A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.

Progranulin expression in brain tissue and cerebrospinal fluid levels in multiple sclerosis.

BACKGROUND: Progranulin (PGRN) is a fundamental neurotrophic factor, and is also involved in inflammation and wound repair. PGRN may have pro- or anti-inflammatory properties, depending upon proteolysis of the anti-inflammatory parent PGRN protein and the generation of pro-inflammatory granulin peptides. OBJECTIVES: Our objectives were as follows: (1) to evaluate the presence and distribution of PGRN in multiple sclerosis (MS) brain tissue, correlating it with demyelination and inflammation; (2) to evaluate cerebrospinal fluid (CSF) PGRN concentrations in patients with MS and controls, in relationship to the clinical features of the disease. METHODS: Our study involved the following: (1) neuropathological study of PGRN on post-mortem tissue of 19 MS and six control brains; (2) evaluation of PGRN CSF concentration in 40 MS patients, 15 non-inflammatory controls and five inflammatory controls (viral encephalitis). RESULTS: In active demyelinating lesions, PGRN was expressed on macrophages/microglia. In the normal-appearing white matter (NAWM), expression of PGRN was observed on activated microglia. PGRN was expressed by neurons and microglia in cortical lesions and in normal-appearing cortex. No expression of PGRN was observed in controls, except on neurons. PGRN CSF concentrations were significantly higher in patients with relapsing-remitting MS during relapses and in progressive MS patients, compared with relapsing-remitting MS patients during remissions and with non-inflammatory controls. CONCLUSIONS: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS.

Repeated courses of granulocyte colony-stimulating factor in amyotrophic lateral sclerosis: clinical and biological results from a prospective multicenter study.

Granulocyte colony-stimulating factor (G-CSF) induces a transient mobilization of hematopoietic progenitor cells from bone marrow to peripheral blood. Our aim was to evaluate safety of repeated courses of G-CSF in patients with amyotrophic lateral sclerosis (ALS), assessing disease progression and changes in chemokine and cytokine levels in serum and cerebrospinal fluid (CSF). Twenty-four ALS patients entered an open-label, multicenter trial in which four courses of G-CSF and mannitol were administered at 3-month intervals. Levels of G-CSF were increased after treatment in the serum and CSF. Few and transitory adverse events were observed. No significant reduction of the mean monthly decrease in ALSFRS-R score and forced vital capacity was observed. A significant reduction in CSF levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-17 (IL-17) was observed. G-CSF treatment was safe and feasible in a multicenter series of ALS patients. A decrease in the CSF levels of proinflammatory cytokines MCP-1 and IL-17 was found, indicating a G-CSF-induced central anti-inflammatory response.

Body Schema Self-Awareness and Related Dream Content Modifications in Amputees Due to Cancer.

PURPOSE: the evaluation of body image perception, pain coping strategies, and dream content, together with phantom limb and telescoping phenomena in patients with sarcoma who underwent surgery for limb amputation. MATERIAL AND METHODS: consecutive outpatients were evaluated at T0 (within 3 weeks after surgery) and T1 (4-6 months after surgery) as follows: demographic and clinical data collection; the Groningen Questionnaire Problems after Arm Amputation; the West Haven-Yale Multidimensional Pain Inventory; the Body Image Concern Inventory, a clinical trial to identify telescoping; and a weekly diary of dreams. Dream contents were coded according to the Hall and Van de Castle coding system. RESULTS: Twenty patients completed the study (15 males and 5 females, mean age: 53.9 ± 24.6, education: 7.8 ± 3.4). All subjects experienced phantom limb and 35% of them experienced telescoping soon after surgery, and 25% still after 4-6 months. Both at T0 and T1, that half of the subjects reported dreams about still having their missing limbs. At T1 the patients' perceptions of being able to deal with problems were lower, and pain and its interference in everyday life were higher yet associated with significant engagement in everyday activities and an overall good mood. The dream content analysis highlighted that males were less worried about health problems soon after amputation, and women showed more initial difficulties that seemed to be resolved after 4-6 months after surgery. CONCLUSIONS: The dream content analysis may improve clinicians' ability to support their patients during their therapeutic course.

Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter.

Gray matter (GM) lesions are recognized as important components of the pathology of multiple sclerosis (MS), and involvement of the deep gray matter (DGM) is suggested by magnetic resonance imaging. The aims of this study were to determine the frequency and distribution of lesions and characterize the inflammatory and neurodegenerative changes in DGM of MS patients. Histochemistry, immunohistochemistry, and morphometry were performed on whole coronal sections of 14 MS and 12 control (6 normal, 6 from amyotrophic lateral sclerosis patients) brains. Demyelinating lesions were frequent in MS DGM; most often in the thalamus and caudate, but they were also seen in the putamen, pallidum, claustrum, amygdala, hypothalamus, and substantia nigra. Most DGM lesions involved both GM and white matter. Inflammation in active DGM lesions was similar to that in lesions only in white matter but was less intense, and there was a preponderance of activated microglia, scarce myelin-laden macrophages, and a lesser extent of axonal damage. Neuronal loss was observed both in DGM lesions and nondemyelinated DGM with neuron atrophy in nondemyelinated DGM. In conclusion, demyelination and neurodegenerative changes are common in MS DGM and may contribute to clinical impairment. Inflammation in DGM lesions is intermediate between the destructive inflammation of white matter lesions and the minimal inflammation of cortical lesions. We hypothesize that alterations of glutamate reuptake mechanisms may contribute to these differences.

ALS in Italian professional soccer players: the risk is still present and could be soccer-specific.

We previously found an increased risk for ALS in Italian professional soccer players actively engaged between 1970 and 2001 (n =7325). The present study extends previous work with a prospective follow-up of the original cohort to 2006 and investigates the risk of ALS in two other cohorts of professional athletes, basketball players (n =1973) and road cyclists (n =1701). Standardized morbidity ratios (SMRs) were calculated. Among soccer players three new cases of ALS were identified, reaching a total of eight ALS cases (mean age of onset, 41.6 years). The number of expected cases was 1.24, with an SMR of 6.45 (95% CI 2.78-12.70; p<0.00001). The risk of ALS was higher for careers lasting >5 years, for midfielders, and for players engaged after 1980. No basketball player and no cyclist developed ALS. This prospective extension of the Italian soccer players cohort survey confirms the highly significant risk of developing ALS, the young age of onset, the dose-effect risk and a predilection for midfielders. The absence of ALS cases in professional road cyclists and basketball players indicates that ALS is not related to physical activity per se.

Neuropsychological and functional study in a case of partial cerebellar agenesis.

Cerebellar agenesis is a rare disorder. We present the neurological and neuropsychological features of a patient with partial cerebellar agenesis (TZ), together with SPECT perfusion and fMRI activation during a finger tapping task. TZ shows only mild cerebellar signs, while neuropsychological testing discloses severe deficits in many domains, in accordance with the theorized role of the cerebellum in cognition. FMRI and SPECT demonstrate an activation and a symmetrical perfusion of the cerebellar remnants, that can be related to the residual cerebellar motor function. The left frontal and parieto-temporal cortex hypoperfusion can explain the severe cognitive impairment and could be linked to the abnormal cerebellar development.

Involvement of the choroid plexus in multiple sclerosis autoimmune inflammation: a neuropathological study.

An immunological function has been proposed for the choroid plexus (CP). In multiple sclerosis (MS) brains, CPs show (immunohistochemistry to HLA-DR, CD3, CD20, CD68, VCAM-1, CD138) T lymphocytes in vessels and stroma, VCAM-1 expression on endothelia, intense HLA-DR immunostaining on cells in CP stroma, among CP epithelium and on epiplexus cells. CPs in control or amyotrophic lateral sclerosis brains do not show such inflammatory changes. Intense CP inflammation is observed in viral encephalitis. Changes in MS CPs suggest persisting immune activation, with intensity similar to acute encephalitis, even in MS phases in which neurodegeneration prevails. In MS, CPs could represent a site for lymphocyte entry in the CSF and for CSF antigens presentation.

Sleep on a high heat capacity mattress increases conductive body heat loss and slow wave sleep.

Environmental temperature can strongly affect sleep. The habitual sleep phase is usually located between evening decline and morning rise of the circadian rhythm of core body temperature (CBT). However, the thermophysiological mechanisms promoting or disturbing sleep are not yet fully understood. The purpose of this study was to examine the effects of a high heat capacity mattress (HHCM) on CBT, skin temperatures and sleep in comparison to a conventional low heat capacity mattress (LHCM). Based on the higher heat capacity of HHCM an increase in conductive body heat loss enhances the nocturnal decline in CBT can be expected. Based on previous findings this may then be accompanied by an increase in slow wave sleep (SWS). The mattresses were studied in a randomized single-blind crossover design in fifteen healthy young men (Age: 26.9±2.1yr, BMI: 22.2±0.4kg/m2) by overnight in laboratory standard video-polysomnography in a temperature stabilized setting. CBT, room temperature, and skin and mattress surface temperatures were continuously recorded in order to get information about inner and outer body heat flow. Additionally, subjective sleep quality was estimated by visual analogue scale. In comparison to LHCM sleep on HHCM exhibited a selective increase in SWS (16%, p<0.05), increased subjective sleep quality and sleep stability [reduced cyclic alternating pattern (CAP) rate; 5.3%, p<0.01]. Additionally, analyses of the sleep stages showed in the second part of the night a significant increase in SWS and a decrease in REMS. In addition, HHCM induced a greater reduction in CBT (maximally by -0.28°C), reduced the increase in proximal skin temperatures on the back (PROBA; maximally by -0.98°C), and delayed the increase in mattress surface temperature (maximal difference LHCM-HHCM: 6.12°C). Thus, the CBT reduction can be explained by an increase in conductive heat loss to the mattress via proximal back skin regions. Regression analysis identified PROBA as the critical variable to predict inner conductive heat transfer from core to shell and SWS. In conclusion, the study expands the previous findings that a steeper nocturnal decline in CBT increases SWS and subjective sleep quality, whereas inner conductive heat transfer could be identified as the crucial thermophysiological variable, and not CBT.

Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage.

Cortical involvement in multiple sclerosis (MS) is emerging as an important determinant of disease progression. The mechanisms responsible for MS cortical pathology are not fully characterized. The objective of this study was to assess the role of excitotoxicity in MS cortex, evaluating excitatory amino acid transporter (EAAT) expression and its relationship with demyelination, inflammation, gliosis, and neuronal and synaptic pathology. EAATs are essential in maintaining low extracellular glutamate concentrations and preventing excitotoxicity. Ten MS brains (3 relapsing-remitting MS cases and 7 secondary progressive MS cases) were evaluated by immunohistochemistry for myelin basic protein, CD68, HLA-DR, EAAT1, EAAT2, glial fibrillary acidic protein, phosphorylated c-Jun N-terminal kinase (pJNK), synaptophysin, and neurofilaments. Cortical lesions were frequently observed in MS brains in variable numbers and extensions. In cortical lesions, activated microglia infiltration correlated with focal loss of EAAT1, EAAT2, and synaptophysin immunostaining, and with neuronal immunostaining for pJNK, a protein involved in response to excitotoxic injury. No reduction of EAATs or synaptophysin immunostaining was observed in demyelinated cortex in the absence of activated microglia. Alterations of the mechanisms of glutamate reuptake are found in cortical MS lesions in the presence of activated microglia and are associated with signs of neuronal and synaptic damage suggestive of excitotoxicity. Excitotoxicity may be involved in the pathogenesis of demyelination and of neuronal and synaptic damage in MS cortex.

Diuretics in obstructive sleep apnea with diastolic heart failure.

BACKGROUND: Upper airway edema might contribute to pharyngeal collapsibility and account for the high prevalence of obstructive sleep apnea (OSA) in patients with heart disease. The aim of this study was to evaluate if intensive unloading with diuretics improves sleep-disordered breathing and increases pharyngeal caliber in patients with severe OSA and diastolic heart failure. METHODS: Fifteen patients with severe OSA, hypertension, and diastolic heart failure were hospitalized to receive IV furosemide, 20 mg, and spironolactone, 100 mg, bid for 3 days. Polysomnography was performed for assessment of apnea-hypopnea index (AHI), acoustic pharyngometry was performed for assessment of the oropharyngeal junction (OPJ) area, and forced midinspiratory flow (FIF(50)), forced midexpiratory flow (FEF(50))/FIF(50) percentage, and exhaled nitric oxide (FeNO) were measured before and after diuretic treatment. RESULTS: Diuretic treatment produced a significant decrease in body weight, BP, and AHI (from 74.89 +/- 6.95 to 57.17 +/- 5.40/h, p < 0.001), associated with an improvement in OPJ area (from 1.33 +/- 0.10 to 1.78 +/- 0.16 cm(2), p = 0.007), FIF(50) (from 3.16 +/- 0.4 to 3.94 +/- 0.4 L/s, p = 0.006), and FEF(50)/FIF(50) percentage (from 117.9 +/- 11.8 to 93.15 +/- 10.1%, p = 0.002). Weight loss was significantly related to the decrease of AHI (R = 0.602; p = 0.018), to the increase of FIF(50) (R = 0.68; p = 0.005), and to the decrease of FEF(50)/FIF(50) (R = 0.635; p = 0.011). CONCLUSIONS: These findings suggest that pharyngeal edema contributes to sleep-disordered breathing in obese patients with severe OSA, hypertension, and diastolic heart failure. Upper airway edema may contribute to the frequent occurrence of OSA in patients with heart disease.

Angiotensin-converting enzyme inhibitors and obstructive sleep apnea.

Angiotensin-converting enzyme (ACE) inhibitors may induce cough and rhinopharyngeal inflammation. Obstructive sleep apnea (OSA) is characterized by upper airway inflammation. We describe a patient who, during enalapril treatment, developed cough, upper airway symptoms, and diurnal sleepiness, with an increased number of obstructive apnea-hypopnea episodes (apnea-hypopnea index [AHI], 25) during sleep. Her symptoms and AHI improved 1 month after enalapril was discontinued and diuretic therapy (hydrochlorothiazide-spironolactone) was initiated. Similar findings were observed in 4 other patients with OSA who had ACE inhibitor-induced cough. The mean +/- SD AHI was 33.8+/-21.0 during enalapril treatment and 20.0+/-17.0 after withdrawal of this drug (P = .04). Exhaled nitric oxide, a marker of airway inflammation, was increased during enalapril treatment (15.0 +/- 4.3 parts per billion) and decreased after discontinuation of this drug (9.0 +/- 2.6; P = .03). No significant difference in the AHI and exhaled nitric oxide was observed in 4 patients with OSA who did not experience cough, before or after withdrawal of ACE inhibitor treatment. These findings suggest that ACE inhibitor treatment may contribute to OSA by inducing upper airway inflammation.

Tooth loss and obstructive sleep apnoea.

BACKGROUND: Complete tooth loss (edentulism) produces anatomical changes that may impair upper airway size and function. The aim of this study was to evaluate whether edentulism favours the occurrence of obstructive sleep apnoea (OSA). METHODS: Polysomnography was performed in 48 edentulous subjects on two consecutive nights, one slept with and the other without dentures. Upper airway size was assessed by cephalometry and by recording forced mid-inspiratory airflow rate (FIF50). Exhaled nitric oxide (eNO) and oral NO (oNO), were measured as markers of airway and oropharyngeal inflammation. RESULTS: The apnoea/hypopnoea index (AHI) without dentures was significantly higher than with dentures (17.4 +/- 3.6 versus 11.0 +/- 2.3. p = 0.002), and was inversely related to FIF50 (p = 0.017) and directly related to eNO (p = 0.042). Sleeping with dentures, 23 subjects (48%) had an AHI over 5, consistent with OSA, but sleeping without dentures the number of subjects with abnormal AHI rose to 34 (71%). At cephalometry, removing dentures produced a significant decrease in retropharyngeal space (from 1.522 +/- 0.33 cm to 1.27 +/- 0.42 cm, p = 0.006). Both morning eNO and oNO were higher after the night slept without dentures (eNO 46.1 +/- 8.2 ppb versus 33.7 +/- 6.3 ppb, p = 0.035, oNO 84.6 +/- 13.7 ppb versus 59.2 +/- 17.4 ppb, p = 0.001). CONCLUSION: These findings suggest that complete tooth loss favours upper airway obstruction during sleep. This untoward effect seems to be due to decrease in retropharyngeal space and is associated with increased oral and exhaled NO concentration.

Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players.

The cause of amyotrophic lateral sclerosis (ALS) is still unknown. A possible relationship between ALS and sport participation has been supposed, but never definitely demonstrated. We studied a cohort of 7325 male professional football players engaged by a football team from the Italian First or Second Division in the period 1970-2001. ALS cases were identified using different concurrent sources. Standardized morbidity ratios (SMRs) were calculated. During the 137,078 person-years of follow-up, five ALS cases were identified (mean age of onset, 43.4 years). Three cases had a bulbar onset, significantly more than expected (P = 0.003). Since the number of expected cases was 0.77, the overall SMR was 6.5 [95% confidence interval (CI), 2.1-15.1]. The SMR was significantly increased for an ALS onset before 49 years, but not for older subjects. A significant increase of the SMR was found in the periods 1980-1989 and 1990-2001, whereas no ALS case was found in the 1970-1979 period. A dose-response relationship between the duration of professional football activity and the risk of ALS was found (>5 years, 15.2, 95% CI, 3.1-44.4; < or =5 years, 3.5, 95% CI, 0.4-12.7). Our findings seem to indicate that playing professional football is a strong risk factor for ALS.

Grey matter pathology in multiple sclerosis.

The aim of our study is to evaluate the extent and distribution of grey matter demyelinating lesions in multiple sclerosis (MS), addressing also neuronal loss and synaptic loss. Whole coronal sections of 6 MS brains and 6 control brains were selected. Immunohistochemistry was performed for myelin basic protein, neurofilaments, synaptophysin, ubiquitin, and activated caspase-3. Neuronal density and optical density of synaptophysin staining were estimated in cortical lesions and compared with those observed in corresponding areas of normal (i.e. nondemyelinated) cortex in the same section. Demyelinating lesions were observed in the cerebral cortex, in the thalamus, basal ganglia, and in the hippocampus. The percentage of demyelinated cortex was remarkable in 2 cases of secondary progressive MS (48% and 25.5%, respectively). Neuronal density was significantly reduced in cortical lesions (18-23% reduction), if compared with adjacent normal cortex, in the 2 cases showing the higher extent of cortical demyelination; in the same cases, very rare apoptotic neurons expressing caspase-3 were observed in cortical lesions and not in adjacent normal cortex. No significant decrease in optical density of synaptophysin staining was observed in cortical lesions. Grey matter demyelination and neuronal loss could contribute to disability and cognitive dysfunctions in MS.

Validity of hospital morbidity records for amyotrophic lateral sclerosis. A population-based study.

The validity of discharge diagnosis of amyotrophic lateral sclerosis (ALS) and of the main procedures performed during hospitalization was assessed using as gold standard the data from the Piemonte and Valle d'Aosta Register for ALS (PARALS), a collaborative population-based registry aimed at determining prospectively the incidence and the factors related to ALS outcome. All patients discharged with ICD code 335.2 (primary and secondary diagnoses) in the period 1995-1996 in Piemonte, Italy, were considered. Out of the 1,049 cases identified, 433 remained after excluding patients not resident in Piemonte and repeated admissions. Of these, 258 had a correct diagnosis of ALS (168 incident and 90 prevalent cases) after a review of clinical records. The sensitivity of discharge diagnoses was 78.9%, and the positive predictive value was 38.8%. The sensitivity for main procedures (percutaneous endoscopic gastrostomy, noninvasive ventilation, and tracheostomy) ranged between 76 and 100%. ICD codes allowed to identify 22 cases that had not been ascertained with other sources. In conclusion, hospital discharge records appear to poorly reflect the incidence of ALS, and can be used only after clinical verification of the diagnosis.

Effects of deep brain stimulation of the subthalamic nucleus on sleep architecture in parkinsonian patients.

Patients affected by Parkinson's disease (PD) often complain of disturbed sleep resulting from nighttime motor disabilities such as nocturnal akinesia, tremor and rigidity, motor behaviour during REM sleep or periodic leg movements (PLM) during sleep. Sleep may also be affected by dopaminergic and anticholinergic drugs or coexisting depressive syndrome. Deep brain stimulation (DBS) of subthalamic nucleus (STN) effectively reduces PD motor disability. The aim of this study is to evaluate the sleep architecture modifications after STN DBS. We assessed five patients (two men and three women, mean age 63.8+/-3.3 years, with a mean history of PD of 13.8+/-4.9 years) who underwent STN DBS. The mean levodopa equivalent dosage (LED) was 1010+/-318 mg before surgery and 116+/-93 mg 3 months after surgery. Polysomnography (PSG) with audiovisual recordings was performed on two separate nights, the first assessment in the week before surgery and the second 3 months after surgery. Three months after surgery, PSG showed an increase in total sleep time, in the longest period of uninterrupted sleep, and in the percentage of stage 3-4 NREM sleep, while there was a reduction of wakefulness after sleep onset. PLM, apnea-hyopnea index and REM sleep behaviour disorder were unaffected by STN DBS. STN DBS seems to be an effective therapeutic option for the treatment of advanced Parkinson's disease because it improves the cardinal symptoms and also seems to improve sleep architecture.

Management of brain metastases.

Brain metastases occur in 20-40% of patients with cancer and their frequency has increased over time. Lung, breast and skin (melanoma) are the commonest sources of brain metastases, and in up to 15% of patients the primary site remains unknown. After the introduction of MRI, multiple lesions have outnumbered single lesions. Contrast-enhanced MRI is the gold standard for the diagnosis. There are no pathognomonic features on CT or MRI that distinguish brain metastases from primary malignant brain tumors or nonneoplastic conditions: therefore a tissue diagnosis by biopsy should be always obtained in patients with unknown primary tumor before undergoing radiotherapy and/or chemotherapy. Some factors are prognostically important: a high Performance Status, a solitary brain metastasis, an absence of systemic metastases, a controlled primary tumor and a younger age. Based on these factors, subgroups of patients with different prognosis have been identified (RPA class I, II, III). Symptomatic therapy includes corticosteroids to reduce vasogenic cerebral edema and anticonvulsants to control seizures. In patients with newly diagnosed brain metastases prophylactic anticonvulsants should not be used routinely. The combination of surgery and whole-brain radiotherapy (WBRT) is superior to WBRT alone for the treatment of single brain metastasis in patients with limited or absent systemic disease and good neurological condition. Complete surgical resection allows a relief of intracranial hypertension, seizures and focal neurological deficits. Radiosurgery, alone or in conjunction with WBRT, yields results which are comparable to those reported after surgery followed by WBRT, provided that lesion's diameter does not exceed 3-3.5 cm. Radiosurgery offers the potential of treating patients with surgically inaccessible metastases. Still controversial is the need for WBRT after surgery or radiosurgery: local control seems better with the combined approach, but overall survival does not improve. Late neurotoxicity in long surviving patients after WBRT is not negligible; to avoid this complication patients with favorable prognostic factors must be treated with conventional schedules of RT, and monitoring of cognitive functions is important. WBRT alone is the treatment of choice in patients with single brain metastasis not amenable to surgery or radiosurgery, and with an active systemic disease, and in patients with multiple brain metastases. A small subgroup of these latter may benefit from surgery. The response rate of brain metastases to chemotherapy is similar to the response rate of the primary tumor and extracranial metastases, some tumor types being more chemosensitive (small cell lung carcinoma, breast carcinoma, germ cell tumors). New radiosensitizers and cytotoxic or cytostatic agents, and innovative technique of drug delivery are being investigated.

Risk of cancer in patients with Guillain-Barré syndrome (GBS). A population-based study.

The possible relationship between Guillain-Barré syndrome (GBS) and cancer is still controversial and the existence of a paraneoplastic GBS remains unconfirmed. To better define whether there is a relationship between GBS and malignancy, we compared the observed and the expected number of patients with tumours in a population-based cohort of subjects with GBS. Clinical differences between GBS patients with or without malignancies were analysed. Data were obtained from the Piemonte and Valle d'Aosta Register for GBS (PARGBS) (years 1990-1998). GBS was diagnosed according to NINCDS criteria. The number of expected cases of malignancy in the PARGBS population was calculated using the incidence rate of all types of cancer (ICD codes 140-208) in Piemonte [1985-1987], and in the most important town of this region, that is Turin (years 1993-1997). In the nine-year period, 435 incident patients with GBS were found. Nine of them developed cancer in the six months preceding or following GBS; in seven of them, the diagnosis of cancer and GBS was concomitant. The expected number of malignant tumours was 3.7 (using the incidence in Piemonte) and 3.8 (using the incidence in Turin); therefore, the odds ratios were 2.43 (95 % CI, 1.11-4.62) and 2.37 (95% CI, 1.09-4.50), respectively (p<0.01). Although the cases with malignancies were clinically similar to the other cases of GBS observed through the Register, the mortality in GBS patients with cancer was higher and was the final cause of death in two patients affected by severe cancer. These results suggest a possible correlation between some cases of GBS and cancer. However, GBS in cancer patients does not meet all the criteria for paraneoplastic diseases.