The nation's leading medical specialists could not figure out what was wrong with Anna McAllister.
They were stumped by the repetitive seizures she suffered - what her mother described as "being bashed in the head 100 times a day." Nearly three years of testing and misguided medical care failed to eliminate the seizures.
In the end, it took a different kind of specialist - a determined mother - to discover the rare genetic disorder that afflicted Anna. With dogged persistence, the Internet and a bottle of vitamin B6, Tamara McAllister not only cured her daughter but delivered her from a lifetime of drugs and other ineffective treatments.
Now 3 1/2 years old, Anna is seizure-free and trying to overcome the ravages of her faulty genetics. To look into her blue eyes as she learns to walk, as she coaxes her body to do something other children her age already take for granted, is to see a vision of determination and resolve.
Perhaps that is a gift handed down from her mother, for in the genes of everyone are molecular secrets that unravel as gifts and hardships.
The genetic hardship in Anna's life began to reveal itself within a few months after birth.
McAllister noticed there were numerous short eye flickers in which Anna's head would drop momentarily. At times, she looked "spacey." McAllister also noticed that Anna's feet twitched while she was nursing.
"Until she was 6 months old, I just thought she was quirky," McAllister said.
At 7 months, Anna's parents had her examined by a pediatric neurologist at Children's Hospital of Wisconsin in Wauwatosa.
That was the first of what would be nearly 21/2 years of visits to medical experts at Children's Hospital and other top facilities around the country, including the Mayo Clinic in Rochester, Minn.; the Waisman Center at the University of Wisconsin Medical School in Madison; and the Kennedy Krieger Institute in Baltimore, an affiliate of Johns Hopkins University School of Medicine.
Although electroencephalograms (EEGs) confirmed Anna's seizures, possibly as many as several hundred a day, no one could pinpoint the cause. But everyone, it seemed, offered a solution.
Over parts of the last three years, Anna has taken several strong drugs, has eaten the high-fat ketogenic diet and has lived with a vagus-nerve stimulator, believed to protect against seizures by disrupting abnormal brain activity, implanted in her chest.
"Everybody wanted to offer me drugs," McAllister said. "Nobody knew what was wrong with her, but they wanted me to give her drugs. If she had stayed on drugs, I would have never found out what was wrong with her."
The treatments had only limited success in controlling her seizures and resulted in other troubling side effects.
A mysterious disorder
While physicians were offering up flawed remedies, her mother was submerged in a monumental diagnostic quest of her own.
"When she was having seizures, I just got so tired of looking in her eyes and seeing them," she said. "I felt so sorry for her. There was nothing I could do about it. It was like she was drowning in quicksand and all I had was a spoon."
She spent hundreds of hours on the Internet, reading about childhood epilepsy. She visited chat groups. She badgered doctors all over the country.
Eventually, she learned of a rare genetic disorder known as pyridoxine dependency. Pyridoxine is vitamin B6.
People with the disorder need unusually high amounts of B6 to facilitate a chemical process in the brain that produces an important inhibitory neurotransmitter, one that can control brain signals that otherwise would cause the seizures.
In a few cases, children with the disorder have died. More commonly, numerous milder seizures plague the child, causing physical or cognitive problems. There is some evidence that the IQ of a child can improve if the disorder is discovered early in life and the child is put on an adequate amount of B6.
The condition was first identified in 1954, and there is still not a lot known about it.
Only about 100 cases have been described in medical literature, although most pediatric neurologists probably are aware of the disorder, said Sidney Gospe, a professor of neurology and pediatrics at the University of Washington and one of the leading U.S. experts on pyridoxine dependency.
A British study suggests it exists in about 1 in 100,000 children.
"Nobody really knows how common this is," Gospe said. "We have the feeling that this disorder is underdiagnosed."
Gospe said he diagnosed his first case about eight years ago - an infant who was put on B6 and whose seizures stopped almost immediately. Since then, he has diagnosed five cases, he said.
"When you make the diagnosis, it's like an epiphany," he said. "It's miraculous."
In the case of Anna, the miracle worker was her mother, now 38, who has a part-time job in a medical lab testing blood and body fluid samples.
McAllister and her husband, Don, a chemical engineer, also have two sons, ages 6 and 9. The family lives in Greenfield.
McAllister said her four-year degree in medical technology helped her read medical reports about seizure disorders. But she thinks she would have accomplished what she did even without her training.
McAllister first mentioned pyridoxine dependency to Richard Jacobson, a pediatric neurologist at Children's Hospital, in spring 1999, shortly after she and Jacobson had agreed to put Anna on the ketogenic diet. The diet, which is similar to the popular Atkins weight loss diet, is high in fat and low in carbohydrates. For reasons that are not entirely understood, the diet can help control epileptic seizures in some children.
McAllister told Jacobson she had found the personal Web site of a physician in Tennessee with two children who have pyridoxine dependency. Jacobson approved giving Anna a 50 mg dose of B6 a day.
The recommended daily level of B6 is 2 mg for an adult male, 1.6 mg for a woman. For infants, it is 0.3 mg. But a 1998 study in the Journal of Pediatrics said there is no consensus on the proper dose when B6 is used as a medical treatment, with reports recommending anywhere from 2 mg to 300 mg.
McAllister gave the 50 mg dosage, but Anna did not improve.
The toddler continued seeing other specialists and getting tested for other possible causes. All the tests came back negative.
"We have a really, really long list of things she doesn't have," McAllister said.
While nearly all of Anna's seizures had been very short and mild, lasting for as little as one second, last fall she had three generalized, or grand mal, seizures with shaking that lasted at least 10 seconds.
A short time later, McAllister was reading an article she found on the Internet about the nutritional treatment of childhood autism, including doses of B6 of between 350 mg and 1,000 mg. Perhaps, she wondered, Anna's earlier dosage was too small.
"I thought that was interesting," McAllister said. "I went out and bought more B6."
Thinking her daughter was too small to handle the higher doses mentioned in the article, she began giving Anna 300 mg a day.
"Two days after that," she said, "the seizures stopped completely."
Hugs and tears
McAllister took her daughter off anti-seizure drugs a short time later. Then she took her off the ketogenic diet, which Anna had been on for nearly two years and which - combined with nutritional supplements and a multiple vitamin - had reduced the number of seizures to between five and 12 a day. Finally, McAllister increased the dose to 400 mg, on which Anna has remained ever since.
It was not until February, about two months later, that she told Jacobson what she had done. "He was thrilled, maybe a bit surprised, but pleased," she said.
Still, he wanted to reserve judgment until an EEG confirmed that the seizures had stopped. That was done in March.
"He came in and read it," she recalled. "He said it was a 100 percent improvement. He said I did a great job figuring it out."
There were hugs and tears from the staff in the neurology department.
Jacobson also apologized for not figuring it out himself, she said.
In a recent interview at Children's Hospital, Jacobson acknowledged apologizing for not finding the problem sooner. However, given the circumstances, he said he does not think the medical community failed Anna.
Part of the problem is that there is no blood test for pyridoxine dependency. The best way to find out is to give an intravenous dose of B6 while doing an EEG.
In addition, Jacobson initially did not want to administer a dose of more than 100 mg because of concerns that high doses of B6 might cause nerve damage - a side effect that has been chronicled in patients who took very high doses of the vitamin for months or years. He said he has since learned that higher doses such as those Anna now gets are safe.
But it was McAllister who found information suggesting that doses of several hundred milligrams could be safe in children.
"The parent has one patient to take care of," Jacobson said. "That's her whole career. The parent has the time to spend to figure out what is going on with the child.
"When you have to see a couple hundred patients a month, it gets overwhelming. I feel like we put a lot of effort in for her. I don't think the medical community has failed her, because our knowledge about this is evolving."
'Nothing comes easy'
Jacobson said there are hundreds of kids with unknown neurological problems who are developmentally delayed. Their brain scans look normal, and tests for metabolic disorders come back negative.
They also may have parents, like the McAllisters, who are determined to find an answer.
Not a month would go by when she wouldn't contact Jacobson and say, " 'Have we tested for this or tested for that?' " Jacobson said of Tamara McAllister. "She is a special case in how determined she is, but she is not unique. What's unique is that something finally worked."
McAllister said she is more disappointed than angry at the care that Anna received. She doesn't plan to sue over Anna's care, but she is telling Anna's story in hopes more doctors and parents will become aware of the disorder, she said.
She said that while other specialists were more closed-minded, Jacobson always was willing to listen and try new things.
"He always supported whatever I wanted to do," she said.
Gospe, of the University of Washington, noted that pyridoxine dependency is rare.
"If I hadn't diagnosed my first case, I could be in the shoes of Dr. Jacobson," said Gospe, who knows Jacobson. "It is unfortunate that somebody at one of those places did not think of this. The bottom line is, you just need to think of this diagnosis."
Now that Anna's seizures have stopped, the big question is how far her development can go. Nearly three years of seizures have taken a toll.
Anna did not learn to crawl until age 2. She started walking only recently. She has not yet started talking.
"Nothing comes easy to her," McAllister said.
McAllister said she does not know how much permanent disability Anna will have but expects she never will be completely normal.
Her development won't be for lack of effort. You can see her determination as her long, thin legs slowly move across the living room floor.
Just how far those legs will take her is a question that her parents think about often.
"When I want to make myself crazy, I do that," McAllister said. "I would like to see her talk. I would like to see her approach normal."
Appeared in the Milwaukee Journal Sentinel on June 24, 2001.
A doctor's Web site was answer
By JOHN FAUBER of the Journal Sentinel staff
Christine Parker, a Chattanooga, Tenn., physician, said she thinks medical specialists are doing an "abysmal" job of testing for pyridoxine dependency in infants who are having unexplained seizures.
Parker, an internist, knows something about the rare genetic disorder. Her two children have it.
The children, Bill, 13, and Jennifer, 5, are doing fine now and are receiving daily high doses of vitamin B6, but it took a long time before the problem was correctly diagnosed.
It was after seeing Parker's Web site, which chronicles the plight of her children, that Tamara McAllister of Greenfield first wondered whether her daughter, Anna, might also have pyridoxine dependency. Eventually, that led to Anna's being cured.
Parker said she thinks some parents are doing a better job of pinpointing the problem than doctors are.
She also said she believes there are other children who have the disorder but who have not been correctly diagnosed.
"It is really sad how many kids are out there with seizures," she said.
Parker's Web site can be found at www.geocities.com/HotSprings/villa/4542.
Infantile Spasms and Pyridoxine Dependency: Bill and Jennifer's Story
Hello! My name is Christine, the mother of two wonderful children, Bill and Jennifer. I hope by sharing our miraculous story that it may eventually help someone who has a child with a serious seizure disorder. Both our children developed infantile spasms at six months of age. They have only recently been properly diagnosed with Pyridoxine Dependency, a rare genetic (autosomal recessive) defect of glutamic acid decarboxylase (an enzyme which helps make GABA in the brain) which responds completely to high doses of vitamin B6 (pyridoxine). Both my children are seizure-free taking just pyridoxine and are doing great now. I also happen to be a physician (Internist) who read extensively on infantile spasms for eight years and met and spoke with many pediatric neurologists across the United States. Still, it took having two children to make the correct diagnosis.......
Bill was born on October 14, 1987, nineteen days overdue after a long and difficult labor. He had heavy meconium staining but good apgars and seemed to be fine. When Bill was 5 months old, my husband and I left for a week-long trip and I stopped breastfeeding. After we returned, Bill became increasingly fussy over a few days and then he started to have seizures. We rushed him to the hospital where he had a normal spinal tap, CT scan, MRI, EEG, and blood work. The initial EEG showed a left temporal lobe spike but otherwise looked okay. The pediatric neurologist put him on phenobarbital. We were told that the most likely cause of the seizures was from the difficult labor and because I had gone so far overdue. Bill's seizures became more frequent on phenobarb, and so Klonopin was added. After 3 weeks on both medications, Bill had worsening of his seizures and a repeat EEG showed hypsarrhythmia. We were referred to another major medical center where the doctor diagnosed (as it turned out, incorrectly) that Bill had idiopathic infantile spasms. The neurologist attempted unsuccessfully to get an IV line started for a pyridoxine challenge, and he was sent home on ACTH injections. Since Bill seemed to respond to the ACTH, at least initially, the neurologist said that Pyridoxine Dependency was "most unlikely" and never suggested trying B6 again. After eight weeks, the neurologist determined that ACTH had not been effective overall and the EEG was still very abnormal. Klonopin was gradually increased up to 3.5 mg/day (a whopping dose) and then Bill's seizures stopped and his EEG normalized when he was about ten months old. He stayed on the phenobarb and Klonopin for several years and was very developmentally delayed. Bill attended a special school for infants and preschoolers with neurological problems from about 8 months old until about 4 years of age.
After Bill was about 10 months old, we never saw obvious seizure activity but Bill had poor eye contact and was not very "aware" of his surroundings. Over the next 3 years, we saw slow improvements in motor and cognitive skills, although he was still behind. Bill eventually came off all anticonvulsants by the time he was four years old but no one could explain his improvement. (In retrospect this is when I had started giving him daily Flintstones vitamins and he ate lots of Cheerios-loaded with B vitamins). I was still concerned that Bill was having subclinical seizures (sometimes his eyes would water and he would just stare) but repeat EEGs were always normal. We continued to take Bill back to the major medical center periodically and we got second opinions from other university centers around the country. They all concurred with the initial "thorough assessment". In 1991, I met a leading pediatric neurologist who specialized in infantile spasms. I told him about my son and he suggested that I bring him (across the country) for a PET scan. This pediatric neurologist was interested in the fact that Bill had a temporal lobe spike on his initial EEG and wanted to see if they could find an abnormality in the same area on the PET scan. (We were told that if his seizures ever came back that he might be a surgical candidate). The PET scan showed a slight abnormality in the left temporal lobe area but otherwise was normal. We always asked the doctors if it would be safe to have another child. We were reassured that this didn't happen twice in the idiopathic form. Bill saw 6 different neurologists for evaluation before he was six years old. (I also spoke to several others by phone). Virtually all the pediatric neurologists were associated with university teaching programs.
Jennifer was born on February 26, 1996, when Bill was 8 years old. She had a completely normal delivery and was on time. When she was about one week old, I noticed Jennifer's eyes seemed to flutter upon awakening. I immediately had the horrible feeling that we were going to go through the whole thing again! We found yet another pediatric neurologist (number 7) at another major medical center. (I had lost all confidence in the previous centers who had reassured us about having another child). Also, during the first month of Jennifer's life, Bill started fluttering his eyes when I took pictures of him with a flash camera and when the morning sun flickered through the trees as I drove Bill to school. (He remained completely conscious and could talk to me during these episodes). The pediatric neurologist did EEGs on both children, and they were completely normal. We all went home reassured that Jennifer had just not "myelinated her brainstem" yet and that Bill's eye fluttering was probably just a tic.(A strobe light during the EEG did not induce seizures). (In retrospect, Bill was probably growing out of his B6 dose from the Flintstones vitamins and cereal). We were also referred to a pediatric opthalmologist at another major medical center for Bill's eye fluttering with everything being completely normal.
Several days later, I started seeing brief upward deviations of Jennifer's eyes. We went back to the neurologist but this time for a video EEG. We caught some of the eye movements on the video but the EEG remained completely normal throughout. We were again reassured and told that it was not uncommon to worry about a second child after all that we had been through with Bill. At this point everyone thought that I (the paranoid mother) had completely lost my sanity and suggested that I get counseling and go back to work. Everyone thought that I was having some sort of post-traumatic stress reaction or was suffering from sleep deprivation. I decided to go back to work when Jennifer was two months old convinced that I had imagined the whole thing.
When Jennifer was 5 months old, I stopped breast feeding and my husband and I went to Puerto Rico for a week. (There are large amounts of B6 in breast milk, especially if the mother is taking prenatal vitamins with 10mg B6 per tablet, as I was) After we came home, Jennifer became increasingly fussy, and a few days later Jennifer started having obvious (to everyone) myoclonic seizures. Jennifer had a another EEG which was very abnormal with multifocal polyspike discharges. MRI, lactate, and metabolic screens were normal. The neurologist felt that my children had some rare kind of genetic myoclonic epilepsy and he started Jennifer on Tegretol and Klonopin. (We have no other family history of seizures). I also consulted by phone with the neurologist who had done the PET scan on Bill (he offered to do PET scans on both children) as well as another professor of a pediatric neurology program. The Tegretol helped but did not completely stop her seizures so Vigabatrin (from Canada) was added. Jennifer's seizures improved but she started becoming much less aware (as Bill had done). Going through the experience of having one child with infantile spasms is devastating. I cannot even begin to describe what it was like to watch our second child go through the same thing.
After about three weeks into all of this, I was wracking my brain trying to figure out what we could have missed. Then I came across this quote "The important thing is to never stop questioning"- Albert Einstein. Suddenly the light went on! I had never questioned the doctor who didn't complete the IV B6 challenge! The current neurologist was immediately contacted to see how to do the IV B6 challenge with the EEG. He recommended that since Jennifer was already on three(3) anticonvulsants and she was six months old to just give her 50 mg of pyridoxine twice a day by mouth, and that WE WOULD KNOW if this was it. (I felt like Dorothy in Oz with her red slippers). After the first dose that evening, Jennifer was noticeably calmer. The next morning, she was focusing on her teddy bears again. Three days later, she had her last seizure.....ever. She immediately became much more alert. Another EEG 2 weeks later was completely normal, and we weaned her off the Tegretol, Klonipin and Vigabatrin. She has had no further seizure activity or eye fluttering. We immediately started Bill on 100 mg of B6 twice a day by mouth. He became more verbal, and his eye contact improved. The fluttering of his eyes with light flashes completely stopped after we started the B6. We have not seen any of this eye fluttering since.
Then I found an article that recommended 10 mg/kg/day for Pyridoxine Dependency in an attempt to normalize brain glutamic acid levels. Later on I found another article saying that increased B6 was related to improved IQ in this disorder so we increased both children to 15mg/kg/day. Jennifer's verbalization improved immediately on this increased dose. She is a very precocious 2 year old and is normal in every way. We have now switched both children to time release B6 with even better results (still on a twice per day schedule).
Bill's standardized testing scores have improved dramatically since he has been on high dose B6 beginning in September 1996:
|Testing Date / Age||January 22,1996 (before B6) /8 years, 3 months||July 10, 1997 / 9 years, 9 months|
|Letter/Word Ident.||Grade 4.4||Grade 10.9|
|Applied Math Problems||3.6||10.1|
|Word Attack||Not Tested||Grade 16.9!!!|
We are currently having Bill tested again to see how he has done over the past year. Bill has continued to improve, especially in verbalization and awareness. He plays first cello in a youth orchestra and has perfect pitch (this is not new). He also has his senior purple belt in Taekwondo.
The Wadsworth Center in New York State is currently looking for the defective gene for glutamic acid decarboxylase in my children. This center has been doing research looking for a gene defect for ALS (Lou Gehrig's Disease). I contacted them when I found out that both ALS and Pyridoxine Dependency have elevated glutamic acid levels. Since Bill and Jennifer's grandmother died of ALS they were interested in my theory that maybe the same gene defect could be involved. (ALS being a heterozygous expression of the defect). I don't know if this theory will hold true. It may just be a coincidence but my husband and I take 200mg of B6 a day anyway.
Since being on the internet I have found fourteen other families with a child (or two) with Pyridoxine Dependency. Most had delays in the correct diagnosis. One family lost their first child to intractable seizures before the diagnosis was made in their second child. Since there is not a blood test to diagnose this (yet), it is often not considered til everything else has failed. Traditionally, it was only considered if there was NO response to anticonvulsants, but a response to anticonvulsants does not rule it out. Also, the EEG may not initially change or improve immediately on initial infusion of B6. A few days of oral B6 (100-300mg/day) is now recommended before the diagnosis is abandoned. CLOSE SUPERVISION BY A PHYSICIAN IS NECESSARY WHEN BEGINNING B6 IN CHILDREN WHO MAY HAVE THIS DEFECT BECAUSE OF POSSIBLE RESPIRATORY/NEUROLOGICAL DEPRESSION THAT CAN OCCUR INITIALLY FROM THE RESULTING INCREASED GABA LEVELS. Stopping the B6 will result in recurrence of the seizures if this is the correct diagnosis (another way to confirm the diagnosis) so treatment with B6 is life-long. The oldest child that I have found with this disorder was over three years old when the seizures started, but most seizures associated with Pyridoxine Dependency begin in infants and can even begin in the uterus. LARGE DOSES OF PYRIDOXINE CAN CAUSE A PERIPHERAL NEUROPATHY (nerve damage) WHEN TAKEN FOR LONG PERIODS OF TIME so this diagnosis should be confirmed before committing a child to life-long B6.
An excellent review article on Pyridoxine Dependency is found in the June 1998 issue of the Journal of Pediatrics: Gospe, SM. Current perspectives on pyridoxine-dependent seizures. J Pediatr 1998;132:919-23
Never stop questioning and learning. Even though we didn't get to the right diagnosis for many years, everything we learned as we went along helped us to get closer to the correct diagnosis. (We had ruled out many potential causes along the way which really narrowed down the possibilities) Idiopathic really means "we don't know the cause". It does NOT mean there is no cause, just that it hasn't been found. Mothers are always right - they should be taken seriously. Videotape any kind of seizure activity, and keep a detailed diary of seizures and when medications are given. Do not make more than one change at a time on meds, vitamins, whatever. It makes it much harder to sort out what is helping and what is not when multiple things are done around the same time. "It's not rare if they are sitting in your chair"- a really smart guy. Don't be too hard on the doctors. Our children can be their best teachers. My children have been mine....
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