Disease-a-Month 60 (2014) 460–464
Contents lists available at ScienceDirect
Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth
Wilson’s disease: Neurological and psychiatric manifestations Arif Dalvi, MD, MBA
Wilson’s disease (WD) is eponymous with the British neurologist Samuel Alexander Kinnier Wilson. Wilson described the pathology as progressive lenticular degeneration, referring to the degeneration of the lentiform nucleus of the brain (putamen and globus pallidus), presenting as an extrapyramidal syndrome and associated with concomitant liver cirrhosis.1 Earlier reports by Westphal, in 1853, had described cases of “pseudosclerosis” with symptoms similar to multiple sclerosis, including tremor. Fleischer along with Kayser had reported similar cases in association with a pigmented corneal ring, in 1912. Hall and Neale,2 in 1921, brought these various stands together and coined the term hepatolenticular degeneration and also observed the heritable nature of the disease. Cumings made a major contribution by describing copper accumulation in the liver and the brain.3 The concept of chelation therapy was introduced by Denny-Brown and Porter4 who used British Anti-Lewisite, which was superseded by the introduction of penicillamine by Walshe,5 which was less toxic and could be administered orally. A further advance in understanding the etiology was the elucidation of the genetic basis of Wilson’s disease and its linkage to ATP7B mutations localized to chromosome 13q14-q21.6 The historical aspects of WD have been reviewed in detail by Barbosa et al.7 WD is an autosomal recessive disorder of copper metabolism resulting in progressive deposition of copper in various organs, primarily in the liver and the brain. Mutations in the WD protein (ATP7B) gene are the underlying etiology.6,8 WD is rare and affects approximately 1 in 30,000 individuals with a heterozygote carrier rate of about 1 case per 100 persons. Patients with WD most often present with hepatic or neurological symptoms, although some may be asymptomatic. Onset of symptoms is rare before 5 years of age, and most patients are symptomatic by 40 years of age. In a large series of 282 cases, the initial presentation was hepatic, 42 (14.9%); hepato-neurologic, 10 (3.5%); neurologic, 195 (69.1%); pure psychiatric, 7 (2.4%); osseomuscular, 6 (2.1%); and “presymptomatic,” 15 (5.3%).9 Presentation with neurological symptoms is more common when the onset of symptoms is delayed beyond 40 years.10 However, cases with neurological presentations have been described in patients younger than 5 years11 and older than 70 years.12 Awareness of the manifestations and treatment of WD is important both to primary care physicians and specialists in gastroenterology, neurology, psychiatry, and pediatrics. WD can cause severe disability and can be fatal if left untreated. With the protean and multisystem manifestations, it is easy to overlook the diagnosis. However, when diagnosed early, treatment http://dx.doi.org/10.1016/j.disamonth.2014.07.003 0011-5029/& 2014 Mosby, Inc. All rights reserved.
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options that can prevent or reverse many manifestations of WD and restore life expectancy to near normal are available.13 The neuropsychiatric manifestations of WD are discussed below.
Neurological manifestations A presentation with neurological symptoms is more common in the second and third decades of life.14 It is typical for the disease to initially present with a symptom or group of symptoms in a particular category, for example, parkinsonism, and further features to manifest as the disease progresses. Onset of symptoms in WD is usually insidious with some combination of dysarthria, tremor, rigidity, gait disorder, and cognitive decline.1,15,16 An abrupt presentation with transient hemiparesis and encephalopathy has also been described.17 Dysarthria is the most common sign, while chorea and athetosis affect only about 11%.16 If left untreated, cognitive dysfunction in the form of an executive dysfunction may develop. Seizures, myoclonus, and pyramidal tract signs may also occur.10 The vast majority of WD patients with neurological symptoms manifest Kayser–Fleischer (KF) rings either on visual inspection of the eyes or on slit-lamp examination.10 Clinical subtypes of neurological Wilson’s disease Three broad presentations are known to occur with some overlap in symptomatology. Imaging in the form of MRI of the brain has some correlation with the clinical manifestations.15,18 Table describes the 3 variants with their typical symptomatology and MRI correlates. The “pseudosclerotic” neurological variant is the most common, with the onset of a typical wing-beating tremor, ataxia, and dysarthria. It is so named due to an overlap with some of the clinical manifestations of multiple sclerosis. In other patients, dystonia or an akinetic-rigid syndrome may dominate. Dysarthria is the most common sign, while chorea and athetosis affect only about 10%. If left untreated, cognitive dysfunction in the form of an executive dysfunction may develop. Seizures, myoclonus, and pyramidal tract signs may also occur.8,10 Signs and symptoms Dysarthria is the most common symptom of Wilson’s disease and occurs in about 90% of patients.16 It takes the form of a mixed dysarthria and can have spastic, ataxic, and dystonic features. In the parkinsonian variant, the dysarthria may have a hypokinetic or hypophonic quality similar to that in Parkinson’s disease. In the pseudosclerotic form, an ataxic dysarthria with variation in word spacing and volume may be seen. Scanning speech similar to multiple sclerosis may also be seen. The pathophysiological basis is a motor dysfunction in the territory of the bulbar musculature and thus drooling of saliva, dysphagia, and craniofacial dystonia may also be observed.19 Wilson’s original report described a fixed sardonic smile with retracted lips
Table Clinical subtypes of neurological Wilson’s disease. Clinical subtype
Neurological findings
MRI correlate
Pseudosclerotic
Tremor Ataxia Reduced functional capacity Bradykinesia Rigidity Cognitive impairment Dystonic posturing Chorea Organic personality syndrome
Focal thalamic lesions
Parkinsonism
Dystonic/choreic syndrome
MRI may show dilatation of the third ventricle
Focal lesions in the putamen and globus pallidus
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and an open jaw, the so-called vacuous look. He described the dysarthria as one that “reproduces the slurring but not the staccato element of multiple sclerosis.”1 Neurological WD presents with tremor in one or both hands in 22–55% of cases. A variety of tremor subtypes may exist, including rest tremor, action tremor, and Holmes tremor.20 The action tremor in WD resembles that seen in cerebellar dysfunction. However, additional symptoms such as dysdiadochokinesia and nystagmus are usually absent. The tremor most commonly affects the hands and the head. The typical resting tremor in Parkinson’s disease is less commonly seen. When present, the rest tremor is usually accompanied by postural and action tremor that are often more severe than the tremor at rest.21 Some patients or family members may present with a postural tremor similar to that seen in essential tremor. The arms are most frequently involved but it may also affect the head and the legs. Unlike essential tremor, it is uncommon to have the voice involved. The postural tremor of WD also tends to show a more persistent asymmetry. The classical description of tremor in WD is that of a “wing-beating” tremor, best elicited when the arms are held forward and flexed horizontally, bringing out a proximal tremor resembling the beating of a bird’s wings. When such a tremor is seen, imaging studies may reveal a lesion in the dentatorubrothalamic pathway. In practice, it is less common than other tremor subtypes in WD.10 Given the variety of ways in which WD can present as tremor, it is important to keep this diagnostic consideration in mind when evaluating younger individuals presenting with tremor.22,23 WD may present as an akinetic-rigid form of parkinsonism with bradykinesia, rigidity, and difficulty with gait in 19–62% of patients. Onset with a unilateral rest tremor is much less commonly seen, although various forms of tremor may be seen as part of the overall presentation as noted above. Like idiopathic PD, the disease state tends to be asymmetric at onset.10,15 Chorea and athetosis occur in about 10% of cases with WD.16,24 Chorea is characterized by irregular rapid involuntary movements of the face, head, trunk, and extremities that are superimposed on and interrupt normal movement. These movements can range from subtle and small “piano-playing” movements in the fingers to uncontrolled flailing movements of the extremities, termed ballism. They may occasionally be mistaken for fidgetiness or may be incorporated into purposeful movements. Chorea is frequently accompanied by a slow writhing movement of the limbs, trunk, or neck, called athetosis. The choreoathetoid form of WD is more common in patients with young onset disease, about 20% of whom may have this symptom.15 Dystonia can be focal, segmental, or generalized. The severity may range from mild to disabling. It is present in 11–65% of cases.18,21 Manifestations of focal dystonia may include facial dystonia, dystonia of the vocal cords, dystonia of the pharyngeal muscles, blepharospasm, cervical dystonia, and writer’s cramp. It may be unilateral at the onset but can progress to a bilateral or generalized involvement. Severe dystonia can lead to extreme posturing in the form of opisthotonus. Status dystonicus (frequent and relentless episodes of devastating generalized dystonia) may also occur.25 The presence of dystonia has been shown to correlate with MRI abnormalities in the putamen.19 Ataxia has been reported as a variable feature in WD.26 Cerebellar findings are generally not present in combination with other neurological symptoms. Limb ataxia is infrequent, but dysmetria of the eyes and limbs or ataxic dysarthria may occur. Seizures may occur at any age in patients with WD.27 About 6% of WD patients were reported as having seizures in a series of 200 patients.28 Nonconvulsive status epilepticus may rarely occur.29 It should be kept in mind that in treated patients, hypocupremia from overzealous treatment may be the provocative factor.30 Ophthalmological manifestations of WD include KF rings and sunflower cataracts. Kayser and Fleischer, in the 1900s, described the presence of corneal pigmentation in patients with pseudosclerosis.7,31 Subsequent work revealed that KF rings represent copper deposition in the corneal Descemet’s membrane. These may be visible to the naked eye as greenish or brownish discoloration at the outer circumference of the cornea. KF rings can be visualized using light directed tangentially at the cornea in a patient with a light-colored iris. However, in early stages
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or in patients with a dark iris, a slit-lamp examination is required. The rings do not impair vision and will clear with chelation therapy. In one large series, over 95% of patients with neurologic symptoms and over 85% of those with liver involvement had KF rings.9 Sunflower cataracts are present in about 17% and do not impair vision. They require a slit-lamp examination for detection.32 Extraocular movement abnormalities are rare and possibly secondary to copper deposition in the midbrain. The absence of nystagmus can be useful in making a diagnosis of WD.32
Psychiatric manifestations One-third of WD patients may present with psychiatric symptoms. It is not uncommon for these patients to be incorrectly diagnosed as having a progressive psychiatric illness. Most patients with neurological symptoms will also have some degree of psychiatric symptoms and the progression tends to parallel that of the neurological manifestations.10 Wilson’s initial description included 8 out of 12 cases with psychiatric symptoms.1 However, in early descriptions, psychiatric feature were not given prominence. At best, it was considered that psychiatric symptoms were an accompaniment of the neurological disorder. The current literature recognizes that psychiatric symptoms may occur independently as well. The most common psychiatric symptoms at onset include personality change, irritability, anxiety, and depression. As the disease progresses, other features can develop, including impulsivity, disinhibition, catatonia, and mania. Reckless behavior and substance abuse may also be seen. Depression may occur in 20–30% of cases. Psychotic features are relatively uncommon.33 In a longitudinal study, the most common psychiatric symptoms were depression (30%), incongruous behavior (30%), cognitive impairment (28%), and irritability (22%). Cognitive impairment was seen to decrease over time and only 5% of patients at the second follow-up visit were found to be cognitively impaired. In contrast, 25% of patients were diagnosed as depressed on follow-up, a rate relatively unchanged from that at onset.34 Psychiatric symptoms, like neurological symptoms, may also worsen with chelation therapy, although this is less common. Patients who were previously bed bound and in an akinetic-mute state may begin to show a propensity towards psychosis and agitation. However, with continued treatment, the agitation may subside, suggesting that a latent psychosis was masked by the severity of the motor symptoms and mutism. This phenomenon has been described as a reemergent psychosis.35
Natural history Like the variable symptomatic presentation, the clinical course is also highly variable. Disease progression is usually insidious. However, sudden worsening may occur, and medication choice and adjustments may play a role. Penicillamine is associated with an initial worsening to a greater extent than other treatments. The tremor predominant form may have a slower course and better prognosis than the dystonic form.36 In untreated WD, neurologic symptoms relentlessly progress, resulting in a severely dystonic state with akinetic mutism. Prior to the availability of treatments, the median survival following development of neurologic symptoms was less than 5 years. Current treatment with chelation therapy considerably slows progression, and life expectancy can be close to normal.14,37 References 1. Compston A. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver, by S. A. Kinnier Wilson, (From the National Hospital, and the Laboratory of the National Hospital, Queen Square, London) Brain 1912: 34; 295-509. Brain. 2009;132:1997–2001. 2. Hall G, Neale FC. Wilson’s disease. Lancet. 1957;272:1089–1090.
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3. Cumings JN. The copper and iron content of brain and liver in the normal and in hepato-lenticular degeneration. Brain. 1948;71:410–415. 4. Denny-Brown D, Porter H. The effect of BAL (2,3-dimercaptopropanol) on hepatolenticular degeneration (Wilson’s disease). Trans Am Neurol Assoc. 1951;56:79–84. 5. Walshe JM. Penicillamine, a new oral therapy for Wilson’s disease. Am J Med. 1956;21:487–495. 6. Tanzi RE, Petrukhin K, Chernov I, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993;5:344–350. 7. Barbosa ER, Machado AA, Cançado EL, et al. Wilson’s disease: a case report and a historical review. Arq Neuropsiquiatr. 2009;67:539–543. 8. Ala A, Walker AP, Ashkan K, et al. Wilson’s disease. Lancet. 2007;369:397–408. 9. Taly AB, Meenakshi-Sundaram S, Sinha S, et al. Wilson disease: description of 282 patients evaluated over 3 decades. Medicine (Baltimore). 2007;86:112–121. 10. Lorincz MT. Neurologic Wilson’s disease. Ann N Y Acad Sci. 2010;1184:173–187. 11. Abdel Ghaffar TY, Elsayed SM, Elnaghy S, et al. Phenotypic and genetic characterization of a cohort of pediatric Wilson disease patients. BMC Pediatr. 2011;11:56. 12. Ala A, Borjigin J, Rochwarger A, Schilsky M. Wilson disease in septuagenarian siblings: raising the bar for diagnosis. Hepatology. 2005;41:668–670. 13. Huster D. Wilson disease. Best Pract Res Clin Gastroenterol. 2010;24:531–539. 14. Rosencrantz R, Schilsky M. Wilson disease: pathogenesis and clinical considerations in diagnosis and treatment. Semin Liver Dis. 2011;31:245–259. 15. Walshe JM, Yealland M. Wilson’s disease: the problem of delayed diagnosis. J Neurol Neurosurg Psychiatry. 1992;55: 692–696. 16. Aggarwal A, Bhatt M. Update on Wilson disease. Int Rev Neurobiol. 2013;110:313–348. 17. Carlson MD, Al-Mateen M, Brewer GJ. Atypical childhood Wilson’s disease. Pediatr Neurol. 2004;30:57–60. 18. Starosta-Rubinstein S, Young AB, Kluin K, et al. Clinical assessment of 31 patients with Wilson’s disease. Correlations with structural changes on magnetic resonance imaging. Arch Neurol. 1987;44:365–370. 19. Svetel M, Kozić D, Stefanova E, et al. Dystonia in Wilson’s disease. Mov Disord. 2001;16:719–723. 20. Stremmel W, Meyerrose KW, Niederau C, et al. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med. 1991;115:720–726. 21. Machado A, Chien HF, Deguti MM, et al. Neurological manifestations in Wilson’s disease: report of 119 cases. Mov Disord. 2006;21:2192–2196. 22. Dalvi A, Premkumar A. Tremor: etiology, phenomenology, and clinical features. Dis Mon. 2011;57:109–126. 23. Nicholl DJ, Ferenci P, Polli C, et al. Wilson’s disease presenting in a family with an apparent dominant history of tremor. J Neurol Neurosurg Psychiatry. 2001;70:514–516. 24. Oder W, Grimm G, Kollegger H, et al. Neurological and neuropsychiatric spectrum of Wilson’s disease: a prospective study of 45 cases. J Neurol. 1991;238:281–287. 25. Teive HA, Munhoz RP, Souza MM, et al. Status dystonicus: study of five cases. Arq Neuropsiquiatr. 2005;63:26–29. 26. Oder W, Prayer L, Grimm G, et al. Wilson’s disease: evidence of subgroups derived from clinical findings and brain lesions. Neurology. 1993;43:120–124. 27. Prashanth LK, Sinha S, Taly AB, et al. Spectrum of epilepsy in Wilson’s disease with electroencephalographic, MR imaging and pathological correlates. J Neurol Sci. 2010;291:44–51. 28. Dening TR, Berrios GE, Walshe JM. Wilson’s disease and epilepsy. Brain. 1988;111(Pt 5):1139–1155. 29. Pestana Knight EM, Gilman S, Selwa L. Status epilepticus in Wilson’s disease. Epileptic Disord. 2009;11:138–143. 30. Benbir G, Gunduz A, Ertan S, Ozkara C. Partial status epilepticus induced by hypocupremia in a patient with Wilson’s disease. Seizure. 2010;19:602–604. 31. Walshe JM. History of Wilson’s disease: 1912 to 2000. Mov Disord. 2006;21:142–147. 32. Wiebers DO, Hollenhorst RW, Goldstein NP. The ophthalmologic manifestations of Wilson’s disease. Mayo Clin Proc. 1977;52:409–416. 33. Dening TR. The neuropsychiatry of Wilson’s disease: a review. Int J Psychiatry Med. 1991;21:135–148. 34. Dening TR, Berrios GE. Wilson’s disease: a longitudinal study of psychiatric symptoms. Biol Psychiatry. 1990;28: 255–265. 35. Aggarwal A, Aggarwal N, Nagral A, et al. A novel Global Assessment Scale for Wilson’s Disease (GAS for WD). Mov Disord. 2009;24:509–518. 36. Burke JF, Dayalu P, Nan B, et al. Prognostic significance of neurologic examination findings in Wilson disease. Parkinsonism Relat Disord. 2011;17:551–556. 37. Bruha R, Marecek Z, Pospisilova L, et al. Long-term follow-up of Wilson disease: natural history, treatment, mutations analysis and phenotypic correlation. Liver Int. 2011;31:83–91.
Contents lists available at ScienceDirect
Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth
Wilson’s disease: Neurological and psychiatric manifestations Arif Dalvi, MD, MBA
Wilson’s disease (WD) is eponymous with the British neurologist Samuel Alexander Kinnier Wilson. Wilson described the pathology as progressive lenticular degeneration, referring to the degeneration of the lentiform nucleus of the brain (putamen and globus pallidus), presenting as an extrapyramidal syndrome and associated with concomitant liver cirrhosis.1 Earlier reports by Westphal, in 1853, had described cases of “pseudosclerosis” with symptoms similar to multiple sclerosis, including tremor. Fleischer along with Kayser had reported similar cases in association with a pigmented corneal ring, in 1912. Hall and Neale,2 in 1921, brought these various stands together and coined the term hepatolenticular degeneration and also observed the heritable nature of the disease. Cumings made a major contribution by describing copper accumulation in the liver and the brain.3 The concept of chelation therapy was introduced by Denny-Brown and Porter4 who used British Anti-Lewisite, which was superseded by the introduction of penicillamine by Walshe,5 which was less toxic and could be administered orally. A further advance in understanding the etiology was the elucidation of the genetic basis of Wilson’s disease and its linkage to ATP7B mutations localized to chromosome 13q14-q21.6 The historical aspects of WD have been reviewed in detail by Barbosa et al.7 WD is an autosomal recessive disorder of copper metabolism resulting in progressive deposition of copper in various organs, primarily in the liver and the brain. Mutations in the WD protein (ATP7B) gene are the underlying etiology.6,8 WD is rare and affects approximately 1 in 30,000 individuals with a heterozygote carrier rate of about 1 case per 100 persons. Patients with WD most often present with hepatic or neurological symptoms, although some may be asymptomatic. Onset of symptoms is rare before 5 years of age, and most patients are symptomatic by 40 years of age. In a large series of 282 cases, the initial presentation was hepatic, 42 (14.9%); hepato-neurologic, 10 (3.5%); neurologic, 195 (69.1%); pure psychiatric, 7 (2.4%); osseomuscular, 6 (2.1%); and “presymptomatic,” 15 (5.3%).9 Presentation with neurological symptoms is more common when the onset of symptoms is delayed beyond 40 years.10 However, cases with neurological presentations have been described in patients younger than 5 years11 and older than 70 years.12 Awareness of the manifestations and treatment of WD is important both to primary care physicians and specialists in gastroenterology, neurology, psychiatry, and pediatrics. WD can cause severe disability and can be fatal if left untreated. With the protean and multisystem manifestations, it is easy to overlook the diagnosis. However, when diagnosed early, treatment http://dx.doi.org/10.1016/j.disamonth.2014.07.003 0011-5029/& 2014 Mosby, Inc. All rights reserved.
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options that can prevent or reverse many manifestations of WD and restore life expectancy to near normal are available.13 The neuropsychiatric manifestations of WD are discussed below.
Neurological manifestations A presentation with neurological symptoms is more common in the second and third decades of life.14 It is typical for the disease to initially present with a symptom or group of symptoms in a particular category, for example, parkinsonism, and further features to manifest as the disease progresses. Onset of symptoms in WD is usually insidious with some combination of dysarthria, tremor, rigidity, gait disorder, and cognitive decline.1,15,16 An abrupt presentation with transient hemiparesis and encephalopathy has also been described.17 Dysarthria is the most common sign, while chorea and athetosis affect only about 11%.16 If left untreated, cognitive dysfunction in the form of an executive dysfunction may develop. Seizures, myoclonus, and pyramidal tract signs may also occur.10 The vast majority of WD patients with neurological symptoms manifest Kayser–Fleischer (KF) rings either on visual inspection of the eyes or on slit-lamp examination.10 Clinical subtypes of neurological Wilson’s disease Three broad presentations are known to occur with some overlap in symptomatology. Imaging in the form of MRI of the brain has some correlation with the clinical manifestations.15,18 Table describes the 3 variants with their typical symptomatology and MRI correlates. The “pseudosclerotic” neurological variant is the most common, with the onset of a typical wing-beating tremor, ataxia, and dysarthria. It is so named due to an overlap with some of the clinical manifestations of multiple sclerosis. In other patients, dystonia or an akinetic-rigid syndrome may dominate. Dysarthria is the most common sign, while chorea and athetosis affect only about 10%. If left untreated, cognitive dysfunction in the form of an executive dysfunction may develop. Seizures, myoclonus, and pyramidal tract signs may also occur.8,10 Signs and symptoms Dysarthria is the most common symptom of Wilson’s disease and occurs in about 90% of patients.16 It takes the form of a mixed dysarthria and can have spastic, ataxic, and dystonic features. In the parkinsonian variant, the dysarthria may have a hypokinetic or hypophonic quality similar to that in Parkinson’s disease. In the pseudosclerotic form, an ataxic dysarthria with variation in word spacing and volume may be seen. Scanning speech similar to multiple sclerosis may also be seen. The pathophysiological basis is a motor dysfunction in the territory of the bulbar musculature and thus drooling of saliva, dysphagia, and craniofacial dystonia may also be observed.19 Wilson’s original report described a fixed sardonic smile with retracted lips
Table Clinical subtypes of neurological Wilson’s disease. Clinical subtype
Neurological findings
MRI correlate
Pseudosclerotic
Tremor Ataxia Reduced functional capacity Bradykinesia Rigidity Cognitive impairment Dystonic posturing Chorea Organic personality syndrome
Focal thalamic lesions
Parkinsonism
Dystonic/choreic syndrome
MRI may show dilatation of the third ventricle
Focal lesions in the putamen and globus pallidus
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and an open jaw, the so-called vacuous look. He described the dysarthria as one that “reproduces the slurring but not the staccato element of multiple sclerosis.”1 Neurological WD presents with tremor in one or both hands in 22–55% of cases. A variety of tremor subtypes may exist, including rest tremor, action tremor, and Holmes tremor.20 The action tremor in WD resembles that seen in cerebellar dysfunction. However, additional symptoms such as dysdiadochokinesia and nystagmus are usually absent. The tremor most commonly affects the hands and the head. The typical resting tremor in Parkinson’s disease is less commonly seen. When present, the rest tremor is usually accompanied by postural and action tremor that are often more severe than the tremor at rest.21 Some patients or family members may present with a postural tremor similar to that seen in essential tremor. The arms are most frequently involved but it may also affect the head and the legs. Unlike essential tremor, it is uncommon to have the voice involved. The postural tremor of WD also tends to show a more persistent asymmetry. The classical description of tremor in WD is that of a “wing-beating” tremor, best elicited when the arms are held forward and flexed horizontally, bringing out a proximal tremor resembling the beating of a bird’s wings. When such a tremor is seen, imaging studies may reveal a lesion in the dentatorubrothalamic pathway. In practice, it is less common than other tremor subtypes in WD.10 Given the variety of ways in which WD can present as tremor, it is important to keep this diagnostic consideration in mind when evaluating younger individuals presenting with tremor.22,23 WD may present as an akinetic-rigid form of parkinsonism with bradykinesia, rigidity, and difficulty with gait in 19–62% of patients. Onset with a unilateral rest tremor is much less commonly seen, although various forms of tremor may be seen as part of the overall presentation as noted above. Like idiopathic PD, the disease state tends to be asymmetric at onset.10,15 Chorea and athetosis occur in about 10% of cases with WD.16,24 Chorea is characterized by irregular rapid involuntary movements of the face, head, trunk, and extremities that are superimposed on and interrupt normal movement. These movements can range from subtle and small “piano-playing” movements in the fingers to uncontrolled flailing movements of the extremities, termed ballism. They may occasionally be mistaken for fidgetiness or may be incorporated into purposeful movements. Chorea is frequently accompanied by a slow writhing movement of the limbs, trunk, or neck, called athetosis. The choreoathetoid form of WD is more common in patients with young onset disease, about 20% of whom may have this symptom.15 Dystonia can be focal, segmental, or generalized. The severity may range from mild to disabling. It is present in 11–65% of cases.18,21 Manifestations of focal dystonia may include facial dystonia, dystonia of the vocal cords, dystonia of the pharyngeal muscles, blepharospasm, cervical dystonia, and writer’s cramp. It may be unilateral at the onset but can progress to a bilateral or generalized involvement. Severe dystonia can lead to extreme posturing in the form of opisthotonus. Status dystonicus (frequent and relentless episodes of devastating generalized dystonia) may also occur.25 The presence of dystonia has been shown to correlate with MRI abnormalities in the putamen.19 Ataxia has been reported as a variable feature in WD.26 Cerebellar findings are generally not present in combination with other neurological symptoms. Limb ataxia is infrequent, but dysmetria of the eyes and limbs or ataxic dysarthria may occur. Seizures may occur at any age in patients with WD.27 About 6% of WD patients were reported as having seizures in a series of 200 patients.28 Nonconvulsive status epilepticus may rarely occur.29 It should be kept in mind that in treated patients, hypocupremia from overzealous treatment may be the provocative factor.30 Ophthalmological manifestations of WD include KF rings and sunflower cataracts. Kayser and Fleischer, in the 1900s, described the presence of corneal pigmentation in patients with pseudosclerosis.7,31 Subsequent work revealed that KF rings represent copper deposition in the corneal Descemet’s membrane. These may be visible to the naked eye as greenish or brownish discoloration at the outer circumference of the cornea. KF rings can be visualized using light directed tangentially at the cornea in a patient with a light-colored iris. However, in early stages
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or in patients with a dark iris, a slit-lamp examination is required. The rings do not impair vision and will clear with chelation therapy. In one large series, over 95% of patients with neurologic symptoms and over 85% of those with liver involvement had KF rings.9 Sunflower cataracts are present in about 17% and do not impair vision. They require a slit-lamp examination for detection.32 Extraocular movement abnormalities are rare and possibly secondary to copper deposition in the midbrain. The absence of nystagmus can be useful in making a diagnosis of WD.32
Psychiatric manifestations One-third of WD patients may present with psychiatric symptoms. It is not uncommon for these patients to be incorrectly diagnosed as having a progressive psychiatric illness. Most patients with neurological symptoms will also have some degree of psychiatric symptoms and the progression tends to parallel that of the neurological manifestations.10 Wilson’s initial description included 8 out of 12 cases with psychiatric symptoms.1 However, in early descriptions, psychiatric feature were not given prominence. At best, it was considered that psychiatric symptoms were an accompaniment of the neurological disorder. The current literature recognizes that psychiatric symptoms may occur independently as well. The most common psychiatric symptoms at onset include personality change, irritability, anxiety, and depression. As the disease progresses, other features can develop, including impulsivity, disinhibition, catatonia, and mania. Reckless behavior and substance abuse may also be seen. Depression may occur in 20–30% of cases. Psychotic features are relatively uncommon.33 In a longitudinal study, the most common psychiatric symptoms were depression (30%), incongruous behavior (30%), cognitive impairment (28%), and irritability (22%). Cognitive impairment was seen to decrease over time and only 5% of patients at the second follow-up visit were found to be cognitively impaired. In contrast, 25% of patients were diagnosed as depressed on follow-up, a rate relatively unchanged from that at onset.34 Psychiatric symptoms, like neurological symptoms, may also worsen with chelation therapy, although this is less common. Patients who were previously bed bound and in an akinetic-mute state may begin to show a propensity towards psychosis and agitation. However, with continued treatment, the agitation may subside, suggesting that a latent psychosis was masked by the severity of the motor symptoms and mutism. This phenomenon has been described as a reemergent psychosis.35
Natural history Like the variable symptomatic presentation, the clinical course is also highly variable. Disease progression is usually insidious. However, sudden worsening may occur, and medication choice and adjustments may play a role. Penicillamine is associated with an initial worsening to a greater extent than other treatments. The tremor predominant form may have a slower course and better prognosis than the dystonic form.36 In untreated WD, neurologic symptoms relentlessly progress, resulting in a severely dystonic state with akinetic mutism. Prior to the availability of treatments, the median survival following development of neurologic symptoms was less than 5 years. Current treatment with chelation therapy considerably slows progression, and life expectancy can be close to normal.14,37 References 1. Compston A. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver, by S. A. Kinnier Wilson, (From the National Hospital, and the Laboratory of the National Hospital, Queen Square, London) Brain 1912: 34; 295-509. Brain. 2009;132:1997–2001. 2. Hall G, Neale FC. Wilson’s disease. Lancet. 1957;272:1089–1090.
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