Creutzfeldt-Jakob disease mimicking autoimmune encephalitis with CASPR2 antibodies

Differential diagnosis of severe progressive dementia includes a wide spectrum of inflammatory and neurodegenerative diseases. Particularly challenging is the differentiation of potentially treatable autoimmune encephalitis and Creutzfeldt-Jakob disease (CJD). Such a coincidence may indeed complicate the correct diagnosis and influence subsequent treatment. The diseases can mimic one another to such an extent that one is led to believe that the patient is suffering from CJD when he or she has in fact a treatable autoimmune encephalitis [1]-[3] or vice versa [2],[4],[5]. None of these VGKC complex antibodies in CJD patients have been found to be directed to LG1 or CASPR2, yet.

We here report a recent case of Contactin-associated protein 2-Antibody (CASPR2) production during ongoing CJD, discuss the potential biological causes and the clinical consequences.

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].

The biological cause of this molecular mimicry is currently unknown and deserves further investigation. One may hypothesize that prion-induced neurodegeneration may have triggered an immunological reaction in peripheral lymph nodes causing antibody production against certain neuronal structures such as elements of voltage gated potassium channels.

With the diagnosis still unconfirmed, we chose to initiate therapy for the potentially treatable differential diagnosis. One could argue that global screening for antineural antibodies led us to a false diagnosis triggering intense and potentially dangerous procedures. We believe, however, that potentially treatable causes of dementia should be aggressively sought out and subsequently treated to avoid poor outcome. In fact, encephalitic syndromes are treatable conditions that may mimic CJD [1],[3].

The development of a CJD case into a progressive and untreatable encephalopathy, as presented here, is certainly very rare. Nevertheless, such unique cases are important as they present new opportunities to study the complex role of the immune system in the CNS.