CSF copper concentrations, blood-brain barrier function, and coeruloplasmin synthesis during the treatment of Wilson's disease

During the treatment of four patients with cerebral manifestation of Wilson 's disease, we measured the copper concentration in the cerebrospinal fluid (CSF) and serum, the: serum coeruloplasmin concentration, the free copper concentration in the serum, and the albumin ratio CSF/serum (AR). These mea surements were treated as indicators of the copper-related toxic effects on the brain and the blood-brain barrier (BBB). The half - life of the decrea se in the CSF copper concentration during therapy was 23.5 +/- 5.78 months (mean +/- S.E.M.). The therapeutic - target - copper concentration in the C SF (mean normal concentration) is below 20 mu g/l. The average length of th erapy needed to normalize (CSF - copper values in our patients with an aver age initial value of 76.25 mu g/L was 47 month. During the first 10 month o f treatment there was an increase in all cases of the measured disturbance in the blood-brain barrier (measured as the ratio of albumin in CSF to albu min in serum, AR). All patients showed an initial worsening of the neurolog ical condition, on average after 1.75 +/- 0.25 months. The maximal rise in AR, from the initial values, was on average 18.4 +/- 5.08%; this maximum wa s reached after an average of 6.9 +/- 1.5 months. The AR normalized during therapy, indicating a reduction in toxicity in the blood-brain barrier regi on. The extent of the AR increases in individual patients did not correlate significantly with CSF copper half-life, serum copper half-life, the initi al half - life of the reduction in the ratio (copper in serum)/(coeruloplas min in serum), the initial copper concentration in CSF or serum, the initia l free copper concentration in serum, or the initial dose of penicillamine (within the first 2 months). We conclude that the normalization of the CSF copper concentration in patients with the cerebral manifestation of Wilson' s disease is a slow process, even if therapy is sufficient. The initial wor sening of the neurological condition which has often been reported may be r eflected in the disturbance of blood-brain barrier function, which we have measured here for the first time (using the parameter of the albumin ratio CSF/serum). Based on repeated measurements of the AR during the course of t reatment it seems that the brain toxicity of mobilized copper can be assess ed and the therapy adjusted.