 We're a medical student from the Kirksville College of Osteopathic Medicine in Missouri, and he will be talking about minocycline-induced intracranial hypertension. Okay, thank you for this opportunity. And I think in the interest of time, and we do have a third presentation, correct, then we'll just cruise through this pretty quickly. The case is a patient who presents with a bilateral transient visual obscurations in a vision and the occasional dim-outs. The history of her presentation is a 23-year-old female. In August, she complained of a plugged sensation in her riot ear and a pulsatile tinnitus or a whooshing in the left ear greater than the riot ear. About a week later, she went to her ENT, who treated her for an internal ear infection and gave her mucinex to try to decrease the congested sensation, which offered no relief of her symptoms. About that same time, she began to notice gray spots in her vision. The ENT ordered an MRI of the brain without contrast, which came back unremarkable and recommended that she go to see an ophthalmologist. The ophthalmology exam showed bilateral discodema and decreasing visual acuity from her baseline, and she was then referred here to the Moran Eye Center in her ophthalmology department. Throughout this course of her history, she did have mild, I'm sorry, moderate to severe headaches, which were and postural dim-outs of her vision. As far as her pertinent medical history, it was pretty empty, except that she was being treated for acne vulgaris with minocycling. Family history, social history, and the review of symptoms was unremarkable. Her exam initially was also unremarkable, I'm unsure, about three months, but that does bring up a good question we'll talk about in a little bit. She was able to read the 2020 line on exam, although it did seem to be kind of eccentric and definitely slower than what she was used to. People showed no apparent pupillary defect, no apparent problem on confrontational visual field. Her interocular pressures were normal, and she had full color vision and full extracular movements. Here's a copy of 24-2 Humphrey visual field that was obtained in the clinic. You can see on this exam enlarged blind spots in both eyes, and maybe even a secocentral visual defect here. The foveal threshold in the large blind spots were bilateral in a mean deviation of minus seven in the right eye and minus four in the left eye. On slit lamp exam and neurological exam, those were unremarkable with no focalizing defect or apparent problem on the anterior slit lamp exam. Although fun, this exam, as illustrated here, revealed pretty strong stage four to five papillodema bilaterally with loss of the physiologic cup, parapapillary halos, obfuscation of the vesicles both as they leave the cup and even centrally as well with splinter hemorrhages. We begin thinking of how to build a differential that causes for papillaria edema. The best way to think through this is the Monroe Kelly postulate, which is based on three premises. First that the cranium is of a fixed volume and is non-compliant and non-expansable. The pressure inside the cranium is a function of the volume of the contents, so the contents of the cranium being brain tissue, blood, and CSF. An increase in the volume of any of the three components will either necessitate an increase in the pressure of the cranium or a lessening of the volume of a constituent component. Thinking through a possible differential list, you need to consider changes in brain tissue volume which may include cerebral edema or mass effects, changes in blood volume which may include things like hemorrhages, changes in CSF either by increased production like an inflammatory process or the reduction in outflow of CSF by a process which blocks the outflow. So you can create a differential along those lines and examples of these could include things like venous sinus thrombosis, intracranial mass, hydrocephalus as well as others. On workup, we are going to look to see if indeed she does have increased intracranial pressure associated with her papillodema. So we want to do a lumbar puncture. The opening pressure of this patient was 50 centimeters of water and the CSF analysis otherwise was normal with no left shift or increased proteins and negative cultures. And then we want to review the MRI to look for signs of increased intracranial pressure. On this axial section of a T2 weighted image, you can see here that she does have posterior flattening of the globes in the sclera. You could probably also appreciate some of the papillodema here into the globe although she doesn't have any of the other signs that we may see on MRI which includes increased signal intensity of the optic disc, optic nerve sheathing although it kind of looks like on this picture, it's kind of equivocal as well as a flattening of the pituitary glider and empty cell on a sagittal view. But I think that the negative findings are perhaps just as important especially when considering a diagnosis of increased intracranial pressure. For example, no mass is found, there are no filling defects found in the dural sinuses, no hemorrhage was seen, no edema, no chord plexus adenoma for example. And so these negative findings need to work into our differential as well. Using the modified dandy criteria, we are able to see that this patient does have signs and symptoms of increased intracranial pressure such as visual obscurations, dimouts, papillodema on exam, she does complain of a pulse tinnitus and headache, as well as no other focalizing neurological symptoms. Elevated intracranial pressure on CSF analysis was apparent and there was no ideology seen on imaging for that increased intracranial pressure. So let's talk a little bit about tetracycline and their relationship to intracranial hypertension. The first mention that I was able to find was an editorial comment by a physician Gellis in the yearbook of pediatrics where he was first to kind of put the label as a bulging-Francinel syndrome on infants who were being treated with tetracycline. This was done in 1956. It took a full 11 years for the first description of tetracycline-induced intracranial hypertension to appear by Dr. Koch Weiser and Gilmore in the Journal of the American Medical Association. During the intervening period, there were many descriptions of the bulging-Francinel syndrome and since this time in 1967, there have been quite a few case studies regarding the connection between tetracycline and intracranial hypertension. Minocycline is a semi-synthetic derivative of tetracycline. The advantage for treating acne vulgaris is that it requires only daily or bi-daily dosing rather than the four times a day of tetracycline or the first-generation tetracycline. And that the dosing strength is generally lower due to the increased half-life and the increased activity in the serum. One thing that is important to understand is that it is three to five times more lipophilic than tetracycline or the first-generation tetracycline which means that it penetrates into the CSF through the blood-brain barrier more readily and can sit there and cause effects. The link to intracranial hypertension was first described for minocycline specifically by Monica in 1978 and one of the interesting things through the research is that minocycline may cause intracranial hypertension in the atypical patient meaning non-obese females in males or in adults or children. So a few key questions will come up in relationship to minocycline and intracranial hypertension. First of which is what is the actual incidence of minocycline causing increased intracranial hypertension and that question can't really be answered very well. The reason that can't be answered very well is that there hasn't been any cross-sectional studies to show what the actual incidence is. Minocycline is pretty frequently and commonly used by dermatology to treat acne as a first-line therapy and as a result you would expect that if there was a very strong correlation or a direct action of minocycline raising intracranial pressures that the incidence of minocycline caused intracranial hypertension would be quite high just based on the prevalence of the use of minocycline as that was postulated by Chu in 1998. But in addition doctors Maroon and Mealy in 1971 suggested that there are cases of not only asymptomatic intracranial hypertension and incidental findings of papillodema on exam associated with minocycline use that the actual incidence may be under-reported or the prevalence of increased hypertension may be under-appreciated. Who is the population at risk? Generally the incidence across the broad population of people is about 0.9 per 100,000. That does increase quite a bit if you restrict the population to obese females of child-bearing age and that incidence will increase anywhere from 13 to 19 out of 100,000 in the literature that I have seen. The problem with the incidence associated with minocycline and assessing a population at risk again falls on the same problems of are there unreported cases because of asymptomatic papillodema or asymptomatic intracranial hypertension associated with minocycline use but it does seem that the power of minocycline to induce this is not simply associated with the common risk factors of the general population of gender, of weight and of age because as more Monroe and Brain and Walker have stated that you can have minocycline-induced intracranial hypertension associated with males, with children and as well as non-obese females. What is the prognosis? Prognosis for minocycline-induced intracranial hypertension is generally good but that comes with a caveat and one of the caveats is that some of these case studies have reported an apparent division in the population of those who are affected by minocycline and that is that some of them will have an indolent course. Often the majority of cases in the case studies will have a slowly progressive course on set of headaches that gradually worsen visual obscurations which gradually worsen and those respond very well and quickly to cessation of minocycline as well as treatment with dimox. But there is a smaller subset of patients for which the course of the disease may be much more fulminant that there is a more acute presentation of headaches, more acute vision loss and symptoms associated with intracranial hypertension which doesn't respond as quickly or as well to therapy. In fact Gardner has given the possibility that there may be a genetic predisposition in the population to a response from an adverse response to minocycline therapy which creates a debate about whether or not minocycline is directly involved or if it is affecting a different population in a different manner. Perhaps that minocycline may be something that pushes a patient across a threshold into intracranial hypertension which brings up the question of what is the mechanism by which minocycline may cause intracranial hypertension and that has been unknown although there have been reports by Stuart that minocycline has an indirect effect on cyclic adenosine monophosphate within the arachnoid granulation in the subarachnoid where CSF is drained back into the dural sinuses and by decreasing the activity of cyclic adenosine monophosphate you are decreasing the reabsorption of CSF back into the systemic circulation causing congestion but that has not been elicited in the literature. Going back to our case the final diagnosis then is the intracranial hypertension secondary to minocycline use. The plan and the general treatment guidelines include immediate discontinuing of minocycline therapy. Diamox sequels has become the standard of care although it has not been established by any prospective research. The known effects of diamox on reducing intracranial pressure kind of sets itself up for becoming the first line therapy although the dosing that we have given her can vary quite a bit on a per patient basis as you consider the clinical experience of the clinician as well as the clinical signs and symptoms of the patient as well as weight management and patient education regarding intracranial hypertension. On one month follow-up the patient reported improved vision. She denied any headaches and pulse of tiled tinnitus. Her vision was stable and improving. Papillodema was reduced at one month to a stage three and visual fields improved with decreased physiologic blind spots and mean deviations also decreased. She was continuing on diamox at her current dosing with the plan to return one month and reevaluate at that time. Now a lot of the research has been well actually all of the research that I have read on minocycline induced intracranial hypertension has been exclusively case studies or case series presentations and as such there hasn't been a formalized even retrospective study or prospective study of minocycline's connection although there have been reports of varying degrees of the duration of minocycline use leading into intracranial hypertension. Anything from three days from the onset of therapy to weeks or even years later where minocycline may cause this intracranial hypertension syndrome and the cessation of minocycline kind of follows the same course in regards to the resolution of the symptoms. There were some cases where especially in the sorry especially in the older literature in the 70s where cessation of minocycline or tetracycline is generally caused almost an immediate approval of symptoms within the same day to some of the symptoms being recalcitrant to therapy even months and years later. The most common persistent effects would be things such as reduced visual acuity and visual field defects and that's it. Are there any questions? She wasn't incredibly tall and she was obese and that was definitely a confounding variable in this case and something to consider which is why we included in the plan weight loss and education in that regard. I don't think that you can definitively parse out the two in this case although the reports in literature that minocycline has induced this syndrome in non obese females as well. She didn't have a significant weight gain history either. She didn't report sudden weight increases or fluctuations in her weight in the years prior to presenting to us so that may reduce a little bit of suspicion but we can't definitively say that that did not play a role. There are reports in the literature of using topomax based on the idea that it does lower intracranial hypertension but the biggest problem with that is that there's no prospective study comparing topomax to dimox or even alternatives like loop diuretics for example all of which have been used in treatment. I do think that there is a spectrum of therapy options available to the clinician which also includes eventual surgical intervention to help resolve the symptomatology after maximum medical therapy has failed. Unfortunately I have read that topomax has been used and has been used successfully in the literature but there's a pretty bad dearth of support for besides case studies. Dr. Warner.