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Idiopathic intracranial hypertension (IIH), also called pseudotumor cerebri, now affects about 100,000 Americans, and many comprehensive ophthalmologists are likely to see some of these patients in their practices.
Characterized by elevated intracranial pressure and diagnosed most often in women with a history of obesity, IIH can cause temporary or permanent vision loss. Its etiology is unknown, though a prominent theory proposes some mechanism of resistance to cerebrospinal fluid (CSF) outflow. Significantly, perhaps, the incidence of IIH is rising along with the obesity epidemic.
When the patient comes in. While IIH patients are usually referred to neuro-ophthalmologists after diagnosis, comprehensive ophthalmologists can play a vital role in the initial management of IIH. They are often the first to see IIH patients and may then work in concert with a neurologist to monitor treatment in communities where neuro-ophthalmologists are not nearby, said Mark J. Kupersmith, MD, director of neuro-ophthalmology at Roosevelt Hospital and director of the New York Eye and Ear Infirmary.
What to look for. Symptoms of IIH can include headache, pulse synchronous tinnitus, transient visual obscurations, double vision and peripheral vision loss. The vision loss affects about 86 percent of patients and is considered secondary to papilledema, which results in intraneuronal injury and cell death.
The ophthalmologist should ask the patient about a history of weight gain and look for swelling of the optic nerve and visual field deficits. These signs are often accompanied by normal findings on neurologic exams or MRI, said Michael Wall, MD, professor of neurology and ophthalmology at the University of Iowa in Iowa City. IIH patients also tend to be of child-bearing age.
Diagnosis of IIH is made with a clinical exam, documentation of papilledema and visual field defects, and a finding of elevated CSF pressure. Lab studies, a neurologic exam and MRI are used to rule out other causes, such as a tumor or vascular disease.
Without timely treatment, IIH will often progress to vision loss. Unfortunately, early loss usually goes unnoticed by patients because it comes on gradually, in the periphery. About 10 percent of patients with IIH suffer severe vision deficits and 5 percent lose all sight in one or both eyes, Dr. Wall said.
Study of Anecdotal Tx
Typical treatments for IIH, including weight loss, diuretics such as acetazolamide, serial lumbar punctures, CSF shunting procedures and optic nerve sheath fenestration, have been established primarily through case reports and clinical practice over many years.
Weight loss is considered the cornerstone of IIH treatment, and acetazolamide also seems to alleviate symptoms in many patients. Yet whether acetazolamide works because it is a diuretic or because its side effects can include nausea and a metallic taste when drinking carbonated beverages remains an open question, Dr. Wall said. Furosemide (Lasix), a more potent diuretic, also appears to be effective in IIH patients.
Surgeries such as optic nerve sheath fenestration and CSF or stereotactic-guided ventricular shunting are usually reserved for patients with moderate to severe vision deficits who do not respond to medical approaches, Dr. Wall said (see “The Question of Surgery”).
Finally, a formal study. Until now, no prospective clinical trials have proven the effectiveness of current treatments or clarified the cause of the disease, said Dr. Wall. But now diet and acetazolamide in patients with mild visual field defects will be studied in the double-masked, randomized Idiopathic Intracranial Hypertension Treatment Trial.
The study, funded by the NEI, will take place at 43 centers in the United States and Canada and is currently recruiting patients. Participants and their vision deficits will be assessed over a six-month intervention and then followed for up to four years afterward to provide information about long-term outcomes.
The study is the first clinical trial of the Neuro-Ophthalmology Research Disease Investigator Consortium (NORDIC). “Regardless of what we find, by doing things carefully and prospectively, we’re going to learn a lot about the disease—about whether diet or acetazolamide work, and how well they work, as well as the possible causes of the disease,” said Dr. Wall, who is codirector of the IIH trial. “Until our present trial, all the information we have had on treatments has been anecdotal; there have been no large-scale, prospective studies to give us guidance on treatment.”
The Question of Surgery
Although surgery is also used to treat IIH, the NORDIC researchers decided to limit their trial to diet and acetazolamide because the far smaller number of patients who require surgical intervention would not provide the sample size needed to show treatment effects, Dr. Wall said. Surgery is reserved for individuals who do not respond to weight loss and diuretic therapy.
Nine out of 10 do well. Published case series suggest that surgical options—including optic nerve fenestration and shunting procedures—may stabilize or improve symptoms in 90 percent of patients. About 10 percent of patients worsen, unfortunately, even if they receive a nerve fenestration or shunting procedure, Dr. Wall said. The choice of surgical procedure often depends on the experience and preference of the neuro-ophthalmologist, he added.
Dr. Kupersmith noted that, in his experience, fenestrations of the optic nerve sheath often can stabilize or improve vision. However, one type of procedure—the lumbar-peritoneal shunt—can be difficult to monitor and may clog with abdominal fat in obese IIH patients. Putting a shunt in the cerebral ventricles to drain off excess intracranial fluid has become more favored by neuro-ophthalmologists, Dr. Kupersmith said. These shunts have valves by which the surgeon can adjust pressure and more easily monitor effectiveness. With the advent of sterotactic-guided surgery, such procedures have become easier and more likely to succeed, he said.
How the Study Works
The new study will include 154 IIH patients with mean deviation between –2 and –5 on automated perimetry and evidence of bilateral papilledema. All patients will participate in a low-sodium weight loss program run by the New York Obesity Research Center (NYORC) of St. Luke’s-Roosevelt Hospital Center. They will then be randomized to receive either acetazolamide or a placebo.
Checking genetics. Investigators will also be matching the IIH patients to a control group of patients who are similar in body mass index, ethnicity and gender but who do not have IIH. Then all participants will be screened for single nucleotide polymorphisms (SNPs) that might confer risk for the disease. Genetic analysis will center on SNPs for at least 50 candidate genes associated with obesity or metabolism of vitamin A and the hormones leptin and ghrelin.
Checking body fluids. Depending on data provided by the genetic analysis, participants may also be screened for blood and CSF levels of those hormones and vitamin A. This effort is based on a theory that the prevalence of IIH in obese women could be caused by excess vitamin A, which is stored in fat, Dr. Kupersmith said.
Checking the optic disc. The NORDIC study will be the first trial anywhere in which SD-OCT will be used, by way of an ancillary study conducted by Dr. Kupersmith, to document changes in papilledema. SD-OCT images will be taken at baseline, and investigators will use specially designed protocols and software at an expert reading center at the University of California at Davis to analyze images and grade changes in papilledema, Dr. Kupersmith said.
Public Health Benefits
One primary goal of the IIH trial is to achieve a 5 to 10 percent weight loss in participants and maintain the pounds lost, Dr. Wall said. “If you ask people to lose just 5 to 10 percent of their weight and tell them their vision is on the line, a lot of people can be successful in losing the weight and maintaining it,” he said. “But if you go beyond 5 to 10 percent weight loss, it becomes pretty tough to maintain,” he said.
The program includes one-on-one phone and online counseling about weight loss. Investigators say that the quality of the counseling, provided by the NYORC, is high and may be effective whether or not it’s coupled with a diuretic. “I don’t have a bias as to which treatment is more effective—diet alone or diet plus acetazolamide,” said Robert L. Lesser, MD, a NORDIC investigator and clinical professor of ophthalmology, visual science and neurology at Yale University. “I hope that the trial will give us scientific, evidence-based information to tell us what are the effective treatments for IIH,” he said.
Dr. Lesser was the first investigator to recruit a participant for the NORDIC trial, and he has been impressed by the success of the weight loss program. “That first patient, who began the trial at 272 pounds, is getting tremendous nutritional counseling and has lost 37 pounds in 14 weeks—13 percent of her original weight. I think it shows that effective nutritional counseling can make a big difference.”
The physicians interviewed for this story report no related financial interests.