Evaluating for conversion disorder: When to suspect Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease

CJD is a rapidly progressive neurodegenerative disorder characterized by cognitive changes, behavioral changes, gait disturbances, akinetic mutism, and myoclonus.⁵ CJD results from the transition of prion proteins, which are present in the normal human brain, to disease-associated forms that aggregate and propagate and result in neurotoxicity with spongiform changes in neurons.⁶ The transition of normal prions to disease-associated prions may be hereditary, iatrogenic, infectious, or sporadic. Because the pathologic prion protein can be transmitted and normal sterilization procedures do not prevent the spread of CJD, special precautions should be taken to avoid contact with blood or CSF from patients suspected of having CJD.⁵

CJD most commonly occurs in the sporadic form, for which there are no identifiable risk factors, with an average age of onset between age 50 and 70. The disease affects women and men equally at a rate of 1 to 2 persons per million per year worldwide.^6,7 Most patients with CJD die within 12 months of diagnosis⁸; median survival is 4 to 5 months.^7,9 Although there is no approved or standard effective treatment for this uniformly fatal disease, research into the possibility of genetic or post-translational treatments is ongoing. One group reported inhibition of prion propagation by quinacrine and chlorpromazine in vitro.¹⁰ Clinical studies of quinacrine have demonstrated tolerability but no impact on the course of CJD.⁶

Clues to diagnosis. Although there is no treatment for CJD, early diagnosis can help patients and families understand the relentless progression of symptoms and also permits end-of-life planning and palliative care.¹¹ Diagnosing CJD requires a high level of suspicion and traditionally has required brain biopsy or autopsy for conclusive diagnosis, although in some cases rare EEG findings of periodic sharp wave complexes or generalized periodic epileptiform discharges (GPEDs) have suggested the diagnosis.^7,8,12 Recently, specific MRI findings have been described with fluid attenuated inversion recovery (FLAIR) and diffusion sequences.^9,13,14

Routine LP for CSF examination (including cell count, protein, and glucose) frequently is normal.⁸ Specific testing to assess for CJD is required. Elevated levels of CSF neuron-specific enolase (normal <30 ng/mL) and protein 14-3-3 (normal <8 ng/mL) are fairly sensitive and specific for CJD when assessed in patients with the proper clinical history, although normal levels of these proteins have been detected in patients later confirmed to have CJD.^7,15 A large multinational collaborative study of confirmed CJD cases that evaluated diagnostic test characteristics recommended that because each test has limitations and can be falsely negative—even in a case of later-confirmed CJD—a rational approach to diagnosis includes brain MRI with diffusion-weighted imaging, CSF analysis for protein 14-3-3, and EEG to assess for periodic sharp wave complexes or GPEDs.¹⁶

Because CJD presentation varies widely, most clinicians will not consider the diagnosis until the disease has progressed or the patient has died. Patients who present with psychological symptoms or predominant language disturbances and dysphagia may be referred to a psychiatrist or an ear, nose, and throat specialist before seeing a neurologist.⁹ Patients may be extensively evaluated and treated for conversion disorder when the correct diagnosis is CJD.¹⁷

Sporadic CJD traditionally is associated with neurologic presentations, whereas variant CJD is believed to present with psychiatric symptomatology. However, in a 25-year retrospective review of 126 patients with sporadic CJD, 80% of cases demonstrated psychiatric symptoms within the first 100 days of the disease course.¹⁸ Of these, nearly 25% showed psychiatric symptoms at presentation, including sleep disturbances, psychotic symptoms, agitation, and anxiety.

Psychiatrists should be aware of distinguishing features of rapidly progressive dementias and CJD, especially in the setting of psychiatric consultation, to rule out somatic etiologies of unexplained neurologic symptoms. It is important to obtain a history of baseline functioning, duration of decline, and psychiatric symptomatology to differentiate between organic and somatic causes. Differential diagnosis for rapidly progressive cognitive impairment is broad and includes delirium from diverse medical causes; rapidly progressive dementia such as accelerated Alzheimer’s disease, Lewy body disease, or frontotemporal dementia; and psychogenic causes, including conversion disorder (Table 1).^7,8,12Table 2 provides distinguishing features of CJD, Alzheimer’s disease, Lewy body disease, and frontotemporal dementia with motor neuron disease.^7,8,19

Table 1

Differential diagnosis of rapidly progressive dementia