A Case of Rapidly Progressive Dementia

Creutzfeldt-Jakob disease (CJD) is a very rare neurodegenerative disorder that usually presents as rapidly progressive dementia with an extremely poor prognosis. The diagnosis of CJD can be extremely challenging due to its rarity, manifestation with non-specific neurological symptoms, associated broad differentials, and a need for extensive workup. Awareness of disease-specific biomarkers, radiological signs, and diagnostic criteria are crucial for timely diagnosis. Here, we report a case of CJD, which presented as an atypical movement disorder that progressed to dementia and failure to thrive within a few weeks of presentation.


Introduction
Creutzfeldt-Jakob disease (CJD), also known as subacute spongiform encephalopathy, is a rare, lifethreatening neurodegenerative disorder. CJD is caused by the pathological misfolding and aggregation of the prion protein (PrP), a cellular glycoprotein [1]. The majority of the CJD are sporadic (approximately 85% patients) with no recognizable transmission pattern. Still, they can be due to inherited mutations of the PrP gene in a smaller proportion of patients (5% to 15%) [2]. CJD can present clinically as rapidly progressive dementia. Once transmitted to individuals, the pathologic PrP misfolds the normal PrP resulting in progressive disease. Initial manifestations include impaired memory, behavioral disturbances, visual disturbances, and poor coordination. As the disease advances, patients develop symptoms of dementia, involuntary movements, loss of vision, weakness, and coma.

Case Presentation
A 70-year-old female presented to the emergency room with complaints of involuntary movements of the left upper extremity of 10 days duration. Medical history is notable for Stanford type-A aortic dissection status post aortic repair and bioprosthetic aortic valve replacement 18 months ago. According to the patient, involuntary movements of the left upper extremity lasted several minutes, often waking her from sleep, and resolved spontaneously. She denied any fever, chills, or headache. She was seen by a neurologist three days prior. At the neurology clinic, laboratory studies were remarkable for mild thrombocytopenia with platelets 127,000. Erythrocyte sedimentation rate (ESR) was 2, and C-reactive protein (CRP) was 0.16. Electroencephalogram (EEG) was negative for seizure activity but due to clinical suspicion for atypical seizures, she was started on Levetiracetam 1,000 mg twice daily and Divalproex sodium 500 mg twice daily. However, she developed left upper extremity weakness and presented to the hospital. Imaging studies on admission as in Table 1.

Imaging studies on admission
Computerized Tomography (CT) scan of the brain No acute changes Magnetic Resonance Imaging (MRI) scan of the brain with and without contrast Chronic small vessel ischemic changes CT angiogram of the chest abdomen and pelvis Negative for aortic dissection CT angiogram of the head and neck No arterial stenosis or venous abnormality.
MRI scan of the brain with and without contrast with thin slices of the brainstem No acute findings intermittent rigidity, myoclonic jerk-like movements mimicking hemichorea. The neurologist then recommended lumbar puncture and cerebrospinal fluid (CSF) analysis ( Table 2).  Antinuclear antibody (ANA) was weakly positive (0.8 units) and the autoimmune panel was otherwise negative. Autoimmune etiology remained high on the differentials; therefore, she was given hydrocortisone 1000 mg daily and intravenous immunoglobulin for five days. We noted mild improvement in the left upper extremity weakness and involuntary movements. So, she was discharged home with outpatient neurology follow-up in eight days. At the neurology clinic, she reported word-finding difficulties and poor sleep. Her neurologist noted progressive flexor posturing, movements of the left upper extremity and described the findings as "progressive hemi-dystonia." He started her on clonazepam, baclofen and mirtazapine. He then referred her to a movement disorder clinic at a University Hospital.

CSF studies on admission
Her symptoms rapidly progressed over the next five days; she became increasingly weak, developed difficulty swallowing with abnormal movements in bilateral upper extremities and rhythmic jerking of the left arm. There was some motor agitation in the legs, and she could not ambulate.
She was then readmitted to the hospital; initial vitals and lab studies were unremarkable. Repeat lumbar puncture and additional CSF testing were done ( Table 3).

RT-QuiC Positive
T-tau protein 3,699 pg/mL ( range 0-1,149) A repeat MRI of the brain with and without contrast showed subtle, patchy bilateral cortical diffusion restriction, significantly progressing from prior MRIs in a pattern suggestive of CJD (Figures 1, 2). A continuous EEG showed periodic sharp wave discharges lateralized to the right hemisphere. In combination with her rapid decline, these findings were highly suggestive of sporadic CJD.

FIGURE 2: MRI brain showing hyperintensity in the caudate nucleus
There was rapid worsening in her mentation, dementia, involuntary movements of upper extremities, and difficulty with swallowing. Given her ongoing decline and poor prognosis associated with CJD, her family decided to transition to comfort care measures. The patient passed away in the hospital on hospice, within six weeks of initial symptom onset.

Discussion
CJD is the most common human prion disease, with an incidence of one per 1,000,000 person-years. Most of these cases are sporadic (85%-95%). The mean age of disease onset is 62 years [3][4][5]. Discovered initially by Creutzfeldt and Jacob in 1920, CJD was considered an atypical form of dementia until 1968 when Gibbs et al. proved experimental transmission to primates by intracerebral inoculation.
Classic clinical features of CJD are rapidly progressive dementia, ataxia, myoclonic jerks/involuntary movements [6]. The mean duration of illness is six months [7]. This rapid progression of symptoms distinguishes CJD from other common forms of dementia. Evaluation should include detailed clinical history, neuroimaging, lab studies to rule out infectious and autoimmune differential diagnoses (Table 4), electroencephalogram, and CSF analysis.  MRI is superior to a CT scan of the brain to identify changes in CJD. A hyper-intense signal on diffusionweighted imaging (DWI), fluid-attenuated inversion recovery (FLAIR), and T2-weighted images involving the cerebral cortex and corpus striatum, caudate head, and putamen are the most common patterns on MRI in patients with sporadic CJD [8][9][10]. Although a gray matter disease, CJD can affect white matter in earlyintermediate stages [11].

Differential diagnoses to consider when working up CJD
Synchronous bi-or triphasic periodic sharp wave complexes (PSWC) on EEG can support the diagnosis in 67% to 95% of patients with CJD [12].
CSF analysis for specific markers is vital in the diagnosis of CJD ( Table 5) [13][14][15]. The Centers for Disease Control (CDC) and Prevention have proposed diagnostic criteria for probable CJD ( Table 6) and no longer recommend brain biopsy for the definitive diagnosis [16].

Conclusions
CJD is an extremely rare disease that may manifest with a wide range of neurological symptoms as in this case. CJD is to be suspected in any case of rapidly progressive dementia or presentation with unexplained movement disorder of the limbs. A high index of suspicion, awareness of specific biomarkers, and radiologic signs are crucial in the diagnosis of this condition. Unfortunately, there are no effective treatment options for prion diseases and they are universally fatal, with a median disease duration of six months. Once a diagnosis is confirmed, physicians should provide symptomatic treatment for neuropsychiatric symptoms, communicate effectively with family regarding the biology of the disease and the expected poor outcome, and have end-of-life conversations.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.