INTRODUCTION

The aim of this study is to present a clinical case of a 29-year-old female patient who developed delayed encephalopathy after acute carbon monoxide poisoning (DEACMP). Particular attention is given to the effectiveness of hyperbaric oxygen therapy (HBOT) in the acute phase as well as the treatment of long-term neurologi- cal complications. The study also aims to discuss current scientific evidence on therapeutic strategies used in DEACMP and to emphasize the need for developing treatment guidelines.

Case description

A 29-year-old female patient was admitted to the Toxicology Department due to acute carbon mono-xide (CO) poisoning, caused by exposure to CO from a bathroom gas heater. The duration of exposure was approximately 9 hours. Carboxyhemoglobin concentration was 7.8%. At admission, the patient was in a severe condition, unconscious, with a Glasgow Coma Scale score of 8 points, and respiratory and circulatory function within normal limits. Additionally, first-degree pressure ulcers were observed on the left buttock and left scapula.

Magnetic resonance imaging (MRI) of the head revealed increased signal intensity in the basal ganglia on T2 and FLAIR sequences with diffusion restriction. Laboratory tests showed elevated cardiac markers (troponin I, creatine kinase [CK], and creatine phosphokinase-MB [CK-MB]). Electrocardiogram revealed T-wave inversions in leads I, II, III, aVF, and precordial leads V2-V6. Echocardiography demonstrated reduced contractility of the left and right ventricles and akinesia of the left ventricular apex, with an ejection fraction of 30%. Type 2 myocar- dial infarction due to myocardial hypoxia was diagnosed.

The patient received passive oxygen therapy and underwent five hyperbaric chamber sessions (2.5 ATA, 1 hour per day). Her condition improved; follow-up laboratory tests showed decreased cardiac markers and ejection fraction rising to 50%, although apical akinesia persisted. Neuropsychological testing revealed impaired cognitive function with deficits in attention, visual scanning speed, and long-term memory. The patient was discharged home and her family reported normal functioning without noticeable cognitive deficits.

Thirty-eight days post-poisoning, the patient and her family presented to the Emergency Department due to worsening cognitive function over the previous three days. Symptoms included disorientation, illogical speech, psychomotor slowing, slowed speech, and euphoric mood. Upon admission to the Neurology Department, she was conscious but psychomotorically slowed, responding to simple questions, attempting answers to more complex questions and following commands with delay and only after repetitive requests.

Head MRI revealed malacic changes in the basal ganglia, elevated signal in the corpus callosum, and white matter. Follow-up MRI after two weeks showed extensive leukoencephalopathy affecting the entire corpus callosum and white matter, in addition to malacic changes in the basal ganglia.

Electroencephalography was spatially undifferentiated and showed slowing of basic brain activity. Cerebrospinal fluid analysis revealed no abnormalities; viral, bacterial, and autoimmune encephalitis were excluded.

Neuropsychological evaluation revealed psychomotor slowing, limited responses to questions, apathetic and abulic mood, and a loss of emotional expression modu-lation. The patient had significant difficulty initiating motor and speech activities independently and could not follow complex commands. The cognitive profile corresponded to akinetic mutism.

DEACMP was diagnosed based on clinical symptoms and examination results. During hospitalization, transient autonomic disturbances occurred, including paro-xysmal tachycardia, hypertension, and hyperthermia. Sympathetic overactivity was treated with morphine, resulting in improved vital signs. Baclofen and gabapentin were used prophylactically for sympathetic hyperactivity. Worsening neurological status manifested as impaired consciousness, increased muscle tone, and bradykinesia, necessitating temporary tube feeding.

During hospitalization in the Neurology Department, the patient received pulsed methylprednisolone and memantine, but due to lack of efficacy, treatment was discontinued.

The patient was then admitted to the Rehabilitation Department. Upon admission, she was conscious, able to provide her name and age, partially followed simple commands, answered simple questions, but her communication was illogical. No motor deficits were observed. She required one-person assistance during standing, two-person support during walking short distances, and help with all activities of daily living.

Neuropsychological assessment showed orientation to self but disorientation to time and place. The patient understood simple instructions but had difficulty with complex commands. Communication was illogical, with deficits in critical thinking and reasoning. Impaired verbal fluency and deficits in working, semantic, episodic, and procedural memory were observed, with significant difficulties in memory consolidation. Executive functions were severely impaired. Attention, selective focus, and attentional switching were compromised. Visual-spatial function deficits, visual agnosia, and inability to work with abstract material were present. Mood was passive and apathetic.

Upon admission, the patient was unable to perform balance and gait tests (feet-together stance, tandem test, Romberg test, single-leg stance, timed up & go, 10-meter walk test).

During hospitalization, the patient underwent psychological, speech, occupational, and physical therapy, and participated in 24 sessions of HBOT at 1.6 ATA, 1 hour per day. Following rehabilitation, her cognitive, motor, and functional status improved significantly. Balance and gait tests were normal. Pre-discharge neuropsychological testing revealed only mild attention and verbal fluency deficits.

Six months after discharge from the Rehabilitation Department, the patient returned to work as a government official in the finance department, performing tasks requiring high cognitive performance, including attention, working memory, and analytical thinking. Neuropsychological testing before returning to work was within normal limits. Thirty months post-discharge, the patient functions normally both in her professional and social life.

Comment

This case demonstrates the development of early and late sequelae of CO poisoning. According to the literature, delayed neurological sequelae occur in approximately 3-40% of adult CO poisoning cases. The most frequent symptoms include memory, speech, and behavioral disturbances; akinetic mutism; extrapyramidal symptoms (parkinsonism, chorea, dystonia); dementia; psychosis; and sphincter dysfunction [1-3].

DEACMP typically develops after asymptomatic CO exposure or a transient period of improvement, ranging from 3 to 60 days [4, 5]. In the presented case, the patient’s period of transient improvement lasted 38 days.

Attempts have been made to define predictors of DEACMP. Wang et al. [6], in a review, analyzed available studies and highlighted the potential significance of cli-nical factors (duration of unconsciousness, days unable to walk, severity of acute-phase symptoms), labora-- tory markers (e.g., neuron-specific enolase [NSE], S100B protein, glial fibrillary acidic protein [GFAP]), imaging features (e.g., MRI changes, including diffusion sequences), and molecular/genetic markers (e.g., myelin injury biomarkers, exosomal microRNAs). However, none of these factors currently possess sufficient prognostic power for routine clinical use, and studies are characterized by high heterogeneity and methodological limitations. The authors emphasize the need for prospective validation studies and the development of next-generation biomarkers, such as exosomes, which may become promising prognostic tools.

Suzuki [7], in a retrospective study, identified the number of days the patient was unable to walk during the acute phase as an important risk factor for delayed neurological sequelae. He also proposed an index combining peak CK levels and “days without walking,” which showed 100% sensitivity and 82% specificity in predicting delayed neurological symptoms.

Cerebral hypoxia leads to neuronal damage and de-myelination, mainly affecting the basal ganglia, periventricular white matter, hippocampus, thalamus, cerebellum, medial temporal lobes, and frontal lobes – consistent with acquired leukoencephalopathy [8]. MRI shows diffuse hyperintense lesions on T2-weighted and FLAIR sequences corresponding to demyelination and neuronal injury.

In this case, a close correlation was observed between MRI changes and clinical progression. Initial basal ganglia lesions typical of acute CO poisoning corresponded with consciousness disturbances and cognitive deficits. Subsequent MRI revealed new hyperintense lesions in the corpus callosum and white matter, corresponding to cognitive impairment, psychomotor slowing, and executive function deficits, typical of fronto-subcortical and commissural fiber damage. Diffuse white matter and corpus callosum involvement ultimately manifested as deficits in working memory, attention, reasoning, and akinetic mutism.

This course aligns with reports from larger DEACMP cohorts, where basal ganglia changes are considered early markers of toxic-hypoxic injury. In the delayed phase, white matter and corpus callosum lesions, as in this case, correlate with cognitive deficits and leukoencephalopathy clinical features [9-13].

Guo et al. [14] suggested that oligodendrocyte dysfunction and inadequate regeneration of oligodendrocyte precursors in the white matter may be key mechanisms underlying delayed neurological sequelae. CO toxicity may impair precursor differentiation into mature oligodendrocytes and affect existing oligodendrocytes, leading to progressive demyelination and neuronal dysfunction. Future therapeutic strategies should aim not only at neuro-protection but also at promoting oligodendrocyte rege-neration and remyelination.

The main treatment for acute CO poisoning is 100% oxygen therapy and HBOT [15]. HBOT, in addition to acute-phase treatment, may significantly reduce the risk of delayed neurological complications [4, 16, 17].

Therapeutic hypothermia is another potential treatment, usually applied in patients experiencing sudden cardiac arrest or central nervous system injury due to hypoxia and ischemia [18]. Experimental therapies include mesenchymal stem cells (MSC) and N-butyl-phthalide (NBP). Wang et al. [19] showed that combining MSC with NBP improved cognitive outcomes (Mini-Mental State Examination – MMSE) and functional independence (Barthel Index) more than HBOT alone.

Xu et al. [20], in a narrative review, emphasized MSC potential but highlighted the limited number of studies, lack of randomization, and heterogeneous protocols (different MSC sources, doses, timing). Song et al. [21] provided evidence of NBP’s multifaceted neuroprotective effects (reducing oxidative stress, protecting the blood–brain barrier, supporting remyelination), though most data are from experimental and observational studies.

Strengths of these methods include theoretical neuro-protective and regenerative effects and preliminary evidence of improved MMSE and Barthel scores. Limitations include small, often single-center studies, lack of randomization, short follow-up, and protocol heterogeneity (MSC source, NBP administration, timing relative to CO exposure).

Xiang et al. [22] noted the potential use of HBOT alone or combined with dexamethasone or NBP in DEACMP. In a randomized clinical trial (n = 120), HBOT + dexamethasone (5 or 10 mg/day for 4 weeks) led to better MMSE scores, lower National Institutes of Health Stroke Scale (NIHSS) scores, and higher remission rates than HBOT alone. Another randomised controlled trial (RCT) (n = 184), comparing HBOT + NBP vs. HBOT alone over 8 weeks, showed superior overall remission and MMSE/NIHSS improvement in the HBOT + NBP group [23].

Wang et al. [19] compared MSC + NBP, MSC alone, and HBOT in 42 DEACMP patients. Combined MSC + NBP therapy outperformed other groups in MMSE and Barthel Index at 1, 3, and 6 months.

A recent systematic review with network meta- analysis including 17 RCTs (1293 patients) confirmed that MSC + NBP significantly improves MMSE and Barthel Index outcomes, while NBP + dexamethasone is most effective in improving activities of daily living [21].

Most studies are small, single-center RCTs or case reports, with protocol heterogeneity (doses, therapy duration, HBOT parameters, MSC administration). Large multicenter studies with extended follow-up are lacking to define an optimal therapeutic regimen.

Steroid therapy with pulsed methylprednisolone combined with memantine has been described as potentially effective in DEACMP, but reports are limited to single cases. Iwamoto et al. [24] reported neurological improvement with this therapy. Rudnicka-Czerwiec et al. [27] observed similar effects. These observations suggest a possible neuroprotective effect but do not allow generalization.

Lay-Son Rivas et al. [28] described DEACMP treated with oral citicoline (1000 mg/day), showing significant cognitive improvement (MMSE 19 → 27) and partial regression of white matter lesions over 60 days.

In our patient, HBOT was effective in treating both early and late CO poisoning effects. However, acute-phase HBOT did not prevent DEACMP. HBOT effectiveness in preventing long-term neurological deficits depends on time from exposure to therapy initiation, pressure and protocol (number and duration of sessions), severity of primary brain injury (e.g., unconsciousness, MRI lesions), and individual patient factors [12, 13, 20, 25, 26, 29, 30].

Evidence suggests early HBOT, ideally within 6 hours of exposure, reduces the risk of delayed cognitive deficits. Weaver et al. [29] demonstrated that three HBOT sessions within 24 hours significantly reduced cognitive impairment at 6 weeks and 12 months. Clinical observations and systematic reviews highlight high heterogeneity and therapy-timing dependence [16, 30].

In this patient, CO exposure lasted ~9 hours. HBOT was initiated ~4 hours after admission, consisting of five sessions at 2.5 ATA for 1 hour daily. Despite pressure parameters being near recommended values, the limited number of sessions and delayed initiation may have reduced neuro- protective efficacy. Clinical studies suggest repeated sessions at short intervals, typically three in 24 hours, provide optimal protection against delayed cognitive deficits [26, 29]. Protocol differences may explain why acute-phase HBOT did not prevent DEACMP [20, 25].

MRI basal ganglia lesions and diffusion restriction indicate extensive neuronal and oligodendrocyte damage. In advanced demyelination and oligodendrocyte dysfunction, HBOT may not prevent DEACMP, even when applied in the acute phase [1, 12].

Although DEACMP generally carries a poor prognosis [19], this case documents complete cognitive and functional recovery after severe DEACMP, complicated by neurological (akinetic mutism), cardiological (type 2 myocardial infarction, severe transient left ventricular dysfunction), and autonomic hyperreactivity symptoms. This case demonstrates that integrated rehabilitation (cognitive, speech, motor) combined with HBOT can achieve full recovery even in severe DEACMP.

Further research is warranted, including integrated DEACMP therapy models combining HBOT with comprehensive rehabilitation and the development of treatment guidelines.