Rapidly Progressive Dementia and Prion Disease

By Valeriy Sabodash, MD

Because most dementias develop slowly, rapidly progressive dementia (RPD) present a unique challenge to neurologists. Even though there is no consensus on a duration of the clinical symptoms the majority of physicians consider any dementia with symptoms duration in less than 24 months to be rapidly progressive.

Based on data analysis from UCSF, Memory and Aging Center, the diagnostic breakdown of RPD has been 62% prion disease, 15% other neurodegenerative diseases, 8% autoimmune, 4% infectious, and 2% each psychiatric, cancer, toxic-metabolic, and vascular causes; 4% were of undetermined etiology. Some of these conditions are potentially treatable making establishing correct diagnosis critically important in the earliest stages of a disease.

Prion Disease or Jakob–Creutzfeldt disease is the most common form of RPD. The original description of the condition is attributed to Alfons Jakob, who noted that his five RPD cases were nearly identical to one described by Hans Creutzfeldt in 1920.

The most common form of human prion disease, sporadic CJD (sCJD), occurs spontaneously, and the cause remains unknown. Sporadic CJD accounts for about 85% of human prion disease cases. Genetic forms account for 10–15% and acquired cases account for less than 1%.

The reported median survival time of sCJD is about four months, the vast majority (85–90%) of patients die within a year of disease onset.

Combination of clinical symptoms such as rapidly progressive cognitive decline, abnormal body and limb movements, muscle jerks, visual, cerebellar dysfunction, weakness, stiffness, inability to speak with or without family history of similar symptoms and confirmatory laboratory tests as abnormal electroencephalography, cerebral spinal fluid analysis and MRI of the brain establishes clinical diagnosis of sCJD.

For many years, prion disease was mistakenly thought to be caused by “slow viruses.” In 1997, Stanley Prusiner received the Nobel Prize in Medicine and Physiology for his discovery that the prion protein is indeed the culprit.

In humans, the cellular form of the prion protein (PrPC) is encoded by the gene PRNP. In prion diseases, PrPC changes its conformation into an abnormally shaped, disease-causing form of PrP called the prion, or PrPSc (where Sc stands for scrapie, the prion disease in sheep and goats). The process by which PrPSc is made from PrPC is incompletely understood. It is likely that when PrPC comes into contact with PrPSc, the latter protein induces the former to take on its shape.

Sporadic fatal insomnia (SFI) is a rare form of prion disease that presents similarly to fatal familial insomnia. Symptoms for both conditions include insomnia, dysautonomia, and cerebellar ataxia.

Genetic prion diseases have been divided into three forms based on their clinical presentation: familial CJD (fCJD), Gerstmann–Sträussler– Scheinker disease (GSS) and fatal familial insomnia.

Clinically, fCJD typically presents either identically to sCJD, as rapidly progressive dementia with motor features, or it can present as a more slowly progressing dementia.

A typical presentation for GSS is either as a parkinsonian or an ataxic disease, progressing over the years, although a rare spastic form of GSS has also been reported. The mean age of onset is approximately 47 years, with average survival for about 57 months.

Fatal familial insomnia is similar to SFI with variable duration but usually lasts 1 to 2 years.

In 1995, a new form of human prion disease called variant CJD (vCJD) was identified in the UK and shortly after linked to the consumption of meat from cows with bovine spongiform encephalopathy. The clinical features of vCJD are similar to those of sCJD, with some exceptions. Patients with vCJD tend to be younger than patients with sCJD (mean age 28 years). Early in the illness, patients usually experience profound psychiatric symptoms, which commonly take the form of depression or schizophrenia-like psychosis. This psychiatric prodrome is often the only symptom before the onset of other neurological features. Patients frequently have painful paresthesia. Motor features typically include ataxia, muscle jerks, abnormal limb movements, and dystonia. Cognitive impairment is an early feature.

Several non-prion diseases can present as rapidly progressing dementia known as CJD mimics.

Atypical rapid forms of other neurodegenerative diseases often misdiagnosed as prion disease, particularly Alzheimer’s disease and atypical parkinsonian dementias, such as corticobasal degeneration and Lewy body dementia.

Paraneoplastic (related to neoplasm) and non-paraneo-plastic autoimmune conditions also can mimic CJD. Hashimoto’s encephalopathy is one of such diseases.

Some cancers can cause limbic encephalopathies such as small cell lung cancer, germ cell tumors (ovarian or testicular), thymoma, Hodgkin’s lymphoma, and breast cancer. Other diseases like intravascular and primary CNS lymphoma, gliomatosis cerebri, CNS vasculitis, ischemic and hemorrhagic strokes may clinically resemble CJD, although the MRI can differentiate these conditions.

Infections, such as subacute sclerosing panencephalitis from German measles or rubella, can look somewhat like CJD, particularly variant CJD (vCJD) in a young person. Lyme disease, Whipple’s disease, syphilis, and human immunodeficiency virus (HIV) should always be ruled out.

Toxins, such as bismuth, when taken in large quantities can cause a CJD-like clinical picture, with ataxia, myoclonus, and encephalopathy. Exposure to heavy metals, such as arsenic, mercury, aluminum, lithium, and lead, can lead to cognitive decline, particularly if the exposure is acute.

Thiamine deficiency causing Wernicke’s encephalopathy is readily treatable and should always be considered.

Quite often self-diagnosed “scrapie disease” is seen in the neurological clinic as a result of a somatoform and anxiety disorder.

Sometimes the diagnosis is quite challenging, and the tissue biopsy needed to be performed.

Negrosky Neurology
(941) 487-2160
5741 Bee Ridge Road, Suite 530
Sarasota, FL 34233
Located in the Sarasota Medical Centre next to Doctors Hospital of Sarasota (Corner of Bee Ridge Road and Cattlemen off of Maxfield Drive)