Vestibular migraine (VM), a common cause of vestibular symptoms within the general population, is a disabling and poorly understood form of dizziness. We sought to examine the underlying pathophysiology of VM with three studies, which involved the central synthesis of canal and otolith cues, and present preliminary results from each of these studies: (1) VM patients appear to have reduced motion perception thresholds when canal and otolith signals are modulated in a co-planar manner during roll tilt; (2) percepts of roll tilt appear to develop more slowly in VM patients than in control groups during a centrifugation paradigm that presents conflicting, orthogonal canal and otolith cues; and (3) eye movement responses appear to be different in VM patients when studied with a post-rotational tilt paradigm, which also presents a canal–otolith conflict, as the shift of the eye’s rotational axis was larger in VM and the relationship between the axis shift and tilt suppression of the vestibulo-ocular reflex differed in VM patients relative to control groups. Based on these preliminary perceptual and eye movement results obtained with three different motion paradigms, we present a hypothesis that the integration of canal and otolith signals by the brain is abnormal in VM and that this abnormality could be cerebellar in origin. We provide potential mechanisms that could underlie these observations, and speculate that one of more of these mechanisms contributes to the vestibular symptoms and motion intolerance that are characteristic of the VM syndrome.
vestibular; migraine; cerebellum; perception; oculomotor
Biobanks raise challenges for developing ethically sound and practicable consent policies. Biobanks comprised of dried bloodspots (DBS) left over from newborn screening, maintained for long-term storage, and potential secondary research applications are no exception. Michigan has been a leader in transforming its DBS collection, marketing its biobank of de-identified samples for health research use. The Michigan BioTrust for Health includes approximately 4 million unconsented retrospective samples collected as early as 1984 and prospective samples added since the fall of 2010 with blanket parental consent. We engaged Michigan citizens to ascertain public attitudes, knowledge, and beliefs about the BioTrust and informed consent. A convenience sampling of 393 participants from communities around the state of Michigan (oversampling for minority populations) participated in meetings addressing newborn screening, the BioTrust and informed consent, yielding quantitative and qualitative survey and discussion data. Participants affirmed the principle of voluntary informed participation in research and advocated for greater public awareness of the existence of the BioTrust. Most expressed support for the use of DBS for research and a desire for greater involvement in granting permission for research use. Opinions varied as to which specific research uses were acceptable. Participants indicated a desire for greater engagement, public awareness, and more active decision making on the part of biobank participants and parents. Diversity of opinion over which research areas were deemed acceptable problematizes the blanket consent model that currently applies to the BioTrust’s prospective DBS collection and that could become the new norm for research using de-identified data under proposed changes to the Common Rule.
Electronic supplementary material
The online version of this article (doi:10.1007/s12687-013-0162-0) contains supplementary material, which is available to authorized users.
Biobank; Public health; Informed consent; Newborn screening; Community engagement
In 1999, Ontario implemented a policy to offer HIV counseling and testing to all pregnant women and undertook measures to increase HIV testing. We evaluated the effectiveness of the new policy by examining HIV test uptake, the number of HIV-infected women identified and, in 2002, the HIV rate in women not tested during prenatal care. We analyzed test uptake among women receiving prenatal care from 1999 to 2010. We examined HIV test uptake and HIV rate by year, age and health region. In an anonymous, unlinked study, we determined the HIV rate in pregnant women not tested. Prenatal HIV test uptake in Ontario increased dramatically, from 33% in the first quarter of 1999 to 96% in 2010. Test uptake was highest in younger women but increased in all age groups. All health regions improved and experienced similar test uptake in recent years. The HIV rate among pregnant women tested in 2010 was 0.13/1,000; in Toronto, the rate was 0.28 per 1,000. In the 2002 unlinked study, the HIV rate was 0.62/1,000 among women not tested in pregnancy compared to 0.31/1,000 among tested women. HIV incidence among women who tested more than once was 0.05/1,000 person-years. In response to the new policy in Ontario, prenatal HIV testing uptake improved dramatically among women in all age groups and health regions. A reminder to physicians who had not ordered a prenatal HIV test appeared to be very effective. In 2002, the HIV rate in women who were not tested was twice that of tested women: though 77% of pregnant women had been tested, only 63% of HIV-infected women were tested. HIV testing uptake was estimated at 98% in 2010.
The cerebellum plays an important role in programming accurate saccades. Cerebellar lesions affecting the ocular motor region of the fastigial nucleus (FOR) cause saccadic hypermetria; however, if a second target is presented before a saccade can be initiated (double-step paradigm), saccade hypermetria may be decreased. We tested the hypothesis that the cerebellum, especially FOR, plays a pivotal role in programming sequences of saccades. We studied patients with saccadic hypermetria due either to genetic cerebellar ataxia or surgical lesions affecting FOR and confirmed that the gain of initial saccades made to double-step stimuli was reduced compared with the gain of saccades to single target jumps. Based on measurements of the intersaccadic interval, we found that the ability to perform parallel processing of saccades was reduced or absent in all of our patients with cerebellar disease. Our results support the crucial role of the cerebellum, especially FOR, in programming sequences of saccades.
fastigial nucleus; double-step; saccade; latency; spinocerebellar ataxia; hypermetria; parallel processing
Disturbance of vertical saccadesis a cardinal feature of progressive supranuclear palsy (PSP). We investigated whether the amplitude and peak velocity of saccades is affected by the orbital position fromwhich movements start in PSP patients and age-matched control subjects. Subjects made vertical saccades in response to ± 5 degree vertical target jumps with their heads in one of three positions: head “center,” head pitched forward ~15 degrees, and head pitched back ~ 15 degrees.All patients showed some effect of starting eye position, whether beginning in the upward or downward field of gaze, on saccade amplitude, peak velocity (PV), and net range of movement. Generally, reduction of amplitude and PV were commensurate and bidirectional in the affected hemifield of gaze. Such findings are unlikelyto be due to orbital factors and could be explained by varying degrees of involvement of rostral midbrain nucleiin the pathological process.
saccades; midbrain; neural integrator; eyeball; parkinsonian disorders
Paraneoplastic syndromes affecting the brainstem and cerebellum are reported to cause a variety of abnormalities of eye movements. Recent studies have begun to account for the mechanisms underlying several syndromes, characterized by opsoclonus, slow, or dysmetric saccades, as well as downbeat nystagmus. We provide evidence that upbeat nystagmus in a patient with pancreatic cancer reflected a cerebellar-induced imbalance of otolithic pathways: she showed marked retropulsion, and her nystagmus was dependent on head position, being absent when supine, and suppressed with convergence. In addition to anti-Hu antibodies, we demonstrated antibodies to a novel neuronal cell surface antigen. Taken with other recent studies, our findings suggest that paraneoplastic syndromes arise due to antibodies against surface neuronal antigens, including receptors and channels. Abnormal eye movements in paraneoplastic syndromes offer insights into the pathogenesis of these disorders and the opportunity to test potential therapies, such as new drugs with effects on neuronal channels.
upbeat nystagmus; oscillopsia; pancreatic endocrine; neoplasm
Studying saccades can illuminate the more complex decision-making processes required for everyday movements. The double-step task, in which a target jumps to two successive locations before the subject has time to react, has proven a powerful research tool to investigate the brain’s ability to program sequential responses. We asked how patients with a range of cerebellar disorders responded to the double-step task, specifically, whether the initial saccadic response made to a target is affected by the appearance of a second target jump. We also sought to determine whether cerebellar patients were able to make corrective saccades towards the remembered second target location, if it were turned off soon after presentation. We tested saccades to randomly interleaved single- and double-step target jumps to eight locations on a circle. Patient’s initial responses to double-step stimuli showed 50% more error than saccades to single target jumps, and often, they failed to make a saccade to the first target jump. The presence of a second target jump had similar, but smaller effects in control subjects (error increased by 18%). During memory-guided double-step trials, both patients and controls made corrective saccades in darkness to the remembered location of the second jump. We conclude that in cerebellar patients, the second target jump interferes with programming of the saccade to the first target jump of a double-step stimulus; this defect highlights patients’ impaired ability to respond appropriately to sudden, conflicting changes in their environment. Conversely, since cerebellar patients can make corrective memory-guided saccades in darkness, they retain the ability to remember spatial locations, possibly due to non-retinal neural signals (corollary discharge) from cerebral hemispheric areas concerned with spatial localization.
Saccades; double-step; dysmetria; cerebellum, fastigial nucleus; efference copy
Rapid shifts of the point of visual fixation between equidistant targets require equal-sized saccades of each eye. The brainstem medial longitudinal fasciculus (MLF) plays a cardinal role in ensuring that horizontal saccades between equidistant targets are tightly yoked. Lesions of the MLF—internuclear ophthalmoparesis (INO)—cause horizontal saccades to become disjunctive: adducting saccades are slow, small, or absent. However, in INO, convergence movements may remain intact. We studied horizontal gaze shifts between equidistant targets and between far and near targets aligned on the visual axis of one eye (Müller test paradigm) in five cases of INO and five control subjects. We estimated the saccadic component of each movement by measuring peak velocity and peak acceleration. We tested whether the ratio of the saccadic component of the adducting/abducting eyes stayed constant or changed for the two types of saccades. For saccades made by control subjects between equidistant targets, the group mean ratio (±SD) of adducting/abducting peak velocity was 0.96 ± 0.07 and adducting/abducting peak acceleration was 0.94 ± 0.09. Corresponding ratios for INO cases were 0.45 ± 0.10 for peak velocity and 0.27 ± 0.11 for peak acceleration, reflecting reduced saccadic pulses for adduction. For control subjects, during the Müller paradigm, the adducting/abducting ratio was 1.25 ± 0.14 for peak velocity and 1.03 ± 0.12 for peak acceleration. Corresponding ratios for INO cases were 0.82 ± 0.18 for peak velocity and 0.48 ± 0.13 for peak acceleration. When adducting/abducting ratios during Müller versus equidistant targets paradigms were compared, INO cases showed larger relative increases for both peak velocity and peak acceleration compared with control subjects. Comparison of similar-sized movements during the two test paradigms indicated that whereas INO patients could decrease peak velocity of their abducting eye during the Müller paradigm, they were unable to modulate adducting velocity in response to viewing conditions. However, the initial component of each eye’s movement was similar in both cases, possibly reflecting activation of saccadic burst neurons. These findings support the hypothesis that horizontal saccades are governed by disjunctive signals, preceded by an initial, high-acceleration conjugate transient and followed by a slower vergence component.
Eye movements; Saccades; Vergence; Medial longitudinal fasciculus; Hering’s law; Multiple sclerosis; Internuclear ophthalmoplegia
Most patients with fibromyalgia use complementary and alternative medicine (CAM). Properly designed controlled trials are necessary to assess the effectiveness of these practices. This study was a randomized, double-blind, placebo-controlled, early phase trial. Fifty patients seen at a fibromyalgia outpatient treatment program were randomly assigned to a daily soy or placebo (casein) shake. Outcome measures were scores of the Fibromyalgia Impact Questionnaire (FIQ) and the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline and after 6 weeks of intervention. Analysis was with standard statistics based on the null hypothesis, and separation test for early phase CAM comparative trials. Twenty-eight patients completed the study. Use of standard statistics with intent-to-treat analysis showed that total FIQ scores decreased by 14% in the soy group (P = .02) and by 18% in the placebo group (P < .001). The difference in change in scores between the groups was not significant (P = .16). With the same analysis, CES-D scores decreased in the soy group by 16% (P = .004) and in the placebo group by 15% (P = .05). The change in scores was similar in the groups (P = .83). Results of statistical analysis using the separation test and intent-to-treat analysis revealed no benefit of soy compared with placebo. Shakes that contain soy and shakes that contain casein, when combined with a multidisciplinary fibromyalgia treatment program, provide a decrease in fibromyalgia symptoms. Separation between the effects of soy and casein (control) shakes did not favor the intervention. Therefore, large-sample studies using soy for patients with fibromyalgia are probably not indicated.
Progressive supranuclear palsy (PSP) is a disease of later life that is currently regarded as a form of neurodegenerative tauopathy. Disturbance of gaze is a cardinal clinical feature of PSP that often helps clinicians to establish the diagnosis. Since the neurobiology of gaze control is now well understood, it is possible to use eye movements as investigational tools to understand aspects of the pathogenesis of PSP. In this review, we summarize each disorder of gaze control that occurs in PSP, drawing on our studies of 50 patients, and on reports from other laboratories that have measured the disturbances of eye movements. When these gaze disorders are approached by considering each functional class of eye movements and its neurobiological basis, a distinct pattern of eye movement deficits emerges that provides insight into the pathogenesis of PSP. Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free. Taken with the prominent early feature of falls, these findings suggest that PSP tauopathy impairs a recently evolved neural system concerned with bipedal locomotion in an erect posture and frequent gaze shifts between the distant environment and proximate hands. This approach provides a conceptual framework that can be used to address the nosological challenge posed by overlapping clinical and neuropathological features of neurodegenerative tauopathies.
saccades; vergence; vestibular; parkinsonian disorders; tauopathy
Lack of immunological tolerance against self-antigens results in autoimmune disorders. During onset of autoimmunity, dendritic cells (DCs) are thought to be critical for priming of self-reactive T cells that have escaped tolerance induction. However, because DCs can also induce T cell tolerance, it remains unclear whether DCs are required under steady-state conditions to prevent autoimmunity. To address this question, we crossed CD11c-Cre mice with mice that express diphtheria toxin A (DTA) under the control of a loxP-flanked neomycin resistance (neoR) cassette from the ROSA26 locus. Cre-mediated removal of the neoR cassette leads to DTA expression and constitutive loss of conventional DCs, plasmacytoid DCs, and Langerhans cells. These DC-depleted (ΔDC) mice showed increased frequencies of CD4 single-positive thymocytes and infiltration of CD4 T cells into peripheral tissues. They developed spontaneous autoimmunity characterized by reduced body weight, splenomegaly, autoantibody formation, neutrophilia, high numbers of Th1 and Th17 cells, and inflammatory bowel disease. Pathology could be induced by reconstitution of wild-type (WT) mice with bone marrow (BM) from ΔDC mice, whereas mixed BM chimeras that received BM from ΔDC and WT mice remained healthy. This demonstrates that DCs play an essential role to protect against fatal autoimmunity under steady-state conditions.
Although maternal screening and the administration of prophylactic intrapartum antibiotics have decreased the incidence of early onset group B streptococcal (GBS) disease in neonates, there is still significant morbidity and mortality as a result of neonatal GBS disease.
Maternal GBS infections are not uncommon, but with appropriate therapy there is almost a uniformly good outcome. Little is written about the appropriate management of well infants born to mothers with postpartum GBS sepsis.
The question of whether well infants born to mothers with GBS puerperal sepsis should be treated empirically with antibiotics and the lack of literature concerning this issue became apparent when an untreated term infant died of late onset GBS meningitis following maternal puerperal GBS sepsis. We describe this event in the following case presentation.
With the current paucity of literature regarding the management of well infants born to mothers with postpartum GBS sepsis, it seems prudent to treat such infants empirically with antibiotics (following a full septic work-up) until this matter has been investigated further.
Group B streptococcus; Postpartum sepsis
The number of antiretroviral agents available for children who are failing existing therapy is limited. Data are lacking on the use of various combination regimens and the resulting viral load dynamics in such children.
Between March 1998 and March 2000, HIV-infected children younger than 18 years of age were studied in an open trial. The study regimen included ritonavir, with at least two drugs to which the virus was known or presumed to be sensitive. Subjects were ritonavir-naive and were included if they had high viral loads while receiving antiretroviral therapy. Patients had clinical assessments, CD4 counts and viral load monitoring.
Fifteen antiretroviral-experienced HIV-infected children were enrolled. Approximately 87% (13 of 15) had perinatally-acquired HIV; median age was 7.9 years (range 1.6 to 14.8). At enrolment, the median CD4 count was 557 cells/mm3 (range 57 to 1702) and the median viral load was 72,600 copies/mL (range 3626 to 796,440). The majority of children (73.3%) had increases in CD4 counts within 12 weeks. During this period, the median increase in CD4 counts over baseline was 30.0%. Approximately 73% (eight of 11) of subjects with initial improvements in CD4 counts had sustained increases at 32 to 48 weeks. Over the first 12 weeks, 60% (nine of 15) had greater than 0.5 log10 decreases in viral load. The improvement was sustained in 88.9% (eight of nine) of these patients at 32 to 48 weeks. Three patients discontinued therapy due to taste aversion.
Among pediatric patients with high viral loads while on existing therapy, the ritonavir-containing regimen was generally well tolerated. In a significant proportion of patients, modification of therapy was associated with sustained improvements in viral loads and CD4 counts over 32 to 48 weeks.
Antiretroviral therapy; HIV infection; HIV viral load; Pediatrics; Protease inhibitor
To evaluate the effect of the antimicrobial agent trimethoprim/sulphamethoxazole (TMP/SMX) on the pharmacokinetic properties of the antiretroviral drug zidovudine (ZDV).
This single dose, open label, crossover study involved the oral administration of ZDV (150 mg/m2) alone and in combination with oral TMP/SMX (2.5 mg/kg) on two separate occasions. Serial blood samples (0 to 8 h) were collected, and concentrations of ZDV and its glucuronide metabolite were quantified using a radioimmunoassay. ZDV pharmacokinetics were determined by noncompartmental analysis.
PATIENTS AND SETTING:
Six HIV-1 infected children aged four months to five years were recruited from the HIV clinic at The Hospital for Sick Children, Toronto, Ontario. Only three patients completed both study phases and were included in the pharmacokinetic analysis.
With TMP/SMX therapy, no statistically significant changes were observed in ZDV pharmacokinetic parameters. However, there was a trend towards increased ZDV half-life and area under the concentration versus time curve, as well as decreased apparent oral clearance. Similarly, a trend towards an increased half-life of the ZDV-glucuronide metabolite was also observed.
The changes in ZDV pharmacokinetics in the presence of TMP/SMX did not reach statistical significance, most likely due to the limited number of patients involved. Despite the limited data, a possible interaction between ZDV and TMP/SMX in young HIV-1 infected children should be considered, and patients may require close clinical monitoring.
Children; Drug interactions; HIV; Trimethoprim/sulphamethoxazole; Zidovudine
A multicentre randomized controlled trial was conducted in children with bacterial meningitis using dexamethasone or placebo for four days within 24 h of starting antibiotics. Primary outcomes were hearing loss and neurological abnormalities at 12 months after meningitis. The dexamethasone (n=50) and placebo (n=51) groups were similar in age, severity of illness and etiological agent. Hearing loss occurred in 10% and 11% of the dexamethasone and placebo groups and neurological deficits occurred in 20% and 18% of patients, respectively. Duodenal perforation occurred in one dexamethasone-treated child. In conclusion, there was no significant benefit in those receiving dexamethasone. The lack of benefit may have been due to the delay in administration of dexamethasone (median delay of 11 h after antibiotics). Therefore, if dexamethasone is used for meningitis it should be given immediately with the antibiotic.
Bacterial meningitis; Dexamethasone; Pediatrics
The morbidity and mortality of patients with bacterial meningitis treated initially with cefuroxime were studied and compared with the results of a previous prospective study of patients treated initially with ampicillin plus chloramphenicol in the same institution from 1979 to 1983. A retrospective chart review was completed in all cases of microbiologically confirmed bacterial meningitis admitted to the Hospital for Sick Children in Toronto, Ontario between January 1, 1984 and August 1, 1988. During this period all patients were treated initially with intravenous cefuroxime. The 167 children reviewed ranged in age from six weeks to 17.1 years (median 11.6 months). The case fatality rate was 7.8% and the rate of hearing deficit 13%. There were no statistically significant differences in abnormal neurological outcome (20 versus 20%, respectively), hearing loss (12.9 versus 13%, respectively), and case fatality rate (6.4 versus 7.8%, respectively) between the cohort of 1979–83 and the present study. The rate of hearing loss following meningitis caused by Haemophilus influenzae type b increased from 7.3 to 11.7% (P=0.26).
Bacterial meningitis; Cefuroxime; Pediatric