I would like to thank the North American Neuro-Ophthalmology Society for this invitation to speak in honor of William F. Hoyt, MD. Bill has been a great influence in my career, and I am grateful for his wisdom and guidance. I would like to discuss 2 intriguing problematic neuro-ophthalmic conditions and hopefully will provide some new insights into these disorders.
Idiopathic intracranial hypertension (IIH), a condition of increased intracranial pressure (ICP), is also known as pseudotumor cerebri (PTC) because it may be associated with signs and symptoms that suggest the presence of a brain tumor. IIH occurs primarily in obese women during their childbearing years. Symptoms often worsen during and after a period of weight gain. The disease is rare in thin men, suggesting a hormonal connection. Although no other specific risk factor other than obesity has been identified, a number of other conditions have been linked to high ICP. For example, any disorder that blocks the flow of cerebrospinal fluid (CSF) between the brain and its drainage system can cause raised pressure. Other clinical associations include withdrawal from systemic corticosteroids, large doses of vitamin A, the use of anabolic steroids, and probably the use of tetracycline and lithium. The precise cause of IIH remains unknown (1,2).
Updated Dandy criteria for the diagnosis of IIH have been proposed (3).
1. If symptoms present, they may only reflect those of generalized intracranial hypertension or papilledema.
2. If signs present, they may only reflect those of generalized intracranial hypertension or papilledema.
3. Documented elevated ICP measured in the lateral decubitus position.
4. Normal CSF composition.
5. No evidence of hydrocephalus and mass, structural, or vascular lesion on MRI or contrast-enhanced CT for typical patients and MRI and magnetic resonance venography (MRV) for all others.
6. No other cause of intracranial hypertension identified.
The clinical manifestations of IIH include headache in 75%-99% of cases (4). The headaches are usually generalized, worse on awakening or with Valsalva maneuver. Visual loss is mild in 50%-90% of patients and severe in 10%-25%. Visual field defects are a result of papilledema and are attributed to axoplasmic stasis with axonal attrition, leading to optic atrophy, as well as vascular compromise associated with central or branch retinal artery occlusion; nerve fiber layer hemorrhages; and infarctions, choroidal folds, and subretinal fluid in the peripapillary or macular area. Transient visual obscurations occur in up to 75% of patients usually related to changes in posture and may represent intermittent axoplasmic stasis secondary to CSF pressure waves. Pulsatile tinnitus occurs in approximately 60% of patients possibly due to transmission by CSF under increased pressure of intensified vascular pulsations to the walls of venous sinuses converting laminar to turbulent flow. Other clinical features include back and neck pain, radiating paresthesias, seventh nerve palsies, and diplopia, generally due to sixth nerve palsy and rarely due to third or fourth cranial nerve involvement.
Treatment of IHH is determined by the presence or absence of visual loss. Patients with no visual impairment are managed with weight loss and symptomatic treatment of headaches until resolution of symptoms. Those with visual loss should be put on a program of weight loss and acetazolamide. If visual loss is progressive, systemic corticosteroids or optic nerve sheath fenestration should be considered (5). Progressive visual failure or intractable headaches may also be treated with a CSF diversion procedure (6).
In the presence of papilledema, MRI (Fig. 1) may demonstrate flattening of the posterior wall of the globe, empty sella, distention of the perioptic nerve sheaths, and enhancement of the optic disc within the globe (7). The use of contrast with MRI is essential as unenhanced imaging may fail to detect venous sinus thrombosis, meningeal infiltration, and isodense brain tumors.
Cerebral venous sinus thrombosis may cause increased ICP as its sole manifestation. Biousse et al (8) reported 160 patients with cerebral venous sinus thrombosis, 59 (37%) of whom presented with a syndrome of isolated intracranial hypertension. In distinguishing these patients from those with IIH, data regarding CSF and neuroimaging proved critical. Eleven patients (25%) had abnormal CSF composition, an important distinguishing feature from IIH. Neuroimaging showed involvement of more than 1 venous sinus in more than 54% of this patient cohort. The authors emphasize the challenges in identifying venous sinus thrombosis and point out in some instances that cerebral angiography may be warranted to establish this diagnosis.
While cerebral venous sinus thrombosis is clearly a cause of raised ICP, the relationship of other venous sinus abnormalities detected with MRV remains problematic. Increased ICP may lead to narrowing and stenosis of the venous sinuses. Conversely, abnormalities in cerebral venous sinus drainage may lead to elevated ICP and clinical findings simulating IIH. Higgins et al (9) reviewed MRV studies from 20 patients with IIH and compared them with 40 controls. Patients underwent evaluation with either phase-contrast or time-of-flight MRV. In 13 of the 20 patients with IIH, focal narrowings and/or signal gaps were detected in the transverse sinuses and in none of the controls. However, the MRV technology used in this study has limitations, which may lead to misinterpretation. For example, time-of-flight MRA is subject to artifactual signal loss due to in-plane flow and turbulence. The transverse and sigmoid sinuses are locations in the dural venous system subject to such artifacts. Farb et al (10) employed ATECO MRV (auto-triggered elyptic-centric-oriented 3-dimensional gadolinium-enhanced MRV) in the study of transverse and sigmoid sinuses in patients with IIH. The factors leading to artifactual signal loss with time-of-flight MRV are greatly reduced with ATECO MRV. These investigators found bilateral sinovenous stenosis in the transverse and sigmoid sinuses in 27 of 29 patients with IIH and only 4 of 59 controls. In addition, manometric measurements have shown a venous pressure gradient between the proximal and distal segments of the transverse sinus in patients with IIH. With cervical puncture, these pressure gradients are no longer present (11,12). Similarly, transverse sinus narrowing detected in patients with IIH has resolved following lumboperitoneal shunt (13). King et al (12) found that in patients with IIH and increased intracranial venous sinus pressure, reduction of CSF pressure following removal of CSF lowered venous sinus pressure. This study suggests that increased venous sinus pressure is actually caused by elevated ICP. As Corbett and Digre (14) point out that the report by King et al provides one answer to this “chicken or the egg” controversy. With these facts in mind, let us now look at some illustrative cases.
A 12-year-old girl weighing 160 pounds complained of intermittent headaches of 3-month duration, increasing in intensity and associated with vomiting. More recently, she developed horizontal double vision. Visual acuity was 20/20 in each eye, visual fields revealed nasal loss bilaterally, and bilateral papilledema was present. MRV showed no abnormalities. An opening pressure of 500 mm of water was found on lumbar puncture, and the patient was treated with acetazolamide.
Comment: This case is an example of how cerebral venography may be normal with markedly elevated ICP.
A 32-year-old woman presented with severe headaches. When initially evaluated, her vision was 20/20 in each eye and she was found to have bilateral papilledema. Brain MRI was normal, and lumbar puncture revealed an opening pressure of 550 mm of water. The patient was treated with acetazolamide but developed left face and arm numbness and was unable to walk. Repeat MRI and MRV demonstrated right transverse sinus thrombosis (Fig. 2) and multiple right hemispheric infarctions. Laboratory studies revealed a protein S level of 12% (normal: 60%-140%), and the patient was treated with heparin and then switched to Coumadin.
Comment: This patient presented with headaches and papilledema without localizing neurologic signs. After progressive neurologic deficits developed, a diagnosis of venous sinus thrombosis and cerebral infarction was established and appropriate treatment instituted.
A 19-year-old obese woman presented with a 2-year history of headaches and progressive worsening of vision in both eyes. A diagnosis of IIH was established, and she was treated with acetazolamide for a brief period. The patient did not lose weight and headaches continued. After a year of medical management, vision deteriorated and a lumboperitoneal shunt was performed with improvement of vision. Headaches and visual loss recurred, but shunt revision was delayed.
Neuro-ophthalmic evaluation revealed vision of 20/200 in the right eye and 20/400 in the left eye. Pupils were sluggish in their response to light with a left relative afferent pupillary defect. Visual fields were severely constricted, and both optic nerves showed chronic atrophic papilledema. A right optic nerve sheath fenestration was performed, and the patient was started on acetazolamide. In addition, the lumboperitoneal shunt was found to be obstructed and was revised. Two months postoperatively, the patient was free of headaches and vision improved to 20/40 in the right eye and 20/60 in the left eye, with expansion of the visual fields.
Comment: This case demonstrates how visual function can be improved despite long-standing diminished visual acuity and chronic swelling of the optic discs.
A 17-year-old boy with a 6-month history of frontal headaches reported seeing “black spots” for 3 weeks and diminished vision for 1 week. Visual acuity was found to be 20/70 in the right eye and counting fingers in the left eye. The right visual field demonstrated mild nasal constriction, and there was severe bilateral papilledema. Brain MRI was normal. Opening pressure on lumbar puncture was 490 mm of water, and the CSF composition was normal. Laboratory studies were unremarkable with the exception of a platelet count of 883,000 (normal: less than 450,000). Bone marrow biopsy was negative, and the hematology consultant felt that the thrombocytosis was unrelated to increased ICP. Brain MRI was normal, but MRV demonstrated bilateral transverse sinus stenosis with normal jugular venous flow (Fig. 3). The patient was treated with acetazolamide, intravenous Solu-Medrol, and bilateral optic nerve sheath fenestrations. He reported diminished headaches, vision improved to 20/50 in the right eye 20/200 in the left eye, and papilledema resolved.
Comment: This is an example of IIH in which the cerebral venous system revealed transverse sinus narrowing without thrombosis, consistent with elevated ICP.
A 46-year-old woman complained of headaches and was found to have a left homonymous hemianopia and papilledema. Brain MRI revealed a meningioma involving the posterior aspect of the superior sagittal sinus and right occipital lobe (Fig. 4). She was treated with radiosurgery.
Comment: This case illustrates that partial compression of the cerebral venous sinuses by a neoplasm can lead to signs and symptoms of increased ICP including headaches and papilledema.
It should be apparent that evaluation of the cerebral venous sinuses is an essential part of the workup of IIH. This is done first to exclude cerebral venous sinus thrombosis and also to monitor external venous sinus compression. Future studies may demonstrate a correlation between venous sinus compromise and the threat to vision in the setting of raised ICP.
I would now like to review posterior cortical atrophy (PCA), a dementia syndrome characterized by signs and symptoms of cortical visual dysfunction (15). First characterized by Benson et al (16), at onset the visual complaints of patients with PCA are often vague and nonspecific and patients may initially present to an ophthalmologist.
Clinical features of PCA include Balint syndrome and often various aspects of Gerstmann syndrome, visual agnosia, alexia, agraphia, and transcortical sensory aphasia. In contrast to typical Alzheimer disease, patients with PCA often retain memory, insight, and judgment until late in the course of their illness (16).
Diagnostic criteria for PCA have been proposed (Table 1). Both clinical findings and neuroimaging abnormalities indicate involvement of the posterior visual association cortices. Patient evaluation consists of 3 types of studies. First, neuropsychological testing will demonstrate dysfunction in the occipitoparietal (dorsal) or occipitotemporal (ventral) visual streams or both. The former will give rise to Balint syndrome, Gerstmann syndrome, dressing apraxia, and aphasia, while the latter to alexia without agraphia, visual object agnosia, and prosopagnosia. Second, neuroimaging studies demonstrate atrophy of the parietal and/or occipital regions and, at times, more generalized cortical atrophy. There is often enlargement of the lateral ventricles with focal enlargement of the atrial region. Third, with the use of PET, there is hypometabolism and with SPECT hypoperfusion in the parietal and/or occipital regions of the brain (17).
The most frequent pathological findings of PCA are senile plaques and neurofibrillary tangles primarily affecting the visual association areas. The cause for this focal involvement with PCA is unknown. No specific environmental or genetic factor has yet been identified. Given the current lack of understanding regarding the etiology of PCA, no treatment has proven effective, and the prognosis for these patients remains poor as shown in the following cases.
A 64-year-old woman complained of visual difficulties for 5 years. She could not recognize objects and had trouble reading and calculating. There was increased memory disturbance, and she was unable to copy geometric figures. On brain MRI, the frontal horns and the frontal area of the brain showed moderate cortical atrophy and severe bilateral parieto-occipital cortical atrophy, enlargement of the atrial portion of the ventricular system, and enlarged occipital horns (Fig. 5). PET demonstrated markedly reduced metabolic activity in the parieto-occipital regions.
Comment: This case illustrates the typical presenting signs and symptoms of a patient with PCA.
A 62-year-old man reported problems with reading for 1.5 years. He would lose his place and stated that there was a “cloud” in front of both eyes. He also noted difficulty with colors, and he misplaced objects. He often could not find food on his plate and was becoming forgetful of names and dates. Although an accountant, he was unable to perform even simple calculations. Visual acuity was 20/25 in the right eye and 20/30 in the left eye. Visual fields demonstrated a right homonymous hemianopia and hemiachromatopsia, but the patient could detect motion in the right homonymous visual fields. He could count fingers if they were moving, but when stationary, they would disappear (Riddoch phenomenon). He could not detect angles or determine the distance of an object before him and was unable to interpret pictures.
Over the ensuing year, the patient experienced increasing difficulty dressing himself, became disoriented to time and person, and developed left homonymous superior visual field extinction. Brain MRI revealed enlargement of the posterior horns of the lateral ventricles with associated cortical atrophy. There was diminished parieto-occipital metabolic activity bilaterally on PET (Fig. 6).
Comment: Early in the clinical course, this patient's visual complaints suggested a primary ophthalmologic disorder, but further evaluation pointed to more widespread neurologic involvement.
A 73-year-old woman had difficulty with reading. Visual acuity was 20/70 in the right eye and 20/40 in the left eye. Letters tended to disappear, and sentences made no sense. She had mild general confusion but could read numbers better than letters. Her interpretation of pictures for content was difficult. For example, in the “cookie theft picture” (Fig. 7), the patient could see the boy, but not interpret the scene. She could not do serial 7 subtractions, 1-minute recall was defective, and she could not copy geometric figures. There was a Riddoch phenomenon in the left homonymous hemifields. Brain MRI demonstrated mild parieto-occipital cortical atrophy with enlargement of the atrial portions of the ventricular system, and PET showed hypometabolism in both parieto-occipital areas, greater on the right.
Comment: Simultanagnosia was a striking feature of this patient's findings consistent with PCA.
A 59-year-old woman with cardiomyopathy underwent heart transplantation. On the fourth postoperative day, the patient noted that the vision was dim as if “looking through a shade.” Visual acuity was 20/50 in both eyes for isolated letters, but she could not identify letters embedded in words. Pupils, eye movements, and fundi were normal. Visual fields were intact but revealed left hemifield Riddoch phenomenon. The patient mislocated objects when reaching for them in space (see the video on the Neuro-Ophthalmology Virtual Education Library [NOVEL] Web site at http://content.lib.utah.edu/u?/jno,1370). Brain CT showed biparietal wedge-shaped infarctions.
Comment: Watershed infarctions of the parieto-occipital region can produce a clinical picture indistinguishable from PCA, but neuroimaging will make the cause clear.
The clinician should be highly suspicious of the diagnosis of PCA in the patient with persistent yet nonspecific visual complaints in the setting of a normal eye examination. By testing higher visual cortical function, one's index of suspicion will be raised further. Finally, employing neuropsychological testing and a combination of structural and functional neuroimaging modalities, the diagnosis of PCA can be established.
To read about the career of Dr. Schatz, see an interview conducted by Editor-in-Chief Emeritus Jonathan D. Trobe, MD, titled “Schatz” (J Neuroophthalmol. 2005;25:237-246).
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