Potential neurotoxicity of titanium implants: Prospective, in-vivo and in-vitro study.

Titanium dioxide (TiO2) is a frequently used biomaterial, particularly in orthopedic and dental implants, and it is considered an inert and benign compound. This has resulted in toxicological scrutiny for TiO2 in the past decade, with numerus studies showing potential pathologic downstream effects. Herein we describe case report of a 77-year-old male with subacute CNS dysfunction, secondary to breakdown of a titanium-based carotid stent and leading to blood levels 1000 times higher (3 ppm) than the reported normal. We prospectively collected tissues adjacent to orthopedic implants and found a positive correlation between titanium concentration and time of implant in the body (r = 0.67, p < 0.02). Rats bearing titanium implants or intravascularly treated with TiO2 nanoparticles (TiNP) exhibited memory impairments. A human blood-brain barrier (BBB) in-vitro model exposed to TiNP showed paracellular leakiness, which was corroborated in-vivo with the decrease of key BBB transcripts in isolated blood vessels from hippocampi harvested from TiNP-treated mice. Titanium particles rapidly internalized into brain-like endothelial cells via caveolae-mediated endocytosis and macropinocytosis and induced pro-inflammatory reaction with increased expression of pro-inflammatory genes and proteins. Immune reaction was mediated partially by IL-1R and IL-6. In summary, we show that high levels of titanium accumulate in humans adjacent to orthopedic implants, and our in-vivo and in-vitro studies suggest it may be neurotoxic.

Migraine and vascular risk factors in the elderly.

AIM: The association between migraine and cerebrovascular disease is well documented in younger migraine patients, especially those with aura. Prevalence estimates of vascular risk factors among elderly migraine sufferers are lacking. The present study was designed to estimate the prevalence of vascular risk factors in the elderly population with late onset of migraine without aura. METHODS: The medical records of 163 patients aged 50 years and older suffering from migraine without aura were assessed for vascular risk factors, including hypertension, elevated serum lipid levels, diabetes mellitus and cardiovascular disease. Prevalence was estimated and compared with age- and sex-matched vascular risk factor estimates for the general population extracted from the 2003-2004 Israeli National Health Interview Survey, and to a group of patients matched by age suffering from migraine with aura. RESULTS: Among women with migraine without aura, hypertension, hyperlipidemia and diabetes mellitus were significantly less prevalent than among women without migraine without aura. Prevalence estimates for vascular risk factors did not differ by migraine among males. The group of older patients suffering from migraine with aura showed a higher incidence of vascular risk factors in respect to the group of migraine patients without aura. CONCLUSIONS: The findings of the present study might have an important clinical relevance, suggesting another pathophysiological process in respect to patients suffering from migraine with aura, and this evidence might have different therapeutic implications.

Seizures after very mild head or spine trauma.

Traumatic brain injury (TBI) is a major cause of seizures in the general population. Several studies have shown an increased risk of epilepsy after traumatic brain injury, depending on risk factors, such as severity and time post trauma. The aim of our study was to evaluate the appearance of late seizures after a very mild head trauma or whiplash injury. All patients admitted to the emergency room after a very mild head trauma or whiplash injury during 2008-2010 were evaluated prospectively within 24 hours of the event and followed up 1 year later for evaluation of seizure appearance. The appearance of seizures in the head trauma or whiplash injury group was compared to a control group of orthopedic injury patients. A total of 2999 patients were included in the study--2005 patients with involvement of head and spine trauma and 994 in an orthopedic control group. Three patients (0.1%) out of the whole study group developed seizures: 2 (0.18%) in the head trauma group and 1 (0.1%) in the control group. The conclusion of the study was that post trauma seizure incidence is not significantly different in patients with very mild head or spine trauma and is similar respective to subjects with no non-head or cervical spine injury. This may have medico-legal repercussions.

SPECT-DTPA as a tool for evaluating the blood-brain barrier in post-stroke seizures.

Stroke is a well-known cause for seizures in the adult population. Research in animal models indicates that abnormalities in the blood-brain barrier (BBB) permeability can play a role in the development of spontaneous seizures or status epilepticus. The integrity of the BBB was investigated in patients with late post-stroke seizures by performing DTPA-SPECT studies to evaluate the correlation of BBB dysfunction in late post-stroke seizures. All patients with late-onset post-cortical stroke seizures hospitalized during 2009-2010 underwent a brain DTPA-SPECT within 72 h of the first seizure and were compared to a control group of stroke patients without seizures. Twenty-eight patients were included in the study. Twelve out of 14 (85.7%) in the group of seizure post-stroke patients had a positive brain DTPA-SPECT showing disruption of the BBB in the region of the stroke respective to four patients out of 14 (28.6%) in the control group of stroke patients without seizures (p = 0.001). The results of this study suggest that there is a correlation between late post-stroke seizures and BBB disruption, as revealed by DTPA-SPECT examination. Perhaps, this finding could lead to the hypothesis that the BBB disruption can predict developing seizures in patients with cortical stroke.

Are post intracerebral hemorrhage seizures prevented by anti-epileptic treatment?

Prophylactic antiepileptic treatment in patients with non-traumatic, non-aneurysmatic spontaneous intracerebral hemorrhage (SICH) is controversial. The purpose of our study was to assess the occurrence of seizures and neurologic outcome in SICH patients who were treated with valproic acid or a placebo for a period of one month and follow-up of one year in a hospital inpatient neurologic department and ambulatory clinic settings. The study is a prospective randomized, double-blind, placebo-controlled clinical trial. The patients were treated for one month with either valproic acid (VPA) or placebo immediately after a SICH and were followed-up for one year to evaluate seizure rate and neurologic function as measured by the National Institutes of Health Stroke Scale (NIHSS). Seventy-two patients participated in the study--36 were treated with VPA and 36 with placebo. During follow-up, 21% of the patients developed seizures. A by-treatment difference in incident seizures was not detected. However, a difference between reduction in early seizures and late one was observed in the VPA group. VPA-treated patients exhibited improved neurological outcome as measured by NIHSS. Early prophylaxis with VPA in SICH patients did not prevent the occurrence of seizures post intracerebral hemorrhage, but was found to reduce early seizures. VPA-treated patients had improved NIHSS scores, suggesting that this treatment may confer some neuroprotective effect. Further studies with a larger number of patients and with other antiepileptic drugs are needed to properly clarify this finding.

Chronic non-paroxysmal neuropathic pain - Novel phenotype of mutation in the sodium channel SCN9A gene.

BACKGROUND: Gain-of-function mutations in the SCN9A gene (encoding to NaV1.7 voltage-gated sodium channel) cause two rare paroxysmal pain disorders: inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEDP). These phenotypes are characterized by episodic extreme localized pain with cutaneous autonomic signs. So far, no other phenotypes have been associated with mutation in the SCN9A gene. OBJECTIVE: To investigate mutations in the SCN9A gene in patients with chronic non-paroxysmal neuropathic pain. PATIENTS: 9 patients with chronic severe unexplained neuropathic pain. RESULTS: Of the nine patients one had predicted pathologic mutations in the SCN9A gene. This patient had a heterozygous change of n.4648 T-C in exon 27 resulting in a substitution of W1550R, a highly conserved amino acid, predicting damage in the transmembrane S2 region, repeat IV. This mutation was not found in 50 controls. CONCLUSIONS: SCN9A mutations cause pain syndromes other than IEM and PEPD. These mutations should be considered in patients with resistant unexplained chronic neuropathic pain.

Early outcome of acute ischemic stroke in hyperlipidemic patients under atorvastatin versus simvastatin.

BACKGROUND: Studies designed to evaluate the efficacy of atorvastatin on stroke suggest that, in addition to cholesterol lowering, this drug may play a role in poststroke neuroprotection. The objective of this historical-prospective study was to analyze the efficacy of atorvastatin (40-80 mg) or simvastatin (at an optimal dose) during the first 2 weeks after stroke in hyperlipidemic patients treated with simvastatin before stroke onset. METHODS: Medical records of all adult (aged >18 years) patients diagnosed with acute stroke were reviewed. Subjects were categorized on the basis of poststroke treatment exposure: atorvastatin (40 or 80 mg) or simvastatin (at an optimal dose). Each patient was examined using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS). Blood lipid profile was determined. All tests were performed at baseline and at 4 weeks after stroke. RESULTS: A total of 371 patients (249 male and 122 female) were included. Subjects who received simvastatin were significantly older than those who received either dose of atorvastatin. Baseline differences in functional scores were not detected across treatment groups. Two weeks after stroke, subjects exposed to simvastatin had significantly poorer NIHSS and mRS scores than did subjects exposed to either atorvastatin dose. Atorvastatin 80 mg was associated with significantly better outcome compared with either of the other treatment groups. These differences persisted even after controlling for age and baseline scores. CONCLUSIONS: Early outcome measured by NIHSS and mRS was better in acute stroke patients treated with atorvastatin than in those treated with simvastatin. These differences may reflect a neuroprotective effect unique to atorvastatin.

Simultaneous bilateral Bell's palsy during pregnancy.

Idiopathic bilateral facial paralysis, although rare, seems to be more frequent during the last trimester of pregnancy and in the early puerperium. Unlike unilateral facial paralysis where the cause is mostly idiopathic, bilateral facial palsy is less often idiopathic, and various etiologies had been suggested.We present herein, an unusual case of simultaneous idiopathic bilateral Bell's palsy during the third trimester of pregnancy.

Use of a single [123I]-FP-CIT SPECT to predict the severity of clinical symptoms of Parkinson disease.

The aim of this study was to assess the ability of a single SPECT performed in the early stage of Parkinson's disease (PD) to predict disease severity in 19 patients with early PD. [(123)I]-FP-CIT striatal uptake was expressed as a ratio of specific:nonspecific uptake for defined brain areas. Clinical severity was determined by the UPDRS at baseline and 12-15 months following the SPECT procedure. [(123)I]-FP-CIT uptake in the contralateral putamen and striatum was correlated with UPDRS score at baseline, with a more significant correlation after 1-year interval. [(123)I]-FP-CIT uptake in all areas was correlated with bradykinesia and rigidity subscores only at follow up visit. Significant correlations were found between [(123)I]-FP-CIT uptake in the contralateral striatum, putamen and caudate and the difference between motor scores of 1-year interval (DeltaUPDRS). These results suggest that disease severity might be anticipated by a single SPECT at an early stage of the disease.

Acute painful neuropathy induced by rapid correction of serum glucose levels in diabetic patients.

We report on acute painful neuropathy following reduction of high serum glucose levels in six diabetic patients, aged 27-52 (5 males). Initial glucose levels ranging between 270 and 600 mg/dL decreased to 60-160 mg/dL following insulin, pharmacologic or dietary treatment. Four patients had long-standing untreated diabetes (3-5 years). All six patients experienced severe excruciating neuropathic pain 2-4 weeks after initiation of treatment. Pain was generalized in all, starting in the feet in 4 cases. Pain intensity prompted the use of combination therapy with various anti-neuropathic pain agents. Symptoms gradually improved in all patients, allowing discontinuation of symptomatic therapy within 3-8 months. We conclude that acute painful neuropathy can complicate the correction of high glucose levels in diabetic patients. Therefore, careful correction of glucose levels should be considered in patients with long-standing uncontrolled diabetes.

[Guideliness for the management of stroke--2008 invasive measures for prevention of ischemic stroke].

Stroke is a major cause of morbidity and mortality in Israel and the main cause for neurological disability among adults. Continued efforts for its prevention and treatment began a long time ago and currently persist. During the last decade, these efforts have resulted in a number of significant breakthroughs. Consequently, several new guidelines and consensus statements from Europe and North America have been published. In Israel, up to date, guidelines have been published only for acute stroke treatment, as well as for its prevention by medical means. The present guideline is supplemental to the previous papers and focuses on the invasive options to treat specific risk factors and conditions, when appropriate, for primary and secondary stroke prevention.

Surgical resection of left atrial myxoma presenting with acute multiple hemorrhagic cerebral infarctions: a case report.

Brain ischemia resulting from left atrial myxoma embolization has been well documented. In contrast, the link between the development of intracerebral hemorrhage and myxoma in these patients has little coverage in the literature. The main theory describing this relationship stems from the fact that cardiac myxoma cells metastasize to the brain's vessels, causing destruction of the arterial wall with subsequent formation of fusiform aneurysm and further intracranial bleeding. It is assumed that when a diagnosis of left atrial myxoma with neurologic manifestations is made, surgical resection should be performed without delay to prevent repeated tumor embolization; however, systemic anticoagulation treatment during cardiac surgery with cardiopulmonary bypass is not recommended immediately after intracerebral hemorrhage occurs because of the possibility of extending the infarct's size. We describe a patient with acute hemorrhagic brain infarction and an echocardiographically demonstrated left atrial myxoma that was surgically resected successfully in the acute phase after the onset of the neurologic symptoms.

DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke.

BACKGROUND AND PURPOSE: DP-b99 is a chelator of zinc and calcium ions that acts selectively within cell membranes and has neuroprotective properties in animal models of stroke. We present the results of a multicenter, double-blind, placebo-controlled, randomized trial to assess the safety and potential protective effects of DP-b99 in acute ischemic stroke. METHODS: One hundred and fifty stroke patients with signs of cortical involvement and a National Institutes of Health Stroke Scale (NIHSS) score of 7 to 20 received a 4-day course of intravenous 1 mg/kg per day DP-b99 or placebo within 1 to 9 hours of stroke onset. Treatment with recombinant tissue plasminogen activator was not allowed. RESULTS: No major differences in mortality rate, causes of death, adverse events, safety laboratory tests, and ECG parameters were found between the 2 groups. The baseline NIHSS score of the 72 DP-b99- and 75 placebo-treated patients in the intent-to-treat cohort was (mean+/-SD) 12.2+/-4.0 and 12.6+/-3.3, respectively; the time to needle (mean+/-SD) was 6:36+/-1:47 and 6:28+/-1:33 hours, respectively; and the age (mean+/-SD) was 73.3+/-9.9 and 72.0+/-9.6 years, respectively. The 90-day median change from baseline (the primary end point) was -6.0 and -5.0 NIHSS points in the DP-b99 and placebo groups, respectively (nonsignificant). At 90 days, there was a significantly better outcome in the DP-b99 group compared with the placebo group (modified Rankin scale score of 0, 1, or same as prestroke): 30.6% and 16.0%, respectively (P=0.05). The recovery rate was unaffected by the time to needle. Further analyses indicated that the 90-day median change from baseline in patients with an entry NIHSS score of 10 to 16 was 8.0 and 5.0 points in the DP-b99 and placebo groups, respectively (P=0.03). CONCLUSIONS: In this small-scale study, the primary end point of change in NIHSS score from baseline to 90 days was not met. However, secondary end points demonstrated a significantly improved 90-day recovery rate with treatment with DP-b99 when compared with placebo. In addition, in patients with baseline NIHSS scores of 10 to 16, a significant post hoc change in NIHSS score from baseline to day 90 was observed. No major safety problems were identified. These findings need to be confirmed with a larger prospective study of strokes involving the cortex.

Lamotrigine and catamenial epilepsy.

Catamenial epilepsy (CE) is characterized by epileptic seizures in the female occurring rhythmatically with the menstrual cycle. Hormonal mechanisms have been proposed as a cause of this epileptic form. Few reports about the efficacy of anti-epileptic drugs (AEDs) have been published. We studied prospectively women with CE who were treated with lamotrigine (LTG) for a period of 3 months in order to evaluate its efficacy, measuring the progesterone levels before and after LTG at the same time. LTG seemed to be efficacious in 66% of women, meaning the disappearance of seizures or reduction of 50% or more of the number of seizures. The reported side effects were few and mild, and the drug was well tolerated. Serum progesterone levels were found to rise during LTG treatment.

I-123 MIBG cardiac scintigraphy and autonomic test evaluation in multiple sclerosis patients.

Autonomic symptoms are common in multiple sclerosis (MS) patients and may cause significant disability. The purpose of this study was to evaluate direct cardiac sympathetic denervation in MS patients with I-123 MIBG cardiac scintigraphy compared with other parasympathetic electrophysiological examinations of autonomic dysfunction. Ten patients with MS and 7 age- and sex-matched control subjects were prospectively evaluated. The neurological deficit and disability stages of the patients were rated according to the Kurtzke Expanded Disability Status Scale (EDSS). Autonomic tests included the R-R interval, Valsalva ratio and standup test. All patients and control subjects had planar and SPECT cardiac scintigraphy with I-123 MIBG injection. Seven MS patients had relapsing-remitting (R-R) type and three had secondary progressive type (SP). A pathological MIBG cardiac washout rate was found in 3/10 MS patients, all of them with SP-MS. The other seven had normal washout rates. No correlation was found between the scan and the individual parasympathetic autonomic test results. I-123 MIBG myocardial scintigraphy may detect direct disturbances of the sympathetic cardiac function in patients with MS in addition to parasympathetic dysfunction tests and can be an important additional means of assessing autonomic pathways. Determination in MS of the co-existence of autonomic dysfunction, especially the cardiac sympathetic involvement in the SP type, may aid in evaluation of disease severity and cardiac function follow-up.

Monotherapy of lamotrigine versus carbamazepine in patients with poststroke seizure.

OBJECTIVES: The incidence of seizures is known to be high in the elderly. The most common cause of an unprovoked seizure in the elderly population is stroke. These patients require effective and well-tolerated antiepileptic treatment because they frequently experience other medical conditions and use other medications that can interact with the antiepileptic treatment. The aim of the study was to analyze the tolerability and efficacy of lamotrigine (LTG) versus sustained-release carbamazepine (CBZ) treatment in newly diagnosed symptomatic poststroke seizure. METHODS: Sixty-four patients with a first post episode of seizures were randomized in a 1:1 ratio to either LTG or CBZ treatment and were followed up prospectively for up to 12 months for efficacy and tolerability of the drugs. RESULTS: More patients in the LTG group were seizure-free (72%) versus those in the CBZ group (44%; P = 0.06), but the numbers did not reach statistical significance because of a relative small number of study patients. The number of patients who withdraw from the study because of adverse events was statistically significantly less in the LTG group (3%) compared with the CBZ group (31%; P = 0.02). CONCLUSIONS: The LTG treatment in poststroke seizures versus CBZ treatment is a relatively better-tolerated drug and can be acceptable as initial treatment in this specific group of patients.

Laser treatment for stroke.

Low-level laser therapy is an irradiation technique that has the ability to induce biological processes using photon energy. There are studies showing proliferation and angiogenesis after irradiation in skeletal muscle post-myocardial infarction tissue cells. Most evidence of efficacy is based on the increase in energy state and the activation of mitochondrial pathways. In the brain, there is similar evidence of cellular activity with laser irradiation. In vivo studies reinforced the efficacy of this technique for a better neurological and functional outcome post-stroke. The evidence is based on in vivo animal studies of various models and one human clinical study. Although the data is very promising, some fundamental questions remain to be answered, such as the exact mechanism along the cascade of post-stroke interconnective molecular disturbance, the optimal technique and time of treatment, and the long-term safety aspects. The answers to these questions are expected to evolve within the next few years.

[Guidelines for the management of stroke--2007 prevention of ischemic stroke--general approach and medical treatment].

Stroke is a major cause of morbidity and mortality in Israel, the third most common cause of death and the main cause for neurological disability among adults. During the last decade several significant breakthroughs have occurred in the management of stroke and consequently several new guidelines and consensus statements from Europe and North America have been published. The new data necessitate a reappraisal of our approach to the management of stroke as well as to its primary prevention. The present guidelines focus on primary and secondary stroke prevention by medical means and provide detailed, updated, clinical guidelines for most specific risk factors and conditions, ways to investigate the underlying stroke mechanism and its preferred medical treatment. Invasive (surgical, stent insertion, correction of cardiac anomalies etc.) will be dealt with separately.

Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the NeuroThera Effectiveness and Safety Trial-1 (NEST-1).

BACKGROUND AND PURPOSE: The NeuroThera Effectiveness and Safety Trial-1 (NEST-1) study evaluated the safety and preliminary effectiveness of the NeuroThera Laser System in the ability to improve 90-day outcomes in ischemic stroke patients treated within 24 hours from stroke onset. The NeuroThera Laser System therapeutic approach involves use of infrared laser technology and has shown significant and sustained beneficial effects in animal models of ischemic stroke. METHODS: This was a prospective, intention-to-treat, multicenter, international, double-blind, trial involving 120 ischemic stroke patients treated, randomized 2:1 ratio, with 79 patients in the active treatment group and 41 in the sham (placebo) control group. Only patients with baseline stroke severity measured by National Institutes of Health Stroke Scale (NIHSS) scores of 7 to 22 were included. Patients who received tissue plasminogen activator were excluded. Outcome measures were the patients' scores on the NIHSS, modified Rankin Scale (mRS), Barthel Index, and Glasgow Outcome Scale at 90 days after treatment. The primary outcome measure, prospectively identified, was successful treatment, documented by NIHSS. This was defined as a complete recovery at day 90 (NIHSS 0 to 1), or a decrease in NIHSS score of at least 9 points (day 90 versus baseline), and was tested as a binary measure (bNIH). Secondary outcome measures included mRS, Barthel Index, and Glasgow Outcome Scale. Primary statistical analyses were performed with the Cochran-Mantel-Haenszel rank test, stratified by baseline NIHSS score or by time to treatment for the bNIH and mRS. Logistic regression analyses were conducted to confirm the results. RESULTS: Mean time to treatment was >16 hours (median time to treatment 18 hours for active and 17 hours for control). Time to treatment ranged from 2 to 24 hours. More patients (70%) in the active treatment group had successful outcomes than did controls (51%), as measured prospectively on the bNIH (P=0.035 stratified by severity and time to treatment; P=0.048 stratified only by severity). Similarly, more patients (59%) had successful outcomes than did controls (44%) as measured at 90 days as a binary mRS score of 0 to 2 (P=0.034 stratified by severity and time to treatment; P=0.043 stratified only by severity). Also, more patients in the active treatment group had successful outcomes than controls as measured by the change in mean NIHSS score from baseline to 90 days (P=0.021 stratified by time to treatment) and the full mRS ("shift in Rankin") score (P=0.020 stratified by severity and time to treatment; P=0.026 stratified only by severity). The prevalence odds ratio for bNIH was 1.40 (95% CI, 1.01 to 1.93) and for binary mRS was 1.38 (95% CI, 1.03 to 1.83), controlling for baseline severity. Similar results held for the Barthel Index and Glasgow Outcome Scale. Mortality rates and serious adverse events (SAEs) did not differ significantly (8.9% and 25.3% for active 9.8% and 36.6% for control, respectively, for mortality and SAEs). CONCLUSIONS: The NEST-1 study indicates that infrared laser therapy has shown initial safety and effectiveness for the treatment of ischemic stroke in humans when initiated within 24 hours of stroke onset. A larger confirmatory trial to demonstrate safety and effectiveness is warranted.