Neurology Advisor
Michael O'Leary
With that, the definition of dementia has broadened over time from a focus on memory loss to a focus on impairment in one or more cognitive domains — particularly memory, language, frontal executive function, organizing, planning, and multitasking — that is severe enough to interfere with a person's daily function.1
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Typically, chronic degenerative dementias are characterized by damage or wasting away of brain tissue usually progressing over seven to 10 years. These include Alzheimer's disease, frontal lobe dementia, and Pick's disease. Dementias associated with progression of other diseases or conditions include Huntington's disease, Lewy body dementia, and other parkinsonian dementias, such as corticobasal degeneration.
Michael Geschwind, MD, PhD, associate professor of neurology at the Memory and Aging Center at the University of California, San Francisco said that although there is no defined time frame for rapidly progressing dementias (RPDs), he uses the term to describe patients that go from normal cognition to dementia within a year or less. However, he has seen some patients with Creutzfeldt-Jakob Disease (CJD) take as long as two years to develop dementia.
Although there can be overlap with some typical degenerative dementias presenting in a rapid fashion, in general, patients who may have an RPD need clinicians to consider a different set of disorders, because these conditions can be both treatable and quickly fatal in some cases, Geschwind explained.
RPDs include prion diseases such as CJD, autoimmune dementias, paraneoplastic conditions, infections that can mimic prion diseases, and fungal infections as well as some viral and toxic metabolic conditions, such as Wernicke's encephalopathy (a condition that stems from thiamine deficiency often due to malnutrition) and even conditions stemming from complications from an overdose of Pepto-Bismol.
In a 2007 monograph on RPD published in Neurology Clinic, Geschwind's team observed that 15% to 20% of the 825 patients referred to UCSF with rapidly progressing dementia presumed to be CJD turned out to have other non-prion conditions.2 One explanation is that the WHO criteria for CJD are designed for epidemiologic purposes and aren't useful for making a clinical diagnosis.
“What I mean by that is the criteria are designed to ascertain the prevalence CJD within a population,” Geschwind said. “Epidemiologic surveillance for CJD looks at [cases proven at autopsy], but a lot of cases never make it to autopsy. [Researchers] want to have criteria so they can say with a high degree of certainty in a patient who didn't have an autopsy how likely it was that they had CJD.”
As a result, those criteria are not very sensitive. In the era of treatment trial, clinicians need criteria that can be used to diagnose patients while they are still alive.
A Challenging Diagnosis
In terms of sensitivity, the diagnosis of RPDs continues to evolve. In one case report, six patients were shown to have rare rapidly progressing fatal prion dementia with prominent degeneration in the thalamus that may or may not be a completely new prionopathy. It was not found with standard tests for human prion diseases. They showed that an additional test called conformation-dependent immunoassay (CDI) might be needed when prion disease is suspected but not found with standard tests.3
Because some RPDs can be reversed with early treatment, Geschwind has been advocating for an efficient differential diagnostic algorithm based on the acronym VITAMIN, which is short for Vascular, Inflammatory (infectious and noninfectious), Trauma/Toxins, Autoimmune, Metabolic, Idiopathic, and Neoplastic.
“Many [RPDs] are treatable if diagnosed early enough, which is why I got into this field," said Geschwind. "The ones that aren't treatable are neurodegenerative, and if the toxic metabolic ones are diagnosed too late, those also might not be treatable.”
Steven Vernino, MD, professor of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas, specializes in autoimmune encephalopathies. As a referral center, he said they see a fair number of treatable autoimmune RPDs each year. These include anti-N-methyl D-aspartate (anti-NMDA) receptor antibody encephalitis, paraneoplastic limbic encephalitis (PLE), and autoimmune limbic encephalitis associated with potassium channel-related antibodies, such as leucine-rich, glioma-inactivated 1 (LGI-1) antibody.
Vernino said anti-NMDA disorder was only recognized in the last 10 years, so the incidence is unknown. According to the Encephalitis Society, it is associated with prominent psychiatric symptoms at onset including anxiety, mania, social withdrawal, and psychosis.4 It has been seen in young children, women, and older adults, presenting as either encephalopathy and dementia or seizures.
PLE is a rapidly progressing dementia in cancer patients caused by autoimmune attack on the brain. Most individuals with PLE will turn out to have a rarely seen cancer of the lung, thymus gland, breast, or testes.
Voltage-gated potassium channel-complex antibody-associated limbic encephalitis (VGKC-LE) affects men at roughly twice the rate of women. Initially, family members notice that their relative becomes forgetful, drowsy, and withdrawn. Patients can also develop mood disorders (like depression) or bizarre thoughts and behaviors.5
“If a patient presents with what we think might be an autoimmune encephalopathy because of the tempo and other features,” Vernino said, “then we typically order a panel of antibodies that would include paraneoplastic antibodies, anti-NMDA antibodies, and potassium channel-related antibodies. If all [those] come back negative, it is hard to be sure about the diagnosis."
Those are the most challenging to diagnose, he said, because they are all potentially treatable, especially the anti-NMDA receptor encephalitis and the potassium channel antibody-related encephalitis.
“Patients can do quite well, but sometimes you have to be pretty aggressive in terms of the immune treatments, which is challenging without a diagnostic test that confirms the diagnosis,” Vernino said.
“This is an evolving field, however, and there is a lot of excitement in the autoimmune world about finding better diagnostic tests and perhaps [identifying more treatable] patients than we know about now, which is always a good thing.”
Michael O'Leary is a freelance medical writer based in the greater Seattle Area. This article was medically reviewed by Pat F. Bass III, MD, MS, MPH
References
- Encyclopedia of Mental Disorders. http://www.minddisorders.com/Del-Fi/Dementia.html
- Geschwind MD, Haman A, Miller BL. Rapidly progressive dementia. Neurol Clin. 2007;25(3):783-807.
- Kovacs GG, Peden A, Weis S et al. Rapidly progressive dementia with thalamic degeneration and peculiar cortical prion protein immunoreactivity, but absence of proteinase K resistant PrP: a new disease entity?Acta Neuropathol Commun. 2013;1(1):72.
- Irani SR, Vincent A. The Encephalitis Society. “NMDA Receptor Associated Encephalitis.” April 2010/ February 2014. Available at: http://www.encephalitis.info/information/types-of-encephalitis/types-of-autoimmune-encephalitis/nmda-receptor-associated-encephalitis/
- Miller T. The Encephalitis Society. “Voltage-gated Potassium Channel-complex Antibody-associated Limbic Encephalitis' (VGKC-LE).” May 2014. Available at: http://www.encephalitis.info/information/types-of-encephalitis/types-of-autoimmune-encephalitis/voltage-gated-potassium-channel-complex-antibody-associated-limbic-encephalitis/
All electronic documents accessed Nov. 10, 2014.
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