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CNS Annual Meeting

Friday, November 6, 2020

Children treated with cannabidiol to control seizures caused by Lennox Gastaut syndrome (LGS) benefited from the therapy for at least three years, researchers reported at the 2020 virtual conjoint meeting of the Child Neurology Society and International Child Neurology Association.

After 156 weeks of treatment, the median percentage of reduced drop seizures in 12-week windows were 48 percent to 71 percent and 48 percent to 68 percent for total seizures, said Anup D. Patel, MD, FAAN, section chief of neurology and associate professor of clinical pediatrics at Nationwide Children's/Ohio State University in Columbus.

“Long-term treatment with add-on cannabidiol in patients with LGS produced sustained seizure reductions with no new safety concerns," Dr. Patel stated in his presentation of the data.

Participants in the open-label extension study were gleaned from two phase 3, randomized, controlled clinical trials, known as GWPCARES3 and GWPCARES4. They included 366 patients who had been diagnosed with LGS, a rare and severe childhood-onset epilepsy, characterized by multiple and concurrent seizure types, cognitive dysfunction, and slow spike waves on EEG. The mortality of the syndrome is 5 percent in childhood, and seizures may persist into adulthood in more than 80 percent of patients.

 In the open-label extension trial, 99 percent of the patients in the controlled clinical trials were treated with plant-derived, highly purified cannabidiol (100 mg/mL oral solution of Epidiolex). The mean age of the patients was 16 years of age and 54 percent were boys. At baseline, the median drop seizure frequency over 28 days was 80 seizures; the median total seizures was 168 events in 28 days.

After a median follow-up of 150 weeks, Dr. Patel reported that 113 participants dropped out of the study—about 33 percent of the original patient population. Overall, 96 percent of the patients in the studies reported adverse events, including diarrhea, pyrexia, vomiting, upper respiratory tract infection, and decreased appetite. Forty-two percent of the adverse events were considered serious, which led to discontinuing the therapy in 12 percent, the researchers reported in their abstract. There were 11 deaths during the study, but the investigators did not find that any of those deaths were related to their treatment.

The study was supported by GW Research Ltd.

Commenting on the study, Fred A. Lado, MD, PhD, Northwell Health's regional director of epilepsy for Queens and Great Neck, NY, said, “LGS is one of the conditions with an FDA indication for use of cannabidiol. While this study validates the benefits of cannabidiol, it also provides an important perspective that cannabidiol—like other seizure medications—is associated with adverse effects, including liver function abnormalities in 8 percent. 

“There is still an impression among the lay public that cannabidiol, being derived from the hemp plant, is a more 'natural' molecule than antiseizure medications developed in the laboratory," Dr. Lado told Neurology Today At the Meetings. “These data show that the incidence of serious adverse effects may be high—42 percent—leading to discontinuation of cannabidiol in 12 percent of the study participants."

“Hopefully these data will enable neurologists to help patients to understand that like other antiseizure medications, cannabidiol may be of sustained benefit in seizure control, but the risk of adverse effects must be taken into consideration as well," he said.

Dr. Patel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Greenwich Biosciences and Medscape. Dr. Patel has received research support from GW Research Ltd. Dr. Lado did not disclose any relationships with industry.

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CNS-ICNA PL12: Patel A, Gil-Nagel A, Chin R, et al. Long-term safety and efficacy of cannabidiol (CBD) treatment in patients with Lennox Gastaut syndrome (LGS): 3-year results of an open-label extension (OLE) Trial (GWPCARE5).

Tuesday, October 27, 2020

A gene therapy using autologous stem cells appears to slow the progression of cerebral adrenoleukodystrophy (CALD), but some safety questions remain, according to findings presented at the virtual 2020 conjoint meeting of the International Child Neurology Association (ICNA) and Child Neurology Society (CNS).

Most children with evaluable data who received the therapy—elivaldogene, also called eli-cell by investigators—had no major functional disabilities, reported researchers overseeing a phase 2/3 study and a phase 3 study, both of which are ongoing and sponsored by bluebird bio, the maker of the therapy.

ALD, an X-linked disease caused by mutations of the ABCD1 gene, is most commonly seen in its cerebral and most severe form, involving rapidly progressive inflammatory cerebral demyelination leading to progressive and irreversible loss of neurologic function and death.

If the results continue to pan out as hoped, the therapy could offer a new option for CALD patients, whose only option has been allogeneic hematopoietic stem cell transplantation (allo-HSCT), which brings major immunologic risks such as graft versus host disease.

"[Elivaldogene therapy] appears to stabilize CALD disease progression, continues to show a favorable safety profile, and may offer an alternative to [allogeneic hematopoietic stem cell transplantation] for the treatment of early CALD," said Florian S. Eichler, MD, director of the leukodystrophy service at Massachusetts General Hospital who presented the findings.

The therapy involves mobilizing hematopoietic stem cells (HSCs) from the bone marrow, collecting them, transducing CD34-positive HSCs with a normal copy of the ABCD1 gene using a vector, and returning them to the patient,—where they move from the bone marrow to the blood and then to the brain—becoming microglia-like cells, Dr. Eichler said.

In the phase 2/3 ALD-102 trial, 32 patients have been treated, with an average follow-up of 30 months; 10 have reached their five-year visit. Twenty of 23 children with data able to be evaluated had no major functional disabilities; two withdrew on investigator discretion, and one had rapid disease progression and died.

In the phase 3 ALD-104 trial, follow-up is only at an average of six months. One patient developed transverse myelitis with an unknown cause. That patient had been partially responsive to steroids and plasmapheresis two months after onset, and in more recent follow-up has had episodic urinary incontinence and ongoing deficits in walking because of inversion of the left foot.

But researchers have been heartened by the overall safety profile, with no cases of graft versus host disease, or graft failure or replication of the viral vector or insertional oncogenesis, Dr. Eichler reported.

As of the patients' last visits in the ALD-102 trial, neurological function scale scores and Loes scores of brain abnormalities on MRI were both "stable," Dr. Eichler said.

Keith Van Haren, MD, assistant professor of neurology and pediatrics at the Stanford University Medical Center, said this is just a "limited snapshot of the data," but appears similar to the encouraging, previously published data seen with the original 17 patients. However, longer-term data on safety will be important, he added.

"The original data were very encouraging overall, suggesting that this product may offer a viable alternative for patients who lack a strong HLA-matched donor—but questions of long-term stability and risk remained," said Dr. Van Haren, who has done paid consulting for bluebird bio and other companies developing ALD therapies and is a site investigator for the ALD-104 trial.

"The current data," he said, "appears to include six additional patients and a longer period of follow-up for the original 17. The longer follow-up here is key. Though the trial is still a modest sample size and duration, the lack of insertional oncogenesis, graft failure, or late-onset increase in Loes score"—lesion size on MRI—"are all reassuring. The appearance of transverse myelitis, however, is unusual and requires further investigation and explanation."

As the therapy is explored further, he said he would like to see historical comparisons of elivaldogene's outcomes versus allogeneic therapy, long-term data on the stability of the vector, and more details on the transverse myelitis case, he said.

Dr. Eichler has received consulting fees from Ionis Pharmaceuticals, SwanBio Therapeutics, Alnylam, Pfizer, and Origin Biosciences. He has received financial support from bluebird bio, Inc., and Minoryx Therapeutics to conduct clinical trials and is co-founder of SwanBio Therapeutics.

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CNS-ICNA PL7: Eichler F, Duncan C, Orchard P, et al. Interim results from phase 2/3 (ALD-102) and phase 3 (ALD-104) studies of elivaldogene autotemcel (Lenti-D) gene therapy for the treatment of cerebral adrenoleukodystrophy.

Tuesday, October 27, 2020

Parents of critically ill infants in the intensive care unit often have different perceptions about their children's prognosis than those of the physician, according to findings presented here at the virtual 2020 conjoint meeting of the International Child Neurology Association (ICNA) and Child Neurology Society (CNS).

This discordance, measured in surveys that followed conferences between parents and clinicians, could have an impact on crucial decisions, said Sarah Bernstein, MD, MHA, a neonatology fellow at Duke University who presented the findings.

"The majority of childhood deaths occur during infancy often following decisions to withdraw or withhold life-sustaining treatments," Dr. Bernstein said. "Parents and clinicians caring for infants with neurologic conditions often use information about expected outcomes to make important decisions regarding infant care."

In the study, 56 pairs of parents and their clinicians completed surveys after a conference about an infant with neurologic conditions. The survey involved questions about expected motor, language, and cognitive outcomes. Parents, for example, were asked, "Will your child have normal speech (know and say at least 50 words) by age 2?" and answered definitely yes, probably yes, possibly yes, possibly no, probably no, or definitely no. They were also asked how they thought their doctor would answer that question.

Differences in beliefs were identified when a parent's prognostic estimate differed from the parent's best guess of the clinician's prognostic estimate. Differences in understanding were identified when the parent's best guess of the clinician's prognostic estimate differed from the clinician's actual prognostic estimate.

A difference of more than one notch on the response scale was considered discordance. Researchers found discordance about prognosis in at least one domain in 37 of the 56 pairings, or 66 percent. This disagreement was typically moderate and most common in the motor domain—even though, as Dr. Bernstein noted, it is the domain with the most research on long-term outcomes.

Discordance was more frequently due to differences in understanding, which was seen in 25 out of 37 examples of discordance, rather than belief, seen in 14 out of 37. When discordance was seen, parents were usually more optimistic than clinicians—this was the case in 32 out of 37 instances of discordance.

"These findings can be used to develop targeted interventions to improve prognostic communication," Dr. Bernstein said.

Dennis Simon, MD, director of neurocritical care at the UPMC Children's Hospital of Pittsburgh, said the findings dovetail with what he has seen in his practice.

"There's always going to be a tendency to want to soften the blow a little bit when you're giving bad news—and that's coming from a good place, it's coming from an empathetic place," he said. "You're trying to give them hope about the situation. But that can influence how you present information to the parents." This can be unintentional, he said, with physicians, "maybe giving a more positive impression than they even realize."

Neuroprognostication, he said, is challenging for a child with acute brain injury because these cases involve a brain that is still developing.

"When there is uncertainty, there is a tendency amongst physicians to focus on that uncertainty rather than areas of the prognosis that are more clearly negative," he said.

 Previous research has found that honest and complete information is a top priority for parents of critically ill children in their communication with physicians, he said.

Effective communication with parents in these situations is a skill that can be improved upon with scenario-based training, he said.

And he said conveying information about prognoses is best accomplished with a series of conversations, not just one.

"There's only so much somebody can take in at one point," Dr. Simon said. "I think this study highlights that we can be doing better."

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CNS-ICNS PL6: Bernstein S, Farley S, Barks M, et al. Prevalence of prognostic discordance for infants in the intensive care unit.

Tuesday, October 27, 2020

Levels of neurofilament light chain (NFLC) in cerebrospinal fluid (CSF) and serum may be promising biomarkers of neurotoxicity after the infusion of chimeric antigen receptor T-cell (CAR T) therapy, but the abnormal baseline serum NFLC concentrations remain unexplained and require further study, according to preliminary data reported at the virtual 2020 conjoint meeting of the International Child Neurology Association (ICNA) and Child Neurology Society (CNS).

CAR T-cell therapy uses specially altered T cells to target cancer.

The latter finding surprised researchers during their quest to learn whether serum NFLC and glial fibrillary acidic protein (GFP) levels could predict neurotoxicity after CAR T-cell infusion, the lead researcher told Neurology Today At the Meetings.

"We surprisingly did not find that CSF neurofilament levels were predictive of CAR T-cell neurotoxicity and do not change during acute neurotoxicity," said Juliane Gust, MD, PhD, acting assistant professor of pediatric neurology at Seattle Children's Hospital.

Dr. Gust noted that around 40 percent of children and young adults treated with CAR T-cells for hematologic malignancies develop acute neurotoxicity, which results in altered mental status, seizures, coma, and rarely, cerebral edema.

She and her colleagues at Seattle Children's Hospital and Children's Hospital Los Angeles measured CSF levels in a consecutive cohort of 82 patients, aged 1- to 26-years-old, with relapsed or refractory acute lymphoblastic leukemia or non-Hodgkin's lymphoma.  

CSF NFLC levels prior to CAR T-cell infusion positively correlated with the risk of subsequently developing severe neurotoxicity (p=0.0182 for severe vs. none; p=0.0458 for severe vs. mild).

In serum, Dr. Gust found that pre-treatment NFLC levels were highly abnormal in many patients—in the healthy control patients, the median level was 4 pg/mL, but the median for the patients in her sample at baseline was 368 pg/mL.

"The one finding that was most surprising and that posed a lot of new questions was that we found highly abnormal baseline levels of NFLC in serum in more than 70 percent of the patients and in CSF in nearly 80 percent of patients," she said.

A normal serum level is less than 30 pg/mL, and a normal CSF level is less than 300 pg/mL, Dr. Gust noted, adding: "I think this is the real story in this study."

"To everyone's complete shock, the results raised more questions than they answered," Dr. Gust noted. She said that preliminary data gathered last year revealed that serum NFLC levels are higher in patients who later develop neurotoxicity. "However, there is no increase in NFLC during toxicity," she added.

Dr. Gust noted that since this is a relatively small sample, "we may discover some effect as we add more subjects, especially post-treatment."

There was no correlation of baseline NFLC levels with a history of CNS radiation or prior intrathecal chemotherapy, she pointed out.

Commenting on the study, Nirali Shah, MD, head of the hematologic malignancies section at the National Cancer Institute's Pediatric Oncology Branch, told Neurology Today At the Meetings that "the ability to predict who may be at high-risk for neurotoxicity would be highly informative and potentially allow for risk-mitigation strategies to try to prevent more severe complications. In this regard, Gust and colleagues report on their quest to evaluate for such predictive parameters in leukemia patients based on biomarkers associated with neurologic disorders."

She added that "the etiology for CD19 CAR T-cell associated neurotoxicity remains largely elusive," although a recent study suggests that CD19 expression on brain mural cells may potentially be a reason for on-target, off-tumor side effects of CD19 targeting and other data suggest a role for endothelial activation and blood-brain barrier fragility as contributory.

Dr. Shah added that since the patient population receiving CD19 CAR T-cells is largely comprised of those with relapsed and/or refractory disease, "their findings that a large majority of patients had abnormal NFLC levels in serum and CSF, which serves as a marker of neurologic disorders, is particularly compelling. It also warrants further investigation into baseline CNS toxicity that these patients may have accumulated from prior therapies, which include intrathecal therapy, systemic chemotherapy, and often radiation."

Dr. Gust reports consulting for Johnson & Johnson on CAR T cell clinical trials.

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CNS-ICNA PL1: Gust J, Wilson A, Sherman A, et al. Biomarkers of CART T cell neurotoxicity: CSF NFL and GFAP in an expansion cohort of pediatric ALL patients.

Monday, October 26, 2020

Gene therapy slowed the pace of decline among children diagnosed with Batten's disease, according to findings presented at the virtual 2020 conjoint annual meeting of the International Child Neurology Association (ICNA) and Child Neurology Society (CNS).

"The therapy was tested for effectiveness and safety in extensive preclinical studies before moving forward to the first-in-human clinical trial," said the first study author Emily de los Reyes, MD, attending pediatric neurologist at Nationwide Children's and professor of clinical pediatrics and neurology at The Ohio State University College of Medicine in Columbus.

Batten's disease, or neuronal ceroid lipofuscinosis, is an autosomal recessive, lysosomal storage disease, Dr. de los Reyes explained. "Nerve cells and other cells of the nervous system are very sensitive to accumulation of trash such as misfolded or old proteins, lipids, and other components of the cell since they are highly active," she told Neurology Today At the Meetings. "The accumulation and lack of clearance of these components from the cells are hallmarks of all Batten diseases."

The gene therapy trial focused on CLN6 type Batten's disease, one of 13 genotypes of the disorder. CLN6 type Batten's disease—which is caused by mutations in the CLN6 gene that encodes for a protein with unknown function called CLN6 protein— is characterized by progressive declines in language, motor skills, cognitive abilities, visual loss, and intractable myoclonic epilepsy, Dr. de los Reyes said.

"The symptom onset of variant late infantile CLN6 is approximately 3 to 4 years of age. There is rapid clinical deterioration of their abilities to walk and talk. Most children die during late childhood or in their early teens," she added.

The researchers injected AT-GTX-501, a non-replicating, recombinant, self-complementary adeno-associated virus-9 vector containing the human CLN6 gene, into the lumbar spinal cord of children. The patients were followed weekly for the first month after gene transfer, and every three months after, Dr. de los Reyes said.

After 12 months, the 12 children treated with gene therapy experienced a 0.4-point decline in the validated Hamburg Motor and Language Scale, compared with a 1.2-point decline observed in the natural history decline seen in 16 children who were also diagnosed with CLN6 type Batten's disease.

Despite the small numbers of patients in the study, the difference achieved statistical significance (p<0.01), Dr. de los Reyes said.

At two years, eight children treated with the gene therapy experienced a 0.6-point decline in function compared to a projected 2.4-point decline in the natural history of the disease (p>0.0001), she said.

"We continue to follow the last patients enrolled in the protocol, which involves monitoring safety and efficacy, in addition, to collecting further natural history data, to which we will compare our clinical results, " Dr. de la Reyes said. "Next steps will be informed by this data in the near future."

This study was funded by Amicus Therapeutics, Inc.

Commenting on the study, Bruce H. Cohen, MD, FAAN, director of the NeuroDevelopmental Science Center at Akron Children's Hospital and professor of pediatrics at Northeast Ohio Medical University, noted how devastating the illness is to the children and their families. "These children are healthy during their first few years of life but then develop regression in cognitive and language skills, changes in behavior and seizures, followed by a sleep disturbance and vision loss. Death generally occurs in early adolescence."

Dr. Cohen, who was not involved with the study, said the disease usually occurs by inheriting a mutation from each parent in the CLN6 gene, which is on chromosome 15. He noted that the vector could be used to treat only one form of the disease.

The study aimed to uncover "the safety and effectiveness of this gene therapy," he said. "Using a scale of motor and language function, the eight children [out to 24 months] treated with the gene therapy had a dramatically slower rate of disease progression when compared to the natural history of 16 children cared for before this therapy was available.

Five patients had adverse events, four of whom had side effects possibly related to the therapy (vomiting, fever, and abdominal pain), and all four children recovered, he noted.

"These are preliminary findings, and it is very encouraging that the therapy has benefited the patients," he said. "There is a lot of work to do, and issues such as if earlier treatment may provide greater benefit is still not known."

Dr. de los Reyes received grants and consulting fees from Amicus and Biomarin. Dr. Cohen had no relevant disclosures.

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CNS-ICNA PL67: de los Reyes E, Meyer K, Lehwald L, et al.  Single-dose AAV9-CLN6 gene transfer stabilizes motor and language function in CLN-6 Batten disease: Interim results from the first clinical gene therapy trial.