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 (r 2 = 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.
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.
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.
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.
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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