Note: This is the research paper I wrote earlier this year for my Biochemistry of Nutrition graduate school class. I haven’t looked at it since I turned it in. I originally wanted to add more to it on specific IH research topics (coagulation factors, thyroiditis) that I didn’t have the time or space to write about originally, but my health took a turn this spring and I’m just now recovering from it.
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Nutritional Management of Biochemical Abnormalities
in Idiopathic Intracranial Hypertension
Idiopathic Intracranial Hypertension [IIH], historically known as Pseudotumor Cerebri and Benign Intracranial Hypertension, is a rare disorder where there is greatly increased cerebrospinal fluid pressure in the skull without an obvious cause like a head injury or chiari malformation. It can occur in any age group and any sex, but the largest population is obese women of child bearing age. IIH mimics the symptoms of a brain tumor and common symptoms include: chronic headaches, visual disturbances or vision loss from papilledema, tinnitus or pulsating heartbeat in head, nerve pain and paresthesia, dizziness and lightheadedness, nausea and vomiting, fatigue, memory and cognitive difficulties, and exercise intolerance. There are a number of hypotheses about the biochemical mechanisms involved with IIH but recent research implicates increased levels of pro-inflammatory cytokines associated with the reduction in cerebrospinal fluid drainage. High levels of cortisol and several other pro-inflammatory cytokines are also associated with impaired secretion and absorption of cerebrospinal fluid. Nutrient deficiencies and genetic polymorphisms that affect absorption of one or more of the vitamins required for one carbon metabolism are not uncommon with IIH; those vitamins include riboflavin, folic acid, vitamin B12, and vitamin B6. Typical medical treatments for IIH include: lifestyle changes like weight loss and reductions in salt and caffeine in the diet; medications like acetazolamide or loop diuretics to help reduce the build-up of fluids in the skull; and medical procedures or surgeries such as multiple lumbar punctures to remove cerebrospinal fluid, optic nerve sheath fenestration to improve visual field, and shunt or stent implantation to control cerebrospinal fluid drainage. Nutritional management of IIH includes normalizing homocysteine levels with the appropriate bioavailable forms of B vitamins and healthful, low calorie or low carbohydrate diets to promote weight loss, reduce cortisol levels, and control inflammation.
Signs, Symptoms, and Diagnosis
Idiopathic Intracranial Hypertension [IIH] involves a dysfunction in the mechanisms that secrete or absorb cerebrospinal fluid in the brain. It is a rare disease that is becoming increasingly more common. There’s some debate whether this increase is due to rising obesity rates or improved diagnostics; it is likely a combination of both. 92% of those diagnosed with IIH are obese women between the ages of 22-44, but it can be found in any population. Occurrence rates in the general population are approximately 1/100,000; however, in obese women of childbearing age the rate is 20/100,000. A small but significant population of those prone to IIH are astronauts. 29% of astronauts experience either intracranial hypertension or other visual changes related to changes in cerebrospinal fluid dynamics. NASA has partnered with The Intracranial Hypertension Research Foundation to study causes and improve diagnostics and treatment of Intracranial Hypertension.
Associated risk factors for the development of IIH include disorders like hypothyroidism, hyperthyroidism, Cushing’s disease, Lyme’s disease, and aldosteronism. Secondary intracranial hypertension has been associated with sleep apnea, pregnancy, anemia, meningitis, medications or drugs (antibiotics, lithium, vitamin A, steroids, hormone birth control), chiari malformation, and living in a microgravity environment.
Severity of symptoms vary but disabling chronic headaches is the most common symptom and permanent vision loss is experienced by nearly a quarter of IIH patients. Due to the diverse and often nonspecific nature of the symptoms, it takes an average of 5 years before the diagnosis of IIH is made. IIH is commonly misdiagnosed as chronic migraines or dismissed as symptoms of other health problems. The previous name of IIH, Psuedotumor Cerebri (meaning: false brain tumor), clearly shows the symptoms apply to other diseases. Because symptoms and treatments can be disabling, the medical profession has moved away from the name Benign Intracranial Hypertension because it undermines the seriousness of the condition.
A diagnosis of IIH is usually made after brain imaging, an ophthalmological exam, and a lumbar puncture. Brian imaging is used to rule out brain tumors, hydrocephalus, lesions, venous sinus thrombosis, or other structural problems. Signs of IIH that appear in imaging include flattening of posterior globe near the optic nerve and an empty cella. These occur 80% and 70% of the time in IIH, respectively.
An ophthalmological exam looks for papilledema, swelling of the optic disc from increased intracranial pressure. It is another common, though not universal, symptom of IIH. Permanent vision loss, either partial or full, is a serious complication of IIH. Permanent vision loss is more likely in patients who don’t receive a prompt diagnosis and appropriate treatment.
Measuring the opening pressure of cerebrospinal fluid during a lumbar puncture is the gold standard for diagnosing IIH. Opening pressure must be 250mm (25cm) or greater for a diagnosis of IIH. Occasionally a second lumbar puncture is required because the opening pressure was low on the first one and other causes for the symptoms were ruled out. A lumbar drain for 6 to 24 hours to monitor cerebrospinal fluid pressure is seldom required to make a diagnosis.
Physiological and Biochemical Mechanisms
While IIH is characterized by increased intracranial pressure, the exact physiological processes is yet unknown though four possible mechanisms of impaired cerebrospinal fluid dynamics have been suggested: increased cerebrospinal fluid secretion in the choroid plexus, increased cerebral volume, increased cerebrospinal fluid outflow resistance at the arachnoid granulations, and increased cerebrospinal venous pressure. There is no consensus though small studies show some IIH patients exhibit signs of at least one of these fluid dynamics disorders.
There are a number of hypotheses about the biochemical mechanisms involved with IIH, including endocrine dysfunction since IIH occurs most often in women. However, if hormones were the only factor involved, IIH would be more common. Another major factor in the development of IIH is obesity, with 94% of patients diagnosed with IIH falling into the clinically obese category. But again, if obesity was the only factor, there would be more cases of IIH. It is possible that both endocrine dysregulation and obesity, along with a combination of other factors, play a role in the development of IIH. Recent research implicates systemic inflammation along with glucocorticoid dysregulation, and one carbon metabolism errors due to nutrient deficiencies or genetic polymorphisms, though no group of patients exhibits abnormalities in every biomarker. However, it gives doctors and researchers alternative diagnostics using laboratory testing and can help establish new treatments.
Obesity is an established cause of low grade systemic inflammation. Numerous studies show pro-inflammatory cytokines in adipose tissue in those with obesity. Those cytokines include: CC-chemokine ligand 2 [CCL2], interleukin-1β [IL-1β], interleukin-6 [IL-6], interleukin-8 [IL-8], tumor necrosis factor-α [TNF-α], hepatocyte growth factor [HGF], nerve growth factor [NGF], and plasminogen-activtor inhibitor type 1 [PAI-1]. Resistance to the adipose hormone that controls appetite, leptin, and elevated serum leptin levels are also associated with obesity.
Pro-inflammatory cytokines associated with obesity, TNF-α, IL-1β, Il-6, and leptin also regulate the glucocorticoid enzyme 11β-hydroxysteroid dehydrogenase type 1 [11β-HSD1]. 11β-HSD1 regulates corticosteroid hormone activity by activating cortisol from cortisone. Elevated 11β-HSD1 is associated with altered lipid metabolism and insulin resistance because it controls cortisol availability which drives gluconeogenessis. Dysregulation of 11β-HSD1 can disrupt sex hormone metabolism and cortisol production. Cortisol dysregulation through altered 11β-HSD1 activity may have an effect on cerebrospinal fluid homeostasis through the regulation of the arachnoid granulation. There is also evidence of 11β-HSD1 immunoreactivity in the cerebrospinal fluid secreting cells in the choroid plexus.
Hematological and cerebrospinal fluid laboratory analysis in patients with IIH show high levels of pro-inflammatory cytokines, both ones associated with obesity and ones not associated with it. Systemic inflammation is linked to changes in cerebrospinal fluid dynamics and could be one of the underlying causes of IIH. Recent research implicated pro-inflammatory cytokines CCL2 and IL-17 in the reduction of cerebrospinal fluid outflow resistance and the association of high levels of homocysteine, cortisol, TNF-α, and IL-6 with altered compensatory mechanisms in the secretion and absorption of cerebrospinal fluid. Transforming growth factor-β [TGF- β], C reactive protein [CRP], leptin, and cortisol are also often elevated in patients with IIH. The leptin levels in patients with IIH is much greater than the levels found in obese patients without IIH.
One carbon metabolities, namely homocysteine, are also often elevated in patients with IIH, indicating B vitamin deficiencies or genetic polymorphisms that affect one carbon metabolism. Two genetic polymorphisms have been identified as increasing the risk for elevated homocystine as well as increasing the risk of developing IIH: gene MTRR with one or two G alleles and gene SHMT1 1420 with C alleles. The two identified genetic polymorphisms affect absorption of one or more of the vitamins required for one carbon metabolism; those vitamins include riboflavin, folic acid, vitamin B12, and vitamin B6. Improving the nutritional status of patients with elevated homocysteine could improve IIH symptoms and reduce the likelihood of recurrence.
Conventional Medical Treatments
Since IIH is linked to obesity, conventional treatment for IIH includes a recommendation for weight reduction. Besides extreme dieting that includes very low caloric intake, weight loss surgery is often suggested. More reasonable dietary advice for patients with IIH is to reduce sodium and caffeine intake in order to improve fluid dynamics. Excess sodium can increase intracranial pressure while caffeine increases the production of cerebrospinal fluid.
Besides lifestyle changes, medications are the first line of treatment. Carbonic anhydrase inhibitors act as a mild diuretic as well as reduce the reabsorption of bicarbonate and sodium chloride thereby slowing down fluid transport and reducing intraocular and intracranial pressure. Two popular carbonic anhydrase inhibitors used to treat IIH are acetazolamide and topiramate. Topiramate has the added benefits of reducing chronic headaches and acting as an appetite suppressant, which can aid in weight loss. If carbonic anhydrase inhibitors are not tolerated, loop diuretics that reduce the production of cerebrospinal fluid are used. Furosemide is the most popular loop diuretic prescribed for IIH. Glucocorticoids like Prednisone are sometimes used on a short term basis to reduce inflammation. They are thought to improve the outflow of cerebrospinal fluid at the arachnoid granulations in the brain. Other drugs used to treat migraines may be prescribed since chronic headaches is one of the most debilitating symptoms of IIH.
Medical procedures aren’t uncommon in severe cases of IIH that are resistant to treatment with medications. Repeated lumbar punctures to remove excess cerebrospinal fluid are often used on a temporary basis before surgical interventions are attempted or scheduled. Repeated lumbar punctures aren’t without risk. There’s always a possibility of permanent nerve damage and increased risk for serious infection.
Optic nerve sheath fenestration is used after rapid or progressive vision loss occurs due to increased pressure on the optic nerves. Incisions are made in the meninges in order to relieve the intracranial pressure on the optic nerve and improve the visual field. It’s not a cure for IIH but it can reduce further vision loss from chronic papilledema due to high intracranial pressure. Optic nerve sheath fenestration can lead to permanent blindness or other complications.
Venous sinus stents are a relatively new procedure in the treatment of IIH, but they’re gaining in popularity. A tubular support is placed in the venous sinus in order to widen an area narrowed by either intracranial pressure or blockage in order to improve cerebrospinal fluid flow. They seem to be nearly as effective as shunts but with fewer complications. The biggest complication is the risk for blot clots but that is usually controlled with medication. In IIH patients with confirmed venous sinus stenosis that impedes cerebrospinal fluid absorption, venous sinus stenting across the arachnoid granulation normalizes cerebrospinal fluid pressure and reduces IIH symptoms. Long term studies are still required but currently stenting is a surgical alternative to shunts.
Two different type of shunts are used to improve cerebrospinal fluid drainage with IIH. Shunts involve the placement of a catheter either in the brain or the spine connected to a drain tube in the peritoneal cavity in the abdomen in order to drain cerebrospinal fluid more effectively. Neuronavigation-assisted ventriculoperitoneal (VP) shunts with programmable valves are have a slightly higher risk of initial failure (14% vs 11%), but revision rates of lumboperitoneal (LP) shunts is much higher (60% vs 30%). Both often require multiple surgeries and the risk of infection is high. Shunts should be considered as a last resort.
There are three nutritional targets for the management of IIH: weight loss, reduction of inflammation, and normalization of homocysteine levels. Low sodium and limited caffeine intake may also be helpful in the management of IIH.
Studies show that weight loss using a short term (3 months) very low carbohydrate diet improves abnormal 11β-HSD1 activity and normalizes cortisol levels. Very low calorie diets have also shown to improve IIH symptoms, though biochemical markers weren’t checked. While doctors often recommend surgical weight loss procedures in the treatment of IIH, diet based weight loss has fewer complications as long as micronutrient needs are met.
Research into diets that mitigate pro-inflammatory cytokines and other pro-inflammatory biochemicals have identified a few factors that should be included in a diet in order to reduce systemic inflammation. Those factors include: monounsaturated and omega-3 fatty acids like those found in avocados, olive oil, nuts, flaxseed, chia seed, and oily fish; a greater quanity of fruits, vegetables, and nuts; minimally processed whole grains; and polyphenols including tea, cocoa, red wine, and berries. Studies suggest that diets with higher fruit and vegetable intake are associated with reduced levels of pro-inflammatory cytokines including IL-1, IL-6, and TNF-α and CRP.
Dietary factors that increase inflammation include: trans fats and omega-6 fatty acids like those found in vegetable oils; highly processed foods with a high glycemic index; and diets without adequate fruits, vegetables, and nuts.
New research shows that diets which contain mostly fresh foods with limited sugar and processed foods reduce inflammation. A Mediterranean style diet and a Paleolithic style diet were used in the trial and both decreased CRP. Pro-inflammatory cytokine levels weren’t tested.
Normalization of homocysteine levels can be managed through diet alone if genetic polymorphisms aren’t present. The micronutrients required for one carbon metabolism can easily be gained from food as long as genetic polymorphisms don’t hinder the conversion of them into usable forms. Bioavailable or coenzymated vitamins may be added to the patient’s treatment regime if vitamin conversion is a problem. Folate can be obtained from leafy greens, citrus, beans, nuts, and whole grains. Vitamin B12 is in mollusks, liver, red meat, fish, poultry, eggs, and dairy products. Vitamin B6 can be found in organ meats, fish, beans, potatoes, and bananas. Riboflavin (vitamin B2) is most plentiful in dairy products, nuts, red meat, fish, eggs, and pork.
Designing a diet that the patient can turn into a lifestyle change for the long term is key to any nutritional management of disease. Neither very low carbohydrate nor very low calorie diets are easy or safe for long term, though both can be used for short term weight loss in order to improve biomarkers and symptoms of IIH. For the treatment of IIH, a whole food diet rich in omega-3 fatty acids, vegetables, fruits, nuts, and nutrient rich meats and low in highly processed foods with high glycemic index and high omega-6 fatty acids seems to be the best place to start.
Idiopathic Intracranial Hypertension is a disabling disease that can cause permanent vision loss and chronic headaches that mostly affects obese women between the ages of 22-44. While the cause of the symptoms are well documented, increased cerebrospinal fluid pressure, the underlying causes of the abnormal cerebrospinal fluid dynamics are still heatedly debated and researched. Newer research implicates a number of biochemical changes including systemic inflammation, glucocorticoid dysregulation, and one carbon metabolism errors. Conventional medical treatment for IIH currently does little to identify or treat these underlying biochemical abnormality. Nutritional management of the biochemical irregularities though a carefully designed diet and supplemental vitamins, if required, is a good adjunct treatment to conventional medicine that should reduce symptoms and recurrence of IIH.
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