Hello, my name is Alicia Alcamo and I am from the Children's Hospital of Philadelphia. This lecture will be on inborn errors in metabolism and rheumatological diseases. This is a large topic to review. We will talk through algorithms for diagnosis of inborn errors in metabolism, talk through some key points for mitochondrial disorders, and then review some key rheumatological disorders. In inborn errors in metabolism, you have an enzyme that becomes deficient or dysfunctional. This typically occurs during and is unmasked in a period of stress. This may include acute infection, surgery, trauma, fasting. This enzyme deficiency or dysfunction leads to a decrease in the metabolite. Or on the other hand, you may have a point where you actually increase the substrate. A prime example of this would be when a baby switches from breast milk to cow's milk and there's an increase in protein consumption. This increase in substrate or decrease in metabolite is what leads to the clinical manifestations that are seen within that inborn error in metabolism. This lecture will not review all the different types of inborn errors of metabolism, but we will highlight a select few. This slide here just demonstrates the wide spectrum of inborn error of metabolisms that you may see throughout your career. Presentations of inborn error of metabolism disorders are typically acute and involve multiple different systems. Presentations with neurological symptoms such as altered mental status, encephalopathy, seizures are the most common. And this is followed by the presence of GI symptoms as the second most common presenting sign or symptoms. And this includes vomiting, diarrhea, poor feeding. Most cases will appear in infancy or childhood, but there are cases that do present in later adolescence or adulthood. And really inborn errors of metabolism should be considered when there is an overwhelming illness that does not rapidly prove its etiology. It's important to have rapid identification or suspicion that an inborn error of metabolism may be present. Seeking through the different types of presentations that the inborn errors of metabolism may have, you will see that there are some that present with kind of classical symptoms that should be considered. For instance, those that have primarily altered mental status or encephalopathy tend to be the ureo-cycle defects, maple syrup urine disease, methylmalonic aciduria, proprionic and isobaleric acidemias. There are the neurotransmitter disorders that typically present with seizures. And then those that present with jaundice and liver dysfunction may be your galactosemia, your fructose intolerance, and your tyrosaminia. And then those that present with persistent hypoglycemia include disorders of cryogenesis and fatty acid oxidation. This is an oversimplification of how certain disorders will present. There are many different ways for which a child will present, and we've already talked about the fact that this is typically a multi-system presentation, and so this is just an introduction to the things that you should consider. When you're deciding that you should pursue a workup for a metabolic disorder, there are many different labs that you should be sending. Things that include are your basics, kind of glucose, electrolytes, get a gas and understand your acid-base status, liver function, understand the level of the ammonia in your lactate and your pyruvate. There are also several different urine studies that you can obtain, quantitative studies for both your plasma and your urine for amino acids, your urine organic acids. Those tests are a little bit more to help with understanding what is the actual disorder that you are identifying. However, those key findings down at the bottom of the slide, an elevated ammonia, a metabolic acidosis, and hypoglycemia are three key findings that are present in metabolic disorders and really should raise concern for a potential metabolic disorder if present. And then for overview, we talk about just the general principles for management of a child with a suspected inborn error of a metabolism. It's the importance of really just supportive care, so support the ventilation and any potential circulatory failure as needed, correct electrolyte imbalances, identify if there's any potential secondary infections or concomitant infections that need treated, knowing that the presence of infection will worsen the presence of an inborn error of metabolism. Understanding the basics of nutrition and that nutrition is a key component, again, balancing substrate needs for which is important in that patient. And then if you do have the concerns for an inborn error of metabolism, remember you have to think early about this diagnosis and ensuring that all those appropriate diagnostics have been sent. Now we're going to walk through different algorithms for how to think through a potential diagnosis of an inborn error of metabolism. First, we're going to start with hyperammonemia and the presence of an elevated ammonia. You will see that if you then kind of go through this pathway, if acidosis is present versus if acidosis is not present, it will change how you potentially classify the patient. If acidosis is present, on the left side of the algorithm, you will see that you then need to clarify whether or not there's ketones present. No ketones would suggest a fatty oxidation disorder. The presence of ketones would suggest that this may be an organic acidemia. On the right side of the diagram, if you have an elevated ammonia level but no acidosis, you may consider then a potential urea cycle defect. We will spend a few minutes reviewing some of the different urea cycle defects as part of the highlight of this lecture. A quick review of the urea cycle. So the urea cycle is important for the hepatic removal of ammonia from the bloodstream and detoxification of ammonia from our body. The urea cycle takes ammonia and then turns it into urea to allow for excretion through our kidneys. Urea cycle disorders in themselves are there for inborn errors in metabolism where there is a deficiency in one of the enzymes that is crucial along this cycle. And therefore, when that enzyme does not function appropriately, there's an elevated ammonia and hence why these disorders present with hyperammonemia. This algorithm shows how to diagnose the various urea cycle defects. You will see on the right side of the algorithm, those disorders will present with specifically elevated amino acids. On the left side of the algorithm, there is no amino acid elevation, but you need to then evaluate whether or not the urine erotic acid is high or low. If high, this suggests OTC deficiency. If normal or low, it suggests either CPS or NAGS deficiency. Of note of these urea cycle defects, OTC is inherited in an X-linked manner. The rest are autosomal recessive. Now we will specifically talk about the presentations of urea cycle defects after the neonatal period. As we've talked already in general about inborn errors of metabolism, these presentations tend to occur at different time points throughout life. In neonates, there's these naturally occurring events where a neonate is weaned from either breast milk or formula. There's also times in which the diet has a higher protein content. Other times that urea cycle defects might present themselves is when there's a period of rapid growth, acceleration, metabolic stress such as infections, surgery, or fasting, and exposure to medications like valproic acid or haloperidol, which both increase ammonia production. As I showed earlier, urea cycle defects commonly present with neurological signs and symptoms. These include mental status changes. If the child's older, it may be some personality changes. They may present with different degrees of encephalopathy, may present with significant cerebral edema, especially in the setting of extremely elevated hyperammonemia. And then for those patients that have a urea cycle defect and maybe have these acute on chronic presentations, they may have more of a chronic encephalopathy with recurrent behavioral problems. There are some physical exam findings that you may find in a child with a urea cycle defect. Some of these findings are more pronounced in some of the defects compared to the others, but these children tend to be microcephalic. Those with long-standing symptoms will be malnourished. They will both be underweight as well as they will have poor linear growth. Because of the protein restriction and insufficiency, they will have poor narrow hair and nail growth, and typically their hair is very brittle. And then they tend to have a pedomegaly, and this is very pronounced actually in patients with ASL deficiency. There may be several different laboratory findings that you will find in a patient that's presenting with the urea cycle defect. First, as we talked about through that algorithm, you'll have an elevated ammonia level. The ammonia in these patients tend to be greater than 150 millimoles per liter, and it's important to note that the level or the severity of the elevation of the ammonia level does not necessarily correlate with the symptoms. You will evaluate the plasma amino acids, and here you may see elevation of the different urea cycle intermediates, if it's suggestive of the different type of deficiency. It's not uncommon to find a respiratory alkalosis, and this is very common in children here, their stimulation of the brain that triggers hyperventilation. You may see metabolic acidosis, but this is important to note that this is more in a chronic course and not necessarily in the acute presentation. As you may remember, that metabolic acidosis is actually part of the algorithm for evaluation of acute hyperemia or pneumonia. And then in these patients, they tend to have elevations in their liver enzymes. Looking for the diagnosis of urea cycle defects, you'll see several different things. First, there's a decreased production of many of the serum proteins, such as albumin and prealbumin. When you look at specialized metabolic testing, especially in periods of acute illness or acute episodes, you will see for your plasma amino acids that you'll have increased glutamine, alanine, and asparagine. Citrulline will tend to be increased in ASS and ASL deficiencies when citrulline is usually decreased in CPS and OTC deficiency. Remember, we already talked about the high erotic acid in OTC deficiency to differentiate the two. Liver biopsy can be helpful for diagnosis of NAGs, OTC, and CPS deficiencies, and then arginase levels within the fibroblasts and erythrocytes are helpful for ASS, ASL, and arginase deficiencies. Management of the urea cycle defects can really be split up into acute management versus long term management. The goals for acute management are to remove ammonia from the body and limit the production of further ammonia within the body. This includes for removal, the use of hemodialysis, whether that be intermittent dialysis or continuous dialysis, depending on the size of the patient. Use of nitrogen scavengers such as aminol, which includes sodium benzoate and sodium phenyl acetate. These nitrogen scavengers turn ammonia into byproducts that can be excreted through the urine. Supplementations of essential amino acids such as arginine or citrulline, which pushes the urea cycle forward further, and then limiting protein intake. Long term management includes optimization of nutrition, as well as potential liver transplantation for patients who have recurrent episodes of hyperammonemia. Okay, we will do a question now about the urea cycle defects. Administration of arginine or citrulline is contraindicated in patients with A, arginase deficiency, B, CPS, C, OTC, or D, NAGs. The answer to this question is arginase deficiency. Arginase deficiency is a rare urea cycle defect, where actually the clinical presentation is typically one of spastic diplegia, and this deficiency does not present with elevated ammonia levels. Therefore, administration of arginine will not be helpful, and as you can see within the urea cycle itself, would not provide any benefit. You can also see that in hyperammonemia, where you are not dealing with the urea cycle defect, administration of something like arginine would not be helpful, such as within the organic acidemia. So to review in our algorithm for hyperammonemia, we can assess whether or not there is presence of acidosis. If there is no acidosis, then we go down the pathway of the urea cycle defects. If there is acidosis, which is the left side of the algorithm, we would assess whether there's ketones present or not present. If they are present, then you consider organic acidemias. If not present, you would consider fatty oxidation disorders. Further, we want to explore the algorithm for thinking about metabolic acidosis in the setting of the presentation of a new inborn error of metabolism. We've already talked about the left side of this algorithm. We've talked about the presence of having metabolic acidosis in the setting of hyperammonemia. Here, typically, there is a normal lactate, and you can see that if there was ketones present versus not present, we would get our organic acidemias versus our fatty oxidation disorders. However, we can also consider if metabolic acidosis was present, and there's an elevated lactate, what potential inborn errors of metabolism there would be. There's several different things that we would consider here. First, we would consider whether or not there's a low pyruvate level. This would mean, since there's a high pyruvate, or excuse me, a high lactate and a low pyruvate, this would be a high lactate to pyruvate ratio. That would be indicating a mitochondrial disorder. However, if we had an elevated pyruvate level in the setting of an elevated lactate, which is these other two at the bottom here, then we would have a normal lactate to pyruvate ratio, and then we would differentiate by the presence of whether or not there's a normal glucose or a low glucose. You can see those that have a low glucose would be disorders such as glycogen storage or disorders of gluconeogenesis, while those that would have normal glucoses would be pyruvate dehydrogenase or carboxylase deficiency. We are now going to spend a little bit of time to focus on those organic acidemias, the ones where the blue star. So these are patients that are going to present with typically a metabolic acidosis, hyperammonemia. They typically have a normal lactate, but may have an elevated lactate and typically have ketones present. We're going to spend some time now talking about the organic acidemias. Here, these organic acidemias deal with the breakdown of the branch chain amino acid of maline, isoleucine, and leucine. These disorders that we typically think about within this category are the ones that are that we typically think about within this category are maple syrup urine disease, propionic acidemia, isovaleric acidemia, and methylmalonic acidemia. We're first going to start with maple syrup urine disease. This is a breakdown of that first step of metabolism of the branch amino acids, where there is decarboxylation of the branching amino acids, and that is the enzyme that is impaired during maple syrup urine disease. It is the accumulation of these branch chain amino acids that actually result in the specific odor of the urine. And it's important to note that the accumulation of these different organic acids are what present for different presentations, but that leucine itself is specifically neurotoxic compared to vaneline and isoleucine. There are several different clinical phenotypes for maple syrup urine disease, and these present at different ages for the patients. However, the most common form is classic maple syrup urine disease, and this tends to present in newborns. These, the patients tend to present within the first few days to weeks of life, and actually breastfeeding can delay the presentation to the second week of life, basically because of the protein content within the breast. And the breast milk. The typical presentation is an infant that is feeding very poorly and vomiting, but then progresses to alter mental status, lethargy, and coma. They tend to be hypertonic, they have apnea, they have seizures, they have cerebral edema, and present with significant hypoglycemia. As we already talked about, they tend to have a very peculiar odor of their secretions, and this tends to be from the accumulation of those branch chain amino acids. So the diagnosis of maple syrup urine disease is actually by evaluating the different levels of the branch chain amino acids within the plasma. So there'll be elevations in leucine, isoleucine, and vaneline, as expected based on the pathophysiology that we've already talked about. Aloe isoleucine is actually the stereoisomer of isoleucine, and this is typically not found in blood, and so when it is present, it's sufficient enough to make the diagnosis of maple syrup urine disease. It's important to note, though, that you cannot detect aloe isoleucine until about six days of life. These patients will also have depressed levels of alanine, and then if you were to take their urine and add a few drops of this reagent here, you'll see that there actually forms a yellow precipitant, and what that is identifying is the presence of the keto acids and the high levels of the branch chain amino acids within the urine. Finally, you can also evaluate the enzyme activity within leukocytes and cultured fibroblasts as another form of diagnosis. Management of an acute crisis for maple syrup urine disease is similar to management for any other inborn error of metabolism. You're going to promote effective cardiopulmonary resuscitation. You're going to ensure replacement of any electrolytes. Another key component to maple syrup urine disease management is reducing the level of the leucine that is elevated. As we've already talked about, leucine is particularly neurotoxic, and these significant elevations of leucine can cause pretty significant cerebral edema. So there's various different components to the management that would then pursue. One is ensuring hyperhydration. This is a forced diuresis that allows for detoxification. The other is providing glucose infusions with or without insulin, and this promotes really a protein catabolic state and enhances protein synthesis. You will also have to therefore restrict protein intake and provide potentially isoleucine and valine supplementation. Providing these additional branch chain amino acid actually promotes the anabolic state. Again, you're going to ensure that there's sufficient calories and nutrition, especially in the setting of the protein restriction. Hemodialysis is really important for reducing the leucine level, and then you would treat the cerebral edema in any other way that you would treat cerebral edema with mannitol, hypertonic saline, and ensuring a normal sodium level. So now we have a question. Which of the following conditions is associated with an extremely low plasma level of isoleucine? A. Scurvy, B. Rickets, C. Acrodermatitis Enteropathica, or D. Seizures? The answer is C, acrodermatitis enteropathica. So the deficiency in isoleucine actually causes a dermatosis where there is epidermal dysfunction and it creates a presentation similar to that of acrodermatitis enteropathica. And really what this is, is showing the importance of these branched chain amino acids to the growth and differentiation of keratinocytes as well as enterocytes. In addition to maple syrup urine disease, the other inborn errors of metabolism that relate to branched chain amino acids would include methylmalonic acidemia, propionic acidemia, and isovaleric acidemia. Each of these occur at different points of the metabolism of those branched chain amino acids, valine, isoleucine, and leucine. Starting on the right of the diagram, you have leucine after being decarboxylated to isovaleric CoA, that's where the breakdown is for isovaleric acidemia. For valine and isoleucine, these get converted after decarboxylation to propanil CoA and then further to succinyl CoA. And based on where the breakdown is here, you either have propionic acidemia or methylmalonic acidemia. Similar to the presentation of other inborn errors of metabolism, patients that present with these branched chain amino acid acidemias will present with vomiting, dehydration, failure to thrive, and eventually progress to lethargy and coma. It should also be noted that many of these patients will also present with metabolic strokes or stroke-like syndromes, especially involving the basal ganglia. The timing of presentation may vary based on the different acidemias. Those with MMA tend to present in the first few weeks of life. Those with propionic acidemia will tend to either present early or maybe present later. And it really should be thought about in a child that may present with these episodic, unexplained periods of ketoacidosis and encephalopathy. And then isovaleric acidemia tends to present in the neonatal period, but also can present later, and the presentation will vary. In infants, they tend to have seizures, temperature instability, and they will smell like sweaty feet, versus older children will have this chronic intermittent form of the disease. Laboratory evaluation will be important for diagnosis. In these acidemias, you'll see a large anion gap acidosis with a ketonuria. Some will have hyperammonemia and then hyperglycemia. They tend to have leukopenia, thrombocytopenia, anemia, and hyperuricemia from marrow suppression. And then urine studies will help aid in the diagnosis of which acidemia you are diagnosing based on the presence of the metabolite that's there. So in MMA, they have an elevated methylmalonic and propionic acidemia, they have an elevated propionic acid, and isovaleric acidemia, you have an elevated isovaleric acid. And then finally, treatments of these diseases are similar to the other disorders that we have talked about. In an acute crisis mode, you want to limit protein. You want to inhibit any types of endogenous catabolic states. So make sure that you're treating things like infection. Ensure that there's adequate energy being supplied. Need to supplement carnitine and other vitamins. You want to treat hyperammonemia when it's present. And then sometimes, especially in MMA and propionic acidemia, you can use metronidazole to improve neurologic symptoms. And this is basically by treating intestinal bacteria and limiting bacterial byproducts. Long-term management consists of a low-protein and high-energy diet, carnitine and B12 supplementation, and then eventually liver transplantation. And there are some genetic therapies as well. Okay, now we're going to quickly talk about mitochondrial disorders. So just as a reminder, the respiratory chain has five linked enzymes. Their first four enzymes drive oxidation, while the last enzyme is important for generation of ATP. And then the mitochondrial disorders that are present usually have some sort of abnormality along this chain. It's important to remember that succinate, riboflavin, thymine, and coenzyme Q10 all are cofactors along this electron transport chain. Mitochondrial disorders will present with effects of multiple different organ systems. It's important to remember that the presentation will be more common in certain organs than others. For instance, the CNS system is the most common to have some sort of presentation, especially when it comes to vision and hearing issues. This is followed quickly by the heart, the muscle, and then lastly, the kidney and liver. Infants that tend to present with mitochondrial disorders will have developmental delay, stroke or stroke-like events, hypertonia, seizures, and then oculomotor abnormalities. And they tend to have a lactic acidemia with an elevated lactate to pyruvate ratio, either in the CSF or the serum. And then in order to diagnose, typically you need muscle biopsies, which you'll see ragged red fibers, or mitochondrial DNA testing. Treatment for the mitochondrial disorders is mostly supportive. This includes adequate nutrition, limiting acidosis, improving cardiac function, and sometimes also ventilatory support. The mito cocktail is something that we typically give, and again, this reflects back to those necessary co-factors within the electron transport chain, so coenzyme Q10, and then carnitine, creatine, and folate. And then the importance of making sure that we're avoiding drugs that may impair that respiratory chain further, so valproic acid, carbazepine, phenytoin, phenobarb, and topiramate. We are going to transition now to rheumatological disorders. Amy, hand is in sight. Although there have been many studies that have examined the global outcome of the various pediatric rheumatological diseases, there are actually very few studies that examined outcomes for children with rheumatological disorders that were admitted to the PICU. The largest one, and really the most recent one, was from 2012. And here, this is a 15-year study that evaluated children admitted to an ICU with rheumatological disease. You will see here that the most common diagnosis during the admission was lupus, or SLE, at about 60%. You have systemic vasculitides at 20%, as well as some other vasculitides. And then JIA being at another 60%. The majority of these patients here were females, about 70% of them, and this is in about 90 patients, and 65% were Hispanic. Of the 122 admissions in this cohort study, you will see that half of the admissions were related to the rheumatological disease themselves, as well as 21% of the admissions were secondary to infection. Commonly listed causes for infection included pneumonia, bacteremia, and meningitis. Of the 90 patients in this study, there were a total of 17 deaths, so 15%. Although this did seem higher than our typical ICU mortality rates, when compared to the standardized mortality ratio for other global outcome studies, the mortality rate was similar. Many of the patients presented with organ dysfunctions that were notable in many different organs. But as you can see, one-third of the admissions did have a multi-organ dysfunction, and this occurred in many of the different rheumatological diagnosis. We will first talk about lupus. So lupus is rarely diagnosed before the age of five, and there's increasing prevalence after the first decade of life. However, it should be noted that children that are diagnosed before the age of 10 tend to have more severe disease. Lupus is more common in females, as well as it's more frequently diagnosed in individuals of Asian, African, Indigenous North American, or Hispanic and Latino descent. Of adults that actually suffer from lupus, about 10 to 20% had onset in childhood. Lupus is a multi-system autoimmune disorder, and its pathophysiology is thought to be multifactorial. There are genetic, hormonal, and environmental factors that play a role. There have been many different genes that have been identified, and this actually accounts for only about one-third of cases. And many of the highest genetic predispositions occur at the major histocompatibility locus or the MHC, and these are genes that really encode many of the HLA molecules. There's thought to be hormonal effects, and that's why it's presumed to have a higher proportion of women, especially those diagnosed in childbearing years. And then there are many environmental factors that may impact the immune system, such as viral and bacterial infections, exposure to medications, exposure to silica dust, and smoking. Overall, the pathophysiology is related to immune dysregulation, production of autoantibodies, and then this uncontrolled autoreactivity of B and T lymphocytes. These autoantibodies that are formed are basically then against self-directed antigens, and that leads to tissue destruction. There are several different autoantibodies that are produced within those patients with lupus. Anti-double-stranded DNA is important for diagnosis, and of those that have double-stranded DNA autoantibodies that are detected, usually 80% of those patients will have clinically active disease within five years of producing that antibody. And then there's several other potential presentations that will occur with different autoantibodies. We know that anti-Rho and Lha are related to fetal heart conducting system abnormalities. Anti-NMDA receptors can relate to different presentations with brain disease. Anti-nucleosomal can relate to skin rash and renal presentations. And then the antiplatelet autoantibodies may produce thrombocytopenia. The clinical presentation for a new diagnosis of lupus is usually over weeks to months, and has presentations with fever, weight loss, fatigue, arthralgias. Overall, major organ involvement will occur within the first few years of disease onset, and it's important to note that some initial presentations may present with very severe acute presentations. These include macrophage activation syndrome, or NAS, severe renal disease, neuropsychiatric manifestations, and acute thromboembolic disease events. As already noted, lupus is a disease that affects many of the different organs. It's most common that patients present with constitutional findings. These may include malaise, fever, weight loss. And that in roughly 80% of patients, they will have findings of arthritis, and this is typically a symmetric polyarthritis that involves both small and large joints. And then patients may present with symptoms of any of the other organ systems. Renal involvement tends to be high as well, with over 50% of patients having some sort of renal disease. Treatment in lupus is really directed at the presenting symptoms. Steroids are kind of the main therapy, and this is important for rapid control of both acute symptoms and moderate to severe symptoms. And then there's different immunomodulator therapies that may be used. Hydroxychloroquine is really used to treat skin disease, and it can decrease the production of autoantibodies. Cyclophosphamide is commonly used in severe disease and in those patients that have life-threatening organ involvement. So it's typically used in presentations of lupus nephritis and neuropsychiatric manifestation. And then MMF is usually reserved for steroid-sparing type of agent and is also used within lupus nephritis. Next, we will talk briefly about juvenile idiopathic arthritis, or JIA, and specifically the systemic form of JIA. Overall, this accounts for about 10% to 20% of all cases of JIA. Tends to affect males and females similarly, and usually the diagnosis is before 16 years of age, with a peak incidence actually between 1 and 5 years of age. The typical clinical presentation for systemic JIA includes an intermittent fever, a macular rash, that's usually salmon pink in color, arthritis, and it's important to note that in early disease, this tends to be more arthralgias than arthritis. There tends to be a prolonged interval between the actual presentation of systemic symptoms and this arthritis. And typically, it's the wrists, the knees, and the ankles that are most likely to be affected. There may be a lymphadenopathy, and then patients tend to have a serocitis, so there tends to be pericardial revolvement, and pleural fusions, pericardial fusions, and the like. Similar to lupus and other rheumatological diseases, systemic JIA may have a severe complication and present with macrophage activation syndrome. This can happen within the first few days to weeks of disease onset, and is classified like all other presentations of MAS, with fever, rash, coagulopathy, pancytopenia, hepatitis, and elevated ferritin, and this is a true rheumatological emergency that needs to be treated. The typical laboratory findings that you'll see in systemic JIA include an elevated white blood cell count, reactive thrombocytosis, and anemia, elevated inflammatory markers, including an ESR and CRP, an elevated ferritin, and it's important to note that ferritin will be elevated in systemic JIA even in the absence of MAS, an elevated D-dimer, AST and ALT elevations, a hypoalbuminemia, a normal UA, and then negative ANA and rheumatoid factor. Treatment for systemic JIA really depends on the disease severity. For mild to moderate disease, these are typically just treated with NSAIDs, while moderate to severe disease may use interleukin-1 or 6 inhibitors, glucocorticoids or methotrexate, and then if presenting with MAS, this is typically a combination treatment with both steroids as well as IL-1 or IL-6 inhibitors. Next we will talk about systemic vasculitis. So it's important to know that or to remember that systemic vasculitis are separated into both primary presentations as well as secondary presentations. The most common primary systemic vasculitis that you'll see in children are HSP or IgA vasculitis and Kawasaki disease, and then secondary systemic vasculitis disease that will be seen may occur in response to systemic diseases such as lupus or JIA, may occur secondary to infections or to exposures to various different medications. Patients that present with systemic vasculitis will have many nonspecific complaints. So they may report fever, fatigue, weight loss, and then additional manifestations will really depend on the vessels that are involved. When large and medium-sized vessels are involved, you tend to have presentations that suggest arterial insufficiency. So you may have claudication, abdominal pain, chest pain. And then when small vessels are involved, this will typically include dysfunction of some richly vascularized organs, whether that be the skin, the lungs, the kidneys. So patients may present with hemoptysis, abdominal pain, hematuria, and some various different skin findings. Diagnosis for systemic vasculitis really depends on the physical exam and the various clinical symptoms. Typically, CBC, UA, liver enzymes, biline, creatinine, and inflammatory markers are obtained, as well as various other important labs, such as von Willebrand's factors, your ANCAs, your ANAs complement anti-glomerular basement membranes and infectious workup. And then there needs to be evaluation of the different organs that are involved. However, diagnosis can be tricky, and typically, tissue biopsy is the gold standard, although not always feasible to obtain. Treatment for systemic vasculitis really depends on the severity of the presentation. For primary systemic vasculitis, this may include use of antihistamines, NSAIDs, steroids, or immunosuppression. And then for secondary systemic vasculitis presentations, the most important treatment is to treat the underlying cause for the vasculitis itself. Lastly, we will talk about the presentation of primary CNS vasculitis. Patients that have CNS vasculitis will tend to present with a new neurological deficit, with a stroke-like event, and potentially with new onset seizures or new psychiatric symptoms. In order to be considered a primary CNS vasculitis, there needs to be no underlying systemic disorder. And these are classified into two different types. There can be large vessel involvement, which is angiograft positive, or small vessel involvement, which is angiograft negative. Primary CNS vasculitis can present in any age. There's a male predominance for those patients with angiograft positive CNS vasculitis, while there is a female predominance in those with angiograft negative. And this is typically, again, that small vessel childhood vasculitis. As we've already talked about, there's a wide variety of potential presentations. And many of the acute stroke symptoms that patients present with can actually lead to progressive cognitive decline. This slide provides recommendations for both blood evaluation, as well as imaging evaluation for patients that have a potential suspicion of having inflammatory brain disease or CNS vasculitis. You will see throughout this algorithm that workup from laboratory perspective includes many different inflammatory markers. And then there's evaluation via different imaging modalities, including MRI and conventional angiography. And then a CSS analysis. This slide demonstrates some neuroimaging from a 10-year-old child diagnosed with a primary CNS vasculitis and the presentation of a stroke, as you can see in the MRI sequence, as well as evidence of contrast wall enhancement in a stenotic internal carotid artery that confirmed inflammatory vessel wall disease in PNLP. Treatment for primary CNS vasculitis includes immunosuppressive therapies, the use of anticoagulation and anti-platelet therapies, and then in refractory disease, using TNF blockade. We have now completed the whirlwind tour of inborn errors and metabolism in rheumatological diseases in preparation for your boards. Best of luck. Please contact me with any questions.

inborn errors in metabolism

deficiency in enzyme

neurological symptoms

metabolic acidosis

rheumatological diseases

juvenile idiopathic arthritis

macrophage activation syndrome

primary CNS vasculitis