Gian Carlo Muscas

Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies.

Limbic encephalitis (LE) is a neurological syndrome that may present in association with cancer, infection, or as an isolate clinical condition often accompanying autoimmune disorders. Here we have characterized the clinical and laboratory features of two patients presenting with subacute onset, and chronic evolution, of anterograde amnesia and drug-resistant epilepsy associated with thyroid autoimmunity and in absence of tumoral pathology despite long follow-up. Antibodies against onconeural antigens, voltage gated potassium channel and glutamate receptors, which may accompany paraneoplastic as well as non-paraneoplastic LE, were negative. However, biochemical studies showed high titers, and sustained intrathecal synthesis, of antibodies directed against neuronal glutamic acid decarboxylase (GAD). In one patient, plasma exchange determined a dramatic improvement of the neurological deficits along with the decrease of autoantibodies.

Correlations of Topographical EEG Features with Clinical Severity in Mild and Moderate Dementia of Alzheimer Type

Quantitative electroencephalography (qEEG) and the Folstein Mini Mental State examination (MMSE) were obtained from 31 patients affected by probable dementia of Alzheimers type (DAT). qEEG data were examined both by spectral analysis (Fast Fourier Transformation) and by single frequency band topographical centroid, and compared with those of 24 healthy subjects of the same age group. DAT patients were found to have higher absolute power in the slow (delta and theta) frequency bands. Quantitative topographical assessment showed significantly more anteriorly located centers of gravity for the alpha and beta activity. Only alpha anteriorization was correlated with the degree of cognitive impairment as measured by the global deterioration scale and MMSE. It is concluded that quantitative topographical assessment was successful for the statistical handling of the EEG power maps, and to identify a potential parameter for the functional staging of the disease.

Clinical Features, Pathogenesis and Management of Drug-Induced Seizures

SummaryMany classes of pharmacological agents have been implicated in cases of drug-induced seizures. The list includes antidepressant drugs, lithium salts, neuroleptics, antihistamines (H1-receptor antagonists), anticonvulsants, central nervous system stimulants, general and local anaesthetics, antiarrhythmic drugs, narcotic and non-narcotic analgesics, non-steroidal anti-inflammatory drugs, antimicrobial agents, antifungal agents, antimalarial drugs, antineoplastic drugs, immunosuppressive drugs, radiological contrast agents and vaccines. For each of these classes of drugs, this article offers a revision of the literature and emphasises in particular the frequency of the adverse reaction, its clinical presentation, its presumed epileptogenic mechanism and the therapeutic strategy for the management of drug-induced seizures. An attempt is also made to distinguish seizures induced by standard dosages from those provoked by accidental or self-induced intoxication. For some classes of drugs such as antidepressants, neuroleptics, central nervous system stimulants (e.g. theophylline, cocaine, amphetamines) and β-lactam antibiotics, seizures are a well recognised adverse reaction, and a large body of literature has been published discussing exhaustively the major aspects of the issue; sufficient data are available also for the other classes of pharmacological agents mentioned above. In contrast, several other drugs [e.g. allopurinol, digoxin, cimetidine, protirelin (thyrotrophin releasing hormone), bromocriptine, domperidone, insulin, fenformin, penicillamine, probenecid, verapamil, methyldopa] have not been studied thoroughly under this aspect, and the only source of information is the occasional case report. This review does not address the issue of seizures induced by drug withdrawal.

A functional polymorphism in the SCN1A gene does not influence antiepileptic drug responsiveness in Italian patients with focal epilepsy

A splice site variation (c.603‐91G>A or rs3812718) in the SCN1A gene has been claimed to influence efficacy and dose requirements of carbamazepine and phenytoin. We investigated the relationship between c.603‐91G>A polymorphism and response to antiepileptic drugs (AEDs) in 482 patients with drug‐resistant and 401 patients with drug‐responsive focal epilepsy. Most commonly used AEDs were carbamazepine and oxcarbazepine. The distribution of c.603‐91G>A genotypes was similar among drug‐resistant and drug‐responsive subjects, both in the entire population and in the groups treated with carbamazepine or oxcarbazepine. There was no association between the c.603‐91G>A genotype and dosages of carbamazepine or oxcarbazepine. These findings rule out a major role of the SCN1A polymorphism as a determinant of AED response.

Antidepressant-associated myoclonic status in a patient with symptomatic generalized epilepsy: Does risk occur with therapeutic doses?

The clinical and EEG data of a 49-year-old man with myoclonic and generalized tonic-clonic seizures resulting from early childhood encephalitis are described. He experienced no tonic-clonic seizure for 10 years before brief exposure first to 60 mg/day duloxetine and then to 20mg/day paroxetine for depressive symptoms. These drugs were separately prescribed at a 9-month interval, and after beginning each drug, the patient experienced tonic-clonic seizures of worsening intensity and myoclonus of increasing frequency. Clinical features correlated with subcontinuous, generalized spike-wave discharges on the EEG. Discontinuation of antidepressant treatment resulted in rapid disappearance of clinical and electrophysiological manifestations of myoclonic status. We suggest care must be taken when using serotonin-noradrenaline reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs), as these drugs pose the risk of complications in the specific population of people with myoclonic seizures.

Conversion from thrice daily to twice daily administration of gabapentin (GBP) in partial epilepsy: analysis of clinical efficacy and plasma levels

Gabapentin has been administered in placebo-controlled studies with a thrice daily (T.I.D.) schedule, because of its short half-life. However, clinical efficacy does not seem strictly related to plasma levels: a twice daily (B.I.D.) schedule might therefore be possible. The aim of our study was to verify if the conversion from a T.I.D. to a B.I.D. regimen affected the efficacy and safety of gabapentin therapy. Out of 171 patients treated with add-on gabapentin, we selected 29 stable responders, who were followed for three months with a T.I.D. schedule and then switched to B.I.D. regimen for further three months. Seizure number, side-effects and trough plasma levels of gabapentin were collected during both periods. Gabapentin mean dose was 2117.2 mg/day. Mean number of seizures/months was: 4.2 at baseline, 1.0 during the T.I.D., and 0.9 during the B.I.D. period. Mean trough plasma level of gabapentin was 5.9 microgram/ml during the T.I.D. and 5.2 microgram/ml during the B.I.D. period. Twelve side-effects were reported by 11 patients during the T.I.D. and 6 by 5 patients during the B.I.D. period., sedation and vertigo were the most frequent in both. Results of our study suggest that gabapentin can be administered safely and effectively either with a T.I.D. and a B.I.D. regimen.

Topographic CNV activity mapping, presenile mild primary cognitive decline and Alzheimer-type dementia.

The CNV complex evoked with a standard paradigm (S1-2 sec-S2-motor response) and reaction time (RT) to the imperative signal (S2) were recorded and measured in 12 patients with initial presenile idiopathic cognitive decline (PICD), 12 with presenile Alzheimer-type dementia (PAD) and 10 healthy age-matched controls. Significant group differences were obtained for measures of some CNV components, particularly of the late pre-S2 CNV. No significant CNV activity, very prolonged RTs and sometimes characteristic post-imperative negative variations (PINV) were observed in the majority of patients with PAD. These results suggest that similar CNV complex and RT changes to those observed in our patients may constitute a valuable clue in the study of pathophysiological brain functioning in the early stages of presenile idiopathic mental deterioration.

GAD antibodies associated neurological disorders: Incidence and phenotype distribution among neurological inflammatory diseases

We investigated the prevalence and the clinical association of high titer of antibodies against glutamic acid decarboxylase (hGADAb) among unselected patients with inflammatory/autoimmune disorders of the nervous system. By indirect immunofluorescence examination of samples from 1435 patients, we identified 7 cases (0.48%) with hGADAb. Although stiff-person plus syndrome was the commonest clinical accompaniment, most of the patients presented with a combination of different symptoms, including psychiatric disturbances and intestinal motility disorders. Diagnosis delay and chronic evolution were common findings. In two cases persistently high values of hGADAb over the years were observed. The rarity and the phenotype heterogeneity of hGADAb clinical association should not discourage clinicians from antibody screening, at least in selected cases, as an early immunotherapy can change the otherwise chronic progression of this complex disorder spectrum.

Changes in bit-mapped contingent negative variation (CNV) activity due to initial normal involutional processes of the human brain

Bit-color mapped multicomponent CNV complexes and RTs to S2 evoked with a simple warned CNV/RT paradigm were recorded and measured in 20 selected right-handed very healthy volunteers (10 young adults and 10 presenile subjects, mean age 28.3 and 59.6, respectively). EEG and CNV components (post S1, N1, P2, P3; early CNV; N1200; late CNV; CNV resolution) were recorded from Fz, C3, Cz, C4, P3, Pz, and P4 referenced to linked mastoid electrodes. EOG, RT and stimuli were also recorded. The presenile group differed significantly from the younger group in the auditory post-S1 N1 and early (O-wave) and late (P-wave) CNV complex components. A progressive amplitude reduction limited to frontal leads between O-wave and P-wave, the lowest point being reached in the P-wave, was characteristic in the presenile group. Moreover, presenile subjects showed relatively flat CNV waveshapes of low amplitude and, on the whole, performed a little less well than young ones. This finding suggests that the statistically significant changes in auditory post-S1 N1 and CNV activity recorded in our presenile subjects, without any appreciable deficits in behavioral or mental performance, could be alerting signs of early brain involutional processes related to minimal and subclinical decline in orienting, attentiveness and response preparation capabilities. If such is the case, and it could be confirmed in a larger sample of very healthy subjects, these age-related changes in the presenium might prove to be of considerable practical importance for clinical research.

COMPARATIVE ANALYSIS OF THE PHARMACOKINETIC TECHNIQUES AVAILABLE FOR INDIVIDUALIZING PHENYTOIN DOSAGE

Over the past few years, numerous pharmacokinetic techniques based on Michaelis‐Menten principles have been proposed to individualize PHT dosage and predict plasma levels. The choice of one of these techniques for clinical use depends on the number of steady state concentration‐versus‐dose (Css‐D) data pairs that are known in the patient for whom the predictive technique is to be applied. The most frequent clinical situations in which these predictions are made can be divided into three groups for each patient considered—Case A: only one previous Css‐D data pair is known; Case B: two previous Css‐D data pairs are known; Case C: three previous Css‐D data pairs are known.