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Spontaneous cerebrospinal fluid leak
SpecialtyNeurology Edit this on Wikidata

Spontaneous cerebrospinal fluid leak syndrome (SCSFLS) is a medical condition in which the cerebrospinal fluid (CSF) held in and around a human brain and spinal cord leaks out of the surrounding protective sac, the dura, for no apparent reason. The dura, a tough, inflexible tissue, is the outermost of the three layers of the meninges, the system of meninges surrounding the brain and spinal cord. (The other two meningeal layers are the pia mater and the arachnoid mater).

A spontaneous cerebrospinal fluid leak is one of several types of cerebrospinal fluid leaks and occurs due to the presence of one or more holes in the dura. A spontaneous CSF leak, as opposed to traumatically caused CSF leaks, arises idiopathically. A loss of CSF greater than its rate of production leads to a decreased volume inside the skull known as intracranial hypotension. A CSF leak is most often characterized by a severe and disabling headache and a spectrum of various symptoms which occur as a result of intracerebral hemorrhage (ICH). These symptoms can include: dizziness, nausea, fatigue, a metallic taste in the mouth (indicative of a cranial leak), myoclonus, tinnitus, tingling in the limbs, and facial weakness amongst others. A CT scan can identify the site of a cerebrospinal fluid leakage. Once identified, the leak can often be repaired by an epidural blood patch, an injection of the patient's own blood at the site of the leak, fibrin glue injection or surgery.

SCSFLS afflicts 5 out of every 1,000 people. On average, the condition is developed at the age of 42, and women are twice as likely as men to develop the condition. Some people with SCSFLS chronically leak cerebrospinal fluid despite repeated attempts at patching, leading to long-term disability due to pain and nerve damage. SCSFLS was first described by German neurologist Georg Schaltenbrand in 1938 and by American physician Henry Woltman of the Mayo Clinic in the 1950s.

Classification

SCSFLS is classified into two main types, cranial leaks[1] and spinal leaks.[2] Cranial leaks occur in the head. In some cases, CSF can be seen dripping out of the nose,[3][4] or ear.[1] Spinal leaks occur when one or more holes form in the dura along the spinal cord.[2] Both cranial and spinal spontaneous CSF leaks cause neurological symptoms as well as spontaneous intracranial hypotension, diminished volume and pressure of the cranium.[5] While referred to as intracranial hypotension the intracranial pressure may be normal, but low-volume CSF is instead the underlying issue. For this reason SCSFLS is referred to as CSF hypovolemia as opposed to CSF hypotension.[6][7][8][9]

Signs and symptoms

Symptoms resulting from nerve impact[10]
Nerve Function Symptoms
optic
(2)		 optic nerve
crossing		 blurred and or
double vision
chorda tympani
(Branch of 7)		 taste taste distortion
facial
(7)		 facial nerve facial weakness
and numbness
vestibulocochlear
(8)		 hearing,
balance		 hearing and
balance problems
glossopharyngeal
(9)		 taste taste distortion

Most people who develop SCSFLS feel a sudden onset of a severe and acute headache.[9][11] It is a headache usually but not necessarily orthostatic in nature, typically becoming prominent throughout the day, in which usually the pain is worse when the person is vertical and less severe when horizontal.[12] Other symptoms include dizziness and vertigo, facial numbness or weakness, unusually blurry or double vision, neuralgia, fatigue, a metallic taste in the mouth, nausea, or vomiting.[9] Leaking CSF can sometimes be felt or observed as discharge through the nose or ear.[13] Orthostatic headaches can be incapacitating;[14][15] these ailments often become chronic and can be sufficiently disabling to make those afflicted unable to work.[9][15][16] Some patients with CSF leak will develop headaches that begin in the afternoon. This is known as second-half-of-the-day headache. This may be an initial presentation of CSF leak or appear after treatment and likely indicates a slow CSF leak.[17]

Lack of CSF pressure and volume allows the brain to descend through the foramen magnum, or occipital bone, the large opening at the base of the skull. The lower portion of the brain is believed to stretch or impact one or more cranial nerve complexes, thereby causing a variety of sensory symptoms. Nerves that can be affected and their related symptoms are detailed in the table at right.[9][10][16]

Causes

The two main theories as to the underlying cause of SCSFLS are as a result of a connective tissue disorder or spinal drainage problems.

Connective Tissue Theory

A spontaneous CSF leak is idiopathic; it can arise spontaneously or from an unknown cause.[16][18] Various scientists and physicians have suggested that this condition may be the result of an underlying connective tissue disorder affecting the spinal dura.[9][10][19][20] It may also run in families and be associated with aortic aneurysms and joint hypermobility.[10][21] Up to two thirds of those afflicted demonstrate some type of generalized connective tissue disorder.[10][20] Marfan syndrome, Ehlers-Danlos syndrome and autosomal dominant polycystic kidney disease are the three most common connective tissue disorders associated with SCSFLS.[10]

Roughly 20% of patients with SCSFLS exhibit features of Marfan syndrome, including tall stature, chest divot (pectus excavatum), joint hypermobility and arched palate. However these patients do not exhibit any other Marfan syndrome presentations.[10]

Spinal Drainage Theory

Some other studies have proposed that issues with the spinal venous drainage system may cause a CSF leak.[22] According to this theory, dural holes and intracranial hypotension are symptoms caused by low pressure in the epidural space due to outflow to the heart through the inferior vena cava vein.[22]

Other causes

Patients with a nude (absent) nerve root are at increased risk for developing recurrent CSF leaks.[23] Cranial CSF leaks are as a result of intracranial hypertension in a vast majority of cases. The increased pressure causes a rupture of the cranial dura mater, leading to CSF leak and intracranial hypotension.[24][25] Lumbar disc herniation has been reported to cause CSF leak in at least one case.[26] Degenerative spinal disc diseases cause a disc to pierce the dura mater, leading to a CSF leak.[10]

Another view of the cause of orthostatic headaches proposes a malformed distribution of craniospinal elasticity as a result of the collapse of the lower spine's CSF space resulting in the collapse of the dura sac.[10]

Pathophysiology

Cerebrospinal fluid is produced by the choroid plexus in the brain and contained by the dura and arachnoid layers of the meninges.[9][19][27] The brain floats in CSF, which also transports nutrients to the brain and spinal cord. As holes form in the spinal dura mater, CSF leaks out into the surrounding space. The CSF is then absorbed into the spinal epidural venous plexus or soft tissues around the spine.[10][28] Due to the sterile conditions of the soft tissues around the spine there is no risk of meningitis.[10]

Diagnosis

The primary place of first complaint to a physician is a hospital emergency room.[11][29] Up to 94% of those suffering from SCSFLS are initially misdiagnosed. Incorrect diagnoses include migraines, meningitis, and psychiatric disorders. The average time from onset of symptoms until definitive diagnosis is 13 months.[30] A study found a 0% success rate for proper diagnosis in the emergency department.[29]

Diagnosis of CSF leak can be done through various imaging techniques, chemical tests of bodily fluid discharged from a head orifice, or clinical exam. The use of CT, MRI, and assays are the most common types of CSF leak instrumental tests. Many CSF leaks are occult and do not show up on imaging and chemical assays, thus such diagnostic tools are not definitive to rule out CSF leaks. A clinician may often depend upon patient history and exam to diagnose, for example: discharge of excessive amount of clear fluid from the nose upon bending over, the increase in headache following a Valsalva maneuver or the reduction of headache when the patient takes a prone position are positive indicators.

As most candidates for CSF leak do not have access to imaging and laboratory tools (modern medicine), clinical exam is the most often used means to diagnose CSF leaks. Improved patient response to conservative treatment may further define a positive diagnosis. The lack of clinician awareness of the signs -symptoms and ailments- of a CSF leak is the greatest challenge to proper diagnosis and treatment, in particular: the loss of the orthostatic characteristic of headache and that every chronic CSF leaker will have a unique symptom set which as a whole contributes to the underlying condition, and diagnosis of, a CSF leak.

CT

A typical CT scan machine used in the imaging and diagnosis of spinal fluid leak by using non-ionic contrast

Diagnosis of a cerebrospinal fluid leak is performed through a combination of measurement of the CSF pressure and a computed tomography myelogram (CTM) scan of the spinal column for fluid leaks.[10] The opening fluid pressure in the spinal canal is obtained by performing a lumbar puncture, also known as a spinal tap. Once the pressure is measured, radiopaque contrast material is injected into the spinal fluid. The contrast then diffuses out through the dura sac before leaking through dural holes. This allows for a CTM with fluoroscopy to locate and image any sites of dura rupture via contrast seen outside the dura sac in the imagery.[9][13][19]

MRI

Magnetic resonance imaging is historically less effective at directly imaging sites of CSF leak. MRI studies may show pachymeningeal enhancement (when the dura mater looks thick and inflamed) and an Arnold-Chiari malformation in many, but not all, cases.[10] An Arnold-Chiari malformation occurs when the brain sags and has a downward displacement due to the decreased volume and buoyancy of cerebrospinal fluid in which the brain floats.[10] MRIs can present as completely normal, however, and are not the study of choice.[10][19] An alternate method of locating the site of a CSF leak is to use heavily T2-weighted MR myelography.[10] This has been effective in identifying the sites of a CSF leak without the need for a CT scan, lumbar puncture, and contrast and at locating fluid collections such as CSF pooling.[31] MRIs done on patients sitting upright demonstrated no difference in MRI results compared to those lying down.[29] The use of intrathecal contrast and MR Myelography is also an alternative method of locating CSF leaks with a very high degree of success.[10]

Assay

When cranial CSF leak is suspected because of discharge from the nose or ear that is potentially CSF, the fluid can be collected and tested with a beta-2 transferrin assay.[32] This test can positively identify if the fluid is cerebrospinal fluid.[32]

CSF analysis

Spinal needles used in lumbar puncture and introduction of contrast into the spine

Patients with CSF leak have been noted to have very low or even negative opening pressures. However, patients with confirmed CSF leaks may also demonstrate completely normal opening pressures. In 18–46% of cases, the CSF pressure is measured within the normal range.[10][33][34][35] Analysis of spinal fluid may demonstrate lymphocytic pleocytosis and elevated protein content or xanthochromia. This is hypothesized to be due to increased permeability of dilated meningeal blood vessels and a decrease of CSF flow in the lumbar subarachnoid space.[10]

Clinical presentation

The diagnostic criteria for SCSFLS is based on the 2004 International Classification of Headache Disorders, 2nd edn (ICHD-II) (Table 1) (50) criteria. However, the presentation of patients with confirmed diagnosis may be very different from that of the clinical diagnostic criteria and cannot be considered authoritative.[10]

Treatment

Epidural Blood Patch

The epidural syringe is filled with autologous blood and injected in the epidural space in order to close holes in the dura mater.

The treatment of choice for this condition is the surgical application of epidural blood patches,[14][36][37] which has a 90% success rate in treating dural holes;[16][38] a rate higher than that of a conservative treatment of bed rest and hydration.[39] Through the injection of a person's own blood into the area of the hole in the dura, an epidural blood patch uses blood's clotting factors to clot the sites of holes. The volume of autologous blood and number of patch attempts for patients is highly variable.[14] One quarter to one third of SCSFLS patients do not have relief of symptoms from epidural blood patching.[10]

Fibrin glue sealant

If blood patches alone do not succeed in closing the dural tears, placement of percutaneous fibrin glue can be used in place of blood patching, raising the effectiveness of forming a clot and arresting CSF leakage.[2][10][10][40]

Surgical drain technique

In extreme cases of intractable CSF leak, a surgical lumbar drain has been used.[41][42][43] This procedure is believed to decrease spinal CSF volume while increasing intracranial CSF pressure and volume.[41] This procedure restores normal intracranial CSF volume and pressure while promoting the healing of dural tears by lowering the pressure and volume in the dura.[41][43] This procedure has led to positive results leading to relief of symptoms for up to one year.[41][42]

Neurosurgical repair

For patients who do not respond to either epidural blood patching or fibrin glue, neurosurgery is available to directly repair leaking meningeal diverticula. The areas of dura leak can be tied together in a process called ligation and then a metal clip can be placed in order to hold the ligation closed.[10] Alternatively, a small compress called a muscle pledget can be placed over the dura leak and then sealed with gel foam and fibrin glue.[10] Primary suturing is rarely able to repair a CSF leak and in some patients exploration of the dura may be required to properly locate all sites of CSF leak.[10]

Other treatments

The use of an abdominal binder has also been employed as a treatment.[10]

Prognosis

Final outcomes for people with SCSFLS remain poorly studied.[10] Some of those afflicted continue to leak CSF from one or more sites and may suffer from unremitting symptoms for many years.[9][19][44] People with chronic SCSFLS may be disabled and unable to work.[10][15] Recurrent CSF leak at an alternate site after recent repair is common.[45]

Complications

Several complications can occur as a result of SCSFLS including decreased cranial pressure, brain herniation, infection, blood pressure problems, transient paralysis, and coma.The primary and most serious complication of SCSFLS is spontaneous intracranial hypotension, where pressure in the brain is severely decreased.[9][19][46] This complication leads to the hallmark symptom of severe orthostatic headaches.[10][46]

People with cranial CSF leaks have a higher chance of developing meningitis than those with spinal CSF leaks.[32] Additionally, if cranial leaks last more than seven days, the chances of developing meningitis are significantly higher.[32] Spinal CSF leaks do not usually result in meningitis due to the mostly aseptic conditions of the spinal dura.[32] When a CSF leak occurs at the temporal bone surgery becomes necessary in order to prevent infection and repair the leak.[47] Orthostatic hypotension is another complication which occurs due to autonomic dysfunction when blood pressure drops significantly.[44] The autonomic dysfunction is caused by compression of the brain stem, which controls breathing and circulation.[44]

Arnold-Chiari malformation is a complication of spontaneous CSF leak, where brain tissue moves down through the opening at the base of the skull due to low volume and pressure of CSF

An Arnold-Chiari malformation is a downward displacement of lower parts of the brain through the skull opening that occurs due to a lack of CSF volume and pressure. A further, albeit rare, complication of CSF leak is transient quadriplegia due to a sudden and significant loss of CSF. This loss results in hindbrain herniation and causes major compression of the upper cervical spinal cord. The quadriplegia dissipates once the patient lays supine.[48][48] An extremely rare complication of SCSFLS is third nerve palsy, where the ability to move one's eyes becomes difficult and interrupted due to compression of the third cranial nerve.[49] Although other sources consider 3rd nerve palsy a common manifestation of CSF leaks. [50]

There are documented cases of reversible frontotemporal dementia and coma.[51] Coma due to a CSF leak has been successfully treated by using blood patches and/or fibrin glue and placing the patient in the Trendelenburg position.[52] Empty sella syndrome, a boney structure that surround the pituitary gland, occurs in CSF leak patients.[24][53]

Epidemiology

A 1994 community-based study indicated that two out of every 100,000 people suffered from SCSFLS, while a 2004 emergency room-based study indicated five per 100,000.[10][19] SCSFLS generally affects the young and middle aged;[41] the average age for onset is 42.3 years, but onset can range from ages 22 to 61.[54] In an 11-year study women were found to be twice as likely to be affected as men.[55][56]

Studies have shown that SCSFLS runs in families and it is suspected that genetic similarity in families includes weakness in the dura mater, which leads to SCSFLS.[10][57] Large scale population-based studies have not yet been conducted.[19] While a majority of SCSFLS cases continue to be undiagnosed or misdiagnosed, an actual increase in occurrence is unlikely.[19]

History

Spontaneous CSF leaks have been described by notable physicians and reported in medical journals dating back to the early 1900s.[58][59] German neurologist Georg Schaltenbrand reported in 1938 and 1953 what he termed "aliquorrhea", a condition marked by very low, unobtainable, or even negative CSF pressures. The symptoms included orthostatic headaches and other features that are now recognized as spontaneous intracranial hypotension. A few decades earlier, the same syndrome had been described in French literature as "hypotension of spinal fluid" and "ventricular collapse". In 1940, Henry Woltman of the Mayo Clinic wrote about "headaches associated with decreased intracranial pressure". The full clinical manifestations of intracranial hypotension and CSF leaks were described in several publications reported between the 1960s and early 1990s.[59] Modern reports of spontaneous CSF leak have been reported to medical journals since the late 1980s.[60]

Research and experimental treatments

IV Cosyntropin, a corticosteroid that causes the brain to produce additional spinal fluid to replace the volume of the lost CSF and alleviate symptoms, has been used to treat CSF leaks.[61][62]

In two small studies of two patients and another with one patient who suffered from recurrent CSF leaks where repeated blood patches failed to form clots and relieve symptoms, the patients received temporary but complete resolution of symptoms with an epidural saline infusion.[63][64] The saline infusion temporarily restores the volume necessary for a patient to avoid SIH until the leak can be repaired properly.[10] Intrathecal saline infusion is used in urgent cases such as intractable pain or decreased consciousness.[10]

The gene TGFBR2 has been implicated in several connective tissue disorders including Marfan syndrome, arterial tortuosity and thoracic aortic aneurysm. A study of patients with SCSFLS demonstrated no mutations in this gene.[10] Minor features of Marfan syndrome has been found in 20% of CSF leak patients. Abnormal findings of fibrillin-1 has been documented in these CSF leak patients but only one patient demonstrated a fibrillin-1 defect consistent with Marfan syndrome.[10][65]

See also

References

  1. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18710972, please use {{cite journal}} with |pmid=18710972 instead.
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  3. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17211180, please use {{cite journal}} with |pmid=17211180 instead.
  4. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 14750917, please use {{cite journal}} with |pmid=14750917 instead.
  5. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16859268, please use {{cite journal}} with |pmid=16859268 instead.
  6. ^ Greenberg, Mark (2006). Handbook of neurosurgery. New York, NY: Thieme Medical Publishers. p. 178. ISBN 0-86577-909-0. Retrieved 18 December 2009. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help)
  7. ^ Neil R. Miller; William Fletcher Hoyt (2005). Walsh and Hoyt's clinical neuro-ophthalmology. Lippincott Williams & Wilkins. pp. 1303–. ISBN 978-0-7817-4811-7. Retrieved 8 November 2010.
  8. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 10560599, please use {{cite journal}} with |pmid=10560599 instead.
  9. ^ a b c d e f g h i j Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16859269, please use {{cite journal}} with |pmid=16859269 instead.
  10. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19037970, please use {{cite journal}} with |pmid=19037970 instead.
  11. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17901290, please use {{cite journal}} with |pmid=17901290 instead.
  12. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19012477, please use {{cite journal}} with |pmid=19012477 instead.
  13. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19636501, please use {{cite journal}} with |pmid=19636501 instead.
  14. ^ a b c Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19495908, please use {{cite journal}} with |pmid=19495908 instead.
  15. ^ a b c Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19415418, please use {{cite journal}} with |pmid=19415418 instead.
  16. ^ a b c d Victor, Maurice; Ropper, Allan H.; Adams, Raymond Delacy; Brown, Robert F. (2005). Adams and Victor's principles of neurology. New York: McGraw-Hill Medical Pub. Division. pp. 541–543. ISBN 0-07-141620-X.{{cite book}}: CS1 maint: multiple names: authors list (link)
  17. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21811806, please use {{cite journal}} with |pmid=21811806 instead.
  18. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17698794, please use {{cite journal}} with |pmid=17698794 instead.
  19. ^ a b c d e f g h i Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16705110, please use {{cite journal}} with |pmid=16705110 instead.
  20. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21220378, please use {{cite journal}} with |pmid= 21220378 instead.
  21. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18184297, please use {{cite journal}} with |pmid=18184297 instead.
  22. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19591547, please use {{cite journal}} with |pmid=19591547 instead.
  23. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 14580290, please use {{cite journal}} with |pmid=14580290 instead.
  24. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19225307, please use {{cite journal}} with |pmid=19225307 instead.
  25. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 12962187, please use {{cite journal}} with |pmid=12962187 instead.
  26. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 20157378, please use {{cite journal}} with |pmid=20157378 instead.
  27. ^ Michael Schuenke; Udo Schumacher; Erik Schulte (2007). Head and neuroanatomy. Thieme. ISBN 978-3-13-142101-2. Retrieved 8 November 2010. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  28. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16934734, please use {{cite journal}} with |pmid=16934734 instead.
  29. ^ a b c Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18071632, please use {{cite journal}} with |pmid=18071632 instead. Cite error: The named reference "Schievink2007" was defined multiple times with different content (see the help page).
  30. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 14676045, please use {{cite journal}} with |pmid=14676045 instead.
  31. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19949036, please use {{cite journal}} with |pmid=19949036 instead.
  32. ^ a b c d e Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17767107, please use {{cite journal}} with |pmid=17767107 instead.
  33. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15111706, please use {{cite journal}} with |pmid=15111706 instead.
  34. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15249640, please use {{cite journal}} with |pmid=15249640 instead.
  35. ^ Mark S. Greenberg (2006). Handbook of neurosurgery. Thieme. pp. 178–. ISBN 978-3-13-110886-9. Retrieved 8 November 2010.
  36. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18380287, please use {{cite journal}} with |pmid=18380287 instead.
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  49. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18726726, please use {{cite journal}} with |pmid=18726726 instead.
  50. ^ "Chronic Daily Headache for Clinicians".
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