Greek Researchers Investigate Octreotide
In 2007, researchers at Athens General Hospital in Greece published the results of a clinical study in which 26 patients with 
idiopathic intracranial hypertension (IIH) were treated with octreotide, a synthetic hormone that is sometimes used in the treatment of tumors and in certain endocrine disorders. This was an expansion of an earlier study from 1993.
What Is Octreotide? How Does It Work?
Octreotide is a man-made version of a natural hormone called somatostatin. It is a long-acting, complex protein known as an octapeptide. For a substance like octreotide to have the same effects of the hormone it is mimicking, it must be able to attach to special sites on certain cells called receptor sites. Octreotide has a strong affinity for the usual somatostatin receptor sites.
Once attached to these receptors, octreotide produces pharmacological actions that mirror somatostatin’s effects. Octreotide and natural somatostatin inhibit insulin secretion to a similar degree. Octreotide, like somatostatin, also suppresses the release of gastrointestinal peptide hormones, including serotonin, gastrin, vasoactive intestinal peptide (VIP), secretin, motilin, and pancreatic polypeptide, all of which have vital gastrointestinal functions.
In some cases, octreotide is even more potent than somatostatin. For example, it has stronger inhibitory power in blocking secretion of growth hormone and glucagons—a substance that causes blood sugar to rapidly rise—than somatostatin.
There are other differences between octreotide and somatostatin. Octreotide also has a longer duration of action than somatosatin. Because of this pharmacological distinction, octreotide is used to treat various endocrinological disorders and certain gastrointestinal, colorectal and pancreatic tumors; it is usually administered by subcutaneous injection, two or three times daily.
Octreotide is also widely recognized as an effective treatment for acromegaly—a disorder of excess body growth from excessive growth hormone secreted by a pituitary tumor.
The 2007 Study
In the study, the researchers recognized that the origin or pathophysiology of idiopathic IH is unknown. But they believe that growth
hormone plays a role, in some way. As evidence, they offer the established fact that children treated with recombinant growth hormone often develop intracranial hypertension. (Editor’s note: When growth hormone is discontinued, the intracranial hypertension usually disappears.)
They also point to presumptive evidence that in acromegaly, in which high levels of growth hormone are present, using octreotide—which inhibits the production of growth hormone—reduced the severe, chronic headaches associated with acromegaly. And they stated that, in a previous study published in 1993, 3 patients with IIH responded well to octreotide treatment.
Study Design
The authors’ plan was to expand the original study to include a larger number of patients with longer follow-up. They recruited 26 patients who met the study requirements, with the signs and symptoms of intracranial hypertension. Their inclusion criteria were:
1. Unilateral or bilateral papilledema (swollen optic nerves).
2. CSF pressures greater than 200mm H2O.
3. Normal composition of cerebrospinal fluid (CSF) (i.e. normal lab tests of CSF).
4. Absence of enlarged ventricles (indicating hydrocephalus) or an intracranial mass in brain MRI study.
5. Absence of focal neurological signs. (No neurological findings that are characteristic of specific neurological
diseases.)
Twenty-six patients were selected for the study; twenty-three were female and 3 were male. The mean age was 27.5 +/-5.1 years. Eighteen of the 26 patients were overweight (Body Mass Index (BMI) >25), mean BMI was 26.65 +/– 2.25. All patients reported headache and all had papilledema.
The study protocol required that eye examinations be performed on all 26 patients and this included the examination of visual acuity, visual fields, as well as fluoroangiography (photography of the retinal blood vessels and the optic nerve). All patients had a spinal tap in the lateral decubitus position (lying on one’s side) to determine the opening pressure prior to treatment.
Patients received subcutaneous injection of .3mg. of octreotide each day. This initial dose was increased every third day by 0.1mg. until the headache was relieved or until maximum dose of 1 mg. a day was reached. This dose was continued for six to eight months. After this period, the dosage was gradually decreased. The mean duration of treatment was 42 weeks.(The treatment range ran 5 -130 weeks.)
Patients were then examined every month, including eye exams, for the next three years. They checked the opening pressure readings (spinal taps) at the end of the first month.
Results
The authors reported that 24 of the 26 patients (92%) were significantly improved. Two patients did not have any improvement, and after 15 weeks of octreotide treatment, it was stopped. In 24 patients, headache was relieved within 10 days (median: 7 days) and papilledema subsided in all of these patients within the time period of 35 to 68 days, (median: 45 days). Th e 24 patients have remained free of signs and symptoms of intracranial hypertension for three years after cessation of octreotide treatment.
In the 26 patients, the pre-treatment mean opening pressure was 34 +/–12.5cm H2O (range: 21 to 66). After treatment, the mean CSF pressure was 14.82 +/– 4.52cm (range: 8 to 23). Th is represented, a mean pressure drop of 20.72+/–10.7cm H2O (2 to 48).
Adverse side-effects included nausea (5 patients) and diarrhea (4 patients). The symptoms were mild and did not required interruption of treatment.
Analysis Of The Study
While these initial results are impressive and encouraging, the standard, unbiased evaluation of any treatment requires,
as the researchers themselves have duly noted, a double-blind study. In this type of study, patients are given either the drug to be tested or a placebo on a random basis. Neither the patient nor the researcher knows whether the drug or the placebo was given to any patient until the end of the study. Results are often tabulated by a third party to determine if there is a significant difference in outcome between drug and non-drug treatment.
A double-blind study could also compare present treatment, such as weight reduction or weight reduction plus Diamox (acetazolamide) therapy or medical therapy alone. It’s also important to note that long, asymptomatic remissions have been described in cases of idiopathic IH, as the result of weight loss alone.
It is not clear how the study’s authors determined the duration of treatment. Patients are described as being treated with up to1mg. per day for six to eight months, although neither the number of daily injections nor the amount of octreotride required in each patient to produce the desired results are described in the study results. All 24 patients who responded to octreotide treatment were free of headache by 10 days and had their papilledema resolved by two months. No explanation is given regarding why the patients are continued for so long thereafter on octreotide or why they were able to be symptom-free after cessation of octreotide for a follow-up period of three years.
Two advantages of a double-blind study are that durations and dosage would be applied equally to all patients.At least one (or more) of the 24 patients was treated for as long as 130 weeks (2.5 years) without explanation. Did the patient (or patients) become symptomatic if octreotide was discontinued earlier and, therefore, octreotide had to be continued?
It is also difficult to reach specific conclusions about outcomes since individual patients are not separately identified and the
severity of their disorders are not delineated. Important factors like age and weight are not identified for each patient. Since approximately 50% of children with IIH under the age of 10 spontaneously get better, it is important to know whether young children were included in the group of 24 patients.
It is hard to evaluate if weight loss played a role. Did any of the 24 patients lose significant weight while on octreotide? Was this a factor in a favorable outcome? Did any patients who may have lost weight regain it and remain asymptomatic? This question is particularly important.
It would be helpful to understand if any of the 24 patients had other important medical ailments and/or were taking other medications. Was the group previously treated for IIH? Knowing ophthalmologic details such as the initial degree of papilledema and the actual visual field findings pre- and post-treatment would be of value in assessing outcomes, too.
Although the authors describe very few and mild side effects from octreotide, the issue of whether more adverse reactions would be found in a large, well-controlled study is important. If octreotide was beneficial, would patients continue long-term injections?
Since the drug cannot be used orally, could it be delivered in some other form, such as by dermal patch or by inhalation? There are many questions to be addressed, but first and foremost, octreotide must be evaluated in a controlled, double-blind study.
What It Means For IIH Patients
Overall, given the exceptionally positive results of this paper, the authors are aware of the need for additional study, which is appropriate and warranted. If a double-blind study can confirm octreotide as clinically capable of lowering intracranial pressure, it might open new avenues of investigation into its relationship with IH and its potential use as a treatment option.
Receptors for somatostatin are found in the choroid plexus, the place in the brain where cerebrospinal fluid (CSF) is formed, and in the arachnoid granulations, where CSF exits the brain.
A very important question to ask would be whether octreotide works at both sites—suppressing production and enhancing egress (or exiting) of CSF—or if another mechanism is at work. If octretide works at the CSF exiting site, it would be the first known drug to do so. Not only would this finding advance our understanding about how CSF leaves the head, it would open the door to developing other drugs to work at this location.
*This review is based on an article that originally appeared in our In Sight newsletter in 2008.
Medication and Surgery
Both drugs and surgery are used to treat chronic IH. Medical (or Drug) therapy is generally tried first, but if there is an immediate risk to vision, chronic pain that cannot be relieved or a poor response to drug therapy, then surgery is performed. It is not unusual for people with chronic IH to undergo both drug therapy and surgery in an effort to control their intracranial pressure.
Drug Therapy
Carbonic Anhydrase Inhibitors
Carbonic anhydrase is a crucial enzyme needed in the production of cerebrospinal fluid. When this enzyme is suppressed, production of CSF decreases, which also lowers intracranial pressure.
The most common carbonic anhydrase inhibitor and the main drug used to treat chronic IH is acetazolamide (Diamox). Methazolamide (Neptazane), a similar drug from the same family as acetazolamide, can also be prescribed. Other drugs with carbonic anhydrase inhibiting properties include furosemide (Lasix) and topiramate (Topamax).
Acetazolamide was originally developed to treat glaucoma by reducing the production of aqueous fluid within the eye, which lowers intraocular pressure. Acetazolamide is a sulfonamide but its molecular structure differs from sulfa drugs, which means that certain people who are allergic to sulfa antibiotics may still be able to take acetazolamide. However, any treatment should first be discussed with and supervised by your physician.
Daily dosages of acetazolamide can range from 1-4 grams depending on the individual. In addition, potassium supplements may be necessary since most carbonic anhydrase inhibitors are diuretics, as well. Many people notice tingling in their face, hands and feet; a metallic taste when drinking carbonated beverages; fatigue; and a lack of appetite when they first begin taking acetazolamide. These initial side-effects tend to dissipate over time.
If drug therapy is successful, surgery can sometimes be avoided. However, carbonic anhydrase inhibitors have several drawbacks. The drugs block other similar enzyme systems elsewhere in the body (i.e. the eyes and the kidneys), with unknown effects. Some who take acetazolamide may develop kidney stones; the drug also carries a very rare risk of aplastic anemia, a serious blood disorder.
Carbonic anhydrase inhibitors can be difficult to tolerate long-term and for some people, the drugs are just not effective. But since no drug has been specifically developed to treat chronic IH, they are currently the only option.
Other Drugs
Treatment of pain, especially headache pain, can be challenging. In addition to using carbonic anhydrase inhibitors, some physicians try to treat the headache that accompanies chronic IH. Medications for chronic headache like tricyclic anti-depressants, beta-blockers and calcium-channel blockers may be used, depending on the individual.
The long-term use of corticosteroids to treat chronic IH has fallen out of favor, unless there is a secondary inflammatory process caused by an underlying disease like lupus or Behcet disease. While corticosteroids may lower intracranial pressure in the short-term, the drawbacks to steroids include weight gain, fluid retention and a rebound in intracranial pressure during the drug’s withdrawal.
Prescription pain medication may also be a part of drug therapy. While most pain medications have little effect on headaches caused by intracranial hypertension, they may temporarily affect the intensity of a headache for some people.
It’s not uncommon, especially among those who are undiagnosed, to turn to over-the-counter headache medications in search of relief. But excessive use of these drugs can lead to rebound headaches, as well as other conditions, like thinning of the blood. While the relationship between headache pain and IH is not fully understood, lowering intracranial pressure remains key to reducing chronic IH pain.
In 2007, researchers at Athens General Hospital in Greece published the results of a clinical study in which 26 patients with idiopathic intracranial hypertension (IIH) were treated with octreotide, a synthetic hormone that is sometimes used in the treatment of tumors and in certain endocrine disorders. The results were very positive but octreotide as a possible therapy for IIH needs to be evaluated in a controlled, double-blind study, something both the study’s researchers and IHRF advocate.
To read more: http://www.ihrfoundation.org/hypertension/info/C172
Surgery
Optic Nerve Fenestration
When sight is at risk and drug therapy has been unsuccessful, an optic nerve fenestration (also called an optic nerve sheath decompression) is usually performed. The operation can be done on one optic nerve sheath (unilateral) or on both optic nerve sheaths (bilateral).
During surgery, a small window-like opening is made in the sheath around the optic nerve, which allows cerebrospinal fluid (CSF) to drain behind the eye and relieves optic nerve swelling. This surgery is done primarily to save vision, rather than to alleviate headaches.
Neurosurgical Shunts
Shunt operations are also performed when drug therapy has been unsuccessful. Shunts may be used to control papilledema and prevent vision loss, as well as to treat headaches that have been unresponsive to any medication. A neurosurgical shunt is a surgically-implanted catheter that is used to drain CSF into another area of the body such as the abdomen. A shunt lowers intracranial pressure by removing CSF to another site, where it can be absorbed.
Most Common Types of Shunts
Lumboperitoneal shunt (LP shunt)
An LP shunt diverts CSF from the lumbar sub-arachnoid space (spine) to the peritoneum (abdominal cavity).
Ventriculoperitoneal shunt (VP shunt)
A VP shunt diverts CSF from a ventricle in the brain to the peritoneum (abdominal cavity).
Cisterna magnum shunt
A cisterna magnum shunt diverts CSF from the cervical cistern (back of the head) to the peritoneum (abdominal cavity). These types of shunts are generally used when it is not possible to use an LP or VP shunt.
Other areas of the body into which CSF can be drained include the pleural cavity (chest), and the atrium (heart).
Many shunts used today have programmable valves, which means that the valves are externally adjustable. The advantage of a programmable valve is that after surgery, a physician can adjust the valve’s rate of drainage non-invasively, with the use of a magnetized device. Shunts with programmable valves can be affected by magnets used to produce MRIs, and may need to be adjusted after the imaging is completed.
Shunts have a checkered history with an initial 50% success rate and alternately, a high revision rate of 50%.The most common problem with shunts is that the catheter becomes blocked and has to be replaced. Shunts are the most common pediatric neurosurgical procedure and the second most common neurosurgical procedure for adults.
Cerebrospinal Stenting
Some people with IH who are either non-responsive to medication or are intolerant of it, and who have also been found to have a true narrowing (stenosis) of a major venous channel at the base of their brain, may be candidates for a surgical procedure known as stenting.
The stenosis is detected on imaging studies (CT or MR venography), which is then confirmed by actual direct pressure measurement within the narrowed vein (direct angiography). The presence of a true stenosis restricts blood flow through a large venous blood vessel, thereby raising blood pressure within the cerebral venous system. (This pressure is different than arterial blood pressure, which is measured by your doctor with an arm cuff)
As fresh CSF is continually produced within the brain, “used” CSF normally drains unidirectionally into the cerebral venous sinuses, after circulating in the subarachnoid space. If the venous blood pressure is abnormally high from a stenosis, then CSF pressure must correspondingly rise in order to flow into the venous sinus. This cause of intracranial hypertension can be relieved by surgically placing a stent (a small, tube-like device) in the stenotic area, which improves blood flow and lowers both venous blood pressure and the cerebrospinal fluid pressure.
While cerebral venous sinus stenosis is not a common finding for most people with IH, people who do have stenosis and undergo stenting often experience a significant improvement in the signs and symptoms of intracranial hypertension. Therefore, all patients with unexplained intracranial hypertension should undergo imaging (venography) to rule out the presence of a true stenosis.
There is no “perfect” treatment for chronic IH, especially since every person’s experience is different. While surgery certainly helps some people, it can also lead to repeat operations, which can sometimes produce serious, even life-threatening complications. To make an informed decision, it is always best to discuss both the risks and benefits of any treatment with your physician.
Resources for Finding a Doctor
Here are some resources to help you locate doctors near you who may treat chronic intracranial hypertension. Keep in mind that there is a spectrum of philosophies when it comes to treating this illness and that each doctor is an individual. IHRF does not recommend or endorse any specific doctor; we simply provide this information as a resource. Some of the following sites list doctors located internationally, as well as in the U.S.
The following websites may help you find board-certified doctors near you:
American Academy of Neurology (AAN)
http://www.aan.com
The website of the American Academy of Neurology. Note: AAN no longer offers its neurologist search services to patients.
American Medical Association (AMA)
https://apps.ama-assn.org/doctorfinder/recaptcha.jsp
Neuro-Ophthalmology: North American Neuro-Ophthalmology Society (NANOS)
http://www.nanosweb.org/i4a/member_directory/feSearchForm.cfm?directory_id=1&pageid=3390&showTitle=1&showDebugOutput=false&widgetPreview=0&page_version=
Neurosurgery: American Association of Neurological Surgeons (AANS)
http://www.aans.org/Find%20a%20Board%20Certified%20Neurosurgeon/Search.aspx
Ophthalmology: American Academy of Ophthalmology (AAO)
https://secure.aao.org/aao/find-an-eye-md
Finding A Doctor
The first doctor to discover symptoms of intracranial hypertension may be your primary care physician. Or it may be your ophthalmologist during a routine eye exam. Or it could be your neurologist. Once you are diagnosed, specialists like neurosurgeons, neuro-radiologists, neuro-ophthalmologists and many others may be called in to help. Because the treatment of chronic IH often requires a team of physicians, it’s important to find one doctor who will be the team leader.
Who’s in charge of my care?
The physician you choose should be able to act as your advocate and provide honest answers to your questions. Ask the physician directly if he or she will be the central director in charge of your care. Your team leader could be your primary care physician, your pediatrician, your neuro-surgeon or any of the doctors that you see regularly. Most importantly, he or she should be willing to oversee your care, facilitate communication between all of your physicians and act as your advocate.
Some general tips on finding doctors:
You may need to do a bit of homework to discover if a particular doctor is right for you.
Some of this information can be found on the Internet.
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Check out where the physician works.
- Are there good diagnostic facilities?
- Does your physician have access to state-of-the-art imaging and labs?
- Does your M.D. work in a multi-specialty team setting?
- Are there peers in his/her specialty available for consultation, review and discussion?
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Check out the physician’s background. Medical societies in the communities where a physician is licensed, can provide some of the following information. If a physician is affiliated with a university, the university itself can be a source of information on the doctor.
- Is the doctor board-certified in his/her specialty?
- Where did he or she train (educational background and medical internships/ fellowships/ residencies)?
- Does he or she seem interested in patients with chronic intracranial hypertension?
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Determine the physician’s experience in treating chronic IH.
- Does he or she have experience treating chronic intracranial hypertension?
- Is the doctor involved in IH research? Has he or she published on the subject?
- Is the physician passionate—and compassionate—about this disorder?
- How many cases does the physician treat each year?
("A lot of cases,” or “pretty experienced,” are general descriptions. It’s better to be specific and ask: “How many cases like mine do you treat (or operate on) per year?) - What are the outcomes of his/her medical and/or surgical management?
- If he/she is not a surgeon, who does he/she refer chronic IH cases to and why?
- If he/she is a surgeon, will he/she monitor your recovery and be readily available to manage any complications?
- What is the treatment plan for you? What is the outcome that he or she expects in your case?
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The Doctor/Patient Relationship.
- Are you comfortable with the doctor?
- Does he/she listen to what you have to say?
- Do you trust him/her?
- Does he or she want to help inform you to make the best medical decisions?
(Suggests articles on treatment and options.) - Does he/she encourage questions and answer them to the best of his or her ability?
As a patient, be empowered by learning about your condition. If you’d like a second opinion, don’t hesitate to ask for one. Keep in mind that doctors have a limited range of tools to use when treating chronic IH. The most successful doctor/patient relationships are working partnerships.
Who Treats IH?
Intracranial hypertension is not treated exclusively by one type of doctor. A specialist will treat one particular area while another specialist will address a different set of issues related to his or her area of expertise. For example, you may see a neurologist to treat headaches. For vision issues, you may visit an ophthalmologist or neuro-ophthalmologist. If you need shunt surgery, you will see a neurosurgeon. Like many neurological disorders, chronic IH can affect the entire body. As a result, you may encounter doctors from a range of specialties, including:
- Anesthesiology
- Bariatric Surgery
- Endocrinology
- Family Medicine
- Gastroenterology
- Internal Medicine
- Nephrology
- Neurology
- Neurosurgery
- Neuro-Ophthalmology
- Neuro-radiology
- Obstetrics / GYN
- Ophthalmology
- Pain Management
- Pediatrics
- Pediatric Neurosurgery
- Psychiatry
- Radiology
- Surgery
There may be other specialties, depending on your circumstances.
Because of this “fragmentation” of medical care, many specialists may only see a small slice of the big picture, which is why it’s important to gather enough information so that you can find the right people to help you and assist your physicians in communicating with one another about your care.