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Hyponatremia Following Transsphenoidal Surgery

Epidemiology

Delayed hyponatremia following transsphenoidal surgery is a known complication, with a peak incidence of 4-7 days post-operatively 1) 2) 3).

It is a common cause of hospital readmission, due to fluid retention resulting in reduction of plasma sodium concentration below physiologic levels 4).


In a database of 466 consecutive patients who underwent endoscopic transsphenoidal surgery at a tertiary care center between April 2006 and July 2014 was reviewed for 30-day causes for readmission, length of stay, level of care required, and average cost.

Twenty-nine readmissions were identified within the study period, indicating a 30-day readmission rate of 6.2%. Among all patients, rates of 30-day readmission were 2.1% for epistaxis, 1.5% for hyponatremia, 0.9% for cerebrospinal fluid leak, and 1.7% for other medical conditions. Average cost per readmission ranged from $6011 for hyponatremia to $24,613 for cerebrospinal fluid leak 5).

Etiology

The development of Delayed Symptomatic Hyponatremia (DSH) after transsphenoidal surgery has been ascribed mostly to elevations in the secretion of ADH following mechanical manipulation of the pituitary gland, or less frequently as a result of excessive urinary excretion of salt resulting in cerebral salt wasting syndrome (CSWS) 6).

Patients with Cushing’s disease were at a significantly higher risk than other patients to experience DSH 7) 8).

Clinical features

Patients can present with a range of symptoms, from minor nausea, vomiting headache to confusion, and in severe cases, seizures and death 9).

Management

Close symptom monitoring may be a reasonable alternative to routine screening 10).

Age, gender, tumor size, rate of decline of blood sodium, and Cushing disease are potential predictors of Delayed Symptomatic Hyponatremia (DSH) (defined as serum sodium level <135 mEq/L with associated symptoms) after postoperative day 3. By identifying patients at high risk for DSH, preventative efforts can be implemented in the perioperative setting to reduce the incidence of potentially catastrophic hyponatremia following transsphenoidal surgery 11).

Modern skull base surgeons suggest that improved visualization and identification provided by the endoscope can lead to greater visualization and reduced trauma to the posterior pituitary gland 12) 13) 14).

Systematic review

A systematic search of the literature was conducted using MEDLINE/PUBMED, EMBASE, and Cochrane databases. Inclusion criteria were 1) case series with at least 10 cases reported, 2) adult patients who underwent eTSS or mTSS for pituitary tumors, and 3) reported occurrence of Delayed Symptomatic Hyponatremia (DSH) (defined as serum sodium level <135 mEq/L with associated symptoms) after postoperative day 3. Data were analyzed using CMA V.3 Statistical Software (2014).

Ten case series satisfied the inclusion criteria for a total of 2947 patients. Various factors including age, gender, cerebrospinal fluid leak, and tumor size were investigated as potential predictors of DSH. DSH event rates for both mTSS and eTSS fell between around 4 and 12 percent and included a variety of proposed predictors.

Age, gender, tumor size, rate of decline of blood sodium, and Cushing disease are potential predictors of DSH. By identifying patients at high risk for DSH, preventative efforts can be implemented in the perioperative setting to reduce the incidence of potentially catastrophic hyponatremia following transsphenoidal surgery 15).

Case series

2017

Data from before and after delayed hyponatremia (DH) care pathway implementation were retrospectively reviewed. Patient demographics and clinical characteristics were compared. Readmission causes, clinical pathway failures, sodium trends, and symptoms were evaluated.

Before the DH care pathway implementation, 229 (55%) patients were treated (group 1); afterward, 188 (45%) were treated (group 2). Baseline characteristics were equivalent between groups, except for glucocorticoid supplementation, which was higher in group 2. The incidence of detected DH was significantly lower in group 1 (16/229, 7%) than group 2 (29/188, 15%) ( P = .006) likely due to the impact of routine screening in group 2. Ten group 1 patients (4%) were readmitted for hyponatremia and 6 (3%) were managed as outpatients. Eleven group 2 patients (6%) were readmitted and 17 (9%) were managed as outpatients. Readmission rates between groups were similar ( P = .49). Patients readmitted with severe hyponatremia experienced symptoms ≥24 h before presentation. The protocol failed to prevent readmission because outpatient management for mild or moderate DH (n = 4) failed, sodium levels precipitously declined after normal screening (n = 3), and severe hyponatremia developed after scheduled screenings were missed (n = 3).

Although more DH patients were identified after care pathway implementation, readmission rates were not reduced and clinical outcomes were not changed. Because DH onset timing varies, some patients have highly acute presentation, and most readmitted patients develop symptoms before reaching their sodium nadir, close symptom monitoring may be a reasonable alternative to routine screening 16).


Of 303 patients who had transsphenoidal surgery, 27 (8.9%) were readmitted within 30 days. Most of the 27 (15 [55.6%]) had delayed hyponatremia. Other causes were diabetes insipidus (4 [14.8%]), adrenal insufficiency (2 [7.4%]), and cerebrospinal fluid leak, epistaxis, cardiac arrhythmia, pneumonia, urinary tract infection, and hypoglycemia (1 each [3.7%]). Outpatient sodium screening was performed as needed. In cases of hyponatremia, the mean postoperative day of readmission was day 8 (range, 6-12 days) and the mean serum sodium was 119 mmol/L (range, 111-129 mmol/L). Numerous patient and surgical factors were examined, and no specific predictors of readmission were identified. We developed an outpatient care pathway for managing hyponatremia with the goal of improving readmission rates.

This study establishes a quality benchmark for readmission rates after transsphenoidal surgery for pituitary lesions and identifies delayed hyponatremia as the primary cause. Implementation of an outpatient care pathway for managing hyponatremia may improve readmission rates 17).

2013

A retrospective analysis of a single-institution prospective database was conducted; all patients undergoing TSS for lesions involving the pituitary gland were followed up in a multidisciplinary neuroendocrine clinic, and demographic, imaging, and clinical data were prospectively collected. Patients were examined preoperatively and followed up postoperatively in a standardized fashion, and their postoperative sodium levels were measured at Weeks 1 and 2 postoperatively. Levels of hyponatremia were rated as mild (serum sodium concentration 130-134 mEq/L), moderate (125-129 mEq/L), or severe (< 125 mEq/L). Routine clinical questionnaires were administered at all postoperative office visits. Postoperative hyponatremia was analyzed for correlations with demographic and clinical features and with immediate postoperative physiological characteristics. RESULTS: Over a 4-year interval, 373 procedures were performed in 339 patients who underwent TSS for sellar and parasellar lesions involving the pituitary gland. The mean (± SD) age of patients was 48 ± 18 years; 61.3% of the patients were female and 46.1% were obese (defined as a body mass index [BMI] ≥ 30). The overall prevalence of DPH within the first 30 days postoperatively was 15.0%; 7.2% of the patients had mild, 3.8% moderate, and 3.8% severe hyponatremia. The incidence of symptomatic hyponatremia requiring hospitalization was 6.4%. The Fisher exact test detected a statistically significant association of DPH with female sex (p = 0.027) and a low BMI (p = 0.001). Spearman rank correlation detected a statistically significant association between BMI and nadir serum sodium concentration (r = 0.158, p = 0.002) and an inverse association for age (r = -0.113, p = 0.031). Multivariate analyses revealed a positive correlation between postoperative hyponatremia and a low BMI and a trend toward association with age; there were no associations between other preoperative demographic or perioperative risk factors, including immediate postoperative alterations in serum sodium concentration. Patients were treated with standardized protocols for hyponatremia, and DPH was not associated with permanent morbidity or mortality. CONCLUSIONS: Delayed postoperative hyponatremia was a common result of TSS; a low BMI was the only clear predictor of which patients will develop DPH. Alterations in immediate postoperative sodium levels did not predict DPH. Therefore, an appropriate index of suspicion and close postoperative monitoring of serum sodium concentration should be maintained for these patients, and an appropriate treatment should be undertaken when hyponatremia is identified 18).

2011

Kinoshita et al. evaluated (i) the incidence of post-operative hyponatremia (serum Na levels ≤ 135 mEq/L) and the emergence of hyponatremic symptoms, and assessed (ii) the risk factors under a uniform protocol of i.v. infusion with steroid and electrolyte fluid. We examined 88 consecutive operated patients (female: 60; male: 28) with pituitary adenoma. Apart from reconfirming the effects of the purported risk factors, we focused on the degree of serum Na decline on post-operative hyponatremia. Although remained stable during early post-operative period (4 days after surgery), the serum Na levels subsequently decreased after post-operative day 4 in 81 of 88 cases (92.0%). Of 88 patients, 27 (30.7%) and 9 (10.2%) cases suffered from hyponatremia, and developed hyponatremic symptoms. Interestingly, the degree of serum Na levels decline (from pre-operative levels) indicated a useful independent risk factor for monitoring hyponatremic symptoms (p = 0.006) and the degree of decline tended to be greater in elder patients (> 60 years) (p = 0.0346). Serum Na levels should be monitored from, at least, post-operative day 7 to detect early development of hyponatremia. Special attention and recovery effort should be given to elder patients with marked serum Na level decline after surgery 19).

2008

The incidence and risk factors of symptomatic and asymptomatic hyponatremia were investigated in 94 patients who underwent transsphenoidal surgery and serum sodium level monitoring between January 2002 and December 2006. The records were retrospectively reviewed to determine the incidence and risk factors (age and sex, tumor size, endocrinologic findings) of hyponatremia. Postoperatively, the serum sodium levels of the patients were measured at least once within 2 or 3 days. Hyponatremia was found in 17 of the 94 patients, of whom 7 became symptomatic. The mean sodium level of symptomatic patients with hyponatremia at diagnosis was 123.5 mEq/l, compared with 129.8 mEq/l of asymptomatic patients. The serum sodium levels began to fall on mean postoperative day 7 and reached nadir on mean day 8. All 17 patients with hyponatremia were treated with mild fluid restriction. Four symptomatic patients with severe hyponatremia were treated with 3% hypertonic saline infusion in addition to fluid restriction. One symptomatic patient with severe hyponatremia was treated with fluid restriction only. All patients recovered within 5 days of management. Sex, tumor type, and tumor size did not correlate with development of delayed hyponatremia, but patients aged >/=50 years were more likely to develop hyponatremia. Postoperative hyponatremia after transsphenoidal surgery is more common than previously reported and may lead to fatal complications. Therefore, all patients should undergo serum electrolyte level monitoring regularly for at least 1 or 2 weeks after transsphenoidal surgery 20).

2007

Patients who underwent transsphenoidal surgery at the University of Southern California University Hospital between 1997 and 2004 had serum sodium levels drawn on an outpatient basis on postoperative Day 7. Patient records were retrospectively reviewed to determine the incidence of, and risk factors for, symptomatic and asymptomatic hyponatremia. Two hundred forty-one patients had routine serum sodium levels drawn as outpatients on postoperative Day 7. Twenty-three percent of these patients were found to be hyponatremic (Na < or =135 mEq/L). The overall incidence rate of symptomatic hyponatremia in the 241 patients was 5%. The majority of hyponatremic patients (80%) remained asymptomatic, whereas 20% became symptomatic. In patients with symptomatic hyponatremia, the mean sodium level at diagnosis was 120.5 mEq/L, compared with 128.4 mEq/L in asymptomatic, hyponatremic patients (p < 0.0001). Female patients were more likely to develop hyponatremia than male patients (33% compared with 22%, p < 0.03). Fifty-two percent of patients who had transient diabetes insipidus (DI) early in their postoperative course subsequently developed hyponatremia, compared with 21% of those who did not have DI (p < 0.001). Patient age, tumor type, and tumor size did not correlate with development of delayed hyponatremia. Outpatients with moderately and severely low sodium levels were 5 and 12.5 times more likely, respectively, to be symptomatic than were patients with mild hyponatremia.

Delayed hyponatremia occurs more frequently than was previously suspected in patients who have undergone transsphenoidal surgery, especially in female patients and those who have previously had transient DI. The majority of hyponatremic patients remain asymptomatic. Obtaining a serum sodium value on an outpatient basis 1 week after pituitary surgery is helpful in recognition, risk stratification, and subsequent intervention, and may prevent potentially serious complications 21).

1999

1571 patients with pituitary adenomas (238 Cushing’s disease, 405 acromegaly, 534 hormonally inactive adenomas, 358 prolactinoma, 23 Nelson’s syndrome, and 13 thyrotropinoma) were daily examined within a 10-day postoperative inpatient observation period. Prevalence of patterns of polyuria (> 2500 ml) and oliguria/hyponatraemia (< 132 mmol/l) were surveyed as well as predictors of postoperative morbidity. RESULTS: 487 patients (31%) developed immediate postoperative hypotonic polyuria, 161 patients (10%) showed prolonged polyuria and 37 patients (2.4%) delayed hyponatraemia. A biphasic (polyuria-hyponatraemia) and triphasic (polyuria-hyponatraemia-polyuria) pattern was seen in 53 (3.4%) and 18 (1.1%) patients, respectively. Forty-one patients (2.6%) displayed immediate postoperative (day 1) hyponatraemia. Altogether, 8.4% of patients developed hyponatraemia at some time up to the 10th day postoperative, with symptomatic hyponatraemia in 32 patients (2.1%). Risk analysis showed that patients with Cushing’s disease had a fourfold higher risk of polyuria than patients with acromegaly and a 2.8-fold higher risk for postoperative hyponatraemia. Younger age, male sex, and intrasellar expansion were associated with a higher risk of hypotonic polyuria, but this was not considered clinically relevant.

The analysis illustrates that disturbances in osmoregulation resulting in polyuria and pertubations of serum sodium concentration are of very high prevalence and need observation even after selective transsphenoidal surgery for pituitary adenomas, especially in patients with Cushing’s disease22).

1995

To clarify the frequency, presentation, and outcome of this poorly understood complication, Taylor et al. reviewed the database of 2297 patients who underwent transsphenoidal pituitary surgery between February 1971 and June 1993. Of 53 patients (2.3%) treated for symptomatic hyponatremia, 11 were excluded (2 received arginine vasopressin within 24 hours, 1 had untreated hypothyroidism, 4 had untreated adrenal insufficiency, and 4 had incomplete records). The remaining 42 patients (1.8%), 11 men and 31 women aged 21 to 79 years, presented 4 to 13 days (mean, 8 d) postoperatively with nausea and vomiting (20 patients), headache (18 patients), malaise (12 patients), dizziness (4 patients), anorexia (2 patients), and seizures (1 patient). Hyponatremia was unrelated to sex, age, adenoma type, tumor size, or glucocorticoid tapering. Although the clinical picture in our patients is consistent with SIADH, this was not supported by the antidiuretic hormone levels, which were normal or low-normal in the two patients in whom they were measured, suggesting the possibility that low serum sodium may not reflect SIADH. In all patients, hyponatremia resolved within 6 days (mean, 2 d); treatment consisted of salt replacement and mild fluid restriction in 37 patients and fluid restriction only in 4 (treatment unknown in 1). Delayed hyponatremia after transsphenoidal resection of pituitary adenoma is not as rare as previously thought, nor is it necessarily associated with SIADH or with hypoadrenalism during glucocorticoid tapering 23).

1) , 21)

Zada G, Liu CY, Fishback D, Singer PA, Weiss MH. Recognition and management of delayed hyponatremia following transsphenoidal pituitary surgery. J Neurosurg. 2007 Jan;106(1):66-71. PubMed PMID: 17236489.

2) , 7) , 22)

Hensen J, Henig A, Fahlbusch R, Meyer M, Boehnert M, Buchfelder M. Prevalence, predictors and patterns of postoperative polyuria and hyponatraemia in the immediate course after transsphenoidal surgery for pituitary adenomas. Clin Endocrinol (Oxf). 1999 Apr;50(4):431-9. PubMed PMID: 10468901.

3) , 6)

Kelly DF, Laws ER, Jr., Fossett D. Delayed hyponatremia after transsphenoidal surgery for pituitary adenoma. Report of nine cases. J Neurosurg. 1995;83(2):363-367.

4)

Bohl MA, Ahmad S, Jahnke H, et al. Delayed Hyponatremia Is the Most Common Cause of 30-Day Unplanned Readmission After Transsphenoidal Surgery for Pituitary Tumors. Neurosurgery. 2015.

5)

Hendricks BL, Shikary TA, Zimmer LA. Causes for 30-Day Readmission following Transsphenoidal Surgery. Otolaryngol Head Neck Surg. 2016 Feb;154(2):359-65. doi: 10.1177/0194599815617130. Epub 2015 Nov 17. PubMed PMID: 26577772.

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Whitaker SJ, Meanock CI, Turner GF, et al. Fluid balance and secretion of antidiuretic hormone following transsphenoidal pituitary surgery. A preliminary series. Journal of neurosurgery. 1985;63(3):404-412.

10) , 16)

Bohl MA, Ahmad S, White WL, Little AS. Implementation of a Postoperative Outpatient Care Pathway for Delayed Hyponatremia Following Transsphenoidal Surgery. Neurosurgery. 2017 Apr 25. doi: 10.1093/neuros/nyx151. [Epub ahead of print] PubMed PMID: 28449052.

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Cote DJ, Alzarea A, Acosta MA, Hulou MM, Huang KT, Almutairi H, Alharbi A, Zaidi HA, Algrani M, Alatawi A, Mekary RA, Smith TR. Predictors and Rates of Delayed Symptomatic Hyponatremia after Transsphenoidal Surgery: A Systemastic Review. World Neurosurg. 2016 Apr;88:1-6. doi: 10.1016/j.wneu.2016.01.022. Epub 2016 Jan 22. PubMed PMID: 26805685.

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Ammirati M, Wei L, Ciric I. Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2013;84(8):843-849.

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Gao Y, Zhong C, Wang Y, et al. Endoscopic versus microscopic transsphenoidal pituitary adenoma surgery: a meta-analysis. World J Surg Oncol. 2014;12(94).

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Cavallo LM, Dal Fabbro M, Jalalod’din H, et al. Endoscopic endonasal transsphenoidal surgery. Before scrubbing in: tips and tricks. Surg Neurol. 2007;67(4):342-347.

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Bohl MA, Ahmad S, Jahnke H, Shepherd D, Knecht L, White WL, Little AS. Delayed Hyponatremia Is the Most Common Cause of 30-Day Unplanned Readmission After Transsphenoidal Surgery for Pituitary Tumors. Neurosurgery. 2016 Jan;78(1):84-90. doi: 10.1227/NEU.0000000000001003. PubMed PMID: 26348011.

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Hussain NS, Piper M, Ludlam WG, Ludlam WH, Fuller CJ, Mayberg MR. Delayed postoperative hyponatremia after transsphenoidal surgery: prevalence and associated factors. J Neurosurg. 2013 Dec;119(6):1453-60. doi: 10.3171/2013.8.JNS13411. Epub 2013 Sep 20. PubMed PMID: 24053496.

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Update: Medulloblastoma

Epidemiology

It is the most common malignant pediatric intracranial tumor.

Classification

Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment related morbidities.

Medulloblastoma, genetically defined

Under the current consensus classification of medulloblastoma four principle subgroups are identified:

Medulloblastoma WNT activated

Sonic hedgehog Medulloblastoma and TP53 Mutant

Medulloblastoma non WNT/non SHH

Group 3 medulloblastoma

Group 4 medulloblastoma

Medulloblastoma, histologically defined

Medulloblastoma, classic

Medulloblastoma, Desmoplastic/nodular

Medulloblastoma with extensive nodularity.

The data show that medulloblastomas of Group 3/4 differ metabolically as measured using Magnetic resonance spectroscopy (MRS) when compared with SHH molecular subgroups. MRS is a useful and accurate tool to determine medulloblastoma molecular subgroups 1).

The evidence suggests that each of the four principle subgroups will likely have distinct ‘subsets’ that are biologically and clinically homogeneous as compared to other subsets from within the same subgroup. As the nature and number of subsets for each subgroup are currently unknown, the consensus classification suggests that each subset be named using a Greek letter (α, β, γ, etc.) until such time as they are sufficiently characterized to be named based on their molecular etiology 2).


see Cerebellar medulloblastomas

see Cerebellopontine angle medulloblastoma

see Multifocal medulloblastoma

Etiology

Several lines of evidence implicate granule neuron precursors (GNP) in the external granule layer (EGL) of the developing cerebellum as likely cells of origin for certain classes of medulloblastomas.

1). For example, cells that compose a preneoplastic stage of medulloblastoma colocalize with GNPs in the EGL and they express molecular markers of immature granule neurons ( 2). Another possible medulloblastoma cell of origin has been identified: a neural progenitor located in the cerebellar white matter and expressing both nestin and prominin ( 3). Signal transduction pathways that stimulate proliferation and inhibit differentiation of GNPs and other neural progenitor cells during development have been implicated in medulloblastoma. Thus, understanding the mitogenic functions of these pathways will yield insights into medulloblastoma formation.

The overexpression of proteins that normally stimulate proliferation of neural progenitor cells may initiate medulloblastoma formation. Two known mitogens for neural progenitors are the c-Myc oncoprotein and Sonic hedgehog (Shh), a crucial determinant of embryonic pattern formation in the central nervous system.

Several genes have been implicated in the development of medulloblastoma in children, including Patched-1 and Smoothened. The protein products of these genes function within the sonic hedgehog molecular signaling pathways, which are important in neural development and disease.

Pathogenesis

Medulloblastoma, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2.

Tumor necrosis-initiated complement activation stimulates proliferation of medulloblastoma cells 3).

Combined activation of the Shh/Ptc and IGF signaling pathways is an important mechanism in MB pathogenesis 4).

Both pathways are essential regulators of granule neuron precursors (GNP) proliferation during cerebellar development. In cultured GNPs, IGF signaling stabilizes the oncogenic transcription factor N-myc by inhibiting glycogen synthase kinase 3beta-dependent phosphorylation and consequent degradation of N-myc. However, determinants of Shh and IGF tumorigenicity in vivo remain unknown

Activation of the Sonic hedgehog (Shh)/Patched signaling pathway in the postnatal cerebellum is sufficient to induce medulloblastoma in mice. Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by insulin-like growth factor-II, inactivation of the p53 tumor suppressor protein, loss of DNA damage repair mechanisms, and ectopic expression of Myc oncoproteins cooperate with Shh/Patched signaling to enhance tumor formation in mice. Ectopic expression of alpha and beta interferons in the developing brain also induces Shh-mediated medulloblastoma formation, suggesting a possible role for antiviral response in the genesis of medulloblastoma 5).

Dissemination

Cerebrospinal fluid (CSF) dissemination to the cranio-spinal axis occurs in 30% to 40% of cases 6).

However, medulloblastoma primarily presenting with symptoms related to spinal metastasis is extremely rare 7) 8).

To date, there are only a limited number of cases that have been reported in the literature 9) 10) 11).

Diagnosis

It appears as a homogenously enhancing hyperdense mass on computed tomography scan and is associated with the clinical picture of posterior fossa syndrome. This unique clinic-radiological pattern in considered “typical” medulloblastoma, but medulloblastomas does not follow the typical clinic-radiological pattern in a significant number of children and adult cases and should be considered in all midline posterior fossa tumors, hemisphere and cerebellopontine angle despite having clinical and radiological features suggestive of other tumors. Definitive diagnosis requires histologic confirmation in all cases 12).

MRI

Tumor location and enhancement pattern were predictive of molecular subgroups of pediatric medulloblastoma and may potentially serve as a surrogate for genomic testing 13).

Enhancing medulloblastomas exhibited strong VEGFR1/2 and CD31 expression relative to nonenhancing tumors. There was no significant difference in perioperative complications or patient survival between the 2 groups.

These results suggest that in patients with medulloblastoma the presence of enhancement on MRI may correlate with increased vascularity and angiogenesis, but does not correlate with worse patient prognosis in the short or long term 14).

Apparent diffusion coefficient

Using only apparent diffusion coefficient (ADC) values measured on ADC maps. One hundred and three pediatric patients with pre-operative magnetic resonance imaging scans showing a posterior fossa tumor with histological verification were retrospectively identified from a ten-year period at a tertiary care medical center. A single observer measured the lowest ADC values in all tumors to determine the mean minimum ADC (ADCmin) value that provided greatest accuracy in distinguishing medulloblastomas from other tumors, which was determined to be 0.66×10(-3) mm(2)/s. Imaging studies, including ADC maps, from 90 patients were provided to two neuroradiologists, who provided a diagnosis, which was later dichotomized as medulloblastoma or other. Two medical students measured ADCmin within tumors and those with ADCmin < 0.66×10(-3) mm(2)/s were recorded as medulloblastoma; any other value was recorded as other. Diagnostic accuracy was measured. ADCmin values allowed a correct identification of lesions as either medulloblastoma or other in 91% of cases. After diagnoses by the two neuroradiologists were categorized as either medulloblastoma or other, their diagnoses were correct in 90% and 84% of cases, respectively. In 19 cases, at least one neuroradiologist was incorrect; the addition of ADC values to clinical interpretation would have allowed a correct diagnosis in 63% of such cases. Diagnostic accuracy based on ADC values by medical students was comparable to that of subspecialty-trained neuroradiologists. This findings suggest that the addition of ADC values to standard film interpretation may improve the diagnostic rate for these tumors 15).

Both ADCmin and nADC could serve as the basis for a CAD program to distinguish medulloblastoma from other posterior fossa tumors with a high degree of accuracy 16).

Differential diagnosis

Ewing’s Sarcoma peripheral primitive neuroectodermal tumor

Fourth ventricle ependymoma:

Usually arises from the floor of the 4th ventricle

Typically squeezes out the foramen of Luschka

Treatment

Genomics-based classification has identified four major subgroups and provides greater opportunity for developing targeted therapies more successful than current conventional therapy.

Surgery

Surgical resection is undertaken with the goal of gross total resection. Postoperative neuroimaging studies are compared with preoperative studies to determine the amount of residual disease.

The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection 17).

Cerebrospinal fluid is obtained from a lumbar puncture done at the conclusion of the surgical resection or 2 weeks after surgery in order to determine microscopic leptomeningeal spread. Children are enrolled, when possible, in open clinical trials.

Chemotherapy and radiation

Chemotherapy and radiation are given as per protocol. The goal of current treatment approaches is to tailor therapy based on clinical risk factors, with intensification of treatment for children with high-risk disease and reduction of radiation therapy for those with standard-risk disease.

Chemotherapeutic trials have been developed to assess the safety and efficacy of various multi-agent therapies to improve the poor results of high-risk patients and to allow reduction in the dose of radiation needed to cure standard-risk patients, which may allow a decrease in late cognitive sequelae. Currently, it is policy to evaluate all children with posterior fossa tumors characteristic of medulloblastoma with preoperative, staging neuroimaging studies of the craniospinal axis.

Outcome

Although surgery, radiation and high-dose chemotherapy have led to increased survival, one-third of patients succumb to their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment.

Through analysis of several well-designed multi-institutional trials, much has been learned about the clinical factors that influence outcome in children with medulloblastomas. Age younger than 3 years, bulky residual disease postoperatively, and metastasis constitute adverse prognostic features and indicate patients who are considered “high risk” for recurrence with standard therapy using 3600 cGy craniospinal radiation in conjunction with a posterior fossa dose of 5400 cGy. Patients lacking these features are considered “standard risk.”

Evaluation of biologic predictors of outcome, which may further refine treatment stratification, is in progress.

Response Assessment

Lack of standard response criteria in clinical trials for medulloblastoma and other seeding tumors complicates assessment of therapeutic efficacy and comparisons across studies. An international working group was established to develop consensus recommendations for response assessment. The aim is that these recommendations be prospectively evaluated in clinical trials, with the goal of achieving more reliable risk stratification and uniformity across clinical trials. Current practices and literature review were performed to identify major confounding issues and justify subsequently developed recommendations; in areas lacking scientific investigations, recommendations were based on experience of committee members and consensus was reached after discussion. Recommendations apply to both adult and pediatric patients with medulloblastoma and other seeding tumors. Response should be assessed using MR imaging (brain and spine), Cerebrospinal fluid cytology, and neurologic examination. Clinical imaging standards with minimum mandatory sequence acquisition that optimizes detection of leptomeningeal metastases are defined.

Warren et al. recommend central review prior to inclusion in treatment cohorts to ensure appropriate risk stratification and cohort inclusion. Consensus recommendations and response definitions for patients with medulloblastomas and other seeding tumors have been established; as with other RANO recommendations, these need to now be prospectively validated in clinical trials 18).

Case series

2015

A total of 67 pediatric cases of newly diagnosed medulloblastoma were included in a study. All of the children were treated at Xinhua Hospital between January 2007 and June 2013. The authors retrospectively analyzed the clinical data, treatment modalities, and outcome. The male-to-female ratio was 2:1, and the patients’ median age at diagnosis was 51.96 months (range 3.96-168.24 months). The median duration of follow-up was 32 months (range 3-70 months).

At the most recent follow-up date, 31 patients (46%) were alive, 30 (45%) had died, and 6 (9%) had been lost to follow-up. The estimated 3-year overall survival and progression-free survival, based on Kaplan-Meier analysis, were 55.1% ± 6.4% and 45.6% ± 6.7%, respectively. Univariate analysis showed that standard-risk group (p = 0.009), postoperative radiotherapy (RT) combined with chemotherapy (p < 0.001), older age (≥ 3 years) at diagnosis (p = 0.010), gross-total resection (p = 0.012), annual family income higher than $3000 (p = 0.033), and living in urban areas (p = 0.008) were favorable prognostic factors. Multivariate analysis revealed that postoperative RT combined with chemotherapy was an independent prognostic factor (p < 0.001). The treatment abandonment rate in this cohort was 31% (21 of 67 cases).

There was a large gap between the outcome of medulloblastoma in Chinese children and the outcome in Western children. Based on this data, treatment abandonment was the major cause of therapeutic failure. Parents’ misunderstanding of medulloblastoma played a major role in abandonment, followed by financial and transportation difficulties. Establishment of multidisciplinary treatment teams could improve the prognosis of medulloblastoma in Chinese children 19).


Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases.

The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality of life than for patients in other subgroups 20).

1995

Sure et al describe the incidence of secondary tumour manifestations in 66 patients of a single centre who underwent surgery for medulloblastoma between 1975 and 1990. No patient was excluded due to a poor postoperative course. Thirty-five patients showed evidence of secondary tumour growth. Of these, 17 suffered from local recurrence, and 27 developed metastastatic disease. The median latencies for secondary manifestations were 25 months for local recurrence (n = 17), 11 months for spinal metastases (n = 10), 15 months for supratentorial metastases (n = 8), 8 months for subleptomeningeal dissemination (n = 6), and 23 months for systemic metastases (n = 8). Two patients developed primary metastatic spread to the posterior fossa. Of 8 patients with supratentorial metastases, 6 developed fronto-basal lesions. In our patients, 89% of secondary lesions occurred within less than 3 years after primary diagnosis. 85% of patients with extra-axial tumour spread had been treated with a permanent shunt. Radical tumour resection and radiotherapy with 30 Gy to the neuraxis and 20 Gy boost to the posterior fossa was an important prognostic factor in this series. Patients with additional chemotherapy did not benefit significantly from this treatment. We conclude that optimal management of the primary lesions should aim at (i) total resection, (ii) avoid permanent shunting, and (iii) completion of the radiotherapy with inclusion of the medial frontobasal cisterns in the radiotherapeutic regimen. Our analysis suggests that adequate postoperative screening programmes should consist of 3-monthly scans of the neuraxis in the first three postoperative years and 6-monthly scans thereafter 21).

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Blüml S, Margol AS, Sposto R, Kennedy RJ, Robison NJ, Vali M, Hung LT, Muthugounder S, Finlay JL, Erdreich-Epstein A, Gilles FH, Judkins AR, Krieger MD, Dhall G, Nelson MD, Asgharzadeh S. Molecular subgroups of medulloblastoma identification using noninvasive magnetic resonance spectroscopy. Neuro Oncol. 2015 Aug 8. pii: nov097. [Epub ahead of print] PubMed PMID: 26254476.
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Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012 Apr;123(4):465-72. doi: 10.1007/s00401-011-0922-z. Epub 2011 Dec 2. PubMed PMID: 22134537; PubMed Central PMCID: PMC3306779.
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Maurer AJ, Bonney PA, Toho LC, Glenn CA, Agarwal S, Battiste JD, Fung KM, Sughrue ME. Tumor necrosis-initiated complement activation stimulates proliferation of medulloblastoma cells. Inflamm Res. 2015 Jan 22. [Epub ahead of print] PubMed PMID: 25603857.
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Rao G, Pedone CA, Del Valle L, Reiss K, Holland EC, Fults DW. Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene. 2004 Aug 12;23(36):6156-62. PubMed PMID: 15195141.
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Fults DW. Modeling medulloblastoma with genetically engineered mice. Neurosurg Focus. 2005 Nov 15;19(5):E7. Review. PubMed PMID: 16398471.
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Stanley P, Suminski N. The incidence and distribution of spinal metastases in children with posterior fossa medulloblastomas. Am J Pediatr Hematol Oncol. 1988;10:283–287. doi: 10.1097/00043426-198824000-00002.
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Meshkini A, Vahedi A, Meshkini M, Alikhah H, Naghavi-Behzad M. Atypical medulloblastoma: A case series. Asian J Neurosurg. 2014 Jan;9(1):45-7. doi: 10.4103/1793-5482.131077. PubMed PMID: 24891891; PubMed Central PMCID: PMC4038867.
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Perreault S, Ramaswamy V, Achrol AS, Chao K, Liu TT, Shih D, Remke M, Schubert S, Bouffet E, Fisher PG, Partap S, Vogel H, Taylor MD, Cho YJ, Yeom KW. MRI Surrogates for Molecular Subgroups of Medulloblastoma. AJNR Am J Neuroradiol. 2014 May 15. [Epub ahead of print] PubMed PMID: 24831600.
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Hervey-Jumper SL, Garton HJ, Lau D, Altshuler D, Quint DJ, Robertson PL, Muraszko KM, Maher CO. Differences in vascular endothelial growth factor receptor expression and correlation with the degree of enhancement in medulloblastoma. J Neurosurg Pediatr. 2014 Jun 6:1-8. [Epub ahead of print] PubMed PMID: 24905841.
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Pierce T, Kranz PG, Roth C, Leong D, Wei P, Provenzale JM. Use of apparent diffusion coefficient values for diagnosis of pediatric posterior fossa tumors. Neuroradiol J. 2014 Apr;27(2):233-44. doi: 10.15274/NRJ-2014-10027. Epub 2014 Apr 18. PubMed PMID: 24750714.
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Pierce TT, Provenzale JM. Evaluation of apparent diffusion coefficient thresholds for diagnosis of medulloblastoma using diffusion-weighted imaging. Neuroradiol J. 2014 Feb;27(1):63-74. Epub 2014 Feb 24. PubMed PMID: 24571835.
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Thompson EM, Hielscher T, Bouffet E, Remke M, Luu B, Gururangan S, McLendon RE, Bigner DD, Lipp ES, Perreault S, Cho YJ, Grant G, Kim SK, Lee JY, Rao AA, Giannini C, Li KK, Ng HK, Yao Y, Kumabe T, Tominaga T, Grajkowska WA, Perek-Polnik M, Low DC, Seow WT, Chang KT, Mora J, Pollack IF, Hamilton RL, Leary S, Moore AS, Ingram WJ, Hallahan AR, Jouvet A, Fèvre-Montange M, Vasiljevic A, Faure-Conter C, Shofuda T, Kagawa N, Hashimoto N, Jabado N, Weil AG, Gayden T, Wataya T, Shalaby T, Grotzer M, Zitterbart K, Sterba J, Kren L, Hortobágyi T, Klekner A, László B, Pócza T, Hauser P, Schüller U, Jung S, Jang WY, French PJ, Kros JM, van Veelen MC, Massimi L, Leonard JR, Rubin JB, Vibhakar R, Chambless LB, Cooper MK, Thompson RC, Faria CC, Carvalho A, Nunes S, Pimentel J, Fan X, Muraszko KM, López-Aguilar E, Lyden D, Garzia L, Shih DJ, Kijima N, Schneider C, Adamski J, Northcott PA, Kool M, Jones DT, Chan JA, Nikolic A, Garre ML, Van Meir EG, Osuka S, Olson JJ, Jahangiri A, Castro BA, Gupta N, Weiss WA, Moxon-Emre I, Mabbott DJ, Lassaletta A, Hawkins CE, Tabori U, Drake J, Kulkarni A, Dirks P, Rutka JT, Korshunov A, Pfister SM, Packer RJ, Ramaswamy V, Taylor MD. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. Lancet Oncol. 2016 Mar 11. pii: S1470-2045(15)00581-1. doi: 10.1016/S1470-2045(15)00581-1. [Epub ahead of print] PubMed PMID: 26976201.
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Warren KE, Vezina G, Poussaint TY, Warmuth-Metz M, Chamberlain MC, Packer RJ, Brandes AA, Reiss M, Goldman S, Fisher MJ, Pollack IF, Prados MD, Wen PY, Chang SM, Dufour C, Zurakowski D, Kortmann RD, Kieran MW. Response Assessment in Medulloblastoma and Leptomeningeal Seeding Tumors: Recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee. Neuro Oncol. 2017 Apr 25. doi: 10.1093/neuonc/nox087. [Epub ahead of print] PubMed PMID: 28449033.
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Wang C, Yuan XJ, Jiang MW, Wang LF. Clinical characteristics and abandonment and outcome of treatment in 67 Chinese children with medulloblastoma. J Neurosurg Pediatr. 2016 Jan;17(1):49-56. doi: 10.3171/2015.5.PEDS1573. Epub 2015 Oct 9. PubMed PMID: 26451721.
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Schneider C, Ramaswamy V, Kulkarni AV, Rutka JT, Remke M, Tabori U, Hawkins C, Bouffet E, Taylor MD. Clinical implications of medulloblastoma subgroups: incidence of CSF diversion surgery. J Neurosurg Pediatr. 2015 Mar;15(3):236-42. doi: 10.3171/2014.9.PEDS14280. Epub 2014 Dec 19. PubMed PMID: 25525930.
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Sure U, Bertalanffy H, Isenmann S, Brandner S, Berghorn WJ, Seeger W, Aguzzi A. Secondary manifestation of medulloblastoma: metastases and local recurrences in 66 patients. Acta Neurochir (Wien). 1995;136(3-4):117-26. PubMed PMID: 8748840.

Update: Low grade glioma treatment

Choosing the best treatment strategy for each patient with a diffuse low grade glioma, in other words optimizing the oncologic and functional balance, implies not only a full knowledge of the natural history of this chronic disease, but also an understanding of the adaptation of the brain in response to growth and spread of the glioma1).

The ideal management of suspected low-grade gliomas (LGGs) has historically been controversial in neurosurgery and neurooncology 2) 3) 4).

The management of low-grade glioma (LGG) still remains controversial because the effectiveness of early and extensive resection is unclear, and the use of radiation therapy or chemotherapy is not well-defined.

Surgery

Despite the lack of randomized controlled trials hampering the performance of appropriate metaanalysis, the increasing amount of evidence pointed toward an aggressive surgical strategy.

Although a large amount of data supports resection for symptomatic diffuse low-grade glioma (LGG), the therapeutic strategy regarding incidental LGG (ILGG) is still a matter of debate. Indeed, early “preventive” surgery has recently been proposed in asymptomatic patients with LGG, after showing that the extent of resection was larger than in symptomatic patients with LGG. However, the quality of life should be preserved by avoiding both neurological deficit and epilepsy 5).

The largest study in patients with low-grade gliomas, performed by Capelle et al. 6) , showed a strong impact of the extent of resection EOR on survival, especially when a radiological complete resection was obtained.

Although non-controlled series have a potential selection bias, similar results were found in a study with an unusual geographic and medical constellation that essentially eliminated the selection bias: two hospitals in Norway, each taking exclusive care of a large, stable population, followed different strategies for patients with low-grade glioma. One of the hospitals favoured a biopsy followed by a “wait-and-see” strategy, delaying further therapy until malignant progression while the other hospital preferred to perform maximal safe resection whenever possible. Outcome comparison between the two hospitals revealed that patients of the surgery-preferring hospital had a significantly better survival rate, suggesting that a proactive and aggressive treatment plan improves survival of low-grade glioma patients. Moreover, the rate of malignant transformation was twice as high in the “wait-and-see” cohort. Taken together, these findings support a proactive and radical surgical approach for low-grade gliomas rather than a “wait-and-see” strategy 7).

This surgery has to be performed with the appropriate armamentarium, which is the availability of intraoperative stimulation mapping, especially for those lesions occurring in cortical and subcortical eloquent sites.

According to the recently published guidelines, surgical treatment has been increasingly recognized as the initial therapeutic act of choice for patients diagnosed with a presumed low grade glioma, given that total resection can improve seizure control, progression free survival and overall survival, while reducing the risk of malignant transformation and preserving patients’ functional status 8).


Treatment options include observation, surgery, radiation, chemotherapy, or a combined approach, and management is individualized based on tumor location, histology, molecular profile, and patient characteristics. Moreover, in this type of brain tumor with a relatively good prognosis and prolonged survival, the potential benefits of treatment must be carefully weighed against potential treatment-related risks 9).

Patients with clinically and radiographically suspected LGG have two initial surgical options, biopsy or resection. Biopsy can provide a histological diagnosis with minimal risk but does not offer a direct treatment. Resection may have additional benefits such as increasing survival and delaying recurrence, but is associated with a higher risk for surgical morbidity. There remains controversy about the role of biopsy versus resection and the relative clinical outcomes for the management of LGG.

Evidence suggests that a greater extent of resection (EOR) extends malignant progression-free survival among patients with low-grade gliomas (LGGs). These studies, however, rely on the combined analysis of oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas-3 histological subtypes with distinct genetic and molecular compositions 10).

The following electronic databases were searched in 2012 for the first version of the review: Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11), MEDLINE (1950 to November week 3 2012), Embase (1980 to Week 46 2012). For this updated version, the following electronic databases were searched: Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5), MEDLINE (Nov 2012 to June week 3 2016), Embase (Nov 2012 to 2016 week 26). All relevant articles were identified on PubMed and by using the ‘related articles’ feature.

Jiang et al. also searched unpublished and grey literature including ISRCTN-metaRegister of Controled Trials, Physicians Data Query and ClinicalTrials.gov for ongoing trials.

Jiang et al. planned to include patients of any age with a suspected intracranial LGG receiving biopsy or resection within a randomized clinical trial (RCT) or controlled clinical trial (CCT). Patients with prior resections, radiation therapy, or chemotherapy for LGG were excluded. Outcome measures included overall survival (OS), progression-free survival (PFS), functionally independent survival (FIS), adverse events, symptom control, and quality of life (QoL).

A total of 1375 updated citations were searched and critically analyzed for relevance. This was undertaken independently by two review authors. The original electronic database searches yielded a total of 2764 citations. In total, 4139 citations have been critically analyzed for this updated review.

No new RCTs of biopsy or resection for LGG were identified. No additional ineligible non-randomized studies (NRS) were included in this updated review. Twenty other ineligible studies were previously retrieved for further analysis despite not meeting the pre-specified criteria. Ten studies were retrospective or were literature reviews. Three studies were prospective, however they were limited to tumor recurrence and volumetric analysis and extent of resection. One study was a population-based parallel cohort in Norway, but not an RCT. Four studies were RCTs, however patients were randomized with respect to varying radiotherapy regimens to assess timing and dose of radiation. One RCT was on high-grade gliomas (HGGs) and not LGG. Finally, one RCT evaluated diffusion tensor imaging (DTI)-based neuro-navigation for surgical resection.

Since the last version of this review, no new studies have been identified for inclusion and currently there are no RCTs or CCTs available on which to base definitive clinical decisions. Therefore, physicians must approach each case individually and weigh the risks and benefits of each intervention until further evidence is available. Some retrospective studies and non-randomized prospective studies do seem to suggest improved OS and seizure control correlating to higher extent of resection. Future research could focus on RCTs to determine outcomes benefits for biopsy versus resection 11).


Based on results of three randomized clinical trials (RCT), radiotherapy (RT) may be deferred in patients with low risk low grade glioma (defined as age <40 years and having undergone a complete resection), although combined chemoradiotherapy has never been prospectively evaluated in the low-risk population. The recent RTOG 9802 RCT established a new standard of care in high-risk patients (defined as age >40 years or incomplete resection) by demonstrating a nearly twofold improvement in overall survival with the addition of PCV (procarbazine, CCNU, vincristine) chemotherapy following RT as compared to RT alone. Chemotherapy alone as a treatment of LGG may result in less toxicity than RT; however, this has only been prospectively studied once (EORTC 22033) in high-risk patients. A challenge remains to define when an aggressive treatment improves survival without impacting quality of life (QoL) or neurocognitive function and when an effective treatment can be delayed in order to preserve QoL without impacting survival. Current WHO histopathological classification is poorly predictive of outcome in patients with LGG. The integration of molecular biomarkers with histology will lead to an improved classification that more accurately reflects underlying tumor biology, prognosis, and hopefully best therapy 12).

Chemotherapy

Radiotherapy

Radiation therapy has been proven effective in increasing time to progression in LGG, and emerging data support a role for combined modality therapy incorporating chemotherapy.

Postoperative Radiotherapy

Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who undergo early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remains unclear whether there are differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated 13).

1)

Duffau H. Diffuse low-grade gliomas and neuroplasticity. Diagn Interv Imaging. 2014 Sep 10. pii: S2211-5684(14)00220-4. doi: 10.1016/j.diii.2014.08.001. [Epub ahead of print] PubMed PMID: 25218490.
2)

Keles GE, Lamborn KR, Berger MS: Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome. J Neurosurg 95:735–745, 2001
3)

Lang FF, Gilbert MR: Diffusely infiltrative low-grade gliomas in adults. J Clin Oncol 24:1236–1245, 2006
4)

Wessels PH, Weber WE, Raven G, Ramaekers FC, Hopman AH, Twijnstra A: Supratentorial grade II astrocytoma: biological features and clinical course. Lancet Neurol 2:395–403, 2003
5)

de Oliveira Lima GL, Duffau H. Is there a risk of seizures in “preventive” awake surgery for incidental diffuse low-grade gliomas? J Neurosurg. 2015 Jun;122(6):1397-405. doi: 10.3171/2014.9.JNS141396. Epub 2015 Feb 27. PubMed PMID: 25723301.
6)

Capelle L, Fontaine, D, Mandonnet E, Taillandier L, Golmard JL, Bauchet L, et al. Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases. J Neurosurg. 2013;118(6):1157–68.
7)

Jakola A, Mymel KS, Kloster R, Torp SH, Lindal S, Unsgard G. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA. 2012;308(18):1881–8.
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Riva M, Bello L. Low-grade glioma management: a contemporary surgical approach. Curr Opin Oncol. 2014 Nov;26(6):615-21. doi: 10.1097/CCO.0000000000000120. PubMed PMID: 25279963.
9)

Forst DA, Nahed BV, Loeffler JS, Batchelor TT. Low-Grade Gliomas. Oncologist. 2014 Mar 24. [Epub ahead of print] PubMed PMID: 24664484.
10)

Snyder LA, Wolf AB, Oppenlander ME, Bina R, Wilson JR, Ashby L, Brachman D, Coons SW, Spetzler RF, Sanai N. The impact of extent of resection on malignant transformation of pure oligodendrogliomas. J Neurosurg. 2014 Feb;120(2):309-14. doi: 10.3171/2013.10.JNS13368. Epub 2013 Dec 6. PubMed PMID: 24313617.
11)

Jiang B, Chaichana K, Veeravagu A, Chang SD, Black KL, Patil CG. Biopsy versus resection for the management of low-grade gliomas. Cochrane Database Syst Rev. 2017 Apr 27;4:CD009319. doi: 10.1002/14651858.CD009319.pub3. [Epub ahead of print] Review. PubMed PMID: 28447767.
12)

Le Rhun E, Taillibert S, Chamberlain MC. Current Management of Adult Diffuse Infiltrative Low Grade Gliomas. Curr Neurol Neurosci Rep. 2016 Feb;16(2):15. doi: 10.1007/s11910-015-0615-4. PubMed PMID: 26750130.
13)

Sarmiento JM, Venteicher AS, Patil CG. Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas. Cochrane Database Syst Rev. 2015 Jun 29;6:CD009229. doi: 10.1002/14651858.CD009229.pub2. PubMed PMID: 26118544; PubMed Central PMCID: PMC4506130.

Update: Magnetic resonance imaging for chronic subdural hematoma

The Magnetic Resonance Imaging (MRI) examination better shows the location of the chronic subdural hematoma and evidences its dimensions much clearer together with the mass effect of the adjacent structures1).

Moreover, it is more useful in cases of bilateral chronic subdural hematoma and isodense chronic subdural hematomas. The MRI examination is superior to the CT examination as far as the membranes dimensions of the chronic subdural haematoma and the presence of the septa inside the haematoma are concerned, and in determining the size and internal structures of chronic subdural hematomas 2).

In these conditions the surgical approach could be modified 3).

Even though MRI has advantages, CT remains the procedure of choice in the acute setting because of shorter examination time, which is important in acutely ill patients, reliability in identifying other lesions 4).

Classification

Based on MRI, CSDHs can be classified into five types on both T(1)- and T(2)-weighted images: low, high, and mixed intensity, isointensity, and layered.

Usually, CSDHs are hyperintense on both T1- and T2-weighted MRI (the T1 values of CSDHs are significantly shorter than gray matter values and significantly longer than white matter values and the T2 values are significantly longer than both gray matter and white matter values) 5).

Axial T1-weighted magnetic resonance imaging demonstrates bilateral subacute subdural hematomas with increased signal intensity. Areas of intermediate intensity represent more acute hemorrhage into the subacute collections.

In the series of Hosoda et al. in many ways, MRI was superior to CT for demonstrating the hematomas. In general, chronic subdural hematomas were hyperintense on both T1- and T2-weighted MRI. The T1 values of chronic subdural hematomas were significantly shorter than gray matter values and significantly longer than white matter values. The T2 values were significantly longer than both gray matter and white matter values. These findings were consistent with previous reports. However, six hematomas (30%) were iso- or hypointense on T1-weighted images. Possible mechanisms responsible for the difference in intensity of chronic subdural hematoma on MRI are discussed, and the important role of methemoglobin formation is emphasized 6)

Case series

2017

Ninety-three patients with bilateral CSDH who underwent unilateral bur hole surgery at Aizu Chuo Hospital were included in a retrospective analysis. Findings on preoperative MRI, preoperative thickness of the drained hematoma, and the influence of antiplatelet or anticoagulant drugs were considered and evaluated in univariate and multivariate analyses.

The overall growth rate was 19% (18 of 93 hematomas), and a significantly greater percentage of the hematomas that were iso- or hypointense on preoperative T1-weighted imaging showed growth compared with other hematomas (35.4% vs 2.3%, p < 0.001). Multivariate logistic regression analysis showed that findings on preoperative T1-weighted MRI were the sole significant predictor of hematoma growth, and other factors such as antiplatelet or anticoagulant drug use, patient age, patient sex, thickness of the treated hematoma, and T2-weighted MRI findings were not significantly related to hematoma growth. The adjusted odds ratio for hematoma growth in the T1 isointense/hypointense group relative to the T1 hyperintense group was 25.12 (95% CI 3.89-51.58, p < 0.01).

The findings of preoperative MRI, namely T1-weighted sequences, may be useful in predicting the growth of hematomas that did not undergo bur hole surgery in patients with bilateral CSDH 7).

2015

Preoperative MRI and postoperative computed tomography (CT) were performed and the influence of the preoperative use of antiplatelet or anticoagulant drugs was also studied. The overall recurrence rate was 9.3% (47 of 505 hematomas). The MRI T1-iso/hypointensity group showed a significantly higher recurrence rate (18.2%, 29 of 159) compared to the other groups (5.2%, 18 of 346; p < 0.001). Multivariate logistic regression analysis showed T1 classification was the solo significant prognostic predictor among various factors such as bilateral hematoma, antiplatelet or anticoagulant drug usage, residual hematoma on postoperative CT, and MRI classification (p < 0.001): adjusted odds ratio for the recurrence in T1-iso/hypointensity group relative to the T1-hyperintensity group was 5.58 [95% confidence interval (CI), 2.09-14.86] (p = 0.001). Postoperative residual hematoma and antiplatelet or anticoagulant drug usage did not increase the recurrence risk. The preoperative MRI findings, especially T1WI findings, have predictive value for postoperative recurrence of CSDH and the T1-iso/hypointensity group can be assumed to be a high recurrence risk group 8).

2010

CT and MR images of 48 chronic subdural haematomas of 34 patients were reviewed retrospectively. The thickness measurements and imaging characteristics of haematomas were compared.

Levelling was observed in 25% of haematomas, and most of them (60%) had intrahaematomal membranes. All membranes could be delineated by MR imaging, whereas only 27% were defined by CT. Mixed density (52%) and T1 hyperintensity (59%) were commonly observed in membraned haematomas, but the difference was not statistically significant. Haematomas were measured significantly thicker on MR images. All patients had been treated with burr hole craniotomy and irrigation.

MR imaging is more sensitive than CT in determining the size and internal structures of chronic subdural haematomas 9).

1987

Magnetic resonance imaging (MRI) and computerized tomography (CT) scans of 18 patients with 20 chronic subdural hematomas were compared. In many ways, MRI was superior to CT for demonstrating the hematomas. In general, chronic subdural hematomas were hyperintense on both T1- and T2-weighted MRI. The T1 values of chronic subdural hematomas were significantly shorter than gray matter values and significantly longer than white matter values. The T2 values were significantly longer than both gray matter and white matter values. These findings were consistent with previous reports. However, six hematomas (30%) were iso- or hypointense on T1-weighted images. Possible mechanisms responsible for the difference in intensity of chronic subdural hematoma on MRI are discussed, and the important role of methemoglobin formation is emphasized 10).

1)

Williams VL, Hogg JP. Magnetic resonance imaging of chronic subdural hematoma. Neurosurg Clin N Am. 2000 Jul;11(3):491-8. Review. PubMed PMID: 10918019.

2) , 9)

Senturk S, Guzel A, Bilici A, Takmaz I, Guzel E, Aluclu MU, Ceviz A. CT and MR imaging of chronic subdural hematomas: a comparative study. Swiss Med Wkly. 2010 Jun 12;140(23-24):335-40. doi: smw-12867. PubMed PMID: 20349366.

3)

Iliescu IA. Current diagnosis and treatment of chronic subdural haematomas. J Med Life. 2015 Jul-Sep;8(3):278-84. Review. PubMed PMID: 26351527; PubMed Central PMCID: PMC4556906.

4)

Adhiyaman V, Asghar M, Ganeshram KN, Bhowmick BK. Chronic subdural haematoma in the elderly. Postgrad Med J. 2002;78:71–5.

5)

Fujisawa H, Nomura S, Kajiwara K, Kato S, Fujii M, Suzuki M. Various magnetic resonance imaging patterns of chronic subdural hematomas: indicators of the pathogenesis? Neurol Med Chir (Tokyo) 2006;46:333–9.

6) , 10)

Hosoda K, Tamaki N, Masumura M, Matsumoto S, Maeda F. Magnetic resonance images of chronic subdural hematomas. J Neurosurg. 1987 Nov;67(5):677-83. PubMed PMID: 3668635.

7)

Fujitani S, Ishikawa O, Miura K, Takeda Y, Goto H, Maeda K. Factors predicting contralateral hematoma growth after unilateral drainage of bilateral chronic subdural hematoma. J Neurosurg. 2017 Mar;126(3):755-759. doi: 10.3171/2016.1.JNS152655. PubMed PMID: 27081904.

8)

Goto H, Ishikawa O, Nomura M, Tanaka K, Nomura S, Maeda K. Magnetic resonance imaging findings predict the recurrence of chronic subdural hematoma. Neurol Med Chir (Tokyo). 2015;55(2):173-8. doi: 10.2176/nmc.oa.2013-0390. PubMed PMID: 25746312; PubMed Central PMCID: PMC4533403.

Update: Infantile acute subdural hematoma

Etiology

Acute subdural hematoma in infants is distinct from that occurring in older children or adults because of differences in mechanism, injury thresholds, and the frequency with which the question of nonaccidental injury is encountered.

When trauma occur the motor vehicle accidents are the most frequent.

In the series of Loh et al. the most common cause of injury was shaken baby syndrome 1).

The accuracy of the history obtained from the caregivers of infants may be low in severe infantile head trauma. Therefore, medical professionals should treat the mechanism of injury obtained from caregivers as secondary information and investigate for possible abusive head trauma (AHT) in cases with inconsistencies between the history that was taken and the severity of the injury observed 2).


Chronic subdural effusions in infancy may arise from trauma, from various types of meningitis, from severe dehydration, or “idiopathically” 3).

Diagnosis

Diagnosis can be made by computed tomography or magnetic resonance imaging 4).

Large subdural hematoma of the right convexity up to 3 cm thick, which causes severe cerebral compression, with cingulate herniation and transtentorial herniation.

The hematoma shows liquid-liquid levels, with a higher density lower in relation to sedimented hematoma.

Signs of diffuse brain edema.

Outcome

Early recognition and suitable treatment may improve the outcome of this injury. If treatment is delayed or the condition is undiagnosed, acute subdural hematoma may cause severe morbidity or even fatality 5).

Case series

2002

Medical records and films of 21 cases of infantile acute subdural hematoma were reviewed retrospectively. Diagnosis was made by computed tomography or magnetic resonance imaging. Medical records were reviewed for comparison of age, gender, cause of injury, clinical presentation, surgical management, and outcome.

Twenty-one infants (9 girls and 12 boys) were identified with acute subdural hematoma, with ages ranging from 6 days to 12 months. The most common cause of injury was shaken baby syndrome. The most common clinical presentations were seizure, retinal hemorrhage, and consciousness disturbance. Eight patients with large subdural hematomas underwent craniotomy and evacuation of the blood clot. None of these patients developed chronic subdural hematoma. Thirteen patients with smaller subdural hematomas were treated conservatively. Among these patients, 11 developed chronic subdural hematomas 15 to 80 days (mean = 28 days) after the acute subdural hematomas. All patients with chronic subdural hematomas underwent burr hole and external drainage of the subdural hematoma. At follow-up, 13 (62%) had good recovery, 4 (19%) had moderate disability, 3 (14%) had severe disability, and 1 (5%) died. Based on GCS on admission, one (5%) had mild (GCS 13-15), 12 (57%) had moderate (GCS 9-12), and 8 (38%) had severe (GCS 8 or under) head injury. Good recovery was found in 100% (1/1), 75% (8/12), and 50% (4/8) of the patients with mild, moderate, and severe head injury, respectively. Sixty-three percent (5/8) of those patients undergoing operation for acute subdural hematomas and 62% (8/13) of those patients treated conservatively had good outcomes.

Infantile acute subdural hematoma if treated conservatively or neglected, is an important cause of infantile chronic subdural hematoma. Early recognition and suitable treatment may improve the outcome of this injury. If treatment is delayed or the condition is undiagnosed, acute subdural hematoma may cause severe morbidity or even fatality 6).

2000

Hwang et al., reviewed a total of 16 infant head injury patients under 12 months of age who were treated in from 1989 to 1997. Birth head injury was excluded. The most common age group was 3-5 months. Early seizures were noted in 7 cases, and motor weakness in 6. Three patients with acute intracranial hematoma and another 3 with depressed skull fracture were operated on soon after admission. Chronic subdural hematomas (SDHs) developed in 3 infants. Initial CT scans showed a small amount of SDH that needed no emergency operation. Resolution of the acute SDH and development of subdural hygroma appeared on follow-up CT scans within 2 weeks of injury. Two of these infants developed early seizures. Chronic SDH was diagnosed on the 68th and 111th days after the injuries were sustained, respectively. The third patient was the subject of close follow-up with special attention to the evolution of chronic SDH in view of our experience in the previous 2 cases, and was found to have developed chronic SDH on the 90th day after injury. All chronic SDH patients were successively treated by subduro-peritoneal shunting. In conclusion, the evolution of chronic SDH from acute SDH is relatively common following infantile head injury. Infants with head injuries, especially if they are associated with acute SDH and early development of subdural hygroma, should be carefully followed up with special attention to the possible development of chronic SDH 7).

1987

A retrospective analysis of the infantile acute subdural hematoma was made by Ikeda et al., with special reference to its pathogenesis.

In 11 of 15 cases, the hematomas were bilateral or a contralateral subdural fluid collection was present. In 7 of 11 patients who underwent operation the collection was bloody fluid and/or clotted blood. In 3 patients, a subdural membrane, as seen in adult chronic subdural hematoma, was found. In only 1 patient with unilateral hematoma was clotted blood present without subdural membrane. The thickest collection of clotted blood was in the parasagittal region. It is postulated that in most cases hemorrhage occurs after minor head injury, from the bridging veins near the superior sagittal sinus, into a pre-existing subdural fluid collection such as chronic subdural hematoma or subdural effusion with cranio-cerebral disproportion, and that infants without intracranial disproportion are unlikely to have acute subdural hematoma caused by minor head injury 8).

1986

Aoki et al. report six Japanese cases of child abuse with subdural hematoma and discuss differences from those in the United States. The majority of abused children with subdural hematomas in Japan have suffered direct violence to the face and head, resulting in external signs of trauma. Failure to detect these external traces of trauma, however, might result in an incorrect diagnosis of infantile acute subdural hematoma attributed to accidental trivial head injury. Child abuse with subdural hematoma in the United States is frequently caused by whiplash shaking injury in which external signs of trauma may not be evident. In the United States, retinal hemorrhage and subdural hematoma together suggest child abuse; some cases of infantile acute subdural hematoma might be mistakenly diagnosed as child abuse. Thus, the constellation of retinal bleeding and subdural hematoma combined with the absence of visible signs of trauma is differently interpreted in the United States and Japan 9).

1984

Twenty-six cases of infantile acute subdural hematoma treated between 1972 and 1983 were reviewed. The series was limited to infants with acute subdural hematoma apparently due to minor head trauma without loss of consciousness, and not associated with cerebral contusion. Twenty-three of the patients were boys, and three were girls, showing a clear male predominance. The patients ranged in age between 3 and 13 months, with an average age of 8.1 months, the majority of patients being between 7 and 10 months old. Most of the patients were brought to the hospital because of generalized tonic convulsion which developed soon after minor head trauma, and all patients had retinal and preretinal hemorrhage. The cases were graded into mild, intermediate, and fulminant types, mainly on the basis of the level of consciousness and motor weakness. Treatment for fulminant cases was emergency craniotomy, and that for mild cases was subdural tapping alone. For intermediate cases, craniotomy or subdural tapping was selected according to the contents of the hematoma. The follow-up results included death in two cases, mild physical retardation in one case, and epilepsy in one case. The remaining 23 patients showed normal development. The relationship between computerized tomography (CT) findings and clinical grading was analyzed. Because some mild and intermediate cases could be missed on CT, the importance of noting the characteristic clinical course and of funduscopic examination is stressed 10).

Case reports

 2008

An unusual case of ruptured infantile cerebral aneurysm. An eight-month-old infant was delivered to the hospital in poor condition, after convulsions, with no history of trauma. His emergent CT study revealed acute subdural hematoma. The clinical and radiological picture evoked suspicion that the hematoma was of aneurysmal origin. The infant was operated with special preparations and precautions appropriate for aneurysmal surgery, and has shown a good recovery. It is important to consider the possibility of vascular accident in infants with subdural hematoma of nontraumatic origin. A good outcome may be achieved when appropriate preparations are made prior to surgery 11).

2005

Huang et al. the case of an infant with a traumatic acute subdural hematoma that resolved within 65 hours. A 23-month-old boy fell from a height of approximately 10 m. Brain computed tomography disclosed a left subdural hematoma with midline shift. The associated clots resolved spontaneously within 65 hours of the injury. Although they may mimic more clinically significant subdural hematomas, such collections of clots are likely to be located at least partly within the subarachnoid space. Their recognition may influence decisions regarding both surgical evacuation and the likelihood of non-accidental injury. Clinical and radiographic features distinguishing these “disappearing subdural hematomas” from more typical subdural hematomas are discussed 12)

Own case report

A 1 year old , according to anamnesis provided by the parents, they consulted in the last month for cough clinic with low expectoration, nasal congestion, Tº up to 38ºC of 24 hrs evolution. According to an emergency report: the previous week the patient presents right facial edema, of 2 days duration.

Scratch injuries in legs.

In the next days vomiting with progressive decay.

In the following hours after admission coma, respiratory arrest with bradycardia

Large subdural hematoma of the right convexity up to 3 cm thick, which causes severe cerebral compression, with cingulate herniation and transtentorial herniation.

The hematoma shows liquid-liquid levels, with a higher density lower in relation to sedimented hematoma.

Signs of diffuse brain edema.

In the surgical intervention xanthochromia appears at the beginning, later dark red liquid without clots. Later a subdural membrane is seen on the arachnoid surface, very characteristic of chronic subdural hematoma.


1) , 4) , 5) , 6)

Loh JK, Lin CL, Kwan AL, Howng SL. Acute subdural hematoma in infancy. Surg Neurol. 2002 Sep-Oct;58(3-4):218-24. PubMed PMID: 12480224.

2)

Amagasa S, Matsui H, Tsuji S, Moriya T, Kinoshita K. Accuracy of the history of injury obtained from the caregiver in infantile head trauma. Am J Emerg Med. 2016 Sep;34(9):1863-7. doi: 10.1016/j.ajem.2016.06.085. PubMed PMID: 27422215.

3)

Amacher AL, Li KT. Indirect trauma as a cause of acute infantile subdural hematomas. Can Med Assoc J. 1973 Jun 23;108(12):1530. PubMed PMID: 4714878; PubMed Central PMCID: PMC1941542.

7)

Hwang SK, Kim SL. Infantile head injury, with special reference to the development of chronic subdural hematoma. Childs Nerv Syst. 2000 Sep;16(9):590-4. PubMed PMID: 11048634.

8)

Ikeda A, Sato O, Tsugane R, Shibuya N, Yamamoto I, Shimoda M. Infantile acute subdural hematoma. Childs Nerv Syst. 1987;3(1):19-22. PubMed PMID: 3594464.

9)

Aoki N, Masuzawa H. Subdural hematomas in abused children: report of six cases from Japan. Neurosurgery. 1986 Apr;18(4):475-7. PubMed PMID: 3703222.

10)

Aoki N, Masuzawa H. Infantile acute subdural hematoma. Clinical analysis of 26 cases. J Neurosurg. 1984 Aug;61(2):273-80. PubMed PMID: 6737052.

11)

Adeleye AO, Shoshan Y, Cohen JE, Spektor S. Ruptured middle cerebral artery aneurysm in an infant presenting as acute subdural hematoma: a case report. Pediatr Neurosurg. 2008;44(5):397-401. doi: 10.1159/000149908. PubMed PMID: 18703887.

12)

Huang SH, Lee HM, Lin CK, Kwan AL, Howng SL, Loh JK. Rapid resolution of infantile acute subdural hematoma: a case report. Kaohsiung J Med Sci. 2005 Jun;21(6):291-4. PubMed PMID: 16035574.

Update Cerebellopontine angle epidermoid cyst

The cerebellopontine angle epidermoid cyst is a posterior fossa epidermoid cyst.

It account for 3-6% of cerebellopontine angle tumors. Comparatively, vestibular schwannomas, the most common CPA angle tumor, account for 85%.

Men and women are equally affected and the symptoms usually arise between the mid-20’s and early 50’s 1) with a mean age of 38.8 years at presentation 2).

Pathophysiology

Although several mechanisms for cranial nerve dysfunction due to these tumors have been proposed.

Hasegawa et al. report the first direct evidence of etiology of cranial nerve dysfunction caused by cerebellopontine angle epidermoid tumors. Young age and rapidly progressive neurological deficit might be the characteristics for strangulation of the affected nerves by the cyst capsule 3).

Clinical features

CPA epidermoid cysts can compress the surrounding cranial nerves, brainstem, and cerebellum. Ataxia and cranial nerve palsies often result 4).Thirty cases of cerebellopontine angle epidermoid cysts treated over a period of 20 years werw reviewed with regard to their clinical features, the pathophysiology of their symptoms and their management. The predominating symptoms were related to the 7th and 8th cranial nerves and headaches. The signs and symptoms were present for an average period of 4 months. It was not always possible to determine if the signs and symptoms were due to local involvement by the epidermoid, increased intracranial pressure, or both 5).

Diagnosis

Diagnostic procedures evolved from angiography and ventriculography to non-invasive computed tomography and MRI 6).


cerebelloponineangleepidermoidcyst.jpg

Treatment

The posterior cranial fossa approach was used in 27 cases in the case series of deSouza et al. Total excision of the epidermoid was the aim and was carried out in five (18%) patients but concern regarding the preservation of nearby important neurovascular structures forced partial removal in 22 patients. To minimise reformation, the residual epidermoid was carefully coagulated with the aid of the operating microscope and bipolar cautery without damaging surrounding neurovascular structures 7).


The characteristics of epidermoid cysts make them amenable to whole course neuroendoscopic resection. Use of physiologic/pathologic interspaces and neuroendoscopic angulations decreases traction on the brain, improves complete resection rates, and decreases postoperative complications 8).

Case series

2016

Twenty-two cases with epidermoid cysts of CPA micro-neurosurgically treated since 2005 were reviewed. Clinical status of the patients before the surgery and post-operative functional outcome were recorded. Available data from the English literature were summarized for comparison. Mass reduction of cyst contents in most cases was usually associated with prompt and marked improvement of the symptoms suggesting neuroapraxia caused by compression of the tumor content and/or mild ischemia. Among them, two cases showed strangulation of the affected nerves by the tumor capsule whose preoperative dysfunction did not improve after surgery in spite of meticulous microsurgical removal of the lesion. Involved facial and abducent nerves in these two cases showed distortion of nerve axis and nerve atrophy distal to the strangulation site.

Hasegawa et al. report the first direct evidence of etiology of cranial nerve dysfunction caused by cerebellopontine angle epidermoid tumors. Young age and rapidly progressive neurological deficit might be the characteristics for strangulation of the affected nerves by the cyst capsule. Even though the number of cases might be limited, immediate decompression and release of the strangulating band might be urged in such patients to prevent irreversible deficits 9).


17 patients, including 7 with tumor limited to the cerebellopontine angle, 7 with cerebellopontine angle tumor penetrating supratentorially, and 3 with cerebellopontine angle tumor extending along skull base to contralateral cerebellopontine angle. All patients were followed-up for the mean duration of 126 months.

On admission cranial nerve symptoms predominated. Total tumor removal was achieved in 5 patients, and incomplete removal (with small tumor remnants left on vessels, nerves, or brainstem) in 12 patients. Postoperatively, preoperative deficits worsened in 2 and new postoperative deficits occurred in 10 patients. The extent of tumor expansion had no effect on postoperative morbidity and risk of recurrence. During long-term follow-up, improvement or resolution of preoperative deficits was seen in 11 of 17 patients, and new postoperative deficits in 8 of 10 patients. Symptomatic recurrences after an average of more than 9 years were noted in 5 patients, 3 of whom were reoperated. Recurrences occurred in some younger patients and always in area of primary tumor. No effect of extent of tumor removal on risk of recurrence was found.

The extent of tumor removal had no effect on the risk of recurrence, and thus it may be acceptable to leave tumor capsule fragments adhering closely to nerves, vessels, or brainstem. During long-term follow-up, resolution or improvement of present preoperatively and new postoperative neurological deficits may be expected in most patients 10).

2015

In a case series, pathophysiology of cranial nerve dysfunction in CPA epidermoid cysts was evaluated with special attention to a new mechanism of capsule strangulation caused by stratified tumor capsule. Twenty-two cases since 2005 were reviewed. Clinical status of the patients before the surgery and post-operative functional outcome were recorded. Available data from the English literature were summarized for comparison. Mass reduction of cyst contents in most cases was usually associated with prompt and marked improvement of the symptoms suggesting neurapraxia caused by compression of the tumor content and/or mild ischemia. Among them, two cases showed strangulation of the affected nerves by the tumor capsule whose preoperative dysfunction did not improve after surgery in spite of meticulous microsurgical removal of the lesion. Involved facial and abducent nerves in these two cases showed distortion of nerve axis and nerve atrophy distal to the strangulation site. Hasegawa et al. report the first direct evidence of etiology of cranial nerve dysfunction caused by cerebellopontine angle epidermoid tumors. Young age and rapidly progressive neurological deficit might be the characteristics for strangulation of the affected nerves by the cyst capsule. Even though the number of cases might be limited, immediate decompression and release of the strangulating band might be urged in such patients to prevent irreversible deficits 11)


Hu et al. performed a retrospective analysis of clinical data of 13 male and 17 female patients (mean age: 42.4 ± 11.4 years) who presented with a CPA epidermoid cyst and underwent whole course neuroendoscopy. Complications and tumor recurrence were assessed at follow-up. Results Clinical manifestations included an initial symptom of headache (n = 21), gait instability (n = 6), intracranial hypertension (n = 13), posterior cranial nerve symptoms (n = 6), ataxia (n = 5), and hydrocephalus (n = 1). All patients tolerated tumor resection with subsequent symptomatic improvement, and the results of the postoperative magnetic resonance imaging scan did not show any remnants of tumor. Mean duration of surgery was 2.61 ± 0.47 hours, mean loss of blood was 96.8 ± 35.4 mL, and the mean duration of hospitalization was 7.5 ± 2.25 days. Postoperative complications (8 of 30 [26.7%]) included fever (n = 5), communicating hydrocephalus (n = 1), facial nerve paralysis (n = 1), and abducens nerve palsy (n = 1). Tumor recurrence was observed in two patients (6.7%). No deaths or intracranial hemorrhage was reported.

The characteristics of epidermoid cysts make them amenable to whole course neuroendoscopic resection. Use of physiologic/pathologic interspaces and neuroendoscopic angulations decreases traction on the brain, improves complete resection rates, and decreases postoperative complications 12).

2010

Between 1996 and 2004, 10 patients with typical symptoms of trigeminal neuralgia were found to have cerebellopontine angle epidermoids and treated surgically.

Total resection was done in 6 patients (60%). Surgical removal of tumor and microvascular decompression of the trigeminal nerve were performed simultaneously in one case. One patient died due to postoperative aseptic meningitis. The others showed total relief from pain. During follow-up, no patients experienced recurrence of their trigeminal neuralgia (TN).

The clinical features of TN from CPA epidermoids are characterized by symptom onset at a younger age compared to TN from vascular causes. In addition to removal of the tumor, the possibility of vascular compression at the root entry zone of the trigeminal nerve should be kept in mind. If it exists, a microvascular decompression (MVD) should be performed. Recurrence of tumor is rare in both total and subtotal removal cases, but long-term follow-up is required 13).

1989

Thirty cases of cerebellopontine angle epidermoid cysts treated over a period of 20 years are reviewed with regard to their clinical features, the pathophysiology of their symptoms and their management. The predominating symptoms were related to the 7th and 8th cranial nerves and headaches. The signs and symptoms were present for an average period of 4 months. It was not always possible to determine if the signs and symptoms were due to local involvement by the epidermoid, increased intracranial pressure, or both. Diagnostic procedures evolved from angiography and ventriculography to non-invasive computed tomography and MRI. The posterior cranial fossa approach was used in 27 cases. Total excision of the epidermoid was the aim and was carried out in five (18%) patients but concern regarding the preservation of nearby important neurovascular structures forced partial removal in 22 patients. To minimise reformation, the residual epidermoid was carefully coagulated with the aid of the operating microscope and bipolar cautery without damaging surrounding neurovascular structures 14).

Case reports

2016

Malignant transformation of a residual cerebellopontine angle epidermoid cyst 15).

2015

Guan et al. the case of a 13-year-old female with a newly diagnosed cerebellopontine angle EC who presented with worsening headaches, photophobia, and emesis. Magnetic resonance imaging demonstrated significant pericystic brainstem edema and mass effect with effacement of the fourth ventricle. Refractory symptoms prompted repeat imaging, revealing cyst enlargement and dense rim enhancement. Resection of the EC resolved both her symptoms and the brainstem edema. This case documents the radiographic evolution of EC rupture and subsequent clinical course 16).


A case of an unusual epidermoid cyst of the cerebellopontine angle extending into the upper cervical canal that appeared hyper-dense on computed tomography scanning, hyper-intense on T1-weighted magnetic resonance (MR) images, and hypo-intense on T2-weighted MR images 17).

1)

Fleming JF, Botterell EH. Cranial dermoid and epidermoid tumors. Surg Gynecol Obstet. 1959;109:403–411.
2)

Fawcitt RA, Isherwood I. Radiodiagnosis of intracranial pearly tumours with particular reference to the value of computer tomography. Neuroradiology. 1976;11:235–242.
3) , 11)

Hasegawa M, Nouri M, Nagahisa S, Yoshida K, Adachi K, Inamasu J, Hirose Y, Fujisawa H. Cerebellopontine angle epidermoid cysts: clinical presentations and surgical outcome. Neurosurg Rev. 2015 Nov 14. [Epub ahead of print] PubMed PMID: 26566990.
4)

Berger M, Wilson C. Epidermoid cysts of the posterior fossa. J Neurosurg. 1985;62:214–219.
5) , 6) , 7) , 14)

deSouza CE, deSouza R, da Costa S, Sperling N, Yoon TH, Abdelhamid MM, Sharma RR, Goel A. Cerebellopontine angle epidermoid cysts: a report on 30 cases. J Neurol Neurosurg Psychiatry. 1989 Aug;52(8):986-90. PubMed PMID: 2795068; PubMed Central PMCID: PMC1031839.
8) , 12)

Hu Z, Guan F, Kang T, Huang H, Dai B, Zhu G, Mao B, Kang Z. Whole Course Neuroendoscopic Resection of Cerebellopontine Angle Epidermoid Cysts. J Neurol Surg A Cent Eur Neurosurg. 2015 Aug 24. [Epub ahead of print] PubMed PMID: 26302403.
9)

Hasegawa M, Nouri M, Nagahisa S, Yoshida K, Adachi K, Inamasu J, Hirose Y, Fujisawa H. Cerebellopontine angle epidermoid cysts: clinical presentations and surgical outcome. Neurosurg Rev. 2016 Apr;39(2):259-66; discussion 266-7. doi: 10.1007/s10143-015-0684-5. PubMed PMID: 26566990.
10)

Czernicki T, Kunert P, Nowak A, Wojciechowski J, Marchel A. Epidermoid cysts of the cerebellopontine angle: Clinical features and treatment outcomes. Neurol Neurochir Pol. 2016;50(2):75-82. doi: 10.1016/j.pjnns.2015.11.008. PubMed PMID: 26969562.
13)

Son DW, Choi CH, Cha SH. Epidermoid tumors in the cerebellopontine angle presenting with trigeminal neuralgia. J Korean Neurosurg Soc. 2010 Apr;47(4):271-7. doi: 10.3340/jkns.2010.47.4.271. PubMed PMID: 20461167; PubMed Central PMCID: PMC2864819.
15)

Pikis S, Margolin E. Malignant transformation of a residual cerebellopontine angle epidermoid cyst. J Clin Neurosci. 2016 Nov;33:59-62. doi: 10.1016/j.jocn.2016.04.008. Review. PubMed PMID: 27519146.
16)

Guan Z, Hollon T, Bentley JN, Garton HJ. Ruptured pediatric cerebellopontine angle epidermoid cyst: a case report detailing radiographic evolution and clinical course. J Neurosurg Pediatr. 2015 Aug 21:1-5. [Epub ahead of print] PubMed PMID: 26295366.
17)

Lim J, Cho K. Epidermoid cyst with unusual magnetic resonance characteristics and spinal extension. World J Surg Oncol. 2015 Aug 7;13:240. doi: 10.1186/s12957-015-0651-1. PubMed PMID: 26245481; PubMed Central PMCID: PMC4527251.

Update: Molsidomine

Molsidomine is an orally active, long acting vasodilator. Molsidomine is metabolized in the liver to the active metabolite linsidomine. Linsidomine is an unstable compound that releases nitric oxide (NO) upon decay as the actual vasodilating compound.

Belongs to the drug class of sydnones . SIN-1A metabolite of Molsidomine has pharmacologically active group of NO, which by increasing levels of cGMP, decreases levels of intracellular calcium ions in smooth muscle cells. This effect leads to relaxation of smooth muscle vasculature, inhibits platelets aggregation and has indirect antiproliferative effect. In clinical observations no effect of tolerance to the drug was observed. Experimental data show additional mechanism of action of the drug: SIN-1C metabolites protects the reoxygenated cardiomyocyte from post-reperfusion damage. Indications for use of Molsidomine are: ischaemic heart disease, chronic heart failure and pulmonary hypertension. Effects of Molsidomine use in acute myocardial infarction and unstable angina were compared in clinical trials to effects of nitroglycerin use. Both drugs were found equally potent, but authors underline the fact of better Molsidomine tolerability comparing NTG, but longer serum half-time of Molsidomin effects that control of the treatment is worse. In clinical trials it was suggested that intravenous use of Molsidomine metabolite SIN-1 during PTCA procedures is more effective than use of isosorbide dinitrate in the same procedures. In other clinical trials molsidomin was found to produce beneficial effects in patients with heart failure due to ischaemic cardiomyopathy, dilatative cardiomyopathy, in essential hypertension, pulmonary artery hypertension in COPD patients and in congestive heart failure 1).

Ehlers et al. examined the effects of treatment with molsidomine with regard to decreasing the incidence of spasm-related delayed cerebral infarctions and improving clinical outcome in patients with SAH.

Seventy-four patients with spontaneous aneurysmal subarachnoid hemorrhage (SAH) were included in this post hoc analysis. Twenty-nine patients with SAH and proven cerebral vasospasm (CVS) received molsidomine in addition to oral or intravenous nimodipine. Control groups consisted of 25 SAH patients with proven vasospasm and 20 SAH patients without. These patients received nimodipine therapy alone. Cranial computed tomography (CCT) before and after treatment was analyzed for CVS-related infarcts. A Modified National Institutes of Health Stroke Scale (mNIHSS) and the modified Rankin Scale (mRS) were used to assess outcomes at a 3-month clinical follow-up.

Four of the 29 (13.8%) patients receiving molsidomine plus nimodipine and 22 of the 45 (48%) patients receiving nimodipine therapy alone developed vasospasm-associated brain infarcts (p < 0.01). Follow-up revealed a median mNIHSS score of 3.0 and a median mRS score of 2.5 in the molsidomine group compared with scores of 11.5 and 5.0, respectively, in the nimodipine group with CVS (p < 0.001). One patient in the molsidomine treatment group died, and 12 patients in the standard care group died (p < 0.01).

In this post hoc analysis, patients with CVS who were treated with intravenous molsidomine had a significant improvement in clinical outcome and less cerebral infarction. Molsidomine offers a promising therapeutic option in patients with severe SAH and CVS and should be assessed in a prospective study 2).


Durak et al., investigated the protective and therapeutic effects of molsidomine (MOL) in a rat model of whole brain radiotherapy (RT). Forty female rats were divided into five groups of eight: group 1, control; group 2, 15 Gy single dose RT (RT); group 3, 4 mg/kg MOL treated for 5 days (MOL); group 4, 4 mg/kg MOL for 5 days, 10 days after RT treatment (RT + MOL); group 5, 4 mg/kg MOL treatment for 5 days before RT treatment and for 5 days after RT treatment (MOL + RT). All rats were sacrificed on day 16. Neurodegenerative changes in the brain and tissue levels of oxidants and antioxidants were evaluated. The oxidative parameters were increased and antioxidant status was decreased in group RT compared to groups MOL + RT and RT + MOL. Histopathological examination showed that treatment with MOL after RT application and treatment with MOL before RT treatment decreased neuronal degeneration. No difference in neuronal appearance was found between groups RT + MOL and MOL + RT. MOL treatment protected the nervous system of rats and may be a treatment option for preventing RT induced neural injury 3)


1) Kmieć M, Ochmański W. [Molsidomine: importance in treatment of circulation disorders]. Przegl Lek. 1998;55(10):532-6. Review. Polish. PubMed PMID: 10224868.
2) Ehlert A, Schmidt C, Wölfer J, Manthei G, Jacobs AH, Brüning R, Heindel W, Ringelstein EB, Stummer W, Pluta RM, Hesselmann V. Molsidomine for the prevention of vasospasm-related delayed ischemic neurological deficits and delayed brain infarction and the improvement of clinical outcome after subarachnoid hemorrhage: a single-center clinical observational study. J Neurosurg. 2016 Jan;124(1):51-8. doi: 10.3171/2014.12.JNS13846. Epub 2015 Jul 10. PubMed PMID: 26162034.
3) Durak MA, Parlakpinar H, Polat A, Vardi N, Ekici K, Ucar M, Ozhan O, Yildiz A, Pasahan R. Protective and therapeutic effects of molsidomine on radiation induced neural injury in rats. Biotech Histochem. 2017 Feb 6:1-10. doi: 10.1080/10520295.2016.1271454. [Epub ahead of print] PubMed PMID: 28166419.