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Dextromethorphan (DM)/quinidine (Q) is an approved treatment for pseudobulbar affect (PBA) based on trials in amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness and tolerability for PBA secondary to dementia, stroke, or traumatic brain injury; dementia cohort results are reported.
This was an open-label, multicenter, 90 day trial; patients received DM/Q 20/10 mg twice daily. Primary outcome was change in Center for Neurologic Study–Lability Scale (CNS-LS) score. Secondary outcomes included PBA episode count and Clinical and Patient/Caregiver Global Impression of Change scores with respect to PBA (CGI-C/PGI-C).
134 patients were treated. CNS-LS improved by a mean (SD) of 7.2 (6.0) points at Day 90/Endpoint (P<.001) vs. baseline. PBA episodes were reduced 67.7% (P<.001) vs. baseline; global measures showed 77.5% CGI-C and 76.5% PGI-C “much”/”very much” improved. Adverse events included headache (7.5%), urinary tract infection (4.5%), and diarrhea (3.7%); few patients dropped out for adverse events (10.4%).
DM/Q significantly reduced PBA symptoms in patients with dementia; reported adverse events were consistent with the known safety profile of DM/Q.
Excellent treatment for Alzheimer's disease remains an unmet medical need. Although current therapies improve patients' abilities compared to placebo and temporarily maintain performance above baseline on a number of outcome measures, additional therapies are needed to augment the benefits over baseline and to prolong these improvements.
Today’s therapies must be put in the context of both currently available treatments as well as treatment trials with exciting potential for use in the near future. Current clinical trial methodologies do not allow for clear separation of symptomatic treatments from disease-modifying therapies; it may be unproductive to maintain this distinction given the current range of treatments available. A more currently relevant focus is added value. Therapies should aim to provide added value through incremental benefits above and beyond existing treatments, as well as enduring benefits.
Alzheimer’s disease (AD) treatment guidelines are not used by physicians only. Healthcare payers often make use of these guidelines to delimit coverage. Cost concerns will also impact AD treatments after generic cholinesterase inhibitors are made available; it is widely believed that a great number of patients will switch to generics. Therefore, treatment guidelines must account for the possible adverse effects of switching therapies as well as the desirability of persistent treatment. There are many AD treatment guidelines, among them the American Academy of Neurology (AAN) Management of Dementia Guidelines, which are currently being revised. The Institute for the Study on Aging (ISOA) Management of Alzheimer’s Disease in Managed Care Guideline also presents a different approach for a different audience.
The first step to creating evidence-based best practices guidelines is to determine what is meant by “evidence.” A system of classification exists for examining forms of evidence: Class I evidence is provided by one or more well-designed, randomized, controlled clinical trials, including overviews or meta-analyses of such trials. Class II evidence is provided by well-designed observational studies with concurrent controls; for example, case-control studies that generate hypotheses about epidemiologic associations. Class III evidence is provided by expert opinion, case series, case reports, and studies with historical controls.
This chapter presents a case study of a 60-year-old man who had complained of stumbling for 2 years without dizziness or stiffness of the legs. There is an impression of mild dementia on neuro-cognitive examination with obvious slowness of mental processing. Neurological examination of the upper body and head is unremarkable. His feet are high-arched, and power in the flexor and extensor muscles of the feet is diminished to grade MRC 4 on the left side and grade MRC 3 on the right side with an inverse position of the right foot. Taking the information from history, neurological, and neuro-cognitive examination together, the chapter concludes that the old man suffers from cognitive impairments in combination with a bi-pyramidal syndrome with poly-neuropathy and urine incontinence. It appears that the cognitive impairment leads to a presenile form of dementia, characterized not only by memory deficits but also by mental slowness and dysfunction.
The incidence of clinically apparent asymmetric
profiles of neuropsychological deficits in Alzheimer's
disease (AD) patients similar to those reported in the
PET literature is currently unclear. This study investigated
lateral neuropsychological asymmetry using principal component
factor analysis in a sample of 153 patients diagnosed with
probable AD. Using factor scores, patients were classified
into groups exhibiting asymmetric or symmetric profiles
of neuropsychological deficits. In the analysis of lateral
asymmetry, 27.5% of patients were classified as asymmetric
(10% verbally and 17% visuospatially). Consistent with
reports of continued asymmetry beyond the mild dementia
stage, asymmetry was exhibited in the mild, moderate, and
severely demented groups. These findings of neuropsychological
asymmetry across stages of dementia are consistent with
the picture of significant neuropsychological heterogeneity
in AD that has been emerging in the decade. (JINS,
1997, 3, 420–427.)
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