Giada Giovannini

Claustrum damage and refractory status epilepticus following febrile illness

Objective: To characterize the clinical, EEG, and brain imaging findings in an adult case series of patients with de novo refractory status epilepticus (SE) occurring after a febrile illness. Methods: A retrospective study (2010–2013) was undertaken with the following inclusion criteria: (1) previously healthy adults with refractory SE; (2) seizure onset 0–21 days after a febrile illness; (3) lacking evidence of infectious agents in CSF; (4) no history of seizures (febrile or afebrile) or previous or concomitant neurologic disorder. Results: Among 155 refractory SE cases observed in the study period, 6 patients (17–35 years old) fulfilled the inclusion criteria. Confusion and stupor were the most common symptoms at disease onset, followed after a few days by acute repeated seizures that were uncountable in all but one. Seizures consisted of focal motor/myoclonic phenomena with subsequent generalization. Antiepileptic drugs failed in every patient to control seizures, with all participants requiring intensive care unit admission. Barbiturate coma with burst-suppression pattern was applied in 4 out of 6 patients for 5–14 days. One participant died in the acute phase. In each patient, we observed a reversible bilateral claustrum MRI hyperintensity on T2-weighted sequences, without restricted diffusion, time-related with SE. All patients had negative multiple neural antibodies testing. Four out of 5 surviving patients developed chronic epilepsy. Conclusions: This is a hypothesis-generating study of a preliminary nature supporting the role of the claustrum in postfebrile de novo SE; future prospective studies are needed to delineate the specificity of this condition, its pathogenesis, and the etiology.

Mortality, morbidity and refractoriness prediction in status epilepticus: Comparison of STESS and EMSE scores

PURPOSE Status epilepticus (SE) is a neurological emergency, characterized by high short-term morbidity and mortality. We evaluated and compared two scores that have been developed to evaluate status epilepticus prognosis: STESS (Status Epilepticus Severity Score) and EMSE (Epidemiology based Mortality score in Status Epilepticus). METHODS A prospective observational study was performed on consecutive patients with SE admitted between September 2013 and August 2015. Demographics, clinical variables, STESS-3 and -4, and EMSE-64 scores were calculated for each patient at baseline. SE drug response, 30-day mortality and morbidity were the outcomes measure. RESULTS 162 episodes of SE were observed: 69% had a STESS ≥3; 34% had a STESS ≥4; 51% patients had an EMSE ≥64. The 30-days mortality was 31.5%: EMSE-64 showed greater negative predictive value (NPV) (97.5%), positive predictive value (PPV) (59.8%) and accuracy in the prediction of death than STESS-3 and STESS-4 (p<0.001). At 30 days, the clinical condition had deteriorated in 59% of the cases: EMSE-64 showed greater NPV (71.3%), PPV (87.8%) and accuracy than STESS-3 and STESS-4 (p<0.001) in the prediction of this outcome. In 23% of all cases, status epilepticus proved refractory to non-anaesthetic treatment. All three scales showed a high NPV (EMSE-64: 87.3%; STESS-4: 89.4%; STESS-3: 87.5%) but a low PPV (EMSE-64: 40.9%; STESS-4: 52.9%; STESS-3: 32%) for the prediction of refractoriness to first and second line drugs. This means that accuracy for the prediction of refractoriness was equally poor for all scales. CONCLUSIONS EMSE-64 appears superior to STESS-3 and STESS-4 in the prediction of 30-days mortality and morbidity. All scales showed poor accuracy in the prediction of response to first and second line antiepileptic drugs. At present, there are no reliable scores capable of predicting treatment responsiveness.

Non-convulsive status epilepticus of frontal origin as the first manifestation of Hashimoto's encephalopathy

Hashimoto’s encephalopathy is an often misdiagnosed, life threatening, but treatable, condition which improves promptly with steroid therapy. Since clinical manifestations are heterogeneous and non-specific, the diagnosis is often difficult. Several case reports of Hashimoto’s encephalopathy presenting with partial or generalised seizures are described, but only a few have focused on status epilepticus as the first clinical manifestation. We report two patients presenting with repetitive and prolonged seizures characterised by progressive reduction in contact and reactivity associated with frontal/diffuse polyspike-and-wave activities. This condition, which can be interpreted as a formof non-convulsive status epilepticus (NCSE) of frontal origin, was refractory to antiepileptic drugs but responded promptly to high doses of intravenous steroid treatment. In cases of unexplained encephalopathy with EEG documentation of NCSE, the early recognition and treatment of Hashimoto’s encephalopathy may lead to a favourable prognosis.

Decreased allopregnanolone levels in cerebrospinal fluid obtained during status epilepticus

Neuroactive steroids are increasingly considered as relevant modulators of neuronal activity. Especially allopregnanolone (AP) and pregnenolone sulfate (PS) have been shown to possess, respectively, anticonvulsant or proconvulsant properties. In view of the potential role of these steroids, we aimed at evaluating AP and PS levels in cerebrospinal fluid (CSF) and blood samples obtained from patients with status epilepticus (SE). To this purpose, we enrolled 41 patients affected by SE and 41 subjects investigated for nonepileptic neurologic disorders. Liquid chromatographic procedures coupled with electrospray tandem mass spectrometry and routine laboratory investigations were performed. Significantly lower AP levels were found in the CSF of patients affected by SE (−30%; p < 0.05, Mann‐Whitney test). Notably, AP was not detectable in 28 of 41 patients affected by SE (p < 0.01 vs. controls, Fishers exact test). In serum, AP levels did not differ in the two considered groups. Conversely, PS was present at similar levels in the investigated groups. Finally, differences in AP levels could not be explained by a variation in CSF albumin content. These findings indicate that AP is defective in the CSF of patients affected by SE. This phenomenon was not dependent on carriers for steroids, such as albumin.

Ictal asystole as the first presentation of epilepsy: A case report and systematic literature review.

We report the case of a 69-year-old woman who presented with recurring episodes of mental confusion/dizziness followed by loss of consciousness, intense pallor, and sweating. Cardiologic investigations were unremarkable. The electroencephalogram recorded during one typical episode allowed the demonstration of a right frontotemporal seizure with progressive bradycardia leading to a 9-second asystole. Following levetiracetam treatment up to 2500 mg/day, seizures with ictal asystole (IA) recurred. An MRI compatible pacemaker was then implanted. At 26-month follow-up, the patient has not had further episodes of loss of consciousness. A systematic review (1950–Apr 2014) searching for cases in which IA was an early manifestation of epilepsy led to the observation of 31 cases. The time lag between the first seizures and the correct diagnosis of IA was long (average: 27 months; median: 12 months). Clinical history alone was not sufficient to prompt a correct diagnosis of IA, and only 11 out of 31 cases presented with symptoms suggestive of a seizure disorder. The majority of patients had a frontotemporal epilepsy with a slight prevalence of left-side involvement (19 out of 31). Ictal bradycardia–asystole is an important condition that should be recognized by epileptologists, neurologists, as well as emergency department physicians. It is important to underscore that IA not only can occur in patients with drug-resistant epilepsy but also may be the first manifestation of the patients epilepsy.

New-Onset Refractory Status Epilepticus with Claustrum Damage: Definition of the Clinical and Neuroimaging Features

New-onset refractory status epilepticus (NORSE) is a rare but challenging condition occurring in a previously healthy patient, often with no identifiable cause. We describe the electro-clinical features and outcomes in a group of patients with NORSE who all demonstrated a typical magnetic resonance imaging (MRI) sign characterized by bilateral lesions of the claustrum. The group includes 31 patients (12 personal and 19 previously published cases; 17 females; mean age of 25 years). Fever preceded status epilepticus (SE) in 28 patients, by a mean of 6 days. SE was refractory/super-refractory in 74% of the patients, requiring third-line agents and a median of 15 days staying in an intensive care unit. Focal motor and tonic–clonic seizures were observed in 90%, complex partial seizures in 14%, and myoclonic seizures in 14% of the cases. All patients showed T2/FLAIR hyperintense foci in bilateral claustrum, appearing on average 10 days after SE onset. Other limbic (hippocampus, insular) alterations were present in 53% of patients. Within the personal cases, extensive search for known autoantibodies was inconclusive, though 7 of 11 patients had cerebrospinal fluid lymphocytic pleocytosis and 3 cases had oligoclonal bands. Two subjects died during the acute phase, one in the chronic phase (probable sudden unexplained death in epilepsy), and one developed a persistent vegetative state. Among survivors, 80% developed drug-resistant epilepsy. Febrile illness-related SE associated with bilateral claustrum hyperintensity on MRI represents a condition with defined clinical features and a presumed but unidentified autoimmune etiology. A better characterization of de novo SE is mandatory for the search of specific etiologies.

The role of AMPA receptors and their antagonists in status epilepticus

Status epilepticus (SE) is typically defined as a prolonged self‐sustaining seizure or repeated seizures showing an incomplete recovery between them. SE represents a medical emergency often associated with significant disability, morbidity, and mortality. Despite the clinical impact, the mechanisms underlying the transition from self‐limited seizures to protracted, medically refractory seizures are not completely understood. About 40% of patients in established SE are refractory to antiepileptic drugs (first‐line treatment); therefore, there is a need for more efficacious drugs. In this review, we focused on the current knowledge about the involvement of alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors during SE, the preclinical efficacy of its antagonists, and the currently published clinical studies involving drugs with this mechanism of action. We carried out an extensive literature search to recognize experimental and clinical articles both on AMPA receptors and AMPA antagonists and SE. Recently, the role of AMPA receptors during and after SE has become clearer, and it is now widely accepted that early changes occur in the initial stages and probably contribute both to the maintenance of SE and to its refractoriness to treatment. The therapeutic potential of AMPA receptor inhibition has been sustained by studies in which AMPA receptor antagonists have been shown to terminate seizures in several SE animal models. To date, promising, but limited, data in humans support the use of AMPA receptor antagonists in patients with SE. AMPA receptor antagonists could become a new therapeutic option in patients with established SE when the first trials with second‐line agents have failed or probably even better after failure of benzodiazepines as a second‐line option.

Acute hemichorea as unusual first multiple sclerosis presentation

Patient 1 was a 39-year-old woman with an unremarkable medical history who developed acute involuntary right arm and leg movements. Neurologic examination revealed moderate dysarthria and subcontinuous, choreic movements in her right limbs, prevailing in the arm, which worsened during postural tasks. She occasionally had ballistic movements in her right limbs and abnormal dystonic postures. Continuous peribuccal and tongue involuntary movements were noted. Moreover, bilateral upper limb ataxia, gait and trunk ataxia, and brisk right tendon reflexes were found. There was no strength or sensory loss (video 1 at [Neurology.org/cp][1]). Brain MRI revealed a tumefactive, T2/fluid-attenuated inversion recovery (FLAIR) hyperintense, T1 hypointense contrast-enhancing demyelinating lesion in the left cerebral peduncle, extending to the substantia nigra and subthalamic nucleus (STN) (figure, A–C). Multiple hyperintense T2/FLAIR, T1 hypointense, non-contrast-enhancing demyelinating lesions in the hemispheric and periventricular deep white matter, brainstem, and cerebellar hemispheres were also found. All serologic tests were within normal limits. Isoelectric focusing (IEF) revealed 9 CSF oligoclonal bands (OCBs). A diagnosis of multiple sclerosis (MS) was made and the patient was treated with high-dose methylprednisolone with improvement of symptoms. [1]: http://cp.neurology.org/lookup/doi/10.1212/CPJ.0000000000000279

Low levels of progesterone and derivatives in cerebrospinal fluid of patients affected by status epilepticus

Neurosteroids such as allopregnanolone may play a role in epilepsy as positive modulators of inhibitory currents mediated by γ‐aminobutyric acid type A (GABAA) receptor. Indeed, these molecules have been consistently shown to be anticonvulsants in animal models, but their role is still unclear in patients. For this reason, we investigated neurosteroids in the cerebrospinal fluid (CSF) of patients with status epilepticus (SE) by liquid chromatography tandem‐mass spectrometry. Patients were retrospectively identified within subjects who received a lumbar puncture in the 2007–2017 period. Seventy‐three patients (median age 65, ranging from 13 to 94 years; 67% women) with SE were evaluated. Controls (n = 52, median age 53, ranging from 16 to 93 years; 65% women) were patients presenting with symptoms for which a lumbar puncture was required by clinical guidelines, and who were negative at the end of the diagnostic work‐up. Progesterone was 64% lower in patients with SE (p < 0.001). With respect to progesterone, upstream pregnenolone sulfate and pregnenolone did not change. Instead, downstream 5α‐dihydroprogesterone, pregnanolone and allopregnanolone were, respectively, 49% (p < 0.001), 21% (p < 0.01) and 37% (p < 0.001) lower than in controls. Duration or type of SE, age and sex did not consistently affect CSF neurosteroid levels in the SE cohort. Instead, pregnenolone sulfate (Spearmans ρ = 0.4335, p < 0.01), allopregnanolone (ρ = 0.4121, p < 0.05) and pregnanolone (ρ = 0.592, p < 0.001) levels significantly increased by aging in controls. We conclude that neurosteroidogenesis is defective in patients with SE.

Post-infectious sensory neuropathy with anti-GT1a and GQ1b antibodies associated with cold urticaria

A 64 years-old woman presented subacute onset distal paraesthesia concurrently with cold-induced urticaria, a rare form of physical urticaria. Both the disturbances developed a fortnight after an upper respiratory tract infection. EMG confirmed an exclusively sensory polyneuropathy, with prolongation of distal latencies and reduction of amplitudes. Anti-GQ1b and anti-GT1a antigangliosides antibodies were found in serum. The clinical workout included CSF analysis, cryoglobulin and paraprotein search, neurotropic infective agents, neoplastic markers and extensive autoimmune disease antibodies analysis, all of which resulted negative. Intravenous immunoglobulins were administered, leading to progressive resolution of the sensory disturbance, while a combination of steroid and anti-histaminics treatment was used for the urticaria. The positivity for anti-ganglioside search with an EMG pattern characterized by a mixture of demyelinating and axonal features may suggest a nodo-paranodopathy at early stages. This is the first case of an association between an acute sensory neuropathy and cold urticaria, two immune mediated conditions apparently due to very different hypersensitivity pathways. A proposed mechanism for the co-occurence of these two conditions is presented, whereas this case expands the clinical spectrum of autoimmune diseases associated with anti-GQ1b and anti-GT1a antibodies.