Background

Although the precise function of PrPC in healthy tissues is not yet known, recent research has demonstrated that it binds copper (Cu) in an unusual and highly conserved region of the protein termed the octarepeat domain [1, 2]. A possible synergistic role of the prion protein in the pathologic metabolism of copper occurring in the context of Wilson’s disease has also been suggested [3, 4]. The transmissible spongiform encephalopathies (TSEs) arise from the conversion of the membrane-bound prion protein from PrPc to PrPSc. Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease (CJD) in humans. Sporadic and inherited prion diseases fall into the same class as Alzheimer’s and Parkinson’s disease, insofar that they are all associated with the accumulation of endogenous protein aggregates [5,6,7,8,9].

We present a case of co-morbidity of hepatolenticular degeneration (Wilson’s disease) and CJD that suggests a possible association of copper metabolism with the pathogenesis of CJD disease.

Case presentation

A 44-year-old male with a known history of inherited Wilson’s disease (both his brother and father suffered from the same disease), who had mild liver problems for 12 years and bipolar psychosis in the months prior to presenting himself, was admitted to the emergency services of our University neurological department with a month-long progressive episode of aphasia.

The diagnosis of Wilson’s disease was based on the patients’ metabolic profile, the increased urine copper excretion combined with decreased ceruloplasmin plasma levels. Psychiatric symptoms were present from the initial states of the disease. Almost all family members showed agitation or bipolar disorder. Liver pathology relevant to the disease was present in both siblings whereas the father’s liver biopsy was normal. No focal neurological deficit was present at the time diagnosis was established in all three men. PCR testing for the most prevalent ATP78 variants in the Greek population was negative; however, Sanger sequencing analysis was not performed.

Upon his admission to our clinic, he had motor aphasia and psychomotor retardation without any other neurological signs and with a Glasgow Coma Scale score of 13/15 (5-4-4). Laboratory tests, including liver enzymes, copper and serum ammonia were all normal, whereas the brain MRI showed an increased T2 signal in the caudate nuclei attributed to copper deposition in the context of Wilson’s disease (Fig. 1). The EEG revealed slowing and lateralized periodic discharges, slow (< 2.5 Hz) spikes and waves over the left hemisphere (less often involving the right one) with spatiotemporal evolution. These EEG findings raised the suspicion of non-convulsive status epilepticus, thus they were suppressed by iv benzodiazepines but without clinical improvement (Fig. 2) and antiepileptic treatment with iv levetiracetam was initiated.

Fig. 1
figure 1

Brain MRI revealed increased DWI and T2 signal in the caudate nuclei (left>right)

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Fig. 2
figure 2

EEG: Lateralized periodic discharges -LPDs stopped by intravenous benzodiazepines

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CSF examination showed normal cell count, glucose and protein levels and there was no intrathecal viral antibody production. The CSF culture was negative while negative was also the search for antibodies to an autoimmune encephalitis antigen panel.

The patient’s clinical condition deteriorated very rapidly. As his aphasia evolved to mutismus, he developed myoclonic jerks and there was gradual worsening of his level of consciousness. Finally, within a few days, the patient demonstrated myoclonic status epilepticus which remained unresponsive to benzodiazepines or other antiepileptic treatment. An empirical treatment with high-dose iv methylprednisolone for 7 days was also administered with no benefit. The rapid cognitive deterioration and the myoclonic status raised the hypothesis of CJD.

A second brain MRI, performed 15 days later, showed increased DWI and T2(FLAIR) signal not only in the basal ganglia but also in the cerebral cortex (cortical ribbon sign), also suggesting CJD [10, 11] (Fig. 3). A second EEG showed periodic sharp wave complexes (PSWC) with predominance over the left frontocentral regions demonstrating the triphasic morphology, typical of CJD (Fig. 4).

Fig. 3
figure 3

Second brain MRI showing increased DWI and T2 (FLAIR) signal in basal ganglia and cerebral cortex (cortical ribbon sign)

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Fig. 4
figure 4

New EEG showed periodic sharp wave complexes (PSWC) suggesting CJD

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Finally, a second CSF examination revealed positive values for all CSF biomarkers tested: protein 14–3-3 (CircuLex ELISA, MBL, Japan), Tau and phosphoTau (Fujirebio/Innotest ELISA) and PrPSc detection by RT-QuIC [12, 13] (Table 1).

Table 1 CSF biomarkers
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The clinical picture, the highly positive 14–3-3 protein, Tau and Tau/pTau levels in the CSF and the new brain MRI that demonstrated elevated DWI signal not only in the basal ganglia but also in the cerebral cortex (cortical ribbon sign) all made the diagnosis of CJD possible. The detection of PrPSc in the CSF using the RT-QuIC method, which has been reported to have a 99.4–100% specificity for CJD [12, 13], made the diagnosis of CJD highly probable [14].

The patient kept deteriorating and passed away 2 months after his initial presentation. At the request of the family no autopsy was performed.

Discussion and conclusions

The present case may well be the first report of Wilson’s and Creutzfeldt-Jakob diseases co-morbidity, suggesting a possible association of copper metabolism with the pathogenesis of CJD. Several recent studies investigate the relationship of copper and prion protein and its role in the pathogenesis of the CJD which remains unclear [7,8,9]. This case sparks a new clinical interest in pursuing further research in this direction.