Spinal intramedullary schwannomas-report of a case and extensive review of the literature.

Intramedullary schwannomas (IMS) represent exceptional rare pathologies. They commonly present as solitary lesions; only five cases of multiple IMS have been described so far. Here, we report the sixth case of a woman with multiple IMS. Additionally, we performed the first complete systematic review of the literature for all cases reporting IMS. We performed a systematic review of the literature in PubMed, EMBASE and Cochrane Central Register of Controlled (CENTRAL) to retrieve all relevant studies and case reports on IMS. In a second step, we analysed all reported studies with respect to additional cases, which were not identified through the database search. Studies published in other languages than English were included. One hundred nineteen studies including 165 reported cases were included. In only five cases, the patients harboured more than one IMS. Gender ratio showed a ratio of nearly 3:2 (male:female); mean age of disease presentation was 40.2 years; 11 patients suffered from neurofibromatosis (NF) type 1 or 2 (6.6%). IMS are rare. Our first systematic review on this pathology revealed 166 cases, including the here reported case of multiple IMS. Our review offers a basis for further investigation on this disease.

Expression analysis of GADD45γ, MEG3, and p8 in pituitary adenomas.

Preceding studies have indicated that aberrant expression levels rather than genetic changes of GADD45γ, MEG3, and p8 gene might play a role in the pathogenesis of pituitary adenomas. We analysed their expression in various normal human tissues and in different pituitary tumour types, and investigated GADD45γ mutations in a subset of adenomas. Absolute quantification by real-time RT-PCR was performed in 24 normal tissues as well as in 34 nonfunctioning, 24 somatotroph, 12 corticotroph adenomas, 4 prolactinomas, 1 FSHoma, and in 6 normal pituitaries. Furthermore, we investigated the relationship between clinical data and gene expression. A subset was screened for GADD45γ mutations by single strand conformation polymorphism analysis (SSCP) and sequencing. All normal human tissues expressed GADD45γ, MEG3, and p8 mRNA. For GADD45γ, significantly lower expression levels were found in nonfunctioning adenomas compared with normal pituitary and somatotroph adenomas. P8 and MEG3 mRNA levels were significantly lower in nonfunctioning and corticotroph adenomas compared with normal pituitary. Expression of GADD45γ was significantly higher in pituitary adenomas of female patients. No mutation was found in the GADD45γ gene. GADD45γ, MEG3, and p8 appear to have physiological functions in a variety of human tissues. GADD45γ, MEG3, and P8 may be involved in the pathogenesis of nonfunctioning and corticotroph pituitary tumours. Female gender seems to predispose to slightly higher GADD45γ expression in pituitary adenomas. Mutations of the GADD45γ are unlikely to be involved in the pathogenesis of pituitary adenomas.

[Schwannoma of the femoral nerve: a rare differential diagnosis of leg pain]. / Das Schwannom des Nervus femoralis: Eine seltene Differenzialdiagnose bei Oberschenkelschmerzen.

BACKGROUND: Schwannomas (neurinomas) are among the most frequent peripheral nerve tumors. Nevertheless, these are seldom located in the lower extremities in association with the femoral nerve. CLINICAL PRESENTATION: In this case, the occurrence of a schwannoma adjacent to the femoral nerve is described in a patient presenting with nonspecific pain in the thigh accompanied by a palpable mass. Sensory and motor deficits were not present. Further examinations by MRI and biopsy followed by histopathology, revealed the diagnosis of a schwannoma. The tumor was completely excised. CONCLUSION: Although schwannomas of the lower extremities are rare, they should be included in the differential diagnosis. Knowing the typical clinical symptoms, radiological signs, and histopathological findings, diagnosis should be straight forward.

The management of arteriovenous malformations.

Arteriovenous malformations (AVM) can occur in the entire central nervous system with a predilection of the supratentorial intracranial compartment. Intracerebral hemorrhage is the most common clinical presentation of AVM and associated with a high morbidity and mortality rate. Correct management of these lesions is therefore of utmost importance. In this review, the authors present actual diagnostic and interdisciplinary treatment modalities based on their experience in a major neurovascular center and taking into consideration actual literature data. Different treatment strategies are discussed.

Venous air embolism during semi-sitting craniotomy evokes thrombocytopenia.

Venous air embolism activates platelets in vitro and can evoke platelet dysfunction in swine. We tested the hypothesis that venous air embolism during semi-sitting craniotomy induces thrombocytopenia in humans. We analysed the charts of 799 patients who had an elective craniotomy in the semi-sitting position between 1990 and June 2009. Venous air embolism occurred in 52 patients (6.5%) and was associated with a decrease in mean (SD) in platelet count from 270 (75) × 109 l⁻¹ to 194 (62) × 109 l⁻¹ (p < 0.001). In age-matched controls without venous air embolism mean (SD) platelet count did not change (254 (82) × 109 l⁻¹ vs. 250 (97) × 109 l⁻¹ (NS). While mean (SD) haematocrit fell slightly in both groups (venous air embolism: 0.40 (0.05) to 0.32 (0.04), p <0.001; no venous air embolism: 0.41 (0.04) to 0.35 (0.05), p < 0.001), normalising platelet count to haematocrit did not alter the results.

[Complete skull-base reconstruction with a Galea Periost-Calvaria Split-Sandwich (GAP-CAS) technique]. / Rhinobasis-Rekonstruktion durch "Galea-Periost-Calvarian-Split-Sandwich (GAP-CAS) -Technik.

The frontal skull base represents an important barrier between the intracranial structures and the nasal sinuses preventing rhinoliquorrhea, ascending infections and brain prolaps.We reconstructed complete frontal skull base defects after interdisziplinary oncosurgery using a "Galea Periost ­ Calvaria Split ­ Sandwich (GAP-CAS) technique" with one half of the galea frontalis myofasccial flap torn to the nasal cavity, in-between the bone graft with the other half of the galea flap on top. By this technique it was possible to sufficiently cover the frontal skull base preventing cerebrospinal fluid leakage, meningitis and brain prolaps.

Transdural Blood Supply in Cerebral Arteriovenous Malformations: A Systematic Evaluation of Angioarchitecture.

BACKGROUND AND PURPOSE: Arterial transdural blood supply is a rare angiographic phenomenon in cerebral AVMs. This study aimed to evaluate angiographic transdural blood supply characteristics and to describe the clinical peculiarities of these lesions. MATERIALS AND METHODS: A prospective AVM data base of 535 patients, enrolled from 1990 to 2016, was analyzed retrospectively. Clinical information was reviewed through patients' medical charts and radiologic studies. Patients with previous AVM treatment were excluded (n = 28). RESULTS: Patients with (n = 32, male/female ratio = 10:22; mean age, 46 ± 15 years; range, 13-75 years) and without transdural blood supply (n = 475, male/female ratio = 260:215; mean age, 40 ± 18 years; range, 2-87 years) did not show significant differences in clinical presentation (age, hemorrhage, seizures, chronic headache). The predominant nidus size in patients with transdural blood supply was ≥30 mm, with significantly more patients with large AVMs (>60 mm, P = .001). To describe the transdural blood supply, we used 3 grades based on the angiographic transdural blood supply proportion and intensity of AVM nidus perfusion (I-III). Fifty-seven percent of patients with chronic headache had a strong and substantial transdural nidus perfusion (III) and a high-flow transdural blood supply. CONCLUSIONS: Cerebral AVMs with transdural blood supply represent a rare and heterogeneous subgroup. Lesions can be graded by quantifying the transdural blood supply of the nidus and by capturing hemodynamic characteristics. The broad spread of angiographic features and comparable clinical patterns of patients with or without transdural blood supply raises questions about the relevance of the transdural blood supply to the natural history risk of an AVM and the intention for treatment.

Quantification of G protein Gaalphas subunit splice variants in different human tissues and cells using pyrosequencing.

The G protein Galphas is derived from four alternatively spliced transcripts, two long variants (Galphas(L)+CAG and Galphas(L)-CAG), which include an extra 45-bp segment, and two short variants (Galphas(S)+CAG and Galphas(S)-CAG). The long and short forms differ in each case by splicing in or out of a serine residue encoded at the 3' end of the variable exon 3. The relative expression of all four variants in human tissues is poorly investigated due to experimental limitations. We therefore established a method for reliable relative mRNA quantification of these splice variants based on the Pyrosequencing technology, and determined Galphas transcript ratios in various human tissues and cells. Galphas(S)/Galphas ratio was highest in blood mononuclear cells (0.84 +/- 0.02, n = 16) and lowest in the brain (0.51 +/- 0.14, n = 3). The different ranges resulted from differences in Galphas(S)+CAG ratios, which ranged from a total Galphas ratio of 0.32 +/- 0.07 (n = 12) in heart tissue to 0.57 +/- 0.03 (n = 16) in blood mononuclear cells (p < 0.0001), whereas the Galphas(S)-CAG ratio was rather constant and ranged from 0.22 +/- 0.04 (n = 7) in retinoblastoma cells to 0.27 +/- 0.04 in lymphocytes (p = 0.19). The Galphas(L)+CAG ratio ranged from 0.02 +/- 0.02 in heart tissue to 0.05 +/- 0.01 in retinoblastoma cells, with a varying proportion of Galphas(L)-CAG, which ranged from 0.14 +/- 0.02 in blood mononuclear cells to 0.41 +/- 0.08 in heart tissue. Stimulation of immortalized B lymphoblasts with isoproterenol resulted in significant changes of splice variant ratios. Our data indicate that changes of long and short ratios of Galphas in different tissues affected Galphas(L)-CAG and Gas(S)+CAG rather than Galphas(L)+CAG and Galphas(S-)CAG. Furthermore, stimulation of cells seemed to affect splice variant ratios. These results are, therefore, suggestive of different biological functions of these variants.

Does intraoperative aneurysm rupture influence outcome? Analysis of 169 patients.

OBJECTIVES: The aim of this study was to evaluate the prognostic value of intraoperative aneurysm rupture (IAR) in patients with subarachnoid hemorrhage (SAH) undergoing surgery for cerebral aneurysms. PATIENTS AND METHODS: Between July 1997 and April 2000, 292 consecutive patients were admitted to our institution with SAH due to ruptured intracranial aneurysms. Of these, 169 patients were treated surgically according to standard microsurgical procedures and were included in this study. Mean age was 47 years. Initial clinical state was graded according to the classification of Hunt and Hess (HH). Outcome was classified according to the Glasgow Outcome Scale as favorable (grades IV and V) and unfavorable (grades I-III). Outcome of patients with intraoperative ruptured and non-ruptured aneurysms was analyzed in correlation to the preoperative clinical state and with respect to the time of surgery and to aneurysm localization. RESULTS: Different rupture rates were observed with respect to the localization of the aneurysm: anterior circulation (n=69) 39.1%, middle cerebral artery (n=46) 34.8%, internal carotid artery (n=48) 31.2%, and posterior circulation (n=6) 16.7%. Patients with HH-grades I-III showed a favorable outcome in 72.2% (61 of 84 patients) without intraoperative rupture and in 71.7% (33 of 46 patients) with intraoperative aneurysm rupture. The corresponding values for patients with HH-grades IV/V were: favorable outcome in 34.6% (9 of 26 patients) and 23.1% (3 of 13 patients), respectively. Poor initial clinical condition (HH IV and V) as well as the initial Fisher grades III and IV were strongly associated with poor clinical outcome. CONCLUSIONS: Intraoperative aneurysm rupture has no impact on the outcome, neither in patients with good initial condition nor for poor grades patients.

Association of aneurysms and variation of the A1 segment.

BACKGROUND AND PURPOSE: Previous studies have described a correlation between variants of the circle of Willis and pathological findings, such as cerebrovascular diseases. Moreover, anatomic variations of the anterior cerebral artery (ACA) seem to correspond to the prevalence of aneurysms in the anterior communicating artery (ACoA). The aim of this study was to assess the prevalence of aneurysms in patients with anatomical/morphological variations of the circle of Willis. METHODS: We retrospectively analyzed 223 patients who underwent cerebral angiography between January 2002 and December 2010 for aneurysm of the ACoA. Diagnostic imaging was reviewed and statistically evaluated to detect circle of Willis anomalies, aneurysm size, and rupture. 204 patients with an unrelated diagnosis served as the control group. RESULTS: Variations of the A1 segment occurred significantly more frequently in the aneurysm group than in the control group. Mean aneurysm size in patients with grades I and III hypoplasia or aplasia was 6.58 mm whereas in patients with grade II hypoplasia it was 7.76 mm. CONCLUSIONS: We found that variations in the A1 segment of the ACAs are correlated with a higher prevalence of ACoA aneurysms compared with patients with a symmetric circle of Willis.

Silent embolism after stent-assisted coiling of cerebral aneurysms: diffusion-weighted MRI study of 75 cases.

PURPOSE: New ischemic brain lesions are common findings after cerebral diagnostic angiography and endovascular therapy. Diffusion-weighted MRI (DWI) can be used for detection of these lesions. The aim of the present study was to investigate the incidence of DWI lesions after stent-assisted coiling and the evaluation of possible risk factors. METHODS: The study included a total of 75 consecutive patients treated with stent-assisted coiling. Post-procedural DWI of the brain was performed to detect ischemic lesions. Demographic data, aneurysm characteristics and angiographic parameters were correlated with properties of DWI lesions. RESULTS: In post-procedural DWI, 48 of the 75 patients (64%) had 163 DWI lesions in a pattern consistent with embolic events. The number of patients with DWI lesions was significantly increased in older patients (≥55 years) and longer intervention times (≥120 min). The ischemic brain volume was significantly increased in older patients (≥55 years) as well as in patients who were implanted with a shorter stent (<20 mm). CONCLUSIONS: Thromboembolic events are common after stent-assisted coiling with an incidence comparable to DWI studies after coiling alone. Despite several devices and low operator experience, stent-assisted coiling for intracranial aneurysms has a very low risk of permanent neurologic disability. Further studies are necessary to improve the safety of stent-assisted coiling for patients in conditions with increased risk potential (age, procedure time, stent length).

[3-year follow-up after endovascular aneurysm treatment with Silk® flow diverter]. / 3-Jahres-Follow nach Aneurysmabehandlung mit dem Silk® Flow Diverter.

PURPOSE: Flow diverters may occlude aneurysms by endoluminal reconstruction of the parent artery and by reducing the blood flow into the aneurysm. The purpose of this study was to assess the rate of intervention-associated complications and a 3-year-follow-up. MATERIALS AND METHODS: We retrospectively analyzed 18 patients treated with Silk® FD. Only patients with unruptured aneurysms were included. Treatment indications were fusiform, giant or recurrent aneurysms. We considered all aneurysms to have a high likelihood of failure and/or recurrence when treated with conventional endovascular techniques. RESULTS: Silk FD could directly be placed in a proper position across the whole length of the aneurysm in 16/18 patients. In one case an additional PTA was necessary. In another case the first FD could not be properly deployed. 17 of 18 aneurysms (95 %) were occluded immediately, in the mid-term follow-up after 6 months or 3 years after treatment. The overall complication rate including technical (11.1 %), acute or delayed thromboembolic complication without (11.1 %) or with (16.6 %) severe complications was documented. CONCLUSION: FD treatment is effective with a high occlusion rate of aneurysms also in long-term follow-up. In these complex aneurysms the complication rate is higher than in conventional stent-assisted coiling.

Cardiac risk in patients with treatment naïve, first-line medically controlled and first-line surgically cured acromegaly in comparison to matched data from the general population.

INTRODUCTION: Coronary risk factors in patients with acromegaly after first-line transsphenoidal surgery (TSS) or first-line somatostatine analogue (SSA) treatment have rarely been examined. Aim of this study was an evaluation of cardiovascular risk factors and left ventricular hypertrophy (LVH) in 3 different patient groups with treatment naïve, active (ACT), first-line medically controlled (MED) and first-line surgically treated (SUR) acromegaly and a calculation of the Framingham Weibull Risk Score (FS). DESIGN: Retrospective comparative matched case-control study. PATIENTS & METHODS: 40 acromegalic patients (cases aged 45-74 years, 23 men) were matched with respect to age and gender to 200 controls from the general population. 13 patients had treatment-naïve acromegaly (ACT), 12 patients were SSA treated (MED) and 15 patients were operated by TSS (SUR). Coronary risk factors were assessed after 12 months of treatment by interviews and direct laboratory measurements. Only patients normalized for IGF-I in MED and SUR group were included. FS and odds ratios (OR) from multiple conditional logistic regression (matched for age and gender, adjusted for BMI) were calculated. RESULTS: Compared to matched controls ACT patients had higher HbA1c levels (6.9±1.4 vs. 5.5±0.7% (p<0.0001)) and an increased prevalence of left ventricular hypertrophy (LVH) (30.8 vs. 3.2% (p=0.007). MED and SUR groups were similar for gender, age, disease duration and IGF-I levels at diagnosis. Compared to matched controls, MED patients had a significantly increased diastolic blood pressure (89±9 vs. 79±11 mmHg (p=0.001), prevalence of LVH (41.7 vs. 1.7% (p<0.0001), prevalence of diabetes mellitus (33.3 vs. 10.0% (p=0.03)), higher HbA1c levels (6.8±1.3 vs. 5.5±0.7% (p=0.0005)) and a higher FS (21.2±9.7 vs. 12.4±7.7% (p=0.002), OR 1.11 [1.02-1.21] (p=0.01)) while in the SUR group only higher prevalences of LVH (40.0 vs. 4.1% (p<0.0001)) and HbA1c levels (6.4±1.2 vs. 5.5±0.8% (p=0.006)) were found compared to controls. CONCLUSION: When comparing treatment naive, medically treated and surgically cured patients with acromegaly to age- and gender-matched subjects from the general population, we have found an increased cardiovascular risk in patients at 12 months after first-line SSA treatment but not in patients after first-line surgery.

Indication, technique and benefit of intraoperative spinal digital subtraction angiography with a new setting in a patient with spinal arteriovenous malformation.

BACKGROUND AND OBJECT: A new setting of intraoperative spinal angiography within an angiography suite is presented. PATIENT AND METHODS: In a patient with thoracic arteriovenous malformation, the resection was performed within an angiography suite. Therefore a long sheath was applied, which remained sterile during the procedure and allowed a catheter to be introduced which is navigated into the noted segmental artery for contrast injection. RESULTS: Digital subtraction angiography was performed prior to and after the resection at the AVM in order to visualize recent feeders and to ensure the complete occlusion. CONCLUSIONS: This method leads to an increased image quality and a shorter operation time in comparison to an angiography within an operating room.

Role of the GNAS1 T393C polymorphism in patients with glioblastoma multiforme.

The T393C polymorphism of the GNAS1 locus, which encodes the Gαs protein, has recently been found to be associated with patient outcome in various malignancies. We investigated the association between GNAS1 genotype and survival among patients suffering from glioblastoma multiforme (GBM). One hundred and sixty-two patients with GBM were retrospectively investigated. Inclusion criteria were availability of DNA and, for surviving patients, a follow-up of at least 24 months. The results were analysed based on clinical data, type of surgical intervention, adjuvant therapy, and 2-year survival. At the 2-year follow up, 79.6% of patients had died. Two-year survival rates were as follows: CC-homozygous patients, 15.8%; CT-heterozygous patients, 23.1%; and TT-homozygous patients, 18.2% (p = 0.461). Subgroup analysis revealed different 2-year survival rates in the group that underwent stereotactic biopsy, with 0% for CC-homozygous, 2.8% for CT-heterozygous, and 15.4% survival for TT-homozygous patients, but the differences were not statistically significant (p = 0.229). Our results indicate that there is no association between the GNAS1 T393C polymorphism and 2-year survival among patients with GBM.

Onyx embolization as a first line treatment for intracranial dural arteriovenous fistulas with cortical venous reflux.

PURPOSE: Our purpose was to present our experience regarding embolization of intracranial dural arteriovenous fistulas (DAVFs) with cortical venous reflux using Onyx, a non-adhesive liquid embolic agent. MATERIALS AND METHODS: From January 2006 to December 2007, 16 patients (12 men and 4 women) with a mean age of 61 years (range 42 - 78) with an intracranial DAVF with cortical venous reflux underwent at least one transarterial embolization using Onyx. According to the Cognard classification, 2 lesions were grade V, 5 were grade IV, 6 were grade III, 2 were grade IIa+b, and 1 was grade IIb. The clinical presentation included 5 hemorrhagic deficits, 10 non-hemorrhagic manifestations, and 1 patient was asymptomatic. RESULTS: Twenty-four embolization sessions were performed in 16 patients with an average of 3 arterial feeders (range 1 - 9) embolized per DAVF. Immediately after embolization, complete occlusion was achieved in 9/16 (56%) patients after the first session. Further postembolization surgical treatment was performed in 3 patients. Partial reperfusion occurred in 1 patient at the time of mean follow-up of 3.7 months (range 0 - 12). Treatment has been completed for 11/16 patients with angiographic cure in 10/11 (91%). An infratentorial bleeding complication related to embolization occurred in one patient with temporary worsening of the patient's gait disturbance. At the time of mean clinical follow-up of 4.5 months (range 0 - 12), no procedure-related permanent morbidity was added to our cohort. CONCLUSION: According to our experience, embolization of intracranial DAVFs with cortical venous drainage using Onyx is feasible with promising results, indicating stability at the time of mid-term follow-up. In very complex DAVFs additional embolization material might be necessary, and in some cases surgery is warranted.

Extensive brain swelling with neurological deterioration after intracranial meningioma surgery - venous complication or 'unspecific' increase in tissue permeability.

OBJECTIVE: We retrospectively analyzed a series of patients who deteriorated after resection of an intracranial meningioma due to extensive brain edema (EBE) with regard to etiology of the neurological worsening and outcome. METHODS: Out of a series of 376 consecutive patients who underwent resection of an intracranial meningioma, 13 (3.5%) experienced postoperative deterioration due to EBE which necessitated prolonged artificial ventilation, tracheal reintubation, or decompressive craniectomy. Clinical data, radiological findings, operative records and follow-up data of these patients were retrospectively reviewed. RESULTS: The study revealed two different patient groups: Patients in group A (n=7) demonstrated edema due to typical venous infarction (VI). A decompressive craniotomy was performed in all but one patient in this group; nonetheless, an acceptable neurological outcome (Glasgow Outcome Scale (GOS) 4) was achieved in only two cases. Patients in group B (n=6) deteriorated due to an EBE of unknown etiology. Mean tumor volume in this group was higher when compared to group A (75 ml vs. 30 ml). In addition, 83% of patients in group B displayed extensive preoperative peritumoral edema compared to only 14% in group A. Three patients in group B required decompressive surgery; however, neurological outcome was more favorable in this group as 83% achieved a GOS of 4 or 5. CONCLUSION: Extensive brain swelling during or after intracranial meningioma surgery may be due to VI or possibly due to increased postoperative tissue permeability. It is recommended to preserve all venous structures as patients with VI had an unfavorable neurological outcome.

Predictive value of intrathecal interleukin-6 for ventriculostomy-related Infection.

BACKGROUND AND STUDY AIM: Early diagnosis of ventriculostomy-related infection (VRI) is crucial for the early treatment and course of this disease. In neurosurgical patients the diagnostic criteria are equivocal, mostly because of bloodstained cerebrospinal fluid (CSF). The predictive value, sensitivity and specificity of intrathecal interleukin-6 (IL-6 (CSF)) has been proven for VRI compared with classical diagnostic CSF parameters, i.e. cell countCSF (CC (CSF)) and total protein (CSF). PATIENTS AND METHODS: We prospectively analyzed the daily clinical data and CSF samples of 75 neurosurgical patients with an external ventricular drainage (EVD), which had been inserted predominantly because of poor-grade subarachnoid hemorrhage (SAH). The intrathecal interleukin-6 concentrations (IL-6 (CSF)) were correlated with the clinical course and VRI incidence, as diagnosed by the classical VRI criteria (CC (CSF), total protein (CSF), clinical symptoms). RESULTS: Based on classical criteria, bacterial meningitis occurred in 26.7% of patients. Patients with VRI manifested significantly (p<0.001) higher median values of IL-6 (CSF) (up to 2,000-fold increase) the day before (day -1) infection was diagnosed by conventional parameters. Using a cut-off value of IL-6 (CSF)>or=2,700 pg/ml [4,050 pg/ml after WHO standardization] on day -1, the relative risk for VRI was 6.09 (95% CI: 2.62-14.18%). A predictive value of IL-6 (CSF)>or=2,700 pg/ml [4,050 pg/ml] for VRI was calculated of 89% (95% CI: 79.6-98.0%), a sensitivity of 73.7% and a specificity of 91.4%. The amount of intrathecal blood was an independent risk factor for VRI occurrence, whereas the mean duration of EVD in place showed no impact on the rate of infection. CONCLUSION: Our data indicate that IL-6 (CSF) is a reliable marker for predicting VRI prior to clinically manifest meningitis, one day earlier than the common diagnostic criteria of CSF infection (CC (CSF), total protein (CSF), clinical symptoms).