Leptomeningeal disease in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the western hemisphere, with an annual incidence of 3:100000. Commonly patients are asymptomatic but not rarely disease progression occurs in the setting of lymphadenopathy and extensive leukemic burden. Leptomeningeal involvement in patients with CLL is infrequent, with presenting symptoms of headache (23%), acute or chronic changes in mental status (28%), cranial nerve abnormalities (54%) including optic neuropathy (28%), weakness of lower extremities (23%) and cerebellar signs (18%). In this report, we discuss a CLL patient with leptomeningeal involvement, who presented with neurological symptoms as the first clinical sign, and a diagnosis of leptomeningeal was made based on CSF cytology and flow cytometry. Treatment consisted of radiation therapy and intrathecal chemotherapy with arabinoside-cytosine and systemic chemotherapy. On the basis of this patient-report together with 37 other previously reported cases, the clinical characteristics together with treatment options and outcome of leptomeningeal involvement in CLL are reviewed. Our case together with data from the literature indicate that a timely diagnosis and intensive treatment of leptomeningeal disease of CLL may lead to longstanding and complete resolution of neurological symptoms.

[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.

Intrathecal injection of GDNF and BDNF induces immediate early gene expression in rat spinal dorsal horn.

Glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) are potent trophic factors for dorsal root ganglion cells. In addition, these factors are produced in subsets of dorsal root ganglion cells and transported anterogradely to their terminals in the superficial dorsal horn of the spinal cord, where they constitute the only source of GDNF and BDNF. We investigated the effect of 10 mug GDNF and BDNF injected by lumbar puncture on the expression of the immediate early gene (IEG) products c-Fos, c-Jun, and Krox-24 in the adult rat dorsal horn. In the dorsal horn of S1 spinal segments, GDNF and BDNF induced a strong increase in IEG expression, which was most pronounced in laminae I and II (2.9- to 4.5-fold). More distal from the injection site, in the dorsal horn of L1/L2 spinal segments, the increase in IEG expression was less pronounced, suggesting a concentration-dependent effect. In order to explain the effects of intrathecally injected GDNF, we investigated whether lumbo-sacral dorsal horn neurons expressed RET protein, the signal-transducing element of the receptor complex for GDNF. It was found that several of these neurons contained RET immunoreactivity and that some of the RET-labeled neurons had the appearance of nociceptive-specific cells, confirming their presumed role in pain transmission. Additionally, using double-labeling immunofluorescence combined with confocal microscopy, it was found that after intrathecal GDNF injection 35% of c-Fos-labeled cells were also labeled for RET. These results demonstrate that intrathecally administered GDNF and BDNF induce IEG expression in dorsal horn neurons in the adult rat, supposedly by way of their cognate receptors, which are present on these neurons. We further suggest that the endogenous release of GDNF and BDNF, triggered by nociceptive stimuli, is involved in the induction of changes in spinal nociceptive transmission as in various pain states.

The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study.

To assess the benefit of intraventricular chemotherapy, patients with leptomeningeal metastasis (LM) from breast cancer were randomised to treatment including intraventricular (IT) chemotherapy (n=17) or to non-intrathecal (non-IT) treatment (n=18). Appropriate systemic therapy and involved field radiation therapy (RT) were given in both arms. Intention-to-treat analysis showed neurological improvement or stabilisation in 59% of the IT and in 67% of the non-IT group, with median time to progression of 23 weeks (IT) and 24 weeks (non-IT). Median survival of IT patients was 18.3 weeks and 30.3 weeks for non-IT patients (difference 12.9 weeks; 95% Confidence Interval (CI) -5.5 to +34.3 weeks; P=0.32). Neurological complications of treatment occurred in 47% (IT) vs 6% (non-IT) (P=0.0072). In conclusion, standard systemic chemotherapy with involved field RT for LM from breast cancer is feasible. Addition of intraventricular chemotherapy does not lead to survival benefit or improved neurological response, and is associated with an increased risk of neurotoxicity.

[Not every TIA is primarily vascular]. / Niet iedere TIA is primair vasculair.

Three patients, two women aged 72 and 45 years, and a man aged 80 years, presented with transient neurological deficits due to a brain tumour, a glioblastoma multiforme and two meningiomas respectively. A fourth patient, an 84-year-old man, had a transient ischaemic attack (TIA) with a meningioma as an incidental finding. The first woman had normal CT findings, but MRI revealed the neoplasm. Symptoms included motor loss, sensory disturbances, dysphasia and dysarthria, lasting from 30 seconds up to 10 minutes. The first two patients had surgery; the first one later died when the tumour recurred. The other two patients still exhibit a spontaneous recovery. Of all patients with a clinical presentation of a TIA, 0.4-1% harbour a brain tumour. Clinical symptoms do not distinguish 'transient tumour attacks' from TIAs with a primarily vascular origin. Transient tumour attacks are mainly seen with meningiomas, and to a lesser extent with high-grade gliomas. Changes in intracranial pressure leading to focal ischaemia may explain the occurrence of this phenomenon. A part from intracerebral tumours, non-vascular entities mimicking TIAs can also be seen with demyelinating processes, metabolic disturbances, epilepsy or migraine. Brain imaging is always required in patients with transient neurological deficits. A CT scan may provide false-negative results and in case of doubt, MRI is the preferred diagnostic tool.

[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.

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971.

PURPOSE: Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. PATIENTS AND METHODS: In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed. RESULTS: Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION: TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.

[Levetiracetam: an anti-epileptic drug with interesting pharmacokinetic properties]. / Levetiracetam: een anti-epilepticum met interessante farmacokinetische eigenschappen.

Levetiracetam is a new anticonvulsant for adjunctive treatment of partial epilepsy. It is well tolerated, with no significant risks, at a dose of 1000-3000 mg/day in adults. The efficacy (> 50% reduction in attacks) in refractory partial epilepsy is 22-40%, depending on the dose. Efficacy was also seen with levetiracetam monotherapy in more than half of the positive responders. Levetiracetam does not cause induction or inhibition of the P450 enzyme system or other enzyme systems, there is no active metabolite and it exhibits almost no protein binding. These factors mean that this drug undergoes no significant interactions with other medication and appears suitable for elderly patients and for conditions requiring complex pharmacotherapy. Compared with other recently registered anti-epilepsy drugs, levetiracetam appears promising in terms of efficacy, tolerability and pharmacokinetics. The simple dosing schedule is an additional benefit.

EORTC Brain Tumor Group: achievements and perspectives.

The EORTC Brain Tumor Group has a long standing history of achievements. The activities of the Brain Tumor Group have recently been re-structured in order to face the challenge of large intergroup/intercontinental trials and be a reference address for early drug development needed for gliomas. Constant adaptation to higher quality assurance criteria and implementation of translational research studies are now priorities for the Brain Tumor Group. Due to such activities, the EORTC Brain Group has become a major player in clinical research. The number of centres and patients joining its trials have greatly increased over the past 2 years. Achievements and strategies are detailed in this article.