Speech recovery after single-dose zolpidem in two minimally conscious patients with severe traumatic brain injuries: a case report.

BACKGROUND: In rare cases, zolpidem administration has been found to paradoxically improve cognition in patients with brain injury in disorders of consciousness. CASE PRESENTATION: Two minimally conscious plus (MCS+) patients at baseline, a 24-year-old woman 8 weeks post-traumatic brain injury (TBI) and 23-year-old man 6 weeks post-TBI, demonstrated behavioral improvements after off-label, single-dose administration of 10 mg of zolpidem. DISCUSSION/CONCLUSION: The patients demonstrated improved cognition on Coma Recovery Scale-Revised assessment after ingesting zolpidem. In particular, speech was substantially restored as one patient recovered functional communication and both demonstrated intelligible verbalizations for the first-time post-injuries following zolpidem. Overall, evidence is limited regarding the underlying mechanisms of various cognitive improvements in zolpidem response although studies incorporating neuroimaging are promising. The outcomes and similarities between these cases contribute to the current literature and highlight the need for rigorous studies in the future to guide zolpidem trials in patient care for those with DOC.

[Neuromodulatory pharmacotherapy individualization in prolonged and chronic consciousness disorders after severe traumatic brain injury]. / K probleme individualizatsii neiromodulyatornoi farmakoterapii pri prolongirovannykh i khronicheskikh narusheniyakh soznaniya vsledstvie tyazheloi cherepno-mozgovoi travmy.

One of the most probable causes of effective therapy for post-comatose disorders of consciousness is the lack of individualization of drug prescriptions. In this observational study, we analyzed 48 courses of neuromodulatory therapy in 28 patients with prolonged and chronic disorders of consciousness following severe traumatic brain injury. Comparison of 24 effective and 24 ineffective courses demonstrated higher effectiveness of pharmacotherapy through its individualization, i.e. the choice of a drug whose neuromodulatory spectrum would correspond to neurological syndromes of neurotransmitter dysfunction. In this approach, 74% of therapy courses were effective while opposite management resulted only 34% of effective courses.

[Recovery of consciousness under therapy with benzodiazepines. A case report and literature review]. / Vosstanovlenie yasnogo soznaniya na fone priema benzodiazepinov. Opisanie sluchaya i obzor literatury.

BACKGROUND: Treatment of patients with prolonged and permanent disturbance of consciousness is still an extremely difficult problem. Nowadays, management is based on pathophysiological and molecular mechanisms of impaired consciousness. Several electrophysiological and pharmacological methods were proposed to restore consciousness in appropriate patients. OBJECTIVE: We present recovery of clear consciousness under therapy with phenazepam and literature review devoted to therapy of these disorders. RESULTS AND CONCLUSION: This case confirms available data on drug neuromodulation in complex treatment of patients with prolonged impairment of consciousness and substantiates the need for individual multimodal assessment of structural and functional disorders in prolonged and chronic impairment of consciousness for adequate therapy.

A decreasing plasma concentration of a toxicologically active metabolite 9-carboxymethoxymethylguanine after dialysis - A potential new clinical biomarker for improving encephalopathy in patients treated with acyclovir.

Although acyclovir is a key drug for the treatment of herpes infections, a consciousness disorder known as "acyclovir encephalopathy" is among its side effects. We encountered a patient with encephalopathy and measured the plasma and cerebrospinal fluid concentrations of acyclovir and its toxicologically active metabolite 9-carboxymethoxymethylguanine (CMMG). Before dialysis, cerebrospinal fluid concentrations of acyclovir and CMMG in this patient with a consciousness disorder were approximately 10% and 1%, respectively, of their plasma concentrations. After 3 days of dialysis, plasma CMMG levels decreased to detectable but below quantitative levels (<0.1 µg/mL), resulting in normal consciousness. These results suggest that decreasing plasma CMMG concentration could be one of clinical biomarkers for improving consciousness in patients with encephalopathy associated with acyclovir.

High-risk factors associated with refractory childhood bacterial meningitis in Southwest China.

BACKGROUND: Refractory bacterial meningitis is acute, develops rapidly, and has higher mortality and morbidity than common bacterial meningitis. This study was undertaken to investigate the high-risk factors related to refractory bacterial meningitis in children with positive pathogens. METHODS: We retrospectively analyzed the clinical data of 109 patients who had bacterial meningitis. The patients were divided into a refractory group (96 patients) and nonrefractory group (13 patients) based on the classification criteria. Seventeen clinical variables on risk factors were extracted and evaluated by univariate and multivariate logistic regression analyses. RESULTS: There were 64 males and 45 females. The onset age ranged from 1 month old to 12 years old, and the median age was 181 days old. The pathogenic bacteria included 67 cases of gram-positive (G+) bacteria (61.5%) and 42 cases of gram-negative (G-) bacteria. In patients who were 1 to 3 months old, E. coli was the most common (47.5%), followed by Streptococcus agalactiae and Staphylococcus hemolyticus (10.0%); in patients > 3 months old, S. pneumoniae was the most common (55.1%), followed by E. coli (8.7%). The multivariate analysis indicated that consciousness disorder (odds ratio [OR] = 13.050), peripheral blood C-reactive protein (CRP) ≥ 50 mg/L (OR = 29.436), and the isolate bacteria being gram-positive bacteria (OR = 8.227) were independent risk factors for predicting who would progress to refractory bacterial meningitis in this group. CONCLUSION: For patients who have pathogenic positive bacterial meningitis along with consciousness disorder, CRP ≥ 50 mg/L, and/or have an isolate bacteria that is a G + bacteria, it is important to be alert to the potential for progression to refractory bacterial meningitis, which demands the physicians' significant attention.

Pharmacologic Therapies to Promote Recovery of Consciousness.

Pharmacologic interventions are commonly used to support rehabilitation efforts of patients with disorders of consciousness (DoC). The 2018 practice guidelines recommend amantadine in adults with traumatic DoC to promote functional recovery, though several other stimulants are used off-label in clinical practice and trials, such as methylphenidate, bromocriptine, levodopa, and zolpidem. Differences in the mechanisms of action, adverse effects, pharmacokinetics, and drug-drug interactions should be considered when selecting the best agent for each individual patient. Overall, pharmacologic stimulants may provide a safe and inexpensive pathway to increased functionality and participation in rehabilitation. This article provides a concise summary of scientific evidence supporting the use of pharmacologic therapies to stimulate recovery of consciousness in patients with DoC.

Weaning from antiseizure drugs after new onset status epilepticus.

OBJECTIVE: In patients with status epilepticus (SE) without prior epilepsy, there are limited data on the safety of discontinuing antiseizure drugs (ASDs) after seizure control. We aimed to describe seizure recurrence when weaning from ASDs following new onset SE (NOSE). METHODS: Retrospective review of adult patients with NOSE admitted to Mayo Clinic, Rochester, Minnesota between January 1, 1990 and December 31, 2015 was performed. Weaning was defined as a discontinuation of ASDs following discharge. Patient demographics, SE characteristics, timing of ASD withdrawal, and seizure recurrence were collected. RESULTS: One hundred seventy-seven patients with mean age 63 ± 18 years were identified; 96 (54.2%) patients had refractory SE (RSE), and 81 (45.8%) had nonrefractory SE. Mean follow-up was 3.8 ± 3.2 years for those successfully weaned off ASDs. One hundred thirty (73.4%) with outpatient follow-up were included in the analysis; 128 (98.5%) patients were discharged on an ASD; 44 of 128 (34.4%) patients underwent weaning from at least 1 ASD following discharge, including 27 of 128 (21.1%) who were completely weaned off of all ASDs. Younger patients (P = 0.009) and those with RSE (P = 0.048, odds ratio = 2.12, 95% confidence interval = 1.00-4.48) tended to undergo weaning. Six of 44 (13.6%) patients had seizure recurrence when weaned off of any ASD, and two of 27 (7.4%) patients completely weaned off all ASDs had seizure recurrence. Two of seven (28.6%) patients who underwent attempted barbiturate weaning experienced seizure recurrence. SIGNIFICANCE: We found a rate of 13.6% for late seizure recurrence after weaning from at least one ASD in patients with NOSE; seizure recurrence was more likely in patients with RSE treated with barbiturates. Systematic collection of longitudinal data in patients requiring multiple ASDs for NOSE control will provide more conclusive guidance on weaning from ASDs.

An analysis of the effects of using Zolpidem and an innovative multimodal interdisciplinary team approach in prolonged disorders of consciousness (PDOC).

Zolpidem has been used with mixed effects in patients presenting with Prolonged Disorders of Consciousness (PDOC). This single case report describes an interdisciplinary team (IDT) protocol combined with Zolpidem 10 mg in a single case of a patient in PDOC. 'Emily', a 44-year-old lady was admitted to a rehabilitation unit in Ireland one year post onset of subarachnoid haemorrhage. Standardized assessments diagnosed her as being in a minimally conscious state (MCS). An IDT protocol was devised to stimulate and record responses to sensory and pharmacological stimuli. The protocol was applied pre and post administration of Zolpidem 10 mg. Across standardized measures of awareness, improved results post-Zolpidem were recorded. Spontaneous, appropriate verbalization was the most significant change observed 30 min after administration of Zolpidem 10 mg. This ceased after approximately 2 h with Emily reverting to a non-verbal state. The combined effect of Zolpidem and the IDT protocol applied over an eight-week period resulted in durable functional and communicative gains for Emily, inferring neuro-plasticity. This report highlights the impact of a combined approach of intensive IDT intervention in conjunction with Zolpidem. The use of Zolpidem with this patient population warrants further investigation.

Efficacy of Thyrotropin-Releasing Hormone Analog for Protracted Disturbance of Consciousness due to Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: The efficacy of thyrotropin-releasing hormone tartrate (TRH-T) for treating prolonged disturbance of consciousness due to aneurysmal subarachnoid hemorrhage (SAH) remains unclear. The purpose of the present study was to determine whether TRH-T was really effective, and what was the recovery factor when it was valid. This was a retrospective study of a single facility. METHODS: We treated 208 patients with aneurysmal SAH at our hospital between 2011 and 2017. Among them, we investigated 97 cases in which TRH-T was administered to prolonged disturbance of consciousness. Thirty one patients with Hasegawa dementia rating scale-revised (HDS-R) score less than 20 were included. Patients' HDS-R scores were evaluated 7 days after clipping the aneurysm and 2 days after completing a course of TRH-T treatment. HDS-R score increases of greater than or over equal to 8 and less than 8 were defined as good and poor outcomes, respectively. Outcomes were compared to 11 patients who did not receive TRH-T treatment. RESULTS: Average initial and post-treatment HDS-R scores were 9 ± 6.6 and 19 ± 9.5, respectively. The good outcome group included 19 patients. Statistically significant differences in HDS-R score changes were observed between the group with initial HDS-R scores of 0-4 and the other groups. Poor outcomes were significantly correlated with age of greater than 60 years and initial HDS-R scores less than oroverequal to 4 points. The improvement in HDS-R score was significantly greater in the TRH-T administration group than the control group. CONCLUSIONS: TRH-T was effective for treating prolonged disturbance of consciousness due to aneurysmal SAH, especially in young patients with HDS-R scores between 5 and 20.

Selegiline in Patients With Disorder of Consciousness: An Open Pilot Study.

This open study investigated the clinical effects of 10-week selegiline administration in six patients in vegetative state and in four patients in a minimally conscious state, at least 6 months after onset. Clinical outcome was assessed by Coma Recovery Scale-Revised once a week during selegiline administration and 1 month later. Three patients stopped treatment because of possible side effects. After treatment and at 1 month of follow-up, four patients showed improvements in clinical diagnosis, and three patients showed an increase in arousal level only. Selegiline might represent a relatively safe option to enhance arousal and promote recovery in brain-injured patients with disorders of consciousness.

Disorders of consciousness after severe brain injury: therapeutic options.

PURPOSE OF REVIEW: Very few options exist for patients who survive severe traumatic brain injury but fail to fully recover and develop a disorder of consciousness (e.g. vegetative state, minimally conscious state). RECENT FINDINGS: Among pharmacological approaches, Amantadine has shown the ability to accelerate functional recovery. Although with very low frequency, Zolpidem has shown the ability to improve the level of consciousness transiently and, possibly, also in a sustained fashion. Among neuromodulatory approaches, transcranial direct current stimulation has been shown to transiently improve behavioral responsiveness, but mostly in minimally conscious patients. New evidence for thalamic deep brain stimulation calls into question its cost/benefit trade-off. SUMMARY: The growing understanding of the biology of disorders of consciousness has led to a renaissance in the development of therapeutic interventions for patients with disorders of consciousness. High-quality evidence is emerging for pharmacological (i.e. Amantadine) and neurostimulatory (i.e. transcranial direct current stimulation) interventions, although further studies are needed to delineate preconditions, optimal dosages, and timing of administration. Other exciting new approaches (e.g. low intensity focused ultrasound) still await systematic assessment. A crucial future direction should be the use of neuroimaging measures of functional and structural impairment as a means of tailoring patient-specific interventions.

The Effectiveness of Zolpidem for the Treatment of Disorders of Consciousness.

Approximately, five million people in the United States live with the residual effects of brain injury. The causes of acquired brain injury can be categorized as traumatic brain injury or non-traumatic brain injury. There are currently no treatments shown to consistently enhance recovery from disorders of consciousness (DOC). Sporadic recovery from DOC after the administration of various pharmacological agents has been described in several case reports. Increase in arousal after zolpidem administration is seen in patients with vegetative state or minimally conscious state for treatment of restlessness and disturbances of their sleep-wake cycle. The use of zolpidem could be reasonable in select patients with neurologic injury but promising integrity of brain structures, such as intact deep and superficial gray matter structures and white matter connections.

Intrathecal baclofen: effects on spasticity, pain, and consciousness in disorders of consciousness and locked-in syndrome.

Disorders of consciousness (DOCs) include coma, vegetative state (VS), and minimally conscious state (MCS). Coma is characterized by impaired wakefulness and consciousness, while VS and MCS are defined by lacking or discontinuous consciousness despite recovered wakefulness. Conversely, locked-in syndrome (LIS) is characterized by quadriplegia and lower cranial nerve paralysis with preserved consciousness. Intrathecal baclofen (ITB) is a useful treatment to improve spasticity both in patients with DOCs and LIS. Moreover, it supports the recovery of consciousness in some patients with VS or MCS. The precise mechanism underlying this recovery has not yet been elucidated. It has been hypothesized that ITB may act by reducing the overload of dysfunctional sensory stimuli reaching the injured brain or by stabilizing the imbalanced circadian rhythms. Although the current indication of ITB is the management of severe spasticity, its potential use in speeding the recovery of consciousness merits further investigation.

Successful treatment of refractory Guillain-Barré syndrome with alemtuzumab in a patient with chronic lymphocytic leukemia.

This is the case of a 79-year-old man with chronic lymphocytic leukemia who presented with Guillain-Barré syndrome with features overlapping with the Miller Fisher syndrome and Bickerstaff brainstem encephalitis and positive antiganglioside GQ1b antibody about 6 months after treatment with bendamustine and rituximab. His clinical and neurologic condition continued to deteriorate despite sequential treatment with corticosteroids, intravenous immunoglobulin and plasmapheresis, but in the end, he had a complete and durable response to treatment with alemtuzumab.

Intrathecal baclofen associated with improvement of consciousness disorders in spasticity patients.

OBJECTIVE: Intrathecal baclofen (ITB) pump is a therapeutic option for persistent vegetative state and minimal conscious state patients that have associated spasticity. We investigated whether this treatment modality can affect their level of consciousness. METHOD: In this prospective, open label, observational study, we implanted ITB pumps for the treatment of spasticity in eight patients with disorders of consciousness (vegetative state and minimally conscious state) and we followed them with the Coma Recovery Scale-Revised, the Eastern Cooperative Oncology Group (ECOG) performance scale, and the Modified Ashworth spasticity scale. Baclofen dose and complications also were noted. RESULTS: The offending pathologies were traumatic brain injury in six, anoxia due to cardiac arrest in one, acute obstructive hydrocephalus in one. Two of the patients showed a marked, persistent improvement that fulfilled the criteria of emergence from minimally conscious state. Two of patients had their ITB pumps prematurely removed because of complications. The ECOG score was 4 for all patients and did not change during the study. CONCLUSION: ITB might be associated with a significant improvement in the disorder of consciousness of two patients from a total of six that had a chronic ITB treatment.

Whole brain modelling for simulating pharmacological interventions on patients with disorders of consciousness.

Disorders of consciousness (DoC) represent a challenging and complex group of neurological conditions characterised by profound disturbances in consciousness. The current range of treatments for DoC is limited. This has sparked growing interest in developing new treatments, including the use of psychedelic drugs. Nevertheless, clinical investigations and the mechanisms behind them are methodologically and ethically constrained. To tackle these limitations, we combined biologically plausible whole-brain models with deep learning techniques to characterise the low-dimensional space of DoC patients. We investigated the effects of model pharmacological interventions by including the whole-brain dynamical consequences of the enhanced neuromodulatory level of different neurotransmitters, and providing geometrical interpretation in the low-dimensional space. Our findings show that serotonergic and opioid receptors effectively shifted the DoC models towards a dynamical behaviour associated with a healthier state, and that these improvements correlated with the mean density of the activated receptors throughout the brain. These findings mark an important step towards the development of treatments not only for DoC but also for a broader spectrum of brain diseases. Our method offers a promising avenue for exploring the therapeutic potential of pharmacological interventions within the ethical and methodological confines of clinical research.

Restoring consciousness with pharmacologic therapy: Mechanisms, targets, and future directions.

Severe brain injury impairs consciousness by disrupting a broad spectrum of neurotransmitter systems. Emerging evidence suggests that pharmacologic modulation of specific neurotransmitter systems, such as dopamine, promotes recovery of consciousness. Clinical guidelines now endorse the use of amantadine in individuals with traumatic disorders of consciousness (DoC) based on level 1 evidence, and multiple neurostimulants are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem. However, the relative contributions of monoaminergic, glutamatergic, cholinergic, GABAergic, and orexinergic neurotransmitter systems to recovery of consciousness after severe brain injury are unknown, and personalized approaches to targeted therapy have yet to be developed. This review summarizes the state-of-the-science in the neurochemistry and neurobiology of neurotransmitter systems involved in conscious behaviors, followed by a discussion of how pharmacologic therapies may be used to modulate these neurotransmitter systems and promote recovery of consciousness. We consider pharmacologic modulation of consciousness at the synapse, circuit, and network levels, with a focus on the mesocircuit model that has been proposed to explain the consciousness-promoting effects of various monoaminergic, glutamatergic, and paradoxically, GABAergic therapies. Though fundamental questions remain about neurotransmitter mechanisms, target engagement and optimal therapy selection for individual patients, we propose that pharmacologic therapies hold great promise to promote recovery and improve quality of life for patients with severe brain injuries.

Does amantadine improve cognitive recovery in severe disorders of consciousness after aneurysmal subarachnoid hemorrhage? A double-blind placebo-controlled study.

BACKGROUND: Severe disorders of consciousness (sDoC) are a common sequela of aneurysmal subarachnoid hemorrhages (aSAH), and amantadine has been used to improve cognitive recovery after traumatic brain injury. OBJECTIVE: This study evaluated the effect of amantadine treatment on consciousness in patients with sDoC secondary to aSAH. METHODS: This double-center, randomized, prospective, cohort study included patients ≥ 18 years old with sDoC after aSAH from February 2020 to September 2023. Individual patient data of patients were pooled to determine the effect of amantadine, in comparison to placebo. The primary outcomes at 3 and 6 months after the ictus were evaluated using the modified Rankin scale (mRS) and Glasgow outcome scale (GOS). In addition to all-cause mortality, secondary endpoints were assessed weekly during intervention by scores on Rappaport's Disability Rating Scale (RDRS) and Coma Recovery Scale-Revised (CRSR). RESULTS: Overall, 37 patients with sDoC and initial Glasgow Coma Scale (GCS) varying between 3 and 11 were recruited and randomized to amantadine (test group, n = 20) or placebo (control group, n = 17). The average age was 59.5 years (28 to 81 year-old), 24 (65%) were women, and the mean GCS at the beginning of intervention was 7.1. Most patients evolved to vasospasm (81%), with ischemia in 73% of them. The intervention was started between 30 to 180 days after the ictus, and administered for 6 weeks, with progressively higher doses. Neither epidemiological characteristics nor considerations regarding the treatment of the aneurysm and its complications differed between both arms. Overall mortality was 10.8% (4 deaths). During the study, four patients had potential adverse drug effects: two presented seizures, one had paralytic ileus, and another evolved with tachycardia; the medication was not suspended, only the dose was not increased. At data opening, 2 were taking amantadine and 2 placebo. CONCLUSION: Despite some good results associated with amantadine in the literature, this study did not find statistically significant positive effects in cognitive recovery in patients with delayed post-aSAH sDoC. Further large randomized clinical trials in patients' subgroups are needed to better define its effectiveness and clarify any therapeutic window where it can be advantageous.

Medical complications during inpatient rehabilitation among patients with traumatic disorders of consciousness.

OBJECTIVE: To assess the incidence of medical complications in patients with recent traumatic disorders of consciousness (DOCs). DESIGN: Data on adverse events in a placebo controlled trial of amantadine hydrochloride revealed no group difference, which allowed these events to be reanalyzed descriptively as medical complications experienced by the 2 groups collectively. SETTING: Eleven clinical facilities in the United States, Denmark, and Germany with specialty rehabilitation programs for patients with DOCs. PARTICIPANTS: Patients (N=184) with nonpenetrating traumatic brain injury enrolled from acute inpatient rehabilitation programs between 4 and 16 weeks postinjury. INTERVENTIONS: Participants were randomized to receive 200 to 400mg of amantadine hydrochloride or placebo daily for 4 weeks, and followed for an additional 2 weeks. Adverse events were recorded and categorized with respect to their nature, timing, and severity. MAIN OUTCOME MEASURE: Number, type, and severity of medical complications occurring during the 6-week study interval. RESULTS: A total of 468 medical complications were documented among the patients (.40 events per week per patient). More than 80% of patients experienced at least 1 medical complication, and 41 of these were defined as serious adverse events. New medical complications declined over time in rehabilitation and were not dependent on time since injury. Hypertonia, agitation/aggression, urinary tract infection, and sleep disturbance were the most commonly reported problems. Hydrocephalus, pneumonia, gastrointestinal problems, and paroxysmal sympathetic hyperactivity were the most likely to be severe. CONCLUSIONS: Patients with DOCs have a high rate of medical complications early after injury. Many of these complications require brain injury expertise for optimal management. Active medical management appears to contribute to the reduction in new complications. An optimal system of care for DOC patients must provide expert medical management in the early weeks after injury.