Long-term outcome of epilepsy and cortical malformations due to abnormal migration and postmigrational development

Laura Licchetta, Luca Vignatelli, Francesco Toni, Andrea Teglia, Laura Maria Beatrice Belotti, Lorenzo Ferri, Veronica Menghi, Barbara Mostacci, Lidia Di Vito, Francesca Bisulli, Paolo Tinuper. Long-term Outcome of Epilepsy and Cortical Malformations Due to Abnormal Migration and Postmigrational Development. A Cohort Study. Neurology Jul 2022, 99 (1) e23-e32; DOI: 10.1212/WNL.0000000000200352

Abstract

Objective To evaluate the long-term outcomes of patients with epilepsy and malformations of cortical development (MCD).

Methods We conducted a historical cohort study of patients with epilepsy and MCD due to impaired neuronal migration and postmigration organization with a follow-up period of ≥5 years. For each patient, MCD was classified after accurate neuroimaging reappraisal by an expert neuroradiologist. The primary outcome was remission, defined as a period of seizure freedom ≥5 years at any time from epilepsy onset. We used Kaplan-Meier estimates for survival analysis and univariate and multivariate Cox regression analyses to evaluate baseline variables as possible factors associated with remission.

Results The cohort included 71 patients (M/F 31/40) with a 17-year median follow-up (1,506 person-years). About half (49.3%) had heterotopia, 35.2% polymicrogyria, 7% lissencephaly, and 8.5% the combination of 2 MCD. The mean age at seizure onset was 12.4 ± 7.2 years. Intellectual disability and neurologic deficits were observed in 30.4% and 40.9%, respectively. More than 60% of patients had refractory epilepsy. In 3 patients who underwent epilepsy surgery, MCD diagnosis was confirmed by histology. At the last visit, 44% of patients had been seizure-free during the previous year, but none of them had stopped antiseizure medication. Thirty patients achieved remission (42.2%) at some point in their disease history, whereas 41 individuals (57.8%) had never been in remission for ≥5 years. The cumulative remission rate was 38% by 20 years from inclusion. In the Cox model, unilateral distribution of MCD (hazard ratio [HR] 2.68, 95% CI 1.04–6.92) and a low seizure frequency at onset (HR 5.01, 95% CI 1.12–22.5) were significantly associated with remission.

Discussion Patients with epilepsy and MCD showed a remission rate of 38% by 20 years from onset. Unilateral distribution of the MCD is associated with a 3-fold probability of achieving remission. About 40% of patients showed a drug-sensitive condition with risk of relapse during their epilepsy course.

Classification of Evidence This study provides Class II evidence that in patients with epilepsy and MCD, unilateral MCD and low seizure frequency at onset are associated with achieving epilepsy remission.

Recovery from brain injury

A little girl who miraculously survived being struck by a car three years ago is defying the odds, as

she celebrates a special milestone amid her continuous recovery.

After months of surgeries and years of therapies, Shaylie Edwards, now 6, was able to achieve the incredible: She graduated from kindergarten. 

"This kid was just meant to do something amazing," Shaylie’s mom, Erica Edwards of Reno, Nevada, told Fox News Digital. 

On June 6, 2019, Shaylie had finished her last day of preschool and was ready for summer break. 

After dinner, she and her then-7-year-old sister Emma convinced their dad, Shannon Edwards, to take them to a nearby park to play. 

Erica Edwards stayed behind to do the dishes and had the windows open. Suddenly, she heard a commotion outside.

"I ran out back, looked over my fence and right in my vision was Shaylie on the road," Edwards said.

A car coming along the crosswalk hit both Shaylie and her father. 

When he saw the car coming toward them, dad Shannon Edwards lifted Shaylie up to get her out of the way — but when the car hit him, he lost his grip on his daughter. 

Shaylie hit the hood of the car and flew 40 feet in the air before she landed on the pavement, Erica Edwards told Fox News Digital.

The helmet the girl had been wearing — because she was planning to ride her scooter in the park — was smashed to pieces.

Erica and a bystander performed CPR on little Shaylie until paramedics arrived. 

Shaylie rode in one ambulance while Erica Edwards and her husband rode in another to Renown Medical Center in Reno.

Dad Shannon Edwards, 46, suffered seven fractures in his face; he needed full facial reconstruction. In total, he spent two-and-a-half weeks in the hospital. Today he has four permanent titanium plates in his face, said Erica Edwards.

Young Shaylie had suffered a broken jaw in two places, a broken neck in two places, a broken femur, a fractured sacrum and a brain injury. 

As the hospital's trauma team performed tests on Shaylie to determine her treatment, Erica Edwards asked to stay with her daughter. 

Because the mom was surprisingly calm, the hospital team let her in the room. That calm, Erica explained, came from God. 

"I was a very spiritual person before this — I always believed in God, but I [wasn’t] much of a churchgoer, not much of a follow-the-Bible-to-the-book type of person," she said.

"But I'm a full believer now … God speaks to me all the time. And it was through this accident that this voice came to me."

"It was a lot of just, ‘Stay calm, just stay calm,’" she said. "It has to be a higher power, a God, a somebody who was just kind of grounding me for what was to come."

"If it wasn't for that grounding, I wouldn't have gotten through the last three years of fighting to get my baby back, because it has been a literal fight every single day."

Shaylie was moved to the pediatric ICU (PICU), where she was in the care of Dr. Kris Deeter, a pediatric intensivist at Renown Children’s Hospital in Reno and the medical director for Pediatrix Critical Care and Hospitalists of Nevada. 

"I could tell right away that we were dealing with a pretty severe brain injury," Dr. Deeter told Fox News Digital. "She was completely unresponsive, she had no reflexes at that time, no motor movement right away … I knew that she was going to have a hard, long road."

During Shaylie’s first five days in the hospital, doctors focused on protecting her brain from further injury, such as swelling or bleeding.

Once her brain was stabilized, the medical team checked Shaylie’s lungs, kidneys and liver to ensure they were functioning properly, Deeter said. 

Then, doctors moved to get Shaylie off the ventilator and off sedatives, so she could start to regain her strength and begin the recovery process.

After two weeks in the PICU, Shaylie finally opened her eyes. That, for Dr. Deeter, was a turning point in Shaylie’s care.

"When we started seeing that little twitch and that little smile come out, we all knew we were good," Deeter said. "She's a fighter."

It was also the moment that Erica Edwards knew her baby girl was going to be OK. 

"When you saw her eyes open, you knew that something was going to come of this young lady," Erica said. "She wasn’t going to be in the hospital forever."

"I think it’s that moment when her eyes opened, and they were so clear that the fire just started in me," Erica added. "I knew I had to do whatever I could … to get her back."

After three months in the hospital, Shaylie headed to rehab in Los Angeles. Weeks later, she returned

home to Reno to complete outpatient care.

"For us to get released from Renown and go home was scary, but such a relief," Erica said. "Our family hadn’t been home in three months, so that part was amazing. But then the rehabilitation started and it was scary."

Shaylie was 4 years old at the time, but when doctors evaluated her, they determined she was at the level of a 5-month-old. 

"She couldn't lift her head, she couldn't eat, she couldn't walk, she couldn't talk, she couldn't do anything," Erica said. "That was scary to hear that news." 

For the first year-and-a-half, Shaylie attended rehab five days a week. When she wasn’t in therapy, her parents were working with her at home. 

Finally, after months of hard work, Shaylie regained her ability to eat, talk and walk, with the help of a walker that she used. 

"So many steps were involved in doing that," Erica said of Shaylie’s therapies. "The list is amazingly huge of all the work her therapists did."

Through it all, Erica said faith helped her family move forward. 

"Faith for me and my journey has been a number-one priority," said Erica Edwards. "To recognize that and follow it just makes things a lot easier on the day-to-day, because this fight is real." 

"I’m going to have to continue to fight for her for years," she added. "I don’t know that it’ll ever stop. I hope that there’s a day, but I’m not sure. And my faith is what’s getting me through. It’s a beautiful thing." 

Today, Shaylie is still in speech, occupational and physical therapies, but she continues to improve. The family is also looking for new and improved intensive therapies to help Shaylie move forward, said Erica.

"We are willing to do whatever it takes to get this little girl her life back," she said.

Though it took roughly over a year for her to start forming words again, Shaylie is now just as chatty as she was before the accident.

Other things have returned, too. 

"Some memories are even coming back," Erica Edwards said. "It's pretty amazing to hear her have memories and be the same sassy, funky, happy little girl."

"All those things are a huge, huge blessing, a blessing from God," the mom continued. "There's just something about her that God, the universe, whatever, didn't want to let go of. And I'm excited to see where this little girl's life takes off to," she added.

In June, Shaylie graduated from kindergarten. To celebrate, the Edwards family traveled to Disneyland. "We had a blast," Erica said.

https://www.foxnews.com/lifestyle/nevada-girl-car-age-3-odds-mom-leans-faith-god?cmpid=prn_newsstand

 

 

 

Chiropractic manipulation and arterial dissection

 A recent college graduate in Georgia was reportedly left paralyzed after a routine chiropractor visit. 

Caitlin Jensen, 28, graduated from Georgia Southern University in May with a degree in chemistry and biology and went to an unnamed chiropractor on June 16 where she received a neck adjustment, according to a GoFundMe page dedicated to raising money for her medical expenses. 

But she was soon after rushed to an emergency room by ambulance, and tests revealed she had four dissected arteries in her neck, according to the page set up by Linda Foster. The damage caused her to go into cardiac arrest and suffer a stroke. She lost a pulse for 10 minutes before she was revived. 

"That morning we were up and talking to her before work. You're talking to her and then 30 minutes later, she's in the hospital and now in the ICU," Jensen’s brother, Caleb Johnson, told WJCL. 

After Jensen was stabilized, she was rushed into surgery, and doctors managed to repair some of the tears and placed a stent in one artery, according to the GoFundMe page. 

The woman’s mother, Darlene Jensen, told WSB-TV that her daughter’s doctors said the injury was a direct result of the neck adjustment and the family has retained legal counsel on her daughter’s behalf. 

"The surgeon that performed the surgery on her that saved her life, and every other doctor that has looked at her, have all agreed that this happened as a direct result of the neck manipulation," the elder Jensen said in the story published Tuesday. "The chiropractor called 911 and then called me and told me that she was ‘having a reaction to the treatment.’"

The chiropractor has not been named in local reports. WJCL reported reaching out to the chiropractor, who declined to comment on the incident and cited HIPAA privacy laws. 

Jensen remains hospitalized in critical condition at the neuro ICU in Memorial Hospital in Savannah, Georgia. She suffered a traumatic brain injury, according to the fundraising page, and is currently conscious and able to respond to verbal commands by blinking her eyes, as well as wiggling her the toes of her left foot. But the rest of her body sits in a state of paralysis due to the injury, the pages says. 

"She's able to open her eyes every now and then and wake up a little bit. And kind of move her hands to squeeze a little. But that's it," Johnson told WJLC for a story published Tuesday. 

As of Thursday morning, the GoFundMe page raised $56,676 of its $100,000 goal. Jensen’s family aims to have her transferred from the ICU to the Shepherd Center in Atlanta once she’s stable enough. 

"It's huge just to know that people are out there supporting as we to get her into therapy. She's just a young college student with not the best health care," Johnson said.

A site on Caring Bridge has also been established to provide updates on Jensen’s condition. The most recent update published Wednesday asked for prayers for Jensen, her family and medical staff, noting how Jensen had a "rough day" with mucus collecting in her lung, causing issues with her trachea tube. 

https://www.foxnews.com/us/georgia-college-graduate-left-paralyzed-routine-chiropractor-visit-neck-pain-goes-wrong

Jones J, Jones C, Nugent K. Vertebral artery dissection after a chiropractor neck manipulation. Proc (Bayl Univ Med Cent). 2015 Jan;28(1):88-90. doi: 10.1080/08998280.2015.11929202. PMID: 25552813; PMCID: PMC4264725

Abstract

The differential diagnosis for ischemic central nervous system infarcts in young patients includes paradoxic emboli through cardiac shunts, vasculitis, and vascular trauma. We report a young woman who developed headache, vomiting, diplopia, dizziness, and ataxia following neck manipulation by her chiropractor. A computed tomography scan of the head revealed an infarct in the inferior half of the left cerebellar hemisphere and compression of the fourth ventricle causing moderate acute obstructive hydrocephalus. Magnetic resonance angiography revealed severe narrowing and low flow in the intracranial segment of the left distal vertebral artery. The patient was treated with mannitol and a ventriculostomy and had an excellent functional recovery. This report illustrates the potential hazards associated with neck trauma, including chiropractic manipulation. The vertebral arteries are at risk for aneurysm formation and/or dissection, which can cause acute stroke.

Morton, A. Internal carotid artery dissection following chiropractic treatment in a pregnant woman with Systemic Lupus Erythematosus. Chiropr Man Therap 20, 38 (2012). https://doi.org/10.1186/2045-709X-20-38

Abstract

A case of internal carotid artery dissection in a pregnant woman with Systemic Lupus Erythematosus (SLE) immediately following chiropractic treatment is presented. The literature regarding complications of neck manipulation during pregnancy, spontaneous dissection of craniocervical arteries in pregnancy and the postpartum period, and dissection of craniocervical arteries in SLE are reviewed. To the best of the author’s knowledge, this is the first case of carotid artery dissection following chiropractic treatment in a pregnant woman published in the literature.

Turner CR (2018) The potential dangers of neck manipulation & risk for dissection and devastating stroke: An illustrative case & review of the literature. Biomed Res Rev 2: DOI: 10.15761/BRR.1000110

Abstract

Chiropractic cervical manipulation is a common practice utilized around the world. Most patients are never cleared medically for manipulation, which can be devastating for those few who are at increased risk for dissections. The high velocity thrust used in cervical manipulation can produce significant strain on carotid and vertebral vessels. Once a dissection has occurred, the risk of thrombus formation, ischemic stroke, paralysis, and even death is drastically increased. In this case report, we highlight a case of a 32-year-old woman who underwent chiropractic manipulation and had vertebral artery dissection with subsequent brainstem infarct. She quickly deteriorated and passed away shortly after arrival to the hospital. Although rare, one in 48 chiropractors have experienced such an event. We utilize this case to highlight the risk associated with cervical manipulation and urge open dialogue between chiropractors and physicians. Receiving medical clearance prior to cervical manipulation in potential at risk patients would drastically reduce morbidity and mortality. 

See: https://childnervoussystem.blogspot.com/2016/05/chiropractic-care-and-cervical-artery.html

ADCY5 mutations

Inspired by a patient (and perhaps a grandpatient)

 Summary

ADCY5-related dyskinesia is a neurologic disorder with a variety of movement abnormalities. Dyskinesia means that affected individuals have trouble controlling voluntary movements. Voluntary movements are any movements that a person does intentionally such as lifting their arms, walking, or turning one’s head. Affected individuals experience uncontrolled, involuntary movements including sudden jerks, writhing motions, twitches, twisting, or tremors. The arms and legs, neck, and face are commonly affected. Symptoms usually begin during infancy, childhood, or adolescence and continue throughout life, although there are periods of time when no symptoms occur (remission). The severity of the disorder can vary significantly from one person to another. Intelligence and life span are generally not affected. ADCY5-related dyskinesia is caused by a variation (mutation) in the ADCY5 gene. This variation may be inherited from a parent, or it may occur spontaneously as a new variation without a previous family history (de novo mutation).

https://rarediseases.org/rare-diseases/adcy5-related-dyskinesia/#:~:text=ADCY5%2Drelated%20dyskinesia%20is%20a,walking%2C%20or%20turning%20one's%20head.

Ferrini A, Steel D, Barwick K, Kurian MA. An Update on the Phenotype, Genotype and Neurobiology of ADCY5-Related Disease. Mov Disord. 2021 May;36(5):1104-1114. doi: 10.1002/mds.28495. Epub 2021 May 2. PMID: 33934385.

Abstract

Adenylyl cyclase 5 (ADCY5)-related phenotypes comprise an expanding disease continuum, but much remains to be understood about the underlying pathogenic mechanisms of the disease. ADCY5-related disease comprises a spectrum of hyperkinetic disorders involving chorea, myoclonus, and/or dystonia, often with paroxysmal exacerbations. Hypotonia, developmental delay, and intellectual disability may be present. The causative gene encodes adenylyl cyclase, the enzyme responsible for the conversion of adenosine triphosphate (ATP) to cyclic adenosine-3',5'-monophosphate (cAMP). cAMP is a second messenger that exerts a wide variety of effects via several intracellular signaling pathways. ADCY5 is the most commonly expressed isoform of adenylyl cyclase in medium spiny neurons (MSNs) of the striatum, and it integrates and controls dopaminergic signaling. Through cAMP pathway, ADCY5 is a key regulator of the cortical and thalamic signaling that control initiation of voluntary movements and prevention of involuntary movements. Gain-of-function mutations in ADCY5 have been recently linked to a rare genetic disorder called ADCY5-related dyskinesia, where dysregulation of the cAMP pathway leads to reduced inhibitory activity and involuntary hyperkinetic movements. Here, we present an update on the neurobiology of ADCY5, together with a detailed overview of the reported clinical phenotypes and genotypes. Although a range of therapeutic approaches has been trialed, there are currently no disease-modifying treatments. Improved in vitro and in vivo laboratory models will no doubt increase our understanding of the pathogenesis of this rare genetic movement disorder, which will improve diagnosis, and also facilitate the development of precision medicine approaches for this, and other forms of hyperkinesia. 

Méneret A, Roze E, Maranci JB, Dodet P, Doummar D, Riant F, Tranchant C, Fraix V, Anheim M, Ekmen A, McGovern E, Vidailhet M, Arnulf I, Leu-Semenescu S. Sleep in ADCY5-Related Dyskinesia: Prolonged Awakenings Caused by Abnormal Movements. J Clin Sleep Med. 2019 Jul 15;15(7):1021-1029. doi: 10.5664/jcsm.7886. PMID: 31383240; PMCID: PMC6622513.

Abstract

Study objectives: ADCY5 mutations cause early-onset hyperkinetic movement disorders comprising diurnal and nocturnal paroxysmal dyskinesia, and patient-reported sleep fragmentation. We aimed to characterize all movements occurring during sleep and in the transition from sleep to awakening, to ascertain if there is a primary sleep disorder, or if the sleep disturbance is rather a consequence of the dyskinesia.

Methods: Using video polysomnography, we evaluated the nocturnal motor events and abnormal movements in 7 patients with ADCY5-related dyskinesia and compared their sleep measures with those of 14 age- and sex-matched healthy controls.

Results: We observed an increased occurrence of abnormal movements during wake periods compared to sleep in patients with ADCY5-related dyskinesia. While asleep, abnormal movements occurred more frequently during stage N2 and REM sleep, in contrast with stage N3 sleep. Abnormal movements were also more frequent during morning awakenings compared to wake periods before falling asleep. The pattern of the nocturnal abnormal movements mirrored those observed during waking hours. Compared to controls, patients with ADCY5-related dyskinesia had lower sleep efficiencies due to prolonged awakenings secondary to the abnormal movements, but no other differences in sleep measures. Notably, sleep onset latency was short and devoid of violent abnormal movements.

Conclusions: In this series of patients with ADCY5-related dyskinesia, nocturnal paroxysmal dyskinesia were not associated with drowsiness or delayed sleep onset, but emerged during nighttime awakenings with subsequent delayed sleep, whereas sleep architecture was normal.

See: https://childnervoussystem.blogspot.com/2020/08/adcy5-dyskinesia.html

Antiepileptic drug monotherapy for epilepsy

Nevitt SJ, Sudell M, Cividini S, Marson AG, Tudur Smith C. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Database Syst Rev. 2022 Apr 1;4(4):CD011412. doi: 10.1002/14651858.CD011412.pub4. PMID: 35363878; PMCID: PMC8974892.

Abstract

Background: This is an updated version of the original Cochrane Review published in 2017. Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for focal onset seizures and sodium valproate for generalised onset seizures; however, a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices.

Objectives: To compare the time to treatment failure, remission and first seizure of 12 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, eventrate, zonisamide, eslicarbazepine acetate, lacosamide) currently used as monotherapy in children and adults with focal onset seizures (simple focal, complex focal or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).

Search methods: For the latest update, we searched the following databases on 12 April 2021: the Cochrane Register of Studies (CRS Web), which includes PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Epilepsy Group Specialised Register and MEDLINE (Ovid, 1946 to April 09, 2021). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators and experts in the field.

Selection criteria: We included randomised controlled trials of a monotherapy design in adults or children with focal onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types).

Data collection and analysis: This was an individual participant data (IPD) and network meta-analysis (NMA) review. Our primary outcome was 'time to treatment failure', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', and 'time to first seizure post-randomisation'. We performed frequentist NMA to combine direct evidence with indirect evidence across the treatment network of 12 drugs. We investigated inconsistency between direct 'pairwise' estimates and NMA results via node splitting. Results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs) and we assessed the certainty of the evidence using the CiNeMA approach, based on the GRADE framework. We have also provided a narrative summary of the most commonly reported adverse events.

Main results: IPD were provided for at least one outcome of this review for 14,789 out of a total of 22,049 eligible participants (67% of total data) from 39 out of the 89 eligible trials (43% of total trials). We could not include IPD from the remaining 50 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions. No IPD were available from a single trial of eslicarbazepine acetate, so this AED could not be included in the NMA. Network meta-analysis showed high-certainty evidence that for our primary outcome, 'time to treatment failure', for individuals with focal seizures; lamotrigine performs better than most other treatments in terms of treatment failure for any reason and due to adverse events, including the other first-line treatment carbamazepine; HRs (95% CIs) for treatment failure for any reason for lamotrigine versus: eventrate 1.01 (0.88 to 1.20), zonisamide 1.18 (0.96 to 1.44), lacosamide 1.19 (0.90 to 1.58), carbamazepine 1.26 (1.10 to 1.44), oxcarbazepine 1.30 (1.02 to 1.66), sodium valproate 1.35 (1.09 to 1.69), phenytoin 1.44 (1.11 to 1.85), topiramate 1.50 (1.23 to 1.81), gabapentin 1.53 (1.26 to 1.85), phenobarbitone 1.97 (1.45 to 2.67). No significant difference between lamotrigine and eventrate was shown for any treatment failure outcome, and both AEDs seemed to perform better than all other AEDs. For people with generalised onset seizures, evidence was more limited and of moderate certainty; no other treatment performed better than first-line treatment sodium valproate, but there were no differences between sodium valproate, lamotrigine or eventrate in terms of treatment failure; HRs (95% CIs) for treatment failure for any reason for sodium valproate versus: lamotrigine 1.06 (0.81 to 1.37), eventrate 1.13 (0.89 to 1.42), gabapentin 1.13 (0.61 to 2.11), phenytoin 1.17 (0.80 to 1.73), oxcarbazepine 1.24 (0.72 to 2.14), topiramate 1.37 (1.06 to 1.77), carbamazepine 1.52 (1.18 to 1.96), phenobarbitone 2.13 (1.20 to 3.79), lacosamide 2.64 (1.14 to 6.09). Network meta-analysis also showed high-certainty evidence that for secondary remission outcomes, few notable differences were shown for either seizure type; for individuals with focal seizures, carbamazepine performed better than gabapentin (12-month remission) and sodium valproate (six-month remission). No differences between lamotrigine and any AED were shown for individuals with focal seizures, or between sodium valproate and other AEDs for individuals with generalised onset seizures. Network meta-analysis also showed high- to moderate-certainty evidence that, for 'time to first seizure,' in general, the earliest licensed treatments (phenytoin and phenobarbitone) performed better than the other treatments for individuals with focal seizures; phenobarbitone performed better than both first-line treatments carbamazepine and lamotrigine. There were no notable differences between the newer drugs (oxcarbazepine, topiramate, gabapentin, eventrate, zonisamide and lacosamide) for either seizure type. Generally, direct evidence (where available) and network meta-analysis estimates were numerically similar and consistent with confidence intervals of effect sizes overlapping. There was no important indication of inconsistency between direct and network meta-analysis results. The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders; however, reporting of adverse events was highly variable across AEDs and across studies.

Authors' conclusions: High-certainty evidence demonstrates that for people with focal onset seizures, current first-line treatment options carbamazepine and lamotrigine, as well as newer drug eventrate, show the best profile in terms of treatment failure and seizure control as first-line treatments. For people with generalised tonic-clonic seizures (with or without other seizure types), current first-line treatment sodium valproate has the best profile compared to all other treatments, but lamotrigine and eventrate would be the most suitable alternative first-line treatments, particularly for those for whom sodium valproate may not be an appropriate treatment option. Further evidence from randomised controlled trials recruiting individuals with generalised tonic-clonic seizures (with or without other seizure types) is needed.

 

Differing perceptions

Freeman JM. On learning humility: a thirty-year journey. Hastings Cent Rep. 2004 May-Jun;34(3):13-6. PMID: 15281722.

When I returned to Johns Hopkins as an associate professor in 1969, the physician's role was quite paternalistic. The concept of informed consent was just beginning to enter the patient-physician relationship, and the idea of shared decisionmaking had not begun. Parents had responsibility for the surrogate decisionmaking for their child, and the idea that disabled persons have the same rights as everyone else was still new. I had been hired to direct the pediatric neurology division at Johns Hopkins. I was also to run the March of Dimes Birth Defects Clinic which primarily cared for children with spina bifida, a congenital malformation of the spine associated with varying degrees of paralysis of the legs, bladder, and bowels, and often associated with hydrocephalus (water on the brain).

During the mid-1960s, newborns affected with spina bifida were sent home or to an institution, typically to die. Children who did not die had treatment begun when they were a year old. As surgical and anesthetic techniques improved, however, surgery for the newborn with spina bifida became increasingly feasible, and John Lorber, of Sheffield, England, showed that early closure of the back to avoid meningitis increased the child's chances of survival. 

When I began to work in the Birth Defects Clinic, early surgery was the norm but was not mandatory. As director of the clinic, it became my responsibility to elicit the parent's informed consent for the operation to repair the back. I needed to discuss the likelihood of the child's future ability to walk, with or without braces and crutches, and to explain the consequences and management of the probable incontinence of bowel and bladder and the likelihood of hydrocephalus and of mental retardation. I had been trained in the paternalistic era when the physician directed the patient's care and convinced the parents to make the correct decision, and this was typically the approach I put into practice myself.

I have recently had occasion to look back on my work and to see what happened to some of the patients I have worked with over the years. What I find leads me to think differently about much of what I have done. I had been a biology major in college and had little patience for philosophy and ethics. I found them lacking the precision that had led me to science and eventually into medicine. Through my medical school and residency training there were no courses in medical ethics, caring and compassion, or communication. We were taught "medicine" and to make good decisions for the patients. But my journey with spina bifida has led me toward humility and, I hope, greater wisdom.

About one year after I began directing the clinic, I saw a newborn with spina bifida whose story has become emblematic for me of my ever-growing uncertainty. The infant had a high spinal lesion, and I explained to her parents that she would spend most of her life in a wheelchair and never have normal control of her bowel or bladder. She was likely to develop hydrocephalus, and if we did not operate to close the back, she was likely to develop meningitis. They were a churchgoing family and asked to consult with their minister. The following day they returned and told me that, with their minister's guidance, they had decided to let God make the decision. They did not want to have a surgeon interfere with God's will. They wanted to take the baby, now named Faith, home and provide her with love and care.

I knew that if she were taken home, she would probably die of meningitis. Was death with love preferable to life with love and suffering? At that time, society's attitudes toward the child with Down Syndrome were changing; the prevailing sentiment now was that if the child had an intestinal blockage she should be operated on, with or without parental permission, and then either taken home by the family, put up for adoption, or placed in foster care. I wondered whether Faiths case was similar, and I worried about my obligations both to her and to her family. My paternalistic bent was to do everything possible to give her the best life available, to close the back and embark on the multiple medical procedures, recognizing that she faced a lifetime of medical complications. She would likely be of normal intelligence and thus aware of her condition. Yet the family was apparently making its decision out of love and compassion, not because they wanted to avoid caring for a disabled child. They wanted to give Faith their best care, and then leave the outcome to higher powers. I decided that it was not my role to interfere, even if it meant a higher probability of Faith's dying. I let them take her home and asked to see her in the clinic in a month.

When Faith returned for the four-week visit, she had been well cared for. Her back had largely healed, but she also had all of the clinical signs of meningitis. I explained to the parents that we had two choices: to hospitalize her and treat her with antibiotics, or to pretend not to recognize the infection and let them take her home to die. Again, after a long discussion, they convinced me of the validity of their choice to leave the outcome in God's hands, and Faith went home.

Three weeks later, the family returned to the clinic because Faith was vomiting and not feeding. Her meningitis seemed to have resolved on its own, but she had now developed hydrocephalus, which if left untreated would certainly kill her, although possibly not for months, even years. A minor operation to place a shunt and siphon off the fluid could control the hydrocephalus. I explained to the parents that if Faith were to survive, she should survive in the best condition possible. She should have her back repaired so it would be less disfiguring; she should begin to have orthopedic procedures on her legs so that they would be as straight as possible. She should have her bladder and kidneys evaluated and treated, if necessary, to avoid permanent damage. At this point, Faiths family agreed to treatment. From their perspective, God had shown His wisdom and had not allowed Faith to die. He would want her to be the best she could be. We performed the shunt.

As a teen she was beautiful, walking with crutches, seemingly happy, but somewhat slow mentally. I lost track of her when she outgrew pediatrics, but I have recently reviewed her medical history. Over the ensuing twenty years, she has had many hospitalizations, many shunt revisions, and many bed sores requiring plastic surgery. She has had repeated renal infections, and one kidney has been removed. In short, she has endured a grueling medical history.

In retrospect, Faiths case has been a lesson in humility several times over. It was, to some degree, a lesson in medical humility: she did well even when the family rejected some of my recommendations for treatment. Thinking about these decisions was also an early lesson in moral humility, as I found it necessary to accede to the family's views about how she ought to be treated. Thinking about the outcomes of these decisions has provided yet another lesson in moral humility. When Faith was a teen, she appeared to be doing well, even without receiving as much care as I had recommended. But at this point in her life, perhaps she feels differently, and I wonder what she and her family would say now about the quality of her life. On the basis of her medical history alone, anyway, I am not sure that the decisions we made back then were right.

Even at the time, these matters were obscure. In 1971, shortly after Faith's early surgeries, Lorber re-evaluated at the results of his recommendations for early surgery for children with spina bifida and concluded that the early treatment of all children with spina bifida was a mistake. 

Half of the children he had treated early and vigorously had died anyway, and a substantial number of those who survived would be in wheelchairs or require bracing and crutches. He believed that they would be better off dead. He published criteria that could predict a child's future impairment and recommended "selection" and nontreatment of those who would be in wheelchairs or walk only with braces and crutches. He stated that such selection, at birth, would reduce the suffering of the children and their families, and reduce the resources needed for their care.

Lorber claimed that infants "selected" would die quickly, but having recently been through the events described above with Faith, I knew that was not necessarily true and wrote a commentary for a pediatric journal titled, "Is there a Right to Die Quickly?" The commentary raised questions about the meaning of "quickly" and contended that the definition was in the eye of the beholder. Having seen children like Faith lie around the wards for weeks or months--waiting to die--I treated most children with spina bifida, but I also wrote, in another article, that "If euthanasia were legal, I might feel differently." 

Later in my career, I debated John Lorber in front of the American Academy of Pediatrics. He articulated the results of his study, stating that those not selected for treatment died quickly. What was not apparent to the audience, and initially not to me, was that in England, infants were fed on demand. If they were sedated with morphine and phenobarbital and fed on demand, they demanded less, and died more quickly. Infants in this country were fed every four hours and were patiently waiting to die without their physicians knowing the "trick."

Recently I was asked to write a review of the ethical issues involved in treating spina bifida. It had been years since I had worked with children who had that condition, and both the field and society had changed. Now, prenatal folic acid may prevent spina bifida, routine amniocentesis and ultra sound examination often detect a lesion early in pregnancy, and the abortion of an affected fetus is common. I wondered if these changes had affected perinatal decisionmaking.

I went to the spina bifida groups' annual Christmas Party and spoke with two young women in their 20s who had been poster children for what we could do. I had always believed that if the child was given the proper medical care, if complications were prevented, if adequate education and psychological support were provided, these affected children could be given a good life. If they were dissatisfied with their lot, it was our fault for not having adequately met their needs. During their childhood and early adolescence, I had considered these two to he among my treatment successes.

Although both of these young women have high paraplegia and are in wheelchairs, they are of good intelligence, have graduated from high school, and hold government jobs. One has had twenty-seven operations for shunt blockage and for hip, back, and kidney problems. The other had only one shunt but many other surgical procedures. Both live at home. When I asked about their lives they both complained about having few friends, no social life, little prospect for marriage, and little independence. I mentioned that I was writing an article about decisionmaking for infants with spina bifida. One said that although she was Catholic and did not believe in abortion, nevertheless, she wished she had not been born and would advise parents to terminate an affected fetus. The other agreed.

I was shocked. I was reminded of Lorber's statement, which I had disputed in 1971, that "most [of his survivors] had a quality of life inconsistent with self-respect, earning capacity, happiness, and even marriage."

I consider myself to be a moral, caring, dedicated, compassionate, paternalistic physician whose life's work has been with children and parents of children with disabilities. Over the course of my career I had became increasingly confident in the correctness of my decisions, and therefore grew even more paternalistic. My confidence may even have turned into arrogance as I found and articulated the flaws in Lorber's position. Now, with time and experience, and partly as a result of speaking to these young women, my arrogance has become doubt and ignorance, once again. I now do not know what to recommend to the family of a newborn with a severe birth defect, or how to counsel the family whose fetus has been diagnosed in utero. I no longer know what is "the right decision," or even the ethics underpinning a proper decision.

My patients and parents have taught me that families have amazing abilities to cope. I am repeatedly struck by the families who rise to meet what I would have considered terrible, ongoing adversities. I am awed by those who continue to care lovingly for the profoundly disabled child who does not interact with them or with the environment, and who has constant seizures. I remain overwhelmed by the parent who is constantly demonstrating love, care, and compassion without the immediate positive feedbacks and rewards that I as a parent have come to expect.

Predicting the future for children with major abnormalities may be fraught with hazzard; so also may be predicting the parental response to a handicapped child. I was taught this by three mothers, each referred to me for counseling late in their pregnancies. Each was carrying a fetus who, by ultrasound, had hydrocephalus. One child, when born, had hydranencephalaphy (no cortical mantle) and made almost no development. Stasia had seizures and died at three years of age. Her parents considered her "a gift" and wrote of their experience. The second at birth was found to have massive hydrocephalus with only a very thin cortical mantle. She was shunted and has become an "A" student in high school and a competitive swimmer. The third, similarly treated, made little developmental progress, had major complications, and a devastated, ultimately broken, family who came to curse me for advising them to carry the child to term. When seen in utero, I could not predict the three fetuses' medical outcomes, let alone their parents' future reactions.

Since these problems were detected only late in pregnancy, the only alternative was the currently banned "partial birth abortion." Would that have been better? For which of the children? How do you work to achieve the greatest good for the greatest number when "the good" is so unpredictable both for the children and for their families?

I realized the depths of the biases and prejudices that continue to underlie my personal ethics and my decision making. As I tried to factor my perception of quality of life into my advice, I also realized how limited is my own view of other people's quality of life--how tolerant we must become of those with a different quality of life.

In reflecting on my career, I find that I have progressed from ignorance to paternalism through arrogance to a new humility. I have become more tolerant, perhaps more compassionate, less judgmental, somewhat wiser, more confused. I am still learning how deep my own biases run, and how little I really know about the lives of those with disabilities. I no longer know the ethically correct answer to the specific questions posed by the patients' problems. I have also learned, much to my continued disappointment, that ethical theories and ethicists are rarely helpful in decisionmaking at the bedside or for the individual.

But one lesson I believe I have learned is that decisionmaking should be a process, and the process for arriving at a decision is far more important than the decision arrived at. ( This process cannot be left solely to the family, or to relatives and friends, with their biases and prejudices, any more than it can be left solely to the physician. Physicians and families together must learn to work out a plan for the handicapped or potentially handicapped newborn--and likewise for the premature infant, for the person with late-stage Alzheimer's disease, for the critically ill, for individuals at both ends of life.

Fenfluramine for the treatment of seizures associated With Lennox-Gastaut syndrome

Knupp KG, Scheffer IE, Ceulemans B, et al. Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial. JAMA Neurol. 2022;79(6):554–564. doi:10.1001/jamaneurol.2022.0829

Key Points

Question  Is adjunctive fenfluramine effective in patients with Lennox-Gastaut syndrome (LGS)?

Findings  In this randomized clinical trial of 263 patients with LGS, use of 0.7-mg/kg/d fenfluramine resulted in a greater reduction in drop seizures than with placebo, more patients achieving a 50% or greater reduction in drop seizure frequency, and greater reduction in generalized tonic-clonic seizure frequency. Treatment-emergent adverse events included decreased appetite, but no patient developed valvular heart disease or pulmonary hypertension.

Meaning  Findings from this trial suggest that fenfluramine may be a safe and effective treatment option for patients with LGS.

Abstract

Importance  New treatment options are needed for patients with Lennox-Gastaut syndrome (LGS), a profoundly impairing, treatment-resistant, developmental and epileptic encephalopathy.

Objective  To evaluate the efficacy and safety of fenfluramine in patients with LGS.

Design, Setting, and Participants  This multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted from November 27, 2017, to October 25, 2019, and had a 20-week trial duration. Patients were enrolled at 65 study sites in North America, Europe, and Australia. Included patients were aged 2 to 35 years with confirmed diagnosis of LGS and experienced 2 or more drop seizures per week during the 4-week baseline. Using a modified intent-to-treat method, data analysis was performed from November 27, 2017, to October 25, 2019. The database lock date was January 30, 2020, and the date of final report was September 11, 2021.

Interventions  Patients were randomized to receive either a 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine or placebo. After titration (2-week period), patients were taking their randomized dose for 12 additional weeks.

Main Outcomes and Measures  Primary efficacy end point was percentage change from baseline in drop seizure frequency in patients who received 0.7 mg/kg/d of fenfluramine vs placebo.

Results  A total of 263 patients (median [range] age, 13 [2-35] years; 146 male patients [56%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n = 87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n = 87). The median percentage reduction in frequency of drop seizures was 26.5 percentage points in the 0.7-mg/kg/d fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d fenfluramine group, and 7.6 percentage points in the placebo group. The trial met its primary efficacy end point: patients in the 0.7-mg/kg/d fenfluramine group achieved a −19.9 percentage points (95% CI, −31.0 to −8.7 percentage points; P = .001) estimated median difference in drop seizures from baseline vs placebo. More patients in the 0.7-mg/kg/d fenfluramine group achieved a 50% or greater response (22 of 87 [25%]; P = .02) vs placebo (9 of 87 [10%]). Site investigators and caregivers gave a much improved or very much improved rating on the Clinical Global Impression of Improvement scale to more patients in the 0.7-mg/kg/d fenfluramine group than patients in the placebo group (21 [26%] vs 5 [6%]; P = .001). The seizure subtype that appeared most responsive to fenfluramine was generalized tonic-clonic seizure (120 of 263 [46%]), with a decrease in frequency of 45.7% in the 0.7-mg/kg/d fenfluramine group and 58.2% in the 0.2-mg/kg/d fenfluramine group compared with an increase of 3.7% in the placebo group. Most common treatment-emergent adverse events included decreased appetite (59 [22%]), somnolence (33 [13%]), and fatigue (33 [13%]). No cases of valvular heart disease or pulmonary arterial hypertension were observed.

Conclusions and Relevance  Results of this trial showed that, in patients with LGS, fenfluramine compared with placebo provided a significantly greater reduction in drop seizures and may be a particularly advantageous choice in patients who experience generalized tonic-clonic seizures.