Intrathecal baclofen for dystonia of complex regional pain syndrome.

Dystonia in complex regional pain syndrome (CRPS) responds poorly to treatment. Intrathecal baclofen (ITB) may improve this type of dystonia, but information on its efficacy and safety is limited. A single-blind, placebo-run-in, dose-escalation study was carried out in 42 CRPS patients to evaluate whether dystonia responds to ITB. Thirty-six of the 38 patients, who met the responder criteria received a pump for continuous ITB administration, and were followed up for 12 months to assess long-term efficacy and safety (open-label study). Primary outcome measures were global dystonia severity (both studies) and dystonia-related functional limitations (open-label study). The dose-escalation study showed a dose-effect of baclofen on dystonia severity in 31 patients in doses up to 450 microg/day. One patient did not respond to treatment in the dose-escalation study and three patients dropped out. Thirty-six patients entered the open-label study. Intention-to-treat analysis revealed a substantial improvement in patient and assessor-rated dystonia scores, pain, disability and quality-of-life (Qol) at 12 months. The response in the dose-escalation study did not predict the response to ITB in the open-label study. Eighty-nine adverse events occurred in 26 patients and were related to baclofen (n=19), pump/catheter system defects (n=52), or could not be specified (n=18). The pump was explanted in six patients during the follow-up phase. Dystonia, pain, disability and Qol all improved on ITB and remained efficacious over a period of one year. However, ITB is associated with a high complication rate in this patient group, and methods to improve patient selection and catheter-pump integrity are warranted.

[Nonfunctioning pituitary macroadenomas: diagnosis, treatment and follow-up]. / Niet-functionerende macroadenomen van de hypofyse: diagnostiek, behandeling en follow-up.

*Nonfunctioning pituitary adenomas are benign tumours characterised by the absence of hormone overproduction. *Clinical symptoms are caused by the mass effects of the tumour. The main symptoms are pituitary insufficiency, visual field defects, vision impairment and headache. *Treatment is unnecessary for tumours less than 1 cm, and an expectative approach can be used for some patients with larger tumours but no visual field defects. *Transsphenoidal surgery is indicated for patients with visual field defects. *Because nonfunctioning adenomas can recur, lifelong follow-up after treatment is necessary. *Poor quality of life has been reported in treated patients with nonfunctioning pituitary adenomas, which may be due to the intrinsic imperfections of hormonal replacement therapy.

[Transsphenoidal resection of pituitary adenomas: long-term results from the Leiden University Medical Center]. / Transsfenoïdale resectie van hypofyseadenomen: langetermijnresultaten van het Leids Universitair Medisch Centrum.

OBJECTIVE: To evaluate the long-term outcome of transsphenoidal resection of pituitary adenomas at the Leiden University Medical Center (LUMC), The Netherlands. DESIGN: Retrospective, descriptive. METHOD: 416 consecutive patients undergoing surgery for pituitary adenoma at the LUMC between 1978 and 2004 were included; 174 patients with non-functioning macroadenomas (NFMA), 164 patients with acromegaly and 78 patients with Cushing's disease. RESULTS: Biochemical remission was achieved in 66% of patients with acromegaly, and 72% of patients with Cushing's disease; incidence of pituitary failure was low in these patients (5% and 18% respectively). In 82% of the patients with NFMA visual function improved whereas the percentage with any degree of pituitary failure increased from 85% (preoperatively) to 95% (postoperatively). During follow-up of 10-15 years, the recurrence rate for acromegaly and Cushing's disease was 9% and for NFMA it was 15%. CONCLUSION: Transsphenoidal resection is an effective treatment in most, but not all, patients with pituitary adenomas. The surgical results at the LUMC are comparable with those obtained in important international centres. All patients cured by surgery need lifelong follow-up, because of the real risk of recurrent disease.

Mortality in patients treated for Cushing's disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma.

CONTEXT: Increased mortality in patients with pituitary tumors after surgical treatment has been reported. However, it is unknown to what extent excess mortality is caused by pituitary tumors and their treatment in general and to what extent by previous exposure to hormonal overproduction. OBJECTIVE: The aim of the study was to compare mortality between patients treated for Cushing's disease and nonfunctioning pituitary macroadenomas (NFMAs). DESIGN: This was a follow-up study. PATIENTS: We included 248 consecutive patients with pituitary adenomas treated by transsphenoidal surgery in our hospital for NFMAs (n = 174) and ACTH-producing adenomas (n = 74). The mean duration of follow-up after surgery was 10.1 +/- 7.2 yr for the whole cohort. OUTCOME MEASURES: The standardized mortality ratio (SMR) was calculated for the whole cohort and also for the two diseases separately. Cox regression analysis was used to compare mortality in patients with Cushing's disease with NFMA patients. RESULTS: Patients with Cushing's disease (39.1 +/- 16.1 yr) were significantly younger at time of operation than NFMA patients (55.3 +/- 13.4 yr). The SMR for the whole cohort was 1.41 [95% confidence interval (CI), 1.05-1.86]. The SMR in NFMA patients was 1.24 (95% CI, 0.85-1.74) vs. 2.39 (95% CI, 1.22-3.9) in patients with Cushing's disease. In patients with Cushing's disease, compared with NFMAs, the age-adjusted mortality was significantly increased: hazard ratio 2.35 (95% CI, 1.13-4.09, P = 0.008). CONCLUSIONS: Mortality in patients previously treated for Cushing's disease is increased, compared with patients treated for NFMAs. This implies that previous, transient overexposure to cortisol is associated with increased mortality.

Observation alone after transsphenoidal surgery for nonfunctioning pituitary macroadenoma.

OBJECTIVE: Transsphenoidal surgery is the treatment of choice for nonfunctioning pituitary macroadenomas (NFMA). In this study we evaluated the long-term effects of a treatment strategy in which postoperative radiotherapy was not routinely applied to patients with NFMA. DESIGN: This was a retrospective follow-up study. PATIENTS: We included 109 consecutive patients (age 56 +/- 13 yr) operated for NFMA between 1992 and 2004. RESULTS: Radiological imaging revealed a macroadenoma in all patients, with suprasellar extension in 96% and parasellar/infrasellar extension in 36% of cases. Visual field defects were present in 87% of the patients and improved in 84% of these patients after surgery. Only six patients received postoperative radiotherapy. Ten patients died during the follow-up period. Ninety-seven patients could be assessed for tumor regrowth or tumor recurrence after a mean follow-up period of 6.0 +/- 3.7 yr. In nine patients there was evidence for tumor regrowth, and in one patient tumor recurrence was observed. The mean time to tumor growth/recurrence after initial therapy was 6.9 (range 3-12) yr. Follow-up duration was found to be an independent predictor for tumor regrowth. CONCLUSION: Transsphenoidal surgery without postoperative radiotherapy is an effective and safe treatment strategy for NFMA, without evidence for tumor regrowth in 90% of all patients, at least for the duration of follow-up presented in this study. Additional studies are required to exclude higher regrowth and recurrence rates during prolongation of the duration of follow-up.

Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy.

BACKGROUND AND METHODS: Patients with reflex sympathetic dystrophy (also known as the complex regional pain syndrome) may have dystonia, which is often unresponsive to treatment. Some forms of dystonia respond to the intrathecal administration of baclofen, a specific gamma-aminobutyric acid-receptor (type B) agonist that inhibits sensory input to the neurons of the spinal cord. We evaluated this treatment in seven women who had reflex sympathetic dystrophy with multifocal or generalized tonic dystonia. First, we performed a double-blind, randomized, controlled crossover trial of bolus intrathecal injections of 25, 50, and 75 microg of baclofen and placebo. Changes in the severity of dystonia were assessed by the woman and by an investigator after each injection. In the second phase of the study, six of the women received a subcutaneous pump for continuous intrathecal administration of baclofen and were followed for 0.5 to 3 years. RESULTS: In six women, bolus injections of 50 and 75 microg of baclofen resulted in complete or partial resolution of focal dystonia of the hands but little improvement in dystonia of the legs. During continuous therapy, three women regained normal hand function, and two of these three women regained the ability to walk (one only indoors). In one woman who received continuous therapy, the pain and violent jerks disappeared and the dystonic posturing of the arm decreased. In two women the spasms or restlessness of the legs decreased, without any change in the dystonia. CONCLUSIONS: In some patients, the dystonia associated with reflex sympathetic dystrophy responds markedly to intrathecal baclofen.

Glioblastoma causing granulocytosis by secretion of granulocyte-colony-stimulating factor.

We describe a patient with a glioblastoma multiforme with excessive granulocytosis in the peripheral blood. Shown at both protein and mRNA levels, the tumor produced very high levels of granulocyte-colony-stimulating factor (G-CSF). G-CSF is a growth factor that induces the recruitment of granulocytes. The paraneoplastic phenomenon described here partly mimicked a brain abscess. Production of G-CSF by (brain) tumor cells might be related to the granulocytosis common in malignant disease.

Clinimetric issues of screening for responsiveness to intrathecal baclofen in dystonia.

OBJECTIVES: In this study we address clinimetric issues that pertain to the screening of responsiveness to intrathecal baclofen (ITB) in dystonia. METHODS: Eight patients with severe dystonia, who did not respond to oral medication, were evaluated in a double-blind placebo controlled ascending dose screening procedure, which included a randomised sequence of injections of 25, 50 and 75 microg baclofen and placebo. Self-assessments of dystonia severity on a visual analogue scale (VAS) and the Dyskinesia Rating Scale (DRS) were carried out at baseline 1, 4 and 8 hours after a bolus injection. RESULTS: Compared to the VAS, the DRS lacked responsiveness in all patients. Baseline scores of the VAS scores varied considerably between and within patients and underscore the need to express response scores in relation to the baseline. After placebo administration some patients showed a persistent improvement of about 30% across the day, while at some assessments improvements of >50% were noted. Based on the aforementioned findings, a responsiveness coefficient was used which relates the baclofen effect size to the non-specific score changes that may occur as a placebo effect or as random fluctuations in dystonia. Four patients with a responsiveness coefficient >2 received pump implantation and did well on continuous infusion of ITB. Several side effects occurred during the screening procedure, but none interfered with the execution of the screening procedure. CONCLUSIONS: This study demonstrates important clinimetric issues that need to be taken into account when screening for responsiveness to ITB.

Cervical spondylarthrotic myelopathy with early onset in Down's syndrome: five cases and a review of the literature.

Progressive walking difficulties and bladder dysfunction may be attributed to Alzheimer disease or atlanto-axial subluxation in people with Down's syndrome (DS). The present authors describe five patients with DS suffering from the above symptoms as a result of cervical spondylarthrotic myelopathy. Clinical and radiological data were collected from all patients with DS who underwent surgery for cervical spondylarthrotic myelopathy at the Leiden University Medical Centre during the period between 1991 and 1995. Five patients with DS (four males and one female) were identified. Their mean age at diagnosis was 42 years. The main clinical features were weakness of the arms and legs, ataxic gait, hyperreflexia and bilateral Babinski signs. Radiological examination showed spondylarthrosis, compression of the spinal cord and myelomalacia. The mean delay in diagnosis was 3 years. All five individuals showed clinical stabilization after laminectomy. Cervical spondylarthrotic myelopathy seems a rather frequent disorder in DS, occurring at a relatively young age. Early diagnosis may prevent irreversible neurological deficits.

Immunocytochemical localization of neurofilaments in the fibre systems of the developing rat spinal cord white matter.

The appearance and localization of the protein subunits of neurofilaments in the ascending and descending fibre systems of the developing rat spinal cord white matter were studied. The monoclonal antibody NF-90 (specific for the phosphorylated NF-L, NF-M and NF-H subunits) was used as neurofilament marker in fresh cryostat and Bouin fixed paraffin sections. The results were compared with Nissl and Bodian stained sections. Within the white matter, phosphorylated neurofilament proteins were expressed with regional variations. At embryonal day 12 (E12), the first positive fibres were found in the lateral funiculus. During further development, the peripheral region of the lateral funiculus showed an intense neurofilament staining, due to the presence of a higher number of fibres. From postnatal day 12 (P12) on, an increased amount of neurofilaments was found in the region close to the periphery, probably due to the presence of large calibre fibres. The dorsolateral part of the lateral funiculus filled in with fibres after birth, which indicated the extended development of the rubrospinal tract. At E13, positive fibres were present in the ventral commissure and the ventral funiculus. At E14, an increased amount of neurofilaments was detected in the periphery of the ventral funiculus. At maturity, an intense staining in the subsurface region could be found, due to the presence of large calibre fibres of the fasciculus longitudinalis medialis. At E13, the first neurofilament positive fibres were present in the dorsal funiculus. At this day, a concentration of fibres was found in the dorsal part of the dorsal root bifurcation zone and three days later, more fibres were detected in the medial part of the dorsal funiculus. At E18, a higher number of fibres was present in the dorsal region of the fasciculus gracilis. The mature fasciculus cuneatus showed an intense neurofilament staining, which was mainly present in large calibre fibres. The ventral part of the dorsal funiculus filled in with neurofilament positive fibres after birth. This indicated the relative late arrival of the corticospinal tract.

Microvascular decompression for trigeminal neuralgia: a critical reappraisal.

The results of posterior fossa explorations for trigeminal neuralgia over the period 1980-1990 in 58 patients and in 59 procedures were studied retrospectively. In 51 procedures vascular compression was treated by microvascular decompression (MVD). In the absence of such a compression, partial sensory rhizotomy (PSR) was performed in 5 cases and only adhesiolysis of thickened arachnoidea in 2 cases. In one additional case the procedure was terminated prematurely due to the development of cerebellar edema. Two months postoperatively a good or fair result was obtained in 80% of the procedures. At long-term follow-up (mean 77.3 months, range 8-146 months), a good or fair result was maintained in 71%. There was no significant difference in outcome between the MVD group and the other procedures, or between the three groups formed according to the type of vascular compression. However, in the group of 10 patients with a history of a procedure affecting the trigeminal ganglion or nerve root the result was worse. In the group of 41 MVD patients rendered free of pain at 2 months postoperatively, 8 patients perceived a recurrence. The annual recurrence rate was calculated to be 2.6%. There was no mortality in this series but the morbidity rate was 22% including 1.7% persistent neurological deficit. Compared to the literature results of percutaneous controlled differential thermocoagulation (PCDT), the recurrence and failure rates in the present series appear to be more or less the same. As neither of the two is an unequivocally more effective treatment, we are of the opinion that the less invasive procedure should be preferred.(ABSTRACT TRUNCATED AT 250 WORDS)

The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age.

PURPOSE: To determine if in patients with single brain metastasis the addition of neurosurgery to radiotherapy leads to lengthening of survival or to better quality of life. METHODS AND MATERIALS: From 1985 to 1990, 66 patients with single brain metastasis from a solid tumor were entered in a randomized trial of neurosurgery plus radiotherapy vs. radiotherapy alone. Patients were stratified for lung cancer vs. other sites of cancer and for progressive vs. stable systemic cancer. Radiotherapy was given to the whole brain by a novel scheme of two fractions of 2 Gy per day for a total dose of 40 Gy in 2 weeks, to obtain a relatively high total dose and short overall time, with minimal risk of late damage to normal tissue in long-term survivors. RESULTS: In the whole group of 63 evaluable patients, both with lung cancer as with other tumors, the combined treatment led to a better duration of survival (median 10 vs. 6 months; p = 0.04). The largest difference between both treatment arms was observed in patients with inactive extracranial disease (median 12 vs. 7 months; p = 0.02). Patients with active extracranial disease had an equal median survival of only 5 months, irrespective of given treatment. Age proved to be a strong and independent prognostic factor: patients older than 60 years had a hazard ratio of dying of 2.74 (p = 0.003) compared with younger patients. Following treatment, most patients remained functionally independent until a few weeks before death. In the majority of patients the cause of death was systemic tumor progression. CONCLUSION: Patients with single brain metastasis and with controlled or absent extracranial tumor activity should be treated with surgery and radiotherapy, especially when they are younger than 60 years. For patients with progressive extracranial disease, radiotherapy alone seems to be sufficient. The accelerated radiotherapy scheme of 40 Gy in 2 weeks to the whole brain is tolerated well and should also be considered for patients in a good performance status with surgically unaccessible single metastasis or even with multiple brain metastases.

Aneurysmal bleeding. A plea for early surgery in good-risk patients.

From 1985 onwards we have aimed at operating on good-risk patients, i.e., those graded I-III on the WFNS SAH Scale, within 3 days after the aneurysmal bleed. We report on a series of 100 consecutive operations for saccular aneurysm, covering a period of 5 1/2 years. Early operations (in the above sense) were done in 57 good-risk but otherwise unselected patients. After a one year follow-up, 47 of them (82%) were found to have made a good recovery (Glasgow Outcome Score I). The outcome of (mostly early) surgery in 15 selected poor-risk patients (WFNS SAH Scale IV and V) was much less favourable. Late surgery (4 or more days after SAH) was performed in 28 good-risk patients, most of whom had been admitted several days or weeks after the bleeding. Almost all of these patients had a good outcome. It is argued that the known management results of delayed surgery, which during the deliberately chosen interval exposes the patient to the risk of rebleeding and vasospasm, have by now been surpassed by those of early surgery. However excellent the surgical results of delayed operations may be, early operation should become the treatment of choice in good-risk patients.

Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery?

Most patients treated for single or multiple brain metastases die from progression of extracranial tumor activity. This makes it uncertain whether the combination of neurosurgery and radiotherapy for treatment of single brain metastasis will lead to better results than less invasive treatment with radiotherapy alone. The effect of neurosurgical excision plus radiotherapy was compared with radiotherapy alone in a prospectively randomized trial with 63 evaluable patients with systemic cancer and a radiological diagnosis of single brain metastasis. Radiotherapy was given to the whole brain by a novel scheme of 2 fractions per day of each 2 Gy for a total of 40 Gy. Before randomization, patients were stratified by site (lung cancer vs nonlung cancer) and status of extracranial disease (progressive vs stable). Survival as such and functionally independent survival (FIS; defined as World Health Organization performance status < or = 1 and neurological function < or = 1) were compared between both treatment arms. The combined treatment compared with radiotherapy alone led to a longer survival (p = 0.04) and a longer FIS (p = 0.06). This was most pronounced in patients with stable extracranial disease (median survival, 12 vs 7 mo; median FIS, 9 vs 4 mo). Patients with progressive extracranial cancer had a median overall survival of 5 months and a FIS of 2.5 months irrespective of given treatment. Improvement in functional status occurred more rapidly and for longer periods of time after neurosurgical excision and radiotherapy than after radiotherapy alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Interphase cytogenetics: a new tool for the study of genetic changes in brain tumors.

Interphase cytogenetics is the application of nonradioactive in situ hybridization with chromosome-specific DNA probes to interphase nuclei. In this study, interphase cytogenetics was used to investigate 66 primary brain tumors (33 gliomas, 30 meningiomas, and three medulloblastomas) for numerical chromosomal aberrations of chromosomes 1, 6, 7, 10, 11, 17, 18, X, and Y. Of the 33 gliomas (17 astrocytomas grades II, III, and IV, five oligoastrocytomas, seven oligodendrogliomas, and four ependymal tumors), 22 were near diploid, while the remaining 11 showed a significant triploid or tetraploid component. The predominant specific aberrations in gliomas were an over-representation of chromosome 7 (13 cases) and an under-representation of chromosome 10 (16 cases). These changes were observed in grade III and grade IV astrocytomas, as well as in oligodendrogliomas. Other frequent numerical changes were a gain of chromosome 17 (six cases) and a loss of chromosome 18 (seven cases). This loss of chromosome 18 seemed relatively specific for gliomas with an oligodendroglial component (six cases). Only two of 33 gliomas displayed no genetic abnormality with the probes used. Seven patients with astrocytomas died of their brain tumor during the clinical follow-up period. Their astrocytomas did not show a different chromosomal constitution compared to the other gliomas. For the meningiomas, the probe panel was extended with a probe specific for chromosome 22. Loss of chromosome 22 was obvious in 21 of the 30 meningiomas, and was the sole abnormality in 11 meningiomas; in the other 10, this loss was associated with other chromosomal changes. Five of these tumors with additional aberrations were recurrent or atypical meningiomas. It is suggested that interphase cytogenetics can contribute to a better understanding of the biological behavior of these tumors and possibly result in better insights into prognosis and strategies for therapy.

Arachnoid cysts of the middle cranial fossa. Surgical management for headache.

To answer the question whether headache in association with a middle cranial fossa arachnoid cyst without other signs warrants surgery, an analysis of five cases is performed. Three of 5 patients became free of symptoms, compared with 15 of 19 (79%) patients that have been collected in the literature. Both failures were treated with a low pressure cysto-peritoneal shunt without fenestration. They complained of headache resembling postural headache after lumbar puncture. Surgical treatment in the form of a craniotomy with fenestration can be advised, but is major neurosurgery. Alternatively, the merit of a cysto-ventriculo-peritoneal shunt should be considered in this group of patients.

Interphase cytogenetics of brain tumors.

The development and application of a procedure for interphase cytogenetics on brain tumor material is described. Nuclei isolated from freshly removed brain tumor tissue were investigated for chromosomal aberrations by nonradioactive in situ hybridization with a panel of chromosome-specific probes. The panel consisted of nine satellite DNA probes specific for the centromeric regions of chromosomes 1, 6, 7, 10, 11, 17, 18, X, and Y. For each probe, the number of hybridization signals per cell was determined in 200 nuclei. It was inferred from the hybridization results that in 11 gliomas (seven astrocytomas grade II-IV, three oligodendrogliomas, and one ependymoma) the numerical aberrations were gains of chromosomes 1 (once), 7 (twice), 10 (once), 11 (twice), and X (twice); losses of chromosomes 1 (once), 10 (twice), 17 (twice), and Y (once); and complete tetraploidy (once). Among the 18 investigated meningiomas monosomy 18 and trisomy 17 were observed once and twice, respectively. An additional hybridization with a cosmid probe for the BCR gene on 22q11 indicated monosomy 22q in 11 meningiomas. These results show the value of interphase cytogenetics for the analysis of solid tumors for which it is relatively difficult to obtain sufficient metaphases of good quality for conventional cytogenetics.