Online newspaper of professor Yasser Metwally

The author:Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

Background:

• Idiopathic intracranial hypertension (IIH) is a disorder of unknown etiology.

• It predominantly affects obese women of childbearing age.

• The primary problem is chronically elevated intracranial pressure (ICP) and the most important neurological manifestation is papilledema, which may lead to progressive optic atrophy and blindness.

Pathophysiology:

• A dominant early theory concerning the pathogenesis of elevated intracranial pressure in these patients was cerebral edema.

• Against this, is the fact that there is no altered level of alertness, cognitive impairment or focal neurological findings. In addition, there is no pathological documentation of cerebral edema in these patients.

• Early reports describing edema were later considered to represent fixation artifact (during tissue preparation) rather than in vivo edema.

• Current theories include increased resistance to cerebrospinal fluid (CSF) outflow at the arachnoid granulations that line the dural venous sinuses and through which CSF reabsorption is thought to occur by bulk flow. Alternatively, occult cerebral venous outflow abnormalities may produce IIH.

• CSF production rate (cc/min) should be equal to the CSF reabsorption rate. If production exceeds absorption, ICP would rise until it exceeds mean arterial pressure, which, if sustained, would be fatal. In IIH the production rate equals the reabsorption rate; however, a higher than normal pressure is required to achieve this, due to the increased resistance at the arachnoid granulations.

Frequency:

• In the US:

  • Annual incidence in Iowa & Louisiana (Durcan, Corbett and Wall, 1988):

    • 0.9/100,000 population

    • 13/100,000 (Iowa) and 14.85/100,000 (Louisiana) in women aged 20-44 years and 10% over the ideal weight

    • 19.3/100,000 in women 20% over the ideal weight

    • Female to male ratio is 8:1 for mean weight 38% over the ideal weight for height.

  • Annual incidence at Mayo Clinic (Rochester, MN) between 1976-1990 (Radhakrishnan, 1993):

    • 0.9/100,000 population

    • 1.6/100,000 women

    • 3.3/100,000 females aged 15-44 years

    • 7.9/100,000 obese women aged 15-44 years

• Internationally:

  • In a study (Radhakrishnan, 1993) conducted during 1982-1989 in Benghazi, Libya comprised of 81 patients (76 women and 5 men) in the age group of 8-55 years it was found that the annual incidence was:

    • 2.2/100,000 in all patients

    • 4.3/100,000 women in all ages

    • 12/100,000 women aged 15-44 years

    • 21.4/100,000 obese women aged 15-44 years

Mortality/Morbidity:

• There is no known IIH specific mortality risk. The increased mortality of morbid obesity has a selective expression in this group because of the strong predilection of the disease to affect obese females.

• Vision Loss:

  • The only permanent morbidity in IIH is vision loss from decompensation of papilledema with progressive optic atrophy. The frequency and degree to which visual loss occurs in this disease is difficult to establish (with the existing literature).

  • As outlined by Radhakrishnan in 1994, the reported incidence of vision impairment is much higher in series published from referral centers (up to 96% of cases with some degree of visual field loss) compared to population-based series (22% in Iowa in Durcan, Corbett & Wall, 1988).

  • There are two equally valid explanations for this discrepancy.

    • The referral centers perform more extensive vision testing, including Goldmann and computerized automated threshold perimetry and discovered visual deficits that were not tested for in the community-based studies.

    • The worst cases are referred for tertiary care consultation and the referral center series are biased toward more severe vision loss cases than in the community based studies.

Race: There is no evidence to suggest predilection for any particular racial or ethnic group apart from variation in the prevalence of obesity in the different groups.

Sex:

• Obese females of childbearing age are selectively affected by IIH.

• Specific numbers are available from the recent epidemiological studies.

  • Durcan, Corbett & Wall, 1988 – the female to male ratio is 8:1

  • Radhakrishnan (Mayo series, 1993) – the female to male ratio is 8:1 (N=9)

  • Radhakrishnan (Libyan series, 1993) – the female to male ratio is 8:1 (N=76)

Age: Please refer to the incidence statistics. The highest incidence is among obese women of “childbearing age”. For most of the epidemiological series this was between 15-44 years.

CLINICAL PICTURE

History:

• Symptoms of elevated intracranial pressure:

  • Headache that is non-specific and varies in type, location and frequency.

  • Pulsatile tinnitus: a rhythmic sound, heard in one or both ears with pulse synchronous rhythm that may be exacerbated by the supine or bending position

  • Horizontal diplopia: a symptom of a false-localizing sixth cranial nerve palsy

  • Radicular pain (usually in the arms) is an uncommon symptom.

• Symptoms of papilledema:

  • Transient visual obscurations (e.g. dimming or blackout of vision in one or both eyes lasting for a few seconds) may be present. It may be predominately or uniformly orthostatic (i.e. after bending over).

  • There may be progressive loss of peripheral vision in one or both of the eyes, most often starting in the nasal inferior quadrant followed by loss of central visual field (possibly affecting visual acuity) and lastly, the loss of color vision.

  • There may be blurring and distortion (i.e. metamorphopsia) of central vision from macular wrinkling and subretinal fluid spreading from the swollen optic disc.

  • There may rarely be sudden visual loss from intraocular hemorrhage secondary to peripapillary subretinal neovascularization related to chronic papilledema.

Physical: Visual function testing, in particular, visual field, fundoscopy and ocular motility examination are the most important parts of the neurological examination for diagnosing and following patients with IIH.

• Visual Field:

  • The first sign of incipient post-papilledema optic atrophy is constriction of the inferior nasal quadrant of the visual field with a border respecting the nasal horizontal midline (nasal step). This starts in the most peripheral points in the visual field (i.e. 50 degrees from fixation) and progresses inward.

  • Goldmann-type dynamic perimetry is the best test, since it provides reliable information concerning the most peripheral parts of the visual field.

  • Computerized automated Humphrey-type static perimetry is generally unreliable beyond 30 degrees eccentricity and may not be as sensitive as dynamic perimetry for this problem.

• Visual Acuity:

  • This is usually normal until there has been significant peripheral visual field loss with progressive post-papilledema optic atrophy.

• Color Vision:

  • It is usually tested in the office with color-confusion type plates most commonly the Ishihara or Hardy-Rand-Rittler (HRR). Unlike the visual acuity testing, it is not sensitive in picking up early post-papilledema optic atrophy since color perception is concentrated in the central visual field.

• Ocular Motility Examination:

  • Occasionally limited abduction of one or both of the eyes results from increased ICP. This is termed as a false-localizing sixth cranial nerve palsy.

  • This can usually be observed as the patient follows the examiner’s hand to the right and the left with both eyes. The involved eye does not move fully outward (abduction), leaving some white sclera showing lateral to the cornea on the involved side compared to the other side.

    Speed of the abducting movement in the paretic eye will also usually be slower than in the normal eye.

  • Some patients with full abduction still show some sclera, therefore when using this sign it is important to demonstrate asymmetry between the eyes in abduction .

  • Diplopia testing is another way to detect even a low-grade sixth nerve paresis.

    • The patient is told to look at a focal light source (e.g. penlight, Finoff head), preferably placed more than 10 feet away. Either a red glass or Maddox rod is placed in front of the patient’s right eye. The Maddox rod creates an image of a vertical red line when the patient views a focal light source through it.

    • In a positive test for limited abduction, the red image (focal light or line) is displaced to the right of the light (homonymous or uncrossed diplopia) in the patient’s view. This indicates that the visual axes are convergent with respect to one another (esotropia, relative weakness of the lateral rectus muscle(s), sixth cranial nerve palsy).

    Alternate Cover testing may also reveal a slight corrective saccade when the other eye is covered in patients with sixth nerve palsies.

Figure 1. Right optic disc with post-papilledema optic atrophy in a patient with pseudotumor cerebri. There is diffuse pallor of the disc and absence of small arterial vessels on the surface. There is very little disc elevation. The disc margin at the upper and lower poles and nasally is obscured by some residual edema in the nerve fiber layer, and gliosis that often persists even after all the edema has resolved., Left optic disc with moderate chronic papilledema in a patient with pseudotumor cerebri. Paton’s lines (arc shaped retinal wrinkles concentric with disc margin) are seen along the temporal side of the inferior pole of the disc. (Click to magnify figure)

Causes:

• In 1994, Radhakrishnan reviewed the literature on IIH associated with other diseases and with drugs. These authors insisted that in order to be included in the list of causally related associations the following criteria should be met:

  • At least two cases should have been described

  • The reported cases should have met all the criteria for the diagnosis of IIH

  • Intracranial dural sinus thrombosis should have been ruled out with reasonable certainty

• The following data were obtained from this 1994 study and subsequent case reports. The authors’ organization of categories is preserved here.

  • Risk factors confirmed in epidemiological studies (endocrine):

    • Female sex

    • Reproductive age-group

    • Menstrual irregularity

    • Obesity

    • Recent weight gain

  • Meet minimal criteria, unconfirmed in case control studies (endocrine):

    • Adrenal insufficiency

    • Cushing’s disease

    • Hypoparathyroidism

    • Hypothyroidism

    • Excessive thyroxine replacement in children (low thyrotrophin levels)

  • Meet minimal criteria, unconfirmed in case control studies (medications):

    • Cimetidine, corticosteroids, danazol, isotretinoin (Accutane), levothyroxine, lithium, minocycline, nalidixic acid, nitrofurantoin, tamoxifen, tetracycline, trimethoprim-sulfamethoxazole {Radhakrishnan et al}

    • All-transretinoic acid (ATRA) used in the treatment of promyelocytic leukemia, cyclosporine, norplant (levonorgestrel implant) [39 women reported to FDA from February 1991 to December 1993], pancreatin (pancreatic enzyme replacement for cystic fibrosis patients).

    • Recombinant human growth hormone (seven children in three papers)/natural growth hormone (somatotropin)

    • Vitamin A in infants

  • Meet minimal criteria, unconfirmed in case control studies (miscellaneous):

    • Chronic renal failure

    • Systemic lupus erythematosus

WORK-UP

Lab Studies:

• Blood tests:

  • Reasons for blood tests:

    • To rule out systemic lupus erythematosus or other collagen-vascular disease since these have been reported as underlying conditions in some patients who present with IIH (Nampoory, 1997).

    • An increased incidence of anti-cardiolipin antibodies has been reported in patients with IIH. Some authors advocate anti-cardiolipin antibody assessment in IIH patients regardless of prior history of thrombosis (Leker and Steiner, 1998). Some authors advocate screening for anticardiolipin antibodies and other pro-coagulant states in all patients with IIH who are either male or non-obese (Sussman, 1997).

    • Cases of IIH associated with Lyme disease have been reported (Bachman and Srivastava, 1998).

  • Blood tests include:

    • Complete blood count (CBC)

    • Erythrocyte sedimentation rate

    • Serum iron and iron binding capacity

    • Anticardiolipin antibodies/lupus anticoagulant

    • ANA profile (anti dsDNA, ssDNA etc.)

    • Full pro-coagulant profile including: protein S, protein C, homocysteine levels, antithrombin III, factor V Leiden variant, anti-phospholipid/anti-cardiolipin antibodies, lupus anticoagulant, and platelet aggregation studies (in patients with previous history of thrombosis or MRI evidence of dural venous sinus occlusion)

    • Lyme screening test (ELISA) in patients who have a history of exposure to Lyme in endemic areas.

• Cerebrospinal fluid (CSF) Studies:

  Opening pressure

  • White blood cell and differential counts

  • Red blood cell count

  • Total protein

  • Quantitative protein electrophoresis

  • Glucose

  • Aerobic bacterial culture and sensitivity

    Tumor markers and cytology

  • Acid fast bacilli (AFB) culture

  • Cryptococcal antigen (especially in HIV patients)

  • Syphilis markers (RPR)

  • Tumor markers (in patients with a history of cancer or with clinical features suggesting occult malignancy)

  • Most patients with typical history, gender and body habitus will need only routine CSF tests. However, extra fluid should be frozen in case the preliminary workup reveals unexpected abnormalities, such as pleocytosis or elevated gamma globulin, indicating that more complete investigation for autoimmune, infectious or neoplastic conditions is warranted.

Imaging Studies:

• MRI:

  • Brain MRI with gadolinium enhancement is probably the study of choice for all IIH patients since it provides sensitive screening for hydrocephalus, intracerebral masses, meningeal infiltrative or inflammatory disease and dural venous sinus thrombosis.

• MRV:

  • MRV can be reserved for patients who are at greater risk for dural venous sinus thrombosis, such as those with suggestion of thrombosis on MRI, non-obese or male individuals, or those with a documented pro-coagulant state. Sagittal T1-weighted images often provide excellent views of the superior sagittal sinus, and these are typically included in routine MRI.

• CT:

  • Brain CT is less expensive than MRI and is adequate to rule out larger tumors or lesions, but is not as sensitive as MRI for meningeal infiltration and/or dural venous sinus thrombosis.

Other Tests:

• None

Procedures:

• Lumbar puncture:

  • Lumbar puncture is ideally carried out with the patient in the lateral decubitus position. Because it is difficult to find landmarks in obese patients, it is frequently necessary to perform the tap with the patient seated.

  • It is important to remember that the normal CSF pressure at the foramen magnum in the seated position is nearly 500 mm from the lumbar entry point in persons of average height.

  • Therefore, it is important to emphasize that an opening pressure of 500 mm water is extremely high in the lateral decubitus position, but is normal for sitting. If possible, the patient should be moved to lateral decubitus position before measuring the pressure.

  • Another approach to lumbar puncture in obese patients utilizes fluoroscopic guidance in the radiology department. The prone positioning on the x-ray table and the increased abdominal pressure in this position may falsely elevate the CSF pressure.

  • If the pressure is normal with the patient in the prone position, then the measurement is probably accurrate. However, if it is high, the patient must be rolled into lateral decubitus and allowed to relax before a reliable pressure reading can be completed.

  • Obviously, there is risk of displacing the needle from the thecal space with such maneuvers. However, there is no alternative for obtaining an accurate pressure reading.

MANAGEMENT

Medical Care:

• Patients without visual loss are most often treated with a carbonic anhydrase inhibitor (e.g. acetazolamide) to lower the ICP. Some authors believe digoxin has the same effect and is associated with fewer side effects.

• In patients with severe symptoms, early visual field loss, or failed standard medical therapy, some clinicians will utilize a short course of high dose corticosteroids (e.g. prednisone).

• When new visual field loss is documented, medical management should be coupled with plans for emergency surgical intervention, if the visual function continues to deteriorate or does not improve immediately with corticosteroid treatment.

Surgical Care: For IIH patients with progressive visual field loss, currently two general surgical approaches can be considered: CSF shunting procedures or optic nerve sheath fenestration.

• Neurosurgical Operations:

  • Lumbo-peritoneal shunt is the traditional method for providing prompt reduction of intracranial pressure in IIH patients (Burgett, R. A. 1997).

  • Some neurosurgeons prefer ventriculo-peritoneal or ventriculo-atrial shunts over lumbo-peritoneal shunting.

  • The reason for this preference is that ventricular shunts can be monitored for function using an extracranial subcutaneous compressible bulb and one-way valve (intracranial to abdominal flow) in series with the intracranial and abdominal ends of the shunt.

    • The bulb will resist digital compression if the distal (abdominal or atrial) end is obstructed.

    • The bulb will collapse under digital pressure but will fail to re-inflate if the intracranial end is obstructed.

    Other neurosurgeons are reluctant to place ventricular shunts in IIH patients because the ventricles are small and difficult to cannulate without radiographic guidance.

• Ophthalmic approach – optic nerve sheath fenestration:

  • The ophthalmic surgical approach to managing patients with progressive vision loss and papilledema involves cutting slits or rectangular patches in the dura surrounding the optic nerve immediately behind the globe (Goh, K. Y. 1997).

  • This allows egress of CSF directly into the orbital fat where it is absorbed into the venous circulation.

  • Lumbar puncture following this procedure does not consistently show significant reduction of CSF pressure and headache is not reliably relieved by this approach.

  • Despite general lack of an intracranial pressure lowering effect, there may be regression of papilledema in both eyes following fenestration of one optic nerve.

Consultations:

• Diagnosis and long-term management of IIH patients requires the performance of lumbar puncture, typically performed by neurologists or internists and careful monitoring of visual status (most importantly peripheral visual field and fundus photography). Vision examination and fundus photography are in the domain of ophthalmologists, and neuro-ophthalmologists are especially expert in examining visual fields. A team approach is, therefore, needed for most, if not all, patients.

• Neurosurgical consultation is required when patients are losing visual field and medical management does not arrest or reverse the process promptly (within hours to days).

Diet: On initial diagnosis, a weight-reduction diet coupled with exercise programs should be strongly advised to all patients with IIH. There is some recent evidence suggesting that weight loss is associated with improvement of papilledema in these patients (Rowe, F. J. and Sarkies, N. J. 1999; Kupersmith, M. J. et al 1998). Often, a formal weight loss program is required.

Activity: There is no activity restriction in this disease. In fact, exercise programs are strongly recommended along with a weight-reduction diet.

MEDICATIONS

• Specific therapy for IIH is aimed at lowering intracranial pressure pharmacologically.

• Carbonic anhydrase inhibitors and other diuretics are thought to have their effect on intracranial pressure by reducing CSF production at the choroid plexus.

• Cardiac glycosides have a similar effect.

• Corticosteroids are effective in reducing ICP. However, the mechanism of action is unknown. Corticosteroids are often used as maximum medical management when rapid lowering of intracranial pressure is required.

FOLLOW-UP

Further Inpatient Care:

• Admission for pain management:

  • Even for initial diagnosis, most patients will not require inpatient care as lumbar puncture is usually performed in the ambulatory care setting.

  • An occasional patient may develop intractable low-tension headache following lumbar puncture and may require a short hospital stay for IV hydration and analgesic management.

  • A blood patch (by an anesthesiologist) is sometimes indicated if the post-lumbar puncture headache does not subside spontaneously within a few days.

• Admission for surgical management of intracranial pressure:

  • Patients who complain of progressive visual loss (typically constriction of peripheral vision and/or dimming of vision in one or both eyes) and have documented new visual field loss may respond to high-dose corticosteroids and hospital admission with daily monitoring of visual function.

  • If the visual field worsens or fails to recover promptly (i.e. within twenty-four to forty-eight hours) with corticosteroids, then emergency CSF shunting (lumbo-peritoneal or ventriculo peritoneal/atrial) or optic nerve sheath fenestration should be carried out.

  • If any delay in implementing surgical decompression of the failing optic nerve is anticipated, then the patient should be moved to the ICU or a ‘step-down’ unit for lumbar CSF drainage until the definitive procedure can be performed. Another short-term treatment option is IV mannitol, but definitive pressure lowering surgery must be done within 2-3 days.

  • A very small number of patients with normal visual fields may require surgical relief of CSF pressure because of intractable headache. Optic nerve sheath fenestration does not provide reliable CSF pressure normalization or headache relief, and thus these patients will require one of the shunting procedures outlined above.

Further Outpatient Care:

• Office visits for visual field examination:

  • Patients with normal visual field or stable minor field loss (infero-nasal step with little concentric constriction of isopters) can be managed with office visits approximately once every 3 months.

  • The interval between visits should be shortened if there are any questionable symptoms of vision worsening or if visual field examination reveals a minor or questionably significant new deficit.

In/Out Patient Meds:

• Acetazolamide:

  • Most patients have adequate relief of symptoms, typically headache, using the first-line agent, acetazolamide.

• Headache prophylaxis:

  • For patients with stable visual function but inadequate headache relief with first-line pressure-lowering drugs, treatment with primary headache prophylaxis should be considered.

  • Patients with idiopathic intracranial hypertension and headaches with many features of migraine have been encountered. Headache control can often be acheived with amitriptyline, inderal or any of the other commonly prescribed migraine prophylaxis agents.

• Corticosteroids/digoxin/lasix:

  • Patients undergoing progressive loss of visual field in one or both eyes should be immediately placed on a high dose (60-100 mg/day) of oral prednisone (or equivalent corticosteroid treatment). Digoxin and lasix have been advocated by some investigators but these are on an effectiveness level with acetazolamide and are not appropriate as sole therapy for patients who are losing vision.

  • If a moderate new visual field loss is detected on a routine office visit and the patient is not experiencing progressive symptoms, outpatient management can continue. However, visual fields should be measured every few days or at one to two week intervals depending on the magnitude and progression of the defect. If the visual field continues to worsen on corticosteroid treatment, the patient should be admitted for immediate surgical management.

  • If the patient presents with symptomatic deterioration of vision, and the examination documents worsening of visual field despite adequate standard medical therapy, the patient should be started immediately on corticosteroids as previously outlined.

    • They should also be admitted to the hospital for consideration of emergency surgical decompression.

    • Visual field examination should be performed daily and surgical decompression should be carried out if there is no improvement or if there is further worsening in the subsequent twenty-four to forty-eight hours.

Complications:

• Optic Atrophy:

  • The only severe and permanent complication of IIH is progressive blindness from post-papilledema optic atrophy.

  • As optic nerve axons die, the apparent degree of papilledema may diminish, giving a false sense of improvement. For this reason (and others) the patients must be followed with frequent visual field examinations.

  • The earliest visual loss is in the peripheral fields (outside 30 degrees) and thus Goldmann-type dynamic perimetry is preferred over computerized, automated visual fields.

  • For reasons that are not clear, the earliest field loss tends to be in the inferior nasal quadrant.

  • Visual acuity and color vision are not affected until late in the disease, when the peripheral visual field isopters are quite contracted.

Prognosis:

• Visual Loss:

  • Depending on the referral population and the rigor with which visual function is tested, the prognosis for visual loss in IIH has varied considerably in different series. Authors writing in the 1960s and 1970s indicated that less than 25% of these patients had functionally significant blindness; however, more recently that figure has been revised upwards.

  • In a unique major prospective study of visual function in IIH, Wall and George found that 96% of the 50 patients in a series had some degree of visual field loss using Goldmann-type perimetry, while 92% had abnormal automated perimetry; 50% had abnormal contrast sensitivity and 22% abnormal Snellen visual acuity. During follow-up (two to 39 months, average 12.4 months), visual fields improved in 60% of patients and deteriorated in 10% (Wall and George. 1991).

Patient Education:

• Weight Management:

  • It is important for the physician to educate patients concerning the potential for dire consequences in terms of disabling blindness. The importance of weight loss as the only effective means of reducing the papilledema and with it, the threat of progressive blindness, cannot be over emphasized (Kupersmith, 1998; Rowe and Sarkies, 1999).

  • Patients should be urged to enroll in an aggressive weight loss program, ideally with a multi-disciplinary approach, including diet and exercise, along with psychological and lifestyle counseling.

  • Despite these measures, many patients cannot sustain significant weight reduction and may even require drastic steps such as gastric stapling or resection. These measures can be effective for patients who lose vision despite aggressive medical and surgical management (Sugerman,1995 and Sugerman, 1999).

• Medical/Legal Pitfalls:

  • Visual loss in one or both eyes can rapidly evolve despite the best efforts to arrest the process. In this author’s experience, IIH has been the most frequent cause of litigation encountered. Almost uniformly, the cases center on the delay of maximum medical and surgical management beyond what has to be considered ideal and standard practice in the U.S. for patients who present with rapidly declining vision.

  • The exact time window within which vision loss can be reversed after symptomatic decline is not known. Opinions among experts in the field will vary as to how rapidly and aggressively any given patient should have been treated. It is usually better to err on the side of rapid intervention (hours to days) in such patients.

  • This is a dramatic opportunity to save vision that can be easily lost. A major medico-legal pitfall is created when poor outcome is coupled with the perception of delayed treatment.

Special Concerns:

• One of the standard teachings has been that pregnancy exacerbates or triggers the onset of symptomatic IIH.

• However, at present there is little statistical evidence of a causal association between the two conditions, beyond the fact that both events are common in the age group and gender that is predominantly affected by the disease (Digre, 1984; Giuseffi, 1991).

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