Symptomatic aggravation after corticosteroid pulse therapy in definite sporadic Creutzfeldt-Jakob disease with the feature of Hashimoto's encephalopathy

Creutzfeldt-Jakob disease (CJD) is fatal prion disease characterized by rapidly progressive dementia, myoclonus, pyramidal and extrapyramidal signs, visual field defect, and cerebellar symptoms [1]. Hashimoto's encephalopathy is corticosteroid-responsive autoimmune encephalitis with antithyroid antibodies that may have overlapping clinical symptoms with CJD, especially in the early phase of disease [2]. Hashimoto's encephalopathy is more common in female individuals, typically presenting in middle age with a fluctuating encephalopathy including rapid progressing dementia, seizure, psychiatric manifestations, myoclonus, ataxia, stroke-like episodes, and coma, although the clinical phenotype is variable [3]. Cerebrospinal fluid (CSF), electroencephalogram (EEG), and brain magnetic resonance imaging (MRI) findings are non-specific, and CJD diagnosis is based on an appropriate clinical phenotype with exclusion of other conditions, in addition to raised anti-thyroid antibodies (Tg-Ab and TPO-Ab). However, anti-thyroid antibodies are not specific to Hashimoto’s encephalopathy and are common in healthy elderly people [4]. There is no obvious correlation between antibody levels and disease severity, and it is likely that the antibodies are not pathogenic but simply an epiphenomenon reflecting an underlying autoimmune inflammatory state [5]. Thus, it is widely considered that Hashimoto’s encephalopathy should be relabeled as `corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis' [6], and that lack of such corticosteroid response should prompt review of diagnosis [4]. Among CJD mimics, Hashimoto’s encephalopathy is particularly important as it is treatable with corticosteroids [7]. In our thorough review of the literature on CJD mimicking Hashimoto’s encephalopathy or Hashimoto’s encephalopathy mimicking CJD, we found no evidence of definite markers for differential diagnosis of CJD and Hashimoto’s encephalopathy [2],[8]-[14]. Here, we describe a case of a patient with definite CJD with high titers of anti-thyroid antibodies whose clinical symptom was aggravated as a dominant seizure after initiation of corticosteroid pulse therapy.

A 59-year-old woman was admitted because of blurred vision, dysarthria, myoclonic movement of bilateral upper and lower limbs, and rapidly progressive dementia. The symptoms had started approximately 1 month prior and progression was so rapid that she became akinetic and occasionally showed just a slight smile as a response to questioning over the last 2 weeks.

Her CSF was acellular with no evidence of bacterial or viral infection, but her 14-3-3 protein was positive. EEG showed periodic sharp waves (1.5 Hz) at the bilateral frontal or occipital areas with predominance in the left side. Contrast-enhanced MRI showed high signal intensities at the bilateral cerebral cortex, caudate nucleus, and putamen with left predominance (Figure 1). She was diagnosed with probable CJD according to the World Health Organization diagnostic criteria for sporadic CJD [15]. Sodium valproate (1200 mg/day) and clonazepam (0.5 mg/day) were used for intermittent myoclonic jerk. Laboratory analysis showed high titers of anti-thyroid peroxidase antibody (TPO-Ab) (1370 IU/mL; normal value <60 IU/mL) and anti-thyroglobulin antibody (Tg-Ab) (167 IU/mL; normal value <60 IU/mL). However, the levels of thyroid-stimulating hormone (2.24 IU/mL; normal value 0.4-4.0 IU/mL) and FT4 (1.23; normal value 0.89-1.79) were normal. Follow-up laboratory study shows persistent high titers of TPO-Ab, while the titer of Tg-Ab was fluctuating around the normal upper limit. Thyroid sonography showed no gross abnormality.

Although she was diagnosed as probable CJD, corticosteroid pulse therapy with methylprednisolone (1 g per day) was started on the 6^th day of admission for differential diagnosis with Hashimoto’s encephalopathy, which is known to show excellent response to corticosteroid therapy. We observed alertness and myoclonic movement after careful initiation of corticosteroid therapy. Over the 2 days after starting corticosteroid treatment, she was in a akinetic mute state with no response to pain or visual response. We also observed two episodes of generalized clonic movement with eyeball deviation. We elevated the dose of sodium valproate, titrated to 1800 mg/day, without subsequent improvement of myoclonic jerk. Her alertness kept worsening with aggravation of myoclonus, and she had a first generalized tonic-clonic seizure on the 4^th day of corticosteroid therapy. We added levetiracetam (1000 mg/day) and elevated the dose of sodium valproate (2400 mg/day). However, the frequency of seizures was increased and the EEG showed more periodic sharp waves in the bilateral hemispheres with background slowing compared with the previous EEG. Generalized myoclonic movement was observed almost continuously when she was awake. Thus, we elevated the dose and frequency of clonazepam, which effectively alleviated the myoclonic jerk, although she subsequently exhibited decreased mentality. As the five days of corticosteroid pulse therapy were suspected to aggravate the seizures, we performed a brain biopsy with family consent to confirm a diagnosis of CJD. Brain biopsy revealed neuronal loss, vacuolation and gliosis (Figure 2). Western blot demonstrated a protease-resistant pathogenic form of prion protein in the brain tissue. Genetic analysis demonstrated no known mutation in the PRNP gene. A diagnosis of definite CJD was made based on the above findings.

CJD and Hashimoto’s encephalopathy often share similar clinical features. However, there are no definite markers for differential diagnosis except for brain biopsy (Table 1). Clinical manifestation, EEG, brain imaging, and CSF findings including 14-3-3 protein can overlap between both disorders. The response to corticosteroid therapy is generally considered the only effective method for differential diagnosis before brain biopsy. Thus, in middle-aged female patients with a high titer of anti-thyroid antibodies, and who show dementia, myoclonus, ataxia, and altered consciousness, there is a mandatory recommendation to start corticosteroid therapy to rule out Hashimoto’s encephalopathy [2]. Thus, we performed corticosteroid pulse therapy in our case.

What was unique in our patient is that her myoclonic seizure was distinctly aggravated as epilepsia partialis continua and secondary generalized tonic clonic seizure just after initiation of coritcosteroid pulse therapy. The semiology of her seizure was composed of mostly multifocal myoclonic movement, epilepsia partialis continua, and ballistic dyskinesia, which showed obvious improvement by clonazepam in addition to other anti-epileptic drugs. The response to clonazepam was so marked that an elevation of only 0.25 mg decreased her mentality with subsequent improvement of myoclonic jerk.

To our knowledge, an aggravated seizure just after initiation of corticosteroid pulse therapy in definite CJD has not been previously reported. Although our case was in a course of deterioration, there was clear temporal correlation with the initiation of corticosteroid pulse and abrupt increase in seizure activity. From both acute and chronic models of epilepsy, there is evidence that high corticosteroid levels may exacerbate seizure occurrence [16],[17]. Nevertheless, the symptomatology of our patient cannot be fully explained.

Focal motor or generalized seizures have been reported in 15-21% of patients with CJD during the later stage of the disease [18]. However, seizures as the presenting symptom of CJD are uncommon and occur in only approximately 3% of cases [19]. Based on five case reports in the literature, epilepsia partialis continua is reported as a presenting feature of CJD, although none of those cases were related to corticosteroid pulse therapy. The irritative, rather than destructive, nature of the cerebral damage may be the cause of the continuous jerks [20], while the loss of basal ganglia influence on the brain stem can also cause muscular twitches [21]. Our patient also showed ballistic movement, which was reduced by clonazepam treatment. Coexistence of generalized chorea and epilepsia partialis continua as the initial signs was previously reported in probable CJD, although the movement disorder typically appears during the later disease stage [22].

This is the first definite case of CJD with symptomatic aggravation after corticosteroid pulse therapy for differential diagnosis with Hashimoto’s encephalopathy. In our patient, the high titer of anti-thyroid antibodies may have been an incidental finding, as the thyroid sonography was normal and brain biopsy confirmed final diagnosis as sporadic CJD that was abruptly aggravated by corticosteroids. When a middle-aged woman diagnosed with probable CJD shows a high titer of anti-thyroid antibodies, corticosteroid treatment is typically used as histopathological confirmation with brain biopsy is not easily available, with expectations of near complete recovery in cases of Hashimoto’s encephalopathy. However, if corticosteroid pulse therapy can cause rapid deterioration or seizure aggravation of CJD, the use of corticosteroids in probable CJD patients with high titers of anti-thyroid antibodies should be cautioned. Our patient showed very typical clinical symptoms, and EEG, MRI and CSF findings (14-3-3 protein) of CJD. Thus, it may be reasonable to selectively start corticosteroid pulse therapy in cases of uncertain diagnosis. If seizures are aggravated by corticosteroid treatment, clonazepam may be a good choice to reduce myoclonic jerk, in addition to anti-epileptic drugs. Further studies are required to prove a correlation between corticosteroid treatment and symptomatic aggravation of CJD.

Written informed consent was obtained from the caregiver of our patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.