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Wednesday, May 4, 2016


Patients who had a transient ischemic attack (TIA) or minor stroke and were treated at a clinic specializing in TIA were less likely to have a recurrent stroke one year later compared to historical cohorts, according to a study published in the April 21 issue of the New England Journal of Medicine. The lower risk may be explained by better and faster implementation of secondary stroke prevention strategies in contemporary TIA clinics, said the study's authors.

The researchers analyzed data on 4,789 patients in, a patient registry encompassing 61 specialized stroke care sites in 21 countries. Enrollees had experienced a TIA or a minor stroke within the previous seven days and were treated at sites with a "dedicated system for the care of patients with TIA" and "a yearly volume of at least 100 patients during the previous 3 years." Follow-up occurred at one, three, and 12 months after the qualifying event and every 12 months thereafter for 5 years, at which points patients were evaluated for "clinical events, medical treatment, and main risk factors" for stroke, including blood pressure and a lipid profile.

Researchers found that at one year after TIA or minor stroke, a total of 274 primary outcomes (major fatal or nonfatal cardiovascular outcomes) had occurred, corresponding to an event rate of 6.2 percent, and that the overall estimate of the risk of stroke was 5.1 percent. The risk of recurrent stroke was 1.5 percent at two days, 2.1 percent at seven days, and 3.7 percent at 90 days after symptom onset. These risks, noted the study's authors, were "less than half" of those observed in historical cohorts.  For example, the risk of stroke and other vascular events at 90 days in the historical cohorts was 12 to 20 percent, as compared with 3.7 percent in the TIAregistry group.

The findings also confirmed that three variables were "independently associated with one-year stroke risk": a patient's ABCD2 score, which factors age, blood pressure, clinical findings, duration of symptoms, and presence or absence of diabetes; brain imaging; and status of large-artery atherosclerosis. Patients with an ABCD2 score of 6 or 7, who showed multiple infarctions on brain imaging, or who had large-artery atherosclerosis each had "more than a doubling in the risk of stroke."

The results, say the study's authors, show that prompt and targeted treatment of TIA and minor stroke in specialized TIA clinics or dedicated stroke care delivery units is associated with a reduced risk of recurrent stroke. The findings may be explained by "better and faster" implementation of secondary stroke prevention strategies at specialized stroke clinics, including "immediate initiation of antiplatelet drugs, oral anticoagulation in the event of atrial fibrillation, urgent revascularization inpatients with critical carotid stenosis, and other secondary prevention measures such as treatment with statins and blood-pressure–lowering drugs."

Furthermore, the study's authors noted that registered patients showed "good adherence to treatment recommendations," suggesting that "the risk observed during the follow-up was the risk that remained after treatment of risk factors."

The authors noted several limitations of the study, including that sites were chosen "on the basis of the existence of a TIA clinic or dedicated care for patients with TIA." The study was also biased "toward more specialized stroke physicians." However, the study's authors refute the notion that their study cohort was simply healthier than historical cohorts: "More than two thirds of the cohort had an ABCD2 score of 4 or more, and the risk that we obscured was low in each stratum of the ABCD2 score."

In an accompanying editorial, Ralph L. Sacco, MD, FAAN, chairman of neurology, and Tatjana Rundek, MD, PhD, professor of neurology, epidemiology, and public health, both at the University of Miami, noted additional study limitations. They noted that the study was "not a randomized trial" and "there was no comparison group to assess whether specialized units performed better than nonspecialized units."

However, the editorial authors said the results were "striking" and showed that "urgent care for patients with a TIA or minor stroke in specialized TIA clinics or dedicated care delivery units with stroke specialists undoubtedly works." As a result, they concluded, the study should "prompt health care providers and policymakers" to "deliver the most effective care not only to patients with acute stroke, but also to those with a TIA or minor stroke."

Look for more discussion about the study in the May 19 issue of Neurology Today.


Thursday, April 28, 2016


Credit: Michael Polydefkis​


In a case-control longitudinal study, investigators at the Johns Hopkins University reported that patients with small fiber neuropathy (SFN), irrespective of cause, experienced progressive axon loss during two to three years of follow-up, with many developing large fiber dysfunction.

Moreover, they found that SFN, which is associated with painful attacks that begin in the hands and legs, causes damage along the entire length of sensory nerve fibers, rather than just at the longest ends of the fiber first.

The findings, which were published in the April 11 online edition of JAMA Neurology, challenge the conventional thinking about SFN pathogenesis, which posits that the longest nerves degrade first.

In order to measure the natural course of SFN, the researchers tested and monitored 62 people, including 52 people with predominant SFN and 10 healthy controls, over the course of three years. Of those with SFN, 25 people had idiopathic SFN, 13 people had prediabetes or impaired glucose tolerance-associated SFN, and 14 people had diabetes-related SFN. Researchers took biopsies of patients' skin from three locations – the distal leg, the distal thigh, and the proximal thigh – at a baseline visit and at a follow-up appointment three years later.

Among their results, they observed that intraepidermal nerve fiber density (IENFD) "decreased over time in all patients at a similar rate" and that the "decrease in IENFD was similar across the three sites in all three groups of patients." The mean yearly rates of IENFD change over time at the distal leg, distal thigh, and proximal thigh were –1.42, –1.59, and –2.8 fibers per millimeter, respectively, which the study's authors say "indicate comparable rates of decrease across biopsy sites."

In addition, the data suggest that SFN is most damaging to people with diabetes and prediabetes compared with people who have idiopathic SFN. Nerve fiber density was "lower in all sites at baseline in patients with [diabetes and prediabetes] compared with [patients with idiopathic neuropathy]," the researchers reported, noting that people with diabetes and prediabetes who had SFN are "more likely to develop large fiber involvement" than those with idiopathic SFN.

"[Small fiber neuropathy] signals the beginning of nerve deterioration that with time involves other types of nerve fibers and becomes more apparent and dramatically affects people's quality of life," said the study's lead author, Michael Polydefkis, MD, FAAN, professor of neurology at the Johns Hopkins University School of Medicine and director of the Cutaneous Nerve Lab, in a news release about the study. "The results of this new study add urgency to the need for more screening of those with [prediabetes] and faster intervention."

In an accompanying editorial, John T. Kissel, MD, FAAN, chair of the department of neurology at The Ohio State University Wexner Medical Center, and Gordon Smith, MD, FAAN, professor of neurology at the University of Utah, wrote that the study had several strengths, including an "impressive" duration of material collection — 8 years — and the inclusion of a comparison group of healthy control participants who showed no decrease in IENFD.

However, they noted that the study had a number of important limitations. Among them, they cited the small sample size and "the fact that the data were collected at a single major peripheral nerve center." They also pointed out that the IENFD values measured were "surprisingly high," which could indicate that the study population "had greater disease severity, was uniquely vulnerable to progression, or that there was some unrecognized bias in the sample." These weaknesses, according to the authors of the editorial, challenge "the central conclusion that SFN may not be length dependent."​



Friday, April 1, 2016

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People as young as 40 can show signs of arterial stiffening that can be an early indicator of cognitive decline, Alzheimer's disease, and stroke, according to a new study published online on March 10 ahead of the April 4 print edition of Stroke: Journal of the American Heart Association.


Researchers at the University of California, Davis School of Medicine culled data from 1,903 adults who participated in the Framingham Heart Study (FHS), a longitudinal study designed to identify risk factors for cardiovascular and cerebrovascular diseases. The adults studied were generally young, with an average age of 46.2 years, and healthy; they were "less likely to smoke, to receive treatment for hypertension, or have diabetes" compared to the rest of the adults in the FHS, according to the study's authors.


In order to assess the relationship between stiffening of the arteries and brain health, researchers measured various pulses and pressures in the arteries (via tonometry) and examined brain MRI on patients in the study cohort. They found that increased carotid-femoral pulse wave velocity (CFPWV), which measures the force of arterial blood flow and is "the standard noninvasive measure of aortic stiffness," was associated with injury to the brain's white matter and atrophy of gray matter. In fact, researchers found that these measures of brain health "worsened continuously with increasing" arterial stiffness. The results were accentuated in patients that were older, the study's authors said.


"This study shows for the first time that increasing arterial stiffness is detrimental to the brain, and that increasing stiffness and brain injury begin in early middle life, before we commonly think of prevalent diseases such as atherosclerosis, coronary artery disease or stroke having an impact," said the study's lead author Pauline Maillard, PhD, a researcher in the UC, Davis department of neurology and Center for Neuroscience, in a news release about the study. "These results may be a new avenue of treatment to sustain brain health," she said.


The study also noted that elevated arterial stiffness is the earliest manifestation of systolic hypertension. "Measures of arterial stiffness may actually be a better measure of vascular health, and should be identified, treated and monitored throughout the lifespan," Dr. Maillard said.


Damage to the integrity of both gray and white matter has been tied to an increased risk of cognitive decline and Alzheimer's disease in other studies of the FHS cohort, the study's authors noted. Additionally, an increase in arterial stiffness has been associated with an elevated risk of cardiovascular injury and microvascular brain injury, including stroke. The reason, the study's authors hypothesized, may be that arterial stiffness exposes brain vessels to fluctuations in blood pressure and pulse, which "may impact supply of oxygen and nutrients to the brain."


The good news? Current treatments for hypertension may help reduce the risk. The study's authors noted that "treated hypertension is associated with more normal" brain pulse values, suggesting that "early life treatment of hypertension may be substantially more beneficial" than late life treatment for hypertensive adults.


The study's authors noted that arterial stiffness, which is associated with an increased risk of hypertension, is "easily measurable" by physicians through the same tonometric methods used in the study. Doctors should therefore consider measuring arterial stiffness in patients who are at the "greatest risk of hypertension progression" so that they may begin treatment as early as possible, the study authors concluded.




  1. Maillard P, Mitchell GF, Himali JJ, et al. Effects of arterial stiffness on brain integrity in young adults from the Framingham Heart Study. Stroke 2016;47(4):1030-1036. Epub 2016 Mar 10.

Tuesday, March 29, 2016




Rosacea, a common, inflammatory skin disorder characterized by facial flushing, erythema, edema, and other symptoms, may be associated with a two-fold increased risk in the incidence of Parkinson's disease (PD), according to the results of a 15-year study published in the March 21 online edition of JAMA Neurology.


In order to assess the link between Parkinson's and rosacea, the researchers, led by Alexander Egeberg, MD, PhD, of the University of Copenhagen, followed a cohort of approximately 5.4 million Danish adults between 1997 and 2011. The study cohort excluded adults with prevalent PD or rosacea, or who were taking anti-Parkinson's agents. At the end of the study, the adults were divided into two populations: a reference population, consisting of adults who never developed rosacea, and a group of rosacea patients. Researchers surveyed inpatient and outpatient hospital records as well as prescription records in order to determine the diagnosis and treatment of both Parkinson's disease and rosacea for patients in the rosacea group.


Among findings, the PD incidence rate (per 10,000 person-years) in those with rosacea was 7.62 (95% CI, 6.78-8.57) compared with 3.54 (95% CI, 3.49-3.59) in the reference population. The disease was diagnosed an average of 2.4 years earlier in patients with rosacea than in the reference group. Moreover, the researchers reported that treatment with tetracycline in moderate to severe rosacea was associated with a reduced risk of PD.


These results may indicate a "neuroprotective effect" provided by treatment with tetracylines, the researchers wrote. But they noted that that their findings were "hypothesis generating," and further research involving randomized drug trials would be needed to corroborate the study results.


In an accompanying editorial, Thomas S. Wingo, MD, of Emory University, wrote that one study limitation was that individuals with "rosacea had increased exposure to medical professionals, potentially prompting earlier recognition of PD." But, he noted, dermatologists and general practitioners are usually not focused on neurologic illnesses.


Parkinson's disease has long been associated with neuroinflammation and other skin conditions, including seborrheic dermatitis and hyperhidrosis. Recent studies demonstrate a higher-than-average incidence of rosacea among Parkinson's patients; in one German study cited by researchers, "rosacea was present in 18.6% of participants" with Parkinson's disease.


Additionally, research has linked the increased expression of a common genetic culprit, metalliproteinases (MMPs), to both Parkinson's and rosacea. However, the study authors emphasized that "the basis for the pathogenic link between rosacea and Parkinson's disease is unknown." 


Still, researchers determined that the link between rosacea and Parkinson's is strong enough that doctors may consider "rosacea or rosacea-associated features, such as facial flushing" to "support a Parkinson disease diagnosis at an early phase of the disease."           




Thursday, March 17, 2016


In a case-control study based in French Polynesia, researchers provided the strongest evidence yet linking the fast-growing outbreak of Zika virus infections to a concurrent, albeit much smaller, outbreak of Guillain-Barré syndrome (GBS) that occurred between October 2013 and April 2014. 
Published in the February 29 online edition of The Lancet, the study found that 41 of 42 patients diagnosed with GBS in Tahiti had anti-Zika virus immunoglobulin M (IgM) or IgG, and all had neutralizing antibodies against Zika virus compared with 54 (56 percent) of 98 people in an age-matched control group (p<0.0001) admitted to the hospital with a non-febrile illness. 
Neuroepidemiologists and neuroinfectious specialists who were not involved with the study praised the research, and said it added the best evidence to date of a potential link between GBS and Zika. But they agreed that it nonetheless lacked decisive proof of whether and how the virus might cause GBS. Indeed, some questioned whether the diagnosis of GBS in these cases was appropriate. 
"It’s not classical Guillain-Barré syndrome. I'm not 100 percent sure what it actually is," Avindra Nath, MD, FAAN, chief of the section of infections of the nervous system and clinical director of the National Institute of Neurological Disorders and Stroke, told Neurology Today in a telephone interview from Liberia, where he was following up cases of Ebola infection that occurred last year.  “They didn't find antibodies to the myelin lipids, which one would normally see in GBS,” said Dr. Nath, who was not involved with the current study. “They found it affected the axon, not the myelin. So these differences tell me it's an acute motor axonal neuropathy. It could still be caused by the Zika virus, but it may have nothing to do with the immune system." 
As researchers around the world scrambled to answer such questions, the director-general of the World Health Organization (WHO) emphasized in a news conference on March 8 that public health responses cannot await definite proof of mechanisms. "We can expect to see more cases and further geographical spread," said Margaret Chan, MD. 
Mosquito-borne transmission of the Zika virus, she noted, had been detected in 31 countries and territories in Latin America and the Caribbean [at press time], including three territories of the United States: Puerto Rico, American Samoa, and the US Virgin Islands. 
Nine of those countries have reported an increased incidence of GBS or confirmation of Zika infection among GBS cases, she said, including Colombia and Venezuela. 
"GBS has been detected in children and adolescents but is more common in older adults and slightly more common in men," Dr. Chan said. "The anticipated need for expanded intensive care adds a further burden on health systems. Reports and investigations from several countries strongly suggest that sexual transmission of the virus is more common than previously assumed. All of this news is alarming."

Frédéric Ghawché, MD, a neurologist at the Centre Hospitalier de Polynésie Française in Papeete, Tahiti, and colleagues reported in The Lancet study that 93 percent (39) of the patients with GBS had Zika virus IgM, and that 88 percent (37) had experienced a transient illness in a median of six days before the onset of neurological symptoms. That suggested a recent Zika infection, the team of two dozen researchers from France, Tahiti, and Scotland concluded. 
Electrophysiological findings were compatible with the acute motor axonal neuropathy (AMAN) type of GBS, the team reported, and had an unusually rapid evolution of disease, with a median duration of the installation and plateau phases of six and four days, respectively. 
No patients died, but 29 percent (12 people) required respiratory assistance. 
The researchers detected anti-glycolipid antibody activity in 31 percent (13) of the patients, and notably against glycolipid GA1 in eight (19 percent) patients by ELISA and 19 (46 percent) by glycoarray at admission. 
As Dr. Nath noted, the researchers found that the typical AMAN-associated anti-ganglioside antibodies were rarely present. Past dengue virus history did not differ significantly between patients with GBS and those in control groups. 
Despite the uncertainties, Dr. Nath called the study the most convincing evidence to date linking Zika infection to a GBS-like condition. 
"The researchers did take considerable efforts to ensure that the serological reactions they observed were directed toward Zika and not just cross-reacting with dengue," he said. "The results are pretty impressive from an epidemiologic as well as laboratory standpoint. Having said that, it's not quite a slam dunk. It's one study. One would like to see the results replicated." 
A commentary accompanying the paper in The Lancet noted the same unusual presentation of the cases in Tahiti as Dr. Nath observed. "The researchers did not find the expected pattern of antibodies, nor did they find evidence for molecular mimicry between Zika virus antigens and the anti-glycolipid antibodies that might induce an autoimmune response," wrote David W. Smith, MD, a pathologist at the University of Western Australia, and John Mackenzie, PhD, a professor of tropical diseases at Curtin University in Australia. 
"Flavivirus antibodies are widely cross-reactive across the species," the commentary stated, "and there are also cross-species immune recall phenomena that can lead to spurious early antibody responses when the person has had another flavivirus infection in the past. In fact, only one of the 42 cases showed the standard criterion of neutralization titres to Zika virus that are four-fold or higher than the titre to the dengue viruses."
Even so, the commentary concluded that it is "very likely" that most of the patients had recently been infected with Zika. "Suffice it to say Zika virus can be added to our list of viruses that can cause Guillain-Barré syndrome," Dr. Smith and Dr. Mackenzie wrote. 
But Daniel M. Pastula, MD, MHS, a neurologist and medical epidemiologist at the University of Colorado Anschutz Medical Campus in Denver, who also was not involved with the study, questioned the diagnosis of GBS in these cases. He noted that the study failed to use recently developed criteria for diagnosing GBS by the Brighton Collaboration, an independent global vaccine safety safety research network for health care professionals.
"The Brighton Collaboration criteria is now used across epidemiologic studies for GBS," Dr. Pastula said. "This paper would have been more robust if they had used the criteria."

All 42 of the GBS patients in the Tahiti case-control study received the standard therapy for the disorder, intravenous immunoglobulin, and one also underwent plasmapheresis. The median duration of hospital stay was 11 days (with a range of seven to 20) for all patients, and 51 days (with a range of 16 to 70) for the 16 patients who were admitted into intensive care. Three months after discharge, 24 of the patients (57 percent) were able to walk without assistance.
Those outcomes, while within historical norms and reassuring to the majority of patients, nevertheless demonstrate that the illness is not self-limiting for all patients, said Dr. Pastula. 
"Previous data suggests about 85 percent of people are walking independently at one year," he said. "But others may not fully recover.  At one year, full recovery of motor strength occurs in about 60 to 70 percent of patients. Severe motor problems persist in about 15 percent." 
Because it remains unclear whether the neurologic effects observed in Tahiti are due to an immune reaction to the virus or a direct injury by the virus itself, Dr. Nath questioned whether immune therapies make sense.
"Currently the recommendation is to treat with immune therapies," he said. "I'm not sure that will do anything. We need to do clinical trials.  We may be doing the wrong thing."
Compared to immune-mediated disorders like classical GBS, Dr. Nath added, "Usually neuropathies don't recover as well."
Even so, immune therapies would be unlikely to have any ill effect on the AMAN subtype of GBS, said Kenneth L. Tyler, MD, FAAN, professor and chair of neurology at the University of Colorado Anschutz Medical Campus in Denver. 
"We have no reason to believe that IVIG, which we normally use to treat Guillain-Barré, would have any harmful effect in these cases," Dr. Tyler said. "Whether they would have a beneficial effect, I don't know. But I'm not aware of any data that would suggest that the usual therapies would be harmful. The outcomes for the patients in Tahiti were not bad based on this preliminary data."

“In 2015, Brazil most definitely had a Zika outbreak and an accompanying increase in GBS cases," said James J. Sejvar, MD, a neuroepidemiologist in the Division of High-Consequence Pathogens and Pathology at the CDC's National Center for Emerging and Zoonotic Diseases in Atlanta. 
"We haven't heard of any increased reporting of either Zika or GBS in Brazil this year yet. If Zika is going to recur there, we're only now getting into the period where we should start to see it. The rainy season has now ended; that's when the mosquito larvae start to hatch. We would expect the peak of Zika cases to be around March, April, May."
The CDC, he noted, already has a team there prepared to run a case-control study of GBS cases should they recur. 
GBS clusters are already clustering, he said, in Colombia, El Salvador, Venezuela, and Honduras. 
In a report on its website, the WHO noted that Colombia typically registers about five cases of GBS per week, but saw 86 GBS in a recent five-week period, three times higher than average.  During the month of January, Venezuela recorded 252 GBS cases with a spatiotemporal association to Zika virus.
J. David Beckham, MD, an associate professor of medicine in the divisions of infectious diseases, neurology, and immunology & microbiology at University of Colorado-Denver, told Neurology Today that he is working with the CDC to analyze serum samples from patients in Colombia.  
"They'll be sending us blood from these patients who are acutely infected so we can look at T-cell responses and antibody responses," he said. 
As for the United States, Zika transmission has already begun, said Dr. Sejvar. "There's definitely Zika transmission in Puerto Rico," he said. "We've set up active surveillance for GBS in Puerto Rico in anticipation that they may experience an outbreak of GBS."
For the continental United States, it is likely only a matter of months until Zika infections are seen in Florida and the Gulf states, said Dr. Nath. 
"We're very worried that the southern parts of the United States," he said.  "The CDC is already monitoring the mosquito population in Florida and elsewhere." 
Whatever the number of Zika infections might turn out to be in the United States, any associated cases of GBS are certain to be far fewer, according to epidemiologic evidence. A study published in 2013 in Lancet Neurology calculated a GBS rate of 0.24 per 1,000 Zika virus infections, or about one case for every 4,000 infections. 
"Be watchful and be observant for unexpected clusters of Guillain-Barré syndrome, either in its conventional form or, based on this paper, in its ANAM form," Dr. Tyler said. "If you begin to see a higher than expected incidence of this disease, which in most settings is sporadic, then that would be of concern."