A narrative review of pharmacologic approaches to symptom management of pediatric patients diagnosed with anti-NMDA receptor encephalitis

Abstract

Anti-N-Methyl-D-Aspartate Receptor Encephalitis (ANMDARE) is one of the most common autoimmune encephalitis in the pediatric population. Patients with ANMDARE initially present with a prodrome of neuropsychiatric symptoms followed by progressively worsening seizures, agitation, and movement disorders. Complications can include problems such as aggression, insomnia, catatonia, and autonomic instability. Due to the complexity of this disease process, symptom management can be complex and may lead to significant polypharmacy. The goal of this review is to educate clinicians about the challenges of managing this disorder and providing guidance in symptom management.

Keywords

Anti-NMDA receptor encephalitis ANMDARE pharmacology treatment behavior

1 Introduction

Anti-NMDA (N-Methyl-D-aspartate)- receptor encephalitis (ANMDARE) is an acute autoimmune disorder that typically presents with a flu-like syndrome and then progresses with a cascade of other syndromes, including psychiatric syndromes, seizures, movement disorders, and cognitive dysfunction. It was initially described in 2007 in a case series of young women with ovarian tumors who presented with psychiatric symptoms [1]. Since its initial identification, it has become a well recognized cause of encephalitis in children and adults. In 2012, the California Encephalitis Project reported that ANMDARE occurs over 4 times as frequently as other enteroviruses, herpes simplex virus 1, varicella-zoster virus, and West Nile virus [2]. Furthermore, in this cohort it was observed that 65% of the cases identified were in the pediatric population.

The syndrome typically begins with a constellation of “flu”-like symptoms, which can include nausea, vomiting, fever, headache, and fatigue [3]. They began to manifest typically in the first 2 weeks following the prodrome and within the first month 87% of patients will demonstrate neuropsychiatric and autonomic sequealae [4]. Symptoms include hypoventilation, loss of consciousness, autonomic instability, movement disorders, behavior and speech problems, disorders of consciousness, and seizures [3]. Common neuropsychiatric features can include irritability, mutism, behavioral regression, hallucinations, aggression, agitation, and depression. Due to these features, these patients often may be referred to psychiatric services and misdiagnosed with a psychiatric illness [2].

Treatment for the primary disease process includes tumor resection, if a tumor is identified, and immunotherapies such as corticosteroids, intravenous immunoglobulins (IVIG), plasmapheresis (PLEX), rituximab, and cyclophosphamide [4 –9]. However, response to immunotherapy may be variable and often second line treatments are needed. Titulaer 2013 documented that 44% of patients failed first line immunotherapy [4]. The interim symptom management may be quite challenging for the medical team.

Compared to other encephalopathies, ANMDARE is more likely to present with psychiatric symptoms and thus may be initially treated accordingly. Based on data from a national autoimmune encephalitis case registry, 40% of patients were first hospitalized in a psychiatric hospital and 47% were transferred to a medical unit based on suspicion of antipsychotic intolerance [10]. The multitude of symptoms, degree of behavior dysfunction, and refractory responses to psychotropic medications can quickly all result in aggressive polypharmacy. Once ANMDARE is identified, patients who are agitated or have a movement disorder may require the use of restraint in order to safely receive intravenous medications, PLEX, or even mechanical ventilation. Both physical and chemical restraints may enhance agitation and subsequently increase the degree of medications are used.

Although the literature discusses many protocols to treat the immunological challenges of this condition, there is no literature that discusses the symptomatic challenges of these patients. Satori et al note that all the patients in their case series had behavioral, psychiatric, and movement disorders but there are no published guidelines for the management of the medical complications [8]. The challenge of the physiatrist or neurologist is to identify and control symptoms and appropriately wean medication, so that the patient can actively participate in the rehabilitation process. The purpose of this report is to provide a focused narrative review of the current literature regarding the symptomatic treatment of pediatric patients with ANMDARE. A comprehensive literature search in PubMed from selected articles published between 2007 and 2019 were used in formulation of this paper. The keywords “anti-NMDA receptor encephalitis” and “pediatrics” yielded 108 titles. Narrowing the search criteria using key words “management” AND/OR” “treatment” AND/OR “pharmacology” resulted in 69 titles. However, only 5 briefly discussed pharmacologic management beyond psychiatric symptoms or disease management.

As mentioned previously, the first presenting signs of ANMDARE may be psychiatric symptoms. Although some studies have found no difference in the frequency of psychiatric presentations between younger children and adolescents [11], other studies have reported a higher prevalence with increasing age [4 , 12]. It is estimated that between 50–75% of patients are first seen by a psychiatrist [3 , 13–15]. Initial presenting signs of ANMDARE may be behaviors such as disorders of thought, disorientation, psychosis, hallucinations, agitation, and mania. The majority of affected children also present with changes in behavior. However, pediatric changes may be more subtle when compared to those of an adult. Children may demonstrate signs of irritability, tantrums, or hyperactivity [16].

A prevalent theory for schizophrenia is the role of NMDA receptor hypofunction and symptoms. In 2010, Kantowitz et al described NMDA receptor dysfunction as the “final common pathway” linking the positive and negative symptoms of schizophrenia. Often, treatment considerations are based on the premises of approaching these patients from a psychiatric symptom point of view.

In contrast to newly diagnosed schizophrenics, patients with ANMDARE more frequently manifest the “negative” symptoms of schizophrenia: unusual thought content, disorientation, difficulty in abstract thinking, and poor rapport [13]. However, those with higher antibody titers had a greater likelihood of experiencing positive symptoms such as hallucinations and/or delusions. This finding was mirrored by Gibson et al who found that their adult patient population also tended to have more disorders of thought compared to hallucinations and delusions [15].

However, it is challenging treating ANMDARE with antipsychotics as many medications have side effects such as akathisia and rigidity which also mimic the movement disorders that accompany ANMDARE [17 –20]. Patients with ANMDARE may also present with dystonia and dyskinesias which may be difficult to distinguish from extrapyramidal symptoms associated with the administration of antipsychotics. Furthermore, even in the absence of antipsychotics, those with ANMDARE have a significant risk of developing fever, rigidity, and autonomic instability that mimic neuroleptic malignant syndrome [13 , 21]. In a study by Mohammad et al, it was found that 7 out of 12 pediatric patients with ANMDARE who received antipsychotics had adverse reactions including: neuroleptic malignant syndrome, dystonic reactions, prolonged QT, dysarthria, and worsening agitation [18]. In the brain injury population, psychotropic medications were associated with an increase in length of stay on an acute inpatient rehabilitation unit [22]. Therefore, when clinicians are managing the behaviors of patients with ANMDARE, antipsychotics should be used as secondary or tertiary options when treating aggression or cognitive dysfunction. Alternative medications for behavior control are suggested later in this article.

Moreover, there are limited options for treating “positive” psychotic symptoms such as hallucinations, delusions, or racing thoughts when treating ANMDARE, in which case antipsychotics may be the only treatment option. The literature does not support a single antipsychotic as having the best efficacy in these patients. The NMDA receptor (NMDAR) hypofunction model of psychosis theorizes that agents such as olanzapine, clozapine, and lamotrigine could arrest the acute neurotoxic process associated with NMDAR hypofunction [23 –25]. However, clozapine does carry a risk for serious side effects such as neutropenia, agranulocytosis, seizures, and cardiomyopathy [26]. Many clinicians will use haloperidol to acutely treat psychosis and agitation in patients with ANMDARE [9 , 28]. However, the risk of extrapyramidal symptoms (EPS) posed by this medication is not uncommon and may be amplified in patients with ANMDARE. Furthermore, it is well documented in the brain injury literature that patients who have received haloperidol have worse outcomes than patients that do not [29 –31]. In initial treatment of ANMDARE psychosis, one may want to consider use of a medication such as quetiapine which has a low affinity for D2 receptors and is less likely to cause EPS [32]. In addition to its antipsychotic properties, quetiapine can be utilized for insomnia due to its H₁ receptor affinity [32 –34]. Quetiapine becomes more challenging to use in the rehabilitation setting when it is administered more frequently due to its sedating properties. Also there are times when a medication with a higher affinity for D₂ receptors may be needed if the patient has developed a movement disorder/akathisia in addition to psychotic symptoms, in which case clinicians would consider prescribing medications such as risperidone or aripiprazole [27]. Chew and Zafonte theorized that since aripiprazole is a partial D2 and D3 agonist, it may be an appropriate antipsychotic choice for patients with traumatic brain injury. As of yet there are no clinical studies to support that hypothesis [35]; however, Chapman and Vause documented a case of a 16 year old boy who had worsening motor symptoms after a trial of aripiprazole [27]. Olanzapine, because it is structurally similar to clozapine, may be another option but its risk of EPS is higher than risperidone and aripiprazole [24, 32]. In order to address the high prevalence of dystonia and to reduce the risk of EPS, anticholinergics such as trihexyphenidyl or benztropine could be considered as an adjunct treatment [17].

2 Agitation

Agitation management in patients with ANMDARE is quite challenging. In contrast to their work in the setting of acute hospitalization, physicians dealing with rehabilitation are challenged with the task of managing behavior while not interfering with cognitive processes that help with the rehabilitation process. Based on the neurophysiologic processes described above that occur in the brain of the patient with ANMDARE, should the clinician approach the patient as if they are a psychiatric patient or approach them from a brain injury medicine perspective? From the brain injury literature, we know that medications used to decrease agitated behavior in psychiatric patients, such as neuroleptics, benzodiazepines, and some antiepileptic medications, may worsen motor symptoms associated with ANMDARE and may have a negative impact on outcomes in patients with brain injuries [36].

Prior to use of medications, non-pharmacologic strategies should be implemented. Consider utilizing strategies that are useful in agitated brain injured patients such as reducing overstimulation and clustering care, lessening physical restraints, and evaluating the environment [26, 37]. Reassessing the sleep-wake cycles to determine if they are contributing to agitation is important as irregular sleep-wake cycles often agitate patients with both brain injuries and ANMDARE [16, 38]. High dose steroids which are used in the treatment of ANMDARE may also be a contributing factor to agitation and insomnia [39].

Beta blockers, such as propranolol, are often chosen as first line medications to treat agitation [40]. This class of medication has a long history in not only being prescribed for hypertension, but also migraines, anxiety, akathisia and aggression in traumatic brain injury [40] as well as in patients with intellectual disabilities [41]. Propranolol is a short-acting, lipophilic nonselective beta-blocker, which inhibits both Beta 1- and Beta 2-adrenergic receptors. Since beta blockers are lipophilic they can penetrate the blood-brain barrier, diminishing circulating catecholamine and reducing the rate of resting metabolism [42]. Also beta-blockers can be helpful in treating the symptoms of dysautonomia such as hypertension, diaphoresis, hyperpyrexia, and tachycardia [43] which are associated with ANMDARE.

Clonidine may have some efficacy in treating aggression in ANMDARE [18 , 44]. It is a central and peripheral alpha-adrenergic agonist that acts on presynaptic neurons and inhibits noradrenergic release and transmission at the synapse. In addition it reduces central sympathetic outflow from the hypothalamus and ventrolateral medulla and enhances sympathetic inhibition through the brain stem which may also assist with autonomic dysfunction in ANMDARE [45]. Also, besides working peripherally to manage symptoms of hypertension, clonidine can stimulate the postsynaptic α2A adrenoceptors in the dorsolateral prefrontal cortex. For this reason clonidine is effective in managing agitation and is utilized in the treatment for ADHD [46].

Guanfacine is a selective norepinephrine and α2A−adrenoreceptor agonist in the prefrontal cortex [47]. It improves prefrontal cortex function by mimicking norepinephrine’s actions at the α−2A adrenoreceptor agonist receptor, post synaptic of the NMDA receptor synapse [48]. However, in comparison to clonidine, it is significantly weaker in locus coeruleus inhibition and has less effect on decreasing central nervous system arousal [47]. Although there are some studies that demonstrate a reduction in oppositional, self-injurious, and repetitive behaviors in autistic children [49], there is no significant literature studying its use in behavior on patients with brain injury or ANMDARE.

Benzodiazepines are often advocated in literature for the treatment of agitation in ANMDARE [32 , 51]. They have been utilized in the management of agitation and insomnia in those who have ANMDARE [27]. However, there are potential complications in utilizing benzodiazepines. They are known to impair memory and other aspects of cognition, particularly in patients with brain injuries [31, 52]. However, prior to utilizing benzodiazepines, one may consider using buspirone which is non-sedative and does not block GABAergic or benzodiazepine receptors [26, 53]. Furthermore buspirone, which antagonizes D2 receptors, acts on presynaptic 5 HT1A receptors as an agonist and on the post-synaptic 5 HT1A receptors as a partial agonist [53]. Although the exact mechanism of action is unclear, there is evidence to suggest that buspirone can be effective in the treatment of aggressive behaviors and agitation after traumatic brain injury [26]. However, it has the potential to reduce the seizure threshold [54].

The use of antiepileptics to mitigate symptoms of aggression and impulsivity have limited support in the literature [55]. In animal models, valproic acid has been shown to antagonize NMDA receptors, reduce cortical glutamate release, increase dopamine in the pre frontal cortex, and enhance the activity of GABA [56]. Although, there are limited studies which support the efficacy of valproic acid in management of agitation in brain injury, many experts will advocate for its use [26, 57]. Mohammad et al have suggested using antiepileptic medications such as sodium valproate, phenobarbital, or long acting benzodiazepines for seizure control so that they may improve behavioral symptoms but there is no evidence to support that there is an adjunctive benefit [18].

3 Seizures

Seizures may be the presenting sign for ANMDARE in approximately one third of children [8]. Typically, they present in the early stages of the disease process. The EEG in ANMDARE is abnormal in over 90% of cases; however, epileptogenic abnormalities are only identified in 24–50% of cases [58]. Gildiner et al identified 294 cases of clinical seizures (65.9%); however, only 39 had seizures that were recognized on EEG [59]. An abnormal EEG is often one of the criteria to help diagnose ANMDARE, as well as the extreme delta brush pattern which may be highly indicative when identifying the condition [60, 61]. Although delta brush patterns are not unique to ANMDARE, they may be highly suggestive of the diagnosis in conjunction with clinical symptoms that may prompt early recognition and treatment [62].The overlap of movement disorders with seizures can lead to misinterpretation of the abnormal movements and lead to over-escalation of seizure medications or under recognition of seizures [16, 21]. The use of antipsychotics may also contribute to EEG abnormalities making it more difficult to interpret [63]. Unfortunately, seizures can reappear at any time during the disease process as well [21]. An argument can be made to consider seizure medications that may hel with other symptoms that are present in ANMDARE. As mentioned previously, sodium valproate, phenobarbital, or long acting benzodiazepines may play a role in behavior control [18]. Additionally, antiepileptic medications such as clobazam, carbamazepine, levetiracetam, or valproic acid as may also play a role in the management of autoimmune movement disorders as well as seizures [50].

4 Sleep

It has been documented that in cases of ANMDARE, insomnia will precede the onset of movement disorders and continue even after those disorders recede. This may signify that sleep disturbances which accompany ANMDARE may be a primary sleep disruption as opposed to a component of the psychiatric and motor components of this disorder [64]. This can be quite challenging to the clinician as one has to balance medication selections that will function to improve the sleep cycle without interfering with cognitive processing. In general, behavior modifications and sleep hygiene strategies are preferred prior to the introduction of medications. However, in many cases it is not reasonable to assume that they can work in isolation and should function in conjunction with each other.

Despite being advocated for in the treatment of movement disorders in patients with ANMDARE, dosing and anticholinergic selections for sleep may not be the best clinical choice in a rehabilitation setting. In patients who have brain injuries, they can produce negative cognitive effects such as disturbances in memory and new learning. In addition, when used for doses that induce sleep, they can produce a “hang over” effect [65].

The use of melatonin in the literature is variable. Melatonin is secreted by the pineal gland during darkness and its secretion is suppressed by light. It is believed to play a key role in regulating circadian rhythms. Also, melatonin can improve sleep wake rhythm disturbances and decrease sleep onset latency in children with sleep disorders; however, it does not decrease night awakenings [66]. In this case, it may have to be used in conjunction with other medications. It is also important to note that melatonin may be more effective when given two hours prior to bedtime [67]. It is also important to note that melatonin may increase the anxiolytic effects of benzodiazepines [65].

As mentioned in this article, clonidine is used by many clinicians in the management of sleep disorders in the pediatric population and as a medication that may be helpful in the management of aggression in patients with ANMDARE. Clonidine α2-agonists mimic some aspects of natural sleep and cause sedation via a mechanism involving inhibition of the locus coeruleus and subsequent increase of ventrolateral preoptic nucleus firing [46].

Alternatively, one may consider trazodone. It is one of the most commonly prescribed medications for sleep difficulties encountered in traumatic brain injury as well as an insomnia medication for children with mood and anxiety disorders [57 , 68–72]. Trazodone is a serotonin antagonist reuptake inhibitor which decreases sleep latency and increases total sleep time [73]. A literature review by Holloway et al suggests that trazodone may be the safest and most effective antidepressant for insomnia in children [74]. It has a long history of demonstrated efficacy in brain injury patients. Furthermore, it has a low risk of inducing mania [75]. However, it may increase risk of prolonged QT syndrome when used in conjunction with psychotropic medications.

Mirtazapine is a noradrenergic serotonergic antidepressant that works by inhibiting presynaptic α2, 5HT2, and 5HT3 receptors [76]. It has been shown to improve various sleep parameters, including sleep latency, and total sleep time but does not alter REM latency [77]. It may also increase appetite.

As noted elsewhere, benzodiazepines are also noted to be used for sleep in the literature for ANMDARE [27]. However, patients with ANMDARE may require sleep assistance during and beyond the acute hospitalization. Benzodiazepines have deleterious side effects that can interfere with the rehabilitation process. They have effects on memory and cognition, and the patient may develop a physical dependency [78]. In addition, benzodiazepines may alter sleep architecture by increasing the time spent in non-REM sleep [38].

Medications that have been effective in brain injury include zolpidem and zaleplon [69 , 79]. Zolpidem has an affinity for the GABA receptor containing the alpha-1 subunits [76, 77]. It does not have significant rebound insomnia, withdrawal effects, or tolerance that are usually associated with benzodiazepines [76, 80]. It works by increasing sleep time and decreasing awakenings. However, during the time the medication is “active” it can cause sedation and amnesia. Zaleplon has a similar action; however, it retains some of the muscle relaxation, anxiolytic, and anticonvulsant properties of the benzodiazepines[76].

5 Movement disorder/dystonia

More children than adults present with movement disorders [4]. It is often difficult for some clinicians to distinguish complex partial seizure from them. Stereotypies and motor perseverations such as repetitive oral facial movements or violent thrashing movements are common [19]. It is thought that this is most likely due to the loss of fronto-striatal inhibition or cortico-limbic control in the hypothalamus and brainstem [19].

ANMDARE is associated with movement disorders such as dystonia, chorea, and athetosis. It inactivates GABAergic neurons leading to disinhibition of excitatory pathways and increase of extracellular glutamate [21]. The striatum receives inputs from the cortex and substantia nigra and projects to the globus pallidus internus through direct and indirect pathways. The direct pathway mediates GABA-ergic inhibition of the globus pallidus internus. As ANMDARE causes the excitatory pathway to be disinhibited, the thalamic projections to the cortex produce dystonia [81]. As a result, anticholinergic medications are commonly used to treat ANMDARE induced dystonia [18, 51]. Typically, trihexyphenidyl and benztropine are the most common. Trihexyphenidyl has a long history of being effective and well tolerated in the pediatric population [82, 83]. The anticholinergic activity can be used to also treat hyper-salivation which may occur with ANMDARE as well [84, 85].

Medications used for hypertonia can also be used to treat ANMDARE induced dystonia. Oral medications have demonstrated proven efficacy by inhibiting excitatory neurotransmitters or enhancing inhibitory neurotransmitters at the level of the spinal cord [86]. Many of the excitatory cortical spinal pathways that lead to spasticity are believed to be influenced by Gamma-aminobutyric acid (GABA), which is the main rationale for some of the pharmacologic options of treatment [87]. There are currently two recognized GABA receptors: GABA_A and GABA_B.

Oral medications provide some advantages in the treatment of spasticity. They are noninvasive, impermanent, and have proven to be clinically effective [86, 88]. However, some may be accompanied by side effects, including weakness and drowsiness that may limit their effectiveness. Benzodiazepines act near the GABA_A receptor to hyperpolarize the cell membrane and thus cause a presynaptic inhibition of polysynaptic and monosynaptic reflexes [86 , 89]. Benzodiazepine medications like diazepam and clonazepam are the most common. However, the effect that these medications have on the central nervous system is a limiting factor. These medications have the potential to cause sedation that can exacerbate potential cognitive deficits. Benzodiazepine overdose may also lead to somnolence, coma, or death. These medications also carry the risk of physiologic addiction as well as a life-threatening withdrawal syndrome if they are abruptly weaned or discontinued. There also has been clinical evidence to demonstrate that these medications may interfere with neurologic recovery after brain injury and stroke, which may make some clinicians hesitant to use them during the rehabilitation course of treatment [87].

Baclofen is a GABA_B agonist which acts both presynaptically and postsynaptically by crossing the blood brain barrier and acting at the spinal cord. Because of these properties, it is recommended for spasticity resulting from cerebral and spinal cord origin [88]. Potential side effects can also include sedation, confusion, dizziness, and nausea [88]. Baclofen can also lower seizure threshold in patients who have seizures [88]. Abrupt withdrawal can also lead to seizures, mental status changes, or cardiovascular collapse. Gabapentin is an anticonvulsant with a chemical structure very similar to GABA. Although most commonly used now for neuropathic pain, it has shown some efficacy for decreasing spasticity and dystonia at very high doses [87, 90]. Its side effects include ataxia, headaches, tremors, somnolence, fainting, and nystagmus [86, 88].

Another class of medications that has been used in treating spasticity is the imidazolines, alpha-2 adrenergic agents. These include clonidine, which is known as a blood pressure medication, and tizanidine. These are believed to inhibit presynaptic afferents at the level of the spinal cord as well as inhibit the release of glutamate, an excitatory neurotransmitter [88]. These agents are less utilized than the other medications mentioned above due to side effect profile and clinical efficacy [86, 87]. Potential side effects include hypotension, sedation, dizziness, hallucinations, fatigue, and hepatotoxicity [86, 88].

Dantrolene is another possible mediation that could be considered in patients with ANMDARE. It is the only medication utilized for hypertonia that does not have its site of action within the central nervous system but instead works directly on the muscle peripherally [86]. Its mechanism of action is to block calcium release from the sarcoplasmic reticulum which results in decreased contractility of the muscle. Dantrolene has shown efficacy in not only reducing tone but athetoid features as well [89, 91]. Because it limits muscle contraction in all muscles, generalized weakness can also be a potential side effect. The major concerns regarding dantrolene are that it has significantly higher risks of hepatotoxicity and interacts with other medications. In a disease process such as ANMDARE in which polypharmacy is often needed to control a constellation of symptoms, the risk of interaction may be greater. Risks for hepatotoxicity with dantrolene are increased at higher doses and in women older than 40 [86].

6 Cognition

Patients with ANMDARE are at significant risk for cognitive deficits, predominantly in the areas of working memory and executive functioning [92 –94]. A meta-analysis by McKennon et al identified neuropsychological deficits in over 75% of patients in the acute, subacute, and long-term phases of recovery. Over time, there was a preservation in intellect in the majority of patients; however, high rates of executive function and memory remained impaired [95]. When patients were followed several years post infection, more than half of them were found to have persistent deficits in attention, memory, language skills and executive function [96, 97]

Following brain trauma, there have been several articles recommending the use of catecholamine based pharmacologic interventions to assist in functional recovery after brain injury [98 –103]. The efficacy of D₂ receptor agonists such as methylphenidate and amantadine have been long debated [98]. There is evidence to suggest benefits in mood, agitation, and attentional deficits. However, review of the literature for acute care management reveals several limitations including small numbers of participants, heterogeneous outcome measures, and variable study designs [104]. Furthermore, one should use caution when administering neurostimulants in the acute and subacute phase of ANMDARE. For example, amantadine has antagonistic qualities on NMDA receptors as it stimulates dopamine release, delays its reuptake, and increases the total number of dopamine receptors [105]. However, due to the dysfunction in the NMDA receptors in ANMDARE, it may be difficult to predict the psychological or motor sequelae to dopamine agonists in certain phases of this disease process. However, based on persistent neuropsychological deficits, there may be a more definitive role for these medications in the post-acute phase. Guanfacine, which works as an alpha-adrenergic agonist, may have a reduced risk of potential behavior or movement exacerbation. There are some limited case studies in which guanfacine demonstrates improvement in working memory in mild traumatic brain injury and acute disseminated encephalomyelitis [106, 107]. However, there is no significant literature studying its benefit in moderate to severe brain injury or ANMDARE. In addition, there are case reports of its usefulness in improving working memory in schizophrenia and schizotypical disorder [108, 109].

7 Conclusion

Symptomatic management of ANMDARE can be very challenging clinically. Patients may present with a constellation of varying symptoms that have inconsistent responses to medications. The literature surrounding symptomatic management of these patients primarily addresses them from a psychiatric standpoint based on early symptoms of behavior and psychiatric changes. They often have erratic behaviors in the acute care setting that compel clinicians to utilize excessive chemical restraints. However, utilization of neuroleptic medications carries the risk of exacerbating potentially life-threatening conditions. It is important to note that those with ANMDARE do not have a true psychiatric condition nor have they experienced a traumatic brain injury. Many behavioral algorithms for symptom management and treatment are written solely from a traumatic brain injury or a psychiatric perspective. It is important to take note of the pathophysiology that is associated with this condition and recognize both approaches to maximize symptom management. Communication between critical care, neurology, psychiatry, and physiatry are important in determining appropriate clinical care and reducing the polypharmacy that is often associated in treatment.

Conflict of interest

The author has no conflicts of interest to report.

Funding

None.

References

Dalmau

, Tüzün

, Wu

, Masjuan

, Rossi

, Voloschin

, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25–36. doi: 10.1002/ana.21050

Gable

, Sheriff

, Dalmau

, Tilley

, Glaser

. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the california encephalitis project. Clin Infect Dis. 2012;54(7):899–904. doi: 10.1007/s10096-009-0799-0

Dalmau

, Gleichman

, Hughes

, Rossi

, Peng

, Dessain

, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091–8. doi: 10.1016/S1474-4422(08)70224-2

Titulaer

, McCracken

, Gabilondo

, Armangué

, Glaser

, Iizuka

, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study. Lancet Neurol. 2013;12(2):157–65. doi: 10.1016/S1474-4422(12)70310-1

Bartolini

, Muscal

. Differences in treatment of anti-NMDA receptor encephalitis: results of a worldwide survey. J Neurol. 2017;264(4):647–53. doi: 10.1007/s00415-017-8407-1

Salvucci

, Devine

, Hammond

, Sheth

. Pediatric anti-NMDA (N-methyl D-Aspartate) receptor encephalitis. Pediatr Neurol. 2014;50(5):507–10. doi: 10.1016/j.pediatrneurol.2014.01.012

Suppiej

, Nosadini

, Zuliani

, Pelizza

, Toldo

, Bertossi

, et al. Plasma exchange in pediatric anti-NMDAR encephalitis: A systematic review. Brain Dev. 2016;38(7):613–22. doi: 10.1016/j.braindev.2016.01.009

Sartori

, Nosadini

, Cesaroni

, Falsaperla

, Capovilla

, Beccaria

, et al. Paediatric anti-N-methyl-d-aspartate receptor encephalitis: The first Italian multicenter case series. Eur J Paediatr Neurol. 2015;19(4):453–63. doi: 10.1016/j.ejpn.2015.02.006

Ryan

. Anti-N-Methyl-d-Aspartate Receptor-Mediated Encephalitis: Recent Advances in Diagnosis and Treatment in Children. Curr Probl Pediatr Adolesc Health Care. 2016;46(2):58–61. doi: 10.1016/j.cppeds.2015.11.005

10.

Lejuste

, Thomas

, Picard

, Desestret

, Ducray

, Rogemond

, et al. Neuroleptic intolerance in patients with anti-NMDAR encephalitis. Neurol - Neuroimmunol Neuroinflammation. 2016;3(5):e280. doi: 10.1212/NXI.0000000000000280

11.

Wang

, Zhang

, Yin

, Lu

, Yin

, He

, et al. Anti-N-methyl-D-aspartate receptor encephalitis in children of Central South China: Clinical features, treatment, influencing factors, and outcomes. J Neuroimmunol. 2017;312(January):59–65. doi: 10.1016/j.jneuroim.2017.09.005

12.

Sai

, Zhang

, Feng

MEI

, Tang

, Liao

, Tan

. Clinical diagnosis and treatment of pediatric anti-N-methyl-D-aspartate receptor encephalitis: A single center retrospective study. Exp Ther Med. 2018;16:1442–8. doi: 10.3892/etm.2018.6329

13.

Wang

, Zhang

, Chen

, Deng

, Wang

, et al. Comparisons between Psychiatric Symptoms of Patients with Anti-NMDAR Encephalitis and New-Onset Psychiatric Patients. Neuropsychobiology. 2018;75(2):72–80. doi: 10.1016/j.jns.2017.04.007

14.

Maat

, De Graaff

, Van Beveren

, Hulsenboom

, Verdijk

, Koorengevel

, et al. Psychiatric phenomena as initial manifestation of encephalitis by anti-NMDAR antibodies. Acta Neuropsychiatr. 2013;25(3):128–36. doi: 10.1111/acn.12013

15.

Gibson

, Pollak

, Blackman

, Thornton

, Moran

, David

. The Psychiatric Phenotype of Anti-NMDA Receptor Encephalitis. J Neuropsychiatry Clin Neurosci. 2019;31(1):70–9. doi: 10.1176/appi.neuropsych.17120343

16.

Florance

, Davis

, Lam

, Szperka

, Zhou

, Ahmad

, et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009;66(1):11–8. doi: 10.1002/ana.21756.Anti

17.

Haddad

, Dursun

. Neurological Complications of Psychiatric Drugs: clinical features and management. Hum Psychopharmacol Clin Exp. 2008;23:15–26. doi: 10.1002/hup

18.

Mohammad

, Jones

, Hong

, Nosadini

, Sharpe

, Pillai

, et al. Symptomatic treatment of children with anti-NMDAR encephalitis. Dev Med Child Neurol. 2016;58(4):376–84. doi: 10.1111/dmcn.12882

19.

Mohammad

, Fung

VSC

, Grattan-Smith

, Gill

, Pillai

, Ramanathan

, et al. Movement disorders in children with anti-NMDAR encephalitis and other autoimmune encephalopathies. Mov Disord. 2014;29(12):1539–42. doi: 10.1002/mds.25999

20.

Goenka

, Jain

, Nariai

, Spiro

, Steinschneider

, Dalmau

. Extended clinical spectrum of Anti NMDA receptor encephalitis in children: A case series. Pediatr Neurol. 2017;71(0):1921–3. doi: 10.1016/j.pediatrneurol.2017.03.010

21.

Dalmau

, Lancaster

, Martinez-Hernandez

, Rosenfeld

, Balice-Gordon

. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10(1):63–74. doi: 10.1016/S1474-4422(10)70253-2

22.

Hammond

, Barrett

, Shea

, Seel

, McAlister

, Kaelin

, et al. Psychotropic medication use during inpatient rehabilitation for traumatic brain injury. Arch Phys Med Rehabil. 2015;96(8):S256–S273e14. doi: 10.1016/j.apmr.2015.01.025

23.

Farber

. NMDA receptor hypofunction model of psychosis. Ann NY Acad Sci. 2003;6(1003):6119–30. doi: 10.1196/annals.1300.008

24.

Kuppuswamy

, Takala

, Sola

. Management of psychiatric symptoms in anti-NMDAR encephalitis: A case series, literature review and future directions. Gen Hosp Psychiatry. 2014;36(4):388–91. doi: 10.1016/j.genhosppsych.2014.02.010

25.

Kantrowitz

, Javitt

. N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: The final common pathway on the road to schizophrenia? Brain Res Bull. 2010;83(3-4):108–21. doi: 10.1016/j.brainresbull.2010.04.006

26.

Luauté

, Plantier

, Wiart

, Tell

, Luaute

. Care management of the agitation or aggressiveness crisis in patients with TBI. Systematic review of the literature and practice recommendations. Ann Phys Rehabil Med. 2016;59(1):58–67. doi: 10.1016/j.rehab.2015.11.001

27.

Chapman

, Vause

. Anti-NMDA Receptor Encephalitis: Diagnosis, Psychiatric Presentation, and Treatment. Am J Psychiatry. 2011;168(3):245–51. doi: 10.1176/appi.ajp.2010.10020181

28.

Lazar-Molnar

, Tebo

. Autoimmune NMDA receptor encephalitis. Clin Chim Acta. 2015;438:90–7. doi: 10.1016/j.cca.2014.08.010

29.

Hoffman

, Cheng

, Zafonte

, Kline

. Administration of haloperidol and risperidone after neurobehavioral testing hinders the recovery of traumatic brain injury-induced deficits. Life Sci. 2008;83(17-18):602–7. doi: 10.1016/j.lfs.2008.08.007

30.

Folweiler

KAKA

, Bondi

COCOCOCO

, Ogunsanya

EAEAEA

, LaPorte

MJMJMJMJMJ

, Leary

JBJBJB

, Radabaugh

HLHLHL

, et al. Combining the Antipsychotic Drug Haloperidol and Environmental Enrichment after Traumatic Brain Injury Is a Double-Edged Sword. J Neurotrauma. 2017;34(2):451–8. doi: 10.1089/neu.2016.4417

31.

Goldstein

. Common drugs may influence motor recovery after stroke. The Sygen In Acute Stroke Study Investigators. Neurology. 1995;45(5):865–71. doi: 10.1212/wnl.45.5.865

32.

Schumacher

, Mann

, MacKenzie

. Agitation Management in Pediatric Males with Anti-N-Methyl-D-Aspartate Receptor Encephalitis. J Child Adolesc Psychopharmacol. 2016;26(10):939–43. doi: 10.1089/cap.2016.0102

33.

Joyce

, Witcher

, Herrup

, Kaur

, Mendez-Rico

, Silver

, et al. Evaluation of the safety of quetiapine in treating delirium in critically ill children: A retrospective review. J Child Adolesc Psychopharmacol. 2015;25(9):666–70. doi: 10.1089/cap.2015.0093

34.

Cohen

, Bonnot

, Bodeau

, Consoli

, Laurent

. Adverse effects of second-generation antipsychotics in children and adolescents: A bayesian meta-analysis. J Clin Psychopharmacol. 2012;32(3):309–16. doi: 10.1097/JCP.0b013e3182549259

35.

Chew

, Zafonte

. Pharmacological management of neurobehavioral disorders following traumatic brain injury–a state-of-the-art review. J Rehabil Res Dev. 2009;46(6):851–79. doi: 10.1682/JRRD.2008.09.0120

36.

Mysiw

, Bogner

, Corrigan

, Fugate

, Clinchot

, Kadyan

. The impact of acute care medications on rehabilitation outcome after traumatic brain injury. Brain Inj. 2006;20(9):905–11. doi: 10.1080/02699050600743972

37.

Plantier

, Hamonet

, Wiart

, Luaute

, Luauté

, Stefan

, et al. Non pharmacological treatments for psychological and behavioural disorders following traumatic brain injury (TBI). A systematic literature review and expert opinion leading to recommendations. Ann Phys Rehabil Med. 2016;59(1):31–41. doi: 10.1016/j.rehab.2015.10.003

38.

Ouellet

, Beaulieu-Bonneau

, Morin

. Sleep-wake disturbances after traumatic brain injury. Lancet Neurol. 2015;14(7):1514–21. doi: 10.1016/S1474-4422(15)00068-X

39.

Neyens

, Gaskill

, Chalela

. Critical Care Management of Anti-N-Methyl-d- Aspartate Receptor Encephalitis. Crit Care Med. 2018;46(9):1514–21. doi: 10.1097/CCM.0000000000003268

40.

Fleminger

, Greenwood

, Oliver

. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane Database Syst Rev. 2006;(1).

41.

Tsiouris

. Pharmacotherapy for aggressive behaviours in persons with intellectual disabilities: Treatment or mistreatment? J Intellect Disabil Res. 2010;54(1):1–16. doi: 10.1111/j.1365-2788.2009.01232.x

42.

Welle , Stephen , Schwartz Ronald

. Reduced Metabolic Rate During B-Adrenergic Blockade in Humans. . Metabolism. 1991;40(6):419–622. doi: 10.1016/0026-0495(91)90053-y

43.

Rabinstein

. Paroxysmal autonomic instability after brain injury. Arch Neurol. 2004;61(10):321–8. doi: 10.1001/archneur.61.10.1625-b

44.

Granata

, Matricardi

, Ragona

, Freri

, Zibordi

, Andreetta

, et al. Pediatric NMDAR encephalitis: A single center observation study with a closer look at movement disorders. Eur J Paediatr Neurol. 2018;22(2):301–7. doi: 10.1016/j.ejpn.2018.01.012

45.

Baguley

, et al. A critical review of the pathophysiology of dysautonomia following traumatic brain injury. Neurocrit Care. 2008;8(2):293–300. doi: 10.1007/s12028-007-9021-3

46.

Crassous

P-A

, Denis

, Paris

, Sénard

. Interest of alpha2-adrenergic agonists and antagonists in clinical practice: background, facts and perspectives. Curr Top Med Chem. 2007;7(2):187–94. doi: 10.2174/156802607779318190

47.

Arnsten

AFT

. Catecholamine modulation of prefrontal cortical cognitive function. Trends Cogn Sci. 1998;2(11):436–47. doi: 10.1016/S1364-6613(98)01240-6

48.

Arnsten

AFT

. Guanfacine’s Mechanism of Action in Treating Prefrontal Cortical Disorders: Successful Translation Across Species. Neurobiol Learn Mem. 2020;176:1–15. doi: 10.1002/aic

49.

Coleman

, Adams

, Anderson

, Frye

. Rating of the effectiveness of 26 psychiatric and seizure medications for autism spectrum disorder: Results of a national survey. J Child Adolesc Psychopharmacol. 2019;29(2):107–23. doi: 10.1089/cap.2018.0121

50.

Mohammad

, Dale

. Principles and approaches to the treatment of immune-mediated movement disorders. Eur J Paediatr Neurol. 2018;22(2):292–300. doi: 10.1016/j.ejpn.2017.11.010

51.

Kruse

, et al. Anti- N -methyl- D -aspartate receptor encephalitis: A targeted review of clinical presentation,diagnosis, and approaches to psychopharmacologic management 2014;26(2):111–9.

52.

Arciniegas

, McAllister

. Neurobehavioral Management of Traumatic Brain Injury in the Critical Care Setting. Crit Care Clin. 2008;24(4):737–65. doi: 10.1016/j.ccc.2008.06.001

53.

Loane

, Politis

. Buspirone: What is it all about? Brain Res. 2012;1461:111–8. doi: 10.1016/j.brainres.2012.04.032

54.

Zafonte

, Cullen

, Lexell

. Serotonin agents in the treatment of acquired brain injury. J Head Trauma Rehabil. 2002;17(4):322–34. doi: 10.1097/00001199-200208000-00006

55.

Huband

, Ferriter

, Nathan

, Jones

, et al. Antiepileptics for aggression and associated impulsivity (Review). Cochrane Database Syst Rev. 2010;(2).1–123. doi: 10.1002/14651858.CD003499.pub3

56.

Sher

, Miller Cramer

, Ament

, Lolak

, et al. Valproic Acid for Treatment of Hyperactive or Mixed Delirium: Rationale and Literature Review. Psychosomatics. 2015;56(6):615–25. doi: 10.1016/j.psym.2015.09.008

57.

Francisco

, Walker

, Zasler

, Bouffard

. Pharmacological management of neurobehavioural sequelae of traumatic brain injury: A survey of current physiatric practice. Brain Inj. 2007;21(10):1007–14. doi: 10.1080/02699050701559558

58.

Irani

, Bera

, Waters

, Zuliani

, Maxwell

, Zandi

, et al. N-methyl-d-aspartate antibody encephalitis: Temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain. 2010;133(6):1655–67. doi: 10.1093/brain/awq113

59.

Gillinder

, Warren

, Hartel

, Dionisio

, Gorman

. EEG findings in NMDA encephalitis - A systematic review. Seizure:Eur J Epilepsy. 2019;(65):20–4. doi: 10.1016/j.seizure.2018.12.015

60.

Schmitt

, Pargeon

, Frechette

, Hirsch

. Extreme Delta Brush:A unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094–100. doi: 0.1212/WNL.0b013e3182698cd8

61.

Graus

, Titulaer

, Balu

, Benseler

, Bien

, Cellucci

, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15:391–404.

62.

Baykan

, Gungor Tuncer

, Vanli-Yavuz

, Baysal Kirac

, Gundogdu

, Bebek

, et al. Delta Brush Pattern Is Not Unique to NMDAR Encephalitis: Evaluation of Two Independent Long-Term EEG Cohorts. Clin EEG Neurosci. 2018;49(4):278–84. doi: 10.1177/1550059417693168

63.

Centorrino

, Price

, Tuttle

, Bahk

, Ph

, Hennen

, et al. EEG Abnormalities During Treatment With Typical and Atypical Antipsychotics. Am J Psychiatry. 2002;159(1):109–15. doi: 10.1176/appi.ajp.159.1.109

64.

Poloni

, Korff

, Ricotti

, King

, Perez

, Mayor-Dubois

, et al. Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: Evidence for anti-N-methyl-d-aspartate receptor encephalitis. Dev Med Child Neurol. 2010;52(5). 10.1111/j.1469-8749.2009.03542.x

65.

Thaxton

, Myers

. Sleep disturbances and their management in patients with brain injury. J Head Trauma Rehabil. 2002;17(4):335–48. doi: 10.1097/00001199-200208000-00007

66.

Bruni

, Alonso-Alconada

, Besag

, Biran

, Braam

, Cortese

, et al. Current role of melatonin in pediatric neurology: Clinical recommendations. Eur J Paediatr Neurol. 2015;19(2):122–33. doi: 10.1016/j.ejpn.2014.12.007

67.

Pelayo

, Yuen

. Pediatric Sleep Pharmacology. Child Adolesc Psychiatr Clin N Am. 2012;21(4):861–83. doi: 10.1016/j.chc.2012.08.001

68.

Nash

, Weinberg

, Laughon

, McCall

, Bateman

, Rosenstein

. Acute Pharmacological Management of Behavioral and Emotional Dysregulation Following a Traumatic Brain Injury: A Systematic Review of the Literature. Psychosomatics. 2019;60(2):139–52. doi: 10.1016/j.psym.2018.11.009

69.

Greenwald

, Lombard

, Watanabe

. Managing sleepiness after traumatic brain injury. PM R. 2011;3(5):480–5. doi: 10.1016/j.pmrj.2011.04.010

70.

Meltzer

, Mindell

, Owens

, Byars

. Use of sleep medications in hospitalized pediatric patients. Pediatrics. 2007;119(6):1047–55. doi: 119/6/1047 [pii] 10.1542/peds.2006-2773

71.

Plantier

, Luaute

, Luauté

, Luaute

. Drugs for behavior disorders after traumatic brain injury: Systematic review and expert consensus leading to French recommendations for good practice. Ann Phys Rehabil Med. 2016;59(1):42–57. doi: 10.1016/j.rehab.2015.10.003

72.

Kinnaman

, Mannix

, Dawn Comstock

, Meehan

. Management strategies and medication use for treating paediatric patients with concussions. Acta Paediatr Int J Paediatr. 2013;102(9):424–8. doi: 10.1111/apa.12315

73.

Barshikar

, Bell

. Sleep Disturbance After TBI. Curr Neurol Neurosci Rep. 2017;17(11):87. doi: 10.1007/s11910-017-0792-4

74.

Hollway

, Aman

. Pharmacological treatment of sleep disturbance in developmental disabilities: A review of the literature. Res Dev Disabil. 2011;32(3):939–62. doi: 10.1016/j.ridd.2010.12.035

75.

Wichniak

, Jarkiewicz

, Okruszek , Wierzbicka

, Holka-Pokorska

, Rybakowski

. Low risk for switch to mania during treatment with sleep promoting antidepressants. Pharmacopsychiatry. 2015;48(3):83–8. doi: 10.1055/s-0034-1396802

76.

Flanagan

, Greenwald

, Wieber

. Pharmacological treatment of insomnia for individuals with brain injury. J Head Trauma Rehabil. 2007;22(1):67–70.

77.

Troester

, Pelayo

. Pediatric Sleep Pharmacology: A Primer. Semin Pediatr Neurol. 2015;22(2):135–47. doi: 10.1016/j.spen.2015.03.002

78.

Larson

, Zollman

. The effect of sleep medications on cognitive recovery from traumatic brain injury. J Head Trauma Rehabil. 2010;25(1):61–7. doi: 10.1097/HTR.0b013e3181c1d1e1

79.

Bhatnagar

, Iaccarino

, Zafonte

. Pharmacotherapy in rehabilitation of post-acute traumatic brain injury. Brain Res. 2016;1640:164–79. doi: 10.1016/j.brainres.2016.01.021

80.

Roehrs

, Randall

, Harris

, Maan

, Roth

. Twelve months of nightly zolpidem does not lead to rebound insomnia or withdrawal symptoms: A prospective placebo-controlled study. J Psychopharmacol. 2012;26(8):1088–95. doi: 10.1177/0269881111424455

81.

Janavs

, Aminoff

. Dystonia and chorea in acquired systemic disorders. J Neurol Neurosurg Psychiatry. 1998;65(4):436–45. doi: 10.1136/jnnp.65.4.436

82.

Deon

, Gaebler-Spira

. Assessment and treatment of movement disorders in children with cerebral palsy. Orthop Clin North Am. 2010;41(4):507–17. doi: S0030-5898(10)00055-6 [pii]∖n10.1016/j.ocl.2010.06.001 [doi]

83.

Jankovic

. Medical treatment of dystonia. Mov Disord. 2013;28(7):1001–12. doi: 10.1002/mds.25552

84.

Staley

, Jamy

, Phan

, Figge

, Pham

. N-Methyl- d -aspartate Receptor Antibody Encephalitis: A Concise Review of the Disorder, Diagnosis, and Management. ACS Chem Neurosci. 2019;10(1):132–42. doi: 10.1021/acschemneuro.8b00304

85.

Hutchinson

, Yeshokumar

, Armangue

Antibody-Mediated Encephalitis in Children: Focus on Diagnostic Clues and Acute Symptom Management. Semin Pediatr Neurol. 2021 epub; doi: 10.1016/j.spen.2021.100873

86.

Watanabe TK . Role of Oral Medications in Spasticity Management. PM R. 2009;1(9):839–41. doi: 10.1016/j.pmrj.2009.07.014

87.

Thibaut

, Chatelle

, Ziegler

, Bruno

, Laureys

, Gosseries

, et al. Spasticity after stroke: Physiology, assessment and treatment. Brain Inj. 2013;27(10):1093–105. doi: 10.3109/02699052.2013.804202

88.

Zafonte

, Elovic

, Lombard

. Acute Care Management of Post-TBI Spasticity. J Head Trauma Rehabil. 2004;19(2):89–100. doi: 10.1097/00001199-200403000-00002

89.

Ronan

, Gold

. Nonoperative management of spasticity in children. Childs Nerv Syst. 2007;23(9):943–56.roi: 10.1007/s00381-007-0396-4

90.

Liow

NYK

, Gimeno

, Lumsden

, Marianczak

, Kaminska

, Tomlin

, et al. Gabapentin can significantly improve dystonia severity and quality of life in children. Eur J Paediatr Neurol. 2016;20(1):100–7. doi: 10.1016/j.ejpn.2015.09.007

91.

Vadivelu

, Stratton

, Pierce

. Pediatric Tone Management. Phys Med Rehabil Clin N Am. 2015;26(1):69–78. doi: 10.1016/j.pmr.2014.09.008

92.

Finke

, Kopp

, Prüss

, Dalmau

, Wandinger

, Ploner

. Cognitive deficits following anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry. 2012;83(2):195–8. doi: 10.1136/jnnp-2011-300411

93.

McKeon

, Scott

, Spooner

, Ryan

, Blum

, Gillis

, et al. Cognitive and social functioning deficits after Anti-N-Methyl-D-aspartate receptor encephalitis: An exploratory case series. J Int Neuropsychol Soc. 2016;22(8):828–38. doi: 10.1017/S1355617716000679

94.

Howarth

RARA

, Vova

, Blackwell

LSLS

. Early Functional Outcomes for Pediatric Patients Diagnosed with Anti-N-Methyl-d-Aspartate Receptor Encephalitis during Inpatient Rehabilitation. Am J Phys Med Rehabil. 2019;98(7):529–35. doi: 10.1097/PHM.0000000000001087

95.

McKeon

, Robinson

, Ryan

, Blum

, Gillis

, Finke

, et al. Cognitive outcomes following anti-N-methyl-D-aspartate receptor encephalitis: A systematic review. J Clin Exp Neuropsychol. 2018;40(3):234–52. doi: 10.1080/13803395.2017.1329408

96.

Matricardi

, Patrini

, Freri

, Ragona

, Zibordi

, Andreetta

, et al. Cognitive and neuropsychological evolution in children with anti-NMDAR encephalitis. J Neurol. 2016;263(4):765–71. doi: 10.1007/s00415-016-8056-9

97.

De Bruijn

MAAM

, Aarsen

, Van Oosterhout

, Van Der Knoop

, Catsman-Berrevoets

, Schreurs

MWJ

, et al. Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis. Neurology. 2005;90(22):e1997–2005. doi: 10.1212/WNL.0000000000005605

98.

Osier

, Dixon

. Catecholaminergic based therapies for functional recovery after TBI. Brain Res. 2016;1640:15–35. doi: 10.1016/j.brainres.2015.12.026

99.

Tenovuo O . Pharmacological enhancement of cognitive and behavioral deficits after traumatic brain injury. Curr Opin Neurol. 2006;19(6):528–33. doi: 10.1097/WCO.0b013e328010944f

100.

Dymowski

, Ponsford

, Owens

, Olver

, Ponsford

, Willmott

. The efficacy and safety of extended-release methylphenidate following traumatic brain injury: A randomised controlled pilot study. Clin Rehabil. 2017;31(6):733–41. doi: 10.1177/0269215516655590

101.

Kurowski

, Epstein

, Pruitt

, Horn

, Altaye

, Wade

. Benefits of Methylphenidate for Long-Term Attention Problems After Traumatic Brain Injury in Childhood. J Head Trauma Rehabil. 2019;34(2):1–12. doi: 10.1097/HTR.0000000000000432

102.

McDonald

, Flashman

, Arciniegas

, Ferguson

, Xing

, Harezlak

, et al. Methylphenidate and memory and attention adaptation training for persistent cognitive symptoms after traumatic brain injury: A randomized, placebo-controlled trial. Neuropsychopharmacology. 2017;42(9):1766–75. doi: 10.1038/npp.2016.261

103.

Johansson

, Wentzel

, Andréll

, Mannheimer

, Rönnbäck

. Methylphenidate reduces mental fatigue and improves processing speed in persons suffered a traumatic brain injury. Brain Inj. 2015;29(6):758–65. doi: 10.3109/02699052.2015.1004747

104.

Sami

, Faruqui

. The effectiveness of dopamine agonists for treatment of neuropsychiatric symptoms post brain injury and stroke. Acta Neuropsychiatr. 2015;27(6):317–26. doi: 10.1017/neu.2015.17

105.

Blanpied

, Boeckman

, Aizenman

, Johnson

, Zheng

, Yang

, et al. Trapping Channel Block of NMDA-Activated Responses By Amantadine and Memantine Trapping Channel Block ofNMDA-Activated Responses By Amantadine and Memantine. 2011;309-23. doi: 10.1152/jn.1997.77.1.309

106.

Mcallister

, Mcdonald

, Flashman

, Ferrell

, Tosteson

, Yanofsky

, et al. Alpha-2 Adrenergic Challenge with Guanfacine One Month after Mild Traumatic Brain Injury: Altered Working Memory and BOLD Response. Int J Psychophysiol. 2011;82(1):107–14. doi: 10.1016/j.ijpsycho.2011.06.022.Alpha-2

107.

Singh-Curry

, Malhotra

, Farmer

, Husain

. Attention deficits following ADEM ameliorated by guanfacine. J Neurol Neurosurg Psychiatry. 2011;82(6):688–90. doi: 10.1136/jnnp.2009.195792

108.

McClure

, Barch

, Romero

, Minzenberg

, Triebwasser

, Harvey

, et al. The Effects of Guanfacine on Context Processing Abnormalities in Schizotypal Personality Disorder. Biol Psychiatry. 2007;61(10):1157–60. doi: 10.1016/j.biopsych.2006.06.034

109.

Arnsten

AFT

, Wang

. Targeting Prefrontal Cortical Systems for Drug Development: Potential Therapies for Cognitive Disorders. Annu Rev Pharmacol Toxicol. 2016;56(1):339–60. doi: 10.1146/annurev-pharmtox-010715-103617