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.

[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.

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.

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.

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.

Dextromethorphan-Induced Altered Level of Consciousness in Children: A Case Series.

BACKGROUND: Dextromethorphan, an N-methyl-d-aspartate receptor antagonist, has been used as cold and cough medication. Serious adverse events with therapeutic doses of dextromethorphan are rarely observed. Here, we report three cases of altered levels of consciousness in children with a therapeutic dose of dextromethorphan. CASE PRESENTATION: In all three cases, children developed an altered level of consciousness after taking the first dose of syrup dextromethorphan. Children were unresponsive to any verbal command and pain stimuli. Medical history revealed no pre-existing comorbidities. Other systemic, cardiovascular, abdominal, respiratory and nervous system examinations were normal. All patients were hospitalised and managed with symptomatic and supportive care. Dextromethorphan was stopped. After adequate treatment, all of them recovered satisfactorily. The causality assessment was done based on the World Health Organization Uppsala Monitoring Centre causality scale, and it was probable/likely in all three cases. CONCLUSION: In children, an altered level of consciousness could occur with therapeutic doses of dextromethorphan; hence, health care professionals should prescribe dextromethorphan with extreme caution.

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.

Evaluation of the effect of analgesic treatment on signs of nociception-related behaviors during physiotherapy in patients with disorders of consciousness: a pilot crossover randomized controlled trial.

ABSTRACT: Neuro-orthopedic disorders are common in patients with disorders of consciousness (DOC) and can lead to potential pain. However, the patients' inability to communicate makes pain detection and management very challenging for clinicians. In this crossover randomized double-blind placebo-controlled study, we investigated the effects of an analgesic treatment on the presence of nociception-related behaviors. At baseline, the Nociception Coma Scale-Revised (NCS-R) was performed in 3 conditions: a non-noxious stimulation, a noxious stimulation, and during a physiotherapy session. Patients with a NCS-R total score during physiotherapy equal or above the score observed after the noxious stimulation could participate to the clinical trial, as well as patients with a score above 5. They received an analgesic treatment and a placebo on 2 consecutive days in a randomized order followed by an assessment with the NCS-R. Of the 18 patients, 15 displayed signs of potential pain during physiotherapy. Patients showed higher NCS-R scores during physiotherapy compared with the other conditions, suggesting that mobilizations were potentially painful. Of these 15 patients, 10 met the criteria to participate in the placebo-controlled trial. We did not find any effect of analgesic treatment on the NCS-R scores. This study highlights that physiotherapy may be potentially painful for patients with DOC, while analgesic treatments did not reduced NCS-R scores. Therefore, careful monitoring with appropriate assessment and treatment before and during mobilization should become a priority in clinical settings. Future studies should focus on the development of assessment tools sensitive to analgesic dosage to manage pain in DOC.

Spasticity Management in Persons with Disorders of Consciousness.

INTRODUCTION: Spasticity is one of the most frequent neurological impairments affecting persons with disorders of consciousness (DoC). If left untreated, it can mask signs of consciousness by inhibiting one's ability to interact with the environment. The lack of information about spasticity specific to patients with DoC may result in insufficient or even inappropriate treatment. OBJECTIVE: To report spasticity characteristics and management in a large dedicated DoC rehabilitation program. DESIGN: Retrospective chart review. SETTING: An inpatient rehabilitation hospital. PARTICIPANTS: Patients admitted to the DoC rehabilitation program from 1 January 2014 to 31 October 2018. MAIN OUTCOME MEASUREMENTS: Spasticity characteristics; impact of interventions on spasticity as well as other clinical measures. RESULTS: A total of 146 patients were included, of whom 95.2% were affected by spasticity; 52.7% had spasticity affecting all four limbs. The most commonly affected muscle groups were shoulder internal rotators (72.6%) in the upper extremity and ankle plantar flexors (59.8%) in the lower extremity. The more commonly affected muscle groups were also more spastic (R = 0.993 and 0.989 in the upper and lower extremity, respectively; P < .01). Atypical posture patterns were also commonly observed, making positioning difficult. Chemoneurolytic injections (botulinum toxin and/or phenol) were performed in over 69.9% patients, and 26.7% had intrathecal baclofen (ITB) pump placement. All patients received individualized physical modalities and therapies. With focal managements, systemic spasmolytic medications, including enteral baclofen, were reduced by at least 50.0%, which appeared to be associated with improvements in the level of consciousness. CONCLUSIONS: Almost all DoC patients were affected by spasticity, often to a moderate or severe degree. Extensive use of focal spasticity interventions allowed for weaning of systemic spasmolytic medications, which seemed to result in improvements in the level of consciousness.

Additive effect of cerebrolysin and amantadine on disorders of consciousness secondary to acquired brain injury: A retrospective case-control study.

BACKGROUND: Acquired brain injury can cause disorders of consciousness. An additive effect of cerebrolysin and amantadine has been postulated, but not systematically studied. The present study aimed to investigate this additive effect in patients with disorders of consciousness secondary to acquired brain injury. METHODS: The medical records of patients diagnosed with disorders of consciousness after acquired brain injury were reviewed. The patients were categorized into 2 groups: single regimen (amantadine only) and dual regimen (amantadine plus cerebrolysin). The patients' conscious states were assessed using the Coma Recovery Scale-Revised (CRS-R) before, and after 4 weeks of drug administration. RESULTS: Data for a total of 84 patients were analysed. The degree of change in CRS-R and the proportion of patients in the disorders of consciousness category showing a change was higher in the dual regimen group than in the single regimen group. Analysis of patients who had initially been in a prolonged vegetative state or minimally conscious state minus before administration showed that the patients in the dual regimen group had greater increases in CRS-R scores than those in the single regimen group. CONCLUSION: This study identified that an amantadine-plus-cerebrolysin regimen additively affects patients with prolonged disorders of consciousness. A future controlled trial is needed to investigate the efficacy of each regimen in patients with prolonged disorders of consciousness secondary to acquired brain injury, particularly for patients who have remained in a prolonged vegetative state after acquired brain injury.

[Bromocriptine in disorders of consciouness due to traumatic brain injury]. / Uso de bromocriptina en pacientes con alteración de conciencia secundaria a traumatismo craneoencefálico.

INTRODUCTION: The aim of this study was to assess the results and adverse effects of bromocriptine in patients with traumatic brain injury-vegetative state (TBI-VS) or traumatic brain injury-minimally conscious state (TBI-MCS). METHODS: We conducted a retrospective review of 10 patients, six with TBI-VS and four with TBI-MCS. All patients received bromocriptine at a starting dose of 2.5mg twice daily. Bromocriptine was titrated up to 7.5 or 12.5mg twice daily according to response and was maintained for at least 4 weeks. Various assessment scales were used in the following stages: before bromocriptine administration, at 4 weeks post bromocriptine prescription, and at hospital discharge. The assessment scales used were the Coma Recovery Scale-Revised (CRS-R), Disability Rating Scale, Glasgow Coma Scale, Barthel Scale, and Marshall Scale. RESULTS: Of the 10 patients, four with TBI-MCS and four with TBI-VS achieved a score of 23 points at discharge in the CRS-R, thus emerging from VS or MCS and regaining functional status. There were only two patients who emerged from VS but remained in MCS (8 to 11 and 5 to 10 points in CRS-R). CONCLUSIONS: Considering the poor prognosis for recovery in these patients, bromocriptine use has a positive risk-benefit ratio at a dosage of at least 7.5mg twice daily for 4 weeks.

Therapeutic interventions in patients with prolonged disorders of consciousness.

The management of patients with severe brain injuries and prolonged disorders of consciousness raises important issues particularly with respect to their therapeutic options. The scarcity of treatment options is challenged by new clinical and neuroimaging data indicating that some patients with prolonged disorders of consciousness might benefit from therapeutic interventions, even years after the injury. Most studies of interventions aimed at improving patients' level of consciousness and functional recovery were behavioural and brain imaging open-label trials and case reports, but several randomised controlled trials have been done, particularly focused on the effects of drugs or use of non-invasive brain stimulation. However, only two studies on amantadine and transcranial direct current stimulation provided class II evidence. Although new therapeutic approaches seem to be valuable for patients with prolonged disorders of consciousness, optimised stimulation parameters, alternative drugs, or rehabilitation strategies still need to be tested and validated to improve rehabilitation and the quality of life of these patients.

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.

[A case of meningoencephalitis associated with pembrolizumab treated for squamous cell lung cancer].

A 61-year-old man with squamous cell lung cancer was admitted to our hospital because of consciousness disturbance after treated with pembrolizumab. Cerebrospinal fluid examination revealed increased protein level (209.2 mg/dl) and lymphocytic pleocytosis(79/µl). He was diagnosed as a meningoencephalitis probably caused by an immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs), and was successfully treated with 1,000 mg methylprednisolone intravenously for 3 days twice and the consequent oral 1 mg/kg prednisolone. As ICIs, which activate the immune systems, are becoming important choices of the treatments against malignancies, we should keep the possibility of irAE in mind and, when needed, start the treatment as soon as possible.

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.