Neurology News

Follow our Neurology News blog for the latest news on neurologic diseases and research.

Sunday, January 21, 2018

BY GINA SHAW

 Convulsive status epilepticus (CSE) in children without prior neurologic abnormalities is not associated with long-term cognitive or other neurologic deficits, according to a large new population-based study published online December 5, 2017 in The Lancet Child and Adolescent Health.

Previous smaller, hospital-based studies had reached similar conclusions, but independent experts told Neurology Today that the size, duration, and structure of this study, which included participants in the north London convulsive status epilepticus surveillance study cohort, allows clinicians to offer stronger reassurance to parents of children with CSE, defined as continuous or rapid sequential seizure activity for 30 minutes or more.

"This reinforces some of what we already knew, but for the first time in a population-based study, which followed almost all patients for eight or nine years," said Kelly Knupp, MD, associate professor of pediatrics and neurology at the University of Colorado, who was not involved with the study.

"Previous studies were more hospital-based and across a shorter period of time with smaller populations, and usually in only one or two institutions. This study involved 21 institutions. It was very nice to see that in such a cohort once you get past the 18-month mark, almost all the children who are going to develop epilepsy will have presented already. This is very helpful to guide families, because their biggest question after an episode of status epilepticus is 'What can I expect next?'"

STUDY DESIGN

The study, an initiative of the North London Epilepsy Research Network, involved 203 survivors of the first population-based study focused on childhood CSE (90 percent of the inception cohort); 134 (66 percent) of those survivors could be assessed at eight to nine years of follow-up. "To our knowledge, this is the first prospective population-based study to comprehensively describe the natural history and the long-term outlook after childhood CSE due to all causes," wrote the study authors, led by Suresh S. Pujar, MRCPCH, professor of clinical neurosciences at the UCL Great Ormond Street Institute of Child Health in London

Of the 134 survivors assessed at follow-up, 35 had experienced prolonged febrile seizures; 15 acute symptomatic CSE; 15 idiopathic epilepsy-related CSE; four cryptogenic epilepsy-related CSE; 53 remote symptomatic CSE; and 12 unclassified CSE.The cumulative incidence of epilepsy overall was 24.7 percent, with the highest cumulative incidence in the remote symptomatic CSE (45.5 percent) and unclassified CSE groups (50 percent). Of the children who developed epilepsy after CSE, 90 percent had developed it within 18 months of the first episode of CSE.

Only five of 35 children with prolonged febrile seizures (14.3 percent) and two of 15 with acute symptomatic CSE (13.3 percent) experienced incident epilepsy. At the time of follow-up, active epilepsy was present in 55 (41 percent) participants, primarily in those who had idiopathic and cryptogenic CSE or remote symptomatic CSE, and none who had prolonged febrile seizures All five participants in the prolonged febrile seizures group who developed epilepsy after CSE were seizure free and off drug treatment in the preceding two years before the follow-up visit. The full analysis found that epilepsy before CSE was the only predictor of active epilepsy at follow-up.

Similarly, pre-existing epilepsy at CSE was the only predictor of intellectual disability in this analysis. Cumulative incidence of intellectual disability was 8.8 percent, and was seen predominantly in participants with remote symptomatic CSE and those with idiopathic and cryptogenic CSE. Only one participant with prolonged febrile seizures developed intellectual disability. Of 19 participants with idiopathic and cryptogenic CSE, intellectual disability was seen in 16 (84.2 percent), reflecting pre-existing disabilities in 68.4 percent of the group.

"Our findings provide strong population-based data suggesting the cause of childhood CSE is the main determinant of long-term outcome after the event," the study authors concluded. "Incidence of neurological sequelae is high in those with symptomatic causes and pre-existing neurological abnormalities, and seemingly low in previously neurologically normal children."

The study was funded by the BUPA Foundation, the Academy of Medical Sciences, Wellcome Trust, the National Institute for Health Research, and Young Epilepsy. The study authors reported no conflicts of interest or competing interests.

EXPERT COMMENTARY

The study confirms the 1993 findings published in JAMA (by the Epilepsy Foundation of America's Working Group on Status Epilepticus) that the outcome of CSE depends primarily on etiology, said Shlomo Shinnar, MD, PhD, FAAN, professor of neurology, pediatrics and epidemiology and population health and director of the Comprehensive Epilepsy Management Center at Montefiore Medical Center of Albert Einstein College of Medicine. 

"The majority of kids who have CSE remain typically neurologically normal," said Dr. Shinnar, who was not involved with the study. "For a proportion of them, this episode will end up being the first seizure and they will go on to have epilepsy. In terms of cognitive outcomes, those who are neurologically abnormal continue to be so. With properly treated status, as far as we can tell, it would be very unusual to have a new neurologic deficit from somebody who had CSE that was not associated with an acute insult."

Eric T. Payne, MD, MPH, consultant in child and adolescent neurology and assistant professor of pediatrics and neurology at the Mayo Clinic, praised the length of follow-up and population size. "Some patients from the original cohort had been lost to death, but it's quite impressive to assess 66 percent of the 203 that would have been available at follow-up, given that this was almost a decade out," he said. "While it's not surprising that the underlying etiology of the status epilepticus is what drives long-term outcomes, it's nice to have this well-characterized longitudinal confirmation study."

The experts all stressed the importance of adherence to new guidelines issued in 2016 by the American Epilepsy Society, which emphasize that CSE is a medical emergency with a high mortality rate, and provide a treatment algorithm that recommends initiating medical intervention after five minutes of continuous seizures. During this first therapy phase, a benzodiazepine (specifically IM midazolam, IV lorazepam, or IV diazepam) is recommended as the initial therapy of choice. If the initial therapy is unsuccessful by 20 minutes of seizure activity, the guideline notes that reasonable second therapy options include fosphenytoin, valproic acid and levetiracetam, with no clear evidence that any one of these options is better than the others. "Because of adverse events, IV phenobarbital is a reasonable second-therapy alternative if none of the three recommended therapies are available," the guidelines add.

"We know that for every minute you delay medical intervention after the initial five-minute stabilization phase, the risk that your patient will experience prolonged seizures and require intensive care goes up," said Dr. Payne. "Although this paper suggests that convulsive status epilepticus seizure duration is not an independent predictor of outcome, without continuous video-EEG monitoring, seizure burden was certainly under-appreciated since numerous studies have shown that these children continue to experience seizures and status epilepticus without clear clinical signs. In a paper we published in Brain in 2014, we demonstrated that while etiology is by far the most important determinant of outcomes, seizure burden in and of itself was associated with neurological decline in a seemingly dose-dependent manner.

The independent experts reported no competing interests with the current study.

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Pujar SS, Martinos MM, Cortina-Borja M, et all, on behalf of the North London Epilepsy Research Network. Long-term prognosis after childhood convulsive status epilepticus: A prospective cohort study. Lancet Child Adolesc Health; Epub 2017 Dec 5.

Epilepsy Foundation of America Working Group on Status Epilepticus. Treatment of convulsive status epilepticus: recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus. JAMA 1993; 18;270(7):854-890

 Payne ET, Zhao XY, Frndova H, et al. Seizure burden is independently associated with short term outcome in critically ill children. Brain 2014; 137; 1429–1438.


Sunday, January 21, 2018

BY JAMIE TALAN

An international team of scientists from Italy, France, and the United States have delivered gene-packed viral vectors to the liver and successfully engineered the tailored genes to make the missing or deficient protein that causes Pompe disease, a rare and potentially lethal glycogen storage disease caused by the lack of the enzyme acid-alpha glucosidase (GAA). So far, they have shown in mice and a handful of non-human primates that the protein is secreted into plasma, where it circulates and is taken up by vulnerable tissues in muscle, brain, and the spinal cord. 

The findings, published in the November 29 issue of Science Translational Medicine, offer proof of concept that adeno-associated vector-mediated liver delivery can be used successfully to make and secrete an engineered version of the GAA enzyme. The scientists are now conducting more studies aimed at initiating a clinical trial in patients.  

Pompe disease is a severe neuromuscular disorder caused by mutations in the gene that encodes for the GAA enzyme. Normally, the enzyme does its job in the lysosomes – the cellular housekeeping system.  These molecular scavengers ingest glycogen, a sugar, and the enzyme converts glycogen to glucose, which is used to fuel muscles. Patients with Pompe can’t metabolize glycogen. Without the enzyme, glycogen accumulates in tissues, primarily in the heart and other muscles such as the diaphragm.  

Fatal forms of the disease manifest in infancy and other forms can trigger symptoms in adolescence or adulthood. All the mutations (about 300 have been identified) are linked back to an enzyme deficiency.

A drug to replace the GAA enzyme replacement therapy — lysosomal glycogen-specific enzyme alglucosidase alfa (Lumizyme) — was approved by the Food and Drug Administration in 2006 but the treatment has several limitations; among them, it requires twice monthly infusions, it’s unable to deliver enzyme to the brain and spinal cord, and it’s immunogenic. 

With these concerns in mind, Federico Mingozzi, PhD, Giuseppe Ronzitti, PhD, scientists at Genethon, Inserm, and Pierre and Marie Curie University in Paris, and their colleagues set about to design a gene therapy that could work in the liver to produce the missing enzyme.

Dr. Ronzitti explained that they have developed liver-targeted vectors for other diseases and believe that the approach to use the liver as a manufacturing site for the gene product could overcome some of the limitations of enzyme replacement therapy.
STUDY METHODS, FINDINGS
To conduct the research, the team developed transgenes that encode for GAA and could be efficiently expressed and secreted by liver cells. They then used an adeno-associated virus serotype 8 (AAV8) vector to target the liver and establish a steady supply of the GAA enzyme. They introduced a low vector and high vector dose of gene therapy in GAA knockout mice — an animal model of Pompe disease — and performed a series of tests to see whether it prevented the accumulation of glycogen in muscle and in the central nervous system. The knockout animals generally take six to ten months before severe symptoms develop. They delivered the therapy intravenously at the first sign of muscle weakness, around four months. 

Dr. Ronzitti said that the AAV8 vectors, because of their high affinity for the liver, targeted hepatocytes and started manufacturing the missing protein. The enzyme was then secreted into the circulatory system and delivered to skeletal muscle and other organs. And unlike enzyme replacement therapy, the needed protein also made it into the brain and spinal cord. 

The scientists reported that the enzyme reduced abnormal levels of glycogen, almost 100 percent in skeletal muscle and 50 percent in the central nervous system. The mice that received the gene therapy had no evidence of cardiac hypertrophy, muscle weakness, and respiratory problems compared to the knockout mice who did not receive the active treatment. 

Pompe symptoms were averted and the animals lived longer. Normally, the knockout mice start dying at seven months. The mice that received gene therapy were still living at 14 months. The animals also did not mount an antibody response to the treatment.
The researchers also performed tests comparing the secretable transgene to a native form of GAA that was also delivered through viral vectors and found much higher levels of the enzyme in muscle. The enzyme levels peaked by the third month of treatment and remained stable for the rest of the study. Dr. Ronzitti said the treatment preserves muscle structure and normalizes autophagy, cell damage, and death. 

The scientists also showed that delivering these transgenes to the liver induces a strong peripheral immune tolerance towards the transgene. This prevented an immune reaction against the foreign protein. Dr. Ronzitti said that this is critically important. One of the real worries with enzyme replacement therapy, he said, is that some patients develop antibody to the enzyme and this abnormal immune response makes it too risky to keep administering the therapy. 

They also delivered the gene therapy to monkeys as a proof of concept as they move forward in designing a clinical trial in patients with Pompe disease. Again, there was strong evidence that the liver was secreting the enzyme. There was higher GAA activity in plasma and in peripheral tissues. 

“These findings suggest that we may be able to develop a similar strategy for patients,” said Dr. Mingozzi. He said that they are conducting more studies to compare the gene therapy to enzyme replacement therapy. 

The study was funded mostly by grants by Genethon, a nonprofit research institute focused on developing gene therapies for rare genetic diseases, and the French Multiple Dystrophy Association. Several of the authors, including Dr. Mingozzi and Dr. Ronzitti hold patents related to AAV-mediated liver gene transfer and/or Pompe disease.

EXPERT COMMENTARY
“The key [to the success here] is that the scientists are targeting the liver,” said Juan M. Pascual, MD, PhD, director of the Complex and Undiagnosed Brain Diseases Program at The University of Texas Southwestern Medical Center at Dallas and professor of neurology and neurotherapeutics, physiology, and pediatrics. “Having the gene in the liver is enough to make the enzyme and have it circulate into muscle, brain and spinal cord. It is a very complete study. We think it is very possible that it will work in patients.”

“I think it is an encouraging step,” said Jeffery M. Vance, MD, PhD, director of the Center for Genomic Education & Outreach in the John P. Hussman Institute for Human Genomics and professor of neurology in the Dr. John T. Macdonald Foundation department of human genetics at the University of Miami Health System. 

Dr. Vance said that there are several advantages of this experimental approach compared with enzyme replacement therapy. “They were able to get a relatively longstanding induction of the enzyme through the hepatic system with a much lower immune response,” he explained. “And it looks like it is getting into the central nervous system. It has the potential to be a one-time treatment.”

“This is good preclinical data,” said Priya Kishnani, MD, C.L. and Su Chen professor of pediatrics and medical director of the Alice and YT Chen Pediatric Genetics and Genomics Center and division chief of medical genetics at Duke University Medical Center. “There have been similar gene therapy approaches for Pompe disease and other conditions where the transgene was optimized for hepatic expression and the liver secretes the therapeutic protein. In this case, it is GAA, the enzyme missing in Pompe disease. What is important data in this paper is the ability to get enzyme into the central nervous system."
 
“Using a liver-specific promoter, as done by the authors on this paper has the advantage that it can induce immune tolerance and builds on previous reports that have shown the same," Dr. Kishnani said. "There is more of a risk for an immune response when genes are delivered directly to muscle. One of the biggest challenges with enzyme replacement therapy has been the development of antibodies against the therapeutic enzyme.”

The commentators disclosed no competing conflicts of interest.​

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Puzzo F, Colella P, Biferi MG, et al. Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid a-glucosidase. Science Transl Med 2017; Epub 2017 Nov 29.


Thursday, January 18, 2018

BY LIZETTE BORRELI

Using mRNA-sequencing data from post-mortem human brains, researchers identified common patterns of gene activity related to immune processes and inflammatory pathways in Huntington's disease (HD) and Parkinson's disease (HD).

The study, published online on January 11 in the journal Frontiers in Molecular Neuroscience, suggests there exists a set of consistently altered genes in these two distinct neurodegenerative diseases. This pattern of commonality between HD and PD could potentially have clinical implications when it comes to mitigating the effects of various neurological conditions of the central nervous system, the study authors said.

"A better understanding of the molecular similarities and differences between these two diseases may lead to a more complete mechanistic picture of both the individual diseases and the neurodegenerative process in general," the study authors, led by Adam Labadorf, PhD, director of the Boston University Bioinformatic Hub, wrote.

To assess the common transcriptional signature of HD and PD, and the genes uniquely implicated in these diseases, the researchers performed RNA-sequencing in 29 HD, 29 PD, and 49 healthy control prefrontal cortex samples from post-mortem human brain specimens.

A total of 2,427, 1,949, and 4,843 significantly differentially expressed genes were identified for HD, PD, and the controls, respectively: 145 gene sets were highly enriched in both differentially expressed gene sets for HD and PD, and 81 gene sets in HD and 54 in PD were uniquely significant. In the controls, there were 24 genes that were uniquely significant.

If a pathway was enriched in more than one list, it was enriched in the same direction, either positively — showing more abundant genes in the disease— or negatively — with less abundance.

The findings suggest that the underlying molecular responses to neurodegeneration for PD and HD are more similar than different, despite having disparate pathological features. Specifically, processes that include nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and transcription factor cAMP response element-binding protein (CREB) are notable in genes common to both diseases.

Differentially expressed genes unique to HD reflect far more coherent biological processes than those unique to PD, the study authors wrote, which suggests PD could be a more heterogeneous disorder.

The findings are still too preliminary due to the complexity of biological processes in this analysis of HD and PD. Further investigation is warranted as to whether neuroinflammatory response in HD and PD is protective, deleterious or both, and what specific role these processes play, the study authors wrote.

The research was supported by grants from US National Institutes of Health, the National Brain and Tissue Resource for Parkinson's disease and Related Disorders, and the Jerry McDonald Huntington Disease Research Fund.

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Labadorf A, Choi SH, Myers RH. Evidence for a pan-neurodegenerative disease response in Huntington's and Parkinson's disease expression profiles. Front Mol Neurosci 2018; Epub 2018 Jan 11.


Tuesday, January 16, 2018

BY SARAH OWENS

A new prediction model drawing upon findings from computed tomography (CT) scan and a blood test showed nearly 100 percent sensitivity for predicting ICH associated with cerebral amyloid angiopathy (CAA), according to a study published online on January 10 in The Lancet Neurology.

If the new method, named the Edinburgh CT-based diagnostic method can be externally validated, it will be "potentially widely applicable for diagnostic, prognostic, and therapeutic decisions in everyday clinical practice if MRI is contraindicated, intolerable, or unavailable," the study authors, led by Mark A. Rodrigues, MD, of the Center for Clinical Brain Sciences at the University of Edinburgh in Edinburgh, Scotland, wrote.

Between June 2010 and February 2016, researchers at the University of Edinburgh, Newcastle University, and the University of Southampton in the UK and the University of Lille in Lille, France prospectively reviewed postmortem histopatholic, blood tests, and CTs of  110 adult participants of the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome  study, a prospective, population-based study of the causes of ICH.. All participants had a first-ever ICH that was diagnosed by non-contrast CT, died, and subsequently underwent a research autopsy.

The researchers used a blood test to determine which participants carried the APOE ε4 allele, the strongest genetic predictor of sporadic CAA.

On CTs, the radiologists. Who were blinded to the histopatholic and blood tests,  looked for two identifying predictive features of CAA-associated ICH – finger-like projections from ICH and subarachnoid hemorrhage. A similarly blinded neuropathologist analyzed participants' postmortem brain tissue samples to measure the pathological severity of small vessel disease, including CAA, characterizing it as absent, mild, moderate, or severe.

Sixty-two of the patients had lobar ICH; among these, 36 (58 percent) had moderate or severe CAA compared with 26 (42 percent) who had absent or mild CAA. Intracerebral hemorrhage was independently associated with subarachnoid hemorrhage in 32 of 36 patients in the mild-to-severe group (89 percent) compared to 11 of 26 patients (42%) in the absent-or-mild group (p=0.014); with finger-like projections in 14 of 36 patients (39 percent) vs 0, respectively (p=0.043); and with APOE ε4 carrier status in 18 of 26 (50 percent) vs 2 of 26 (8 percent), respectively (p=0.0020).

Based on the CT and blood test data, the researchers developed a multivariable prediction model to predict CAA-associated lobar ICH. To minimize bias, the model assessed both inter-rater and intra-rater agreement on both CT features.

The researchers established criteria that could be used to rule in or rule out moderate or severe CAA. Among rule-out criteria, subarachnoid hemorrhage or APOE ε4 carrier status had a sensitivity of 100 percent (95% CI 88–100), indicating that the absence of these two predictors with lobar ICH ruled out moderate or severe CAA. Among the rule-in criteria, subarachnoid hemorrhage and either APOE ε4 possession or finger-like projections had 96% specificity (95% CI 78–100), meaning their presence ruled in moderate or severe CAA.

When the researchers repeated the prediction modelling using CT ratings from a second independent investigator, they found that the sensitivity of the rule-out criteria remained 100 percent and the and specificity of the rule-in criteria increased to 100 percent.

Among the study limitations, the researchers noted that finger-like projections on CT can be difficult to define, and CT features of ICH will evolve unpredictably over time, which may affect their diagnostic accuracy.

Several researchers reported grants from the Alzheimer's Society of the United Kingdom, Alzheimer's Research UK, and the British Heart Council, among others; participation on the advisory boards of Bayer, Medtronics, and other companies involved in the development of neurovascular products and services; and participation in studies supported by AstraZeneca, Pfizer, and other pharmaceutical companies.

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Friday, January 12, 2018

​BY SARAH OWENS

Plasma levels of neurofilament-light (NfL) were associated with Charcot-Marie-Tooth disease (CMT) status and severity, according to a study published online on January 10 in Neurology.

Currently, there are no validated blood biomarkers for peripheral neuropathies, including CMT. NfL has shown promise as a biomarker for several neurologic diseases, including amyotrophic lateral sclerosis, traumatic brain injury, multiple sclerosis, and frontotemoral dementia.

The current findings suggest that "plasma NfL concentration holds promise as a biomarker of disease activity, not only for inherited neuropathies but for peripheral neuropathy in general," the study authors, led by Asa Sandelius, PhD, of the department of psychiatry and neurochemiatry at the University of Gothenburg in Gothenburg, Sweden, wrote.

For the cross-sectional study, researchers at several institutions in Sweden and the United Kingdom collected blood samples from 75 patients with a genetically confirmed diagnosis of CMT and 67 age-matched healthy controls at the National Hospital for Neurology and Neurosurgery in London between January 2011 and May 2013.

The researchers assessed the severity of CMT patients' disease using several CMT and nerve conduction studies. Finally, the researchers compared NfL levels with CMT disease status and severity.

They found a significant association between plasma NfL and both disease status and severity. The median plasma NfL level was 26 pg/mL in patients with CMT compared with 14.6 pg/mL in healthy controls (p<0.0001). Statistical analysis showed that plasma NFL was significantly associated with disease severity as measured by scores on the CMT (r=0.43, p<0.0001) and neuropathy (r=0.37, p=0.044) scales.

The researchers found that, compared with controls, NfL levels remained significantly higher across genetic CMA subtypes – CMT1A, SPTLC1, and GJB1 – and demyelinating and axonal forms of CMT.

This finding suggests that "a role for plasma NfL in monitoring disease activity may be extended to multiple forms of CMT," the study authors concluded.

The researchers noted that the study limitations included its short duration and cross-sectional design, so they could not detect changes in plasma NfL concentrations over time.

Drs. Zetterburg and Blennow reported serving as consultants for pharmaceutical companies and participation in Brain Biomarker Solutions, a company at the University of Gothenburg; no other conflicts of interest were reported.

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in the inherited peripheral neuropathies. Neurology2018; Epub 2018 Jan 10.​