Drugs for the acute treatment of migraine in children and adolescents.

BACKGROUND: Numerous medications are available for the acute treatment of migraine in adults, and some have now been approved for use in children and adolescents in the ambulatory setting. A systematic review of acute treatment of migraine medication trials in children and adolescents will help clinicians make evidence-informed management choices. OBJECTIVES: To assess the effects of pharmacological interventions by any route of administration versus placebo for migraine in children and adolescents 17 years of age or less. For the purposes of this review, children were defined as under 12 years of age and adolescents 12 to 17 years of age. SEARCH METHODS: We searched seven bibliographic databases and four clinical trial registers as well as gray literature for studies through February 2016. SELECTION CRITERIA: We included prospective randomized controlled clinical trials of children and adolescents with migraine, comparing acute symptom relieving migraine medications with placebo in the ambulatory setting. DATA COLLECTION AND ANALYSIS: Two reviewers screened titles and abstracts and reviewed the full text of potentially eligible studies. Two independent reviewers extracted data for studies meeting inclusion criteria. We calculated the risk ratios (RRs) and number needed to treat for an additional beneficial outcome (NNTB) for dichotomous data. We calculated the risk difference (RD) and number needed to treat for an additional harmful outcome (NNTH) for proportions of adverse events. The percentage of pain-free patients at two hours was the primary efficacy outcome measure. We used adverse events to evaluate safety and tolerability. Secondary outcome measures included headache relief, use of rescue medication, headache recurrence, presence of nausea, and presence of vomiting. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 'Summary of findings' tables. MAIN RESULTS: We identified a total of 27 randomized controlled trials (RCTs) of migraine symptom-relieving medications, in which 9158 children and adolescents were enrolled and 7630 (range of mean age between 8.2 and 14.7 years) received medication. Twenty-four studies focused on drugs in the triptan class, including almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, sumatriptan + naproxen sodium, and zolmitriptan. Other medications studied included paracetamol (acetaminophen), ibuprofen, and dihydroergotamine (DHE). More than half of the studies evaluated sumatriptan. All but one study reported adverse event data. Most studies presented a low or unclear risk of bias, and the overall quality of evidence, according to GRADE criteria, was low to moderate, downgraded mostly due to imprecision and inconsistency. Ibuprofen was more effective than placebo for producing pain freedom at two hours in two small studies that included 162 children (RR 1.87, 95% confidence interval (CI) 1.15 to 3.04) with low quality evidence (due to imprecision). Paracetamol was not superior to placebo in one small study of 80 children. Triptans as a class of medication were superior to placebo in producing pain freedom in 3 studies involving 273 children (RR 1.67, 95% CI 1.06 to 2.62, NNTB 13) (moderate quality evidence) and 21 studies involving 7026 adolescents (RR 1.32, 95% CI 1.19 to 1.47, NNTB 6) (moderate quality evidence). There was no significant difference in the effect sizes between studies involving children versus adolescents. Triptans were associated with an increased risk of minor (non-serious) adverse events in adolescents (RD 0.13, 95% CI 0.08 to 0.18, NNTH 8), but studies did not report any serious adverse events. The risk of minor adverse events was not significant in children (RD 0.06, 95% CI - 0.04 to 0.17, NNTH 17). Sumatriptan plus naproxen sodium was superior to placebo in one study involving 490 adolescents (RR 3.25, 95% CI 1.78 to 5.94, NNTB 6) (moderate quality evidence). Oral dihydroergotamine was not superior to placebo in one small study involving 13 children. AUTHORS' CONCLUSIONS: Low quality evidence from two small trials shows that ibuprofen appears to improve pain freedom for the acute treatment of children with migraine. We have only limited information on adverse events associated with ibuprofen in the trials included in this review. Triptans as a class are also effective at providing pain freedom in children and adolescents but are associated with higher rates of minor adverse events. Sumatriptan plus naproxen sodium is also effective in treating adolescents with migraine.

Changes in intracortical excitability after transient ischemic attack are associated with ABCD² score.

BACKGROUND AND PURPOSE: A transient ischemic attack (TIA) is a brief ischemic episode characterized by rapid clinical resolution and not associated with permanent cerebral infarction. Whether changes in intracortical excitability persist and are related to clinical predictors of stroke risk after TIA remains unknown. METHODS: Participants were individuals with clinically resolved motor TIA with no structural lesions and healthy age-matched control participants. Single and paired-pulse transcranial magnetic stimulation was used to measure intracortical excitability. Recruitment curves for percent inhibition and facilitation were used to derive excitability thresholds. Correlations between threshold asymmetries and ABCD(2) score were performed. RESULTS: Results showed a significant 3-way interaction with reduced inhibition and enhanced facilitation in the affected compared with unaffected hemisphere after TIA. No significant differences were present in healthy participants. Asymmetries in intracortical inhibition and facilitation were significantly correlated with ABCD(2) score. CONCLUSIONS: The present study is the first, to our knowledge, to demonstrate altered intracortical inhibition and facilitation in the affected hemisphere after TIA. These changes occurred on average 2 weeks after clinical signs of TIA resolved and in the absence of structural lesions and were not present in healthy age-matched control participants. Furthermore, this study is the first, to our knowledge, to report that changes in intracortical excitability after TIA are associated with ABCD(2) score.

Excitatory repetitive transcranial magnetic stimulation to left dorsal premotor cortex enhances motor consolidation of new skills.

BACKGROUND: Following practice of skilled movements, changes continue to take place in the brain that both strengthen and modify memory for motor learning. These changes represent motor memory consolidation a process whereby new memories are transformed from a fragile to a more permanent, robust and stable state. In the present study, the neural correlates of motor memory consolidation were probed using repetitive transcranial magnetic stimulation (rTMS) to the dorsal premotor cortex (PMd). Participants engaged in four days of continuous tracking practice that immediately followed either excitatory 5 HZ, inhibitory 1 HZ or control, sham rTMS. A delayed retention test assessed motor learning of repeated and random sequences of continuous movement; no rTMS was applied at retention. RESULTS: We discovered that 5 HZ excitatory rTMS to PMd stimulated motor memory consolidation as evidenced by off-line learning, whereas only memory stabilization was noted following 1 Hz inhibitory or sham stimulation. CONCLUSION: Our data support the hypothesis that PMd is important for continuous motor learning, specifically via off-line consolidation of learned motor behaviors.

Changes in thresholds for intracortical excitability in chronic stroke: more than just altered intracortical inhibition.

PURPOSE: The purpose of the present study was to assess changes in thresholds for the onset of short intracortical inhibition (SICI) and intracortical facilitation (ICF) in individuals with chronic stroke compared to age-matched healthy adults and evaluate the relationship between these thresholds and motor function in the chronic stroke group. METHODS: Paired-pulse transcranial magnetic stimulation was used to derive thresholds for the onset of SICI and ICF in 12 neurologically healthy and 12 individuals with chronic stroke. Motor evoked potentials were elicited by a test stimulus of fixed intensity preceded by a conditioning stimulus ranging from 0%-125% of active motor threshold to generate recruitment curves. Regression functions were fit to these recruitment curves to identify thresholds for the onset of SICI and ICF. Mixed measures analysis of variance was used to compare thresholds for each hemisphere within and between groups. RESULTS: Results showed a significant three-way interaction between Group (stroke, healthy), Hemisphere (ipsilesional, contralesional) and Stimulus interval (2 ms, 12 ms). Significant differences in the thresholds for the onset of both SICI and ICF were present in individuals with chronic stroke, with no between hemisphere differences for the control group. When compared to age-matched controls, comparisons revealed significant reductions in ipsilesional, but not contralesional thresholds for the onset of ICF, and significant reductions in contralesional, but not ipsilesional, thresholds for the onset of SICI in individuals with chronic stroke. In addition, as thresholds for ICF and SICI in stroke patients approached the level of healthy adults, higher function on the Wolf Motor Function Test was observed. CONCLUSIONS: Reduced thresholds for the onset of SICI and ICF observed in the present study indicate that both inhibitory and facilitatory systems mediate changes in cortical excitability in chronic stroke patients. The association between higher onset thresholds and motor function in the stroke group also suggests that these thresholds have potential utility for tracking functional motor improvements in patients with chronic stroke. This study provides new insights to further characterize changes in intracortical neurotransmission that play an important role in modulating neuroplasticity and the potential relationship between inhibitory and facilitatory networks and motor function post-stroke.

Interhemispheric enhancement of somatosensory cortical excitability through contralateral repetitive transcranial magnetic stimulation.

OBJECTIVES: Somatosensory evoked potentials (SEPs) were used to index somatosensory-somatosensory interhemispheric interactions and highlight potential mechanisms by which TMS alters contralateral somatosensory cortex excitability. METHODS: Fifteen healthy individuals participated in three sessions on separate days. On each day participants received either: (1) continuous theta burst (cTBS), (2) 1 Hz repetitive transcranial magnetic stimulation (rTMS) or (3) control TMS over left somatosensory cortex. SEPs from right somatosensory cortex were recorded before and after TMS while participants were at rest, performed sensorimotor tracking or the sustained attention to response task (SART). Left-handed tracking performance was also indexed. RESULTS: N20-P27 amplitude was increased following 1 Hz rTMS while participants were at rest. This increased amplitude was not observed during right-handed tracking or the SART. N20-P27 amplitude was not influenced by cTBS or control TMS. P15-N20 and N34-P50 SEP components were not influenced by TMS. Right- and left-handed tracking performance was not transiently influenced by TMS. CONCLUSIONS: The results support TMS induced somatosensory-somatosensory interactions and offer converging evidence for an intercortical, rather that intracortical, mechanism that mediates contralateral sensory processing. These interactions appear to be dependent on concurrent attention/task demands. SIGNIFICANCE: Somatosensory-somatosensory interactions are reflected by intercortical mechanisms that are state and task dependent.

Continuous theta burst stimulation over the contralesional sensory and motor cortex enhances motor learning post-stroke.

The current study investigated the contributions of contralesional primary somatosensory cortex (S1c) to motor learning deficits post-stroke. For three days, continuous theta burst (cTBS) was delivered over the contralesional hemisphere prior to practicing a serial targeting task. cTBS was delivered over either S1c, contralesional primary motor cortex (M1c) or as control stimulation (n=4/group). Change in motor ability was assessed from initial performance to a delayed retention test using a serial targeting task and a subset of items from the Wolf Motor Function Test. Practice preceded by cTBS over either M1c or S1c resulted in large decreases in movement time compared to practice preceded by control stimulation. M1c cTBS resulted in larger decreases in peak velocity and peak acceleration compared to control and S1c cTBS. In contrast, S1c cTBS resulted in larger reductions in time to initiate movement and time to complete the WMFT compared to control and M1c cTBS. These preliminary findings suggest that stimulation of either M1c or S1c can enhance the benefits of practice. However, changes in M1c and S1c excitability may contribute to different aspects of post-stroke motor deficits that may differentially impact rehabilitation.

Reduced quadriceps motor-evoked potentials in an individual with unilateral knee osteoarthritis: a case report.

One male with unilateral osteoarthritis (OA) of the knee underwent testing of corticospinal (CS) excitability (as quantified from motor-evoked potentials (MEPs) in the rectus femoris (RF) using transcranial magnetic stimulation) and quadriceps muscle strength. Baseline data indicated reduced MEP amplitudes in the RF of the affected limb compared to the unaffected limb. Increases in RF MEP amplitudes from both limbs were observed immediately following a 30-minute exercise session focusing on muscle strengthening. Following an 8-week muscle strengthening intervention, the participant exhibited increased MEP amplitudes and muscle strength in the affected limb. These findings suggest that alterations in peripheral muscle function found in patients with knee OA may have an origin centrally within the motor cortex and that interlimb differences may be evident in those with unilateral disease. These findings also suggest that CS excitability may be improved following a muscle strengthening intervention.