R. Zappoli

Hyperammonemia and Valproate-Induced Alterations of the State of Consciousness

Sodium valproate was administered to 38 patients, admitted to our unit in the last 18 months, and chosen because they had: (1) poor control of their seizures; (2) therapeutic concentrations in their plasma of at least two major antiepileptic drugs. In 8 of them, a therapeutic dosage of VPA caused modifications of the state of consciousness ranging from coma to drowsiness and stupor. These patients also showed gastrointestinal disturbances, asterixis, ataxia, tremor and a worsening of EEG abnormalities. The side effects of the drug were constantly associated with increased concentration of blood ammonia. Better penetration of ammonia into the CNS of patients undergoing frequent seizures and possibly having imperfectly functioning biological barriers, could explain our observations. In view of the unusually high percentage of patients suffering from serious VPA side effects, it is probably advisable to carefully monitor ammonemia in the first few days of VPA therapy in every patient treated with multiple anticonvulsants.

Acute changes of blood ammonia may predict short‐term adverse effects of valproic acid

Valproic acid (VPA) was given to 24 epileptic patients who were already being treated with other antiepileptic drugs. A standardized loading dose of VPA was administered, and venous blood was sampled at 0,1,2,3, and 4 hours. Ammonia (NH,) was higher in patients who, during continuous therapy, complained of drowsiness (7 patients) than in those who were symptom-free (17 patients), although VPA plasma levels were similar in both groups. By measuring VPA-induced changes of blood NH3, content, it may be possible to identify patients at higher risk of obtundation when VPA is given chronically.

Electrophysiological Investigations of the Brainstem in the Vertebrobasilar Reversible Attacks

A total of 70 selected patients affected by reversible ischemic attacks in the vertebrobasilar system were studied. 50 patients presented transient ischemic attacks (TIA), while the other 20 patients suffered from 1-2 protracted transient ischemic attacks (PTIA). All patients underwent brainstem acoustic evoked potentials (BAEP) and electrooculography (EOG) 7-20 days from the last reversible ischemic attack, when all signs and symptoms completely disappeared. The combination of BAEP and EOG gave objective evidence of brainstem dysfunction in 61 out of 70 patients. BAEP resulted abnormal in 26 patients (16 TIA, 10 PTIA), EOG in 49 (36 TIA, 13 PTIA). Serial controls at 3, 6, and 12 months were conducted in 27 patients. 5 patients showed a normalization for BAEP and 7 for EOG 12 months after the first examination.

Combined Partial Temporal and Secondary Generalized Status Epilepticus

A right-handed 32-year-old woman had recurrent combined partial temporal and secondary generalized epileptic states almost constantly related to menstruations. During such more or less prolonged episodes sometimes the patient presented right adversive attacks with short postictal dysphasia. The catamenial status epilepticus observed in this cas was manifested in two clear-cut behavioral phases. The first phase was characterized by frequently recurrent left temporal epileptiform discharges without tendency to diffusion, progressively more prolonged and pseudorhythmic associated with a signalized feeling of intense fear without apparent impairment of consciousness or speech disturbances. The electroclinical features of the first phase suggest a depth origin of the paroxysms, probably due to a primary epileptogenic focus in the left amygdaloid-hippocampal complex. In the second phase the left temporal focal semirhythmic discharges associated with fear bouts became more frequent and prolonged and began to be followed by long-lasting generalized discharges resulting in a trance-like state with severe impairment of consciousness. The diffuse paroxysmal activity regularly preceded by the left temporal focal discharges was interpreted as a form of secondary bilateral synchrony constantly triggered from a focal pacemaker represented by the primary epileptogenic focus. During the very short transient periods of sudden cessation of the epileptiform activity the patient returned immediately to an apparent normal mental state. Good correlation could be established between different seizure patterns and predominant clinical signs. Intravenous diazepam rapidly decreased and then completely stopped the catamenial status epilepticus. Some problems related to the classification of these rare epileptic events are discussed.

The effects on auditory neurocognitive evoked responses and contingent negative variation activity of frontal cortex lesions or ablations in man: three new case studies

Our previous research in patients with extensive surgical ablations of the prefrontal cortex contradict the hypothesis of some authors that the generators of several auditory event-related potentials (ERPs) (N100; P200; N200; P300; SW), recordable in humans with depth/scalp electrodes and MEG over the prefrontal dorsolateral cortical areas, are essentially located in medial prefrontal and anterior cingulate-limbic cortices. Using a standard CNV paradigm, 21 EEG electrodes and topographic mapping analysis, the post-warning (S1) auditory N100a b c, P200, P300 (binaural clicks) and CNV activity were recorded in three additional patients after extensive dorsolateral and/or medial prefrontal cortex ablations, verified through CT/MRI examinations. No true post-S1/CNV components were recordable over the ablated frontal areas, only sporadic volume-conducted ERPs probably generated in the temporo-parietal lobes or posterior cingulate gyrus. For one of these patients, after excision of a vast right frontal epileptogenic cortical region (including extensive dorsolateral areas, but sparing the fronto-medial cortex and anterior/middle cingulate gyrus), no post-S1/CNV components were recordable over the ablated regions. These latest observations again indicate that independent neuronal generators of several post-S1 auditory and CNV components are located in the dorsolateral supramodal premotor/prefrontal cortical areas which are directly, ipsilaterally connected to the uni/multimodal temporo-parieto-occipital sensory and associative regions through the long, two-way, fairly superficial, superior arcuate-longitudinal and deeper superior and inferior occipito-frontal bundles. Clear and almost constant differences in the latency of some post-S1 N100 subcomponents (especially the time-lapses between onset and the highest amplitude of the N100 a and c) over various posterior, central and anterior cortical areas sequentially involved, roughly measured in 10 normal subjects along the scalp and with MRI cerebral imaging, may probably be accounted for by the transcortical homohemispheric conduction time, which varies in our scalp recordings from 1 cm/0.74-1.28 ms, mean approximately 1 cm/1.02 ms ( approximately 9.8 ms).

Auditory evoked potentials (early, middle, late components) and audiological tests in Friedreich's ataxia

A functional assessment of the acoustic pathways in a group of 9 patients with Friedreichs ataxia was performed. In none of them was symptomatic auditory impairment noticeable. All patients were submitted to audiological tests and AEP recording. AEPs included early (BAEPs), middle (MLCs) and long (LLCs) latency components. The absence of one or more BAEP waves was observed in 5 out of 9 patients. N85 latency was significantly increased in all but one patient. MLCs, particularly P12, N15, P25 were often normal in amplitude and latency, scarcely showing a positive relationship with abnormalities of preceding and following waves. Pure tone audiometry revealed cochlear or neural impairment only in 2 patients. Speech audiometry showed deficits in all patients. These investigations, taken as a whole, showed a prevalent involvement of the brain-stem acoustic pathways, presumably at different levels, seldom associated with eighth nerve impairment. In some cases LLC (N85) abnormalities could not be interpreted as a consequence of impaired function in peripheral and brain-stem acoustic sites and might suggest a cortical dysfunction. Major BAEP abnormalities were observed in patients with longer disease duration, while N85 changes were unrelated to the duration and the severity of the illness. The former may prove to be a reliable means of monitoring the progression of the disease, the latter could be employed as a complementary procedure in its early diagnosis.

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.

Cognitive potentials: ipsilateral corticocortical interconnections in prefrontal human cortex ablations

The research deals with the possible role of the essentially monosynaptic bidirectional corticocortical connections between occipito-temporo-parietal association cortical areas and frontal areas in the genesis of some contingent negative variation (CNV) components, especially on the supramodal dorsolateral prefrontal regions. With standard and topographic mapping methods of analysis, the multicomponent CNV complex formation was examined in 7 patients with extensive frontal cortex ablations exactly identified through CT/MRI examinations, and in 10 normal subjects. On the scalp over the ablated frontocortical areas, no consistent post-warning auditory N100 a-b-c, P200, P300, early and late CNV components were recordable. The hypothesis is proposed that the bidirectional ipsilateral long-distance pathways which interconnect uni-polymodal occipito-temporo-parietal cortical areas to prefrontal ones, in particular the arcuate-superior longitudinal and superior/inferior occipito-frontal fasciculi, play an important role in the genesis of several CNV complex components, especially the multicomponent post-S1 auditory N100. The posteroanterior sequential latency differences of these neurocognitive components, roughly measured along the scalp or on MRI imagings, is probably accounted for by the transcortical ipsilateral conduction time of about 1 cm/ms (10 m/s).

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.

Valproate-induced hyperammonaemia in two epileptic identical twins

SummaryThe cases of two epileptic identical twins are described, one of whom had presented an episode of valproate (VPA)-induced stupor associated with very high blood ammonia (NH3) concentrations. Both twins showed a similar marked increase of venous NH3 concentrations after the administration of a single loading dose of VPA (800 mg).