By Finsterer, Josef; Kuntscher, Dagmar; Brunner, Simon; Krugluger, Walter
Abstract
Objective. The association of pseudotumor cerebri, visual impairment, hypothyroidism, polycystic ovary syndrome (PCOS), and a hypercoagulable state due to a factor V and a prothrombin mutation has not been reported previously.
Case report. A 20-year-old obese woman developed menstrual cycle irregularities since age 14 years, initially bitemporal and latter diffuse headache since age 14 years, and bilateral visual impairment, described as sparkling black points. Ophthalmologically there was a recurrent papilledema. Clinical neurologic investigations revealed sore neck muscles and hirsutism. Magnetic resonance imaging of the brain, orbita and cervical spine, and investigations of cerebrospinal fluid were non-informative. Visually evoked potentials revealed demyelination of the optic nerves. Gynecologic investigations revealed PCOS and endocrinologic investigations hypothyroidism and hyperandrogenism. Tests for thrombophilia disclosed a heterozygote state for the G1.697A factor V Leiden and the G20.210A prothrombin mutation. A possible relationship between pseudotumor cerebri and the ophthalmologic, gynecologic, endocrinologic and coagulation abnormalities is discussed.
Conclusions. For the first time we describe the association of pseudotumor cerebri, optic nerve demyelination, PCOS, other endocrinologic abnormalities, and thrombophilia due to a factor V and prothrombin mutation. A causal relationship between these abnormalities remains elusive.
Keywords: Endocrine system, headache, optic nerve, polycystic ovary, hypothyroidism, idiopathic intracranial hypertension
Introduction
There are reports which describe the association of pseudotumor cerebri (PC), also known as idiopathic or benign intracranial hypertension, and polycystic ovary syndrome (PCOS), also known as Stein-Leventhal syndrome [1]. It also has been described that PC and PCOS may be associated with coagulation disorders [1]. However, the combination of PC, hypothyroidism with acanthocytosis, PCOS with elevated testosterone levels, obesity and hirsutism, and a heterozygote factor V and a prothrombin mutation has not been reported previously.
Case report
The patient, a 20-year-old, Caucasian, HFV-negative woman with height 169 cm and weight 90 kg, had initially bitemporal and later diffuse headache since age 14 years and bilateral visual impairment (described as sparkling: many moving black points) since September 2004 that was associated with visual loss for a few seconds, four or five times so far at presentation. Ophthalmologic investigations in October 2004 revealed a papilledema for the first time. Ultrasonography of the extracerebral arteries was normal. Clinical neurologic investigation at that time was normal and since the cerebral magnetic resonance imaging (MRI) scan was also noninformative, a PC was suspected. A lumbar puncture was normal and promptly relieved headache and visual impairment. Under acetazolamide (500 mg/ day) for 4 weeks, given after the lumbar puncture, headache disappeared completely. Additionally, the patient had a previous history of allergic bronchial asthma since age 9 years, for which she took steroids, resulting in weight gain and menstrual cycle irregularities since menarche at age 14 years. The family history was positive for glaucoma (father), deep venous thrombosis (father), cardiac rhythm abnormalities (mother), short stature (mother), and an undetermined ophthalmologic disease (grandmother from her father’s side).
In March 2005 visual impairment recurred and she complained about easy fatigability and tiredness, but did not report headache. Ophthalmologic investigation in July 2005 revealed a prominent papilla nasally. Otolaryngologic investigation in July 2005 was normal. Clinical neurologic examination disclosed sore neck muscles and hirsutism exclusively. MRI scans of the cerebrum, orbita and the cervical spine were normal. There was no indication for an empty sella or dilation of the optic nerve sheaths. Investigations of cerebrospinal fluid (CSF) were nonconclusive (14/3 leukocytes). Blood sedimentation rate was normal. Antibodies against various viruses, Borrelia burgdorferi and Cryptococcus neoformans were negative in serum and CSF. Search for B. burgdorferi DNA was non- informative. Anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, circulating immune complexes and complement factor C3 were normal; complement factor 4 was elevated slightly. This time acetazolamide (1000 mg/day) was without effect and the patient withdrew the medication by herself after 7 days. An ex juvantibus therapy with prednisolone (1000 mg/day) for 5 days in August 2005 was clinically ineffective, although the following ophthalmologic investigation was normal. Endocrine investigations in August 2005 revealed struma diffusa and hypothyroidism. Levothyroxine 0.05 mg/ day was prescribed.
In September 2005 slight headache recurred. MRI scan of the cerebrum was normal. Visually evoked potentials showed demyelination of the optic nerves bilaterally. From October 2005 she noted recurrent nausea and in November 2005 she experienced permanent emesis for 1 week. Fatigue and sleep desire increased despite levothyroxine. Endocrinological work-up in November 2005 revealed elevated serum testosterone. Gynecologic examinations suspected PCOS. Ophthalmologic investigations in November 2005 revealed a prominent optic disk for the third time and acteazolamide (1000 mg/ day) was given for 2 weeks but was discontinued by the patient because of increase in headache and dizziness. The papilledema resolved in December 2005, but visual impairment subjectively worsened and she noted difficulties in focusing objects. Erythrocyte morphology showed acanthocytosis in 0.05% of the cells. Investigations for thrombophilia disclosed a heterozygote state of the G1.697A factor V Leiden mutation and a heterozygote state of the G20.210A prothrombin mutation. She was advised to inject low- molecular-weight heparin subcutaneously during immobilization. There was no indication for malignancy. Since March 2006 the patient received topiramate, which resulted in complete resolution of headache but did not affect visual impairment.
Discussion
According to the modified Dandy criteria presented in 1985, PC is defined as idiopathic intracranial hypertension, characterized by elevated CSF pressure of > 20 mmHg, normal CSF composition, papillary edema, headache, and exclusion of an underlying structural or systemic cause [2-5]. Visual loss is a serious complication and requires careful monitoring and management. Therapy of PC comprises dietary measures to achieve weight loss, discontinuation of contributing medication, provision of diuretics, and surgical techniques such as lumbo-peritoneal shunting, ventriculo-peritoneal shunting, optic nerve sheath fenestration and venous sinus stenting [6,7]. The main goal of PC therapy is to prevent or arrest progressive visual loss [6]. Manifestations attributable to PC in the described patient were headache, papillary edema, and nausea and emesis in October 2005. This is supported by the prompt relief of headache and visual impairment after the lumbar puncture in October 2004.
The exact cause and pathogenesis of PC are unknown, but principally it may derive from increased CSF production or decreased CSF absorption (absorptive block), either from increased pressure in the durai venous sinuses or lesions of the arachnoidal villi [8]. Cerebral edema or increased cerebral blood volume may play an additional pathogenetic role. Once the intracranial pressure raises above a certain level, pressure in the superior sagittal sinus increases due to collapse of the transverse sinuses [4,9]. According to this hypothesis, high pressures measured in the sinuses might therefore be rather the consequence of raised intracranial pressure than its cause [4]. A further pathogenetic theory outlines high pressures in the venous sinuses as causative, occasionally secondary to systemic venous hypertension, but more often apparently the result of stenotic lesions of the venous sinuses, particularly bilateral lateral venous sinus lesions, causing partial obstruction to cranial outflow [4,10]. Since PC occurs more frequently in women than men and is predominantly associated with obesity [11], intake of oral contraceptives, pregnancy, menstrual cycle irregularities, galactorrhea, hypothyroidism, recent weight gain and short stature, endocrine factors are suspected to play an additional role [11,12]. However, PC has also been reported after administration of tetracyclines, isotretinoin and trimethoprim-sulfamethoxazole [5,12,13]. Risk factors for the development of PC, in addition to PCOS, are oral contraceptives, adrenocortical insufficiency [14], cystinosis [15], vitamin A intake [16] or a septal defect [17].
Demyelination of the optic nerve neurons in the described patient may be a direct consequence of the increased intracranial pressure, may represent a second trouble, or may be just part of a multi- system disease. An argument for one of the latter explanations is the fact that visually evoked potential latencies are not prolonged in patients with PC [18,19]. An argument for a causal relationship between PC and demyelination of the optic nerve is the improvement of v\ision after the lumbar puncture in October 2004. Differential diagnoses of optic nerve demyelination are listed in Table I. All of these conditions were excluded in the present patient.
PCOS is the commonest endocrine disorder in women [20]. PCOS is not only a frequent cause of anovulatory infertility, menstrual cycle disturbances and hirsutism, but also a major risk factor in the development of overweight, insulin resistance, diabetes mellitus, cardiovascular disease (increased intima media thickness, impaired vascular elasticity) and gynecological cancer later in life [20-23]. PCOS is characterized by multiple ovarian cysts, hyperandrogenism with hirsutism and obesity [24]. PCOS may be also associated with hypothyroidism, steatosis hepatis and insulin resistance, independent of total or fat-free body mass [25-27]. Hyperandrogenism in PCOS may be a consequence of hyperinsulinism due to peripheral insulin resistance [28]. Following these observations, metformin and insulin sensitizers (thiazolidinediones) may be a potential therapeutic tool for PCOS [25,28]. The close relationship between PCOS, hypothyroidism and insulin resistance is supported by the finding that treatment of one of these conditions also improves the two others [27]. The etiology of PCOS is uncertain but there is increasing evidence for a genetic basis [20]. There may be a genetic predisposition of the fetal ovary to hypersecrete androgen [20]. Stress and sympathetic innervation may be additional triggers [29]. That the present patient’s endocrine problems derived from a hypophysial problem is rather unlikely given her normal levels of thyroid-stimulating hormone, luteinizing hormone, follicle- stimulating hormone and prolactin.
Table I. Differential diagnoses of prolonged visually evoked potentials.
The term acanthocytosis describes a crenated shape of erythrocytes. Acanthocytosis is associated with at least three neurologic disorders: chorea acanthocytosis, abetalipoproteinemia and McLeod syndrome, which are summarized under the term neuroacanthocytosis. None of these entities was present in the described patient. Neuroacanthocytosis was also excluded because of only the mild prevalence of acanthocytes: in neuroacanthocytosis the frequency of acanthocytes is usually much higher. Although 90% of the patients with acanthocytosis suffer from hypothyroidism [30], it is rather unlikely that hypothyroidism in the described patient resulted from the low number of acanthocytes. Most likely the minimal acanthocytosis was attributable to hypothyroidism and not the other way round.
The factor V Leiden mutation and the prothrombin mutation were detected during diagnostic workup of a questionable hypercoagulability in PCOS, as has been previously reported [1,31]. In these studies PC was associated with PCOS and thrombophilia due to increased factor VIII. No mutations in the factor V or prothrombin genes were detected. The mutations of the present patient were regarded not to be connected to her endocrinologie problems, although it cannot be definitively excluded that genes encoding for endocrine pathway products neighboring the factor V and the prothrombin genes were also affected by these mutations, or together affected by a more widespread deletion or translocation. However, cytogenetic studies did not provide any evidence for this assumption.
In conclusion, this case shows for the first time that PC, endocrinologic abnormalities including PCOS, and a hereditary hypercoagulable state due to a factor V and prothrombin mutation may occur in a single patient. A causal relationship between these abnormalities remains elusive.
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JOSEF FINSTERER1, DAGMAR KUNTSCHER2, SIMON BRUNNER3, & WALTER KRUGLUGER2
1 Krankenanstalt Rudolfstiftung, Vienna, Austria, 2 Central Laboratory, Krankenanstalt Rudolfstiftung, Vienna Austria, and 3 Department of Ophthalmology, Krankenanstalt Rudolfstiftung, Vienna, Austria
(Received 13 July 2006; revised 19 January 2007; accepted 23 January 2007)
Correspondence: J. Finsterer, Postfach 20, 1180 Vienna, Austria. Tel: 43 1 71165 92085. Fax: 43 1 4781711. E-mail: [email protected]
Copyright Taylor & Francis Ltd. Mar 2007
(c) 2007 Gynecological Endocrinology. Provided by ProQuest Information and Learning. All rights Reserved.
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