Recovery of chronic motor neuropathy due to acute intermittent porphyria after givosiran treatment in a young boy: a case report.

BACKGROUND: We describe the first case of a pediatric patient with acute intermittent porphyria and severe chronic porphyric neuropathy treated with givosiran, a small-interfering RNA that drastically decreases delta-aminolevulinic acid production and reduces porphyric attacks' recurrence. CASE REPORT: A 12-year-old male patient with refractory acute intermittent porphyria and severe porphyric neuropathy was followed prospectively for 12 months after givosiran initiation (subcutaneous, 2.5 mg/kg monthly). Serial neurological, structural, and resting-state functional magnetic resonance imaging (MRI) evaluations were performed, including clinical scales and neurophysiological tests. Delta-aminolevulinic acid urinary levels dropped drastically during treatment. In parallel, all the administered neurological rating scales and neurophysiological assessments showed improvement in all domains. Moreover, an improvement in central motor conduction parameters and resting-state functional connectivity in the sensory-motor network was noticed. At the end of the follow-up, the patient could walk unaided after using a wheelchair for 5 years. CONCLUSIONS: A clear beneficial effect of givosiran was demonstrated in our patient with both clinical and peripheral nerve neurophysiologic outcome measures. Moreover, we first reported a potential role of givosiran in recovering central motor network impairment in acute intermittent porphyria (AIP), which was previously unknown. This study provides Class IV evidence that givosiran improves chronic porphyric neuropathy.

Expanding the spectrum of SOX1-antibodies in neuropathy: the coexistence of anti-SOX1 and Guillain-Barré syndrome-a case report.

BACKGROUND AND AIMS: Antibodies against SOX1 (or anti-glial nuclear antibody, AGNA) are partially characterized onconeural antibodies, firstly described in association with small cell lung cancer (SCLC). Lambert-Eaton myasthenic syndrome is the most frequent paraneoplastic syndrome (PNS) found in patients with anti-SOX1-antibody positivity. Other associations are chronic axonal polyneuropathy, paraneoplastic limbic encephalitis, and paraneoplastic cerebellar degeneration. METHODS: We describe a case of Guillain-Barré syndrome (GBS) with classical demyelinating phenotype associated with a positivity for anti-SOX1-antibodies. RESULTS: A therapy with intravenous immunoglobulin led to progressive clinical improvement. After 12 months, clinical and neurophysiological pictures showed complete recovery. A thorough paraneoplastic screening was negative for underlying tumors. CONCLUSIONS: This is the first case of GBS associated with anti-SOX1-antibodies described in literature. Although the concept of paraneoplastic GBS is controversial, different cases have been reported and GBS is considered a non-classical paraneoplastic syndrome. Our case expands the anti-SOX1-antibody clinical spectrum with relevant implications for the clinical practice.

Lacosamide in monotherapy in BTRE (brain tumor-related epilepsy): results from an Italian multicenter retrospective study.

PURPOSE: Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients. METHODS: We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints). RESULTS: Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence. CONCLUSIONS: This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.

Factors affecting the outcome of delayed intravenous thrombolysis (>4.5hours).

INTRODUCTION: Evidence of the intravenous tissue plasminogen activator (tPA) efficacy beyond the 4.5hours window is emerging. We aim to study the factors affecting the outcome of delayed thrombolysis in patients of clear onset acute ischemic stroke (AIS). METHODS: Data of patients with AIS who received intravenous thrombolytic after 4.5hours were reviewed including: demographics, risk factors, clinical, laboratory, investigational and radiological data, evidence of mismatch, treatment type and onset, National Institutes of Health Stroke Scale (NIHSS) score at baseline, 24hours, 7days after thrombolysis and before discharge, and 3 months follow-up modified Rankin Scale (mRS). RESULTS: We report 136 patients treated by intravenous tPA between 4.53 and 19.75hours with average duration of 5.7h. The ASPECT score of our patients was≥7. Sixty-four cases showed intracranial arterial occlusion. Perfusion mismatch was detected in 117 (84.6%) patients, while clinical imaging mismatch was detected in 19 (15.4%). Early neurological improvement after 24hours occurred in 114 (83.8%) patients. At 90days, 91 patients (67%) achieved good outcome (mRS 0-2), while 45 (33%) had bad outcome (mRS 3-6). Age, endovascular treatment, NIHSS, AF, and HT were significantly higher in the bad outcome group. Age (P=0.001, OR: 1.099, 95% CI: 1.042-1.160) and baseline NIHSS were predictive of the poor outcome (P=0.002, OR: 1.151, 95% CI: 1.055-1.256). The best cutoff value of age was 72.5 with AUC of 0.76, sensitivity 73.3% and specificity 60.4%. While for NIHSS at admission, the cutoff value of 7 showed the best results with AUC of 0.73, sensitivity 71.1% and specificity 63.7%. Combination of age and admission NIHSS raised the sensitivity and specificity to 84.4% and 63.7%, respectively. CONCLUSION: Increased age and admission NIHSS may adversely affect the outcome of delayed thrombolysis and narrow the eligibility criteria. Age and baseline NIHSS based stratification of the patients may provide further evidence as regards the efficacy of the delayed thrombolysis.

Efficacy of mechanical thrombectomy in patients with ischemic stroke and cancer.

Cancer-related coagulopathy is a known cause of stroke and can lead to formation of thrombi with a unique composition. The effectiveness of mechanical thrombectomy in cancer patients is still unknown. The aim of the study was to evaluate the rate of successful reperfusion and the clinical outcome in cancer patients with stroke treated with endovascular therapies, compared to patients without cancer. We performed a retrospective analysis of consecutive patients with ischemic stroke treated with endovascular therapies at our hospital between January 2008 and January 2016. A sub-group analysis was performed including only patients with cryptogenic stroke. We included in the final analysis 14 patients with active cancer and 267 patients without cancer. Successful reperfusion was achieved in 79% of patients without cancer, and 71% of patients with active cancer (P = 0.68). Patients with cryptogenic stroke and active cancer had a lower reperfusion rate compared to patients with cryptogenic stroke without active cancer, although not significantly so (2/4 cancer patients, 50% vs 37/50, 74%, p: 0.31). Mortality rate was higher among cancer patients. Hemorrhagic transformation occurred in similar proportions in the two groups. Endovascular treatment in cancer patients seems, thus, effective.

fMRI-Based Effective Connectivity in Surgical Remediable Epilepsies: A Pilot Study.

Simultaneous EEG-fMRI can contribute to identify the epileptogenic zone (EZ) in focal epilepsies. However, fMRI maps related to Interictal Epileptiform Discharges (IED) commonly show multiple regions of signal change rather than focal ones. Dynamic causal modeling (DCM) can estimate effective connectivity, i.e. the causal effects exerted by one brain region over another, based on fMRI data. Here, we employed DCM on fMRI data in 10 focal epilepsy patients with multiple IED-related regions of BOLD signal change, to test whether this approach can help the localization process of EZ. For each subject, a family of competing deterministic, plausible DCM models were constructed using IED as autonomous input at each node, one at time. The DCM findings were compared to the presurgical evaluation results and classified as: "Concordant" if the node identified by DCM matches the presumed focus, "Discordant" if the node is distant from the presumed focus, or "Inconclusive" (no statistically significant result). Furthermore, patients who subsequently underwent intracranial EEG recordings or surgery were considered as having an independent validation of DCM results. The effective connectivity focus identified using DCM was Concordant in 7 patients, Discordant in two cases and Inconclusive in one. In four of the 6 patients operated, the DCM findings were validated. Notably, the two Discordant and Invalidated results were found in patients with poor surgical outcome. Our findings provide preliminary evidence to support the applicability of DCM on fMRI data to investigate the epileptic networks in focal epilepsy and, particularly, to identify the EZ in complex cases.

New onset status epilepticus in influenza associated encephalopathy: The presenting manifestation of genetic generalized epilepsy.

We hereby present a case of a young woman with no history of seizures or epilepsy who experienced a de novo generalized Non Convulsive Status Epilepticus (NCSE) followed by encephalopathy lasting for several days during influenza B infection. Influenza can have a broad spectrum of presentation ranging from an uncomplicated illness to many serious conditions as is the case of influenza associated encephalitis/encephalopathy (IAE). In this context however, it is possible to observe seizures and/or status epilepticus as the presenting manifestation of a genetic generalized epilepsy.

Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band-negative patients with suspected multiple sclerosis.

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) kappa free light chains (FLCs) may be a more sensitive marker of intrathecal immunoglobulin (Ig)G synthesis compared with oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a multiple sclerosis (MS) diagnosis in a group of OCB-negative patients with suspected MS. METHODS: The CSF and serum kappa and lambda FLCs were tested using the Freelite kit (serum) and Freelite Mx (CSF) assay (The Binding Site Group, Bimingham, UK) in 391 OCB-negative patients with suspected/possible MS and in 54 OCB-positive patients with MS. RESULTS: The CSF kappa FLC levels were below the detection limit (0.27 mg/L) in 61% of patients. Using quantitative data, we found the best kappa index cut-off value for the prediction of MS to be 5.8. A kappa index ≥5.8 was present in 25% of OCB-negative MS (23/92) and in 98% of OCB-positive patients with MS. Using a qualitative approach and a kappa index cut-off of 5.9, based on literature data, we likewise found that 24% of OCB-negative patients with MS had a kappa index ≥5.9, compared with 5.4% of OCB-negative patients without MS (P < 0.001). No reliable data could be obtained for the lambda index; lambda FLCs were below the detection limit (0.68 mg/L) in 90% of CSF samples. CONCLUSIONS: The kappa index could contribute to the identification of OCB-negative patients with a high probability of an MS diagnosis. Using more sensitive techniques might even improve the diagnostic performance of the kappa index and better define the role of the lambda index.

Neurosteroids and epileptogenesis.

Epileptogenesis is defined as the latent period at the end of which spontaneous recurrent seizures occur. This concept has been recently re-evaluated to include exacerbation of clinically-manifested epilepsy. Thus, in patients affected by pharmacoresistant seizures, the progression toward a worse condition may be viewed as the result of a durable epileptogenic process. However, the mechanism potentially responsible for this progression remains unclear. Neuroinflammation has been consistently detected both in the latent period and in the chronic phase of epilepsy, especially when brain damage is present. This phenomenon is accompanied by glial cell reaction, leading to gliosis. We have previously described rats presenting an increased expression of the cytochrome P450 cholesterol side-chain cleavage (P450scc) enzyme, during the latent period, in glial cells of the hippocampus. The P450scc enzyme is critically involved in the synthesis of neurosteroids and its up-regulation is associated with a delayed appearance of spontaneous recurrent seizures in rats that experienced status epilepticus induced by pilocarpine. Moreover, by decreasing the synthesis of neurosteroids able to promote inhibition, such as allopregnanolone, through the administration of the 5α-reductase blocker finasteride, it is possible to terminate the latent period in pilocarpine-treated rats. Finasteride was also found to promote seizures in the chronic period of epileptic rats, suggesting that neurosteroids are continuously produced to counteract seizures. In humans, exacerbation of epilepsy has been also described in patients occasionally exposed to finasteride. Overall, these findings suggest a major role of neurosteroids in the progression of epilepsy and a possible antiepileptogenic role of allopregnanolone and cognate molecules.

Neuroethological approach to frontolimbic epileptic seizures and parasomnias: The same central pattern generators for the same behaviours.

The aim of this report is not to make a differential diagnosis between epileptic nocturnal seizures and non-epileptic sleep-related movement disorders, or parasomnias. On the contrary, our goal is to emphasize the commonly shared semiological features of some epileptic seizures and parasomnias. Such similar features might be explained by the activation of the same neuronal networks (so-called 'central pattern generators' or CPG). These produce the stereotypical rhythmic motor sequences - in other words, behaviours - that are adaptive and species-specific (such as eating/alimentary, attractive/aversive, locomotor and nesting habits). CPG are located at the subcortical level (mainly in the brain stem and spinal cord) and, in humans, are under the control of the phylogenetically more recent neomammalian neocortical structures, according to a simplified Jacksonian model. Based on video-polygraphic recordings of sleep-related epileptic seizures and non-epileptic events (parasomnias), we have documented how a transient "neomammalian brain" dysfunction - whether epileptic or not - can 'release' (disinhibition?) the CPG responsible for involuntary motor behaviours. Thus, in both epileptic seizures and parasomnias, we can observe: (a) oroalimentary automatisms, bruxism and biting; (b) ambulatory behaviours, ranging from the classical bimanual-bipedal activity of 'frontal' hypermotor seizures, epileptic and non-epileptic wanderings, and somnambulism to periodic leg movements (PLM), alternating leg muscle activation (ALMA) and restless legs syndrome (RLS); and (c) various sleep-related events such as ictal fear, sleep terrors, nightmares and violent behaviour.

Early-onset dementia with prolonged occipital seizures: an atypical case of Kufs disease.

OBJECTIVE: Kufs disease is the adult-onset form of neuronal ceroid lipofuscinosis (NCL). Its two clinical phenotypes are type A (progressive myoclonus epilepsy with dementia) and type B (behavioral abnormalities and dementia, associated with pyramidal and extrapyramidal signs). METHODS: We describe the clinical evolution of an atypical case characterized by progressive dementia and focal occipital seizures. RESULTS: A healthy 37-year-old woman began showing memory deficits and behavioral disturbances (apathy, lack of inhibitions, untidiness). After 4 years, she developed rare clusters of tonic-clonic seizures, as well as focal seizures originating from the temporo-occipital regions, clinically associated with visual hallucinations, wandering, and agitation. When she was 44 years old, neuropsychological assessment revealed severe frontotemporal dementia. MRI showed cortical atrophy and, on T2-weighted images, hypointensity of the basal ganglia, and hyperintensity and reduction of the deep white matter. On the basis of these findings, a diagnosis of Kufs disease was hypothesized. A skin biopsy was negative, but electron microscopy examination of a right frontal lobe brain biopsy revealed the presence of typical storage material (fingerprint inclusions). The patient never developed myoclonus or extrapyramidal signs. DISCUSSION: Kufs disease is difficult to diagnose on account of its heterogeneous clinical pattern and pathologic features, and the lack of a specific genetic locus alteration. The neuropsychological pattern and MRI findings observed in patients with early-onset frontotemporal dementia and seizure disorder suggest that Kufs disease should be considered in their differential diagnosis. Extracerebral biopsy can be nondiagnostic, and when alternative diagnoses have been ruled out, cerebral biopsy should be considered.

Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach.

Central pattern generators (CPGs) are genetically determined neuronal aggregates in the mesencephalon, pons and spinal cord subserving innate motor behaviours essential for survival (feeding, locomotion, reproduction etc.). In higher primates CPGs are largely under neocortical control. We describe how certain motor events observed in parasomnias and epileptic seizures could have similar features and resemble motor behaviours, which can be the expression of the same CPG. Both epilepsy and sleep can lead to a temporary loss of control of neomammalian cortex that facilitates through a common platform (arousal) the emergences of stereotyped inborn fixed action patterns. Therefore we suggest that, independently from the nature of the trigger, be it a seizure or a parasomnia, the same CPGs can be involved, "caught up", leading to a common motor semiology (the "Carillon theory").

Rhythmic teeth grinding induced by temporal lobe seizures.

The authors report the clinical and polygraphic features of rhythmic teeth grinding observed in a patient as the predominant symptom related to temporal lobe seizures during sleep and wakefulness. This observation demonstrates that exceptionally a teeth-grinding event can be not only a parasomnia (sleep bruxism) but also an epileptic-related motor event. Electromyographic and autonomic features of seizure-related teeth grinding support the interpretation of this motor phenomenon as a particular form of masticatory activity.

Atypical familial motor neuropathy in patients with mutant TTR Ile68Leu.

Two sisters from an Italian family shared progressive motor symptoms, preceding the onset of sensory and autonomic disturbances. The familial occurrence of axonal and slowly progressive polyneuropathy led us to consider these patients as candidates for TTR molecular analysis. We found a missense mutation causing Ile68Leu TTR substitution in both. The aims of this work are to report the possibility of a motor onset of amyloid polyneuropathy and to suggest the search for TTR mutations in familial cases of axonal polyneuropathy. Second, to stress the possible occurrence of amyloid within the spinal canal as the potential pathogenesis and responsible for motor presentation.

Impaired facial emotion recognition in early-onset right mesial temporal lobe epilepsy.

BACKGROUND: Anteromedial temporal lobe regions, particularly the amygdala, participate in the recognition of emotions from facial expressions. The authors studied the ability of facial emotion recognition (ER) in subjects with symptomatic epilepsy, evaluating whether mesial temporal lobe damage is related to an impairment in the recognition of specific emotions and whether the onset of seizures in a critical period of life could prevent the development of ER. METHODS: Groups included patients with temporal lobe epilepsy (TLE) with MRI evidence of mesial temporal sclerosis (MTS) (n = 33); patients with TLE with MRI evidence of temporal lobe lesions other than MTS (n = 30); and patients with extratemporal epilepsy (n = 33). Healthy volunteers (n = 50) served as controls. ER was tested by matching a facial expression with the name of one of the following basic emotions: happiness, sadness, fear, disgust, and anger. A face-matching task was used to control visuoperceptual abilities with face stimuli. RESULTS: No subject showed deficits in the face-matching task. ER was impaired in patients with right MTS, especially for fearful faces. Patients presenting left MTS, right or left temporal lobe lesions other than MTS, or extratemporal seizure foci showed ER performances similar to controls. In all subjects with right TLE, the degree of emotion recognition impairment was related to age at first seizure (febrile or afebrile) and age at epilepsy onset. CONCLUSIONS: Early-onset right-sided mesial temporal lobe epilepsy is the key substrate determining a severe deficit in recognizing emotional facial expressions, especially fear.

Early ictal speech and motor inhibition in fronto-mesial epileptic seizures: a polygraphic study in one patient.

OBJECTIVE: To investigate ictal motor inhibition occurring during seizures in a patient with a tumor located in the left fronto-mesial pre-central cortex. METHODS: Awake and sleep video-polygraphic monitoring, recording scalp EEG and EMG activities from several cranial, trunk and limbs muscles, was performed in a patient with drug-resistant recurrent focal motor seizures before surgical treatment. Speech/motor tasks were repeatedly administered to the patient during the recording sessions in order to evaluate the occurrence of early ictal motor inhibition. RESULTS: Thirty-four seizures were recorded during wakefulness showing a stereotyped pattern of inhibition of speech and voluntary movements followed by sequential activation of upper limb-trunk-lower limb muscles contralateral to the tumor. Polygraphic recordings showed that: (1) initial speech and motor arrest were associated with the EMG evidence of progressive muscle tone suppression in cranial and right distal upper limb muscles; (2) tonic contraction of right deltoid, biceps brachii, intercostalis and paraspinalis muscles appeared after motor inhibition; (3) tonic-clonic activity in the right tibialis anterior muscle occurred at the end of seizures. Eleven subclinical seizures were recorded during sleep showing mild focal tonic EMG activity in right side trunk muscles. CONCLUSIONS: Our findings evidenced early and somatotopically organized inhibition of voluntary movement at the beginning of epileptic seizures with fronto-mesial onset. The demonstration that speech and motor arrest were associated with progressive EMG suppression in cranial and limb muscles supports the hypothesis of motor inhibitory seizures originating in the mesial aspect of pre-motor frontal cortex.

Motor pattern of periodic limb movements in sleep in idiopathic RLS patients.

OBJECTIVE: Periodic limb movements in sleep (PLMS) are recurrent sleep-related movements that often occur in association with restless legs syndrome (RLS). The purpose of the present study was to examine the pathophysiology of PLMS in patients with idiopathic RLS. METHODS: Ten patients with idiopathic RLS who were medication-free or who had withdrawn from medication at least 2 weeks prior to the study underwent an extensive neurophysiological investigation that included nocturnal video-polysomnographic recording (VPSG), EMG recording, and the Multiple Sleep Latency Test (MSLT). Sleep efficiency and PLMS index were calculated during VPSG. RESULTS: All patients had an increased PLMS index, decreased sleep efficiency, and a pathological MSLT score. Leg muscles were the first to be activated, often with alternation of side, and no constant recruitment pattern could be found from one episode of PLMS to another, even in the same patient. No ordinate caudal or rostral spread of the EMG activity was observed. CONCLUSIONS: The results suggest that there are different, independent, and unsynchronized generators for PLMS. The direct participation of the cerebral cortex in the origin of PLMS is unlikely, suggesting that abnormal spinal cord hyperexcitability may act as the primary cause of PLMS, triggered by unidentified sleep-related factors.

Leber's hereditary optic neuropathy (LHON/11778) with myoclonus: report of two cases.

The previously unrecognised association of myoclonus in two patients with LHON with the 11778/ND4 pathogenic mutation is described. EEG failed to disclose epileptic figures, and a back averaging study suggested that myoclonus was cortical in origin in both patients.

Propriospinal myoclonus at the sleep-wake transition: a new type of parasomnia.

STUDY OBJECTIVES: To describe the clinical, neurophysiological, and polysomnographic characteristics of propriospinal myoclonus (PSM) at the sleep-wake transition. DESIGN: Patients referred for insomnia due to myoclonic activity arising during relaxed wakefulness preceding sleep, or complaining of muscular jerks also during intrasleep wakefulness and upon awakening in the morning were considered. SETTING: All patients underwent EEG-EMG recordings during wakefulness and night sleep. Back-averaging of the EEG activity preceding the jerks was performed. Somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS) and spinal and cranial MRI were also done. PARTICIPANTS: Four patients were studied all affected with involuntary jerks arising when falling asleep, and one with jerks also during sleep and upon awakening in the morning. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Polysomnographic investigations revealed jerks arising during the sleep-wake transition period. Myoclonic activity was neurophysiologically documented to be of the propriospinal type. SEPs, TMS and MRI were normal CONCLUSIONS: PSM may have a peculiar relationship with the state of vigilance and represent a sleep-wake transition disorder. In this regard we consider PSM a new type of parasomnia.