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!

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!)

Neurology Follow-up

A first! Today was the first of Bertrand's numerous neurology exams I was able to leave with a light spirit--or at least without a heavy heart.

Bertrand's neurologist was VERY impressed with his appearance at this exam--although this was his seizeiest day in two weeks probably due to his cold. First, she remarked at how big Bertrand has gotten (35.5 inches and 30 pounds) and quickly thereafter she got excited by how steady he's become and how great his eye contact has gotten. His neuropathy appears much reduced, his tone is now normal (yay!) and this was the first time she was able to get some of his reflexes!

She asked if we were having any problems with Bertrand's ketogenic diet. I said no, but we're dealing with constipation now and trying to find the right dose of miralax. The doctor said that her daughter is age two and a teaspoon and a half of daily miralax works for her. I asked her if she knew how many grams that was and the doctor started laughing! "You already sound like a keto parent!" I took that as a great compliment. ;)

Next we discussed Bertrand's EEG, which after a month on the ketogenic diet had minor improvements, but nothing drastic. She fully expects to keep seeing improvements over the next 6 months, and wants another EEG in June. We'll schedule it during our next neurology exam on April 1st. Anyone have suggestions for a fun April Fools joke for a neurologist? :)

December MRI-wise she also saw the white matter issue. If it were up to her, she'd get another MRI next December. The current loss has not progressed since April 2009, but she wants the University of Utah's leukodystrophy expert, Josh Bonkowsky MD, PhD, to look at it. I got excited! Everyone knows how much I love PhDs--the ones who treat Bertrand, not just my husband! Dr. Bonkowsky's clinical specialties are neurogenetics, language development, leukodystrophies and cortical development. "His clinical studies are focused on understanding the clinical features of novel leukodystrophies, and on the genetics of complex human neurobehavioral traits, especially language impairments." You don't get much more novel than Bertrand, so I have a feeling there will be a good fit. :)

Ever since we saw possible remote "ischemic insult" on B's MRI reading, the stem cell torch was rekindled. Now, Bertrand's white matter damage (leukodystrophy) is very symmetrical, which tends to reinforce the opinion that it's root cause is genetic, resulting in an ongoing metabolic process. Stem cells, in particular Bertrand's banked cord blood stem cells, wouldn't help this at all because the genetic fault causing the damage would be found in them as well. However, it is possible that Factor V is at play in Bertrand's family tree (Matthew's mother's embolism and my paternal grandmother's strokes), if this is the case then ischemic insult is a possibility and Bertrand's very own stem cells could help--no chemotherapy necessary, just a transfusion of his own blood. The stem cells simply know to go to the point of insult in the brain and repair. We saw Dr. Kurtzberg work miracles of this kind for children with stroke and cerebral palsey at Duke University.

Our neurologist at the University of Utah didn't shoot this wild theory down. She asked that we bring her the publications on this form of autologus stem cell therapy. If Bertrand's brain damage doesn't progress, or we can reasonably say it has stopped, his own cord blood stem cells may be back on the table as a very real treatment possibility. And we MAY be able to have it done at home in Utah!

Getting back to immediate treatment, however, Dr. Sakonju did mention adding more AEDs for Bertrand. The drug B would've started today is Klonopin. However, given that B had a significant Keppra increase 2 weeks ago, it'll be another month until we see it's full effect, so I didn't want to complicate the experiment by adding another drug. Furthermore, we'll be seeing the keto team in late February. I would like to tweak Bertrand's keto ratio (going to 3.5:1 and possibly 4:1) first before adding any additional medications. (Tweaking the diet doesn't cause side effects like sleepiness, rage, cognitive impairment or liver failure like adding another medication can.) This would give us a month to see the effects of an increased ratio before our April neurology follow-up where we'll readdress medication.

Lastly, of course we couldn't leave without discussing blood work. Bertrand does not present like a child with Dravet's Syndrome (he's had none of the requisite febrile seizures). His epilepsy seems to be a form of Myoclonic-Astatic Epilepsy (MAE) a.k.a. Doose Syndrome. In order to better treat either of these specific kinds of severe intractable epilepsy, and for the purposes of family planning, we'll start with testing Bertrand's SCN1 gene (for deletions etc.) and move from there. I promised Bertrand that he would get at least one month of 2010 poke-free, so we'll likely do that draw in late February, after our insurance approves the test, and grouped with the rest of his keto blood work.

PS - Bertrand threw a massive fit when we went by the lab to drop off his urine sample. He seemed genuinely shocked when they let him off the table without drawing blood. I was proud of him for being so smart, fiesty and having such good recall! You can tell I'm a special needs mom because I can turn my child's loud public bout of hysterics into a positive. :)

Impending NIH Visit

This Monday, Bertrand and I will be traveling to Bethesda, Maryland to see the SEGEN group (section on endocrinology and genetics) at the NIH. Why endocrinology and genetics? There is a very rare and peculiar genetic disorder called Allgrove's Syndrome, or Triple A Syndrome, that is an increasingly likely match for Bertrand.

Below is a paraphrase of a paper entitled "Clinical and genetic characterization of families with triple A (Allgrove) syndrome" by Henry Houlden et al. published in BRAIN.

Triple A (Allgrove) syndrome is characterized by achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. Affected individuals have between two and four of these relatively common clinical problems; hence the diagnosis is often difficult in all but the classical presentation. The inheritance is autosomal recessive, and most cases of triple A have no family history. Using genetic linkage analysis in a small number of families, a locus on chromosome 12q13 was identified. The triple A gene was identified recently at this locus and called ALADIN (alacrima, achalasia, adrenal insufficiency, neurologic disorder). Associated neurological abnormalities include optic atrophy, autonomic neuropathy and upper and lower motor neurone signs including distal motor neuropathy and amyotrophy with severe selective ulnar nerve involvement.

So how does this relate to Bertrand? Bertrand doesn't cry tears. This condition is called alacrima and it ranges from simply no tears, to absolutely no eye moisture causing corneal blistering. This is the earliest indicator of Allgrove's. Fortunately, Bertrand has some moisture in his eyes, but not enough to keep them from appearing increasingly red. Achalasia and adrenal insufficiency (the other two A's in Triple A) can develop later in life.

Both a nerve conduction study and an EMG have confirmed that Bertrand has neuropathy. In particular, he is said to have carpal tunnel syndrome which is definitely "ulnar nerve involvement". Bertrand's excessive sweating, low body temperature and cold extremities could be symptoms of autonomic neuropathy. Also, as we've mentioned before, it is believed that B has the beginning of optic nerve atrophy.

Allgrove's is the only condition in it's literature to specifically mention Puerto Rican ancestry. That makes me (a Puerto Rican) particularly wary.

Positive Thinking

I'm back and I apologize to everyone who reads this blog regularly for having been remiss in my reporting duties! I got burnt-out a few weeks ago. The "not knowing" finally took its toll on me. So, I took a break from being Bertrand's executive assistant and focused on being his mommy. I enjoyed time with Bertrand, friends and family. I threw myself into planning an 18 month birthday party for Bertrand and did what, in my mind, constituted "normal" mommy things.

Coming out of this funk has left me with a mantra (a modified serenity prayer). "Have the serenity to accept the things you can't change. Have the courage to change the things you can. Have the wisdom to know the difference. And, take a deep breath." :) It works for me.

Bertrand had his neurology check-up yesterday and his 18 month well baby check-up today. Both of his doctors were AMAZED at how well he is doing. His neurologist even went so far to say he could be walking by age three to five, *and* she thinks we'll get to see him grow-up. :') I was emotional on the car ride back. So many parents take it for granted that they'll see their child grow up, but for me--hearing that it is now a possibility--I still tear up. I always will.

Bertrand is beautiful and healthy looking. His weight is down to 50th percentile (yay!) and his height is still 50th percentile--so he is finally proportional. :) He was prescribed a once a day dose of valium to be taken before therapy and a new, stronger acid reflux medication. His liver functions will be drawn again tomorrow to see if his weight loss has improved them.

Bertrand still can't get to sitting on his own. He can't stand on his own. He can't hold his bottle or feed himself or crawl. But, cognitively Bertrand is fine! He loves to read... and boss me around. His personality is very strong. He is serious, stubborn, manipulative, arrogant (I never knew one could consider a baby arrogant until him) and often times charming. His displays shock his doctors--and amuse me. :) His therapists frequently don't know what to make of him.

None of his doctors know what is causing Bertrand's movement disorder and neuropathy. They are still very confused. The next MRI in October will tell us a lot. A liver biopsy in July is looking very likely. What's not looking likely is a diagnosis. Matthew and I are prepared to never get one. As long as Bertrand stays happy, healthy and mentally okay, we can make do with that. :)