Neurology February 2009 Volume 72 Issue 6

Background: The myotonic dystrophies (DM1, DM2) are the most common adult muscle diseases and are characterized by multisystem involvement. DM1 has been described in diverse populations, whereas DM2 seems to occur primarily in European Caucasians. Both are caused by the expression of expanded microsatellite repeats. In DM1, there is a reservoir of premutation alleles; however, there have been no reported premutation alleles for DM2. The (CCTG)DM2 expansion is part of a complex polymorphic repeat tract of the form (TG)n(TCTG)n(CCTG)n(NCTG)n(CCTG)n. Expansions are as large as 40 kb, with the expanded (CCTG)n motif uninterrupted. Reported normal alleles have up to (CCTG)26 with one or more interruptions.Methods: To identify and characterize potential DM2 premutation alleles, we cloned and sequenced 43 alleles from 23 individuals. Uninterrupted alleles were identified, and their instability was confirmed by small-pool PCR. We determined the genotype of a nearby single nucleotide polymorphism (rs1871922) known to be in linkage disequilibrium with the DM2 mutation.Results: We identified three classes of large non-DM2 repeat alleles: 1) up to (CCTG)24 with two interruptions, 2) up to (CCTG)32 with up to four interruptions, and 3) uninterrupted (CCTG)22-33. Large non-DM2 alleles were more common in African Americans than in European Caucasians. Uninterrupted alleles were significantly more unstable than interrupted alleles (p = 10-4 to 10-7). Genotypes at rs1871922 were consistent with the hypothesis that all large alleles occur on the same haplotype as the DM2 expansion.Conclusions: We conclude that unstable uninterrupted (CCTG)22-33 alleles represent a premutation allele pool for DM2 full mutations.(C)2009AAN Enterprises, Inc.

Objective: To investigate clinical differences in warm and cold complex regional pain syndrome (CRPS) phenotypes.Background: CRPS represents inhomogeneous chronic pain conditions; approximately 70% patients with CRPS have "warm" affected limbs and 30% have "cold" affected limbs.Methods: We examined 50 patients with "cold" and "warm" CRPS (n = 25 in each group). Both groups were matched regarding age, sex, affected limb, duration of CRPS, and CRPS I and II to assure comparability. Detailed medical history and neurologic status were assessed. Moreover, quantitative sensory testing (QST) was performed on the affected ipsilateral and clinically unaffected contralateral limbs.Results: Compared with patients who had warm CRPS, patients who had cold CRPS more often reported a history of serious life events (p < 0.05) and chronic pain disorders (p < 0.05). In cold CRPS, the incidence of CRPS-related dystonia was increased (p < 0.05), and cold-induced pain had a higher prevalence (p < 0.01). Furthermore, QST revealed a predominant sensory loss in patients with cold CRPS (p < 0.05). In contrast, patients with warm CRPS were characterized by mechanical hyperalgesia (p < 0.05) in the QST of affected limbs.Conclusion: Our results indicate that warm and cold complex regional pain syndromes (CRPS) are associated with different clinical findings, beyond skin temperature changes. This might have implications for the understanding of CRPS pathophysiology.(C)2009AAN Enterprises, Inc.

Objective: To measure the association of cognition, visual perception, and motor function with driving safety in Alzheimer disease (AD).Methods: Forty drivers with probable early AD (mean Mini-Mental State Examination score 26.5) and 115 elderly drivers without neurologic disease underwent a battery of cognitive, visual, and motor tests, and drove a standardized 35-mile route in urban and rural settings in an instrumented vehicle. A composite cognitive score (COGSTAT) was calculated for each subject based on eight neuropsychological tests. Driving safety errors were noted and classified by a driving expert based on video review.Results: Drivers with AD committed an average of 42.0 safety errors/drive (SD = 12.8), compared to an average of 33.2 (SD = 12.2) for drivers without AD (p < 0.0001); the most common errors were lane violations. Increased age was predictive of errors, with a mean of 2.3 more errors per drive observed for each 5-year age increment. After adjustment for age and gender, COGSTAT was a significant predictor of safety errors in subjects with AD, with a 4.1 increase in safety errors observed for a 1 SD decrease in cognitive function. Significant increases in safety errors were also found in subjects with AD with poorer scores on Benton Visual Retention Test, Complex Figure Test-Copy, Trail Making Subtest-A, and the Functional Reach Test.Conclusion: Drivers with Alzheimer disease (AD) exhibit a range of performance on tests of cognition, vision, and motor skills. Since these tests provide additional predictive value of driving performance beyond diagnosis alone, clinicians may use these tests to help predict whether a patient with AD can safely operate a motor vehicle.GLOSSARY: AD = Alzheimer disease; AVLT = Auditory Verbal Learning Test; Blocks = Block Design subtest; BVRT = Benton Visual Retention Test; CFT = Complex Figure Test; CI = confidence interval; COWA = Controlled Oral Word Association; CS = contrast sensitivity; FVA = far visual acuity; JLO = Judgment of Line Orientation; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; NVA = near visual acuity; SFM = structure from motion; TMT = Trail-Making Test; UFOV = Useful Field of View.(C)2009AAN Enterprises, Inc.

Objective: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFN[beta]-1a) combined with methotrexate (MTX), IV methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFN[beta]-1a monotherapy.Methods: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and >=1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFN[beta]-1a monotherapy. Participants continued weekly IFN[beta]-1a 30 [mu]g IM and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center.Results: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFN[beta]-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFN[beta] neutralizing antibody titers.Conclusions: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.GLOSSARY: ACT = Avonex Combination Trial; BPF = brain parenchymal fraction; DEXA= dual energy X-ray absorptiometry; EDSS = Expanded Disability Status Scale; GdE = gadolinium-enhancing; IFN[beta]-1a = interferon beta-1a; IVMP = IV methylprednisolone; MSFC = MS Functional Composite; MTX = methotrexate; N/E = new or enlarged; NAb = neutralizing antibody; OR = odds ratio; RRMS = relapsing-remitting multiple sclerosis; SENTINEL = Safety and Efficacy of Natalizumab in Combination with Interferon [beta]-1a in Patients with Relapsing-Remitting MS.(C)2009AAN Enterprises, Inc.

Objective: To document unusual, nonviolent behaviors during REM sleep behavior disorder (RBD) and evaluate their frequency in Parkinson disease (PD).Background: Most behaviors previously described during RBD mimic attacks, suggesting they proceed from archaic defense generators in the brainstem. Feeding, drinking, sexual behaviors, urination, and defecation have not been documented yet in RBD.Methods: We collected 24 cases of nonviolent behaviors during idiopathic and symptomatic RBD (narcolepsy, dementia with Lewy bodies, PD), reported or observed in videopolysomnography. The frequency of violent and nonviolent behaviors during RBD was evaluated by face to face interview of patients and their cosleepers in a prospective series of 100 patients with PD.Results: Incidental cases of nonviolent behaviors during RBD included masturbating-like behavior and coitus-like pelvic thrusting, mimicking eating and drinking, urinating and defecating, displaying pleasant behaviors (laughing, singing, dancing, whistling, smoking a fictive cigarette, clapping and gesturing "thumbs up"), greeting, flying, building a stair, dealing textiles, inspecting the army, searching a treasure, and giving lessons. Speeches were mumbled or contained logical sentences with normal prosody. In PD with RBD (n = 60), 18% of patients displayed nonviolent behaviors. In this series (but not in incidental cases), all RBD patients with nonviolent behaviors also showed violent behaviors.Conclusions: Although they are less frequent than violent behaviors, nonviolent behaviors during REM sleep behavior disorder (RBD) fill a large spectrum including learned speeches and culture-specific behaviors, suggesting they proceed from the cortex activation. Sexual behaviors during RBD may expose patients and cosleepers to forensic consequences.GLOSSARY: PD = Parkinson disease; RBD = REM sleep behavior disorder.(C)2009AAN Enterprises, Inc.