Osteopontin in subarachnoid hemorrhage

Osteopontin in subarachnoid hemorrhage

Experimental studies reported that osteopontin (OPN), is induced in the brain after subarachnoid hemorrhage (SAH).

OPN may increase MAPK phosphatase-1 that inactivates MAPKs, upstream and downstream of vascular endothelial growth factor A, by binding to L-arginyl-glycyl-L-aspartate-dependent integrin receptors, suggesting a novel mechanism of OPN-induced post-SAH BBB protection 1).


The relationships between osteopontin (OPN) expression and chronic shunt-dependent hydrocephalus (SDHC) have never been investigated. In 166 SAH patients (derivation and validation cohorts, 110 and 56, respectively), plasma OPN levels were serially measured at days 1-3, 4-6, 7-9, and 10-12 after aneurysmal obliteration. The OPN levels and clinical factors were compared between patients with and without subsequent development of chronic SDHC. Plasma OPN levels in the SDHC patients increased from days 1-3 to days 4-6 and remained high thereafter, while those in the non-SDHC patients peaked at days 4-6 and then decreased over time. Plasma OPN levels had no correlation with serum levels of C-reactive protein (CRP), a systemic inflammatory marker. Univariate analyses showed that age, modified Fisher scaleacute hydrocephaluscerebrospinal fluid drainage, and OPN and CRP levels at days 10-12 were significantly different between patients with and without SDHC. Multivariate analyses revealed that higher plasma OPN levels at days 10-12 were an independent factor associated with the development of SDHC, in addition to the more frequent use of cerebrospinal fluid drainage and higher modified Fisher grade at admission. Plasma OPN levels at days 10-12 maintained similar discrimination power in the validation cohort and had good calibration on the Hosmer-Lemeshow goodness-of-fit test. Prolonged higher expression of OPN may contribute to the development of post-SAH SDHC, possibly by excessive repairing effects promoting fibrosis in the subarachnoid space 2).


Abate et al. included 44 patients with the following criteria: (1) age 18 and 80 years, (2) diagnosis of SAH from cerebral aneurysm rupture, (3) insertion of an external ventricular drain. Plasma and CSF were sampled at day 1, 4, and 8. OPN levels, in CSF and plasma, displayed a weak correlation on day 1 and were higher, in CSF, in all time points. Only in poor prognosis patients, OPN levels in CSF significantly increased at day 4 and day 8. Plasma OPN at day 1 and 4 was predictor of poor outcome. In conclusion, plasma and CSF OPN displays a weak correlation, on day 1. The higher levels of OPN found in the CSF compared to plasma, suggest OPN production within the CNS after SAH. Furthermore, plasma OPN, at day 1 and 4, seems to be an independent predictor of poor outcome 3).


The aim of the study was to investigate the relationships between plasma OPN levels and outcome after aneurysmal SAH in a clinical setting. This is a prospective study consisting of 109 aneurysmal SAH patients who underwent aneurysmal obliteration within 48 h of SAH. Plasma OPN concentrations were serially determined at days 1-3, 4-6, 7-9, and 10-12 after onset. Various clinical factors as well as OPN values were compared between patients with 90-day good and poor outcomes. Plasma OPN levels were significantly higher in SAH patients compared with control patients and peaked at days 4-6. Poor-outcome patients had significantly higher plasma OPN levels through all sampling points. Receiver-operating characteristic curves demonstrated that OPN levels at days 10-12 were the most useful predictor of poor outcome at cutoff values of 915.9 pmol/L (sensitivity, 0.694; specificity, 0.845). Multivariate analyses using the significant variables identified by day 3 showed that plasma OPN ≥ 955.1 pmol/L at days 1-3 (odds ratio, 10.336; 95% confidence interval, 2.563-56.077; p < 0.001) was an independent predictor of poor outcome, in addition to increasing age, preoperative World Federation of Neurological Surgeons grades IV-V, and modified Fisher grade 4. Post hoc analyses revealed no correlation between OPN levels and serum levels of C-reactive protein, a non-specific inflammatory parameter, at days 1-3. Acute-phase plasma OPN could be used as a useful prognostic biomarker in SAH 4).


1)

Suzuki H, Hasegawa Y, Kanamaru K, Zhang JH. Mechanisms of osteopontin-induced stabilization of blood-brain barrier disruption after subarachnoid hemorrhage in rats. Stroke. 2010 Aug;41(8):1783-90. doi: 10.1161/STROKEAHA.110.586537. Epub 2010 Jul 8. PMID: 20616319; PMCID: PMC2923856.
2)

Asada R, Nakatsuka Y, Kanamaru H, Kawakita F, Fujimoto M, Miura Y, Shiba M, Yasuda R, Toma N, Suzuki H; pSEED group. Higher Plasma Osteopontin Concentrations Associated with Subsequent Development of Chronic Shunt-Dependent Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage. Transl Stroke Res. 2021 Jan 9. doi: 10.1007/s12975-020-00886-x. Epub ahead of print. PMID: 33423213.
3)

Abate MG, Moretto L, Licari I, Esposito T, Capuano L, Olivieri C, Benech A, Brucoli M, Avanzi GC, Cammarota G, Dianzani U, Clemente N, Panzarasa G, Citerio G, Carfagna F, Cappellano G, Della Corte F, Vaschetto R. Osteopontin in the Cerebrospinal Fluid of Patients with Severe Aneurysmal Subarachnoid Hemorrhage. Cells. 2019 Jul 10;8(7):695. doi: 10.3390/cells8070695. PMID: 31295895; PMCID: PMC6678172.
4)

Nakatsuka Y, Shiba M, Nishikawa H, Terashima M, Kawakita F, Fujimoto M, Suzuki H; pSEED group. Acute-Phase Plasma Osteopontin as an Independent Predictor for Poor Outcome After Aneurysmal Subarachnoid Hemorrhage. Mol Neurobiol. 2018 Jan 20. doi: 10.1007/s12035-018-0893-3. [Epub ahead of print] PubMed PMID: 29353454.

Cerebrospinal fluid shunt malfunction diagnosis

Cerebrospinal fluid shunt malfunction diagnosis

The diagnosis of cerebrospinal fluid shunt malfunction based on a careful clinical history, examination, and investigations such as computed tomography (CT) scanning and plain X-ray shunt series is not always straightforward 1).

For example, ventricular size may not change in cases with a blocked shunt. Pumping a shunt prechamber is notoriously unreliable and potentially dangerous 2).

Admission for observation is expensive and excessive CT scanning carries a radiation burden. Many patients may be admitted and subjected to CT scanning on multiple occasions. There is a need to develop more reliable methods of assessing shunt function and monitoring intracranial pressure (ICP) 3) 4) 5) 6) 7) 8).

Optic nerve sheath diameter may be assessed using ultrasound or magnetic resonance imaging (MRI). Implantable ICP sensors within a shunt system have been blighted by poor long-term stability. Long-term studies of the recently introduced Raumedic NEUROVENT-P-tel and the Miethke SENSOR RESERVOIR are awaited with a keen interest 9).


Several attempts have been made to measure the cerebrospinal fluid flow velocity utilizing different Phase contrast magnetic resonance imaging techniques. In a study, König et al. evaluated 3T (Tesla) MRI scanners for their effectiveness in determining of flow in the parenchymal portion of ventricular shunt systems with adjustable valves containing magnets.

At first, an MRI phantom was used to measure the phase-contrasts at different constant low flow rates. The next step was to measure the CSF flow in patients treated with ventricular shunts without suspected malfunction of the shunt under observation.

The measurements of the phantom showed a linear correlation between the CSF flow and corresponding phase values. Despite many artifacts resulting from the magnetic valves, the ventricular catheter within the parenchymal portion of shunt was not superimposed by artifacts at each PC MRI plane and clearly distinguishable in 9 of 12 patients. Three patients suffering from obstructive hydrocephalus showed a clear flow signal.

Cerebrospinal fluid flow detected within the parenchymal portion of the shunt by phase contrast magnetic resonance imaging may reliably provide information about the functional status of a ventricular shunt. Even in patients whose hydrocephalus was treated with magnetic adjustable valves, the CSF flow was detectable using PC MRI sequences at 3 T field strength 10).


Non-invasive techniques to assess ‘semi-quantitatively’ whether intracranial pressure is raised or not include optic nerve sheath diameter (ultrasound or MRI), tympanic membrane displacement and transcranial Doppler but none have yet been shown to be sufficiently accurate for routine clinical use in patients with potential shunt malfunction. Provision of a separate subcutaneous CSF reservoir is of proven benefit in allowing access to the cerebral ventricles to measure ICP and allow removal of CSF in an emergency


Various invasive diagnostic test procedures for the verification of shunt function have been described:

Invasive CSF pressure and flow measurements

CSF tap test and drip interval test

Infusion tests

Radioactive shuntogram.

By comparison, publications addressing the noninvasive pumping test are rare.

Noninvasive pumping test of all formerly published results are values derived from tests with a variety of reservoirs and valves (at least 2 types).

In a few reports, the shunt/reservoir type used is not even specified, although the technical parameters of such reservoirs and valves are obviously essential.

To judge occlusions distally from the reservoir other authors have had to close the pVC transcutaneously by manual compression.

This is never possible with a sufficient certainty and, if ever undertaken, it usually does provide a source of error.


Rapid cranial MRI was not inferior to CT for diagnosing ventricular shunt malfunction and offers the advantage of sparing a child ionizing radiation exposure 11).


1)

Spirig JM, Frank MN, Regli L, Stieglitz LH (2017) Shunt agerelated complications in adult patients with suspected shunt dysfunction . A recommended diagnostic workup. 1421–1428
2)

Bromby A, Czosnyka Z, Allin D, Richards HK, Pickard JD, Czosnyka M (2007) Laboratory study on “intracranial hypotension” created by pumping the chamber of a hydrocephalus shunt. Cerebrospinal Fluid Res 9:1–9
3)

Dupepe EB, Hopson B, Johnston JM, Rozzelle CJ, Oakes WJ, Blount JP, Rocque BG (2016) Rate of shunt revision as a function of age in patients with shunted hydrocephalus due to myelomeningocele. Neurosurg Focus 41(November):1–6
4)

Korinek AM, Fulla-Oller L, Boch AL, Golmard JL, Hadiji B, Puybasset L (2011) Morbidity of ventricular cerebrospinal fluid shunt surgery in adults: an 8-year study. Neurosurgery 68(4):985–994
5)

Paulsen AH, Lundar T, Lindegaard KF (2015) Pediatric hydrocephalus: 40-year outcomes in 128 hydrocephalic patients treated with shunts during childhood. Assessment of surgical outcome, work participation, and health-related quality of life. J NeurosurgeryPediatrics 16(6):633–641
6)

Richards H, Seeley H, Pickard J (2009) Who should perform shunt surgery? Data from the UK Shunt Registry. Cerebrospinal Fluid Res 6:S31
7)

Spiegelman L, Asija R, Da Silva SL, Krieger MD, McComb JG (2014) What is the risk of infecting a cerebrospinal fluid–diverting shunt with percutaneous tapping? J Neurosurg Pediatr 14(4):336– 339
8)

Tamber MS, Klimo P, Mazzola CA, Flannery AM (2014) Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. Part 8: management of cerebrospinal fluid shunt infection. J Neurosurg Pediatr 14(Suppl1):60–71
9)

Antes S, Stadie A, Müller S, Linsler S, Breuskin D, Oertel J (2018) Intracranial Pressure–Guided Shunt Valve Adjustments with the Miethke Sensor Reservoir. World Neurosur 642–650
10)

König RE, Stucht D, Baecke S, Rashidi A, Speck O, Sandalcioglu IE, Luchtmann M. Phase-Contrast MRI Detection of Ventricular Shunt CSF Flow: Proof of Principle. J Neuroimaging. 2020 Nov 4. doi: 10.1111/jon.12794. Epub ahead of print. PMID: 33146931.
11)

Boyle TP, Paldino MJ, Kimia AA, Fitz BM, Madsen JR, Monuteaux MC, Nigrovic LE. Comparison of rapid cranial MRI to CT for ventricular shunt malfunction. Pediatrics. 2014 Jul;134(1):e47-54. doi: 10.1542/peds.2013-3739. Epub 2014 Jun 2. PubMed PMID: 24918222.

Ventriculoperitoneal shunt abdominal complications

Ventriculoperitoneal shunt abdominal complications

Abdominal complications include peritonitisascites, bowel and abdominal wall perforation, and inguinal hernias.

Abdominal complications are reported in 5–47 % of ventriculoperitoneal shunt cases 1) 2).

Ascites

Abdominal pseudocyst

Bowel perforation

Hydrocele

Shunt extrusion

Shunt migration

CSF leaks

Viscous perforations

Protrusion of the catheter from the anus

Spontaneous knotting of the peritoneal catheter is a rare complication of the VP shunt 3).

Peritoneal catheter knot formation

Liver abscess

Pyogenic liver abscess in Taiwan is most commonly due to Klebsiella pneumoniae infection in diabetic patients, and less frequently due to biliary tract infections. Liver abscess caused by ventriculoperitoneal (VP) shunt is very rare. We report a case of liver abscess caused by methicillin-resistant Staphylococcus aureus (MRSA), which developed as a complication of an infected VP shunt. A 53-year-old woman, who had shad a VP shunt implanted 3 months previously for hydrocephalus due to intracranial hemorrhage, presented with fever off and on, drowsiness and seizure attacks for 1 week. Computed tomography (CT) of the brain showed only mild right-sided hydrocephalus, and was negative for intracranial hemorrhage and intracranial mass. Analysis of cerebrospinal fluid showed significant pleocytosis and hypoglycorrhachia. CT scan of the abdomen disclosed a huge abscess in the right lobe of the liver. Cultures of both the cerebrospinal fluid and aspirated liver abscess isolated MRSA. The patient was treated with intraventricular and intravenous vancomycin, intravenous teicoplanin and oral rifampicin, followed by oral chloramphenicol and rifampicin. Percutaneous drainage of the liver abscess and externalization of the VP shunt were performed. The liver abscess had resolved almost completely on ultrasonography after 2 weeks of therapy. Liver abscess in patients with a VP shunt should be considered a possible abdominal complication of the VP shunt, and may be caused by unusual pathogens. Diagnosis requires CT scan and direct aspiration and culture of the liver abscess. Treatment requires management of both the liver abscess and the infected shunt 4).

Liver pseudocyst

The formation of a liver pseudocyst is a rare occurrence, and its mechanisms are still largely unknown.

Mallereau et al. reported the case of a 69-year-old woman with a ventriculoperitoneal shunt, inserted for the management of hydrocephalus after aneurysmal subarachnoid hemorrhage, presenting to the Accident and Emergency for acute cholecystitis. Besides confirming the diagnosis, an ultrasound investigation revealed the presence of a hepatic cyst. Conservative treatment with antibiotics and non-steroidal anti-inflammatory drugs was performed with favorable outcomes and resorption of the cyst. Interestingly the patient kept on presenting several similar episodes managed well by non-steroidal anti-inflammatory drugs alone, each of them associated with transient symptoms and signs of ventriculoperitoneal shunt malfunction. Computerized Tomography brain and lumbar puncture were normal, whereas the CT abdomen showed the ventriculoperitoneal shunt distal catheter passing through the hepatic cyst. Given the ventriculoperitoneal shunt malfunction, in the context of an infective/inflammatory process, a conversion of the ventriculoperitoneal shunt into a ventriculoatrial shunt was carried out with a successful clinical outcome.

Based on current literature they propose a clinical and radiological classification of such pseudocysts related to ventriculoperitoneal shunt. Clinical presentation, diagnostic findings, and management options are proposed for each type: purely infective, spurious (infective/inflammatory), and purely inflammatory. In the absence of system infection, a simple replacement of the distal catheter seems to be the best solution 5).

References

1)

Chung J, Yu J, Joo HK, Se JN, Kim M. Intraabdominal complications secondary to ventriculoperitoneal shunts: CT findings and review of the literature. American Journal of Roentgenology. 2009;193(5):1311–1317.
2)

Murtagh FR, Quencer RM, Poole CA. Extracranial complications of cerebrospinal fluid shunt function in childhood hydrocephalus. American Journal of Roentgenology. 1980;135(4):763–766.
3)

Borcek AO, Civi S, Golen M, Emmez H, Baykaner MK. An unusual ventriculoperitoneal shunt complication: spontaneous knot formation. Turkish Neurosurgery. 2012;22(2):261–264.
4)

Shen MC, Lee SS, Chen YS, Yen MY, Liu YC. Liver abscess caused by an infected ventriculoperitoneal shunt. J Formos Med Assoc. 2003 Feb;102(2):113-6. PubMed PMID: 12709741.
5)

Mallereau CH, Ganau M, Todeschi J, Addeo PF, Moliere S, Chibbaro S. Relapsing-Remitting Hepatic Pseudo-Cyst: a great simulator of malfunctioning ventriculoperitoneal shunt. Case report and proposal of a new classification. Neurochirurgie. 2020 Oct 10:S0028-3770(20)30399-4. doi: 10.1016/j.neuchi.2020.08.001. Epub ahead of print. PMID: 33049283.
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