Disorders of Consciousness: Practical Management in an Emergency Room

Lowering of the level of consciousness is a very common presentation at the emergency room, often without any history that helps finding an etiology. This emergency requires quick empirical measures to reduce neuronal mortality, with additional protection against sequelae. According to the Advanced Cardiac Life Support (ACLS) guidelines, there are current emergency neurological support protocols, such as the Emergency Neurological Life Support (ENLS) created by the Neurocritical Care Society. The present paper shows how to approach unconscious patients, highlighting possible etiologies and proposed treatments.

Inactivation of the medial mammillary nucleus attenuates theta rhythm activity in the hippocampus in urethane-anesthetized rats.

Although the importance of the mammillary body for memory and learning processes is well known, its exact role has remained vague. The fact, that many neurons in one nucleus of the mammillary body in rats, i.e. the medial mammillary nucleus (MM), fires according with hippocampal theta rhythm, makes this structure crucial for a theta rhythm signaling in so-called extended hippocampal system. These neurons are driven by descending projections from the hippocampal formation, but it is still unknown whether the mammillary body only conveys theta rhythm or may also modulate it. In the present study, we investigated the effect of pharmacological inactivation (local infusion of 0.5µl of 20% procaine hydrochloride solution) of the MM on hippocampal theta rhythm in urethane-anesthetized rats. We found that intra-MM procaine microinjections suppress sensory-elicited theta rhythm in the hippocampus by reduction of its amplitude, but not the frequency. Procaine infusion decreased the EEG signal power of low theta frequency bands, i.e. 3-5Hz, down to 9.2% in 3-4Hz band in comparison to pre-injection conditions. After water infusion (control group) no changes of hippocampal EEG signal power were observed. Our findings showed for the first time that inactivation of the MM leads to a disruption of hippocampal theta rhythm in the rat, which may suggest that the mammillary body can regulate theta rhythm signaling in the extended hippocampal system.

Single-unit analysis of the human posterior hypothalamus and red nucleus during deep brain stimulation for aggressivity.

OBJECTIVE Deep brain stimulation (DBS) of the posterior hypothalamus (PH) has been reported to be effective for aggressive behavior in a number of isolated cases. Few of these case studies have analyzed single-unit recordings in the human PH and none have quantitatively analyzed single units in the red nucleus (RN). The authors report on the properties of ongoing neuronal discharges in bilateral trajectories targeting the PH and the effectiveness of DBS of the PH as a treatment for aggressive behavior. METHODS DBS electrodes were surgically implanted in the PH of 1 awake patient with Sotos syndrome and 3 other anesthetized patients with treatment-resistant aggressivity. Intraoperative extracellular recordings were obtained from the ventral thalamus, PH, and RN and analyzed offline to discriminate single units and measure firing rates and firing patterns. Target location was based on the stereotactic coordinates used by Sano et al. in their 1970 study and the location of the dorsal border of the RN. RESULTS A total of 138 units were analyzed from the 4 patients. Most of the PH units had a slow, irregular discharge (mean [± SD] 4.5 ± 2.7 Hz, n = 68) but some units also had a higher discharge rate (16.7 ± 4.7 Hz, n = 15). Two populations of neurons were observed in the ventral thalamic region as well, one with a high firing rate (mean 16.5 ± 6.5 Hz, n = 5) and one with a low firing rate (mean 4.6 ± 2.8 Hz, n = 6). RN units had a regular firing rate with a mean of 20.4 ± 9.9 Hz and displayed periods of oscillatory activity in the beta range. PH units displayed a prolonged period of inhibition following microstimulation compared with RN units that were not inhibited. Patients under anesthesia showed a trend for lower firing rates in the PH but not in the RN. All 4 patients displayed a reduction in their aggressive behavior after surgery. CONCLUSIONS During PH DBS, microelectrode recordings can provide an additional mechanism to help identify the PH target and surrounding structures to be avoided such as the RN. PH units can be distinguished from ventral thalamic units based on their response to focal microstimulation. The RN has a characteristic higher firing rate and a pattern of beta oscillations in the spike trains. The effect of the anesthetic administered should be considered when using microelectrode recordings. The results of this study, along with previous reports, suggest that PH DBS may be an effective treatment for aggression.

GABAergic Signaling within a Limbic-Hypothalamic Circuit Integrates Social and Anxiety-Like Behavior with Stress Reactivity.

The posterior hypothalamic nucleus (PH) stimulates autonomic stress responses. However, the role of the PH in behavioral correlates of psychiatric illness, such as social and anxiety-like behavior, is largely unexplored, as is the neurochemistry of PH connectivity with limbic and neuroendocrine systems. Thus, the current study tested the hypothesis that GABAergic signaling within the PH is a critical link between forebrain behavior-regulatory nuclei and the neuroendocrine hypothalamus, integrating social and anxiety-related behaviors with physiological stress reactivity. To address this hypothesis, GABAA receptor pharmacology was used to locally inhibit or disinhibit the PH immediately before behavioral measures of social and anxiety-like behavior in rats. Limbic connectivity of the PH was then established by simultaneous co-injection of anterograde and retrograde tracers. Further, the role of PH GABAergic signaling in neuroendocrine stress responses was tested via inhibition/disinhibition of the PH. These studies determined a prominent role for the PH in the expression of anxiety-related behaviors and social withdrawal. Histological analyses revealed divergent stress-activated limbic input to the PH, emanating predominantly from the prefrontal cortex, lateral septum, and amygdala. PH projections also targeted both parvicellular and magnocellular peptidergic neurons in the paraventricular and supraoptic hypothalamus. Further, GABAA receptor pharmacology determined an excitatory effect of the PH on neuroendocrine responses to stress. These data indicate that the PH represents an important stress-integrative center, regulating behavioral processes and connecting the limbic forebrain with neuroendocrine systems. Moreover, the PH appears to be uniquely situated to have a role in stress-related pathologies associated with limbic-hypothalamic dysfunction.

Involvement of endothelins in deoxycorticosterone acetate-salt hypertension through the modulation of noradrenergic transmission in the rat posterior hypothalamus.

NEW FINDINGS: What is the central question of this study? Does ex vivo administration of endothelin-1 and endothelin-3 regulate noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate-salt hypertensive rats compared with normotensive rats? What is the main finding and its importance? Endothelin-1 and endothelin-3 enhanced diverse mechanisms leading to increased noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate-salt hypertensive rats. Unveiling the role of brain endothelins in hypertension would probably favour the development of new therapeutic targets for the treatment of essential hypertension, which still represents a challenging disease with high mortality. Brain catecholamines participate in diverse biological functions regulated by the hypothalamus. We have previously reported that endothelin-1 and endothelin-3 (ET-1 and ET-3) modulate catecholaminergic activity in the anterior and posterior hypothalamus of normotensive rats. The aim of the present study was to evaluate the interaction between endothelins and noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We assessed the effects of ET-1 and ET-3 on tyrosine hydroxylase activity and expression, neuronal noradrenaline (NA) release, neuronal NA transporter (NAT) activity and expression, monoamine oxidase activity and NA endogenous content and utilization (as a marker of turnover) in the posterior hypothalamus of DOCA-salt hypertensive rats. In addition, levels of ETA and ETB receptors were assayed in normotensive and hypertensive rats. Results showed that tyrosine hydroxylase activity and total and phosphorylated levels, NAT activity and content, NA release, monoamine oxidase activity and NA utilization were increased in DOCA-salt rats. Both ET-1 and ET-3 further enhanced all noradrenergic parameters except for total tyrosine hydroxylase level and NA endogenous content and utilization. The expression of ETA receptors was increased in the posterior hypothalamus of DOCA-salt rats, but ETB receptors showed no changes. These results show that ET-1 and ET-3 upregulate noradrenergic activity in the posterior hypothalamus of DOCA-salt hypertensive rats. Our findings suggest that the interaction between noradrenergic transmission and the endothelinergic system in the posterior hypothalamus may be involved in the development and/or maintenance of hypertension in this animal model.

Blunted autonomic response in cluster headache patients.

BACKGROUND: Cluster headache (CH) is a disabling headache disorder with chronobiological features. The posterior hypothalamus is involved in CH pathophysiology and is a hub for autonomic control. We studied autonomic response to the head-up tilt table test (HUT) including heart rate variability (HRV) in CH patients and compared results to healthy controls. METHODS AND MATERIALS: Twenty-seven episodic and chronic CH patients and an equal number of age-, sex- and BMI-matched controls were included. We analyzed responses to HUT in the time and frequency domain and by non-linear analysis. RESULTS: CH patients have normal cardiovascular responses compared to controls but increased blood pressure. In the frequency analysis CH patients had a smaller change in the normalized low- (LF) (2.89 vs. 13.38, p < 0.05) and high-frequency (HF) (-2.86 vs. -13.38, p < 0.05) components as well as the LF/HF ratio (0.81 vs. 2.62, p < 0.05) in response to tilt. In the Poincaré plot, the change in ratio between long- and short-term variation was lower in patients (SD1/SD2, -0.05 vs. -0.17, p < 0.05). CONCLUSIONS: CH patients show decreased autonomic response to HUT compared to healthy controls. This can be interpreted as dysregulation in the posterior hypothalamus and supports a theory of central autonomic mechanisms involvement in CH.

Role of posterior hypothalamus in hypobaric hypoxia induced pulmonary edema.

To investigate the role of posterior hypothalamus and central neurotransmitters in the pulmonary edema due to hypobaric hypoxia, rats were placed in a high altitude simulation chamber (barometric pressure-294.4 mmHg) for 24 h. Exposure to hypobaric hypoxia resulted in increases in mean arterial blood pressure, renal sympathetic nerve activity, right ventricular systolic pressure, lung wet to dry weight ratio and Evans blue dye leakage. There was a significant attenuation in these responses to hypobaric hypoxia (a) after lesioning posterior hypothalamus and (b) after chronic infusion of GABAA receptor agonist muscimol into posterior hypothalamus. No such attenuation was evident with the chronic infusion of the nitric oxide donor SNAP into the posterior hypothalamus. It is concluded that in hypobaric hypoxia, there is over-activity of posterior hypothalamic neurons probably due to a local decrease in GABA-ergic inhibition which increases the sympathetic drive causing pulmonary hypertension and edema.

Reorganization of supramammillary-hippocampal pathways in the rat pilocarpine model of temporal lobe epilepsy: evidence for axon terminal sprouting.

In mesial temporal lobe epilepsy (MTLE), spontaneous seizures likely originate from a multi-structural epileptogenic zone, including several regions of the limbic system connected to the hippocampal formation. In this study, we investigate the structural connectivity between the supramammillary nucleus (SuM) and the dentate gyrus (DG) in the model of MTLE induced by pilocarpine in the rat. This hypothalamic nucleus, which provides major extracortical projections to the hippocampal formation, plays a key role in the regulation of several hippocampus-dependent activities, including theta rhythms, memory function and emotional behavior, such as stress and anxiety, functions that are known to be altered in MTLE. Our findings demonstrate a marked reorganization of DG afferents originating from the SuM in pilocarpine-treated rats. This reorganization, which starts during the latent period, is massive when animals become epileptic and continue to evolve during epilepsy. It is characterized by an aberrant distribution and an increased number of axon terminals from neurons of both lateral and medial regions of the SuM, invading the entire inner molecular layer of the DG. This reorganization, which reflects an axon terminal sprouting from SuM neurons, could contribute to trigger spontaneous seizures within an altered hippocampal intrinsic circuitry.

[A practical algorithm for polydipsia in children]. / Een praktisch algoritme voor polydipsie bij kinderen.

There is a lack of consent on a clinical diagnostic work-up for children with polydipsia. This can result in a delay in diagnosis in some children and unnecessary investigations in others. We describe three children who presented with polydipsia. Two of them were diagnosed with psychogenic polydipsia and one with central diabetes insipidus. We discuss the differential diagnosis and relevant clinical signs before going on to propose a clinical diagnostic algorithm that can be used in children with polydipsia. A systematic diagnostic work up for children with polydipsia helps to differentiate between those in whom polydipsia is unlikely to have a somatic cause and those where a water deprivation-test is indicated. A water deprivation test in children is an invasive procedure and should be performed by a paediatric endocrinologist or nephrologist.

SUNCT, SUNA and trigeminal neuralgia: different disorders or variants of the same disorder?

PURPOSE OF REVIEW: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) and trigeminal neuralgia are considered different disorders, thus grouped in separate sections of the International Classification of Headache Disorders 3 beta. However, the clinical, radiological and therapeutic overlap between SUNCT, SUNA, and trigeminal neuralgia has challenged this traditional view. This review summarizes the available clinical and pathophysiological evidence on whether SUNCT, SUNA and trigeminal neuralgia should be considered separate entities or variants of the same disorder. RECENT FINDINGS: Data on the clinical phenotype and effective management strategies in SUNCT and SUNA syndromes have shown striking similarities with trigeminal neuralgia. Moreover, studies exploring radiological findings supported the hypothesis of common aetiological and pathophysiological basis between SUNCT/SUNA and trigeminal neuralgia. However, a limitation of most studies is that they have included small samples of patients and therefore any conclusions need to be drawn cautiously. SUMMARY: Despite being considered distinct conditions, emerging clinical and radiological evidence supports a broader nosological concept of SUNCT, SUNA, and trigeminal neuralgia. These conditions may constitute a continuum of the same disorder, rather than separate clinical entities. Further evidence is required to shed light on this nosological issue, given its potential impact on clinical practice and further research studies in this area.

Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT).

BACKGROUND: SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) is a rare syndrome characterized by the sudden onset of excruciating unilateral periorbital pain that is accompanied by conjunctival injection and lacrimation or further autonomic signs. Similar to patients with chronic cluster headache, Leone and Lyons showed a beneficial effect of deep brain stimulation of the posterior hypothalamic region in two patients with a chronic SUNCT. CASE: Here, we present the case of a man with a chronic SUNCT responding to deep brain stimulation of the posterior hypothalamic area. CONCLUSION: This case supports the idea of a central origin of SUNCT and shows that deep brain stimulation of the hypothalamic region can be effective in the treatment of the chronic form of this rare disorder.

[Review of the target for the deep brain stimulation of chronic cluster headache]. / Revision de la diana para la estimulacion cerebral profunda de la cefalea en racimos cronica.

Cluster headache is included in the group of trigeminal autonomic cephalalgias. Although the pathophysiology of cluster headache has not yet been sufficiently established, the theory of a central origin tells us that this headache is produced by hypothalamic dysfunction. More than 50 patients have been treated with deep brain stimulation of the posterior nucleus of the hypothalamus from 2001. The results show clinical improvement in more than 60% of the cases, opening a promising issue for the treatment of the cluster headache persistent after medical treatment. The surgical target that have been used until now is based on the origin of the cluster headache in the hypothalamic dysfunction. Nevertheless, It has still some open questions as the lack of proving the posterior nucleus of the hypothalamus is the real origin of the cluster headache, the lack of consensus about the anatomy of the surgical target and the variability of the structures stimulated with the surgery. The aim of this article is a review of the target used and propose another surgical target based on physiopathological concepts to explain the improvement with the deep brain stimulation in these patients.

[Hypothalamic deep brain stimulation for treatment of cluster headache]. / Stymulacja podwzgórza w leczeniu klasterowego bólu glowy.

Extremely severe, unilateral, recurrent facial pain and headache, accompanied by autonomic symptoms and signs, can be identified as cluster headache attacks (CH). Despite optimal pharmacological treatment, 20% of patients will not achieve satisfactory improvement. The severity of pain is so extreme that CH has been a cause of multiple suicidal attempts among patients ineffectively treated because of CH. Hypermetabolism of ipsilateral posterior hypothalamus observed in PET studies led to multiple attempts of deep brain stimulation (DBS) utilization in CH treatment. The authors present current opinions about DBS treatment in CH. A socioeconomic analysis of neuromodulatory treatment of CH is presented.

Revisión de la diana para la estimulación cerebral profunda de la cefalea en racimos crónica / Review of the target for the deep brain stimulation of chronic cluster headache

La cefalea en racimos pertenece al grupo de las cefalalgias trigeminales autosómicas. Aunque su fisiopatología no está suficientemente clara, se cree que una disfunción hipotalámica es la causante de este tipo de cefaleas. Desde 001 se ha tratado a más de 50 pacientes con estimulación cerebral en el hipotálamo posterior. Los resultados obtenidos hasta la fecha son de mejoría en más del 60% de los casos y se ha abierto un camino prometedor para el tratamiento de la cefalea en racimos crónica rebelde a tratamiento farmacológico. La diana quirúrgica utilizada hasta ahora se basa en la disfunción del hipotálamo posteroinferior como origen de la cefalea en racimos; sin embargo, hay varias cuestiones no resueltas como son, entre otras, la falta de demostración de que el hipotálamo posteroinferior es el generador de las cefaleas, no existe un consenso sobre la anatomía de la diana quirúrgica y la variabilidad de estructuras anatómicas neuroestimuladas en estos pacientes. El objetivo de este artículo es hacer una revisión crítica de la diana utilizada en esta patología y proponer, sobre la base de conceptos fisiopatológicos, otra diana que explique el efecto beneficioso de la estimulación cerebral profunda en estos pacientes (AU)

Cluster headache is included in the group of trigeminal autonomic cephalalgias. Although the pathophysiology of cluster headache has not yet been sufficiently established, the theory of a central origin tells us that this headache is produced by hypothalamic dysfunction. More than 50 patients have been treated with deep brain stimulation of the posterior nucleus of the hypothalamus from 2001. The results show clinical improvement in more than 60% of the cases, opening a promising issue for the treatment of the cluster headache persistent after medical treatment. The surgical target that have been used until now is based on the origin of the cluster headache in the hypothalamic dysfunction. Nevertheless, It has still some open questions as the lack of proving the posterior nucleus of the hypothalamus is the real origin of the cluster headache, the lack of consensus about the anatomy of the surgical target and the variability of the structures stimulated with the surgery. The aim of this article is a review of the target used and propose another surgical target based on physiopathological concepts to explain the improvement with the deep brain stimulation in these patients (AU)

Pathophysiology of trigeminal autonomic cephalalgias.

Cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) are primary headaches recently classified together as trigeminal autonomic cephalalgias (TACs). The causes of these headaches have long been debated, with "peripheral" hypotheses in opposition to "central" hypotheses. The available information indicates that the pain originates from within the brain in cluster headache. The hypothalamic activation observed during TAC attacks by use of functional neuroimaging, and the success of hypothalamic stimulation as a treatment, confirm that the posterior hypothalamus is crucial in the pathophysiology of these headaches. The posterior hypothalamus is now known to modulate craniofacial pain, and hypothalamic activation occurs in other pain disorders, suggesting that this brain area is likely to have a more complex role in the pathophysiology of TACs than that of a mere trigger. Hypothalamic activation might play a part in terminating rather than triggering attacks, and might also give rise to a central permissive state, allowing attacks to take place.

Local field potentials reveal a distinctive neural signature of cluster headache in the hypothalamus.

Cluster headache (CH) is a debilitating neurovascular condition characterized by severe unilateral periorbital head pain. Deep brain stimulation of the posterior hypothalamus has shown potential in alleviating CH in its most severe, chronic form. During surgical implantation of stimulating macroelectrodes for cluster head pain, one of our patients suffered a CH attack. During the attack local field potentials displayed a significant increase in power of approximately 20 Hz. To the authors' knowledge, this is the first recorded account of neuronal activity observed during a cluster attack. Our results both support and extend the current literature, which has long implicated hypothalamic activation as key to CH generation, predominantly through indirect haemodynamic neuroimaging techniques. Our findings reveal a potential locus in CH neurogenesis and a potential rationale for efficacious stimulator titration.

Deep brain stimulation of the posterior hypothalamic nucleus reverses akinesia in bilaterally 6-hydroxydopamine-lesioned rats.

Deep brain stimulation (DBS) of the basal ganglia motor circuitry is a highly effective treatment for the debilitating motor symptoms of Parkinson's disease (PD). However, recent findings have indicated promising potential for PD therapy with DBS in brain structures outside the basal ganglia. For example, high frequency stimulation of the posterior hypothalamic nucleus (PH) can reverse haloperidol-induced akinesia in rats [Jackson J, Young CK, Hu B, Bland BH (2008) High frequency stimulation of the posterior hypothalamic nucleus restores movement and reinstates hippocampal-striatal theta coherence following haloperidol-induced catalepsy. Exp Neurol 213:210-219]. In the current study, we used the bilateral 6-hydroxydopamine lesion model of Parkinsonian akinesia in male Long-Evans rats to further explore the efficacy of PH DBS. The application of PH DBS in lesioned animals reversed akinesia in an active avoidance paradigm with increased latency compared to pre-lesion performance. The dramatic reversal of akinesia in two models of rodent Parkinsonism by PH DBS warrants further exploration of its therapeutic potential.