Paraneoplastic AQP4-IgG-Seropositive Neuromyelitis Optica Spectrum Disorder Associated With Teratoma: A Case Report and Literature Review.

OBJECTIVES: To assess a case of paraneoplastic aquaporin-4 (AQP4)-immunoglobulin G (IgG)-seropositive neuromyelitis optica spectrum disorder (NMOSD) associated with teratoma and determine whether it is a paraneoplastic neurologic disorder. METHODS: A single case study and literature review of 5 cases. RESULTS: A 27-year-old woman presented with diplopia, facial nerve palsy, paraplegia, sensory dysfunction of lower limbs, dysuria, nausea, and vomiting. Spinal cord MRI detected an extensive longitudinal lesion in the spinal cord, and brain MRI detected abnormal lesions in the right cerebral peduncle and tegmentum of the pons. CSF analysis revealed positive oligoclonal IgG bands (OCBs). The patient tested positive for AQP4-IgG, confirming a diagnosis of NMOSD. An abdominal CT scan detected an ovarian tumor. After steroid therapy and tumor removal, the patient progressively improved, with only mild sensory dysfunction. Histopathologic analysis of the tumor revealed a teratoma and the presence of glial fibrillary acidic protein (GFAP)+ neural tissue with AQP4 immunoreactivity, accompanied by lymphocyte infiltration. Including the present case, there have been 6 reported cases of AQP4-IgG-seropositive NMOSD associated with ovarian teratoma (mean onset age, 32.7 years). Of these patients, 5 (83%) presented with nausea and/or vomiting, positive OCB, and dorsal brainstem involvement. Pathologic analyses of the teratoma were available in 5 cases, including the present case, revealing neural tissue with AQP4 immunoreactivity and lymphocyte infiltration in all cases. CONCLUSIONS: This study suggests that ovarian teratoma may trigger the development of AQP4-IgG-seropositive NMOSD. Further studies are needed to elucidate the pathogenesis of teratoma-associated NMOSD.

TERTp Mutation Detection in Plasma by Droplet-Digital Polymerase Chain Reaction in Spinal Myxopapillary Ependymoma with Lung Metastases.

BACKGROUND: Spinal myxopapillary ependymoma (SP-MPE) is a subgroup of ependymomas in which after initial gross tumor resection, recurrences occur in more than half of the patients. Anaplastic transformation may also occur and contributes to intraneural and extraneural metastatic dissemination. Extraneural metastases from SP-MPE are rare and worsen the prognosis. In this situation, the noninvasive detection of recurrent somatic mutations in the circulating tumor DNA (ctDNA) from plasma is challenging. Telomerase-reverse transcriptase gene promoter (TERTp) mutation has been identified in a subset of ependymomas with aggressive behavior. CASE DESCRIPTION: We report on a patient with TERTp mutated SP-MPE presenting with an extraneural anaplastic metastatic dissemination after iterative local recurrences. From the initial SP-MPE to pleural anaplastic lesion, TERTp C228T mutation was present with allele frequency varying from 33% to 39%. Interestingly, TERTp mutation was also detected by droplet digital polymerase chain reaction in the plasma with a frequency of 2.1% at the time of pleural metastases, highlighting that ctDNA is released in plasma of patients suffering from SP-MPE with extraneural metastatic dissemination. CONCLUSIONS: Despite the rarity of this evolution, plasmatic liquid biopsy appears to be a useful diagnostic and follow-up tool in a subset of primary brain tumors.

Spinal myxopapillary ependymomas: a retrospective clinical and immunohistochemical study.

BACKGROUND: Myxopapillary ependymoma (MPE) is a rare subtype of ependymoma that develops almost exclusively within the spinal cord. Despite its benign biological nature, MPE has a propensity to recur locally or distantly. Although variables influencing the prognosis, such as age, the extent of surgery and radiotherapy, have been widely discussed, no definitive standard has been established. Compared to other spinal tumors, many fewer histological markers have been elucidated to assist the determination of the prognosis. METHODS: Twenty-seven patients who underwent resection of MPE were enrolled. We determined their demographic features, imaging characteristics, clinical presentations and outcomes, surgical procedures and histological properties by chart review, telephone contact, reviewing of surgical notes, pre-/postoperative imaging and immunohistological staining. RESULTS: GTR (gross total resection) was achieved in 18 patients (66.7 %) and STR (subtotal resection) in 9 (33.3 %). Although GTR rendered a better disease control rate, the difference was not significant. Pediatric patients suffered from a greater risk of recurrence as well as a shorter period to disease relapse. In the majority of cases, we observed the overexpression of platelet-derived growth factor receptor α (PDGFRα), matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-14 (MMP14). Epidermal growth factor receptor (EGFR) was observed in the tumors of 7 of 23 nonrecurrent patients, but not in any recurrent tumors. CONCLUSIONS: The results of the present study indicate that the extent of resection and age are major factors related to tumor recurrence. Therefore, gross total resection is recommended whenever possible unless following neurological dysfunction is predictable. Moreover, pediatric patients need considerable attention after surgery, particularly in the early stages. PDGFRα, MMP2 and MMP14 may be new diagnostic and therapeutic targets and EGFR a potential predictor of improved prognosis for MPE.

Sacrococcygeal teratoma with intradural extension: case report.

Intradural sacrococcygeal teratoma (SCT) is a rare entity that has been reported in only a few cases previously. The authors present the case of a 2-week-old, otherwise healthy neonate with a mass in the buttock. The imaging findings and the high level of serum alpha-fetoprotein were highly suggestive of SCT. On operation the authors found intradural extension of the teratoma. The lesion was managed successfully without any remaining sequelae. The authors briefly review the currently proposed etiology regarding teratoma formation and the intradural extension of SCT.

A rare case of multifocal intramedullary germinoma in cervical spinal cord.

STUDY DESIGN: Case report. OBJECTIVES: We present for the first time a patient with multifocal intramedullary cervical spinal cord germ cell tumors with elevated serum alpha-fetoprotein (AFP). SETTING: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. METHODS: A 19-year-old girl experienced numbness in her right leg 10 months before diagnosis. The numbness gradually became severe and extended up to the thorax. Magnetic resonance imaging (MRI) visualized several intramedullary masses with intensive enhancement and extensive peritumoral edema in the spinal cord at the C3-T1 vertebral body levels. Administration of methylprednisolone caused no treatment effect. The largest mass, which was located at the T1 level inside the normal spinal cord and confirmed by naked eye observation, was completely extracted under a microscope. Postoperative pathological examination demonstrated the so-called 'two-cell pattern,' which is typical of germinoma with placental alkaline phosphatase expression. The serum level of AFP was 64.50 ng ml(-1) (normal range: 0-5 ng ml(-1)). The residual tumor was eliminated through radiation therapy (local 30 Gy) following surgery. Afterward, the patient's neurological deficits were improved but not resolved. RESULTS: Six years after surgery, no recurrence was encountered and the patient remained stable. CONCLUSION: Radiotherapy is the salvage therapy for spinal cord germinoma. Steroids were of no therapeutic value in the treatment of intramedullary spinal cord germinoma.

A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a Children's Oncology Group phase 1 consortium study.

PURPOSE: We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies. PATIENTS AND METHODS: Vorinostat, followed by temozolomide approximately 1 hour later, was orally administered, once daily, for 5 consecutive days every 28 days at three dose levels using the rolling six design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on Day 1 at 0, 6, and 24 hours after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed. RESULTS: Nineteen eligible patients were enrolled and 18 patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in four patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat. CONCLUSION: Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300 mg/m(2) /day and temozolomide, 150 mg/m(2) /day.

Extramedullary tumors and leukemia: a diagnostic pitfall for the neurologist.

OBJECTIVE: To describe neurologic presentations and radiologic findings of extramedullary myeloid tumor (EMT). METHODS: This is a retrospective case series of patients with neurologic presentations of EMT from January 1, 1981, until May 30, 2011. Clinical data abstracted included demographics, presentation, bone marrow involvement, history of hematologic malignancy, complete blood count at presentation, EMT location, imaging findings, treatments, and outcomes. RESULTS: Of 21 patients, EMT was the initial presentation of underlying hematologic disorder in 12 (57%). Six patients (29%) presented with primary EMT (no bone marrow involvement at presentation). The most common location was the thoracic spine (n = 9), usually manifesting as an epidural mass with vertebral body involvement. The initial diagnosis was incorrect in most (n = 17 [81%]). Treatments included radiation (n = 17 [ 81%]), chemotherapy (n = 14 [67%]), and surgery (n = 6 [29%]). Fifteen patients (71%) died. Estimated Kaplan-Meier median survival from diagnosis for 20 patients with adequate follow-up was 8 months. Of the 6 patients with primary EMT (no known systemic leukemia at diagnosis), 5 died at a median of 24 months (range 8-36 months) and 1 is still alive at 1 year. Of the 6 patients whose leukemia was diagnosed upon presenting with EMT, 3 are still alive. CONCLUSIONS: EMT affecting the nervous system can present in patients without a known hematologic disorder and is often not recognized. Thoracic paraspinal masses are the most common presentation. The prognosis for patients with neurologic presentation of EMT is generally poor, but longer survival is possible in patients presenting with isolated EMT or leukemia first diagnosed at the time of EMT presentation.

Venous thromboembolism after spine surgery: changes of the fibrin monomer complex and D-dimer level during the perioperative period.

OBJECT: The goal of this study was to determine the incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) after spine surgery. Another purpose was to clarify the rapid changes of the fibrin monomer complex (FMC) and D-dimer levels during the perioperative period of spine surgery for early diagnosis of venous thromboembolism (VTE). METHODS: The participants were 72 patients who underwent spine surgery between September 2007 and March 2008. The FMC and D-dimer levels were measured 6 times: 1) at induction of general anesthesia; 2) just after implantation or during surgery; 3) immediately following surgery; 4) 1 day after surgery; 5) 3 days postsurgery; and 6) 7 days after surgery. All patients received mechanical prophylaxis, including compression stockings and intermittent pneumatic compression devices, and all were examined with duplex ultrasonography assessments of both lower extremities and with lung perfusion scintigraphy 7-10 days after surgery. If DVT or PE was suspected, the patient underwent multidetector CT venography. RESULTS: There were no patients with clinical signs of DVT and PE, but 6 (8.3%) showed VTE, among whom 5 had DVT and 3 had PE. Patients with VTE had significantly higher FMC levels 1 day after surgery, compared with those without VTE (55.9 ± 17.2 µg/ml vs 11.1 ± 2.89 µg/ml; p < 0.01). Patients with VTE had significantly higher D-dimer levels 7 days postsurgery, compared with those without VTE (12.5 ± 2.95 µg/ml vs 4.3 ± 0.39 µg/ml; p < 0.01). Receiver operating characteristic analysis showed that the FMC result was more useful than the D-dimer assay for diagnosis of VTE. When the cutoff value was set to 20.8 µg/ml for FMC, sensitivity was 100% and specificity was 86.3%. CONCLUSIONS: In this study the prevalence of VTE after spine surgery was 8.3%. The FMC measured 1 day after spine surgery is considered to be useful as an indicator of VTE.

Intensity of pain and biochemical changes in blood plasma in spinal cord trauma.

STUDY DESIGN: Cross-sectional, observational and longitudinal. OBJECTIVES: The aim of the study was to analyze the relationship between pain intensity, plasma lipids and severity of spinal cord injuries in patients with paraplegia (n = 11), tetraplegia (n = 16) and polytrauma (n = 15). We concentrated on the hospitalization period immediately following injury. METHODS: Pain intensity was assessed on a visual analog scale immediately after patients were transported to hospital, again 14 days after injury and before discharge from hospital. Blood samples were also obtained at these same times. We measured following biochemical parameters: total protein, albumin, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glycemia, and C-reactive protein. Data were analyzed with respect to type of injury, state of unconsciousness immediately after injury, hemorrhage, measure of liability (self-inflicted injuries vs casualties), cause of the accident and pre-injury cholesterol levels. RESULTS: On the day of injury, pain intensity correlated positively with HDL cholesterol (r = 0.48, P = 0.04); on the day of discharge from hospital, pain intensity correlated positively with blood glucose levels (r = 0.67, P = 0.0002). Diagnostic subgroups did not differ either in pain intensity or in pain dynamics during hospitalization. Total cholesterol level was lowest in patients with polytrauma. In all patients, the lowest total cholesterol level was observed immediately after injury. HDL cholesterol was highest after injury. CONCLUSION: After spinal cord injury, lower total cholesterol levels reflected more serious trauma intensity and HDL cholesterol predicted more intensive pain. Subjects responsible for their own injuries suffered less intensive pain than those who were not responsible for their injuries.

Changes in thyroid hormone state in children receiving chemotherapy.

OBJECTIVE: The concentrations of thyroid function determinants may change during severe illness. Our goal was to quantify their changes in children with cancer during chemotherapy, and to correlate them to clinical condition and type of drugs. DESIGN: During a 3-month period all patients admitted for chemotherapy to the paediatric oncology ward were evaluated for inclusion. Patients with brain tumours, neuroblastoma (cranio)spinal irradiation and use of dexamethasone before the first blood sample were excluded. MEASUREMENTS: Plasma concentrations of T4, T3, rT3, thyroxine-binding globulin (TBG), thyroglobulin (Tg), TSH, IGF-1, cortisol, PRL and physical well-being by means of questionnaires were measured before and during chemotherapy. RESULTS: In 19 children, 46 courses of chemotherapy and 123 plasma samples were analysed. During chemotherapy, mean concentrations of TSH, T3, Tg and cortisol decreased to 53, 67, 69 and 15% of the baseline value, respectively. Mean plasma rT3 increased to 217% of baseline. In 87% of all courses, one or more thyroid parameter(s) was aberrant. Furthermore, in 23 samples (19%) from 10 patients (53%), the concentration of IGF-1 was below the reference value (adjusted for sex and age). Small changes were seen in scores for clinical condition but none was related to a change in thyroid function determinant. Most changes in thyroid hormones could be attributed to using dexamethasone. CONCLUSIONS: These results demonstrate that, in children, thyroid hormone state changes significantly during chemotherapy, apparently not related to physical well-being but to the drugs administered. Future investigations should focus on the impact for patient care and possibilities of (preventive) intervention.

[Precocious puberty secondary to an intramedullary germinoma]. / Puberté précoce secondaire à un germinome intramédullaire.

BACKGROUND: hCG secreting tumors are responsible for 21% of precocious puberties in boys. Usual localizations are hepatic, cerebral, mediastinal and gonadic. CASE REPORT: A 4-year-old boy developed precocious puberty with rapid evolution. Serum beta hCG suggested germinal etiology, but radiological procedures failed to find any usual localization. Further occurrence of pain in the legs led to carry out a lumbar puncture. The high cerebrospinal fluid/blood gradient of beta hCG suggested the presence of an intramedullar tumor. Medullar magnetic resonance imaging found a large tumor facing L1 and L2. CONCLUSION: To our knowledge, this localization is described for only the second time.

Pregnancy associated highly vascularized tumours negatively correlate with the levels of anti-angiogenic 17 alpha-hydroxy-progesterone.

Seventeen alpha hydroxyprogesterone (17-OHP, is an anti-angiogenic steroid. The existence of a significant negative correlation between the levels of 17-OHP and the appearance of highly vascularized brain and spinal tumours seen during pregnancy is described. However, glioma appears to be an exception to this rule. This exception may be due to the blood brain barrier which permits only a small proportion of the synthesized 17-OHP to reach the brain and may be due to gliomas not being highly vascularized. It is proposed that testing the efficacy of 17-OHP as an anti-angiogenic agent in the highly vascularized brain and spinal tumours would be useful since 17-OHP is essentially without any foreseeable side effects even in large doses, inexpensive, widely available, and in some cases may be conveniently administered via a nasal inhaler.

ACTH-producing pituitary carcinoma presenting as the cauda equina syndrome.

A 43-year-old woman presented with incontinence, weakness, and paresthesia, consistent with the cauda equina syndrome, 10 years after having a pituitary tumor surgically removed and 4 years after excision of two "meningiomas" of the cervical cord. The patient was also hypertensive and had a cushingoid habitus. Emergent surgical decompression of the spinal cord revealed intradural metastatic adrenocorticotropic hormone-producing pituitary carcinoma. Pituitary carcinomas are rare. The majority of reported cases of adrenocorticotropic hormone-producing carcinoma have exhibited metastases outside the central nervous system. To our knowledge, this represents the first case of an adrenocorticotropic hormone-producing pituitary carcinoma presenting with the cauda equina syndrome. A review of all reported cases of pituitary carcinoma indicated that central nervous system metastases were more common than metastases to distant sites, and patients with distant metastases experienced a shorter duration of disease than did those with central nervous system metastases.

[The pseudotumorous course of ischemic myelopathies]. / Psevdotumoroznoe techenie ishemicheskikh mielopatii.

Study of 36 cases of ischemic myelopathy following a pseudotumorous course and 30 cases of spinal cord tumors revealed similarity and differences in the clinical manifestations which should be taken into account in differential diagnosis. Authentic differences in the content of serotonin and its metabolites in the cerebrospinal fluid and blood of this group of patients are pointed out.

Soluble interleukin-2 receptors in cerebrospinal fluid from individuals with various neurological disorders.

Soluble interleukin-2 (IL-2R) levels in the cerebrospinal fluid (CSF) were studied in infectious, inflammatory, degenerative, and neoplastic disorders to evaluate their usefulness as a marker for the presence of activated T cells, thus indicating an inflammatory process. CSF from control subjects and patients with stationary, progressive, and treated multiple sclerosis (MS); aseptic meningitis; lymphoid and nonlymphoid central nervous system (CNS) tumors; Alzheimer's disease, as well as serum from MS patients and control subjects were studied for levels of soluble IL-2R. A significant increase in CSF IL-2R levels was observed in patients with MS, meningitis, and lymphoid CNS tumors; the MS group showed the highest values. CSF from individuals with Alzheimer's disease and from patients with nonlymphoid tumors did not show significantly elevated values. Serum IL-2R levels were significantly higher in MS patients than in control subjects, but there was no significant correlation between individual serum and CSF IL-2R levels. This study suggests the presence of activated T-lymphocytes in the CNS of patients with MS.

Dry drop of blood plasma--a new approach in the diagnosis of neoplastic diseases.

The dried drop of blood plasma and serum was first described by Bialowas in 1967. The dry drop as a method for diagnosis of neoplasms was introduced in 1984 by Hungarian authors from Cancer Research Group. The aim of our investigations was to estimate the usefulness of this method in diagnostic of central nervous system's tumours and lung cancers. We worked out our own modification of dry drop test, i.e., we used the blood plasma instead the blood serum. In 93% of neoplasms the result of test was positive (in 92% of neoplasms of central nervous system and in 83% of lung cancers). In the control group occurred the large number of falsely positive results, as well as in group of patients with lung tuberculosis (70%), multiple sclerosis (63%) and myasthenia (45%). The results of our investigations showed the usefulness of this method in the screening diagnostic of neoplasia. The further investigations are necessary, especially correlation of dry drop test results with erythrocyte sedimentation test and antibodies and fibrinogen's level in the blood.

Serum neuronal growth factor levels in von Recklinghausen's neurofibromatosis.

A single neuronal cell biological assay was used to quantitate neuronal growth factors in 87 serum samples from 69 patients in 48 families with von Recklinghausen's neurofibromatosis, plus 16 samples from 16 comparison subjects. Mouse nerve growth factor was used as a standard for the bioassay, and results of serum assays were expressed as nerve growth factor equivalents. Antiserum to mouse nerve growth factor inhibited fractionally serum-induced neurite outgrowth, while kinetics of neurite outgrowth and maximal cellular response to serum differed from those induced by mouse nerve growth factor. The mean values (+/- SD) of neuronal growth factors for the patients were 20.5 +/- 15.7 pg/mg serum protein, while mean values for the comparison group as a whole were 22.3 +/- 15.6 pg/mg serum protein. Sex, race/ethnicity, patient age, and date of sample collection did not significantly influence serum levels among patients or comparison subjects. Three to six serial samples taken from women before pregnancy, during the course of pregnancy, during delivery, and in the postpartum period did not show significant differences from one period to another. These data suggest that human serum does contain non-nerve-growth-factor neuronal growth factors, but that levels of the factors do not contribute to the identification of patients with von Recklinghausen's neurofibromatosis.

Serum MBP immunoreactivity and immunoglobulin level as markers of tumour type.

Forty three patients, admitted to the department of Neurological Surgery for management of central nervous system tumours, were studied pre-operatively for serum myelin basic protein immunoreactivity as a marker of central nervous system lesion and for circulating immunoglobulins and complement (C3) levels. Myelin basic protein concentration did not appear to correlate with tumour type or grade. Serum immunoglobulin levels were found to be within the normal range but the mean IgM level was significantly higher in the glioma group when compared with meningiomas.