Sunday, November 11, 2012

B12 Deficiency and Psychosis, A Case Study

I'm a little few and far between here lately. Besides the day job and the children, between my weekly class, natural disasters, and presenting (almost every week, it seems), all my spare time for looking up papers and blogging has been sucked away. I'm eager to engage on another bigger project instead of doing these posts on single papers, and in that vein I'm hopeful to pursue OCD and then a lot of work on eating disorders.

If you are a stranger who has emailed me or commented on a specific clinical issue, I'm sorry, but I can't help you right now. If you have emailed me to follow up about some other issue, give me a week or two to get back to you, please. The presentations are over for the year, at least, with my last one at Xavarian Brothers High School on the disaster that is processed food and the brain. I've already been invited for two more grand rounds in the spring, PaleoFx13, and for a physicians and ancestral health get-together in February. I was invited also to be part of a proposed panel for the American Psychiatric Association on diet and psychiatry, but we have not heard back from the APA about whether it has been accepted. Fingers crossed. So! Very busy and trying to get the word out about all of these interesting intersections between ancestral health and pathology, and mental health so the real academics can do some awesome research and answer some questions for us.

Brahms Symphony No. 3 Poco Allegretto (ad to start. sorry. right click to open in new tab or window)

In the mean time, a search for vegetarian diets and mood brought up this new (free full text) paper which is both interesting and a nice review of B12 deficiency symptoms and signs in general. (The young man was not a vegetarian, by the way).

B12 is an essential vitamin, and in medical school we are taught mainly the neurologic and hematologic (blood) findings of a severe deficiency, which are a particular kind of nerve damage (subacute combined degeneration of the spinal cord which is on pretty much every board exam I ever took), peripheral neuropathy, cognitive problems reminiscent of dementia, and an enlargement and numerical reduction of the red blood cells called "megaloblastic anemia."  What I didn't know until psychiatry residency is that psychiatric symptoms can precede all the more obvious medical findings*, and the psychiatric symptoms include irritability, insomnia, confusion, negativism, and impaired attention, and folks with B12 deficiency can be diagnosed with depression, bipolar disorder, panic disorder, dementia, and even psychotic disorders.

B12 is vital for making neurotransmitters, for methylation, and for making DNA, so a deficiency can cause all sorts of issues with the nerves. If caught early on, these issues are largely reversible. Our serum test for B12 is also not as reliable an indicator of B12 available at the tissue level, and for this reason it is recommended that patients with depressive disorders (and I would broaden this recommendation to most psychiatric patients, as occult deficiency can masquerade as many psychiatric disorders) be checked for deficiency and be repleted to a level of at least 400 ng/ml (normal range is 200-1200 in most of the lab ranges I've seen). This recommendation is printed right at the bottom of the lab results from the lab I commonly use, so not terribly controversial, though many of my patients come in at a level in the mid 300s.

We are taught that most people with B12 deficiency have a problem with absorption, not a dietary deficiency. There is a test called the Schilling Test to determine if malabsorption exists, but I've never seen it done in practice (though it is another common board exam question). As it involves a radioactive dose of B12 and 24 hour urine and several stages, I can see why it is not typically done.

In general, practitioners try oral or sublingual B12 at extra doses to try to prop up the levels (which normally works in practice, suggesting that maybe some of us are consuming less B12 than we think, even us non-vegans**), and if that doesn't help or the level is low enough, you start off with B12 shots to bypass the pesky gut. Often the malabsorption is due to something obvious, such as a gastric bypass, so the Schilling Test would probably be a waste of time. I also think it is easier to check for bacterial overgrowth by other (non radioactive) means these days, and since bacterial overgrowth or celiac or some other condition are typically the cause, and gastronenterologists are often pursuing the diagnosis of B12 deficiency, they will tend to look for those causes if oral repletion of B12 fails rather than chase down the Schilling Test. I think that might be enough background, so...

On to the case study! In this paper, a young Turkish man, age 16 (unusual, since most B12 deficiencies are thought to be in the elderly) who is not a vegan presented with one year of complaints of anxiety, weepiness, lethargy, and skipping school. He began to stop sleeping and eating, withdrew from his friends, and spent a lot of time online buying things. Before this change, the young man had been extroverted and active with no previous episodes of compulsive buying or obsessive behavior. He had always had trouble paying attention since at least the second grade, and was described as "fidgety," especially in math class. On mental status exam, the patient had impaired attention and several varieties of hallucinations, including olfactory***, visual, and auditory. He had other symptoms of a major depressive episode, with slow thought and speech, decreased interest, suicidal ideation, and other psychotic symptoms including delusions that others could read his mind ("thought broadcasting") and paranoia that others were thinking and talking about him.

The patient had no history of drug use or use of antipsychotics, toxic screens (including those for heavy metals and pesticide exposure) were negative. On physical exam he had prominent neurologic findings including glossitis (a swollen, discolored tongue), cogwheeling and shoulder rigidity, decreased coordination (specifically with certain muscular movement and ability to correct posture called ataxia.)  He had a positive Romberg's sign (stand up, close your eyes and don't fall over) but no other obvious symptoms of peripheral neuropathy (which normally begins with complaints of numbing, tingling, or burning in the hands and feet). In short, he had a lot of neurologic signs that many areas of his brain were, to some extent, shorting out and going offline.

His team did a massive medical work-up, including bone marrow biopsy, MRI, EEG, EMG, HIV testing and other blood testing, almost all of which were normal (including folate and transcobalamine), and he did not have the classic megaloblastic anemia. He did have slightly low hemoglobin and his red blood cell size was on the high end of normal. His serum B12 test was low, at 166 ng/ml (measured twice, fasting). The doctors went further to biopsy his intestines, did not find evidence of celiac, but did find a positive Schilling Test for B12 malabsorption and an overgrowth of H pylori bacteria, which was thought to be the cause of his malabsoprtion. He was treated with antibiotics, daily B12 shots, and a low dose of an antipsychotic, and his symptoms began to improve. In two weeks his psychosis was gone, and many of his worst neurologic symptoms (such as the ataxia) were gone, and his mood, anxiety, and tearfulness were improving. After two weeks of daily injections, his B12 levels were 595. His antipsychotic was discontinued and his shots were changed to once monthly. He was followed closely for the next 6 months and there was no recurrence of the psychiatric symptoms, and his H pylori overgrowth was resolved.

It was thought that the patient may have had a genetic polymorphism called C677T of the MTHFR gene of the folate cycle which is more prevalent in Mediterranean countries, and this genetic change may have caused him not to have the hematologic signs before presenting with a great many neurologic signs.  It is also interesting he presented with what are called "extrapyramidal" symptoms (postural problems and rigidity, similar to Parkinson's disease, which is why the doctors were busy looking for pesticide exposure or antipsychotic use) rather than the more common neurologic problems from B12 deficiency (such as peripheral neuropathy) and it may also have been due to genetic differences in his folate cycle machinery.  Biochemists and medical folks should read the last paragraph of the case presentation in the paper itself, as it goes into all the gory details and possibilities with respect to cysteine, SAMe, folate, dopamine, and motor neurons.

All in all, this case is a fascinating but rare presentation of what I would call a relatively common vitamin deficiency. I plan to update my previous post on vegetarian diets and mental disorders later today, and get to work on some of the projects…

*I do my best to test all my patients for B12 deficiency at least once. One time, a patient with recurrent and resistant depression along with some peripheral neuropathy symptoms had a low B12 in a laboratory measure, but her primary care doctor refused to write an order for the standard of care, which is B12 shots for a period of time, because she didn't have the megaloblastic anemia. After a very confusing phone call with the primary, I decided to go over his head and order the shots myself, and her peripheral neuropathy symptoms resolved, along with the insomnia and agitation that had accompanied her tough longstanding depression. I still shake my head over that one, because it is a relatively low cost test and a very inexpensive treatment, with possible dire permanent consequences if left untreated.

** I now have several "paleo" patients in my practice, and all of them have had terrific B12 levels (usually in the 600s), I would say about 200 ng/ml above the typical patient, who tends to hover in the 300-400 range. Strict daily multivitamin takers also tend to have robust B12 levels. Anecdotal but interesting.

***general rule of thumb in psychiatry is that olfactory (smell) hallucinations are neurologic from say a seizure or a brain tumor until proven otherwise. They are almost always unpleasant smells of burning rubber or old mouldering flowers or something of that nature.

11 comments:

  1. Great pick up. One of the problems with B-12 is that many labs have an equivocal range and in that case I have tested for homocysteine and methylmalonic acid, although the more it is studied the more equivocal it seems to be. I have not seen a Shilling Test done in a long time. The other learning point here as you have pointed out is the need for rapid B-12 replacement as was done in this case. I also see a lot of higher than average B-12 and folate levels in daily vitamin takers.

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  2. To list the few other B12-deficiency etiologies that are immediately conjured up in the mind of a well-trained med student: pernicious anemia, D. latum infection, and Crohn's (the stomach is responsible for intrinsic factor production, but it's mostly absorbed in the terminal ileum). I see they did not test for antiparietal autoantibodies, but the others aren't addressed. I wonder how long ago his symptoms improved: I would think that significant B12 dosing could replete his liver stores, pushing the need for an etiology search back several months or years.

    Parts of his presentation are reminiscent of the symptoms I saw in severely malnourished women in the eating disorders unit, although clearly those women had many things going on. It reminds you how the effects of an eating disorder can perpetuate the problem.

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    1. Looks like he was double dipped because they did celiac biopsies and gastric biopsies for H pylori, so they would have ruled out Crohns, Diphyllobothrium Latum (another nice boards question!). The point of the whole Schilling Test ordeal is to figure out if there is an intrinsic factor issue or where the B12 problems are occuring.

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    2. Chris Kresser has an article about B12, and how people with IBD and IBS have B12 malabsorption for life (very few recover fully regarding this). Might be a good article to look at.

      I had IBS for 10 years, which started going away when I found Paleo. Fast forward many months later, and I went to a dermatologist about something unrelated, and he said he would check for B12 too. I almost told him not to, since I was eating meat/fish by the pound. I thought to myself: "what a useless test, with all this meat I eat". It turned out I was severely B12-deficient, and I was probably much worse when I had IBS. I couldn't believe it! IMHO, everyone with gut problems should be tested for B12. I semi-fixed it with B12 Cyanocobalamin pills, daily for 2 months. I got my range up to 1100, up from 380 (I expect to have spent many years below 200 while having IBS).

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  3. Low serum vitamin D concentrations in patients with schizophrenia.
    http://www.ima.org.il/imaj/ar12feb-04.pdf

    "We recruited 50 patients with schizophrenia and compared them to 33 patients with major depression and 50 controls with no major psychopathology. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia and the Hamilton Depression scale for depression were administered on the same day the blood samples were drawn. We used LIAISON 25-OH vitamin D (DiaSorin) immunoassay to measure serum concentrations of 25-OH vitamin D.
    RESULTS:
    Lower serum vitamin D concentrations were detected among patients with schizophrenia (15.0 +/- 7.3 ng/ml) compared to patients with depression (19.6 +/- 8.3 ng/ml) and to controls (20.2 +/- 7.8 ng/ml, P < 0.05). We found no correlation between disease activity, measured by the PANSS score, and vitamin D levels.
    CONCLUSIONS:
    Serum vitamin D levels were lower in patients with schizophrenia as compared to patients with depression and to healthy controls. No correlation was found between serum concentration and disease activity. Additional studies are needed to elucidate the role of vitamin D in the autoimmune mechanism and in the pathogenesis of schizophrenia."

    So 25-OH vit D is significantly lower in schizophrenics, correlates with the disease but not with active symptoms.
    But what of 1,25(OH)2 D?

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  4. Dr. Stasha Gominak emphasized the importance of vitamin B12 in patients with sleep and headache problems (along with vitamin D). She recommends maintaining B12 levels of 600.
    http://www.youtube.com/watch?v=h7cbBB1c0IM

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  5. If you are not in touch with Dr Bransfield in NJ, he runs a list focused on Microbes in Mental Illness that you would find alot of interesting information on.

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  6. I've got this. Seriously. Just been started on B12 shots, every other daily. Apart from the usual fatigue, weepiness, pins and needles etc. I had a permanent smell of woodsmoke in my nose. I could hear whole orchestras, let alone voices in my head. And I could taste nothing at all. I feel like I am wearing socks and gloves, and yet can't feel my real clothes on my skin. My aphasia is spectacular. I haven't been able to remember a noun for a long time, although I can write plenty! Recently, I called the TV "that box thing in the corner with morning people on it." I have coeliac disease. I've been diagnosed with pernicious anaemia, and am awaiting confirmation of Sub Acute Combined... etc. So perhaps this case isn't an unusual presentation at all. Mood back to normal (better than normal. Best ever) with the first shots. Absolutely shocking. Improvements all round, but some things not resolving and may never, I now find. Wonder how common this really is?

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  7. Sorry to bang on about this, and it's not strictly psychiatric, but it is worthy of mention that my IBS resolved completely in the first week. And I haven't had a migraine since the first shot - after suffering with at least three a month, and ultimately three a week, by the time of the B12 diagnosis. Sanity and continence!

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  8. The day following my B12 injections, my mood was very low (depressed/weepy). For the following few days I felt like I was having pms symptoms--a lot of irritability and some cramping. I just read that high doses of B12 can cause folate levels to drop significantly. I've discontinued B12 shots for now until I get this figured out. What are your thoughts on this--do you think low folic acid could produce these effects?

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