata were also atrophic.

In the three patients the T2-weightedimages revealed several abnormalities of signalintensity. In normal subjects, the putamenpresents a signal intensity slightly higher thanthe cerebral cortex, and the globus pallidusshows a marked hypo-intensity. In cases 1 and2, marked hypo-intensity was observed in theposterolateral part of the putamen, while areasof spotty hyper-intensity were seen in the restof the putamen. Diffuse hyper-intensity of theputamen was found in case 3, without any areaof hypo-intensity. A hyper-intense area wasobserved in the globus pallidus in cases 1 and2 (fig 1).The superior colliculus, which in normal

subjects shows the same signal intensity ascerebral white matter, showed a remarkabledecrease in signal intensity in the patientswith Wilson's disease. A reversal of signalintensity' was seen in the lateral portion of thesubstantia nigra, that is, the marked hypo-intensity chracteristic of the normal substantianigra, was lost in cases 1 and 2. In thesepatients, it showed almost the same signallevel as cerebral white matter; case 3 showed anormal hypo-intensity in that area. Thethalamus and the tegmentum of the mid-brainshowed a marked hyper-intensity, especiallyaround the red nucleus, which retained theirnormal hypo-intensity. As a result, the T2-weighted horizontal section of the mid-brainin these patients showed the "face of giantpanda" appearance, which we describe for thefirst time and is specific for Wilson's disease (fig2). Hyper-intensity in the T2-weighted imagewas also observed in the pontine tegmentum,medulla oblongata, and the cerebellar whitematter around the dentate nucleus; the latterstructures were thought to be normal (fig 3).

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Mid-brain pathology of Wilson's disease: MRI analysis of three cases

Figure I Axial T2-weighted MRI made at thelevel of the basal ganglia infour subjects revealabnormal signal intensitiesin the putamen (P), globuspallidus (GP), andthalamus (T) in threecases of Wilson's disease.NC = normal control, a= case 1, b = case 2, c =case 3.

Figure 2 Axial T2-weighted MRI of the mid-brain in four subjects reveal the

"face ofgiant panda" appearance in three cases of Wilson's disease. NC

normal control, a case 1, b case 2, c case 3 SN substantia nigra,

SC superior colliculus., R =red nucleus.

DiscussionSeveral descriptions have been given of theabnormalities found in Wilson's disease, asshown by CT25 and MRI."'0 Atrophy of thecortex of the cerebral and cerebellar hemis-pheres and the brain-stem has also been des-cribed, as well as abnormalities of the lenticularand caudate nuclei. MRI studies reportedhyper-intensity in T2-weighted images of thethalamus, mid-brain, pons, and dentatenucleus. Most of these studies used MRIsystems with a magnetic field lower than 0 5Tesla.8 Alternatively, studies made with ahigh field MRI system (1 5 Tesla) have shownhypo-intense basal ganglia in T2-weightedimages"90; so far there have been no reports onthe superior colliculus, substantia nigra, andmid-brain tegmentum in Wilson's disease.Microscopic examinations of the brain in

cases of Wilson's disease have revealedneuronal loss, spongiform degeneration,gliosis, or cavitation in the basal ganglia, brainstem, and the cerebral and cerebellar whitematter. 11-12 Increased signal intensity in theT2-weighted MRI, which is seen in thecerebral and cerebellar white matter and the

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Hitoshi, Iwata, Yoshikawa

Figure 3 T2-weightedimages at the levels ofpons(a) and cerebellum (b) incase 2, reveal hyper-intensity in the pontinetegmentum and thecerebellar white matteraround dentate nucleus(D).

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lenticular nucleus, may reflect these patho-logical changes, or the oedema they provoke.Necropsy examination in cases of Wilson'sdisease does not usually reveal any significantabnormality ofthe superior colliculus, substan-tia nigra, or mid-brain tegmentum.The precise pathogenesis of the marked

hypo-intensity of the corpus striatum andsuperior colliculus in the T2-weighted MRI isunknown, but it is possible that the paramag--netic effects of the deposition of heavy metals,such as iron and copper may be Lesponsible.' '3

Quantitative analysis of the iron and coppercontent of the brains of patients with Wilson'sdisease has shown increased amounts of copperin the caudate and lenticular nuclei, and thethalamus.""'6 The amount of iron was normalin the lenticular nucleus, but increased in thecaudate nucleus and thalamus. Iron is assumedto play a more important part than copper inreducing the signal intensity in the T2-weighted MRI, because the content of iron ismuch greater in cases of Wilson's disease thancopper, and because the two patients in thisseries who were treated for many years with D-penicillamine showed identical appearances,that is, considerably reduced signal intensity inthe T2-weighted MR images, similar to theuntreated patient. To date no reports havecompared heavy metal amounts in the substan-tia nigra or superior colliculus between normalsubjects and cases with Wilson's disease. It willbe necessary to correlate the changes in signalintensity in MRI imaging with the heavy metalcontent of each structure in the basal gangliaand brain stem.A recovery in signal intensity in the substan-

tia nigra in cases of Parkinson's disease and theParkinson-plus syndrome was first reported byRutledge et al.' Although it is difficult tocorrelate neurological findings with abnor-malities on MRI, cases 1 and 2 showed arecovery of signal intensity in the lateral part ofthe substantia nigra and presented clinicallywith rigidity, which can be attributed to alesion of the substantia nigra. Case 2 exhibiteda resting tremor, another characteristic featureof the Parkinsonian syndrome. Case 3 alsopresented with rigidity, but showed the moreusual finding, hypo-intensity in the lateral partof the substantia nigra in the T2-weightedimages. It is possible that the duration of thedisease process may contribute to the MRIchanges, or that treatment with D-peni-cillamine may be responsible for them.The mid-brain tegmentum, especially the

red nucleus, contains the cerebello-rubro-thalamic tract, and damage to this tract causessevere tremor of the intention type. None of thethree patients in this series exhibited anyintention tremor at the time of the MRIexamination. The MRI of these patientsrevealed this fibre system to be intact, and thesuperior cerebellar peduncle and its decussa-tion to be relatively well preserved in both theTi- and the T2-weighted images, and normalhypo-intensity of the dentate and red nuclei inthe T2-weighted images was also noted. Case 1however, had shown very severe intentiontremor before the start of D-penicillaminetreatment 14 years previously.'7 The lesion ofthis fibre system might be reversible withoutmajor structural damage. Abnormalities in thebasal ganglia on CT examination were reportedto improve after treatment.4 It will be interest-ing to follow up the MRI of case 3 aftertreatment.

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2 Nelson RF, Guzman DA, Grahovac Z, et al. Computerizedcranial tomography in Wilson disease. Neurology1979;29:866-8.

3 Ropper AH, Hatten HP, Davis KR. Computed tomographyin Wilson disease: report of 2 cases. Ann Neurol1979;5: 102-3.

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5 Takano K, Kuroiwa Y, Shimada Y, et al. CT manifestationof cerebral white matter lesion in Wilson disease. AnnNeurology 1983;13:108-9.

6 Lawler GA, Pennock JM, Steiner RE, et al. Nuclearmagnetic resonance (NMR) imaging in Wilson disease.J Comp Ass Tomog 1983;7:1-8.

7 Aisen AM, Martel W, Gabrielsen TO, et al. Wilson diseaseof the brain: MR imaging. Radiology 1985;157:137-41.

8 Starosta-Rubinstein S, Young AB, Kluin K, et al. Clinicalassessment of 31 patients with Wilson's disease. Correla-tions with structural changes on magnetic resonanceimaging. Arch Neurology 1987;44:365-70.

9 Tsuchiya K, Makita K, Furui S, et al. Unusual MR signals(prolonged TI and shortened and partially prolonged T2)in the basal ganglia in Wilson's disease. Journal ofMedicalImagings 1988;8:1204-9.

10 Uchino A, Miyoshi T, Maeoka N, et al. MR imaging of thebrain in Wilson's disease. Japanese Journal of ClinicalRadiology 1989;34:1413-16.

11 Wilson SAK. Progressive lenticular degeneration: a familialnervous disease associated with cirrhosis of the liver.Brain 1912;34:295-509.

12 Greenfield JG. Familial hepatolenticular degeneration (Wil-son's disease). In: Corsellis JAN, Adams JH, eds.Neuropathology. London: Arnold, 1984:595-9.

13 Drayer B, Burger P, Darwin R, et al. Magnetic resonanceimaging of brain iron. Am J Neuroradiol 1986;7:373-80.

14 Cumings JN. The copper and iron content of brain and liverin the normal and in the hepato-lenticular degeneration.Brain 1948;71:410-15.

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16 Cumings JN. Trace metals in the brain and in Wilson'sdisease. J Clin Path 1968;21:1-7.

17 Iwata M. Pathodynamics of tremor. Shinkei Kenkyu noShinpo (Tokyo) 1985;29:210-21.

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analysis of three cases.Mid-brain pathology of Wilson's disease: MRI

S Hitoshi, M Iwata and K Yoshikawa

doi: 10.1136/jnnp.54.7.6241991 54: 624-626 J Neurol Neurosurg Psychiatry

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