Cognitive impairment in Wilson's disease (2024)

Language: English | Portuguese

Abstract

Wilson's disease (WD) or hepatolenticular degeneration is a rare, genetic andsystemic disease, caused by a deficit in the metabolism of copper, leading toits accumulation in different organs, mainly the liver, followed by the centralnervous system, especially the basal ganglia. When symptoms begin between thesecond and third decades of life, approximately 50% of the patients showneurological symptoms. Although dystonia and dysarthria are the most commonneurological signs, cognitive changes have been reported since the first caseswere described in 1912. Memory change is one of the most common impairments, butother cognitive changes have been reported, including dementia in untreatedcases. In this article we review the cognitive changes in WD patients and theoccurrence of dementia.

Keywords: Wilson's disease, cognition, dementia

Abstract

Doença de Wilson (DW) ou degeneração hepatolenticularé uma doença sistêmica genética rara, causada por umdéficit no metabolismo do cobre, levando a sua acumulaçãoin diferentes órgãos, principalmente o fígado, seguido pelosistema nervoso central, especialmente os gânglios da base. Quando ossintomas iniciam entre a segunda e terceira décadas de vida,aproximadamente 50% dos pacientes apresentam sintomas neurológicos.Apesar de distonia e disartria serem as alteraçõesneurológicas mais comuns, mudanças cognitivas tem sido relatadasdesde os primeiros casos em 1912. Alteração de memóriaé o comprometimento mais comum, mas outras alterações foramdescritas, incluindo demência em casos não tratados. Nesse artigonós revisaremos as alterações cognitivas em pacientes comDW e a ocorrência de demência.

Wilson's disease (WD) or hepatolenticular degeneration is a rare genetic andmultisystemic condition which affects mainly the liver, followed by the central nervoussystem (CNS), cornea and kidneys. Its incidence is 1–2 cases per 100,000 persons, withprevalence of 1:30,000 (hom*ozygotes) and 1:100 to 1:2,000 (heterozygotes).¹

The first description of a patient with this condition was reported by Friedrich Theodorvon Frerichs in 1861.² However, it wasonly after Alexander Kinnier Wilson described a series of cases in 1912 that thecondition became well known. At the time, four young members of the same family werestudied; the clinical features involved involuntary movement, spasticity, dysarthria,dysphagia and psychiatric symptoms with a fatal evolution which consisted, from apathological perspective, of cirrhosis and softening of the lenticularnucleus.³ In the following yearRumpel linked this condition to copper.⁴ The locus of WD is now known to lie in the long arm of chromosome13, responsible for encoding ATP7B expressed predominantly in the liver. ATP7B isresponsible for transporting copper within cells so that it can be subsequentlyincorporated into ceruloplasmin and excreted through the bile. This is the mainexcretion pathway for copper. Thus, defects in this enzyme cause the copper toaccumulate inside the hepatocyte cytoplasm and lead to later necrosis and release intothe blood plasma. Subsequently, this metal accumulates elsewhere, such as in the basalganglia and cornea.^5-8 Over 250 types of mutations have been found to date,making clinical features heterogeneous. In Brazil, the most common mutations are foundin loci 3402DelC and L708P.⁹

Where symptoms of WD appear in childhood, hepatic features are the most commonlyoccurring. When symptoms manifest between the second and third decades of life,approximately 50% of the patients show neurological symptoms. The most common of these,according to a study of a Brazilian sample, are: dysarthria (91%), abnormal gait (75%),risus sardonicus (72%), dystonia (69%), rigidity (66%),bradykinesia (58%), rest tremor (55%), dysphagia (50%), postural instability (49%),cerebellar alterations (28%), chorea (16%) and athetosis (14%).¹⁰

There are several structures or regions in the CNS which can be affected, including thecerebellum, thalamus and subcortical white matter, although the basal ganglia ispredominantly affected.¹¹

The medical treatment of Wilson disease's patients can be based on the use of chelatingagents. These are capable of raising blood copper concentration and its renal excretionand this could explain why some patients may experience worsening of symptoms in thebeginning of treatment. This initial toxicity is the reason why some authors prefer theuse of zinc sulphate or acetate, which has a less aggressive profile in terms ofcollateral symptoms and is a copper lowering agent from the outset. Zinc treatment hasbeen indicated ideally for medical treatment naïve individuals.¹²

Cognitive abnormalities, although acknowledged since the first description by Wilson, areunder discussion to this day. Cummings cited the study conducted by Wilson as the firstdescription of a case of subcortical dementia, a dementia pattern consisting ofexecutive dysfunction, apathy and depression, as opposed to cortical dementias, in whichaphasia, agnosia, apraxia and amnesia are predominant, such as in Alzheimer'sdisease.¹³ This kind ofdementia has been associated to serum free copper. Patients with Alzheimer's disease anda high level of blood free copper have a worse outcome than patients with normallevels.¹⁴

Several studies have since tried to evaluate the cognitive abnormalities of WD,classifying it as a cause of reversible subcortical dementia. However, results areconflicting.

In this paper we discuss the cognitive abnormalities shown by patients suffering from WDand investigated whether they lead to functional impairment.

Cognitive abnormalities

Cognitive deterioration in patients suffering from WD has been described since thefirst cases were reported in the early 20^th century.³ Patients showing neurological motorsymptoms usually also present with, from the outset, changes in behavior orcognitive decline.¹⁵ This declineappears in approximately 25% of the patients.¹⁶ Depending on the test used and whether the patients presentwith more hepatic or neurological symptoms, this figure can reach up to40%.¹⁷

Patients displaying exclusively hepatic symptoms tend to perform the same as normalvoluntary participants on cognitive tests.^18,19 Patientsdisplaying neurological symptoms performance worse in comparison with controlgroups^18-21 and with asymptomatic patients or those who haveexclusively hepatic conditions. Only one study found slightly higher performance inexecutive functions when comparing patients with neurological manifestations againstthose with hepatic symptoms.²⁰

Patients suffering from WD show a significantly poorer performance on globalcognitive tests such as the Mini-Mental State Examination¹⁷ and the Mattis Dementia Rating Scale¹⁸ compared to healthy voluntaryparticipants.^17,18 Motor features may have influencedthis impaired performance.¹⁸Intelligence tests such as the WAIS^18,19 and other similarinstruments²¹ have shownconflicting results. One study found poorer performance on the WAIS test, restrictedto the non-verbal part¹⁸ whileanother found performance to be worse in both verbal and non-verbalcomponents.¹⁹ Otherintelligence tests have revealed no statistical difference in relation to controlgroups.²¹ Even in thosestudies which have encountered differences in performance, these lay within therange of normality (low average).^18,19

Memory deficits have been described by several authors.^18,19,22 These authors have found thatpatients suffering from WD show lower capacity to both learn words and recall themacross all stages of the Rey Auditory-Verbal Learning Test (RAVLT). They alsoobserved a small difference in learning rate between the first and the secondexposure to stimuli in this patient group.¹⁹ However, no difference was observed in the rate of loss ofinformation between the last exposure and recall after interference, nor anydifference in recognition.^19,22 The results profile in this memorytest resembled that of patients suffering from Huntington's disease which differsfrom the profile found in Alzheimer's dementia. Results are conflicting innon-verbal memory tests such as Benton's, and in computerized tests. AlthoughSeniow¹⁹ encounteredpoorer performance in relation to control groups, Lang²¹ and Portala et al.²⁰ observed no significant difference. These studieswith negative findings pooled all patients with WD into a single group regardless ofthe clinical features (neurological, hepatic or asymptomatic). This may havecontributed to the negative findings.

Tests which evaluate executive functions such as Raven's Progressive Matrices, alsoshow poorer performance by patients with WD compared with healthy controls. Testswhich also evaluate reasoning have shown a difference between patients displayingneurological symptoms and control groups.^18,20,21 No differences have been observed compared withperformance of control groups on semantic verbal fluency (animals)¹⁸ although performance wassignificantly worst in phonemic fluency.²³ The study by Lang also observed a difference in phonemicfluency between the two groups, although the author did not consider this result tobe clinically significant.²¹Language tests such as the Boston Naming Test have not shown any difference betweenthe two groups.¹⁸ These findingssuggest that the difference in performance between the two types of fluency might bemore strongly attributable to dysfunction in frontal-subcortical circuits than to alanguage problem or dysarthria. Similar findings were found in Friedreich'sataxia.²³ This differencein fluency has previously been described as a differential between Alzheimer'sdisease and frontotemporal dementia.²⁴

Other tests which evaluate this circuit, such as forward and backward digit span,have shown no differences between WD patients and controls,^18,21 although it did display abnormal results in anotherevaluation.¹⁹ Theperformance on the Wisconsin Card Sorting Test has also been described not to differbetween patients and controls, revealing a similar number of responses andperseverant errors.¹⁸ Evaluationscarried out using computerized tests have shown lower performance in digit span anddivided attention tests, with an increase in perseverating responses.²¹ An increase in response time forboth visual and auditory stimuli, as well as in perception speed wasevident.^20,21 In spite of these findings, no greater difficultyin information processing was observed.²⁵

The summary of cognitive changes described in WD patients is depicted in Table 1.

Cognitive abnormalities and clinical features/imaging

Initially, abnormalities in memory and some other cognitive tests were associatedwith the impact of the motor features on such patients.¹⁸ However, following evaluation of the motorfeatures by means of scales, no relationship has been observed between the degree ofmotor impairment and performance on the WAIS. Similarly, no correlation has beenfound between the psychiatric symptoms and cognitive features. These three domainsof impairment seem to act independently.²⁶

Patients who have had the disease for a longer period show poorer performance onvisuospatial tests while older subjects show impaired performance on executivefunction tests. Patients who have an earlier onset also present poorer visuospatialperformance and take longer to carry out motor activities.²⁰ No correlation has been found between the motor orcognitive features and copper levels or ceruloplasmin.¹⁷

Evaluation of patients displaying both neurological symptoms and cranial computedtomography (CT) scan abnormalities revealed poorer performance on digit arrangementtests than patients showing no CT abnormalities. However, the author did not specifythe nature of the abnormalities found.²¹

Patients displaying WD neurological symptoms with lesions confined to the basalganglia were compared with patients displaying additional lesions in other areasusing brain magnetic resonance imaging (MRI) exams. It was evident that patients whohad lesions restricted to the basal ganglia also showed lower performance to that ofcontrol groups across all tests, although with less statistical significance whenevaluated together with the patients who had additional lesions in other areas.Comparing both groups of neurological patients, there was a tendency toward betterIQ performance and execution, albeit statistically insignificant, and with regard tocomprehension, digit span, object assembly, block design and digit symbol subscores,better performance was seen by patients who had lesions limited to basal ganglia.However there was no difference between Rey's and Benton's memory tests, nor Raven'smatrices, which suggests that even if the condition were restricted to the basalganglia it can also lead to cognitive abnormalities.¹⁹

Although two studies have already made clear that functional SPECT exams can be moresensitive than MRI for diagnosing abnormalities in patients suffering fromWD,^27,28 such exams can show abnormalities even in patientswho have hepatic symptoms only. No study has yet compared these abnormalities withmotor clinical features or cognitive abnormalities.

Dementia in Wilson's disease

The accounts produced by Wilson³ inthe early 20^th century described, together with the motor symptoms of thecondition, neuropsychiatric abnormalities which caused functional impairment inthese patients. These features led Cummings to refer to WD as an etiology ofdementia of the subcortical type.¹³

Several clinical accounts have since described cases of WD which showed cognitiveabnormalities leading to functional impairment, corresponding to clinical featuresthat resemble a dementia syndrome.^3,29,30 All these studies demonstrated motor and cognitiveimprovement after initiating clinical treatment for WD. This observation led to WDbeing categorized as a reversible dementia, both after clinical treatment^29,30 or after hepatic transplant.³¹ Cognitive abnormalities may persist even aftertreatment, as discussed previously.

Performance by WD patients on the several tests discussed earlier, although inferiorto that of control groups, has proven to be mostly within normal levels (on averagewithin 1 standard deviation).^18,19,21 The fact that components such as language, semantic verbalfluency and performance on the Wisconsin Card Sorting Test were preserved hasprevented some authors from considering WD as a dementia syndrome.¹⁸ Another point raised was that themajority of patients were ambulatory and independent with regard to their daily androutine activities,²¹ althoughnone of the studies evaluated functional performance.

Systematic studies involving a greater number of WD patients have excluded subjectswhose neurological state was more severely impaired. This might have contributed tothe negative finding of dementia in WD for treated patients.¹⁹ A recent Brazilian studyevaluating a large number of cases, including subjects manifesting various levels ofneurological impairment, found a prevalence of dementia of 5% among thesepatients.¹⁰

Criteria for dementia diagnosis applied when most of the studies were carried out,considered memory impairment and progressive clinical decline to be necessary toreach this diagnosis. Nowadays, it is known that a static pattern for cognitivedeficits is sufficient, and that memory impairment involves the learning domain andnot only delayed recall. The diagnosis of some types of dementia is now evendismissing the mandatory presence of memory impairment, as is the case for dementiawith Lewy bodies,³² dementiaassociated with Parkinson's disease³³ and frontotemporal lobar degeneration.³⁴ Thus, the lack of WD patientsdiagnosed with dementia even after clinical treatment could be the result ofunderestimated data. Regardless of this, it is already known that early treatmenthas an important impact on the course of WD.³⁵

Conclusion

WD is a rare neurological condition associated not only to motor impairment but alsoto cognitive abnormalities that can be severe in the initial stages if not treatedand that remain, albeit in mild form, after commencing treatment. Theseabnormalities occur mainly with regard to attention, executive functions and memory(encoding), but may also appear even when only the basal ganglia are affected. Earlydiagnosis and treatment are crucial for better prognosis.

Footnotes

References