[Ischemic stroke patients following intravenous thrombolysis. Outcome in a regional stroke center]. / Intravenöse Thrombolyse des ischämischen Schlaganfalls. Ergebnisse in einem regionalen Schlaganfallzentrum.

BACKGROUND: We wanted to compare the outcome following IV thrombolysis in our patients with ischemic stroke with the outcome reported from the phase 3 registration trials and other large trials. PATIENTS AND METHODS: From January 2008 through December 2009 we treated 225 patients with ischemic stroke with IV thrombolysis. Retrospectively, we analyzed their clinical data upon admission, during their stay, and upon discharge with special reference to eligibility criteria for IV thrombolysis, symptomatic hemorrhage, and clinical outcome. RESULTS: The average age of the patients was 74 years, with 34% being older than 80 years. The median time between stroke onset and initiation of treatment was 112 min. The initial median NIHSS was 11 points (Rankin score ≥ 4 in 79% of patients). The rate of symptomatic hemorrhage was 3%. The median follow-up was 14 days. At the end of the observation period, clinical symptoms had improved in 73% of patients (Rankin score ≤ 2 in 45% of patients). The mortality rate was 12%. In 55% of patients, IV thrombolysis was off label (age > 80 years in 34% of patients). CONCLUSION: The clinical results of IV thrombolysis in our stroke center are similar to the outcome reported from the registration trials and larger clinical series although we treated off label in more than half of the patients. Even larger studies have since shown that the age limit under 80 years for patients is not reasonable. The eligibility criteria should be adapted to reality at this point.

[Miller-Fisher syndrome and the spectrum of oculomotor palsies with anti-GQ1b antibodies]. / Das Miller-Fisher-Syndrom im Spektrum GQ 1b-Antikörper-positiver Erkrankungen der Augenmuskelnerven.

The author reports his experience with his own case of Miller-Fisher syndrome (MFS) and discusses the spectrum of GQ 1b-positive oculomotor nerve diseases, including MFS, Bickerstaff's brainstem encephalitis, Guillain-Barré syndrome, ophthalmoplegia without ataxia and isolated oculomotor palsies.

Adult medulloblastoma: prognostic factors and response to therapy at diagnosis and at relapse.

Adult medulloblastoma is a rare tumor with few retrospective studies published so far. The role of adjuvant chemotherapy or chemotherapy at relapse is unclear. This study reports therapy and outcome in all adult (>or=16 years old) medulloblastoma (n=34) and supratentorial primitive neuroectodermal tumor (PNET) patients (n=2) treated in 2 neuro-oncological centers between 1976 and 2002. The median age was 24.5 years (range 16-76). After resection, 16 patients were treated with craniospinal radiotherapy alone, 20 patients also received adjuvant chemotherapy (8 vincristine, CCNU, cisplatin; 7 methotrexate alone or methotrexate/vincristine-based polychemotherapy; 5 other protocols). Median survival in the whole cohort was 126 months (2+ - 200+months). Five-year and 10-year survival rates were 79 % and 56%. Adjuvant chemotherapy was associated with a non-significant trend to prolonged survival (relative risk (RR) 1.89; p=0.068). The median progression-free survival (PFS) after primary therapy was 83 months. At relapse, 10 of 12 evaluable patients achieved a complete response upon second-line therapy. The median survival times from first (n=17) and second relapse (n=9) were 21 months (0-67+ months; 5/17 without second relapse) and 20 months (1-29 months). Cox regression analysis revealed the infiltration of the floor of the 4(th) ventricle at diagnosis as the only therapy-independent prognostic factor (RR 0.48; p=0.03). In conclusion, adjuvant chemotherapy may prolong survival in adult medulloblastoma patients. Moreover, second-line therapy may be beneficial for these patients. As in pediatric medulloblastoma patients, primary infiltration of the floor of the 4(th) ventricle indicates a poor prognosis.

Response of radiochemotherapy-associated cerebral edema to a phytotherapeutic agent, H15.

Twelve patients with brain tumors and progressive edema caused by tumor progression or radiochemotherapy-related leukoencephalopathy were treated with H15, a phytotherapeutic anti-inflammatory agent. Edema was reduced in two of seven patients with glioblastoma with tumor progression and in three of five patients with treatment-related leukoencephalopathy. All patients with leukoencephalopathy improved clinically for several months.

Primary central nervous system lymphoma 1991-1997: outcome and late adverse effects after combined modality treatment.

BACKGROUND: This retrospective single-center study assesses the feasibility, therapeutic outcome, and late side effects of combined modality therapy with intravenous methotrexate, whole brain radiotherapy (WBRT), and intravenous cytarabine in patients with primary central nervous system lymphoma (PCNSL). METHODS: All 28 consecutive patients diagnosed with PCNSL between 1991 and 1997 were scheduled to receive combined modality therapy. Seven of 28 patients did not receive combined modality treatment: 6 patients had WBRT alone because of poor physical condition, and 1 patient died before receiving treatment. Of the remaining 21 patients, 5 received the complete regimen, and 16 received a modified regimen with reduced dose intensity. RESULTS: Fourteen of 21 patients (67%) treated with combined modality therapy had a complete response; 1 had a partial response. Median survival was 11 months in all 28 patients, 23 months in all patients with combined modality treatment, and 41 months in patients receiving the complete regimen. Of 15 examinable patients with a follow-up of 8 months or more, 10 developed severely symptomatic and 5 mildly symptomatic or asymptomatic diffuse white matter changes. CONCLUSION: Only a small subgroup of all patients with PCNSL appears to be eligible for receiving all parts of the combined modality regimen. Treatment in these patients leads to a marked prolongation of survival. The risk of late side effects is high even with modified, dose intensity-reduced versions of combined modality treatment.

A role for preirradiation PCV chemotherapy for oligodendroglial brain tumors.

Oligodendroglial tumors have been identified as a subgroup of glial neoplasms with a distinctly better response to chemotherapy and overall survival than purely astrocytic gliomas. Here we report our experience with adjuvant postirradiation and preirradiation chemotherapy using procarbazine, lomustine, and vincristine (PCV) in 27 patients with WHO grade II or III oligodendroglioma or oligoastrocytoma. The efficacy of chemotherapy was assessed according to the Macdonald response criteria (complete response, CR; partial response, PR; stable disease, SD; progressive disease, PD) and progression-free survival intervals by computed tomography or magnetic resonance imaging. First, we confirm that PCV salvage therapy for patients progressing after radiotherapy is highly effective (n = 11, 1 CR, 5 PR, 5 SD; median progression-free survival has not yet been reached, but is longer than 18 months). Second, 3 patients who received radiotherapy plus PCV as first-line therapy achieved CR and 2 achieved SD, and all 5 are progression-free with a median follow-up of 12 months. Third, given these encouraging results, 11 patients received postoperative preirradiation PCV chemotherapy and were given radiotherapy only upon progression. Preirradiation PCV chemotherapy was also effective (2 CR, 3 PR, 6 SD; median progression-free survival has not been yet reached, but is longer than 14 months). Patients with anaplastic oligoastrocytomas were as likely to respond to PCV chemotherapy, as were patients with anaplastic oligodendroglioma. Three patients who had previously responded to PCV were successfully treated with a second course of PCV upon recurrence. PCV chemotherapy was also effective in patients with leptomeningeal spread of oligodendrogliomas. A randomized prospective trial is required to compare the effectiveness and neurotoxicity of first-line PCV chemotherapy followed by radiotherapy to the traditional reverse sequence.

Elevated CSF lactoferrin in superficial siderosis of the central nervous system.

This study sought to identify abnormalities in the levels of iron transport proteins in patients with superficial siderosis of the central nervous system. We compared patients with superficial siderosis (n = 7) with patients suffering from various other neurological disorders (n = 176, total). CSF and serum levels of lactoferrin, and CSF levels of transferrin were measured by enzyme-linked immunosorbent assay. Serum transferrin was measured by nephelometry. Lactoferrin, but not transferrin, levels in the CSF were significantly elevated in superficial siderosis. Unexpectedly, CSF transferrin was decreased in multiple sclerosis patients. Enhanced CSF lactoferrin may reflect an increased iron transport requirement in the central nervous system in superficial siderosis and might be a useful measure for monitoring response to therapy.

Epidemiology of primary CNS lymphoma.

In the beginning of the nineties the National Cancer Institute Surveillance, Epidemiology, and End Results Program calculated the incidence of primary central nervous system non-Hodgkin's lymphoma (PCNSL) as 1:100000. The incidence of PCNSL has been increasing since the seventies in immunocompetent patients. The main increase, however, is taking place since the mid-eighties and is due to the increase of immunodeficiency and immunosuppression. The risk is 2-6% in AIDS patients according to clinical data and will probably further increase with the length of survival in these patients. Transplant patients carry a risk of 1-5% to develop a PCNSL. The risk is 1-2% for renal, and 2-7% for cardiac, lung or liver transplant recipients. Patients with congenital immune deficiency have a risk of 4%. PCNSL may also present as a secondary malignancy.

Primary central nervous system lymphoma: from clinical presentation to diagnosis.

Immunocompetent patients with primary central nervous system lymphoma (PCNSL) present with a median age of 55 years, immunosuppressed patients with a median age of 40 years. They show a broad range of signs and symptoms. Symptoms of increased intracranial pressure and personality change are most frequent, followed in frequency by ataxia and hemiparesis. The median time from onset of symptoms to diagnosis is 3-5 months in immunocompetent patients and 2 months in immunodeficient patients. The time to diagnosis can be considerably longer in patients with slowly developing personality change or fluctuating symptoms due to spontaneous or steroid-induced remission of so-called sentinel lesions. Native CT scans show iso- or hyperdense lesions with homogenous contrast enhancement. T1-weighted MRI scans show hypointense and T2-weighted scans hyperintense lesions. The definitive diagnosis of PCNSL requires biopsy. In some cases, however, the definitive diagnosis may exclusively be made by the demonstration of malignant B-lymphocytes in the cerebrospinal fluid.

[Cochlear prosthesis implantation in superficial leptomeningeal hemosiderosis]. / Cochlear-implant-Versorgung bei superfizieller leptomeningealer Hämosiderose.

Superficial leptomeningeal hemosiderosis is a rare disease of the central nervous system. Chronic bleeding into the subarachnoid space causes deposition of hemosiderin in glial cells and subsequent damage to adjacent brain tissue. There is a characteristic predilection for the cerebellum and eighth cranial nerve. Accordingly, among a variety of symptoms, cerebellar ataxia and sensorineural hearing loss progressing to total deafness commonly occur. To date, the hearing loss has been believed to be purely neural. We present a case of superficial hemosiderosis in a patient with total deafness who was successfully provided with a cochlear implant. Audiometry demonstrated total bilateral cochlear hearing losses but with preserved function of the eighth cranial nerve. These findings make us conclude that in contrast to current opinion, superficial hemosiderosis can initially damage the cochlea alone. Thus, patients with total deafness due to this disorder may benefit from cochlear implantation. All patients require careful audiometric assessment, including promontory stimulation.

Topotecan-based combination chemotherapy for human malignant glioma.

BACKGROUND: Topotecan has been considered a promising agent for the adjuvant chemotherapy of human malignant glioma because of its novel mode of action, its activity against other solid tumors, and its good penetration across the blood-brain barrier. However, the clinical effects of topotecan monotherapy in malignant glioma have been disappointing. MATERIALS AND METHODS: We sought to identify suitable partners for topotecan combination chemotherapy of malignant glioma using two well-characterized human malignant glioma cell lines, T98G and LN-229. The effects of co-exposure to topotecan and other chemotherapy drugs were assessed in cytotoxic and clonogenic cell death assays. RESULTS: We found additive, less-than-additive, or occasional antagonistic effects, but never synergistic activity of topotecan with either CCNU, VM26 or vincristine, in acute cytotoxicity or in clonogenic cell death assays, with simultaneous or sequential drug exposure. VM26 or vincristine followed by topotecan yielded the most favourable results. Further, prolonged exposure of the glioma cells to topotecan and either CCNU, VM26, vincristine, cisplatin, doxorubicin or cytarabine resulted in additive but not synergistic growth inhibition. CONCLUSIONS: The present study fails to identify a specific partner for topotecan-based combination chemotherapy of malignant glioma among the chemotherapeutic drugs examined here. While this does not exclude a possible synergy of the drug combinations examined here in vivo, a focus on novel partners for topotecan or topotecan-based chemoimmunotherapy may be more promising.

Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity.

Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are phytotherapeutic anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low micromolar concentrations. In-situ DNA end labelling and electron microscopy reveal that boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with free radical formation nor blocked by free radical scavengers. The levels of BAX and BCL-2 proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression is induced by boswellic acids via a p53-independent pathway. Ectopic expression of wild-type p53 also induces p21, and facilitates boswellic acid-induced apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells enhances rather than decreases boswellic acid toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of boswellic acids do not interfere with cancer drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect is probably mediated by inhibition of RNA synthesis and is not associated with changes of CD95 expression at the cell surface. Further studies in laboratory animals and in human patients are required to determine whether boswellic acids may be a useful adjunct to the medical management of human malignant glioma.

Gender-related effects of indomethacin on cerebrovascular CO2 reactivity.

Prostaglandins are believed to play an important role in the regulation of resting cerebral blood flow and in the vasodilatory response to hypercapnia. Recently, we reported an increased CO2 reactivity (CR) in premenopausal women and, in the past, evidence has accumulated that estrogens might increase basal levels of prostaglandin secretion from endothelial cells. Therefore, one may speculate that gender differences in CR are possibly mediated by higher prostaglandin levels in women. Using transcranial Doppler sonography, we assessed CR before and 90 min after a single dose of 100 mg of indomethacin in 22 healthy volunteers (11 men, 11 women). Before intake of indomethacin, women had a significantly higher CR (4.53+/-0.49 vs. 3.61+/-0.74, P<0.01). Ninety minutes after indomethacin administration, CR decreased to 1.53+/-0.93 in women and 1.60+/-0.92 in men, respectively. The change of CR was 3.00+/-1.29 in women vs. 2.01+/-1.06 in men (P=0.07). For the entire study population, the decrease of CR was linearly correlated with the initial value of CR (rs=0.74, P<0.001). This gender-related difference possibly relates to higher prostaglandin levels as mediators of an increased CR in premenopausal women, although the exact features remain to be clarified.

Manifestation of Hashimoto's encephalopathy years before onset of thyroid disease.

Patients with Hashimoto's encephalopathy (HE), a steroid-responsive disorder, associated with Hashimoto's disease and high levels of thyroid-related autoantibodies usually present with a subacute onset of confusion, focal or generalized seizures. Frequent EEG abnormalities include generalized, rhythmic bifrontal or temporal slowing. Elevated protein levels or an intrathecal IgG synthesis may be present in cerebrospinal fluid (CSF). A 39-year-old woman underwent a relapsing course of myocloni and generalized seizures. Initially, thyroid function, thyroid-related autoantibody screening and cerebral MRI were unrevealing. CSF showed oligoclonal bands. Short-term treatment with high doses of prednisolone resolved the myocloni. During the 5th episode of myocloni, signs of hyperthyroidism and elevation of thyroid microsomal antibody titer developed. Hashimoto's thyroiditis and HE were diagnosed. After subtotal thyroidectomy the patient remained asymptomatic.

Exteroceptive suppression of temporalis muscle activity in patients with fibromyalgia, tension-type headache, and normal controls.

Changes of the second suppressive period (ES2) of the exteroceptive suppression of the temporalis muscle activity are found in patients with chronic tension-type headache (TTH) and are suggested to reflect an abnormal endogenous pain control system. We investigated whether similar changes are found in patients with the fibromyalgia syndrome (FMS) that is also believed to result from disturbed central pain processing. The ES2 values of 27 patients with FMS were compared with those of 18 patients with TTH and 40 healthy volunteers. The duration of ES2 (+/-SD) in FMS patients was 30.6+/-7.5 ms and was not significantly different from the control group (33.1+/-7.8 ms), whereas it was significantly shortened in TTH patients (22.9+/-11.5 ms). Our results indicate that, despite similar concepts on the pathophysiology of the two chronic pain disorders, there are no comparable changes of this brain stem reflex activity in FMS.

No effect of prophylactic treatment with metoprolol on cerebrovascular CO2 reactivity in migraineurs.

The prophylactic effect of metoprolol in the treatment of migraine is well known, but its mode of action is still unclear. In the past, increased CO2 reactivity has been reported as one pathognomic finding in interictal migraineurs. Using transcranial Doppler we assessed CO2 reactivity in 20 migraineurs before and 3 h after the first intake of 50 mg metoprolol, and subsequently twice after 1 and 8 weeks of continuous therapy with 150 mg metoprolol/d. Before initiation of therapy, migraineurs as a group had increased CO2 reactivity (p=0.07) compared to 20 age- and sex-matched volunteers. While treatment with metoprolol has been reported to affect amplitudes of increased contingent negative variation or visual evoked potentials in interictal migraineurs, it had no influence on enhanced CO2 reactivity in the present study. Moreover, the pretreatment value of CO2 reactivity did not correlate with the clinical efficacy of metoprolol after a 2-month treatment period.

Animal models of leptomeningeal metastasis.

Animal models of leptomeningeal metastasis (LM) should give insight into pathophysiological mechanisms and allow to evaluate new treatments including their neurotoxicity. Syngeneic models use tumor cells of mouse, rat, rabbit or guinea pig origin. Allogeneic models usually rely on human tumor cells injected into nude mice or rats. A review of the literature revealed 2 (4) different glioma, 3 medulloblastoma, 3 (3) carcinoma, 3 (1) melanoma, 1 rhabdomyosarcoma, 2 (8) leukemia and 2 (2) non-Hodgkin's lymphoma allogeneic (syngeneic) models of LM. These models have been used to study the evolution of LM and to evaluate systemic or intrathecal chemotherapy, intrathecal immunotherapy (interleukin-2, interferon-beta, uncoupled, toxin- or radionuclide-conjugated antibodies), and recently gene therapeutic approaches. On the whole, pathophysiological, therapeutic and neurotoxic findings have been well transferable to the clinical situation. Therefore, it seems rational to preclinically test new treatments in an appropriate animal model of LM before using them in patients.

New aspects of immunotherapy of leptomeningeal metastasis.

Immunotherapeutic approaches to leptomeningeal metastasis (LM) include the intrathecal application of cytokines such as interleukin-2 (IL-2) and interferon-alpha (IFN-alpha), and lymphokine-activated killer cells (LAK cells). Results in a rodent model of leptomeningeal gliomatosis with intrathecal IL-2 application are discouraging, but some clinical improvement and clearance of neoplastic cells from CSF have been seen in patients with LM from melanoma treated with intrathecal IL-2 alone, and in patients with LM from primary brain tumors and squamous cell carcinoma of the tongue treated with intrathecal LAK cells and IL-2. The neurotoxicity of this therapy, mainly increased intracranial pressure, has been considerable but generally manageable. However, IFN-alpha caused severe neurotoxicity in form of an only partly reversible progressive vegetative state in the majority of patients. Considering the small number of patients treated with IL-2 and LAK cells, its value for the treatment of LM could only be stated by further investigation. In future, the application of recently discovered cytokines such as Fas-ligand, the continuous paracrine cytokine release by genetically modified cells, or vaccination strategies using genetically modified tumor cells might offer new immunotherapeutic approaches in LM.

Changes of cerebrovascular CO2 reactivity during normal aging.

BACKGROUND AND PURPOSE: During the past decade, transcranial Doppler sonography has widely been used to assess blood flow velocities in the basal intracranial arteries and cerebrovascular reactivity (CR) to various stimuli. Although numerous studies have shown a decline of cerebral blood flow velocity with age, the age dependency of CR, including cerebrovascular CO2 reactivity, however, is controversial. Recently, we have reported a significant sex-related difference in CR, stressing the need to study the relation between normal aging and CR in both sexes separately. METHODS: By means of transcranial Doppler sonography, CR was determined in 100 healthy, nonsmoking volunteers (age 20 to 70 years, 10 men and 10 women per decade). RESULTS: In men, no change of CR with increasing age could be observed (P=0.98). In contrast, CR in women declined significantly, with a step decrease from the 4th to the 5th decades (F=4.413; P<0.01) and was significantly higher in the 3rd and 4th compared with the 5th, 6th, and 7th decades (P<0.05). Information on hormone replacement therapy (HRT) in women of the 6th and 7th decades was obtained retrospectively. HRT was associated with enhanced CR (HRT, n = 7 versus non-HRT, n = 13; P<0.001), with values similar to those found in premenopausal women. CONCLUSIONS: There are no changes of CR during normal aging in men, whereas CR declines significantly from the 4th to the 5th decades in women. HRT in postmenopausal women appears to enhance CR.