Accepted Manuscript Spontaneous intracranial hypotension: Characteristics of the serious form in a series of 24 patients Aïcha Lyoubi Idrissi, Jean-Christophe Lacour, Olivier Klein, Emmanuelle Schmitt, Xavier Ducrocq, Sébastien Richard PII:
S1878-8750(15)00868-2
DOI:
10.1016/j.wneu.2015.07.002
Reference:
WNEU 3029
To appear in:
World Neurosurgery
Received Date: 30 April 2015 Revised Date:
3 July 2015
Accepted Date: 4 July 2015
Please cite this article as: Idrissi AL, Lacour J-C, Klein O, Schmitt E, Ducrocq X, Richard S, Spontaneous intracranial hypotension: Characteristics of the serious form in a series of 24 patients, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Spontaneous intracranial hypotension: Characteristics of the serious form in a series of 24 patients Running title: Serious form of spontaneous intracranial hypotension Aïcha Lyoubi Idrissia, Jean-Christophe Lacoura, Olivier Kleinb, Emmanuelle Schmittc, Xavier
a
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Ducrocqa, Sébastien Richarda .
Department of Neurology, University Hospital of Nancy, 29 avenue du Marechal de Lattre
b
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de Tassigny-CO n° 34 54035 NANCY Cedex, France.
Department of Neurosurgery, University Hospital of Nancy, 29 avenue du Marechal de
c
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Lattre de Tassigny-CO n° 34 54035 NANCY Cedex, France.
Department of Neuroradiology, University Hospital of Nancy, 29 avenue du Marechal de
Lattre de Tassigny-CO n° 34 54035 NANCY Cedex, France.
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Corresponding author
Dr Sébastien Richard. CHU Nancy, Department of Neurology, Email: [email protected]
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tel +33.3.83.85.16.56. fax +33.3.83.85.11.59.
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[email protected]; [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Keywords Cerebrospinal fluid leak, epidural blood patch, orthostatic headache, severity, spontaneous intracranial hypotension, subdural hematoma.
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ACCEPTED MANUSCRIPT Abstract Background: Recommended treatments for spontaneous intracranial hypotension (SIH) range from bed rest only to neurosurgery. However, the serious form of SIH is poorly defined. A better description of patient characteristics and their outcome may help define therapeutic
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options.
Methods: We reviewed 24 cases of patients with SIH and separated them into two groups according to whether or not they presented with signs of severity at admission: disturbance of
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consciousness, subdural hematomas (SDHs) and cerebral venous thrombosis.
Results: Nine patients (37%) were classified as having a serious form of SIH: six (25%)
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presented SDHs; three (12%) disturbance of consciousness; and one (4%) cerebral venous thrombosis. Bed rest and epidural blood patches (EBPs) were sufficient to treat all patients in the non-serious form group and four patients in the serious form group. Two patients (8%) had to undergo cerebrospinal fluid leak repair, and three others (12%) evacuation of SDHs.
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Outcome was good in both groups, with only one (4%) death due to extensive SDHs. Times to diagnosis in the serious form group (63 vs. 35 days, p=0.052), and to recovery (9 months vs. 5 months, p=0.088) tended to be higher without reaching difference.
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Conclusions: The presence of SDHs, disturbance of consciousness and a trend toward a longer time to diagnosis and recovery seem to define the serious form of SIH. These patients
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may require exploration and surgical repair of cerebrospinal fluid leak, only after failure of conservative measures - bed rest and time - and EBP, with good outcome.
Keywords Cerebrospinal fluid leak, epidural blood patch, orthostatic headache, severity, spontaneous intracranial hypotension, subdural hematoma.
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ACCEPTED MANUSCRIPT Introduction Even if spontaneous intracranial hypotension (SIH) is usually described as benign (32), it can lead to severe complications such as subdural hematoma (SDH) (6, 16), cerebral venous thrombosis (CVT) and (28, 35), exceptionally, to death (33). A clear definition of the serious
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form of SIH may help to choose the best treatment which ranges from bed rest to neurosurgery. We set out to describe the characteristics and outcome of patients with SIH
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according to whether they presented with or without signs of severity at admission.
Material and methods
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We reviewed 24 consecutive cases of patients with SIH who were admitted to the department of Neurology of the University Hospital of Nancy in France from February 1993 to April 2011. Patients were included if they met the following criteria: 1) orthostatic headache; 2) the presence of at least one of the following: a) sustained improvement of symptoms after
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epidural blood patch (EBP), b) active cerebrospinal fluid (CSF) leak, c) brain magnetic resonance imaging (MRI) changes of intracranial hypotension (brain sagging or pachymeningeal enhancement); 3) no recent history of dural puncture before symptom onset;
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4) the symptoms were not attributable to another disorder (34). Demographic characteristics, clinical features, results of investigations (cerebral MRI, radiological procedures to identify
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CSF leak, and CSF analysis), treatments administered (conservative measures, EBPs, surgical repairs of CSF leak, and surgical evacuation of SDH) and outcome were collected by review of medical charts. Brain MRI performed at diagnosis were re-examined to assess brain sagging and pachymeningeal enhancement. Brain sagging was defined as the presence of one of the following signs on MRI (32): downward displacement of the brain, effacement of perichiasmatic cisterns with bowing of the optic chiasm over the pituitary fossa, effacement of the prepontine cistern with flattening of the pons against the clivus and descent of the
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ACCEPTED MANUSCRIPT cerebellar tonsils. Patients were classified into two groups depending on whether they presented signs of severity (defined as altered level of consciousness, SDH and CVT) or not at admission. This was an observational study without any intervention on a human being. All
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presented data are anonymized.
Results
The population consisted of eight men and sixteen women with an age ranging from 25 to 70
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years (Table1). All patients presented a recent history of headache. Location was occipital or cervical in nine cases, frontal in six, temporal in two and undefined in seven. The most
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common associated symptoms were nausea (75%), neck stiffness (71%) and hearing disturbances (46%). All symptoms presented orthostatic features. CSF examination was performed in twelve cases with a protein level ranging from 50 to 3900 mg/dL, and pleiocytosis observed in ten patients, ranging from 5 to 59 cells/µL, mostly lymphocytes.
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Brain MRI was performed in 23 patients with both diffuse pachymeningeal enhancement and brain sagging observed in twenty patients (87%). Spinal MRI was performed in 16 patients (67%) and showed evidence of CSF leak in two. Radioisotope cisternography was performed
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in eight patients (33%) and showed direct signs of leakage in five. Three of these underwent a spinal MRI that located the CSF leak site in one. Bed rest was applied in all patients. Fifteen
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patients (63%) without signs of severity, were diagnosed after a mean interval of 35 days following the beginning of symptoms, and became symptom-free after a mean interval of 5 months (Table 2). Bed rest only was sufficient in eight cases of this group (53%) and EBPs were performed in the other seven cases (47%) with repeated injections in three. Nine patients (37%) had signs of severity, with a mean time to diagnosis of 63 days. Three patients (12%) presented altered levels of consciousness. Six (25%) presented SDH: one treated with bed rest only, one with bed rest and EBP only, one with identified and surgically repaired CSF leak,
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ACCEPTED MANUSCRIPT and surgical evacuation in the three others (12%) with one (4%) death. A CVT was observed in one patient (4%) and treated with anticoagulant therapy. Bed rest and EBP were a sufficient treatment for four patients in this group. Mean time to first EBP was 94 days in the serious form group against 38 days in the non-serious form group. Clinical outcome was good for all
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patients, except for one, with complete or near complete resolution of symptoms after a mean interval of 9 months. One patient died: the only one presenting both SDH and altered consciousness at diagnosis. Overall, 19 (79%) of the patients fully recovered after a mean
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follow-up of 6 months. Data about outcome was lacking for three patients. Times to diagnosis, first EBP and recovery tended to be higher in the serious form group but without
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reaching significant difference (all p > 0.05, Table 2).
Discussion
Characteristics of the population of patients with SIH in this study are in accordance with
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these described in the literature. Most of them were women with a peak of incidence during the fourth decade (27, 38). We counted only 24 cases in our university department of Neurology over the nearly 18-year period, annual incidence being estimated at 5 for 100 000
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adults (36). Thirty-seven percent of the patients presented with a serious form of SIH according to our definition (i.e. altered consciousness, SDH or CVT). However, this case
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series describes hospitalized patients only and more benign forms may often be misdiagnosed and therefore under-represented in our series (36). A loss of CSF volume is usually recognized as being responsible for SIH, but exact causes remain hypothetic (21, 22). A CSF leak between the subarachnoid and the epidural spaces can be identified in some patients presenting SIH (32). This could be the result of a general weakness of the dural mater, as seen with connective tissue disorders (Marfan, Ehler-Danlos syndromes), or located at the level of CSF collection and generally called meningeal diverticulae (25). This includes perineural
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ACCEPTED MANUSCRIPT cysts, which is a dilatation of the nerve root between the endo- and perineurium in continuity with the subarachnoid space (figure 1) (37). It has to be differentiated from collection in the epidural space which would rather be the consequence of a leak in the dura mater. The theory of an imbalance of gradient of pressure between CSF and veins in the epidural space has also
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been suggested: low pressure in the inferior vena cava could increase resorption of CSF by the epidural veins and could be the cause of the leak in the dura mater (8). Diagnosis is essentially based on clinical and radiological criteria. In our series, some symptoms of SIH were atypical,
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such as mimic thunderclap headache, scapular pain or oculomotor nerve palsy, but the classic orthostatic features were always present. Cerebral MRI is an essential examination to reveal
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brain sagging with descent of cerebellar tonsils, obliteration of basal citerns, decreased size of the ventricles, and venous engorgement with diffuse pachymeningeal enhancement, enlarged pituitary and dilated cerebral venous sinuses (figure 2) (10, 23). Low opening pressure (≤ 60 mm H20) is one of optional diagnostic criteria stated by Schievink et al. but was not used in
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our series as it was only measured in a few patients and found in only two (34). Similarly to previous publications, our study suggests that the serious form of SIH may develop because of delayed diagnosis and thus of treatment initiation (20). However we failed to demonstrate a
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significant difference of time to diagnosis between both groups, possibly because of a too small sample size. While bed rest and EBP were sufficient to treat patients with the non-
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serious form, surgical treatment was necessary for more than half of the patients with the serious form, and for four of the six with SDHs. The closure of CSF leak, by surgical repair or direct EBP, represents an effective etiologic treatment of SIH, but identifying a dural defect remains difficult (15). Spinal MRI, performed in 16 of our patients, revealed a CSF leak in only two and a radioisotope cisternography was more often needed for detection. However it should be noted that some cases date from the beginning of the nineties, when radioisotope cisternography was considered the most effective technique for identifying CSF leak. This
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ACCEPTED MANUSCRIPT technique has the advantage of confirming diagnosis with the indirect signs of absence of the tracer at the encephalic level and early appearance in the bladder. The leak can also often be identified directly but with a low spatial resolution which could prevent accurate enough localization for surgical repair (27). Recent more accurate methods of spinal imaging are now
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able to detect CSF leak as well as cisternography. Spinal MRI only detects CSF leak through the presence of the resulting collection of extradural fluid (figure 3). It represents, however, a non-invasive radiological procedure for a first examination of the spine in patients with SIH
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to diagnose manifest extradural fluid collection, perineural cysts, or more uncommon complications like syringomyelia (14, 26, 37). The most accurate radiological procedures to
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identify and localize the leak require intrathecal injection. Computed tomography myelography is described in literature as being the most reliable method and can be further improved by dynamic acquisition (38). MR myelography could be even better but requires intrathecal injection of gadolinium which is not allowed by the Food and Drug Administration
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due to a potential toxicity on the central nervous system (1, 3). Overall though, in view of the risk of worsening intracranial hypotension due to dural puncture, myelography procedures should be reserved for patients with SIH after failure of conservative measures and EBP to
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identify and close the CSF leak. Conservative measures and EBP were sufficient to treat all patients included in the group with no criteria of severity. Maintaining a recumbent position
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reduces pressure at the CSF leakage site and restores volume at the encephalic level. This therapeutic measure alone resulted in self-sealing of the leak in 10 of our patients, one of whom had SDHs. Other common measures were also used. Caffeine for instance, is purported to increase pressure in the venous compartment by vasoconstriction, and thus contain CSF resorption (27). Other treatments like intravenous administration of factor XIII to favor healing of the leak, or oral fludrocortisone are described in the literature but only in a few cases (24, 29). In both groups, EBP represented the first-line invasive treatment after
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ACCEPTED MANUSCRIPT conservative measures - bedrest and time - were considered ineffective (18). It consists of injecting between 10 and 30 mL of homologous blood into the epidural space. Use of fibrin glue has also been described (8). The effect of an EBP is certainly more complex than a direct sealing of the leak. First, because most first EBPs, and all of them in our series, are performed
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at the lumbar level while CSF leaks usually occur at the cervicothoracic junction and thoracic level. The goal of a blind EBP is to generate a dural tamponade to increase pressure in the subarachnoid spaces, and also to reverse the gradient between the CSF and blood
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compartments (8). In our series 24% of patients required a repeated EBP to improve SIH. Following our personal experience, we advocate a second blind EBP in case of no
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improvement 7 days after the first one and conservative measures. Failure of blind EBPs should lead to investigation and localization of the CSF leak. Once a leak has been identified directed EBP can be applied. Even if this technique was not used to heal CSF leaks in our series, it is becoming more widespread and constitutes an alternative treatment before surgical
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repair (4, 10). Two of our patients, both in the serious form group, required surgical repair of the CSF leak. Several surgical techniques are used as described in the literature: suturing dural defects, ligating diverticula or healing with gel form and fibrin glue, especially when the dura
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mater is too weak for suture (19). Nevertheless, a CSF leak can remain either undetected or, on the contrary, present at different levels. Then, enlarged EBPs can be applied at multiple
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sites, taking into account the ability of blood to spread into the epidural space (figure 4) (11). Altered consciousness and HSD were both considered as signs of severity in our series and the consequence of progression of SIH. The first is due to sagging and squeezing of the brainstem. The loss of volume in the subarachnoïd space may lead to subdural hygromas at the encephalic level, which could be complicated by the rupture of bridging veins leading to SDHs and self-worsening. More than a quarter of SDHs have been reported to be caused by CSF leak in non-geriatric patients (2). Male gender, age, dural enhancement, venous
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ACCEPTED MANUSCRIPT distension and a longer time to diagnose SIH would promote this complication (5, 39). In our series, surgical evacuation of SDHs was an ultimate symptomatic treatment which did not resolve the SIH and failed to save one patient. On the other hand, SDH resolved in one patent after repair of a CSF leak and in another with bed rest only. Overall, presence of uni- or
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bilateral SDHs, especially with the shift of encephalic structures, would incite to urgent surgical evacuation (figure 5). Nevertheless, SDHs are only the result of a downward displacement of the brain due to SIH which could be worsened by surgical evacuation (13,
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17). The best therapeutic strategy thus remains immediate treatment of SIH with EBP, conservative measures and attentive monitoring (5, 12). In the case of a life-threatening
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condition with SDH or clinical signs of severity, intrathecal saline infusion constitutes a transient solution to promptly increase pressure in the subarachnoid spaces until the gain of etiological treatment (13, 30). CVT is a known complication of SIH but poses a particular challenge as it requires anticoagulation therapy. It is caused by the drop in CSF volume and
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pressure in the subarachnoid spaces inducing a compensatory dilatation of cerebral veins which, in turn, leads to a decrease in blood flow velocity and may promote thrombosis (31). One patient in our series presented a CVT. Once again, treatment of the underlying SIH
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remains priority (35). Anticoagulation can then be initiated or discontinued depending on realization of myelography, EBP or any other surgical procedure. However, anticoagulation
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has to be carefully monitored due to the high risk of intracranial hemorrhage (7, 9). One patient died following SDH in our series but overall prognosis was good even though there was a trend toward a higher time to recovery in the serious form group. We did not observe any recurrence in our series in contrast to the 10% estimated recurrence reported in the literature (32). The main limitation of this study is due to its design. The retrospective collection of data, especially spanning a long period, meant that our patients were assessed by different
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ACCEPTED MANUSCRIPT radiological procedures, in particular to identify the CSF leak, and managed by different therapeutic strategies. The scarcity of SIH requires multicenter studies to validate any decision algorithm on a higher sample size (40).
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Conclusions
Presence of SDHs, disturbance of consciousness and a trend towards a longer time to diagnosis and recovery seem to define the severity of SIH. Severe patients are more likely to
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require neurosurgery, with exploration and repair of a possible CSF leak only after the usual conservative therapeutic measures and EBP have been applied. We do not support surgical
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despite a longer time to recovery.
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evacuation of SDH but advocate rather rapid etiologic treatment of SIH. Outcome is good
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ACCEPTED MANUSCRIPT Captions
Figure 1. Axial computed tomography myelography showing left perineural cyst on a nerve
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root
Figure 2. Brain magnetic resonance imaging changes of spontaneous intracranial hypotension Sagittal T1-weighted image (a) showing brain sagging with lower displacement of the
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brainstem and cerebellar tonsils, axial T1-weighted sequences with gadolinium (b, c) showing
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dural enhancement.
Figure 3. Cerebrospinal fluid leak on spinal magnetic resonance imaging Sagittal (a) and axial (b) T2-weighted images showing cerebrospinal fluid leak (1) and
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extradural fluid collection (2).
Figure 4. Algorithm for the diagnosis and management of patients with spontaneous intracranial hypotension
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MRI: Magnetic resonance imaging, SDH: Subdural hematoma, CVT: Cerebral venous thrombosis, EBP: Epidural blood patch, CSF: Cerebrospinal fluid, CT: Computed
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tomography, *: Diagnostic criteria, Schievink WI et al. (34).
Figure 5. Subdural collections at different times in a patient with spontaneous intracranial hypotension Cerebral axial computed tomography showing bilateral subdural hygromas (a), with rupture of bridging veins resulting in subdural hematomas three months later (b), and mass effect four months later (c).
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Table 1. Patients’ demographic characteristics, clinical and paraclinical features SD: Standard deviation, MRI: Magnetic resonance imaging, CSF: Cerebrospinal fluid.
groups
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Table 2. Patients characteristics, treatment, outcome and times in the non-serious/serious
SD: Standard deviation, CSF: Cerebrospinal fluid, EBP: Epidural blood patch, SDH: Subdural
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hematoma, *: Mann-Whitney U test, p: p-value.
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Female
16 (67%)
24 ACCEPTED MANUSCRIPT
Patients, n (%)
Age, mean±SD [range], year
46 ± 10 [25-70]
Headache
24 (100%) 5 (21%)
Neck pain/stiffness
17 (71%)
Nausea, vomiting
18 (75%)
Vertigo
75 (29%)
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“Thunderclap” headache
Diplopia Clinical presentation, n (%)
7 (29%)
24 Auditory changes
11 (46%)
Cranial nerve palsy
8 (33%)
Behavioral changes
Signs of severity, n (%)
9
1 (4%) 1 (4%)
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Scapular pain
3 (12%)
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Altered level of consciousness
Dysarthria
1 (4%)
Altered level of consciousness
3 (12%)
Subdural hematoma
6 (25%)
Cerebral venous thrombosis
1 (4%)
Brain MRI, n (%)
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Brain sagging 23
Pachymeningeal enhancement
20 (87%)
Subdural fluid collections
17 (74%)
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Subdural hematoma
16
Evidence of CSF leak
Radioisotope cisternography, n (%)
8
Evidence of CSF leak
CSF analyses
12
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Spinal MRI, n (%)
20 (87%)
16 (67%) Cervical 2 (12%) Thoracic Lumbar Cervical 5 (62%) Thoracic Lumbar
Median cell count [range], µL Median protein level [range], mg/dL
27 [5-59] 400 [50-3900]
Table 1. Patients’ demographic characteristics, clinical and paraclinical features SD: Standard deviation, MRI: Magnetic resonance imaging, CSF: Cerebrospinal fluid.
0 2 0 1 2 2
Non-serious form group
Serious form group
24
15
9
46 ± 10 [25-70]
44 ± 9 [25-59]
49 ± 11 [35-70]
0.194*
Time to diagnosis, mean ± SD [range], days
45 ± 43 [4-150]
35 ± 38 [4-150]
63 ± 47 [14-150]
0.052*
Time to first EBP, mean ± SD [range], days
66 ± 55 [17-180]
38 ± 31 [17-100]
94 ± 62 [17-180]
0.087*
6 ± 5 [1-18]
5 ± 4 [1-11]
9 ± 7 [1-18]
0.088*
Death or disability, n (%)
1 (4%)
0 (0%)
1 (11%)
Identified CSF leak, n (%)
6 (25%)
ACCEPTED MANUSCRIPT Overall Patients Age, mean ± SD [range] , years
p
3 (20%)
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Treatments
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Time to recovery, mean ± SD [range], months
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Times
Bed rest only, n (%) One EBP, n (%) Several EBP, n (%)
Surgical repair of CSF leak, n (%)
8 (53%)
2 (22%)
5 (21%)
4 (27%)
1 (11%)
8 (24%)
3 (20%)
5 (56%)
19 (79%)
15 (100%)
4 (44%)
2 (8%)
0 (0%)
2 (22%)
3 (12%)
0 (0%)
3 (33%)
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Surgical evacuation of SDH, n (%)
10 (42%)
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Bed rest +/- EBP only, n (%)
3 (33%)
Table 2. Patients characteristics, treatment, outcome and times in the non-serious/serious
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groups
SD: Standard deviation, CSF: Cerebrospinal fluid, EBP: Epidural blood patch, SDH: Subdural hematoma, *: Mann-Whitney U test, p: p-value.
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ACCEPTED MANUSCRIPT Highlights We describe features of serious form of spontaneous intracranial hypotension
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Times to diagnosis and treatment trend to be higher in the serious form
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Severe patients are more likely to require neurosurgery
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Neurosurgery is required only after failure of conservative measures
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Outcome is good despite a trend towards a longer time to recovery
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ACCEPTED MANUSCRIPT List of abbreviations
CSF: Cerebrospinal fluid
EBP: Epidural blood patch MRI: Magnetic resonance imaging SDH: Subdural hematoma
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SIH: Spontaneous intracranial hypotension
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CVT: Cerebral venous thrombosis
S1878-8750(15)00868-2
DOI:
10.1016/j.wneu.2015.07.002
Reference:
WNEU 3029
To appear in:
World Neurosurgery
Received Date: 30 April 2015 Revised Date:
3 July 2015
Accepted Date: 4 July 2015
Please cite this article as: Idrissi AL, Lacour J-C, Klein O, Schmitt E, Ducrocq X, Richard S, Spontaneous intracranial hypotension: Characteristics of the serious form in a series of 24 patients, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Spontaneous intracranial hypotension: Characteristics of the serious form in a series of 24 patients Running title: Serious form of spontaneous intracranial hypotension Aïcha Lyoubi Idrissia, Jean-Christophe Lacoura, Olivier Kleinb, Emmanuelle Schmittc, Xavier
a
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Ducrocqa, Sébastien Richarda .
Department of Neurology, University Hospital of Nancy, 29 avenue du Marechal de Lattre
b
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de Tassigny-CO n° 34 54035 NANCY Cedex, France.
Department of Neurosurgery, University Hospital of Nancy, 29 avenue du Marechal de
c
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Lattre de Tassigny-CO n° 34 54035 NANCY Cedex, France.
Department of Neuroradiology, University Hospital of Nancy, 29 avenue du Marechal de
Lattre de Tassigny-CO n° 34 54035 NANCY Cedex, France.
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Corresponding author
Dr Sébastien Richard. CHU Nancy, Department of Neurology, Email: [email protected]
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tel +33.3.83.85.16.56. fax +33.3.83.85.11.59.
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[email protected]; [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Keywords Cerebrospinal fluid leak, epidural blood patch, orthostatic headache, severity, spontaneous intracranial hypotension, subdural hematoma.
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ACCEPTED MANUSCRIPT Abstract Background: Recommended treatments for spontaneous intracranial hypotension (SIH) range from bed rest only to neurosurgery. However, the serious form of SIH is poorly defined. A better description of patient characteristics and their outcome may help define therapeutic
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options.
Methods: We reviewed 24 cases of patients with SIH and separated them into two groups according to whether or not they presented with signs of severity at admission: disturbance of
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consciousness, subdural hematomas (SDHs) and cerebral venous thrombosis.
Results: Nine patients (37%) were classified as having a serious form of SIH: six (25%)
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presented SDHs; three (12%) disturbance of consciousness; and one (4%) cerebral venous thrombosis. Bed rest and epidural blood patches (EBPs) were sufficient to treat all patients in the non-serious form group and four patients in the serious form group. Two patients (8%) had to undergo cerebrospinal fluid leak repair, and three others (12%) evacuation of SDHs.
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Outcome was good in both groups, with only one (4%) death due to extensive SDHs. Times to diagnosis in the serious form group (63 vs. 35 days, p=0.052), and to recovery (9 months vs. 5 months, p=0.088) tended to be higher without reaching difference.
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Conclusions: The presence of SDHs, disturbance of consciousness and a trend toward a longer time to diagnosis and recovery seem to define the serious form of SIH. These patients
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may require exploration and surgical repair of cerebrospinal fluid leak, only after failure of conservative measures - bed rest and time - and EBP, with good outcome.
Keywords Cerebrospinal fluid leak, epidural blood patch, orthostatic headache, severity, spontaneous intracranial hypotension, subdural hematoma.
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ACCEPTED MANUSCRIPT Introduction Even if spontaneous intracranial hypotension (SIH) is usually described as benign (32), it can lead to severe complications such as subdural hematoma (SDH) (6, 16), cerebral venous thrombosis (CVT) and (28, 35), exceptionally, to death (33). A clear definition of the serious
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form of SIH may help to choose the best treatment which ranges from bed rest to neurosurgery. We set out to describe the characteristics and outcome of patients with SIH
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according to whether they presented with or without signs of severity at admission.
Material and methods
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We reviewed 24 consecutive cases of patients with SIH who were admitted to the department of Neurology of the University Hospital of Nancy in France from February 1993 to April 2011. Patients were included if they met the following criteria: 1) orthostatic headache; 2) the presence of at least one of the following: a) sustained improvement of symptoms after
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epidural blood patch (EBP), b) active cerebrospinal fluid (CSF) leak, c) brain magnetic resonance imaging (MRI) changes of intracranial hypotension (brain sagging or pachymeningeal enhancement); 3) no recent history of dural puncture before symptom onset;
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4) the symptoms were not attributable to another disorder (34). Demographic characteristics, clinical features, results of investigations (cerebral MRI, radiological procedures to identify
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CSF leak, and CSF analysis), treatments administered (conservative measures, EBPs, surgical repairs of CSF leak, and surgical evacuation of SDH) and outcome were collected by review of medical charts. Brain MRI performed at diagnosis were re-examined to assess brain sagging and pachymeningeal enhancement. Brain sagging was defined as the presence of one of the following signs on MRI (32): downward displacement of the brain, effacement of perichiasmatic cisterns with bowing of the optic chiasm over the pituitary fossa, effacement of the prepontine cistern with flattening of the pons against the clivus and descent of the
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ACCEPTED MANUSCRIPT cerebellar tonsils. Patients were classified into two groups depending on whether they presented signs of severity (defined as altered level of consciousness, SDH and CVT) or not at admission. This was an observational study without any intervention on a human being. All
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presented data are anonymized.
Results
The population consisted of eight men and sixteen women with an age ranging from 25 to 70
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years (Table1). All patients presented a recent history of headache. Location was occipital or cervical in nine cases, frontal in six, temporal in two and undefined in seven. The most
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common associated symptoms were nausea (75%), neck stiffness (71%) and hearing disturbances (46%). All symptoms presented orthostatic features. CSF examination was performed in twelve cases with a protein level ranging from 50 to 3900 mg/dL, and pleiocytosis observed in ten patients, ranging from 5 to 59 cells/µL, mostly lymphocytes.
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Brain MRI was performed in 23 patients with both diffuse pachymeningeal enhancement and brain sagging observed in twenty patients (87%). Spinal MRI was performed in 16 patients (67%) and showed evidence of CSF leak in two. Radioisotope cisternography was performed
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in eight patients (33%) and showed direct signs of leakage in five. Three of these underwent a spinal MRI that located the CSF leak site in one. Bed rest was applied in all patients. Fifteen
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patients (63%) without signs of severity, were diagnosed after a mean interval of 35 days following the beginning of symptoms, and became symptom-free after a mean interval of 5 months (Table 2). Bed rest only was sufficient in eight cases of this group (53%) and EBPs were performed in the other seven cases (47%) with repeated injections in three. Nine patients (37%) had signs of severity, with a mean time to diagnosis of 63 days. Three patients (12%) presented altered levels of consciousness. Six (25%) presented SDH: one treated with bed rest only, one with bed rest and EBP only, one with identified and surgically repaired CSF leak,
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ACCEPTED MANUSCRIPT and surgical evacuation in the three others (12%) with one (4%) death. A CVT was observed in one patient (4%) and treated with anticoagulant therapy. Bed rest and EBP were a sufficient treatment for four patients in this group. Mean time to first EBP was 94 days in the serious form group against 38 days in the non-serious form group. Clinical outcome was good for all
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patients, except for one, with complete or near complete resolution of symptoms after a mean interval of 9 months. One patient died: the only one presenting both SDH and altered consciousness at diagnosis. Overall, 19 (79%) of the patients fully recovered after a mean
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follow-up of 6 months. Data about outcome was lacking for three patients. Times to diagnosis, first EBP and recovery tended to be higher in the serious form group but without
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reaching significant difference (all p > 0.05, Table 2).
Discussion
Characteristics of the population of patients with SIH in this study are in accordance with
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these described in the literature. Most of them were women with a peak of incidence during the fourth decade (27, 38). We counted only 24 cases in our university department of Neurology over the nearly 18-year period, annual incidence being estimated at 5 for 100 000
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adults (36). Thirty-seven percent of the patients presented with a serious form of SIH according to our definition (i.e. altered consciousness, SDH or CVT). However, this case
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series describes hospitalized patients only and more benign forms may often be misdiagnosed and therefore under-represented in our series (36). A loss of CSF volume is usually recognized as being responsible for SIH, but exact causes remain hypothetic (21, 22). A CSF leak between the subarachnoid and the epidural spaces can be identified in some patients presenting SIH (32). This could be the result of a general weakness of the dural mater, as seen with connective tissue disorders (Marfan, Ehler-Danlos syndromes), or located at the level of CSF collection and generally called meningeal diverticulae (25). This includes perineural
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ACCEPTED MANUSCRIPT cysts, which is a dilatation of the nerve root between the endo- and perineurium in continuity with the subarachnoid space (figure 1) (37). It has to be differentiated from collection in the epidural space which would rather be the consequence of a leak in the dura mater. The theory of an imbalance of gradient of pressure between CSF and veins in the epidural space has also
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been suggested: low pressure in the inferior vena cava could increase resorption of CSF by the epidural veins and could be the cause of the leak in the dura mater (8). Diagnosis is essentially based on clinical and radiological criteria. In our series, some symptoms of SIH were atypical,
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such as mimic thunderclap headache, scapular pain or oculomotor nerve palsy, but the classic orthostatic features were always present. Cerebral MRI is an essential examination to reveal
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brain sagging with descent of cerebellar tonsils, obliteration of basal citerns, decreased size of the ventricles, and venous engorgement with diffuse pachymeningeal enhancement, enlarged pituitary and dilated cerebral venous sinuses (figure 2) (10, 23). Low opening pressure (≤ 60 mm H20) is one of optional diagnostic criteria stated by Schievink et al. but was not used in
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our series as it was only measured in a few patients and found in only two (34). Similarly to previous publications, our study suggests that the serious form of SIH may develop because of delayed diagnosis and thus of treatment initiation (20). However we failed to demonstrate a
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significant difference of time to diagnosis between both groups, possibly because of a too small sample size. While bed rest and EBP were sufficient to treat patients with the non-
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serious form, surgical treatment was necessary for more than half of the patients with the serious form, and for four of the six with SDHs. The closure of CSF leak, by surgical repair or direct EBP, represents an effective etiologic treatment of SIH, but identifying a dural defect remains difficult (15). Spinal MRI, performed in 16 of our patients, revealed a CSF leak in only two and a radioisotope cisternography was more often needed for detection. However it should be noted that some cases date from the beginning of the nineties, when radioisotope cisternography was considered the most effective technique for identifying CSF leak. This
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ACCEPTED MANUSCRIPT technique has the advantage of confirming diagnosis with the indirect signs of absence of the tracer at the encephalic level and early appearance in the bladder. The leak can also often be identified directly but with a low spatial resolution which could prevent accurate enough localization for surgical repair (27). Recent more accurate methods of spinal imaging are now
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able to detect CSF leak as well as cisternography. Spinal MRI only detects CSF leak through the presence of the resulting collection of extradural fluid (figure 3). It represents, however, a non-invasive radiological procedure for a first examination of the spine in patients with SIH
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to diagnose manifest extradural fluid collection, perineural cysts, or more uncommon complications like syringomyelia (14, 26, 37). The most accurate radiological procedures to
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identify and localize the leak require intrathecal injection. Computed tomography myelography is described in literature as being the most reliable method and can be further improved by dynamic acquisition (38). MR myelography could be even better but requires intrathecal injection of gadolinium which is not allowed by the Food and Drug Administration
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due to a potential toxicity on the central nervous system (1, 3). Overall though, in view of the risk of worsening intracranial hypotension due to dural puncture, myelography procedures should be reserved for patients with SIH after failure of conservative measures and EBP to
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identify and close the CSF leak. Conservative measures and EBP were sufficient to treat all patients included in the group with no criteria of severity. Maintaining a recumbent position
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reduces pressure at the CSF leakage site and restores volume at the encephalic level. This therapeutic measure alone resulted in self-sealing of the leak in 10 of our patients, one of whom had SDHs. Other common measures were also used. Caffeine for instance, is purported to increase pressure in the venous compartment by vasoconstriction, and thus contain CSF resorption (27). Other treatments like intravenous administration of factor XIII to favor healing of the leak, or oral fludrocortisone are described in the literature but only in a few cases (24, 29). In both groups, EBP represented the first-line invasive treatment after
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ACCEPTED MANUSCRIPT conservative measures - bedrest and time - were considered ineffective (18). It consists of injecting between 10 and 30 mL of homologous blood into the epidural space. Use of fibrin glue has also been described (8). The effect of an EBP is certainly more complex than a direct sealing of the leak. First, because most first EBPs, and all of them in our series, are performed
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at the lumbar level while CSF leaks usually occur at the cervicothoracic junction and thoracic level. The goal of a blind EBP is to generate a dural tamponade to increase pressure in the subarachnoid spaces, and also to reverse the gradient between the CSF and blood
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compartments (8). In our series 24% of patients required a repeated EBP to improve SIH. Following our personal experience, we advocate a second blind EBP in case of no
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improvement 7 days after the first one and conservative measures. Failure of blind EBPs should lead to investigation and localization of the CSF leak. Once a leak has been identified directed EBP can be applied. Even if this technique was not used to heal CSF leaks in our series, it is becoming more widespread and constitutes an alternative treatment before surgical
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repair (4, 10). Two of our patients, both in the serious form group, required surgical repair of the CSF leak. Several surgical techniques are used as described in the literature: suturing dural defects, ligating diverticula or healing with gel form and fibrin glue, especially when the dura
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mater is too weak for suture (19). Nevertheless, a CSF leak can remain either undetected or, on the contrary, present at different levels. Then, enlarged EBPs can be applied at multiple
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sites, taking into account the ability of blood to spread into the epidural space (figure 4) (11). Altered consciousness and HSD were both considered as signs of severity in our series and the consequence of progression of SIH. The first is due to sagging and squeezing of the brainstem. The loss of volume in the subarachnoïd space may lead to subdural hygromas at the encephalic level, which could be complicated by the rupture of bridging veins leading to SDHs and self-worsening. More than a quarter of SDHs have been reported to be caused by CSF leak in non-geriatric patients (2). Male gender, age, dural enhancement, venous
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ACCEPTED MANUSCRIPT distension and a longer time to diagnose SIH would promote this complication (5, 39). In our series, surgical evacuation of SDHs was an ultimate symptomatic treatment which did not resolve the SIH and failed to save one patient. On the other hand, SDH resolved in one patent after repair of a CSF leak and in another with bed rest only. Overall, presence of uni- or
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bilateral SDHs, especially with the shift of encephalic structures, would incite to urgent surgical evacuation (figure 5). Nevertheless, SDHs are only the result of a downward displacement of the brain due to SIH which could be worsened by surgical evacuation (13,
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17). The best therapeutic strategy thus remains immediate treatment of SIH with EBP, conservative measures and attentive monitoring (5, 12). In the case of a life-threatening
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condition with SDH or clinical signs of severity, intrathecal saline infusion constitutes a transient solution to promptly increase pressure in the subarachnoid spaces until the gain of etiological treatment (13, 30). CVT is a known complication of SIH but poses a particular challenge as it requires anticoagulation therapy. It is caused by the drop in CSF volume and
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pressure in the subarachnoid spaces inducing a compensatory dilatation of cerebral veins which, in turn, leads to a decrease in blood flow velocity and may promote thrombosis (31). One patient in our series presented a CVT. Once again, treatment of the underlying SIH
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remains priority (35). Anticoagulation can then be initiated or discontinued depending on realization of myelography, EBP or any other surgical procedure. However, anticoagulation
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has to be carefully monitored due to the high risk of intracranial hemorrhage (7, 9). One patient died following SDH in our series but overall prognosis was good even though there was a trend toward a higher time to recovery in the serious form group. We did not observe any recurrence in our series in contrast to the 10% estimated recurrence reported in the literature (32). The main limitation of this study is due to its design. The retrospective collection of data, especially spanning a long period, meant that our patients were assessed by different
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ACCEPTED MANUSCRIPT radiological procedures, in particular to identify the CSF leak, and managed by different therapeutic strategies. The scarcity of SIH requires multicenter studies to validate any decision algorithm on a higher sample size (40).
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Conclusions
Presence of SDHs, disturbance of consciousness and a trend towards a longer time to diagnosis and recovery seem to define the severity of SIH. Severe patients are more likely to
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require neurosurgery, with exploration and repair of a possible CSF leak only after the usual conservative therapeutic measures and EBP have been applied. We do not support surgical
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despite a longer time to recovery.
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evacuation of SDH but advocate rather rapid etiologic treatment of SIH. Outcome is good
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ACCEPTED MANUSCRIPT Captions
Figure 1. Axial computed tomography myelography showing left perineural cyst on a nerve
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root
Figure 2. Brain magnetic resonance imaging changes of spontaneous intracranial hypotension Sagittal T1-weighted image (a) showing brain sagging with lower displacement of the
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brainstem and cerebellar tonsils, axial T1-weighted sequences with gadolinium (b, c) showing
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dural enhancement.
Figure 3. Cerebrospinal fluid leak on spinal magnetic resonance imaging Sagittal (a) and axial (b) T2-weighted images showing cerebrospinal fluid leak (1) and
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extradural fluid collection (2).
Figure 4. Algorithm for the diagnosis and management of patients with spontaneous intracranial hypotension
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MRI: Magnetic resonance imaging, SDH: Subdural hematoma, CVT: Cerebral venous thrombosis, EBP: Epidural blood patch, CSF: Cerebrospinal fluid, CT: Computed
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tomography, *: Diagnostic criteria, Schievink WI et al. (34).
Figure 5. Subdural collections at different times in a patient with spontaneous intracranial hypotension Cerebral axial computed tomography showing bilateral subdural hygromas (a), with rupture of bridging veins resulting in subdural hematomas three months later (b), and mass effect four months later (c).
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Table 1. Patients’ demographic characteristics, clinical and paraclinical features SD: Standard deviation, MRI: Magnetic resonance imaging, CSF: Cerebrospinal fluid.
groups
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Table 2. Patients characteristics, treatment, outcome and times in the non-serious/serious
SD: Standard deviation, CSF: Cerebrospinal fluid, EBP: Epidural blood patch, SDH: Subdural
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hematoma, *: Mann-Whitney U test, p: p-value.
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Female
16 (67%)
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Patients, n (%)
Age, mean±SD [range], year
46 ± 10 [25-70]
Headache
24 (100%) 5 (21%)
Neck pain/stiffness
17 (71%)
Nausea, vomiting
18 (75%)
Vertigo
75 (29%)
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“Thunderclap” headache
Diplopia Clinical presentation, n (%)
7 (29%)
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11 (46%)
Cranial nerve palsy
8 (33%)
Behavioral changes
Signs of severity, n (%)
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1 (4%) 1 (4%)
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Scapular pain
3 (12%)
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Altered level of consciousness
Dysarthria
1 (4%)
Altered level of consciousness
3 (12%)
Subdural hematoma
6 (25%)
Cerebral venous thrombosis
1 (4%)
Brain MRI, n (%)
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Brain sagging 23
Pachymeningeal enhancement
20 (87%)
Subdural fluid collections
17 (74%)
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Subdural hematoma
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Evidence of CSF leak
Radioisotope cisternography, n (%)
8
Evidence of CSF leak
CSF analyses
12
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Spinal MRI, n (%)
20 (87%)
16 (67%) Cervical 2 (12%) Thoracic Lumbar Cervical 5 (62%) Thoracic Lumbar
Median cell count [range], µL Median protein level [range], mg/dL
27 [5-59] 400 [50-3900]
Table 1. Patients’ demographic characteristics, clinical and paraclinical features SD: Standard deviation, MRI: Magnetic resonance imaging, CSF: Cerebrospinal fluid.
0 2 0 1 2 2
Non-serious form group
Serious form group
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9
46 ± 10 [25-70]
44 ± 9 [25-59]
49 ± 11 [35-70]
0.194*
Time to diagnosis, mean ± SD [range], days
45 ± 43 [4-150]
35 ± 38 [4-150]
63 ± 47 [14-150]
0.052*
Time to first EBP, mean ± SD [range], days
66 ± 55 [17-180]
38 ± 31 [17-100]
94 ± 62 [17-180]
0.087*
6 ± 5 [1-18]
5 ± 4 [1-11]
9 ± 7 [1-18]
0.088*
Death or disability, n (%)
1 (4%)
0 (0%)
1 (11%)
Identified CSF leak, n (%)
6 (25%)
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3 (20%)
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Treatments
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Time to recovery, mean ± SD [range], months
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Times
Bed rest only, n (%) One EBP, n (%) Several EBP, n (%)
Surgical repair of CSF leak, n (%)
8 (53%)
2 (22%)
5 (21%)
4 (27%)
1 (11%)
8 (24%)
3 (20%)
5 (56%)
19 (79%)
15 (100%)
4 (44%)
2 (8%)
0 (0%)
2 (22%)
3 (12%)
0 (0%)
3 (33%)
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Surgical evacuation of SDH, n (%)
10 (42%)
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Bed rest +/- EBP only, n (%)
3 (33%)
Table 2. Patients characteristics, treatment, outcome and times in the non-serious/serious
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groups
SD: Standard deviation, CSF: Cerebrospinal fluid, EBP: Epidural blood patch, SDH: Subdural hematoma, *: Mann-Whitney U test, p: p-value.
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ACCEPTED MANUSCRIPT Highlights We describe features of serious form of spontaneous intracranial hypotension
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Times to diagnosis and treatment trend to be higher in the serious form
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Severe patients are more likely to require neurosurgery
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Neurosurgery is required only after failure of conservative measures
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Outcome is good despite a trend towards a longer time to recovery
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ACCEPTED MANUSCRIPT List of abbreviations
CSF: Cerebrospinal fluid
EBP: Epidural blood patch MRI: Magnetic resonance imaging SDH: Subdural hematoma
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SIH: Spontaneous intracranial hypotension
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CVT: Cerebral venous thrombosis
