Impact of the PSA-NCAM system on pathophysiology in a chronic rodent model of temporal lobe epilepsy

Polysialylation is a posttranslational modification of the neural cell adhesion molecule (NCAM). In the adult brain, polysialylated NCAM (PSA-NCAM) is restricted to regions of neurogenesis and neuroplasticity, where PSA promotes plastic changes. Because a variety of plastic changes including neurogenesis have been suggested to be functionally involved in the pathophysiology of epilepsies, it is of specific interest to define the impact of the PSA-NCAM system on development and progression of this disease and associated comorbidities. Here, we studied the impact of transient enzymatic depolysialylation of NCAM on the pathophysiology in the amygdala kindling model, a chronic rodent model of temporal lobe epilepsy. The investigations focused on seizure-induced neurogenesis, seizure progression, and on the development of kindling-associated changes in behavior and cognition. Loss of PSA decreased the number of hippocampal newborn cells that incorporated BrdU during the kindling process and the number of new neurons that were ectopically located in the hilus. The persistence of basal dendrites has been suggested to be a hallmark of newborn granule cells in the epileptic brain. Loss of PSA increased the number of cells with persistent basal dendrites. The modification of the hippocampal cell proliferation rate and the fate of newborn neurons which occurred as a consequence of PSA removal did not affect the generation of a hyperexcitable kindled network or associated behavioral changes. Kindling progression was comparable in rats with and without removal of PSA. In contrast, loss of PSA increased acute seizure susceptibility as indicated by reduced seizure thresholds before kindling. The data indicate that hippocampal proliferation rates and ectoptic hilar newborn neurons are less critical for epileptic network generation. The PSA-NCAM system was not substantiated as a target for antiepileptogenic strategies. However, its impact on ectopic newborn neurons gives evidence that modulation of PSA-NCAM function may be a strategy to promote neuroregeneration in different central nervous system insults.     

Influence of age, gender and severity of tremor on outcome after thalamic and subthalamic DBS for essential tremor

Deep brain stimulation (DBS) is an established treatment for essential tremor (ET). The nucleus ventralis intermedius thalami (Vim) is the target of choice, but promising results have been presented regarding DBS in the posterior subthalamic area (PSA). The aim of this study was to evaluate the possible influence of gender, age and severity of disease on the outcome of these procedures.Sixty eight patients (34 Vim, 34 PSA) with ET were included in this non-randomised study. Evaluation using the Essential Tremor Rating Scale (ETRS) was performed before, and one year after surgery concerning PSA DBS, and at a mean of 28 ± 24 months concerning Vim DBS. Items 5/6 and 11–14 (hand tremor and hand function) were selected for analysis of tremor outcome.The efficacy of DBS on essential tremor was not related to age or gender. Nor was it associated with the severity of tremor when the percentual reduction of tremor on stimulation was taken into account. However, patients with a more severe tremor at baseline had a higher degree of residual tremor on stimulation. Tremor in the treated hand and hand function were improved with 70% in the Vim group and 89% in the PSA group.     

Harmaline-induced tremor as a potential preclinical screening method for essential tremor medications.

No preclinical method to evaluate potential new medications for essential tremor (ET) is available currently. Although harmaline tremor is a well known animal model of ET, it has not found utility as a preclinical drug screen and has not been validated with anti-ET medications. We measured harmaline tremor in rats (10 mg/kg s.c.) and mice (20 mg/kg s.c.) with a load sensor under the cage floor and performed spectral analysis on 20-minute epochs. The motion power over the tremor frequency bandwidth (8-12 Hz in rats; 10-16 Hz in mice) was divided by the motion power over the full motion frequency range (0-15 Hz in rats; 0-34 Hz in mice). The use of these measures greatly reduced data variability, permitting experiments with small sample sizes. Three drugs that suppress ET (propranolol, ethanol, and octanol) all significantly suppressed harmaline-induced tremor. We propose that, with this methodology, harmaline-induced tremor may be useful as a preclinical method to identify potential medications for ET.     

Effect of Antiepileptic Drugs on Absence-Like Seizures in the Tremor Rat

Summary: We examined the effects of conventional antiepileptic drugs (AEDs) on absence-like seizures in homozygous tremor rats (tm/tm) to determine if they corresponded pharmacologically to human absence seizures and absence-like seizures in spontaneously epileptic rats (SER: zi/zi, tdtm) with both tonic convulsive and absence-like seizures. Cortical and hippocampal EEG activity was recorded with chronically implanted electrodes. The effects of AEDS on seizures of the tremor rat showed profiles similar to those observed in human absence seizures and also in absence-like seizures of SER. The absence-like seizures, associated with paroxysmal bursts of 5–7–Hz spike-wave complexes, were inhibited by trimethadione (TMO 200 mg/kg intraperitoneally, i.p.), ethosuximide (ESM100 and 200 mg/kg, i.p.), valproate (VPA100 mg/kg, i.p.), and phenobarbital (PB10 and 20 mg/kg, i.p.1. Phenytoin (PHT 20 mg/kg, i.p.) was ineffective. These results are consistent with the conclusion that the tremor rat is a useful model for evaluating new AEDS for human absence seizures.     

Benzodiazepine receptor binding in the spontaneously epileptic rat and its parent strains.

Central type benzodiazepine (BDZ) receptor binding in spontaneously epileptic rats (SER) and their parent strains, tremor rats and zitter rats, and Kyoto/Wistar rats were investigated. Significantly lower BDZ receptor densities (Bmax) and no differences in affinity (KD) were found in the hippocampus of the two epileptic strains, SER and tremor rats, in comparison with Kyoto/Wistar rats and zitter rats. This abnormality is considered to be due to a tremor gene and to be related to absence-like seizures in SER and tremor rats. A significant decrease of KD and an increase of Bmax in the brain stem were found in SER in comparison with Kyoto/Wistar rats. These changes may be due to a zitter gene, since zitter rats show the same tendency, and they may be related to tonic seizures in SER. Bmax was significantly increased in the cerebellum and hippocampus of the zitter rats, while KD was not changed, in comparison with Kyoto/Wistar rats and tremor rats. These changes may reflect the relatively selective loss of tissue lacking BDZ receptors or an upregulation in response to the loss of GABAergic neurons in zitter rats.     

Aberrant reduction of an inhibitory protein factor in a rat epileptic model

Certain forms of seizure involve excessive glutamate transmission. We have recently identified a protein, referred to as the inhibitory protein factor (IPF), which potently inhibits glutamate uptake into isolated synaptic vesicles. In an effort to understand the mechanism underlying excessive glutamate transmission associated with seizure, we have analyzed IPF content in various brain regions of the spontaneously epileptic rat, SER (tm/tm, zi/zi), the absence-seizure tremor rat, TM (tm/tm), and the seizure-free control rats zitter ZI (zi/zi) and Wistar tremor control, each at 13 weeks of age. IPF content was found to be markedly reduced in the hippocampus, but not in the other brain regions, of SER, compared to the control and TM rats. TM rats also exhibited reduced IPF content compared to seizure-free controls. These changes appear developmentally regulated; no such alteration was observed in 8-week-old rats, which rarely show seizure. These observations indicate that an aberrant decrease in IPF is associated with certain forms of seizure; this decrease could lead to an abnormal increase in the amount of exocytotically released glutamate through its excessive accumulation in synaptic vesicles.     

Decreased Dopamine and Increased Norepinephrine Levels in the Spontaneously Epileptic Rat, a Double Mutant Rat

Summary: Dopamine (DA) and norepinephrine (NE) brain levels and turnover rate were examined in the spontaneously epileptic rat (SER: zi/zi, tm/tm), a double mutant rat obtained by mating tremor heterozygotes (tml +) with zitter homozygotes associated with epileptic seizures composed of spontaneously occurring tonic convulsion and absence-like seizure. DA and NE levels were also determined in age-matched male zitter, tremor and Kyo:Wistar rats. DA levels in caudate nucleus were significantly lower in adult age (10–12 weeks) SER, which showed epileptic seizures, and zitter rats than in adultKyo:Wistar and tremor rats. DA levels in other areas such as thalamus-hypothalamus, midbrain, and ponsmedulla were not different among SER, zitter, tremor, and Kyo:Wistar rats at age 10–12 weeks. Except in cerebral cortex and hippocampus, there were no differences in brain DA levels between young seizure-free SER (age 5 weeks) and young Kyo:Wistar rats. Furthermore, the turnover rate of DA was significantly lower in caudate nucleus of adult SER than of Kyo:Wistar rat, whereas in pons-medulla there was no difference between the two strains. In contrast, NE levels in the thalamushypothalamus, midbrain, cerebellum and pons-medulla were higher in SER and zitter rats at age 10–12 weeks than in age-matched tremor and Kyo:Wistar rats. Higher NE levels were also observed in midbrain, cerebellum, and pons-medulla of young SER as compared with young Kyo:Wistar rats. Turnover rates of NE were significantly lower in pons-medulla and cerebellum of the adult SER than in those of Kyo:Wistar rat. In genetic studies using backcross mating of zitter and BN rats, decreased DA was also observed in caudate nucleus of backcrossed zitter rats as compared with BN, F₁, and zitter wild-type rats. Increased NE contents were observed in the thalamus-hypothalamus, midbrain, and pons-medulla of zitter rats as compared with other rats, although the increase was also observed in the thalamus-hypothalamus and midbrain of zitter wild-type rats. Results suggest that a decrease in DA in caudate nucleus and an increase in NE in midbrain and pons-medulla are due to the homozygous zi gene, and together with previous findings, suggest that the decrease in DA, although probably not the only cause, facilitates appearance of tonic and absence-like seizures by lowering the threshold triggering such seizures.     

Isolated high-frequency jaw tremor relieved by botulinum toxin injections.

Jaw tremor can be seen as a component of various neurological disorders such as essential tremor, Parkinson's disease, dystonia, branchial myoclonus, hereditary geniospasm, task-specific tremor, and Whipple's disease, as well as in normal situations such as shivering, and subclinical physiological jaw tremor. In most of these conditions, the jaw tremor is usually associated with tremor or other abnormal involuntary movements affecting additional body parts, and its frequency is lower than 12 Hz. Schrag and colleagues reported a patient with a high-frequency idiopathic jaw tremor, and they speculated it could be related to orthostatic tremor affecting the masseter muscles. We encountered a similar patient with intermittent rapid focal jaw tremor that was successfully treated with botulinum toxin injections to the masseters.     

Epileptogenic action of fluvoxamine. Apropos of a case

A case of status epilepticus with transient motor deficit is reported in a 66 year old male treated with fluvoxamine. Fluvoxamine is supposed to induce few epileptic seizures. The patient had no previous history of epilepsy. Two factors seem to have favoured the occurrence of epilepsy: presence of an incipient arteriopathic impairment, cortical and subcortical brain atrophy and perhaps drug overdosage causing a tremor in the days before the epileptic fit.     

Clinical case: vermis hypoplasia with features of Smith-Lemli-Opitz syndrome

This article attempts to describe a very unusual case of a boy aged 15, who has had intractable epileptic phenomena, mental retardation, megalocephaly, micrognathy, syndactyly, small tongue, hypoplastic genitalia, gynecomasty, obesity, and slight left body hemiatrophy. Neurologically the patient has had hypotonia of the lower limbs, cerebellar dysfunction including horizontal nystagmus, bilateral intention tremor, dysdiadokokinesia, gait ataxia. The clinical investigation revealed low plasma cholesterol and hypoplasia of the vermis in MRI. The epileptic phenomena were intractable and polymorphous. One should have thought that this is an unusual case of Smith-Lemli-Opitz syndrome associated with features of Joubert syndrome.     

CLINICAL CASE: VERMIS HYPOPLASIA WITH FEATURES OF SMITH-LEMLI-OPITZ SYNDROME

This article attempts to describe a very unusual case of a boy aged 15, who has had intractable epileptic phenomena, mental retardation, megalocephaly, micrognathy, syndactyly, small tongue, hypoplastic genitalia, gynecomasty, obesity, and slight left body hemiatrophy. Neurologically the patient has had hypotonia of the lower limbs, cerebellar dysfunction including horizontal nystagmus, bilateral intention tremor, dysdiadokokinesia, gait ataxia. The clinical investigation revealed low plasma cholesterol and hypoplasia of the vermis in MRI. The epileptic phenomena were intractable and polymorphous. One should have thought that this is an unusual case of Smith-Lemli-Opitz syndrome associated with features of Joubert syndrome.     

Deep brain stimulation and tremor

Deep brain stimulation (DBS) has been used to treat various tremor disorders for several decades. Medication-resistant, disabling essential tremor (ET) is the most common tremor disorder treated with DBS. The treatment has been consistently reported to result in significant benefit in upper extremity, as well as head and voice tremor, all of which were improved more dramatically with bilateral procedures. These benefits have been demonstrated to be sustained for up to 7 years. DBS has also been shown to be beneficial for the tremor associated with multiple sclerosis and post-traumatic tremor; however, fewer cases have been reported and the benefit is less consistent, less dramatic, and more transient than that seen with ET. The ventral intermediate nucleus of the thalamus is the most common DBS target for tremor disorders, but more recent studies have demonstrated benefits in tremor from DBS of the subthalamic area, primarily the zona incerta. Surgical complications are relatively uncommon and are generally less frequent than those seen with thalamotomy. Stimulation-related effects are usually mild and resolve with adjustment of stimulation parameters. DBS is thus a relatively safe and effective treatment for tremor disorders, particularly for medication-resistant, disabling ET, but may also have some role in medication-resistant, disabling tremor associated with multiple sclerosis and traumatic head injury.     

It is time to remove the 'benign' from the essential tremor label

In recent years, studies of essential tremor (ET) have demonstrated that the disease is associated with functionally-relevant cognitive abnormalities, a mood disturbance and other psychiatric co-morbidities, a functionally significant gait disorder, hearing deficits, and a variety of types of tremor. The tremor has been shown to be progressive in nature and quite disabling for a large number of sufferers. Also, recent clinical-epidemiological studies have linked prevalent ET to other neurodegenerative diseases and at least one study has demonstrated an increased risk of mortality in an ET cohort. While many of these studies are derived from clinic-based samples, population-based studies have also substantiated these findings, suggesting that even in the general population, the disease is associated with disability and with co-morbidity. Based on these available studies, it would seem inaccurate to append the word "benign" to ET. Not unlike the word "essential" itself, the word "benign" is an antiquated and outdated term that reflects an era where little was understood about ET. Historically, the general doctors who frequently encountered the disorder would educate patients that it was a benign, non-progressive condition not associated with any co-morbidity or risk of long-term worry. This notion, conceived by prior generations of physicians, is now known to be inaccurate. It is therefore our recommendation that the medical community open the dialog to consider formally discontinuing this nosology ("benign essential tremor") and to adopt the use of the term "essential tremor." Use of the word "benign" is a mischaracterization of the disease course, and could be prove misleading especially in the evolving doctor-patient relationship. In those cases with currently-mild tremor, the nosology "mild essential tremor" would be a more accurate reflection of disease.     

How to establish causality in epilepsy surgery

Focality in electro-clinical or neuroimaging data often motivates epileptologists to consider epilepsy surgery in patients with medically-uncontrolled seizures, while not all focal findings are causally associated with the generation of epileptic seizures. With the help of Hill’s criteria, we have discussed how to establish causality in the context of the presurgical evaluation of epilepsy. The strengths of EEG include the ability to determine the temporal relationship between cerebral activities and clinical events; thus, scalp video-EEG is necessary in the evaluation of the majority of surgical candidates. The presence of associated ictal discharges can confirm the epileptic nature of a particular spell and whether an observed neuroimaging abnormality is causally associated with the epileptic seizure. Conversely, one should be aware that scalp EEG has a limited spatial resolution and sometimes exhibits propagated epileptiform discharges more predominantly than in situ discharges generated at the seizure-onset zone. Intraoperative or extraoperative electrocorticography (ECoG) is utilized when noninvasive presurgical evaluation, including anatomical and functional neuroimaging, fails to determine the margin between the presumed epileptogenic zone and eloquent cortex. Retrospective as well as prospective studies have reported that complete resection of the seizure-onset zone on ECoG was associated with a better seizure outcome, but not all patients became seizure-free following such resective surgery. Some retrospective studies suggested that resection of sites showing high-frequency oscillations (HFOs) at >80 Hz on interictal or ictal ECoG was associated with a better seizure outcome. Others reported that functionally-important areas may generate HFOs of a physiological nature during rest as well as sensorimotor and cognitive tasks. Resection of sites showing task-related augmentation of HFOs has been reported to indeed result in functional loss following surgery. Thus, some but not all sites showing interictal HFOs are causally associated with seizure generation. Furthermore, evidence suggests that some task-related HFOs can be transiently suppressed by the prior occurrence of interictal spikes. The significance of interictal HFOs should be assessed by taking into account the eloquent cortex, seizure-onset zone, and cortical lesions. Video-EEG and ECoG generally provide useful but still limited information to establish causality in presurgical evaluation. A comprehensive assessment of data derived from multiple modalities is ultimately required for successful management.     

Can Seizure-Alert Dogs predict seizures?

An index observation where a dog was trained to alert to, as well as respond to, human tonic-clonic seizures led to further research and refinement of training techniques. This was followed by anecdotal reports of pet dogs spontaneously anticipating human epileptic seizures. An industry has since developed training Seizure-Alert Dogs (SADs) to give humans warnings of their seizures. In some cases this has been accompanied by a reduction in seizure frequency. SADs may be trained along with the person with epilepsy, responding specifically to that person's seizures, or may be trained separately. Recent sceptical reports of non-epileptic seizures in some people with SADs have cast doubt on dogs' ability to anticipate true epileptic seizures. This may reflect selection criteria for training programmes as well as training methods used, but does not necessarily indicate that SADs might not be able to predict epileptic seizures. Whether the seizures are epileptic or non-epileptic, it is speculated that SADs probably alert to subtle pre-ictal human behaviour changes, but may also be sensitive to heart rate or olfactory cues. As yet, however, no rigorous data exist as to whether seizure prediction by SADS is better than chance, and what false positive and negative prediction rates might be.     

A comparison of post-ictal headache between patients with occipital lobe epilepsy and temporal lobe epilepsy.

We investigated post-ictal headaches (PIH) using a questionnaire to ascertain their characteristics and compare them among different types of epilepsy. The subjects consisted of 34 patients with occipital lobe epilepsy (OLE) and 75 patients with temporal lobe epilepsy (TLE). PIH occurred in 62% of OLE and 23% of TLE (P < 0.05). The quality of pain in PIH was 'steady' in 71% of OLE and 29% of TLE (P < 0.05) as opposed to 'pounding'. Other factors, such as frequency, severity, duration, and accompanying symptoms showed no significant differences. We found very few patients with migraine-like headaches. Analyses of clinical factors, such as age at onset, duration of epilepsy, seizure frequency, family history of headache, and interictal headache did not reveal any relationship to PIH, although generalized tonic-clonic seizures are associated with PIH in TLE (P < 0.05). These results suggest that the nature of PIH may be different between OLE and TLE, and that the region of epileptic focus or spreading area of epileptic discharge may have a close relation to the induction of PIH. An association with migraine, which has been reported previously, was unclear in our study.     

Evidence for prenatal competition among the central arbors of trigeminal primary afferent neurons.

Previous studies have shown that damage to vibrissa follicles in newborn rats and mice does not alter the brainstem representations of the remaining vibrissa as demonstrated by staining for mitochondrial enzymes such as cytochrome oxidase (CO) succinic dehydrogenase. This study asked whether this lack of effect might be due to the fact that the trigeminal primary afferents in rodents are already quite well developed at birth. We assessed this possibility by using CO staining the evaluate patterns in the brainstems of pre- and postnatal rats. A vibrissa-related pattern began to emerge in trigeminal nucleus principalis and subnucleus interpolaris (Spl) by embryonic day (E-) 19 and appeared fully developed by the day of birth (P-0). We also made partial lesions of the vibrissa pad on E-15-20 and on P-0, killed pups on P-5-7, and measured the size of the CO-stained patches in Spl on both sides of the brainstem. The correspondence between CO patches and clusters of primary afferent terminal arbors was verified in some animals by combining transganglionic horseradish peroxidase tracing and CO staining. Vibrissa pad damage on E-15-18 resulted in significant (20.1-36.9%) increases in the average area of the remaining CO patches in Spl ipsilateral to the lesion. Vibrissa pad damage on E-19, E-20, and P-0 produced small (6.2-8.9%), but insignificant, increases in patch size in Spl ipsilateral to the lesion. We used anatomical and electrophysiological methods to determine whether our lesions altered the trigeminal innervation of surviving vibrissa follicles. We recorded single trigeminal ganglion cells from 12 rats that sustained vibrissa pad lesion on E-17. As in normal rats, all of the 49 vibrissa-sensitive ganglion cells isolated in the lesioned animals were responsive to deflection of one and only one vibrissa. We also dissected 11 deep vibrissal nerves from intact follicles in adult rats that sustained fetal vibrissa pad damage on E-17, and counted numbers of myelinated axons in 1 microns plastic sections. These data were compared with counts from corresponding follicles on the intact side of the face. The average number of myelinated axons innervating follicles in the damaged vibrissa pads was 196.8 +/- 27.9, and that for the corresponding contralateral nerves was 194.6 +/- 25.7. These data suggest that competitive interactions among the central arbors of trigeminal primary afferents in fetal life may influence the development of central vibrissa representations and, further, that lesion-induced central changes need not be correlated with alterations in the peripheral innervation of undamaged follicles.     

Decreased catalepsy response to haloperidol in the genetically dystonic (dt) rat

The ontogeny of petit mal-like seizures induced by gamma-hydroxybutyrate (GHB) was investigated. The prodrug of GHB, gamma-butyrolactone (GBL) was administered in varying dosages under continuous EEG monitoring from cortical and depth electrodes to rats varying in postnatal age from 1 to 85 days. The brain pharmacokinetics of GHB were determined at various ages as was the effect of ethosuximide on GBL-induced EEG changes. In adult rats, GBL produced a predictable sequence of electrical events beginning with spike bursts and progressing to polyspiking separated by low voltage activity. In 1-day-old rats, GBL produced voltage suppression with stupor. Poorly organized spiking appeared at postnatal day 3 and by day 9 marked burst suppression with polyspiking separated by low voltage activity was noted. However, the full array of electrical events seen in adult rats did not appear until day 28. Ethosuximide was ineffective against GHB seizure until the third postnatal week of life. GHB had a longer half-life in brain in the first week of postnatal life. These data suggest that in the rodent, petit mal-like seizure activity may require a fully mature brain and raise the possibility of different mechanisms being responsible for the various stages of EEG changes induced by GBL.     

Inducción del temblor mandibular por lesión electrolítica del estriado ventrolateral y por el tratamiento subcrónico con haloperidol en rata macho: un contraste electromiográfico

Introduction

Tremulous jaw movement (TJMs) in rats can be induced pharmacologically by striatal dopaminergic manipulation or electrolytic lesion of ventrolateral striatum (VLS). This tremor has neurochemical, anatomical and electromyographic (EMG) characteristics similar to those of tremor in Parkinson patients. However, the EMG characteristics of tremors generated by electrolytic lesion to the VLS have not yet been studied.

Method

This study used electromyography to describe tremulous jaw movement generated by bilateral electrolytic lesion in the VLS and compare it to tremors induced using subchronic IP treatment with haloperidol, a dopaminergic D2 receptor antagonist. The experimental groups contained rats with a lesion in the ventrolateral striatum and rats on subchronic haloperidol treatment; the control group received only the vehicle. The EMG signal from the temporal muscle was recorded at baseline and during TJMs in all groups.

Results

TMJ frequencies were heterogeneous among the groups. Rats with VLS lesion showed higher amplitude and frequency values than the haloperidol-treated rats. Amplitudes at baseline also differed among the groups.

Conclusions

We conclude that TMJs associated with electrolytic lesion to the VLS show a higher frequency and amplitude than tremors induced by haloperidol. This may be related to the way striatum neurons are affected.