Timeline

At Bertrand’s neurology appointment last week, the doctor laid out the following timeline:

• Follow-up appointment in 4-6 months
• Revisit medication in 4-6 months
• Repeat EEG in 6 months
• Repeat MRI in 2-3 years

I’ll admit to feeling some frustration upon hearing this but, as I noted in an earlier post, some times it takes doctors a bit longer to get on the right page. ;)

Fortunately, the neurologist is no longer key to understanding Bertrand’s case management. She never was. Bertrand was the key.

While some extra non-invasive tests, like an EEG & MRI, would give me peace of mind and validate the vitamin deficiency theory, these test are not necessary. I can see, with my own eyes, Bertrand’s seizures disappear, and I can see him progressing developmentally.

This is just a crazy theory, but I think that if we didn’t completely miss Bertrand’s growth spurt, his head measurement may increase since being on the vitamins B12 and A. He has microcephaly (his head measures 48 cm), but that can be caused by B12 deficiency. In young B12-deficient children, the microcephaly can correct itself in a few months with supplementation. I hope this is the case with Bertrand.

Last but not least, Bertrand’s seizure medications have already been decreased (without MD buy-in) with no additional seizures. And, in another few weeks, given continued seizure freedom, we will cautiously and slowly reduce the medication further. I would love to have a doctor’s help with this, but she wants us to wait months just to discuss the drugs!?

Despite the fact that Bertrand has been on Lamictal since November (9 months) and Depakote since February (6 months), she implied that the sudden disappearance of Bertrand’s seizures, within one week of starting the vitamin-B12 in late August, was most likely due to the lamictal and depakote! If we don’t lower the drugs ourselves, Bertrand’s neurologist will claim that the drugs are to thank for the seizure control. And, she is wrong.

She is not listening to me. If she doesn’t listen to me, then how can I listen to her?

My "Ph.D.": A diagnosis for Bertrand

Today, Bertrand saw a corneal specialist for his eyes. Followers of this blog know of Bertrand's protracted battle against corneal erosion and his alacrima (lack of tears) since birth.

The two ophthalmologists who saw Bertrand today, noted the scar on his right cornea but, other than that, found no evidence of corneal erosion. Bertrand did NOT have dry eyes.

Furthermore, at home, Bertrand has been crying tears. This is especially remarkable because Bertrand still had severe xerophthalmia (dry eyes) just four short days ago.

This was the second successful test of what I am calling "my thesis". If every parent claims to be the expert in their child, I am attempting to get my PhD in Bertrand Might.

MY THESIS:

Liver damage, resulting in vitamin B12 & vitamin A deficiency, induced developmental delays, neuropathy, seizures, and alacrima.

Now, please let me explain.

I believe that Bertrand was born with liver damage because the jaundice Bertrand had at birth was not severe, but he could not shake it on his own. He had so much difficulty that he was hospitalized in the NICU. Bilirubin, the cellular byproduct that causes jaundice, is usually processed by the liver.

This liver damage could be the result of an unknown genetic disorder or the result of an infection.

While I took the best of prenatal care with Bertrand (vitamins, diet, doctors appointments, etc.), I caught "colds" twice: once in the 1st trimester and once in the 3rd trimester. I was pretty miserable.

Bacterial and viral infections can cause liver damage. Obviously, the most well-known of the viral ones are called Hepatitis A, B and C, but Mononucleosis (commonly referred to as "mono") can cause liver damage as well, and there are others.

Such an infection could have damaged Bertrand's liver prenatally and possibly my own.

(This is a big assumption, but it can in part be tested by checking Bertrand for antibodies of liver damaging viruses & bacteria. Since he hasn't had such an illness in his life, the presence of such antibodies would have come from in utero.)

The liver is where vitamins A, B12 and D are stored. It holds approximately a 3 year supply of each. If this supply is damaged, one is reliant solely on diet. Bertrand's diet for the first 5 months was breast milk. I wager that my milk was low on these vitamins, and the amount of these vitamins found in formula just were not sufficient given any pre-existing liver damage.

And here is where things get a little perverse. Certain medications block the absorption of vitamins B12 and A: proton pump inhibitors and H2 receptor antagonists. These are the antacids also known as prevacid and zantac.

What was Bertrand's very first medication? You guessed it. Zantac, followed by Prevacid. (In hindsight, this is also around when his seizures started. Coincidence?)

Based on this, could Bertrand be vitamin B12 and vitamin A deficient?

What are signs of severe vitamin B12 deficiency?

• Neuropathy
• Movement disorder (chorea, twitching)
• Seizures
• Macrocytic anaemia

Obviously, Bertrand has these. Multiple nerve conduction studies, EMGs, EEGs and MRIs serve as evidence.

B12 is a primary component of the myelin sheath found on all nerves.

Do you remember the MRI which I posted a few days ago? That was a case of B12 deficiency and it closely resembled Bertrand's MRI.

B12 deficiency is almost always associated with malnutrition. It is not a first world disease. So, hematologically, it is associated with macrocytic anaemia, which can include folate, B6 and iron deficiency as well.

However, Bertrand's case is NOT one of malnutrition. Bertrand has plenty of the vitamins which don't require liver storage.

What does B12, and only B12, deficiency look like in the blood? It looks like really fat red blood cells (macrocytosis) and/or excess platelets (thrombocytosis), for unknown reasons.

Yup, at his last blood draw, Bertrand had elevated MCH and MCV (measures of macrocytosis). And early on, he had elevated platelets.

What are signs of severe vitamin A deficiency?

• Nyctalopia - night blindness
• Xerophthalmia - dry eyes
• Follicular hyperkeratosis - a kind of bumpy skin

I don't know about Bertrand's night vision, but he definitely had xerophthalmia and follicular hyperkeratosis.

I say "had" because by this point, you can probably guess that we began vitamin B12 supplementation 2 weeks ago and vitamin A supplementation 4 days ago.

With vitamin B12, he became more vocal and alert within hours. By day 3 his myoclonic seizures (jerks) stopped. By day 6, his night seizures stopped. By day 7, he was walking in his gait trainer. By day 11, we lowered his seizure medication and we have seen no seizures.

Back to today's ophthalmology appointment, that was the first test of the success of vitamin A. We could tell that his eyes (& skin) had improved some within about 24 hours, but we've proceeded cautiously with the dose. Unlike B12 which is water-soluble, Vitamin A is fat-soluble and can be toxic. We're being cautious not to overdose.

According to the medical literature, in cases of vitamin B12 deficiency, symptoms can be completely reversed--if caught early. EEGs normalize after about 5 weeks and there are MRI changes by 10 weeks.

Unfortunately, Bertrand's case, if it is one of vitamin B12 and A deficiency, was NOT caught early. We should assume that there will be permanent brain and nerve damage.

But that hasn't stopped me from shooting him up with omega-3 fatty acids for myelin sheath repair or researching intensive therapy options. As with most "scientists" (if I dare call myself such), optimism comprises my core. ;)

SO...

The way I see it, my "thesis proposal" is this Thursday, with Bertrand's neurologist. Then I get a few months to test and, in essence, watch "my dissertation" develop. And at some point, an EEG and MRI should serve as my defense!

And, better than any sheepskin diploma, I will get a healthy, happy son!

Crying Tears.

Bertrand is crying real tears. The only change in his daily regimen has been the addition of a B-12 supplement.

We are using a transdermal B12 patch and oral B12 supplement.

Of course, I've been on a research binge for the past few days. Here are some bits and pieces floating through my head...

• B12 is stored in the liver. (Bertrand has liver damage.)
• B12 is water soluble. (An overdose on B12 is near impossible.)
• B12 is expressed in bile.
• Actigall (ursodiol) is a bile acid. (Bertrand's liver has improved on actigall.)
• B12 deficiency in infants causes movement disorder & developmental delay...

When Bertrand was a baby, we'd thought for certain that he was a case of B12 deficiency. His neurologists shot this theory down because of the important fact that Bertrand was/is not anemic. Folate can mask B12 deficiency, but he should still show some signs of anemia.

But this image is haunting me:

The MRI above is from THIS article, entitled "Involuntary Movements and Magnetic Resonance Imaging Findings in Infantile Cobalamine (Vitamine B12) Deficiency", published in PEDIATRICS: Official Journal of the American Academy of Pediatrics back in 2003.

Does "bilateral periventricular symmetric high-signal lesions in the white matter on T2-weighted images" sound familiar?

You can bet this will be discussed with Bertrand's pediatrician on Tuesday!

Cleveland Clinic MRI Report

EDIT: The "lay interpretation" is that this is about as good a report as we could expect. Findings are mostly, and confoundingly, normal. :)

* * *Final Report* * *

DATE OF EXAM: Jan 6 2011 1:32PM

MRI BRAIN WO CONTRAST
MR SPECTROSCOPY OF THE BRAIN

PROCEEDURE REASON: Epilepsy and recurrent seizures

INDICATION:
Intractable epilepsy and neurodevelopmental delay

RESULTS:
There is bilaterally symmetrical, nonspecific T2/FLAIR hyperintense areas noted in the periventricular deep white matter adjacent to the atrium of bilateral lateral ventricles, extending to the occipital lobes. Compared to multiple prior outside MR studies, there has been interval increase in size of these abnormal periventricular lesions. Small T2 hyperintense white matter foci are also seen within the left front centrum semi ovale (series 5, image 7), nonspecific in nature. No other parenchymal mass, mass effect or extra-axial fluid collections are identified. Diffusion weighted images demonstrate no evidence of restricted diffusion.

The ventricular system is normal in size, shape and configuration. The cortical sulci are unremarkable. No abnormal intra- or extra-axial fluid collections are identified. The midline structures are unremarkable. The cerebellar tonsils are above the foramen magnum. The myelination is appropriate for age.

The major intracranial vessels are patent. The visualized portions of the orbits, paranasal sinuses, and mastoid air cells are unremarkable.

MR Spectroscopy: Multi voxel MR spectroscopy images demonstrate normal pattern. No evidence of abnormal neuronal activity or increased lactate formation is identified.

IMPRESSION: Bilaterally symmetrical, periatrial T2/FLAIR hyperintense deep white matter signal abnormality. There has been mild interval progression of this abnormality compared with multiple prior outside MR_s. No specific associated MR spectroscopic changes. The MR features are nonspecific and the differentials include metabolic, mitochondrial and dysmyelinating disorders. A contrast enhancement MRI may be performed if there is clinical concern for adrenoleukodystrophy.

Cleveland Clinic Wrap-Up

Bertrand coming out of general anesthesia, post-MRI.

Bertrand was transferred from the Pediatric Intensive Care Unit Thursday afternoon and discharged from the Pediatric Epilepsy Monitoring Unit late that night. He is fully recovered from his urinary tract infection and almost fully recovered from his hectic 4-day hospital stay. (A restful sleep in a comfortable bed can do wonders!)

As expected, we came away with no answers, diagnosis or prognosis, BUT a treatment plan has been put into place! While in some ways we learned little from our time at Cleveland Clinic, in many ways we learned a LOT--starting with the importance of proper EEGs, serum medication level monitoring, medical team communication and attention to detail.

Bertrand was asked to return for follow-up in 6-12 months. We'll aim for sometime between August and October at the latest. (Can you tell we've been scarred by all the winter flight delays, cancellations, and reroutings?! Matthew, who was supposed to arrive early yesterday evening, is currently stuck in Phoenix!)

THE RESULTS
Bertrand was seen by experts in epilepsy, neurogenetic/metabolic conditions and movement disorders. He had an MRI, an MR Spectroscopy, over 3 days of EEG monitoring, and blood work.

The preliminary reading of Bertrand's MRI stated that it was unchanged from his December 2009 MRI. The myelination of his brain white matter has neither improved nor worsened.

According to the EEG, Bertrand's main seizure type is myoclonus. He has them in clusters awake and many in his sleep. Many of his atonic episodes were actually large myoclonus. His random laughter is not a gelastic seizure, but rather a reaction post-seizure because it feels good somehow.

Most of Bertrand's abnormal movements are in fact a movement disorder. They are called stereotypies: repetitive or ritualistic movement, posture, or utterance, found in people with mental retardation, autism spectrum disorders, tardive dyskinesia and stereotypic movement disorder.

A few drugs could help a little with the movements, but they wouldn't eliminate the movements entirely. The same drugs also greatly reduce seizure threshold, which is why they should be approached with caution.

Since seizures prove the greater hurdle for development and learning, over the next few months, Bertrand's current drug & diet regimen will be optimized for maximum seizure control and minimum side-effects. This means frequent blood draws to check serum medication and liver function levels.

Speaking of liver function, Bertrand's AST was 83 and ALT was 98. These values are still elevated slightly but FAR lower than the 600s at which they once were! We're not sure if this is simply part of their downward trend (like his AFP), the result of his ursodiol/actigall regimen, or the result of his stem cell infusion last August.

This makes the ideal medication for Bertrand's seizures a combination of lamictal and depakote (valproic acid), or perhaps even just lamictal or depakote. Bertrand was just raised to 100mg daily of lamictal and will need his serum levels drawn for that. We need to keep tracking his seizures.

In the meantime, we will proceed with a zonegran wean, then a keppra wean and then a ketogenic diet wean (or vice versa). All three treatments caused severe sleepiness, reflux, constipation issues, elevated heart rate, bone density loss, and possible kidney stones. He may be able to drop his prevacid (for reflux but causes bone density loss) and miralax along with these.

(I can't even begin to imagine what it would be like! 2 medications instead of 6 plus countless supplements?! Bertrand being able to eat a cupcake at his own birthday?! Without seizing?! It sounds like a pipe dream, but hey, we'll give it a whirl!)

From a testing standpoint, the neurogeneticist seemed pretty impressed with all the testing done so far. For glycogen storage diseases, Bertrand's testing to date had been for carbohydrate deficiency transferase & oligosaccharides--markers for those diseases. While these markers had come back negative repeatedly over the past 2+ years, a new genetic panel for this family of diseases had come out--all 30 can be tested quickly and cheaply--so this was sent out to be done.

Two more X-linked diseases, CDLK5 (another form of Rett Syndrome) & ARX, were put on the table, but since these will be covered by the genome sequencing being done by Duke University (results due late this month or next), these tests were held off on.

We'll stay in touch with the team at Cleveland Clinic while we implement Bertrand's seizure treatment changes. And, when we return in a few months, they'll be able to address more of the movement disorder and neuropathy/demyelenation aspects of his condition. (He'll see FOUR neurologists at Cleveland next time!)

Stem Cells: Response from Duke University

I received your emails about Bertrand and also had his MRI reviewed by the neuroradiologists at Duke. Unfortunately when they reviewed Bertrand's MRI, they didn't see any areas consistent with hypoxic injury. They also thought that the scan was a little worse as compared to the scan that Bertrand had at Duke. They were specifically concerned about the area in the Post Centrum Semiovale. They did comment that the quality of the scan was suboptimal. With this information, I don't see a reason to think that infusing Bertand's cord blood cells would help him. On the other hand, they wouldn't hurt him so we'd be willing to do it if you would like. Just let me know.

Matthew and I have some thinking to do.

End of Year Medical Marathon

Tuesday and Wednesday of this week became an end of year medical marathon for Bertrand. For a variety of reasons, not the least of which because our insurance deductible is met through December 31st, several of Bertrand's procedures were shoehorned into last minute holiday cancellations. Things went about as smoothly as one could hope for, and the preliminary results are very good!

Sleep Study
Results in 2-3 weeks.

EEG
Results in 1-2 weeks.

MRI & MR Spec
Results next week.

VER & ERG
Results same day: normal! Rules out Batten's disease (CLN3) and the other CLNs.

Donnell Creel, Ph.D, was the doctor who administered Bertrand's VER and ERG, and all I can say is that both Matthew and I are in love with Dr. Creel! Having a Ph.D rather than an M.D. was refreshing. Dr. C has a great sense of humor and he even gave us a mini-tutorial on electrophysiology! It was awesome! I wish more doctors would encourage such learning in their patients and patient's parents.

Labs
Unfortunately, in spite of being stuck SEVEN times, Bertrand's blood draws were unsuccessful. We will have to go next week to deliver a urine sample and draw blood samples for Dr. Longo.

Flu Shots, Knee Update and More

Flu Shot Odyssey
Before being admitted to the hospital in November to start the diet, Bertrand needs his flu shots: seasonal and H1N1. This morning we were able to procure the first of his H1N1 shots (kids under age ten need two doses, a month apart, for full immunity) from the Salt Lake City Department for Public Health. Unfortunately, they were out of seasonal flu vaccines. Even more unfortunately, so is every clinic and pharmacy in the valley (excusez-moi, "intermountain region")! BUT, hallelujah! we have a savior! (and no one who knows me should be surprised...) CostCo has come to the rescue! Tomorrow, October 22 from 10AM to 2PM is the very last day they will be offering the seasonal flu vaccine! (Apparently there are shortages of the seasonal vaccine because all production has been shifted to H1N1.) After Bertrand's physical therapy session, we will fly to the CostCo and hopefully get needlified before they too run out!

Get Well
Speaking of the flu, my dear friend Karen and her two adorable little boys are now sick! :( We're keeping them in our thoughts and hearts. This is the same wonderful, darling Karen who has been there for us every time life has gotten rough the past few months. (Just last week she was bringing over meals when my knee was out!) We hope they get well soon.

My Knee
Today I went to see orthopaedic surgeon, Dr. Steve Aoki. As I was being funneled through the admitting process at the University of Utah Orthopaedic Center (awesome facility, BTW), the receptionist, billing person, x-ray technician, and nurse, upon hearing that I was going to see Dr. Aoki all said, "Oh! He's the best one!" "He's the doctor I go to!" "He's the doctor I take my daughter to!" "I loooove Dr. Aoki!" So, I am pretty impressed before I even see the guy. Boy was I surprised when a human being, no god-like resemblance at all, walked into the exam room. ;) Anyway, Dr. Aoki seems nice. The x-rays, as expected, show no damage. Also as expected, he thinks I likely have a torn meniscus and ordered the MRI. My follow-up appointment to go over the MRI is next Wednesday.

Big Boy Room
Tonight is the big night! Bertrand is graduating from his crib in the nursery to the queen sized bed in his "Big Boy" bedroom! We finally got and assembled his extra-long, super-fancy, bed rails! Tomorrow morning I'll take pictures to share of my big boy in the bed! :)

Photo Update: Medical Imaging, Family, Easter Bunny

Bertrand with the Easter Bunny.

Bertrand, Matthew and I are exhausted. So, this is just a quickie update to let everyone know that his testing today went more smoothly than we could've expected. It the past few days have been a fun reintroduction to southern culture (the "north" in North Carolina is a misnomer.) While used to the sweet tea and y'alls, "Lil' Sugah Bugah" (translation: small sucrose mucose) was new to us as well as Bertrand--at whom it was directed! :) We had a great time with Bertrand's cousins, Ben & Luke, along with the Easter Bunny this afternoon!

Before Versed (sedative). He was mad--we tried to explain it was a gown not a dress.

After Versed (sedative). A very relaxed baby--still not happy about the dress.

Taking X-rays for skeletal survey. Bertrand's arm was still strapped onto a board with the IV.

Please note the "Save the Gonads" heart-shaped flexible lead shield. :)

At the Southpoint Mall play area. Bertrand was *not* happy that kids kept coming up to pinch his cheeks.

Matthew and Bertrand with Ben (right) and unknown child (center).

Matthew, Bertrand and cousin Kelly (Ben & Luke's mom).

Bertrand with great aunt Julie (Ben & Luke's grandma).

Ben & Luke chillin' on the Easter Bunny's "throne"--following Cristina's rebel lead.

Luke, Bertrand and Ben. (Ben & Luke loved helping with Bertrand's stroller.)

In Good Hands

I met with a fellow professor, Guido Gerig, today. Professor Gerig is in both the School of Computing and the interdisciplinary Scientific Computing and Imaging (SCI) Institute here at the University of Utah. Coincidentally, Prof. Gerig used to be at UNC, joint between Computer Science and Psychiatry, and he knows many of the physicians we'll be seeing personally. He's even done research with several of them!

Prof. Gerig has many specialties and research interests, but one of them is advanced brain imaging and visualization, and he happens to have studied the brains of children with Krabbe's disease following bone-marrow transplantation. (Krabbe's disease is one of the lysosomal storage disorders for which Bertrand is being tested.)

Prof. Gerig assured me that Bertrand will be in the best possible hands at Duke and UNC. As parents, we can't ever hear those words enough.

Given how rare these disorders are, it's almost impossibly lucky to have a distinguished colleague so knowledgeable about Bertrand's condition.

Ruled Out: Lesch-Nyhan Disorder

We got the Metabolic Clinic Medical Report in the mail today. Included with the report were some lab results I hadn't seen yet--in particular the uric acid test results. Bertrand's uric acid came back normal, which discounts another dreadful disease called Lesch-Nyhan Syndrome. So, it's back to the drawing board--or rather--back to medical imaging.

The MRI next week (4/8/09) will really be able to tell us what direction to move in. MRI gives information about the structure of the body (the distribution of water and fat). With the MRI he'll also be getting a MR spectroscopy and a MR angiography. The Magnetic Resonance Spectroscopy is used to obtain biochemical information. The Magnetic Resonance Angiography is used to generate images of the arteries.

A procedure that, while not for a diagnosis, may help guide Bertrand's treatment is a Lumbar Puncture (LP)--also known as a spinal tap. As mentioned in a prior post, Bertrand's prolactin levels were elevated. The movement disorder portion of his presentation could be caused by too much neurotransmitter--which is treatable. I am certain that reducing his involuntary movements would decrease Bertrand's frustration and improve his quality of life.

Carolina Bound

We're working on the arrangements for our evaluation visit at Duke University. We'll be there the week of April 6th. Bertrand will be getting a few more tests, including another MRI, here at the University of Utah next week in preparation.

Matthew's family in North Carolina (Julie, Kelly, Rob, Ben and Luke) has been kind enough to invite us to stay with them. :) We're really looking forward to spending time with them!

I'll be reporting more intel tomorrow. ;)