Treatment of post-traumatic brain injury using high-dose neurotrophic factors – a case report study

Introduction

Post-traumatic brain injury (TBI) dementia is a progressive degenerative disease associated with a history of brain trauma, including symptomatic concussions (e.g., traffic-related accidents, falls, sports injuries, shock waves from battlefield explosions) and asymptomatic subconcussive impacts to the head⁽¹⁾.

Post-TBI dementia is a nosologic entity defined by both the International Classification of Diseases, Eleventh Revision (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR)^(2,3).

According to the ICD-11, the essential features of the diagnosis of dementia due to injury to the head (6D85.7) state that all diagnostic requirements for dementia should be met and that dementia is certainly attributable to an injury to the head, supported by clinical examinations and history. The additional clinical features state that dementia is caused by damage inflicted on brain tissue, which is known to have resulted in loss of consciousness, along with amnesia, disorientation, confusion or neurological signs. Furthermore, the symptoms’ onset is after trauma or regaining of consciousness, and neurocognitive deficits are dependent on the specific brain areas affected by the injury and its severity⁽²⁾. According to DSM-5-TR, the diagnosis of major or mild neurocognitive disorder due to TBI is met if all criteria for major or mild neurocognitive disorder are present, one or more evidences of TBI exist (loss of consciousness, posttraumatic amnesia, disorientation and confusion, and neurological signs), and the neurocognitive disorder was present right after the TBI or after regaining consciousness and persisted past the acute post-injury period. Additional coding notes exist depending on the severity and presence or absence of behavioral disturbances. There are various specific cognitive impairments that help establish the severity of the neurocognitive disorder, although severe TBIs with brain contusion, intracranial hemorrhage or penetrating injury are frequently associated with aphasia, apraxia or disturbances in perceptual-motor function, depending on the affected region of the brain and the lost volume of brain tissue⁽³⁾.

The available treatment options of TBIs are empirical and target the associated symptoms, considering that TBIs are associated with dementia and other neurodegenerative diseases, along with behavioral disturbances. Several pharmacological options have been reported, including medication to reduce the secondary damage after TBI (omega-3 polyunsaturated fatty acids, melatonin, N-acetylcysteine, statins) and medication to manage symptoms post-TBI (methylphenidate, sertraline, amitriptyline, guanfacine, donepezil). There are reports that support the use of antiepileptic drugs as potential dementia prophylactics following TBI due to their ability to reduce neuronal hyperexcitability and network instability, pathological states that promote neurodegenerative diseases^(4,5).

The treatment of dementia is usually based on neuroprotective and disease-modifying treatments, while the associated neuropsychiatric symptoms are treated with specific medications, such as antipsychotics, antidepressants, and sedative-hypnotics⁽⁶⁾. In the case of post-TBI dementia, possible treatment options include the porcine brain-derivate hydrolysate (PBDH). PBDH is a mixture of peptides and amino acids with nootropic properties that act like endogenous neurotrophic factors. These neurotrophic factors can mediate brain development and provide neuroprotective effects, which are essential features in developing disease-modifying therapies in dementia. While the common treatment regimen consists of 10 mL/administration, 10 days/months, for three months, there are literature reports that support the administration of high doses, up to 50 mL, in post-TBI dementia^(7-9).

This report aimed to present the effects of PBDH in a severe case of post-TBI dementia and the gradual improvement of symptoms based on cognitive function tests.

Case report

In early November 2024, a 68-year-old patient, without a documented history of psychiatric illness, was transferred from the “Dr. Constantin Opriș” County Emergency Hospital, Baia Mare, Romania, to the Neurosurgery Clinic inside Cluj County Emergency Clinical Hospital, Cluj-Napoca, Romania, following a TBI with loss of consciousness after a fall from height (from a ladder in unknown circumstances). The initial CT scan revealed an enlarging temporal-basal subdural hematoma, a progressive hemorrhagic contusion in the temporal lobe, and an associated temporal lobe laceration (Figure 1). The initial neurological examination had the following characteristics: conscious patient, partially cooperative, dysphasic, disoriented to time and place, with a Glasgow Coma Scale (GSC) = 14 points⁽¹⁰⁾. There were no signs of meningeal irritation, intracranial hemorrhage or paresthesia. The patient underwent a temporal craniotomy to evacuate the hematoma.

The patient was discharged eight days later from the neurosurgery clinic, and carbamazepine 400 mg/day p.o. was initiated. Ten days later, he was brought to the First Psychiatric Clinic of the Cluj County Emergency Clinical Hospital, Cluj-Napoca, Romania, by family members, for aggressive behavior directed at them, bizarre behavior, characterized by ideas of reference, persecutory delusions (the patient was thinking that the family targeted him) and visual hallucinations (the patient was talking with unknown people whom he claimed to see in the room). The psychiatric symptoms emerged after the recent craniotomy.

Mental state examination revealed a patient with poor hygiene, an unkempt appearance, and disheveled but appropriate clothing, indicating neglected self-care. Expressive language was severely impaired due to motor aphasia, making it incomprehensible. His speech was of heightened volume and occasionally he vocalized words in Spanish and obscene words. Non-verbal communication, such as gestures and facial expressions, was present but disorganized. At times, the patient engaged in repetitive actions like picking at his clothing. He exhibited episodes of psychomotor agitation, restlessness, occasional aimless wandering, and hetero-aggressiveness towards family members, leading to overall disorganized behavior. Self-care abilities were significantly impaired, requiring constant supervision.

Cognitive assessmentdemonstrated markedly impaired attention, with distractibility and a difficulty in maintaining focus, severe both short- and long-term memory deficits, false recognitions and relatively preserved semantic aspects from autobiographical memory. The patient was disoriented to time and place.

The patient experienced complex auditory and visual hallucinations revealed through heteroanamnesis and inappropriate reactions to unseen or unheard stimuli. Thought processes were incoherent, marked by tangentiality and general bradypsychia, alternating with episodes of tachypsychia. Fragmented persecutory and interpretative delusions dominated the thought content. The patient exhibited emotional lability, irritability, and low frustration tolerance.

The patient displayed a lack of motivation and overall passiveness in his interactions. Basic instincts, such as self-preservation and social engagement, were diminished. He experienced disrupted sleep, characterized by frequent agitation during the night and a reduced total sleep duration. The patient lacked insight into his psychiatric condition and its consequences.

The physical examination was unremarkable. Another neurological examination was conducted and revealed cognitive deterioration and post-TBI sequelae. Concluding from the clinical presentation, the patient was diagnosed with dementia due to injury to the head (according to the International Classification of Diseases, Eleventh Revision – ICD-11) or major neurocognitive disorder due to traumatic brain injury (according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision – DSM-5-TR)^(2,3).

The psychological examination revealed bradypsychia, bradylalia, bradykinesia, disorientation in time and space (2 out of 70 total score on orientation items), nominative and motor aphasia, and apraxia. Psychometric evaluations scored 5 out of 30 points in the Mini-Mental State Examination (MMSE)⁽¹¹⁾, 4 out of 30 points in the Montreal Cognitive Assessment (MoCA)⁽¹²⁾, 19 out of 100 points on the Global Assessment of Functioning Scale (GAFS)⁽¹³⁾, and 1 out of 10 points in the clock-drawing test⁽¹⁴⁾, indicating a severe cognitive impairment.

During the admission, a follow-up CT scan was performed one month after craniotomy, revealing a left temporal-parietal epicranial collection, with mixed density, approximately 5 mm thickness (sequelar aspect), a millimetric epidural collection adjacent to the internal surface of the bone flap (sequelar aspect), and right petrous temporal bone fracture with a transmastoid pathway, extending into the right temporal-mandibular joint and the sphenoid sinus. Several cerebral lacunes were also noted (Figure 2).

The treatment during admission consisted of several molecules. Memantine 20 mg/day p.o. was employed as first-line antidementia drug. The initial treatment with carbamazepine, used as mood stabilizer, was titrated up to 600 mg/day p.o., while risperidone 2 mg/day p.o. (later reduced to 1 mg/day p.o.) was used to control agitation. Supplementary sedation was provided using lorazepam 2 mg/day i.m., which was later transitioned to 2 mg/day p.o., tapered to 1 mg/day p.o., and later administered only when needed during agitation states or insomnia. Enalapril 10 mg/day p.o. was used to control hypertension throughout the admission, while other treatments included two nootropic food supplements (one containing sodium citicoline 500 mg and choline 210 mg, administered as drinkable formulation, later switched to the other one containing citicoline 200 mg, dry root extract of Polygonum cuspidatum 150 mg, dry aerial parts extract of Bacopa monieri 100 mg, phosphatidylserine 50 mg, and homotaurine 25 mg, administered as one capsule/day) and fluid therapy for five days, consisting of saline solution 500 mL/day i.v., concentrated solution of sodium chloride 5.85% 15 mEq/day i.v., and dextrose 5% 500 mL/day i.v. A new antidementia drug, donepezil, was additionally added when the patient was discharged, initially 5 mg/day p.o. for one month, then 10 mg/day p.o.

After 19 days, the patient was discharged with improved symptoms and transferred to a nursing home. However, three days later, the patient was readmitted to the First Psychiatric Clinic of the Cluj County Emergency Clinical Hospital, Cluj-Napoca, Romania, by police and an emergency medical team, due to verbal and physical aggression towards the staff of the nursing home and inappropriate behavior. On admission, the patient was aphasic (0 points in the Aphasia Severity Rating – ASR⁽¹⁵⁾), disoriented to time and place, and was speaking in Spanish, despite being a Romanian native.

Considering the severity of the clinical presentation, a high dose regimen of neurotrophic factors was initiated, consisting of PDBH 30 mL/administration, 10 days/month, for three months. The regimen would be repeated three months later, as recommended by the neurologist. The rest of the psychopharmacological treatment consisted of antidementia drugs (memantine 20 mg/day p.o. and donepezil 5 mg/day p.o., stopped due to possible concerns of it exacerbating agitation) and mood stabilizers (carbamazepine 600 mg/day p.o., switched to valproic acid 600 mg/day due to drug-drug interactions concerns, which was also stopped due to skin rash and replaced with gabapentin 800 mg/day p.o., ultimately stopped as well after somatic complications appeared). Sedation and control of agitation states were ensured using risperidone 4 mg/day p.o. (later tapered to 2.5 mg/day p.o.), benzodiazepines (lorazepam 1 mg/day i.m. initially, then switched to 1 mg/day p.o., followed by a switch to clonazepam 1.5 mg/day p.o., gradually tapered and stopped after somatic complications, and finally to nitrazepam 2.5 mg/day p.o.), and sedative antidepressants (trazodone 150 mg/day p.o., which was later switched to mirtazapine, initially 15 mg/day p.o., then 30 mg/day p.o.).

During the admission, the patient developed aspiration pneumonia, confirmed by CT angiography scan. The patient was somnolent, and SaO₂ was constantly decreasing (70%), thus necessitating oxygen therapy and secretion aspiration. Empirical antibiotic therapy was initiated, consisting of piperacillin-tazobactam 4 g/0.5 g every six hours for seven days, with favorable evolution of the symptoms. Additionally, the patient had hypernatremia (158 mg/dL), which was corrected with 0.45% saline solution 1 liter/day and adequate rehydration, while venous blood gas analysis was performed until normalization of electrolytes.

The additional treatment consisted of acetylcysteine 600 mg/day i.v. (stopped after pneumonia symptoms subsided), probiotics and prebiotics (Bifidobacterium animalis lactis and Lactobacillus rhamnosus 1.5 billion CFUs and fructooligosaccharides 45 mg, two capsules/day, timed post-antibiotic administration, seven days), clopidogrel 75 mg/day p.o. and rosuvastatin 20 mg/day p.o. (both recommended for the prevention of cardiovascular events), enoxaparin 4000 IU/day s.c. (prevention of deep vein thrombosis after prolonged bed rest), and enalapril 10 mg/day p.o. (ultimately stopped due to frequent low blood pressure levels).

Because prolonged treatment and institutionalized care were needed, the patient was transferred to the Borșa Hospital for Chronic Psychiatric Diseases after 33 days of hospitalization. The final treatment consisted of PDBH 30 mL/administration, 10 days/month, two more months, memantine 20 mg/day p.o., risperidone 2.5 mg/day p.o., nitrazepam 2.5 mg/day p.o., mirtazapine 30 mg/day p.o., clopidogrel 75 mg/day p.o., rosuvastatin 20 mg/day p.o., and potassium and magnesium supplement 117 mg/36 mg/day p.o. (until correction of hypokalemia).

Once the high-dose regimen of neurotrophic factors was finished, repeat psychometric evaluations were performed. The patient scored 8 out of 30 points on the MoCA, 12 out of 30 points on the MMSE, and 31 out of 100 points on the GAFS, indicating a moderate cognitive impairment.

The Health Utilities Index Mark III (HUI Mark III) was applied to evaluate the health-related quality of life of the patient⁽¹⁶⁾. The patient obtained an index of 0.136, describing a general poor health condition, particularly due to the cognitive impairment. However, it is worth mentioning that the patient’s health status gradually improved after the transfer to the Borșa Hospital for Chronic Psychiatric Diseases.

Finally, one month after regimen completion, the patient scored 12 out 30 points on the MoCA, 14 out of 30 points on the MMSE, and 40 out of 100 points on the GAFS, indicating continuous progress in the improvement of the cognitive function. The PBDH regimen would be repeated three months later to maintain or improve the current results.

Discussion

The initial psychiatric examination and neuroimaging observations supported the diagnosis of post-TBI dementia, while the serial psychometric evaluations showed an improvement in cognition and functionality, following the high dose regimen of neurotrophic factors. As illustrated in Figure 3, all three MMSE, MoCA and GAFS scores have increased from the initial until the final assessment. Currently, the patient’s psychiatric status has improved and is now actively included in the activities organized by the hospital for the patients.

Conclusions

Post-TBI dementia is a diagnosis with significant impact on both patients and their families. The current case report underscored the severity of post-TBI dementia, the urgent need for effective treatment, and the high risk of somatic complications that increase mortality. The high-dose regimen of neurotrophic factors initiated in this case showed promising results, thus heralding a positive outcome for this patient.    

Corresponding author: Roland Stretea E-mail: roland.miha.stretea@elearn.umfcluj.ro

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.