thiaminase

In the not too distant past, before sophisticated brain imaging tests became available, it was the job of the neuropsychologist to assess brain function and brain damage based upon an array of cognitive and behavioral tests. These tests measured the functional capacity of different brain regions. They were entirely behavioral and performance based and could, with a fair degree of accuracy, identify whether and where a brain injury was located and the extent of the damage. Results from these tests could then indicate a need for surgical intervention and/or suggest a prognosis and therapeutic options; options that generally involved a cognitive therapy of sorts to retrain or regain lost capacities.

And then, technology caught up; brain imaging became possible and physicians no longer needed the neurocognitive assessment as a diagnostic, but only for rehabilitation purposes once the brain damage was identified. Non-invasive brain imaging was a remarkable technological advancement. How much better and more accurate diagnoses and interventions could be if physicians were able to see the damage in advance, and indeed, at every phase of treatment. No need to delineate the subtle behavioral signs linked to brain injury in order to diagnose, just scan the brain to rule in or rule out trauma and deal with the deficits after the fact.

Functional Cognitive Testing – A Missed Opportunity

I can’t help but wondering though, if we’ve lost something important by switching so completely to visually based diagnoses. For example, what if the damage is at the molecular level and unable to be detected via imaging, or even via current laboratory markers? How do we even know which lab markers to look for if we don’t ascertain that there are in fact decrements in functioning? Do we even recognize brain injuries as extant if they are not visible by current imaging or laboratory techniques?  I have a sense that we don’t. Cognitive deficits, especially those occurring in previously healthy individuals, following an illness, medication, vaccine or even post pregnancy, may be disregarded along with further diagnostic and therapeutic possibilities when the indices of injury exclude assessing functional capacity.

I was reminded of this recently from a patient story. She, and others like her, experienced a loss of reading comprehension post-fluoroquinolone reaction. Medication and vaccine induced cognitive disruptions are not uncommon. In elderly populations they are quite well documented. In the younger adult populations, however, the research is sketchy at best. In the case I mentioned, the patient was a previously healthy, active young woman. After taking a course of fluoroquinolone antibiotics, and in addition to a myriad of other side effects, she reports losing her ability to comprehend text; something that would be quite disabling in our current text-based world.

I lost a lot of my reading comprehension while I was floxed. I could still officially read – if you gave me a short memo that said, “buy milk,” or something like that, I could read it. But reading a novel or complex materials for work became really difficult. I lost track of the content of the beginning of a paragraph by the time I reached the end of the paragraph. I struggled to understand things that I used to be able to read with ease.

Another fluoroquinolone patient describes her deficit:

I remember going into a restaurant a few months after being floxed. I sat down, looked at the menu, and couldn’t understand a single thing. I couldn’t make sense of anything. It was as though trying to read a foreign language. I put it down, and wanted to stand up and start screaming, and breaking glasses and dishes.

Read any of the fluoroquinolone social media and these observations are not uncommon. Similarly, decrements in cognitive function have been reported in our research on the side effects of the HPV vaccine, during and after Lupron treatments, and even with oral contraceptives.

What I find both most interesting and most troubling is that the loss of attentional capacity, loss of short term memory and loss of language comprehension following the administration of a medication or vaccine may be indicative of a broader health issue; one that should be investigated further. No doubt in many patients these deficits were not explored, at least not functionally, as imaging tests are often negative. That is a shame. Functional cognitive assessments, like those common in clinical practice in the past, and yet still in academic research, would more finely delineate the patterns of medication induced cognitive disorders. These tests could tell us the brain regions susceptible to the medication-induced events in the absence imaging or lab markers. In fact, these tests might help us design more appropriate lab markers. More importantly, functional neurocognitive testing could provide clues about the patient’s overall health. Let me explain.

Linking Cognitive Performance to Overall Health

Each of the medications I mentioned above have distinctly different pharmacological mechanisms of action; so different, one might wonder why I would even consider looking for commonalities in their adverse reaction patterns. Initially, I didn’t. But then the data from our research began flowing in, and along with the data, patient stories began arriving. Slowly, pattern similarities began emerging; similarities that I could not explain by solely looking at the drug’s specific mechanisms of action. There had to be an underlying factor or factors that somehow connected these medications and vaccine reactions. What were they? And per the current topic at hand, how might have functional neurocognitive assessments inspired or expedited our understanding? Not all of the pieces to the puzzle are clear, but here are the clues thus far.

Clue 1. Three of the medications we study negatively affect the thyroid (Lupron, Fluoroquinolones and Gardasil). Thyroid influence on central nervous system functioning, cognitive and behavioral performance is well known.

Clue 2. Thyroid damage is linked to cerebellar ataxia, acute and chronic, via white matter demyelination. Cerebellar ataxia has been noted post fluoroquinolone, post Gardasil and post Lupron.

Clue 3. Thyroid damage is linked to peripheral demyelination. Again, all three medications include demyelination syndromes as part of their reaction profiles.

Thyroid dysfunction alone, without any other intervening variables could explain the cognitive and many of the neurological symptoms we were seeing, but was it sufficient to explain all of them? Probably not, there must something else at play. What could it be?

Clue 4. Each of these drugs are linked to mitochondrial damage (mitochondria are an unrecognized target for many pharmaceuticals and environmental agents). These drugs increase the production of reactive oxygen species (ROS) and decrease cellular energetics via changes in mitochondrial functioning. Mitochondrial damage evokes multi-system, seemingly disparate illnesses, much like what we are seeing. Cerebral mitochondrial dysfunction can cause serious cognitive and behavioral symptoms.

Clue 5. Thyroid and mitochondrial health are reciprocally connected. Damage the thyroid and mitochondrial functioning diminishes. Damage the mitochondria and thyroid functioning diminishes. We have two factors that are inherently related.

Thyroid and Mitochondrial Functioning

What factor could initiate a thyroid – mitochondrial cascade and connect completely dissimilar drugs to these reactions; reactions which are often complex, affect multiple physiological systems, but are also integrally dependent upon proper thyroid and/or mitochondrial function (because of their reciprocal relationship)?  Could there be such a connection?  A few more clues.

Clue 6. A heartwrenching patient story: A Long and Complicated History Topped by Levaquin, highlights a particular set of neurological symptoms that every neuropsych student should immediately recognize.

Clue 7.   Patients from the post fluoroquinolone and the Gardasil groups have been identified clinically with thiamine deficiency. I suspect post Lupron patients may also have thiamine deficiencies, but none have been tested yet.

Clue 8. Both the fluoroquinolones and Gardasil increase thiaminase, an enzyme that blocks thiamine. Higher thiaminase means lower thiamine. Oral contraceptives are believed to increase thiaminase and so women using oral contraceptives in combination with a fluoroquinolone and/or the HPV vaccine Gardasil or Cervarix would be at higher risk for thiamine deficiencies.

Drug Induced Thiamine Deficiency, Cognitive Deficits – The Mechanism

It turns out, thiamine deficiency, or more specifically, a medication induced blockade of thiamine may be at the root of these adverse reactions. Thiamine is a co-factor in mitochondrial and cellular energy, the currency of which is adenosine triphosphate (ATP).  Without thiamine, the mitochondria become defunct, as do the cells in which they reside, and they eventually die. High energy organs like the brain, the heart and the GI tract are often affected dramatically. Similarly, given the reciprocal relationship between the thyroid and mitochondrial functioning and their combined influence on cerebral, cardiac and metabolic homeostasis, diminished drugs that attack the thyroid and diminish thiamine may be doubly dangerous.

In most recent work, thiamine deficient syndromes have been expanded to include five conditions, with fair degree of overlap between them.

1. Gastrointestinal beriberi: abdominal pain, lactic acidosis, vomiting.
2. Neuritic beriberi: sensorimotor polyneuropathy, peripheral neuropathy (likely multiple B vitamins involved).
3. Dry beriberi: high output cardiac disruption without edema
4. Wet beriberi: high output cardiac disruption with edema (dysautonomias, including POTS)
5. Wernicke’s encephalopathy: mental status changes, ocular abnormalities, gait ataxia

Given the current nutritional trends with high intake of sugar, fats and processed foods, it is likely that when these medications directly block thiamine production, they do so against the backdrop of already suboptimal thiamine intake. When we consider that oral contraceptives block also block thiamine and that women are more likely to already suffer from low thyroid function, the effects of either the fluoroquinolones or Gardasil on the mitochondrial thiamine could be devastating. How many other medications or vaccines affect mitochondrial functioning and/or thyroid health? How many other medications or vaccines contain anti-thiamine components and diminish this critical mitochondrial co-factor?

Loss of Reading Comprehension and Other Missed Opportunities

Thiamine deficient cognitive decline is well characterized and includes the loss of language comprehension, in more severe cases, deficits in language production, cerebellar ataxia, tremors and as it progresses, seizures, coma, and death. All reversible with thiamine replacement. The cognitive deficits reported by patients, post medication or vaccine reaction, when observed alone but especially when taken in combination with the other tell tale signs of incipient thiamine deficiency, could have lead researchers or clinicians to these diagnoses. At the very least, it should have lead clinicians to thyroid dysfunction, but more often than not, this was not the case.

Cognitive deficits in previously high functioning individuals are reported regularly after medication or vaccine reactions. Almost to a tee, most are ignored once imaging tests rule out blatant injury, but they shouldn’t be. These deficits, when functionally assessed, would provide valuable clues regarding the regions of the brain most susceptible to medication or vaccine induced injuries; clues that could identify damage and disease processes well before detected by imaging tests. By dismissing patient complaints of cognitive deficits we lose valuable research, diagnostic, and therapeutic opportunities. And perhaps, even more importantly, when we segregate symptoms by organ or body part and fail to see the inherent connections among symptoms and physiological systems, we miss the opportunity to help patients heal.

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This post was published originally on Hormones Matter on May 21, 2014.

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