History of Present illness
A male in his 40s presents with six weeks of gradually progressive neurologic complaints. He initially noticed blurred vision and a sensation of ear fullness. He was evaluated multiple times at an outside hospital for those complaints, and his evaluation and treatment included a negative head CT and two courses of antibiotics for presumed otitis media. His symptoms persisted, so he was referred to a neurologist who scheduled an outpatient MRI which had not yet been performed. On presentation to the ED, he reports progressive and new neurologic symptoms including clumsiness, intermittent numbness in his hands, balance problems, and slurred speech. His symptoms have become so severe that he is no longer able to perform his daily activities.
Past Medical History: Bell's palsy
Past Surgical History: None
Vitals: T 97.9°F BP 168/94 P 78 RR 13 SaO2 98% on room air
Physical Exam: The patient is a well-appearing male who is awake, alert, and oriented. Respiratory, cardiovascular, and abdominal examinations are normal. Neurologic examination reveals diplopia with left gaze, spastic dysarthria, and dysphonia. The patient also exhibits dysmetria on the left with finger-nose and heel-shin testing as well as truncal ataxia and a wide-based, unsteady gait. Otherwise, cranial nerve testing, motor strength, and sensation are normal.
Glucose: 109 BUN: 28, BMP otherwise normal
WBC: 6.4 Hgb: 16.0 Platelet: 169
AST: 42 ALT: 67
CT angiography of the head and neck: No flow-limiting stenosis, aneurysm, or evidence of dissection.
Neurology was consulted from the ED and recommended admission for further workup. The patient underwent an extensive laboratory workup including thyroid studies, B12, HIV, syphilis, hepatitis, vitamin E, ceruloplasmin, antinuclear antibody, tissue transglutaminase, gliadin, and heavy metal testing. These tests were normal. Initial cerebrospinal fluid (CSF) studies included cell count, protein, glucose, gram stain, flow cytometry, paraneoplastic panel, cytomegalovirus, herpes simplex virus, enterovirus, varicella, West Nile, and Lyme disease. These tests were also normal. MRI head was obtained which demonstrated findings consistent with Creutzfeldt-Jakob disease (CJD) (figure 1). Confirmation with CSF RT-QuIC testing was sent for testing at an outside facility.
The patient was discharged on hospital day four and had progressive neurologic deterioration including seizure-like activity and rapidly progressive dementia. Two weeks after his initial presentation, the RT-QuIC testing returned positive, further suggesting a diagnosis of CJD. The family declined a brain biopsy for definitive diagnosis. Palliative care was consulted, and the patient expired 12 days later. Family declined an autopsy.
CJD is a transmissible, rapidly progressive, uniformly fatal neurodegenerative condition caused by the misfolding and pathologic aggregation of human prion protein. The condition is rare, affecting an estimated 1 in 1,000,000 people annually. CJD classically presents as a rapidly progressive dementia with focal neurologic deficits, akinetic mutism, and myoclonus. MRI and CSF studies may be suggestive of CJD, but the diagnosis should only be considered after all potentially treatable causes have been excluded.
Multiple clinical variants exist, including spontaneous (sporadic CJD, 85% of cases), genetic (familial CJD, 10% of cases), and iatrogenic or acquired (variant CJD). There are case reports of CJD transmission from grafts of dura mater, transplanted corneas, implantation of inadequately sterilized electrodes in the brain, and injections of contaminated pituitary growth hormone derived from human pituitary glands taken from cadavers. All human growth hormone used in the United States is now synthesized by recombinant DNA procedures, eliminating the risk of transmitting CJD by this route. All variants are transmissible via blood, CSF, and CNS tissue, and there is overlap among variants in terms of clinical presentation, disease course, and diagnostic testing.
CJD has classically been described as a rapidly progressive dementia with focal neurologic deficits and myoclonus. In practice, there is marked variability in the presenting symptoms of patients with CJD. Sporadic CJD most commonly presents in individuals 60-70 years of age, whereas variant CJD tends to affect younger individuals with a mean age at diagnosis of 28 years. Early symptoms are often non-specific and psychiatric in nature, including depressive personality changes, sleep disorders, behavioral disturbances and other psychiatric complaints. Interestingly, 12% of referrals for suspected CJD are made by psychiatrists. An unrelenting, rapidly progressive dementia typically follows; symptoms include diminished cognition, impaired memory and generalized loss of higher cerebral function. Focal neurologic deficits tend to develop as the disease progresses, but rarely may be the presenting complaint. Cerebellar dysfunction predominates, with gait ataxia present in a majority of cases. Visual disturbances are common and range from subjective blurriness to visual hallucinations and cortical blindness. Myoclonus is often a late finding and may be elicited via the startle response to tactile or auditory stimuli. A hallmark of the late stage of disease is akinetic mutism, a term which describes a patient’s inability to purposefully move or vocalize. Seizures occur in approximately 15% of cases.
Care is supportive and palliative. Opiates, valproate, and benzodiazepines may be considered for symptomatic management. There are no treatments that alter disease progression or mortality. The disease is invariably fatal; death occurs on average five months after the onset of symptoms in patients with sporadic CJD.
The differential diagnosis of rapidly progressive dementia is broad, and importantly contains both treatable and non-treatable causes. Autopsy studies from the US National Prion Disease Pathology Surveillance Center, which analyzes tissue samples and clinical information for all referred cases of suspected CJD in the US, demonstrate that over 30% of cases referred as suspected prion disease were negative for pathologic evidence of CJD. The majority of these cases were diagnosed post-mortem as Alzheimer disease, vascular dementia, or another incurable neurodegenerative condition. More importantly, 23% of prion-negative autopsies demonstrated evidence of a potentially treatable disease. These treatable conditions included immune-mediated conditions, neoplasms, infections, and toxic and metabolic encephalopathies. It is of paramount importance that patients presenting to the ED with dementia receive a thorough evaluation for treatable causes if such a workup has not yet been completed, as the treatable and non-treatable causes cannot reliably be distinguished on history and physical examination alone. One mnemonic to recall common treatable causes of dementia is “IMIT”, as these conditions can imitate the more common, incurable causes of dementia (Table 1).
All patients with suspected CJD should undergo CSF studies, MRI, and EEG. CSF studies are typically normal. Pleocytosis should raise suspicion for an etiology other than CJD. 14-3-3 proteins, a family of regulatory proteins that function in gene regulation, have a reported sensitivity of 85-95% in cases of autopsy-proven CJD. Nonetheless, elevated 14-3-3 is not specific for CJD (specificity 71%). Elevation of these proteins may also be present with neoplasia and paraneoplastic syndromes, subarachnoid hemorrhage, stroke, encephalitis, and metabolic encephalopathy.
MRI brain with and without contrast has a reported sensitivity of 63-96% and a specificity of 92-93%.[1,2] In general, MRI is abnormal in 80.9% of cases.[1,2] MRI findings may be suggestive of a particular variant (e.g., pulvinar sign in variant CJD refers to bilateral FLAIR hyperintensities involving the pulvinar thalamic nuclei).
Periodic sharp wave discharges (PSWC) on EEG are highly suggestive of sporadic CJD.4 However, this characteristic pattern is found in only 37.5% of cases. EEG interpretation may be difficult as CJD occasionally presents as seizures and even status epilepticus.
Neural tissue, obtained by brain biopsy or post-mortem, is the only means of definitive diagnosis of CJD. However, a probable diagnosis of CJD may be made through a combination of symptoms and testing, as highlighted by the WHO diagnostic criteria (Table 2) Additionally, there is a real-time quaking-induced conversion (RT-QuiC) CSF assay with a reported sensitivity of 77-97% and a specificity of 99-100% for the diagnosis of sporadic CJD. This is a send-out test at most institutions, but it does provide a near-definitive diagnosis if positive, as it was in the case highlighted above.
Neurologic consultation should be obtained with any case of suspected CJD. As emergency physicians, it is our responsibly to maintain a broad differential and thorough evaluation in patients with altered mental status, new-onset dementia, and unexplained neurologic deficits. A diagnosis of CJD or dementia should only be considered when all potentially treatable diagnoses have been sufficiently investigated and reasonably excluded.
Authored by James Makinen, MD
Posted by Matthew scanlon, md
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