Paroxysmal Sympathetic Hyperactivity After Acute ...

Curr Neurol Neurosci Rep (2013) :370 DOI 10.1007/s11910-013-0370-3

CRITICAL CARE (SA MAYER, SECTION EDITOR)

Paroxysmal Sympathetic Hyperactivity After Acute Brain Injury H. Alex Choi & Sang-Beom Jeon & Sophie Samuel & Teresa Allison & Kiwon Lee

# Springer Science+Business Media New York 2013

Abstract Paroxysmal sympathetic hyperactivity is a syndrome associated with brain trauma, stroke, encephalitis, and other forms of brain injury. It is characterized by uncontrolled episodes of unbalanced sympathetic surges causing hyperthermia, diaphoresis, tachycardia, hypertension, tachypnea, and dystonic posturing. Patients who develop paroxysmal sympathetic hyperactivity have worse neurologic outcomes, longer hospital stays, and more complications. Despite the clear negative impact on outcome, consensus regarding diagnostic criteria, risk factors, pathophysiology, and treatment approaches is lacking. Recently, the importance of consensus regarding diagnostic criteria has been emphasized, and new theories of pathophysiology have been proposed. Many treatment options are available, but only a few systemic studies of the efficacy of treatment algorithms exist. Treatments should focus on decreasing the frequency and intensity of episodes with regularly scheduled doses of medications, such as longacting benzodiazepines, nonselective β-blockers, α2-agonists, morphine, baclofen, and gabapentin, usually in combination. Treatment of acute breakthrough episodes should focus on doses of as-needed morphine and short-acting benzodiazepines. A balance between control of symptoms without oversedation is the goal. This article is part of the Topical Collection on Critical Care H. A. Choi (*) : K. Lee Departments of Neurology and Neurosurgery, The University of Texas Medical School at Houston, 6431 Fannin St., MSB 7.154A, Houston, TX 77030, USA e-mail: [email protected] S.120 beats/min, RR>30 breaths/min, BT>38.5 °C, SBP>160 mmHg, increased muscle tone, posturing, and hyperhidrosis 1 episodes or more per day of 5 of more of 7 features, for 3 days or more: HR>120 beats/min, RR>30 breaths/min, BT>38.5 °C, SBP>160 mmHg, increased muscle tone, posturing, and hyperhidrosis 1 episode or more per day of 5 or more of 7 features, for 3 days or more: HR>120 beats/min, RR>30, BT>38.5 °C, SBP>160, increased muscle tone, posturing, and hyperhidrosis 5 or more of 9 features, for 2 weeks or more: HR>120 beats/min, RR>30 breaths/min, SBP>160 mmHg, increased or decreased BT, hyperhidrosis, posturing, increased muscle tone, horripilation, and flushing 4 or more of 6 features: increased BT, HR>120 mmHg (or HR>100 mmHg with a β-blocker), SBP >160 mmHg or pulse pressure greater than 80 mmHg, RR>30 breaths/min, hyperhidrosis, and posturing/ dystonia 5 or more of 7 features, for 2 weeks or more: increased HR, increased RR, increased BP, increased BT, posturing, dystonia, and hyperhidrosis 5 or more of 7 features, to day 14 after injury: HR>120 beats/min, RR>30 breaths/min, BT>39 °C, SBP> 160 mmHg, dystonia, posturing, and hyperhidrosis 5 or more of 7 features: increased HR, increased RR, increased BP, increased BT, posturing, dystonia, and hyperhidrosis 5 or more of 8 features: increased HR, increased RR, increased BP, hyperhidrosis, mydriasis, decreased consciousness, increased muscle rigidity, and posturing Dysrhythmia, increased or decreased BT, increased or decreased BP, hyperhidrosis, sialorrhea, increased RR, and adynamic ileus

5 of more of 8 features: increased HR, increased BP, increased RR, decreased consciousness, increased muscle rigidity, increased BT, hyperhidrosis, and mydriasis

5 or more of 9 features, for 2 weeks or more: HR>120 beats/min, RR>30 breaths/min, SBP>160 mmHg, increased or decreased BT, hyperhidrosis, posturing, increased muscle tone, horripilation, and flushing Dysrhythmias, increased BT, and increased or decreased BP

Definition of PSH

Table 1 Sample of studies on paroxysmal sympathetic hyperactivity (PSH) with more than five cases

Decreased variability of BP and HR

Common (69 %) in patients with NMDAE

Focal lesions and poor functional outcome

Decreased HR variability

Poor functional outcome

Positive effect of gabapentin

Prospective survey


Deep lesions and poor functional outcome

Younger age and diffuse axonal injury

Positive effect of hyperbaric oxygen therapy

Interval since injury (5.9 days), duration (31 min), and frequency (5.6/day) of episodes; positive effect of clonidine, β-blocker, opiates, bromocriptine, and baclofen

Severe sinus nodal abnormalities in 80 % of patients

Recent decrease in the incidence (single center)

Comments on PSH

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NA 9 TBI, ICH, hydrocephalus Rossitch and Bullard [21]

NA

TBI Baguley et al. [36]

BP blood pressure, BT body temperature, HR heart rate, ICH intracranial hemorrhage, NA not available, NMDARE NMDA-receptor-associated encephalitis, PVS persistent vegetative state, RR respiratory rate, SAH subarachnoid hemorrhage, SBP systolic blood pressure, TBI traumatic brain injury, NTBI nontraumatic brain injury

Positive effect of morphine, dantrolene and bromocriptine; duration of episode (minutes to hours)


5 or more of 7 features, for 2 weeks or more: increased HR, increased RR, increased BP, increased BT, posturing, dystonia, and hyperhidrosis Increased BT, increased HR, increased BP, increased RR, mydriasis, posturing, and hyperhidrosis 21 35

35 NA TBI Baguley et al. [65]

NA

Positive effect of morphine, benzodiazepine, propranolol, bromocriptine, and intrathecal infusion of baclofen 5 or more of 7 features, for 2 weeks or more after injury: increased HR, increased RR, increased BT, increased BP, posturing, dystonia, and hyperhidrosis 5 or more of 7 features: increased HR, increased RR, increased BP, increased BT, posturing, dystonia, and hyperhidrosis 21

Comments on PSH Mean age (years) Cases Prevalence (%) Brain injury Publication

Table 1 (continued)

Curr Neurol Neurosci Rep (2013) :370

Definition of PSH

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typically appears in the ICU setting and is first noticed when weaning the patient off sedation after the acute brain injury ,making it difficult to differentiate PSH from opiate withdrawal or agitation from mechanical ventilation. It may persist into the rehabilitation phase, and may last for weeks to months after the injury. In severe cases, it may persist for more than 1 year [6••, 9•]. Few systemic ICU-population-based studies are available for accurate descriptions of risk factors. In general, the main risk factor for developing PSH after acute brain injury is the severity of acute brain injury. Patients with mild brain injury do not develop this disorder and are usually not included in studies of PSH. Younger age and male gender have been cited as risk factors, but may also simply be a reflection of the general TBI population having a higher proportion of young men [1•, 5, 6••]. Some have speculated that the response of the autonomic nervous system to external stimulation is stronger in younger patients than in elderly ones, which could explain the higher risk of PSH in younger patients [1•]. Past studies suggested that intracranial pressure elevations were a component of PSH episodes [20, 21]. However, a more recent study showed contrary results suggesting that elevations of intracranial pressure were not seen during episodes of PSH [6••]. In TBI, some imaging qualities have been shown to increase the risk of PSH. CT studies have suggested that patients with focal lesions (extradural hematoma, subdural hematoma, and other focal space-occupying lesions) may be commoner in patients who develop PSH [6••, 14]. In contrast, other studies have reported a significant presence of diffuse lesions in PSH [22, 23] or very heterogeneous lesions in both intracerebral and extracerebral structures [11]. MRI is superior to CT for detecting lesions in those areas of the brain which may be important for the development of PSH, namely, the corpus callosum, deep nuclei, and brainstem [24, 25]. Recent MRI studies have shown evidence that injury to the deep brain structures, periventricular white matter, corpus callosum, diencephalon, or brainstem seems to be associated with the development of PSH, suggesting the importance of diffuse axonal injury as a causative agent [1•, 26•]. Patients with PSH have an increased number of lesions in the dorsolateral aspect of the midbrain and upper pons compared with the number of lesions in the cortex, subcortex, corpus callosum, and diencephalon [26•, 27]. Bilateral diencephalic lesions have also been attributed to PSH in hypoxic ischemic encephalopathy [28]. The evidence from imaging studies showing damage to brainstem structures emphasizes the importance of the diencephalic and mesencephalic regions to the pathophysiology of PSH. Multiple microbleeds on susceptibility-weighted imaging have also been suggested to be associated with PSH in a patient with TBI [29].


Measurement of plasma catecholamine levels has been used for investigation of sympathetic surge during acute brain injury. Increases in dopamine, adrenaline, and noradrenaline levels during the episodes have been reported [30]. Elevated plasma levels of catecholamines in patients with TBI have been shown to be proportional to the severity of injury and neurologic outcome, which may have an association as manifestations of PSH [30, 31]. Elevated plasma levels of catecholamines in subarachnoid hemorrhage have also been documented [32, 33]. Although absolute levels of plasma catecholamines do not directly correlate with sympathetic outflow severity, they seem to have a causative relationship with end-organ dysfunction [34]. Given the brief elevations in plasma levels of catecholamines, the wide variability between patients, and complex factors that affect serum catecholamine levels, an absolute threshold level of catecholamines to diagnose PSH is unrealistic. Although the risk factors and causative agents for the disease are controversial, the impact on clinical outcomes are clear. Consistently, PSH has been associated with poor clinical outcome. Patients who experience PSH have worse Glasgow Outcome Scale scores and worse functional independent measures than their counterparts [6••, 8, 14, 35]. Additionally, patients with PSH have longer ICU stays, longer hospital stay, more mechanical ventilation days, more infectious episodes, more tracheostomy, and higher healthcare costs [2, 6••, 11, 14–16, 26•, 36, 37]. The mechanisms by which PSH causes worse outcomes are multifactorial. The symptoms and treatments for the symptoms result in more ventilation days, leading to more tracheostomy and longer hospital stays. PSH has a direct impact on fever burden after brain injury, which has been associated with worse outcomes [38, 39]. In addition, the influence of the autonomic nervous system and its effects on inflammation have been studied in other disease states and may be very active in the acutely brain injured population. The dysregulated autonomic nervous system may have an influence in causing unopposed inflammation and leading to secondary brain injury [40].

Diagnostic Workups The overlapping symptoms of PSH and other neurologic sequelae of acute brain injury and critical illness makes the diagnosis difficult, and often it is only made after other causes of the symptoms have been excluded. Clinical suspicion and careful examination are of paramount importance in the detection of PSH. Infections and sepsis should be ruled out in patients with fever and tachycardia. Secondary causes of tachycardia and hypertension should be also be sought. Opiate withdrawal from prolonged sedation should be addressed. The high incidence of seizures in the critically ill population supports the need for continuous EEG to rule

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out seizures in patients with abnormal repetitive movements and encephalopathy [41].

Mechanisms The pathophysiology of PSH has undergone very little empiric testing. Initially, the episodic nature of the syndrome with abnormal movements, which is reflected in the initial naming of the syndrome, targeted diencephalic discharges as the cause of PSH [3, 42]. Attempts to identify epileptic discharges as the cause of PSH have come up empty handed, and the consensus is that PSH is not caused by epileptic activity [43–47]. This is not to say that seizures cannot occur as well as PSH. In fact, in some encephalitis syndromes, seizures and PSH can occur independently, complicating the diagnosis and treatment [17]. The most commonly proposed mechanism causing PSH is the functional disconnection or unbalanced activation of systems important for autonomic control. Initial reports focused on heightened activity of the diencephalon and its connections due to either direct activation or disinhibition, i.e., a release phenomenon [13, 44, 47]. However, the anatomic location of the dysfunction is not clear, and studies have implicated regions from the cortex to the anterior hypothalamus, to the medulla and the connections in between [45, 48–50]. Regardless of the location of the lesion, the final common pathway is an imbalance of adrenergic outflow. More recently, the excitatory–inhibitory ratio (EIR) model has been developed to explain the pathophysiology of PSH and takes into account the hypersensitive, overreactive nature of the responses to normal stimuli. The EIR model is not specific for PSH, and also includes other diseases with paroxysmal dysautonomias. Autonomic efferents at the level of the spinal cord are modulated centrally by a balance of sympathetic and parasympathetic input. Additionally, afferents from the spinal cord can modulate this balance with input, such as noxious stimuli, from the environment [9•, 10, 51]. This model proposes that the afferent stimulus from the spine has an allodynic tendency which is normally controlled by tonic inhibitory drive from diencephalic centers. Damage to these inhibitory centers or their inhibitory processes down to the mesencephalon releases the control of the allodynic tendency. Once the tonically inhibitory cycle is broken, there is a positive-feedback loop that produces sympathetic overactivity to any afferent stimuli [10]. This model explains how a normally nonnoxious stimulus can become a very noxious stimulus associated with an uncontrolled sympathetic response.

Management Effective treatment of PSH can be challenging as a balance between effective treatment and avoidance of overmedication

GABA γ-aminobutyric acid

Decreases muscle contraction Scheduled doses to prevent episodes Muscle rigidity, posturing Peripherally Dantrolene

Scheduled doses to prevent episodes Hypertension, tachycardia, fever

Hypertension, agitation, tachycardia Intravenously to prevent episodes

Nonselective β-blocker Propranolol

α2-Receptor agonist Centrally decreased sympathetic outflow

Peripherally decreasing effect of catecholamines

Dexmedetomidine

Scheduled doses to prevent episodes Spasticity, allodynic response

Scheduled doses to prevent episodes Hypertension

GABA agonist

Clonidine(orally or patch)

α2-Receptor agonist

Centrally

Centrally decreased sympathetic outflow

Gabapentin

Agitation, hypertension, tachycardia, posturing

Agitation, hypertension, tachycardia, posturing Use as needed to abort episodes GABA agonist Centrally

GABA agonist Centrally

Diazepam

Both prevents and aborts episodes

Agitation, hypertension, tachycardia, posturing

Lorazepam

GABA agonist Centrally

Scheduled doses to prevent episodes Agitation, hypertension, tachycardia, posturing

Pain, clonus, rigidity

Clonazepam

Both prevents and aborts episodes Centrally

Preventative treatment GABAB-specific agonist

GABA agonist

Baclofen (oral or intrathecal) Centrally

Benzodiazepines

Tachycardia, peripheral vasodilation, allodynic response

Tachycardia, allodynic response Preventative treatment

Centrally medullary vagal nuclei and peripherally μ-Opioid receptor agonist Morphine

Fentanyl (patch) (every 72 h) Centrally medullary vagal nuclei and Peripherally μ-Opioid receptoragonist

Dystonia, fever, posturing

Scheduled doses to prevent episodes Both prevents and aborts episodes Dopamine agonist Centrally at hypothalamus Bromocriptine

Comments Mechanism Location of action Medication

Table 2 Medications used for treatment of PSH

and side effects can be difficult to achieve. Although a large number of case reports and case series describe different medications and treatment strategies, only a few prospectively designed studies exist and no randomized trials exist to help guide our treatments. The treatments have focused on control of symptoms as no direct treatment options are available, as the underlying cause of the syndrome itself is not clearly understood. Medical treatments for PSH include α2-agonists, βblockers, benzodiazepines, dopamine agonists, opioids, GABAergic agents, dantrolene, and gabapentin (see Table 2). In the acute phase of brain injury, patients usually receive continuous intravenous sedative medications for control of agitation, comfort while intubated, and control of intracranial pressure. The manifestation of PSH is noticed usually once the patient has been weaned off these sedative agents in attempts to minimize sedation, to wake up the patient, liberate patients from mechanical ventilation, and begin the rehabilitation process. In this setting when confronted with PSH, two types of strategies should be used. First, regularly dosed standing medications should be started to decrease the frequency and intensity of episodes. These medications include nonselective β-blockers, α2-receptor agonist, bromocriptine, baclofen, gabapentin, and long-acting benzodiazepams such as clonazepam. Usually a combination of medications from different classes is the most effective. Abortive medications with shorter-acting properties should be used to control discrete breakthrough episodes. The targets of the abortive treatment usually depend on the predominant symptoms: treating hyperthermia with antipyretics, agitation with sedatives, and hypertension with antihypertensive medications. Morphine and short-acting benzodiazepines are the most effective method of treatment. The challenge is controlling the symptoms of PSH while concurrently minimizing sedation and the side effects of medication. Clonidine is a presynaptic α2-receptor agonist which reduces central sympathetic outflow from the hypothalamus and ventrolateral medulla and may enhance sympathetic inhibition in the brainstem [13, 52]. Since increased blood pressure due to excitation of the sympathetic nervous system is one of the major features of PSH, clonidine is often used as a first-line agent for managing this symptom. Clonidine reduces circulating plasma catecholamine levels in TBI patients [53]. However, because clonidine is ineffective in controlling the other manifestations of PSH, additional agents with different mechanisms of action may be required [43]. Dexmedetomidine is an intravenous sedative and the first and only currently approved intravenous α2-agonist. A recent case report showed it may be effective for the management of PSH symptoms, and given its favorable effects on heart rate, blood pressure, and agitation and its mechanism of action it is an attractive medication to use [20]. The main problem is that the intravenous form of delivery makes it difficult to use it anywhere except in an ICU setting.


Symptoms treated

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β-Blockers diminish the effect of circulating catecholamines and attenuate the resting metabolic rate [54, 55]. βBlockers have long been the mainstay of treatment for hypertension, tachycardia, and hyperpyrexia associated with PSH [44, 56]. Additional manifestations of PSH, including diaphoresis and dystonic posturing, have also been shown to respond to β-blockers [7]. In a small study, propranolol was compared with hydralazine for the treatment of hypertension and tachycardia due to PSH after brain injury. Both drugs effectively normalized blood pressure. Additionally, propranolol decreased heart rate by 21 %, cardiac index by 26 %, cardiac work by 35 %, pulmonary venous admixture by 15 %, and oxygen consumption by 18 %. In contrast, hydralazine increased these hemodynamic parameters [57]. In addition to the cardiovascular effects, propranolol has been shown to decrease the hyperthermic response to brain injury [58]. The broad actions of propranolol make it an effective and attractive medication for the treatment of PSH. Morphine is a potent μ-opioid receptor agonist. Although morphine’s analgesic action is helpful, the benefit from this drug probably results from stimulating medullary vagal nuclei, increasing the production of cholinergic effects, such as bradycardia, and inducing the release of histamine, causing peripheral vasodilation [44, 47, 59]. We recommend starting with intravenously administered morphine and then switching to a scheduled oral route of administration of morphine or oxycodone. The appropriate dose should be based on individual patient responses. Baclofen is a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA); it is a GABAB-specific agonist. Clinically, it is indicated for treatment of spasticity and to improve mobility. It decreases the number and severity of spasms, thus relieving associated pain, clonus, and muscle rigidity. The use of intrathecal infusion of baclofen (ITB) has been reported in some case studies with good effect. Generally before initiating ITB, one should use conventional therapy with sedatives, β-antagonists, and α-antagonists [60, 61]. Gabapentin is an analog of GABA. It was originally developed as an anticonvulsant, but it is perhaps more useful in the treatment of painful neuropathies, spasticity, and tremor [62, 63]. Although gabapentin and baclofen have a similar action and indications to treat spasticity, there is no head-to-head trial comparing these two agents. Baguley et al. [8] reported a case of a patient who received ITB 2 months after hospital admission. ITB markedly reduced tone and dysautonomic features while at rest, but when stimulated, the patient continued to experience dysautonomic episodes, specifically with muscle stretches and ranging of joints. The patient was then given gabapentin (300 mg three times daily) for treatment of suspected neuropathic pain syndrome. The addition of gabapentin immediately decreased dysautonomia and pain, with improved outcomes for sleep and agitation. They concluded that ITB was less effective than gabapentin when the

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two interventions were used concomitantly. They also presented another case where gabapentin was titrated to 600 mg three times daily without ITB, but in this case the patient had ongoing symptoms 1 month after initiation of treatment with gabapentin. Benzodiazepines are GABA receptor agonists that are frequently used for the treatment of PSH. The agents have favorable effects on physiologic parameters, including heart rate and blood pressure, and especially potent effects on agitation. They have been used with some success [7, 64, 65]. The concern with benzodiazepines is the possibility of worsening neurologic functioning in newly injured brain [66]. Short-acting benzodiazepines are preferable for patients early in the course and having severe bouts of PSH. As the need for standing benzodiazepines becomes established in a patient, we recommend longer-acting agents to decrease the bouts of hyperactivity. Bromocriptine is a synthetic dopamine agonist that stimulates dopamine type 2 receptors and antagonizes type 1 receptors in the hypothalamus and the neostriatum of the brain. The clinical similarities between PSH and neuroleptic malignant syndrome have led to the use of bromocriptine in PSH. However, as opposed to the role of dopamine in the pathophysiology of neuroleptic malignant syndrome, its role in the pathophysiology of PSH is very unclear. Case reports have reported the usefulness of bromocriptine, with the effectiveness probably enhanced when it is used in combination with other agents, especially morphine [7, 67]. In contrast to dopamine agonists, dopamine antagonists, such as chlorpromazine and haloperidol, have been used to manage PSH, but exacerbation of cognitive deficits, psychosis, and neuroleptic malignant syndrome as consequences have been reported [68, 69]. The symptoms from PSH, such as dystonia, hyperpyrexia, and posturing, can resemble the findings in neuroleptic malignant syndrome or side effects from the use of dopamine antagonists. On the basis of these case reports, the use of dopamine antagonists is discouraged because of possible worsening of symptoms. In cases where dystonia or posturing continues to persist, dantrolene can be added to the regimen. Dantrolene decreases muscle contraction by directly interfering with calcium ion release from the sarcoplasmic reticulum within skeletal muscle cells. Dantrolene can possibly be effective for the treatment of dystonic posturing, but the risk of causing hepatotoxicity can limit its use [21, 36, 70]. Monitoring liver function tests while patients are receiving dantrolene might help prevent hepatic failure. Management of PSH after brain injury remains a challenge. There is a wide variability in clinical practice with regard to drug choices, dosing, and the duration of therapy in these patients. This variability is partly due to a paucity of data from randomized clinical trials. Most of the published literature is in the form of case reports and is from small case

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series. Interpretation is difficult given the number of medications simultaneously started and the lack of comparison groups. Additionally, most studies failed to mention the drug dosage used in managing PSH, leaving us with limited evidence to optimize clinical management. Most often these agents will be used in combination on the basis of patient signs and symptoms. Future Directions To better understand PSH, a clear-cut definition must be proposed and a consensus adopted, without which concerted efforts are difficult. Attempts at finding valid biomarkers for the disease, whether neuroimaging or laboratory cutoff values, need to be made, and would help define the disease with diagnostic testing. Importantly, there is a need for further systemic measurements of treatment efficacy of the many different treatment approaches. As outlined, the medications for treatment of PSH have very plausible mechanisms of action and treat the underlying symptoms of the disease. However, the efficacy of one treatment versus another has not been studied. As patients need more than one medication, treatment algorithms need to be developed and tested against each other. This is not a call for randomized clinical trials as such trials would be exceedingly difficult to run and most likely would not be helpful. A more economic approach with different centers reporting different treatment algorithms, comparisons between centers, or comparisons between changes in treatment algorithms within centers would be most practical, economical, and helpful.

Conclusions Clinical examples of PSH have been described since 1929. Since then we have refined our understanding of the disease, starting with discrediting the epilepsy theory and moving to the development of the more accurate EIR model. We understand the many causes of PSH, from TBI to encephalitis, and the risk factors of young age and male gender. The negative impact on clinical outcomes has been shown in many populations. The treatment options have increased, with many case reports of responsiveness of symptoms to different medications. The next steps to advance our understanding are to develop a consensus definition of the syndrome, better understand the pathophysiology, and compare different treatment algorithms to refine our treatment strategies. Compliance with Ethics Guidelines Conflict of Interest H. Alex Choi declares no conflict of interest. Sang-Beom Jeon declares no conflict of interest. Sophie Samuel declares no conflict of interest. Teresa Allison declares no conflict of interest. Kiwon Lee declares no conflict of interest.

Curr Neurol Neurosci Rep (2013) :370 Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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