OBJECTIVE: This ongoing, Phase 3 trial is evaluating the efficacy and safety of 3 doses of arbaclofen placarbil (AP), compared with placebo, for treatment of spasticity in patients with multiple sclerosis (MS).

The indications for using steroids when performing occipital nerve blocks (ONBs) are not completely clear. We report a patient with chronic migraines who was allergic to local anesthetics, for whom ONBs using only corticosteroid proved useful. To our knowledge, this is only published case describing the effects of ONBs using only corticosteroid, without local anesthetic.

Dimebon is a novel drug in Phase 3 development for the treatment of Alzheimer's disease (AD). A previous study demonstrated improvement in cognition, function, and behavior in AD patients compared to placebo. The basis for its clinical effects is unknown; preclinical studies suggest dimebon may enhance mitochondrial function in the setting of cellular stress and promote neurite outgrowth. This study evaluated the safety and tolerability of dimebon in AD patients already treated with donepezil. AD patients stable on donepezil (10 mg daily) for at least 60 days and tolerating it well were randomized to dimebon (n=15) or placebo (n=9). The first 14 patients enrolled (9 dimebon, 5 placebo) underwent gradual within- patient dose-titration including 2.5 mg three times daily (TID) x 7 days, then 5.0 mg TID x 7 days, then 10 mg TID x 7 days, then 20 mg TID x 7 days. The next 10 patients (6 dimebon, 4 placebo) underwent more rapid dose-titration from 10 mg TID x 7 days to 20 mg TID x 7 days. Standard safety and tolerability assessments were collected, including PK of dimebon and donepezil. All patients completed the treatment period except one placebo patient. No serious adverse events (AEs) or deaths occurred. 13/15 (87%) dimebon and 5/9 (56%) of placebo patients reported an AE. All dimebon AEs were mild in severity except 1 fall (moderate, without loss of consciousness) and 1 neuralgia (severe) both assessed as unrelated to study drug. AEs reported in at least 2 Dimebon patients and more frequently than in the placebo group were: fatigue (3/15, 20% vs. 0%), abdominal distension (2/15, 13% vs. 0%), dizziness (2/15, 13% vs. 1/9, 11%), fall (2/15, 13% vs. 0%), hyperkalemia (2/15, 13% vs. 1/9,11%), and nightmare (2/15,13% vs. 0%). These AEs were mild/moderate and resolved with continued treatment. Those patients who underwent the shortened titration period did not have an increased incidence of AEs as compared to those on the gradual titration. Co-administration of Dimebon and donepezil did not result in an increase in Cmax or AUC of either drug. Dimebon was well-tolerated in this study of AD patients already treated with donepezil.

Introduction.— Occipital nerve block (ONB) is a promising treatment for headaches. Its indications, selection criteria, and best techniques are not clear, however. Objective.— To summarize in narrative format what is known about ONBs and what needs to be learned. Methods.— MD Consult and Google Scholar were searched using the terms occipital, suboccipital, block, and injection to identify relevant articles that were reviewed. This process was repeated for all additional pertinent articles identified from these articles, and so on, until no additional articles were identified. Results.— A total of 21 articles were identified. Conclusions.— Occipital nerve block is an effective treatment for cervicogenic headache, cluster headache, and occipital neuralgia. While a double blinded randomized placebo controlled clinical trial is lacking, multiple open label studies reported favorable results for migraine. Two other possible uses of ONB worthy of further study are use as a rescue treatment and as an adjunctive treatment for medication overuse headache. ONB may be effective for tension headache, but only under very specific circumstances. ONB is either ineffective or only effective under as yet unstudied circumstances for hemicrania continua and chronic paroxysmal hemicrania. Some practitioners use occipital nerve (ON) tenderness to palpation (TTP) or reproduction of headache pain with ON pressure (RHPONP) as selection criteria for identifying appropriate patients. While only a clinical trial can produce a definitive answer, current evidence suggests that these selection criteria are not necessary for cervicogenic headache or cluster headache. Occipital neuralgia by definition involves TTP of the ONs. Whether RHPONP or ON TTP predicts success in migraine is unclear, and may relate to whether steroids are used. A single blinded randomized controlled trial evaluating local anesthetic with steroids vs local anesthetic alone for transformed migraine reported slightly worse results with steroids, but there are several alternate explanations for this finding other than steroids being counterproductive. The technique of repetitive ONBs deserves further study.

Correspondence and Clinical Notes† Cluster-Like Headaches Associated With Internal Carotid Artery Dissection Responsive to Verapamil Joshua Tobin MD, Joshua Tobin MD From 21st Century Neurology, Phoenix, AZ, USA.Search for more papers by this authorStephen Flitman MD, Stephen Flitman MD From 21st Century Neurology, Phoenix, AZ, USA.Search for more papers by this author Joshua Tobin MD, Joshua Tobin MD From 21st Century Neurology, Phoenix, AZ, USA.Search for more papers by this authorStephen Flitman MD, Stephen Flitman MD From 21st Century Neurology, Phoenix, AZ, USA.Search for more papers by this author First published: 21 February 2008 https://doi.org/10.1111/j.1526-4610.2007.01047.xCitations: 12 Joshua Tobin, MD, 21st Century Neurology, 2601 North 3rd Street, Suite 125, Phoenix, AZ 85004, USA. Conflict of Interest: None Clinical Notes Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume48, Issue3March 2008Pages 461-466 RelatedInformation

Objective: To investigate the utility of a clinical laboratory ELISA format assay that measures neural thread protein (NTP) in urine in the assessment of patients presenting with cognitive symptoms.Design: A prospective blinded multicentered studySetting: Eight US specialty clinics for the evaluation of cognitive or memory disorder or dementia, including memory disorder and dementia clinics, neurology clinics, and psychiatry clinics, in 8 states.Participants: Prospectively enrolled consecutive patients who were newly referred to a specialty clinic for assessment of cognitive or memory disorder symptoms or dementia to rule out or rule in Alzheimer's disease (AD).Measurements: Participants provided a first morning urine sample for UNTP measurement for testing at a central core laboratory and subsequently went through specialized diagnostic evaluations in accordance with established clinical criteria. Urine NTP measurement was compared to the diagnostic categorization of the patients as probable or possible AD (according to National Institute of Neurological Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association [NINCDS-ADRDA] criteria), mild cognitive impairment (MCI) (according to Quality Standards Subcommittee of the American Academy of Neurology [AAN] criteria) or definite non-AD. Clinical diagnoses were made without reference to UNTP measurement; the testing laboratory was blinded to both patient identity and clinical diagnoses.Results: A total of 168 enrolled and consented patients provided qualifying urine samples and completed specialized diagnostic workups. There were 91.4% of subjects with probable AD, 37.7% of subjects categorized as possible AD, and 48.6% of subjects with MCI who had an elevated NTP measurement (>22 mu g/mL). There were 90.7% of subjects diagnosed as definite non-AD who had a normal NTP measurement (<= 22 mu g/mL).Conclusion: Noninvasive UNTP test results are potentially helpful as part of the workup of dementia for the nonspecialist to help in the decision as to whether referral and/or more detailed investigation is advisable.

This article describes current pharmacological appr oaches to Alzheimer's disease. The author delineates the two families of drug treatments curr ently available and the aspects of Alzheimer's pathophysiology which these drugs assess. The chol inesterase inhibitors are described along with their history of development. The newly appro ved NMDA inhibitor memantine is described along with how it will be used in practic e given the prevalence of the cholinesterase inhibitors.

Background: AD is characterized by cerebral deposition of beta-amyloid plaques with amyloid beta-peptide (Abeta) 42 as the major peptide constituent, along with neurofibrillary tangles and neuronal loss. In transgenic mice, active immunization against Abeta42 removes these plaques and improves cognitive function. A Phase I study in AD patients demonstrated good safety and tolerability of multiple injections of aggregated Abeta42 (AN1792) with QS-21 as adjuvant. Methods: Three hundred seventy-two patients with mild to moderate AD were randomized to receive IM injections of AN1792 or placebo (4:1) at baseline and at months 1, 3, 6, 9, and 12 in a multicenter Phase II safety, tolerability, and pilot efficacy study. Dosing was terminated after four early reports of meningoencephalitis, but follow-up continued. The study remains blinded, and further results will be reported after its termination. Results: Symptoms and laboratory findings consistent with meningoencephalitis occurred in 18 of 298 (6%) patients treated with AN1792 compared with 0 of 74 on placebo (p = 0.020). Sixteen of the 18 had received two doses, one had received one dose, and one had received three doses of the study drug before symptoms occurred. The median latency from the first and last injections to symptoms was 75 and 40 days. No case occurred later than 6 months after the first immunization. Anti-Abeta42 antibody titers were not correlated with the occurrence or severity of symptoms or relapses. Twelve patients recovered to or close to baseline within weeks, whereas six remain with disabling cognitive or neurologic sequelae. All 18 patients remain alive to date (December 31, 2002), 6 months to >1 year after symptom onset. Conclusions: Postvaccination meningoencephalitis occurred without clear relation to serum anti-Abeta42 antibody titers. Potential mechanisms such as T-cell and microglial activation may be responsible and are under consideration to develop a safer anti-Abeta immunotherapy for AD.

Objective: This prospective, randomized, controlled study was designed to investigate the safety, feasibility, and preliminary efficacy of long-term CSF drainage via a low-flow ventriculoperitoneal shunt in subjects suffering from AD. Methods: Twenty-nine subjects selected for probable AD (National Institute of Neurological and Communicative Diseases and Stroke–Alzheimer’s Disease and Related Dementias Association criteria) were screened to exclude normal pressure hydrocephalus or other etiologies of dementia and randomized to treatment (shunt) or no treatment groups. The study endpoint was the comparison of group performance on psychometric testing at quarterly intervals for 1 year. Shunted subjects had CSF withdrawn for MAP-tau and Aβ(1-42) assays at the same time intervals. Results: There was no mortality from the surgical procedure, and no patient sustained a subdural hematoma. Five notable postoperative adverse events, which resolved without permanent neurologic deficit, were reported in the shunt group. Group mean Mattis Dementia Rating Scale total scores showed little change over the year in the shunt-treatment group, in contrast to a decline in the control group (p = 0.06). Mini-Mental State Examination mean scores supported a trend in favor of shunt treatment (p = 0.1). There was a concomitant decrease in ventricular CSF concentrations of AD biomarkers MAP-tau and Aβ(1-42). Conclusions: The surgical procedure and the device are reasonably safe. Adverse events were consistent with shunt procedures for hydrocephalus in this older population. The endpoint data show a trend in favor of the treated group. A larger, randomized, double-blinded, controlled, clinical trial is underway.

OBJECTIVE:This prospective, randomized, controlled study was designed to investigate the safety, feasibility, and preliminary efficacy of long-term CSF drainage via a low-flow ventriculoperitoneal shunt in subjects suffering from AD. METHODS:Twenty-nine subjects selected for probable AD (National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Dementias Association criteria) were screened to exclude normal pressure hydrocephalus or other etiologies of dementia and randomized to treatment (shunt) or no treatment groups. The study endpoint was the comparison of group performance on psychometric testing at quarterly intervals for 1 year. Shunted subjects had CSF withdrawn for MAP-tau and Abeta((1-42)) assays at the same time intervals. RESULTS:There was no mortality from the surgical procedure, and no patient sustained a subdural hematoma. Five notable postoperative adverse events, which resolved without permanent neurologic deficit, were reported in the shunt group. Group mean Mattis Dementia Rating Scale total scores showed little change over the year in the shunt-treatment group, in contrast to a decline in the control group (p = 0.06). Mini-Mental State Examination mean scores supported a trend in favor of shunt treatment (p = 0.1). There was a concomitant decrease in ventricular CSF concentrations of AD biomarkers MAP-tau and Abeta((1-42)). CONCLUSIONS:The surgical procedure and the device are reasonably safe. Adverse events were consistent with shunt procedures for hydrocephalus in this older population. The endpoint data show a trend in favor of the treated group. A larger, randomized, double-blinded, controlled, clinical trial is underway.

To explore brain areas involved in basic numerical computation, functional magnetic imaging (fMRI) scanning was performed on college students during performance of three tasks; simple arithmetic, numerical magnitude judgment, and a perceptual-motor control task. For the arithmetic relative to the other tasks, results for all eight subjects revealed bilateral activation in Brodmann’s area 44, in dorsolateral prefrontal cortex (areas 9 and 10), in inferior and superior parietal areas, and in lingual and fusiform gyri. Activation was stronger on the left for all subjects, but only at Brodmann’s area 44 and the parietal cortices. No activation was observed in the arithmetic task in several other areas previously implicated for arithmetic, including the angular and supramarginal gyri and the basal ganglia. In fact, angular and supramarginal gyri were significantly deactivated by the verification task relative to both the magnitude judgment and control tasks for every subject. Areas activated by the magnitude task relative to the control were more variable, but in five subjects included bilateral inferior parietal cortex. These results confirm some existing hypotheses regarding the neural basis of numerical processes, invite revision of others, and suggest productive lines for future investigation.

Several brain regions associated with analogical mapping were identified using 15O-positron emission tomography with 12 normal, high intelligence adults. Each trial presented during scanning consisted of a source picture of colored geometric shapes, a brief delay, and a target picture of colored geometric shapes. Analogous pictures did not share similar geometric shapes but did share the same system of abstract visuospatial relations. Participants judged whether each source–target pairing was analogous (analogy condition) or identical (literal condition). The results of the analogy-literal comparison showed activation in the dorsomedial frontal cortex and in the left hemisphere; the inferior, middle, and medial frontal cortices; the parietal cortex; and the superior occipital cortex. Based on these results as well as evidence from relevant cognitive neuroscience studies of reasoning and of executive working memory, we hypothesize that analogical mapping is mediated by the left prefrontal and inferior parietal cortices.

To determine if linguistic processing could be selectively disrupted with repetitive transcranial magnetic stimulation (rTMS), rTMS was performed during a picture-word verification task. Seven right-handed subjects were trained in two conditions: picture-word verification, which required the subject to verify whether the picture of an object matched the subtitle name on the same page, and frame verification, which required subjects to verify whether there was a rectangular frame around the combined object picture and subtitle. Half of the trials were performed during rTMS. The effects of rTMS on performance were evaluated at the following four scalp positions: left anterior (the area where rTMS produced speech arrest), a mirror site on the right, and two positions in the left and right parietal region. Stimulation over the left deltoid muscle served as a control. Subjects had less difficulty in making picture-word matching decisions during unstimulated compared with stimulated trials at the left anterior and posterior positions. No significant difference in accuracy was detected in the frame verification condition, but response times in the frame verification condition were longer with stimulation at the left anterior position. Because rTMS of the dominant hemisphere affected linguistic processing independent of speech motor output, we confirm that rTMS may be used to investigate language and other cognitive functions.

Covered maze traversal models nonverbal planning, involving sequential execution of moves using learned spatial maps. To determine the neural substrate involved in maze processing, eleven adults underwent [H215O]-PET while performing motor control, following the computer; visual control, choosing the wall with more dead-ends; uncovered maze, traversing fully visible mazes; covered maze, traversing mazes only locally visible. Maze processing lateralizes to the right hemisphere: uncovered maze versus controls revealed area 23 and 29 activation; covered maze versus controls activated areas 8, 10 and 19. The extrastriate region may store path information, evoked by prefrontal areas for spatial planning and navigation.