Spontaneous CSF leaks: Underlying disorder of connective tissue

Methods and patients.

We reviewed the records of 58 consecutive patients with spontaneous CSF leaks evaluated at our institution for clinical evidence of a connective tissue disorder. We identified nine patients (seven women and two men) with findings on history or examination suggestive of a disorder of connective tissue. Follow-up was obtained in all cases through correspondence, telephone calls, referring physician’s reports, or patient evaluation. Age ranged from 11 to 62 years. Mean age was 37 years. All patients had undergone head MRI, including gadolinium-enhanced images, and all had undergone CT myelography. A spine MRI had been done in six patients, and Indium-111 cisternography had been done in five.

Results.

In all nine cases, the primary complaint was severe headache with orthostatic features. CSF opening pressure on lumbar punctures was low in six patients, within normal limits in two patients, and unrecorded in one patient. All patients had undergone gadolinium-enhanced head MRI. Diffuse pachymeningeal gadolinium enhancement was noted in all, and MR evidence of sagging of the brain was seen in eight. One patient had bilateral subdural fluid collections. CT myelography in each patient had demonstrated a CSF leak. In the five patients who had undergone radioisotope cisternography, paucity or absence of activity over the cerebral convexities and early appearance of activity in the kidneys and urinary bladder were noted in all, and CSF leaks were identified in four. Meningeal diverticula were demonstrated by CT myelography and sometimes also by spine MRI or radioisotope cisternography in seven patients. These were single in three patients and multiple in four patients. Overall, the level of the leak was identified in all patients (cervical spine level in two, thoracic spine level in six, and lumbar level in one). The actual site of the leak was identified in six patients. Seven patients had a single site of CSF egress, and one had multiple sites. One patient with a single site of CSF egress from a large diverticulum at T₁₂ became asymptomatic after surgical repair of the leak. She later became symptomatic again after a fall from a flight of stairs and was noted to have a CSF leak at a different site (T₁ level).

The signs of connective tissue disorder noted in these patients are listed in the table and are partly illustrated in figures 1 and 2⇓.

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Figure 1. Myelogram (A) and CT myelogram (B) in Patient 1 demonstrating a meningeal diverticulum at the T₁₂-L₁ interspace level. The egressed contrast material is well seen (arrows). The denser appearing intrathecal contrast is marked by asterisks (C). Panels D and E demonstrate the patient’s joint hyperflexibility.

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Figure 2. (A) CT myelogram demonstrating the egressed extra-arachnoid fluid (arrows) in Patient 8. (B) On head MRI, this patient was also noted to have bilateral internal carotid artery dissections (arrows).

One patient responded to conservative management, although she has been left with chronic lingering but tolerable headaches. Three patients were treated surgically, with one of them requiring subsequent epidural blood patches. All finally became asymptomatic. The remaining four patients were treated with epidural blood patches. One required subsequent surgery, and another who had failed three epidural blood patches responded to epidural infusion of saline.

Discussion.

The etiology of spontaneous CSF leak often remains undetermined. In a substantial minority of patients, there is a history of a trivial or minor trauma. The overwhelming majority of spontaneous CSF leaks are at the level of the spine.1 Some patients display structural spinal dural abnormalities, including single or multiple meningeal diverticula or dilatation of nerve root sleeves. At surgery, patches of attenuated or even absent dura have been noted in some patients (D.G. Piepgras, J.L.D. Atkinson, personal communication, 1995). Some disorders of connective tissue are known to be associated with meningeal abnormalities. Meningeal diverticula are also known to occur in Marfan’s syndrome, neurofibromatosis, autosomal dominant polycystic kidney disease, and familial osteosclerosis.2-4⇓⇓ Furthermore, spontaneous CSF leak has been reported in Marfan’s syndrome,2 and it has been demonstrated that patients with Marfan’s syndrome also show a high incidence of dural sac ectasia. In a study of 83 patients with Marfan’s syndrome who had undergone MRI of the thoracic aorta and lumbosacral spine, 76 (92%) demonstrated dural ectasia,5 although none of the 100 individuals who had undergone MRI of the lumbar spine for routine clinical indications demonstrated this abnormality. Mutations in the coding of gene for fibrillin-1 have been shown in patients with Marfan’s syndrome.6 Fibrillin acts as a scaffolding for deposition of tropoelastin and is essential in maturation of elastin fibers. Mutations in different domains of the gene are likely responsible for the variable phenotypic expression of the syndrome. Furthermore, other inherited fibrillinopathies may manifest clinically with some of the features of Marfan’s syndrome.7 Six of our nine patients had hyperflexible joints; of these six patients, four were tall and slender, four had arachnodactyly, and two had hyperextensible skin. Additional features noted in some of these patients included pectus excavatum, high arched palate, mitral valve prolapse, and dilated aortic root. One of these patients had a strong family history of abdominal aorta aneurysm (four family members). Only one of these six patients had been diagnosed with Marfan’s syndrome (Patient 6; see the table). Two of our patients had spontaneous retinal detachment at a young age. Spontaneous retinal detachment has been reported in several connective tissue disorders such as Marfan’s syndrome, Ehlers-Danlos syndrome, and osteogenesis imperfecta.1,8⇓ One patient had additional bilateral spontaneous internal carotid artery (ICA) dissections. Carotid or vertebral artery dissections also have been noted in inherited disorders of connective tissue, including Marfan’s syndrome, Ehlers–Danlos, pseudoxanthoma elasticum, and osteogenesis imperfecta.9 Abnormal or deficient elastin, fibrillin, or both have been noted in cultured dermal fibroblasts some patients with spontaneous ICA dissections, especially in patients with multivessel dissections. Ultrastructural abnormalities of collagen and elastin have been demonstrated in patients with carotid dissections.10 The occurrence of ICA dissection and spontaneous CSF leak in one of our patients is likely more than just a coincidence. The previous observations suggest that in at least some patients with spontaneous CSF leaks, a disorder of connective tissue exists that likely leads to dural weakness. The referral pattern to our institution and patient selectivity should be considered, however. A prospective study to further address this hypothesis is warranted. Furthermore, analysis of collagen and, particularly, fibrillin and elastin in cultured dermal fibroblasts or ultrastructural studies of collagen and elastin fibers in skin biopsies from patients with spontaneous CSF leaks may provide additional evidence on the presence of connective tissue abnormalities in some patients.