IF ALL ELSE FAILS . . .
Despite recent developments in neuroimaging techniques, accurate diagnosis of dementia is often difficult, and a definitive diagnosis before death can only be achieved by examining brain tissue obtained through biopsy. According to an article by Jason D. Warren, MD, of the Dementia Research Centre, Institute of Neurology, University College London, United Kingdom, and colleagues, brain biopsy should be considered in cases of dementia where a specific diagnosis cannot be made by standard noninvasive means.4
Brain biopsy may be especially useful in younger patients, in whom the likelihood of a reversible (usually inflammatory) process, such as isolated vasculitis of the CNS, is relatively high. "This disorder may present as insidious cognitive decline, and diagnosis remains notoriously difficult," the authors observe.
In a retrospective analysis of 90 consecutive cerebral biopsies undertaken for the investigation of dementia in adults referred to a tertiary center between 1989 and 2003, Warren and colleagues found that 57% of biopsies were diagnostic, with most (18%) of the patients having AD. Twelve percent of patients had Creutzfeldt-Jakob disease, and an inflammatory disorder was diagnosed in 9%.
In most cases, biopsy consisted of a right frontal full-thickness resection of cortex, white matter, and overlying leptomeninges, the investigators reported. Complications occurred in 11% of patients and included seizures, wound or intracranial infections, and intracranial hemorrhage, but there were no deaths or lasting neurological sequelae attributable to the procedure.
Information obtained at biopsy influenced treatment in only 11% of patients; however, performing a brain biopsy has other advantages, according to Warren and colleagues. It eliminates diagnostic uncertainty and facilitates informed counseling of the patient's family. Moreover, as disease-modifying therapies for neurodegenerative conditions, such as AD, become available, the value of brain biopsy in the management of dementia is likely to increase, the authors suggest.
Findings of a study presented at the 59th Annual Meeting of the American Academy of Neurology (AAN) in May in Boston also indicate that the potential benefits of brain biopsy outweigh the risks in patients with dementia who had received no clear diagnosis despite being thoroughly evaluated using less invasive means.7 Brain biopsy has a 25% to 33% chance of revealing a diagnosis in an unexplained encephalopathic illness, according to lead researcher Joseph D. Burns, MD, a clinical instructor of neurology at Tufts-New England Medical Center in Boston.
"Although these might not sound like very good odds, when one considers how sick these patients are and how many prior tests were not helpful, these numbers are quite good," Burns told Applied Neurology. "And the benefits [of brain biopsy] all come with a relatively low risk to the patient," he added.
To determine the value of brain biopsies in patients with atypical dementia, Burns and colleagues reviewed the charts of 42 consecutive patients who underwent nonstereotactic brain biopsy at the Lahey Clinic in Burlington, Massachusetts. All patients had indeterminate or normal imaging results, and most (79%) had been symptomatic for less than a year.
The researchers found that 12 (29%) of the 42 biopsies led to a specific diagnosis, while 15 (35.5%) of them yielded results that were normal and nonspecific anomalies were found in another 15 (35.5%). There were only 3 (7%) minor complications, and no deaths or major complications occurred as a result of the procedure.
Overall, 11 patients (26%) received meaningful benefit from the biopsy, 5 (12%) of whom had their treatment significantly altered, the investigators reported. According to Burns, these results imply that a brain biopsy should be strongly considered in patients in whom a diagnosis could not be accurately made despite having been thoroughly evaluated by less invasive means. "A biopsy may be needed to find an etiologic diagnosis because this will allow for a more accurate prognosis, avoidance of potentially toxic therapies for erroneous provisional diagnoses, and in the best case scenario, it will allow for the implementation of a specific treatment," said Burns.
As the above studies show, differential diagnosis, either by neuroimaging or biopsy, can help reveal the exact type and origin of dementia and may, in a significant number of patients, lead to successful treatment and a reversal of symptoms. But even when a cure is not possible, identification of the type and appropriate treatment of dementia can help delay, and perhaps even halt, cognitive decline, possibly because of the neuroprotective effects of such treatment.
This was the conclusion of Franz Fazekas, MD, of the Department of Neurology, Karl-Franzens University, Graz, Austria, and colleagues, who, in a recent study, found that patients with AD treated with memantine(Drug information on memantine) (Namenda) had a smaller loss of hippocampal volume during the study period than those treated with placebo.8 The research was aimed at demonstrating the feasibility and potential contribution of multimodal neuroimaging in the investigation of possible morphological and functional effects of drugs for treatment of AD. Clinical effects obtained in the study were consistent with previous results that found a smaller loss of hippocampal volume in patients treated with memantine, suggesting that this drug may have some neuroprotective effects.
"Our study is the first parallel evaluation of several imaging techniques to monitor the evolution of AD and the possible impact of memantine, under the assumption that it may be neuroprotective," Fazekas told Applied Neurology. He stressed, however, that this was a pilot study, "so the results are more interesting in terms of planning future studies for the evaluation of neuroprotective treatment in AD than for influencing current clinical practice."
Another study, which was presented at the AAN meeting, confirms the long-term efficacy of combination therapy with a cholinesterase inhibitor (ChEI) plus memantine for AD in a real-world setting.9 The research was conducted by a team of scientists led by Alizera Atri, MD, PhD, of the Memory Disorders Unit, Massachusetts General Hospital (MGH) in Boston.
Atri and colleagues analyzed longitudinal data from 521 patients with AD (mean age, 74.6) who underwent serial clinical evaluations at the MGH Memory Disorders Unit. A group of 117 patients had been treated with memantine plus a ChEI, while 404 patients were either untreated or had been treated with a ChEI only. An analysis of changes in various indexes of AD severity during a mean follow-up of 30 months showed that patients receiving memantine and a ChEI experienced significantly less annual deterioration in cognitive abilities than did those in the groups who received only a ChEI or were untreated.
These results provide strong support for combination therapy with memantine and a ChEI, showing significant long-term clinical benefits in real-world patients with AD, Atri told Applied Neurology. "In this large, well-characterized, and prospectively assessed cohort of patients with AD, who received clinical care at our memory disorders unit, the benefits of such combined therapy were significant, with small to medium effect sizes that were sustained for years," he said. "The results also raise the intriguing possibility that combined therapy with memantine and a [ChEI] may actually modestly modify the long-term clinical course of AD."