Kidney Stones (Nephrolithiasis): A Pain In My… Flank?

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Kidney stones, or nephrolithiasis, come in different types. There are calcium, struvite, uric acid, and cystine stones. They all form under different conditions with some being more common than others. In addition, when urine is analyzed under a microscope the crystals form unique shapes that help identify one type of stone from another.

Calcium Kidney Stone
Struvite Stone
Uric Acid Stones
Cystine Stones
Calcium stones are the most common. They are composed of either calcium phosphate or calcium oxalate. They form under conditions of hypercalciuria (ie: high calcium in the urine). There are many reasons why someone would have elevated urinary calcium levels. Some examples include hyperparathyroidism (an overactive parathyroid gland), vitamin D toxicity, cancer, and the milk alkali syndrome. In many patients the reason for the elevated urinary calcium is never discovered.

Calcium stones are also associated with hyperoxaluria (ie: too much oxalate in the urine), as well as hyperuricosuria (ie: too much uric acid in urine), and hypocitraturia (ie: too little citrate in the urine).

The second most common type of stone is a struvite stone. A struvite stone is composed of magnesium, ammonium, and phosphate. They form during kidney infections when the "bug" responsible for the infection is a urease spliting bacteria such as proteus vulgaris. These bacteria are capable of producing ammonium from urea. In large enough quantities the ammonium can combine with magnesium and phosphate to form a struvite stone. These stones can be large and in the shape of the draining system of the kidney (ie: calyces); when the have this appearance they are referred to as "staghorn calculi".

Uric acid stones are produced under conditions of high amounts of uric acid in the blood and urine (ie: gout or conditions where cell death is high such as in leukemias and other cancers). Some patients lack elevated levels of uric acid in the blood or urine. However, they are still capable of forming uric acid stones, especially if their urine is acidic. This is because urate precipitates in acidic environments.

Finally, cystine stones form because of certain genetic conditions. The cells that line the urinary tract are normally able to re-absorb amino acids like cysteine. However, certain genetic mutations cause abnormalities in the ability of these cells to transport cysteine from the urine back into the blood. The resultant increase in cysteine in the urine can cause cystine stones to form.

Signs and Symptoms

A fair number of kidney stones are asymptomatic. However, occasionally a stone will pass from the kidney to the bladder through a narrow tube called the ureter. This can produce excruciating pain that is located in the flank region. Sometimes the pain can be referred to the scrotum in males, or labia majora in women.

In addition, sometimes the urine will have blood in it from irritation of the urinary tract. If there is enough blood, the urine will turn pink; although, microscopic hematuria (ie: blood in the urine that can only be picked up by lab testing) can also occur.

Complications

There are several worrisome complications of kidney stones. They include hydronephrosis and pyelonephritis. Hydronephrosis refers to dilation of the urinary tract secondary to blocked urine and increased pressures. The increased pressure is reverberated all the way to the filtration unit of the kidney, the glomerulus. If high enough pressures are reached, irreversible kidney damage can occur leading to chronic kidney disease and renal failure.

Pyelonephritis is a fancy term for an infected kidney. The irritation caused by the stones provides a suitable environment for bacteria to proliferate. These infections can be life threatening, and like hydronephrosis, can lead to irreversible kidney damage and renal failure.

Diagnosis

Diagnosis of kidney stones is made by looking at urine under the microscope. This is known as urine microscopy. Different types of stones have different appearances (see images above), but more importantly also have different treatments.

In addition, a urine analysis is often performed in order to determine the pH. Urine electrolytes including calcium, magnesium, sodium, etc. are also sent, and can be helpful in determining the type of stone.

Imaging studies are also commonly done. The quickest, cheapest, and most readily available is an ultrasound of the kidney. If stones are present they can cast shadows (similar to the ones gallstones cast), which are picked up by the ultrasound machine. CT scans of the kidney can also show stones. Occasionally a procedure known as intravenous pyelography (IVP) is done. In IVP, radio-opaque dye is injected into the veins. It ultimately gets filtered and excreted by the kidneys, at which point an X-ray is taken; the X-ray can provide information about stones if they are present.

CT of Kidney Stones

Treatment

The treatment of kidney stones depends in part on the size of the stone, as well as the type. Stones that contain large amounts of calcium cannot be dissolved with current medicines available; uric acid and cysteine stones can. Medical therapy is designed to either (a) dissolve the stone, or (b) get it to pass with minimal amounts of discomfort.

Expulsive therapy involves using medications to relax the smooth muscles around the "tubes" (ie: ureter, urethra) of the urinary tract. Commonly used medications that do this include:

(1) Alpha-blockers (ie: tamsulosin, terazosin, etc.)
(2) Calcium channel blockers (ie: nifedipine)

These medications help stones pass, especially when they are larger than 3mm in size. In addition, medications for controlling pain associated with kidney stones are paramount to ensuring stone expulsion.

Stones that are larger than 8mm in diameter usually do not pass on their own, even with medical expulsive therapies. These stones must be managed through mechanical or surgical means.

The first approach is to break the stones into smaller fragments using a technology called extracorporeal shockwave lithotripsy. This is a non-invasive method that delivers powerful waves through the body designed to fragment the stone. The second, and more invasive, procedure is ureteroscopy. This refers to placing a tiny camera into the urethra, bladder, and ultimately into the ureter in order to directly visualize the stone. It is then removed with small forceps.

Staghorn calculi larger than 4 cm diameter require a procedure known as percutaneous nephrolithotomy. In essence, a tube is placed through the skin into the kidney. From there the stone can be directly visualized and removed.

Preventing stones from re-forming is also important. Adequate hydration is critical in preventing all stone types, and is probably the single most important preventative measure! Hydration ensures that urine output is high enough to prevent precipitation of minerals that commonly cause stones.

Prevention includes:
(1) adequate hydration
(2) low sodium diet
(3) low protein diet
(4) low oxalate diet
(5) normal or high
       calcium diet
In addition, dietary modifications are also recommended. Paradoxically, excess restriction of calcium from the diet can actually lead to stone formation. This is believed to be due to oxalate being absorbed from the GI tract instead of calcium. The excess absorption of oxalate leads to increased calcium oxalate stone formation in the tubules of the kidneys. Therefore, people with calcium stones should eat a diet that is high in calcium (1 to 4 grams/day); however, supplementing the diet with calcium tablets is not recommended. Diets high in oxalate should be avoided. Avoidance of diets high in salt and protein are also generally recommended.

Treatment for specific types of stones are also given. To prevent the re-formation of uric acid stones, potassium citrate is commonly given to make the urine less acidic (more alkaline). This increases the solubility of urate and keeps it from precipitating into a stone.

Overview

Kidney stones come in different shapes and sizes. The most common type are calcium stones. Many patients are asymptomatic although flank pain that radiates into the scrotum and labia majora are common. Blood tinged urine may also be seen. Diagnosis is based on urine microscopy, kidney ultrasound, CT scan, and urinalysis. Treatment for all kidney stones consists of adequate hydration and analgesics. Stones larger than 8mm often need to be broken up or removed via mechanical means.

Related Articles

References and Resources

Hemangioblastoma of the Central Nervous System

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Hemangioblastomas are benign tumors that occur in the central nervous system, most commonly in the cerebellum. The exact cell from which they arise is unknown; however, they are believed to be meningeal (ie: the cells that make up the covering of the brain) in origin.

Hemangioblastomas can be solid or cystic in appearance. However, all hemangioblastomas have capillary networks that are lined by endothelial cells. Interspersed between the capillaries are pericytes and stromal cells with a polygonal appearance.

The arrangement of these various cell types can occur in three different architectures: juvenile, clear cell, or transitional. Each architecture has a specific ratio of capillaries to stroma (connective tissue), with the juvenile type having the greatest amount of capillary tissue, and the clear cell type having the greatest amount of stromal tissue.

About a quarter of cases are related to a genetic disorder known as von Hippel-Lindau syndrome. von Hippel-Lindau syndrome is the result of a genetic mutation in the VHL gene on chromosome 3. The protein product of this gene is a tumor suppressor; when mutated it is unable to suppress the abnormal growth of tumor cells. As a result, patients with von Hippel-Lindau syndrome develop hemangioblastomas of the brain and retina, renal cell carcinoma, and other tumor types.

Hemangioblastomas are most commonly found in the cerebellum, but on occassion will affect the cervical spinal cord and brainstem. They are most commonly seen in males starting at around 20 years of age.

Signs and Symptoms

Patients with cerebellar hemangioblastomas present with numerous signs and symptoms. Many patients will complain of headache, nausea, and vomiting. This is often due to the tumor compressing the cerebral aqueduct, which causes cerebrospinal fluid to “back up” in the brain leading to hydrocephalus and increased pressure inside the head.

In addition, many people with hemangioblastomas will have evidence of cerebellar dysfunction on physical exam. These signs include ataxia (ie: wobbly gait), dysmetria (ie: uncoordinated movements of the limbs), and dysdiadochokinesia (ie: difficulty repeating rapid alternating movements).

If the tumor is present in the spinal cord, symptoms may include weakness, spasticity, numbness, or other sensory changes.

Interestingly, hemangioblastomas can secrete an analogue of the hormone erythropoietin. This hormone causes bone marrow to pump out more red blood cells. As a result, some patients may have an increased number of red blood cells; this is known as polycythemia.

Diagnosis

Hemangioblastoma MRI
Hemangioblastoma Angiogram
A presumptive diagnosis can be made using epidemiology and imaging studies.

A tumor located in the cerebellum of an adult with certain characteristics on CT, MRI, and cerebral angiogram can make the diagnosis of hemangioblastoma likely.

However, the final diagnosis can only be made by looking at a sample of the tumor under the pathology microscope.

Treating These Bastards

Definitive treatment is surgical resection. However, hemangioblastomas can be highly vascular, which means they tend to bleed like stink! Therefore, preoperative embolization by an interventional neuro-radiologist can decrease the amount of bleeding that occurs during surgery.

Radiation therapy is also sometimes used as an adjunctive treatment. It may help slow the growth of the tumor, but will not cure it. Radiation therapy can be used in patients who are unable to undergo surgical resection, or if the tumor is inaccessible via traditional surgical means.

Recap It All…

Hemangioblastomas are highly vascular, but benign central nervous system tumors of undetermined origin. They are associated with von Hippel-Lindau syndrome. Signs and symptoms include headache, nausea, and vomiting, as well as cerebellar dysfunction. Diagnosis is based on imaging and pathological findings at the time of surgical resection. Surgery is the treatment of choice, although embolization and radiation therapy may also be used as an adjunct.

More Interesting Neurological Problems…

Some More Expert Ideas Below

Diabetes Mellitus: Sugar Pee and A1C

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Diabetes mellitus, or “sugar” diabetes, occurs when the body inappropriately manages its blood sugar levels. The key player in diabetes mellitus is a hormone called insulin. For simplicity we will use the term “glucose” as a relatively generic term for “sugar” going forward, but remember that glucose is actually one type of sugar.

Insulin is a protein secreted by specialized cells in the pancreas known as β-cells. When the body senses a high level of glucose floating around in the blood it causes the pancreas to secrete insulin. Many individual insulin molecules then travel throughout the body where it binds to receptors on many different tissue types. For example, if insulin binds to hepatocytes (liver cells) it instructs those cells to remove glucose from the blood and store it in a polymerized form known as glycogen. Insulin’s goal is to bring blood sugar levels to within normal limits.

The problem in diabetes mellitus is that insulin is either not secreted by the pancreas, or it does not perform its functions appropriately. Either way, glucose is not removed from the blood stream. The result is a higher than normal blood sugar concentration.

There are two distinct forms of diabetes mellitus: type 1 diabetes (sometimes referred to as juvenile onset or insulin dependent diabetes) and type II diabetes (sometimes referred to as adult onset or insulin independent diabetes).

Type 1 diabetes is an auto-immune disorder, which means that the bodies’ immune system attacks itself. In this case, the body attacks the β-cells in the pancreas. Once enough β-cells are destroyed the pancreas can no longer secrete insulin.

The pathology of type 2 diabetes mellitus is more complicated. There is no single "cause" of type 2 diabetes, and as such, it is believed to be the result of a combination of factors. Genetics, lifestyle, and diet all play an important role in the development of this form of the disease. I like to think of type 2 diabetes as a slew of factors that have beaten down the bodies ability to properly manage blood sugar levels.

In type 2 diabetes the pancreas is still able to produce insulin. However, the problem is that insulin does not cause its normal effect on body tissues. This is known as "insulin resistance." In an effort to combat this resistance the pancreas secretes more insulin. Once the insulin resistance becomes too severe the pancreas can not keep up, and blood sugar levels begin to rise. If the levels rise beyond a specific laboratory threshold the diagnosis of diabetes is made.

How Does Diabetes Mellitus Present?

High blood sugar levels lead to the symptoms of diabetes mellitus. One of the most common symptoms of diabetes is a frequent need to urinate. The reason this occurs is because the excess blood sugar exceeds the kidney’s ability to re-absorb it. As a result, glucose leaks into the urine. The body is forced to dilute this excess solute load by secreting more water into the urine. Hence more urine production –> increased trips to the bathroom!

Since diabetics have difficulty using sugar as a fuel they often lose weight (although most type II diabetics are overweight or obese secondary to excessive caloric intake). Diabetes, in metabolic terms, is similar to slowly starving. The body is unable to utilize sugar appropriately, which is the main “fuel” for most people. Normally, excess sugar gets converted to fat (ie: for you “need-to-know it all types” glucose is converted into acetyl-CoA fragments. If these are not “burned” by the Krebs cycle they get polymerized into long chain fatty acids, which get stored in fat tissue). However, in diabetics the sugar is "lost" in the urine and not used for metabolic purposes.

Diabetes, in metabolic terms,
is similar to slowly starving.
If blood sugar levels become ridiculously high severe complications, and potentially death can result. These patients can become very dehydrated and will often have significant electrolyte abnormalities. These factors can lead to coma, heart arrhythmias, and death if left untreated. These severe complications usually occur during periods of "stress." Conditions like infections and certain drugs (both prescription and illicit) can cause the "stress" needed to induce a diabetic crisis.

When a diabetic crisis occurs in type 1 diabetics it is referred to as "diabetic ketoacidosis". It is known as "non-ketotic hyperosmolar syndrome" if it occurs in a patient with type 2 diabetes.

What Else Can Happen to People with Diabetes?

There are many complications of diabetes mellitus. These complications are the result of years of high sugar levels in the blood. Over time the excess sugar undergoes a metabolic transformation known as "glycosylation". Glycosylated sugar is toxic to nerves and blood vessels.

Diabetic Ulcer
Diabetic foot ulcer
If damage occurs to the nerves that innervate the stomach a condition known as "gastric paresis" can occur, which is a fancy term for the stomach not being able to contract as well as it used to.

In addition, nerves that carry sensory information can also be damaged, especially at the finger tips and toes. Patients with this type of nerve damage may not feel cuts and blisters on their toes. These areas can become secondarily infected resulting in gangrenous digits that are often amputated (see image to left). This is part of the reason why all diabetics, especially poorly controlled diabetics, should see a foot specialist regularly.

Perhaps the most frightening complication of diabetes is the havoc it wreaks on the cardiovascular system. Diabetics have a much larger risk of heart attack and stroke.

Patients with diabetes are at risk for retinopathy, or damage to the retina of the eye. This can lead to blindness. Damage to the kidney’s filtering area known as the glomerulus can also occur; this can lead to chronic kidney disease. If severe enough, patients may need permanent dialysis or kidney transplantation.

Diagnosis

The diagnosis of diabetes is made by measuring the amount of sugar in the blood. There are three common ways to diagnose diabetes today. The first is by checking a molecule known as hemoglobin A1C. Diabetes can also be diagnosed with fasting blood sugar levels or by a glucose tolerance test. There are three possible results of these tests: normal, impaired (pre-diabetic), or diabetic.

Hemoglobin A1C levels are drawn from the blood. Two separate results above 6.5% indicate diabetes. Levels between 5.7 and 6.4% indicate pre-diabetes. Levels below 5.7% are normal.

"Fasting" blood glucose levels are usually taken in the morning before breakfast. It is considered "normal" if the blood glucose levels are between 60 and 100 mg/dL. Impaired is between 100 and 126 mg/dL. Diabetes is diagnosed if there are two fasting blood glucose levels greater than 126 mg/dL.

If fasting is not an option, or the patient ate breakfast, the clinician can do a "glucose tolerance test." In this test the patient drinks a liquid that is rich in sugar (75 grams of sugar is used for most adults). The blood sugar levels are then tested two hours later. If the blood sugar level at two hours is less than 140 mg/dL the test is "normal." If the level falls between 140 and 200 mg/dL the patient is impaired or pre-diabetic. And if the levels are greater than 200 mg/dL the diagnosis of diabetes is made.

Diagnosing Diabetes Mellitus

  Hemoglobin A1C Fasting blood glucose levels Glucose tolerance test levels at 2 hours after a 75g sugar load
Normal Less than 5.7% < 100 mg/dL < 140 mg/dL
Impaired 5.7% to 6.4% 100-126 mg/dL 140-200 mg/dL
Diabetes 6.5% or greater > 126 mg/dL > 200 mg/dL

Heal Me Doctor

Treatment of diabetes involves either replacing insulin or improving insulin sensitivity.

Type 1 diabetics require insulin since their bodies no longer produce it. This is why type 1 diabetes was previously referred to as “insulin dependent diabetes”. Insulin as a treatment is discussed in a separate article.

Treatment Options:
(1) Replace insulin
(2) Improve insulin
       sensitivity
A healthy diet and exercise are very important treatments in managing diabetes. However, many patients require medications.

There are numerous medicines used to control blood sugar levels in type two diabetics. One option is a class of medications known as the sulfonylureas. These medications work by increasing pancreatic production of insulin.

A second category of medications, known as the thiazolidinediones, improve the ability of insulin to act on peripheral tissues like fat, muscle, and liver.

The third category of medications, known as the biguanides, perform a similar function to the thiazolidinediones, and also inhibit liver cells from secreting stored sugar into the blood stream.

Regardless of which medications are used, the ultimate goal of medical therapy is to maintain the blood glucose levels within a specified range. Fasting blood glucose levels should ideally be kept between 90 and 130 mg/dL; post-meal glucose levels should ideally be less than 180 mg/dL. Maintaining glucose values within these ranges helps keep glycosylated hemoglobin (aka: hemoglobin A1C) levels below 7%, which decreases the risk of the diabetic complications.

In addition to replacing insulin, or increasing insulin sensitivity, patients with diabetes should also be treated for other co-morbid conditions. For example, statins are often started to control hyperlipidemia. Dialysis might be necessary to control severe kidney disease. Frequent foot and neurological exams are also necessary to prevent complications of diabetic neuropathy (ie: foot ulcers, gastric paresis, etc).

It is currently recommended that patients with diabetes have a blood pressure goal of 130/80 or better. In addition the LDL cholesterol level should be maintained below 100 mg/dL, HDL should be above 40 mg/dL, and triglycerides should be kept below 150 mg/dL.

The Replay…

Diabetes is classified as type 1 or type 2. In type 1 diabetes destruction of the pancreatic cells responsible for insulin secretion occurs through an auto-immune process. In type 2 diabetes, insulin sensitivity is lost by peripheral body tissues causing the pancreas to secrete more and more insulin until it “burns out”. Diagnosis is based off of blood sugar levels, usually measured when the patient is fasting (although other methods exist). Treatment is with insulin or insulin-sensitizing medications.

Just Keep Learning, Just Keep Learning (That’s a Dory Reference)…

References and Resources

  • Swanson A, Watrin K, Wilder L. Clinical Inquiries: How can we keep impaired glucose tolerance and impaired fasting glucose from progressing to diabetes? J Fam Pract. 2010 Sep;59(9):532-3.
  • Judge EP, Phelan D, O’Shea D. Beyond statin therapy: a review of the management of residual risk in diabetes mellitus. J R Soc Med. 2010 Sep;103(9):357-62.
  • Fowler GC, Vasudevan DA. Type 2 diabetes mellitus: managing hemoglobin A(1c) and beyond. South Med J. 2010 Sep;103(9):911-6.
  • Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease. Seventh Edition. Philadelphia: Elsevier Saunders, 2004.
  • Le T, Bhushan V, Grimm L. First Aid for the USMLE Step 1. New York: McGraw Hill, 2009.
  • Flynn JA. Oxford American Handbook of Clinical Medicine (Oxford American Handbooks of Medicine). First Edition. Oxford University Press, 2007.
  • Champe PC. Lippincott’s Illustrated Reviews: Biochemistry. Second Edition. Lippincott-Ravens Publishers, 1992.
  • American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2004 Jan;27 Suppl 1:S15-35.

The ACOMM Aneurysm: Balloons and Blood

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In order to understand the anterior communicating artery, we have to first appreciate the anatomy of the anterior cerebral arteries. The anterior cerebral arteries are one of the two terminal branches of each internal carotid artery (the other being the middle cerebral artery). Each anterior cerebral artery has several sections from A1 to A5.

Each A1 segment branches into an A2 segment and into the anterior communicating artery. The anterior communicating artery connects each anterior cerebral arteries’ A1 segment together to form a circle (see schematic below).

The anterior communicating artery is one of the most common sites for intracranial aneurysm formation. Patients at risk for developing aneurysms include those with atherosclerosis, those with a family history of intracranial aneurysms, those with a history of hypertension or collagen vascular disease, and those with polycystic kidney disease. Smokers are also at a higher risk of developing aneurysms.

Basilar Tip Schematic Drawing
Anterior communicating artery aneurysms form when the lining of the vessel wall is thinned and the muscular layer of the blood vessel (tunica media) becomes weakened.

This thinning allows turbulent blood flow to form out-pouchings in the vessel wall. Typically these out-pouchings occur at points where blood vessels branch.

Signs and Symptoms

Anterior communicating artery aneurysms commonly present after a subarachnoid hemorrhage, which can cause a variety of signs and symptoms. The most common being a severe headache, although cranial nerve dysfunction, stroke, coma, and death can also occur.

Less commonly, aneurysms in this location can compress the optic chiasm or optic nerves leading to problems with vision.

How Do You Diagnose Aneurysms

Anterior cerebral artery aneurysms are most commonly diagnosed after a subarachnoid hemorrhage when a patient presents with the "worst headache of their life". The best imaging methods for diagnosing these aneurysms are CT angiograms (see image below), MR angiograms, and formal cerebral angiograms.

Treatment

Like other intracranial aneurysms, anterior communicating artery aneurysms may be clipped or coiled. Clipping of an aneurysm involves an open surgical procedure where the surgeon dissects down to the aneurysm and places a clip across its neck. This excludes it from the circulation and prevents it from rupturing.

Anterior Communicating Artery Aneurysm CT Angiogram

Aneurysms may also be treated from inside the blood vessel. In this procedure a catheter is threaded from the femoral artery in the groin up towards the location of the aneurysm. Small metallic coils are placed within the dome of the aneurysm, which also excludes it from the normal circulation.

Regardless of how the aneurysm is treated – either with clipping or coiling – the end result is that the aneurysm is excluded from the normal circulation. This prevents it from rupturing.

The merits of clipping versus coiling are still under debate. Ultimately, the treatment depends on the size and location of the aneurysm, as well as other medical problems that the patient may have.

The Highlights…

Anterior communicating artery aneurysms are the most common intracranial aneurysm. They typically present after rupturing into the subarachnoid space and/or adjacent frontal lobes. They are diagnosed using CT angiograms or formal cerebral angiography. Treatment is with clipping and/or coiling.

Related Readings

Not Satisfied? More Reading on the Subject…

  • Bederson JB, Awad IA, Wiebers DO, et al. Recommendations for the management of patients with unruptured intracranial aneurysms. Stroke 2000;31:2742-2750.
    • li>Hunt WE, Hess RM. Surgical Risk as Related to Time of Intervention in the Repair of Intracranial Aneurysms. Journal of Neurosurgery 1968; 28:14-20.
  • Brisman JL, Song JK, Newell DW. Cerebral Aneurysms. NEJM 2006; 355:928-939.
  • Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease. Seventh Edition. Philadelphia: Elsevier Saunders, 2004.
  • Frontera JA. Decision Making in Neurocritical Care. First Edition. New York: Thieme, 2009.
  • Greenberg MS. Handbook of Neurosurgery. Sixth Edition. New York: Thieme, 2006. Chapter 25.

Meningioma and the Arachnoid Cap Cell

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A meningioma is a tumor that arises from the lining of the brain or spinal cord (ie: the “meninges”). They arise from cells known as “arachnoid cap cells”. Meningiomas are usually slow growing, “benign” tumors, which means that they are not usually considered cancerous in the strictest sense of the term.

When viewed under the light microscope, meningiomas can have many different appearances. The most common type is a dense sheet-like formation of cells interspersed with closely packed blood vessels. Sometimes the sheets of cells can be separated by connective tissue.

Frequently, meningiomas will have calcium deposits in them known as “psammoma bodies”. Uncommonly, meningioma cells may take on a malignant appearance characterized by increased cellular division (ie: “mitotic figures”) and invasion of the tumor cells into surrounding brain or bone.

Meningiomas test positive for epithelial membrane antigen (EMA) and vimentin (a marker of connective tissue). Ki-67 (a marker of proliferation) can be elevated in more aggressively behaving tumors.

The most common genetic abnormality seen in patients with meningiomas is found on chromosome 22. If present, a mutation in the NF2 gene on this chromosome causes type 2 neurofibromatosis. This disease predisposes individuals to developing multiple tumor types including meningiomas. Other less common genetic abnormalities can be seen on other chromosomes as well.

Signs and Symptoms

Due to their slow growing and benign nature, many meningiomas cause no symptoms. However, if they become too large or start to compress adjacent brain tissue they can cause headache, seizures, confusion, or visual problems. Spinal cord compression can result in myelopathy.

The most common location for a meningioma is in between the two hemispheres of the brain – the so called “parasagittal” location. Parasagittal meningiomas near the portion of the brain responsible for muscle movements may cause weakness of the opposite leg.

Diagnosis

Diagnosis of meningioma can reliably be made on characteristic findings seen on CT or MRI scans. Interestingly, many meningiomas are found incidentally when a CT or MRI is done for other reasons.

Meningioma MRIs

However, like any other tumor, meningiomas can only be truly diagnosed once a specimen is sent to the pathology lab for analysis. Pathologists can reliably make the diagnosis based on typical histological features.

Meningiomas must be distinguished from a more malignant tumor known as a hemangiopericytoma. Hemangiopericytomas can look similar to meningiomas on imaging studies.

Dish Me Up Some Treatment Sir

Many meningiomas can be watched over time with repeat imaging studies; this is especially true if they are small and not causing neurological signs or symptoms.

On the other hand, large or symptomatic meningiomas require surgical resection. Many meningiomas can be removed completely. However, some meningiomas may be near vital structures such as the carotid artery, cranial nerves, or venous draining systems of the brain where complete surgical removal may be very difficult without causing significant neurologic impairment. In these cases the tumor is debulked as much as possible. The residual tumor can be followed or irradiated depending on the grade of meningioma.

Residual tumor after incomplete surgical resection, or meningiomas in difficult to access locations are candidates for radiation therapy. Many studies have shown long term growth control rates.

Overview

Meningiomas are considered “benign” tumors of the brain. They arise from arachnoid cap cells, which are located in a layer of the meninges (ie: the covering of the brain) known as the arachnoid. Symptoms include headache, weakness, vision problems, paresthesias (ie: abnormal sensations), amongst many other possible symptoms. Diagnosis can be made reliably from imaging studies such as CT or MRI. If symptomatic, or large, treatment is surgical resection. Small asymptomatic meningiomas can be managed with repeat imaging to assess for growth over time.

Related Articles

Curated References for Your Pleasure…

Chordoma and that Pesky Notochord

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In order to understand chordomas we have to first learn a little bit about how the nervous system develops. Enter the notochord.

The notochord is a midline structure in the developing fetus that sends out various molecules (the most well known of which is “sonic hedgehog”). These molecules influence the development of the layers of embryonic cells that surround the notochord. One of these layers, the ectoderm, which is immediately behind (ie: posterior) the notochord eventually forms the brain and spinal cord. The mesoderm, which is immediately adjacent to the notochord forms the vertebral column and axial skeleton (amongst other things).

The purpose of the notochord is to ensure that each layer of tissue forms what it is supposed to. Once this occurs, the notochord ultimately becomes the nucleus pulposus of the intervertebral discs.

In some people, nests of cells that composed the fetal notochord remain (unnaturally) after birth. These collections of cells are known formally as ecchordoses physaliphora (try saying that 5 times fast). These cells can divide and turn into a slow growing tumor… What is that tumor called? You guessed it! A chordoma!

Chordomas are slow growing tumors that are most commonly located at the ends of the vertebral column. The most common place to see them is in the sacrococcygeal region, followed in frequency by a bone known as the clivus at the base of the skull. However, chordomas can occur anywhere along the vertebral column. The reason they occur most frequently at the "ends" of the vertebral column (ie: skull base and sacrum) is because these are the last areas to fuse in-utero.

Additionally, since the notochord is a midline structure in the fetus, chordomas are almost always midline in location.

Microscopically chordomas contain large polygonal shaped cells embedded in a mesh of long repetitive sugar and nitrogen containing molecules known as mucopolysaccharides.

Chordoma Highlights:
– Arise from notochord cells
– S-100 positive
– Cytokeratin positive
– Polygonal cells
– Slow growing
– Midline location
– Sacrum and clivus most
   common locations
– Worse prognosis than
   chondrosarcomas
Less than a third of chordomas will show cartilage like features. These chordomas are classically called “chondroid” chordomas because of the chondrocyte-like (ie: cartilage-like) cells and extracellular material within them. Chondroid chordomas must be distinguished from a similar looking tumor known as a chondrosarcoma.

Distinguishing chondrosarcomas from chordomas is possible with immunocytologic staining techniques. Chondromas and chondrosarcomas stain positive for a protein known as S-100. S-100 proteins have numerous intracellular functions and are commonly present in cells such as adipocytes (fat cells), chondrocytes (cartilage forming cells), melanocytes (pigment producing cells), and Schwann cells, amongst others.

So if chondrosarcomas and chordomas can look alike, and both stain positive for S-100, how the heck do we distinguish between the two? Using another molecule known as cytokeratin! Cytokeratin is a molecule that forms part of the intracellular frame for many cells. It is present in chordomas, but not in chondrosarcomas.

On to the Clinic I Say…

Chordomas are slow growing tumors and will usually start to cause symptoms in mid-adulthood. Symptoms are based on the location of the tumor.

If the tumor is located in the sacrum or coccyx then pain is the most frequent presenting symptom. If undiscovered this may progress to bowel and bladder problems as the tumor slowly envelopes the sacral nerves that go to the bowel and bladder. Additionally, patients may present with radicular symptoms such as numbness, tingling, or sharp pain in the distribution of the sacral nerves.

Clivus Chordoma
Chordomas of the clivus, the second most common location, can present with headache and if large enough symptoms of brainstem or upper cervical spinal cord compression. These symptoms may include vertigo, difficulty moving the tongue, double vision, hearing problems, spastic gait, increased reflexes, clumsiness, amongst other symptoms.

Diagnose Me McCoy

Diagnosis of chordoma can only be officially made by looking at the specimen under a microscope. However, imaging studies with x-rays, CT scans, and MRI imaging can support the diagnosis. Imaging studies will typically show a midline lytic lesion centered in the bone. Invasion of adjacent anatomical structures can occur, but is a late manifestation of the disease course.

Treating These Ugly Tumors

The gold-standard treatment for chordomas is en-bloc surgical resection with wide margins followed by radiation therapy. Complete resection is difficult, if not impossible to achieve in the skull base, but may be possible in the spine and/or sacrum with very skilled surgical teams.

Without an en-bloc surgical resection the risk of tumor re-growth and recurrence is very high. If you are planning to biopsy of a sacral lesion you should mark the biopsy tract with methylene blue so that the tract can also be resected during surgery as tumor cells can seed the tract as the needle is being pulled out.

Let’s Remix This Overview

Chordomas are slow growing, but malignant tumors that arise from notochord cells that fail to regress after birth. They are most frequently found in the sacrum and clivus (one of the bones constituing . Diagnosis is made with CT, MRI, and x-rays, as well as via tissue diagnosis at the time of surgical removal. Chordomas stain positive for S-100 and cytokeratin proteins, which helps distinguish them from chondrosarcomas that only stain positive for S-100. Symptoms are based on where the lesion is located (skull base or spine). Treatment is surgery followed by radiation therapy.

Just Warming Up…

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Cerebral Cavernous Malformations: Leaky Vessels

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Cavernous malformations (aka: cavernomas or cavernous hemangiomas) can be thought of as vascular tumors. They are composed of a capillary-like network of endothelial cells (the cells that normally line blood vessels). However, unlike normal capillaries throughout the body, the capillaries of cavernomas can leak.

Interestingly, cavernous malformations do not have any brain tissue within them. This helps distinguish them from another related vascular abnormality known as an arteriovenous malformation.

The genetics of cavernous malformations have been elucidated by studying familial forms of the disorder. There are at least three known genetic defects that predispose patients to develop cavernomas. These genes appear to be important in the formation of blood vessels (a process known as "angiogenesis") and the blood brain barrier. Therefore, mutations in these genes can cause the abnormal growth of vascular tissue.

What Havock Do These Guys Cause?

Cavernomas can cause numerous signs and symptoms depending on their location within the brain. Seizures are the most common symptom. However, progressive neurological impairment such as worsening weakness can also occur.

Sometimes cavernomas can block the flow of cerebrospinal fluid leading to hydrocephalus. Hydrocephalus can cause increased intracranial pressure leading to headaches, nausea, and vomiting. However, it is important to realize that many patients with cavernomas have no symptoms at all!

If symptoms are present, they tend to progress over time. This is because cavernous malformations bleed and re-bleed resulting in an expansion of its size over time. As the malformation increases in size it can push on adjacent brain tissue causing worsening symptoms.

Unlike arteriovenous malformations, life threatening and severe hemorrhages are rare. Cavernomas bleed at an initial yearly rate of anywhere between 1% to 5%. After the first bleed, the risk of re-bleeding increases to as high as 10% per year. In other words, if a cavernoma bleeds, it is more likely to re-bleed at a later date.

How Do You Diagnose These Buggers?

Cavernoma Marked

The diagnosis of cavernous malformations are made via imaging studies. They are usually detected via MRIs that are ordered for evaluation of neurological symptoms. Cavernomas are seen best on T2 and gradient echo MRI sequences. They typically look like a piece of popcorn.

Select patients undergo a more invasive imaging procedure known as angiography. Angiography is used to rule out another similar lesion known as an arteriovenous malformation. Since cavernomas are venous malformations they are not seen on angiograms.

How Are These Treated?

Depending on the location, most cavernous malformations in the brain or spinal cord are removed surgically. Some institutions offer radiation as a means of treatment, especially in difficult to access areas (ie: where the risk of surgical removal is very high).

Let’s Recap this MoFo

Cavernous malformations of the brain are abnormal vascular growths composed of capillary networks. They are likely the result of genetic mutations in genes responsible for blood vessel growth. Depending on their location they can cause numerous neurological symptoms such as seizures and weakness. MRI often shows the characteristic “popcorn” lesion. Treatment is usually with surgical resection, although some cavernomas may be radiated depending on their location.

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Pager PTSD… A Beep that Won’t Go Away

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It’s Friday night and I’m not on call. It’s a welcome break from a hectic and stressful 80+ hour work week. We are about to sit down to watch a movie – popcorn included of course – and enjoy a nice relaxing evening. The microwave starts beeping to let us know that the popcorn is ready. As the beeping continues my heart rate and blood pressure increase ever so slightly, and I reach down towards my left hip. But something is amiss…

The beep of our microwave is eerily similar to the sound my pager makes when I’m on call at the hospital. Of course, the weird thing is that tonight I’m not on call! Yet I still reflexively reach towards my hip, my mind assured that there is a threat to someone’s life, a threat that I might be able to fix. It’s “pager PTSD”, a condition that seems to afflict many young medical trainees.

I’ve tried battling this baffling condition, but to no avail. Perhaps a different beep tone on my pager’s settings would do the trick? It worked for a little while, but invariably my mind would pick out the tone in a favorite TV show and I’m right back to square one… Reaching for that damn left hip.

I’ve even tried putting my pager on vibrate mode. This also worked for a little while until my psyche accommodated… The gentle pull of a blanket, or even my shirt moving in the wind would mimic the vibration, and of course I would reach down. Clearly, someone needed my help, and if I wasn’t there to answer the chirp (or this time vibration) of the pager something catastrophic might happen.

A close friend of mine has a similar story… Although his is a bit more intense! As a soldier in Afghanistan, he would carry a 9mm handgun on his left hip. In hairy situations he’d reach towards his "nine" in case he needed to quickly defend himself. After his second tour he confided that whenever he heard a loud sound, like a car backfiring, or an ambulance siren, he would instinctively reach towards his left hip, hoping that his gun was there to keep him safe.

Unlike my buddy, we are never personally in danger when our pager’s start chirping. And please don’t get me wrong, most pages a doctor receives are not "life and death" situations. In fact, most are easy to handle, a potassium replacement order here, or a Tylenol order there. However, the real problem lies in the fact that every time the pager starts beeping it’s dealer’s choice. It might be something simple, or it might be someone bleeding to death. You don’t know until you reach down and check the message sitting on your left hip.

It’s funny, but humans are not that much different than animals. We can be conditioned to experience a surge of catecholamines. Like a mouse that gets an electric shock a couple of seconds after a tone is played. As the tone goes off the mouse gets visibly nervous, its heart rate and blood pressure start to rise until the shock is administered. It’s similar in pager PTSD, although the mouse is some poor intern, nervously navigating the hospital, waiting for the next medical emergency to present itself.

As I’ve become more senior in my training I fortunately no longer have the visceral reaction when my pager beeps. This is probably because I am more confident in my ability to handle most of the things that might be waiting for me. But interestingly, I still find myself reaching for my left hip even when I am not on call… It’s ingrained in the deepest part of my being. It’s part of being a doctor…

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Middle Cerebral Artery: A Common Site for Stroke

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Middle cerebral artery (MCA) strokes occur when the MCA or its branches are occluded. With occlusion, blood, and along with it, oxygen and nutrients fail to reach the brain. If blood flow is not restored quickly the affected brain tissue dies leading to permanent neurological injury.

Risk factors for MCA strokes are the same for other strokes. They include hypertension, diabetes, smoking, atrial fibrillation, and a whole slew of hypercoagulable states (ie: pathologic increases in the bodies’ propensity to form blood clots).

In order to understand MCA strokes we have to first appreciate the anatomy of the MCAs, as well as the brain that they serve. The MCAs are subdivided into four parts. The M1 segment is one of the terminal branches of the internal carotid artery. The MCAs then become progressively more narrow and form more and more branches as they reach out towards the cortical surfaces of the brain. The most distal portions of the MCA are deemed the M4 branches. The lateral lenticulostriate arteries are small branches that branch from the M1 segments; these small arteries feed some of the deeper structures of the brain.

Importantly, the MCAs and their branches provide blood flow to an extremely large portion of the brain. These areas include the lateral and inferior frontal lobes, superior portion of the temporal lobes, insula, and lateral parietal lobes. Branches of the first portion of the MCAs (aka: the lateral lenticulostriate arteries) also provide blood flow to the deep sections of the brain including the putamen, head and body of the caudate, external globus pallidus, and parts of the posterior limb of the internal capsule.

The segmental anatomy of the MCAs is important because strokes that occur in the outer segments (ie: M3 and M4) cause less neurological injury than the inner MCA segments (ie: M1 and M2). This is because less total brain volume is affected by outer segment strokes.

The most common cause of MCA strokes are clots that break off and travel from the heart or the carotid arteries to the MCA (aka: emboli). Less commonly, a blood clot will form directly in the MCA itself (aka: thrombus). Atherosclerotic disease is the most common cause of thrombus formation in the MCA and atrial fibrillation (an abnormal heart rhythm) is the most common cause of emboli from the heart.

Signs and Symptoms

Middle cerebral artery strokes present with one of two types of syndromes depending on which MCA – right or left – is involved, as well as which segments of the MCA are involved.

In the worst case scenario, a stroke of the right or left M1 segment of the MCA causes weakness of the opposite side of the body. This is a result of cortical damage to the primary motor cortex as well as possible infarction of the posterior limb of the internal capsule (ie: the location of descending motor tracts). MCA strokes usually present with face and arm weakness that is worse than leg weakness. Remember that the motor cortex that controls leg function is served by the anterior cerebral arteries.

M1 strokes also cause decreased ability to feel sensation on the opposite side of the body as a result of damage to the parietal lobes.

Damage to the optic radiations, which course in the parietal (Baum’s loop) and temporal lobes (Meyer’s loop) can cause problems with vision. Finally, injuries to the frontal eye fields cause the eyes to deviate towards the side of the stroke (ie: the frontal eye fields normally allow you to make fast eye movements in the opposite direction, therefore damage prevents patients from looking to the non-affected side).

Right and left sided M1 strokes will give you all of the above symptoms; however, laterality can be determined based on specific symptoms caused by only a left or a right sided strokes.

The poor patients with left M1 strokes have a decreased ability to speak and/or understand language because of damage to Broca’s area in the left frontal lobe (speech production) and Wernicke’s area in the left temporal lobe (speech comprehension). Remember this is in addition to all the other stuff above.

Right M1 strokes can cause "anosognosia", in which the patient is unaware of certain deficits they may have; these patients also often fail to recognize the left side of their body (ie: they "neglect" or fail to appreciate the entire left side of the world) and may have difficulty appreciating people or objects presented in their left visual field.

Right MCA stroke
Less "severe" cases, in which M2, M3 or M4 branches are affected can produce a variety of signs and symptoms depending on the specific branches involved.

Diagnosis

Diagnosis of MCA strokes are based on symptoms, CT scans, and MRI images. CT and MR angiograms frequently show the blocked blood vessel causing the stroke. CT perfusion scans are a newer technology that give information regarding the amount of blood flow to affected brain tissue.

Treatment

Treatment depends on the timing of the stroke. If the patient presents within 3 hours of symptom onset, and the head CT reveals no bleeding, than intravenous tissue plasminogen activator (tPA) may be given to help "break" up the blood clot causing the stroke.

Other treatments using catheter based approaches are frequently used in patients who are unable to receive tPA. Such treatments include mechanical clot removal with special catheter and wire devices. In addition, in patients more than 3 hours, but less than 6 hours out from symptom onset intra-arterial (not to be confused with intravenous) tPA may be used.

Less commonly, large "malignant" MCA strokes may cause significant swelling, which can put pressure on the brainstem. These patients sometimes undergo an open surgical procedure known as a "craniectomy", in which the bone overlying the affected brain tissue is removed. This surgery allows the edematous brain tissue to swell outwards preventing it from herniating downwards towards vital brainstem structures.

Overview

Middle cerebral artery strokes are most commonly caused by blood clots that break off from the heart or carotid artery. Symptoms of MCA strokes depend on the segment involved, as well as which MCA (right versus left) is involved. Diagnosis is made with a combination of MRI, CT, and symptomatology. Treatment consists of intravenous or intra-arterial tPA and/or mechanical clot removal depending on the time frame of the symptoms.

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References and Resources

Hemangiopericytoma: A Tumor of Pericytes

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In order to understand hemangiopericytomas we have to define a few terms. The first term is mesenchyma. Mesenchyma is a word used to describe the different tissues that provide structure to the bodies’ organ systems. A type of mesenchymal cell known as a “pericyte” provides structural support to blood vessels. When pericytes go haywire they form hemangiopericytomas.

Hemangiopericytomas can occur anywhere blood vessels are located, but are most commonly located in the lower extremities, pelvis, head, and neck.

Intracranial hemangiopericytomas are uncommon. They represent less than 1% of tumors within the confines of the skull. They typically arise from blood vessels adjacent to the dura (ie: lining of the brain) and often form dural attachments. They are therefore commonly lumped into the category of “dural-based tumors”, but should be distinguished from their more benign meningeal cousins (ie: meningiomas).

Since hemangiopericytomas are mesenchymal in origin, they typically have lots of reticulin (a collagen fiber) that envelopes individual cells (see pathology slide). They are highly cellular tumors, and vascular channels in the shape of "staghorns", may be seen under the microscope. Actively dividing cells (aka: "mitotic" figures) are commonly seen and are a testament to their more malignant nature. Unlike meningiomas, calcifications are absent.

Hemangiopericytomas test positive for vimentin (a marker of connective tissue), Ki-67 (a marker of proliferation), vascular endothelial growth factor (VEGF, a marker of blood vessel proliferation), CD34 (a marker of blood and vascular cell lineage), and reticulin (a collagen fiber). These tumors do not stain positive for epithelial membrane antigen. Genetic mutations have been found on different chromosomes , but the importance of these abnormalities is not well understood.

Intracranial hemangiopericytomas are considered malignant tumors. This means that they can spread to other areas of the body. In addition, hemangiopericytomas that have been removed surgically have a high recurrence rate.

Hemangiopericytoma

Signs and Symptoms

Hemangiopericytomas are relatively slow growing and often do not cause symptoms until they become quite large. However, once they start to compress adjacent brain tissue they may cause headaches, seizures, confusion, weakness, or visual problems.

Diagnosis

MRIs and CT scans of the brain typically reveal a contrast enhancing dural-based lesion. Cerebral angiograms show a highly vascular tumor with blood supply coming from the dura, as well as the underlying brain tissue.

Based on imaging alone, hemangiopericytomas are often mistaken for meningiomas. Subtle characteristics such as a lack of calcification seen on CT scans may help distinguish one from the other, but this is not reliable.

The only reliable way to diagnose hemangiopericytoma is to look at a specimen of the tumor under a microscope. Special stains and features of the tumor can help delineate it from a meningioma (see pathology section above).

Did I Hear Someone Say “Treatment”?

Intracranial hemangiopericytomas should be surgically resected when feasible. Unfortunately, even after complete resection, they frequently recur and/or spread to other areas of the body.

Because of their aggressive nature, patients with hemangiopericytomas should also have adjuvant radiation therapy. Radiation treatment after surgical removal of the tumor has been shown to lengthen survival and slows (but doesn’t appear to prevent) the time to recurrence.

The role of chemotherapy is less clear and is still being investigated. At this point, chemotherapy is typically used in patients where radiation and surgery have failed to control the disease.

Let’s Recap It…

Intracranial hemangiopericytomas are malignant dural-based tumors that arise from pericytes. They are highly vascular tumors that enhance on MRI and CT scans. Symptoms are variable and depend on the size and location of the tumor. Treatment is with surgical removal followed by radiation therapy. Recurrence rates are high despite optimal treatment.

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