Individualizing treatment goals and interventions for people with MS.

PURPOSE OF REVIEW: The aim of this article is to consider factors that should be evaluated in the selection of therapy for people with multiple sclerosis (MS). This includes a review of current approaches to treatment selection and how to align this process with patients' treatment goals. These issues have increased in importance with the availability of new disease-modifying therapies and will continue to do so as more novel treatments are approved. RECENT FINDINGS: The model for decision making in the management of people with MS as well as other chronic diseases has evolved from one in which medication is prescribed by the neurologist and the person is expected to comply with treatment, to one in which the neurologist and individual with MS achieve concordance with respect to both the expectations and goals of therapy and the means to achieve them. This shift has resulted in a requirement for easily understood evidence-based information about the risks and benefits of different treatment alternatives. It has been demonstrated that providing MS sufferers with such information increases effective self-management and satisfaction. SUMMARY: Healthcare providers involved in the treatment of MS have an increased responsibility to ensure people with this disease, their partners, and when appropriate, their families are involved in all decisions regarding care. This includes helping to select and adjust therapy on the basis of the individual MS sufferer's characteristics and needs that are likely to evolve as the disease progresses.

New treatments and treatment goals for patients with relapsing-remitting multiple sclerosis.

PURPOSE OF REVIEW: The aims of this article are to review emerging therapies for multiple sclerosis (MS) and to consider new approaches to assessment and achievement of treatment success in patients with this disease. RECENT FINDINGS: A number of disease-modifying therapies for MS, including oral agents, are in advanced development and likely to be available soon. Fingolimod has been approved recently by the US Food and Drug Administration. Agents in development include alemtuzumab, BG-12, daclizumab, teriflunomide, laquinimod, and B-cell-targeted monoclonal antibodies ocrelizumab and ofatumumab. The advent of emerging efficacious therapies has set the stage for re-evaluation of treatment goals for patients with MS. Freedom from disease, defined by the absence of relapses, disability progression, and radiologic evidence of disease activity, is increasingly seen as the measure of treatment success. SUMMARY: New MS treatments may provide the basis for aggressive early intervention in patients with MS and intensification of treatment when disease is not controlled. The availability of therapies that can achieve higher treatment goals may significantly improve long-term outcomes for MS patients.

Treatment of relapsing-remitting multiple sclerosis: current approaches and unmet needs.

PURPOSE OF REVIEW: The aim of this review is to summarize unmet needs for patients with multiple sclerosis (MS). It is important to understand the current status of these patients and both the benefits and limitations of the most commonly used MS treatments as new medications with the potential to simplify therapy and improve outcomes may soon be available. RECENT FINDINGS: Current treatments for MS decrease the frequency of relapses and slow progressive disability. However, nearly all of these medications require frequent administration, and some patients also experience side effects. In some patients, adherence to MS treatment may be less than optimal. This may be associated with increased risk for relapses and hospitalizations and higher cost of care. SUMMARY: Healthcare providers involved in the treatment of MS must be aware of the unmet needs of their patients and intervene as needed to improve adherence and/or modify treatment regimens to optimize outcomes.

Cryolipolysis for noninvasive fat cell destruction: initial results from a pig model.

BACKGROUND: Liposuction is one of the most frequently performed cosmetic procedures in the United States, but its cost and downtime has led to the development of noninvasive approaches for adipose tissue reduction. OBJECTIVE: To determine whether noninvasive controlled and selective destruction of fat cells (Cryolipolysis) can selectively damage subcutaneous fat without causing damage to the overlying skin or rise in lipid levels. METHODS: Three Yucatan pigs underwent Cryolipolysis at 22 sites: 20 at cooling intensity factor (CIF) index 24.5 (-43.8 mW/cm(2)), one at CIF 24.9 (-44.7 mW/cm(2)), and one at CIF 25.4 (-45.6 mW/cm(2)). Treated areas were evaluated using photography, ultrasound, and gross and microscopic pathology. Lipids were at various times points. One additional pig underwent Cryolipolysis at various days before euthanasia. RESULTS: The treatments resulted in a significant reduction in the superficial fat layer without damage to the overlying skin. An inflammatory response triggered by cold-induced apoptosis of adipocytes preceded the reduction in the fat layer. Evaluation of lipids over a 3-month period following treatment demonstrated that cholesterol and triglyceride values remained normal. CONCLUSIONS: Cryolipolysis is worthy of further study because it has been shown to significantly decrease subcutaneous fat and change body contour without causing damage to the overlying skin and surrounding structures or deleterious changes in blood lipids.

Boundary-limited serotonergic influences on pattern organization in rat sensory cortex.

In neonatal rodents, elevated levels of cortical serotonin (5-HT) blur the normally segmented vibrissae-related pattern of thalamocortical afferents (TCAs) in the posteromedial barrel subfield (PMBSF) of primary somatosensory cortex. We employed 5-HT immunocytochemistry or anterograde transport of 1'1'-dioctadecyl-3,3,3',3' tetramethyl-indocarbocyanin (Di-I) to label TCA arbors to study the effects of 5-HT manipulations on space occupied by TCAs within the PMBSF and the total area labeled. In rats treated to increase cortical 5-HT from birth to postnatal day (P) 6, the percentage of PMBSF area occupied by terminal labeling was significantly higher from that in controls (79.0% versus 23.7%, P < 0.05) for the highest levels of cortical 5-HT and was raised, although not significantly, for lower levels of 5-HT. The TCA coverage was significantly correlated with treatment dose. In animals exposed to a selective 5-HT1B agonist, 5-nonyloxytryptamine, or elevated endogenous 5-HT, the total areas of TCA aggregates in the PMBSF and those in visual cortex were similar to the controls. These results suggest that TCAs have a graded response to increasingly higher 5-HT concentrations. The lack of TCA expansion beyond normal cortical areas further implies that 5-HT-induced axon outgrowth is restricted at cortical boundaries.

Organization, Development and Enucleation-induced Alterations in the Visual Callosal Projection of the Hamster: Single Axon Tracing with Phaseolus vulgaris leucoagglutinin and Di-I.

The distribution of callosal axons interconnecting lateral area 17 and medial area 18 of the rodent's occipital cortex is dramatically altered by neonatal enucleation, but it is not known how this manipulation affects the morphology of individual callosal axons or whether the enucleation-induced changes in this pathway reflect maintenance of a transient developmental state by these fibres. In the present study, these questions were addressed by tracing the individual callosal axons in normal adult and neonatally enucleated adult hamsters with Phaseolus vulgaris leucoagglutinin (PHAL) and by anterograde labelling of developing callosal axons with the carbocyanine dye, Di-I. In normal adults, injections of PHAL into the region of the 17 - 18a border produced dense labelling in all layers in the region of the contralateral 17 - 18a border. Larger injections resulted in callosal labelling that extended across the lateral one-half of area 17, primarily in layers I and V. Thirty-four callosal axons from normal adult hamsters were reconstructed through all the cortical laminae. Most of these had very simple terminal arbors. They gave off short collaterals in the infragranular layers and branched more extensively in the uppermost part of layer II - III and in lamina I. Small injections of PHAL into the occipital cortex of neonatally enucleated adult hamsters resulted in labelled axons throughout most of areas 17 and 18a in the contralateral hemisphere. The terminal arbors of most individual callosal axons in eyeless hamsters were not appreciably different from those in sighted animals. However, 26.8% of 28 fibres reconstructed through all cortical laminae in the neonatally enucleated hamsters had much more widespread branches than any of the axons recovered from normal hamsters. As a result, the average total length of the callosal axons from the blinded hamsters was significantly greater than that for such fibres from the sighted animals. Anterograde labelling with Di-I demonstrated axons in the anterior commissure and anterior part of the corpus callosum on P-0. Labelled fibres extended into the white matter underlying the occipital cortex on P-1 and entered the cortical plate on P-2. Some of these axons reached into the marginal layer. Many developing callosal axons had short branches in the white matter, but generally extended only a single collateral into the cortical grey matter. Callosal axons in perinatal animals branched very little within the cortex and, in this respect, resembled fibres labelled with PHAL in adult hamsters. These results support the conclusion that the expanded tangential distribution of the occipital callosal projection in neonatally enucleated adult hamsters results, at least in part, from individual axons with abnormally widespread terminal arbors which are not present in large numbers at any time during normal development.

Comparison of reorganization of the somatosensory system in rats that sustained forelimb removal as neonates and as adults.

Studies of sensory pathways in several species indicate that the extent and form of reorganization resulting from deafferentation early in life vs. adulthood are not the same. The reasons for such differences are not well understood. To gain further insight into age-dependent mechanisms of reorganization, this study compared the consequences of neonatal vs. adult forelimb amputation in rats at multiple levels of the sensory pathway, including primary somatosensory cortex, brainstem, and dorsal root ganglia. At the cortical level, the average area of the functional forelimb-stump representation from rats amputated as adults was significantly smaller (P < 0.05) than that of neonatally amputated rats (4.3 +/- 1.3 mm(2) vs. 6.6 +/- 1.5 mm(2), respectively). At the brainstem level, neonatally amputated rat cuneate neurons possessed the following responsivities: 20% stump responsive, 40% responsive to both stump and hindlimb, 30% responsive to another body region, and 10% unresponsive. In contrast, cuneate neurons of adult amputated rats were 70% stump responsive, 2% responsive to both stump and hindlimb, and 30% unresponsive. A significantly (P < 0.001) greater percentage of the C(6)-C(8) dorsal root ganglia neurons of adult amputated rats were unresponsive to peripheral stimulation vs. neurons from neonatally amputated rats (48% vs. 16%, respectively). These results indicate that the reorganization that occurs in response to forelimb amputation at birth vs. adulthood is distinctly different at each of these levels of the dorsal column-medial lemniscal pathway. Possible mechanisms to account for these differences are considered.

Effects of elevated serotonin levels on patterns of GAP-43 expression during barrel development in rat somatosensory cortex.

Elevating cortical serotonin (5-HT) in rats with clorgyline, a monoamine oxidase A (MAO(A)) inhibitor, from postnatal day (P-0) to P-6 delays the organization of thalamocortical afferent fibers into a vibrissae-related pattern in the somatosensory cortex (S-I). Despite continued elevation of cortical 5-HT through P-8, the thalamocortical fibers do form, albeit with some delay, a characteristic vibrissae pattern of barrels in layer IV of S-I by P-8. The growth-associated protein, GAP-43, is transiently expressed in developing S-I cortex of normal rats in a vibrissae related pattern until P-7. After P-7, GAP-43 expression is reduced in the barrel centers and increased in the septa. The present study evaluated the effect of elevated 5-HT levels on the distribution of GAP-43 immunoreactivity in S-I. We employed 5-HT immunocytochemistry and 1,1'-dioctadecyl-3,3,3",3'-tetramethylindocarbocyanine perchlorate (DiI) labeling of thalamic radiations to confirm a 'barrelless' phenotype in P-6 clorgyline-treated animals and a recovered barrel pattern in treated animals allowed to survive until P-8 and P-10. GAP-43 immunocytochemistry was used to evaluate the cortical distribution of this protein in similarly treated littermates. Continuous inhibition of MAO(A) from P-0 to P-6 resulted in a corresponding loss of the GAP-43 vibrissae-related pattern at P-6. Despite continued elevation of cortical 5-HT until P-8 and P-10, the characteristic vibrissae-complementary pattern of GAP-43 emerged with expression concentrated in the septa and rows. GAP-43 vibrissae-related thalamocortical axon pattern never appeared in the clorgyline-treated animals. Thus, while elevated 5-HT delays development of a vibrissae-related pattern of thalamocortical afferents, it does not appear to alter the time when a GAP-43 vibrissae-related complementary pattern emerges.

Systematic reviews of assessment measures and pharmacologic treatments for agitation.

BACKGROUND: Agitation is a common behavioral emergency associated with high risk of injury to patients and health care professionals. There are a wide variety of approaches to assessing the severity of agitation and the risk of violence/aggression, and many different pharmacotherapies have been used to manage this condition. OBJECTIVES: Two systematic reviews were carried out. The first focused on measures used to assess agitation and predict aggression/violence and/or the need for medication. The second focused on clinical trials of the efficacy and tolerability of pharmacotherapies for agitation. METHODS: Publications relevant to each topic were identified by searches of MEDLINE through December 24, 2009. The search concerning the assessment of agitation included the terms agitation AND assessment AND (scale OR instrument); the search for clinical trials of pharmacotherapies for agitation included the terms agitation and treatment AND (emergency OR acute). Both searches were limited to reports of studies published in English involving patients aged > or =18 years. RESULTS: The literature search identified 13 scales used to assess the severity of agitation across multiple patient populations; only 3 of these reports involved the prediction of aggression/violence in patients with agitation, and 1 involved prediction of the need for medication. Thirty-one clinical trials of pharmacotherapy for agitation were identified by the literature search. Based on their results, orally administered olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, and lorazepam; intramuscularly administered olanzapine, lorazepam, ziprasidone, haloperidol, aripiprazole, midazolam, and droperidol; and intravenously administered droperidol and lorazepam were effective for the treatment of agitation. The intramuscular route of administration was associated with a more rapid onset of action compared with the oral route (eg, for olanzapine, 30 minutes vs 1 hour, respectively). CONCLUSIONS: Agitation is a common behavioral emergency that may require pharmacotherapy. The management of agitated patients may be improved through the use of easy-to-administer instruments that predict the need for medication and the availability of rapid-acting treatments that are well accepted by patients and health care professionals.

Reducing contralateral SI activity reveals hindlimb receptive fields in the SI forelimb-stump representation of neonatally amputated rats.

In adult rats that sustained forelimb amputation on the day of birth, >30% of multiunit recording sites in the forelimb-stump representation of primary somatosensory cortex (SI) also respond to cutaneous hindlimb stimulation when cortical GABA(A+B) receptors are blocked (GRB). This study examined whether hindlimb receptive fields could also be revealed in forelimb-stump sites by reducing one known source of excitatory input to SI GABAergic neurons, the contralateral SI cortex. Corpus callosum projection neurons connect homotopic SI regions, making excitatory contacts onto pyramidal cells and interneurons. Thus in addition to providing monosynaptic excitation in SI, callosal fibers can produce disynaptic inhibition through excitatory synapses with inhibitory interneurons. Based on the latter of these connections, we hypothesized that inactivating the contralateral (intact) SI forelimb region would "unmask" normally suppressed hindlimb responses by reducing the activity of SI GABAergic neurons. The SI forelimb-stump representation was first mapped under normal conditions and then during GRB to identify stump/hindlimb responsive sites. After GRB had dissipated, the contralateral (intact) SI forelimb region was mapped and reversibly inactivated with injections of 4% lidocaine, and selected forelimb-stump sites were retested. Contralateral SI inactivation revealed hindlimb responses in approximately 60% of sites that were stump/hindlimb responsive during GRB. These findings indicate that activity in the contralateral SI contributes to the suppression of reorganized hindlimb receptive fields in neonatally amputated rats.

Local GABA receptor blockade reveals hindlimb responses in the SI forelimb-stump representation of neonatally amputated rats.

In adult rats that sustained forelimb amputation on the day of birth, there are numerous multi-unit recording sites in the forelimb-stump representation of primary somatosensory cortex (SI) that also respond to cutaneous stimulation of the hindlimb when cortical receptors for GABA are blocked. These normally suppressed hindlimb inputs originate in the SI hindlimb representation and synapse in the dysgranular cortex before exciting SI forelimb-stump neurons. In our previous studies, GABA (A + B) receptor blockade was achieved by topically applying a bicuculline methiodide/saclofen solution (BMI/SAC) to the cortical surface. This treatment blocks receptors throughout SI and does not allow determination of where along the above circuit the GABA-mediated suppression of hindlimb information occurs. In this study, focal injections of BMI/SAC were delivered to three distinct cortical regions that are involved in the hindlimb-to-forelimb-stump pathway. Blocking GABA receptors in the SI hindlimb representation and in the dysgranular cortex was largely ineffective in revealing hindlimb inputs ( approximately 10% of hindlimb inputs were revealed in both cases). In contrast, when the blockade was targeted at forelimb-stump recording sites, >80% of hindlimb inputs were revealed. Thus GABAergic interneurons within the forelimb-stump representation suppress the expression of reorganized hindlimb inputs to the region. A circuit model incorporating these and previous observations is presented and discussed.

Effects of alterations of the vibrissae-related organization of thalamocortical axons upon the organization and outgrowth of intracortical connections in the barrelfield of the rat.

Previous studies have shown that intracortical projections in layer IV of the vibrissae representation of primary somatosensory cortex (S-I) are arrayed in a pattern complementary to that of thalamocortical axons (TCAs). Elevation of cortical serotonin (5-HT) in rats during the first postnatal week results in a transient disruption of the vibrissae-related pattern of TCAs and layer IV neurons in S-I. The present study examines the influence of elevated cortical 5-HT levels and the attendant loss of vibrissae-related TCA clusters on the organization of S-I intracortical connections. Cortical 5-HT was elevated in neonatal rats via chronic injections of clorgyline from birth until P-6. Animals were euthanized on P-6 or allowed to survive an additional 4 days without further clorgyline treatment. Distributions of TCAs and intracortical axons were assessed via application of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Di-I) and 4-(4-(dihexadecylamino)styryl)-N-methylpyridinium iodide (Di-A) to the thalamic radiations and directly into the cortical barrelfield, respectively. Chronic administration of clorgyline resulted in a loss of the vibrissae-related organization of TCAs in layer IV of S-I. There was also a loss of the complementary pattern of intracortical projections in layer IV of this region. Discontinuation of clorgyline treatment resulted in a return of the vibrissae-related pattern of TCAs as well as the complementary pattern of intracortical projections. These results are consistent with the conclusion that the normal organization of intracortical projections in this region of S-I depends on the presence of the orderly array of TCAs.

Role of development in reorganization of the SI forelimb-stump representation in fetally, neonatally, and adult amputated rats.

Rats that sustain forelimb removal on postnatal day (P) 0 exhibit numerous multi-unit recording sites in the forelimb-stump representation of primary somatosensory cortex (SI) that also respond to hindlimb stimulation when cortical GABAA+B receptors are blocked. Most of these hindlimb inputs originate in the medial SI hindlimb representation. Although many forelimb-stump sites in these animals respond to hindlimb stimulation, very few respond to stimulation of the face (vibrissae or lower jaw), which is represented in SI just lateral to the forelimb. The lateral to medial development of SI may influence the capacity of hindlimb (but not face) inputs to "invade" the forelimb-stump region in neonatal amputees. The SI forelimb-stump was mapped in adult (>60 days) rats that had sustained amputation on embryonic day (E) 16, on P0, or during adulthood. GABA receptors were blocked and subsequent mapping revealed increases in nonstump inputs in E16 and P0 amputees: fetal amputees exhibited forelimb-stump sites responsive to face (34%), hindlimb (10%), and both (22%); neonatal amputees exhibited 10% face, 39% hindlimb, and 5% both; adult amputees exhibited 10% face, 5% hindlimb, and 0% both, with approximately 80% stump-only sites. These results indicate age-dependent differences in receptive-field reorganization of the forelimb-stump representation, which may reflect the spatiotemporal development of SI. Results from cobalt chloride inactivation of the SI vibrissae region and electrolesioning of the dysgranular cortex suggest that normally suppressed vibrissae inputs to the SI forelimb-stump area originate in the SI vibrissae region and synapse in the dysgranular cortex.