Worsening of Neurologic Syndrome in Patients With Wilson's Disease With Initial Penicillamine Therapy George J. Brewer, MD; Carol A. Terry; Alex M. Aisen, MD; Gretchen M. Hill, PhD \s=b\ We describe a patient with Wilson's disease who presented with neurologic disease, was treated with D-penicillamine, and suffered sudden neurologic deterioration coincident with therapy. Replicate brain magnetic resonance imaging examinations after six weeks and 11 months of penicillamine therapy documented the development of new brain lesions during this period, while liver biopsy specimen data disclosed that excellent hepatic decoppering had occurred. To develop information on the relative rarity or frequency of neurologic worsening with the initiation of penicillamine therapy, we conducted a retrospective survey of 25 additional patients with Wilson's disease who met the criteria of presenting with neurologic disease and having been treated with penicillamine. The replies indicate that, at least from the patient's viewpoint, this syndrome occurs frequently. We suggest that the cause of this distressing syndrome, and ways to mitigate or circumvent it, must be discovered. (Arch Neurol 1987;44:490-493) Accepted for publication Oct 20, 1986. From the Departments of Human Genetics (Drs Brewer and Hill), Internal Medicine (Dr Brewer), and Radiology (Dr Aisen), University of Michigan, Ann Arbor, and the Wilson's Disease Association, Dumfries, Va (Ms Terry). Reprint requests to Department of Human Genetics, 4708 Medical Science II, Box 015, Ann Arbor, MI 48109 (Dr Brewer). T^he standard decoppering therapy of patients diagnosed as having Wilson's disease is treatment with D-penicillamine.1 This drug increases excretion of copper in the urine, and if given in adequate doses, produces a strongly negative copper balance. Since a negative copper balance is thought to be the sine qua non of effective therapy for Wilson's disease, the initiation of adequate penicilla¬ mine treatment hopefully should be followed by a halt in the progression of symptoms, and then improvement. However, there has been occasional observations that neurologic symp¬ toms of Wilson's disease may become worse with the initiation of penicilla¬ mine therapy.2"7 This point was force¬ fully driven home to us by a patient with Wilson's disease whom we saw after penicillamine therapy had been initiated. REPORT OF A CASE A 19-year-old man developed emotional outbursts and was admitted temporarily to a psychiatric hospital. Over the next three years, the patient developed mild tremors in both arms, some drooling, and lost his ability to carry out fine motions, such as writing and tying his shoes. At age 22 years, he was admitted to a psychiatric hospital, where a diagnosis of Wilson's disease was made, which was based on the presence of Kayser-Fleischer rings and a urinary copper excretion of 1148 Mg/24 h (18.0 µ /g) (normal, 20 to 50 Mg/24 h [0.3 to 0.8 µ /d]). Plasma ceruloplasmin level was 6.6 mg/dL (66 mg/L) (normal, 18 to 45 mg/dL [180 to 450 mg/L]). The patient was given D-penicillamine, 250 mg, four times per day. His drooling became worse, and within one or two weeks he became so dysarthric that his speech was incompre¬ hensible. He became dystonic in his legs and arms, and had so much trouble with posture after three to four weeks of peni¬ cillamine therapy that he was bedridden, and developed a sacral bedsore. The patient was referred to the Univer¬ sity of Michigan Medical Center, Ann Arbor, where he was seen after approxi¬ mately six weeks of penicillamine therapy. The clinical abnormalities previously not¬ ed were seen. He was unable to sit or talk. His urinary excretion of copper while receiving 1.0 g of penicillamine per day was 2400 Mg/d (37.7 µ / ). His hepatic cop¬ per, determined by percutaneous needle biopsy specimen, was 1224 Mg/g of dry weight (normal, 20 to 45 Mg/g)· His nonce- ruloplasmin plasma copper was 28 Mg/dL (4.4 Mmol/L) (normal, 10 to 15 Mg/dL [1.6 to 2.3 Mmol/L]). A brain magnetic resonance imaging (MRI) study was performed, which showed basal ganglia abnormalities (increased signal on T2-weighted spin-echo images) characteristic of Wilson's disease (Fig 1, top and center), minimal lesions in the frontal lobe gray matter (Fig 1, bot¬ tom), and atrophy. At the time of admission, we were aware of and concerned about the syndrome of neurologic worsening with the initiation of penicillamine therapy. However, because we believed that this patient had already been through the worst of this syndrome, and because he had a substantial negative copper balance while receiving penicilla¬ mine, we continued penicillamine therapy. Over the next several months, the patient developed a severe seizure disorder and Downloaded From: http://archneur.jamanetwork.com/ by a Karolinska Institutet University Library User on 05/29/2015 Fig 2.—Magnetic resonance imaging scan performed after 11 months of penicillamine therapy. Left, Note new white-matter lesions in frontal lobe in image (a). Right, Basal ganglia lesions are essentially unchanged. Fig 3.—Magnetic resonance imaging scan performed nine months after scan in Fig 2. Left, Image demonstrates continued presence of white-matter lesion (only one side is shown, although at different levels, lesion on other side is still present). Right, Image shows improvement in basal ganglia lesions. Hospital for réévaluation. A repeated liver biopsy specimen showed a value for hepat¬ ic copper of 35 Mg/g of dry weight, indicat¬ ing excellent copper removal. However, a repeated MRI scan showed significant new white-matter lesions in the frontal lobes Fig 1.—Magnetic resonance imaging perform¬ ed on commercial imager based on supercon¬ ducting magnet (0.35 Tesla), using multislice acquisition with T2-weighted spin-echo pulse sequences. Top and Center, Images show increased signal in basal ganglia characteris¬ tic of Wilson's disease. Bottom, Image shows some atrophy, but minimal lesions in frontallobe gray matter. Images were taken after six weeks of penicillamine therapy. (Fig 2, left), with the basal ganglia lesions unchanged or minimally improved (Fig 2, right). Neurologically, he showed signifi¬ cant improvement, was able to walk to a certain extent, and could write legibly, although not normally. His speech remained severely impaired. At this time, he was switched to zinc acetate therapy, the penicillamine was dis¬ continued, and his antiseizure medications discontinued without recurrence of seizures. He continued to improve neuro¬ logically, and after nine months of zinc therapy (20 months after diagnosis) the patient could walk, but still had postural abnormalities and some tremor and dys- were required sodium phenytoin and phénobar¬ bital therapy for control. After 11 months of penicillamine therapy, the patient was admitted to the University of Michigan tonia. He still had dysarthria, but could be understood relatively well. His overall neu¬ rologic status was not as good as when he started penicillamine therapy. Repeated brain MRI scans disclosed little change in the white-matter lesions (Fig 3, left), but improvement was noted in the basal gan¬ glia lesions (Fig 3, right). His copper status was good, with a urine copper of only 98 Mg/d, and a nonceruloplasmin plasma cop¬ per of 10 Mg/dL. COMMENT This patient exhibited the syn¬ drome of neurologic worsening with the initiation of penicillamine thera¬ py, which has been previously noted in the literature. All of his symptoms became markedly worse shortly after the initiation of penicillamine. This case is unique because MRI scans per- Downloaded From: http://archneur.jamanetwork.com/ by a Karolinska Institutet University Library User on 05/29/2015 Results of Survey of Patients Registered With the Wilson's Disease Association on Neurologic Worsening With the Initiation of Penicillamine Therapy Length of Time of Penicillamine Treatment When Symptoms Worsened 2 wk or less No. of Respondents Whose Neurologic Symptoms Worsened Out of the Initial Sample (N = 25) No. of Respondents From Column 2 Who Did Not Recover to Prepenicillamine Baseline 3 to 4 wk 6 to 12 mo Total 13 formed after six weeks and 11 months of penicillamine therapy documented the appearance of new brain lesions occurring in the interim. Further¬ more, during this period, the patient was receiving a dose of penicillamine adequate to control copper balance and bring about excellent removal of copper from the liver (value of 1224 Mg/g of dry weight at six weeks reduced to 35 Mg/g of dry weight at 11 months). Clearly, the therapy was adequate for copper removal pur¬ poses, but did not prevent the develop¬ ment of new brain lesions and neuro¬ logic symptoms. Impressed by the present case, we began to note the syndrome of wors¬ ening of neurologic disease with the initiation of penicillamine therapy in other patients with Wilson's disease who were referred to us for our zinc therapy program. It became apparent that this syndrome was not infre¬ quent. However, we could find no information in the literature with regard to the frequency of this prob¬ lem. We therefore undertook a retro¬ spective survey of 55 patients with Wilson's disease whose names and addresses were on the mailing list of the Wilson's Disease Association (Dumfries, Va, a nonprofit lay organi¬ zation of patients with Wilson's dis¬ ease, their families, and other inter¬ ested persons), excluding those pa¬ tients we had already seen. Patients surveyed were either known to have had neurologic involvement, or there was no knowledge of the extent of their disease. Patients who were known not to have neurologic involve¬ ment were not contacted. The survey questionnaires were filled out by either the patients themselves or a member of the patient's family who had been with the patient during the course of his or her illness. Twentyeight of the 54 patients surveyed responded. Of those 28, three had nev¬ er had neurologic symptoms, and therefore, were not included in the study. Of the 25 respondents who had experienced neurologic symptoms, 13 reported a worsening of at least some of their neurologic symptoms after initial treatment with penicillamine (Table). This group of 13 patients con¬ sisted of five males and eight females, ranging from 13 to 50 years of age at the time of the survey. These patients had been treated with penicillamine for periods ranging from six months to 26 years. As can be seen in the Table, the majority of patients whose neurologic symptoms worsened on penicillamine deteriorated quickly. The symptoms of seven of these 13 patients became worse within two weeks, and ten of the 13 within four weeks. About half of the patients (six of 13) never recovered to their prepenicillamine baseline (Table, column 3). That is, they never improved neurologically from their worsened state to reach even their level of neurologic impairment before treatment. This occurred in spite of becoming increas¬ ingly decoppered as penicillamine therapy continued. The point is not that penicillamine failed to decopper, but that the patients became worse initially during copper mobilization by the drug. The patients who did recover to prepenicillamine baseline reported significant improvement on penicillamine. A retrospective survey such as this has some obvious problems. For example, patients with residual dis¬ ease and their families may have been more likely to join the Wilson's Dis¬ ease Association. Patients who deteri¬ orate during penicillamine therapy may have been more likely to respond to our questionnaire. A retrospective study depends on the memory of the patient or the family, and may have some inaccuracy as a result. Not all of the patients were medically examined in a consistent manner to test for worsening, so we are left with some nonmedicai judgments about worsen¬ ing. However, we examined the records of three of the patients, and were convinced that marked worsen¬ ing occurred after penicillamine. Per- haps the patients who became worse after six months should not be consid¬ ered, because of possible problems with compliance over that period of time (although all appeared to have been decoppered ultimately). Thus, the numbers in the Table should not be viewed as particularly accurate in the estimation of the frequency of this syndrome. However, the main point of the survey is a qualitative one, namely that this syndrome is not uncommon, and may itself add to the extent of irreversible neurologic damage. We know from our own experience that the patients may end up much worse than when they started penicillamine therapy. The main purposes of our case report and survey are to call attention to the problem of neurologic worsen¬ ing with the initiation of penicilla¬ mine therapy, and hopefully to pro¬ voke more studies addressing this area. This case report documents objectively with MRI scans that new brain lesions can develop while ade¬ quate copper removal is occurring. As mentioned previously, the survey is not intended as an accurate estima¬ tion of the frequency of this syn¬ drome. The actual incidence could be substantially lower than our estimate, because our estimate may be biased upward by the factors already dis¬ cussed. However, it is also possible that the actual incidence of detectable neurologic deterioration could be higher than our estimate, if sensitive measures such as MRI scans and detailed neurologic testing are used. Our own clinical experience suggests that the 50% incidence indicated by the survey will turn out to be approx¬ imately correct. However, whether the problem occurs in 10% or 90% of patients, it deserves study because it can be extremely distressing when it occurs. The first question that requires an answer is the cause of the syndrome. Our hypothesis is that while penicilla¬ mine is mobilizing the very large store of hepatic copper, it temporarily fur¬ ther elevates blood and brain levels of copper in the process. Work might be done with copper-loaded animal mod¬ els, to see if initiation of penicillamine therapy temporarily elevates brain levels of copper. If it does, methods might be found to circumvent this process, such as starting with smaller doses of penicillamine. We have not yet attempted this approach, but we have plans to do so. A second area that deserves study is the use of alternate drugs, triethylene tetramine (trientine) or zinc, for initi- Downloaded From: http://archneur.jamanetwork.com/ by a Karolinska Institutet University Library User on 05/29/2015 ation of copper removal. If our hypothesis on mechanism is correct, trientine8 may show the same prob¬ lem, since it acts by mobilizing copper for urinary excretion. The other alter¬ native, zinc, which we have been active in developing,914 has been thought of more as a maintenance therapy than a primary copper removal agent. This is because zinc produces a relatively modest negative copper balance of perhaps 1 mg/d. However, zinc has the theoretical advantage of blocking the intestinal uptake of copper, including the reab- sorbtion of copper secreted in sali¬ vary, gastric, and certain other ali¬ mentary juices.15 Thus, the dynamics of zinc action involves a "pulling" of copper from the blood, rather than a "pushing" of copper into the blood for excretion in the urine, as is the case with penicillamine. Accordingly, we have recently initi¬ ated copper removal therapy in three neurologically symptomatic patients with zinc acetate, 50 mg of elemental zinc five times per day. The patients have been treated for 13, 7, and 2 months, respectively, and have done well, without neurologic worsening, and with neurologic improvement. Hoogenraad et al16 also recently reported the successful initial treat¬ ment with zinc of a patient with Wil¬ son's disease with neurologic disease. An important immediate question for the physician planning to use pen¬ icillamine for the initial treatment of neurologically affected patients with Wilson's disease is how to avoid or mitigate the syndrome of neurologic worsening. At present, we can not give definitive recommendations because of the lack of data. Our interim rec¬ ommendation is to begin with a small dose of penicillamine, and increase the dosage in increments, depending on the copper excretion in the urine. We suggest beginning with 250 mg/d, and increments of 250 mg/d, every four days, until a 24-hour urine copper concentration of about 2 mg is reached, without increasing the peni¬ cillamine dosage further until urine copper decreases. If a patient has already been started on the standard initial dose of 1 to 2 g of penicillamine per day, and then begins exhibiting neurologic deterioration, the dose should immediately be reduced to 250 mg/d. Subsequently, the dose can be increased by 250 mg/d every four days, until a 24-h urine copper concen¬ tration of about 2 mg is reached as described above. Since the intake of copper in the American diet averages 1.0 ± 0.3 mg, and there is a more or less obligatory loss of about 0.8 mg in feces and from skin surface, an excre¬ tion of 2 mg in the urine will dictate a modest negative copper balance, which, in our opinion, should be the therapeutic goal in this setting. In the long run, a carefully con¬ structed prospective study is needed, documenting more precisely the fre¬ quency and the severity of the compli¬ cations brought about by initial decoppering with penicillamine in standard doses compared with alter¬ native approaches. We are planning such a study, although the rarity of the disease and the accumulation of enough data on newly diagnosed cases present serious obstacles to carrying out a proper prospective study of ran¬ domized treatments. This study was supported in part by the National Institute of Diabetes and Digestive and Kidney Disease (Bethesda, Md) grant R01-AM1 26050; the Herrick Foundation, the Sage Founda¬ tion (Tecumseh, Mich), and the Ervin Founda¬ tion, Ann Arbor, Mich. We also gratefully acknowledge the support of the Generic Pharma¬ ceutical Industry Association and four pharma¬ ceutical companies (Lemmon Co, Sellersville, Pa; Henry Schein Pharmaceuticals Ine, Port Wash¬ ington, NY; Rugby Laboratories, Rockville Cen¬ ter, NY; and Sandoz Ine Pharmaceuticals Divi¬ sion, East Hanover, NJ). References 1. Walshe JM: Penicillamine, a new oral therapy for Wilson's disease. Am J Med 1956;21:487\x=req-\ 495. 2. Deiss A, Lynch RE, Lee GR, et al: Longterm therapy of Wilson's disease. Ann Intern Med 1971;75:57-65. 3. Sternlieb I, Scheinberg IH: Penicillamine therapy for hepatolenticular degeneration. JAMA 1964;189:146-152. 4. Strickland GT, Blackwell RQ, Watten RH: Metabolic studies in Wilson's disease: Evaluation of efficacy of chelation therapy in respect to copper balance. Am J Med 1971;51:31-39. 5. Walshe JM: The physiology of copper in man and its relation to Wilson's disease. Brain 1967; 90:149-177. 6. Walshe JM: Brief observations on the mamagement of Wilson's disease. Proc R Soc Med 1977; 70:1-3. 7. Walshe JM: Wilson's disease: Questions and answers, in Davidson CS (ed): Problems in Liver Disease. New York, Stratton International Medical Book Corp, 1979, pp 220-231. 8. Walshe JM: Treatment of Wilson's disease with trientine (triethylene tetramine) dihydrochloride. Lancet 1982;1:643-647. 9. Brewer GJ, Hill GM, Prasad AS, et al: Oral zinc therapy for Wilson's disease. Ann Intern Med 1983;99:314-320. 10. Brewer GJ, Prasad AS, Cossack ZT, et al: Treatment of Wilson's disease with oral zinc, abstracted. Clin Res 1981;29:758A. 11. Hill GM, Brewer GJ: Establishment of a new therapy for Wilson's disease: Negative copper balance for Wilson's disease patients on oral zinc therapy, abstracted. Clin Res 1982;30:716A. 12. Hill GM, Brewer GJ, Prasad AS, et al: Oral zinc therapy for Wilson's disease patients, abstracted. Clin Res 1983;31:466A. 13. Hill GM, Brewer GJ, Prasad AS, et al: Simplified zinc therapy regimens for control of Wilson's disease, abstracted. Clin Res 1984;82:478A. 14. Brewer GJ, Hill GM, Prasad AS: Simplified approaches to controlling Wilson's disease with zinc therapy, abstracted. Clin Res 1984; 32:740A. 15. Menard MP, McCormick CC, Cousins RJ: Regulation of intestinal metallothionein biosynthesis in rats by dietary zinc. J Nutr 1981; 111:1353. 16. Hoogenraad JU, Van Der Hamer CJA, Van Hattum J: Effective treatment of Wilson's disease with oral zinc sulphate: Two case reports. Br Med J 1984;289:273-276. Downloaded From: http://archneur.jamanetwork.com/ by a Karolinska Institutet University Library User on 05/29/2015