Primary headache and epilepsy: a multicenter cross-sectional study.

The prevalence and characteristics of interictal headache, epilepsy and headache/epilepsy comorbidity were assessed in 858 women and 309 men aged 18-81 years from headache and epilepsy centers in Italy. The research hypothesis was that comorbidity among patients with either disorder would be expected to be higher than in the general population. Interictal headache was diagnosed in 675 cases (migraine 482; tension-type headache 168; other types 25), epilepsy in 336 (partial 171; generalized 165) and comorbidity in 156 (1.6% from headache centers; 30.0% from epilepsy centers). Patients with epilepsy, headache and comorbidity differed in a number of demographic and clinical aspects. However, for both headache and epilepsy, a family history of the same clinical condition was equally prevalent in patients with and without comorbidity. These findings do not support the purported association between headache and epilepsy.

Predictors of epilepsy surgery outcome: a meta-analysis.

The potential efficacy of temporal and extratemporal resection in patients with partial epilepsy uncontrolled by anti-epileptic drugs is undisputed. However, there are still uncertainties about which patients will benefit most. A systematic review of the available literature has been undertaken by four pairs of reviewers to assess the overall outcome of epilepsy surgery and to identify factors better correlated to seizure outcome. A Medline search for studies on epilepsy surgery published since 1984 was performed. Studies were included if they had a well-defined population and design, a sample size of at least 30 patients, an MRI performed in least 90% of cases, an expected duration of follow-up of at least one year, and a post-operative outcome measured as seizure remission. A good outcome was considered as seizure control or seizure-free status for at least one year or Engel class I. Based on the review of 47 articles meeting all the eligibility criteria, febrile seizures (odds ratio, OR, 0.48; 95% confidence interval, CI, 0.27-0.83), mesial temporal sclerosis (OR 0.47; 95% CI 0.35-0.64), tumors (OR 0.58; 95% CI 0.42-0.80), abnormal MRI (OR 0.44; 95% CI 0.29-0.65), EEG/MRI concordance (OR 0.52; 95% CI 0.32-0.83), and extensive surgical resection (OR 0.24; 95% CI 0.16-0.36) were the strongest prognostic indicators of seizure remission (positive predictors); by contrast, post-operative discharges (OR 2.41; 95% CI 1.37-4.27) and intracranial monitoring (OR 2.72; 95% CI 1.60-4.60) predicted an unfavorable prognosis (negative predictors). Firm conclusions cannot be drawn for extent of resection, EEG/MRI concordance and post-operative discharges for the heterogeneity of study results. Neuromigrational defects, CNS infections, vascular lesions, interictal spikes, and side of resection did not affect the chance of seizure remission after surgery. Despite a number of limitations, the results of the review provide some insight into the selection of the best surgical candidates in clinical practice but raise concerns on the quality of published reports, and may serve as the basis for the identification of better standards to assess surgical outcome in observational studies.

Early predictors of peripheral neurotoxicity in cisplatin and paclitaxel combination chemotherapy.

BACKGROUND: We investigated the possible use of clinical signs of chemotherapy-induced peripheral neurotoxicity (CIPN) or of nerve growth factor (NGF) circulating levels to predict the final outcome of CIPN. PATIENTS AND METHODS: Sixty-two women affected by locally advanced squamous cervical carcinoma treated with TP (paclitaxel 175 mg/m2 over a 3 h infusion plus cisplatin 75 mg/m2) or TIP (TP plus ifosphamide 5 mg/m2) were examined and scored according to the Total Neuropathy Score (TNS), before and during chemotherapy. RESULTS: A correlation with the final severity of CIPN was observed with vibration perception and deep tendon reflex evaluation, while pin sensibility, strength, and autonomic symptoms and signs were not informative. A highly significant correlation existed between the decrease in circulating levels of NGF and the severity of CIPN (r = -0.579; P < 0.001; 95% confidence limits -0.702 to -0.423). However, circulating levels of NGF were not effective as predictors of the final neurological outcome of each patient. CONCLUSION: Our study indicates that a precise clinical evaluation of the peripheral nervous system of patients treated with platinum and taxane combination polychemotherapy not only gives reliable information regarding the course of CIPN, but also can be used to predict the final neurological outcome of the treatment.

Grading of chemotherapy-induced peripheral neurotoxicity using the Total Neuropathy Scale.

The authors compared clinically based neurotoxicity scales with the Total Neuropathy Scale, with the aim of improving the grading of the severity of chemotherapy-induced peripheral neuropathy (CIPN). The severity of CIPN was evaluated in a series of 60 women treated with cisplatin- and paclitaxel-based chemotherapy. A reduced version of TNS (TNSr) was also compared. The authors concluded that the TNS and TNSr can be used to assess the severity of CIPN effectively, and the results of this evaluation can be reliably correlated with the oncologic grading of sensory peripheral neurotoxicity.

Chronic alcohol use and first symptomatic epileptic seizures.

OBJECTIVE: To establish whether chronic alcoholism and alcohol consumption are risk factors for developing a first symptomatic epileptic seizure. METHODS: Multicentre case-control study of 293 patients (160 men, 133 women) with a first seizure symptomatic (either acute or remote) of head trauma, stroke, or brain tumour, matched to 444 hospital controls for centre, sex, age (+/-5 years), and underlying pathology. RESULTS: The risk of first seizure in alcoholics was no higher than in non-alcoholics for men (odds ratio 1.2, 95% confidence interval 0.4 to 3.2) or women (1.5, 0.1 to 54.4). The odds ratio (both sexes) was 1.2 (0.8 to 1.7) for an average intake of absolute alcohol of 1-25 g/day, 0.9 (0.5 to 1.5) for 26-50 g/day, 1.6 (0.8 to 3.0) for 51-100 g/day, and 1.4 (0.5 to 3.5) for >100 g/day. CONCLUSIONS: We found no evidence of an association between alcohol use or alcoholism and a first symptomatic seizure.

Validity of hospital discharge diagnoses for public health surveillance of the Guillain-Barrè syndrome.

We assessed the validity of hospital discharge diagnoses (HDDs) as a tracer of the Guillain-Barrè syndrome (GBS) in Lombardy Region, Northern Italy. The total number of HDDs with the ICD-9 code 357.0 as primary or any secondary diagnosis for the year 1996 was obtained from the Lombardy Region archives and matched to three sources of cases (an active GBS regional registry, a list of patients enrolled in an ongoing case-control study, regional hospital record files). Sensitivity and positive predictive value were calculated for the whole hospital population, by hospital department (neurology vs. other), and by diagnostic level (primary vs. other). Of a total of 1 443 071 HDDs, 361 had the ICD-9 code 357.0. Of these, 100 represented repeated admissions of the same patient. Of the 261 patients, 15 had been hospitalized in 1995, 15 were seropositive for human immunodeficiency virus, and three patients had unavailable records. Of the remaining 228 patients with complete medical records, the diagnosis of GBS was not confirmed in 103 cases. The sensitivity of the HDDs was 90.6% and the positive predictive value was 54.8%. The values were 81.9% and 76.4% for patients discharged from the neurology departments, and 79.7% and 61.8% when only the primary diagnostic level was considered. The crude annual incidence rate (calculated from the three sources combined) was 1.6 per 100 000 (95% CI, 0.8-2.8); the rate was 2.6 (95% CI, 1.7-3.7) when we used HDDs from all hospitals as tracers of disease, 1.7 (95% CI, 0.9-2.9) when only the HDDs from the neurology departments were considered, and 2.0 (95% CI, 1.1-3.2) when the analysis was limited to the primary diagnostic level. HDDs from neurology departments are a fairly valid surrogate of GBS incidence in Lombardy, Italy.

Rational use of EEG in adults in clinical practice.

The electroencephalogram (EEG) is still widely used for the diagnosis of several clinical conditions and symptoms. To assess the information provided by the EEG in relation to its duration, and to identify the shortest recording providing a conclusive report, the tracing was tested in 290 adult patients seen in a hospital neurophysiology unit for epilepsy (definite or uncertain), headache, head trauma, fainting, syncope, undefined loss of consciousness, vertigo, and cerebrovascular disease. Two neurophysiologists participating in the study read the same EEG independently. The record was based on a standardized timed sequence of montages. At each step any changes from the previous step were noted. Sixty-seven percent of the EEGs were coded as normal or aspecific, 24.1% were slow, and 8.6% were epileptiform. Normal tracings ranged from 38.8% (definite epilepsy) to 87.5% (vertigo), and epileptiform EEG from 0 (uncertain epilepsy) to 28.6% (definite epilepsy). The final report was clear in 80% of cases at the end of a 2-minute reading and almost 90% after 4 minutes. Hyperventilation and intermittent photic stimulation contributed little to the final report. Only for definite epilepsy were there changes along the whole sequence of montages. Thus, only for epilepsy need the EEG recordings last more than 20 minutes, whereas for the other clinical indications the total recording time could be limited to 4 minutes at most.

Neuro- and ototoxicity of high-dose carboplatin treatment in poor prognosis ovarian cancer patients.

BACKGROUND: Hematopoietic toxicity of high-dose carboplatin (HD-CBDCA) chemotherapy can be managed effectively with autologous blood cell support, but no conclusive data are available on its neuro- and ototoxicity. PATIENTS AND METHODS: We determined the neuro- and ototoxicity of HD-CBDCA in 10 patients affected by advanced ovarian cancer. HD-CBDCA was delivered as 24-hour continuous infusion or as 5-day schedules. Each patient underwent an extended clinical and instrumental neurological and otological evaluation before, during and after treatment. RESULTS: After HD-CBDCA only 1 patient had a clinically-evident peripheral neuropathy, while 3 additional patients had only distal paresthesias. Neurophysiological examination evidenced mild, although diffuse, sensory nerve impairment. Motor nerve impairment was also occasionally observed. All the sensory and motor pathological changes had a favorable course during the follow-up period. Ototoxicity was more severe than neurotoxicity and, in one case it was dose-limiting and audiologic impairment tended to remain constant also in the follow-up period. CONCLUSIONS: HD-CBDCA treatment can be tolerated by most of the patients, but careful monitoring of neuro- and, especially, ototoxicity should be planned.

Diazepam binding inhibitor (DBI) in the plasma of pediatric and adult epileptic patients.

The polypeptide diazepam binding inhibitor (DBI) displays epileptogenic activity by binding to benzodiazepine receptors. We analyzed DBI concentrations in the plasma of pediatric and adult epileptic patients, as a possible peripheral marker in epilepsy. DBI plasma concentrations are significantly higher (+ 62%, P < 0.001) in adult patients and slightly but significantly higher (+15%, P < 0.01) in pediatric patients, compared to age-related controls. Strikingly, plasma DBI is much higher (+81%, P < 0.001) in generalized epilepsy in adults and in drug-resistant pediatric and adult patients. Based on these findings, plasma DBI may be considered as a peripheral biological marker of epilepsy and, in association with lymphocyte benzodiazepine receptor density, of anticonvulsant drug responsiveness.

Decreased density of lymphocyte benzodiazepine receptors in drug-resistant epileptic patients.

Peripheral benzodiazepine receptors (PBR) may have a role in epilepsy and in mediating antiepileptic drug effects. Since PBR in blood mononuclear cells may be acted on by anticonvulsant drugs, we investigated possible modifications of these receptors in newly diagnosed patients, before and after antiepileptic treatment and in drug-resistant epileptic patients. A significantly lower receptor density, with no difference in affinity, was observed in drug-resistant patients, compared to newly diagnosed patients and to normal age-related controls. We suggest the possible use of PBR as a peripheral marker of drug response.

Antibodies of the anti-Yo and anti-Ri type in the absence of paraneoplastic neurological syndromes: a long-term survey of ovarian cancer patients.

In recent years several authors have described a close correlation between circulating antineuronal antibodies of different types and the occurrence of paraneoplastic neurological syndromes. Because this has not been widely accepted, we screened 300 serum samples from 181 ovarian cancer patients for the presence of circulating antineuronal antibodies by immunofluorescence. The findings were confirmed by immunoblotting. In 11 patients circulating antineuronal antibodies were detected. In 4 patients they were classified as anti-Yo and in 7 as anti-Ri, titres ranging from 1:400 to 1: 204,800. All the patients underwent thorough neurological and neurophysiological investigations, with special regard to paraneoplastic syndrome. None of them had symptoms pointing to a paraneoplastic neurological syndrome, although patients were followed up to 2 years after the first examination. Thus the frequency of circulating antineuronal antibodies in ovarian cancer patients is higher than the frequency of paraneoplastic syndromes, and antibody positivity does not necessarily lead to the appearance of a neurological paraneoplastic syndrome.

Neurotoxicity and ototoxicity of cisplatin plus paclitaxel in comparison to cisplatin plus cyclophosphamide in patients with epithelial ovarian cancer.

PURPOSE: To compare the neurotoxicity and ototoxicity of combination cisplatin plus paclitaxel versus cisplatin plus cyclophosphamide using extensive clinical and instrumental evaluation. PATIENTS AND METHODS: Forty-six of 51 consecutive patients affected by-epithelial ovarian cancer seen in our institution between October 1994 and August 1995 entered the study. After randomization, they were assigned to receive cisplatin 75 mg/m2 every 3 weeks associated with cyclophosphamide 750 mg/m2 (CC group, n = 22) or paclitaxel 175 mg/m2 over a 3-hour infusion (CP group, n = 24). Treatment was repeated six times in 43 patients and nine times in 25. Before treatment and after three, six, and nine courses of chemotherapy, patients underwent clinical and instrumental neurologic and otologic examinations. RESULTS: Mild sensory impairment was evident even after only three courses of both treatments and signs and symptoms were more severe at the end of treatment. On clinical grounds only, it was possible to demonstrate after six and nine courses a difference between CC and CP treatment, due to the involvement in some CP patients of pain and thermal sensory modalities. However, the overall severity of the neuropathy was similar. Audiometric parameters demonstrated a more negative outcome after treatment in CC compared with CP patients. However, the different severity of the involvement was closely correlated to this initial difference in audiologic performance. CONCLUSION: Up to nine courses of chemotherapy, the CC and CP schedules are similar in terms of severity of neurotoxicity and ototoxicity when patients are evaluated during and immediately after treatment. With the doses used in our study, these toxicities are not dose-limiting. Our results suggest that most of the toxic effects observed during the treatment were due to cisplatin.

Risk factors for the development of severe cisplatin neurotoxicity.

Cisplatin sensory neuropathy is not equally severe in all patients and may progress even after drug withdrawal. A major goal in cisplatin chemotherapy would be the identification of early predictors of an unfavorable neurological outcome in order to adjust the schedules of administration. The final neurological outcome of 63 women treated with the same schedule of cisplatin (CDDP) was compared with the general demographic and oncological parameters and with the baseline neurological results. No definite association could be drawn between any of the parameters evaluated and peripheral neuropathy. Further studies are needed to investigate the individual factors which are at the basis of the remarkable variability of this severe side effect of CDDP.

The Guillain-Barrè syndrome (GBS). Implementation of a register of the disease on a nationwide basis. Italian GBS Study Group.

A register of the Guillain-Barrè syndrome (GBS) has been started in Lombardy on February 1 1994, aiming at: 1) Making more correct estimates of the incidence and time and geographic trends of the disease; 2) Having a target population which serves for reference for analytical and experimental epidemiological studies; 3) Contributing to the validation of selected diagnostic procedures; 4) Implementing an audit of the diagnosis and treatment of GBS; 5) Collecting biochemical, hemathological and electrophysiological data to be stored in ad-hoc data-banks. In a pilot study undertaken during the period February 1 1994-May 31 1995 a total of 109 patients (M 63; F 46) were recruited in 32 hospitals. The crude annual incidence rate of GBS was 0.92 per 100,000 population. Typical GBS had been diagnosed in 87% of cases, followed by atypical GBS (7%). The disease could not be classified according to the available criteria in 6% of cases. Electrophysiological features suggesting demyelination were present in 29% of cases; axonopathy was documented in 14%, and mixed patterns in 34%. Plasma exchange was the suggested treatment in 51% of cases, followed by immunoglobulins (24%) and steroids (23%).

Peripheral neurotoxicity of taxol in patients previously treated with cisplatin.

BACKGROUND: Taxol is a new anticancer drug that acts as a tubulin polymeration enhancer. Its major toxicities are myelosuppression, hypersensitivity, and mucositis, but it also induces peripheral nerve damage. The use of taxol has recently been proposed for platinum-resistant cancers, but in these cases there is a possibility of cumulative toxicity in the peripheral nervous system. METHODS: Twenty-two patients affected by a relapse of cisplatin-treated ovarian cancer were examined clinically and neurophysiologically to determine the evolution of taxol-induced peripheral somatic and autonomic neurotoxicity and the possible cumulative effect of a combination of taxol and cisplatin. Each patient was examined before, during, and after taxol treatment (using a dose of 135 or 175 mg/m2 in 3 hours every 3 weeks). RESULTS: No patients were excluded from the study because of unacceptable toxicities of any kind. The serial examinations demonstrated that taxol induced onset of (or worsening of preexisting) neuropathic symptoms and signs in almost all the patients. The features were those of a distal, symmetrical, sensory polyneuropathy due to an axonopathy. Motor nerves and the autonomic nervous system were unaffected. Taxol neurotoxicity appeared early in the course of the treatment (i.e., after three courses) and was not severely disabling. In most cases after the early onset of peripheral neuropathy, stabilization of this side effect occurred. CONCLUSIONS: Considering the low doses of taxol used in this study, the sensory nerve damage was unexpectedly severe. It appears that a cumulative, but not dose-limiting, neurotoxic effect occurs using taxol in patients previously treated with cisplatin.

Weekly cisplatin +/- glutathione in relapsed ovarian carcinoma.

On the basis of experimental data showing the efficacy of glutathione (GSH) as a protective agent on cisplatin-induced neurotoxicity and the clinical evidence of the low incidence of neurotoxicity in high-dose cisplatin + GSH treated patients we evaluated the neuroprotective effect of GSH in a randomized phase II study. Thirty-three patients with relapsed ovarian cancer after a disease-free interval of at least 1 year and a cumulative dose of prior cisplatin ranging 450-650 mg m-2 were randomized to receive cisplatin 50 mg m-2 weekly +/- 2.5 g GSH for 9 consecutive weeks. Clinical and instrumental neurologic and otologic evaluations were made at the baseline and at the end of the study. Overall response rate in 31 evaluable patients was: 9/15 in group A and 12/16 in group B, including 4/15 vs 7/16 complete responses. The administered dose intensity of cisplatin was higher in the GSH treated patients (100% dose intensity was received by 56% vs 27%). A trend in terms of neuroprotection was detected in the GSH treated group, and no major difference was observed in the other toxicities between the two groups. It is concluded that possible benefit can be expected from the concomitant administration of GSH and cisplatin in patients at high risk of developing neurotoxicity, without decreasing the anti-tumor activity.

Long-term peripheral neurotoxicity of cisplatin in patients with successfully treated epithelial ovarian cancer.

We evaluated clinically and neurophysiologically the immediate and long-term involvement of the peripheral nervous system in 22 selected patients with epithelial ovarian cancer successfully treated with DDP alone or in combination with non-neurotoxic drugs. While the motor nerves were unaffected, generally the involvement of sensory nerves was more severe at the examination performed several months after DDP discontinuation than at the evaluation performed after the "induction phase". We conclude that up to now the importance of long-term DDP-induced peripheral nerve damage has probably been underestimated. DDP-induced long-term damage is at least as severe as the immediate toxicity and, moreover, it is likely that complete recovery can occur, if ever, only years after DDP discontinuation.

Epilepsy and psychiatric disturbance. A cross-sectional study.

One hundred patients with cryptogenic epilepsy and normal intelligence and 100 age- and sex-matched controls were submitted to psychiatric interview using the Clinical Interview Schedule. Nineteen patients and 15 controls were identified as having psychiatric disorders. Anxiety and depression were the predominating diagnoses in both groups. Personality disorders were occasionally present in subjects with epilepsy. The study shows that patients with cryptogenic epilepsy and normal neuropsychological abilities should not be considered at any higher risk of psychiatric disturbance than a non-neurological patient population.

Antiepileptic drugs and peripheral nerve function: a multicenter screening investigation of 141 patients with chronic treatment. Collaborative Group for the Study of Epilepsy.

One hundred forty-one adult patients treated for no less than 6 months with standard daily doses of the commonest antiepileptic drugs (AEDs) were recruited in five Italian centers and submitted to intensive clinical and electrophysiologic investigation to assess the effects of AEDs on peripheral nerves. Eighty percent of the patients were receiving monotherapy. Carbamazepine (CBZ) was the most common AED (51 cases), followed by phenytoin (PHT) (46), phenobarbital (PB) (42), and valproate (VPA) (25). Fifty-three percent of the patients had one or more symptoms of polyneuropathy (paresthesias being the most common complaint). The neurologic examination was abnormal in 32%. Electrophysiologic findings in two or more separate nerves were abnormal in 77 patients (54.6%); of these, 27 (19.1%) had abnormal neurologic findings and 21 (14.9%) also had symptoms of polyneuropathy. Sensory functions were most frequently impaired. Sural nerve biopsy was performed in 4 patients receiving monotherapy with CBZ, PHT, PB, and VPA. Except in patients receiving VPA (in whom no morphologic abnormalities were detected), mild predominantly axonal damage with secondary myelin changes was noted. A correlation was noted between polyneuropathy, age of the patient and, to a lesser extent, receipt of two or more AEDs.