Marco Fedi

Reduced striatal D1 receptor binding in autosomal dominant nocturnal frontal lobe epilepsy

Background: Mutations of the neuronal nicotinic acetylcholine (nACh) receptor identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) lead to increased sensitivity to ACh. As activation of presynaptic nicotinic receptors augments the release of dopamine in the striatum and the prefrontal regions, we tested the hypothesis that that the α4-Ser248Phe mutation affects dopaminergic transmission. Methods: We measured D1 receptor binding using [11C]-SCH23390 and PET in 12 subjects with the α4-Ser248Phe mutation (3 men, mean age 41 ± 16 years) and 19 controls (8 men, mean age 36 ± 13 years) matched for gender, smoking status, and age. Parametric images were produced using the simplified reference region method. Both MRI-based regions of interest and voxel based analyses were used. Results: Reduced striatal [11C]-SCH23390 binding occurred with the mutation (controls 1.1 ± 0.1; ADNFLE 0.97 ± 0.2; p < 0.01). Statistical parametric mapping confirmed a region of reduced [11C]-SCH23390 binding in the right putamen in α4-Ser248Phe subjects compared to controls (309 voxels, local maxima 20 16 −2 mm; Zscore 3.57, p < 0.05). Conclusions: Reduced D1 receptor binding may represent increased extracellular dopamine levels or, more likely, receptor downregulation. Alterations in mesostriatal dopaminergic circuits may contribute to nocturnal paroxysmal motor activity in autosomal dominant nocturnal frontal lobe epilepsy.

A GABAA receptor mutation causing generalized epilepsy reduces benzodiazepine receptor binding

Understanding the consequences of newly discovered single gene mutations causing human epilepsy has the potential to yield new insights into the underlying mechanisms of this disorder. A mutation of the gamma2 subunit of the GABA(A) receptor, which substitutes glutamine for arginine at position 43 (R43Q) has been found in a familial generalized epilepsy. We tested the hypothesis that individuals affected by the GABRG2(R43Q) mutation have reduced binding to the GABA(A) receptor complex using positron emission tomography (PET) and the benzodiazepine receptor ligand [(11)C]-flumazenil. Fourteen subjects with the GABRG2(R43Q) mutation and 20 controls were studied. Benzodiazepine receptor binding was reduced in subjects with the mutation (mean whole brain binding potential for [(11)C]-flumazenil: GABA(A) mutation 0.66+/-0.1; controls 0.89+/-0.1; P<0.003). The greatest change in benzodiazepine binding occurred anteriorly, with peak differences in insular and anterior cingulate cortices revealed by statistical parametric mapping. Our findings provide in vivo evidence of reduced benzodiazepine receptor binding in subjects with the mutation. As synaptic inhibition in the human brain is largely mediated by the GABA(A) receptor, these findings are likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.

Exercise-induced temporal lobe epilepsy

Although precipitation of seizures by exercise has been described, the reproducible induction of temporal lobe seizures by exercise is unusual. The authors report two patients with left temporal lobe seizures induced by exercise. In one patient the family history suggested autosomal-dominant inheritance. Prolonged hyperventilation, simple movements, and visualization of a competitive game did not produce epileptiform discharges on the interictal EEG.

Glioneuronal tumours in neurofibromatosis type 1: MRI-pathological study.

Neurofibromatosis type 1 (NF1) is an inherited disorder in which affected individuals develop both benign and malignant tumours at an increased frequency. Glioneuronal tumours, such as ganglioglioma and dysembryoplastic neuroepithelial tumour, have been previously reported in patients with NF1. We describe two patients with glioneuronal tumours and typical clinical features of NF1. Molecular analysis of these tumours did not demonstrate loss of the NF1 gene by fluorescence in situ hybridization (FISH) or immunohistochemistry analysis, suggesting they might not be causally associated with gross defects in NF1 expression. Because of the excellent prognosis following the resection of these tumours, it is important to distinguish them from other NF1-associated tumours.

Spontaneous intracranial hypotension presenting as a reversible dorsal midbrain syndrome

A 47-year-old woman with postural headache, episodic stupor, and vertical gaze palsy had brain imaging findings consistent with spontaneous intracranial hypotension (SIH), including severe descent of the mesodiencephalic structures and diffuse pachymeningeal enhancement. The source of the cerebrospinal fluid leakage was a ruptured dorsal perineural cyst. Clinical symptoms improved after a targeted epidural blood patch was performed. Dorsal midbrain syndrome has not been reported previously as a manifestation of SIH. Perhaps distortion of structures in this brain region can occur in SIH as it does in obstructive hydrocephalus.

Cystic meningioangiomatosis in neurofibromatosis type 2: an MRI–pathological study

We report cerebral cystic meningioangiomatosis in a patient with neurofibromatosis type 2. An 18-year-old woman presented with progressive hemiparesis secondary to a meningioma at the foramen magnum. Her MR examination also demonstrated three small cortical and subcortical cystic lesions. She underwent surgery for the meningioma, but died from brainstem infarction. Post-mortem histopathological examination of the cystic lesions showed enlarged subcortical perivascular spaces with overlying meningioangiomatosis. The unusual features and possible pathogenesis are discussed.

Neuropsychological function in patients with a single gene mutation associated with autosomal dominant nocturnal frontal lobe epilepsy.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a nonlesional condition associated with mutation of the gene coding for the alpha4 nicotinic acetylcholine receptor (nAChR). The nAChR modulates aspects of memory and attention. We examined the neuropsychological phenotype of ADNFLE, with a particular emphasis on understanding the impact on frontal lobe functions. We used standard clinical tests as well as focused measures of frontal lobe function in a well-defined group of patients with ADNFLE. Their performance was compared with that of a group of age-, sex-, and education-matched control participants. Patients with ADNFLE showed impairments on tasks requiring cognitive flexibility against a background of well-preserved intellectual abilities. In accord with existing research, verbal memory impairments were identified in the patient group; the level of impairment on these tasks correlated with disease-related factors. In our study of ADNFLE associated with one mutation, cognitive flexibility appears to be the core cognitive deficit.

The heat is on: a case of hyperthermia-induced posterior reversible encephalopathy syndrome (PRES).

Severe burn injury remains a major burden on patients and a significant health issue for the society. Following severe burns, patients develop a systemic inflammatory response (SIRS) and hypermetabolic phenomena [1, 2]. This can lead to severe hyperthermia which is resistant to commonly employed treatments. Experimental and clinical studies suggest that the central nervous system is exceptionally sensitive to thermal damage [3, 4]. We present a case of posterior reversible encephalopathy syndrome (PRES) in the setting of prolonged and severe hyperthermia ([40 C) and burns. The possible mechanisms and functional consequences of hyperthermic brain injury in this patient are discussed.

101 Dispelling the curse: improvement of ventilatory drive in central alveolar hypoventilation syndrome after medullary infarction

Introduction Central alveolar hypoventilation syndrome (CAHS) is a rare complication of stroke affecting the medullary respiratory centre. CAHS is characterised by impaired ventilatory response to CO2 leading to hypoventilation, hyper-capnoea and coma. Experimental studies have linked this syndrome to areas in the dorsal and ventrolateral medulla. CAHS is associated with long-term invasive ventilatory support, high mortality and morbidity. It is unclear whether sensitivity to CO2 can improve after the initial ischaemic medullary insult. Case A 78 year old woman presenting with CAHS secondary to a unilateral left posterior inferior cerebellar artery infarction. MRI images confirmed that dorsal and ventrolateral medullary areas were affected. The patient was intubated initially for hyper-capnoeic respiratory failure and required a tracheostomy for ongoing respiratory support. To assess progress of respiratory recovery, we measured the patient’s ventilatory response to PaCO2 at 5, 7, and 14 days of admission. Parameters recorded included PaO2, ETCO2, PaCO2, pH, respiratory rate, and minute ventilation. During this time the patient underwent progressive periods of unsupported ventilation with close monitoring. Statistical correlation between respiratory rate and CO2 was measured by Pearson’s correlation coefficient (R). Her RR initially did not increase with PaCO2 during spontaneous ventilation (R=0.2604 p=0.077). Apnoeic episodes were frequent up to 41 episodes per 30 min of observation lasting up to 30 s. On day 7(R=0.7203 p<0.05) and up to day 14 (R=0.6295 p<0.05), there was a progressive statistically significant improvement in positive correlation between PCO2 and respiratory rate. This was associated with a reduction in apnoeic episodes possibly reflecting a recovery in ventilatory drive. Conclusion This is the first detailed report demonstrating spontaneous recovery in CO2 responsiveness in the setting of CAHS secondary to unilateral medullary stroke. Plasticity of structures such as the retro-trapezoid nucleus are likely to play a role in recovery of CO2 sensitivity. References . Harper, et al. Functional neuroanatomy and sleep-disordered breathing: implications for autonomic regulation. Anatomical record2012;295(9):1385–95. . Mishina, et al. Efficacy of tracheostomy for central alveolar hypoventilation syndrome caused by lateral medullary infarction. Journal of Nippon Medical School2014;81(4):276–84.