Monthly Archives: April 2010

Dutch study- 152 PSP cases (20%=frontal presentation)

Date
Posted by

This 2007 article is really about the 20% of the 152 patients studied with clinical diagnoses of PSP who had “predominant behavioral and cognitive presentation, often resulting in an incorrect initial diagnosis of dementia. Patients with this presentation were younger at onset, but did not differ in their disease progression into typical PSP.” These patients are described as having a “frontal presentation.” “Why patients with PSP with frontal presentation have an earlier age at onset is unclear. Future studies are needed to confirm our observations and additional data on educational level may clarify this issue.” The most common initial misdiagnosis was FTD, which makes sense given the younger age at onset.

These are the most interesting findings that relate to all 152 patients in the study (not just the 20% with a “frontal presentation”):

* Old age at onset (greater than 72 years), “the early presence of supranuclear gaze palsy, urge incontinence, dysphagia, as well as cognitive decline and falls were all associated with a reduced survival.”

* “The observed worse performance in the verbal fluency …emphasizes the importance of this sign, which may differentiate PSP from multiple system atrophy and PD.”

* “Two recent studies showed that the severity of frontal atrophy in patients with PSP correlated with the degree of executive dysfunction in patients with PSP.”

* “Another interesting finding is the correlation between the FAB and UPDRS scores in our study. This is in line with an observed association between behavioral changes and increased motor disability in one study, and between decline in FAB scores and increased midbrain atrophy in another study. It suggests that in PSP behavioral and cognitive changes occur in parallel with motor impairment.”

[Robin’s notes: FAB = Frontal Assessment Battery. I believe this short exam was designed by a French expert on PSP, Dr. Bruno Dubois along with others, including Dr. Irene Litvan, a US expert on PSP. UPDRS = Unified Parkinson’s Disease Rating Scale]

* “A correct initial diagnosis of PSP found in only 26% of the present cohort is similar to that found in other studies, which may largely be explained by the absence of supranuclear gaze palsy in the initial phase. It has frequently led to the misdiagnosis of dementia in patients with neuropsychiatric features and to the misdiagnosis of PD in patients with bradykinesia and rigidity. … Our observations support the findings of Osaki et al. that the inclusion of frontal lobe signs and personality changes into diagnostic criteria may improve the positive predictive value of PSP.”

Here’s the abstract of the article:

Neurology. 2007 Aug 21;69(Eight):723-9.

Frontal presentation in progressive supranuclear palsy.

Kaat LD, Boon AJ, Kamphorst W, Ravid R, Duivenvoorden HJ, van Swieten JC.
Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive hypokinetic rigid disorder with supranuclear gaze palsy and frequent falls. Although clinical consensus criteria are available, an atypical presentation may lead to clinical misdiagnosis in the initial phase. In the present study we investigated the clinical presentation of PSP and its relationship to initial clinical diagnosis and survival.

METHODS: We ascertained patients with PSP in a prospective cohort by nationwide referral from neurologists and nursing home physicians. All patients underwent a structural interview and clinical examination before entering the study. Medical records were reviewed for the presence of symptoms during the first 2 years.

RESULTS: A total of 152 patients ascertained between 2002 and 2005 fulfilled the international consensus criteria for PSP. Categorical principal component analysis of clinical symptoms within the first 2 years showed apart from a cluster of typical PSP symptoms, the clustering of cognitive dysfunction and behavioral changes. Further analysis showed that 20% of patients had a predominant frontal presentation with less than two other PSP symptoms. Survival analysis showed that this subgroup had a similar prognosis to that of the total group of patients with PSP.

CONCLUSIONS: There exists a subgroup of patients with progressive supranuclear palsy (PSP) with a predominant frontal presentation, who progressed into typical PSP over the course of the disease.

PubMed ID#: 17709703 (see pubmed.gov for the abstract)

Survival time similar with FTD but shorter than AD (UCSF)

Date
Posted by

In contrast to the 2010 Dutch study that says those with PSP progress faster than those with FTD, this UCSF study shows that they are about the same.

There’s not much in the UCSF article about PSP and CBD. The article’s focus is on frontotemporal lobar degeneration (FTLD), which is an umbrella term for three separate clinical syndromes — FTD (frontotemporal dementia), semantic dementia (SD), and progressive aphasia (PA). The authors compare the progression and survival time of the three FTD subtypes with AD and CBD/PSP. (Because of the smaller number of CBD and PSP participants, they were combined into one group.) According to this study, FTD progresses faster than AD and about the same as CBD/PSP.

Most interesting to me was the Discussion section of the article. The authors suggest that those disorders where frontal and subcortical areas are affected — FTD and CBD/PSP — have shorter survival than those disorders where the temporal lobe is more affected — AD and SD. “Frontal lobe disease might hasten mortality more than temporal degeneration either because its attendant apathy contributes to the akinetic–mute state that is a common final pathway to death in neurodegenerative disease or because behavioral problems associated with frontal lobe disease lead to overmedication or other differences in the quality of medical care delivered.”

Finally, the authors’ statements with regard to FTD certainly about to PSP and CBD: An “accurate understanding of the natural history of FTLD is important for patient care and counseling about prognosis.” And, “this research has implications for future clinical studies; for example, longitudinal therapeutic trials must consider the more rapid course of FTD, possibly following patients at shorter intervals.”

I’ve copied the abstract below.

Robin

Neurology 2005;65:719-725

Frontotemporal dementia progresses to death faster than Alzheimer disease

E. D. Roberson, MD, PhD, J. H. Hesse, BA, K. D. Rose, BA, H. Slama, BA, J. K. Johnson, PhD, K. Yaffe, MD, M. S. Forman, MD, PhD, C. A. Miller, MD, J. Q. Trojanowski, MD, PhD, J. H. Kramer, PsyD and B. L. Miller, MD

From the Memory and Aging Center and Department of Neurology (Drs. Roberson, Johnson, Yaffe, Kramer, and B.L. Miller, J.H. Hesse, K.D. Rose, and H. Slama), Gladstone Institute of Neurological Disease (Dr. Roberson), and Department of Psychiatry and Epidemiology (Dr. Yaffe), University of California, San Francisco; Center for Neurodegenerative Disease Research (Drs. Forman and Trojanowski), Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia; and Department of Pathology (Dr. C.A. Miller), Keck School of Medicine, University of Southern California, Los Angeles.

Background: Frontotemporal lobar degeneration (FTLD) is a common cause of non-Alzheimer dementia, but its natural history and the factors related to mortality in affected patients are not well understood.

Methods: This retrospective, longitudinal study compared survival in FTLD (n = 177) with Alzheimer disease (AD; n = 395). Hazards analysis investigated the contribution of various demographic, neuropsychiatric, and neuropsychological variables and associated neurologic and neuropathologic findings.

Results: The frontotemporal dementia (FTD) subtype of FTLD progressed faster than AD (median survival from retrospectively determined symptom onset, 8.7 ± 1.2 vs 11.8 ± 0.6 years, p < 0.0001; median survival from initial clinic presentation, 3.0 ± 0.5 vs 5.7 ± 0.1 years, p < 0.0001). Survival was similarly reduced in the related conditions corticobasal degeneration and progressive supranuclear palsy. Survival in the semantic dementia subtype of FTLD (11.9 ± 0.2 years from onset and 5.3 ± 0.4 years from presentation), however, was significantly longer than in FTD and did not differ from AD. Hazards analysis to determine factors affecting survival in FTLD showed no effect of age at onset, sex, education, family history, or neuropsychiatric profile. Among neuropsychological measures examined, impaired letter fluency had a significant association with reduced survival. Associated ALS significantly reduced survival in FTLD. The presence of tau-positive inclusions was associated with the slowest progression.

Conclusions: Frontotemporal lobar degeneration progresses more rapidly than Alzheimer disease, and the fastest-progressing cases are those with the frontotemporal dementia clinical subtype, coexisting motor neuron disease, or tau-negative neuropathology.

PubMed ID#: 16157905 (see pubmed.gov for this abstract)

Survival time is shorter in PSP than FTD (Dutch study)

Date
Posted by

This very interesting Dutch study compares survival times in 197 PSP patients and 354 FTD patients. Of the 197 PSP patients, 121 were classified as Richardson Syndrome (RS), 7 as PSP-parkinsonism (PSP-P), and the remainder could not be subdivided into a phenotype.

I believe the researchers attempted to limit the FTD causes to those with tau-positive pathology including Pick disease and FTDP-17.

A low percentage of patients participated in brain donation. During the follow-up phase, 133 patients died. Only 24 of them donated brain tissue. All of the PSP patients who died had the RS (Richardson Syndrome) type of PSP. Reading between the lines, it seems that the diagnostic accuracy was over 83%, which is similar to previous studies. If dementia was present, the diagnostic accuracy was over 96%. (The diagnostic accuracy of PSP-P is much lower — in the mid-40s.)

The researchers found that:

* “median survival of PSP patients (8.0 years) was significantly shorter than that of FTD patients (9.9 years).”

* “In PSP, male gender, older onset-age and higher PSP Rating Scale score were identified as independent predictors for shorter survival, whereas in FTD a positive family history and an older onset-age were associated with a poor prognosis.” Older onset age is greater than 72 years.

* “Comparing PSP phenotypes, RS (6.8 years) was found to have a shorter median survival than PSP-P (10.9 years) and the non-conclusive group (8.8 years).”

* The mean “interval between onset and ascertainment [ie, diagnosis]” of PSP was 5.3 years.

* “This study replicates, for the first time, the prognostic value of the PSPRS [PSP Rating Scale] with a sharp increase in probability of death above a score of 60. … Only the subsections supranuclear ocular motor exam, bulbar exam and gait exam were of prognostic value in our study. The replication of Golbe’s findings on the PSPRS has implications for its potential use in clinical trials.”

I’ve copied the abstract below.

Robin

Journal of Neurology, Neurosurgery, & Psychiatry. 2010 Apr;81(4):441-5.

Survival in progressive supranuclear palsy and frontotemporal dementia.

Chiu WZ, Kaat LD, Seelaar H, Rosso SM, Boon AJ, Kamphorst W, van Swieten JC.
Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Objective
To compare survival and to identify prognostic predictors for progressive supranuclear palsy and frontotemporal dementia.

Background
Progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) are related disorders. Homozygosity for H1 haplotype is associated with PSP, whereas several MAPT mutations have been identified in FTLD-tau. Survival duration probably reflects underlying pathophysiology or disease.

Methods
Patients with PSP and FTD were recruited by nationwide referral. Survival of 354 FTD patients was compared with that of 197 PSP patients. Cox regression analysis was performed to identify prognostic predictors.

FTLD-tau was defined as Pick disease and FTDP-17 with MAPT mutations. Semiquantitative evaluation of tau-positive pathology was performed on all pathologically proven cases.

Results
The median survival of PSP patients (8.0 years; 95% CI 7.3 to 8.7) was significantly shorter than that of FTD patients (9.9 years; 95% CI 9.2 to 10.6). Corrected for demographic differences, PSP patients were still significantly more at risk of dying than FTD patients.

In PSP, male gender, older onset-age and higher PSP Rating Scale score were identified as independent predictors for shorter survival, whereas in FTD a positive family history and an older onset-age were associated with a poor prognosis.

The difference in hazard rate was even more pronounced when comparing pathologically proven cases of PSP with FTLD-tau.

Conclusion
Survival of PSP patients is shorter than that of FTD patients, and probably reflects a more aggressive disease process in PSP.

Independent predictors of shorter survival in PSP were male gender, older onset-age and higher PSP rating scale score, whereas in FTD a positive family history and higher onset-age were predictors for worse prognosis.

PubMed ID#: 20360166 (see pubmed.gov for this abstract)

FDA Looking Into Stalevo and Possible Increased Cancer Risk

Date
Posted by

This post will only be of interest to those taking Stalevo, a combo drug that includes carbidopa/levodopa and entacapone (Comtan). I imagine only a handful of you are dealing with this medication.

The FDA issued notice today about a possible increased risk of prostate cancer with Stalevo.

The FDA’s MedWatch alert is here:
http://www.fda.gov/Drugs/DrugSafety/Pos … 206363.htm

Medscape’s article is here:
http://www.medscape.com/viewarticle/719599

The Medscape article is copied below.

From Medscape Medical News
FDA Reviewing Data on Possible Increased Prostate Cancer Risk With Stalevo in PD
Susan Jeffrey

April 1, 2010 ­ The US Food and Drug Administration (FDA) today notified healthcare professionals that the agency is evaluating data from a clinical trial indicating that patients with Parkinson’s disease (PD) receiving treatment with a combination of entacapone, carbidopa, and levodopa (Stalevo, Novartis) may be at increased risk for prostate cancer.

The trial, called Stavelo Reduction in Dyskinesia Evaluation – Parkinson’s Disease (STRIDE-PD), is a randomized comparison of entacapone/carbidopa/levodopa vs carbidopa/levodopa (Sinemet) in patients with PD.

“At this time, FDA’s review of Stalevo is ongoing and no new conclusions or recommendations about the use of this drug have been made,” the MedWatch alert cautions. Healthcare professionals should be aware of this possible risk, they add, and follow current guidelines for prostate cancer screening.

STRIDE-PD

The STRIDE-PD trial was a double-blind, randomized, parallel group, controlled clinical trial conducted at 77 centers in 14 countries, including the United States, the release notes. The primary endpoint was time to onset of dyskinesia in PD patients between treatment groups. A total of 745 PD patients were enrolled, and 541 completed treatment, 265 receiving entacapone/levodopa/carbidopa and 276 receiving carbidopa/levodopa only.

Mean treatment duration was 2.7 years, ranging up to 4 years. The average age of patients was approximately 60 years, the age at which prostate cancer is most commonly diagnosed, the alert points out; most were white (95.2%) and male (62.7%).

“An unexpected finding in the trial was that a greater number of patients taking Stalevo were observed to have prostate cancer compared to those taking carbidopa/levodopa,” the alert notes.

Specifically, 9 of 245 men (3.7%; 95% confidence interval [CI], 1.69% – 6.86%) had prostate cancer in the entacapone/levodopa/carbidopa group vs 2 of 222 men (0.9%) in the carbidopa/levodopa group, for an incidence rate of 14 cases per 1,000 with entacapone/levodopa/carbidopa compared with 3.2 cases per 1,000 with carbidopa/levodopa.

The odds ratio for the occurrence of prostate cancer in men taking entacapone/levodopa/carbidopa was 4.19 (95% CI, 0.90 – 19.63) vs carbidopa/levodopa.

Duration of entacapone/levodopa/carbidopa therapy before a diagnosis of prostate cancer ranged from 148 to 949 days, with a mean of 664 days. Previous trials of this entacapone/levodopa/carbidopa therapy did not indicate any such increased risk for prostate cancer, but most of these trials were conducted for less than a year, the alert points out.

The additional drug in this combination, entacapone, is also sold as a single-ingredient product (Comtan), also used to treat PD symptoms, and likewise has not been previously associated with an increased risk for prostate cancer.

“The agency is exploring additional ways to better understand if Stalevo actually increases the risk of prostate cancer,” they write. “This communication is in keeping with FDA’s commitment to inform the public about its ongoing safety review of drugs. The agency will update the public as soon as this review is complete.”

Authors and Disclosures
Journalist Susan Jeffrey
Susan Jeffrey is the news editor for Medscape Neurology & Neurosurgery. Susan has been writing principally for physician audiences for nearly 20 years. Most recently, she was news editor for thekidney.org and also wrote for theheart.org; both of these Web sites have been acquired by WebMD. Prior to that, she spent 10 years covering neurology topics for a Canadian newspaper for physicians. She can be contacted at SJeffrey AT webmd.net.