Symptomatic treatment of neurologic symptoms in Wilson disease

Handbook of Clinical Neurology, Vol. 142 (3rd series) Wilson Disease A. Członkowska and M.L. Schilsky, Editors http://dx.doi.org/10.1016/B978-0-444-63625-6.00018-5 © 2017 Elsevier B.V. All rights reserved

Chapter 18

Symptomatic treatment of neurologic symptoms in Wilson disease 1 2

TOMASZ LITWIN1, PETR DUŠEK2,3, AND ANNA CZŁONKOWSKA1* Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, First Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic 3

Institute of Neuroradiology, University Medicine Goettingen, Goettingen, Germany

Abstract Wilson disease (WD) is a potentially treatable neurodegenerative disorder. In the majority of cases, treatment with drugs that induce a negative copper balance (usually chelators or zinc salts) leads to improvements in liver function and neurologic signs. However, some patients show severe neurologic symptoms at diagnosis, such as tremor, dystonia, parkinsonism, and chorea. In this patient group, some neurologic deficits may persist despite adequate treatment, and further neurologic deterioration may be observed after treatment initiation. Such patients may require additional treatment to alleviate neurologic symptoms. Apart from general recommendations for WD anticopper treatment, there are currently no guidelines for managing neurologic symptoms in WD. The aim of this chapter is to summarize possible treatments of neurologic symptoms in WD based on the presently available medical literature.

INTRODUCTION The etiology of Wilson disease (WD) is related to copper toxicity; thus, most investigations of WD management focus on the safety and efficacy of anticopper treatment (Roberts and Schilsky, 2008; EASL, 2012). This subject is described in detail in Chapter 15. On the other hand, data are scarce regarding treatment of the WD-associated neurologic signs and symptoms that occur in 40% of WD patients at diagnosis (described in Chapter 10) and that severely affect quality of life among WD patients (Holscher et al., 2010; Aggarval and Bhatt, 2014). In other neurologic diseases with different etiologies, neurologic signs that are considered movement disorders can be alleviated by various symptomatic therapies (Puschmann and Wszolek, 2011; Frank, 2014;

Schneider and Deuschl, 2014; Thenganatt and Jankovic, 2014). Thus, it can be assumed that these treatments may also be effective in WD. However, to date, such treatments in WD patients have only been documented in case reports (Gelmers et al., 1973; Hirabayashi et al., 1985; Pal et al., 2007; Paliwal et al., 2010; Teive et al., 2012; Sidiropoulos et al., 2013; Lerose et al., 2014) (Table 18.1). To properly evaluate the costs and benefits of symptomatic neurologic WD treatment we need further information regarding the likelihood of liver function worsening and the possibility of neurologic deterioration due to drug-related adverse events, especially drug-induced acute and tardive movement disorders (Litwin et al., 2008, 2013a; Dusek et al., 2015). Below, we summarize the possible methods for symptomatic treatment of different neurologic symptoms based on the presently available literature.

*Correspondence to: Anna Członkowska, MD., PhD, Institute of Psychiatry and Neurology, Second Department of Neurology, Sobieskiego 9, 02-957 Warsaw, Poland. Tel: +48-22-4582-537, Fax: +48-22-8424023, E-mail: [email protected]

Table 18.1 Case studies describing the symptomatic treatment of Wilson disease (WD) neurologic symptoms.

Symptom

Class/drug or procedure

Tremor Tremor mimicking Beta-blockers/ propranolol essential tremor (ET)

Dystonic tremor

Dosage

40–240 mg/day for ET

Barbiturates/ primidone

62.5–750 mg/day

Benzodiazepines/ clonazepam

0.5–4 mg/day

Neurosurgical treatment

Thalamotomy Ventrointermedius (Vim nuclei thalamic stimulation) DBS

Anticholinergics/ trihexyphenidyl Clonazepam

Starting dose 5 mg/day 0.5–4 mg/day

Botulinum toxin (BTX)

Not provided

Number of WD patients treated (reference)

Treatment effect

3 Good (n ¼ 1) Moderate (Holscher et al., 2010) (n ¼ 1) General information Slight (n ¼ 1) (Brewer et al., 1999) Propranolol less effective than primidone 5 Very good (n ¼ 2) (Holscher et al., 2010) Good (n ¼ 1) General information Moderate (n ¼ 2) (Brewer et al., 1999) Good effect (the exact number of patients not provided) None 1 (Holscher et al., 2010) Used as a second-line Not described (Brewer drug (effect not described) et al., 1999) Good (n ¼ 1) 1 Good (n ¼ 2) (Pal et al., 2007) 2 (Dwarakanath et al., 2014) Not described (Brewer Partial et al., 1999) Not described (Brewer Slight et al., 1999) 1 Slight (Holscher et al., 2010)

Comments

The beta-blocker dose used in the analysis is not provided (Holscher et al., 2010) The doses are not provided; the analysis included 100 neurologic WD patients (Brewer et al., 1999)

The exact doses are not provided (Holscher et al., 2010) The doses started at 25 mg at bedtime, and were gradually increased up to 500 mg/day (in two doses) The analysis included 100 neurologic WD patients (Brewer et al., 1999)

The dose was titrated according to clinical effect or adverse drug reactions

Currently used as a first-line treatment in dystonic tremor

Dystonia BTX

Anticholinergics/ trihexyphenidyl Biperiden

Baclofen

Benzodiazepines/ clonazepam

Dopamine agonists Ropinirole Presynaptic monoamine depletors/ tetrabenazine Antiepileptic drugs oxcarbamazepine Gabapentin

Neurosurgical treatment

3 (Holscher et al., 2010) 1 (Litwin et al., 2013a) 5 (Teive et al., 2012) Not described (Brewer Starting dose et al., 1999) 5 mg/day (mean dose 30 mg/day) 5 Starting dose 2 mg/day, (Holscher et al., 2010) usually 6 mg/day, up to 1 16 mg/day (Holscher et al., 2010) 60–120 mg/day 2 (Holscher et al., 2010) Not described (Brewer et al., 1999) 0.5–4 mg/day Not described (Brewer et al., 1999) 1 (Holscher et al., 2010) Dose not provided 1 (Holscher et al., 2010) Starting dose 12.5 mg/day, 1 mean dose 50–75 mg/day (Holscher et al., 2010)

Good (n ¼ 2) Slight (n ¼ 1) Good (n ¼ 1) Good (n ¼ 5)

300 mg/day

Good (n ¼ 1)

Not provided Not provided 35 units for each lateral pterygoid muscle (jaw dystonia)

900 mg/day

GPi DBS

1 (Micheli et al., 2011) 3 (Paliwal et al., 2010) 1 (Lerose et al., 2014) 1 (Sidiropoulos et al., 2013)

Partial Good (n ¼ 1) Moderate (n ¼ 3) None (n ¼ 1) Moderate (n ¼ 1)

The dose was titrated according to clinical effect or adverse drug reactions

Good (n ¼ 1) Moderate (n ¼ 1) Moderate Slight None

Good (n ¼ 1) Good (n ¼ 1)

Good (n ¼ 3) Good (n ¼ 1) Good (n ¼ 1)

Continued

Table 18.1 Continued

Symptom

Class/drug or procedure

Dosage

Number of WD patients treated (reference)

Treatment effect

Comments

None (n ¼ 1) None (n ¼ 1) Moderate (n ¼ 1) Moderate (n ¼ 3)

Motor complications occurred with a dose of 1250 mg, temporarily interrupting treatment

Good (n ¼ 2) None (n ¼ 5)

Starting dose of 1 mg (subcutaneous), with increments of 1 mg at intervals of at least 1 hour until improvement or adverse drug reaction Could predict the reaction to levodopa treatment

None

Parkinsonism Levodopa

Dose not provided 2500 mg 1000 mg Dose not provided

Apomorphine

Mean dose 4 mg (1–6 mg) subcutaneously

1 (Holscher et al., 2010) 1 (Morgan et al., 1970) 1 (Barbeau and Friesen, 1970) 3 (Gondim et al., 2013) 7 (Frankel et al., 1989)

Amantadine

300 mg/day divided in 2–3 daily doses

1 (Berio et al., 1973)

Presynaptic monoamine depletors/ tetrabenazine

Starting dose 12.5 mg/day, 1 mean dose 50–75 mg/day (Holscher et al., 2010)

Chorea Good (n ¼ 1)

Tested for unspecific “hyperkinesias”

Neuromuscular Performed 1 hour per day, 5 1 electric stimulation times a week, 10 sessions (Lee et al., 2012) (NMES) per cycle

Good (n ¼ 1)

Improvement in pharyngeal phase

Botulinum toxin A (BTX-A)

Good (n ¼ 1)

The study included 19 patients with extrapyramidal disorders and sialorrhea, including 1 WD patient

Dysphagia

Drooling Injection in parotid gland

GPi, globus pallidus internus; DBS, deep-brain stimulation.

1 (Svetel et al., 2009)

SYMPTOMATIC TREATMENT OF NEUROLOGIC SYMPTOMS IN WILSON DISEASE

TREMOR The treatment of WD-related tremor is challenging, since WD can manifest with many types of tremors that presumably differ in pathophysiology (described in Chapter 10). Correct tremor classification can help in choosing an appropriate treatment option (Lorincz, 2010). In general neurology, tremor treatment varies depending on the tremor type, e.g., essential or essential-like, dystonic, cerebellar, thalamic, rubral, neuropathic, orthostatic, senile, functional (Puschmann and Wszolek, 2011; Schneider and Deuschl, 2014). Based on the diagnosis, treatment can comprise a wide spectrum of pharmacologic agents, including beta-blockers (e.g., propranolol, atenolol, sotalol, nadolol), benzodiazepines (e.g., clonazepam, alprazolam, diazepam), antiepileptic drugs (e.g., primidone, gabapentin, topiramate, levetiracetam, pregabalin), neuroleptics (e.g., clozapine, olanzapine), calcium channel blockers (e.g., flunarizine, nimodipine, nicardipine), levodopa, anticholinergics (e.g., trihexyphenidyl, biperiden), botulinum toxin (BTX), and immunoglobulins (neuropathy-related tremor). Due to the high prevalence of liver injury in WD patients, potentially hepatotoxic drugs (e.g., antiepileptics) should be used very carefully (Roberts and Schilsky, 2008; Puschmann and Wszolek, 2011; EASL, 2012; Schneider and Deuschl, 2014). In patients with pharmacologic-refractory tremor, treatment may include neurosurgical procedures, such as thalamotomy, or deep-brain stimulation (DBS) of the thalamic ventralis intermedius nucleus (Vim) (Puschmann and Wszolek, 2011; Schneider and Deuschl, 2014).

Tremor mimicking essential tremor (ET) Tremor mimicking ET predominantly affects hands, but can also impact the head and voice. ET is postural, but may be accompanied by some tremor at rest or intention. Beta-blockers are the best treatment option for this tremor type – typically propranolol 40–240 mg divided into two doses in the morning and afternoon (Holscher et al., 2010). This treatment has additional benefits for patients with cirrhosis and liver failure, due to its positive action on portal hypertension (Roberts and Schilsky, 2008; EASL, 2012). The second-line treatment for postural ET-like tremor in WD is primidone – typically 62.5–750 mg divided into three doses. However a lower dose should be used in cases with liver failure, due to the possibility of toxic barbiturate accumulation (Brewer et al., 1999). Other less effective treatment options include benzodiazepines, such as alprazolam (typical dose 0.75–1.5 mg/day) or clonazepam (typical dose 0.5–4 mg/day), and antiepileptics, such as gabapentin (typical dose 900–1800 mg/day). There is only one

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published retrospective investigation of the pharmacologic treatment of neurologic symptoms in WD. The results in a very small number of patients showed that beta-blockers (n ¼ 3) and primidone (n ¼ 5) were slightly to moderately effective in tremor treatment for most patients, while clonazepam was ineffective in 1 case (Holscher et al., 2010). Similarly, Brewer et al. (1999) performed a study in 100 neurologic WD patients, reporting some positive effects (in few cases) with primidone (starting at 25 mg/day and increasing to as much as 500 mg/day) alone or combined with propranolol.

Dystonic tremor In cases of dystonic tremor, the preferred treatment option depends on the clinical presentation. BTX injections are considered the best treatment for dystonic head, jaw, and voice tremor (Puschmann and Wszolek, 2011; Schneider and Deuschl, 2014). On the other hand, treatment of dystonic hand tremor is initiated with anticholinergics or beta-blockers, often with later addition of benzodiazepines, primidone, or tetrabenazine (Puschmann and Wszolek, 2011). Some reports have also indicated the effectiveness of anticholinergic treatment with trihexyphenidyl (starting with 5 mg in divided doses, and increasing if needed) and benzodiazepines (Brewer et al., 1999).

Rubral tremor Another form of tremor that is sometimes observed in WD is rubral tremor, also called midbrain tremor, which may be clinically indistinguishable from thalamic tremor. Although rubral tremor is frequently refractory to pharmacologic treatment, there are sporadic reports of positive effects with high doses of levodopa, anticholinergic drugs (trihexyphenidyl 2–12 mg), benzodiazepines (clonazepam 0.5–4 mg), and levetiracetam (Puschmann and Wszolek, 2011; Schneider and Deuschl, 2014). However, no data are available regarding the use of these drugs in WD. DBS has been successfully used to treat refractory rubral tremor in WD (Hedera, 2014). One report also describes the effective use of dimercaprol (an anticopper drug administered by intramuscular injections, which is now difficult to obtain) as rescue therapy in a case of refractory rubral tremor (Chakor et al., 2015). However, the neurologic improvement may have been due to the strong anticopper treatment. Anecdotal reports of WD tremor treatment using other drugs, such as nimodipine, acetazolamide, carbamazepine, have produced disappointing results (Brewer et al., 1999).

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Intention tremor Intention tremor, similar to cerebellar tremor observed in multiple sclerosis, is fairly common in WD. However, there is presently a lack of data to guide effective pharmacologic treatment of this type of tremor in WD (Holscher et al., 2010). Parkinsonian rest tremor is also sometimes observed in WD and its management is described in Chapter 18. Finally, in cases of severe disabling tremor, symptoms can sometimes be alleviated by neurosurgical approaches, namely DBS of the Vim thalamic nucleus or thalamotomy (Hedera, 2014). This is further described in Chapter 18.

DYSTONIA Dystonia is among the most disabling neurologic symptoms in WD (Svetel et al., 2001; Lorincz, 2010; Burke et al., 2011; Dusek et al., 2015). Independently of etiology, symptomatic treatment of dystonia generally depends on its severity and localization (Thenganatt and Jankovic, 2014). Focal dystonias are treated with BTX injections, while oral drugs are recommended in cases of multisegmental or generalized dystonia (Pal et al., 2007; Sidiropoulos et al., 2013; Dwarakanath et al., 2014; Thenganatt and Jankovic, 2014). Drugs used for oral pharmacologic treatment include anticholinergics, baclofen, benzodiazepines, dopamine receptor antagonists, dopamine-depleting drugs, and carbamazepine/oxcarbamazepine (for paroxysmal dyskinesias) (Brewer et al., 1999; Thenganatt and Jankovic, 2014). When pharmacologic treatment is ineffective, dystonia can be treated neurosurgically (Dwarakanath et al., 2014; Thenganatt and Jankovic, 2014). When bothersome to the patient, focal dystonias in WD can be treated with BTX injections, as demonstrated by Holscher et al. (2010) (n ¼ 3), Litwin et al. (2013a) (n ¼ 1), and Teive et al. (2012) (jaw-opening dystonia; n ¼ 5). Symptomatic dystonia treatment in WD patients most often involves administration of anticholinergic agents, such as trihexyphenidyl (usually starting at a dose of 2 mg, and slowly increasing until achieving optimal effects, typically at 30 mg/day) or biperiden (with a starting dose of 2 mg/day, usually given three times daily for a total dose of 6 mg/day, and up to 16 mg/day) (Hirabayashi et al., 1985; Brewer et al., 1999; Litwin et al., 2013a). Anticholinergic drugs can also decrease saliva production, thus alleviating drooling (Brewer et al., 1999). On the other hand, their central and peripheral anticholinergic mode of action can lead to adverse events, including cognitive impairment, drowsiness, blurred vision, urinary retention, constipation, and tachycardia. Such anticholinergic side-effects are mostly observed in older patients, while younger patients can

tolerate higher doses, which is typical in cases of WD (Brewer et al., 1999). Holscher et al. (2010) reported that dystonia treatment with anticholinergic drugs had good effects in 4 patients, and no effect in 1 case. The presynaptic gamma-aminobutyric acid agonist baclofen can also be an effective treatment for segmental or generalized dystonia treatment, with typical doses of 60–120 mg/day. Unfortunately, there are only 3 case reports describing baclofen use in WD. Holscher et al. (2010) described 2 cases of successful dystonia treatment with baclofen. Brewer et al. (1999) only mentioned trying baclofen for dystonia treatment in a case of WD. Teive et al. (2005) reported a slight effect with the use of baclofen in combination with biperiden and levodopa. Dystonia treatment can also involve the use of benzodiazepines as muscle relaxants, most commonly clonazepam at a typical dose of 0.5–4 mg/day (Brewer et al., 1999). However, again, there is a lack of data regarding the efficacy of benzodiazepine treatment for dystonia in WD. The only report in the literature describes a lack of effectiveness following the use of clonazepam in 1 WD patient with dystonia (Holscher et al., 2010). Dopaminergic compounds, such as levodopa and the dopamine agonists apomorphine and ropinirole, have been used to treat both dystonia and parkinsonism. Imaging studies of dopamine transporter and D2 dopamine receptors have revealed presynaptic and postsynaptic nigrostriatal deficits among WD patients (Czlonkowska and Czlonkowski, 1984; Schlaug et al., 1994; Oder et al., 1996; Barthel et al., 2003; Litwin et al., 2013b). Although several case studies have reported benefits of using dopaminergic compounds as additional therapy in WD, most reports show that such treatment is generally ineffective (Barbeau and Friesen, 1970; Berio et al., 1973; Gelmers et al., 1973; Frankel et al., 1989; Gondim et al., 2013; Dusek et al., 2015). Holscher et al. (2010) described the case of 1 WD patient with dystonia and parkinsonian symptoms, who improved after ropinirole treatment (Holscher et al., 2010). Overall, the available data seem to indicate that dopaminergic drugs should be tried in every WD patient with limb dystonia, rubral tremor, or parkinsonism, and treatment should be discontinued if no effect is observed. Dopamine receptor antagonists constitute another group of drugs with potential effects on dystonia in WD. Clozapine, a drug that mainly blocks D4 receptors, is primarily used as an atypical antipsychotic drug in psychiatric care, but has been also tested for the symptomatic treatment of tremor and dystonia (Puschmann and Wszolek, 2011; Thenganatt and Jankovic, 2014). No data are available regarding the use of clozapine in WD, but dopamine-blocking agents should be generally avoided due to their potential to cause acute and tardive

SYMPTOMATIC TREATMENT OF NEUROLOGIC SYMPTOMS IN WILSON DISEASE dyskinesias (Thenganatt and Jankovic, 2014; Litwin et al., 2015; Zimbrean and Schilsky, 2015). Tetrabenazine is a presynaptic neurotransmitter depletor that inhibits vesicular monoamine transporter type 2, consequently depleting dopamine, norepinephrine, and serotonin in the central nervous system. It is often used in tardive dyskinesia and in Huntington disease (HD) for the treatment of involuntary choreodystonic movements (Frank, 2014). The starting dose is typically 12.5 mg/day, which is increased in increments of 12.5 mg until achieving optimal effect or occurrence of adverse events, with a typical final dose of 50–75 mg/day. As with other symptomatic drugs, only limited experience with tetrabenazine in WD has been reported. Holscher et al. (2010) described a single case of dystonic WD that was treated with tetrabenazine with a good effect. Based on the good outcomes of dystonia treatment with tetrabenazine in other disorders, this may be a promising agent for WD dystonia treatment and further investigation is warranted (Thenganatt and Jankovic, 2014). Antiepileptic drugs, such as gabapentin or carbamazepine, are useful for treating dystonic and choreodystonic symptoms, especially in paroxysmal kinesigenic dyskinesias (PKD) (Lerose et al., 2014; Thenganatt and Jankovic, 2014). One case report showed that oxcarbamazepine (up to 300 mg/day) was effective in treating PKD in WD, and gabapentin has been reported to be effective at a dose of 900 mg/day (Paliwal et al., 2010; Micheli et al., 2011; Lerose et al., 2014). Importantly, carbamazepine and its derivatives should be used cautiously in WD due to hepatotoxicity and possible deterioration of liver function (EASL, 2012). Finally, in cases of severe multisegmental or generalized residual dystonia, if no recovery is shown with long-term anticopper treatment, neurosurgical procedures can be considered, including DBS of globus pallidus internus (GPi), pallidotomy, or thalamotomy (Starikov, 2002; Sidiropoulos et al., 2013). These options are described below in the section on neurosurgical treatment of Wilson disease.

PARKINSONISM Similar to dystonia, parkinsonism in WD patients shows a highly variable response to levodopa or dopamine agonists, which are used effectively in Parkinson disease (PD). This is likely because WD patients show combined presynaptic and postsynaptic nigrostriatal deficits (Oder et al., 1996) with presumably large interindividual differences. Several case studies of WD patients have shown positive responses to this treatment (Barbeau and Friesen, 1970; Gelmers et al., 1973; Brewer et al., 1999; Gondim et al., 2013), while other studies report

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no effect (Morgan et al., 1970; Holscher et al., 2010). Frankel et al. (1989) described benefits of apomorphine treatment in 2 out of 7 WD patients with parkinsonism. A therapeutic test levodopa is an easy and cheap test to establish dopaminergic responsiveness, and is warranted in WD patients with disabling parkinsonian symptoms. Amantadine is another drug that could be helpful for treating parkinsonian syndromes in WD (Berio et al., 1973). While its mechanism of action is not entirely understood, it increases dopamine release, and shows some anticholinergic effect and anti-N-methyl-Daspartate (NMDA) glutamatergic properties (Berio et al., 1973). The typical amantadine dose is 300 mg/day divided into 2–3 daily doses. Amantadine use in WD has only been reported once, and did not have any clinical effect (Berio et al., 1973). Similar to dystonia and tremor, the ultimate therapy for parkinsonian symptoms is neurosurgical treatment, such as DBS of GPi, or of the subthalamic nucleus or of neuroablative lesions of this structure (Hedera, 2014). This is further discussed below in the section on neurosurgical treatment of Wilson disease.

CHOREA Chorea is a very rare neurologic symptom of WD, which rarely contributes to disability when present. Accordingly, there are no reports of chorea treatment in WD. Based on experience with HD, tetrabenazine could be an efficacious treatment option, as it was previously used for treatment of tardive dyskinesias in WD (Holscher et al., 2010; Frank, 2014). Classic neuroleptics should not be the first choice for treating chorea in WD due to high risk of neurologic adverse effects, particularly drug-induced movement disorders (Litwin et al., 2015).

NEUROSURGICAL TREATMENT OF WILSON DISEASE For neurologic symptoms in WD that are resistant to other forms of therapy, neurosurgical treatment should be considered. Neurosurgical treatment is supported by the well-documented effectiveness of thalamotomy or thalamic DBS in drug-resistant essential, parkinsonian, or multiple sclerosis tremor, as well as by the effective treatment of dystonia using GPi DBS or ablative neurosurgery (pallidotomy) (Hedera, 2014). As with pharmacologic treatment of neurologic symptoms in WD, there is also a lack of described experiences with DBS or other neurosurgical lesioning procedures in WD treatment, apart from several case reports (Starikov, 2002; Pal et al., 2007; Sidiropoulos et al., 2013; Dwarakanath et al., 2014).

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In 2002, Starikov first described experience with electrical stimulation of the brain in 27 WD patients with various neurologic manifestations: 16 with tremor, 8 with rigidity and tremor, 2 with dystonia, and 1 with an extrapyramidal-cortical form of disease. DBS of the subthalamic region or thalamus (ventrolateral nucleus) completely eliminated or substantially reduced neurologic symptoms in 17 patients (62%). However, this study reported an unusually high mortality rate of 18% (5 patients) (Starikov, 2002). Several single case reports have also shown promising outcomes of neurosurgical treatment in WD (Pal et al., 2007; Sidiropoulos et al., 2013). In 2007, Pal et al. described the favorable effects of left thalamotomy in a 30-year-old WD patient with severely disabling postural-kinetic tremor (i.e., wing-beating tremor) of the upper extremities and head. Surgery led to immediate and complete abolition of contralateral tremor and improvement of ipsilateral tremor. The authors suggested that this excellent outcome may have resulted from targeting the thalamic ventralis oralis posterior nucleus, which is located next to Vim nucleus, as observed on postoperative magnetic resonance imaging (Pal et al., 2007). Similarly, Dwarakanath et al. (2014) described 2 WD patients with severe tremor who were successfully treated by Vim thalamotomy. Other reports show the positive effects of DBS for alleviating dystonia in WD. Sidiropoulos et al. (2013) described a 29-year-old bedridden WD patient with generalized dystonia, severe dysarthria, dysphagia, and ballismus in whom pharmacologic treatment of dystonia was ineffective (gabapentin, benzodiazepines, BTX). Following bilateral GPi DBS, dystonia symptoms were reduced, and the patient regained his ability to walk with assistance, started to vocalize, and experienced improved swallowing (Sidiropoulos et al., 2013). Neurosurgical treatment in WD is potentially limited by structural changes of target structures in basal ganglia, which could conceivably reduce the treatment effect (EASL, 2012; Dusek et al., 2015). While DBS has been successfully used in patients with other secondary dystonias and structural changes in basal ganglia, such as pantothenate kinase-associated neurodegeneration or Fahr’s disease, such observations are limited to only a few cases (Dwarakanath et al., 2014). In summary, DBS or neurosurgical neuroablative procedures are one possible option for the treatment of refractory and persistent tremor or dystonia in WD. However, data regarding the effectiveness of such procedures in WD are presently limited to case studies (Starikov, 2002; Pal et al., 2007; Sidiropoulos et al., 2013; Hedera, 2014). Further investigations are needed to verify the benefit of these procedures in WD symptomatic treatment.

SUPPORTIVE THERAPY Dysphagia Up to 50% of WD patients experience dysphagia (Da Silva-Junior et al., 2008; Lee et al., 2012), which decreases patients’ quality of life and nutritional status and increases the risks of aspiration pneumonia and recurrent respiratory tract infections. A question regarding dysphagia is included in the Unified Wilson’s Disease Rating Scale (Czlonkowska et al., 2007). However, the presently available epidemiologic data concerning dysphagia in WD are limited. Furthermore, prior studies have used different methodologies to asses swallowing – e.g., questionnaires, scintigraphics, videofluoroscopy, and fiberoptic endoscopic evaluation of swallowing (FEES) – and have included different patient groups, rarely focusing on neurologic cases. Thus the actual dysphagia rate among WD patients, including asymptomatic and hepatic patients, could be different and may strongly depend on the assessment methodology. In a Polish registry of WD patients that includes 767 patients, only 137 patients (18%) reported swallowing problems of varying degrees at diagnosis (data not published). However, higher dysphagia rates are reported in other movement disorders similar to WD; for example, up to 80% of patients with PD reportedly have dysphagia, mostly without impact on nutritional status (Bakheit, 2001; Woitalla and Goetze, 2011). Da Silva-Junior et al. (2008) analyzed 8 WD patients, and found that WD patients (even those without neurologic symptoms) showed prolonged oral transit duration and a greater percentage of oral food residue compared to controls. Dysphagia in WD is mainly caused by extrapyramidal symptoms (e.g., bradykinesia and involuntary movements of the perioral muscles and tongue) as well as by impaired coordination of chewing and swallowing reflex. While general rules have been established for dysphagia management (Bakheit, 2001), there are no specific recommendations for dysphagia treatment in cases of WD. Upon WD diagnosis, it is important to use nutritional assessment tools (e.g., subjective global assessment) or objective data assessment (e.g., laboratory tests, anthropometry) to establish the patient’s baseline nutritional status and to monitor the patient’s nutritional status during the course of the disease (Hamada, 2015). Because dysphagia in WD typically results from poor bolus preparation, the initial treatment should include behavioral therapy and physiotherapy. It is generally recommended that patients should not watch television or talk while eating, and should avoid eating when tired. Other basic rules for dysphagia management include eating and drinking slowly, chewing thoroughly, and swallowing everything in the mouth before taking a new bite.

SYMPTOMATIC TREATMENT OF NEUROLOGIC SYMPTOMS IN WILSON DISEASE Patients with weak tongue movement and a poor pharyngeal phase of swallowing may benefit from specific postures; for example, lying down on one side at a 45° angle from flat during swallowing may be preferable to swallowing in an upright position (Bakheit, 2001; Woitalla and Goetze, 2011). At the start of dysphagia treatment, sedatives and other drugs that may impact arousal should be stopped if possible, or administered as only a single dose at bedtime. Anticholinergic drugs prescribed to inhibit saliva production should be stopped upon dysphagia onset, as mouth dryness can aggravate swallowing difficulties. Further dietary modifications should include avoidance of dry and sticky foods, and the use of starch-based fluid thickeners to increase the viscosity of ingested fluids, potentially with the aid of a viscometer device (Bakheit, 2001). In addition to the above-mentioned methods, dysphagia rehabilitation may be performed using neuromuscular electrical stimulation therapy, 3 or 5 times per week for 1 hour during food ingestion (Crary et al., 2007; Lee et al., 2012). In cases of severe uncorrectable dysphagia, tube feeding with direct food delivery into the stomach should be considered to avoid food aspiration and to prevent malnutrition (Bakheit, 2001). When making decisions regarding feeding-tube introduction, it may be helpful to perform objective assessment of aspiration and swallowing impairment using protocols like fiberoptic endoscopic dysphagia severity scale supported by videofluoroscopy or FEES (Bakheit, 2001). A nasoesophageal tube may be temporarily used for supplementary feedings in patients who can orally consume foods with favorable consistency, and for whom prompt improvement is expected. Percutaneous gastrostomy may be considered in patients with persistent or/and progressive severe dysphagia (Loser et al., 2005). However, it should be reserved for patients with severe dysphagia and/or weight loss without signs of neurologic improvement after 1 month of anticopper treatment. It is important to verify the copper contents in tube feedings for WD patients (Brewer et al., 1999).

Drooling Drooling is defined as “the unintentional, involuntary loss of saliva from the mouth due to lack of control over oral secretions” (Lal and Hotaling, 2006). In medical texts, drooling is referred to as sialorrhea (Bax, 1992; Blasco and Allaire, 1992). Drooling is a very common sign of WD. However, there are no published systematic data regarding this problem (EASL, 2012), apart from one study by a French group who found drooling in 46% of analyzed WD patients (68% among neurologic cases) (Trocello et al., 2015). In a registry of 767 Polish WD patients, 32% reported drooling at disease diagnosis

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(not published). Drooling is a symptom with a heterogeneous pathophysiology, potentially occurring due to excessive saliva production, swallowing difficulties, sensory alteration, neuromuscular dysfunction, anatomic abnormalities (e.g., macroglossia), cognitive disorders, posture abnormalities, or orofacial dystonia (Trocello et al., 2015). In WD, drooling is typically related to swallowing dysfunction and orofacial dystonia (e.g., open mouth), rather than saliva overproduction. Drooling should be assessed using questionnaires, such as the Drooling Severity and Frequency Scale (Thomas-Stonell and Greenberg, 1988), and objective measurement of saliva secretion (Friedman and Potulska, 2001; Alves et al., 2006), which is postulated to be elevated in WD (Trocello et al., 2015). When discussing possible methods of drooling treatment, mild drooling may be controlled using nonpharmacologic approaches, such as chewing gum and sucking on hard candies. These actions reduce salivation, probably by triggering automatic swallowing with subsequent reduction of the amount of saliva in the mouth (Chou et al., 2007). On the other hand, severe drooling may require pharmacologic approaches. Several groups of drugs are generally used in sialorrhea treatment, including anticholinergics, adrenergic receptor agonists, and BTX. Anticholinergic drugs inhibit saliva production and salivation by blocking cholinergic muscarinic receptors (Chou et al., 2007). Case reports and clinical trials in PD show that trihexyphenidyl, benzotropine, transdermal scopolamine, ipratropium, pirenzepine, and particularly sublingual 1% atropine drops are effective in reducing sialorrhea. However, use of these drugs is limited by systemic adverse anticholinergic reactions (Chou et al., 2007). It has also been reported that the adrenergic alpha-2 receptor agonists clonidine (0.15 mg/day) and modafinil (100 mg/day) are beneficial in controlling drooling, without inducing anticholinergic side-effects. Increasing evidence also supports the use of BTX type A or B injection in either the parotid or both parotid and submandibular glands. The mechanism of action of this treatment is based on reducing saliva production by inhibiting cholinergic parasympathetic and postganglionic sympathetic activity (Chou et al., 2007; Svetel et al., 2009). There are no specific studies or reports about drooling treatment in the context of WD (Lorincz, 2010; EASL, 2012), apart from 1 case that was successfully treated with BTX-A injection in the parotid glands (Svetel et al., 2009). Although no data are available regarding the effectiveness of symptomatic treatment of drooling in WD, experience in other neurodegenerative disorders (mainly PD) suggests that several drugs and procedures can likely be used as supportive sialorrhea treatment in WD. Importantly, drooling should always be discussed

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within a multidisciplinary team that includes a speech therapist to diagnose the underlying problem. Treatment efficacy should be monitored and scored using quantitative assessment of saliva production, as well as measurement with appropriate scales (Thomas-Stonell and Greenberg, 1988; Chou et al., 2007; Trocello et al., 2015).

Speech therapy Dysarthria is the most common neurologic symptom of WD, reportedly occurring in almost 97% of patients with neurologic manifestation of the disease (Lorincz, 2010), and in 43% of all WD patients. There are several classifications of dysarthria in WD, which are described in detail in Chapter 10. Due to the wide spectrum of neurologic symptoms and the different brain structures affected in WD, multiple forms of dysarthria can be distinguished among WD patients, including hypokinetic, pseudobulbar (spastic), hyperkinetic (dystonic), ataxic, and nonclassified (i.e., dysarthria with complex symptoms, which is the most frequent type) (Lorincz, 2010; Dusek et al., 2015). There are no official recommendations for the treatment of dysarthria in WD (Lorincz, 2010). However, there are general rules for dysarthria management. Firstly, the dysarthria type should be diagnosed, and the primary problem underlying speech difficulties should be determined. Dysarthria treatment (i.e., speech therapy) depends on the specific type of speech disturbance, and is based on compensation, augmentation, or an exercise program (Berry et al., 1974). Therapy for hypokinetic dysarthria focuses on increasing loudness, reducing speech rate, and improving articulation. Such therapy may be supported by the Lee Silverman Voice Treatment program, which was developed and is used in parkinsonism treatment and which teaches patients to “think loud.” On the other hand, therapy for pseudobulbar, spastic dysarthria is mainly based on relaxation techniques that aim to reduce the tone of spastic muscles involved in articulation. Finally, therapy for ataxic dysarthria is based on techniques for modifying the speech rate and prosody. In cases with limited intelligibility of speech, speech therapy should be accompanied by augmentative communication techniques, such as writing, gestures, alternative and augmentative communication devices, computer systems, and smartphone applications to enable sufficient communication and to improve the quality of life of WD patients (Berry et al., 1974; Gage and Storey, 2004; Goodwin et al., 2008; Quinn and Busse, 2012). However, the use of such methods may sometimes be limited by cognitive deficits or disabling involuntary movements.

Physiotherapy No systematic reviews, meta-analyses, or even case reports have described the role of physiotherapy in WD management (Roberts and Schilsky, 2008; EASL, 2012). Regardless, physiotherapy should undoubtedly be considered as supportive care in cases of WD, based on the common pathogenesis of basal ganglia involvement in WD as in other neurodegenerative movement disorders, such as PD and HD, for which physiotherapy is recommended (Gage and Storey, 2004; Goodwin et al., 2008; Quinn and Busse, 2012; Cholewa et al., 2014). Contrary to in other progressive neurodegenerative disorders, in most cases of WD, neurologic symptoms diminish or even disappear in response to adequate anticopper treatment (EASL, 2012). In WD symptomatic treatment, supportive physiotherapy can help to accelerate recovery during the initial stage of the disease before anticopper treatment becomes effective. It is targeted at correcting balance and gait, reducing falls and painful muscle dystonic spasms, and improving muscle strength and movement precision. These symptoms have clear impacts on patients’ activities of daily living and quality of life (Cholewa et al., 2014). In addition to the symptomatic effects of physiotherapy, exercise may enhance brain neuroplasticity related to compensation for dopamine neurotransmission failure in WD (Schlaug et al., 1994; Oder et al., 1996; Fox et al., 2006). Fox et al. (2006) proposed that physiotherapy in PD may improve synaptic plasticity, promote neuron structural adaptation, and increase dopamine levels. They further stated “that dopaminergic neurons are highly responsive to exercise and inactivity (“use” it or lose “it”)” (Fox et al., 2006). Physiotherapy may act via similar mechanisms among WD patients with parkinsonism before removal of brain copper becomes effective, and in cases of residual parkinsonism (Dusek et al., 2015). In cases of WD, physiotherapy can also play roles in protection from contractures, bedsores, and infectious complications in patients who are bedridden due to treatment failure or in cases of late diagnosis where patients show advanced neurologic symptoms. Physiotherapy can be recommended as supportive therapy for treating neurologic symptoms in cases of WD, but only based on empiric data and experience in other movement disorders. There are presently no data regarding the efficacy of physiotherapy or specific treatment plans in WD. There remains a need for physiotherapy studies in WD to improve the treatment of neurologic symptoms of this disease. Physiotherapy should be adjusted in accordance with the neurologic signs and the general condition of the individual patient, since excessive training can potentially lead to deterioration. As in all

SYMPTOMATIC TREATMENT OF NEUROLOGIC SYMPTOMS IN WILSON DISEASE multisystem diseases, treatment should be applied carefully or possibly avoided depending on the patient’s health status.

EFFECT OF LIVER TRANSPLANTATION ON NEUROLOGIC WD SYMPTOMS Liver transplantation (LT) is a method for the ultimate correction of the liver copper metabolism defect in WD and is thus an effective WD treatment option (Roberts and Schilsky, 2008; EASL, 2012). This is further described in Chapter 16. However, the use of LT in WD is limited due to the general effectiveness of pharmacologic WD treatment (Roberts and Schilsky, 2008; EASL, 2012). International guidelines recommend LT only in special clinical situations, such as acute liver failure or decompensated liver cirrhosis that is not responding to anticopper treatment. The concept of using LT as a treatment for neurologic symptoms in WD was postulated because some WD neurologic patients do not respond or even experience neurologic deterioration following anticopper treatment. To date, only case reports have described this treatment option, with conflicting results (Stracciari et al., 2000; Medici et al., 2005; Litwin et al., 2008, 2013c; Catana and Medici, 2012; Weiss et al., 2013; Yagci et al., 2015). Stracciari et al. (2000) reviewed 41 cases in which WD patients with neuropsychiatric signs were treated with LT. LT was performed due to neurologic deterioration in only 5 cases, and due to liver failure in the other 36 cases. Neurologic improvement or stabilization occurred in almost 78% of transplanted patients; however, 4 patients (10%) died during the 1-month observation period. Wang et al. (2001) reported neurologic improvement in 8 of 9 (88%) transplanted patients, while Geissler et al. (2003) found that only 2 of 6 (33%) transplanted patients improved following LT. Medici et al. (2005) analyzed a group of 37 Italian WD patients, and showed that neuropsychiatric presentation of WD is an important factor associated with lower survival after LT, suggesting that this is a relative contraindication for this procedure. Importantly, most published observations of neurologic symptom recovery after LT are in WD patients who were transplanted due to liver failure, with neuropsychiatric evaluation before and after LT performed as an additional analysis (Weiss et al., 2013) or in case reports (Stracciari et al., 2000). Conflicting results have been reported in the few instances in which LT has been performed as a treatment in single cases of WD patients with exclusively neurologic or neuropsychiatric presentations (Bax et al., 1998; Guillaud et al., 2014).

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CONCLUSIONS WD is a rare neurodegenerative disorder that, in most cases, can be successfully treated with pharmacologic agents that lead to a negative copper balance. Aside from limited case reports (Table 18.1), there is no evidence supporting the use of other symptomatic neurologic treatment in WD patients. However, in cases that show persistent disabling neurologic symptoms despite long-term anticopper treatment and in cases with severe initial neurologic presentation, additional symptomatic treatment should be considered, including pharmacotherapy, neurosurgery, physiotherapy, and speech therapy.

ACKNOWLEDGMENTS This work was supported by Charles University in Prague (PRVOUK P26/LF1/4) and by the Czech Ministry of Health (NV15-25602A).

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