Management misadventures

Neuro-ophthalmologists are sometimes accused of concentrating on elucidation of the disease process with little emphasis on treatment, referred to by one of our colleagues as “admiring the disease rather than curing it”. While we share our patients’ frustration over the conditions that we cannot cure, we would dispute this view of what we do, sometimes termed “therapeutic nihilism”. There are conditions in which intervention clearly makes a difference and we would be remiss if we did not highlight some of these situations.

Medical decisions frequently must be made on the basis of incomplete or ambiguous information, a fact of clinical practice that surely adds to our stress as clinicians. Ideally, we would have statistically significant results of multi-center trials and case-based analyses of the literature, but this kind of data is often lacking. Furthermore, practice parameters and recommendations regarding treatment evolve over time, as our understanding of disease process expands and additional information becomes available. Thus, what appears to be the correct course of action at one time may later be seen as ineffective or actually contraindicated. For example, neuromyelitis optica (Devic’s disease) was, at one time, considered a subtype of multiple sclerosis, and patients were treated accordingly. More recently, this condition has emerged as a separate autoimmune entity in which the pathology, diagnostic markers and natural history are disparate from multiple sclerosis. Based on this additional information, it is no longer considered standard

practice to treat patients with neuromyelitis optica using multiple sclerosis protocols.

We recognize that treatment recommendations are therefore not absolute, and are cautious about criticizing management decisions made by others. However, in some situations there are either enough data or sufficient collective clinical experience to recommend a particular course of action over another. In this chapter we look at a few such clinical scenarios. We have tried to emphasize those aspects of management in which there is some consensus and to downplay those that remain controversial.

Management of idiopathic intracranial hypertension

Case: A 26-year-old cashier presented with a onemonth history of daily headaches and pulsatile tinnitus. For the past two weeks she had also experienced brief episodes in which her vision would gray out in both eyes, often precipitated by postural change. She was generally healthy but had been obese since high school and reported an additional 25 pound weight gain since she stopped smoking six months earlier.

Visual acuity was 20/20 in each eye with normal color vision, pupillary responses and ocular motility, and fundus examination showed severe bilateral optic disc edema. Her general neurologic examination was otherwise normal as was an MRI with contrast. A lumbar puncture in the lateral decubitus

position demonstrated an opening pressure of 380 mm of water with normal protein, glucose and cell count. A diagnosis of idiopathic intracranial hypertension (pseudotumor cerebri syndrome) was made and she was treated with oral acetazolamide 250 mg twice per day.

The patient returned for follow-up two weeks later reporting no improvement of symptoms. A lumbar puncture was again performed, this time showing an opening pressure of 300 mm of water. Her headaches improved for a few days but then resumed, along with more frequent and prolonged transient visual obscurations. She worried that she was allergic to the acetazolamide because it caused intense paresthesias, so she stopped the medication. At return visit two weeks later she described dimming of vision, more in the right eye than the left, in addition to episodic visual loss. A third lumbar puncture showed an opening pressure of 340 mm of water and she was then sent for neuroophthalmic consultation.

Goldmann perimetry showed bilateral inferonasal depression and generalized constriction, worse in the right eye. Acetazolamide was restarted at a higher dose (500 mg sustained release form twice daily), and furosemide (40 mg daily) and a potassium supplement were added. She was reassured that paresthesia was a normal side-effect of the medication that typically improves over time. One week later there was some improvement of the visual field in the left eye but mild worsening in the right eye. Acetazolamide was increased to 500 mg three times daily but the visual field in the right eye continued to worsen over the next month, prompting an optic nerve sheath fenestration in the right eye. Two weeks post-operatively, optic nerve function in the right eye was improved and the degree of papilledema was decreased in both eyes. It was not clear whether the improvement of disc edema in the unoperated eye was a consequence of the surgery or due to beneficial effects of the medications, but with stabilization of optic nerve function and only mild disc edema, no additional surgery was recommended. She was continued on acetazolamide and furosemide, the importance of weight reduction for

the long-term management of this condition was discussed and the patient was referred to a nutritionist.

Discussion: In managing patients with IIH, the two primary goals of treatment should always be kept in mind: prevention of visual loss and relief of symptoms (usually headache). While reduction of intracranial pressure is one method of achieving these goals, it is not necessarily the primary aim of treatment. The focus should be on the effects of increased intracranial pressure (ICP), not the high pressure itself. This case illustrates several issues that commonly arise in the management of IIH.

In the large majority of cases, increased ICP is caused by weight gain and in such patients the ultimate effective treatment is weight reduction. Unfortunately, weight loss does not happen overnight; it is difficult to achieve and to sustain. Other therapeutic modalities for IIH can be divided into medical and surgical treatments. Medical treatments include acetazolamide and furosemide for lowering pressure, and amitryptyline, topiramate and various analgesics for symptomatic relief of headache. (Because of its pharmacologic similarity to acetazolamide, topiramate may also exert a beneficial effect on ICP but this has not yet been demonstrated.) Surgical options consist of optic nerve fenestration, cerebrospinal fluid diversion (lumboperitoneal or ventriculoperitoneal shunting) and bariatric procedures.

Although there are no randomized, controlled trials assessing the effectiveness of acetazolamide for IIH, experts in this area generally agree that this medication is effective and recommend it as a first line medical agent. However the recommended daily dosage varies. An early study that measured ICP during acetazolamide infusion found that a dose of 4 grams was required to significantly lower pressure, but few patients are able to tolerate this high a dose. From case series and clinical experience, lower doses of acetazolamide (1–2 grams daily) are associated with improvement of signs and symptoms in most patients. Use of the 500 mg sustained release formulation rather

than the 250 mg tablets achieves higher drug levels and is actually better tolerated in most patients, presumably because it avoids the peaks and troughs of the short acting form. Paresthesia, especially around the mouth and hands, is a common side-effect. Patients should be warned about this side-effect before starting treatment as they are more likely to tolerate this discomfort if they understand that it is not an allergy or a sign that the dose is too high. It should be explained that paresthesia is distinct from a rash, which indicates drug allergy and is an indication to discontinue the medication. A prior history of sulfa allergy does not necessarily predict an adverse reaction to acetazolamide and is not a contraindication to treatment. The use of acetazolamide during the first trimester of pregnancy is discouraged but inadvertent use has not been associated with an increased risk of fetal malformation. If treatment with acetazolamide is not adequate, furosemide can be added, usually with the addition of a potassium supplement.

The majority of patients with IIH can be managed adequately with medication and weight loss, but a subset requires more aggressive treatment in the form of surgery. The usual indication for surgical intervention is progressive visual loss despite maximal medical management, as exemplified in the above case (Table 12.1). In occasional patients, visual loss is so severe at onset that a trial of medical management is not wise, and this too represents an indication for surgery. Intractable headache despite maximal medical management sometimes prompts surgical intervention, but there are usually other treatment options that are preferable for these patients. Specific concerns in this setting include the high incidence of persistent headaches even

Table 12.1 Indications for surgical intervention in IIH

Progressive visual loss despite maximal medical therapy Severe visual loss at presentation

Unreliable patients (poor follow-up or non-organic visual fields)

Patients who are unable to tolerate medication

Patients at high risk for hypotensive events (e.g. dialysis)

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after technically successful shunting, and the relatively frequent need for shunt revision in these patients.

The specific indication for surgery helps to determine which procedure is chosen. When the indication is progressive visual loss, optic nerve sheath fenestration (ONSF) is often preferred. When persistent headache is the indication, shunting may be preferable since only about half of patients who undergo ONSF experience sustained improvement of headache. This remains an area of controversy and not all experts in the field agree with this recommendation. When shunting is undertaken, the ventriculoperitoneal (VP) route is emerging as a better choice than the lumboperitoneal (LP). Although the initial risk of placing a VP shunt is slightly higher, the lower revision rate and better access for using an externally programmable pressure device favor this route over LP shunting. VP shunting for IIH became a more viable option with the development of stereotactic CT guidance for shunt placement, and so there is less information on the long-term safety and efficacy of these shunts compared to the LP route. In a patient who presents with severe, acute visual loss the preferred surgical procedure is whichever one can be obtained most expediently. If a patient suffers subsequent visual loss following either procedure, the other one should be employed as well.

The third surgical option for the management of IIH is gastroplasty. Obviously, this is not an adequate strategy for patients with acute or impending visual loss, but it does appear to be effective for long-term management. In most cases, dramatic weight loss over the first six months following surgery brings significant improvement of signs and symptoms related to increased ICP.

Serial lumbar punctures have a limited role in the management of IIH. The relatively short duration of pressure-lowering limits its utility as a treatment modality. After the initial tap, serial lumbar punctures are rarely needed from a diagnostic standpoint since management is guided by the signs and symptoms of increased ICP rather than the degree of pressure elevation. Recall that the goal of treatment is

194Chapter 12: Management misadventures

not a particular CSF pressure but rather managing the effects of pressure. If a patient is asymptomatic and has minimal or no papilledema then treatment is adequate, regardless of an actual opening pressure measurement. Repeated lumbar punctures sometimes have a role as a temporizing measure, for example in a pregnant patient with IIH (in whom treatment options are more limited) or while waiting to organize a more definitive approach (delay in availability of a surgeon).

Treatment decisions in IIH are guided largely by the severity of symptoms and the status of the optic nerve. At each visit, the frequency and severity of symptoms (headaches, pulsatile tinnitus, transient visual obscurations and diplopia) should be recorded. Fundus photographs are useful for documenting changes in disc appearance. Because loss of central vision is typically a late finding in IIH, regular assessment of the visual field is crucial. This is particularly important when optic disc swelling appears to be improving. Res-

olution of papilledema is generally taken to be a good sign, indicating improvement of axonal transport. However, progressive attrition of nerve fibers will also produce a similar lessening of disc edema. The only way to ensure that resolution of papilledema indicates recovery rather than progressive neuronal death is to quantify optic nerve function, including measurement of visual fields (Table 12.2).

Table 12.2 Common errors in the management of IIH

Delay in initiating treatment

Using serial lumbar punctures for routine management Failure to monitor visual fields

Using inadequate doses of acetazolamide Neglecting to warn patients about acetazolamide

side-effects

Trusting spurious opening pressure measurement on fluoroscopy

Delay in moving from medical to surgical management Failure to provide adequate counseling regarding weight

reduction

Tip: Serial lumbar punctures have a limited role in the treatment of IIH. Optimal management should include regular assessment of visual field status and mindfulness regarding the goals of treatment, namely improvement of symptoms and protection of optic nerve function.

Evaluation and treatment of giant cell arteritis

Case: An 83-year-old, active widow who lived alone suddenly lost vision in her left eye. Examination that day revealed bare light perception vision in the left eye with marked swelling of the left optic disc (Figure 12.1). All findings in her right eye were normal. Review of systems revealed that she had not been well recently. Over a two-month period, she had developed generalized joint pain and stiffness that caused difficulty arising from bed and participating in her daily fitness class. She had also noted scalp tingling and facial tenderness that was so severe that she could not comfortably rest her head on a pillow. Her jaw ached after taking more than two bites of food and everything had a metallic taste. She had lost several pounds due to poor appetite and jaw pain. Her past medical history was significant for hyperlipidemia and carotid artery

Figure 12.1 Fundus photograph of an 83-year-old, active widow with acute visual loss in the left eye and recent systemic symptoms. The left disc exhibits a distinctive combination of pallor and swelling (pallid edema).

stenosis treated with bilateral carotid endarterectomies 15 years previously. A CBC showed mild normochromic normocytic anemia and Westergren erythrocyte sedimentation rate was 50 mm/hour.

A presumptive diagnosis of anterior ischemic optic neuropathy secondary to giant cell arteritis (GCA) was made. She was given a prescription for oral prednisone 80 mg per day and advised to take calcium supplementation, vitamin D and antacids. A temporal artery biopsy performed two days later was negative, as was a contralateral biopsy performed three days later. Within one week on steroids the patient felt much better and had resumed her usual activities. Her appetite and energy were restored, jaw claudication was gone and her joint stiffness was much improved. She complained, however of “the jitters” and suffered severe insomnia. A repeat ESR was just 4 mm/hour. Because of these steroid side-effects and lack of histopathologic evidence of GCA, she was rapidly weaned off prednisone over the next seven days.

Shortly thereafter, she began to experience episodes of foggy vision in her right eye and mild jaw fatigue when eating. Two days after onset of these symptoms she suddenly lost vision in her right eye while watching television. Examination revealed count fingers vision in her right eye and pallid disc edema. Her prednisone was immediately increased back to 80 mg daily but she never recovered vision in either eye and, due to her severe visual disability, eventually moved into an assisted facility.

The occurrence of bilateral sequential AION in very brief succession, as in this case, is virtually diagnostic of giant cell arteritis. The diagnosis had been suspected on clinical grounds but discarded based on a normal erythrocyte sedimentation rate and bilateral negative temporal artery biopsies. This case raises questions regarding the criteria for making a diagnosis of GCA and some aspects of treatment.

Discussion: There is no blood test that is diagnostic for GCA, but serum markers are routinely used to support a clinical suspicion of the diagnosis. The

most commonly employed such test is the erythrocyte sedimentation rate (ESR). Normal values for the ESR increase with age. One commonly used formula defines the normal range as less than age divided by 2 for men and age plus 10 divided by 2 for women. The ESR is elevated in most patients with GCA but 15 to 20% of patients with biopsyproven GCA have an ESR ≤50 mm/hour. Therefore a normal sedimentation rate does not rule out a diagnosis of GCA. The C-reactive protein (CRP) is a more sensitive serum marker of inflammation, reaching about 98% sensitivity in active GCA. Performing both an ESR and CRP has only a slightly higher yield for detecting an abnormal result than performing a CRP alone. Nonetheless, both laboratory tests should be obtained whenever possible because when both the ESR and CRP are elevated in a patient with clinical features suggestive of GCA the specificity approaches 97%. Conversely, normal values for both tests make a diagnosis of GCA unlikely. Other laboratory findings that are common in GCA are normocytic anemia, leukocytosis and thrombocytosis.

Although histopathologic demonstration of vasculitis by temporal artery biopsy remains the gold standard for the diagnosis of giant cell arteritis, biopsy results, even from an adequate specimen (2 cm or longer), are not always reliable. A negative biopsy result is found in 10–15% of patients in whom the diagnosis is subsequently made on clinical grounds, as in the case above. The additional yield from a second biopsy is low, ranging from 5–9% in different series. Thus, negative temporal artery (TA) biopsy, even when bilateral, does not rule out a diagnosis of GCA. Because biopsy results are occasionally misleading, it is important to be aware of those clinical features that should nevertheless suggest a diagnosis of GCA.

In the setting of acute AION, several clinical features are strongly suggestive of GCA. Age greater than 80 years makes GCA highly likely, as the non-arteritic form rarely affects individuals of advanced age. Other historic features that suggest GCA are: recent headache, jaw claudication, preceding episodes of transient visual loss,

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Figure 12.2 Combined disc and retinal edema, due to acute anterior ischemic optic neuropathy and cilioretinal artery occlusion, respectively, in a different patient with GCA.

A

constitutional symptoms (polymyalgia rheumatica, anorexia, fever) and elevated ESR/CRP. Examination findings that point to the arteritic form of AION include: markedly severe visual loss, pallid disc edema, cotton-wool spots in the retina of either eye, associated cilioretinal artery occlusion and a large cup/disc (C/D) ratio in the contralateral eye (Figures 12.2 and 12.3). These clinical features must all be considered when determining the significance of a negative TA biopsy. For example, an 82-year-old patient with light perception vision due to AION and a generous C/D ratio in the contralateral eye should be assumed to have GCA, regardless of the results of ancillary testing, including TA biopsy.

One important reason for distinguishing arteritic AION from the more common non-arteritic form concerns the visual prognosis for the fellow eye. Among patients with arteritic AION, 25–50%, if untreated, will suffer a similar event in the other eye, usually within 1–14 days. With prompt steroid treatment, such additional visual loss is rare.

B