Slow virus infections
Slow virus infections are also known as prion diseases, after the presumed infectious agent, as well as transmissible spongiform encephalopathies (TSEs), after the histopathologic changes associated with these infections.
Prions are proteinaceous infectious particles (PrPs). The brain pathology of prion diseases consists of a vacuolar (spongiform) degeneration of the neuropil, cortical neurons, and subcortical gray matter with neuronal loss and gliosis. Early diagnosis is difficult, in part because prions do not have nucleic acids, making conventional nucleic acid–based viral detection systems ineffective. PrPs also elude detection by not producing a humoral immune response.130,131
Types of slow virus infections
These are the major prion diseases:
Prion diseases are categorized into three groups: sporadic, inherited, and acquired. Most slow virus infections—approximately 85%—are sporadic. The remaining 15% consist of forms (hereditary Creutzfeldt-Jakob disease [CJD], Gerstmann-Straussler-Scheinker disease, fatal familial insomnia) and acquired forms. Acquired forms may be transmitted iatrogenically (through human growth hormone therapy, dura mater grafts, or other neurosurgical procedures) or through cannibalism (kuru).
Inherited prion diseases have an annual of approximately 1 per 10 million in the general population.131 They are associated with coding mutations in the prion protein gene, located on the short arm of chromosome 20. Analysis of these more than 20 mutations has broadened the recognized phenotypes of human prion disease. Pathogenic prion protein gene mutations do not occur with sporadic and acquired prion diseases. Genetic susceptibility to prion disease is conferred by homozygosity of a PrP polymorphism at residue 129, an encoding site for methionine or valine.
Clinical characteristics of major human slow virus diseases
Epidemiology and diagnosis of CJD
CJD is the most common human slow virus infection. A new variant of sporadic CJD, probably caused by the same agent as bovine spongiform encephalopathy, was described in 1996.131
Variability in CJD diagnostic criteria relying solely on clinical manifestations has led to different incidence rates in different series.132 Sporadic CJD has an annual incidence of approximately 1 per 1 million in the general population and occurs randomly worldwide.131
The introduction of 14-3-3 CSF protein Western blot immunodetection greatly improved diagnostic accuracy (sensitivity up to 99% and specificity up to 96%).133 The recognition of characteristic abnormalities on diffusion-weighted imaging (cortical “rib- boning”) has further facilitated CJD diagnosis.134
Sporadic CJD is most often diagnosed in patients aged 50 to 70 years. About one-third of patients initially have systemic complaints, consisting of fatigue, disordered sleep, or decreased appetite. Another one-third have nonfocal neuropsychiatric features at onset (e.g., confusion or atypical behaviors). The remainder can present with focal neurologic features, including ataxia, visual loss, aphasia, hemiparesis, or focal amyotrophy, sometimes leading to an erroneous initial impression of stroke or motor disease.130,135
Diagnosis becomes clearer with onset of decline and startle myoclonus to abrupt sound or touch. Pyramidal, extrapyramidal, and cerebellar signs eventually occur in the majority of patients.130,135 In one study,135 the incidence of various neurologic features of sporadic CJD was:
Seizures occur in fewer than 20% of patients with CJD and were reported to occur in as few as 9% in one series of 124 CJD patients.13 They are even less common in other slow virus infections.
Slow virus infections like CJD can have characteristic EEG changes. Early in the course of sporadic CJD, the EEG may show nonspecific . Later, periodic, biphasic, or triphasic synchronous sharp-wave complexes are superimposed on a slow background rhythm in most patients. These characteristic complexes may disappear as myoclonus subsides in the terminal phase of the disease. Periodic complexes have shown a 67% sensitivity and 86% specificity for CJD detection. If repeated recordings are obtained, more than 90% of patients may show periodic complexes. Generalized periodic sharp- wave complexes (see figure) appear on EEG in more than 90% of cases, usually within 12 weeks of onset.130–132
With typical presentation, rapid course, an EEG showing periodic complexes, and the presence of 14-3-3 protein in CSF, CJD diagnosis is reasonably assured. CJD is uniformly fatal, with progression to death within 12 months.137
Management is supportive; there is no cure. Any seizure complications are treated routinely.
Types of slow virus infections adapted from B Jubelt, S Ropka. Infectious Diseases of the Nervous System. In R Rosenberg (ed), Atlas of Clinical Neurology. Boston: Butterworth–Heinemann, 1998;44–46.
Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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