Received: 24 October 2019 | Revised: 4 February 2020 | Accepted: 13 February 2020 DOI: 10.1002/brb3.1596 ORIGINAL RESEARCH Ammonium tetrathiomolybdate in the decoppering phase treatment of Wilson's disease with neurological symptoms: A case series Oriol De Fabregues1 | Jaume Viñas1 | Antoni Palasí1 | Manuel Quintana1 | Ignasi Cardona2 | Cristina Auger3 | Víctor Vargas4 1 Movement Disorders Unit, Neurology Department, Vall d'Hebron University Abstract Hospital, Neurodegenerative Diseases Objectives: To present our experience with ammonium tetrathiomolybdate (ATTM) Research Group-Vall d'Hebron Research Institute, Autonomous University of in the decoppering phase treatment of Wilson's disease (WD) with neurological Barcelona, Barcelona, Spain symptoms. 2 Pharmacy Department, Vall d'Hebron Methods: An uncontrolled longitudinal study was carried out to describe a case series University Hospital, Barcelona, Spain 3 Magnetic Resonance Unit, Department of of five patients diagnosed of WD with neurological symptoms in our hospital over the Radiology (IDI), Vall d'Hebron University last 5 years and receiving ATTM for 8 (or 16) weeks. Unified Wilson's Disease Rating Hospital, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Scale (UWDRS), Global Assessment Scale (GAS) for WD and the Brewer-adapted Barcelona, Spain Unified Huntington's Disease Rating Scale (UHDRS) for WD, magnetic resonance 4 Liver Unit, Vall d'Hebron University imaging, and monitoring for potential adverse effects were carried out in all patients Hospital, CIBERehd, Vall d'Hebron Research Institute, Autonomous University of before starting ATTM and 3 months later when ATTM was stopped and zinc treat- Barcelona, Barcelona, Spain ment was initiated. Correspondence Results: All five patients presented neurological clinical improvement in UWDRS, Oriol De Fabregues, Movement Disorders GAS, and Brewer-adapted UHDRS for WD. Neuroimaging improvement was present Unit, Neurology Department, Vall d'Hebron University Hospital, Neurodegenerative in 2/5 patients with brain edema reduction. Mild anemia, leukopenia, and elevation Diseases Research Group-Vall d'Hebron of transaminases were detected in 1 patient, with complete remission after stopping Research Institute, Autonomous University of Barcelona, Barcelona, Spain. ATTM for 1 week and then restarting at a half dose. Emails: odefabregues@gmail.com; Conclusion: ATTM could be a good treatment for the initial treatment of WD with odfabregues@vhebron.net neurological symptoms due to its high efficacy, with a lower rate of neurological de- terioration than the drugs currently available, despite the potential adverse effects. KEYWORDS ammonium tetrathiomolybdate, efficacy, neurological symptoms, safety, Wilson's disease 1 | I NTRO D U C TI O N P-type ATPase protein involved in copper transport and excretion. Recent genetic studies reported a prevalence of 1:7,026 for two Wilson's disease (WD) is an inherited autosomal recessive disor- mutant pathogenic ATP7B alleles (Kieffer & Medici, 2017). While der caused by mutations in the ATP7B gene that encodes for a the pathogenesis of WD is related to the altered function of the The peer review history for this article is available at https​://publo​ns.com/publo​n/10.1002/brb3.1596 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. Brain and Behavior. 2020;10:e01596.  wileyonlinelibrary.com/journal/brb3 | 1 of 7 https://doi.org/10.1002/brb3.1596 2 of 7 | DE FABREGUES et al. ATP7B copper transporter, and its accumulation, it is less clear the clinical motor disease, the Global Assessment Scale (GAS) for how ATP7B mutations influence the phenotype (Medici & LaSalle, WD (Aggarwal, Aggarwal, Nagral, Jankharia, & Bhatt, 2009) which 2019). includes psychiatric symptoms and cognitive, and the Brewer- The clinical symptoms are a result of organ dysfunction due to adapted UHDRS for WD (Brewer et al., 1991, 1994) which evaluates the direct or indirect effects of copper accumulation (Litwin et al., the neurological symptoms. 2018). The severity of the symptoms varies widely and can appear Firstly described as a lethal neurological and hepatic familial anytime between early childhood and old age (Kieffer & Medici, disease, WD now has different drug therapies (copper chelators 2017). Subsequent copper accumulation in organs, mainly liver and and zinc salts). Current guidelines (EASL, 2012; Roberts & Schilsky, brain but also other organs, produces clinical manifestations that 2008) recommend the use of chelators as the initial treatment of include hepatic, neurological, psychiatric, and ophthalmologic dis- symptomatic WD patients, with the suggestion that trientine is bet- orders (Ala, Walker, Ashkan, Dooley, & Schilsky, 2007; Kieffer & ter tolerated. However, a particular adverse event that can occur Medici, 2017; Pfeiffer, 2007). with each type of treatment is paradoxical neurological deteriora- Liver manifestations are present in 60% of patients at diagnosis tion, more frequently with d-penicillamine and trientine than zinc and have been reported to first appear in patients aged between (Litwin et al., 2015). Worsening of neurological symptoms soon after 9 months and over 70 years, ranging from mild elevation of liver en- starting treatment is reported in around 10% of patients, though zymes to acute liver failure and cirrhosis (Kieffer & Medici, 2017; much higher prevalence has also been described (Aggarwal & Bhatt, Litwin et al., 2018). After hepatic manifestations, neurological disor- 2018) and it can be irreversible and extremely serious adverse effect ders, such as tremor, dystonia, parkinsonism, dysarthria, dysphagia, that can even lead to death (Svetel, Sternic, Pejovic, & Kostic, 2001). chorea, or gait disturbance (Ala et al., 2007; Kieffer & Medici, 2017; Paradoxical neurological deterioration has prompted the discussion Lorincz, 2010), are the most frequent clinical symptoms of WD and whether d-penicillamine or trientine should be used in neurological may be its initial presentation in 18%–68% of patients (Czlonkowska WD patients and led to the search for safer treatments such as ATTM et al., 2018). In addition to these typical and more frequent neuro- (Brewer & Askari, 2005; Brewer, Terry, Aisen, & Hill, 1987) or a more logical symptoms of WD, other neurological symptoms may occur recent new formulation of TTM (Bis-choline TTM) called WTX101 in the course of WD that include myoclonus, tics, headache, olfac- that has successfully run through a phase 2 trial (Weiss et al., 2017) tory and taste dysfunction, neuropathies, epilepsy, restless legs syn- and started a phase 3 trial comparing WTX101 with standard of care drome, and sleep disorders (Dusek, Ltwin, & Czlonkowska, 2019). (chelation or zinc therapy or a combination of both chelation and zinc The psychiatric symptoms include anxiety, depression, disinhibition, therapy; Brewer & Askari, 2005; Swenson, 2019). and personality changes. The most common ophthalmological sign Recent data support that patients treated with ATTM could have as a result of copper accumulation is the Kayser–Fleischer corneal less probability of neurological deterioration than those treated with ring, whereas sunflower cataracts are observed rarely, and retinal trientine (Appenzeller-Herzog et al., 2019), and the most frequent degeneration may serve as a marker of neurodegeneration (Dzieżyc- side effects found were reversible increases of anemia, leukopenia, Jaworska, Litwin, & Członkowska, 2019; Kieffer & Medici, 2017). and transaminases (Brewer et al., 2006). Patients with WD may also present with renal disturbances (in- Our objective was to present our experience with ATTM in the cluding tubular dysfunction and renal calculi), cardiac involvement treatment of WD with neurological symptoms after eight weeks of (a recent cardiac study has shown a higher risk of atrial fibrillation treatment by using UWDRS, GAS, and Brewer-adapted UHDRS for and heart failure in WD patients than in non-WD patients), and os- WD scales. teoarticular involvement (including osteopenia, osteoporosis, and arthropathy, which may lead to bone fractures and joint problems mainly affecting knees and wrists; Daneshjoo & Garshasbi, 2018; 2 | M E TH O DS Dzieżyc-Jaworska et al., 2019). Other manifestations of WD include autonomic system dysfunc- 2.1 | Study design and patient selection tion (but involvement is subclinical in most cases) and endocrine sys- tem disturbances (which can lead to recurrent abortions, infertility, An uncontrolled longitudinal study was carried out to describe a growth disruption, and parathyroid failure). However, it is possible case series of all patients (five) who were diagnosed of WD with to become pregnant for females with mild WD symptoms and for neurological symptoms in our hospital during the last 5 years and those who are compliant with therapy), hematologic disturbances who were treated in the Department of Neurology with ATTM for (which may include acute hemolytic anemia, leucopenia, anemia, and 8 (or 16) weeks. All patients were over 18 years of age. The study low platelet count), and skin affectation (including lipomas and char- was conducted in compliance with the ethical standards and was ap- acteristic of WD skin changes like hyperpigmentation of the legs, proved by the Ethics Committee for Clinical Research of Hospital xerosis or azure lunulae of the nails; Dzieżyc-Jaworska et al., 2019). Universitari Vall d'Hebron (Barcelona, Spain). Treatment with ATTM For the evaluation of the neurological symptoms of WD, it has was administered as compassionate use, and all patients signed a been proposed the use of few scales: the Unified Wilson's Disease specific informed consent to start this treatment and a specific con- Rating Scale (UWDRS; Czlonkowska et al., 2007) which evaluates sent to use the study data for scientific purposes. DE FABREGUES et al. | 3 of 7 2.2 | Procedure and assessments The UWDRS consists of three subscales representing three main features of clinical manifestations in WD with 35 items in total: Treatment with ATTM was administered as initial decoppering treat- UWDRS I to evaluate the level of consciousness, UWDRS II to eval- ment at a dose of 120 mg per day (20 mg three times daily with meals uate the impact of the neurological symptoms on the daily life ac- and 20 mg three times daily between meals) for 8 weeks. After com- tivities, and UWDRS III to evaluate the neurological signs found in pletion of the 8-week initial decoppering treatment with ATTM, the the neurological examination. Each item scores severity from 0 (no patients were changed to a maintenance treatment with zinc. The dose symptoms) to 4 (severe affectation), except the first item (level of and regimen of ATTM used in our case series was described by Brewer consciousness) where the maximum score is 3. Subsequent clinical in his initial work (Brewer et al., 1991), when he treated 6 patients with evolution regarding neurological sequelae was extracted taking the ATTM as initial decoppering treatment for 8 weeks and zinc as mainte- highest score from UWDRS III: mild for scores 0 and 1, moderate for nance treatment afterward. As ATTM and zinc were not administered score 2, and severe for scores 3 and 4. concomitantly, hospitalization was not needed in our case series. The Brewer scale was a short adaptation of the UHDRS to eval- All patients were followed weekly for clinical and analytical ef- uate the neurological symptoms of WD. ficacy, with an anamnesis, a physical examination, measuring the levels of urinary copper in 24 hr and the levels of plasmatic copper, and monitoring for the presence of potential adverse effects: liver 2.3 | Statistical analysis function alteration, anemia, or leukopenia. To ensure compliance with ATTM treatment, there was a close and exhaustive monitoring The statistical analysis was descriptive and was carried out using the by phone calls and ambulatory visits. SPSS statistical package v17.0 for Windows. A brain magnetic resonance imaging (MRI) and video recording The values from each evaluation scale were presented descrip- were performed 2 weeks before starting ATTM and 3 months later tively for each patient, before and 3 months after starting ATTM when ATTM was stopped (which was 1 month after stopping ATTM) treatment. and zinc treatment was initiated. Three scales were used: The GAS for WD, the UWDRS, and a short adaptation of the Unified Huntington's Disease Rating Scale 3 | R E S U LT S (UHDRS; Young et al., 1986) used by Brewer in WD in several clinical trials (Brewer et al., 1991, 1994, 2003, 2006, 2009). The scales were We present five patients affected of WD with neurological impair- carried out before starting ATTM and 1, 2, and 3 months later when ment treated as compassionate use with ATTM at a dose of 120 mg ATTM was stopped and zinc treatment was initiated. per day for 8 weeks. The characteristics of the five patients are sum- The GAS for WD contains two parts, GAS I to evaluate global marized in Table 1 and detailed here below. disability in four areas: liver, cognition and behavior, motor, and Patient 1: Man of 21 years. At the age of 12 years following an osteoarticular, each item scoring severity from 0 to 5 (scores not episode of acute hepatitis, he was diagnosed of WD with exclu- to be summed up), and GAS II to evaluate neurological and psychi- sive liver involvement and received treatment with d-penicillamine atric dysfunction with 14 items, each item scoring severity from 0 showing good progress and remaining asymptomatic. At 18 years to 4 (scores to be summed up to a maximum of 56 points). old, he decided, alone, to quit medication and two years later he TA B L E 1 Participant characteristics Reason for starting ATTM Patient Gender Age Age of clinical onset Clinical presentation treatment 1 Male 21 12 Liver disease Progression of symptoms one month after restarting treatment with d-penicillamine 2 Female 39 15 Liver disease Intolerance to d-penicillamine (lupus) Progression although receiving treatment with trientine 3 Female 19 18 Neurological syndrome WD with neurological involvement from start 4 Female 24 10 Neurological syndrome Progression of symptoms although receiving treatment with zinc 5 Male 34 34 Neurological/psychiatric WD with neurological involvement from start Abbreviations: ATTM, ammonium tetrathiomolybdate; WD, Wilson's disease. 4 of 7 | DE FABREGUES et al. TA B L E 2 Results by patient GAS I GAS I GAS II GAS II for WD for WD for WD for WD Patient pre-ATTM post-ATTM pre-ATTM post-ATTM UWDRSI pre-ATTM UWDRSI post-ATTM UWDRSII pre-ATTM 1 8 4 30 12 1 0 23 2 6 4 22 12 0 0 14 3 4 2 17 10 0 0 3 4 4 2 20 15 0 0 4 5 5 3 20 11 0 0 7 Note: Postmeasurements were carried out 2–3 months after starting ATTM. Abbreviations: ATTM, ammonium tetrathiomolybdate; GAS, Global Assessment Scale; UWDRS, Unified Wilson's Disease Rating Scale; WD, Wilson's disease. began to have depressive symptoms and paranoid ideation. One disturbance, progressive parkinsonism, with lesions in MRI. Knowing year later, there were motor and vocal tics, with dysarthria, general- the neurological deterioration risk when starting chelation with ized bradykinesia, and mild dystonic posture in left upper extremity. d-penicillamine or trientine, and knowing the slow effect of zinc, it It was then restarted treatment with d-penicillamine with initial clin- was decided to start treatment with ATTM. ical improvement but after one month presented rapidly progressive All five patients received zinc salts after the 8 weeks of treat- neurological impairment. Treatment with zinc was initiated, but pro- ment with ATTM (16 weeks for Patient 2). gressive impairment continued, and it was then decided to initiate All five patients presented neurological clinical improvement treatment with ATTM. between before and 3 months after starting treatment with ATTM, Patient 2: A 39-year-old woman, diagnosed at 15 years of age of measured with UWDRS, GAS, and adapted Brewer scales for WD, WD because of clinical chronic liver disease. She was treated with as shown in Table 2. d-penicillamine between the ages of 15 and 21 years, when she de- There was also a neuroimaging improvement in 2/5 patients veloped a lupus-like syndrome due to this drug which was replaced (Patients 2 and 3) with brain edema reduction 3 months after start- by trientine. She remained asymptomatic until the age of 37 when ing treatment with ATTM, although chronic necrotic lesions of basal she began to have a slow progressive neurological impairment with ganglia were persistent (Figure 1). dysarthria, bradykinesia, and depressive mood. Treatment was then In 1/5 patients (Patient 3), a mild anemia and leukopenia together changed to zinc salts, but the progression of neurological impair- with transaminases elevation was found three weeks after starting ment continued. Treatment with trientine was started again, but ATTM treatment, being discontinued for 1 week and then restarted neurological impairment continued to progress. It was then decided at a lower dose (60 mg/day; Table 2). There was a remission of the to initiate therapy with ATTM. There was a neurological improve- analytical abnormalities, and the 8-week treatment could be finished ment, progressive deterioration was stopped, and the patient was with no more incidences. stabilized. It was decided to extend treatment with ATTM eight In 1/5 patients (Patient 1), there was a transitory depression and weeks more. paranoid ideation for a few days resolved spontaneously while main- Patient 3: A 19-year-old woman who attended our unit with dys- taining the treatment. arthria, dystonic postures in the left distal extremities (fingers and No other adverse effects were found in any other patient. wrist bending and twisting of the foot when walking), and bilateral In 3/5 patients (Patients 3, 4, and 5), the subsequent clinical evo- parkinsonism, symptoms consistent with neurological debut of WD. lution regarding neurological sequelae was mild (Table 2). No previous treatment was administered. It was decided to start treatment with ATTM. Patient 4: A 24-year-old woman with neurological debut at the 4 | D I S CU S S I O N age of 10, with progressive dysarthria, dystonia, and parkinsonism. She started treatment with d-penicillamine, but after 1–2 months, Wilson's disease with neurological symptoms, although being a po- there was a severe neurological deterioration. Treatment was tentially manageable alteration actually, it can be highly incapaci- changed to zinc salts, with mild improvement with sequelae, but at tating if the treatment is inadequate or is started too late once the the age of 24, there was a new severe neurological deterioration. It symptoms are present (Walshe, 2009). was then decided to start treatment with ATTM. In our study, none of the five patients evidenced a neurological Patient 5: A 34-year-old man, who showed an alteration in he- clinical progression after starting ATTM treatment. Moreover, there patic function in an ambulatory analytical control without any other was a significant neurological clinical improvement demonstrated manifestation or symptom at the age of 32. Diagnosed at the age by the three scales used to evaluate the neurological symptoms of 34, when she presented neurological symptoms, dysarthria, gait of WD, except for the UWDRS I subscale (evaluating the level of DE FABREGUES et al. | 5 of 7 UWDRSII UWDRSIII UWDRSIII Brewer scale Brewer scale post-ATTM pre-ATTM post-ATTM pre-ATTM post-ATTM Adverse effects Subsequent clinical evolution 8 61 20 13 9 — Death unrelated to treatment 6 39 14 12 8 — Moderate neurological sequelae 1 25 10 11 8 Mild transaminase elevation, Mild neurological sequelae anemia, and leukopenia 3 15 13 7 4 — Mild neurological sequelae 3 32 24 11 6 — Mild neurological sequelae consciousness). All our patients presented a normal level of con- Concerning WD cranial lesions, some authors consider that im- sciousness (baseline score of 0) except for one case with a baseline provement in radiological lesions in the cranial MRI is a good prog- score of 1 (mild somnolence). This patient improved after ATTM nosis factor in response to the treatment (Prashkanth et al., 2005). treatment, being the level of consciousness of 0. In our study, the neuroimaging improvement found in 2 of the 5 pa- Clinical improvement is the expected result in WD patients start- tients after starting ATTM treatment was consistent with a clinical ing an effective chelation therapy. A study carried out by Brewer improvement. (Brewer et al., 2003), evaluating the efficacy of ATTM, found that The most frequent adverse effects reported after starting ATTM responding patients had a sustained significant improvement even treatment in the Brewer study (Brewer et al., 2003) were mild mye- one year after starting ATTM treatment. losuppression in 5 of the 22 patients and transaminases increase in In our case series, we reproduced the experience presented by 3 cases. We found similar results in our 5 patients, where only one Brewer in his initial work where 6 patients received ATTM as ini- patient presented a mild myelosuppression (with mild anemia and tial decoppering treatment with no worsening of acute neurological leukopenia) and an increase of the hepatic enzymes. Hematological symptoms (Brewer et al., 1991). In our case series, there was a neu- disorders are usually present between weeks 3 and 6 of the treat- rological clinical improvement in all five patients. ment (Brewer et al., 2003, 2006) and have been related to a possible Furthermore, in our study, none of the patients presented neu- effect of lack of copper due to excess chelating treatment (Brewer rological clinical progression, which also supports the evidence et al., 2003). Hepatic enzymes increase usually appears also after from the Brewer study (Brewer et al., 2006) that ATTM could lead week 3 of treatment, and the cause is still unknown, but seems re- a much lower rate of neurological progression associated with lated to a direct effect of the drug. Both adverse effects disappear the start of the treatment than penicillamine (estimated in 50%; after a rest drug period (usually one week) and restarting the drug Brewer et al., 2003) and trientine (26%; Brewer et al., 2006), al- at half dose (60 mg/day; Brewer et al., 2003). The analytical disor- though there were very few patients. While all patients from the ders in our patient were normalized after discontinuing ATTM for Brewer study in 2006 received zinc treatment together with trien- 1 week, with no clinical progression evidenced during this period, tine or ATTM for 8 weeks, being all patients hospitalized (probably and the treatment could be completed for 8 weeks with no further due to the complexity of both medications administered concom- incidences. itantly), patients from the Brewer study in 2003 received ATTM ATTM was administered as initial decoppering treatment for alone for 8 weeks as per his initial work from 1991 and our case 8 weeks. In one patient, treatment was extended eight weeks series. more, keeping the efficacy and safety, which is important as it al- In the decoppering phase treatment of WD, chelators may induce lows to consider ATTM as a rescue treatment, achieving neurologi- further clinical deterioration in some treated patients. This is a par- cal improvement in patients intolerant to penicillamine or trientine adoxical situation of great concern, whose treatment is a challenge. treatment. ATTM would also be considered for use as maintenance In our study, three of the five patients (Patients 1, 2, and 4) started treatment; however, this is hindered by the stability issues of this ATTM treatment due to progression of the neurological symptoms drug together with the too cumbersome treatment schedule with although receiving treatment for WD with other drugs (penicilla- multiple daily dosing. However, the difficulties of ATTM treatment mine, trientine, and zinc, respectively). All three patients evidenced could possibly be solved with a new formulation of Bis-choline TTM clinical improvement after starting ATTM treatment, which could be (Brewer & Askari, 2005; Weiss et al., 2017; Swenson, 2019). an indirect estimation of superiority of ATTM treatment in WD with In summary, there are very limited data in the literature on neurological presentation with respect to the previous treatments ATTM and Wilson's disease (which is dominated by the Brewer as well as an option to rescue the neurological deterioration related publications), and given this scarcity, the present case series to those treatments. may be of interest to the community. A new aspect is that in our 6 of 7 | DE FABREGUES et al. (a) or zinc paradoxical neurological deterioration, despite the potential adverse effects which, in our experience, were mild and reversible. AC K N OW L E D G M E N T S The authors are grateful to all the patients for their participation. The authors thank Esther Pellicer for helping in writing the manuscript. C O N FL I C T O F I N T E R E S T On behalf of all authors, the corresponding author states that there is no conflict of interest. AU T H O R C O N T R I B U T I O N S Oriol De Fabregues designed the study and performed organiza- tion and execution; data acquisition; analysis and interpretation of (b) data; manuscript drafting; and manuscript revision. Jaume Viñas, Antoni Palasí, and Ignasi Cardona performed execution and data ac- quisition. Manuel Quintana performed descriptive analysis. Cristina Auger performed the MRI. Víctor Vargas revised the manuscript. DATA AVA I L A B I L I T Y S TAT E M E N T The data that support the findings of this study are available from the corresponding author upon reasonable request. ORCID Oriol De Fabregues https://orcid.org/0000-0002-3518-5338 REFERENCES Aggarwal, A., Aggarwal, N., Nagral, A., Jankharia, G., & Bhatt, M. (2009). 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