Neurology News

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

Tuesday, October 17, 2017


First- and second-degree relatives of patients with amyotrophic lateral sclerosis (ALS) have an increased risk of neuropsychiatric diseases, including schizophrenia, obsessive-compulsive disorder, autism, and alcoholism, compared to controls, according to a new case-control study published online on October 16 in JAMA Neurology.

Previous studies have suggested that family members of those with ALS have an increased risk of neuropsychological and neuropsychiatric diseases, including schizophrenia and psychotic illness. In addition, up to 10 percent of patients with ALS have a hexanucleotide expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene, which has also been implicated in obsessive-compulsive disorder and bipolar affective disorder.

The current study "confirms previous epidemiologic observations of an association between ALS and schizophrenia" and "extends the finding to other neuropsychiatric conditions characterized by impulse control disorder, addiction, alcoholism, personality rigidity, and autism spectrum disorder," the study authors, led by Margaret O'Brien, PhD, of the department of neurology at Beaumont Hospital in Dublin, Ireland, wrote.

For the study, researchers at Beaumont Hospital and Trinity College Dublin in Dublin, Ireland assessed data on 127 patients with a diagnosis of definite, probable, or possible ALS who were participating in the Irish ALS Register between January 1, 2012 and January 31, 2014. All 127 patients with ALS were genotyped for the C90RF72 repeat expansion. They also used reported data on 924 first-degree relatives, 1,128 second-degree relatives, and 64 third-degree relatives of the participants. The researchers enrolled 132 age- and sex-matched controls, who reported data on 829 first-degree and 1310 second-degree relatives.

They found that a total of 77 patients with ALS (61.4 percent) and 51 control participants (38.6 percent) reported at least one first-degree or second-degree relative with a history of neuropsychiatric disease, including schizophrenia, psychosis, suicide, depression, alcoholism, or autism (relative risk [RR], 1.50; 95%CI, 1.08-2.17; p=0.02). They found that the kin of those with ALS reported a strong family history of schizophrenia (RR, 3.40; 95%CI, 1.27-9.30; p=0.02), suicide (RR, 3.30; 95%CI, 1.07-10.05; p=0.04), autism (RR, 10.10; 95%CI, 1.30-78.80; p=0.03), and alcoholism (RR, 1.48; 95%CI, 1.01-2.17; p=0.045).

However, surprisingly, they found that among the 29 probands who had a strong family history of neuropsychiatric conditions (three or more first-degree or second-degree relatives), only five carried the C9orf72 repeat expansion.

The findings, the study authors concluded, suggest that "neuropsychiatric symptoms in addition to schizophrenia, including obsessive-compulsive disorder, autism, and alcoholism, occur more frequently in ALS kindreds than in controls." The fact that the C9ORF72 expansion was not found, however, suggests that the expansion does not fully account for the association. Instead, this suggests that there may be "additional pleiotropic genes associated with both ALS and neuropsychiatric disease" not yet identified.

In an editorial accompanying the study, Miguel Chuquilin, MD, assistant professor of neurology; Susan Wymer, BSN, MS; and James Wymer MD, PhD, professor of neurology, all at the University of Florida, wrote that the data "are very suggestive of an association between these diseases and may offer insight into newtherapeutic options." However, they concluded that because ALS and neuropsychiatric disorders are different in many important ways, including age of onset and associated environmental exposures, "further study is needed before we can conclude that there is any definitive association between them."

The researchers noted several limitations to their study. Among them, they obtained the neuropsychiatric signal between first- and second-degree relatives by report rather than clinical examination; and probands with ALS may have over-reported the presence of psychiatric disorders in family members.


Friday, October 13, 2017


In a single randomized trial of 97 infants with West syndrome —  a disorder characterized by epileptic/infantile spasms, hypsarrhythmia, and intellectual disability — synthetic adrenocorticotropic hormone (ACTH) and prednisolone were found to be equally effective at controlling seizures at one year, a team of investigators at the University of Colombo in Sri Lanka reported in the August 14 online edition of Pediatric Neurology.

The findings come on the heels of a longstanding debate among pediatric neurologists about which therapy is most cost effective. The question, they say, is this: If the two drugs are similarly effective in controlling seizures, why use the much more expensive treatment?

"The whole issue of infantile spasms therapy is controversial," said E. Steven Roach, FAAN, chief of neurology at Nationwide Children's Hospital in Columbus, OH, and editor-in-chief of Pediatric Neurology, who was not involved with the study. "This is partly because of the shifting science and partly because Questcor bought the rights to ACTH and dramatically increased its price. We have traditionally recommended ACTH injections in the US, but it is extremely costly, and outside of the US people tend to use the cheaper prednisolone alternative. We are talking something on the order of $150,000 per treatment course [for ACTH] versus $200 [for prednisolone]."

"The Sri Lanka study is something we could not easily do here," Dr. Roach acknowledged. "It would be too expensive to purchase natural ACTH for a study."

But it was not always so expensive. The ACTH agent, Acthar, cost $40 a vial when it was first licensed by Questcor Pharmaceuticals in 2001, and over the years, the price hiked, in large part, according to the Federal Trade Commission (FTC), because the company bought the rights to competitive products, monopolizing the market, stifling competition, and keeping prices high.

In January,  Mallinckrodt Pharmaceuticals, which acquired Questcor in 2014, agreed to pay $100 million to settle the lawsuit by the FTC and several state attorneys general, alleging that the company had violated antitrust laws in regard to Acthar. (For more on this story, see the sidebar, "The High Price of Acthar: The Back Story.")

Acthar, after several attempts by Questcor, was approved by the Food and Drug Administration (FDA) for infantile spasms in 2010.


Sri Lanka, where the trial was conducted, has limited access to ACTH, the study author Jithangi Wanigasinghe, MD, a pediatric neurologist at the University of Colombo told Neurology Today. Dr. Wanigasinghe said she assesses and treats two children a month with infantile spasms and has always treated them with prednisolone. But she wants to compare synthetic ACTH and prednisolone. The study was partly funded by the Sri Lanka Medical Association.​

“We were not trying to find that one was superior to the other but whether they were similar in efficacy,” said Dr. Wanigasinghe.​

The investigators randomized half of the 97 infants with untreated West syndrome to intramuscular long-acting synthetic ACTH (40 to 60 IU every other day) and half to 14 days of oral prednisolone (40 to 60 mg/day). Both groups received a subsequent three-week taper with prednisolone. ​The children were evaluated at three, six, and 12 months. Everyone completed the protocol but some were lost to follow-up. They examined 85 children at three months; 82 at six months, and 76 at one year.

The children were always evaluated by the same pediatric neurologist who was blinded to the treatment arm. A spasm-free period was determined by parental reports over the preceding week at each testing period, which the scientists said was a limitation of the study. They also did not have extensive electroencephalogram (EEG) data for every visit.

The investigators reported that 64.6 percent of those on prednisolone were seizure-free at three months compared to 39 percent of patients who had received ACTH (p=0.01). By six months and at one year, there was no statistical difference between the control of spasms in either treatment arm: 58.3 percent were seizure-free on prednisolone versus 44.9 percent for ACTH at six months (p=0.19) and 56.2 percent versus 40.8 percent with ACTH, respectively, at twelve months (p=0.13). 

Also, the rate of relapse during the year was equivalent in both groups. Dr. Wanigasinghe said that there were 28 in the prednisolone group who went into remission by day 14 of the treatment and 18 in the ACTH group. The total number who relapsed at least one time during the 12-month follow up period was 14 (30 percent) – six from the prednisolone group and eight from ACTH group. 

Children who relapsed were re-treated with the same hormonal therapy if it was two months after the first treatment ended. Other alternative oral anticonvulsants were used if the child relapsed earlier. Thirty percent of the children who had gone into remission by day 14 would go on to have at least one relapse by the one-year assessment.

There were eleven deaths during the 12 months follow up, all occurring after the completion of the initial treatment and related to other systemic diseases, Dr. Wanigasinghe said. 

“Our clinical trial provided additional evidence that first-line high-dose oral prednisolone may be superior to ACTH for short-term spasm control,” she said.

The current follow-up data show that the long-term control of spasms is similar for the two treatments, with a statistically insignificant trend favoring prednisolone therapy,” the authors wrote in the paper. “Given the substantially higher cost of ACTH versus prednisolone, even similar efficacy between the two drugs would seemingly favor the use of prednisolone.”​

In a phone interview, the investigator added that it is frustrating "that the field has not reached a consensus on the optimal therapy." Among the reasons, she contends, are that different types of ACTH have been used in the various studies. Clinicians outside of the United States use a synthetic version that contains 24 amino-acids in the ACTH peptide. 

Synthetic ACTH is not approved by the US Food and Drug Administration (FDA) and is rarely used in the US. Mallinckrodt's H.P. Acthar Gel is the only natural ACTH substance available in the US. It contains the full 39 amino acid peptide.

The current study did not use the H.P. Acthar Gel, which is used in the US. Dr. Wanigasinghe noted that it is difficult to make sense of the conflicting results because of varying types, doses, and treatment durations of ACTH and the oral steroids. Most of the studies have had very small numbers of patients, she pointed out.


Tuesday, October 10, 2017


Hematopoietic stem cell transplantation (HSCT) in the first seven weeks of life extended survival and improved function in asymptomatic children with early-infantile Krabbe disease for more than 15 years of follow-up, according to a study published online on August 30 in Neurology.

Caused by a deficiency in the enzyme galactocerebrosidase (GALC) that impairs the growth of myelin, Krabbe disease usually appears in early infancy and causes progressive muscle weakness, stiffness, and slowed mental and physical development. Umbilical cord blood transplantation can improve neurologic outcomes in the short term if performed before symptoms appear, but long-term outcomes are unknown.

The findings demonstrate that "HSCT performed before the onset of severe symptoms delays disease progression and improves both length and quality of life" over the long term, the study authors, led by Matthew D. Wright, MD, of the program for the study of neurodevelopment in rare disorders at the University of Pittsburgh in Pittsburgh, PA, wrote.

The study authors said that infants with a moderate to high risk of Krabbe disease "should be referred to specialized centers for evaluation since clinical expertise is needed to recognize the subtle signs of disease [and to] provide optimal counseling." Counseling could include the potential of of HSCT, to "achieve the best possible outcomes," they said.

For the study, researchers at the Children's Hospital of Pittsburgh enrolled 18 infants who had been diagnosed with early-infantile Krabbe disease through standard newborn screening or prenatal/neonatal diagnosis and who had undergone HSCT within the first seven weeks of life between October 1999 and October 2011. Of these, 15 completed follow-up testing.

At a baseline exam and at follow-up exams over four to 15 years of follow-up (average follow-up: 9.5 years), the researchers performed magnetic resonance imaging (MRI) and measured cerebrospinal fluid protein, as well as other motor, language, cognitive, and adaptive skill assessments.

Thirteen patients are still alive. Among surviving children, cognitive testing showed that one child has developed normally; ten surviving children continue to develop skills at a slightly lower rate compared to normally developing children; and two children's skills plateaued below the developmental age of two years.

Additionally, ten children continue to receive speech therapy; of these, two children require augmentative communication devices. While gross motor development was found to vary widely among the children, three patients are able to walk independently, and seven can walk with assistive devices. The children have spasticity ranging from very mild to severe, but they generally preserved their fine motor skills and can use their hands and fingers.

Finally, on MRI scans, the researchers found that brain myelination and atrophy stabilized in eight patients, improved in four patients, and worsened in one patient over the follow-up period. Nerve conduction velocities initially improved, but remain abnormal in most of the children.

The researchers noted two limitations to their study: Only children with the most severe form of Krabbe disease were enrolled, so the findings may represent only the worst outcomes of the disease; and more extensive follow-up studies are needed to confirm the findings.


Friday, October 6, 2017


A low dose (0.6 mg/kg) of alteplase was no more effective than the standard dose (0.9 mg/kg) at reducing rates of death and disability among patients with acute ischemic stroke (AIS) who were eligible for thrombolysis, according to a new study published online on October 2 in JAMA Neurology.

The treatment effects of both dose groups were consistent across key subgroups of patients with AIS, including older, Asian, and severely affected patients, researchers found.

Low-dose alteplase was approved in Japan on the basis of a single-arm study that showed it was just as safe and effective as a standard dose, but evidence from randomized trials is lacking. Additionally, recent studies have suggested that patients aged 80 and older or with severe neurological deficits may derive the same benefit from a low dose as a standard dose but have a lower risk of adverse events, such as intracerebral hemorrhage, but those effects have not been demonstrated in a randomized trial.

The current findings show that "the effects of low-dose alteplase were not clearly superior to the effects of standard-dose alteplase on death or disability in key demographic subgroups of patients with AIS," the study authors, led by Xia Wang, PhD, of the University of Sydney in Sydney, New South Wales, Australia, wrote.

For the study, researchers performed a prespecified secondary analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) trial, an international, randomized, open-label, blinded, endpoint clinical trial of low-dose vs standard-dose intravenous alteplase for patients with AIS. The ENCHANTED trial enrolled 3,310 patients who were diagnosed with AIS by brain imaging and who fulfilled local criteria for thrombolysis in the trial's alteplase-dose arms.

The patients were randomly assigned to receive a low dose of alteplase (0.6mg/kg; 15 percent as bolus and 85 percent as infusion over 1 hour) or a standard dose (0.9mg/kg; 10 percent as bolus and 90 percent as infusion over 1 hour). The researchers compared outcomes between the low-dose and standard-dose groups. Their primary outcome measure was a poor outcome, defined as a score from 2 to 6 on the modified Rankin scale (mRS, a measure of post-stroke disability, with higher scores indicating worse disability and 6 indicating death) at 90 days.

They found no significant differences in treatment effects between low- and standard-dose alteplase for poor outcomes by age, ethnicity, or stroke severity (all were p>0.37 for interaction). Similarly, the treatment effects of low- vs. standard-dose alteplase on functional outcomes (as measured by an ordinal analysis of the full range of mRS scores) were similar between Asians (odds ratio, 1.05;95%CI, 0.90-1.22) and non-Asians (odds ratio,0.93; 95%CI,0.76-1.14; p=0.32 for interaction).

In addition, reductions in rates of symptomatic intracerebral hemorrhage were generally consistent with low-dose alteplase, but the reduction was not statistically significant according to age, ethnicity, or severity of AIS.

The findings, the study authors concluded, "suggest that decisions about the dose of alteplase used in thrombolysis-eligible patients with AIS should not be based solely on age, ethnicity, or stroke severity."

The researchers noted a few limitations to their study. Among them, interobserver variability in mRS scoring may have caused imprecise estimates of the treatment effect; and the trial included patients who had mild neurological severity and had a longer delay from symptom onset compared to patients in other trials of alteplase for ischemic stroke, which may raise concern over the findings' external validity.


Thursday, October 5, 2017


Arterial spin labeling magnetic resonance imaging (MRI) — a noninvasive imaging technique that measures cerebral perfusion —successfully detected the seizure-onset zone in a majority of patients with drug-resistant focal epilepsy, according to a new study published online on September 29 in Brain.

Changes in blood perfusion in the seizure-generating areas of the brain may be a mechanism by which seizures induce neurological dysfunction, the researchers wrote. By measuring perfusion changes, they said, researchers may be able to localize the seizure onset zone.

Arterial spin labelling (ASL) has the potential to measure these changes, but the technique, they said, has not been widely tested.

The present findings suggest the technique is a "safe, feasible and cost-effective imaging modality that can be used in the postictal period to assist with the localization of the [seizure onset zone]," the study authors, led by Ismael Gaxiola-Valdez, Msc, research associate in the department of clinical neurosciences at the University of Calgary, wrote.

For the study, researchers at the University of Calgary prospectively recruited 21 patients with drug-resistant focal epilepsy who had been admitted to the Seizure Monitoring Unit at the Foothills Medical Centre of the University of Calgary for continuous scalp video electroencephalography monitoring between January 2014 and March 2016. The researchers performed an ASL scan on each of the patients within 90 minutes of a habitual seizure. Then they performed a scan during the patients' interictal period, after they had been free of seizures for at least 24 hours.

They subtracted the patients' postictal data from their interictal ASL data to identify areas of significant postictal hypoperfusion, then compared the location of maximal hypoperfusion to the presumed seizure onset zone to see if they were concordant.

They observed postictal perfusion reductions of 415 units (ml/100 g/l) 15 of the 21 patients (71.4 percent). In 12 out of 15 (80 percent) of these patients, the location of the hypoperfusion was partially or fully concordant with the location of the presumed seizure onset zone.

The researchers compared the success of their technique to that of other neuroimaging modalities, finding that it was favorable: ASL offered better localization than structural MRI in 52 percent of cases; similar or better localization compared to ictal single-photon emission computed tomography (SPECT) in 60 percent of cases; and similar or better localization compared to interictal positron emission tomography (PET) in 71 percent of cases.

The results suggest that "this technique may be incorporated into the battery of conventional investigations for presurgical evaluation of patients with drug resistant focal epilepsy," the study authors concluded. If the findings are reproduced in larger studies, they added, the technique "might eventually be considered as a replacement for ictal SPECT in appropriately selected patients."

The researchers noted several limitations to their study. Among them, since only two of the patients studied had undergone surgery, the researchers could not use post-surgical outcomes to validate the findings; and because the EEG electrodes were removed approximately 20 min prior to each arterial spin labeling scan, it is possible that some electrographic seizures were missed during this period.