Introduction

Idiopathic intracranial hypertension (IIH) is a condition characterized by signs and symptoms of increased intracranial pressure (ICP), such as headache, papilledema and increased cerebrospinal fluid (CSF) pressure, in the presence of an otherwise normal neurological examination (₁). On assessment, patients will exhibit normal CSF composition, normal neuroradiological imaging studies (in particular, computed tomography (CT) and/or magnetic resonance imaging (MRI)), and the absence of specific systemic or structural etiologies to explain the increased ICP (₂).

Originally described by Quincke as “serous meningitis” (₃) and also referred to as pseudotumor cerebri or benign intracranial hypertension, epidemiological studies of IIH suggest a crude annual incidence rate of 0.9-1.7 per 100,000 persons (₄,₅,₆). Several associations have been suggested, including female gender, obesity or recent weight gain, endocrinopathies, and medication use (1,₇,₈). We report a case of minocycline-associated IIH in a young female presenting to the emergency department for evaluation of headaches with visual changes.

Report of a Case

A thin (BMI= 19.5 kg/m2) 17 year old female presented to the emergency department with a bitemporal throbbing headache, intermittently present for 10-14 days. The headache was exacerbated with reading and worsened in severity from morning to evening. The patient experienced nausea without emesis during the most severe exacerbations, and obtained transient pain relief from acetaminophen with codeine.

Within 3-5 days prior to presentation, the patient began to observe sporadic episodes of self-limited horizontal diplopia, usually occurring in conjunction with her most severe headaches or in the evening. Like the headaches, these episodes were exacerbated by reading, and were occasionally accompanied by mild visual blurring without a specific field defect. Although she obtained no relief from medications, the diplopia resolved when either eye was closed during an attack. The patient historically used contact lenses without regard for which eye each lens was designated for, but did not feel that switching contact lenses between eyes altered her symptoms. She denied fever, chills, infectious complaints, neck stiffness, weight change or other symptoms.

Her past medical history was significant for exercise-induces asthma, menstrual irregularities, and acne vulgaris. Other than acetaminophen or acetaminophen with codeine, she had been receiving minocycline for approximately 16 weeks prior to presentation. She stopped the minocycline on the day of presentation and denied any other medication use, including oral contraceptives. Her family history included maternal migraines and Von Willebrand's Disease, as well as an aunt with a pituitary tumor (type unknown) but no other family history of endocrine or other malignancies.

On Examination

Physical examination revealed slightly swollen, mildly hyperemic optic discs with single flame hemorrhages present in each eye and an otherwise normal neurological and general examination. Visual acuity and field were at that time grossly normal and confirmed by an ophthalmologist. Laboratory studies, including CBC, ESR, coagulation studies and urinalysis were normal, and urine HCG was negative. Lumbar puncture revealed an opening pressure of 255 mm H2O with normal cell count, glucose and protein. Head CT (Figure 1) was normal, and head MRI (Figure 2) with MR venous angiography (Figure 3) obtained after referral to a neurologist were normal.

Figure 1

Figure 1: Normal Computed Tomography, Head

Figure 2

Figure 2: Normal Magnetic Resonance Imaging, Head

Figure 3

Figure 3: Dural venous sinus angiography with normal variant hypoplastic proximal left transverse sinus.

Clinical Course

Discussion

This 17-year old female presented with chief complaints of headache, diplopia and visual obscurations, which are among the more common symptoms reported in IIH. A case-control study by Giuseffi et al. examining symptoms among IIH patients noted headache (94%), transient visual obscurations (68%), and pulsatile intracranial noises (58%) as the three most common presenting complaints (7).

Other common symptoms observed in IIH included photopsia (54%), diplopia (38%) and visual loss (30%) (7). Our patient's ophthalmic presentation was complicated by her habit of inserting contact lenses without regard to the correct lens for each eye, although it did not alter our evaluation and management. Population-based studies have suggested that 22% of patients with IIH will suffer some form of visual loss during the course of their disease (4), with severe visual deficits in 25-30% of patients with IIH in referral-based studies (7,₉). Less frequent symptoms such as neck tenderness (₁₀,₁₁), nausea and vomiting (7,10) have also been reported.

The patient in this report also exhibited bilateral papilledema, although unilateral and asymmetric papilledema may also be found among patients with IIH (1). Optic nerve atrophy may result from protracted periods of papilledema, leading to permanent blindness (₁₂). Abducens nerve palsy may occur as a false localizing sign in up to 10-20% of cases of IIH (₁₃), and cranial nerve III (₁₄), IV (₁₅), V (₁₆), and VII (₁₇) palsies have also been reported.

According to Dandy's Modified Criteria for the diagnosis of IIH, the neurological examination should be otherwise normal (2,13,₁₈,₁₉). In addition to the signs and symptoms of increased intracranial pressure above, patients with IIH should also have an increased CSF pressure (>250 mm H2O) but normal CSF composition, normal neuroradiological imaging, and exclusion of other causes of elevated intracranial pressure (2,13,18,19).

A key feature of IIH is that it is a diagnosis of exclusion. Because of the significant morbidity and mortality associated with intracranial hypertension, it is critical to rule out other potential causes of increased intracranial pressure (ICP). Smith and Caldemeyer (₂₀) present a differential diagnosis for increased ICP stratified into three components: 1) increased brain volume (tumor, infarction, hemorrhage, infection, hepatic disease, white matter disease); 2) increased CSF (obstructive hydrocephalus, non-obstructive hydrocephalus, overproduction hydrocephalus, normal pressure hydrocephalus, IIH); and 3) increased blood volume (increased central venous pressure, dural sinus thrombosis). All other causes must be excluded before the diagnosis of IIH may be entertained.

Although the pathogenesis of IIH is uncertain, hypotheses generally revolve around the same three components of increased ICP noted by Smith and Caldemeyer (20). Studies have demonstrated cerebral edema (₂₁,₂₂) associated with increased cerebral free water (₂₃) in cases of IIH. This finding is postulated in the context of impaired CSF absorption at the arachnoid villi (19,₂₄,₂₅), increased CSF production (₂₆), or increased intracranial blood volume (25,₂₇), the latter thought secondary to venous outflow obstruction from increased subarachnoid pressure (1).

Like pathogenesis, the etiology of IIH is similarly uncertain. Obesity and weight gain are modifiable factors that have been significantly associated with IIH in epidemiological studies (7,8) – our patient was clearly atypical in this regard. Demographic factors such as female gender and reproductive age have been associated with an increased risk for IIH, as well. A population-based study from Rochester, Minnesota observed an adjusted annual incidence of 0.9 cases per 100,000 persons, with an annual rate of 1.6 cases per 100,000 females and 3.3 cases per 100,000 females 15-44 years of age (4). Other incidence studies have noted crude annual rates ranging from 0.9 - 1.7 cases per 100,000 persons, with rates approximately 1.5 to 2-fold higher among all females and approximately 3 to 6-fold higher among females 15-44 years of age (4-6) when compared with overall rates.

Radhakrishnan et al. present a variety of additionally described risk factors of varying strength, including the coexistence of endocrinopathies, menstrual irregularities, autoimmune disorders, chronic renal failure, and concurrent medication use - such as steroids, estrogens, Vitamin A, thyroid supplements and antibiotics - among patients with IIH (1). These authors suggest that patients developing IIH may possess an underlying abnormality or predisposition which, when acting in concert with an aggravating agent such as recent weight gain or antibiotic use, produces the disease (1).

Tetracyclines, with minocycline in particular, are among the more frequently described offending agents. Some authors have even suggested that periodic ophthalmologic examination in patients combining tetracyclines with vitamin A should be considered to detect IIH (₂₈). Minocycline, used by the patient in this report, has been described in association with IIH in over 30 cases (28,₂₉,₃₀,₃₁,₃₂,₃₃,₃₄). Presumably, the higher lipophilicity of minocycline when compared to other tetracyclines allows greater penetration of the blood-brain barrier, resulting in higher CSF concentrations and perhaps its association with IIH (34).

Therapy for IIH is generally directed at removing the precipitating factors and intervening on visual disturbances. Critical to overall management is the recognition that IIH is a diagnosis of exclusion that requires careful ophthalmologic and neurological follow-up through resolution of signs and symptoms. Given the possibility of significant visual sequelae, close monitoring with medical or surgical management as needed is reasonable. Acetazolamide, thought to reduce CSF production, is the medication most frequently used, while corticosteroids and serial lumbar puncture have also been utilized (1). Surgical interventions through lumboperitoneal shunt or optic nerve sheath fenestration have been used with rapid or progressive visual loss (1,12). An atypical course should be aggressively evaluated, as Aroichane et al suggest in their report of glioblastoma multiforme which mimicked IIH early in its presentation in a 16-year-old female utilizing minocycline for acne (₃₅).

Although idiopathic intracranial hypertension is an uncommon condition, cases may present to urgent care or emergency facilities as our patient did. Recognition of IIH among the differential diagnoses and appropriate exclusion of other possible conditions is critical in this setting, as is triage for further management and follow-up. An awareness of potentially predisposing conditions for IIH, such as specific medication usage or other risk factors, should assist the physician in guiding management to further evaluate symptoms consistent with this illness. Symptoms are commonly related to the increased intracranial pressure and include headache, visual changes, intracranial noises and abducens nerve palsies. Sequelae of IIH may be severe, so intervention and therapy are directed at identification and removal of offending agents and reversal of modifiable risk factors. Follow-up should be arranged for further evaluation as needed, as well as close neurological and ophthalmologic monitoring for the early detection of possible visual loss.