Hi, everyone. I'm Dr. Deepa Malyandi, and welcome to the neuroendocrine lecture in this series. I have no conflicts to declare. After completing this lecture, you should be able to recognize the clinical presentations for pituitary apoplexy, diabetes insipidus, the syndrome of inappropriate antidiuretic hormone release, cerebral salt wasting, and decompensated hypothyroidism, previously referred to as myxedema coma. You should also be able to list the diagnostic criteria and describe the initial management for each of these. These objectives are taken directly from the specialty certification exam in neurocritical care website regarding their content outline. As you can see, the topics we're focusing on are the ones in orange, so just make sure you set aside some time to review the others on your own. Before we get into the individual diagnoses, we'll do a very brief review of the relevant physiology. For what we'll be covering, we'll be focusing on the hypothalamic pituitary axis. So starting with the hypothalamus, we have all of the releasing hormones that act on the anterior pituitary, as shown here. So that's growth hormone-releasing hormone, or somatotropin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and gonadotropin-releasing hormone. Also there's dopamine here, shown in red, just to emphasize and remind that it acts on the anterior pituitary to inhibit prolactin release. In response to the releasing hormones, the anterior pituitary then releases growth hormone, thyroid-stimulating hormone, adrenocorticotropin hormone, and follicle-stimulating and luteinizing hormones. The intermediate lobe of the pituitary releases beta-endorphins and melanocyte-stimulating hormone. Lastly, the posterior pituitary stores and releases oxytocin and ADH produced by the paraventricular and supraoptic nuclei of the hypothalamus, respectively. As mentioned, our focus will be on thyroid, adrenal, and antidiuretic hormone-related pathologies, and we'll be covering this content through five fictional cases. Our first case is that of a 19-year-old man with no prior past medical history who's admitted to the neuro-IC with multi-compartment TBI following a dirt bike accident. He was intubated in the field for a GCS of 5. He's post-op day zero from craniectomy evacuation and decompression of an acute right epidural and subdural hematoma. The remainder of his trauma complex includes multiple bilateral isolated rib fractures and pneumothorax, and he's status post chest tube placement. There was no other organ injury or sources of blood loss. We're notified by his bedside nurse that he's becoming hypotensive, and his urine output has increased to greater than 300 mLs per hour for the last two hours. So what we're going to cover is what is a suspected diagnosis, how can the diagnosis be confirmed, and what will be the treatment. So the suspected diagnosis for clear polyuria leading to hypotension and severe TBI is central DI until proven otherwise. Severe ADH deficiency results in the free water diuresis that is characteristic of DI. Normally, as seen here on the right, hypovolemia and increased plasma osmolality will result in ADH release from the posterior pituitary where it's stored. This drives thirst as well as water reabsorption from the kidneys. In TBI, as in our case, there's hypothalamic posterior pituitary dysfunction from direct injury, but it can also be seen in inflammatory conditions such as infection, autoimmune disease, and infiltrative processes such as neurosarcoid, histiocytosis, and lymphocytic hypophysitis. Other possible etiologies are vascular, genetic, or congenital, as well as microthrombi or fat emboli, which is what is thought to cause transient DI in postoperative cases, particularly spinal cord injury and other orthopedic surgeries. In order to diagnose DI, serum sodium, osmolality, potassium, calcium, and urine osmolality in specific gravity should be obtained emergently. The potassium and calcium levels are included to evaluate for possible hypokalemia or hypokalemia as an underlying cause for the polyuria. There are no standardized diagnostic criteria, as you can see here, with the various options for urine output thresholds, but I tend to find the 300 mLs per hour for two or more hours the easiest to identify in the unit. Once that threshold has been reached in the appropriate clinical setting, the labs mentioned should be sent. If the sodium is greater than 145, the urine osmolality is less than 300, and the spec grab is less than 1.005, then the diagnosis of DI can be made. Once the diagnosis is made, the medical management involves four main actions. The first goal is to restore volume. If there's hypovolemia causing hemodynamic instability, the priority is to replace the circulating volume with isotonic fluids. Once hemodynamic stability has been achieved, the next goal shifts to replacing free water and ADH. To replace free water, those who are awake and able should be encouraged to drink to thirst. When this is not possible, free water can be replaced via enteral access tubes, which is the preferred route in the neural population. If unable to replace enterally, intravenous free water replacement can be used. ADH is also replaced simultaneously in anyone who cannot drink to thirst or if despite drinking to thirst, the urine output remains above 250 mLs per hour. Typically, the dose is between 0.4 to 1 microgram subcutaneously and titrated to urine output. The fourth step is to monitor treatment results with serial labs about every four hours. Another reason to follow serial labs is to watch for transitions to SIADH or rarely cerebral salt wasting syndrome, which can develop and will be discussed further in the coming slides. There are a few courses of DI to be aware of. So there's early onset DI, which is commonly seen within the first hour of severe TBI. DI can be transient, such as seen in post-surgical, DI or it can be permanent. And lastly, it can follow a triphasic or a triple phase course. This is most often seen in cases where the pituitary stock is transected. Initial shock results in DI followed by an excess release of stored ADH causing a phase of SIADH, which will then eventually transition back to DI on the third phase once the stored ADH has been depleted. The serial labs we send can help identify these phases. Okay, so for case number two, we're still working with our 19-year-old gentleman with the multi-compartmental TBI. So following treatment with intermittent doses of DDAVP and enteral free water from post-op day one and two, his sodiums had normalized. No DDAVP has been required since post-op day three and free water has been discontinued. It's now post-op day four and he is starting to develop hyponatremia. Sodium has decreased from 143 to 133 millicovals per liter in the last 36 hours, despite discontinuation of all his central DI treatment. On exam, he appears euvolemic. He is a net two liters positive and otherwise his labs are within normal limits. So now what is the suspected diagnosis? What are the next steps in the diagnosis and what is the next best step in the management of this patient? So now in this scenario, the trend is moving towards euvolemic or hypervolemic hyponatremia, which raises concern for transition into an SIADH phase of the triple phase DI syndrome. In the SIADH phase, the excess ADH secretion results in free water retention, effectively diluting normal total body sodium. As we know, SIADH is itself extremely common in hospitalized patients and can be caused by nausea, thirst, pain, fever, hypoglycemia, stress, many medications, other electrolyte abnormalities such as hypokalemia, infections, tumors, and so on. So specific neurological injuries with high rates of hyponatremia are listed here. Subarachnoid, TBI, stroke, cerebral tumors, CNS infections, and GBS. And we'll cover them in a little bit more detail in a few slides from now. So SIADH requires euvolemia to mild hypervolemia, but volume status in the ICU patients can be challenging to determine. One of the problems with diagnosing the proper etiology of hyponatremia in the neuro unit is that the full workup is rarely sent. For that reason, the following diagnostic criteria were proposed in 2016. So first, normal thyroid and adrenal function should be confirmed. Most neuropatients do have a TSH with reflex on admission, but cortisol is not always tested. If there is suspicion based on other signs or symptoms, it should be. Then they have to meet any two of these four criteria, which include the absence of hypovolemia findings on exam. There should not be any lab evidence of dehydration. There should be a net positive fluid balance or a CVP of greater than six. So the standard approach to management is free water restriction, which is not always appropriate or safe to trial in all neuro ICU patients. In this case, hypertonic saline boluses as needed to restore sodium concentration by providing a little less, by providing as little free water as possible can be helpful and can be combined with loop diuretics if needed. If it's part of a triple phase DI syndrome, hypernatremia returns around week two. And in refractory cases of SIADH, VAPTANs can be considered, but you do want to make sure that you are certain about the volume status and the diagnosis simply because VAPTANs are contraindicated in patients with hypovolemic hyponatremia. And that brings us to case three. So now we have a 47 year old woman who has length of stay day seven in the neuro ICU with a HUNT S4, modified Fisher IV, right A1-ACOM junction aneurysmal subarachnoid hemorrhage, who has post bleed day seven, post coil day six, and post EVD day seven. Over the past 48 hours, her sodium level has started to trend down from 141 to 137 to 132 this morning. And urine output has been increasing. She's net negative two liters for the past two days. Also she has a slight leukocytosis at 12.5, increase in hemoglobin from 10 to 11.5. Her BUN is up from 17 to 28 and her TCD velocities are increased this morning. She's also complaining of increased headache and nausea. So what's the cause of the hyponatremia here? What diagnostic workup should we pursue? And how should we manage this patient? So this case demonstrates cerebral salt wasting syndrome. We had clues in the stem of hypovolemia and hyponatremia with ongoing inappropriate high urine output. There are two main hypotheses for the pathophysiology that drives this presentation. The first supposes that the juxtaglomerular apparatus dysfunctions because of impaired sympathetic tone leading to decreased sodium urate and water reabsorption in the proximal tubule and decreased renin and aldosterone release. The second theory is that ANP and BNP lead to increased sodium and water loss. The diagnostic criteria for cerebral salt wasting syndrome were also proposed by the same authors in 2016 and also requires normal thyroid and adrenal function, and instead requires two of the opposite four criteria to those proposed for SIADH, and I have them listed here. In terms of management, there is an option to do a trial of normal saline to assist in diagnosis as well, based on the theory that cerebral salt wasting syndrome should improve following the replacement of volume and correction of hyponatremia. In most cases of SIADH, normal saline will result in further sodium drop from retention of the free water component. However, sometimes it's not enough salt and hypertonic saline is needed to adequately correct the sodium in cerebral salt wasting as well. So despite the criteria we reviewed, it can still be clinically challenging to differentiate SIADH from salt wasting because extracellular fluid volume can be hard to assess after days of inpatient stay. Eyes and nose become less accurate as do weights. Also urine output following either aggressive volume resuscitation or diuresis can be misleading. This is a chart summarizing the different diagnostic studies that can help distinguish the two as well as some common pitfalls that can mislead their interpretation. Hopefully this will be helpful to come back to during your review so that they are all on one slide, and we'll review them now in a little bit more detail. So as far as volume status go, you can look at vital signs first. So blood pressure, heart rate, weight, all of these should be about normal to slightly high in SIADH. Blood pressure and weight go down in salt wasting given the hypovolemia, and then you do see that reflex tachycardia. Obviously there's a number of factors that can affect these vital signs in a patient who's been admitted for some time. As far as labs go, you can look at the BUN, the hematocrit, albumin, cerumeric acid, all of these, and you can see that they're also about normal or decreased in SIADH where they're all sort of increased except for the cerumeric acid and cerebral salt wasting where the cerumeric acid level is low in both SIADH and cerebral salt wasting initially, and we'll look at some more information on that in the coming slides. But again, just to be aware, there's a number of factors that can affect each of these labs and how informative they end up being. CVP or wedge pressure from a volume status determination standpoint are both normal to increase in SIADH, decrease in cerebral salt wasting. These are both invasive obviously, and it's not that you would obtain any one of these simply to differentiate the two diagnoses, but if you happen to be monitoring these things anyways because of other things going on with the patient, then they can help provide some insight. As far as the skin mucosa goes, should be normal in SIADH with possible evidence of dehydration or decreased skin turgor with salt wasting syndrome, but we all know this is a subjective assessment as well. And then last, from a perspective of sodium balance, the BNP, which is normal in SIADH, will be expected to be elevated in salt wasting, but it would also be elevated if there's heart or lung disease, age, and some stress settings. Urine output is typically normal or low in SIADH, whereas it's increased in cerebral salt wasting, as far as use of diuretics and replacement IV fluids, which we do commonly, can also make these less accurate. And then lastly, while the urine sodium is increased in SIADH, it's significantly more increased in salt wasting. But this can also be confounded by the use of hypertonic saline or salt tabs and diuretics as well. So we talked about serum uric acid levels in the last slide, but another helpful value is actually the fractional excretion of urate. So the normal range is between 4 to 11%. And as we said, in salt wasting, there's an excess excretion of uric acid. And so while the fractional excretion of urate should normalize after correcting the hyponatremia in SIADH, it will stay high in salt wasting syndrome. So that can be helpful as well. So previously, we briefly covered a list of neurological diagnoses in which hyponatremia commonly develops. We're going to go over this slide in a little bit of detail that shows us a little bit more information on that. So as far as subarachnoid is concerned, you know, there's an incidence of about 40 to 60%, which is fairly high. The risk factors are high-grade subarachnoid anterior location and presence of hydrocephalus. You can see that the timing of the hyponatremia develops around the same time as peak vasospasm. And you can see that SIADH is far more common than salt wasting. However, so the incidence of salt wasting or likelihood goes up with the higher HUNT-TEST grades. With CNS infection, again, a decently high incidence, close to 60%. The risk factors being low, younger and older age, as well as IVIG, and it's italicized here, just to remind us that IVIG can cause a pseudohyponatremia anyways. No real data on timeframe, but some patterns that have been reported are that tubercular meningitis is more likely to lead to salt wasting, though children are more likely to see SIADH with CNS infections. And that in tick-borne encephalitides, you're more likely to have hypovolemia with hyponatremia, which may look like cerebral salt wasting syndrome, but it may actually be different etiology or pathophysiology. In terms of TBI, you know, up to half the patients you can see this in. The risk factors for hyponatremia in this group are higher Rotterdam scores on CT, presence of cranial fractures, higher IV volume given by day three. The timeframe is typically day three to 14. Again, SIADH is more common than salt wasting. On the incidence of salt wasting, the estimates are, you know, pretty far ranging. In terms of GBS, you know, similar rates to TBI of hyponatremia, risk factors here are older age, anemia, alcohol abuse, hypertension, and again, the IVIG, which we discussed above. Typically, the hyponatremia sets in around day eight. Again, SIADH is more common than salt wasting, not to say that salt wasting doesn't occur, and that I should qualify that by saying cerebral salt wasting because rarely renal salt wasting can also be seen. As far as all stroke comers are concerned, hyponatremia is less common but is increased risk factor with increasing age. Typically, in intracerebral hemorrhage, it's within the first seven days, and then SIADH still more common than salt wasting, and rarely you can also see renal salt wasting here as well. And lastly, with brain tumors, we see the lowest incidence range. Again, we see this with the extremes of age, so younger than seven or greater than 60. Things that otherwise affect the rate of hyponatremia development are tumor size, female sex, an increase in the amount of time they're in the OR, presence of Cushing's, hyponatremia by post-op day one or two, and then particularly, tumors that involve the pituitary axis like craniofrangeomas and Rathke's clefts can also increase the risk of this. Typically, you see a delayed hyponatremia, sorry, between post-op day four to ten, and you can also see SIADH between day seven to 14. In adults, SIADH is more common, but interestingly, in children with brain tumors, salt wasting is more common than SIADH. Okay, so our next case is case number four, which is of a 28-year-old woman who presents to the ED with acute onset severe headache, dizziness, and visual disturbances. Her vital signs are a temperature of 38.2 degrees Celsius, a blood pressure of 88 over 40, heart rate is 110, respiratory rate is 15, exam is pertinent for photophobia and bitemporal hemianopsia. A CT scan was done that demonstrates a possible hyperdensity within the pituitary gland. An MRI with and without contrast was recommended and has been ordered. So what's the diagnosis here? What are the MRI findings we can expect? What's the next best step in the management? And does this patient need emergent or surgical intervention at all? So the bitemporal hemianopsia we described localizes to a lesion of the optic chiasm, which fits with the CT findings of a hyperdensity of the pituitary gland. This suggests pituitary apoplexy, given the overall clinical picture. It's typically caused by either hemorrhage or ischemia and infarct, or in most cases, both. Clinically, it can be thought of as the other thunderclap headache. And the reason is that there can be subarachnoid hemorrhage here, as well as the pain of dural traction. They can also complain of blurred vision and nausea and vomiting are common complaints as well. The signs include impaired visual acuity, various field deficits, depending on which part of the optic nerve and chiasm is most affected. Of these, bitemporal hemianopsia is the most common. Of the oculomotor palsies, a third nerve is most common. And less commonly, you can see anosmia, apostaxis, CSF rhinorrhea, and facial pain from cranial nerve 5 compression that can manifest. You may also see a meningeal signs, including signs of, including fever. From a functional standpoint, you can have acute adrenal insufficiency, either hypo or hypernatremia, depending on if ADH secretion is deficient or in excess. And lastly, the most grave presentation would be coma. So, risk factors for apoplexy are present in up to about 40% of cases. The risk is higher in nonfunctioning tumors because they're often diagnosed later when they are also larger and therefore more likely to undergo necrosis. Of note, dopamine treatment for prolactinoma does not seem to increase the rate of pituitary apoplexy compared to those who are not treated with dopamine. The surgeries listed here are all risk factors. If pituitary tumor or history of apoplexy is already known, consider off-pump cardiac surgery for these patients. Obviously, this would require being cared for in a specialized center. And then otherwise, risk factors are hemohypoperfusion, trauma and in response to dynamic hormone testing, as well as prostate cancer treatments and anticoagulation. So, what could be expected to be seen on the MRI you're going to be getting for this patient? So, you can see mixed ages of blood within the gland, which are shown in yellow between the T1 and the T2 weighted images. You can also see mixed and or heterogeneous enhancement within the gland. And then as seen here in the white arrows, you can see that there is expansion of the gland causing compression of the optic chiasm, as well as the adjacent cranial nerve structures. And then lastly, in red here, you can see that there's inflammation of the sphenoid mucosa. And interestingly, the degree of this mucosal thickening correlates with the severity of apoplexy, as well as long-term neurological and endocrinological outcomes. Additional information can be obtained from the diffusion weighted apparent diffusion coefficient and gradient echo sequences shown here. So, the white arrows here and here are essentially showing an area on the DWI that is bright in intensity, and here, which is dark correspondingly on the ADC, indicating infarct within the pituitary gland. And also here on the GRE, we're seeing multiple areas that are showing blooming artifact or that are dark consistent with hemorrhage. And this yellow area is highlighting one of these areas of hemorrhage within the gland. So, the next question is, how do we manage this condition? Acute things to worry about first are if there are, if there is a rare finding of acute hydrocephalus requiring an emergent EVD placement, this is very, very rare. The other is acute hormone insufficiency with adrenal insufficiency being the most urgent. So, you'd want to start high dose hydrocortisone bolus and then schedule dosing. And just remember, for the purposes of treatment thresholds in the ICU, generally a cortisol cutoff of less than 15 is used given we anticipate a high stress or a increased stress response, so there should be cortisol higher than normal resting state. And then central DI can also be seen, but we've already covered sort of how to manage that. And the others require less acute treatment and rarely require acute treatment. The other goal of treatment is to manage the mass effect on local structures such as cranial nerves, and that treatment can be achieved either medically or surgically. So, we'll take a look at that as well. The indications for surgical management are either reduced level of consciousness if there is a severe visual deficit and or other focal neurological signs. Much of the literature has significant enrollment bias, but essentially, for those who do not meet the criteria we covered, there's no significant difference in outcomes with surgery versus medical management. And in some cases, surgery did lead to increased rates of long-term hormone deficiencies and longer duration of central DI, which makes sense because you're actually resecting parts of the gland that may be functioning. We saw from the MRI that the involvement can be very patchy. The main complications to watch for post-operatively if surgical intervention is pursued is a CSF leak. And if it's noted in the OR, there may be primary repair done and may or may not have a lumbar drain place. If the leak presents itself in the ICU, a lumbar drain can be tried. And if there's a persistent leak, then it would be back to the OR for repair. So now we're on to our last case, which is of a 37-year-old woman with a history of epilepsy whose last seizure was a year ago. And she's now admitted to the neuro-ICU in status epilepticus. All anti-seizure medication levels are within normal therapeutic range. Vital signs are temp 35 degrees, heart rate 50, blood pressure is 88 over 53. Her respiratory rate is 18, but she's not breathing above the ventilator, and she's setting 100% on an FiO2 of 0.4. She remains comatose, GCS is 5T, and periorbital edema is noted. Labs are revealing for hyponatremia, hypoglycemia, but no signs of infection. And chest X-ray reveals pulmonary edema. Both a CT and CTA of the head were completed along with an MRI of the brain, and all of these are unrevealing for any acute pathology. Her EEG shows diffuse slowing, but no epileptiform discharges or electrographic seizures are seen. So again, what's the diagnosis, how is the diagnosis made, and what is the next best step in the management of this patient? So the diagnosis here is decompensated hypothyroidism, which was previously called mixed edema coma. And the reason for the change in terminology is that neither mixed edema nor coma are required to make the diagnosis, and the treatment would be the same with or without the mixed edema or the coma. So you want to make sure you consider this diagnosis in anyone with altered mental status, hypothermia, hypotension, or bradycardia. This can present with either a high or low TSH, depending on whether or not the problem is in the pituitary, the hypothalamus, or the thyroid gland itself, right? But you want to make sure that the T3 and the T4 are low. So this is just a summary list of signs and symptoms of decompensated hypothyroidism by system for your review. And as we know, the thyroid hormone and thyroid function affects all the organ systems, so it's a little bit of just a listing. The management always starts with the ABCs. Remember that the airway may be difficult, secondary to mucopolysaccharide deposition, which can cause macroglossia, as well as laryngeal edema. Also, there's already compromised cardiopulmonary reserve. The hypotension can be either from hypothyroidism, relative adrenal insufficiency, or both. So anytime you have refractory shock that's not responsive to fluids and pressors, while most of the time we consider adrenal insufficiency, make sure you consider this diagnosis as well. And just to note that the hypothermia should not be rapidly corrected with warming blankets and bear huggers and all of these things. Best rewarmed at room air because the vasodilation from warming can lead to worsening shock. You also need to make sure you correct the hypoglycemia and electrolyte derangements as you're going. And then make sure you give the hydrocortisone first, so that's 100 milligrams IV Q12 hours. If you give the thyroid hormone first, you can precipitate an adrenal crisis because of the sudden kickstart to the system. So to replace the thyroid hormone itself, current data supports replacing a combination of T3 and T4. So active T3 does increase the risk of tachyarrhythmias and diastolic hypertension. So in those with coronary artery disease or who are elderly and have a history of arrhythmia, consider lower dose ranges or consider T4 supplementation, particularly if you're doing this empirically while you wait for labs to come back, because you're less likely to cause complications with IV T4, which still needs to be converted to T3 to be active in the system. So that's the safer option, but if you have a confirmed diagnosis or a high enough suspicion in someone who's low risk, combination treatment would be ideal. And of note, not every institution has T3 on formulary. The Peel formulation does have a 95% bioavailability, but if you do have the IV option, it would be the best for the first few days, at least, since the gut may not be working at the time of presentation. Okay, so that was our last case, and I just wanted to thank all of you for your attention, and I'm happy to take any questions.

neuroendocrine lecture

clinical presentations

diagnostic criteria

initial management

hypothalamic-pituitary axis

pituitary apoplexy

diabetes insipidus