Epidemiology
In 1912, WD was defined by Kinnear Wilson as a disorder in copper metabolism. Various mutations occurring in chromosome 13q14 disrupt the coding for the protein ATP7B resulting in dysfunctional copper excretion [19]. The disease can either develop sporadically or from an autosomal recessive inheritance pattern. It is a very rare disease process that should be suspected in patients with a strong family history of consanguinity. Usually, symptoms begin during childhood or teenage years, manifesting as liver dysfunction [18]. The World Health Organization (WHO) approximates the global prevalence of WD is 1/10,000 to 1/30,000 [18]. In a study including 604 participants with WD, 47% were found to have the hepatic type WD and 32.2% were found to have the neurological type WD [18]. Other types of WD manifestations can range from psychiatric to ophthalmic characteristics.
The prevalence of WD differs per geographical region and seems to predominate more in the Asian population than the Caucasian population [15]. Several regions statistically display higher rates of WD amongst their population, including Germany, Japan, and Austria [19]. However, the region with the highest incidence of WD in the world is Costa Rica reporting a rate of 4.9/100000 inhabitants [19]. Their incidence rate is thought to be attributed to increased consanguinity within the country [19]. The most common mutation linked to WD in Europe and North America is p.H1069Q [15]. With this knowledge in mind, physicians can utilize genetic testing and take thorough family histories to reveal the diagnosis of WD.
Pathogenesis
One essential barrier in the human body is the blood-brain barrier. Normally, astrocytes are able to detoxify copper via reduction-oxidation reaction, but with the dramatic increase in extrahepatic copper, the astrocytes reach their limited capacity. This allows the copper to infiltrate the brain and damage the oligodendrocytes next. Copper causes swelling of the myelin sheaths that are supplied by oligodendrocytes in the central nervous system (CNS), resulting in demyelination [7]. Along with the demyelination, copper deposits within certain brain regions like the basal ganglia, thalamus, cerebellum, upper brainstem, putamen, and frontal lobe [16]. Deposition causes mitochondrial damage, oxygen-free radical generation, as well as white matter, and extracortical spinal tract damage. The widespread neurological destruction that copper causes make it difficult to precisely pinpoint the dysfunctional brain tissue and associate it with the presenting symptoms. Also, since WD is extrahepatic in nature, the diagnosis is oftentimes delayed. Another potential contributor to the neurological toxicity seen in WD is liver cirrhosis. This leads to portal hypertension, hepatic encephalopathy, and a decrease in the liver's ability to detoxify neurological metabolites and excrete them properly [7].
Clinical Manifestations
Tremor
The diagnosis of neurological type WD is difficult due to the diverse neurological manifestations it can present with. Contemporary literature has reported a delay of diagnosis from the onset of its first symptom by 2.5-6 years [17] The most notable symptom is a tremor which occurs in up to 55% of patients on the initial encounter and is present in about 90% of patients during the duration of the disease [7].
Various forms of tremor can be noted, including resting, postural with "wing-beating" features, or kinetic [5]. Tremor severity progresses from proximal to distal. The pathology of WD is complex, making it challenging to diagnose based on the symptoms alone. The regions affected are the pons, midbrain, thalamus, and the putamen, with the latter being the most notable area affected in 81% of patients [21]. Like many other neurodegenerative diseases, the tremor can be unilateral or bilateral. A study in 2018 analyzing the tremor of WD found that tremor asymmetry was influenced by the asymmetry of fiber volumes between the thalamus and cerebellum as well as the caudate nucleus and the thalamus [22].
Therapeutic options vary to combat the specific type of tremor noted [7]. Non-selective beta-blockers such as propranolol are the first-line treatment for essential, postural, and kinetic tremors affecting the hands. Barbiturates, benzodiazepines, anticholinergics, presynaptic GABA agonists, botulism toxin injections, and even deep brain stimulation have been used on patients with symptomatic tremors [7].
Dystonia
The most severe and recurrent symptom of neurological type WD is dystonia. It is seen in 11- 65% of patients with neurological type WD and can be generalized, focal, or multifocal [7] [5]. However, the most common type of dystonia appreciated in these patients is a focal one affecting the face. This is represented with an open mouth smile, dystonic dropped jaw, or a fixed smile [5]. As the disease progresses, the dystonia transitions from focal to generalized, involving several different segments and resulting in a dystonic state associated with high mortality [5]. A study in 2019 looked at diffusor tensor imaging and MRI scans over 364 patients between the ages of 5 to 42 years that presented with neurological manifestations of WD. They found that out of the 364 patients, 197 had some form of dystonia. Of the 197 patients, imaging displayed damage to the putamen 80.7%, pons 48.2%, and thalamus 37.1% [21].
The treatment for dystonia in WD is also symptom-based. The multifocal or generalized form of dystonia can be treated with anticholinergics, GABA agonists, dopamine agonists, dopamine depletion drugs, antiepileptic drugs, and botulism toxin injection. Usually, the botulism toxin injection is the first-line treatment for the focal form of dystonia. If pharmacotherapy is not showing improvement in symptoms, deep brain stimulation of the globus pallidus internus, pallidotomy, or thalamotomy may be the last resort alternatives [7].
Parkinsonism
Parkinsonism is reported in 19-62% of patients with neurological type WD [7]. This syndrome consists of rigidity, a resting tremor, bradykinesia, and postural imbalance [7]. Like many neurodegenerative diseases, the symptoms are often asymmetrical in nature and are able to affect the signaling and induction of neurotransmitters. From a pathological standpoint, the development of parkinsonism in WD patients is related to the copper accumulation and subsequent damage within the basal ganglia and substantia nigra.
The atypical signals found on MRI are likely caused by glial cell hyperplasia, necrosis, and edema [21]. Out of 364 participants who were diagnosed with neurological type WD, 127 reported parkinsonism symptoms [21]. Of the 364 participants, 81.9% displayed defects in the putamen, 32.3% in the caudate nucleus, and 26.4% in the pons seen on MRI [21].
Treatment includes levodopa and dopamine receptor agonists for patients with disabling symptoms. As disease severity progresses, deep brain stimulation or neuroablative lesions of the globus pallidus internus and subthalamic nucleus could be alternatives [7].
Cerebellar Ataxia
Cerebellar ataxia is a common symptom in neurological type WD with 30% of patients expressing some form of dysfunction [7]. The pathogenesis of cerebellar ataxia is related to the marked atrophy and loss of Purkinje fibers in the cerebellum [20]. This leads to loss of balance, gait, speech, and impairment in fine motor movements. If symptoms of WD do not accompany it, various other neurodegenerative disorders may be suspected, and the true diagnosis could be missed or delayed. Diagnosis of neurologic type WD is commonly made with cerebellar ataxia in conjunction with the other neurological manifestations described in this section [5]. Pharmacotherapy is not an option for patients with cerebellar ataxia; however, the increasing availability in genomics might lead to useful biologics that can prevent disease progression [20].
Choreoathetosis
Choreoathetosis is a symptom present in 6-16% of Wilson's disease patients, but it is not diagnostic of WD alone. The symptom is characterized as an involuntary twitching or writhing movement disorder that affects the head, trunk, and extremities either unilaterally or bilaterally [5]. It was observed that out of 364 patients with neurological type WD, only eight patients had associated choreoathetosis [21]. In all eight patients, there was damage seen in the caudate nucleus [21]. Another study in 2018 found that patients with choreic movement had marked asymmetry of the fiber volumes between the caudate nucleus and the thalamus [22]. The treatment of choreoathetosis is limited to dopamine depletion agents such as tetrabenazine and behavioral therapy.
Dysarthria
Dysarthria, or speech disturbance, is one of the most common neurological symptoms seen in WD patients [7]. The copper collection in the basal ganglia, cerebellar nuclei, corticobulbar nuclei, and their associated tracts causes a number of detrimental symptoms, including dysarthria [7]. It's suspected that the copper accumulation damages these cranial structures over time and leads to improper communication between the basal ganglia and the subthalamic nuclei [13]. As a result, WD patients may have difficulty controlling muscles involved with speech production and subsequent slurring. Dysarthria can be further subcategorized into specific types such as mixed unclassified, ataxic, dystonic, and hypokinetic [7]. Each type presents unique symptoms associated with the neurological structures involved. In the mixed unclassified type dysarthria that is often presented in WD patients, several structures are affected by the copper aggregation causing dystonic and hypokinetic characteristics as well as cerebellar ataxia [10]. Ataxic type dysarthria will display cerebellar symptoms, while dystonic and hypokinetic types will express movement disabilities [7].
Treatment for dysarthria is dependent on the type and severity. Relaxation techniques can be encouraged in patients with dystonic type, and speech rate therapy can be utilized in the cerebellar ataxic type dysarthria [7]. For the hypokinetic type, it may be beneficial to try loudness and articulation techniques [7]. Severe forms of dysarthria might require augmentative communication devices that can be accessed through smart devices [7]. It's imperative to treat dysarthria in WD patients so they can experience a healthy lifestyle and feel like a functioning part of society further increasing the quality of life.
Dysphagia
One of the most noteworthy symptoms found in WD patients is dysphagia. It is defined as difficulty in swallowing, chewing, or oral transit and is present in 50% of patients with neurological type WD [7]. Dysphagia can be due to impairment of muscle tone, an inability to coordinate movements, or even weak muscles involved in the process [7]. Clinically, patients may seem malnourished or experience drooling. A deadly but common complication of dysphagia that should be prevented at all costs is aspiration pneumonia [11]. By completing a thorough physical examination and assessing a patient's nutritional status, a clinician can determine if enteral feeding is necessary. Failure to provide enteral feeding in severe dysphagia cases dramatically increases the risk of aspiration pneumonia, malnutrition, and even mortality [11].
To prevent these fatal complications and preserve the quality of life in a patient with WD, physicians need to consider appropriate therapies and follow up in a timely manner. For mild cases of dysphagia, regular checkups that analyze body weight measurements and nutritional status may be sufficient [7]. However, enteral feeding should be considered in high-risk patients to avoid serious complications. One case study exploring alternative treatment options indicated that neuromuscular electrical stimulation might be beneficial [11]. Additional research is necessary to confirm efficacious treatment for WD patients with dysphagia.
Behavioral and Psychiatric Manifestations
Approximately 30-40% of WD patients present with psychiatric symptoms at the time of diagnosis which is essential to address [14]. Behavioral and psychiatric conditions secondary to WD can range from depression disorders to even acute psychotic episodes [10]. These complications can be due to a patient's reaction to the chronic disease or the metabolic dysfunction itself. The copper levels damage the basal ganglia and hypothalamus, resulting in decreased presynaptic serotonin transporters seen on single-photon emission computed tomography (SPECT) [14]. It's proposed that the chemical imbalance can then disturb mentality. Other studies have correlated mutations of ATP7B with specific personality characteristics, which could also explain these secondary disorders [14]. Some authorities also believe psychiatric and behavioral symptoms actually suggest severe WD and may potentially be a sign of irreversible brain damage [23]. The copper accumulation supposedly overcomes the liver's ability to function, which leads to hyperammonemia and hepatic encephalopathy [23].
Patients with secondary behavioral and psychiatric disorders due to neurological type WD could manifest various symptoms. Mood disturbances, psychosis, sexual dysfunction, insomnia, and impaired social judgement are just a few reported conditions. Behavioral symptoms can consist of family problems, criminal actions, and abnormal verbal aggression [14]. Since about 4-16% of WD patients attempt suicide, physicians should be aware of the treatment options and schedule regular follow-ups to assess their mental health [14].
Treatment options are based on the type of behavioral or psychiatric issue and should be used cautiously in neurological type WD patients. Mood disorders are usually treated with tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). In severe cases, electroconvulsive therapy can be attempted [14]. Medications recommended for psychotic symptoms include olanzapine, clozapine, and quetiapine due to their good efficacy in WD patients [14]. Another option that should be considered for the majority of patients struggling mentally is cognitive-behavioral therapy (CBT) and psychotherapy.
Since half of the patients diagnosed with neurological type WD will have secondary psychiatric conditions, it's important to steer clear of antidepressants with a high risk of liver injury[10]. Physicians should avoid prescribing drugs such as phenelzine, imipramine, iproniazid, amitriptyline, duloxetine, bupropion, and agomelatine due to their potential to further damage the liver in WD patients [14].
After beginning treatment, scheduling regular checkups with neurological type WD patients is extremely critical. There's a potential to develop worsening psychiatric symptoms following therapy initiation, which demands immediate evaluation and treatment adjustment [14].
Other Miscellaneous Characteristics
There are a plethora of other symptoms that neurological type WD patients can manifest. Cognitive deficits that disrupt learning, working memory, and executive domains could be due to lesions in cortico-striatal pathways [14]. Restless leg syndrome (RLS), secondary neuropathies, headaches, new-onset tics, and myoclonus are other noteworthy symptoms of neurological type WD [7]. Interestingly enough, generalized tonic-clonic seizures have been reported in 6% of WD patients and could be a critical warning of paradoxical worsening upon chelation treatment initiation [10].
Diagnostics
A timely diagnosis of neurological type WD relies on high clinical suspicion, biochemical laboratory markers, histological assessment, and genetic findings. Clinical suspicion for WD should be especially high if wing-beating tremor, dysarthria, drooling, dystonia, or atypical facial grimacing is observed [8]. One-third of patients may also present with psychiatric abnormalities [8]. In a study containing 268 subjects with psychiatric symptoms, 15 cases were reported due to a treatable underlying metabolic disorder such as WD [6].
After taking a thorough history and performing a complete neurological examination, a physician can proceed with the diagnostic algorithm for confirming neurological type WD. A common scoring system that is used as a guideline and diagnostic tool for WD is the Leipzig score. The scoring system takes into account the presence of Kayser-Fleischer rings, neurological symptoms, urine copper levels, serum cooper levels, and measured hepatic copper [12]. Depending on the copper laboratory values and the severity of the symptoms, the patient receives points that indicate the likelihood of disease. However, the Leipzig score was found to be the most helpful for hepatic type WD to distinguish it from other hepatic pathologies [9].
The first laboratory test that should be ordered is serum ceruloplasmin, which is usually decreased by 50% in patients with WD [19]. A ceruloplasmin level less than 20 mg/dL is usually consistent with a diagnosis of WD, but additional tests should be completed to rule out the possibility of false negatives [9]. Serum ceruloplasmin is considered an acute phase reactant and could potentially be elevated due to inflammatory states leading to false-negative results [19]. A low ceruloplasmin level of less than 0.1 g/L accompanied with Kayser-Fleischer rings on a slit lamp examination is considered to establish the diagnosis of WD [8]. The sensitivity and specificity of this laboratory test is recorded to be 95% and 84.5% for diagnosing WD [4]. In addition, the slit lamp examination can confirm the presence of Kayser-Fleischer rings if WD is suspected [19].
Measuring the 24-hour urinary copper excretion is the next step in the diagnostic algorithm. Adult patients with WD have levels that usually exceed 100 mcg/24 h, while pediatric patients typically have greater than 40 mcg/24h [19]. If the urinary copper excretion produces borderline values, it may be beneficial to do a D penicillamine challenge [9]. The abnormal copper homeostasis displayed on laboratory tests tends to be most helpful in diagnosing neurological type WD [9].
Other labs that can indicate WD is a serum-free copper greater than 200 mcg/L, but there are limitations to measuring direct copper levels [19]. A couple of new diagnostic tools that aid in diagnosing WD include a radioactive copper ratio and a relative exchangeable copper test [12].
The gold standard for diagnosing WD is performing a liver biopsy which shows hepatic copper content greater than 250 ug/g dry weight [9]. A liver biopsy is only required to establish a diagnosis when the clinical presentation and laboratory tests fail to do so [K10]. At this point, clinicians might question using molecular analysis to aid in diagnosis. Even though genetic tests may reveal a mutation in the ATP7B gene, they are impractical and could create a delay in diagnosis [8].
Imaging techniques can also provide clues for diagnosing neurological type WD but are not considered to be confirmatory tests. A magnetic resonance imaging (MRI) test can detect abnormalities in neurological type WD, most commonly manifest as T2 hyperintensities within the putamen [9]. The "panda sign" is seen when hyperintense signals are displayed around the midbrain, red nucleus, and substantia nigra [9]. A case report of a woman presenting with neurological symptoms was diagnosed with neurological type WD and demonstrated the classic "panda sign" on a brain MRI [2].
The bright claustrum sign may also be appreciated as a thin rim displaying T2 hyperintensity within the claustrum [9]. A single-photon emission computerized tomography (SPECT) image can detect early brain damage that could be used as a guide for treatment purposes [8]. Interestingly enough, magnetic resonance spectroscopy has exhibited decreased levels of N-acetylaspartate and N-acetylaspartylglutamate in specifically neurological type WD patients [9]. Medical imaging advances seem to be very promising for upcoming diagnostic tools for WD.
Differential diagnoses that the clinician should explore include chronic hepatitis, cirrhosis, and psychiatric disorders [8]. However, it's important to stress establishing a prompt diagnosis in WD patients to prevent permanent impairment. Unfortunately, the average time from symptom onset to diagnosis establishment remains to be approximately one year [9]. To avoid delay in diagnosis, physicians should maintain a high suspicion for neurological type WD and follow a methodical diagnostic algorithm.
Treatment Modalities
Chelation therapy
Copper is an essential element within our body that contributes to various biological processes such as mitochondrial respiration, extracellular matrix cross-linking, antioxidant defense, and neurotransmitter biosynthesis [3]. Due to the defect in the ATPase copper-transporting beta (ATP7B), copper homeostasis is deregulated, and copper secretion is impaired. Chelation therapy introduces an element that binds to excess free copper, forms a ring-like structure, and promotes excretion. Copper is removed from tissues, and re-accumulation is prevented with chelation therapy. D-penicillamine, trientine, and dimercaptosuccinic acid are all types of chelation therapies that promote copper excretion through the kidneys. Tetrathiomolybdate, another chelator, promotes excretion through the gastrointestinal (GI) system [3]. Zinc salts are also used as an indirect chelator by decreasing copper absorption in the GI system and inducing metallothionein which promotes copper excretion in urine and feces [3].
D-Penicillamine (D-PCA)
D-PCA was first introduced in the 1950s as an oral chelator with great efficacy in mobilizing copper from tissues into the kidneys for excretion. The chemical make-up of D-PCA includes a thiol with a sulfhydryl group that can bind to copper and promotes its excretion via urine in WD patients [1]. D-PCA is indicated for initial therapy for symptomatic patients and long-term maintenance therapy. There is a direct relationship between the reduction of copper stores within the body and the excretion of D-PCA; therefore, there is little fear of becoming copper-deficient [1]. The effect of this drug can be seen clinically with a reduction in neurological symptoms and a decrease in copper accumulation on MRI.
Lifelong treatment has been successful, but close monitoring is necessary due to the risk of paradoxical deterioration upon initial administration that presents with worsening neurological symptoms. The mechanism of neurotoxicity is unclear; however, it is hypothesized that initial treatment mobilizes copper in the blood, accumulates in the brain, and causes free radical-induced tissue injury. The percentage of patients that have worsening neurological symptoms is unknown and can range from 10-50% of patients. It is proposed to start treatment at low dosages of D-PCA with the administration of vitamin E, which reduces free radicals to avoid the adverse effect of neurotoxicity [1]. Thus, clinically it is important to monitor the patient during the initial treatment. Relative contraindications of D-PCA include patients with severe neurological symptoms or liver failure [15].
Tetrathiomolybdate (TTM)
TTM is a form of chelation therapy that was developed for patients with adverse reactions to D-PCA and Trientine. Radiocopper studies have shown an immediate reduction in dietary copper reabsorption via the gut mucosa when TTM is given orally [1]. The mechanism of action involves TTM forming complexes with copper and proteins in the intestinal lumen, which promotes excretion through the biliary tract. Therefore, TTM is preferentially used in patients with renal complications [3]. TTM has been shown to be more effective than zinc in copper chelation due to its immediate impact [1]. TTM has been shown to cause neurotoxicity rarely and has a short half-life with mild side effects [15]. Adverse effects of acute hepatitis, hypercholesterolemia, excessive triglycerides, and reversible bone marrow depression have been rarely reported [1]. It is important to know that prolonged therapy with TTM could be toxic due to the excess amounts of molybdenum [15].
Unfortunately, its clinical usage is reduced due to the high frequency of dosing which can be up to six times a day [3]. Bis-choline tetrathiomolybdate, a derivative of TTM, has recently been undergoing clinical trials to improve the compliance of the drug. Bis-choline-tetrathiomolybdate has not displayed cases of paradoxical worsening for treating neurological type Wilson's disease [3].
Zinc
Zinc sulfate or zinc gluconate successfully inhibits copper absorption from the gut, effectively chelates copper, and facilitates excretion into the feces or urine [3]. Zinc is used for symptomatic patients that have previously taken copper chelators. In addition, some studies have proven zinc to be more effective in treating neurological type Wilson's disease than hepatic type [1]. When zinc is given orally, it increases the production of metallothionein [1]. Metallothionein is comprised of cysteine-rich proteins with a strong affinity for copper, which can bind dietary copper and encourage copper secretion into the gut [Aggarwal & Bhatt, 2018]. In terms of preventing re-accumulation of copper, zinc sulfate improved clinical symptoms significantly in the third year of patient therapy [15]. Therefore, zinc therapy is used for the maintenance phase after treating with copper chelators.
There is some indication for combination therapy with copper chelators, but the practicality of this therapy is difficult because other copper chelators can potentially bind to zinc and decrease its effectiveness. The adverse effects are mild, including gastric irritation and the potential to induce copper deficiency.
Liver transplant
Splenectomy and orthotopic liver transplantation are the two main surgeries performed for an individual with WD. These operations are reserved for decompensated liver disease where medication cannot alleviate the symptoms alone. It is important to note that even those liver transplantation results in an increase in copper excretion, it is not beneficial for patients with the neurological form of Wilson's Disease. Long-term neurological damage will not be corrected by liver transplantation [15].
Ongoing research in therapy
The two notable ongoing therapies involve cell transplantation methods. It consists of not only utilizing stem cells for the regeneration of hepatocytes but also the regeneration of neurons. This shows promising results for a minimally invasive therapy that can correct both the hepatic and neurological forms of WD. Another therapy that is undergoing clinical trials is the new derivative of TTM. The use of ammonium TTM and bis-choline TTM are in their second and third phase in clinical trials with the potential to be the upcoming first-line therapy of WD [1].