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:

 

Slow virus infection Host
Creutzfeldt-Jakob disease (CJD) Humans
Gerstmann-Straussler-Scheinker disease Humans
Fatal familial insomnia Humans
Kuru Humans
Scrapie Sheep, goats
Bovine spongiform encephalopathy Cattle, humans
Chronic wasting disease Mule deer, elk
Transmissible mink encephalopathy Mink
Feline spongiform encephalopathy Cats

 

 

Prion diseases are categorized into three groups: sporadic, inherited, and acquired. Most slow virus infections—approximately 85%—are sporadic. The remaining 15% consist of hereditary 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 incidence 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

Slow virus infection Onset Manifestations Laboratory findings
Creutzfeldt-Jakob disease
  Sporadic Usually age 50–70 Systemic, neuropsychiatric, or nonfocal
neurologic features (see below);
death within 12 months
Typical EEG changes (generalized periodic sharp wavecomplexes);
14-3-3 protein usually present in CSF
  Hereditary Earlier age More protracted course Typical EEG changes are missing; protein 14-3-3 absent in 50%
  New-variant Earlier age More prolonged course;
early psychiatric manifestations;
cerebellar ataxia, paresthesias,
dysesthesias
Variable EEG changes
  Gerstmann-Straussler-Scheinker disease Midlife onset (mean age at death = 48 yrs) Prolonged course (5–11 yrs)
Early: cerebellar
ataxiaLate: spastic paraparesis, limb ataxia, dysarthria, nystagmus, parkinsonism, 
deafness, blindness, gaze palsies, dementia, corticospinal
tract signs
No typical EEG changes
  Fatal familial insomnia Onset mid to late life Insomnia, dysautonomia, ataxia No typical EEG changes

 

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 MRI 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 neuron disease.130,135

Diagnosis becomes clearer with onset of cognitive 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:

  • memory loss (100%)
  • behavioral disturbance (57%)
  • other neuropsychiatric dysfunction (73%)
  • myoclonus (78%)
  • cerebellar ataxia (71%)
  • pyramidal signs (62%)
  • extrapyramidal signs (56%)
  • lower motor neuron signs (12%)
  • visual disturbances (42%)
  • periodic EEG complexes (60%)

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 slowing. 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

Generalized periodic complexes in a patient with Creutzfeldt-Jakob disease.
 

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.
Clinical characteristics of major human slow virus diseases Table 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; and DM Asher. Slow Viral Infections. In WM Scheld, RJ Whitley, DT Durack (eds), Infections of the Central Nervous System. Philadelphia: Lippincott–Raven, 1997;199–221.
Adapted from: Goldstein MA and Harden CL. Infectious states. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;83-133.
With permission from Elsevier (www.elsevier.com).

I<
Reviewed By: 
Steven C. Schachter, MD
on: 
Monday, March 1, 2004