J Neurol (2014) 261:1957–1960 DOI 10.1007/s00415-014-7438-0

ORIGINAL COMMUNICATION

Echocardiographic findings in patients with spontaneous CSF leak Allen L. Pimienta • David L. Rimoin • Mitchel Pariani • Wouter I. Schievink Eyal Reinstein



Received: 13 May 2014 / Revised: 9 July 2014 / Accepted: 9 July 2014 / Published online: 25 July 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract The presence of cardiovascular abnormalities in patients with spontaneous cerebrospinal fluid (CSF) leaks are not well-documented in the literature, as cardiovascular evaluation is not generally pursued if a patient does not exhibit additional clinical features suggesting an inherited connective tissue disorder. We aimed to assess this association, enrolling a consecutive group of 50 patients referred for spinal CSF leak consultation. Through echocardiographic evaluation and detailed medical history, we estimate that up to 20 % of patients presenting with a spontaneous CSF leak may have some type of cardiovascular abnormality. Further, the increase in prevalence of aortic dilatation in our cohort was statistically significant in comparison to the estimated population prevalence. This supports a clinical basis for echocardiographic screening of these individuals for cardiovascular manifestations that may have otherwise gone unnoticed or evolved into a more severe manifestation.

David L. Rimoin: Deceased. A. L. Pimienta Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel D. L. Rimoin  M. Pariani Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA W. I. Schievink Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA E. Reinstein (&) The Raphael Recanati Genetics Institute, Rabin Medical Center, Petach-Tikva, Israel e-mail: [email protected]; [email protected]

Keywords Spontaneous intracranial hypotension syndrome  Spontaneous CSF leak  Aortic dilatation  Echocardiographic findings

Introduction A spontaneous CSF leak occurs when the leakage of spinal CSF is not due to a preceding dural puncture or other event that may cause a CSF fistula [1]. It is often diagnosed in patients presenting with a positional orthostatic headache, following studies confirming low CSF pressure or evidence of a CSF leak on CT myelography or MRI [2]. Spontaneous CSF leaks are under-diagnosed and frequently misdiagnosed because only a minority of patients undergo the appropriate evaluation, as headache is a commonplace complaint. The incidence of spontaneous cranial hypotension due to leak is estimated at 1:20 000, and presents more commonly in women, with a peak onset age of 40 [2]. Although the exact underlying pathogenic mechanism is unknown, an excessive fragility of the spinal dura has been suggested as a cause. Further, it has been elucidated that spontaneous CSF leaks are associated with a spectrum of connective tissue disorders (CTD) including Marfan syndrome (MFS) and Ehlers-Danlos Syndrome (EDS) [3, 4]. Cardiovascular abnormalities in patients with spontaneous CSF leaks are not well-documented in the literature as they are generally examined for only secondarily to the presence of connective tissue or neurological abnormalities. Thus, it is unknown whether cardiovascular manifestations are part of the clinical spectrum of patients presenting with spontaneous cerebrospinal fluid leaks who do not feature connective tissue or neurological abnormalities. In this study we present the echocardiographic findings in a cohort of 50 patients presenting with spontaneous CSF leaks and

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propose a potential benefit in echocardiographic follow-up with a focus on aortic dilatation.

Materials and methods We enrolled a consecutive group of 50 patients, aged 12–67, referred for consultation of a spontaneous spinal CSF leak over a two-year period at Cedars Sinai Medical Centre. All patients were diagnosed by a single expert according to previously published diagnostic criteria consisting of a. orthostatic headache; b. the presence of at least one of the following: low opening pressure, sustained improvement of symptoms after epidural blood patching, demonstration of an active spinal cerebrospinal fluid leak, cranial MRI changes of intracranial hypotension; and c. no recent history of dural puncture [5]. All patients in the cohort had brain MRI with contrast performed. Spinal imaging (CT or MR myelography) was completed in all patients with 35 showing a CSF leak. Thirty-nine patients had dural puncture with opening pressure measured and confirmation of leak on myelography. Patients were provided with oral and written information detailing the study and asking for their participation at admission to the hospital and informed consent was obtained (CSMC IRB protocol 0463). After being examined by a neurosurgeon and confirmation of a CSF leak, all patients were examined by a single medical geneticist according to the same protocol that included questions pertaining to the medical history, and clinical examination aimed on identifying skin, musculoskeletal, cardiovascular, cranio-facial and vision abnormalities. Transthoracic echocardiographic studies were performed on all patients enrolled and interpreted by cardiologists who were not aware of the clinical history of the patient at the time of interpretation. For statistical analyses, a two-proportion Z-test was used to compare the prevalence of aortic dilatation in patients with and without CSF leaks. All statistical tests and calculations were performed with SPSS version 21 (SPSS IBM, New York, USA).

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spontaneous vertebral artery dissection at age 30. She further reported that she bruises easily. On examination she had normal habitus, soft skin, and mild joint hypermobility. Sequencing of COL5A1 ? COL5A2 genes (mutated in Ehlers Danlos syndrome, classic type) and COL3A1 gene (mutated in Ehlers Danlos syndrome, vascular type) was normal. The patient was determined to have some connective tissue abnormalities, however, did not meet specific clinical criteria for a known syndrome. The patient had no family history of a connective tissue disorder. The second patient, a 26-year-old female, had a pre-existing diagnosis of Marfan syndrome, and had previously undergone replacements of the aortic root and of the mitral valve. Aortic Dilatation The cardiovascular findings observed in this cohort are compiled in Table 1. In six patients a dilatation of the aortic root was observed. Five of these six patients did not have any connective tissue abnormalities. Aortic root diameters ranged from 39-42 mm, with normal values being 31.1 ± 3.9 mm for females and 33.6 ± 4.1 mm for males [6]. Upon testing statistically significant departure from the estimated population prevalence, aortic dilatation in our cohort sufficed (p = 0.0148) at the 0.05 level on a two tailed two-proportion Z-test (b = 0.64). Valvular Abnormalities Three patients in the cohort were shown to have valvular abnormalities, two of which had a diagnosed inherited connective tissue disorder. The first patient was a 26 year old female with Marfan syndrome. The second patient, a 31 year old female with Ehlers-Danlos type II (classic type), had regurgitation of the tricuspid valve but normal aortic diameter and mitral valve. The third patient, found to have a prolapsed mitral valve, was a 12-year-old female with no history or clinical findings indicative of a connective tissue disorder.

Results Discussion Demographics Of the 50 patients enrolled in this study, 38 were women (78 %) and 12 were men (22 %), with a mean group age of 43 years (range 12-67). History of cardiovascular complications Two patients reported significant vascular complications. The first, a 35-year-old female patient had suffered a

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The primary finding of this study was the high frequency of cardiovascular abnormalities detected by echocardiographic screening in patients with CSF leaks (overall 9/50; 18 %). Six patients had dilatation of the aortic root (12 %). Although the prevalence of aortic dilatation in the general population has not been previously reported, a study from 2500 hypertensive and normotensive patients found the prevalence of aortic root dilatation to be 4.6 % [7]. Yet, the majority of the patients enrolled in the study were

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Table 1 Echocardiographic findings in patients with spontaneous CSF leak Patient

Age

Gender

Cardiovascular Anomalies

Other findings suggesting connective tissue involvement

Aortic Dilatation

Vascular rupture

Valvular Disease

Mitral Valve Prolapse

Yes, 40 mm

No

No

No

Easy bruising, slender habitus, scoliosis, myopia

1

59

Female

2

67

Male

Yes, 39 mm

No

No

No

None

3

26

Female

Yes, 39 mm

No

AR/MV replacements

Yes

Marfan syndrome

4

31

Female

No

No

Tricuspid regurgitation

No

EDS type II (Classic)

5

35

Female

No

Vertebral artery dissection

No

No

Soft skin, easy bruising, joint laxity, myopia

6

12

Female

No

No

Yes

Yes

None

7

66

Male

Yes, 39 mm

No

No

No

None

8

41

Male

Yes, 39 mm

No

No

No

None

9

52

Female

Yes, 42 mm

No

No

No

None

hypertensive and not normotensive and thus this bias should be taken into account. The prevalence of mitral valve prolapse (MVP) in the general population varies among studies, mostly due to variable criteria used for the diagnosis and varying echocardiographic techniques. One study, using the currently accepted definition of MVP, estimates the prevalence to be 2.4 % [8]. Although in this cohort we observed two patients with MVP (4 %; one of them with Marfan syndrome) this observation cannot be generalized to all patients with spontaneous CSF leaks and larger scale studies are needed. Finally, it should be highlighted that only two of the nine patients found to have cardiovascular abnormalities, have an underlying inherited disorder of connective tissue (Marfan syndrome and Ehlers-Danlos syndrome), suggesting that the association between spontaneous CSF leaks and cardiovascular abnormalities is not biased by the presence of a connective tissue disorder, but rather it is likely that these patients have another, yet unidentified predisposition for connective tissue (dural) weakness. Cardiovascular abnormalities in patients with spontaneous CSF leaks are not well-documented in the literature. Mokri et al. reported on two patients with spontaneous CSF leak and aortic dilatation, in addition to a family history of thoracic aortic aneurysms. However, neither patients nor family members underwent evaluation for the presence of a connective tissue disorder [10]. Similarly, Schievink et al. reported that the frequency of intracranial aneurysms in a group of patients with spontaneous intracranial hypotension was significantly higher than in a control population [9]. Finally, a retrospective study of 58 patients presenting with CSF leaks revealed nine patients to have some clinical features suggesting an underlying abnormality of

connective tissue. Despite limited cardiac evaluation, two patients were reported to have aortic dilatation, and a third patient had a history of bilateral internal carotid artery dissections [4]. Conversely, in a twenty patient cohort presenting with CSF leaks, four patients (20 %) exhibited minor marfanoid features, yet lacked any ocular or cardiovascular involvement [11]. The limitations of these various studies are that detailed descriptions of all patients and methods of evaluation were incomplete and the clinical evaluation protocols were not aimed to focus on cardiovascular findings. In addition, ancillary studies such as ophthalmologic examination, and genetic studies were not included. Thus, cardiovascular involvement in patients with spontaneous CSF leaks may be more extensive than recorded. There were several limitations to the current study. First, since spontaneous CSF leak is rather rare in addition to being underdiagnosed, our 50 patient cohort yields a relatively low statistical power. Such an issue can be remedied in the future, when a sufficient number of studies have been completed and compiled. Selection bias should also be considered in this study due to the fact that all recruited patients were referred for consultation. Many patients with spontaneous CSF leaks recover spontaneously without seeking a referral and thus it is possible our cohort had more severe additional manifestations. Finally, it is important to note that these patients had only one echocardiographic study performed upon admission. Thus, we cannot confirm if aortic dilatation is progressive or not. Furthermore, in the patients with normal findings, the development of a future aneurysm or valvulopathy cannot be predicted. A neurological and imaging follow-up on this cohort would therefore be ideal to solidify the results.

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In summary, although physicians should be aware of the neurological manifestations accompanying patients with spontaneous CSF leaks and the likelihood of a concurrent connective tissue disorder, there are many instances of weakness of connective tissue that may yield cardiovascular and dural abnormalities while a specific CTD diagnosis remains elusive. Therefore, we propose that these individuals with spontaneous CSF leaks whom have minor features, but do not suffice an exact CTD diagnosis, may benefit from a baseline echocardiographic screening for potential cardiovascular abnormalities that may have otherwise gone unnoticed or evolved into a more severe manifestation. For CSF leak patients with evidence of a dilated thoracic aorta, we suggest a yearly follow-up over the first 3-4 years to determine the risk of progression and rupture. This recommendation mirrors established guidelines by the ACC/AHA Guidelines for the Diagnosis and Management of Patients with Thoracic Aortic Disease, which recommends patients with an established connective tissue disorder, such as MFS, to have yearly echocardiographic follow-up once aortic dilatation is demonstrated [12]. For patients with a normal initial echocardiogram, a less strict protocol can be introduced with follow-up exams in two and five year intervals as their risk of development is still likely higher than in the general population. Acknowledgments The authors bear full responsibility for the content of this publication. Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standard All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Appendix ðp1  p2Þ Z ¼ qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 1 1 pð1  pÞðn1 þ n2 Þ 0:12  0:046 Z ¼ qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ¼ 2:44; 1 1 0:0475ð1  0:0475Þð50 þ 2451 Þ p ¼ 0:01468

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References 1. Liu FC, Fuh JL, Wang YF, Wang SJ (2010) Connective tissue disorders in patients with spontaneous intracranial hypotension. Cephalalgia 31(6):691–695 2. Schievink WI (2006) Spontaneous Spinal Cerebrospinal Fluid Leaks and Intracranial Hypotension. JAMA 295(19):2286–2296 3. Reinstein E, Pariani M, Bannykh S, Rimoin DL, Schievink WI (2012) Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study. EJHG 4:386–390 4. Mokri B, Maher CO, Sencakova D (2002) Spontaneous CSF leaks: Underlying disorder of connective tissue. Neurology 58:814–816 5. Schievink WI, Maya MM, Louy C, Moser FG, Tourje J (2008) Diagnostic criteria for spontaneous spinal CSF leaks and intracranial hypotension. Am J Neuroradiol 29:853–856 6. Mao SS, Ahmadi N, Shah B et al (2008) Normal thoracic aorta diameter on cardiac computed tomography in healthy asymptomatic adults: impact of age and gender. Acad Radiol 15:827–834 7. Palmieri V, Bella JN, Arnett DK et al (2001) Aortic root dilatation at sinuses of valsalva and aortic regurgitation in hypertensive and normotensive subjects: The hypertension genetic epidemiology network study. Hypertension 37:1229–1235 8. Freed LA, Levy D, Levine RA, Larson MG, Evans JC et al (1999) Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med 341:1–7 9. Schievink WI, Maya MM (2011) Frequency of intracranial aneurysms in patients with spontaneous intracranial hypotension. J Neurosurg 115(1):113–115 10. Mokri B (2008) Familial occurrence of spontaneous spinal CSF leaks: Underlying connective tissue disorder. Headache 48:146–149 11. Schrijver I, Schievink WI, Godfrey M, Meyer FB, Francke U (2002) Spontaneous spinal cerebrospinal fluid leaks and minor skeletal features of Marfan syndrome: a microfibrillopathy. J Neurosurg 96:483–489 12. Hiratzka LF, Bakris GL, Beckman JA et al (2010) ACCF/AHA/ AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation 2010(121):e266–e369

Echocardiographic findings in patients with spontaneous CSF leak.

The presence of cardiovascular abnormalities in patients with spontaneous cerebrospinal fluid (CSF) leaks are not well-documented in the literature, a...
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