Creutzfeldt-Jakob disease mimicking autoimmune encephalitis with CASPR2 antibodies

A 75-year-old woman was admitted to our hospital due to rapid progressive cognitive impairment. During the previous year, the patient had shown mild cognitive impairment due to moderate leukoariosis, thought to be associated with arterial hypertension and hypercholesterolemia. There was no positive family history of dementia or dementia-like symptoms in the anamnesis. Ten days before admission, her husband observed a temporal disorientation and confusion, e.g. the patient could not recall the present date and put a saltshaker into the refrigerator. When admitted to our care the patient was conscious but disorientated to place, time and person. The initial neurological examination and an extensive neuropsychological evaluation showed significant impairments in almost all tested cognitive domains including attention, concentration, memory, executive function and visual-constructional ability. In addition, there was evidence of a right-sided visual neglect, aphasia in terms of language comprehension disorder and pronounced apraxic impairments corresponding to dysfunctions of her left-sided parietal circuits. All other neurological functions including motor, sensory and coordinative function were intact. An initial electroencephalography showed unspecific encephalopathy patterns. The MRI showed multiple microangiopathic lesions: left-sided lesions in the thalamus, parietooccipital, temporo mesial, thalamic, frontal and parietal cortices, as well as right-sided lesions in the basal ganglia. The brain-SPECT showed hypometabolism in the frontoparietal and parietooccipital cortices, more obvious on the left side, with normal nuclide accumulation in motor and occipital cortex. The primary investigation of cerebrospinal fluid revealed a pleocytosis of 7 Leukocytes/μl [<5 Leukocytes/μl] with a Total Protein of 701 mg/l [<450 mg/l] and 2,31 mmol/l Lactate [1,2-2,1 mmol/l]. Simultaneously, thyroperoxidase antibodies (serum titre 1606 IU/ml [<60 IU/ml]) were detected. It was initially concluded based on these results that the patient was suffering from autoimmune encephalitis, believed to be caused by autoimmune thyroiditis. High dosage intravenous methylprednisolone therapy was initiated [6]. Despite treatment however, the patient continued to exhibit cognitive and neuropsychological symptoms and presented the first tonic-clonic seizure, leading to the initiation of Levetiracetam therapy. The ongoing diagnostic workup included a broad search for potential autoimmune diseases. Serum and CSF were tested for antibodies to the following antigens: CASPR2, LGI1, NMDAR, GAD65, GAD67, GABABR, AMPAR1/2, GlyR and onconeural antigens, whereby CASPR2-antibodies were detected (serum titre 1:2000, see Figure 1A; no antibody studies in CSF done). This result was interpreted as support for the hypothesis of ongoing autoimmune encephalitis. Treatment was now escalated to eight tryptophan immunoadsorptions processing two liters plasma per session. Although immunoadsorption effectively reduced the titre of CASPR2-antibodies (serum titre 1:32), the patient’s cognitive and general neurological condition worsened. A positron emission tomography was now added to disclose malignancies. Apart from cystic structures in kidneys and liver, no underlying oncological disease was detected. Four weeks after the first MRI, follow up imaging now revealed new hyperintensities in the basal ganglia and both dorsal thalami [Figure 2 right]. Furthermore, the EEG now presented a generalized periodic pattern with triphasic waves. Continuous CSF studies now showed normalization of Leukocytes (1/μl) and Total Protein (292 mg/l), but increased Tau and 14-3-3 proteins leading to the suspicion of a possible Creutzfeldt-Jakob disease [7],[8]. The patient continued to detoriate over the following month after discharge, dying approximately one year after the onset of symptoms. The postmortem examination showed signs of spongiform encephalopathy [Figure 3], supporting our diagnosis of a definitive Creutzfeldt-Jakob disease [7],[8].