D. Andries Bosch

Stimulation of the Subthalamic Region Facilitates the Selection and Inhibition of Motor Responses in Parkinson's Disease

The aim of the present study was to specify the involvement of the basal ganglia in motor response selection and response inhibition. Two samples were studied. The first sample consisted of patients diagnosed with Parkinsons disease (PD) who received deep-brain stimulation (DBS) of the subthalamic nucleus (STN). The second sample consisted of patients who received DBS for the treatment of PD or essential tremor (ET) in the ventral intermediate nucleus of the thalamus (Vim). Stop-signal task and go/no-go task performances were studied in both groups. Both groups performed these tasks with (on stimulation) and without (off stimulation) DBS to address the question of whether stimulation is effective in improving choice reaction time (RT) and stop-signal RT. The results show that DBS of the STN was associated with significantly enhanced inhibitory control, as indicated by shorter stop-signal RTs. An additional finding is that DBS of the STN led to significantly shorter choice RT. The effects of DBS on responding and response inhibition were functionally independent. Although DBS of the Vim did not systematically affect task performance in patients with ET, a subgroup of Vim-stimulated PD patients showed enhanced stop-signal RTs in on stimulation versus off stimulation. This result suggests that the change in performance to stop signals may not be directly related to STN function, but rather results from a change in PD function due to DBS in general. The findings are discussed in terms of current functional and neurobiological models that relate basal ganglia function to the selection and inhibition of motor responses.

Unilateral pallidotomy in Parkinson's disease: a randomised, single-blind, multicentre trial

BACKGROUND The results of several cohort studies suggest that patients with advanced Parkinsons disease would benefit from unilateral pallidotomy. We have assessed the efficacy of unilateral pallidotomy in a randomised, single-blind, multicentre trial. METHODS We enrolled 37 patients with advanced Parkinsons disease who had, despite optimum pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonias, or bradykinesia. Patients were randomly assigned to unilateral pallidotomy within 1 month or to pallidotomy after the primary outcome assessment (6 months later). The primary outcome was the difference between the groups in median changes on the motor examination section of the unified Parkinsons disease rating scale (UPDRS 3) score done in the off phase. Secondary outcome measures included levodopa-induced dyskinesias (dyskinesia rating scale [DRS]) and extent of disability (UPDRS 2). FINDINGS The median UPDRS 3 off score of the pallidotomy patients improved from 47 to 32.5, whereas that of control patients slightly worsened from 52.5 to 56.5 (p<0.001). In the on phase the median DRS score improved 50% in pallidotomy patients compared with no change in controls. The UPDRS 2 off score improved with a median of 7 in the pallidotomy group. Two treated patients had major adverse effects. INTERPRETATION Unilateral pallidotomy is an effective treatment in patients with advanced Parkinsons disease, who have an unsatisfactory response to pharmacological treatment.

Expression and distribution of id helix-loop-helix proteins in human astrocytic tumors

The Id family of helix‐loop‐helix proteins is involved in a variety of processes, such as development, proliferation, and angiogenesis. In this study, we investigated the expression pattern of Id1, Id2, and Id3 in surgical specimens of human glial tumors. Western blot analysis demonstrated that all three Id proteins were expressed in astrocytic tumors. Expression levels in high‐grade tumors were higher than in low‐grade tumors. Immunohistochemical analysis confirmed that many of the tumor astrocytes exhibited strong Id1‐3 IR. In contrast, in adult human normal brain, Id expression was low both in resting astrocytes and in endothelial cells. In tumor cells, Id proteins displayed cytoplasmic as well as nuclear localization. Id1‐3 IR scores in tumor cells were positively correlated with proliferation indices. Moreover, Id1‐3 IR was detected in endothelial cells of the astrocytic tumor blood vessels. The vascular Id1‐3 expression correlated positively with tumor vascularity and grade. These results support the role of the Id gene family in the enhanced proliferative potential of tumor astrocytes. The evidence also supports the involvement of the Id gene family in tumor angiogenesis, a process that critically influences the malignant behavior of glial tumors. GLIA 38:329–338, 2002.

Types and causes of pain in cancer of the head and neck

In a series of 25 patients with head dnd neck cancer who had severe pain, the type and cause of the pain were analyzed. There were two types of pain: nociceptive and nonnociceptive. Nineteen (76%) patients had nociceptive pain that could be subdivided into actual nociceptive pain (9 patients), nociceptive nerve pain (8 patients), or referred pain (2 patients). The cause of nociceptive pain was secondary to tumor recurrence in 16 patients and secondary to benign inflammation in 3 patients. Of the six (23%) cases of non‐nociceptive pain, all were diagnosed as neuropathic pain secondary to the sequels of neck dissection. World Health Organization guidelines were applied for the treatment of symptomatic pain of nociceptive pain; if necessary, nerve blocks were used after this treatment. Non‐nociceptive pain was usually treated with amitriptyline or carbamazepine. If tumor recurrence was the cause of the pain, antitumor‐directed therapy was applied, when possible. Relief was achieved in 52% of the patients after two attempts to treat pain, in 64% after three attempts, and in up to 72% after four attempts. Pain could not be controlled in 28% of the patients. Patients with tumor recurrence had a short median survival time of 3 months, regardless of pain control. Patients with neuropathic pain had a survival time of 16 months or more (median not reached). The authors conclude that the type and cause of the pain in cancer of the head and neck can be determined; this can lead to the administration of proper symptomatic therapy or treatment directed at the underlying cause. In most cases, several successive attempts to treat pain were made before relief was achieved.

Hypofractionation in glioblastoma multiforme.

PURPOSE To compare conventional fractionation with hypofractionation in patients with a glioblastoma multiforme. Endpoints of the analysis are overall survival and palliative effect. MATERIALS AND METHODS From 1988 to 1998, 155 patients with pathologically confirmed glioblastoma multiforme were prospectively analysed. Patients without irradiation and patients receiving an interstitial boost were excluded from this analysis. Three different radiation schemes were used in subsequent periods; 33x2, 8x5 and 4x7 Gy. In the last 5 years a scheme of 4x7 Gy conformal irradiation was given to poor prognosis patients. The more favourable group received the conventionally fractionated scheme up to 66 Gy. RESULTS Median survival was 7, 5.6 and 6.6 months for the 33x2, 8x5 and 4x7 Gy, respectively. In general, patients in the hypofractionation group had far worse prognostic factors compared with patients treated with the conventional scheme. The period of neurological improvement or stabilisation was similar between the 4x7 and 33x2 Gy group. CONCLUSION An extreme hypofractionation scheme of 4x7 Gy conformal irradiation in poor prognostic glioblastoma patients is well tolerated, convenient for the patient and provides equal palliation without negative effects on survival compared with conventional fractionation.

Genetic sub‐types of human malignant astrocytoma correlate with survival

In human malignant astrocytoma, age of the patient and histological grade of the tumor are important prognostic variables. Several genetic changes have been reported to occur in these tumors, which may be of additional and independent prognostic relevance. To determine their prognostic significance, we analyzed 75 high‐grade tumors, 12 anaplastic astrocytomas and 63 glioblastomas multiforme, for the presence of genetic changes that occur frequently in high‐grade astrocytoma, i.e., loss of heterozygosity (LOH) for chromosome 10, p53‐gene alteration (mutation and/or LOH), and EGFR‐gene amplification. We defined 4 groups of patients who showed a specific combination of genetic changes in the tumor: group 1,p53‐gene alteration without complete LOH 10; group 2, complete LOH 10 only; group 3, p53‐gene alteration + complete LOH 10; group 4, complete LOH 10 + EGFR‐gene amplification. In univariate analysis, the log‐rank test revealed significant differences in survival between patients of group 1 (median survival of 13 months) and group 3 (median survival of 5.2 months, p = 0.0058) and between patients of group 1 and group 4 (median survival of 4 months, p = 0.0033). In multivariate analysis, age and genetic sub‐type proved to be important prognostic variables, whereas histological grading was less important. The age‐corrected survival time for group‐4 patients is significantly shorter than that for group‐1 patients (relative risk = 3.79, p = 0.0075). Our data indicate that genetic sub‐type is an important prognostic variable in human high‐grade astrocytoma. Int. J. Cancer (Pred. Oncol.) 79:159–165, 1998.© 1998 Wiley‐Liss, Inc.

Prognostic Factors in Glioblastoma Multiforme 10 Years Experience of a Single Institution

Background: To analyze prognostic factors in patients with a glioblastoma multiforme treated in an academic institute over the last 10 years. Patients and Method: From 1988 to 1998, 198 patients with pathologically confirmed glioblastoma multiforme were analyzed. Five radiation schedules were used mainly based on pretreatment selection criteria: 1. 60 Gy in 30 fractions followed by an interstitial iridium-192 (Ir-192) boost for selected patients with a good performance and a small circumscribed tumor, 2. 66 Gy in 33 fractions for good performance patients, 3. 40 Gy in eight fractions or 4. 28 Gy in four fractions for poor prognostic patients and 5. no irradiation. Results: Median survival was 16 months, 7 months, 5.6 months, 6.6 months and 1.8 months for the groups treated with Ir-192, 66 Gy, 40 Gy, 28 Gy and the group without treatment, respectively. No significant improvement in survival was encountered over the last 10 years. At multivariate analysis patients treated with a hypofractional scheme showed a similar survival probability and duration of palliative effect compared to the conventionally fractionated group. The poor prognostic groups receiving radiotherapy had a highly significant better survival compared to the no-treatment group. Patients treated with an Ir-192 boost had a better median survival compared to a historical group matched on selection criteria but without boost treatment (16 vs 9.7 months, n. s.). However, survival at 2 years was similar. Analysis on pretreatment characteristics at multivariate analysis revealed age, neurological performance, addition of radiotherapy, total resection, tumor size post surgery and deterioration before start of radiotherapy (borderline) as significant prognostic factors for survival. Conclusion: Despite technical developments in surgery and radiotherapy over the last 10 years, survival of patients with a glioblastoma multiforme has not improved in our institution. The analysis of prognostic factors corresponded well with data from the literature. A short hypofractionated scheme seems to be a more appropriate treatment for patients with intermediate or poor prognosis as compared to a conventional scheme. The benefit in median survival for patients treated with an interstitial boost is partly explained by patient selection. Since there were no long-term survivors with this boost treatment, its clinical value, if there is one, is still limited.Hintergrund: Es wurden Prognosefaktoren bei Patienten mit Glioblastoma multiforme ermittelt, die über einen Zeitraum von 10 Jahren in einer Institution behandelt wurden. Patienten und Methoden: Die Analyse beruht auf 198 Patienten, die von 1988 bis 1998 nach histologischer Sicherung fünf verschiedenen Bestrahlungsschemata zugeführt wurden: 1. 60 Gy in 30 Fraktionen gefolgt von einem Ir-192-(LDR-)Boost bei selektierten Patienten mit gutem Performance-Status und kleinen Tumoren, 2. 66 Gy in 33 Fraktionen bei Patienten mit gutem Performance-Status, 3. 40 Gy in acht Fraktionen oder 4. 28 Gy in vier Fraktionen bei Patienten in schlechtem Allgemeinzustand, 5. keine Bestrahlung. Ergebnisse: Das mediane Überleben betrug 16 Monate für die Ir-192-Boost-Gruppe, 7 Monate nach 66 Gy, 5,6 Monate nach 40 Gy, 6,6 Monate nach 28 Gy und 1,8 Monate für unbehandelte Patienten. Über den Behandlungszeitraum von 10 Jahren waren keine signifikanten Verbesserungen der Überlebensraten zu verzeichnen. In der Multivarianzanalyse wiesen Patienten, die hypofraktioniert bestrahlt wurden, ähnliche Überlebenswahrscheinlichkeiten und Palliativeffekte auf wie Patienten nach konventioneller Bestrahlung. Die Strahlentherapie führte bei Patienten mit schlechtem Allgemeinzustand zu signifikanten Überlebenszeitverbesserungen im Vergleich zu Patienten ohne Behandlung. Verglichen mit einer historischen Kontrollgruppe ohne Ir-192-Boost-Bestrahlung hatten Patienten nach Ir-192-Boost-Bestrahlung nicht signifikante Verbesserungen der medianen Überlebensraten (16 Monate v. 9,7 Monate), wobei sich jedoch die 2-Jahres-Überlebensraten wieder angeglichen. In der Multivarianzanalyse waren Alter, neurologischer Status, Radiotherapie, totale Resektion, Resttumorgröße nach Resektion und Verschlecherung vor Anfang der Strahlentherapie (Grenzwert) für das Überleben signifikante Prognosefaktoren. Schlussfolgerungen: Trotz technischer Entwicklungen sowohl im Bereich der Neurochirurgie als auch der Radiotherapie verbesserten sich die Überlebensraten von Patienten mit Glioblastoma multiforme in den letzten 10 Jahren in unserer Institution nicht. Die Analyse der Prognosefaktoren korreliert gut mit Angaben aus der Literatur. Für Patienten mit intermediärer oder schlechter Prognose ist ein abgekürztes hypofraktioniertes Bestrahlungsregime eine angemessene Therapieoption. Die beobachtete Verbesserung der medianen Überlebensraten nach Ir-192-Boost ist zumindest teilweise durch eine Patientenselektion erklärbar. Da diese Behandlungsform zu keinem Langzeitüberleben führt, ist der klinische Stellenwert weiterhin unklar.

Bilateral pallidotomy in Parkinson's disease: A retrospective study

We evaluated the effects of bilateral pallidotomy in patients with advanced Parkinsons disease. Thirteen patients with Parkinsons disease had a staged bilateral pallidotomy if they had severe response fluctuations, dyskinesias, painful dystonia, or bradykinesia despite optimum pharmacological treatment. Assessment scales were the Unified Parkinsons Disease Rating scale (UPDRS), the Schwab and England scale, and a questionnaire on the effects of disability in activities of daily living and adverse effects. Postoperative magnetic resonance imaging was evaluated for lesion location and extension. The median off‐phase UPDRS motor score was reduced from 43.5 to 29 after the first pallidotomy, and it was further reduced to 23.5 after the second pallidotomy (n = 8). The UPDRS activities of daily living off‐phase score improved from 28.5 to 20.5 after the first pallidotomy and to 19 after the second pallidotomy (n = 6). The Schwab and England scale off‐phase score showed an improvement after both procedures, first from 40 to 60, and thereafter to 90 (n = 8). On‐phase dyskinesias were reduced substantially. Eight patients had adverse effects, of whom five had problems with speech. One patient became hemiplegic due to a delayed infarction. Ten patients experienced further benefit from the second procedure. Bilateral pallidotomy reduces dyskinesias. A second contralateral pallidotomy may reduce parkinsonism, although to a lesser degree compared with the first pallidotomy and with an increased risk for adverse effects.

Stereotactic neurosurgery for tremor.

The role of the motor thalamus as surgical target in stereotactic neurosurgery for different kinds of tremor is discussed. For tremor in Parkinsons disease, the subthalamic nucleus becomes more and more often the surgical target, because this target also gives relief of other and more incapacitating symptoms (hypokinesia, rigidity). Stimulation is as effective in tremor suppression as coagulation but has less adverse events and permits bilateral surgery. In selected cases, thalamotomy can still be indicated.

Perineural tumor extension along the trigeminal nerve: magnetic resonance imaging findings

OBJECTIVE To evaluate the magnetic resonance imaging (MRI) findings of 15 patients with perineural tumor extension along the trigeminal nerve in correlation with clinical data. METHODS The clinical records and MRI studies of 15 patients with perineural tumor extension along the trigeminal nerve were retrospectively reviewed. Imaging studies included plain and contrast-enhanced thin section T1-weighted spin echo (T1-WSE) MRI with and without fat-suppression. The studies were compared to determine which sequence provided greatest tumor conspicuity and best depiction of tumor extent. The conspicuity of these tumors was assessed on the available sequences by two observers by consensus. RESULTS The contrast-enhanced T1-weighted spin echo fat-suppressed images (T1-WSECEFS) demonstrated greatest tumor conspicuity and best depiction of tumor extent in the extracranial head and neck and skull base region. The conventional T1-weighted spin echo pre- and postcontrast images were, however, diagnostic of perineural tumor extension in 11 patients due to the presence of considerable tumor bulk and extension well above the skull base. In the other four patients the perineural tumor was poorly visualized on the conventional T1-WSE images and well visualized on the fat-suppressed images. The mandibular division of the trigeminal nerve (V3) was most commonly involved (n = 10), followed by the maxillary (V2; n = 5) and ophthalmic (V1; n = 2) division. Two patients had both mandibular as well as maxillary nerve involvement. The finding of perineural tumor extension had significant impact on patient management: based on the MR imaging study, the primary tumor was considered inoperable (n = 13), the extent of surgery was expanded (n = 2) and radiation therapy (RT) ports were extended (n = 12). CONCLUSION Complete trigeminal nerve imaging is recommended when evaluating (suspected) head and neck malignancies with a high risk for perineural extension. In these cases thin section axial and coronal precontrast T1-WSE MR images and postcontrast T1-WSE MR images with fat-suppression should be obtained. In the rare event that artifacts degrade the quality of the fat-suppressed images, contrast-enhanced T1-WSE sequences without fat-suppression can additionally be used.