Background
Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy that manifests as rapidly progressive dementia and causes devastating consequences like death usually within a year from symptom onset [1,2]. CJD has a global incidence of approximately 1 to 2 cases per million [3]. This rare and fatal brain disorder, characterized by fast cognitive decline and rapidly progressive neurological deterioration, presents a real challenge in both diagnosis and treatment. There are comprehensive studies on CJD, digging into its etiology, pathogenesis, clinical manifestations, diagnostic modalities, therapeutic approaches, and ongoing research endeavors. The different facets of this complex disorder are being investigated through a multidisciplinary lens including neurology, neuroradiology, neuropathology, genetics, epidemiology, and public health [4]. Four types of CJD have been described: sporadic(sCJD), which accounts for 85%-90% of cases [5]. Other forms of CJDs are variant, familial, and iatrogenic. Every form of CJD has some unique features. It needs to be navigated through the labyrinth of CJD’s clinical presentation, from the subtle cognitive changes to the profound neurological deficits and death within a year of onset [6]. Different phenotypic variants of sCJD are the amyotrophic variant (initial presentation: amyotrophic lateral sclerosis-like), [7] Brownell-Oppenheimer variant (cerebellar ataxia as initial presentation), Heidenhain variant (initial visual symptoms such as visual hallucinations, impaired visual acuity and distortions of shapes and colors), and Stern-garcin variant: (initial presentation: extrapyramidal features) [8,9]. Moreover, the intricate landscape of CJD poses challenges to diagnosis due to its rarity, variety of presentation, and the limitations of current diagnostic modalities. From clinical assessment and neuroimaging techniques to cerebrospinal fluid (CSF) analysis and electroencephalography, several tools are available to clinicians in their quest to disentangle the diagnostic puzzle of CJD [10,11]. Furthermore, the therapeutic options of CJD are also required to be explored, although the disease is invariably fatal with a mean survival of 7 months. Despite the lack of disease-modifying therapies, clinicians are exploring emerging avenues of research, from immunotherapeutic approaches to different novel pharmacological agents, offering a twinkle of hope in the pursuit of effective treatments for CJD [12].
Here, we report a unique case of CJD, where the patient’s progressive neurological deterioration has led to an early diagnosis of the disease by a multidisciplinary approach.
Case Presentation
A 49-year-old male presented with complaints of difficulty in walking associated with impaired balance, and jerky movement in left lower and upper limbs for 5 days followed by jerky movements in right upper and lower limbs for 2 days associated with restlessness and agitated behavior with altered mental status. He had a recent history of double vision and vertigo in the last 15 days. His past medical history was non-contributory to the clinical presentation. However, he has a few comorbidities such as type 2 diabetes mellitus and hypertension. He got his blood sugar tested and his HbA1c came as 9.3. He was admitted to Apollo Multispeciality Hospital, Kolkata, for a re-evaluation. He had no history of any previous surgeries, and his family history was significant for fatal leukemia in his mother, but there was no family history of dementia or prion disease. He had no known allergies. There was no recent travel history or exposure to raw livestock or brain matter. He was an engineer by profession, working in Punjab, India. On doing a physical examination, he had significant anomic aphasia and apraxia. His muscle tone was normal in all four extremities and his power was also 5/5 in all four extremities. His cranial nerves were grossly normal. He had normal sensation and normal coordination. His reflexes were symmetric and no Babinski reflexes were demonstrated. He had a slow but non-ataxic gait. He was able to complete the Mini-Mental State Examination. His blood work included a basic metabolic profile, complete blood count, thyroid profile, liver studies, lactic acid, erythrocyte sedimentation rate, vitamin B1, B12, and folate levels, human immunodeficiency virus, angiotensin-converting enzyme levels, and ceruloplasmin; all came normal. Serum tests for pyruvate kinase, Purkinje cell antibody screen, anti-jo antibody, and anti-Hu antibody were also normal. Serum ammonia was sent which was within normal limits. CSF studies were also performed for oligoclonal bands, autoimmune encephalitis panel, neuromyelitis optica (NMO), and myelin oligodendrocyte glycloprotein (MOG). A serum paraneoplastic panel has also been sent. CSF 14- 3- 3 was also sent. A non-contrast magnetic resonance imaging (MRI) of her brain was significant for global parenchymal loss. Relatively asymmetrical areas of subtle diffusion restriction and FLAIR hyperintensities were noted involving the bilateral caudate nuclei, bilateral putamina, bilateral frontal cortical region (right > left), right fronto-parietal parasagittal location, right posterior cingulate gyrus, and right parieto-occipital cortex (Figure 1a-h).
His PET CT was done which showed moderate to severe large areas of hypometabolism in the bilateral occipital cortex, right frontal and parietal cortex, bilateral posterior cingulate cortex, severe hypometabolism in the right thalamus, bilateral basal ganglia, and right mesial temporal lobe (Figure 2a-d).
He was administered intravenous immunoglobulin (IVIG) with the possibility of autoimmune encephalitis after explaining to the patient’s attendant the nature of the disease and costs related to treatment and the need for starting IVIG with its outcome on the overall disease score. His venereal disease research laboratory (VDRL), anti-nuclear antibody, ANCA, ANTI MOG, and ANTI NMO came negative. His serum paraneoplastic and autoimmune encephalitis panel were negative. Cell counts, glucose, and protein were within normal limits. Toxoplasma gondii, Leptospiral antibodies were negative. An electroencephalogram (EEG) was done and it showed background slowing in the delta-Theta range with an intermittent transient triphasic wave, moreover right hemisphere (Figure 3). He had aspiration pneumonia with a WBC count of 11,600 for which appropriate treatment was started. His H1N1 and COVID tests were negative. As his Glasgow comma score deteriorated to E2V1M3 along with pooling of secretion, he was planned for airway protection (intubation or ventilation followed by tracheostomy) but as his neurological status did not improve, so a repeat MRI brain was done which showed no significant change. His CSF 14-3-3 came positive (>2 ng/ml, normal value <1 ng/ml).
Non-contrast MRI BRAIN demonstrates hyperintensities on DWI sequence (green arrow) in (a)Right parieto-occipital (c) Body of right caudate nucleus and posterior cingulate gyrus (e)Bilateral putamina and (g) Right mesial temporal lobe. It shows hypointensities on ADC map (red arrow head) in (b) Right parieto-occipital, (d) Body of right caudate nucleus and posterior cingulate gyrus, (f) Bilateral putamina, and (h) Right mesial temporal lobe. This represents diffusion restriction.
Discussion
CJD is a fatal neurodegenerative disorder caused by an abnormal host-encoded protein called prions [13]. Varying presentation and lack of knowledge make it tough and challenging to diagnose a case of CJD [14]. Confirming prion protein at autopsy or on a brain biopsy is considered the gold standard and conclusive method but is an invasive technique. Therefore, a resource-limited CJD can be diagnosed through meticulous clinical analysis and non-invasive diagnostic workup.
Considering the Centre for Disease Control and Prevention (CDC) criteria for CJD (given below), our case fulfilled the criteria of that of a “Probable case” of sporadic CJD (Table 1).
Our patient exhibited multiple neuropsychiatric symptoms such as cognitive decline and myoclonus along with behavioral abnormalities and higher cortical dysfunctions such as aphasia and apraxia. Signs of cerebellar involvement such as impaired balance, vertigo, and double vision were also seen in the patient. According to Schröter et al. [16] FLAIR, and T2-weighted hyperintensities involving the cerebral cortex, corpus striatum, caudate head, and putamen are some of the most common presentations of sporadic CJD on MRI [16]. A combination of isolated cortical hyperintensity and cortical and deep gray matter (basal ganglia) hyperintensity are two patterns of DWI and/or FLAIR abnormality that have been well described [17]. Another study also demonstrated that 95% of CJD cases show signal abnormality in at least three out of four discrete areas, including the insula, cingulate gyrus, superior frontal gyrus, and occipital gyrus [18]. Similarly, our patient on DWI showed restricted cortical diffusion on parieto-occipital, cingulate gyrus, bilateral parietal, and mesial temporal lobe (Fig 1a-h). Another major advantage of using DWI sequences is that they rule out typical imaging findings of stroke and confirm the presence or absence of an alternative differential diagnosis. According to many studies, the presence of 14–3-3 protein in CSF is considered a complementary test rather than a diagnostic test for prion disease. CSF tau protein levels (>1,150 picogram/ml) have superior accuracy and specificity as compared to 14-3-3 protein as a diagnostic test [19]. Due to financial constraints of the patient party only underwent a 14-3-3 CSF protein test which gave a positive result. EEG was also performed which showed background slowing of delta-theta waves with intermittent and transient triphasic morphology (Fig 3) [20]. Taking into consideration the above features our case fulfilled the diagnostic criteria of sporadic CJD which consists of progressive dementia, with at least two out of the four clinical signs (myoclonus, visual or cerebellar impairment, pyramidal or extrapyramidal dysfunction, and atypical mutism) along with atypical EEG pattern and identification of CSF protein 14-3-3. In addition, on doing PET CT, our patient showed moderate to large areas of hypometabolism (Figure 2a-d). According to many studies [18F], fluorodeoxyglucose positron emission tomography (FDG-PET) is said to be a sensitive investigation in CJD and could be used to differentiate CJD from other neurodegenerative disorders [10]. Before proceeding to the diagnosis, we ruled out other vascular, ischemic, infectious, toxic, metabolic, auto-immune, metastatic, neoplasm-related, iatrogenic, systemic, seizures, and demyelinating causes of rapidly progressive dementia, on the basis of clinical presentation and relevant investigations which were available in our hospital [21]. To conclude cortical diffusion-restriction with positive CSF protein and atypical EEG workup along with PET hypometabolism is a multidisciplinary approach which if used efficiently is an important tool in suspecting prion disease.
| Definite |
| • Diagnosed by standard neuropathological techniques; and/or immunocytochemically; and/or Western blot confirmed protease-resistant PrP; and /or presence of scrapie-associated fibrils. |
| Probable |
| • Neuropsychiatric disorder plus positive real-time quaking-induced conversion in CSF or other tissues OR • Rapidly progressive dementia; and at least two out of the following four clinical features: 1) Myoclonus 2) Visual or cerebellar signs 3) Pyramidal/extrapyramidal signs 4) Akinetic mutism AND a positive result on at least one of the following laboratory tests 1) a typical EEG (periodic sharp wave complexes) during an illness of any duration 2) a positive 14-3-3 CSF assay in patients with a disease duration of less than 2 years 3) High signal in caudate/putamen on MRI brain scan or at least two cortical regions (temporal, parietal, occipital) either on diffusion-weighted imaging (DWI) or fluid attenuated inversion recovery (FLAIR) AND without routine investigations indicating an alternative diagnosis. |
| Possible |
| • Progressive dementia; and at least two out of the following four clinical features: 1) Myoclonus 2) Visual or cerebellar signs 3) Pyramidal/extrapyramidal signs 4) Akinetic mutism AND the absence of a positive result for any of the four tests mentioned above that would classify a case as “probable” AND duration of illness less than 2 years AND without routine investigations indicating an alternative diagnosis. |
Conclusion
Sporadic CJD is a rare and fatal rapidly progressive neurodegenerative disorder, that claims prompt and precise diagnosis to help clinicians distinguish it from potentially treatable neuropsychiatric disorders. This aspect elevates the significance of our report, as it aids not only the medical professionals but also the affected families. Early diagnosis enables the family to prepare for the disease course and appropriate management strategies.
What is new?
Sporadic Creutzfeldt Jacob disease is a rare and fatal rapidly progressive neurodegenerative disorder, which claims prompt and precise diagnosis to help clinicians distinguish it from potentially treatable neuropsychiatric disorders. This aspect elevates the significance of our report, as it aids not only the medical professionals but also the affected families. As it is a relatively rare disease, reporting this case helps clinicians to understand further what to expect as clinical presentation and how to diagnose early by a small seed of suspicion.