Abstract
BACKGROUND:
A few studies specifically addressed medical comorbidities (MCs) in patients with severe acquired traumatic or non-traumatic brain injury and prolonged disorders of consciousness (pDoC; i.e., patients in vegetative state/unresponsive wakefulness syndrome, VS/UWS, or in minimally conscious state, MCS).
OBJECTIVE:
To provide an overview on incidence of MCs in patients with pDoC.
METHODS:
Narrative review on most impacting MCs in patients with pDoC, both those directly related to brain damage (epilepsy, neurosurgical complications, spasticity, paroxysmal sympathetic hyperactivity, PSH), and those related to severe disability and prolonged immobility (respiratory comorbidities, endocrine disorders, metabolic abnormalities, heterotopic ossifications).
RESULTS:
Patients with pDoC are at high risk to develop at least one MC. Moderate or severe respiratory and musculoskeletal comorbidities are the most common MCs. Epilepsy and PSH seem to be more frequent in patients in VS/UWS compared to patients in MCS, likely because of higher severity in the brain damage in VS. Endocrine metabolic, PSH and respiratory complications are less frequent in traumatic etiology, whereas neurogenic heterotopic ossifications are more frequent in traumatic etiology. Spasticity did not significantly differ between VS/UWS and MCS and in the three etiologies. MCs are associated with higher mortality rates, worse clinical improvement and can impact accuracy in the clinical diagnosis.
CONCLUSIONS:
The frequent occurrence of several MCs requires a specialized rehabilitative setting with high level of multidisciplinary medical expertise to prevent, appropriately recognize and treat them. Comprehensive rehabilitation could avoid possible progression to more serious complications that can negatively impact clinical outcomes.
Introduction
Patients with severe acquired traumatic or non-traumatic brain injury and prolonged (more than 28 days from brain insult) disorders of consciousness (pDoC; i.e., patients in vegetative state/unresponsive wakefulness syndrome, VS/UWS, or in minimally conscious state, MCS) (Kondziella et al., 2020) show high risk to develop medical comorbidities (MCs) (Whyte et al., 2013a; Pistoia et al., 2015; Ganesh et al., 2013; Estraneo et al., 2018). Many MCs are directly related to the brain damage, such as paroxysmal sympathetic hyperactivity (PSH) (Baguley et al., 2014) or epileptic seizures, whereas other MCs develop as a consequence of severe disability and immobility, such as respiratory infections (Hansen et al., 2008), or neurogenic heterotopic ossification (Bargellesi et al., 2018; Estraneo et al., 2021a). MCs can make assessment of consciousness level quite difficult (Majerus et al., 2005), as they can hinder clinical manifestation of intentional behaviors (e.g., spasticity) or impact on patients’ vigilance (e.g., severe infections or thyroid hormone alterations). Moreover, several MCs, such as PSH, can hamper care and rehabilitative treatment (Formisano et al., 2017). It has been demonstrated that, during inpatient rehabilitation, common MCs are associated with poor motor and cognitive functions one year after severe traumatic brain-injury (Ganesh et al., 2013) or non-traumatic brain injury (Pistoia et al., 2015). More recently, a long-term longitudinal study on a large cohort of patients with pDoC reported that endocrine-metabolic disorders are associated with higher mortality rate, whereas epilepsy is negatively associated with clinical recovery at 24 months post-onset (Estraneo et al., 2018). This narrative review will briefly overview the MCs most relevant for management of patients with pDoC, as they have been found to hamper the detection of conscious behaviors (e.g., spasticity) and/or impact most negatively the clinical evolution (e.g., seizures) in these patients, whereas there is no room here to address the full spectrum of MCs potentially affecting patients with pDoC (e.g., recurrent urinary infections or pressure sores).
Medical comorbidities related to brain damage
Seizure and epilepsy
The International League Against Epilepsy (ILAE) proposed the operational definition for an epileptic seizure: “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain” (Fisher et al., 2005). Epileptic seizures occurring in close temporal relationship with an acute brain insult, i.e. within 7 days from ischemic or hemorrhagic stroke, anoxic or traumatic brain injury (and beyond 7 days, in case of subdural hematoma without trauma), or central nervous system infection (and beyond if the infection is still active), are called “acute symptomatic (provoked) seizure” (Beghi et al., 2010). The ILAE also proposed a conceptual definition for epilepsy: “a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition” (Fisher et al., 2014). This operational definition of epilepsy requires the occurrence of “at least two epileptic unprovoked (i.e., outside the time period of the causal association with acute brain insult) seizures” or “one unprovoked seizure” with at least 60% probability for the recurrence of further seizures over the next 10 years (Fisher et al., 2014). A condition of structural brain damage, especially if associated with epileptic abnormalities on EEG, significantly increases the likelihood of seizure recurrence; for this reason, in patients with severe brain injury and pDoC only a single unprovoked seizure is sufficient to diagnose epilepsy (Beghi et al., 2010).
The incidence of epileptic seizures and epilepsy in patients with pDoC are not fully established yet, likely due to the difficulty to recognize non-convulsive (i.e., seizure with only alteration of consciousness) or subtle seizures (i.e., seizure with minimal clinical signs) in such non-communicative patients. Although seizures could go unrecognized, available observational studies reported an occurrence ranging from 16 to 46% of patients with pDoC (see Table 1) (Whyte et al., 2013a; Ganesh et al., 2013; Estraneo et al., 2018; Pascarella et al., 2016; Bagnato et al., 2013; Lejeune et al., 2021). Differences could be explained, in part, by the heterogeneity of patient’s inclusion/exclusion criteria of these studies. Cumulating the samples reported in 5 studies (Ganesh et al., 2013; Estraneo et al., 2018; Pascarella et al., 2016; Bagnato et al., 2013; Lejeune et al., 2021; Whyte et al.’s study; 2013a was not included because it excluded epileptic patients at baseline), epileptic seizures occurred in 23.8% of patients, with a significantly higher percentage (25.1%) in patients in VS/UWS with respect to MCS patients (15.5%; chi-square = 8.5, p = .003), but without significant difference among the three etiologies (traumatic = 18.6%, vascular = 21.9%, anoxic = 24.6%; chi-square = 2.09, p = .35). Epileptic seizure can negatively impact the recovery of consciousness at 30 months after brain injury, likely because of the related pathogenic mechanism of seizure might interfere with neuroplasticity for the recovery process (Estraneo et al., 2018). It is also important to remind here that, beyond epileptic seizures, EEG epileptic abnormalities are quite common in patients with pDoC (Pascarella et al., 2016), and are worth to be searched for even though they do not seem to exert the same detrimental effect on recovery of consciousness as epileptic seizures do.
Number (and percentage) of patients with prolonged disorders of consciousness showing medical complications in the total study samples and as a function of clinical diagnosis and aetiology
Number (and percentage) of patients with prolonged disorders of consciousness showing medical complications in the total study samples and as a function of clinical diagnosis and aetiology
VS/UWS = vegetative state/unresponsive wakefulness syndrome; MCS = minimally conscious state; TBI = traumatic brain injury; + = patients with specific medical complication; ES = epileptic seizures; H = hydrocephalus; S = spasticity; PSH = paroxysmal sympathetic hyperactivity; R = respiratory complications; EMD = endocrine-metabolic disorders; NHO = neurogenic heterotopic ossifications; NA = not available. Note: *denotes P < 001, as reported in the original studies; ∧denotes 1 patient with mixed aetiology and NHO + not reported in this table; °Univariate analyses showed that NHO was associated with VS/UWS. This finding was not confirmed by a cluster-corrected binary logistic regression model; ∧sample included 1.8% of sample suffered from mixed etiology; a36% of sample with vascular, anoxic and other etiologies; b25.6% emerged from MCS and 3.8% other etiologies (i.e., infections/tumor benign); §36% encephalitis.
The treatment of seizure/epilepsy in patients with severe brain injury with pDoC could be challenging, as no study addressed this issue specifically (Lejeune et al., 2021). In line with the general recommendation on symptomatic seizures, treatment of epilepsy or seizures in patients with severe brain injury depends on time of occurrence after the injury (Mauritz et al., 2022). Although it is currently recommended to administer anti-seizure medications (ASM) prophylactically within the first 24 hours after traumatic brain injury, to prevent early acute symptomatic seizures, contrasting data have been reported on ASM’s protective effect on later epilepsy occurrence (Mauritz et al., 2022). However, to withdraw ASM in patients with pDoC admitted in neurorehabilitation setting could be challenging, as no specific guidelines are available (Lejeune et al., 2021). Phenytoin was the most studied ASM given for prophylaxis, but, more recently, levetiracetam is likely the most popular choice, because of its equivalent efficacy and of low rates of adverse effects (usually not severe, e.g. agitation and irritability) and drug-drug interactions (Thelengana et al., 2019; Chaari et al., 2017).
In the first week from brain injury, the treatment of acute seizures is recommended, to prevent further acute seizures (Hesdorffer et al., 2009). However, the long-term antiepileptic treatment of acute seizure (more than 2 weeks) is generally not indicated, because risk of recurrence of acute symptomatic seizures is low (Mauritz et al., 2022; Hesdorffer et al., 2009). A pragmatic but not evidence-based approach suggests to guide the long-term antiepileptic treatment, by means of periodic EEG recording for detecting possible epileptic abnormalities in these non-collaborative patients (Pascarella et al., 2016; Lejeune et al., 2021). When unprovoked seizures occur after the first week from the injury, the duration of ASM treatment is generally longer (months or years) (Hung et al., 2012). It is suggested to start treatment with a single ASM, and to use ASM with lower impact on cognitive functions, such as the new ASM (Brunbech et al., 2002). Although data on ASM therapy in patients with pDoC are lacking, a recent international survey of physicians’ attitudes showed that the choice of the ASM is based on a balance between reducing the number of seizures, avoiding adverse effects and toxicity, and promoting cognitive recovery (Briand et al., 2022).
Patients with severe acquired traumatic brain injury are often treated by means of decompressive craniectomy (DC) to manage refractory intracranial hypertension (e.g., for massive intracerebral hemorrhage or malignant edema), although there is no clear information about positive outcome in these cases (Hutchinson et al., 2016). The so-called Syndrome of the Trephined, or Sinking Skin Flap Syndrome (SSFS) is not an exceptional neurosurgical complication of delayed cranioplasty (Hutchinson et al., 2016; Formisano et al., 2020). The SSFS is defined as a progressive (over weeks or months) neurological deterioration with symptoms such as severe headaches, mental changes, focal deficits, or seizures (Sveikata et al., 2022). In patients with pDoC this syndrome can be undiagnosed because of difficulty in detecting worsening of consciousness impairment, or an unexplained slowing of clinical improvement, whereas seizures occurrence could raise suspicion of this syndrome (Hutchinson et al., 2016). Cranioplasty (i.e., reconstruction for skull defect) is the restorative neurosurgical procedure to prevent and treat SSFS, as it provides brain protection, can restore cerebrospinal fluid circulation and cerebral blood flow (Sveikata et al., 2022), and promote clinical recovery in patients with pDoC (Dang et al., 2021). However, appropriateness of cranioplasty, timing, and occurrence of side effects (e.g., infection of site) are still debated. In 2018, an International Consensus Conference on Cranioplasty in Traumatic Brain Injury, promoted by the Neurotrauma Committee of the World Federations of Neurosurgical Societies and involving professionals of rehabilitation phase, provided some recommendations (Iaccarino et al., 2021). Beyond technical recommendations, the main statements of interest for the post-acute management of such MC were: “1. Cranioplasty may improve neurological function, and earlier cranioplasty (i.e., 6 weeks to 3 months from DC) may enhance this effect; 2. The clinical condition of the patient (e.g. systemic infection, systemic instability, antithrombotic medications) should be taken into consideration when deciding the timing of cranioplasty; 3. Poor neurological status is not a contraindication for cranioplasty per se; 4. Patient skin colonization is not a contraindication for cranioplasty but consideration to decolonization pre-operatively should be given” (Iaccarino et al., 2021). However, implementing these recommendations is still difficult, and organizational or procedural protocols on cranioplasty in the post-acute phase of patients with severe brain injury significantly vary across countries and regions (La Porta et al., 2023).
Hydrocephalus is a common neurosurgical complication in severe traumatic and hemorrhagic brain injury (Iaccarino et al., 2021; La Porta et al., 2023), and has been described in 5.4–39% of patients with pDoC (Table 1) (Whyte et al., 2013a; Zhang et al., 2021a). Several predisposing factors have been identified (e.g., subdural hygroma development, elderly patients, delayed (> 3 months) cranioplasty). Although halting/slowing of recovery during neurorehabilitation stay could suggest hydrocephalus development, the symptomatology can be subtle and challenging to be detected in patients with pDoC (Iaccarino et al., 2021; Zhang et al., 2021a). However, early recognition of hydrocephalus is of paramount importance, since its proper management can improve the patient’s neurological status and overall outcome (Zheng et al., 2023). Serial cranial imaging (e.g., CT, MRI) and measures of cerebro-spinal fluid pressure have been recommended for early recognition of any changes in the patient’s ventricular system (Iaccarino et al., 2021).
Spasticity
Spasticity is the velocity-dependent increase in muscle tone due to the exaggeration (i.e., disinhibition) of stretch reflex due to brain lesions damaging the balance of supraspinal inhibitory and excitatory inputs to the spinal cord (Trompetto et al., 2014). Secondary soft tissue rheological changes (e.g., stiffening and shortening of muscles and other soft tissues with tendon retraction, and muscle fibrosis) due to immobilization in the paretic limbs enhance muscle resistance to passive displacements and lead to abnormal limb or trunk posture (Trompetto et al., 2014). Prevalence rates of spasticity in patients with pDoC range between 21% –95% (Table 1) (Whyte et al., 2013a; Ganesh et al., 2013; Estraneo et al., 2021a; Zhang et al., 2021a; 2021b; Martens et al., 2017; Thibaut et al., 2018; Winters et al., 2022). Differences in these percentages may be caused by discrepancies among observational studies in the assessment tools, time after brain injury, etiology and level of consciousness of the enrolled samples. Although spasticity does not differ as a function of clinical diagnosis and etiology, one recent study suggested that upper-limb spasticity is more frequent in non-traumatic patients, while lower-limb spasticity is predominant in patients in VS/UWS compared to patients in MCS (Winters et al., 2022). About 60% of patients with pDoC develops spasticity during the first year after brain injury, but this percentage increases up to 90% in later stages (Martens et al., 2017). In more than half of the cases the degree of spasticity in patients with pDoC is considered severe at any time along the evolution of the disease (Winters et al., 2022).
Severe spasticity has important implications in rehabilitation programs, as it can hinder residual limb movements, and make nursing, hygiene, positioning, and sometimes even breathing difficult (Trompetto et al., 2014; Zhang et al., 2021b). Additionally, the spasticity can hamper the detection of some clinical signs (e.g., reaching objects by upper limb), leading to clinical misdiagnosis or underestimation of intentional behaviors (Majerus et al., 2005). Additionally, muscle shortening, joint stiffness and bone-articular deformities (equine feet, flexed elbows, claw hands) usually cause pain; coexisting muscular spasms, frequently associated with chronic severe spasticity, are also painful (Trompetto et al., 2014). On this basis, treating both pain and spasticity simultaneously should be a priority (Lanzillo et al., 2016). Finally, it is worth mentioning that a sudden increase in spasticity could be a warning sign of other treatable comorbidities (e.g., bladder/bowel problems, infections, pressure ulcers, pain, hydrocephalus) that might trigger stretch reflex.
Despite the high prevalence and the negative consequences of spasticity, no guidelines specifically addressed treatment in pDoC. Current treatment options are limited to those used in other neurological conditions causing spasticity (e.g., stroke). As the first choice, a multidisciplinary targeted approach includes pharmacological therapies (mainly oral baclofen, tizanidine, diazepam, clonazepam, and gabapentin), focal intramuscular botulinum toxin injection associated with conventional physical therapy, and splints or serial casts (Synnot et al., 2017). The botulinum toxin is injected to reduce the spasticity of a specific muscle group and prevent focal osteo-articular deformities and contractures. In case of focal deformities, soft splints applied daily during limited periods of time can reduce spasticity and improve hand opening with good tolerance (Thibaut et al., 2015). However, patients with pDoC frequently suffer from severe global spasticity affecting all four limbs and trunk (Zhang et al., 2021b). In generalized spasticity, early and intensive physiotherapy seem to be more effective than anti-spastic drugs (Thibaut et al., 2018; Synnot et al., 2017). Nonetheless, intractable generalized spasticity needs for more invasive surgical approaches such as intrathecal baclofen, selective dorsal rhizotomy, and orthopedic surgery (Nardone et al., 2020). Baclofen is a gamma-aminobutyric acid derivative which directly binds to presynaptic GABA-B receptors within the brainstem and dorsal horn of the spinal cord and reduces release of excitatory neurotransmitters (glutamate and aspartate), thus inhibiting overactive stretch reflexes. A tiny continuous intrathecal dose is sufficient compared to the oral dose, and this avoids the medication side effects related to the (high) oral baclofen doses needed for adequate treatment of spasticity (Nardone et al., 2020). Continuous intrathecal baclofen seems to be useful to treat generalized spasticity, but it may also modulate dysregulated sleep-wake cycles and promote alertness and awareness with a positive impact on recovery of consciousness (Nardone et al., 2020). More recently, non-invasive neurostimulation techniques aimed to improve awareness have been shown to have promising efficacy on spasticity (Thibaut et al., 2019).
Paroxysmal sympathetic hyperactivity
Paroxysmal sympathetic hyperactivity (PSH) refers to a syndrome of simultaneous, paroxysmal transient increases in sympathetic and motor activity. Its manifestations include increased heart rate, respiratory rate, blood pressure, temperature, and sweating, as well as dystonic posturing (Baguley et al., 2014). When more than one of these symptoms occur simultaneously for at least 3 consecutive days and persist more than 2 weeks post-injury in the absence of alternative explanations, diagnosis of PSH is highly probable (Baguley et al., 2016). PSH is often associated with clinical triggers like pain, repositioning, constipation, and has been often described within two weeks after brain injury. PSH tends to improve over time, but some of its manifestations have been reported up to 18 months after brain injury (Fernandez-Ortega et al., 2006). Pathophysiology of PSH is unclear but the most common hypothesis ascribes it to a sympathetic/parasympathetic unbalance, related to sympathetic excitation and loss of inhibitory pathways (Baguley et al., 2016).
PSH has been described in patients with pDoC (Whyte et al., 2013a; Estraneo et al., 2018; Estraneo et al., 2021a; Zhang et al., 2021a; Fernandez-Ortega et al., 2006; Dolce et al., 2008; Lucca et al., 2021). Cumulating the samples reported in 6 studies (Whyte et al., 2013a; Estraneo et al., 2018; Estraneo et al., 2021a; Zhang et al., 2021a; Dolce et al., 2008; Lucca et al., 2021) the PSH occurred in 26.5% of patients, with a significantly higher frequency (25.4%) in VS/UWS with respect to MCS (14.9%; chi-square = 10.7, p = .001), and a significantly lower frequency in traumatic etiology (traumatic = 18.4%, vascular = 28.8%, anoxic = 25.4%; chi-square = 7.2, p = .03). Most importantly, PSH can interfere with rehabilitation treatment and course of recovery (Estraneo et al., 2018; Estraneo et al., 2021b; Lucca et al., 2021). Patients with PSH have been reported to stay longer in ICU, and to have longer duration of mechanical ventilation and a higher number of MCs (Fernadez-Ortega et al., 2006). The goals in the management of PSH are to prevent the sympathetic excitation, by identifying and avoiding possible clinical triggers (e.g., pain, constipation). Nonetheless, a pharmacological approach is often necessary (Megahed et al., 2017; Russo et al., 2000). In patients with pDoC, the challenge is to use drugs with the least impact on consciousness and arousal. In this perspective, alpha-2 agonists and non-selective beta-blockers should be preferred and can boost each other’s effect when used simultaneously (Megahed et al., 2017). Bromocriptine and dantrolene could be also considered, but they could have adverse effects, some of which are severe (e.g., hepatic failure) (Russo et al., 2000). GABA agonists have been shown to be efficient in PSH but some of them, such as benzodiazepines and oral baclofen, cause important sedation and should be avoided when possible. Finally, gabapentin is also effective and could be considered especially if pain is the trigger (Samuel et al., 2016). To summarize, several alternatives are available for planning a personalized therapeutic approach with the smallest impact on arousal and consciousness, to facilitate rehabilitation program and nursing care.
Medical comorbidities related to the severe disability and immobility
Respiratory comorbidities
Respiratory comorbidities in patients with pDoC include: exacerbations of premorbid chronic respiratory diseases, pulmonary infections, complications derived from prolonged intubation/tracheostomy, such as tracheal stenosis, and central respiratory drive deficits associated with decreased consciousness (Table 1) (Whyte et al., 2013a; Pistoia et al., 2015; Estraneo et al., 2018; Zhang et al., 2021a; Chowdhury et al., 2014). Cumulating the samples reported in 5 studies (Whyte et al., 2013a; Pistoia et al., 2015; Estraneo et al., 2018; Zhang et al., 2021a; Chowdhury et al., 2014) the respiratory comorbidities occurred in 55.5% of patients, with a significantly lower percentage in traumatic etiology (traumatic = 48.2%, vascular = 64.5%, anoxic = 66.5%; chi-square = 34.0, p < 0.001) and no differences between patients in VS/UWS (65.2%) or in MCS (54.3%). As other MCs, respiratory comorbidities might hamper rehabilitation program, and are a negative predictor of survival and clinical improvement (Pistoia et al., 2015; Estraneo et al., 2018). Infections of both upper (i.e., pharyngitis, and laryngotracheitis) and lower respiratory tracts (bronchitis, bronchiolitis, and pneumonia), together with urinary tract infections, are very common in this population (Pistoia et al., 2015; Estraneo et al., 2018; Zhang et al., 2021a; Chowdhury et al., 2014). However, respiratory infections are usually more severe, since they most often require intensive treatment and are a frequent cause of death (Estraneo et al., 2018; Liuzzi et al., 2022). Clinical diagnosis usually is based on non-specific clinic indicators of infection such as hyperthermia, tachypnea or tachycardia and requires radiologic exams to be confirmed, since these patients cannot report symptoms. Pneumonia in patients with pDoC is frequently caused by inhaling food, liquid, or vomit due to co-existence of neurogenic dysphagia associated with central respiratory drive deficits (i.e., decreased airway protective reflex, impaired cough, altered breathing control) (Raciti et al., 2022). Aspiration pneumonitis (i.e., related to aspiration of sterile gastric content) and pneumonia (due to aspiration of colonized oropharyngeal content) have been described in up to 26% of hospitalized patients with pDoC (Table 1) (Chowdury et al., 2014; Kosutova et al., 2021). The clinical signs of an aspiration episode are widely variable from no or mild-moderate respiratory symptoms starting a few hours after aspiration in pneumonitis, to pneumonia symptoms including severe acute dyspnea, hypoxemia, and fever, up to life-threatening respiratory failure such as acute respiratory distress syndrome (Marik, 2011).
The treatment of pulmonary infections does not differ from that used in other populations and includes pharmacological medications to manage symptoms (antipyretics, steroids, mucolytics), oxygen therapy, and targeted antibiotic therapy to treat bacterial infections. In general practice, antibiotics are initiated immediately when pneumonia is diagnosed, whereas in aspiration pneumonitis they are required if symptoms fail to resolve within 48 hours, to prevent possible progression of the disease. In management of patients with pDoC and with tracheostomy strong efforts should aim to prevent respiratory complications, as prolonged hospitalization favors nosocomial infections (Jeon et al., 2012). A regular and accurate suction of mucus through tracheostomy by skilled nurse might prevent complications such as severe airway obstruction due to thick secretions, or mucous plug. The standard treatment for these conditions includes close monitoring of the patient’s oxygen saturation, prevention and treatment of bronchospasm when needed, and supportive management. A rehabilitation program focused on dysphagia should be incorporated in the treatment plan to prevent these comorbidities (Mélotte et al., 2012).
Tracheal stenosis is a late and severe complication that can occur in patients undergoing tracheostomy after prolonged mechanical ventilation (Ghiani et al., 2022). Most cases are due to concentric hyper granulation (originating from the internal stoma of the anterior tracheal wall) at subglottic level (Ghiani et al., 2022). Most of these stenoses are asymptomatic and are only diagnosed when decannulation fails. Diagnosis is based on imaging techniques (high-resolution CT, MR) and confirmed by laryngo-tracheoscopy. Therapeutic options include interventional bronchoscopy (grasping forceps resection, argon plasma coagulation, and photocoagulation) or tracheal surgery according to type and extent of the stenosis and physicians’ experience (Ghiani et al., 2022).
Endocrine disorders and metabolic abnormalities
Endocrine-metabolic disorders could be related to direct damage of the brain structures involved in hormone control (e.g.., thyrotropic axis dysfunction) (Mele et al., 2022) or to consequences of difficulties in the management (e.g., hypoalbuminemia due to poor nutritional status) (Montalcini et al., 2015). Cumulating the samples reported in 3 studies (Table 1) (Estraneo et al., 2018; Estraneo et al., 2021b; Mele et al., 2022) the endocrine-metabolic comorbidities occurred in 34.2% of patients, with a significant lower percentage in traumatic etiology (traumatic = 28.6%, vascular = 49.5%, anoxic = 48.8%; chi-square = 6.65, p = .036) and no significant differences between patients in VS/UWS (47.9%) or MCS (37.7%). In individuals with pDoC an enteral nutrition by percutaneous enteral gastrostomy might be necessary for a long time (even lifetime) because of severe dysphagia (Raciti et al., 2022), and could lead to inadequate metabolic support. A low level of serum albumin has been found to be associated with high short- and long-term mortality risk in post-acute and chronic patients with DoC (Estraneo et al., 2018; Montalcini et al., 2015). Additionally, the thyrotropic axis seems to impact on clinical evolution of pDoC (Mele et al., 2022). The baseline thyrotropin releasing hormone levels, and its increments after neurorehabilitation have been found to predict clinical improvement, whereas low levels of thyroid hormones were associated with poor neurological and functional outcomes in severe traumatic brain injury (Mele et al., 2022). The management of these MCs requires the involvement of multidisciplinary expertise for monitoring specific blood tests and nutritional status. An appropriate artificial nutrition can provide nutrients to maintain metabolic balance and adequate albumin and protein levels, and to preserve and promote immune status and resistance to infections (Kosutova et al., 2021). Targeted therapeutic approaches should be used to correct hormone abnormalities.
Neurogenic heterotopic ossification
Abnormal formation of lamellar bone in extra-skeletal soft tissues (i.e., neurogenic heterotopic ossifications) can develop around one or more joints in a relevant percentage of patients with pDoC (11.2–23.0%). Cumulating the samples reported in 2 studies (Table 1) (Estraneo et al., 2018; Estraneo et al., 2021a) the neurogenic heterotopic ossifications occurred in 16.3% of patients, with a significantly higher percentage in traumatic etiology (traumatic = 23.0%, vascular = 11.6%, anoxic = 18.8%; chi-square = 7.79, p = 0.002) and no differences between patients in VS/UWS (17.5%) or MCS (13.9%). Abnormal ossification is most commonly located around hips, likely due to the high susceptibility of the hip soft tissue to metabolic dysregulation, which in its turn is mediated by inflammatory and immune responses possibly triggering enhanced osteogenesis (Anthonissen et al., 2019). Early clinical diagnosis can be difficult because initial clinical manifestations (e.g., decreased range of movement, local inflammatory signs, pain) can mimic other musculoskeletal diseases, such as osteoarthritis, and become radiologically evident only 4–6 weeks after onset (Bargellesi et al., 2018).
Beyond reduced range of joint movements and local pain, neurogenic heterotopic ossification can cause peripheral nerve entrapment and pressure sores, and hamper nursing, positioning in a wheelchair and rehabilitation, thus negatively impacting functional recovery (Bargellesi et al., 2018). Pharmacological treatment with nonsteroidal anti-inflammatory drugs or pulse low-intensity electromagnetic field therapy have been suggested for preventing heterotopic ossifications in presence of early inflammatory signs around joints, whereas efficacy of early rehabilitation treatment and bisphosphonates and warfarin are still debated (Rizvi et al., 2022). Surgical resection is the only invasive option when pathological ossification produces severe loss of joint motion and precludes patient positioning and nursing.
Discussion and conclusion
To date, most studies on patients with pDoC employed assessment tools not specifically developed for detecting comorbidities frequently occurring in severely brain-injured patients, such as PSH. Nonetheless, the available studies demonstrated that patients with DoC are at a high risk to develop several MCs requiring specific and targeted treatment. MCs often co-occur in patients with pDoC: in a study on a cohort of 194 patients 73% of them were affected by one or more MCs (Estraneo et al., 2018).
Some MCs are a direct consequence of severe brain damage (e.g., epilepsy, spasticity), but most of them are related to prolonged immobility and severe disability (e.g., heterotopic ossification). Moderate or severe respiratory and musculoskeletal comorbidities are among the most common MCs. Respiratory comorbidities are most often due to pulmonary infections, likely related to presence of tracheostomy tube and to systemic immunosuppression that is frequent in populations with severe brain injury. Although the available (scarce) literature on MCs in pDoC did not systematically analyze their incidence as a function of diagnosis and etiology, some specific differences have been reported. Epilepsy and PSH seem to be more frequent in patients in VS/UWS compared to patients in MCS, likely because of higher severity in the brain damage in VS. Endocrine metabolic, PSH and respiratory complications are less frequent in traumatic etiology, whereas neurogenic heterotopic ossifications are more frequent in traumatic etiology. Spasticity did not significantly differ between VS/UWS and MCS and in the three etiologies. The lower occurrence of some MCs in traumatic patients could be likely ascribed to lower severity of traumatic brain damage compared to anoxic and vascular one (Estraneo et al., 2022). Possible mechanisms for explaining further differences should be investigated in larger cohort of patients including enough patients suffering from traumatic, vascular, and anoxic etiologies.
MCs negatively impact clinical evolution, hampering rehabilitation program and nursing procedures (e.g., PSH spasticity, or heterotopic ossification), worsening brain damage (e.g., hydrocephalus), or interfering with neuroplasticity for the recovery process (e.g., seizure) (Estraneo et al., 2018; Pascarella et al., 2016). MCs are also associated with higher mortality rates particularly in the first year, likely because of higher clinical instability compared to the second year after the brain injury (Estraneo et al., 2022). Endocrine metabolic abnormalities have been found to negatively impact survival also at long-term (Estraneo et al., 2018). Additionally, the symptoms related to MCs make the patients less responsive to CRS-R assessment (e.g., fever in pneumonia, pain, and limited movements in spasticity), and further reduce accuracy in clinical diagnosis (Chatelle et al., 2016).
The present narrative review has several limitations, which are in part related to the paucity of available studies. First, we did not consider the impact of the acute phase-related MCs on eventual development and persistence of MCs during inpatients rehabilitation. Indeed, the selected studies had no data available about the clinical course in the intensive care unit and investigated MCs occurring in the rehabilitation settings only. Second, most available studies on MCs in pDoC collected data by scales not specifically developed for patients with pDoC and only considered selected MCs (e.g., urinary infection, pressure sores, cardiac complications and neurogenic heterotopic ossifications have been rarely assessed). A clinical tool to evaluate a large array of MCs in such specific population has been recently proposed, but its prognostic value has not been investigated (Pistoia et al., 2019). Third, the studies included in this review did not evaluate the impact of pharmacological and rehabilitation treatment on MCs occurrence. Fourth, we could not compare the MCs of patients with severe brain injury and pDoC with those of patients with severe brain injury but without DoC, as the current literature does not provide sufficient information on this topic. A systematic review including all these topics could investigate possible differences among distinct population and the impact of therapeutic approaches. Last, we did not analyze the possible impact of MCs duration and of MCs occurring in the chronic phase in non-hospital settings (e.g., chronic facilities or at home). Multicentric and longitudinal studies on large cohort of patients with pDoC from the acute to chronic phase will allow a finer-grained analysis of the frequency of MCs and the impact of targeted interventions. Notwithstanding the above limitations, the present overview confirmed the frequent occurrence of several MCs in the post-acute phase which requires a specialized rehabilitative setting with high level of multidisciplinary expertise to appropriately recognize and treat them (Sattin et al., 2017; Whyte et al., 2013b). Early detection of clinical deterioration can help clinicians to manage some MCs (Seel et al., 2013). For example, worsening of consciousness level or increased spasticity may be one of the first signs of the development of secondary hydrocephalus (Formisano et al., 2020; Zheng et al., 2023) or an increase of PSH occurrence can be triggered by additional complications or pain (Lucca et al., 2021). However, the severity of cognitive-motor disability most often masks these warning signs, and the early recognition of MCs can be challenging. Because of the scarcity of data, no guidelines on treatment of MCs specifically addressed patients with pDoC. In real world clinical practice, clinicians follow the overall recommendations routinely applied to other population of patients with critical illness. However, the possible side effects of pharmacological treatment on consciousness/arousal level should be considered in patients with pDoC. For instance, the therapeutic approach for epilepsy should avoid ASM with high sedating or cognitive side-effects (Lejeune et al., 2021; Thelengana et al., 2019; Briand et al., 2022). Additionally there is no differences of therapeutic approach in the three etiologies, whereas possible contraindications related to comorbidities should be considered (e.g., avoiding ASM that could interfere with oral anticoagulants). Further systematic studies in large cohort of patients with pDoC are recommended to evaluate the efficacy and contraindications of targeted treatment of MCs. A multi-professional rehabilitative team can reduce the risk of further secondary MCs (Seel et al., 2013; Giacino et al., 2018). Most importantly, a systematic assessment should start from the acute phase for early detection, prevention, and treatment of emerging MCs, as recommended by the American guidelines on the management of patients with pDoC (Giacino et al., 2018). Early rehabilitation care would prevent the possible progression to more severe comorbidities that can negatively impact clinical outcomes and substantially increase health care costs in terms of resources and length of hospital stay (Seel et al., 2013).
Conflict of interest
The authors report no disclosures.
Footnotes
Acknowledgments
M.-M. Briand would like to acknowledge the Fonds de Recherche du Québec en Santé for the PhD award.