A case of longitudinally extensive transverse myelitis in an 80-year-old patient with systemic lupus erythematous and anti-aquaporin 4 antibodies.

BACKGROUND: Systemic Lupus Erythematous is a systemic autoimmune disease with multiorgan inflammation. Clinical manifestations are variable and may involve the Central Nervous System. Acute transverse myelitis is a rare complication. Recent studies have shown an association between SLE, transverse myelitis and presence of anti-aquaporin 4 antibodies. CASE PRESENTATION: We describe the case of an 80-year-old woman with a subacute onset of right hemiplegia followed by left-sided ataxia. Cervical MRI revealed longitudinally extensive transverse myelitis. Blood examinations showed positivity for anti-nuclear antibodies, anti-double-stranded DNA antibodies, anti-phospholipid antibodies and anti-aquaporin 4 antibodies. CONCLUSIONS: Anti-aquaporin 4 antibody testing is of paramount importance in order to reach a correct diagnosis and to treat patients with the best therapeutic approach.

Stroke-like events after brain radiotherapy: a large series with long-term follow-up.

BACKGROUND AND PURPOSE: Patients with a history of brain radiotherapy can experience acute stroke-like syndromes related to the delayed effects of brain radiation, including stroke-like migraine attacks after radiation therapy syndrome, peri-ictal pseudoprogression and acute late-onset encephalopathy after radiation therapy syndrome. The aim of this study was to collect evidence on the long-term outcome and treatment of these conditions, whose knowledge is undermined by their rarity and fragmented description. METHODS: Cases were collected, both prospectively and retrospectively, amongst six neuro-oncology departments. Inclusion criteria were as follows: (i) history of brain radiotherapy (completed at least 6 months before the acute episode); (ii) new onset of acute/subacute neurological symptoms; (iii) exclusion of all etiologies unrelated to brain irradiation. A review of current literature on stroke-like syndromes was performed to corroborate our findings. RESULTS: Thirty-two patients with acute neurological conditions attributed to the delayed effects of radiation were identified, including 26 patients with stroke-like syndromes. Patients with stroke-like syndromes commonly presented with a mosaic of symptoms, including focal deficits (77%), encephalopathy (50%), seizures (35%) and headache (35%). Seventy-three percent of them had acute consistent magnetic resonance imaging alterations. Treatment included high-dose steroids in 65% of cases. Twenty-two patients recovered completely (85%). Sixteen patients (62%) experienced relapses (median follow-up 3.5 years). A literature review identified 87 additional stroke-like cases with similar characteristics. CONCLUSIONS: Stroke-like events related to brain irradiation may be associated with permanent sequelae. Steroids are often administered on empirical grounds, as they are thought to accelerate recovery. Relapses are common, highlighting the need to elaborate adequate prevention strategies.

Headache in cerebral venous thrombosis associated with extracranial tumors: a clinical series.

Cerebral venous thrombosis (CVT) may represent the clinical onset of malignancies or complicate their course, also in phase of quiescence. In literature, there are several case reports on the association between CVT and tumors, but there are few articles on its clinical characteristics in cancer patients (Pts). Our aim was to analyze the clinical characteristics of CVT associated with extracranial tumors. We identified nine cases of CVT in adults affected by extracranial tumors in 6 years from six hospitals. The median age was 40 years; eight Pts were female. Associated tumors were: lymphoma (4/9); breast (2/9), rhinopharynges (1/9) and gastric (1/9) carcinomas. One patient presented a kidney tumor and a melanoma at the same time. Multiple sinuses were affected in seven Pts. MRI showed parenchymal lesions in most cases (7/9). Clinical manifestations were: focal deficits (7/9), headache (6/9), early seizures (4/9) and consciousness disorders (3/9). Headache was the onset symptom in six Pts. In four of these Pts, headache preceded the onset of the focal deficit and/or seizures than 2-15 days. The characteristics of the headache were variable in intensity, location and type but all the Pts agreed in saying that it was an unusual headache, unresponsive to common pain medications. Five of the six Pts complaining of headache in the course of CVT presented focal deficits and parenchymal lesions at admission to the emergency room. All nine Pts were anticoagulated without further haemorrhagic complications. At discharge, the Pts presented a complete recovery in four cases, mild sequelae in four and moderate sequelae in one. In conclusion, we would like to underline the importance of particular care to cancer Pts complaining of headache, since the early diagnosis and the appropriate anticoagulant treatment could prevent the appearance of parenchymal lesions and the consequent neurological deficits. Also in the cases of normal brain CT, a brain MRI/MR venography should be performed in emergency setting if CVT is suspected.

Melanoma cells homing to the brain: an in vitro model.

We developed an in vitro contact through-feet blood brain barrier (BBB) model built using type IV collagen, rat astrocytes, and human umbilical vein endothelial cells (HUVECs) cocultured through Transwell porous polycarbonate membrane. The contact between astrocytes and HUVECs was demonstrated by electron microscopy: astrocytes endfeet pass through the 8.0 µm pores inducing HUVECs to assume a cerebral phenotype. Using this model we evaluated transmigration of melanoma cells from two different patients (M1 and M2) selected among seven melanoma primary cultures. M2 cells showed a statistically significant higher capability to pass across the in vitro BBB model, compared to M1. Expression of adhesion molecules was evaluated by flow cytometry: a statistically significant increased expression of MCAM, αvß3, and CD49b was detected in M1. PCR array data showed that M2 had a higher expression of several matrix metalloproteinase proteins (MMPs) compared to M1. Specifically, data suggest that MMP2 and MMP9 could be directly involved in BBB permeability and that brain invasion by melanoma cells could be related to the overexpression of many MMPs. Future studies will be necessary to deepen the mechanisms of central nervous system invasion.

Safety of bevacizumab in patients with malignant gliomas: a systematic review.

Angiogenesis has recently become a major target for the development of new antineoplastic drugs. The most serious adverse events linked to angiogenesis inhibitors are venous or arterial thromboembolism and haemorrhage. Thus, there is need to define with more certainty the impact of these new drugs in terms of adverse effects in neurological patients. The aim of the study is to assess the risk of venous thromboembolism (VTE) and bleeding in patients with malignant gliomas treated with bevacizumab with or without concomitant anticoagulant therapy. A review of published literature was performed in Medline, from which 476 records were identified. A total of 27 full-text articles, including retrospective analyses, retrospective reviews, and open label trials, were assessed for eligibility. The investigated drugs included bevacizumab alone, bevacizumab plus chemotherapy with/without concomitant radiation therapy; only two articles dealt with bevacizumab in association with anticoagulant treatment. A total of 2,208 patients with malignant gliomas, were identified and included in the analysis. From data it appears that patients receiving bevacizumab had a major risk of developing VTE that increased when bevacizumab is associated with radio-chemotherapy (4.27 vs 7.46 %). Regarding bleeding, data showed that patients treated with anticoagulant had a significantly increased risk of severe central nervous system (CNS) bleeding compared to patients not receiving anticoagulant therapy (0.6 vs 8.2 %). The use of bevacizumab combined with chemo-radiotherapy seems to be associated with a higher risk for VTE compared to patients receiving antiangiogenic therapy alone. The associated use of anticoagulants and bevacizumab far increases the risk of developing CNS and non-CNS bleeding higher than grade 3, compared to patients receiving bevacizumab alone.

Short-course radiotherapy in elderly patients with glioblastoma: feasibility and efficacy of results from a single centre.

BACKGROUND: The incidence of glioblastoma (GBM) in the elderly population is currently increasing, with a peak seen between 65 and 84 years. The optimal treatment in terms of both efficacy and quality of life still remains a relevant and debated issue today. The purpose of our study was to evaluate the feasibility of short-course hypofractionated accelerated radiotherapy (HART) in GBM patients aged over 70 years and with a good Karnofsky performance score (KPS). METHODS: A review of medical records at the "Istituto Neurologico C. Besta" was undertaken; patients aged ≥ 70 years who had undergone adjuvant HART for GBM between January 2000 and January 2004 were included in the study. HART was administered to a total dose of 45 Gy, 2.5 Gy/fraction, in three daily fractions for three consecutive days/cycle fractions each, delivered in two cycles (split 15 days). RESULTS: A total of 33 patients were evaluable for the current analysis. Median follow-up was 10 months. According to CTCAE (version 3.0) criteria, none of the patients developed radiation-induced neurological status deterioration or necrosis. KPS evaluation after HART was found to be stable in 73 % of patients, improved in 24 %, and worse in 3 %. The median overall survival time of the entire study population was 8 months (range 2-24). CONCLUSIONS: Our findings suggest that a hypofractionated accelerated schedule can be a safe and effective option in the treatment of GBM in the elderly.

Liposomal cytarabine in neoplastic meningitis from primary brain tumors: a single institutional experience.

Neoplastic meningitis (NM) is diagnosed in 1-2 % of patients with primary brain tumors. Standard treatment of NM includes single-agent or combination chemotherapy, with compounds such as methotrexate, thiotepa, and cytarabine (Ara-C) or its injectable, sustained-release formulation Depocyte(®). In this Report, we reported the data of efficacy and tolerability of an intrathecal Depocyte(®) regimen for patients presenting with NM from primary brain tumors. We described 12 patients with NM confirmed at magnetic resonance imaging (MRI) and with a positive cerebrospinal fluid (CSF) cytology. Patients were treated with repeated courses of intrathecal Depocyte(®) (once every 2 weeks for 1 month of induction therapy and as consolidation therapy on a monthly base in responding patients). Twelve patients (10 males and 2 females) were treated by our Institution. The diagnosis of primitive brain tumor was medulloblastoma in six patients, germinoma in two patients, pylocitic astrocytomas with spongioblastic aspects, teratocarcinoma, meningeal melanoma, and ependimoma in the other four patients. The total number of Depocyte(®) cycles ranged from one to nine. In 7/12 patients, there was clinical and/or radiological response after Depocyte(®), and the toxicity was moderate and transient, mainly due to the lumbar puncture procedure. In the two patients with germinoma, we observed a normalization of MRI Imaging and negativization of CSF with disappearance of the tumor cells. OS was 180 days (range 20-300, CI 95 %).

Neoplastic meningitis from solid tumors: a prospective clinical study in lombardia and a literature review on therapeutic approaches.

Neoplastic dissemination to the leptomeninges is an increasingly common occurrence in patients with both haematological and solid tumors arising outside the central nervous system. Both refinement of diagnostic techniques (Magnetic resonance imaging) and increased survival in patients treated with targeted therapies for systemic tumors account for this increased frequency. Cerebrospinal fluid cytological analysis and MRI confirm clinical diagnosis based on multifocal central nervous system signs/symptoms in a patient with known malignancy. Overall survival in patients with leptomeningeal neoplastic dissemination from solid tumors is short, rarely exceeding 3-4 months. However, selected patients may benefit from aggressive therapies, Apart from symptomatic treatment, intrathecal chemotherapy is used, with both free (methotrexate, Thiotepa, AraC) and liposomal antitumor agents (liposomal AraC). Palliative radiotherapy is indicated only in cases of symptomatic bulky disease, surgery is limited to positioning of Ommaya recervoirs or C5F shunting. We report clinical data on a cohort of 26 prospectively followed patients with neoplastic leptomeningitis followed in Lombardia, Italy, in 2011. Prognostic factors and pattern of care are reported.

Brain tuberculoma (Mycobacterium africanum): high index of suspicion helps in avoiding biopsy/surgery.

Partial seizures can be due to a growing cerebral lesion, which may be tumoral or inflammatory/infectious in nature. The differential diagnosis is obviously important; increasing immigration to Europe from Africa is leading to an increase of infectious disease involving also the central nervous system. The authors report imaging the a case of a brain tuberculoma due to Mycobacterium africanum mimicking brain tumor, in which diagnosis was possible by inoculum in guinea-pig of material obtained by mediastinal biopsy of enlarged lymph nodes. Specific treatment led to marked reduction in the size of the brain lesion.

Adult medulloblastoma: multiagent chemotherapy with cisplatinum and etoposide: a single institutional experience.

In 1991, a prospective phase II trial was initiated to evaluate the efficacy of treatment for adults with medulloblastoma (MB). After surgery, patients were staged with a neuroradiologic examination of the brain and neuroaxis and by cerebrospinal fluid cytology. All patients received three cycles of upfront cisplatinum (cisplatinum) and etoposide (VP16) chemotherapy followed by cranio-spinal radiation therapy. The current article reports on the long-term results from that trial. After a median follow-up of 14.9 years, among a total of 28 adults with MB, the overall progression-free survival and overall survival (OS) rates at 5 years were 57.6 and 80%, respectively. The median OS for the whole group of patients was 11.3 years. The observed toxicity was mainly hematological, with leukopenia and thrombocytopenia (16% of grades 3 and 4). In summary, in our small series of patients, the role of combination administration of CDDP + VP16 started before the initiation of radiotherapy in reducing recurrences, particularly distant recurrences, remains unclear. To know whether adding chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial.

Neuro-oncological diagnosis in patients without histological confirmation.

The impossibility to conduct a histological diagnosis could be due to different reasons: (1) patient's refusal to undergo surgery/biopsy. (2) Technical difficulties: despite the advance in surgical procedures, the removal of lesions that are located either in critical or in deep areas represents a considerable risk for patients. (3) Quality/quantity of the sample. In rare cases even when the surgical sample is achieved it could be impossible to reach a histological confirmation, for example due to the small amount of tissue obtained. The lack of histology leads to suboptimal therapy, incorrect prognosis, and misinterpretation of clinical trials and furthermore undermines the possibility to perform most radiation and chemotherapy protocols. In this setting the morphological data obtained with conventional MR imaging may be integrated with the metabolic, structural and perfusional information provided by new MR and metabolic techniques (spectroscopy, SPECT, PET in particular).

Malignant gliomas: early diagnosis and clinical aspects.

Brain tumor symptoms vary greatly from person to person because of two factors: location and size of tumors. The size of a tumor, however, does not necessarily affect the severity of symptoms. Manifestations depend on the cause of the symptoms: an increase in ICP, direct compression of gray or white matter, shifting of intracranial contents, or secondary cerebral ischemia. Symptoms may be non-specific and include headache, altered mental status, ataxia, nausea, vomiting, weakness, and gait disturbance. Left-sided weakness may be seen in a patient with a tumor pressing on the contra-lateral motor strip or speech difficulties may occur if a tumor is in the dominant hemisphere. Up to a third of people report having seizures prior to being diagnosed with a brain tumor. Rarely, brain tumor can present with psychiatric symptoms but without other neurological signs or symptoms. Evaluation for brain tumor is indicated in any patient with chronic, persistent headache associated with protracted nausea, vomiting, seizures, changes in headache pattern, neurologic symptoms, and change in personality.

Metabolic, electrolytes disorders and tromboembolic risk in malignant glioma patients.

In malignant gliomas, the management of symptoms and minimization of side effects assume major importance. Corticosteroids provide transient relief from neurological symptoms. However, treatment with steroids is also commonly associated with considerable side-effects including: hyperglycemia, osteoporosis, myopathy, lymphopenia and others. Sometimes, antiepileptic drugs may contribute to clinical decline of neuro-oncological patients in stable disease not only by neuropsychological impairment but also by metabolic interations. Several studies have demonstrated a high frequency of hyponatremia among patients treated with carbamazepine and particularly with oxacarbamazepine. Venous thromboembolism is a common complication in patients with cancer and it is particularly high in malignant gliomas, occurring in approximately 20-30% of such patients. Prophylactic treatment in patients with glioblastoma is a key topic. The role of prophylaxis has not yet been established with certainty. Overall the data show a clear reduction of venous thromboembolic events in patients treated with intermittent pneumatic compression (IPC). The addition of enoxaparin dose of 6.000 UI, starting in the perioperative period, induces an increase of major bleeding events. In the absence of availability of IPC, the use of enoxaparin 4.000 UI in addition to graduated compression stockings, reduces thromboembolic events without major bleeding events.

Rechallenge with temozolomide in recurrent glioma.

Despite a confirmed survival benefit associated with adjuvant radio- and chemotherapy, the majority of patients with malignant glioma relapse after initial therapy. Recurrent malignant glioma treatment has not been standardised and usually the response rate to standard chemotherapy protocols for recurrent malignant glioma is less than 30%. The growing body of evidence demonstrating the clinical importance of O6-methylguanine methyltransferase (MGMT) has generated a considerable interest in the exploration of strategies to overcome MGMT-mediated resistance to alkylating agents; for example protracted administration of Temozolomide (TMZ) may result in more extensive and sustained depletion of MGMT; for this reason a variety of dosing schedules that increase the duration of exposure and the cumulative dose of TMZ are being investigated for the treatment of patient with recurrent malignant glioma after standard treatment. The most widely studied regimens in this setting include (1) 21 of 28-day schedule at a dose of 75-100 mg/m(2)/day; (2) 7 of 14-day schedule at a dose of 150 mg/m(2)/day, also referred to as the ''one week on/one week off'' schedule; (3) Continuous daily schedule at a dose of 50 mg/m(2)/day. An alternative dosing schedule of TMZ may be a reasonable option in patients having high-grade gliomas with recurrence after standard therapy.

Lecture: fotemustine in brain tumors.

Fotemustine (FTMS) is a third-generation nitrosourea, in preclinical studies, FTMS compared favorably with carmustine (BCNU) and lomustine (CCNU) against several human tumor cell lines. In conventional schedule, FTMS is administered at a dose of 100 mg/sqm/week for three consecutive weeks as induction (I) treatment, followed by 100 mg/sqm every three weeks, after a 5-week rest, as maintenance (M). Several Italian groups reported the results using FTMS in malignant glioma patients recurring after temozolomide standard treatment. In these papers, the 6-progression free survival are ranging from 20 to 52%. With the schedule (I + M) myelosuppression is observed in more than 30% of patients, and thrombocytopenia and leukopenia are more frequent and significant in Temozolomide pretreated patients. On the bases of the hematological toxicities several authors experimented new schedules of FTMS administrated at low doses. Recently, some authors reported the interesting results of a multicenter study on recurrent glioblastoma multiforme patients combining FTMS with new antiangiogentic agent bevacizumab.

Consent and awareness: mental conditions at diagnosis.

Informed consent is often talked about in an abstract manner, as if consent and information necessarily have to go together, and almost as if consent is "naturally" the quintessence of a good professional relationship in modern medicine. The United States is considered as the place of origin of informed consent. In Italy the concept of informed consent can be found for the first time in the 1990s. Informed consent is based on the principles of autonomy and benefit, on awareness and information. Already at the moment of the diagnosis, in addition to motor deficits, focal cognitive deficits are often present. It is important for the doctor to consider and evaluate the actual ability to comprehend and process the clinical situation on the part of the patient. At the Neuro-Oncology Division of the Carlo Besta Neurological Institute of Milan, we sought to analyse how and to what extent the brain tumour alters and conditions cognitive functionality, and hence the ability to process, comprehend and retain information during a diagnostic communication, and whether and how this moment is influenced by the presence of any global or specific cognitive deficits. Preliminary and performed on a numerically limited sample, 30 patients out of 42, in a specific neuropsychological survey, display cognitive attention and memory deficits despite achieving an adequate score on a global cognitive assessment. The physician's attention to the cognitive faculties of a patient to whom a pathological condition and a therapeutic approach are being presented is fundamental.

Infections in neuro-oncology.

Infections represent a serious and frequent complication in neuro-oncology patients. Decreased immune defences, along with poor nutritional status are the main predisposition factors. The combined therapeutic strategies of chemotherapy and radiotherapy may favour bone marrow depression and further increase the risk of developing opportunistic infections in brain tumour patients. The spectrum of infections in neuro-oncology patients is large and includes opportunistic infections by bacteria, viruses, fungi and parasites. Importantly, a high index of suspicion for opportunistic infections in general should be maintained, especially in glioma patients receiving dose-dense schedules of temozolomide. After neurosurgical procedures, infections most commonly present as meningitis, subdural empyema, or cerebral abscess. Infections represent a frequent and possibly serious complication in general immunocompromised oncology population. It should be underlined that infections are not limited to immunocompromised patients, being also present at the early disease stages, especially due to therapeutic strategies (chemo and radiotherapy, surgical procedures). Therefore this issue deserves more attention in neuroncology setting.

Privacy-solidarity conflict: the communication with the support group.

Actually guidelines require that patient must be informed about his condition so that he can choose the persons he wants to share these information with. Nonetheless, the caregiver usually gets an intermediary role in doctor-patient communication thus becoming the doctor's main conversation partner and claiming to be given more information than the patient himself. A more complex situation is about brain tumours patients sometimes affected by cognitive deficiencies, compromising their comprehension skills or their capability of keeping the information they are being given. A preliminary study allowed to submit separately to brain tumour patients and their family members a semi-structured interview. Although doctors communicate diagnosis and therapeutic plans, patients and their family members often do not seem to remember the information they are given. An important percentage of patients and their carers cannot tell correctly what they was said by the doctors. Only a minor percentage of patients do not want to know all details of their disease. Instead, most of the family members, would rather their beloved were given just partial information on their conditions or even not given information at all. Communication with patients and their carers requires careful re-negotiation in a multiple time-points, rather than a one-off communication episode.