By Joseph E. Safdieh, MD

Vice Chair and Associate Professor, Weill Cornell Medical College

Dr. Safdieh reports no financial relationships relevant to this field of study.

SYNOPSIS: Cerebellar and psychiatric symptoms at diagnosis of Creutzfeldt-Jakob disease may portend a higher risk for more rapid development of akinetic mutism.

SOURCE: Nakatani E, Kanatani Y, Kaneda H, et al. Specific clinical signs and symptoms are predictive of clinical course in sporadic Creutzfeldt-Jakob disease. Eur J Neurol 2016; May 24. doi:10.1111/ene.13064 [Epub ahead of print].

Creutzfeldt-Jakob disease (CJD) is a rare but devastating cause of rapidly progressive dementia. It can be sporadic (sCJD), genetic/familial, iatrogenic, or variant, with the sporadic type being the most common. CJD can manifest with a variety of symptoms, including cognitive impairment, myoclonus, visual perceptual problems, cerebellar dysfunction, psychiatric dysfunction, and pyramidal or extrapyramidal involvement. Once symptoms develop, progression to disability and death is quite rapid with median disease duration of five months. Prognostic factors that predict a somewhat longer survival time include female gender, younger age at diagnosis, and certain laboratory findings, including elevated CSF 14-3-3 protein, pseudo-periodic EEG complexes, and heterozygosity (MV) at codon 129 of the prion protein. However, when initiating therapy and when considering enrollment into trials, death may not be the most reasonable endpoint, as enrolling patients too late into the course of the disease may mask any potential benefit. A more reasonable measurable endpoint may be akinetic mutism, and this study evaluated the prognostic factors that predict the risk for the development of akinetic mutism.

Nakatani et al reviewed all cases of probable and definite CJD reported to the Japanese health ministry from 2003-2008. Probable sCJD was diagnosed in patients with progressive dementia with at least two of the four clinical signs or symptoms: myoclonus, visual or cerebellar disturbance, pyramidal or extrapyramidal dysfunction, or akinetic mutism, a typical EEG with generalized triphasic periodic complexes at approximately one per second, or a positive 14-3-3 assay of the CSF and death in less than two years. Definite sCJD cases were defined as those with a confirmed pathological diagnosis at autopsy or biopsy. The authors excluded from analysis any patients who manifested with akinetic mutism as a presenting symptom, since the purpose of the study was to determine prognostic features for the development of akinetic mutism. The authors then performed multivariate analysis to determine prognostic factors for akinetic mutism as well as to determine the disease course from onset to the development of akinetic mutism.

The analysis included 455 cases of CJD. Sixty-one percent of patients were women. Median age at diagnosis was 70 years. Median time from symptoms to diagnosis was 1.2 months. Ninety-three percent of patients demonstrated typical EEG findings and 93% of patients demonstrated typical MRI hyperintensities. Of the patients tested, 81% had elevated CSF 14-3-3 protein levels. The most common presenting symptoms included cerebellar (50.8%), psychiatric (50.4%), visual (44.8%), pyramidal (32.1%), extrapyramidal (29.2%), and myoclonus (28.7%).

In the cohort, the cumulative incidence of akinetic mutism at 3, 6 and 12 months after diagnosis of sCJD was 67.8%, 78.6%, and 85.7%, respectively. Median time to the development of akinetic mutism was 1.5 months. In multivariate analysis, only the presence of cerebellar (hazard ratio, 2.15) or psychiatric symptoms (hazard ratio, 1.5) at disease onset was significantly correlated with the development of akinetic mutism. The median times to the development of akinetic mutism in patients with psychiatric symptoms and cerebellar disturbance, cerebellar disturbance only, psychiatric symptoms only, and neither condition were 0.99, 1.51, 1.88, and 2.93 months, respectively. Additionally, the authors determined that the presence of cerebellar disturbance at the time of diagnosis was predictive of future development of myoclonus, pyramidal and extrapyramidal dysfunction, and visual disturbance.

COMMENTARY

This study provides some previously unknown insights into the clinical course of CJD, specifically the relationship between the symptoms at disease onset and the subsequent disease course. The major finding of this study is the strong correlation between the onset with cerebellar (and less so psychiatric) symptoms and the more rapid development of akinetic mutism. It is worth recalling that there is no effective therapy for CJD at this time. Clinical trials for CJD are critically important, and if akinetic mutism will be used as an endpoint in these trials, then the factors that predict higher risk for the development of akinetic mutism will be important to understand. Additionally, for the practicing neurologist, it is helpful to know that patients who manifest with cerebellar symptoms are at higher risk for earlier development of this end-stage manifestation of CJD.