Neurology-Medicine

Chorea

2009-09-03T01:36:00.001Z

Athetosis

2009-09-03T01:32:00.001Z

Intentional tremor in cerebellar ataxia

2009-09-03T01:30:00.001Z

Romberg test 2

2009-09-03T01:27:00.000Z

Romberg sign

2009-09-03T01:23:00.001Z

Festinating gait in Parkinson's disease

2009-09-03T01:20:00.001Z

Cerebellar gait

2009-09-03T01:16:00.002Z

Spastic gait

2009-09-03T01:15:00.001Z

Video: Frontotemporal dementia - Diagnosis

2006-12-17T23:52:00.000Z

Video: Multiple Sclerosis

2006-11-21T17:31:00.000Z

Video: FDA Approves First Drug to Help Patients with Parkinson's Disease Dementia

2006-11-15T10:23:00.000Z

Plasmapheresis in Acute Central Nervous System Inflammation

2006-11-13T15:31:00.000Z

Presentation from 2001 International Transverse Myelitis Symposium in Baltimore. Brian G. Weinshenker, MD Professor of Neurology Mayo Clinic Rochester, Minnesota

Video: Lessons from ADEM/Acute Leukoencephalopathies

2006-11-13T15:23:00.000Z

Presentation from 2001 International Transverse Myelitis Symposium in Baltimore. David Irani, MD Assistant Professor of Neurology. Co-Director, Johns Hopkins Transverse Myelopathy Center (JHTMC) Johns Hopkins University School of Medicine

The diagnosis of manganese-induced parkinsonism

2006-05-08T15:32:00.000Z

From NeuroToxicology Volume 27, Issue 3 , May 2006, Pages 340-346

Parkinsonism is a clinical syndrome consisting of tremor, bradykinesia, rigidity, gait, balance problems, in addition to various non-motor symptoms. There are many causes of parkinsonism such as neurodegenerative disease, drugs, vascular causes, structural lesions, infections, and toxicants. Parkinson's disease, or idiopathic parkinsonism, is the most common form of parkinsonism observed in the clinic. There is degeneration of the substantia nigra, pars compacta, which results in loss of striatal dopamine. Parkinson's disease is a slowly progressive condition in which there is a dramatic and sustained responsiveness to levodopa therapy. Manganese is an essential trace element that can be associated with neurotoxicity. Hypermanganism can occur in a variety of clinical settings. The clinical symptoms of manganese intoxication include non-specific complaints, neurobehavioral changes, parkinsonism, and dystonia. Although the globus pallidus is the main structure of damage, other basal ganglia areas can also be involved. MRI scans may show globus pallidus changes during (and for a short period after) exposure. Fluorodopa PET scans that assess the integrity of the substantia nigra dopaminergic system are abnormal in Parkinson's disease. However, these scans re-reported to be normal in a few cases studied with manganese-induced parkinsonism. The parkinsonism due to manganese may have some clinical features that occur less commonly in Parkinson's disease, such as kinetic tremor, dystonia, specific gait disturbances, and early mental, balance and speech changes. The clinical signs tend to be bilateral whereas Parkinson's disease begins on one side of the body. Patients with manganese-induced parkinsonism may be younger at the onset of the disease than with Parkinson's disease. Lastly, there appears to be a lack of response to levodopa therapy in manganese-induced parkinsonism.

Identification of potential CSF biomarkers in ALS

2006-04-30T15:19:00.000Z

From NEUROLOGY 2006;66:1218-1222

Background: The clinical diagnosis of ALS is based entirely on clinical features. Identification of biomarkers for ALS would be important for diagnosis and might also provide clues to pathogenesis.

Objective: To determine if there is a specific protein profile in the CSF that distinguishes patients with ALS from those with purely motor peripheral neuropathy (PN) and healthy control subjects.

Methods: CSF obtained from patients with ALS, disease controls (patients with other neurologic disorders), and normal controls were analyzed using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry proteomics technique. Biomarker sensitivity and specificity was calculated with receiver operating characteristic curve methodology. ALS biomarkers were purified and sequence identified by mass spectrometry–directed peptide sequencing.

Results: In initial proteomic discovery studies, three protein species (4.8-, 6.7-, and 13.4-kDa) that were significantly lower in concentration in the CSF from patients with ALS (n = 36) than in normal controls (n = 21) were identified. A combination of three protein species (the "three-protein" model) correctly identified patients with ALS with 95% accuracy, 91% sensitivity, and 97% specificity from the controls. Independent validation studies using separate cohorts of ALS (n = 13), healthy control (n = 25), and PN (n = 7) subjects confirmed the ability of the three CSF protein species to separate patients with ALS from other diseases. Protein sequence analysis identified the 13.4-kDa protein species as cystatin C and the 4.8-kDa protein species as a peptic fragment of the neurosecretory protein VGF.

Conclusion: Additional application of a "three-protein" biomarker model to current diagnostic criteria may provide an objective biomarker pattern to help identify patients with ALS.

Molecular mimicry in multiple sclerosis

2006-04-30T15:13:00.000Z

From Autoimmunity, Volume 39, Number 1, Number 1/February 2006

Reviewed by Sospedra, Mireia1; Martin, Roland2

Two main etiological components are considered important in human autoimmune diseases including multiple sclerosis (MS), first the immunogenetic background and second environmental factors. Among the latter, infectious organisms are probably the most relevant, and epidemiological studies in MS firmly support that viral infections often precede disease exacerbations or the onset of MS. Infectious agents can contribute to disease development or phenotypic expression in different ways. Our focus will be directed on molecular mimicry, i.e. antigenic similarity between structural epitopes or peptide sequences from infectious organisms with those found in self proteins of the host. The intriguing concept of molecular mimicry has evolved substantially since its introduction over 20 years ago. We will summarize the most important developments and discuss puzzling questions, which remain open despite many claims that molecular mimicry is involved in the development of human autoimmune disease after infections or vaccinations.

Difference in neuropathogenetic mechanisms in human furious and paralytic rabies

2005-10-29T23:18:00.000Z

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

2005-10-28T20:20:00.000Z

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

2005-10-28T20:13:00.000Z

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

2005-10-28T20:06:00.000Z

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

2005-10-02T13:13:00.000Z

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

2005-10-02T12:56:00.000Z

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

2005-10-02T12:46:00.000Z

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

2005-10-02T12:40:00.000Z

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

2005-10-02T12:33:00.000Z

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.

Research Provides First Whole Genome Map Of Genetic Variability In Parkinson's Disease

2005-09-15T19:59:00.000Z

From Mayo Clinic

Mayo Clinic researchers in collaboration with scientists at Perlegen Sciences, Inc. and funded by the Michael J. Fox Foundation for Parkinson's Research have produced the first large-scale whole genome map of genetic variability associated with Parkinson's disease. Their results highlight changes in 12 genes that may increase the risk for Parkinson's disease in some people.

Mayo Clinic and Perlegen Sciences will report their findings in The American Journal of Human Genetics. The paper was published online Friday, Sept. 9 (www.ajhg.org) and will appear in the November 2005 print issue.

Significance of the Findings
Both the findings and the technology that produced them are groundbreaking, representing one of the most comprehensive genetic studies of Parkinson's disease to date with nearly 200 million genetic tests (genotypes) completed. To accomplish this, researchers initially studied the association of about 200,000 single-letter variations in the genome known as single nucleotide polymorphisms, or "SNPs" (pronounced "snips") in patients with Parkinson's disease. The study examined DNA from 775 people with Parkinson's disease (cases) and from 775 people without Parkinson's disease (controls).

"To be most effective, a whole genome association study requires accurate testing of a large number of SNP markers that are distributed across the human genome in a dense and informative pattern," says Dr. Maraganore. "In this respect, our collaborators at Perlegen have set a new standard."

Noteworthy findings include:
Confirmation that variation in two previously known regions of the genome, PARK10 and PARK11, are likely associated with Parkinson's disease susceptibility.

Identification of 10 additional SNPs that appear to be associated with Parkinson's disease susceptibility. Some of these are in or near genes with direct biological relevance to the disease. For instance, one of these, the SEMA5A gene, may play an important role in both the development and programmed death of dopamine-producing nerve cells in the brain. Selective degeneration of dopamine neurons in the brain is a hallmark feature of Parkinson's disease.

Susceptibility genes are genes that may make some people more or less likely to develop a disease but that do not necessarily cause the disease directly. The authors note that in this study, the size of the effect was small for any single SNP; combinations of gene variants or interactions with environmental factors may be necessary to develop Parkinson's disease.

New Study Shows SARS Can Infect Brain Tissue

2005-09-15T19:46:00.000Z

From Infectious Diseases Society of America

Severe acute respiratory syndrome (SARS), by its very name, indicates a disease of the respiratory tract. But SARS can also infiltrate brain tissue, causing significant central nervous system problems, according to an article in the Oct. 15 issue of Clinical Infectious Diseases, now available online.

SARS, a potentially fatal illness caused by a coronavirus, was first reported in Asia in February of 2003. The disease is usually transmitted by contact with coronavirus-laden droplets sprayed into the air by an infected person’s coughing. Other symptoms can include high fever, headache, body aches, and pneumonia. However, some patients also exhibit central nervous system ailments. In a new study, the researchers report the case of a 39-year-old doctor who treated SARS patients in China during the 2003 outbreak and became infected himself.

He showed the usual symptoms of SARS--fever, chills, headache, muscle pain--but after hospitalization, he developed vision problems, then progressively worse central nervous system symptoms, like restlessness and delirium. A computed tomography scan indicated brain damage. He died about a month after being hospitalized, and his brain tissue was examined and found to contain the SARS coronavirus. The researchers also discovered a high level of Mig, a type of immune system regulator called a chemokine, in the man’s bloodstream and brain, which may have resulted from the central nervous system infection. The researchers speculated that Mig could also have contributed to his brain damage by attracting immunological cells to the site of the viral infection in the brain, where their inflammatory effects may have done more harm than good.

Four to five percent of SARS patients treated at the Guangzhou Institute of Respiratory Diseases experienced central nervous system symptoms, said Dr. Xu; therefore, physicians need to be aware of the potential for brain infection when evaluating patients with the disease. Immunosuppressive drugs should be administered carefully and on an individual basis, as they may allow amplification of the SARS coronavirus in the brain. “Superinfection” with other pathogens could also contribute to SARS’ harmful effects on the brain. “Physicians should pay more attention to the prevention of brain damage if [SARS patients] are superinfected with other conditional pathogens,” according to Dr. Xu and Dr. Jiang.

There are a few possibilities for curbing Mig’s possible role in causing brain damage in SARS patients with central nervous system infection, according to lead author Jun Xu, PhD, of the Guangzhou Institute of Respiratory Diseases and senior author Yong Jiang, PhD, of the Key Laboratory of Functional Proteomics of Guangdong Province. “There might be some ways of controlling the release of Mig, such as specific inhibitors that interfere [with] the signaling pathways involved,” Dr. Jiang said. “Other approaches, such as neutralizing antibodies [and] specific binding peptides, could be tried to block brain damage induced by Mig.”

The AD8

2005-09-12T21:05:00.000Z

From NEUROLOGY 2005;65:559-564

The AD8: A brief informant interview to detect dementia

Background: Brief measures that accurately discriminate normal cognitive aging from very mild dementia are lacking. Cognitive tests often are insensitive to very mild dementia. Informant-based measures may be more sensitive in detecting early dementia.

Objective: To identify informant-reported clinical variables that differentiate cognitively normal individuals from those with very mild dementia.

Methods: A 55-item battery of informant queries regarding an individual's cognitive status was derived from a semistructured interview and a consensus panel of dementia experts. The battery was evaluated with informants for 189 consecutive participants of a longitudinal study of memory and aging and compared with an independently obtained Clinical Dementia Rating (CDR) score for the participant. Multiple regression and receiver operator characteristic curves assessed subsets of the items to discriminate between CDR 0 (no dementia) and CDR 0.5 (very mild dementia).

Results: The final version (AD8) querying memory, orientation, judgment, and function was administered to an additional sample of 112 CDR 0 and 68 CDR 0.5 participants. Using a cut-off of two items endorsed, the area under the curve was 0.834, suggesting good to excellent discrimination, sensitivity was 74%, and specificity was 86% (prevalence of 0.38 for very mild dementia). Inclusion of 56 additional individuals with mild to severe dementia (increasing dementia prevalence to 0.53) increased sensitivity to 85%.

Conclusions: The AD8 is a brief, sensitive measure that reliably differentiates between nondemented and demented individuals. Use of the AD8 in conjunction with a brief assessment of the participant could improve diagnostic accuracy in general practice.

Antibody responses against galactocerebroside are potential stage-specific biomarkers in multiple sclerosis

2005-09-12T20:54:00.000Z

From Journal of Allergy and Clinical Immunology Volume 116, Issue 2 , August 2005, Pages 453-459

Background
Galactocerebroside, the major glycolipid of central nervous system myelin, is a known target for pathogenic demyelinating antibody responses in experimental allergic encephalomyelitis (EAE), the animal model of multiple sclerosis (MS).

Objective
To address the importance of anti-galactocerebroside (α-GalC) antibodies in MS and to evaluate them as biomarkers of disease.

Methods
α-GalC IgGs were quantified from sera of patients with MS and in marmoset EAE by a new immunosorbent assay.

Results
We report a significant difference in serum α-GalC IgG titers between patients with relapsing-remitting (RR)–MS and healthy controls (HCs; P < .001). The frequencies of α-GalC antibody-positive subjects (α-GalC titers ≥ mean HC titers + 3 SD) are also significantly elevated in RR-MS compared with HC (40% vs 0%; P = .0033). Immunoaffinity purified α-GalC IgGs from human serum bind to cultured human oligodendrocytes, indicating that the ELISA detects a biologically relevant epitope. Corroborating these findings, α-GalC antibody responses in marmoset EAE were similarly found to be specifically associated with the RR forms and not the peracute or progressive forms, in contrast with other anti-myelin antibodies (P = .0256).

Conclusion
(1) α-GalC antibodies appear MS-specific and are not found in healthy subjects, unlike antibodies against myelin proteins; (2) when present, α-GalC antibodies identify mostly RR-MS and may be an indicator of ongoing disease activity. This novel assay is a suitable and valuable method to increase accuracy of diagnosis and disease staging in MS.

Is motor neuron disease-inclusion dementia a forme fruste of amyotrophic lateral sclerosis with dementia?

2005-09-12T20:46:00.000Z

From NeuropathologyVolume 25 Issue 3 Page 214 - September 2005

Case Report

We report the autopsy findings of a 62-year-old man who exhibited progressive FTD 10 years before the appearance of muscle weakness and wasting, and who died approximately 11 years after onset of the symptoms. Degeneration and atrophy of the frontal and temporal lobes, which contained ubiquitin-positive neuronal inclusions and dystrophic neurites, were evident. Circumscribed degeneration affecting the hippocampal CA1-subiculum border zone was also a feature. Moreover, degeneration was present in both the upper and lower motor neuron systems, the latter being more severely affected. A few lower motor neurons were found to contain the cytoplasmic inclusions characteristic of ALS (i.e. Bunina bodies and ubiquitin-positive skeins). Also of interest was the presence of pallidonigroluysian atrophy, which appeared to be responsible for the chorea-like involuntary movements that developed in this patient approximately 2 months before death. The clinical and pathological features of our patient further support the idea that motor neuron disease-inclusion dementia (MND-ID), which has been classified as a pathological subgroup of FTD, is a forme fruste of ALS with dementia. In other words, if patients with MND-ID live long enough, they may develop ALS.

Alzheimer's disease: an intracellular movement disorder?

2005-09-09T20:12:00.000Z

From Trends in Molecular Medicine, Volume 11, Issue 9, September 2005, Pages 391-393

Axonal transport is essential for maintaining the structure and function of nerve cells. Deficient axonal transport has been implicated in several neurodegenerative diseases, including Alzheimer's disease (AD). In addition to a disturbed cytoskeleton and other abnormalities observed in AD that are suggestive of axonal transport deficits, several AD-related proteins are implicated in the regulation of axonal transport. A recent study has demonstrated that the axonal transport deficit occurs early in the course of AD, preceding amyloid pathology substantially in mouse models of AD; more importantly, the study showed that reduced axonal transport leads to increased amyloid β production and deposition. These data place axonal transport deficits at a central point in the pathogenesis of AD.

New Dye Could Offer Early Test For Alzheimer's

2005-09-02T14:13:00.000Z

From Massachusetts Institute of Technology

MIT scientists have developed a new dye that could offer noninvasive early diagnosis of Alzheimer's disease, a discovery that could aid in monitoring the progression of the disease and in studying the efficacy of new treatments to stop it.

The work will be published in the Aug. 26 issue of Angewandte Chemie. Today, doctors can only make a definitive diagnosis of Alzheimer's-currently the fourth-leading cause of death in the United States-through a postmortem autopsy of the brain.

To that end, Swager and postdoctoral associate Evgueni Nesterov, also from the MIT Department of Chemistry, worked with researchers at Massachusetts General Hospital and the University of Pittsburgh to develop a contrast agent that would first bind to the protein deposits, or plaques, in the brain that cause Alzheimer's, and then fluoresce when exposed to radiation in the near-infrared range. The new dye could allow direct imaging of Alzheimer's plaques through a patient's skull.

Some of the first noninvasive techniques for diagnosing Alzheimer's involved agents labeled with radioactive elements that could enter the brain and target disease plaque for imaging with positron emission tomography (PET). However, these methods were expensive and limited by the short working lifetime of the labeled agents.

Swager and colleagues developed the new dye, called NIAD-4, through a targeted design process based on a set of specific requirements, including the ability to enter the brain rapidly upon injection, bind to amyloid plaques, absorb and fluoresce radiation in the right spectral range, and provide sharp contrast between the plaques and the surrounding tissue. The compound provided clear visual images of amyloid brain plaques in living mice with specially prepared cranial windows.

To make the technique truly noninvasive, scientists must further refine the dye so it fluoresces at a slightly longer wavelength, closer to the infrared region. Light in the near-IR range can penetrate living tissue well enough to make brain structures visible. Swager likens the effect to the translucence produced when one holds a red laser pointer against the side of a finger.

"This procedure could be done in a chamber with a photodetector and a bunch of lasers, and it would be painless," he said, adding that infrared fluorescence and other optical techniques will lead to a whole new class of noninvasive medical diagnostics. Swager says fluorescing dyes like NIAD-4 could be ready for clinical trials in the near future.

"What we have is a dye that lights up when it binds to amyloids that form in the brains of people with Alzheimer's. It's a completely new transduction scheme-a way of translating a physical or chemical event that's invisible to the naked eye, into a recognizable signal. Further wavelength adjustments in these dyes will allow us to perform in vivo analysis through human tissue."

The new dye was developed as part of a broader effort in sensing technology at MIT's Institute for Soldier Nanotechnologies. In addition to its applications as a medical diagnostic, Swager says fluorescing dyes like NIAD-4 could work as signals in a wide variety of sensing schemes.

Clinical applications of surface electromyography in neuromuscular disorders

2005-08-30T21:00:00.000Z

From Neurophysiologie Clinique/Clinical Neurophysiology, Volume 35, Issues 2-3, July 2005, Pages 59-71

Surface electromyography (SEMG) is still rarely used in clinical settings for the detection and analysis of myoelectric signals. The electromyographic signal detected on the skin surface includes information from a greater proportion of the muscle of interest than conventional clinical EMG, acquired using needle electrodes. SEMG is therefore more representative than the localised, and thus very selective needle EMG signals currently used. However, both reliability and interpretation of surface EMG need to be questioned. This review looks at the studies concerned with the characterisation of neuromuscular pathologies using EMG parameters. After introducing principles and limitations of surface EMG, an overview of the main results obtained in clinical settings is presented and discussed. There is a particular focus on high spatial resolution surface EMG as it is currently the best compromise between the selectivity of needle EMG and the representative nature of classical SEMG. Several perspectives are proposed that underline the fact that surface EMG is an evolving discipline and should be worthy of a place in routine clinical examinations.

A new frontier for molecular medicine: Noncoding RNAs

2005-08-30T19:26:00.000Z

From Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Article in Press, Corrected Proof

It is now becoming evident that the variety of noncoding RNA (ncRNA) molecules play important roles in many cellular processes and they are not just mere intermediates in transfer of genetic information from DNA to proteins. Recent data, from the analyses of transcriptional activity of human genome, suggest that it may contain roughly equal numbers of protein- and RNA-encoding transcription units. Many of the ncRNAs described in humans as well as in other mammals have been linked, through specific chromosomal localization or expression patterns, with certain diseases including complex congenital syndromes, neurobehavioral and developmental disorders and cancer. These findings clearly indicate that an expression of genes of which end-products are RNA molecules is crucial for development, differentiation and normal functioning of the cells. The ncRNAs expression patterns can therefore be used as molecular markers for specific diagnostic methods.

Prevalence and patterns of cognitive impairment in sporadic ALS

2005-08-30T18:37:00.000Z

From NEUROLOGY 2005;65:586-590

Objective: To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study.

Methods: Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes.

Results: On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance.

Conclusions: These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.

Frequency of a tau genotype in amyotrophic lateral sclerosis

2005-08-30T18:26:00.000Z

From Journal of the Neurological Sciences Volume 236, Issues 1-2 , 15 September 2005, Pages 13-16

We investigated the susceptibility of the dinucleotide polymorphism A0 in the tau gene to amyotrophic lateral sclerosis (ALS). In 416 unrelated patients with ALS and 242 control subjects the A0/A0 genotype was not associated with the pooled sample of ALS cases. Subgroup analysis revealed that in sporadic ALS the A0 polymorphism was significantly overrepresented. There was no association of the A0/A0 genotype with the age and site of disease onset or the presence of dementia. The studied tau genotype may contribute to the multifactorial genetic background of ALS.

Analgesic Therapy in Postherpetic Neuralgia: A Quantitative Systematic Review

2005-08-23T20:35:00.000Z

From PloS Medicine Vol 2(7); 2005

Background
Postherpetic neuralgia (PHN) is a complication of acute herpes zoster, which is emerging as a preferred clinical trial model for chronic neuropathic pain. Although there are published meta-analyses of analgesic therapy in PHN, and neuropathic pain in general, the evidence base has been substantially enhanced by the recent publication of several major trials. Therefore, we have conducted a systematic review and meta-analysis for both efficacy and adverse events of analgesic therapy for PHN.

Methods and Findings
We systematically searched databases (MEDLINE 1966–2004, EMBASE 1988–2004, CINAHL 1982–2002, and PubMed [29 October 2004]) for trials of PHN. We also searched references of retrieved studies and review articles for further trials. We included trials that examined adult patients with PHN of greater duration than 3 mo, that were blinded, randomised, and had at least one measure of pain outcome. Dichotomous pain outcome data were extracted for 50% decrease in baseline pain using a hierarchy of pain/pain-relief measurement tools. Where available, dichotomous data were also collected for adverse events. Calculated estimates of efficacy included relative benefit and number needed to treat.

Of 62 studies identified, 35 were randomised controlled trials. Of these, 31 were placebo controlled and suitable for meta-analysis, from which it was possible to extract dichotomous efficacy outcome data from 25.
This meta-analysis revealed that there is evidence to support the use of the following orally administered therapies: tricyclic antidepressants, “strong” opioids, gabapentin, tramadol, and pregabalin. Topical therapies associated with efficacy were lidocaine 5% patch and capsaicin. Finally, a single study of spinal intrathecal administration of lidocaine and methyl prednisolone demonstrated efficacy, although this has yet to be replicated.
Data suggest that the following therapies are not associated with efficacy in PHN: certain NMDA receptor antagonists (e.g., oral memantine, oral dextromethorphan, intravenous ketamine), codeine, ibuprofen, lorazepam, certain 5HT1 receptor agonists, and acyclovir. Topical administration of benzydamine, diclofenac/diethyl ether, and vincristine (iontophoresis) are similarly not associated with efficacy, nor are intrathecal administration of lidocaine alone or epidural administration of lidocaine and methylprednisolone, intravenous therapy with lidocaine, subcutaneous injection of Cronassial, or acupuncture. However, many of the trials that demonstrated a lack of efficacy represented comparatively low numbers of patient episodes or were single-dose studies, so it may be appropriate to regard such interventions as “not yet adequately tested” rather than demonstrating “no evidence of efficacy.” Topical aspirin/diethyl ether has not been adequately tested.

Conclusion
The evidence base supports the oral use of tricyclic antidepressants, certain opioids, and gabapentinoids in PHN. Topical therapy with lidocaine patches and capsaicin is similarly supported. Intrathecal administration of methylprednisolone appears to be associated with high efficacy, but its safety requires further evaluation.

Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials

2005-08-23T15:03:00.000Z

From BMJ 2005;331:321-327.

Objectives Pharmacological treatment of Alzheimer's disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents.

Data sources The terms "donepezil", "rivastigmine", and "galantamine", limited by "randomized-controlled-trials" were searched in Medline (1989-November 2004), Embase (1989-November 2004), and the Cochrane Database of Systematic Reviews without restriction for language.

Study selection All published, double blind, randomised controlled trials examining efficacy on the basis of clinical outcomes, in which treatment with donepezil, rivastigmine, or galantamine was compared with placebo in patients with Alzheimer's disease, were included. Each study was assessed independently, following a predefined checklist of criteria of methodological quality.

Results 22 trials met the inclusion criteria. Follow-up ranged from six weeks to three years. 12 of 14 studies measuring the cognitive outcome by means of the 70 point Alzheimer's disease assessment scale—cognitive subscale showed differences ranging from 1.5 points to 3.9 points in favour of the respective cholinesterase inhibitors. Benefits were also reported from all 12 trials that used the clinician's interview based impression of change scale with input from caregivers. Methodological assessment of all studies found considerable flaws—for example, multiple testing without correction for multiplicity or exclusion of patients after randomisation.

Conclusion Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable.

Is carotid endarterectomy safe in patients over 80 years old?

2005-08-22T13:10:00.000Z

From Nature Clinical Practice Cardiovascular Medicine (2005) 2, 382-383

Background
The most effective treatment for carotid artery stenosis is carotid endarterectomy (CEA). To date, randomized trials of this procedure versus best medical care have excluded patients aged 80 years or more, and consequently elderly individuals with this condition have been labeled 'high risk' for CEA, and are often treated with medical therapy or angioplasty and stenting.

Objective
To identify whether age of 80 years or more increases morbidity, mortality and length of hospital stay after CEA.

Design and intervention
This retrospective review of the Jobst Vascular Registry, a prospective record of vascular procedures carried out at the Toledo Hospital, Ohio, USA, analyzed all patients undergoing CEA between January 1993 and August 2004. The pretreatment characteristics, postoperative complications, surgical outcomes and length of hospitalization of patients were reviewed. Before CEA, patients underwent duplex ultrasonography and four-vessel cerebral arteriography. Most CEAs were performed under general anesthesia with intraoperative shunting; an autologous vein or synthetic patch was used to close the arteriotomy. Patients were monitored in intensive care for 24 h after CEA and followed up at day 7−10 postsurgery if no adverse events occurred.

Outcome measures
The main outcomes were procedure-related stroke and death. Length of hospital stay, destination after leaving hospital or in-hospital mortality, and complications were secondary outcomes. Operative mortality was defined as all deaths attributable to the procedure regardless of the time of occurrence, and included all deaths occurring within 30 days postoperatively, regardless of cause.

Results
In 1,961 patients in the registry, 2,217 CEAs were carried out: 334 patients aged 80 years or more underwent 360 procedures, and the remaining 1,627 patients under 80 years old underwent 1,857 CEAs. The occurrence of postoperative stroke did not differ significantly between the two age groups: 14 (0.8%) strokes occurred in patients under 80 years versus 4 (1.1%) in patients 80 years old or more. Operative mortality was slightly lower in the younger group, compared with the older group (0.8% versus 1.9%, respectively, P = 0.053). Mortality was similar in all asymptomatic patients, but was higher in older symptomatic than older asymptomatic patients (P = 0.007). The combined rate of stroke, death or both was higher in the older group than in the younger group (3.1% versus 1.5%, respectively, P = 0.041), the difference arising from the significantly higher rate seen in the older symptomatic patients compared with older asymptomatic patients. The average postoperative and total length of hospitalization was shorter in the younger than older group (P = 0.001). The groups had similar adverse event rates. Survival curve analysis demonstrated higher mortality in the older age group, however, this was similar to mortality in the normal, age-adjusted population.

Conclusion
Although increased, the combined stroke and death rate in patients aged 80 years or more falls within acceptable levels in national guidelines and compares favorably with best medical care. Miller et al. stress that patients over 80 years old should not be arbitrarily deemed 'high risk' for CEA.

Cerebrospinal fluid biomarkers in Creutzfeldt–Jakob disease

2005-08-04T14:48:00.000Z

From Clinical Neurology and Neurosurgery Volume 107, Issue 5 , August 2005, Pages 355-360 [Review]

Abstract
Creutzfeldt–Jakob disease (CJD) is a rare neurodegenerative disorder. Since the emergence of variant CJD (vCJD) vigilance concerning the disease's incidence has increased and the interest in accurate in vivo diagnosis has augmented. So far, a large number of biomarkers has been investigated as aid in the differential diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) and vCJD. These include, among others, neuron-specific enolase (NSE), microtubuli associated protein Tau, S-100β, amyloid-beta (Aβ1–42) and the 14-3-3 protein. Multiple studies have confirmed that CSF detection of 14-3-3 protein by Western blot was the best single biomarker for sCJD with an average sensitivity and specificity of 92%. Also, in genetic and iatrogenic CJD (iCJD) patients with an average disease duration of less than 1 year, 14-3-3 is the best differential biomarker. Unfortunately, the 14-3-3 protein has a lower sensitivity if the disease duration exceeds beyond 1 year in both sporadic CJD and other CJD types (vCJD, and specific genetic or iatrogenic CJD types).

Middle cerebral artery dissections: Differences between isolated and extended dissections of internal carotid artery

2005-08-02T15:25:00.000Z

From Journal of the Neurological Sciences Volume 235, Issues 1-2 , 15 August 2005, Pages 37-44

Abstract
Isolated middle cerebral artery dissection (MCAD) has rarely been encountered clinically and few have reviewed it systemically. The etiologies, clinical manifestations, natural clinical course and prognosis of MCAD remain poorly understood. From 1995 to 2004, there were 5 cases diagnosed clinically and angiographically to have MCAD (isolated MCAD in 1, ICAD-MCAD in 4) from a medical center in Taiwan. MEDLINE (1966–2003) was searched for published articles in English that concerned the diagnosis of MCAD. Clinical presentations, stroke types, angiographic findings, etiologies, treatment strategies and outcomes were compared between cases with isolated MCAD or ICAD-MCAD. There were 23 cases (male, 46%; mean age, 22.9 ± 19.5 years) with 24 events of isolated MCAD and 31 cases (male, 47%; mean age, 22.2 ± 12.9 years) with 35 events of ICAD-MCAD. The types of stroke in isolated MCAD group included subarachnoid hemorrhage (12%) and cerebral infarction (88%); and in ICAD-MCAD group were subarachnoid hemorrhage (6%) and cerebral infarction (94%). The presenting symptoms were similar between both groups. Fluctuating course was more often in isolated MCAD than in ICAD-MCAD (17% vs. 3%, p = 0.061). Recurrence of dissection events in both groups was infrequent (4% vs. 9%, p = 0.56). Both groups had high case-fatality rates (MCAD, 48%; ICAD-MCAD, 58%). The cause of dissection in both groups was idiopathic in the majority. Congenital vessel wall defects were found in 26% of ICAD-MCAD, but in only 4% of isolated MCAD (p = 0.066). In contrast, preceded trauma was more often found in isolated MCAD than ICAD-MCAD (35% vs. 19%, p = 0.085). Arteritis was noted in 16% of ICAD-MCAD patients, but none in isolated MCAD. Angiography revealed segmental stenosis in 72% of isolated MCAD and 96% of ICAD-MCAD. Aneurysmal dilatation of the involved cerebral arteries was noted in 28% of isolated MCAD, but none in MCAD-ICAD. Both isolated MCAD and ICAD-MCAD can cause vascular events with high mortality rates. Several aspects differed between 2 groups, including clinical course, underlying etiologies and angiographic findings.

Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of ALS

2005-08-02T15:13:00.000Z

From Journal of the Neurological Sciences Volume 235, Issues 1-2 , 15 August 2005, Pages 61-68

Abstract
Insulin-like growth factor (IGF)-1 has been shown to have a protective effect on motor neurons both in vitro and in vivo, but has limited efficacy in patients with amyotrophic lateral sclerosis (ALS) when given subcutaneously. To examine the possible effectiveness of IGF-1 in a mouse model of familial ALS, transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) with a G93A mutation were treated by continuous IGF-1 delivery into the intrathecal space of the lumbar spinal cord. We found that the intrathecal administration of IGF-1 improved motor performance, delayed the onset of clinical disease, and extended survival in the G93A transgenic mice. Furthermore, it increased the expression of phosphorylated Akt and ERK in spinal motor neurons, and partially prevented motor neuron loss in these mice. Taken together, the results suggest that direct administration of IGF-1 into the intrathecal space may have a therapeutic benefit for ALS.

CSF from ALS patients preferentially elevates intracellular calcium and toxicity in motor neurons via AMPA/k receptor

2005-08-02T15:10:00.000Z

From Journal of the Neurological Sciences Volume 235, Issues 1-2 , 15 August 2005, Pages 45-54

Abstract
Several lines of evidence in the literature purport the contribution of glutamate mediated excitotoxicity in the etiology of amyotrophic lateral sclerosis (ALS) but the cellular mechanisms responsible for selective loss of motor neurons are still obscure. Elevation of intracellular Ca2+ is considered as the early event in glutamate mediated cell injury. We have studied the changes in [Ca2+]i and cytotoxicity in motor neurons and other spinal neurons in culture upon exposure to cerebrospinal fluid (CSF) from ALS patients. CSFs from 20 ALS patients and 20 disease control patients were examined. Eighteen out of twenty (90%) ALS–CSF samples induced a transient but pronounced elevation of [Ca2+]i in neurons, whereas only 1/20 (5%) sample from disease control patients induced a marginal elevation of [Ca2+]i. Strikingly the [Ca2+]i rise was 2–3-fold higher and longer lasting in motor neurons in comparison to the other spinal neurons. Exposure of cells to ALS–CSF drastically decreased the survival rate of motor neurons to 32.26 ± 2.06% whereas a moderate decrease was observed in case of other spinal neurons (67.90 ± 2.04%). In cultures treated with disease control CSF, a small decrease was observed in the survival rate with 80.14 ± 2.00% and 90.07 ± 1.37% survival of motor neuron and other spinal neurons respectively. The AMPA/kainate receptor antagonist NBQX rendered significant protection against the ALS–CSF induced Ca2+ influx and neurotoxicity while the NMDA receptor antagonist APV showed a mild effect. Our data demonstrate that the exposure of spinal cord neurons to ALS–CSF differentially elevates [Ca2+]i and neurotoxicity in motor neurons by activation of glutamate receptors, the AMPA/kainate receptor playing the major role.

Specificity of autoantibodies to epitopes of myelin proteins in multiple sclerosis

2005-08-02T14:41:00.000Z

Permphan Dharmasaroja, Faculty of Science, Department of Anatomy, Mahidol University, 272 Rama VI Road, Rajthevi, Bangkok 10400, Thailand

From Journal of the Neurological Sciences Volume 206, Issue 1 , 15 January 2003, Pages 7-16

Abstract
An autoimmune response to one or more myelin-protein components is thought to be part of the pathogenesis of multiple sclerosis (MS). The immunodominant-autoantibody epitope may be localized on a linear peptide segment, on a conformation-sensitive epitope, or on an epitope resulting from post-translational modifications. Primary, secondary, and tertiary structures of myelin proteins may determine the specific site for binding of autoantibodies. A myelin protein-specific autoantibody can bind to either a linear or conformational epitope, whereas all of the T cell epitopes are linear. At present, the conformational epitopes of myelin proteins have not been identified; most of the methods used to identify the myelin-protein epitopes corresponding to the pathogenesis of multiple sclerosis are involved in the linear epitope mapping. Polymorphism or mutations may cause inappropriate expression of the myelin proteins with alterations to their linear and/or conformational epitopes, and make them susceptible to autoantibody binding, especially if these changes occur at the surface of the protein. This review focuses on the specificity of autoantibodies to the epitopes of myelin proteins and correlates this to the structures of proteins. Factors that influence the expression of myelin-protein epitopes such as the α-helical or β-sheet structure of the protein, the tri-proline site, and the post-translational modifications as well as physicochemical properties of amino acid changed are included.

Author Keywords: Multiple sclerosis; Myelin basic protein; Myelin proteolipid protein; Myelin oligodendrocyte glycoprotein; Immunoglobulins; Epitope mapping; Epitope specificity; Myelin proteins

Cited by
1. The glycopeptide CSF114(Glc) detects serum antibodies in multiple sclerosis • Journal of Neuroimmunology, In Press, Corrected Proof, Available online 26 July 2005, Francesco Lolli, Benedetta Mazzanti, Marta Pazzagli, Elisa Peroni, Maria Claudia Alcaro, Giuseppina Sabatino, Roberta Lanzillo, Vincenzo Brescia Morra, Lucio Santoro, Claudio Gasperini et al. SummaryPlus Full Text + Links PDF (177 K)

2. A possible link between multiple sclerosis and Creutzfeldt–Jakob disease based on clinical, genetic, pathological and immunological evidence involving Acinetobacter bacteria • Medical Hypotheses, Volume 64, Issue 3, 2005, Pages 487-494 Alan Ebringer, Taha Rashid, Clyde Wilson, Richard Boden and Edward Thompson SummaryPlus Full Text + Links PDF (353 K)

3. Myelin basic protein—diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis • Micron, Volume 35, Issue 7, October 2004, Pages 503-542 George Harauz, Noboru Ishiyama, Christopher M. D. Hill, Ian R. Bates, David S. Libich and Christophe Farès SummaryPlus Full Text + Links PDF (2095 K)

4. Linear epitopes of two different autoantigens-La/SSB and myelin basic protein—with a high degree of molecular similarity, cause different humoral immune responses • Journal of Autoimmunity, Volume 21, Issue 1, August 2003, Pages 47-57 Apostolos G. Terzoglou, John G. Routsias, Constantinos Sakarellos, Maria Sakarellos-Daitsiotis, Haralampos M. Moutsopoulos and Athanasios G. Tzioufas SummaryPlus Full Text + Links PDF (312 K)

Early-onset parkinsonism associated with PINK1 mutations

2005-08-01T13:22:00.000Z

From: NEUROLOGY 2005;65:87-95

Objective: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50>

Methods: The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases.

Results: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later.

Conclusions: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.

Intravenous immunoglobulin for multifocal motor neuropathy (Cochrane Review)

2005-05-28T18:31:00.000Z

Background: Multifocal motor neuropathy is a rare, probably immune mediated disorder characterised by slowly progressive, asymmetric, distal weakness of one or more limbs with no objective loss of sensation. It may cause prolonged periods of disability. The treatment options for multifocal motor neuropathy are sparse. Patients with multifocal motor neuropathy do not usually respond to steroids or plasma exchange, and may even worsen with these treatments. Many uncontrolled studies have suggested a beneficial effect of intravenous immunoglobulin.

Objectives: To review systematically the evidence from randomised controlled trials concerning the efficacy and safety of intravenous immunoglobulin in multifocal motor neuropathy.

Search strategy: We used the search strategy of the Cochrane Neuromuscular Disease Review Group to search the Disease Group register (searched September 2003), MEDLINE (January 1990 to September 2003), EMBASE (January 1990 to September 2003) and ISI (January 1990 to September 2003) databases for randomised controlled trials.

Selection criteria: Randomised controlled studies examining the effects of any dose of intravenous immunoglobulin versus placebo in patients with definite or probable multifocal motor neuropathy.Outcome measures had to include one of the following: disability, strength, or conduction block. Studies which reported the frequency of adverse effects were used to assess safety.

Data collection and analysis: Two authors reviewed literature searches to identify potentially relevant trials, scored their quality and extracted data independently. For dichotomous data, we calculated relative risks, and for continuous data, effect sizes and weighted pooled effect sizes. Statistical uncertainty was expressed with 95% confidence intervals.

Main results: Four randomised controlled trials including a total of 34 patients were suitable for this systematic review. Strength improved in 78% of patients treated with intravenous immunoglobulin and only 4% of placebo-treated patients. Disability improved in 39% of patients after intravenous immunoglobulin treatment and in 11% after placebo (statistically not significantly different). Mild, transient side effects were reported in 71% of intravenous immunoglobulin treated patients. Serious side effects were not encountered.

Authors' conclusions: Limited evidence from randomised controlled trials shows that intravenous immunoglobulin has a beneficial effect on strength. There was a non-significant trend towards improvement in disability. More research is needed to discover whether intravenous immunoglobulin improves disability and is cost-effective.

Citation: van Schaik IN, van den Berg LH, de Haan R, Vermeulen M. Intravenous immunoglobulin for multifocal motor neuropathy. The Cochrane Database of Systematic Reviews 2005, Issue 2.

Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease (Cochrane Review)

2005-05-28T18:24:00.000Z

Orrell RW, Lane RJM, Ross M

Background: Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (or motor neuron disease). A range of antioxidant medications are available, and have been studied.

Objectives: To examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis.

Search strategy: We searched the Cochrane Neuromuscular Disease Group trials register (July 2003), MEDLINE (from January 1966 to July 2003), EMBASE (from January 1980 to July 2003) and other sources.
Selection criteria: All randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis.

Data collection and analysis: The reviewers independently applied the selection criteria, assessed study quality and two reviewers performed independent data extraction.

Main results: The search identified 21 studies for consideration but only eight studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure, (survival at 12 months treatment). Sufficient data were available from three studies to allow analysis of the primary outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed of vitamin E 500 mg twice daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 3 x 10-5g three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta-analysis of antioxidants in general when combining the results. No significant differences were demonstrated in secondary outcome measures.

Authors' conclusions: There is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and patients. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.

Citation: Orrell RW, Lane RJM, Ross M. Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease. The Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD002829.pub3. DOI: 10.1002/14651858.CD002829.pub3.

Cigarette smoking and the progression of multiple sclerosis

2005-05-28T18:15:00.000Z

An increased risk of multiple sclerosis among smokers has been found in several prospective epidemiological studies. The association between smoking and progression of multiple sclerosis has not been examined. We identified patients who had a first multiple sclerosis diagnosis recorded in the General Practice Research Database (GPRD) between January 1993 and December 2000. Their diagnosis and date of first symptoms were confirmed through examination of medical records. Smoking status was obtained from the computer records.

To assess the association between smoking and risk of multiple sclerosis, we conducted a case–control study nested in the GPRD. Up to 10 controls per case were randomly selected, matched on age, sex, practice, date of joining the practice and availability of smoking data. To assess the association between smoking and progression of multiple sclerosis, we conducted a cohort study of multiple sclerosis cases with a relapsing–remitting onset. Our nested case–control study included 201 cases of multiple sclerosis and 1913 controls. The odds ratio [95% confidence interval (CI)] of multiple sclerosis was 1.3 (1.0–1.7) for ever smokers compared with never smokers. Our cohort study included 179 cases with a mean (median) length of follow-up of 5.3 (5.3) years. The hazard ratio of secondary progression was 3.6 (95% CI 1.3–9.9) for ever smokers compared with never smokers. These results support the hypothesis that cigarette smoking is associated with an increased risk of multiple sclerosis, and suggest that smoking may be a risk factor for transforming a relapsing–remitting clinical course into a secondary progressive course.

From Brain 2005 128(6):1461-1465

CLINICAL DIAGNOSIS OF ALZHEIMER'S MAY BE DELAYED

2005-04-13T21:14:00.000Z

In a study of people with mild cognitive impairment (MCI), those who took the drug donepezil were at reduced risk of progressing to a diagnosis of Alzheimer's disease (AD) during the first year of the trial, but by the end of the 3-year study there was no benefit from the drug. Vitamin E was also tested in the study and was found to have no effect at any time point in the study when compared with placebo.

These findings, from the Memory Impairment Study, are the first to suggest than any agent can delay the clinical diagnosis of AD in people with MCI. The effects of the drug measured in this study "did not provide support for a clear recommendation for the use of donepezil" generally to forestall the diagnosis of AD in people with MCI, the researchers stated in their report, but they did note the potential importance of the findings for some patients. The data, they said, "could prompt a discussion" between clinicians and patients on the possibility of donepezil therapy in certain cases.

The findings were reported in the April 14, 2005, online "The New England Journal of Medicine".

"While the delay in progressing to Alzheimer's disease had a limited effect in this case, it comes at an early stage of memory loss, a critically important time for patients and families hoping that the disease can be held at bay," says Neil Buckholtz, Ph.D., chief of the Dementias of Aging Branch at the NIA.

As part of the study, the researchers examined the effect of donepezil and vitamin E on delaying diagnosis of AD among a subset of people with MCI with apolipoprotein E-4 (APOE-e4), the only known genetic risk factor for late-onset AD. While the overall rate of progression to AD was greater in this group, use of donepezil in the APOE-e4 subset was beneficial for up to 36 months in reducing the risk of an AD diagnosis. The researchers did not recommend APOE-e4 genotyping for people with MCI, suggesting more research
would be needed to understand the mechanism of action of the drug and other factors.

Additional important factors in the study were the success in diagnosing MCI on a reliable basis in a multi-site study and the finding that MCI can be predictive of AD. A condition whose characterization in the medical community is relatively new, MCI is a transitional state that occurs between the cognitive changes of normal aging and the very early stage of AD. The amnestic subtype of MCI, the focus of this research, involves memory
problems not severe enough to be classified as dementia. Previous studies have shown that approximately eight in 10 people who meet criteria for amnestic MCI progress to AD within 6 years of diagnosis and that people with the APOE-e4 gene progress to AD more rapidly.

In this trial, donepezil and the antioxidant vitamin E were each compared to placebo to learn whether either treatment might delay or prevent progression to AD among people with MCI. Participants were randomized to three groups, one taking 2000 International Units daily of vitamin E, the second receiving 10 mg of donepezil daily, and the third on placebo. All participants also took daily multivitamins. The average age of the participants at baseline was 73 years.

Among the 769 study participants enrolled at 69 sites in the U.S. and Canada, 212 developed possible or probable AD within the 3-year study period. The overall rate of progression from MCI to AD for all three treatment groups combined was 16% per year. The study found that the group on donepezil's risk of progression to a diagnosis of AD was reduced by 58 percent one year into the study, 36 percent at 2 years, but there was no risk reduction at the end of the full 3 years of the study.

"These findings give me a great deal of hope," says Petersen. "We have not answered the question of whether donepezil reduces the underlying brain changes in Alzheimer's disease, but now we know that for some people, drug therapy did make a real, clinical difference. I think there will be real opportunities in the future to test other therapies for patients with MCI."

Donepezil, a cholinesterase inhibitor, is currently prescribed for mild to moderate stages of AD to improve memory and other cognitive functions. Cholinesterase inhibitors work by delaying the breakdown of the
neurotransmitter acetylcholine in the brain. Acetylcholine helps communication between the nerve cells and is important for memory.

The report will appear in the June 9, 2005, print version of "The New England Journal of Medicine".

Blood Test for Multiple Sclerosis a Possibility

2005-04-04T19:28:00.000Z

A simple blood test may one day detect multiple sclerosis before its debilitating symptoms take hold.

Researchers from Wake Forest University Baptist Medical Center have identified three peptides that are present in people with the degenerative nerve disease, but not in people without the condition. The finding could lead to the development of a blood test to spot the disease, which currently requires a round of tests and exams to arrive at a conclusive diagnosis.

Other doctors, however, caution that while the identification of the peptides is a step forward, it is a long way from becoming a clinical tool in the diagnosis of multiple sclerosis (MS).
Finding a distinct pattern of three biomarkers of peptides among the MS patients "suggests the potential for developing a blood test that could allow us to identify the earliest changes that represent MS, and help in its diagnosis," wrote lead researcher Dr. Jagannadha Avasarala, who was affiliated with Wake Forest University Baptist Medical Center at the time of the study. The findings appear in the March 24 issue of the Journal of Molecular Neuroscience.

For the study, researchers compared blood samples from 25 patients who were newly diagnosed with MS to those from 25 people without the disease to see if there were any pattern of proteins and peptides unique to the MS patients.
The MS patients had the most common form of the disease, which is called relapse-remitting and is characterized by attacks that come only periodically. None of them were taking medication and their average age was 29, while the average age of the control group was 28.
The researchers found three peptide biomarkers in all the MS patients that were not present in those without the disease. Proteins are made by genes, and the information locked in the genes is expressed by the proteins. Peptides are the building blocks of proteins.
The findings were made using mass spectrometry, a tool that analyzes proteins with a special software that can recognize protein patterns. Predictive Diagnostics, a California company, developed the technology and funded the research.
"This is an interesting step in the identification of peptides that are unique to MS, but in terms of making a diagnosis, it isn't useful," said Dr. William Sheremata, director of the Multiple Sclerosis Center at the University of Miami School of Medicine.
He said while work with spectrometry is used in many areas of science in identifying compounds in the brain and does represent a new approach to chemistry, using the information to create a simple blood test would require continued research.

Journal of Molecular NeuroscienceJanuary 2005, Volume 25, Issue 1, pps. 119-126

Aspirin Is Safer Than Warfarin And Just As Effecive For Treating Blocked Arteries In Brain

2005-03-31T22:17:00.000Z

"Comparison of warfarin and aspirin for symptomatic
intracranial arterial stenosis." "NEJM", March 31,2005, Vol.352., No.12, pp.1305-1316.

To reduce the risk of stroke, partial blockage of arteries in the brain (intracranial stenosis) has for decades been treated with drugs such as aspirin and warfarin that reduce blood clotting. However, doctors have never had good evidence for choosing one therapy over the other. Now, results of a double-blind, randomized clinical trial show for the first time that aspirin works as well as warfarin with fewer side effects. The study was funded by the NINDS, part of the NIH.

"This trial is good news. A simple low-cost drug works just as well as one that requires complicated and expensive monitoring and dose adjustments," says John R. Marler, M.D., the Associate Director for Clinical Trials at NINDS.

Intracranial stenosis is caused by atherosclerosis - fatty deposits that build up on the inner walls of the arteries and restrict blood flow. Intracranial stenosis causes about 10 percent of the 900,000 strokes and transient ischemic attacks (TIAs) in the United States each year. TIAs are transient strokes that last only a few minutes and occur when the blood supply to part of the brain is briefly interrupted. People with a stroke or TIA due to intracranial stenosis have a greatly increased risk of a second stroke - as much as 15 percent per year. Studies in the 1950s suggested that anticoagulants (a class of drugs that reduce blood clotting), such as warfarin, can reduce the risk of stroke in people with this disease.

In the new study, called the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial, investigators at 59 medical centers across the United States, led by Marc I. Chimowitz, M.D., of Emory University in Atlanta,
compared warfarin to 1300 milligrams (mg) per day of aspirin in a total of 569 patients for an average of 1.8 years. All of the patients had a greater than 50 percent blockage of a major intracranial artery and had experienced a TIA or non-disabling stroke within the 90 days prior to their enrollment in the study.

The investigators found that about 22 percent of the patients had a subsequent ischemic stroke, brain hemorrhage, or death from other blood vessel-related causes, regardless of whether they received aspirin or warfarin. However, the rates of major hemorrhage and death from all causes were significantly higher in the patients treated with warfarin (event rates for aspirin compared to warfarin, respectively, were 3.2 percent vs. 8.3 percent for major hemorrhage and 4.3 percent vs. 9.7 percent for death). Enrollment in the study was terminated earlier than originally planned on the recommendation of an independent Data and Safety Monitoring Board because of concern for the safety of the patients given warfarin.

Since warfarin treatment is a more expensive and complicated therapy than aspirin, not using warfarin and preventing the bleeding complications associated with it would save more than $20 million per year in the United
States, Dr. Chimowitz estimates.

"The results of this study are only relevant to people with intracranial stenosis," Dr. Chimowitz notes. People who are receiving warfarin for other conditions, such as an irregular heart rhythm (called atrial fibrillation) or clots in the legs or lung, should not stop taking the drug, as studies have found that it is the best option in those conditions, he cautions.

The dose of aspirin used in this study - 1300 mg - is much higher than the daily doses typically prescribed, which range from 81 to 325 mg. While there is some concern that doses of 1300 mg aspirin may increase the risk of
gastrointestinal bleeding, the investigators chose this dose because it was the only amount for which earlier studies had provided good preliminary data. "This is the only dose we know is as effective as warfarin for this disease, since it was the only dose studied. We just don't know how other doses of aspirin would stack up," says Dr. Chimowitz. The major bleeding risk on high dose aspirin in WASID was similar to the major bleeding risk in other stroke trials that have evaluated lower doses of aspirin (e.g. 325 mg per day), he adds. Most experts believe there are no advantages to aspirin doses greater than 325 mg for stroke prevention, and the U.S. Food and Drug Administration-approved dose of aspirin for prevention of vascular events is 50-325 mg. Patients should consult their physicians before beginning any long-term or high-dose aspirin treatment regimen.

Even with treatment, the rates of ischemic stroke in this clinical trial were substantially higher than in stroke prevention trials that have evaluated aspirin and warfarin in patients with other causes of stroke. This underscores that patients with intracranial stenosis are at particularly high risk for stroke and that better therapies are needed, the investigators note.

Complete reconstructed Neanderthal skeleton revealed

2005-03-28T15:03:00.000Z

WHOLE at last. The first reconstruction of a complete Neanderthal skeleton reveals more clearly than ever the similarities and differences between us and them.

The reconstruction makes clear their larger, bell-like chest cavity and wider pelvis. Their bodies were also very compact and dwarf-like in shape, with effectively no waist, possibly as an adaptation against the cold.

Gary Sawyer of the American Museum of Natural History in New York city and Blaine Maley at Washington University in St Louis, Missouri, wanted to shed light on the anatomy and stature of this cousin of modern humans, which died out nearly 30,000 years ago. They assembled the skeleton by taking casts of the most complete skeleton available, the La Ferrassie 1 specimen found in 1909 in the Dordogne valley in France. Then they filled in the blanks using casts taken from other Neanderthal collections from the same period, approximately 60,000 years ago (The Anatomical Record, Part B: The New Anatomist, vol 283B, p 23). "It's the first time any human 'ancestor' has ever been fully reconstructed," says Sawyer.

Meanwhile, the oldest fossilised primate protein to have been sequenced, taken from a Neanderthal, was last week found to be identical to the human equivalent (Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0500450102).

From issue 2491 of New Scientist magazine, 19 March 2005, page 14

Breakthrough In Medical Research: New Chemotherapy Gives Hope To Brain Tumour Patients

2005-03-21T14:26:00.000Z

A large international study conducted by the European Organisation for Research and Treatment of Cancer (EORTC) in collaboration with the National Cancer Institute of Canada (NCIC) Clinical Trials Group demonstrated that the addition of a novel chemotherapy agent, Temozolomide (brand name: Temodal®) to radiation therapy increases survival in patients suffering from glioblastoma, a very aggressive form of a brain tumour. Further, molecular analyses of the tumour allowed for the identification of those patients most likely to benefit from this type of treatment. The findings are leading to a new standard of care for patients with this fast growing and devastating cancer. The results of this landmark trial are published in two companion papers in this weeks' edition of the New England Journal of Medicine (publication date: 10 March 2005).

Prior to the discovery of this new therapy, the average life expectancy of patients with glioblastoma was about 1 year. The results of this study demonstrate a clear improvement of survival. At 2 years only 10% of patients treated with radiotherapy alone were alive, compared to 26% of patients receiving the combination of both radiotherapy and temozolomide chemotherapy. If patients were to be selected according to their molecular profile - the investigators analysed the functionality of a gene responsible for DNA repair, the so called MGMT gene - the improvement is even more dramatic, as almost half of those patients whose tumours carry an inactivated MGMT gene are alive after 2 years. Importantly, the study also showed that this new combined therapy did not impact negatively on the patients' quality of life. Health-related quality of life has become an increasingly important endpoint in cancer studies.

"This landmark study represents the most important advance in the management of glioblastoma since radiotherapy was shown to be of benefit over 35 years ago", comments Dr. Warren Mason, a lead investigators in Canada and head of the neuro-oncology unit at the Princess Margaret Hospital in Torono, Ontario/Canada. "This study also identified MGMT the first clinically relevant molecular marker for glioblastoma which not only serves as a prognositic factor for survival, but also as a predictor for response to chemotherapy. This observation paves the way for using the unique tumor genetic signature as a guide for individualizing therapy and optimizing outcome."

From: European Organisation for Research and Treatment of Cancer

Study Reveals How Brain's Immune System Fights Viral Encephalitis

2005-03-17T21:22:00.000Z

New York University biologists have uncovered how the innate immune system in mice's brains fights viral infection of neurons. The findings, published as the cover study in the latest issue of Virology, show that proteins in neurons fight the virus at multiple stages--by preventing the formation of viral RNA and proteins, and blocking the virus' release, which could infect other cells in the brain.

"There is no magic bullet in fighting viral infections in neurons," said NYU Biology Professor Carol Shoshkes Reiss, the study's senior author. "However, these findings show the redundancy of the immune system--when one response fails to fight infection, others step in."

The study was also conducted at NYU, by a post-doctoral fellow, Mark Trottier, Jr., PhD, now at Michigan State, and Beth Palian, currently a doctoral student at the University of Southern California.
Recently, the West Nile virus has been responsible for a viral encephalitis outbreak in the northeast. The NYU researchers set out to determine how the body can fight viral encephalitis. Specifically, they examined how type I interferons--proteins made by the body that are released in response to stimuli, notably infection--work in neurons and to determine if nerve cells' response to interferons is similar to that of other cells.

Examining the effect of the virus in mice and in cell culture, the researchers found that neurons are sensitive to the protective effect of interferons, inducing pathways to fight the virus' spread. However, their findings showed that interferons fight the virus at different stages of the virus' life cycle. First, they inhibit viral RNA and protein synthesis. If this fails, interferons block the virus from forming particles which can be released and infect other neurons. This is critical, since the immune system does not kill infected precious neurons the way it does other cells, which can be replaced.

The researchers attributed the spread of viral encephalitis to the inability of lab mice to produce sufficient amounts of interferons to fight the virus.

TEST COULD IMPROVE DETECTION OF PRION DISEASE IN HUMANS

2005-03-06T23:30:00.000Z

A highly sensitive post-mortem test could help scientists more accurately
determine if a person died of Creutzfeldt-Jakob disease (CJD), a human
neurological disorder caused by the same class of infectious proteins that
trigger mad cow disease, according to a new study supported in part by the
National Institutes of Health (NIH). The finding opens the possibility that
such testing might be refined in the future so it can be used to detect
prion disease in living people and animals before the onset of symptoms.

The test, called conformation-dependent immunoassay (CDI), was originally
developed to detect various forms of disease-causing proteins called prions
in cows, sheep, deer and other animals.

In the new study, researchers led by
Jiri Safar, M.D., Bruce Miller, M.D., Michael Geschwind, M.D., Stephen
DeArmond, M.D., and Nobel Laureate Stanley B. Prusiner, M.D., of the
University of California, San Francisco, found that CDI not only identifies
prions in human brain tissue but is faster and far more precise than the
standard immunological detection methods, which only detect a small fraction
of the infectious prions that may be in the brain.

The finding appears in the March 1, 2005 issue of the "Proceedings of the
National Academy of Sciences", <http://www.pnas.org>.

In the study, Prusiner and his colleagues extracted brain tissue from 28
people who had died of CJD. They tested these samples using CDI, which uses
highly specific antibodies that bind to all disease-causing prions in the
brain. They also used immunohistochemistry (IHC) to measure only the prion
proteins that are resistant to an enzyme called protease. Protease-resistant
prions are abnormal and usually infectious, meaning they can cause CJD and
other neurodegenerative diseases. CDI detected abnormal prions in all of the
sampled brain regions. In contrast, the researchers found that IHC detected
abnormal prions in less than 25 percent of the sampled brain regions. The
findings, according to the researchers, suggest that CDI could be used to
establish or rule out the diagnosis of CJD with greater accuracy than IHC,
particularly when a small number of samples are available. Prusiner and
colleagues are exploring the possibility of using CDI in living tissue, like
blood or muscle, to detect and diagnose prion diseases, such as CJD or
bovine spongiform encephalopathy (BSE, mad cow disease) while people or
animals are still alive.

"This research not only is an important advance for the detection and
diagnosis of prion diseases, but, with the identification of
protease-sensitive infectious prions, will lead to a better understanding of
the underlying disease processes," said Andrew Monjan, Ph.D., Chief of the
NIA's Neurobiology of Aging Branch.

Why do women develop multiple sclerosis almost twice as often as men?

2005-02-03T20:36:00.000Z

The report from collaborators in Minnesota, Northern Ireland, Belgium and Italy appears in the Jan. 27 online publication of the journal Genes & Immunity

"In practical terms, this is what our findings suggest: How much of the protein known as 'interferon gamma' you produce appears to be a new key variable in understanding who gets MS and who doesn't, and especially why women develop MS more often than men," explains the study's lead author, Mayo Clinic neurologist Brian Weinshenker, M.D.

"If you have a gene that produces high levels of interferon gamma, it may predispose you to developing MS. Under this scenario, men get MS less often because they have a lower frequency of a gene variant that is related to higher secretion of interferon gamma."

To researchers looking for a cure for MS -- where currently there is none -- the finding is helpful for three main reasons:
1) it provides a target at which to direct future investigations into ways to stop MS,
2) it provides leads on ways to improve treatments that can minimize the tissue and nerve damage the disease causes,
and 3) it may advance the search for new treatments for other diseases.

Notes Dr. Weinshenker, "Our finding isn't the whole genetic cause, but it's a helpful step that could lead us to a more complete understanding of MS -- and ultimately, effective treatment. It's also a very promising lead about gender differences that may pertain to susceptibility of other diseases, too, such as rheumatoid arthritis."

The original news release can be found here.

Pharmacology of vertigo/nystagmus/oscillopsia

2005-02-03T16:52:00.000Z

Current Opinion in Neurology. 18(1):11-14, February 2005

Recent findings: In the last 2 years several studies have been published on possible pharmacological treatment options for nystagmus and oscillopsia.

In the treatment of vestibular neuritis two studies showed that cortisone treatment was effective for restoring labyrinthine function. This benefit seems more likely if treatment is started within the first 2 days of onset.

For recurrent vertigo attacks due to Meniere's disease, the titration technique with daily or weekly doses of intratympanic gentamicin until onset of vestibular symptoms, change in vertigo or hearing loss rated best for complete vertigo control.

A new pharmacological treatment option for downbeat nystagmus is the administration of potassium channel blockers (e.g. 4-aminopyridine). They are thought to reinforce the inhibitory action of cerebellar Purkinje cells.

Several case reports have proven the beneficial effect of baclofen on periodic alternating nystagmus, of gabapentin and memantine on acquired pendular nystagmus, and of carbamazepine and gabapentin on superior oblique myokymia.

Physical activity and the association with sporadic ALS

2005-02-03T16:37:00.000Z

NEUROLOGY 2005;64:241-245

Objective: To assess whether lifetime physical activity during work and leisure time is associated with an increased risk of developing ALS and to determine the association between physical activity and duration or age at onset of disease.

Methods: Patients referred to our clinic during the 1-year period 2001 to 2002 who had definite, probable, or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in the study. A case-control study was performed taking into account all occupational and leisure time activities of patients (n = 219) and controls (n = 254). Multivariate analysis included confounding factors (sex, age, level of education, body mass index, alcohol use, and smoking). Three quantitative measures of cumulative physical activity were calculated: until 1 year before the onset of disease (total physical activity), the last 10 years before the onset of disease (late physical activity), and until the age of 25 (early physical activity). In addition, a systematic review of all published data is presented.

Results: Smoking and alcohol use were independently associated with ALS (current smoking increased risk, OR = 1.8, 95% CI = 1.0 to 3.0, p = 0.03, ever/current alcohol use decreased risk, OR = 0.6, 95% CI = 0.3 to 0.9, p = 0.04). No significant association with occupational or leisure time physical activity was found (all ORs 1.7), which was in agreement with most studies with the highest level of evidence in the systematic review. Higher leisure time activities were associated with an earlier age at onset: activity levels before age of 25 (p <>

Conclusions: There is no association between physical activity and the risk of developing ALS.

Update on the Genetics of Stroke and Cerebrovascular Disease 2004

2005-01-25T15:35:00.000Z

Stroke. February 2005; Vol. 36, No. 2, 179

Key Words: Advances in Stroke • intracranial aneurysm • subarachnoid hemorrhage

Intracranial aneurysms (IA): A Finnish study of 222 affected relative pairs with IAs found evidence for linkage near locus D19S246. Several promising candidate genes are located around this locus. Another study involving families from Japan and Utah found evidence for linkage at locus D7S2421, which is near the elastin gene. Some previous studies have failed to confirm linkage of IA to elastin. Perhaps this reflects ascertainment issues to indicate genetic heterogeneity of the IA trait. A recent linkage study using a very large family with apparent autosomal dominant IAs identified a locus on chromosome 1p34–36. A recent study investigated the collagen 2 gene in Japanese patients with IAs. A significant association between an exonic single nucleotide polymorphism and familial IA was found. This single nucleotide polymorphism causes an amino acid change from alanine to proline with a change in thermal stability for the collagen triple-helical domain.

Cerebral cavernous malformations (CCMs): Three loci for CCM have been identified: CCM1 (chromosome 7q), CCM2 (7p), and CCM3 (3q). The genes responsible for all 3 types of CCM have now been identified. CCM1 is caused by KRIT1, CCM2 is caused by MGC4607 (also known as malcavernin), and CCM3 is caused by programmed cell death protein 10.

Ischemic Stroke:
CADASIL:Remains the prototypical inherited type of inherited ischemic stroke. The exact pathogenesis of CADASIL remains a mystery, although mutations in Notch3 are known to cause this autosomal dominant disorder. Several studies have suggested that a gain-of-function process is responsible for the disease phenotype, whereas others have suggested an abnormality in a signaling pathway for some patients.

New information about genetic aspects of ischemic stroke has emerged in several areas. The DeCode group published another study showing that a 4-marker single nucleotide polymorphism in the 5-lipoxygenase activating protein was associated with almost a 2-fold increased risk of stroke. As with the discovery of the association between stroke and the phosphodiesterase 4D gene last year, these advances await confirmation by other research groups and validation in animal models of stroke.

Polymorphisms in a host of other genes have been reported to be associated with ischemic stroke, including the low-density lipoprotein receptor, endothelial nitric oxide synthase, tissue plasminogen activator, serum paraoxonase, and glycoprotein IIIa (a platelet membrane receptor for fibrinogen and von Willebrand factor). In many cases, these associations are only for specific subtypes of ischemic stroke, or the polymorphisms are intronic with no known functional significance for gene expression or protein function.

The ongoing POLARIS study will hopefully address some of these concerns with its large number of patients and careful study design. Perhaps one of the most intriguing new studies report an association between a polymorphism in the COX-2 gene and ischemic events. The polymorphism is at position –765 and causes a G-to-C change. This polymorphism had a protective effect, reducing the risk of myocardial infarction and ischemic stroke, and reducing C-reactive protein and MMP2 and MMP 9 expression. These findings may be relevant in light of recent reports of an increased risk of ischemic events caused by some COX-2 inhibitors.

Studies Link Gene Mutation to Parkinson's Disease

2005-01-18T16:23:00.000Z

Lancet 2005: 365(9455), 15 January 2005

Three teams of scientists have identified a genetic mutation that is linked to about 5 percent of inherited cases of Parkinson's disease.
The fault on the recently discovered LRRK2 gene is one of five genetic defects linked to the progressive nervous system disorder and could lead to improved diagnosis and the development of a genetic test.
"Our results suggest that the mutation we have studied is the most common cause of Parkinson's disease identified to date," said Dr Tatiana Foroud, an associate professor at Indiana University School of Medicine in Indianapolis.
"We found there is a novel mutation which is common in these families," Bonifati said in an interview. "The other groups in the UK and the US found the same mutation independently."
"The main challenge is now to try and understand how this and other Parkinson disease-associated LRRK2 mutations lead to neurodegenerative disease, in order to design novel therapeutic and preventive strategies," he added. (Reuters)

Summary
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause some forms of autosomal dominant Parkinson's disease. We measured the frequency of a novel mutation (Gly2019Ser) in familial Parkinson's disease by screening genomic DNA of patients and controls. Of 767 affected individuals from 358 multiplex families, 35 (5%) individuals were either heterozygous (34) or homozygous (one) for the mutation, and had typical clinical findings of idiopathic Parkinson's disease. Thus, our results suggest that a single LRRK2 mutation causes Parkinson's disease in 5% of individuals with familial disease. Screening for this mutation should be a component of genetic testing for Parkinson's disease.

New tool to detect Alzheimer's early

2005-01-18T15:15:00.000Z

Doctors have long known that smell is one of the first senses to fail as Alzheimer's begins its slow and incurable progression. Tracking the process whereby a person loses their ability to smell could play a pivotal role in early detection and treatment of Alzheimer's. And now researchers at Columbia have developed a tool that will aid early detection.

The system that governs our sense of smell is centered in the same area of the brain that is first attacked, then damaged, during the original stages of Alzheimer's. But for researchers such as Davangere Devanand, professor of psychiatry and neurology at Columbia University Medical Center, the perplexing issue was, exactly which smells people lose the ability to recognize. Could memory loss be detected soon enough to allow for early treatment, and once isolated, what might findings about smell loss suggest for developing detection and treatment methods for Alzheimer's?

To discover possible connections, Deavand and his team assembled a test group of 150 people, from 43 to 85 years old, and with varied degrees of memory loss. To establish a baseline, this group was initially tested then re-tested every six months in order to measure overall ability to identify 10 separate smells: lemon, leather, clove, lilac, menthol, pineapple, natural gas, soap, strawberry and lavender. The results were compared to a control group of 63 healthy volunteer with no memory impairment. Volunteers were given scented cards and asked to identify a series of smells. The results, gathered over nine years, indicated that volunteers who preformed poorly at identifying the smells over time went on to develop Alzheimer's. None of the non-afflicted subjects developed the disease.

Devanand says, "Early diagnosis of Alzheimer's disease is critical for patients and their families to receive the most beneficial treatment and medications." He added that tests such as these may very soon go a long way toward helping detect Alzheimer's far sooner than is currently possible. He recently presented his findings at a meeting of the American College of Neuropsychopharmacology.

The trial conducted by Devanand and his team also lays important groundwork for future advances. In future, medical investigators will be able to build on the work of Devanand and his researchers to perhaps find a cure for Alzheimer's

HRT Linked to Raised Stroke Risk

2005-01-18T01:45:00.000Z

BMJ, doi:10.1136/bmj.38331.655347.8F (published online 7 January 2005)

Association between hormone replacement therapy and subsequent stroke: a meta-analysis

Design Systematic review of randomised controlled trials identified from the Cochrane Library, Embase, and Medline; reviews; and reference lists of relevant papers.
Studies reviewed 28 trials, with 39 769 subjects, were identified.
Review measures Rates for cerebrovascular events analysed with a random effects model. Sensitivity analyses for heterogeneity included phase of prevention (primary or secondary), type of hormone replacement therapy (oestrogen alone or combined with progesterone), type of oestrogen (estradiol or conjugated equine oestrogen), size of trial (<5000>5000 patients), length of follow up (3 years or >3 years), sex (women only or men only), and trial quality (high or low).
Results Hormone replacement therapy was associated with significant increases in total stroke (odds ratio 1.29 (95% confidence interval 1.13 to 1.47), n=28), non-fatal stroke (1.23 (1.06 to 1.44), n=21), stroke leading to death or disability (1.56 (1.11 to 2.20), n=14), ischaemic stroke (1.29 (1.06 to 1.56), n=16), and a trend to more fatal stroke (1.28 (0.87 to 1.88), n=22). It was not associated with haemorrhagic stroke (1.07 (0.65 to 1.75), n=17) or transient ischaemic attack (1.02 (0.78 to 1.34), n=22). Statistical heterogeneity was not present in any analysis.
Conclusions Hormone replacement therapy was associated with an increased risk of stroke, particularly of ischaemic type. Among subjects who had a stroke, those taking hormone replacement therapy seemed to have a worse outcome. Hormone replacement therapy cannot be recommended for the primary or secondary prevention of stroke.

Month of Birth Linked to Risk of Multiple Sclerosis

2005-01-18T01:26:00.000Z

BMJ 2005;330:120 (15 January)

Design Population based study with population and family based controls and a retrospective cohort identified from death certificates. A post hoc pooled analysis was carried out for large northern datasets including Sweden and Denmark.
Setting 19 MS clinics in major cities across Canada (Canadian collaborative project on the genetic susceptibility to multiple sclerosis); incident cases of MS from a population based study in the Lothian and Border regions of Scotland; and death records from the UK Registrar General.
Populations 17 874 Canadian patients and 11 502 British patients with multiple sclerosis.
Results In Canada (n = 17 874) significantly fewer patients with MS were born in November compared with controls from the population census and unaffected siblings. These observations were confirmed in a dataset of British patients (n = 11 502), in which there was also an increase in the number of births in May. A pooled analysis of datasets from Canada, Great Britain, Denmark, and Sweden (n = 42 045) showed that significantly fewer (8.5%) people with MS were born in November and significantly more (9.1%) were born in May. For recent incident data, the effect of month of birth was most evident in Scotland, where MS prevalence is the highest.
Conclusions Month of birth and risk of MS are associated, more so in familial cases, implying interactions between genes and environment that are related to climate. Such interactions may act during gestation or shortly after birth in individuals born in the northern countries studied.

Vitamin E intake and risk of amyotrophic lateral sclerosis

2005-01-18T01:00:00.000Z

Annals of Neurology, 2005 Volume 57, Issue 1, Pages 104-110

Abstract
Oxidative stress may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). We therefore examined prospectively whether individuals who regularly use supplements of the antioxidant vitamins E and C have a lower risk of ALS than nonusers. The study population comprised 957,740 individuals 30 years of age or older participating in the American Cancer Society's Cancer Prevention Study II. Information on vitamin use was collected at time of recruitment in 1982; participants then were followed up for ALS deaths from 1989 through 1998 via linkage with the National Death Index. During the follow-up, we documented 525 deaths from ALS. Regular use of vitamin E supplements was associated with a lower risk of dying of ALS. The age- and smoking-adjusted relative risk was 0.99 (95% confidence interval [CI], 0.69-1.41) among occasional users, 0.59 (95% CI, 0.36-0.96) in regular users for less than 10 years, and 0.38 (95% CI, 0.16-0.92) in regular users for 10 years or more as compared with nonusers of vitamin E (p for trend = 0.004). In contrast, no significant associations were found for use of vitamin C or multivitamins. These results suggest that vitamin E supplementation could have a role in ALS prevention.

The "Eye of the Tiger" Sign

2005-01-17T23:45:00.000Z

The "Eye of the Tiger" Sign
Picture from CMAJ • January 4, 2005; 172 (1)

A 13-year-old boy presented to a pediatric clinic with progressive decreased movements. His vision had been decreasing for 8 years, and he had been unable to walk for 3 years.

The patient was born to a healthy nonconsanguineous couple. His mother's pregnancy and his natal history were unremarkable. During infancy his ability to hold his neck and to sit with and without support was delayed. Motor and speech delay were noticed at 2 years, and at 4 years his night vision began to deteriorate, and he had frequent falls with subsequent injuries. An ophthalmologist diagnosed retinitis pigmentosa (RP). At school, his behaviour and academic ability were normal.
At the age of 10, the patient developed spasticity, decreased movements of his lower limbs and dystonic postural abnormalities. The spasticity and dystonia were progressive and disabling enough to restrict him to a wheelchair. His speech deteriorated, and he gradually stopped talking. His parents also observed an intellectual decline. The patient was seen by a number of physicians, none of whom was able to establish a satisfactory diagnosis, until he presented to the pediatric clinic. Funduscopy confirmed the finding of RP, and an MRI showed marked bilateral high-signal intensities surrounding the globus pallidus — the "eye of the tiger" sign that is characteristic of pantothenate kinase-associated neurodegeneration (PKAN) (Fig. 1left; the right image shows an age-matched normal MRI).1

PKAN, formerly known as Hallervorden–Spatz disease, was first described in 1922.2 It is an autosomal recessive neurodegenerative disorder associated with accumulation of iron in the basal ganglia,1 and it has 2 major forms: early onset and late onset.2 Early-onset PKAN is rapidly progressive and characterized by gait impairment, as seen in our patient. Dystonia develops, leading to loss of ambulation and restriction of activities by mid-adolescence. Intellectual impairment, RP and optic atrophy are also associated with the disease.2 Late-onset PKAN presents by 20 years, manifesting a progressive picture of dementia, parkinsonism, dystonia, anarthria, aphonia and incontinence.2 The pathognomonic "eye of the tiger" sign is seen in both forms of the disease. No prevalence studies have yet been done on this disease or its different forms.
PKAN has been mapped to chromosome 20p12.3-p13.3 Mutations in PANK2, the gene encoding the enzyme pantothenate kinase 2, have been demonstrated in the majority of patients with PKAN.1,3 The presence of mutation in PANK2 leads to a genetic diagnosis and makes presymptomatic testing of family members possible, but an MRI can still be considered the "gold standard" in diagnosing early-onset PKAN.1

The differential diagnosis for progressive dystonia in children includes idiopathic generalized dystonia, dopa-responsive dystonia, myoclonic dystonia, metachromatic leukodystrophy, Niemann–Pick disease type C and Lesch–Nyhan syndrome.4
There is no specific treatment. Some patients show residual activity of the enzyme, but the benefit of pantothenate supplementation in ameliorating symptoms has not yet been proven. However, levodopa, anticholinergics and intrathecal baclofen have been shown to improve the patient's quality of life.2

References
1. Hayflick SJ, Westaway SK, Barbara L, Zhou B, Johnson M, Ching K, et al. Genetic, clinical, and radiographic delineation of Hallervorden–Spatz syndrome. N Engl J Med 2003;348:33-40[Abstract/Free Full Text]
2. Neil Gordon. Pantothenate kinase-associated neurodegeneration (Hallervorden–Spatz syndrome). Eur J Pediatr Neurol 2002;6:243-7.[CrossRef][Medline]
3. Zhou B, Westaway SK, Levinson B, Johnson M, Gitshier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden–Spatz syndrome. Nat Genet 2001;28: 345-9.[CrossRef][Medline]
4. Assmann B, Surtees R, Hoffmann GF. Approach to the diagnosis of neurotransmitter diseases exemplified by the differential diagnosis of childhood-onset dystonia. Ann Neurol 2003;54(Suppl 6):S18-24.

1st Unvaccinated Rabies Survivor

2005-01-17T23:28:00.000Z

1st Rabies Survivor (AP picture)
(Please see comments for more details)

Suggestions and Comments

2005-01-17T21:37:00.000Z