ISSN 0017-8748 doi: 10.1111/head.12242 Published by Wiley Periodicals, Inc.
Headache © 2013 American Headache Society
Clinical Correspondence Can Elevated IGF-1 Levels Among Patients With Ehlers–Danlos Syndrome Cause Idiopathic Intracranial Hypertension? Michelle Kurian, MS; Glen D. Solomon, MD
We offer for consideration a possible association between hypermobility syndrome seen in Ehlers–Danlos syndrome and risk of potential development of idiopathic intracranial hypertension – mediated primarily through the effects of insulin-like growth factor-1. Key words: idiopathic intracranial hypertension, Ehlers–Danlos syndrome, IGF-1, hypermobility syndrome (Headache 2013;53:1666-1669)
Idiopathic intracranial hypertension (IIH) – formerly known as “pseudotumor cerebri” – is a neurological disorder characterized by an increase in intracranial pressure in the absence of a brain tumor or other secondary disease process.The pathophysiology of IIH is controversial: studies have identified the significance of growth hormone (GH) as well as insulin-like growth factor-1 (IGF-1) in mediating the increase in pressure – although the mechanism behind this process is not yet clearly understood. Here, we offer for consideration a possible association between hypermobility syndrome (HMS) seen in Ehlers– Danlos syndrome and risk of potential development of IIH – mediated primarily through the effects of IGF-1.
CASE REPORT In June 2010, a 36-year-old non-obese female (body mass index [BMI] 18.5) presented with sympFrom the Department of Internal Medicine, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA. Address all correspondence to G.D Solomon, Wright State University, Internal Medicine, PO Box 927, Dayton, OH 454010927, USA. Accepted for publication August 8, 2013.
toms of a generalized headache for 8 months. She described the headaches as throbbing, worse in the morning hours, disabling, and exacerbated by recumbency. Moreover, the patient reported that the headaches were similar in nature to those she had experienced as a teenager following a lumbar puncture (LP) performed to investigate visual obscurations following an auto accident. With the current headaches, the patient reported experiencing some nausea as well as occasional double vision. She denied having any sensitivity to light, sound, or smell; she also denied having any symptoms of lacrimation, rhinorrhea, or conjunctival injection associated with her headaches. Physical exam was largely benign: the patient exhibited full range of visual fields and acuity; there was no papilledema observed on fundoscopy; extraocular movements were intact; and neurological exam was within normal limits. The patient was noted to have a prominent frontalis muscle. She was sent for magnetic resonance imaging, which failed to reveal any intracranial mass or lesion. Because there was no evidence of papilledema or focal neurological deficits, an LP was performed – which provided some relief from headaches and revealed an elevated opening Conflict of Interest: None.
1666
Headache cerebrospinal fluid (CSF) pressure of 32 cm H2O. Examination of the CSF itself showed no abnormalities. A diagnosis of IIH was made. Because of the frontal bossing noted on exam, a workup for acromegaly was performed. Lab studies revealed an increased IGF-1 level of 552 (normal range 64-334), with normal glucose and GH level of 0.5 (normal range < or = 10.0). Endocrinology consultation again documented an elevated IGF-1 level of 403, with IGF-1 binding protein 3 level of 5.1 (normal range 3.4-7.0), but ruled out a diagnosis of acromegaly based on examination and normal GH levels during glucose tolerance testing (fasting 0.3). The patient failed treatment with high-dose acetazolamide and furosemide. Subsequent LPs provided modest relief from headaches for several weeks. In September 2010, CSF opening pressure was elevated at 38 cm H2O. In December 2010, the opening pressure was 21 cm H2O. In February 2011, we started therapy with subcutaneous octreotide, based on several reports from the medical literature. The patient had a dramatic clinical response to this treatment – with elimination of her visual symptoms and head pain. In July 2011, her opening pressure was 22 cm H2O. A final LP completed in November 2011 revealed an opening CSF pressure of 19 cm H2O and a closing pressure estimated at 12 cm H2O. At follow-up 2 years later, the patient reported a different quality and location of headaches, which were refractory to octreotide treatment. She was found to have temporomandibular joint (TMJ) luxation. Because of the marked laxity of her TMJ, her dentist referred her for genetic evaluation for connective tissue disease. She was diagnosed with HMS – associated with Ehlers–Danlos syndrome.
DISCUSSION According to the International Classification of Headaches Disorders, 2nd edition (ICHD-2),1 IIH is defined as a progressive headache with at least 1 of the following characteristics: daily occurrence; diffuse and/or constant (non-pulsating) pain; and aggravated by coughing or straining. Furthermore, the patient’s headache is typically observed to occur in close temporal relation to increased intracranial pressure, and
1667 it is seen to improve after withdrawal of CSF via LP in an effort to reduce pressure.1 Patients with IIH may demonstrate abnormal signs on neurological exam: papilledema, an enlarged blind spot, visual field defects, or sixth nerve palsy.1 Although a majority of patients with IIH will exhibit papilledema, there are cases where it is not observed. Likewise, IIH is most commonly described in young obese women – but, again, this is not always the case. Other symptoms observed among patients suffering from IIH including tinnitus, transient visual obscurations, diplopia, and intracranial noises.1 According to the International Classification of Headaches Disorders, 3rd edition (ICHD-3),2 our patient meets diagnostic criteria for IIH by having an increased CSF pressure (>25 cm H2O CSF) and a headache that was relieved by reducing intracranial pressure. She did not have any of the metabolic, toxic, or hormonal causes of intracranial hypertension. LP is an important diagnostic tool in making this assessment: in IIH patients, an elevated opening pressure is revealed – typically >20 cm H2O in non-obese patients and >25 cm H2O in obese patients.1 CSF findings are typically within normal limits; low CSF protein may be observed in some cases but this in itself is not an unusual finding. To make a definitive diagnosis of IIH, an imaging modality is required. Again, a full workup is also important so as to rule out any other intrinsic disease process that may be responsible for elevating pressure within the cranium. The pathophysiology behind IIH remains controversial: some theorize that the increased intracranial pressure is secondary to excess CSF production3,4 or increased blood volume or brain tissue while others argue that it is due to obstruction of veins that drain blood from the brain – leading to increased venous sinus pressure.4-6 Whatever the exact mechanism may be, studies have demonstrated the role of elevated levels of GH and IGF-1 in raising intracranial pressure.7,8 Specifically, there has been evidence suggesting that IGF-1 receptors present at the level of the choroid plexus9-11 – the site of CSF production – are excessively stimulated in high GH-IGF-1 states (as seen in cases of acromegaly or HMS)9-11 leading to excess CSF production and thus increased intracranial pressure.
1668 A recent study out of Greece produced a promising result regarding the use of octreotide – a somatostatin analogue with an inhibitory effect on the GH-IGF-1 axis – in providing relief for patients suffering from IIH-associated headaches.4 It was this study that served as the basis of the treatment plan utilized in our patient described above: octreotide was shown to reduce papilledema and relieve headaches quickly as well as improve any visual disturbances reported by the patient. It is important to note that weight loss is an important element in treating patients with IIH; this was not of particular concern in our patient, whose BMI was within normal range and who had maintained a healthy weight throughout the majority of her adult life. Schneider et al12 measured IGF-1 levels in 6773 adult primary care patients and found elevated levels in 125 of those patients. Forty-nine patients underwent further evaluation: on repeat measurement of IGF-1, levels were found to be normal in 10 patients while acromegaly was diagnosed in 7 patients and excluded in 32. Elevated levels of IGF-1 are reported in very few conditions – pregnancy,13 adolescence,13 hyperthyroidism,13 acromegaly,12 and Ehlers–Danlos syndrome.10 Our patient was not pregnant during the symptomatic time period, and her thyroid-stimulating hormone levels were within normal limits. At this time, we are unaware of any studies specifically measuring IGF-1 levels in patients with IIH. Given our patient’s history of IIH and her diagnosis of HMS associated with Ehlers–Danlos syndrome, we propose a possible association between these 2 disease processes mediated primarily through the actions of IGF-1. Studies have shown increased circulating levels of IGF-1 in the serum of patients suffering from HMS associated with Ehlers–Danlos syndrome.10 As such, we hypothesize that in our patient, the elevated IGF-1 levels incidentally found on laboratory workup were not only a sign of her underlying HMS but also a mediating factor in the development of IIH. It is unclear as to what role, if any, IGF-1 plays in the pathogenesis of HMS seen in Ehlers–Danlos syndrome; this requires further investigation. There is currently an ongoing study in Denmark evaluating the effectiveness of IGF-1 in stimulating collagen synthesis among Ehlers–Danlos
November/December 2013 patients (NCT01446783), but this would – in theory, if our hypothesis is correct – initiate development of and/or worsen IIH among patients. Nevertheless, the role of IGF-1 in IIH has been demonstrated, and the association is worth consideration. Furthermore, if such an association were proven to exist, it would help promote the effectiveness and applicability of octreotide as a potential therapeutic agent in the treatment of HMS seen in Ehlers–Danlos syndrome as well as IIH. Our hope is that this case report stimulates studies on exploring this potential relationship.
CONCLUSION We present a case of HMS of Ehlers–Danlos syndrome and IIH – and present a potential mechanism for the combined syndrome mediated primarily through the effects of IGF-1. REFERENCES 1. Headache Classification Committee of the International Headache Society. The international classification of headache disorders 2nd edition. Cephalalgia. 2004;24:1-160. 2. Headache Classification Subcommittee of the International Headache Society. International classification of headache disorders 3rd edition (beta version). Cephalalgia. 2013;33:714-715. 3. Digre KB, Corbett JJ. Idiopathic intracranial hypertension (pseudotumor cerebri):A reappraisal.Neurologist. 2001;7:2-67. 4. Panagopoulos GN, Deftereos SN, Tagaris GA, et al. Octreotide: A therapeutic option for idiopathic intracranial hypertension. Neurol Neurophysiol Neurosci. 2007;Jul 10:1. 5. Corbett JJ, Digre KB. Idiopathic intracranial hypertension: An answer to, “The chicken or the egg?” Neurology. 2002;58:5-6. 6. King JO, Mitchell PJ, et al. Cerebral renography and manometry in idiopathic intracranial hypertension. Neurology. 1995;4:2224-2228. 7. Malozowski S, Tanner LA, Wysowski D, Fleming GA. Growth hormone, insulin-like growth factor I and benign intracranial hypertension. N Engl J Med. 1993;329:665-666. 8. Price A, Clayton PE, Lloyd IC. Benign intracranial hypertension induced by growth hormone treatment. Lancet. 1995;345:458-459.
Headache 9. Ichimiya Y, Emson PC, Northrop AJ, Gilmour RS. Insulin-like growth factor II in the rat choroid plexus. Brain Res. 1988;464:167-170. 10. Denko CW, Bojo B. Growth hormone, insulin, and insulin-like growth factor-1 in hypermobility syndrome. J Rheumatol. 2001;7:1666-1669. 11. Katz SE, Klisovic DD, O’Dorisio MS, Lynch R, Lubow M. Expression of somatostatin receptors 1 and 2 in human choroid plexus and arachnoid granulations. Arch Ophthalmol. 2002;120:1540-1543.
1669 12. Schneider HJ, Sieverst C, Saller B, Wittchen HU, Stalla GK. High prevalence of biochemical acromegaly in primary care patients with elevated IGF-1 levels. Clin Endocrinol (Oxf). 2008;69:432-435. 13. Freda PU. Monitoring of acromegaly: What should be performed when GH and IGF-1 levels are discrepant? Clin Endocrinol (Oxf). 2009;71:166-170.
Headache © 2013 American Headache Society
Clinical Correspondence Can Elevated IGF-1 Levels Among Patients With Ehlers–Danlos Syndrome Cause Idiopathic Intracranial Hypertension? Michelle Kurian, MS; Glen D. Solomon, MD
We offer for consideration a possible association between hypermobility syndrome seen in Ehlers–Danlos syndrome and risk of potential development of idiopathic intracranial hypertension – mediated primarily through the effects of insulin-like growth factor-1. Key words: idiopathic intracranial hypertension, Ehlers–Danlos syndrome, IGF-1, hypermobility syndrome (Headache 2013;53:1666-1669)
Idiopathic intracranial hypertension (IIH) – formerly known as “pseudotumor cerebri” – is a neurological disorder characterized by an increase in intracranial pressure in the absence of a brain tumor or other secondary disease process.The pathophysiology of IIH is controversial: studies have identified the significance of growth hormone (GH) as well as insulin-like growth factor-1 (IGF-1) in mediating the increase in pressure – although the mechanism behind this process is not yet clearly understood. Here, we offer for consideration a possible association between hypermobility syndrome (HMS) seen in Ehlers– Danlos syndrome and risk of potential development of IIH – mediated primarily through the effects of IGF-1.
CASE REPORT In June 2010, a 36-year-old non-obese female (body mass index [BMI] 18.5) presented with sympFrom the Department of Internal Medicine, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA. Address all correspondence to G.D Solomon, Wright State University, Internal Medicine, PO Box 927, Dayton, OH 454010927, USA. Accepted for publication August 8, 2013.
toms of a generalized headache for 8 months. She described the headaches as throbbing, worse in the morning hours, disabling, and exacerbated by recumbency. Moreover, the patient reported that the headaches were similar in nature to those she had experienced as a teenager following a lumbar puncture (LP) performed to investigate visual obscurations following an auto accident. With the current headaches, the patient reported experiencing some nausea as well as occasional double vision. She denied having any sensitivity to light, sound, or smell; she also denied having any symptoms of lacrimation, rhinorrhea, or conjunctival injection associated with her headaches. Physical exam was largely benign: the patient exhibited full range of visual fields and acuity; there was no papilledema observed on fundoscopy; extraocular movements were intact; and neurological exam was within normal limits. The patient was noted to have a prominent frontalis muscle. She was sent for magnetic resonance imaging, which failed to reveal any intracranial mass or lesion. Because there was no evidence of papilledema or focal neurological deficits, an LP was performed – which provided some relief from headaches and revealed an elevated opening Conflict of Interest: None.
1666
Headache cerebrospinal fluid (CSF) pressure of 32 cm H2O. Examination of the CSF itself showed no abnormalities. A diagnosis of IIH was made. Because of the frontal bossing noted on exam, a workup for acromegaly was performed. Lab studies revealed an increased IGF-1 level of 552 (normal range 64-334), with normal glucose and GH level of 0.5 (normal range < or = 10.0). Endocrinology consultation again documented an elevated IGF-1 level of 403, with IGF-1 binding protein 3 level of 5.1 (normal range 3.4-7.0), but ruled out a diagnosis of acromegaly based on examination and normal GH levels during glucose tolerance testing (fasting 0.3). The patient failed treatment with high-dose acetazolamide and furosemide. Subsequent LPs provided modest relief from headaches for several weeks. In September 2010, CSF opening pressure was elevated at 38 cm H2O. In December 2010, the opening pressure was 21 cm H2O. In February 2011, we started therapy with subcutaneous octreotide, based on several reports from the medical literature. The patient had a dramatic clinical response to this treatment – with elimination of her visual symptoms and head pain. In July 2011, her opening pressure was 22 cm H2O. A final LP completed in November 2011 revealed an opening CSF pressure of 19 cm H2O and a closing pressure estimated at 12 cm H2O. At follow-up 2 years later, the patient reported a different quality and location of headaches, which were refractory to octreotide treatment. She was found to have temporomandibular joint (TMJ) luxation. Because of the marked laxity of her TMJ, her dentist referred her for genetic evaluation for connective tissue disease. She was diagnosed with HMS – associated with Ehlers–Danlos syndrome.
DISCUSSION According to the International Classification of Headaches Disorders, 2nd edition (ICHD-2),1 IIH is defined as a progressive headache with at least 1 of the following characteristics: daily occurrence; diffuse and/or constant (non-pulsating) pain; and aggravated by coughing or straining. Furthermore, the patient’s headache is typically observed to occur in close temporal relation to increased intracranial pressure, and
1667 it is seen to improve after withdrawal of CSF via LP in an effort to reduce pressure.1 Patients with IIH may demonstrate abnormal signs on neurological exam: papilledema, an enlarged blind spot, visual field defects, or sixth nerve palsy.1 Although a majority of patients with IIH will exhibit papilledema, there are cases where it is not observed. Likewise, IIH is most commonly described in young obese women – but, again, this is not always the case. Other symptoms observed among patients suffering from IIH including tinnitus, transient visual obscurations, diplopia, and intracranial noises.1 According to the International Classification of Headaches Disorders, 3rd edition (ICHD-3),2 our patient meets diagnostic criteria for IIH by having an increased CSF pressure (>25 cm H2O CSF) and a headache that was relieved by reducing intracranial pressure. She did not have any of the metabolic, toxic, or hormonal causes of intracranial hypertension. LP is an important diagnostic tool in making this assessment: in IIH patients, an elevated opening pressure is revealed – typically >20 cm H2O in non-obese patients and >25 cm H2O in obese patients.1 CSF findings are typically within normal limits; low CSF protein may be observed in some cases but this in itself is not an unusual finding. To make a definitive diagnosis of IIH, an imaging modality is required. Again, a full workup is also important so as to rule out any other intrinsic disease process that may be responsible for elevating pressure within the cranium. The pathophysiology behind IIH remains controversial: some theorize that the increased intracranial pressure is secondary to excess CSF production3,4 or increased blood volume or brain tissue while others argue that it is due to obstruction of veins that drain blood from the brain – leading to increased venous sinus pressure.4-6 Whatever the exact mechanism may be, studies have demonstrated the role of elevated levels of GH and IGF-1 in raising intracranial pressure.7,8 Specifically, there has been evidence suggesting that IGF-1 receptors present at the level of the choroid plexus9-11 – the site of CSF production – are excessively stimulated in high GH-IGF-1 states (as seen in cases of acromegaly or HMS)9-11 leading to excess CSF production and thus increased intracranial pressure.
1668 A recent study out of Greece produced a promising result regarding the use of octreotide – a somatostatin analogue with an inhibitory effect on the GH-IGF-1 axis – in providing relief for patients suffering from IIH-associated headaches.4 It was this study that served as the basis of the treatment plan utilized in our patient described above: octreotide was shown to reduce papilledema and relieve headaches quickly as well as improve any visual disturbances reported by the patient. It is important to note that weight loss is an important element in treating patients with IIH; this was not of particular concern in our patient, whose BMI was within normal range and who had maintained a healthy weight throughout the majority of her adult life. Schneider et al12 measured IGF-1 levels in 6773 adult primary care patients and found elevated levels in 125 of those patients. Forty-nine patients underwent further evaluation: on repeat measurement of IGF-1, levels were found to be normal in 10 patients while acromegaly was diagnosed in 7 patients and excluded in 32. Elevated levels of IGF-1 are reported in very few conditions – pregnancy,13 adolescence,13 hyperthyroidism,13 acromegaly,12 and Ehlers–Danlos syndrome.10 Our patient was not pregnant during the symptomatic time period, and her thyroid-stimulating hormone levels were within normal limits. At this time, we are unaware of any studies specifically measuring IGF-1 levels in patients with IIH. Given our patient’s history of IIH and her diagnosis of HMS associated with Ehlers–Danlos syndrome, we propose a possible association between these 2 disease processes mediated primarily through the actions of IGF-1. Studies have shown increased circulating levels of IGF-1 in the serum of patients suffering from HMS associated with Ehlers–Danlos syndrome.10 As such, we hypothesize that in our patient, the elevated IGF-1 levels incidentally found on laboratory workup were not only a sign of her underlying HMS but also a mediating factor in the development of IIH. It is unclear as to what role, if any, IGF-1 plays in the pathogenesis of HMS seen in Ehlers–Danlos syndrome; this requires further investigation. There is currently an ongoing study in Denmark evaluating the effectiveness of IGF-1 in stimulating collagen synthesis among Ehlers–Danlos
November/December 2013 patients (NCT01446783), but this would – in theory, if our hypothesis is correct – initiate development of and/or worsen IIH among patients. Nevertheless, the role of IGF-1 in IIH has been demonstrated, and the association is worth consideration. Furthermore, if such an association were proven to exist, it would help promote the effectiveness and applicability of octreotide as a potential therapeutic agent in the treatment of HMS seen in Ehlers–Danlos syndrome as well as IIH. Our hope is that this case report stimulates studies on exploring this potential relationship.
CONCLUSION We present a case of HMS of Ehlers–Danlos syndrome and IIH – and present a potential mechanism for the combined syndrome mediated primarily through the effects of IGF-1. REFERENCES 1. Headache Classification Committee of the International Headache Society. The international classification of headache disorders 2nd edition. Cephalalgia. 2004;24:1-160. 2. Headache Classification Subcommittee of the International Headache Society. International classification of headache disorders 3rd edition (beta version). Cephalalgia. 2013;33:714-715. 3. Digre KB, Corbett JJ. Idiopathic intracranial hypertension (pseudotumor cerebri):A reappraisal.Neurologist. 2001;7:2-67. 4. Panagopoulos GN, Deftereos SN, Tagaris GA, et al. Octreotide: A therapeutic option for idiopathic intracranial hypertension. Neurol Neurophysiol Neurosci. 2007;Jul 10:1. 5. Corbett JJ, Digre KB. Idiopathic intracranial hypertension: An answer to, “The chicken or the egg?” Neurology. 2002;58:5-6. 6. King JO, Mitchell PJ, et al. Cerebral renography and manometry in idiopathic intracranial hypertension. Neurology. 1995;4:2224-2228. 7. Malozowski S, Tanner LA, Wysowski D, Fleming GA. Growth hormone, insulin-like growth factor I and benign intracranial hypertension. N Engl J Med. 1993;329:665-666. 8. Price A, Clayton PE, Lloyd IC. Benign intracranial hypertension induced by growth hormone treatment. Lancet. 1995;345:458-459.
Headache 9. Ichimiya Y, Emson PC, Northrop AJ, Gilmour RS. Insulin-like growth factor II in the rat choroid plexus. Brain Res. 1988;464:167-170. 10. Denko CW, Bojo B. Growth hormone, insulin, and insulin-like growth factor-1 in hypermobility syndrome. J Rheumatol. 2001;7:1666-1669. 11. Katz SE, Klisovic DD, O’Dorisio MS, Lynch R, Lubow M. Expression of somatostatin receptors 1 and 2 in human choroid plexus and arachnoid granulations. Arch Ophthalmol. 2002;120:1540-1543.
1669 12. Schneider HJ, Sieverst C, Saller B, Wittchen HU, Stalla GK. High prevalence of biochemical acromegaly in primary care patients with elevated IGF-1 levels. Clin Endocrinol (Oxf). 2008;69:432-435. 13. Freda PU. Monitoring of acromegaly: What should be performed when GH and IGF-1 levels are discrepant? Clin Endocrinol (Oxf). 2009;71:166-170.
