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Journal of Neuro-Ophthalmology:
doi: 10.1097/WNO.0b013e3181fe1fd4
Jacobson Lecture

Idiopathic Intracranial Hypertension With Dan and Beyond: The 2010 Jacobson Lecture

Friedman, Deborah I MD, MPH

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Flaum Eye Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York.

Completed neurology training at the University of Pittsburgh and neuro-ophthalmology fellowship at the University of Iowa. He joined the staff of the Marshfield Clinic in Marshfield, Wisconsin, in the Departments of Neurosciences and Ophthalmology in 1987 with a faculty appointment at the University of Wisconsin. During a 16-year period at the Marshfield Clinic, he cared for thousands of patients and authored more than 50 scientific manuscripts in the field of neuro-ophthalmology. He was honored with numerous teaching and research awards and recognized for his ability to apply basic science principles to the investigation of the most pressing clinical issues. The Marshfield Clinic Foundation has established a memorial fund in his name. In recognition of the profound impact he has had on the field of neuro-ophthalmology, the North American Neuro-Ophthalmology Society (NANOS) has established a lecture to be presented each year at the NANOS meeting.

FIG. Daniel M. Jacob...
FIG. Daniel M. Jacob...
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Address correspondence to Deborah I. Friedman, MD, MPH, Flaum Eye Institute, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 659, Rochester, New York 14642; E-mail: deborah_friedman@urmc.rochester.edu

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Abstract

Neuro-ophthalmologists frequently care for patients with idiopathic intracranial hypertension (IIH), although many questions remain unanswered regarding its diagnosis, pathogenesis, and treatment. The Friedman-Jacobson criteria for the diagnosis of IIH specify lumbar puncture (LP) opening pressure values that are largely based on experience with little supporting normative data. Until recently, there were sparse data to define normal values of the LP opening pressure in children. Papilledema, the sine qua non of IIH, may not always be present, but the frequency of true IIH without papilledema is controversial and the threshold for diagnosing it varies among clinicians. Concepts regarding the pathogenesis of IIH continue to evolve; venous hypertension is certainly implicated even though it is uncertain whether venous sinus stenosis is the cause or effect of increased intracranial pressure. The 2010 Jacobson Lecture discusses the evidence for some of the prevailing assumptions about normal lumbar puncture opening pressure, venous sinus stenosis, and the phenotypic continuum between chronic daily headaches and IIH.

It is an honor and privilege to deliver the third annual Jacobson Lecture. Dan was a role model for us all; he was a superb teacher and a clinician and an astute observer with an inquisitive mind. He wrote more than 70 articles, including pivotal studies on diverse topics in neuro-ophthalmology such as pupil-sparing oculomotor palsies and their predictive value for discovering an intracranial mass, benign episodic pupillary mydriasis, ventricular size in pseudotumor cerebri, vitamin A levels in idiopathic intracranial hypertension (IIH), cholinergic supersensitivity in Adie's pupils and third nerve palsies, and progressive deficits in microvascular cranial neuropathies. In many ways, Dan changed the way we practice neuro-ophthalmology.

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DIAGNOSTIC CRITERIA: FROM DANDY TO DAN

Dan and I met at a NANOS meeting when I was a fellow, and we started collaborating shortly before he was diagnosed with esophageal cancer. He was a joy to work with, and our first project was to revise the existing criteria for the diagnosis of IIH in the light of advances in neuroimaging and other developments in our understanding of IIH. Although commonly referred to as the “Dandy criteria” for IIH, Dr Walter Dandy never published criteria for diagnosing the disorder. He authored an article in 1937 (1) describing 22 cases he had encountered over a 7-year period.

Dandy's patients ranged in age from 9.5 to 48 years, with presenting symptoms of headache (17 patients), blurred vision (2), headache and blurred vision (2), dizziness (12), nausea (7), vomiting (11), and diplopia (11). All of his patients had papilledema, which was usually symmetrical. Fifty percent had decreased acuity, enlarged blind spots, scotomata, or blindness. Most patients had normal neurological examinations, with the exception of 2 patients with VI nerve palsies and the separation of frontoparietal sutures in a 13-year-old girl. The cerebrospinal fluid (CSF) contents were normal in all but 1 case with opening pressures ranging from 250 to 550 mm CSF. Close scrutiny of the tabulated details leads me to believe that a few of his cases did not have IIH since they also had hallucinations, drowsiness, coma, and CSF pleocytosis.

Dandy also noted small ventricles by ventriculography, and he treated his patients with subtemporal decompression when needed. Although the etiology was (and still is) unknown, he postulated that the variable fluid content must be in the brain rather than in the meningeal space and discussed the possible role of variations in the intracranial vascular bed by vasomotor control, as the ventricles are small and the alteration in pressure occurs in minutes with subtemporal decompression. Prior to the development of imaging techniques to visualize vascular changes in IIH, Dandy realized the importance of the cerebral vasculature in the development and regulation of CSF pressure.

Smith (2) coined the term “modified Dandy criteria” to include:

* Signs and symptoms of increased intracranial pressure (ICP) (headaches, nausea, vomiting, transient obscurations of vision, and papilledema).

* No localizing neurologic signs otherwise, with the single exception being unilateral or bilateral sixth nerve paresis.

* CSF can show increased pressure, without cytologic or chemical abnormalities.

* Normal to small symmetric ventricles must be demonstrated (originally required ventriculography, but now demonstrated by CT).

The Friedman-Jacobson criteria state the following (3):

1. If symptoms are present, they may only reflect those of generalized increased ICP or papilledema. We wished to include asymptomatic patients-most frequently, children who have asymptomatic papilledema discovered on a routine examination-and highlight possible “red flags” in the diagnosis, such as focal symptoms, encephalopathy, seizures, an abrupt onset with rapid progression, and central visual loss in the absence of severe papilledema or macular edema.

2. If signs are present, they may only reflect those of generalized increased ICP or papilledema. This allows for the absence of papilledema in situations precluding its development, such as optic atrophy, an open fontanelle, or in “…rare patients with otherwise typical IIH who do not have papilledema.” A separate intention was to stress the other signs that are considered highly atypical in IIH such as third and sixth nerve palsies, generalized ophthalmoparesis, focal neurologic signs in adults, and altered level of consciousness.

3. Documented elevated ICP measured with the patient in the lateral decubitus position. Based on the work of Corbett and Mehta (4), we defined elevated opening pressure as 250 mm CSF or higher, considering values of 200-249 mm CSF as nondiagnostic. As CSF pressure fluctuates, prolonged monitoring is sometimes necessary to confirm the diagnosis. Valsalva maneuver during the procedures and measuring the pressure with the patient in the prone position under fluoroscopy or in the sitting position were contributors to erroneous values.

4. Normal CSF composition, including glucose, protein, and cell count, with no cellular atypia.

5. No evidence of mass, structural, or vascular lesion on MRI or contrast-enhanced CT for typical patients and MRI and venography for all others. Assuming no contraindications, MRI is the preferred modality for imaging. At the time, studies suggested that venous sinus thrombosis was rare in typical patients without other risk factors, but atypical patients (eg, slim patients, men, children, patients with fulminant IIH) need more comprehensive imaging (5). The ventricles should be normal size for age (6). Imaging findings suggestive of IIH include an empty sella, flattening of the posterior sclerae, widening of the subarachnoid space surrounding the optic nerves, and protrusion of the optic nerve papillae into the vitreous (7).

6. No other cause of intracranial hypertension identified, including medical conditions, medications, and obstruction to cerebral venous outflow.

Numerous variants of IIH have been reported since our criteria were published. The most frequent, and perhaps most hotly debated, is IIH without papilledema. This entity was first reported by headache specialists who performed lumbar punctures (LPs) on patients with refractory headaches and discovered that many of them had increased ICP. Most were obese women of childbearing age, but only a small percentage improved with traditional treatments for IIH, such as acetazolamide or diuretics (8,9). More recently, Digre et al (10) published their experience from the neuro-ophthalmologist's perspective. Only 5% of patients with IIH in their practice had no papilledema. Compared to patients with papilledema, they tended to be diagnosed later, be less responsive to conventional treatment, and have nonorganic visual field loss. Other reported variations include “normal pressure” IIH and IIH with CSF pleocytosis (11,12). I recently evaluated 2 young women with episodic headaches associated with increased CSF pressure, raising yet another possible variant, “paroxysmal” IIH.

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OPENING PRESSURE-WHAT IS NORMAL?

Quincke (13) described the LP more than 100 years ago, yet we still do not have a solid basis for defining a normal opening pressure. It is a bit startling, given the frequency with which the procedure is performed. The generally accepted normal range in adults is 80-200 mm CSF. There remains confusion over the influence of obesity on CSF pressure and whether or not different norms are required based on body mass index (BMI).

Another major confounder is the constant fluctuation of CSF pressure throughout the day. Adson and Lillie (14) recorded ICP hourly for 4 days from the lateral ventricle of a patient with a frontal lobe glioma and found pressures ranging from 130 to 980 mm CSF. Gucer and Viernstein (15) placed an epidural sensor in 4 patients with pseudotumor cerebri before and after medical and surgical treatment, revealing pressures ranging from 50 to 500 mm CSF. The wide fluctuations in CSF pressure in an individual prompted Ford and Murphy (16) to conclude, “… one determination of ICP in a case of disease of the CNS is no more instructive than one determination of a patient's temperature during the course of a fever.” (16)

Does body weight influence CSF pressure? Often quoted, more often misquoted, is the study by Corbett and Mehta (4) that was designed to answer this question. They performed LPs on patients with acute IIH with papilledema (n = 116, 104 women), chronic IIH (n = 18, 15 women, diagnosed 3-41 years prior), and neurologically normal (n = 56) subjects undergoing spinal anesthesia for surgery. Forty-one of the neurologically normal subjects were obese (10 women) and 15 were nonobese (4 women). Patients were not sedated, and the opening pressure was measured in the lateral decubitus position with the neck and legs extended. Their findings are summarized in Figure 1. Patients with acute IIH had opening pressures of 200 mm CSF or greater. Obese normal controls had pressure less than 250 mm CSF, and only 1 nonobese control subject had an opening pressure between 200 and 249 mm CSF. One patient in the chronic group had 2 LPs; one showed a normal opening pressure and the other was elevated. It may or may not be relevant that most patients with IIH were women and most of the control subjects were men. Nonetheless, the 200-249 mm CSF range was a “grey” zone that could not reliably distinguish between patients and control subjects. Their publication led to the erroneous conclusion by some that obesity confers a higher CSF pressure.

Fig. 1
Fig. 1
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A subsequent prospective study by Whiteley et al (17) analyzed opening pressure measurements in 242 adults. Their study population consisted of 45% men, with a median age of 45 years (range: 18-88 years) and a median BMI of 26 kg/m2 (9 patients underweight, 91 normal weight, 98 overweight, and 44 obese). The mean opening pressure was 170 mm CSF (95% reference interval was 100-250 mm CSF). The relationship between BMI and opening pressure was small (r2 = 0.19) and not affected by patient age or sex. This study confirmed 250 mm CSF as the upper limit of normal for opening pressure.

Bono et al (18) reported their findings of LP opening pressure in patients having normal magnetic resonance venography (MRV). They studied 100 subjects (74 women), ages 15-69 years, with a normal MRI and MRV. No patients had papilledema or were taking medications associated with intracranial hypertension. Opening pressure was recorded with the legs and neck straightened. Subjects were categorized as nonoverweight (BMI < 25 kg/m2), overweight, or obese (BMI ≥ 30 kg/m2). All subjects had opening pressures under 200 mm CSF, which this author finds incredulous.

Finally, in a retrospective study of 55 patients with IIH, Randhawa et al (19) found a positive correlation (R = 0.35) between BMI and CSF opening pressure. The mean BMI in this cohort was 38.5 kg/m2, with 86% of the group having a BMI more than 30 kg/m2 and 12% with a BMI of 25-29 kg/m2.

Until recently, normal values of opening pressure in the pediatric population were lacking. Exciting results were presented at the 2010 NANOS meeting by the group at Childrens Hospital of Philadelphia (20). They prospectively evaluated the opening pressures from 439 LPs in subjects aged 1-18 years. The 10th and 90th percentile opening pressures in the 197 children with no known disorder associated with intrancranial pressure were 115 and 280 mm CSF, respectively. Increased opening pressure correlated with the use of moderate to deep sedation and BMI but not with age. Thus, the reference range of “normal” opening pressure extends to at least 250 mm CSF in children and adults, with some outliers having baseline pressures closer to 300 mm CSF.

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HEADACHE, VENOUS SINUS STENOSIS, AND INTRACRANIAL HYPERTENSION

My practice interfaces neuro-ophthalmology and headache medicine, which provides me with perspective shared by a few others in neuro-ophthalmology. Given ongoing controversy regarding the contribution of CSF pressure to chronic headache disorders (including “IIH without papilledema”), is there a continuum of disease ranging from “chronic daily headache with increased CSF pressure” to unquestionable IIH with papilledema? (Fig. 2). There are similarities between patients across the spectrum: patients with chronic daily headache and increased CSF pressure tend to be obese women (9), obesity is a known risk factor for transforming from episodic migraine to chronic migraine (21), obstructive sleep apnea may contribute to both chronic headache and intracranial hypertension (22,23), and patients with “recovered” IIH may continue to experience headaches (24). In the American Migraine Prevalence and Prevention Study (25), the following factors were associated with having chronic migraine headaches (ie, migraine more than 15 days monthly) that also share commonality with IIH: lower household income, depression (odds ratio [OR] = 2), other chronic pain disorders (OR = 2.5), obesity (OR = 1.2), and less likely to be employed full time (P < 0.001). Factors associated with the transformation from episodic to chronic migraine include obesity, stressful life events, and snoring (a possible surrogate for obstructive sleep apnea) (26). Obesity and sleep apnea are known risk factors for IIH. Many of my patients relate stressful life events within weeks to months of developing IIH symptoms. Perhaps, there is a hormonal connection related to the stress response, food for thought.

Fig. 2
Fig. 2
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A recent study prompted many of my thoughts today. Bono et al (27) performed LPs, recorded the opening pressure, and continued to monitor the CSF pressure through the lumbar needle for 1 hour in 85 women and 13 men with chronic migraine and chronic tension-type headaches. The patients failed to improve with various preventive headache medications and had no disorder or were to taking a medication known to be associated with increased CSF pressure. None of the patients had papilledema. All underwent contrast-enhanced MRI and MRV. Notably, the cohort was overweight, with a mean BMI of 29 ± 6 kg/m2.

Results showed bilateral transverse venous sinus stenosis (BTSS) in 48 patients. Fifty-four patients had a normal CSF pressure and 44 had elevated pressures, ranging from 210-444 mm CSF. All patients with elevated pressure had BTSS. Of the 48 patients with BTSS, only 4 had normal pressure during prolonged monitoring (mean: 143.3 ± 31.8, range: 77-197 mm CSF), 26 had intermittent CSF hypertension (mean pressure: 22.9 ± 31.1, range: 210-251 mm CSF), and 18 had consistently elevated pressure (mean: 270.3 ± 55.0, range: 210-444 mm CSF). Most of the patients with elevated pressure (and BTSS) had abnormal pressure waves (B waves) during the monitoring period. Not surprisingly, there was frequently a discrepancy between the opening pressure on the LP and the mean pressure during prolonged monitoring, demonstrating that the “isolated measurement of body temperature during the course of a fever” mantra still holds true. Accordingly, if one suspects that a patient has IIH based on clinical findings but the CSF pressure is normal, the LP should be repeated.

Is this study a “game changer” in the world of headache medicine or the realm of IIH diagnosis? While some patients require prolonged monitoring to confirm the diagnosis of intracranial hypertension, it is unlikely that lumbar monitoring will become widely used in practice due to equipment, time, and reimbursement constraints. The high percentage of patients in the study with significant venous sinus stenosis exceeds my personal experience; this may be attributable to the imaging technique utilized (28) or the level of scrutiny on my part (or theirs). Should an MRV be performed in all patients with chronic migraine and chronic tension-type headache? Most of the patients in the Bono study would not have met the criteria for the diagnosis of IIH. Is our concept of IIH too limited, or are we seeing an epiphenomenon of chronic headache and calling it IIH inappropriately?

I have long suspected that increased CSF pressure may be a response to severe pain, similarly to the rise in blood pressure that often occurs in patients with severe headaches. This may be related to Valsalva maneuver in some instances (29). To try and confirm or dispute my suspicions, I performed a retrospective study of patients evaluated for benign headaches in the emergency department at SUNY Upstate Medical Center from 1997 to 2001. One hundred sixty-eight records were identified of patients having an LP and a discharge diagnosis of migraine, tension-type headache, vascular headache, unspecified headache, or cluster headache. Unfortunately, only 30 patients had their opening pressure measured during the LP. Of the 28 patients who met the inclusion criteria, the opening pressure ranged from 85 to 370 mm CSF. Fourteen patients had an opening pressure above 200 mm CSF, and 10 had an opening pressure above 249 mm CSF; in the appropriate context, the CSF pressures in these patients would have satisfied the criteria for the diagnosis of IIH. There was no correlation between the headache type and the opening pressure. Despite limitations in the study, in the real world of the emergency department, increased CSF pressure occurs with “benign” headache disorders.

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A COMPLEX DISORDER WITH UNMET CHALLENGES

It has been 7 years since Dan died, and we continue to try and solve the puzzle of IIH. There are factors that appear certain; it is a disorder of obese women characterized by intracranial hypertension (Fig. 3). Other associations seem fairly consistent, although the mechanism by which they influence the pathophysiology of the disease process is unknown: vitamin A, sleep apnea, and leptin link to obesity; medications, venous sinus thrombosis, and lymphatic dysfunction (30) cause intracranial hypertension; and there may be a hormonal or genetic component to explain the female preponderance (31,32). Other possible clues include the association with depression and anxiety (33), the preponderance of associated headache symptoms and the role of serotonin and vasopressin (34-37), and the relevance of major life stressors apropos the autonomic nervous system regulation of neurotransmitters and their effect on CSF regulation (38-40). The etiology is probably multifactorial. The search for the best treatment continues, and we are finally on the way to achieving evidence-based guidelines as the Idiopathic Intracranial Hypertension Treatment Trial commences. Dan was part of our interest group that met for many years trying to design a treatment trial for IIH, and we owe him a debt of gratitude for his role in the successful funding of this trial. IIH remains a fascinating disorder to explore and with so many neuro-ophthalmologists worldwide demonstrating an interest in IIH, the future is promising.

Fig. 3
Fig. 3
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ACKNOWLEDGMENTS

The author is grateful to the Dan Jacobson Memorial Fund of the Marshfield Clinic for sponsoring this lectureship at NANOS; to our patients, who constantly educate us all; and to Dan, whose friendship and collaboration she continues to miss.

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© 2010 Lippincott Williams & Wilkins, Inc.

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