Visual-spatial and visuomotor functioning in adults with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a neurodevelopmental genetic disorder associated with visual-spatial and visuomotor deficits, which have not been studied well in adults with NF1. METHODS: In 22 adults with NF1 and 31 controls, visuomotor functioning was assessed by measuring eye latency, hand latency and hand accuracy during visuomotor tasks. Visual-spatial functioning was assessed by measuring eye movement responses during the Visual Threshold Task. RESULTS: The NF1 group had a significantly shorter eye latency than the control group and was less accurate in their hand movements during specific visuomotor tasks. The groups showed no differences in eye movement responses during the Visual Threshold Task and in hand latency during the visuomotor tasks. CONCLUSIONS: In contrast to studies in children with NF1, we found no alterations in visual-spatial information processing in adults. Impairments in eye latency and hand accuracy during specific visuomotor tasks may indicate deficits in visuomotor functioning in adults with NF1.

Plasticity of visual evoked potentials in patients with neurofibromatosis type 1.

OBJECTIVE: The inability to properly process visual information has been frequently associated with neurofibromatosis type 1 (NF1). Based on animal studies, the cause of cognitive disabilities in NF1 is hypothesized to arise from decreased synaptic plasticity. Visual cortical plasticity in humans can be investigated by studying visual evoked potentials (VEPs) in response to visual stimulation. METHODS: VEP plasticity was assessed by measuring the increase of the peak amplitudes C1, P1, and N1 induced by 10-min modulation of checkerboard reversals in 22 adult NF1 patients and 30 controls. VEP signals were recorded pre-modulation, during modulation, and at 2, 7, 12, 17, 22, 27 min post-modulation. RESULTS: The P1 amplitude increased significantly comparing post-modulation to pre-modulation in the control group. This potentiation was not observed in the NF1 group. CONCLUSIONS: Visual cortical plasticity could be measured using VEPs in response to visual stimulation in the control group. Individuals with NF1 may have reduced visual cortical plasticity, as indicated by their non-potentiated response to VEP induction. These findings should be interpreted with caution due to high inter-subject variability. SIGNIFICANCE: The present study contributes to an improved assessment of the feasibility for using neurophysiological outcome measures in intervention studies of cognitive deficits among patients with NF1.

Withdrawal of antiepileptic drugs in patients with low grade and anaplastic glioma after long-term seizure freedom: a prospective observational study.

BACKGROUND: When glioma patients experience long-term seizure freedom the question arises whether antiepileptic drugs (AEDs) should be continued. As no prospective studies exist on seizure recurrence in glioma patients after AED withdrawal, we evaluated the decision-making process to withdraw AEDs in glioma patients, and seizure outcome after withdrawal. METHODS: Patients with a histologically confirmed low grade or anaplastic glioma were included. Eligible patients were seizure free ≥ 1 year from the date of last antitumor treatment, or ≥ 2 years since the last seizure when seizures occurred after the end of the last antitumor treatment. Patients and neuro-oncologists made a shared decision on the preferred AED treatment (i.e. AED withdrawal or continuation). Primary outcomes were: (1) outcome of the shared decision-making process and (2) rate of seizure recurrence. RESULTS: Eighty-three patients fulfilled all eligibility criteria. However, in 12/83 (14%) patients, the neuro-oncologist had serious objections to AED withdrawal. Therefore, 71/83 (86%) patients were analyzed; In 46/71 (65%) patients it was decided to withdraw AED treatment. In the withdrawal group, 26% (12/46) had seizure recurrence during follow-up. Seven of these 12 patients (58%) had tumor progression, of which three within 3 months after seizure recurrence. In the AED continuation group, 8% (2/25) of patients had seizure recurrence of which one had tumor progression. CONCLUSION: In 65% of patients a shared decision was made to withdraw AEDs, of which 26% had seizure recurrence. AED withdrawal should only be considered in carefully selected patients with a presumed low risk of tumor progression.

A systematic review of prognostic factors predicting survival in patients with spinal bone metastases.

PURPOSE: For the selection of treatment in patients with spinal bone metastases (SBM), survival estimation plays a crucial role to avoid over- and under-treatment. To aid clinicians in this difficult task, several prediction models have been developed, consisting of many different risk factors. The aim of this systematic review was to identify prognostic factors that are associated with survival in patients with SBM to support development of predictive models. METHODS: A systematic review was performed with focus on prognostic factors associated with survival in patients with SBM. Two reviewers independently selected studies for inclusion and assessed the risk of bias. A level of evidence synthesis was performed for each prognostic factor. Inter-observer agreement for the risk of bias assessment was determined by the kappa-statistic. RESULTS: After screening, 142 full-text articles were obtained, of which 22 met the eligibility criteria. A total of 43 different prognostic factors were investigated in the included studies, of which 17 were relevant to pre-treatment survival estimation. The prognostic factors most frequently associated with survival were the primary tumor and the performance status. The prognostic factors most frequently not associated with survival were age, gender, number and location of the SBM and the presence of a pathologic fracture. CONCLUSIONS: Prognostication for patients with SBM should be based on an accurate primary tumor classification, combined with a performance score. The benefit of adding other prognostic factors is doubtful.

Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial.

BACKGROUND: Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma. METHODS: In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated. RESULTS: The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log10CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log10CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS. CONCLUSION: CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.

Endothelial CD276 (B7-H3) expression is increased in human malignancies and distinguishes between normal and tumour-derived circulating endothelial cells.

BACKGROUND: Mature circulating endothelial cells (CEC) are surrogate markers of endothelial damage. CEC measured in patients with advanced cancer are thought not only to derive from damaged normal vasculature (n-CEC), but also from damaged (t-CEC). Therefore, assays that allow the discrimination between these two putative types of CEC are thought to improve the specificity of the enumeration of CEC in cancer. METHODS: Identification of tumour-associated endothelial markers (TEM) by comparing antigen expression on normal vs t-CEC and assess the presence of t-CEC in peripheral blood of cancer patients by incorporating TEM in our novel flow cytometry-based CEC detection assay. RESULTS: No difference in antigen expression between normal and malignant endothelial cells (ECs) was found for CD54, CD109, CD137, CD141, CD144 and CXCR7. In contrast, overexpression for CD105, CD146, CD276 and CD309 was observed in tumour ECs compared with normal ECs. CD276 was most differentially expressed and chosen as a marker for further investigation. CD276-expressing CEC were significantly higher in 15 patients with advanced colorectal cancer (median 9 (range 1-293 cell per 4 ml); P<0.005), in 83 patients with a glioblastoma multiforme (median 10 (range 0-804); P<0.0001) and in 14 patients with advanced breast cancer (median 14 (range 0-390) P<0.05) as compared with 24 healthy individuals (median 3 (range 0-11)). Of all patients with malignancies, 58% had CD276(+) CEC counts above the ULN (8 cell per 4 ml). CONCLUSIONS: The present study shows that CD276 can be used to discriminate ECs from malignant tissue from ECs from normal tissue. In addition, CD276(+) CEC do occur in higher frequencies in patients with advanced cancer.

IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) have been implicated in tumorigenesis of gliomas. Patients with high-grade astrocytomas with IDH1 or IDH2 mutations were reported to have a better survival, but it is unknown if this improved survival also holds for low-grade astrocytoma and whether these mutations predict outcome to specific treatment. METHODS: We retrospectively investigated the correlation of IDH1 and IDH2 mutations with overall survival and response to temozolomide in a cohort of patients with dedifferentiated low-grade astrocytomas treated with temozolomide at the time of progression after radiotherapy. RESULTS: IDH1 mutations were present in 86% of the 49 progressive astrocytomas. No mutations in IDH2 were found. Presence of IDH1 mutations were early events and significantly improved overall survival (median survival 48 vs 98 months), but did not affect outcome of temozolomide treatment. CONCLUSION: These results indicate that IDH1 mutations identify a subgroup of gliomas with an improved survival, but are unrelated to the temozolomide response.

[Clinical reasoning and decision-making in practice. An older man with prostate carcinoma and a painless paraparesis of the legs]. / Klinisch denken en beslissen in de praktijk. Een oudere man met prostaatcarcinoom en een pijnloze parese aan de benen.

A 78-year-old man with metastasised prostate carcinoma presented with a painless paraparesis. His cerebrospinal fluid showed elevated protein and a mononuclear pleiocytosis, but cytology investigations of 5 separate samples revealed no malignant cells in the cerebrospinal fluid. Extensive viral and bacterial tests (including ELISA for Borrelia burgdorferi) of serum and cerebrospinal fluid were negative. On the day radiation therapy for presumed leptomeningeal metastases was due to start the IgG and IgM Western blot for Borrelia were found to be positive, indicating neuroborreliosis. Soon after the start of antibiotic therapy the paraparesis began to improve and after four weeks the patient had made a complete recovery. In patients with a progressive paraparesis, neuroborreliosis should be considered even in the absence of pain.

[A patient with sinus thrombosis associated with paroxysmal nocturnal hemoglobinuria]. / Een patiënte met sinustrombose door paroxismale nachtelijke hemoglobinurie.

A 27-year-old woman with a history of aplastic anaemia complained of poor control of her right arm and hand, unsteady gait, and headache that increased while in a recumbent position. She was diagnosed with cerebral sinus thrombosis. Additional investigation revealed paroxysmal nocturnal haemoglobinuria (PNH). Treatment with heparin was initiated but stopped after the patient developed a brain haemorrhage. The patient recovered with no signs of residual symptoms and began taking oral anticoagulants as maintenance therapy. PNH is a rare acquired clonal disorder due to a defective expression of the glycosylphosphatidyl-inositol anchor membrane protein. It is characterised by haemolytic anaemia, diminished haematopoiesis, increased susceptibility for infections and a hypercoagulable state. Patients with aplastic anaemia have an increased risk of developing PNH. In patients with cerebral sinus thrombosis PNH should be considered as a possible underlying disorder. These patients should be questioned for possible clinical symptoms of PNH, such as acute abdominal pain or dark urine in the morning. For patients with these symptoms and in those with a history of aplastic anaemia or recurrent thrombosis, additional testing for PNH should be conducted.

[Favourable result for temozolomide in recurrent high-grade glioma]. / Gunstig resultaat van temozolomide bij een recidiefvan een hooggradig glioom.

OBJECTIVE: To describe the results of the treatment of recurrent glioma with temozolomide. DESIGN: Retrospective. METHOD: This study evaluated 77 patients with a recurrent high-grade glioma who from August 1997-December 2003 were treated with temozolomide (150-200 mg/m2/day for 5 days per 28-day cycle) following surgery and radiotherapy at the Daniel den Hoed Oncology Centre of the Erasmus MC, Rotterdam, the Netherlands. The patients were divided into 4 groups depending on histology and chemotherapy history. RESULTS: 15 patients received temozolomide for a recurrent anaplastic oligodendroglioma or mixed oligo-astrocytoma. The response in this group was 80% and after 12 months in 47% of the patients there was no disease progression. 35 patients underwent second-line chemotherapy with temozolomide after earlier chemotherapy with procarbazine, lomustine and vincristine for recurrent anaplastic oligodendroglioma or mixed oligo-astrocytoma. Response was 26% and after 12 months in 15% of patients there was still no disease progression. 14 patients were treated with temozolomide for a recurrent anaplastic astrocytoma with a response of 35% and after 12 months in 8% of these patients there was no disease progression. Of the 13 patients with a recurrent glioblastoma who were treated with temozolomide 16% responded and after 6 and 12 months 21% were still free from progression. Temozolomide was well-tolerated: 2 patients had to stop because of probable side effects. CONCLUSION. Temozolomide has an acceptable safety profile and may be regarded as the preferred treatment for recurrent anaplastic gliomas after radiotherapy. There is only a limited role for temozolomide in the treatment of recurrent glioblastoma.

[Clinical reasoning and decision-making in practice. A young woman with fever, shortness of breath, and reduced consciousness]. / Klinisch denken en beslissen in de praktijk. Een jonge vrouw met koorts, benauwdheid en een gedaald bewustzijn.

A 23-year-old woman with mild psychomotor retardation presented with fever, coughing, reduced consciousness and a stiff neck. A chest X-ray revealed an infiltrate in the left lower lobe; the cerebrospinal fluid was cloudy with a mild pleocytosis. Ceftriaxone was prescribed and the fever subsided. On the second day of admission she had a seizure, and a paraparesis emerged. Despite changes in the antibiotic regimen, her clinical condition hardly improved. On the fifth day, antibodies against Mycoplasma pneumoniae were found to be strongly positive and the diagnosis was M. pneumoniae infection. This accounted for the pneumonia together with meningoencephalitis and a transverse myelitis. The antibiotics were switched to doxycycline and the clinical condition improved dramatically. Six weeks after discharge, the patient had made a complete recovery. In patients suffering from meningitis with an atypical presentation, uncommon causes of infection should be considered. Together with a pneumonia, M. pneumoniae, Chlamydia pneumoniae, Legionella pneumophila and Listeria monocytogenes should be high on the list of potential causes for bacterial meningitis.

GABA and glycine frequently colocalize in terminals on cat spinal motoneurons.

In this ultrastructural study the colocalization of gamma-amino butyric acid (GABA) and glycine in terminals within cat lumbar motoneuronal cell groups was investigated and the frequency of this colocalization was determined. For this purpose the post-embedding immunogold technique was applied on serial sections, using antibodies directed against either GABA or glycine. Analysis of all labelled terminals in a random area of cat motoneuronal cell groups showed that 25 +/- 5% were labelled for GABA only, 29 +/- 6% were labelled for glycine only and 46 +/- 9% were labelled for both GABA and glycine, meaning that nearly two out of every three GABA-labelled terminals were also labelled for glycine and vice versa. Based on these results and on other data suggesting a high frequency of colocalization, it is concluded that in cat motoneuronal cell groups colocalization of GABA and glycine is the rule rather than the exception.