Cortical afferent inhibition abnormalities reveal cholinergic dysfunction in Parkinson's disease: a reappraisal.

Parkinson's disease (PD) is a multisystem neurodegenerative disorder affecting, besides the dopaminergic function, multiple neurotransmission systems, including the cholinergic system. Central cholinergic circuits of human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation (TMS) of motor cortex; this test is named short latency afferent inhibition (SAI). SAI abnormalities have been reported in PD patients with gait disturbances and many non-motor symptoms, such as visual hallucinations (VHs), REM sleep behavior disorder (RBD), dysphagia, and olfactory impairment. The findings of these TMS studies strongly suggest that cholinergic degeneration is an important contributor to a number of clinical features of PD. TMS and neuropsychological raise the possibility that the presence of RBD, VHs and olfactory dysfunction indicate increased risk of cognitive impairment in patients with PD. Longitudinal studies of the patients are required to verify whether SAI abnormalities can predict a future severe cognitive decline. TMS can provide simple measures that may represent suitable biomarkers of cholinergic neurotransmission in PD. SAI studies enable an early recognition of PD patients with cholinergic system degeneration, and this might allow future targeted cholinergic treatment approaches, in addition to dopaminergic therapy, to ameliorate non-motor and motor clinical symptoms in PD patients.

A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia.

BACKGROUND: Protein aggregate myopathies are increasingly recognised conditions characterised by a surplus of endogenous proteins. The molecular and mutational background for many protein aggregate myopathies has been clarified with the discovery of several underlying mutations. Familial idiopathic hyperCKaemia is a benign genetically heterogeneous condition with autosomal dominant features in a high proportion of cases. METHODS: In 10 patients from three Italian families with autosomal dominant benign vacuolar myopathy and hyperCKaemia, we performed linkage analysis and exome sequencing as well as morphological and biochemical investigations. RESULTS AND CONCLUSIONS: We show, by Sanger and exome sequencing, that the protein aggregate myopathy with benign evolution and muscle inclusions composed of excess CASQ1, affecting three Italian families, is due to the D244G heterozygous missense mutation in the CASQ1 gene. Investigation of microsatellite markers revealed a common haplotype in the three families indicating consanguinity and a founder effect. Results from immunocytochemistry, electron microscopy, biochemistry and transfected cell line investigations contribute to our understanding of pathogenetic mechanisms underlining this defect. The mutation is common to other Italian patients and is likely to share a founder effect with them. HyperCKaemia in the CASQ1-related myopathy is common and sometimes the sole overt manifestation. It is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed, and the condition could be more common than supposed.

Terminology of psychogenic nonepileptic seizures.

Several different terms have been used to describe "psychogenic nonepileptic seizures" (PNES) in the literature. In this study, we evaluated the most common English terms used to describe PNES on Google and in PubMed using multiple search terms (https://www.google.com and http://www.ncbi.nlm.nih.gov/pubmed). The information prevalence of the five terms most frequently used to refer to PNES in PubMed were: psychogenic non(-)epileptic seizure(s), followed by pseudo(-)seizure(s), non(-)epileptic seizure(s), psychogenic seizure(s), and non(-)epileptic event(s). The five most frequently adopted terms to describe PNES in Google were: psychogenic non(-)epileptic seizure(s), followed by non(-)epileptic event(s), psychogenic attack(s), non(-)epileptic attack(s), and psychogenic non(-)epileptic attack(s). The broad spectrum of synonyms used to refer to PNES in the medical literature reflects a lack of internationally accepted, uniform terminology for PNES. In addition to "seizure(s)," lay people use the word "attack(s)" to describe PNES. Although considered obsolete, some terms, e.g., pseudoseizure(s), are still used in the recent medical literature. Adopting a uniform terminology to describe PNES could facilitate communication between epileptologists, physicians without specific expertise in epilepsy, and patients.

Subjective memory impairment and cholinergic transmission: a TMS study.

Subjective memory impairment (SMI) is being increasingly recognized as a preclinical phase of Alzheimer disease (AD). Short latency afferent inhibition (SAI) is helpful in demonstrating dysfunction of central cholinergic circuits, and was reported to be abnormal in patients with AD and amnestic multiple domain mild cognitive impairment. In this study, we found normal SAI in 20 subjects with SMI. SAI could be a useful biomarker for identifying, among individuals with memory complaints, those in whom cholinergic degeneration has occurred.

Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis.

BACKGROUND: Prompt treatment of status epilepticus (SE) is associated with better outcomes. Rectal diazepam (DZP) and nonintravenous (non-IV) midazolam (MDZ) are often used in the treatment of early SE instead of intravenous applications. The aim of this review was to determine if nonintravenous MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE seizures in children and adults. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and MEDLINE for randomized controlled trials comparing non-IV MDZ with DZP (by any route) in patients (all ages) with early SE defined either as seizures lasting >5 min or as seizures at arrival in the emergency department. The following outcomes were assessed: clinical seizure cessation within 15 min of drug administration, serious adverse effects, time interval to drug administration, and time from arrival in the emergency department to seizure cessation. Outcomes were assessed using a random-effects Mantel-Haenszel meta-analysis to calculate risk ratio (RR), odds ratio (OR) and mean difference with 95% confidence intervals (95% CIs). RESULTS: Nineteen studies with 1933 seizures in 1602 patients (some trials included patients with more than one seizure) were included. One thousand five hundred seventy-three patients were younger than 16 years. For seizure cessation, non-IV MDZ was as effective as DZP (any route) (1933 seizures; RR: 1.03; 95% CIs: 0.98 to 1.08). No difference in adverse effects was found between non-IM MDZ and DZP by any route (1933 seizures; RR: 0.87; 95% CIs: 0.50 to 1.50). Time interval between arrival and seizure cessation was significantly shorter with non-IV MDZ by any route than with DZP by any route (338 seizures; mean difference: -3.67 min; 95% CIs: -5.98 to -1.36); a similar result was found for time from arrival to drug administration (348 seizures; mean difference: -3.56 min; 95% CIs: -5.00 to -2.11). A minimal difference was found for time interval from drug administration to clinical seizure cessation, which was shorter for DZP by any route than for non-IV MDZ by any route (812 seizures; mean difference: 0.56 min; 95% CIs: 0.15 to 0.98 min). Not all studies reported information on time intervals. Comparison by each way of administration failed to find a significant difference in terms of clinical seizure cessation and occurrence of adverse effects. The only exception was the comparison between buccal MDZ and rectal DZP, where MDZ was more effective than rectal DZP in terminating SE but only when results were expressed as OR (769 seizures; OR: 1.78; 95% CIs: 1.11 to 2.85; RR: 1.15; 95% CIs: 0.85 to 1.54). Only one study was entirely conducted in an adult population (21 patients, aged 31 to 69 years), showing no difference in efficacy or time to seizure cessation after drug administration between intranasal MDZ and rectal DZP. CONCLUSIONS: Non-IV MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE in children and probably also in adults. Times from arrival in the emergency department to drug administration and to seizure cessation are shorter with non-IV MDZ than with intravenous or rectal DZP, but this does not necessarily result in higher seizure control. An exception may be the buccal MDZ, which, besides being socially more acceptable and easier to administer, might also have a higher efficacy than rectal DZP in seizure control. This article is part of a Special Issue entitled Status Epilepticus.

Clearly written, easily comprehended? The readability of websites providing information on epilepsy.

There is a general need for high-quality, easily accessible, and comprehensive health-care information on epilepsy to better inform the general population about this highly stigmatized neurological disorder. The aim of this study was to evaluate the health literacy level of eight popular English-written websites that provide information on epilepsy in quantitative terms of readability. Educational epilepsy material on these websites, including 41 Wikipedia articles, were analyzed for their overall level of readability and the corresponding academic grade level needed to comprehend the published texts on the first reading. The Flesch Reading Ease (FRE) was used to assess ease of comprehension while the Gunning Fog Index, Coleman-Liau Index, Flesch-Kincaid Grade Level, Automated Readability Index, and Simple Measure of Gobbledygook scales estimated the corresponding academic grade level needed for comprehension. The average readability of websites yielded results indicative of a difficult-to-fairly-difficult readability level (FRE results: 44.0±8.2), with text readability corresponding to an 11th academic grade level (11.3±1.9). The average FRE score of the Wikipedia articles was indicative of a difficult readability level (25.6±9.5), with the other readability scales yielding results corresponding to a 14th grade level (14.3±1.7). Popular websites providing information on epilepsy, including Wikipedia, often demonstrate a low level of readability. This can be ameliorated by increasing access to clear and concise online information on epilepsy and health in general. Short "basic" summaries targeted to patients and nonmedical users should be added to articles published in specialist websites and Wikipedia to ease readability.

Epilepsy-related stigma in European people with epilepsy: correlations with health system performance and overall quality of life.

We aimed to relate the percentages of encountered epilepsy-related stigma in people with epilepsy with quantitative indicators of the quality of health systems and quality of life by country in Europe. The epilepsy-related stigma percentages were obtained from the largest population-based study in people with epilepsy available. We correlated percentages of people with perceived stigma per European country with data on the country's overall health system performance, health expenditure per capita in international dollars, and the Economist Intelligence Unit's quality-of-life index. We found a nonsignificant trend towards negative correlation between the epilepsy-related stigma percentage and the overall health system performance (r=-0.16; p=0.57), the health expenditure per capita in international dollars (r=-0.24; p=0.4), and the Economist Intelligence Unit's quality-of-life index (r=-0.33; p=0.91). Living in a European country with a better health system performance and higher health expenditure per capita does not necessarily lead to a reduction in perceived epilepsy-related discrimination, unless the public health system invests on awareness programs to increase public knowledge and reduce stigma.

Neurostimulation in Alzheimer's disease: from basic research to clinical applications.

The development of different methods of brain stimulation provides a promising therapeutic tool with potentially beneficial effects on subjects with impaired cognitive functions. We performed a systematic review of the studies published in the field of neurostimulation in Alzheimer's disease (AD), from basic research to clinical applications. The main methods of non-invasive brain stimulation are repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Preliminary findings have suggested that both techniques can enhance performances on several cognitive functions impaired in AD. Another non-invasive emerging neuromodulatory approach, the transcranial electromagnetic treatment, was found to reverse cognitive impairment in AD transgenic mice and even improves cognitive performance in normal mice. Experimental studies suggest that high-frequency electromagnetic fields may be critically important in AD prevention and treatment through their action at mitochondrial level. Finally, the application of a widely known invasive technique, the deep brain stimulation (DBS), has increasingly been considered as a therapeutic option also for patients with AD; it has been demonstrated that DBS of fornix/hypothalamus and nucleus basalis of Meynert might improve or at least stabilize cognitive functioning in AD. Initial encouraging results provide support for continuing to investigate non-invasive and invasive brain stimulation approaches as an adjuvant treatment for AD patients.

Repetitive transcranial magnetic stimulation transiently reduces punding in Parkinson's disease: a preliminary study.

Amongst the impulse-control disorders (ICDs) associated with dopamine-replacement therapy in patients with Parkinson's disease (PD) is a repetitive, complex, stereotyped behaviour called punding. Disruption of the reciprocal loops between the striatum and structures in the prefrontal cortex (PFC) following dopamine depletion may predispose patients with PD to these behavioural disorders. The purpose of the present study was to assess the effects of repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral PFC (DLPFC) on punding in PD. We used low-frequency (LF) rTMS in four PD patients presenting with punding. Punding was transiently reversed by LF-rTMS over the DLPFC without enhancing motor impairment. The effect was more sustained after right DLPFC rTMS. Therefore, LF-rTMS produced a transient beneficial effect in PD patients with punding, similar to that reported in PD patients with levodopa-induced dyskinesias. rTMS might have therapeutic potential for the treatment of punding and perhaps other ICDs in PD.

Late-onset seizures and risk of subsequent stroke: a systematic review.

Otherwise unexplained late-onset seizures, conventionally defined as epileptic seizures occurring in subjects older than 60years and in the absence of disorders known to increase the risk of developing epilepsy, have been assumed to be, in most cases, of cerebrovascular origin. We systematically searched the literature to identify the evidence supporting the association between otherwise unexplained late-onset seizures/epilepsy and the risk of subsequent stroke. Most data from the literature indicate that cerebrovascular disease often underlies otherwise unexplained late-onset seizures/epilepsy. Patients presenting with seizures occurring for the very first time in late life and without clinically overt cerebrovascular disease should be considered as at increased risk of stroke. Consequently, these patients should be screened for the presence of vascular risk factors and treated accordingly. Such measures may greatly contribute to prevent strokes in these patients.

Why do people Google epilepsy? An infodemiological study of online behavior for epilepsy-related search terms.

Millions of people worldwide use the Internet daily as a source of health information. Google is the most popular search engine and is used by patients and physicians to search for online health-related information. This study aimed to evaluate changes in web search behavior occurring in English-speaking countries over time for terms related to epilepsy and epileptic seizures. Using Google Trends, data on global search queries for the terms "epilepsy", "seizure", and "seizures" between January 2004 and September 2013 were analyzed. The reduction over time in search queries for the term "epilepsy" (and, to a lesser extent, "seizures") was counterbalanced by an increased trend in searches for the term "seizure". Most terms associated with the search queries were related to symptoms of seizures, especially tonic-clonic seizures, and to seizures occurring in children. Three peaks in search volume over the period studied corresponded to news of celebrities having seizures. The volume of searches for the term "epilepsy SUDEP" was found to be enormously increased over time. Most people appear to use search engines to look for terms related to epilepsy to obtain information on seizure symptoms, possibly to aid initial self-diagnosis. Fears and worries about epileptic seizures and news on celebrities with epilepsy seem to be major factors that influence online search behavior.

Functional evaluation of central cholinergic circuits in patients with Parkinson's disease and REM sleep behavior disorder: a TMS study.

Central cholinergic dysfunction has been reported in patients with Parkinson's disease (PD) and hallucinations by evaluating short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain. REM sleep behavior disorder (RBD) was also found to be associated with cognitive impairment in PD patients. The objective of the study was to assess the cholinergic function, as measured by SAI, in PD patients with RBD (PD-RBD) and PD patients without RBD (PD-nRBD). We applied the SAI technique in 10 PD-RBD patients, in 13 PD-nRBD patients and in 15 age-matched normal controls. All PD patients and control subjects also underwent a comprehensive battery of neuropsychological tests. Mean SAI was significantly reduced in PD-RBD patients when compared with PD-nRBD patients and controls. Neuropsychological examination showed mild cognitive impairment in 9 out of the 10 PD-RBD patients, and in 5 out of the 13 PD-nRBD. SAI values correlated positively with neuropsychological tests measuring episodic verbal memory, executive functions, visuoconstructional and visuoperceptual abilities. Similar to that previously reported in the idiopathic form of RBD, SAI abnormalities suggest a cholinergic dysfunction in PD patients who develop cognitive impairment, and present findings indicate that RBD is an important determinant of MCI in PD.

When one plus one makes three: the quest for rational antiepileptic polytherapy with supraadditive anticonvulsant efficacy.

The experimental and clinical evidence in support of "rational polytherapy" is sparse, and to date, no clear evidence-based indications can be made to help physicians in their choice of a specific drug combination against specific forms of epilepsy. This article briefly reviews the data available in the literature and obtained from studies conducted in humans to evaluate which main AED combinations might possess supraadditive, synergistic effects in terms of efficacy, with infraadditive toxicity. By far, the most documented association resulting in supraadditive anticonvulsant effects against focal seizures is that of VPA and LTG. There are some indications that combinations of drugs with different primary mechanisms of action may be more effective than combining drugs with the same mechanisms of action. However, further animal and human research studies that focus both on toxicity and anticonvulsant effects of various combinations of AEDs are required.

Visual cortex hyperexcitability in idiopathic generalized epilepsies with photosensitivity: a TMS pilot study.

BACKGROUND: The current understanding of the mechanisms underlying photosensitivity is still limited, although most studies point to a hyperexcitability of the visual cortex. METHODS: Using transcranial magnetic stimulation, we determined the resting motor threshold (rMT) and the phosphene threshold (PT) in 33 patients with IGEs (8 with photosensitivity) compared with 12 healthy controls. RESULTS: Eleven controls (92%) reported phosphenes compared with fifteen (46%) patients with idiopathic generalized epilepsy (p=0.015). Phosphenes were reported more frequently among patients with epilepsy with photosensitivity (87.5%) than in patients with active epilepsy without photosensitivity (30.8%) (p=0.038) and patients with epilepsy in remission without photosensitivity (33.3%) (p=0.054); no differences were found between patients with epilepsy with photosensitivity and controls (p=0.648). Resting motor threshold and phosphene threshold were significantly higher among patients with epilepsy (active epilepsy or epilepsy in remission without photosensitivity) compared to healthy controls (p<0.01). Conversely, patients with active epilepsy and photosensitivity had significantly lower values than controls (p=0.03). CONCLUSIONS: The marked decrease in PT and the high phosphene prevalence in patients with IGE with photosensitivity indicate a regional hyperexcitability of the primary visual cortex. Results of this study also suggest that the PT may serve as a biomarker for excitability in patients with IGE and photosensitivity.

Primary visual cortex excitability in migraine: a systematic review with meta-analysis.

The objective is to update and extend previous results of a systematic review of the literature with meta-analysis performed to determine the prevalence of phosphenes and the phosphene threshold (PT) values obtained during single-pulse transcranial magnetic stimulation (TMS) in adults with migraine. Both published and unpublished controlled studies measuring PT by single-pulse TMS in adults with migraine with or without aura (MA, MwA) were systematically reviewed. Prevalence of phosphenes and PT values were assessed calculating mean difference (MD) and odds ratio (OR) with 95 % confidence intervals (CI). Fifteen trials (369 migraine patients and 269 controls), were included. Patients with MA had a statistically significant lower PT compared with controls when a circular coil was used (MD: -22.27, 95 % CI -33.44 to -11.10); with a figure-of-eight coil the difference was not statistically significant. There was a significant higher phosphene prevalence in MA compared with controls (OR: 3.57, 95 % CI 1.16-10.94). No significant differences were found either in phosphene reporting between patients with MwA and controls, or in PT values obtained by figure-of-eight coil in subjects with MwA versus controls. In general, these results slightly support the hypothesis of a primary visual cortex hyper-excitability in MA, providing not enough evidence for MwA. A significant heterogeneity across studies probably reflects relevant clinical and methodological heterogeneity.

A common reference-based indirect comparison meta-analysis of intravenous valproate versus intravenous phenobarbitone for convulsive status epilepticus.

OBJECTIVE: To compare intravenous valproate (IV-VPA) with intravenous phenobarbitone (IV-PB) in the treatment of established generalised convulsive status epilepticus (GCSE). Efficacy and safety were estimated using a common-reference based indirect comparison meta-analysis (CRBMA) methodology. METHODS: Randomised controlled trials (RCTs) investigating the use of IV-VPA or IV-PB versus intravenous phenytoin (IV-PHT) for GCSE were identified by a systematic search of the literature. A random effects model was used to estimate Mantel-Haenszel odds ratios (ORs) for efficacy and safety of IV-VPA or IV-PB versus IV-PHT in a standard meta-analysis. Adjusted indirect comparisons were then made between VPA and PB using the obtained results. RESULTS: CRBMA showed that VPA does not lead to significantly higher seizure cessation (OR 1.00; 95% CI: 0.36-2.76) compared to PB, although it exhibits fewer adverse effects (OR 0.17; 95% CI: 0.04-0.71). Results of this CRBMA are consistent with results of a recently published head-to-head comparison of IV-VPA and IV-PB. CONCLUSION: There is insufficient evidence to demonstrate superiority of IV-VPA over IV-PB for the treatment of GCSE in terms of efficacy. Some direct and indirect comparisons suggest that VPA has a better safety profile than PB. However, the limited numbers of underpowered RCTs included in this meta-analysis are not sufficient to justify a change in clinical practice. More rigorous and appropriately powered RCTs are therefore required to definitively determine the efficacy and tolerability of VPA for the treatment of GCSE.

Thiamine deficiency induced neurochemical, neuroanatomical, and neuropsychological alterations: a reappraisal.

Nutritional deficiency can cause, mainly in chronic alcoholic subjects, the Wernicke encephalopathy and its chronic neurological sequela, the Wernicke-Korsakoff syndrome (WKS). Long-term chronic ethanol abuse results in hippocampal and cortical cell loss. Thiamine deficiency also alters principally hippocampal- and frontal cortical-dependent neurochemistry; moreover in WKS patients, important pathological damage to the diencephalon can occur. In fact, the amnesic syndrome typical for WKS is mainly due to the damage in the diencephalic-hippocampal circuitry, including thalamic nuclei and mammillary bodies. The loss of cholinergic cells in the basal forebrain region results in decreased cholinergic input to the hippocampus and the cortex and reduced choline acetyltransferase and acetylcholinesterase activities and function, as well as in acetylcholine receptor downregulation within these brain regions. In this narrative review, we will focus on the neurochemical, neuroanatomical, and neuropsychological studies shedding light on the effects of thiamine deficiency in experimental models and in humans.

Short latency afferent inhibition differs among the subtypes of mild cognitive impairment.

Mild cognitive impairment (MCI) is considered a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer disease (AD). The role of the cholinergic system in MCI is not clearly defined and needs to be further investigated. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. We aimed to evaluate in the present study the relationship of SAI to the specific clinical subtypes of MCI. SAI was examined in 20 patients with amnestic MCI (10 SD, 10 MD), twenty patients with nonamnestic MCI (10 SD, 10 MD) and ten control subjects. Motor threshold, central motor conduction time, intracortical inhibition and facilitation to paired-TMS were also evaluated. Mean SAI was significantly reduced in amnestic MCI-MD patients when compared with the controls, while it was not significantly different in amnestic MCI-SD patients and in nonamnestic patients. SAI was increased after administration of a single dose of donepezil in a subgroup of four amnestic MCI-MD patients. The other TMS parameters did not differ significantly between the four MCI groups and the control group. We demonstrated that this putative marker of central cholinergic activity differs among MCI subtypes. The amnestic-MD type of MCI might be a phenotype of incipient AD. However, this hypothesis would be better addressed in a longitudinal study of individual patients. TMS studies may be useful in identifying MCI individuals in whom cholinergic degeneration is occurred and therefore at increased risk of conversion to AD.

Tongue biting in epileptic seizures and psychogenic events: an evidence-based perspective.

Tongue biting (TB) may occur both in seizures and in psychogenic non-epileptic events (PNEEs). We undertook a systematic review to determine sensitivity, specificity, and likelihood ratios (LR) of TB. Five studies (222 epilepsy patients and 181 subjects with PNEEs) were included. There was a statistically significant higher prevalence of TB (both without further specifications on site of lesions and lateral TB) in patients with seizures. Pooled accuracy measures of TB (no further specifications) were sensitivity 38%, specificity 75%, pLR 1.479 (95% CI 1.117-1.957), and nLR 0.837 (95% CI 0.736-0.951). Pooled measures of lateral TB were sensitivity 22%, specificity 100%, pLR 21.386 (95% CI 1.325-345.169), and nLR 0.785 (95% CI 0.705-0.875). Only a pooled analysis of data demonstrated a statistically significant pLR for lateral TB. Lateral TB but not 'any' TB has diagnostic significance in distinguishing seizures from PNEEs, supporting the diagnosis of seizures. Tongue biting without further specifications has, therefore, no value in the differential diagnosis between seizures and PNEEs.

Seizure heralding tuberculous meningitis.

Seizures may frequently occur during tuberculous meningitis. We describe a patient with an apparent generalised tonic-clonic seizure, initially not associated with any magnetic resonance imaging (MRI) abnormality, which was the presenting symptom of tuberculous meningitis. Follow-up MRI, performed after gadolinium administration, showed signs of meningeal involvement. Seizures may be the presenting symptoms of tuberculous meningitis even in the absence of evident intracerebral lesions on MRI. Therefore, contrast-enhanced brain MRI should be performed in the diagnostic workup for each first seizure, especially in patients with a clinical suspicion of CNS infectious disease. The term "heraldic seizure", indicating a subset of acute symptomatic seizures presenting at the onset of a brain/systemic injury or preceding the full clinical manifestation of a cerebral insult, may be helpful to classify these seizures retrospectively, based initially on unknown aetiology.