Difference in neuropathogenetic mechanisms in human furious and paralytic rabies

From Journal of the Neurological Sciences Volume 238, Issues 1-2 , 15 November 2005, Pages 3-10

Erawady Mitrabhakdia, , , Shanop Shuangshotib, Pongsak Wannakrairotb, Richard A. Lewisd, Keiichiro Susukic, Jiraporn Laothamatase and Thiravat Hemachudhaa
aNeurology Division, Department of Medicine, Chulalongkorn University Hospital, Rama 4 Road, Bangkok 10330, Thailand
bDepartment of Pathology, Chulalongkorn University Hospital, Bangkok, Thailand
cDepartment of Neurology, Dokkyo University School of Medicine, Mibu, Shimotsuga, Tochigi, Japan
dDepartment of Neurology, Wayne State University, Detroit, MI, USA
eDepartment of Radiology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

Abstract
Whereas paralysis is the hallmark for paralytic rabies, the precise pathological basis of paralysis is not known. It is unclear whether weakness results from involvement of anterior horn cells or of motor nerve fibers. There is also no conclusive data on the cause of the neuropathic pain which occurs at the bitten region, although it has been presumed to be related to sensory ganglionopathy. In this study, six laboratory-proven rabies patients (three paralytic and three furious) were assessed clinically and electrophysiologically. Our data suggests that peripheral nerve dysfunction, most likely demyelination, contributes to the weakness in paralytic rabies. In furious rabies, progressive focal denervation, starting at the bitten segment, was evident even in the absence of demonstrable weakness and the electrophysiologic study suggested anterior horn cell dysfunction. In two paralytic and one furious rabies patients who had severe paresthesias as a prodrome, electrophysiologic studies suggested dorsal root ganglionopathy. Postmortem studies in two paralytic and one furious rabies patients, who had local neuropathic pain, showed severe dorsal root ganglionitis. Intense inflammation of the spinal nerve roots was observed more in paralytic rabies patients. Inflammation was mainly noted in the spinal cord segment corresponding to the bite in all cases; however, central chromatolysis of the anterior horn cells could be demonstrated only in furious rabies patient. We conclude that differential sites of neural involvement and possibly different neuropathogenetic mechanisms may explain the clinical diversity in human rabies.

Anticonvulsant therapy for status epilepticus

From Cochrane Review

Background: Status epilepticus is a medical emergency associated with significant mortality and morbidity, which requires immediate and effective treatment.

Objectives: (1) To determine whether a particular anticonvulsant is more effective or safer to use in status epilepticus compared to another and compared to placebo.(2) To delineate reasons for disagreement in the literature regarding recommended treatment regimens and to highlight areas for future research.

Search strategy: We searched the following electronic databases using the highly sensitive search strategy for identifying published randomised controlled trials: (1) Cochrane Epilepsy Group Specialized Register (July 2005); (2) Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2,2005); (3) MEDLINE (1966 - August 2004); (4) EMBASE (1966 - January 2003).

Selection criteria: Randomised controlled trials of participants with premonitory, early, established or refractory status epilepticus using a truly random or quasi-random allocation of treatments were included.

Data collection and analysis: Two review authors independently selected trials for inclusion, assessed trial quality and extracted data.

Main results: Eleven studies with 2017 participants were included. Few studies used the same interventions. Diazepam was better than placebo in reducing the risk of non-cessation of seizures (RR 0.73, 95% CI 0.57 to 0.92), requirement for ventilatory support (RR 0.39, 95% CI 0.16 to 0.94) or continuation of status epilepticus requiring use of a different drug or general anaesthesia (RR 0.73, 95% CI 0.57 to 0.92). Lorazepam was better than placebo for risk of non-cessation of seizures (RR 0.52, 95% CI 0.38 to 0.71) and for risk of continuation of status epilepticus requiring a different drug or general anaesthesia (RR 0.52, 95% CI 0.38 to 0.71). Lorazepam was better than diazepam for reducing risk of non-cessation of seizures (RR 0.64, 95% CI 0.45 to 0.90) and had a lower risk for continuation of status epilepticus requiring a different drug or general anaesthesia (RR 0.63, 95% CI 0.45 to 0.88). Lorazepam was better than phenytoin for risk of non-cessation of seizures (RR 0.62, 95% CI 0.45 to 0.86). Diazepam (30 mg intrarectal gel) was better than a lower dose (20 mg intrarectal gel) in premonitory status epilepticus for the risk of seizure continuation (RR 0.39, 95% CI 0.18 to 0.86).

Authors' conclusions: Lorazepam is better than diazepam or phenytoin alone for cessation of seizures and carries a lower risk of continuation of status epilepticus requiring a different drug or general anaesthesia. Both lorazepam and diazepam are better than placebo for the same outcomes. In the treatment of premonitory seizures, diazepam 30 mg in an intrarectal gel is better than 20 mg for cessation of seizures without a statistically significant increase in adverse effects. Universally accepted definitions of premonitory, early, established and refractory status epilepticus are required.

Citation: Prasad K, Al-Roomi K, Krishnan PR, Sequeira R. Anticonvulsant therapy for status epilepticus. The Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD003723.pub2. DOI: 10.1002/14651858.CD003723.pub2.

Ginkgo biloba for acute ischaemic stroke

From Cochrane Review

Background: Ginkgo biloba extract is widely used in the treatment of acute ischaemic stroke in China. We aimed to assess the evidence from randomised controlled trials and quasi-randomised controlled trials on the use of Ginkgo biloba extract in acute ischaemic stroke.

Objectives: The primary objective was to determine whether Ginkgo biloba extract improves functional outcome without causing undue harm in patients with acute ischaemic stroke. Secondary objectives were to assess the effect of Ginkgo biloba extract on neurological impairment and quality of life.

Search strategy: We searched the Cochrane Stroke Group Trials Register (last searched October 2004), the Trials Register of the Cochrane Complementary Medicine Field (last searched October 2004) and the Chinese Stroke Trials Register (last searched June 2004). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to June 2004), AMED (1985 to May 2002) and the China Biological Medicine Database (CBM-disc, 1979 to August 2004). We searched relevant clinical trials and research registers and contacted pharmaceutical companies and researchers in an effort to identify further published and unpublished studies.

Selection criteria: Randomised controlled trials or quasi-randomised controlled clinical trials comparing Ginkgo biloba extract with placebo or open control (no placebo) in patients with acute ischaemic stroke.

Data collection and analysis: Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data.

Main results: Fourteen trials were identified, of which 10 trials (792 patients) were included. Four trials are awaiting assessment. In the 10 included trials follow up was performed at 14 to 35 days after stroke. In all studies neurological outcome was assessed but none of them reported on disability (activities of daily living function) or quality of life. Only three trials reported adverse events. In nine trials, all of them assessed to be of inferior quality, significant improvement in neurological deficit at the end of the treatment was used as the outcome measure. When analysing these trials together, Ginkgo biloba extract was associated with a significant increase in the number of improved patients (Peto odds ratio (OR) 2.66; 95% confidence interval (CI) 1.79 to 3.94). One placebo-controlled trial, assessed to be of good quality, reported neurological outcome as a continuous variable. It failed to show an improvement of neurological deficit at the end of treatment (weighted mean difference (fixed) 0.81; 95% CI -8.9 to 10.52). No deaths or major adverse events were reported during the follow-up period.

Authors' conclusions: There was no convincing evidence from trials of sufficient methodological quality to support the routine use of Ginkgo biloba extract to promote recovery after stroke. High-quality and large-scale randomised controlled trials are needed to test its efficacy.

Citation: Zeng X, Liu M, Yang Y, Li Y, Asplund K. Ginkgo biloba for acute ischaemic stroke. The Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD003691.pub2. DOI: 10.1002/14651858.CD003691.pub2.

Antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or TIA

From Cochrane Review

Background: Non-valvular atrial fibrillation (AF) carries an increased risk of stroke. Antiplatelet therapy (APT) is proven effective for stroke prevention in most patients at high-risk for vascular events, but its value for primary stroke prevention in patients with non-valvular AF merits separate consideration because of the suspected cardioembolic mechanism of most strokes in AF patients.

Objectives: To assess the efficacy and safety of long-term APT for primary prevention of stroke in patients with chronic non-valvular AF.

Search strategy: We searched the Cochrane Stroke Group Trials Register (searched August 2004). In addition, we searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to June 2004), and the reference lists of recent review articles. We also contacted experts working in the field to identify unpublished and ongoing trials.

Selection criteria: Randomized trials comparing long-term APT with placebo or control in patients with non-valvular AF and no history of transient ischemic attack (TIA) or stroke. A sensitivity analysis included one additional randomized trial involving primary prevention with aspirin plus very low dose warfarin.

Data collection and analysis: Two authors independently selected trials for inclusion and extracted data for each outcome. Unpublished data were obtained from trial investigators.
Main results: Three trials tested aspirin in dosages ranging from 75 mg to 325 mg per day and 125 mg every other day to placebo (in two trials) or control (in one trial) in 1965 AF patients without prior stroke or TIA. The mean duration of follow up averaged 1.3 years per participant. Aspirin was associated with non-significant lower risks of all stroke (odds ratio (OR) 0.70, 95% confidence interval (CI) 0.47 to 1.07), ischemic stroke (OR 0.70, 95% CI 0.46 to 1.07), all disabling or fatal stroke (OR 0.86, 95% CI 0.50 to 1.49) and all-cause death (OR 0.75, 95% CI 0.54 to 1.04). The combination of stroke, myocardial infarction or vascular death was significantly reduced (OR 0.71, 95% CI 0.51 to 0.97 ). No increase in intracranial hemorrhage or major extracranial hemorrhage was observed.

Authors' conclusions: Aspirin appears to reduce stroke and major vascular events in patients with non-valvular AF similar to its effect in other high-risk patients (ie by about 25%). For primary prevention among AF patients with an average stroke rate of 4% per year, about 10 strokes would likely be prevented yearly for every 1000 AF patients given aspirin.

Citation: Aguilar M, Hart R. Antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. The Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD001925.pub2. DOI: 10.1002/14651858.CD001925.pub2.

Flaws in the literature

From Critical Care 2005, 9:R575-R582

Introduction
Meta-analyses have been suggested to be the highest form of evidence available to clinicians to guide clinical practice in critical care. The purpose of this study was to systematically evaluate the quality of meta-analyses that address topics pertinent to critical care.

Methods
To identify potentially eligible meta-analyses for inclusion, a systematic search of Medline, EMBASE and the Cochrane Database of Systematic Reviews was undertaken, using broad search terms relevant to intensive care, including: intensive care, critical care, shock, resuscitation, inotropes and mechanical ventilation. Predetermined inclusion criteria were applied to each identified meta-analysis independently by two authors. To assess report quality, the included meta-analyses were assessed using the component and overall scores from the Overview Quality Assessment Questionnaire (OQAQ). The quality of reports published before and after the publication of the QUOROM statement was compared.

Results
A total of 139 reports of meta-analyses were included (kappa = 0.93). The overall quality of reports of meta-analyses was found to be poor, with an estimated mean overall OQAQ score of 3.3 (95% CI; 3.0–3.6). Only 43 (30.9%) were scored as having minimal or minor flaws (>5). We noted problems with the reporting of key characteristics of meta-analyses, such as performing a thorough literature search, avoidance of bias in the inclusion of studies and appropriately referring to the validity of the included studies. After the release of the QUOROM statement, however, an improvement in the overall quality of published meta-analyses was noted.

Conclusion
The overall quality of the reports of meta-analyses available to critical care physicians is poor. Physicians should critically evaluate these studies prior to considering applying the results of these studies in their clinical practice.

Johns Hopkins Researchers Discover Key Protein Linked To Transverse Myelitis And Multiple Sclerosis

From Johns Hopkins Medical Institutions

Hopkins researchers have discovered a single molecule that is a cause of an autoimmune disease in the central nervous system, called transverse myelitis (TM), that is related to multiple sclerosis.

In a study published in the October issue of The Journal of Clinical Investigation, it was showed that the levels of the protein, IL-6, are dramatically elevated in the spinal fluid of transverse myelitis (TM) patients.

Although the majority of TM patients suffer a single attack, 15 percent to 30 percent of patients go on to develop full-blown MS.

IL-6 is a chemical messenger that cells of the immune system use to communicate with one another. One of the cell types injured by high levels of IL-6 includes oligodendrocytes, which help produce the protective myelin sheath coating around nerve cells. The findings offer one possible mechanism responsible for demyelinating disorders, such as TM and MS, and may aid in the development of effective therapies against these disorders, the researchers say.

"This is the first time a single culprit has been identified as causing a CNS autoimmune disease," said Kaplin.

Researchers analyzed 42 inflammatory proteins in the cerebrospinal fluid of both TM and healthy patients. They found that IL-6 was consistently elevated in TM patients' spinal fluid. Further, the level of IL-6 directly correlated with the severity of paralysis.

Using cell culture and animal studies, the researchers confirmed that elevated IL-6 levels were directly injurious to the spinal cord. They showed that spinal fluid from TM patients induced death of spinal cord cells when cultured in a dish and that IL-6, when infused in adult rats, induced paralysis. Under the microscope, tissue from IL-6-infused rats showed demyelination and injury of axons, pathology that was nearly identical to that seen in human patients with TM.

MULTIPLE SCLEROSIS LINKED TO HHV-6A VIRUS

MULTIPLE SCLEROSIS LINKED TO HHV-6A VIRUS-- Evidence Presented At American Neurology Association Annual Meeting

Dr. Claude Genain of the University of California San Francisco Medical Center presented evidence at the American Neurology Association Annual Meeting this week that shows a direct link between human herpes virus 6 variant A (HHV-6A) and a multiple sclerosis-like illness.

Dr. Genain injected common marmoset monkeys with HHV-6 variants A & B. Most notably, only infection with HHV-6 variant A resulted in illness. The monkeys developed lab evidence and signs of chronic autoimmune demyelination of the central nervous system, the hallmark of multiple sclerosis. This is the first time that any animal infected with HHV-6A has developed clinical pathology of the central nervous system, and the most direct evidence to date of a possible causal connection between HHV-6A and multiple sclerosis.

In recent years there has been a considerable degree of interest in the relationship between HHV-6A and multiple sclerosis, because HHV-6A DNA has repeatedly been found in brain tissue and the cerebrospinal fluid of affected patients, and increased levels of antibodies to viral antigens in their blood only present during replication of HHV-6A are frequently detected.

From BMN PRESS RELEASE

Study: Diabetic nerve change begins early

ROCHESTER, Minn., Sept. 29 (UPI) -- Mayo Clinic researchers report subtle change in nerve conduction is the first reliable sign of nerve complications from diabetes.

The researchers said that change can be measured long before other symptoms or signs of nerve damage develop.

"We've found what we believe is the earliest sign of nerve change due to diabetes," said Dr. Peter Dyck, a neurologist and lead researcher on the study. "Changes begin much earlier than previously demonstrated."

About 500 patients participated in the longitudinal study, many for 20 years. Patients agreed to periodic measures of their diabetes and of nerve, eye, kidney and blood vessel complications.

About half of people with diabetes develop some type of neuropathy caused indirectly by high blood sugar levels. Symptoms can include pain, tingling, burning and loss of feeling. Serious complications include foot ulcers, amputations and blindness.

In the study, researchers used various techniques to measure nerve changes, but they said nerve conduction tests provided the most consistent and reliable measures.

"Even when patients had nerve conduction values well within the normal range, our serial assessments showed steady, unequivocal and statistically significant worsening," said Dyck.

The study appears in the September issue of Diabetes Care.

From ScienceDaily

Stroke Risk Gene Confirmed

From American Academy of Neurology

In an important confirmation of genetic influences in stroke, researchers have found an association between a major risk gene and stroke in young adults, according to a report presented at the 130th annual meeting of the American Neurological Association in San Diego.


The gene, called phosphodiesterase 4D (PDE4D), had first been found to increase the risk of stroke in a study in Iceland, and other studies involving primarily older white populations have lent support for this finding.

A team of researchers from several institutions has now confirmed this result in a biracial group of young American women. They identified a structural variation, or polymorphism, in the gene that was associated with increased risk of stroke in both young black women and young white women. Furthermore, this association is present for small blood vessel disease as well as for large artery atherosclerosis.

The import of these results is confined to research for the moment. "Before our results can be used clinically, the underlying biological mechanisms for this association must be understood," said study author John W. Cole, MD, MS, of the Baltimore Department of Veterans Affairs Medical Center and the University of Maryland School of Medicine, Baltimore, MD.

Identifying risk genes in stroke is particularly difficult because many genes appear to combine with a variety of environmental risk factors ranging from smoking to use of oral contraceptives.

The identification of the PDE4D gene is thus an important advance. Several other studies have examined the association of PDE4D with stroke in different populations and most studies provide support for the original Icelandic findings. The next challenge is to determine the specific gene variations responsible for the association and how they influence the proteins that are coded for by the PDE4D gene.

"For example, does the genetic variant cause one to produce a defective protein, or decrease or increase the level of a protein, thereby predisposing to stroke? Does the variant make an individual more susceptible to stroke given a specific environmental exposure?" said Cole.

Only when these questions have been answered, would there be a value in developing a genetic test to determine which polymorphisms are present in a person's genome.

"The results of these tests would allow practitioners to counsel patients on stroke risk and to warn patients that specific environmental factors, such as oral contraceptive use, diet or smoking may be particularly harmful," said Cole.

Another important application will be to develop drugs that reduce stroke risk by specifically targeting the gene or its products.