Monday, October 31, 2016

The heart of epilepsy

S. Shmuely, M. van der Lende, R.J. Lamberts, J.W. Sander and R.D. Thijs.  The heart of epilepsy: current views and future concepts.  Seizure: European Journal of Epilepsy.  Article in press.


• Cardiovascular (CV) comorbidities are common in people with epilepsy.

• Epilepsy and CV disorders have a complex relationship.

• Shared risk factors, causal and resultant mechanisms may play a role.

• Great progress in clinical profiles has been made.

• Further studies are needed to aid early identification of CV disorders in epilepsy.

Cardiovascular (CV) comorbidities are common in people with epilepsy. Several mechanisms explain why these conditions tend to co-exist including causal associations, shared risk factors and those resulting from epilepsy or its treatment.

Various arrhythmias occurring during and after seizures have been described. Ictal asystole is the most common cause. The converse phenomenon, arrhythmias causing seizures, appears extremely rare and has only been reported in children following cardioinihibitory syncope. Arrhythmias in epilepsy may not only result from seizure activity but also from a shared genetic susceptibility. Various cardiac and epilepsy genes could be implicated but firm evidence is still lacking. Several antiepileptic drugs (AEDs) triggering conduction abnormalities can also explain the co-existence of arrhythmias in epilepsy.

Epidemiological studies have consistently shown that people with epilepsy have a higher prevalence of structural cardiac disease and a poorer CV risk profile than those without epilepsy. Shared CV risk factors, genetics and etiological factors can account for a significant part of the relationship between epilepsy and structural cardiac disease. Seizure activity may cause transient myocardial ischaemia and the Takotsubo syndrome. Additionally, certain AEDs may themselves negatively affect CV risk profile in epilepsy.

Here we discuss the fascinating borderland of epilepsy and cardiovascular conditions. The review focuses on epidemiology, clinical presentations and possible mechanisms for shared pathophysiology. It concludes with a discussion of future developments and a call for validated screening instruments and guidelines aiding the early identification and treatment of CV comorbidity in epilepsy.

From the article:

Various arrhythmias have been described, occurring during (ictal) or after (postictal)
seizures. Sinus tachycardia is the most common ictal pattern, seen in up to 80% of all
seizures and in 82% of people with epilepsy, but usually without symptoms. The most
frequent clinically relevant arrhythmia is ictal asystole, occurring in 0.318% (95% CI 0.316%
to 0.320%) of people with refractory focal epilepsy admitted for video-EEG. Ictal asystole,
bradycardia and AV block predominantly occur in people with temporal lobe epilepsy. 
Clinically, ictal asystole is characterised by sudden loss of tone during a dyscognitive
seizure. The circulatory pattern resembles vasovagal syncope with a transient,
progressive and self-limiting slowing of the heart rate and decrease of blood pressure.
For many years, ictal asystole was thought to be a possible mechanism underlying sudden 
unexpected death in epilepsy (SUDEP). This appears to be unlikely: all but one reported case
so far of ictal asystole were self-limiting. In this one case successful resuscitation was
started after 44 seconds of asystole and the event was classified as near-SUDEP. The
longest ictal asystole reported so far, however, lasted 96 seconds and appeared self-limiting.
Whether an event is classified as near-SUDEP or not will depend on interventions of
medical personnel: prompt resuscitation in response to ictal asystole will likely lead to more
classified as near-SUDEP cases. While there are no reports of fatal ictal asystole, it remains
debatable whether ictal asystole can cause SUDEP…

Another mechanism explaining the association between arrhythmias and epilepsy is a shared
genetic risk factor. A rapidly increasing number of genes potentially linking epilepsy to
cardiac arrhythmias has been identified. Here we discuss some relevant examples; starting
with the genes predominantly known for their cardiac functions and then the ‘epilepsy

Several genetic ion channel mutations are thought to be expressed in the brain as well as in
the heart, and might thus cause seizures and cardiac arrhythmias. The first reported genetic
link between epilepsy and cardiac arrhythmias was the discovery of cardiac sodium channel
gene SCN5A in the brain. Subsequently, more pathogenic variants in the long QT (LQT)
gene family (i.e. KCNQ1, KCNH2 and SCN5A) were associated with a “seizure phenotype”
(e.g. self-reported diagnosis of epilepsy and AED use). Mice models indicated that
other, non-LQT, cardiac channelopathy genes including RYR2 (associated with
catecholaminergic polymorphic ventricular tachycardia), and HCN1-4 potentially
predispose to epilepsy…

Several AEDs, particularly those with sodium blocking properties are known to trigger
conduction abnormalities or arrhythmias. Atrioventricular (AV) conduction is the most
frequent reported complication. ST changes, Brugada-like patterns, atrial fibrillation and QTc
prolongation have also been reported but the association with AED treatment is less well
established. Most clinically relevant arrhythmias were related to AED overdose.
Carbamazepine is, however, known to cause AV conduction blocks at low or therapeutic
levels; this is almost exclusively reported in elderly women. Rapid administration
of phenytoin may also cause sinus arrest and hypotension; elderly people and those with
pre-existing heart disease seem most vulnerable to these adverse effects. IV administration
should, therefore, be undertaken slowly, with continuous cardiac monitoring.
The above-mentioned AED effects do not seem to play a role in ictal arrhythmias.
Nevertheless, it is important to take these effects into consideration in the selection of an
AED and to monitor adverse effects closely especially in elderly people and those with
cardiovascular comorbidities.

Yoel's story

Our precious baby boy Yoel was coming out of preschool, standing by the door. Out of nowhere a driver collapsed at the wheel with his foot stuck on the accelerator. The car jumped the curb, crossed three lawns, and like a missile hitting its target, the car struck my son’s head throwing him back and pinning him in between two cars.

A team of doctors and nurses were working on him in the emergency room; most were sure he would not make it to the intensive care unit. But he did. And we waited by his side praying to God to let our son live.

He sustained significant brain damage and his skull and facial bones were crushed like an egg into a million pieces. The orbit of his eye was crushed with nerve and muscle damage. He had a stroke in the back of his head during the night and his injuries were so severe the doctors didn’t think he would make it through the night. One doctor told me, “It’s now in God’s hands. We’ve done everything medically that we can do. Now we have to wait.”

There was nothing we could do but pray. I was not leaving the hospital until my son was able to leave with me. I held his hand and cried until I had no more tears left to cry. I prayed to God, “You have to bring my son back home the exact same way he left that Tuesday morning. God I expect nothing less!”

And then the miracles began to happen right before our eyes… This video captures Yoel’s story.

See video at link.


Sunday, October 30, 2016

A walking miracle

After my two strokes, doctors told my parents that I would never walk, talk or learn in a mainstream classroom. God had other plans.

From the time I was a few months old, I have faced many challenges. I suffered two CVAs (cerebral vascular accidents) better known as strokes. The strokes affected the right side of my brain.
The right side of the brain controls the ability to pay attention, recognize things you see, hear or touch, and be aware of your own body. In most people, the left side of the brain controls the ability to speak and understand language. Some people have spatial issues as well.

In my case, the strokes left me with left hemiparesis, meaning my entire left side was paralyzed and later on in life, my parents realized that I am completely deaf in my left ear. After my two strokes, doctors told my parents that I would never walk, talk or be able to learn in a mainstream classroom. My parents didn't listen. Instead they took me for OT and PT, leaving the room because I'd cry out in pain. But I gained movement and now have gross motor skills on my left side.

I started talking when I was about 12 months old and my cousins joke that ever since I've never shut up. Even though I should have difficulty with just one language, I am bilingual; I'm fluent in Hebrew. I took my first steps at the age of two and a half and was walking on my own at the age of three.
I believe in God because I am the recipient of His many miracles and blessings…

From the time I started school, I was in mainstream classrooms and was reading before I began school. At the age of ten, I was able to help my step-sister in high school understand Shakespearean English and by 12, I read Gone With the Wind and books by authors such as Agatha Christie and Jane Austen from the adult section of the library. At the end of 8th grade, I had academic testing and the doctors were shocked when the results showed that my knowledge was grade 12+ in every subject except for in math (I hate math!). I was told I could skip high school but instead went to 9th grade. I was bored and at that point I was home-schooled. Afterward, when I went to college, I obtained high marks and received accolades from my professors when it came to my work.

Having had these challenges in life, I have naturally had my moments of wavering when it comes to my trust in God. When my trust wavers, I remind myself of all the miracles I have personally experienced.

My ability to walk, talk and learn aren’t the only miracles I’ve experienced. At age four, I was sitting on the top of an L-shaped couch which was in front of a window in in my grandparents' second-floor apartment. My mother was on the far end on the other side of the couch when I fell backward and right through the window! I remember seeing the street below and the large pieces of glass that remained in the window…

My mother somehow managed to jump from one side to the other and grabbed my feet as my head was outside the window. She managed to pull me in and called Hatzalah. To this day, I remember them taking shards of glass out of my thick, wavy hair with tape, telling my mother that I had no lacerations to my head or face.

As a child, I was tormented by some of my peers for being different. They’d laugh at the way I walk or taunt me about my inability to play sports. Even in adulthood, I had an employer tell me that I walked funny. Last year, my former employer told me, “Ariel, you won’t get a job in this field or the other field you are interested in because you are different and people want normal.”

What he doesn't know is that different isn't a bad thing. It just means that I've had an interesting journey. I have done things in my life which doctors, the top in their fields, said I would never do. But God runs the world.

I hate being told that I'm handicapped; I’m not. I am handi-capable. So I can play piano with only one hand. Some people can't play with two. So I can't play sports, but I don’t even like sports so that doesn't cause me any issues. I might walk slower than some or have a heavy tread, but does that make me incapable? I don't think so. I can walk, talk, go to college, excel in school, drive, and do almost anything else that "normal" people do.

Trusting in God is not the easiest of things. While I have complete faith in His existence, I do not always have trust in Him. Some days, I want to scream, "Where are you? What is your plan for me?" Faith in God is believing He exists. Having complete trust in God means that living with the awareness that He is an intimate part of your life and that every single thing that happens is for your good. Living with that awareness is a struggle, even though I’ve experienced so many miracles in my life. .

I'm not where I wanted to be at this stage of my life. I believe that God has a plan for me and that I'll be where I'm meant to be, even if it takes me longer than I planned. If He didn't, He would not have given me the abilities that I have. My belief in God has given me the confidence to go to college, live on my own and support myself, and deny the many naysayers who said that I would never be able to achieve my goals. I thank God for blessing me with the strength to overcome adversity and thank Him for my life with all its challenges.

Center for Duchenne Muscular Dystrophy

When Valerie Pappas Llauro’s 5-year-old son Alexander was diagnosed with Duchenne muscular dystrophy – a rare and fatal form of the genetic illness that primarily affects boys – doctors said her son’s only treatment options were “steroids and hope.”

The steroids would help to slow down the muscle damage caused by his progressive disease, while the family held onto the hope that scientific research would lead to new treatments.

After countless doctors told Pappas and her husband, Jorge Llauro, that nothing more could be done, the Los Angeles, California, couple found Stan Nelson, a brilliant researcher who has dedicated his life to understanding and treating the rare disease. 

“Meeting Stan was the first moment where we felt there could actually be some hope,” Pappas Llauro tells PEOPLE.

Stan Nelson knows exactly what to say to parents of boys with Duchenne, because his own son has the diease. Nelson and wife M. Carrie Miceli’s son Dylan was diagnosed with Duchenne in 2004 at 3 years old.

Both professors and researchers at the University of California, Los Angeles, Nelson and Miceli were shocked by Dylan’s doctor’s assertion that nothing could be done to save their son from losing the ability to walk by adolescence and eventually dying from heart or lung failure in his twenties…

So, the couple refocused their already prolific careers and dedicated their lives to fighting the disease that affects one in 5,000 boys worldwide.

Their efforts led to the founding of the Center for Duchenne Muscular Dystrophy (CDMD) at UCLA – one of a few centers in the nation that conduct cutting edge research and give boys with Duchenne access to state-of-the-art care and clinical trials.

Dylan, now 15, is one of more than 100 boys currently enrolled in various treatment programs at the CDMD. These programs, involving coordinated efforts of care specialists, research labs (there are 13 at UCLA alone) and clinicians, are likely to add 10-plus years to many patients’ lives.

“As both scientists and parents of a boy with Duchenne, Carrie and Stan’s unique perspective on the research and their value to the DMD community is unparalleled,” says Dr. Barry Byrne, a professor at the University of Florida School of Medicine and a researcher who studies muscle diseases…
When Dylan found out that his parents’ biggest challenge was Duchenne’s relative obscurity, he reached out to his favorite YouTubers asking for help.

The resulting videos – in which Dylan pranks Smosh with Jennifer Lawrence and throws trick shots with ease from his wheelchair with Dude Perfect – have earned more than 17 million views and brought awareness of Duchenne to a whole new community.

“Raising awareness was my primary goal,” he explains. “I think that’s anybody’s goal if you’re living with a disease.”…

Now, Dylan serves as a role model for boys with disabilities – through his own YouTube channel and his continued advocacy for the CDMD.

“Dylan has handled everything with the most amazing grace,” says Pappas Llauro. “When Alexander sees him and he sees his super cool motorized wheelchair and his videos on YouTube, he looks up to him. He’s an incredible source of inspiration for a lot of kids.”

Dylan’s remarkable optimism will continue to be a necessity, as he and his family know things wont get easier any time soon. Developing successful treatments can take decades and while the FDA is currently reviewing what could be the first drug ever approved to treat Duchenne, only 13 percent of patients will benefit – and Dylan is not among them.

Even so, the whole family takes pride – and comfort – in knowing that strides towards new treatments that can improve quality of life and extend lifespans are happening every day at the CDMD.

Videos at link

Courtesy of my daughter

Saturday, October 29, 2016

Acute flaccid myelitis

Erin Olivera waited weeks for doctors to tell her why her youngest son was paralyzed.

Ten-month-old Lucian had started crawling oddly — his left leg dragging behind his right — and soon was unable to lift his head, following Erin only with his eyes.

She took him to a hospital in Los Angeles, but doctors there didn’t know how to treat what they saw.

Lucian’s legs felt soft as jelly and he couldn’t move them. His breathing became rapid. The left side of his smile drooped as his muscles weakened.

Physicians ran test after test, and Erin began spending her nights on a hospital room couch. After Lucian fell asleep, during her only minutes alone between working and visiting her three other kids, she cried.

A terrifying reality was taking hold: Doctors wouldn’t be able to give her a diagnosis for her paralyzed child….

“How can I make a decision for him when I don’t even know what’s wrong?” she said. “What can I do to help him?”

So one morning in July of 2012, Erin lifted Lucian out of his hospital bed, his body limp and heavy. She rested his cheek on her shoulder, the way he liked to be held since he’d become weak.

Erin returned home to Ventura County with a child she thought might never learn to walk.

In the years since, hundreds of children across the country have shown up at hospitals unable to move their arms or legs. Dozens of kids have become paralyzed in the past few months alone.

They suffer from a mysterious illness that continues to alarm and puzzle scientists. This kind of sudden and devastating paralysis hasn’t been widespread since the days of polio. Lucian, one of the disease’s earliest victims, set off a hunt among doctors to discover its cause….

Now the future felt upended by questions about their youngest son — whether he’d ever be able to drive a car, get married, have kids.

They took him to more doctors, but that failed to bring a diagnosis, let alone a treatment.

Through months of physical therapy, Lucian eventually regained strength in most of his limbs, but still couldn’t move his left leg at all. When he crawled, it dragged behind…

Then one day, she came across an article online about a dozen paralyzed kids. She immediately thought of Lucian.

The article mentioned Dr. Keith Van Haren, a Stanford University child neurologist who had diagnosed many of the other cases.

She called him…

A handful of physicians had seen patients with similar symptoms and asked Dr. Carol Glaser to test them for polio.

“I thought, ‘Well that’s crazy. We don’t have polio here,” said Glaser, then head of the encephalitis and special investigations section at the California Department of Public Health. Glaser quickly determined the patients weren’t suffering from polio. She also tested for pathogens that can sometimes cause such paralysis, including West Nile virus. All negative.

Then she decided to check for other viruses in the same family as poliovirus, known as enterovirus. And in some of the paralyzed patients, she found a possible culprit: enterovirus D-68. 

Enterovirus D-68 was incredibly rare, almost never seen after it was first discovered in 1962 in four California children who had pneumonia. Though a cousin of poliovirus, it was only supposed to cause a runny nose and cough.

Van Haren had never heard of it…

One, two, three or four limbs paralyzed. Sudden onset. No cognitive changes.

Lucian fit the bill.

Within minutes, Van Haren delivered the diagnosis: polio-like paralysis likely caused by enterovirus D-68...

In late summer of 2014, enterovirus D-68 started sending kids struggling to breathe to emergency rooms around the country. News reports called it a rare, cold-causing virus, a danger to children with asthma.

But then an 11-year-old boy in Texas with a seemingly normal fever lost the ability to walk and move his right arm.

A 17-year-old girl in Santa Barbara experienced severe neck pain at her birthday party and ended up in the hospital, paralyzed from the neck down.

In Oregon, a 13-year-old boy’s diaphragm stopped working, so he needed a ventilator to breathe. He was completely paralyzed, able only to wiggle his toes and his right hand.

Whatever was happening to these children was “pretty much, literally, exactly, what polio did,” said Dr. Jean-Baptiste Le Pichon, a child neurologist who treated four such patients in 2014 at Children’s Mercy Hospital in Kansas City, Mo.

Glaser watched from California as the numbers of paralyzed kids grew. She became horrified that her theory about enterovirus D-68 might be correct...

Erin hoped the new cases would lead to a cure for her son.

But doctors say that though the disabled children can regain strength in some limbs, there’s usually also some paralysis that cannot be reversed — just like with polio.

Scientists think a virus travels to the spinal cord and damages motor function there, irreversibly…

Between June and August this year, another 30 children nationwide became paralyzed, and scientists still don’t know why.

Dr. Manisha Patel, who heads the acute flaccid myelitis team for the U.S. Centers for Disease Control and Prevention, said the agency is concerned by the increase and its resemblance to 2014. Experts think case numbers for September and October will be even higher.

But there’s not much public health officials can do, because the paralysis officially remains a medical mystery.

Many suspect that enterovirus D-68 — which gave hundreds of people a severe cold in 2014 — also caused the paralysis outbreak that year. Some of the paralyzed children had enterovirus D-68 in their system, and researchers have found that injecting mice with enterovirus D-68 paralyzes them.

But to confirm the link, doctors need to find enterovirus D-68 in the paralyzed children’s cerebrospinal fluid, to show that the virus traveled to the spinal cord and created the injury there — which they haven’t yet…

And physicians are still baffled that no one had noticed the possible risk of paralysis before.

Some think there hadn’t ever been enough cases of enterovirus D-68 to unmask the horrifying side effect; only 26 people tested positive for the virus in 36 years. Another possibility is that enterovirus D-68 recently mutated to become more likely to paralyze those infected.

For now, experts say that enterovirus D-68 isn’t enough of a threat to make a vaccine and that many people now have immunity to the virus from the 2014 outbreak. Plus, it will probably mutate again, rendering a vaccine that protects against the current strain useless.

“You kind of hold your breath and hope it doesn’t get worse,” Van Haren said.

Courtesy of Doximity 

Friday, October 28, 2016

Placebo better than amitriptyline or topiramate for pediatric migraine

Powers SW, Coffey CS, Chamberlin LA, Ecklund DJ, Klingner EA, Yankey JW,
Korbee LL, Porter LL, Hershey AD; CHAMP Investigators.. Trial of Amitriptyline,
Topiramate, and Placebo for Pediatric Migraine. N Engl J Med. 2016 Oct 27.
Background Which, medication, if any, to use to prevent the headache of pediatric migraine has not been established. Methods We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment. Results A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt. Conclusions There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP number, NCT01581281 ).

A study of amitriptyline and topiramate in children with migraine has been halted early owing to futility.

The analysis of data from the Childhood and Adolescent Migraine Prevention (CHAMP) trial showed that neither of these preventive medications was more effective than placebo in reducing headache frequency or headache-related frequency, and both were associated with higher rates of adverse events (AEs).

Given the "null outcome" and the adverse events reported, "the data do not show a favorable risk-benefit profile for the use of these therapies in pediatric migraine prevention, at least over the 24-week duration of the trial," the authors write.

While amitriptyline and topiramate may be effective in treating headaches in adults, the study results "put doctors in a little bit of a conundrum" when it comes to children, commented lead author Scott W. Powers, PhD, a pediatric psychologist at the Department of Pediatrics, University of Cincinnati College of Medicine, Ohio….

The trial randomly assigned 361 children, mean age 14 years, who were mostly female (68%) and white (70%) and had a mean of 11 headache days per month. The study compared amitriptyline with placebo, topiramate with placebo, and the two drugs against each other.

"Our purpose was to create a 'real world' study that would enroll the type of patients that practitioners see every day," said Dr Powers. "Our hypothesis was that we would find one of these medicines to be the most effective with the least amount of side effects so that pediatricians and family medicine doctors would have sort of a first-line prevention approach for such a chronic, common illness as migraine."

In November 2014, it was determined that criteria for the a priori futility cutoff — below 20% compared with placebo — were met and that adding participants was unlikely to change the outcome. The conditional power at the time of the interim analysis was 16 percentage points for the comparison between amitriptyline and placebo and 14 percentage points for the comparison between topiramate and placebo. Study organizers decided to close down the study.

At that time, researchers had complete data on 225 children and adolescents, with another 103 participants in the midst of finishing the trial, for a total 328 patients to analyze for the primary outcome (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group)…
Dr Powers noted that placebos are "not inert" and "actually change the brain." He and his colleagues hypothesized that half of the kids would get better on placebo and that 70% of them would improve on the medicines.

"The findings were kind of upside down; it was 61% of placebo and around 50% to 55% on the drugs who got better. It wasn't statistically different, but it was in the opposite numerical direction than what you would have predicted," he said…

If there's any "positive news," it's that kids do get a lot better on these therapies, said Dr Powers. "There's a 50% reduction in migraine frequency, and headache disability is pretty much down to little to none — but it's not because of the chemical in the medicine that they have been given."
What was surprising to the investigators, said Dr Powers, was the fact that "it was so clear so early" that the active drugs were no better than placebo.

The findings were clear not just for the primary outcome but for disability outcomes on PedMIDAS and other secondary outcomes, including study completers, said Dr Powers.

"So it was so consistently not going to be effective, and to all of us investigators, once we had seen the information, it made perfect sense that closing the study was what we needed to do."

There were also side effects to consider. A total of 852 AEs occurred (301 with amitriptyline, 419 with topiramate, and 132 with placebo) in 272 patients. There were no deaths.

AEs that occurred significantly more often in the amitriptyline than in the placebo group were fatigue (30% vs 14%; P = .01) and dry mouth (25% vs 12%; P = .03).

AEs that occurred significantly more often in the topiramate group than in the placebo group were paresthesia (31% vs 8%; P < .001) and decreased weight (8% vs 0%; P = .02).

Commenting for Medscape Medical News, Kenneth J. Mack, MD, PhD, professor of neurology and of pediatrics, Mayo Clinic, Rochester, Minnesota, agreed that nonpharmacologic approaches might be the next step in light of this new study.

The "big question" now is "where do we go from here?" said Dr Mack. "Most likely, one response will be to use more behavioral approaches for the treatment of headache pain."

Dr Mack described the study as "well designed and of the highest quality."

"It did not show the expected results, but that is why we have to do studies like this."

Dr Powers has disclosed no relevant financial relationships.


Lliwen A. Jones,  Rhys H. Thomas.  Sudden death in epilepsy: Insights from the last 25 years.  Seizure: European Journal of Epilepsy,   Article in press.


• SUDEP is the leading cause of mortality in chronic refractory epilepsy.

• Pathophysiology remains poorly understood but risk factors identified.

• No proven intervention for its prevention.

• Increasing awareness and research in the last 25 years.

• Several promising future research avenues to minimise SUDEP impact.  


Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with refractory epilepsy, and as such has been a major research focus over the last 25 years. The earliest SUDEP research papers were published in Seizure, as have scores of SUDEP papers since. In this review we discuss the efforts to try and describe the pathophysiological basis of SUDEP, the drive to discover the clinical risk factors that increase the likelihood of SUDEP, and the motivation to increase awareness of SUDEP. These three areas are the prime factors that, when answered, will allow us to better mitigate against SUDEP and help individuals monitor their personal risk. The field has benefited from strong definitions, multinational collaboration, the use of cutting edge genetic analysis, and ensuring that bereaved families are able to take part in research when this is appropriate. Clearly there is much that we do not know and yet, has any area of epilepsy research come so far in the last 25 years?

From the article:

Termed as Sudden Unexpected Death in Epilepsy (SUDEP), this was defined in 1997 by Nashef :

“Sudden, unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death in patients with epilepsy, with or without evidence of a seizure and excluding documented status epilepticus, in which post-mortem examination does not reveal a toxicologic or anatomic cause for death.” 

SUDEP is the leading cause of mortality in patients with chronic refractory epilepsy, estimated to cause 10–50% of deaths. The topic has attracted increasing amounts of interest from both the scientific and epilepsy community since its definition. Given the sudden and devastating nature of SUDEP, most often affecting young people between the ages of 20 and 40, better knowledge of its pathophysiology and associated risk factors is crucial so that attempts at treatment and prevention can be made…

Despite vigorous efforts, the pathophysiology of SUDEP today remains little better understood than when first described in the literature. The publication of several SUDEP epidemiological studies, case series of witnessed and monitored SUDEP and human and animal epilepsy research however, have provided data from which possible SUDEP mechanisms have been proposed …

The most common proposed mechanism reported in other studies is that of seizure-induced respiratory dysfunction.  Although the majority of patients are found in the prone position, the face is usually tilted to one side and the airway is not completely obstructed. A case series of witnessed deaths reported that most patients experienced breathing difficulties before death. This may be due to a combination of obstructive and central apnoea ultimately leading to asystole. The persistence of hypoxia and hypercapnia after respiratory effort has been restored or increased has suggested the possibility of intrinsic pulmonary dysfunction. The evidence remains circumstantial with post-mortem examination showing pulmonary oedema in many SUDEP cases but not significant enough to cause death …

Another proposed mechanism is that of seizure related cardiac arrhythmia. There are many case reports of patients receiving cardiac pacemakers as a result of postictal bradycardia and asystole. Genetic mutations in ion channels have also been studied as a potential cause for SUDEP, particularly long QT syndrome (LQTS) . A study of 61 people with SUDEP (the majority with definite SUDEP) were studied with exome sequencing and four had mutations in genes known to contribute to LQTS; two with  KCNH2  , one  KCNQ1  and a fourth with  SCN5A  . A further nine had variants in candidate genes for cardiac arrhythmia; that is to say genes coding for ion channels that may contribute to LQTS, Brugada syndrome or catecholaminergic polymorphic ventricular tachycardia. An ultra-rare variant in  SCN5A  has previously been identified in in a young woman with SUDEP.  It remains unclear whether patients with LQTS and epilepsy are at increased risk of SUDEP, and this mechanism is unlikely to be the primary cause of SUDEP in the majority of patients.

Other proposed mechanisms include that prolonged PGES leads to electrocerebral shutdown, leading to cardiorespiratory dysfunction. This was proposed in the MORTEMUS study, but studies have been inconsistent in determining the role played by PGES in SUDEP. A study by Shen et al. explored the possibility that adenosine may play a role in centrally-induced cardiorespiratory dysfunction, suggesting that adenosine receptor antagonists such as caffeine may have a protective effect against SUDEP when given at seizure onset. 

The significant but non-modifiable risk factors for SUDEP appear to be male sex, history of GTCS, younger age of onset, longer duration of epilepsy, symptomatic aetiology,  and associated learning disability. Although fixed, the knowledge of these risk factors are useful for clinicians when counselling patients for SUDEP. More importantly for the drive to minimise the risk of SUDEP, several modifiable risk factors have also been identified. Consistently reported are higher frequency of GTCS, and antiepileptic drug (AED) polytherapy , although it is recognised that AED polytherapy may be a surrogate for seizure frequency. Identification that the seizure frequency may increase in the months prior to a SUDEP has implications for SUDEP surveillance and healthcare system delivery. The majority of SUDEP cases occur at night and several studies have reported that a lack of night-time surveillance as a risk factor for SUDEP. Inconsistently reported is the use of lamotrigine and carbamazepine; further research is required to establish their roles as potential SUDEP risk factors ..

There remains no effective evidence-based treatment or prevention against SUDEP. The mainstay of management has been in addressing the modifiable risk factors to reduce SUDEP risk. This includes promoting AED compliance to reduce the incidence of GTCS and making patients and families aware of the potential consequences of uncontrolled nocturnaL . The use of a safety checklist has gained interest since it was first proposed and has subsequently been developed in to a smart-phone app . Patient education is important in promoting adherence to AEDs, avoiding factors that may trigger seizures, appropriately reacting to clusters of seizures and being aware of the interaction of other drugs with AEDs. Lattice pillows have been proposed as an intervention to reduce the risk of airway obstruction, but there have been no studies to evaluate their use in epilepsy. Nocturnal supervision has been found to be protective against SUDEP in one study, possibly suggesting that nocturnal seizure alarms may have a role in improving night-time supervision . The use of selective serotonin reuptake inhibitors (SSRI), opiate receptor inhibitors, adenosine receptor inhibitors, cardiac pacemakers and implantable cardiac defibrillators (ICD) have also been proposed as future targets for SUDEP prevention but there have been no trials examining the benefits of these in the prevention of SUDEP.

Within the hospital setting, several interventions are recommended to reduce the duration of seizures, respiratory dysfunction and EEG suppression. These include repositioning of the patient, oral suctioning and oxygen administration as well as prompt administration of AED if indicated. The MORTEMUS study also showed that in near-SUDEP cases, resuscitation was prompt whereas in the SUDEP cases it was delayed suggesting that close monitoring of patients in hospital with the use of direct supervision, ECG, EEG and oxygen saturations may reduce the risk of SUDEP…

Through the above, a better understanding of SUDEP may lead to effective prevention strategies. It is chilling to recognise that most people with epilepsy who die a SUDEP death, die alone. More research is required particularly for the role of nocturnal supervision of epilepsy patients, as though it is currently suggested in the literature that supervision is protective, to routinely advise this could have a deleterious effect on the quality of life of epilepsy patients and should not be undertaken lightly without substantive evidence for its recommendation. Nocturnal seizure alarms appear to be a promising alternative and these warrant further research to determine whether offer any protection against SUDEP. Further research is also required to determine the effectiveness of SSRIs, opiate and adenosine receptor inhibitors, cardiac pacemakers and ICDs in the prevention of SUDEP. We hope that reducing the treatment gap and ensuring the highest quality epilepsy care for everyone may reduce SUDEP rates; already there is evidence that successful epilepsy surgery reduces mortality, in part, by lowering SUDEP rates .

Thursday, October 27, 2016

Huperzine A protection against seizures in SCN1A mutation

Jennifer C.Wong, StaceyB.B.Dutton, StephenD.Collins, StevenSchachter and Andrew Escayg.  Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice.  Frontiers in Pharmacology  October 2016|Volume7|Article357.

De novo loss-of-function mutations in the voltage-gated sodium channel (VGSC) SCN1A (encoding Nav1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), refractory afebrile epilepsy, cognitive and behavioral deficits, and a 15–20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by early-life FSs and the development of a range of adult epilepsy subtypes. Current antiepileptic drugs often fail to protect against the severe seizures and behavioral and cognitive deficits found in patients with SCN1A mutations. To address the need for more efficacious treatments for SCN1A-derived epilepsies, we evaluated the therapeutic potential of Huperzine A, a naturally occurring reversible acetylcholinesterase inhibitor. In CF1 mice, Hup A (0.56 or 1 mg/kg) was found to confer protection against 6 Hz-, pentylenetetrazole (PTZ)-, and maximal electroshock (MES)-induced seizures. Robust protection against 6 Hz-, MES-, and hyperthermia-induced seizures was also achieved following Hup A administration in mouse models of DS (Scn1a+/−) and GEFS+ (Scn1aRH/+). Furthermore, Hup A-mediated seizure protection was sustained during 3 weeks of daily injections in Scn1aRH/+ mutants. Finally, we determined that muscarinic and GABAA receptors play a role in Hup A-mediated seizure protection. These findings indicate that Hup A might provide a novel therapeutic strategy for increasing seizure resistance in DS and GEFS+, and more broadly, in other forms of refractory epilepsy.

Courtesy of a colleague

Neuro-imaging evaluation after the first afebrile seizure in children

Rana Al-shami1, Abdulhafeez M Khair1, Mahmoud Elseid, Khalid Ibrahim, Amna Al-Ahmad, Ahmed Elsetouhy, Hussein Kamel, Khalid Al Yafei, Khalid Mohamed.    Neuro-imaging evaluation after the first afebrile seizure in children: a retrospective observational study.  Seizure - European Journal of Epilepsy.  Article in press.

•Younger children are more likely to have imaging abnormalities than older children.
•Imaging abnormalities are higher in status epilepticus.
•Focal seizures have a slightly increased incidence of imaging abnormalities.

To evaluate the role of neuro-imaging in children presenting with the first afebrile seizure and determine factors that influence the outcome of imaging in a large pediatric emergency center.

This is a retrospective review of the medical records of all patients presenting with the first non-febrile seizure to a large pediatric emergency center in the state of Qatar.

Seizure classification followed the current ILAE classification system.

Imaging was undertaken in our tertiary hospital and all images were reviewed by experienced neuro-radiologists.

Student T test was used for statistical analysis.

Ninety-six children underwent neuro-imaging following the first afebrile seizure. Of them, thirty-two patients (33%) were reported to have abnormalities.

Children below the age of two demonstrated a significantly higher percentage of abnormal imaging (59%); P value (0.002).

Children presenting with prolonged seizures showed a high percentage of imaging abnormalities (58%); P value (0.003).

Children with focal seizures demonstrated a higher percentage of imaging abnormality compared to those presenting with generalized seizures (35% Vs 31%). This difference did not reach statistical significance.

Children below the age of two demonstrated significantly higher percentages of abnormal imaging (59%), as did children presenting with status epilepticus (58%).

Neuro-imaging should be considered in infants and those with focal or prolonged seizures. Neuro-imaging informed decision making in 6-8% of children.

Courtesy of

Daith piercing for migraine

Living with migraines can be a complete nightmare.

The severe headache usually appears as a throbbing pain at the front or side of the head and often causes feelings of nausea, vomiting and increased sensitivity to light or sound.

But a growing number of migraine sufferers believe they may have found an unusual way to ease symptoms: daith piercings. 

A daith piercing is a piercing in the innermost cartilage fold of the ear. Advocates say it works in the same way as acupuncture, targeting pressure points on the body’s surface to ease discomfort. According to the NHS, acupuncture works by stimulating nerves under the skin and in muscle tissue.

This results in the body producing pain-relieving substances, such as endorphins. It is likely these substances are responsible for any beneficial effects seen with acupuncture.

Many people on social media have come forward to share their positive experiences of getting a daith piercing, including Nicole Bandes.

Writing on Facebook the managing director from Arizona said: “I’ve now had this (piercing) for over six months and can honestly admit that is has worked for me.

“I’ve seen a reduction in frequency and intensity of my migraines where nothing else seemed to help. My husband noticed it before I did (and that’s saying something). Maybe I just wasn’t willing to admit that it was actually working.

“Since getting it, I think I’ve had less than five migraines. Only one of those has actually made me fully non functional for a day. I’ve dramatically reduced my use of drugs to deal with the migraines.”…

So, does the piercing really work?

“There isn’t a lot of hard science behind the correlation between daith piercings and headache relief. Some people have found relief with this method, but it certainly won’t work for everybody,” Dr Thomas Cohn, who specialises in pain relief, writes in a blog.

He goes on to explain that although daith piercings appear to be a recent trend, the “location of the piercing has actually been targeted by acupuncturists to help cure headaches” in the past…

“We are always pleased when people gain some measure of relief from their migraine. Migraine is a term covering a range of similar conditions in which headache can be a symptom,” he tells HuffPost UK Lifestyle.

“Unfortunately what works for one person can make the condition worse in others, so we have to treat this with a degree of caution, especially in these very early days after the procedure has been done.

“As with any technique we would welcome the results of a clinical trial so it can be considered properly, to allow for a full understanding of the long term implications and effects of the piercing on patients.

“We would highly recommend that all migraine patients continue with the treatment that has been prescribed by their medical professional.”

If the idea of a piercing doesn’t appeal, Evans says you do not need to suffer migraines in silence.

He says: “Migraine Action’s helpline - open weekdays 10am-4pm (08456 011 033) - can help guide all affected through acute and preventative medication options.”

He also suggests other treatments, including acupuncture and changing sleeping patterns and diet, may have an impact.

Courtesy of a colleague

Wednesday, October 26, 2016

A rare mitochondrial mutation

The illness ravaged her 25-year-old body and left her family broke and in need of help.

Rachael Miller’s condition, a genetic disorder that 1,000 to 4,000 American children are born with each year, requires six medications administered through IV, a steady flow of nutrients delivered through ports in her chest, and about $35 worth of disinfectant supplies and gauze every day. The Millers declared bankruptcy this summer, having spent nearly 10 years and about $100,000 fighting an illness with no cure.

Rachael’s mother, Karen, turned to Gofundme in August for help despite Rachael’s aversion to public attention…The Gofundme campaign, simply titled “Rachael’s Medical Needs,” has raised $6,100 of the $60,000 requested.

The money is for an automatic hospital bed that Rachael can use on her own, a car to accommodate a wheelchair and medical supplies.

“Rachael’s doctors have told us that her disease has progressed into its final stages,” Karen wrote on Gofundme on Aug. 13. “How long that means she has we don’t know. It terrifies me and grieves me beyond words. Rachael has always been a fighter.”…

The Millers were once an idyllic Lexington family: a father in pharmaceutical sales, a mother who worked at a blood bank and three ebullient children who filled their three-story home in the Beaumont subdivision with noise.

Gabrielle, the oldest child, remembers how close the family was before disease descended. She and Rachael were inseparable. Both girls, only a year apart in age, would make home movies with their brother Seth, now 22. One video was about magic underpants.

If the three Miller children weren’t home playing with their friends, they could be found at the Beaumont YMCA.

“My house was a place for the kids to have what they couldn’t: pizza, candy,” said Gabrielle, 26.

In 2007, Karen started feeling lethargic and was diagnosed with autoimmune hepatitis, a chronic illness in which the body attacks the liver. About the same time, Rachael’s childhood eczema, a common skin condition, started worsening. Eventually her entire body was covered in a rash — even her eyelids. The family’s medical mystery began.

Soon after Karen and doctors helped Rachael fight off the skin condition using prednisone and other medications, she was diagnosed with eosinophilic esophagitis, an immune system disease that can severely affect eating…

The Millers were reeling, and they were desperate to find out what was going on with Rachael’s health. The family spent the next several years searching for answers from more than 30 doctors at renowned hospitals, including the Mayo and Cleveland clinics. Meanwhile, Karen suffered from end-stage liver disease and was in need of a transplant. Karen’s husband, Terry, was diagnosed with bipolar disorder.

“It wasn’t scary,” Rachael said, remembering the early stages of her illness. “I thought, ‘It’ll go away.’ When it didn’t go away, I just wanted to find an answer. It’s not like I was looking for a certain disease. I just wanted to know that I wasn’t crazy. Am I creating this in my own head?”…
The Millers found clarity for Rachael in Atlanta. Dr. John Shoffner, a geneticist, was the first to identify Rachael’s rare mitochondrial mutation. The prognosis was grim, but Rachael found peace in finally knowing what was wrong with her…

Rachael transferred to the closer Xavier University, near Cincinnati, after one semester. She left the school in spring 2011 because of medical reasons. Rachael never returned.

On Christmas Eve 2014, Karen received a new liver at University of Kentucky Chandler Hospital.

“My mom has always been extremely strong,” Gabrielle said. “She’s been the rock of the family. … That was the best gift ever.”

The Miller were evicted from their three-story house in Lexington’s Beaumont subdivision in early August. The family moved to a small single-floor house in Vine Grove, in Hardin County. The home is much quieter now, with the gentle whir from Rachael’s two IV pumps breaking the silence every so often. One is a pain pump with narcotics (which is refilled once a week by a visiting nurse) and the other provides nutrition the only way Rachael can get food without getting sick.

Rachael, the once-svelte high school swimmer — her favorite stroke was the butterfly — has lost more than 60 pounds.

Karen’s tireless support of Rachael over the past decade has forced her to miss the college graduations of her other children. Her life is dedicated to helping Rachael fight her disease.

Rachael spends most of her time sleeping or on an iPad, watching shows including “Friends” and “Vanderpump Rules.” She also listens to NPR. Aside from her mom, her constant companion is Phoebe, her Great Pyrenees. The only time Rachael leaves home is to visit doctors or to have infections around the port in her chest treated. She has had four infections this year.

The money raised thus far on Gofundme has made a considerable impact on the Miller family. For Karen and Rachael, though, the words of support and stories from complete strangers have been priceless.

“No one can say, ‘She’s going to die next week or tomorrow,’” Karen said. “She can last a lot longer.”

There is a video at the link of Dr. John Shoffner talking about mitochondrial disease.

Courtesy of  Doximity

See .

Baseline respiratory abnormalities as a predictor of SUDEP

Heidi L. Grabenstatter (2016) Irregular Respiratory Rhythm: A Physiological Biomarker of SUDEP Risk in Patients With Nocturnal Seizures?. Epilepsy Currents: September/October, Vol. 16, No. 5, pp. 327-329.

A subset of patients with temporal lobe epilepsy (TLE) have been identified as at greater risk for sudden unexpected/unexplained death in epilepsy (SUDEP), specifically, those with generalized tonic-clonic seizures, nocturnal seizures, early onset epilepsy, and long duration of epilepsy that is refractory to antiseizure drugs (ASDs). A few prototypical ASDs (e.g., carbamazepine) have also been associated with SUDEP risk. Over 30% of patients with TLE have seizures that are refractory to commonly used ASDs and 9 in 1000 of these intractable patients will die yearly from SUDEP. Given these contributing factors, there is a need for the 1) identification of reversible indicators (i.e., physiological biomarkers) of SUDEP risk in animal models of epilepsy and most importantly, 2) development of novel therapies to modify SUDEP biomarkers to prevent fatalities in this relatively large patient population…

Animal models and patients with TLE demonstrate more frequent seizures during non–rapid eye movement (NREM) sleep, and relatively infrequent seizures during REM. However, Hajek and Buchanan demonstrate that mice have 100% mortality following MES-induced seizures induced in REM sleep. Furthermore, mice that died following a seizure during any state had increased baseline respiratory rate variability. The added insult of an evoked seizure to an underlying predisposition to cardiorespiratory instability may overwhelm the system causing death. These results suggest respiratory rate variability is a valid biomarker of SUDEP risk and that regular monitoring of epileptic patients for baseline changes to determine increased risk is a reasonable clinical addition to the treatment of refractory epilepsy patients…

Seizures induced during sleep were more likely to be associated with respiratory suppression and death. Additionally, seizures induced during sleep were more severe and longer. All seizures were associated with respiratory arrest regardless of sleep state. However, postictal apnea was longer in mice that survived induced seizures in NREM compared with those occurring in wakefulness, and breathing (i.e., breaths/minute, ventilation, and tidal volume) was impaired upon recovery. In contrast, HRV (a common measure of intact cardiac function) was not significantly different comparing the different sleep states postictally. This may be attributed to the lack of assessment of the REM state due to 100% mortality following MES-induced seizures in REM sleep…

Interestingly, mice that died following a seizure had increased respiratory rhythm irregularity and a nonsignificant trend toward a reduced HRV (i.e., cardiac dysfunction) relative to those that survived. This was an insightful use of the data that could have easily been overlooked and points to future experiments that should be conducted in “at risk” epileptic animals with cardiorespiratory susceptibility at baseline. As animal and human studies have now demonstrated that impaired breathing, cardiac function, and arousal during and after seizures can be attributed to SUDEP, the next step may be to study these in subjects who do not die…

These studies provide the basic science community with an empirically tested result that validates the parental reports to clinicians that their child wakes gasping for breath following nocturnal GTCS that surely span decades. More importantly, the physiological marker of risk that Hajek and Buchanan have identified is not only easily monitored in at risk patients, but there are clinically-approved modes of intervention for patients identified as having irregular respiratory rates. Thus, studies by Hajek and Buchanan have set the stage for a potential means for the prevention of SUDEP-related fatalities. Important directions for future studies (some already in process by the Buchanan group and others) include the role of adenosine, serotonin, acetylcholine, and norepinephrine on autonomic control of the cardiorespiratory system and arousal changes occurring during spontaneous seizures. Additionally, trials should be conducted evaluating the effect of clinically used ASDs on respiratory rate, HRV, and sleep in spontaneously seizing animals.

Hajek MA, Buchanan GF. Influence of Vigilance State on Physiological Consequences of Seizures and Seizure-Induced Death in Mice.  J Neurophysiol 2016;115:2286–2293.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP occurs more commonly during nighttime sleep. The details of why SUDEP occurs at night are not well understood. Understanding why SUDEP occurs at night during sleep might help to better understand why SUDEP occurs at all and hasten development of preventive strategies. Here we aimed to understand circumstances causing seizures that occur during sleep to result in death. Groups of 12 adult male mice were instrumented for EEG, EMG, and EKG recording and subjected to seizure induction via maximal electroshock (MES) during wakefulness, nonrapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Seizure inductions were performed with concomitant EEG, EMG, and EKG recording and breathing assessment via whole body plethysmography. Seizures induced via MES during sleep were associated with more profound respiratory suppression and were more likely to result in death. Despite REM sleep being a time when seizures do not typically occur spontaneously, when seizures were forced to occur during REM sleep, they were invariably fatal in this model. An examination of baseline breathing revealed that mice that died following a seizure had increased baseline respiratory rate variability compared with those that did not die. These data demonstrate that sleep, especially REM sleep, can be a dangerous time for a seizure to occur. These data also demonstrate that there may be baseline respiratory abnormalities that can predict which individuals have higher risk for seizure-induced death.


A biomarker for epileptogenesis?

After a child has an unprovoked seizure, the burning question in everyone's mind is: Does this mean this child is going to have more seizures?  Unfortunately, there is currently no reliable way to answer this question. Dr. Louis Manganas, an Assistant Professor of Pediatric Neurology at Stony Brook University, aims to improve this situation by identifying a biomarker of epileptogenesis.
In many and perhaps all cases, epileptic seizures are caused by the presence of aberrant re-entrant circuits in neural networks. The fact has been known for several decades that epileptic seizures lead to accelerated proliferation of neural progenitor cells (NPCs), which are the mitotically active neuroblasts that give rise to new neurons. Following a single seizure, the newly generated cells may integrate into existing neural circuits, disrupt them, and induce subsequent seizures. This may represent one of the mechanisms underlying epileptogenesis.

Thus, the accelerated NPC proliferation following an unprovoked seizure may have the harmful effect of inducing subsequent epilepsy. It follows that the presence and concentration of NPCs following an unprovoked seizure could serve as a biomarker of epileptogenesis. But, how to detect the NPCs?

Nine years ago, while he was a postdoctoral fellow at Cold Spring Harbor Laboratories, Dr. Manganas and his co-workers discovered that NPCs can be detected by magnetic resonance spectroscopy (MRS). Probably because of their uniquely high concentration of saturated fatty acids and monounsaturated fatty acids, NPCs can be detected as a 1.28 ppm peak on MRS. The identity and origin of this peak are unknown. However, the amplitude of this peak is proportional to the concentration of NPCs. He published his findings in the journal Science.

Dr. Manganas has hypothesized that the aberrant proliferation of NPCs following a single seizure may act as a nidus for epileptogenesis and that the amplitude of this peak on MRS may correlate with the risk of subsequent epilepsy. Following his discovery of the MRS peak associated with NPCs, Dr. Manganas has completed a residency in child neurology and a fellowship in epilepsy. Now, nine years later, Dr. Manganas is conducting the study that tests his hypothesis. As the 2016 recipient of the Pediatric Epilepsy Research Foundation (PERF) grant, Dr. Manganas is examining whether the NPC peak is greater in patients who have had a single seizure than in controls and whether the amplitude of the NPC peak following a single seizure correlates with the risk of developing subsequent epilepsy.

"I am grateful to PERF for providing these funds. The PERF grant is currently my sole source of funding for this research, which I have been planning since 2007."

Daniel J. Bonthius, MD
From CNS Connections Fall/Annual Meeting 2016

Manganas LN, Zhang X, Li Y, Hazel RD, Smith SD, Wagshul ME, Henn F, Benveniste
H, Djuric PM, Enikolopov G, Maletic-Savatic M. Magnetic resonance spectroscopy
identifies neural progenitor cells in the live human brain. Science. 2007 Nov


The identification of neural stem and progenitor cells (NPCs) by in vivo brain imaging could have important implications for diagnostic, prognostic, and therapeutic purposes. We describe a metabolic biomarker for the detection and quantification of NPCs in the human brain in vivo. We used proton nuclear magnetic resonance spectroscopy to identify and characterize a biomarker in which NPCs are enriched and demonstrated its use as a reference for monitoring neurogenesis. To detect low concentrations of NPCs in vivo, we developed a signal processing method that enabled the use of magnetic resonance spectroscopy for the analysis of the NPC biomarker in both the rodent brain and the hippocampus of live humans. Our findings thus open the possibility of investigating the role of NPCs and neurogenesis in a wide variety of human brain disorders.

A PANDAS (or PANS) story

[One day, I may see one.]

My son, Ezra, was kidnapped. It was on October 28, 2008. He was 3 ½.

It didn’t happen because he was unattended in a shopping cart or running around the playground. It was while he slept, tucked safely in his bed. We awoke to his screams and found him soaked in urine. The next morning, a child who physically looked like Ezra woke up. He had Ezra’s blond hair, big green eyes, and long eyelashes. But he didn’t have his personality, compassion, or wit. He was no longer sweet-natured, inquisitive, loving, and incredibly verbal. Instead he screamed for hours, stuttered, made repetitive noises, and became very selective in the foods that he would eat. He was angry, defiant, and raged for hours. We used to snuggle, now he wouldn’t let me hold him — his body stiffened each time I reached out for a hug.

His pupils were huge and dilated, with a confused and vacant look. Ezra had violent, angry, intense tantrums about everything. We were raising a boy that we didn’t recognize, a boy that my husband and I jokingly named Ferdinand—after the storybook bull who looks intimidating but is actually kindhearted.

My background is in behavior therapy—I knew not to give in to his rages because it would reinforce the behavior. So I did what my education and training had taught me, and what I recommended to my clients’ parents. I encouraged him to “use his words.” I used time outs, sticker charts, praise, and positive reinforcement. Nothing worked.

What was wrong? My husband and I agonized over the cause. I’d started back to work—it must be that. His baby bother started to crawl and need more attention—maybe that’s it. Or maybe he’s so intelligent that he knew how to manipulate us. Others suggested it was because he was our first child—or that we weren’t strict enough with him. Most felt that he’d outgrow it.

Our lives continued on eggshells until Ezra was 4 ½. I was giving him a warm bath, which usually calmed him. I drained the tub and asked him to step out. He put one leg out and then put it back in. He did it again and again, crying that “it wasn’t right.” He stood there, cold and shaking, repeating the step over and over. I let him go on and on as my heart sank. This was OCD! I wrapped a towel around him and carried him out of the bathroom. He kicked and screamed, begging me to let him do it again until it was right. It started to make sense to me. Everything had to be “just right.”

But OCD didn’t explain the huge pupils, frequent trips to the bathroom, deterioration in fine motor skills and cognitive ability, or tics. It also didn’t explain his frustration and fits of rage. More trips to the pediatrician were fruitless. I started searching the internet for answers…

I called the doctor immediately and asked if Ezra could have PANDAS. She had never treated it before but agreed to administer a blood test to check for elevated strep titers. The levels were high. We were given an antibiotic and sent to a neurologist for an official diagnosis.

I was excited for that neurology appointment—anticipating that it would bring resolution to our problem. I knew in my gut that PANDAS was the cause and I just needed the neurologist to tell me how to fix it. In my mind, the doctor would provide a key to unlock Ezra from his captor, ridding us of Ferdinand once and for all. My hope was short-lived. We were told that a neurologist won’t ever diagnosis PANDAS because neurologists don’t believe that it is a real disorder. Instead, it was suggested that Ezra was having seizures. An EEG was ordered.

The neurologist became the first in a long line of people my husband and I called “hostage negotiators”—people who we had to work through, and with, as we tried to secure our son’s return.

Meanwhile, my mind was racing. Maybe if it was seizures—and maybe if he took medication we’d get Ezra back. The EEG came back “abnormal” with spikes and waves in the frontal lobe, but not in a typical seizure pattern. Nothing could be done for him—we were told that some kids just have abnormal EEGs and are fine with them…

Meanwhile, Ezra continued to slip away. He’d been a toddler who met every milestone early and talked circles around his peers. Now he was quiet and withdrawn with “Autistic-like features.” At the age of two, he could read hundreds of words and loved math. But as he made his way through first grade, Ezra no longer wanted to go to school, play sports, or attend cub scouts. He didn’t want to leave the house. I had to carry him into school, where staff would hold him back as the doors closed behind me. In school, his handwriting was slow and messy, and he crumbled under the pressure of timed math tests. He was distracted, zoned out, and wouldn’t respond when his name was called.

We would wait months to see a new doctor, only to be told that they didn’t believe in PANDAS. I kept thinking—my child has been stolen—this boy is not him. Where is the AMBER alert?...
We saw five Pediatric Neurologists, three Cognitive Behavior Therapists, a Developmental Pediatrician, Occupational Therapists, Chiropractors, an alternative healer, and a Naturopath. They suggested diagnoses including anxiety, bipolar, mood disorder, ADHD, Transient Tic Disorder, and Tourette’s. We were told to medicate him with Ritalin, Zoloft, and Clonidine. We were put on waiting lists to get appointments with any doctor that I thought could help.

On February 8, 2015, Ezra came inside after playing in the snow. He sat on the couch with a vacant look in his eyes. He turned his head to the side and touched his chin to his shoulder. Then he did it again. And again. I felt his head. He had a low grade fever. The fever was gone by bedtime, but the head-turning tic did not stop. Every 3-5 seconds he turned his head, no matter what he was doing.

The head-turning tic evolved quickly into a full-body twist and facial grimace. Eventually he lost all fine motor control. Ezra stopped eating and went from a skinny 60 pounds to an emaciated 55 pounds in just two weeks. His body never stopped moving, wiggling and swaying in the few seconds that he had between tics. Ezra could not focus and often forgot what he was doing—he began falling off of chairs and walking into walls. He couldn’t dress himself or get his shoes or coat on for school. I’d kiss him goodbye and sit in the idling car, watching him hop, tic, and even fall down in the doorway of the school. I called the pediatrician. The results of a blood test for elevated strep titers came back very high, and Ezra was placed on antibiotics…

We drove for six hours to meet the 14th and final hostage negotiator, a pediatric neurologist who is a PANDAS expert. He listened to my extensive list of Ezra’s symptoms with an understanding that no other doctor had. As I sat, listing the symptoms that had stolen my son’s childhood, I realized the gravity of my words. If I said the right things, the doctor may deem Ezra worthy of one of the rarely given “magic cures” I’d read about. My voice began to crack and tears welled up in my eyes. I could tell that my emotions were making the doctor uncomfortable so I fought to stay strong—like a grief-stricken parent on TV begging for their child’s safe return…

The doctor called two weeks later with the results. Ezra had all of the markers for PANDAS and PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). His immune system was overreacting to Strep bacteria (causing PANDAS) and the Coxsackie virus (causing PANS). He was to continue on antibiotics and have a tonsillectomy. If needed, he’d receive an IVIG treatment. IVIG floods the body with healthy plasma and overrides the misdirected antibodies that cause the PANDAS symptoms.

Finally, we had plans for a cure and not just a band aid.

This doctor provided the key I’d been trying to find for six years. It took thousands of dollars, months of antibiotics, a tonsillectomy, and IVIG. Two days after that magic plasma dripped into Ezra’s veins, my son, the real Ezra, looked into my eyes again. His pupils were small—I could see the beautiful green of his eyes. The cold darkness was gone. This was my child—the one I had lost so many years ago. The one that no one else had noticed go missing.

Courtesy of my daughter.