Clinical, CT and evoked potential manifestations in Wilson's disease with cerebral white matter involvement Nai-Shin Chu Introduction In Wilson's disease, the lenticular nuclei, particularly the putamen, are primarily affected 1. However, involvement of the cerebral cortex and the cerebral white matter are not uncommon 2,3. In approximately 10% of autopsy cases with Wilson's disease, destruction of the cerebral white matter and degeneration of the cerebral cortex are more severe than the damage seen in the basal ganglia 2s. Wilson's disease is also one of the underlying diseases associated with central pontine myelinolysis6'7. These observations seem to indicate that white matter involvement is one of the pathological processes that may account for some of the neurological manifestations in Wilson's disease. Among several CT studies on Wilson's disease 816, two reported cerebral white matter lesions 11,12. Magnetic resonance imaging (MRI) appears to be more sensitive than CT in detecting both gray and white matter lesions in Wilson's disease 1749. White matter involvement was detected in 5 out of 22 patients m9. However, the clinical features of such patients with cerebral white matter involvement have not been specifically described, in particular, the time course of developing white matter lesions and the corresponding clinical presentation. In view that evoked potentials (EPs) are useful in detecting white matter diseases, it would also be of interest to study the correlation between the cerebral white matter involvement and E P findings in Wilson's disease. Summary Four patients with Wilson's disease had CT manifestations of cerebral white matter lesions involving frontal lobes in two patients but extending to other cerebral areas in the remaining two. Two patients with extensive white matter involvement were bed-ridden with generalized flexion rigidity and spasticity, but the other 2 patients led an independent life with minimal extrapyramidal symptoms. Three patients developed tonic focal seizures with or without secondary generalization. Scalp-recorded somatosensory evoked potentials (SEPs) over the affected hemispheres were absent but the spinal SEPs and brain stem auditory evoked potentials were preserved. The evoked potential data support the CT findings that the white matter involvement in Wilson's disease was primarily confined to the cerebral hemispheres. Key words: Wilson's disease, EP, CT, white matter lesion. Report of cases Among 34 patients with Wilson's disease, 4 patients (12%) were selected because of CT findings indicating white matter lesions in the cerebral hemispheres. The diagnosis of Wilson's disease was based on family history, neurological examination, low serum ceruloplasmin and copper levels, elevated 24-hour urinary excretion of copper, presence of Kayser-F!eischer corneal ring by slip-lamp examination, abnor- Address for correspondence and reprint requests: Nai-Shin Chu, Department of Neurology, Chang Gung Memorial Hospital, 199 Tung H~ea North Road, Taipei, Taiwan, R. O. C. Accepted22.9.88 Clin Neurol Neurosurg 1989. Vol.91-1 45 Fig. 1. CT scans of 4 patients with Wilson's disease. In patient 1 (A), there were extensive white matter lesions involving frontal, central and parietal lobes. The left central and parietal lobes were more severely affected. Cerebral cortical convolutions appeared to be relatively preserved. In patient 2 (B), the white matter lesions were seen in frontal 46 lobes and in right central and parietal lobes. In patient 3 (C), the low density was located in the left frontal lobe. A n additional small area of hypodensity was seen in left posterior parietal lobe. In patient 4 (D), the low density was limited to left frontal lobe. mal liver function tests and presence of liver cirrhosis by ultrasound scanning or biopsy2~ All 4 patients had been taking penicillamine, but the first 2 patients tended to take it erratically. The CT scans were obtained with a G.E. Model 8800. Methods and normative data of somatosensory, brain stem auditory and pattern-reversal visual evoked potentials (SEP, BAEP and VEP) were previously reported 21-23. Peak and interpeak latencies were considered abnormal when they were prolonged beyond the upper normal limits (mean + 3 S.D.). Patient 1 was a 16-year-old male who was bed-ridden with quadriplegia, aphonia, and severe dysphagia. His initial neurological symptoms probably dated back 5-6 years ago when he experienced hoarseness of the voice and a tendency to stumble. Gradually, he developed hand tremor, slurred speech, swallowing difficulty and right leg weakness. Initial CT scan in 1980 showed faint hypodensity in the basal ganglia. One year later, he developed episodes of tonic extensor spasm of right limbs with mouth angle deviated to right and the head to left. Each episode lasted one to ten minutes and could be followed by inability to talk for several minutes. His clinical course thereafter deteriorated rapidly. He then developed torsion dystonia, ataxic gait, severe dysarthria, quadriparesis and was eventually bedridden. CT scan in 1984 showed extensive marked attenuation of absorption in the hemispheric white matters, especially in the frontal, central and parietal lobes (Fig. I-A). However, the cerebral cortical convolutions appeared to be relatively preserved. The EEG disclosed marked diffuse slowing. Scalp-recorded median and tibial cortical SEPs were bilaterally absent but the median cervical (N13) and tibial lumbar (N22) SEPs were present with normal latencies (Table 1 and Fig. 2). In BAEPs, the I-III, III-V and I-V intervals were bilaterally prolonged. Table 1. Summary of CT and EP findings Case Age/Sex Duration of illness (yr) CTwhite matter lesion BAEP (l-V) VEP (P100) N13 Median N20 1. 16 M 5-6 Bilateral frontal, central and parietal L. R. 5.8* 5.6* 14.4 14.8 2. 23 M 6 Bilateral frontal and R. centro-parietal L. R. 5.5* 5.4* 13.6 13.9 28.0* 3. 19 M 4 R. frontal and L. parietal L. R. 5.0* 4.9* 121.0" 123.5" 13.6 13.8 26.1" 4. 23 M 3 L. frontal L. R. 4.9* 4.9* 120.0" 116.6" 13.4 13.7 20.3 - Normal 4.0+ 0.2 99.9+1.9 13.8+0.8 19.6+1.3 Case Age/Sex SEP N13-N20 N22 1. 16 M - 23.0 23.3 2. 23 M 14.1" 22.1 21.9 Tibial P40 SEP N22-P40 45.1" 23.2* 3. 19 M 12.3" 20.* 21.0 4. 23 M 6.9 - 21.6 20.9 43.7 44.70 22.1" 23.8* Normal 5.7+0.8 12.8+1.5 39.3+1.8 16.9+1.2 * indicates value prolonged beyond the upper normal limit. Values are in msec. 47 L I.SEP R 14.4 14.8 39.1 t o.5ffv 23.0 Tibial .BAEP 25.5 i 1.7 i 7.5 4.4 7.5 J 10.25flY Inns Fig. 2. SEPs and B A E P s of patient 1. Median cervical (N13) and fibial lumbar (N22) SEPs were well-formed with normal latencies whereas the scalp-recorded cortical responses were bilaterally absent. In BAEPs, the I-III, III-V and I-V interpeak conductions were delayed on both sides. The time calibration was 5 msec for spinal SEPs and 15 msec for cortical SEPs. Stimulation onset at the beginning of the tracings. L = left side stimulation and R = right side stimulation. The same abbreviations in the following figure. Patient 2 was a 23-year-old man with 6 years' history of Wilson's disease. He initially noted slurred speech, hand tremor and left leg clumsiness. Gradually he developed left-sided weakness and spasticity, flexion rigidity of the upper limbs, dysphagia and ataxic gait. Eventually he became bedridden with generalized flexion rigidity. 48 CT scan showed low density lesions confined to the subcortical white matters in the frontal lobes and right centroparietal lobes (Fig. l-B). The E E G disclosed bifrontal and right central marked slowing and left central moderate slowing. Scalp-recorded SEPs following left median and tibial nerve stimulation were absent (Table 1). In median and tibial cortical SEPs following right median and tibial nerve stimulation, the short-latency peaks (N20 and P40) and the cordto-cortex conduction times (N]3-N20 and N22P40) were all prolonged (Table 1). The I-III, III-V and I-V intervals of the BAEP were bilaterally prolonged. Patient 3 was a 19-year-old man who had tremor and unusual posturing of the left hand the basal ganglia and the thalamus. There was an area of low density in right frontal lobe. CT scan 2 years later showed further extension of the white matter lesion and an additional small area of low density in left posterior parietal lobe (Fig. 1C). EEG disclosed intermittent 6-7 Hz slow waves in right fronto-central areas. All 3-modality EPs were abnormal (Table 1). The P100 latency of the VEP and the I-V interval of the BAEP were bilaterally prolonged. The median cortical responses following right side stimulation were absent. The median N13-to-N20 conduction was prolonged with the response amplitude markedly reduced following left side stimulation. Tibial cortical SEPs were absent on both sides. Patient 4 was a 23-year-old man who first noticed in the winter of 1984 shaking of arms and body when he was riding the motorcycle against the cold wind. Because of the shaking, he had fallen from the motorcycle at least 3-4 times. As the shaking of hands and arms became progressively worse, it was often impossible for him to write, to use chopsticks or to turn the door knob. In October of 1985, he had repeated for 4 years and strange behavior for 2 years. For the past 2 years, he had 2 episodes of generalized limb stiffening associated with loss of consciousness that lasted one or two minutes. He also had several episodes of extension stiffening of the left upper limb with minimal twitching that usually lasted 2-3 minutes. More recently, he developed slurred speech, silly laughing, drooping of saliva and ideation of someone wanting to cheat him. His school performance had been slowly deteriorating. Neurological examination revealed scanning dysarthria, intermittent tremor and dystonic posturing of the left hand, and unsteadiness with dystonic posturing in walking. Hyperreflexia was present in left upper limb and both lower limbs. Initial CT scan one year earlier showed cerebral and cerebellar atrophy and hypodensity in Fig. 3. Evoked responses of patient 4. The median cortical SEPs following right side stimulation were almost absent with the N20 component possibly occurring at 25.9 msec. The tibial cortical SEPs were present, but the P40 latency following right side stimulation was prolonged. There was bilateral delay in the I-V interval of the BAEP and the P100 latency of the VEP. I. SEP Median 31.44~.s fibial l~ ~ _ lsm~ _ _ ] 43.7 62.3 II.BAEP 4.2 1.6 ? . 5 u V 15rns 1.5 6.5 i 44./ 65.3 4.2 6.4 1ms I III.VEP I i'1-.5uV 116.5 120.0 25ms 49 episodes of tonic extensor spasm affecting right extremities. The episodes usually lasted one minute, followed by paralysis of right limbs for about 10 minutes. The episodes had continued for one week until treated with Phenytoin. In April of 1986, he had repetitive right facial spasms. When the spasm had subsided 2 days later, he was unable to talk for 3 days. With medication, hand tremor and slurred speech had markedly improved. He was, however, still afraid of riding the motorcycle because of the shaking when he became tense. Initial CT scan in 1984 showed slit-like low density in the lenticular areas in addition to cerebral, cerebellar and brain stem atrophies. Repeated CT scan in 1986 disclosed white matter low density in the left frontal lobe (Fig. l-D). EEG showed bifrontal slowing with left side more severely affected. The median SEPs following left side stimulation had normal N20 latency and normal N13-to-N20 conduction (Fig. 3). On the contrary, the scalp-recorded median SEPs following right side stimulation were absent. Tibial nerve stimulation elicited cortical responses with prolongation of P40 latency on the right and the N22-to-P40 conduction on both sides. The I-V interpeak latency of the BAEP and the P100 latency of the VEP were bilaterally delayed. In summary, 4 patients with Wilson's disease were found to have cerebral white matter lesions in the CT within 2 to 5 years after the onset of neurological symptoms. Those lesions invariably involved the frontal lobe. Neurological deficits were severe in patients with extensive white matter lesions, but relatively mild in patients with lesions restricted to the frontal lobes. Three patients developed tonic type focal seizures with or without secondary generalization. Multi-modality EPs were all abnormal, showing absence of cortical SEPs recorded over the affected hemispheres and widespread delayed conduction in the central sensory pathways. Discussion Neuropathological studies in Wilson's disease have shown that cerebral white matter degeneration varies from softening, spongy necrosis to cavity formation 2'3'4's. Although other cerebral 50 areas can be affected, the white matter lesions have a predilection for the frontal lobes and often spare the occipital and temporal lobes z,3. When there is cavity formation in the white matter, cerebral cortical convolutions are often relatively preserved 25. In 4 patients reported here, the CT distribution of the cerebral white matter lesions was in general agreement with autopsy findings 2,3,18. The frontal lobe was involved in all patients. In two cases reported by Takana et al. 11 and Takano et al.12, the CT white matter involvement was also restricted to the frontal lobes. Those CT findings were in agreement with MRI data showing white matter lesions were generally asymmetric and most common in the frontal lobes 18,19.Furthermore, the present CT findings seem to suggest that cerebral white matter lesions progressed from the frontal lobes to involve the central and parietal lobes, relatively sparing the temporal and occipital lobes. However, the CT of patient 3 also indicates that white matter lesion may develop independently in other cerebral areas, but probably at a later time. The development of cerebral white matter lesions in Wilson's disease appears to be not related to the duration of the illness because many patients with several years' history of this disease did not have such lesions 2~ The present data indicate that white matter lesions may develop quite early in the course of the disease. Patients 3 and 4 developed such lesions 2 and 3 years respectively after the onset of neurological symptoms. The cerebral white matter lesions may also progress quite rapidly. Patient 1 had extensive involvement of the cerebral white matters within 2 years of the initial negative CT finding. Three patients developed seizures characterized by tonic extensor spasms that are usually seen in demyelinating diseases24. The patients of Takano et ai.12 and Ishino et al.5 also developed tonic seizures contralateral to the side of cerebral lesion. Thus, the occurrence of seizures seems to be common in patients with cerebral white matter involvement. Xu et al.Z5 reported that seizures occurred in 3 (4%) out of 76 patients with Wilson's disease, but whether those patients had white matter lesions was not known. The present EP findings are similar to those r e p o r t e d p r e v i o u s l y in a large series study 2~ indicating w i d e s p r e a d a b n o r m a l i t y in the 3 m a j o r s e n s o r y p a t h w a y s in W i l s o n ' s disease. T h e exc e p t i o n was the a b s e n c e of cortical SEPs that was o b s e r v e d only in p a t i e n t s with c e r e b r a l white m a t t e r lesions. A b s e n c e of cortical SEPs a p p e a r e d to correlate w i t h the side a n d the ext e n t of c e r e b r a l white m a t t e r i n v o l v e m e n t . W h e n the lesions e x t e n d e d to involve the central a n d parietal lobes, b o t h m e d i a n a n d tibial cortical SEPs were u n i f o r m l y absent. H o w e v e r , w h e n the white m a t t e r lesions were restricted only to the f r o n t a l lobes, m e d i a n a n d tibial cortical SEPs could still b e separately or t o g e t h e r a b s e n t . T h e s e findings suggest that t h e r e might be white m a t t e r lesions in o t h e r c e r e b r a l areas that m i g h t n o t be d e t e c t e d b y the C T a n d f u r t h e r study with the M R I m a y b e helpful. 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