Non-motor symptoms and cardiac innervation in SYNJ1-related parkinsonism.

INTRODUCTION: PARK20 is a rare autosomal recessive parkinsonism related to the SYNJ1 gene and characterized by early-onset of disease and atypical signs such as supranuclear vertical gaze palsy, dementia, dystonia, and generalized tonic-clonic seizures. OBJECTIVE: Non-motor features and cardiac sympathetic innervation were assessed in two siblings affected by parkinsonism who harboured the homozygous Arg258Gln mutation in the SYNJ1 gene. METHODS: The Non-Motor Symptoms, the SCOPA-AUT, the Mayo Sleep Questionnaires and polysomnography were used to investigate non-motor signs (NMS), autonomic dysfunction and REM Behavioural Disorder (RBD). Cognitive functions were examined by an extensive battery of neuropsychological tests. In addition, motor and sensory nerve conduction studies and evoked laser potentials were performed. Cardiac sympathetic innervation was assessed in the two patients by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, computing early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR). RESULTS: Among the non-motor symptoms and autonomic signs, case 1 had cold intolerance, drooling and dysphagia, while case 2 had pain and urinary dysfunction. Both cases showed mood and behavioural disorders. RBD were not found, whereas the neuropsychological assessment revealed a progressive cognitive impairment. Neurophysiological studies revealed no abnormalities. Indexes of cardiac sympathetic innervation in the two patients did not differ from those of control subjects. CONCLUSIONS: Our findings expand the phenotypic profile of SYNJ1-related parkinsonism. Preserved cardiac sympathetic function and absence of RBD suggest that PARK20 should be explained by a pathogenic mechanism different from Lewy Body pathology, or that the latter is not as widespread as idiopathic Parkinson's disease.

Characterization of reproductive endocrine disorders in women with epilepsy.

An increased frequency of reproductive endocrine disorders has been reported in women with epilepsy. A possible role of the seizure disorder or, alternatively, of the use of antiepileptic drugs (AEDs) has been suggested as the pathogenic mechanism. The aim of the present study was to assess the frequency of reproductive endocrine disorders in a series of women with epilepsy, examining the possible relationships of these disturbances with different epilepsy syndromes and AED treatment. Fifty epileptic women, all of reproductive age and none pubertal, pregnant, or lactating, were submitted to clinical endocrinological evaluation, hormonal assessment, and ovarian ultrasonography. Subjects with abnormal findings in this preliminary study underwent additional evaluations. Reproductive endocrine disorders were diagnosed in 16 (32%), consisting of polycystic ovary syndrome in 13, hypothalamic amenorrhea in 2, and luteal phase deficiency in 1. There was no significant association of these disturbances with epilepsy type or AED treatment. Patients with reproductive endocrine disorders often showed delayed ovulation with shortened luteal phase. The results of this study suggest that the prevalence of disordered ovulation, in particular polycystic ovary syndrome, is increased in epilepsy, independent of antiepileptic medications or type of seizure disorder.

Abnormal pattern of luteinizing hormone pulsatility in women with epilepsy.

Dysfunction of the hypothalamic-pituitary-ovarian axis in epileptic females has been suggested in the latest years. To further elucidate this issue, we assessed reproductive endocrine function in 10 normally cycling, drug-free epileptic women and in 5 normal controls, evaluating the basal hormonal profile and luteinizing hormone (LH) pulsatility in the midfollicular phase. Luteinizing hormone pulse frequency was significantly higher in epileptic women with a consequent reduction of the LH interpulse interval. We suggest that epilepsy may interfere with the functional activity of the gonadotropin-releasing hormone pulse generator. The pathogenetic mechanisms for this phenomenon may be the spreading of paroxysmal activity within the hypothalamic areas or, alternatively, a neurotransmitter dysfunction giving rise both to the seizure disorder and to the abnormal LH pulsatile pattern.

Epilepsia arithmetices: study of four cases.

In a 12-year period, in a total of about 2000 new patients referred to our Epilepsy Centre, we observed four patients with seizures exclusively or predominantly triggered by calculation or by card and board games (epilepsia arithmetices, EA). In agreement with observations reported in the literature, all the patients suffered from idiopathic generalized epilepsy (IGE), and probably from juvenile myoclonic epilepsy of Janz. In only one patient was it possible, during arithmetic tasks of increasing difficulty and stress, to evoke electroencephalographic (EEG) paroxysmal discharges, progressively increasing to clinical seizures. In the remaining patients the diagnosis of EA was exclusively clinical, as it was not possible to record EEG interictal or ictal paroxysmal activity specifically triggered by arithmetic tasks. Consequently, it is emphasized that in some cases the diagnosis of EA in a patient with IGE may be based exclusively on clinical criteria. As reported in the literature, it is possible to observe during mathematical calculation or during games both clinical (myoclonic jerks of the right hand) and EEG (localized small spikes) focal signs, which suggest a localized activation of specific areas in a patient with IGE.

Transient global amnesia of epileptic origin accompanied by fever.

The case of a previously healthy 69-year-old female patient is described who presented, in a period of 6 months, 3 long-lasting (from 2 hour- to 10 hour-duration) episodes of transient global amnesia accompanied by a temperature rise. During one of these episodes an EEG was obtained, showing a diffuse alteration, focal slowing, and bitemporal asynchronous paroxysmal activity giving rise to electrical ictal discharges. Interictal EEGs were normal. Cerebral computed tomography was normal. Carbamazepine was given with complete control of the attacks. These episodes may be interpreted as complex partial status with unusual semeiology.

Derangement of the hypothalamic GnRH pulse generator in women with epilepsy.

An increased frequency of reproductive endocrine diseases has been described in women with epilepsy and a subclinical reproductive dysfunction has been suggested in normally menstruating epileptic women. We assessed the reproductive endocrine function in 11 normally menstruating, drug-free epileptic women, evaluating the basal hormonal profile and LH pulsatile secretion during continuous EEG monitoring. A significant LH hyperpulsatility was observed in epileptic women compared with controls; moreover, a significant increase of gonadotropin basal secretions was observed when inter-ictal paroxysmal activity increased. The derangement of the hypothalamic GnRH pulse generator may represent a subclinical condition associated with epilepsy, not necessarily affecting the regularity of menstrual function. However, it is possible that the alteration of LH pulsatile pattern might eventually cause reproductive endocrine diseases. Paroxysmal activity seems to be an important additional factor in the derangement of gonadotropin secretion.

The role of dural sinus stenosis in idiopathic intracranial hypertension pathogenesis: the self-limiting venous collapse feedback-loop model.

In recent years the efficacy of endovascular venous stenting in idiopathic IIH treatment has been consistently reported, strongly suggesting that sinus stenosis should be viewed as a causative factor rather than a secondary phenomenon. We propose that in subjects carrying one or more collapsible segments of large cerebral venous collectors and exposed to a number of different promoting factors, sinus venous compression and cerebrospinal fluid (CSF) hypertension may influence each other in a circular way, leading to a new relatively stable venous/CSF pressures balance state at higher values. The mechanism relay on self-limiting venous collapse (SVC) feedback-loop between the CSF pressure, that compresses the sinus, and the consequent venous pressure rise, that increases the CSF pressure. The result is the "coupled" increase of both pressure values, a phenomenon not expected in presence of sufficiently rigid central veins. Once the maximum stretch of venous wall is reached the loop stabilize at higher venous/CSF pressure values and become self-sustaining, therefore persisting even after the ceasing of the promoting factor. Notably, the SVC is reversible provided an adequate perturbation is carried to whichever side of the loop such as sinus venous stenting, on one hand, and CSF diversion or even a single CSF withdrawal by lumbar puncture (LP), on the other. The SVC model predicts that any condition leading to an increase of either, cerebral venous pressure or CSF pressure may trigger the feedback loop in predisposed individuals. Migraine with and without aura, a disease sharing with IIH a much higher prevalence among women of childbearing age, is associated with waves of significant brain hyperperfusion. These may lead to the congestion of large cerebral venous collectors and could represent a common SVC promoting condition in susceptible individuals. The SVC model give reason of the high specificity and sensitivity of sinus stenosis as IIH predictor and of the multiplicity of the factors that have been found associated with IIH. Moreover it might explain why, among the sinus stenosis carriers, young and overweight women are at higher risk of developing the disease. Finally, the SVC model fully explain the enigmatic longstanding remissions that can be commonly observed after a single LP with CSF subtraction in IIH with or without papilledema.

Voxel-based morphometry in patients with cryptogenic occipital epilepsies. Preliminary data.

We evaluated the differences in grey matter concentration (GMC) by voxel-based morphometry (VBM) in patients with cryptogenic occipital epilepsies. VBM analysis was performed in 11 patients with cryptogenic occipital epilepsies compared to 11 healthy controls. VBM analysis in patients revealed focal areas of reduced GMC in the occipital cortex and, more interestingly, increased GMC in the midbrain tegmentum and basal ganglia (globus pallidus and thalamus). VBM may disclose slight structural abnormalities in the brain of cryptogenic epilepsy patients, not evident with standard MRI. To the best of our knowledge, this is the first literature report describing areas of altered GMC in patients with occipital epilepsy. We hypothesize that these findings might be related to epileptic discharges and/or their diffusion and suggest that midbrain, globus pallidus and thalamus may be part of a functional network originating from the occipital areas.

Migraine and epilepsy: clinical and pathophysiological relations.

Migraine and epilepsy are both chronic disorders characterised by recurrent neurological attacks, with a partial clinical and therapeutic overlap and frequently occurring together. Although still incompletely clarified, the possible existence of a link between migraine and epilepsy has long been debated. In this paper the epidemiologic evidence of migraine and epilepsy comorbidity, the possible occurrence of both disturbances in close temporal association, possible shared physiopathologic mechanisms and the rationale for antiepileptic drug use in migraine prophylaxis will be discussed.

Epilepsy and polycystic ovary syndrome: where is the link?

Several reports in the literature describe an increased prevalence of polycystic ovary syndrome (PCOS) in women with epilepsy. The possible pathogenesis of the association between epilepsy and PCOS is not clear yet, and different hypotheses have been proposed: while some authors suggest that epilepsy may affect the hypothalamic control of reproductive function, others propose a pathogenic role of the antiepileptic drug valproate. In this article we review the literature on the subject, and propose a pathogenic theory in which both epilepsy and valproate play different and significant roles in inducing reproductive endocrine disturbances in women with seizures.

An unusual case of Kleine-Levin syndrome associated with sleep terrors.

The authors describe a case of Kleine-Levin syndrome (KLS) which in the hypersomniac period presents, together with the classical symptoms, frequent arousals accompanied by sleep terrors. Polygraphic study shows the absence of any nyctohemeral cycle and very frequent parasomnias occurring during arousals from NREM sleep. On the basis of data from the literature, the authors suggest that a disturbance of maintenance of sleep might not be exceptional in KLS, even if none of the previous reports describes such frequent parasomnias.

Sleep apnea syndrome in Thomsen's disease. A case report.

The authors describe the occurrence of a sleep-induced apnea syndrome with daytime hypersomnolence in a patient suffering from Thomsen's disease. Polysomnography showed, during the whole sleep, repetitive obstructive, and rarely mixed, apneas. The patient also had daytime alveolar hypoventilation, primarily obstructive, and waking chronic hypercapnia. Long-term diphenylhydantoin therapy relieved not only myotonia, but sleep-induced apneas, daytime sleepiness and waking breathing as well. This result, together with some EMG features recorded during sleep and with daytime obstructive hypoventilation, suggests that myotonia could be one of the pathogenic factors involved in nocturnal upper airway stenosis.

Recurrent frontal status epilepticus with polymorphic clinical features. A case report.

A patient who, two years after the surgical excision of a right frontal astrocytoma, presented with recurrent episodes of Partial Status Epilepticus of long duration is described. Ictal manifestations are initially inconspicuous from a clinical standpoint, but are accompanied by a marked interictal impairment of consciousness. The EEGs show a persistent depression of the background activity and very frequent subclinical right frontal discharges. Successively, seizures become more evident with polymorphic features (versive, oculoclonic, somatomotor, autonomic, automatic, laughing manifestations). The difficulties of an early definition of the clinical picture and the diagnostic importance of the EEG study are stressed, together with other peculiar features (polymorphism of seizures, difficulties of management, progressive mental impairment occurring after every episode of Status Epilepticus).

[The physiopathology of supranuclear structures in oculomotor disorders]. / Disordini sopranucleari dei movimenti oculari. Fisiopatologia, Semeiologia e valorie topodiagnostico.

Several structures, located at different levels in the Central Nervous System (CNS), collaborate to the control and realization of ocular movements (O.M.) Therefore, alterations of oculomotricity, of varying degree and of different kinds, may be found in a lot of diseases of the CNS. The study of O.M., expecially when carried out by means of specific techniques such as electro-oculography, may represent an useful tool in the diagnosis (both from a topographic and an etiological standpoint) and in the follow-up of patients, possibly also allowing a precise evaluation of therapy effectiveness. In this review the Authors briefly examine the role of the supranuclear structures mostly involved in the control and in the execution of oculomotricity and the characteristics of the different types of O.M. (rapid and slow, vergence movements). Successively, they analyze the semeiological features of supra-nuclear disturbances of O.M., describing alterations of saccadic movements (slowing, dysmetria) and of smooth pursuit, fixation instability (square waves, flutter, opsoclonus, nystagmus,...) and other alterations of O.M. (ocular bobbing, see-saw nystagmus, skew deviation,...). Successively, disturbances of O.M. are analyzed in relation to their topodiagnostic significance, describing oculomotor involvements due to focal lesions of different areas of CNS (frontal cortex, parieto-occipital cortex, basal ganglia, cerebellum, brainstem) and particular syndromes (Foville syndromes, locked-in syndrome, Parinaud syndrome, anterior internuclear ophthalmoplegia, "one and a half" syndrome, Balint syndrome,...). Finally, particular attention is drawn to the oculomotor disturbances observed in degenerative cerebellar and multisystemic diseases, and several abnormal "oculomotor patterns", which seem to be specifically related to particular diseases, are described. In particular, the oculomotor patterns of Steele-Richardson-Olszewsky disease (slowing and hypometria of horizontal saccades, loss of upward saccades with preservation of reflex movements) and of Friedreich ataxia (fixation instability mostly due to the occurrence of square waves, saccadic dysmetria, impairment of smooth pursuit) are stressed.

The use of EEG activating procedures in epileptology.

Epileptic seizures and EEG interictal paroxysmal activity (PA) usually occur in an apparently unpredictable fashion, and a small number of patients with truly epileptic seizures may not present any PA on repeated EEGs. With the aim of increasing the possibility of recording interictal or ictal PA, several activation procedures are routinely carried out. In rarer instances, seizures seem to be more or less specifically evoked by unusual triggering procedures, or are chronologically related to biological rhythms. These different activating procedures may have different effectiveness depending on the type of epileptic syndrome. In the present paper the Authors describe the different activating procedures, both routinely employed and unusual ones. Their possible differential use with regard to the different epileptic syndromes and to the specific epileptologic history of the patient are examined. A selective use of these procedures is suggested, as an accurate choice of such techniques may increase the diagnostic usefulness of the EEG, in particular in patients whose basal recording is not contributory.

Reduced fertility and neuroendocrine dysfunction in women with epilepsy.

A reduction of fertility in women with epilepsy has been reported since 1950 and is confirmed in recent epidemiological studies. This phenomenon has usually been attributed to the increase of medical and socioeconomic problems in these patients or to hyposexuality, which has been consistently observed in epileptic subjects. Recently, a higher occurrence of reproductive endocrine diseases has been reported in epileptic women and proposed as an important cause of reduced fertility. In particular, polycystic ovary syndrome and hypothalamic ovarian failure have been reported in epileptic women with increased frequency compared to the general population. Moreover, an abnormal pattern of luteinizing hormone (LH) pulsatility has been observed in normally cycling, drug-free epileptic women. We suggest that epilepsy may interfere with the functional activity of the gonadotropin releasing hormone (GnRH) pulse generator. It is possible that paroxysmal discharges spreading within the hypothalamus might affect the regularity of the GnRH pulse generator; alternatively, a neurotransmitter dysfunction might at the same time be responsible both for the lowering of the seizure threshold and for the dysfunction of GnRH secretion. The consequent alteration of LH pulsatility might in the long run, under the effect of additional factors, give rise to a clinical reproductive endocrine disorder.

Hearing loss associated with progressive ataxia (Lichtenstein-Knorr disease?). Report of a sporadic case with peculiar neuroradiological findings.

A sporadic case of hearing loss with ataxia, clinically suggesting Lichtenstein-Knorr disease, is described. Magnetic Resonance (MR) shows an involvement of the white matter, which appears diffusely reduced and abnormal, together with a peculiar tickening of the grey matter. The possible relationships with leukodystrophies and with generalized cortical dysplasias are discussed. To our knowledge, MR imaging has never been performed in Lichtenstein-Knorr disease.

Venous angiomas and epilepsy.

The purpose of this study was to evaluate the frequency and characteristics of epilepsy associated with cerebral venous angiomas (VA). We examined epileptic patients in which magnetic resonance imaging (MRI) showed VA. The characteristics of epilepsy and its relationships to VA were studied. Out of 1020 epileptic patients submitted to MRI in a 10-year period, 4 presented with VA. All had partial seizures, most frequently complex partial, with secondary generalizations in 3. Drug resistance was observed in 2. One patient had a small area of cortical dysplasia near the VA; another had a cutaneous angioma. In 2 patients, there was no topographic concordance between the VA and the focus on electroencephalography. Our study reveals that VA are rarely found in epileptic patients, differently from other vascular malformations, in particular cavernomas. Topographic and/or etiological relationships between VA and epilepsy are still undefined.

Reproductive endocrine disorders in women with primary generalized epilepsy.

It is known that women suffering from temporal lobe epilepsy may frequently present reproductive endocrine disorders (REDs). We hypothesized that a high occurrence of REDs could be found also in primary generalized epilepsy (PGE), and therefore investigated the hormonal and ovarian echographic profiles in 20 PGE female patients of reproductive age. Fourteen reported normal menstrual cycles, while 6 complained of longstanding menstrual irregularities. All but three patients were receiving antiepileptic drug (AED) therapy. In all subjects, the basal levels of gonadotropins, prolactin, and gonadal steroids were assayed. The response of luteinizing hormone (LH) to gonadotropin-releasing hormone was also investigated and ovarian ultrasonographic findings were evaluated. In five of six patients with menstrual problems (25% of the group), a well-defined RED was diagnosed (polycystic ovarian disease in three cases and hypothalamic ovarian failure in two). The 14 patients with normal menstrual cycles showed an elevation of mean basal follicle-stimulating hormone and prolactin, and a blunting of mean LH response. Our results suggest that a high occurrence of REDs may be found also in PGE. We hypothesize that a neurotransmitter dysfunction might be the common pathogenetic mechanism resulting in both REDs and PGE. The hormonal alterations observed in the patients with normal menstrual cycles seem to support our hypothesis. Previous data seem to rule out a possible AED effect accounting for the hormonal findings observed in our series. However, further studies are needed to confirm our preliminary results.