We showed that approximately half of our stable WD cohort performed below normal in cognitive function tests regardless of liver or brain disease involvement. More patients sub-performed in the CRT test than in the PSE test. The CRT test measures motor reaction speed, sustained attention and inhibitory control (Elsass 1986; Lauridsen et al. 2013). In the PSE test, patients performed worse in subtest 1 and 2, the Number Connection Tests A and B which also measures attention, as well as working speed, accuracy, visual orientation and visuo-spatial construction (Weissenborn et al. 2001).
Our findings support the known impact of neurological WD on cognition (Hegde et al. 2010; Frota et al. 2013; Seniów et al. 2002). In available reports on cognition in WD patients without neurological symptoms, cognition was found to normal (Seniów et al. 2002; Wenisch et al. 2013; Iwański et al. 2015) except for tests of sustained attention (Iwański et al. 2015). These studies mostly used test batteries designed to detect more severe cognitive impairment (Frota et al. 2013; Hegde et al. 2010; Seniów et al. 2002; Wenisch et al. 2013; Medalia, Isaacs-Glaberman, and Scheinberg 1988; Iwański et al. 2015). Both the PSE and CRT are widely used to detect subclinical cognitive dysfunction in HE patients and may be more sensitive to these subtle changes to cognition in hepatic WD. The test results depend on sustained attention and our results are in agreement with those of Iwanski, 2015 (Iwański et al. 2015) were tests of sustained attention were also impaired in both phenotypes.
Taken together, these data suggest that while severe cognitive dysfunction is exclusive to the neurological phenotype of WD, mild cognitive disturbances involving sustained attention is common in both phenotypes. The pathophysiological mechanism behind this result is not examined in this study. Since structural changes in the brain and elevated hepatic copper is present even in stable patients after long periods of treatment, residual cerebral copper overload was considered (Scheinberg et al. 1987; Frota et al. 2013). Cerebral copper cannot be measured but neither urinary copper or treatment modality correlated with PSE or CRT measurements in our cohort and free intracellular copper is presumably under control in stable patients. Recent advanced MRI reports suggested subtle changes in brain structure even in hepatic WD patients, involving areas with relation to sustained attention which was affected in both phenotypes in our study (Tinaz et al. 2020). Further studies should explore these possibilities.
Alternatively, it was considered whether liver disease itself could be associated with impaired sustained attention, as similar cognitive dysfunctions have been documented in other hepatic diseases, e.g., non-alcoholic fatty liver disease and -steatohepatitis, hepatitis C and alcoholic cirrhosis as well as chronic disease in general (Colognesi, Gabbia, and De Martin 2020; Kjærgaard et al. 2021; Perry, Hilsabeck, and Hassanein 2008; San Martín-Valenzuela et al. 2020; Yohannes et al. 2017). Hepatic disease is also present in most neurologic WD patients, potentially contributing to their cognitive impairments (European Association for the Study of the 2012). However, in our stable treated patients presented with normal or only mildly affected liver function tests (Table 1) and neither MELD nor CP-scores were related to cognition. Minimal HE is thus unlikely to be causative of the measured cognitive impairment.
Our findings thus indicate that the occurrence of subclinical cognitive dysfunction in stable WD is much more common than previously thought and present regardless of phenotype. While current treatment often is highly effective in treating the major neurological and hepatic manifestations of WD, it may be inadequate to treat the cognitive manifestations as well.
The relatively small study population (n = 28) is a limitation of this study but counterbalanced by the well-characterized cohort of stable Danish WD patients and the high rate of participation. Studies in larger populations are clearly needed.
In conclusion, our cohort of stable well treated WD patients performed worse than normal in cognitive function tests regardless of phenotype. These changes persisted after long-term therapy in clinically stable WD patients.