Joseph G. Hentz

Defining mild cognitive impairment in Parkinson's disease

Our purpose was to characterize a state of mild cognitive impairment (MCI) in Parkinsons disease (PD) (PD‐MCI) that would be analogous to the MCI that is posited as a precursor of Alzheimers disease (AD). We categorized 86 PD subjects in a brain bank population as either cognitively normal (PD‐CogNL), PD‐MCI using criteria that included a 1.5 standard deviation or greater deficit upon neuropsychological testing consistently across at least one cognitive domain without dementia, and PD dementia (PD‐D) using DSM‐IV criteria. Twenty‐one percent of our PD sample met criteria for PD‐MCI, 62% were PD‐CogNL, and 17% had PD‐D. The mean duration of PD and MMSE scores of the PD‐MCI group were intermediate and significantly different from both PD‐CogNL and PD‐D. The cognitive domain most frequently abnormal in PD‐MCI was frontal/executive dysfunction followed by amnestic deficit. Single domain PD‐MCI was more common than PD‐MCI involving multiple domains. We conclude that a stage of clinical cognitive impairment in PD exists between PD‐CogNL and PD‐D, and it may be defined by applying criteria similar to the MCI that is posited as a precursor of AD. Defining PD‐MCI offers an opportunity for further study of cognitive impairment in PD and targets for earlier therapeutic intervention.

Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial

We have studied a three-drug combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) on a 28-day cycle in the treatment of newly diagnosed multiple myeloma (MM) patients to assess response and toxicity. The primary endpoint of response was evaluated after four cycles. Thirty-three newly diagnosed, symptomatic patients with MM received bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8 and 11, cyclophosphamide 300 mg/m2 orally on days 1, 8, 15 and 22 and dexamethasone 40 mg orally on days 1–4, 9–12 and 17–20 on a 28-day cycle for four cycles. Responses were rapid with a mean 80% decline in the sentinel monoclonal protein at the end of two cycles. The overall intent to treat response rate (⩾ partial response) was 88%, with 61% of very good partial response or better (⩾VGPR) and 39% of complete/near complete response (CR/nCR). For the 28 patients who completed all four cycles of therapy, the CR/nCR rate was 46% and VGPR rate was 71%. All patients undergoing stem cell harvest had a successful collection. Twenty-three patients underwent stem cell transplantation (SCT) and are evaluable through day 100 with CR/nCR documented in 70% and ⩾VGPR in 74%. In conclusion, CyBorD produces a rapid and profound response in patients with newly diagnosed MM with manageable toxicity.

Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease

We assessed the safety and efficacy of modafinil for the treatment of excessive daytime sleepiness in patients with Parkinsons disease (PD). This was a single‐site, randomized, double‐blind, placebo‐controlled crossover study of 21 PD patients having an Epworth Sleepiness Scale (ESS) score ≥10. They received either placebo or modafinil 200 mg/day for 3 weeks, followed by a washout week, then the alternate treatment for 3 weeks. The ESS data demonstrated a carryover effect, so the changes from baseline ESS scores were compared between the two treatments for period 1 only. The ESS scores for the placebo group went from 16.0 ± 4.2 (mean ± SD) to 17.0 ± 5.1 and for the modafinil group went from 17.8 ± 4.2 to 14.4 ± 5.7 (P = 0.039). There was no significant carryover effect for any other measure. The patient Clinical Global Impression of Change (+3 to −3) improved by 0.75 on modafinil compared with 0.15 for placebo (P = 0.07). A total of 7 of 20 (35%) of the patients reported some improvement on modafinil but not placebo. There was no significant improvement or worsening of the UPDRS subscores I–III, Timed Tap test, or time on. Vital signs, electrocardiograms, and lab tests were unchanged. Modafinil was very well tolerated. Our data demonstrate that, in a small sample size, administration of 200 mg/day of modafinil was associated with few side effects and was modestly effective for the treatment of excessive daytime sleepiness in patients with PD.

Occipital nerve stimulation for chronic headache - Long-term safety and efficacy

The aim of this study was to examine the safety and efficacy of occipital nerve stimulation for medically intractable headache. Electrical stimulation of large sensory afferents has an antinociceptive effect. Occipital nerve stimulation may be effective for the treatment of medically intractable headache. Retrospective analysis was performed of 15 patients with medically refractory headache who underwent implantation of an occipital nerve stimulator. Pre- and postimplant data regarding headache frequency, severity, disability, depression and post-stimulator complications were collected. Twelve patients were female and three male. Ages ranged from 21 to 52 years (mean 39 years). Eight patients had chronic migraine, three chronic cluster, two hemicrania continua and two had post-traumatic headache. Eight patients underwent bilateral and seven had unilateral lead placement. Patients were measured after 5-42 months (mean 19). All six mean headache measures improved significantly from baseline (P < 0.03). Headache frequency per 90 days improved by 25 days from a baseline of 89 days; headache severity (0-10) improved 2.4 points from a baseline of 7.1 points; MIDAS disability improved 70 points from a baseline of 179 points; HIT-6 scores improved 11 points from a baseline of 71 points; BDI-II improved eight points from a baseline of 20 points; and the mean subjective percent change in pain was 52%. Most patients (60%) required lead revision within 1 year. One patient required generator revision. Occipital nerve stimulation may be effective in some patients with intractable headache. Surgical revisions may be commonly required. Safety and efficacy results from prospective, randomized, sham-controlled studies in patients with medically refractory headache are needed.

Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele

Objective: To determine whether memory loss is detectable before the symptomatic presentation of mild cognitive impairment (MCI) in those at greater genetic risk for Alzheimer disease (AD) based upon presence or absence of the e4 allele of APOE. Methods: Participants were age 50 years or older who responded to newspaper advertisements. A total of 212 cognitively normal individuals of known APOE genotype were initially enrolled in a match paradigm that included e4 homozygotes, e3/4 heterozygotes, and e4 noncarriers in a 1:1:2 ratio (53 sets). Of the original 212 individually matched participants, 180 completed at least two epochs of testing including 45 APOE e4/4 homozygotes, 42 APOE e3/4 heterozygotes, and 93 APOE e4 noncarriers, mean age 60 (±6.2) years. Of these, four developed MCI or AD during the follow-up period and were excluded from analysis. Longitudinal neuropsychological study included two verbal (Auditory Verbal Learning Test [AVLT], Selective Reminding Test [SRT]) and two visual (Complex Figure Test [CFT], Visual Retention Test) memory tests. Results: Multiple measures on both verbal memory tests showed poorer performance over a mean interval of 33 months in e4 carriers than noncarriers: AVLT total learning, long term delayed recall; SRT free and cued recall. Among those age 50 to 59 years, AVLT long term delayed recall, SRT free and cued recall, and CFT recall declined more in APOE e4 carriers. No differences were found in the domains of language, spatial skills, or executive function. Conclusions: Memory declined in APOE e4 carriers before the symptomatic presentation of MCI in a cohort whose mean age was 60 years over a median period of 33 months. The decline began prior to age 60.

Pathologic findings in prospectively ascertained essential tremor subjects

Objective: To assess pathologic changes in prospectively characterized subjects with essential tremor (ET). Methods: Subjects enrolled in the Sun Health Research Institute Brain and Body Donation Program were examined annually by a movement disorders neurologist, and semiannually by a behavioral neurologist and neuropsychologist. Twenty-four subjects without a prior diagnosis of dementia or other major movement disorder met clinical criteria for ET and came to autopsy. Subjects with mild cognitive impairment (n = 3) were included. These subjects were compared with 21 controls. Brains were examined postmortem according to standardized protocols for assessment of age-related changes and specific pathologic conditions (e.g., Parkinson disease, Alzheimer disease). Results: Subjects had a mean age of 86.2 years and a mean duration of tremor of 11.1 years. Seven subjects had evidence for cerebellar pathology (Purkinje cell loss, cerebellar cortical sclerosis, and proliferation of Bergmann glia). Pigmented neurons were qualitatively depleted in the locus ceruleus in eight subjects and in the substantia nigra in five subjects. Of these, three had Lewy bodies, one subject had brainstem predominant disease, and two had limbic stage. Three subjects had a nonspecific cerebral tauopathy and another met pathologic criteria for progressive supranuclear palsy. However, when compared with controls, only changes in the locus ceruleus and gliosis of the cerebellum remained significant findings. Conclusions: This study supports previous findings of heterogenous pathology in essential tremor (ET). There is an increased frequency of cerebellar gliosis and locus ceruleus depletion. We did not find an increased incidence of Lewy bodies in subjects with ET. GLOSSARY: ET = essential tremor; LB = Lewy body; MCI = mild cognitive impairment; NA = not available; PD = Parkinson disease; PSP = progressive supranuclear palsy; SHRI = Sun Health Research Institute; SN = substantia nigra; WMR = white matter rarefaction.

Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma

To the editor: After observing high response rates in relapsed multiple myeloma (MM) patients,[1][1] we examined a 3-drug combination of bortezomib, cyclophosphamide, and dexamethasone (CyBorD) in newly diagnosed symptomatic patients. This phase 2 trial was open at Mayo Clinic Arizona and Princess

The Montreal Cognitive Assessment and the Mini-Mental State Examination as Screening Instruments for Cognitive Impairment: Item Analyses and Threshold Scores

Aims: To perform an item analysis of the Montreal Cognitive Assessment (MoCA) versus the Mini-Mental State Examination (MMSE) in the prediction of cognitive impairment, and to examine the characteristics of different MoCA threshold scores. Methods: 135 subjects enrolled in a longitudinal clinicopathologic study were administered the MoCA by a single physician and the MMSE by a trained research assistant. Subjects were classified as cognitively impaired or cognitively normal based on independent neuropsychological testing. Results: 89 subjects were found to be cognitively normal, and 46 cognitively impaired (20 with dementia, 26 with mild cognitive impairment). The MoCA was superior in both sensitivity and specificity to the MMSE, although not all MoCA tasks were of equal predictive value. A MoCA threshold score of 26 had a sensitivity of 98% and a specificity of 52% in this population. In a population with a 20% prevalence of cognitive impairment, a threshold of 24 was optimal (negative predictive value 96%, positive predictive value 47%). Conclusion: This analysis suggests the potential for creating an abbreviated MoCA. For screening in primary care, the MoCA threshold of 26 appears optimal. For testing in a memory disorders clinic, a lower threshold has better predictive value.

Carpal tunnel syndrome with normal nerve conduction studies

The utility of electrodiagnostic testing in the evaluation of carpal tunnel syndrome (CTS) has been questioned. We studied patients who met the clinical criteria for CTS and compared patients who had normal nerve conduction studies (NCS) with patients who had abnormal NCS. We found that 25% of the CTS patients without confounding neurologic disorders had normal NCS with median palmar nerve stimulation. Patients with abnormal NCS were older and heavier and had more clinical features of CTS. NCS results could not be predicted accurately from clinical features by use of logistic regression models. This was especially true in clinically borderline cases. NCS did not predict the outcome of conservative management. We concluded that NCS provide independent information in the evaluation of suspected CTS, especially when fewer clinical criteria are present, but that NCS are not helpful in predicting the outcome of nonsurgical management. Muscle Nerve 29: 515–522, 2004

Gambling and increased sexual desire with dopaminergic medications in restless legs syndrome

Objectives: Do patients with restless legs syndrome (RLS) report gambling or other abnormal behaviors as previously reported in Parkinson disease. Methods: This survey study was sent to 261 idiopathic RLS patients, and it included the Gambling Symptoms Assessment Scale, Altman Self-Rating Mania Scale, and questions pertaining to sexual activity and novelty-seeking behaviors. Results: Ninety-nine patients responded to the survey, and 77 were actively taking 1 or more dopaminergic medications. Of the 70 respondents who answered the gambling questions, 5 (7%) noted a change in gambling, with 4 (6%; 95% confidence interval, 2%-14%) stating that increased urges and time spent gambling occurred specifically after the use of dopaminergic medications (2 on pramipexole, 1 on ropinirole, and 1 on levodopa and pramipexole). Increased sexual desire was reported by 4 (5%) of the 77 respondents, 3 (4%; 95% confidence interval, 1%-11%) reported that this occurred specifically after the use of dopaminergic medications (1 on pramipexole, 1 on ropinirole, and 1 on levodopa). One patient reported both an increase in gambling and sexual habits. Conclusions: This exploratory survey study revealed the development of gambling and/or increased sexuality in patients with RLS. These data raise the possibility that, as in Parkinson disease, RLS patients should be cautioned about potential behaviors that may occur with the use of dopaminergic medications. Further prospective studies are needed to assess the relationship between these medications and compulsive behaviors associated with the treatment of RLS.