Joint Neuropsychological Assessment through Coma/Near Coma and Level of Cognitive Functioning Assessment Scales Reduces Negative Findings in Pediatric Disorders of Consciousness

The present study aimed to: (a) characterize the emergence to a conscious state (CS) in a sample of children and adolescents with severe brain injury during the post-acute rehabilitation and through two different neuropsychological assessment tools: the Rappaport Coma/Near Coma Scale (CNCS) and Level of Cognitive Functioning Assessment Scale (LOCFAS); (b) compare the evolution in patients with brain lesions due to traumatic and non-traumatic etiologies; and (c) describe the relationship between the emergence to a CS and some relevant clinical variables. In this observational prospective longitudinal study, 92 consecutive patients were recruited. Inclusion criteria were severe disorders of consciousness (DOC), Glasgow Coma Scale (GCS) score ≤8 at insult, age 0 to 18 years, and direct admission to inpatient rehabilitation from acute care. The main outcome measures were CNCS and LOCFAS, both administered three and six months after injury. The cohort globally shifted towards milder DOC over time, moving from overall ‘moderate/near coma’ at three months to ‘near/no coma’ at six months post-injury. The shift was captured by both CNCS and LOCFAS. CNCS differentiated levels of coma at best, while LOCFAS was superior in characterizing the emergence from coma. Agreement between scales was fair, and reduced negative findings at less than 10%. Patients with traumatic brain injury (TBI) vs. non-traumatic brain injury (NTBI) were older and had neurosurgical intervention more frequently. No relation between age and the level of consciousness was found overall. Concurrent administration of CNCS and LOCFAS reduced the rate of false negatives and better detected signs of arousal and awareness. This provides indication to administer both tools to increase measurement precision.

The improvement in cognitive functioning results from both the progression across LOCFAS levels and the increase in the saturation percentage (number of domains satisfied for certain level / total number of domains for this level).

Procedures
After admission to our center, the primary researcher (S.S.) contacted each consenting caregiver to arrange an assessment at the hospital. Demographic information was collected during a semistructured interview. GCS recorded by the rescue team (or in the emergency room) was collected. GOS-E score was assessed by each patient's lead physician at admission to the rehabilitation center. Further medical details were obtained from medical records. CNCS and LOCFAS were delivered by two experienced neuropsychologists (K.C. and C.F.) on the same day (when delivered both).
All the patients were proposed a rehabilitation treatment according to the protocol used in our Intensive Rehabilitation Unit. Based on their clinical condition and at least five days a week, they received: -two daily sessions of physical therapy lasting 45 minutes each. Physical rehabilitation aims at preventing secondary damage such as muscle retractions and joint deformities, enhancing normalization of muscular tone, correcting posture and alignment; -one daily session of oro-facial therapy lasting 45 minutes. Oro-facial therapy aims at restoring normal feeding; -two to three daily cognitive-behavioral sessions of 10-20 minutes each, as described in detail in previous studies by our group [10,11]. Since the early days of recovery, cognitive-behavioral stimulations may help patients in a UWS/VS and MCS to reinforce their adaptive responses -either spontaneous or elicited by multisensory stimulations -and rebuild their behavioral repertoire. The underlying principle is conditioning, and techniques can be divided into two large categories: techniques positively reinforcing all the spontaneous adaptive responses and techniques favoring the acquisition and generalization of new behavioral patterns. Cognitive-behavioral stimulations also include techniques and procedures to reduce inappropriate behaviors. Individualized goals are specifically related to the assessed level of functioning.
-one group session of cognitive-behavioral stimulations daily. Furthermore, once a week caregivers took part in a psychoeducational intervention aimed at involving the patients' families in psycho-stimulation.

Extended Results
Supplementary Table S1. Clinical and demographic characteristics of the sub-sample of patients having both CNCS and LOCFAS assessments, 3 and 6 months after injury.

3.2e The Level of Awareness and Responsivity at 3 and 6 Months after Injury (Extended)
The level of awareness and responsivity of each patient was assessed 3 months after injury (T0) and 6 months after injury (T1). For patients older than 48 months (n = 54), this was performed through the administration of both the CNCS and LOCFAS (Supplementary Table S2). At T0, patients were diversely allocated in Levels 1, 2 and 3 of CNCS, corresponding to 'near, moderate and marked coma' for the most part. However, most of them scored into the Level 2 -'generalized response' (66.7% of the sample) of LOCFAS. At T1, almost half of the patients scored 'no coma' at the CNCS. At LOCFAS, half scored into the Level 3 -'localized response', a quarter fell into level 5 'inappropriate, not agitated behavior' and one out of five remained into Level 2 'generalized response'. The probability to fall into a certain CNCS Level resulted not to be significantly influenced by the variable "etiology" (i.e. TBI vs. NTBI), both at T0 (χ 2 = 5.0, p = 0.288) and at T1 (χ 2 = 2.4, p = 0.498). The same was found for LOCFAS Levels (χ 2 = 2.0, p = 0.740 at T0; χ 2 = 1.1, p = 0.778 at T1).
Patients younger than 48 months (n = 38) were administered the CNCS only (Supplementary Table S3). In this subgroup, CNCS scores at T0 and T1 show distributions comparable to those observed in older children. Over all the total sample of 92 children, most patients fell into the Level 2 -'moderate coma'-and the Level 1 -'near coma'-(70.7% of the total sample) of CNCS at T0. At T1, most patients fell into the Level 1 -'near Coma'-and the Level 0 -'no coma'-(80.4% of the total sample) (Supplementary Table S4). The probability to fall into certain CNCS Level still resulted not to be significantly influenced by the variable "etiology" (i.e. TBI vs. NTBI), both at T0 (χ 2 = 5.5, p = 0.242) and at T1 (χ 2 = 2.0, p = 0.576). Figure 1 (main text) shows the confusion matrices (joint representation of scores at CNCS and LOCFAS) at T0 and T1, for patients aged older than 48 months. At T0, patients in CNCS Levels 2 and 3 'moderate and marked coma' were mainly scored at LOCFAS Level 2 'generalized response'; patients in CNCS Level 1 'near coma' were split between LOCFAS Levels 2 and 3 'generalized and localized response'. All cases who scored CNCS Level 0 'no coma' received LOCFAS Level 3 'localized response'. At T1, patients in CNCS Levels 2 were scored at LOCFAS Level 2; patients in CNCS Level 1 were mainly scored 3 at LOCFAS, and those in CNCS 0 scored between 3 and 5 at LOCFAS ('localized response' and above).

3.3e The Evolution of the State of Consciousness From 3 to 6 Months after Injury
Initially, the evolution of the state of consciousness was studied by comparing the CNCS Levels at T0 and T1 in the total sample (n = 92). Similarly, the scores for any of the 11 CNCS items were compared between T0 and T1. The average CNCS Level was 2.9 (SD = 0.9) at T0, while it decreased to 1.8 (SD = 0.8) at T1; the difference proved to be statistically significant (t = 11.0, p < 0.001), meaning that patients showed higher levels of awareness and responsivity at 6 months w.r.t. at 3 months after injury. All 11 items of CNCS significantly changed between T0 and T1 in the direction of higher awareness and responsivity, although medians remained unchanged for the olfactory item and pain was already saturated at T0. The threat item shifted from the lowest to the highest score; the auditory, command responsivity, visual, tactile and vocalization items all stepped up one score (one or more units). For details see Supplementary Table S5. Analogously, in patients older than 48 months, all LOCFAS domains significantly changed between T0 and T1 in the direction of higher awareness and responsivity (see Supplementary Table S6).
Additionally, in patients older than 48 months the evolution of the state of consciousness was studied by comparing the CNCS and LOCFAS Levels at T0 and T1 ( Figure 2 in the main text). According to CNCS evaluation, patients in Level 3 'marked coma' at T0 mainly moved to Levels 2 and 1 'moderate and near coma' at T1. Patients who were in Levels 2 and 1 'moderate and near coma' at T0, chiefly moved to Levels 1 and 0 'near and no coma' at T1. Considering LOCFAS, patients scoring in Level 2 'generalized response' at T0 split between Levels 2 and 3 'generalized and localized response' at T1. Patients scoring in Level 3 'localized response' at T0 split between Levels 3 and 5 'localized response and inappropriate behavior' at T1. Information processing 1 1 1 1 3.4 (0.001)* 5

3.4e The Evolution of the State of Consciousness in Patients with Stable Score at 3 and 6 Months after Injury
Of the 92 patients, 24 (26.1%) scored in the same CNCS Level at T0 and T1, thus showing no modification in their classification at the two time-points. This subgroup was further tested for possible changes of the Average CNCS Score between T0 and T1, which indeed proved to be significantly lower at T1 vs. T0 (mean at T0 = 1.8; mean at T1 = 1.5; t-value = 3.6; p = 0.002), and of the Total CNCS Score (mean at T0=20.1; mean at T1 = 16.2; t-value = 5.3; p < 0.001). Of the 24 patients who failed to show change in CNCS Level at T1, 3 remained in Level 3 'marked coma', 5 in Level 2 'moderate coma', 13 in Level 1 'near coma' and 3 patients remained in Level 0 'no coma'. Moreover, of these 24 patients, 10 where older than 48 months and had LOCFAS evaluations. Of these 10 patients, 5 showed the same LOCFAS score, and 5 showed different LOCFAS scores at T0 and T1.
Of the 54 patients assessed with both scales, 18 (33.3%) failed to show change in LOCFAS Level at T1. Of these, 10 remained in Level 2 'generalized response', 6 in Level 3 'localized response', and 2 patients remained in Level 5 'inappropriate behavior'. Of these 18 patients, 5 showed the same CNCS score at T0 and T1, and 13 showed different CNCS score at the two time-points.

3.7e The Evolution of the State of Consciousness in the Sample Divided by Etiology
The sample was divided by etiology, in order to verify whether the causes of the brain lesions had the potential to affect the evolution of the state of consciousness during the 3-months period considered in this study. Table 2 of the main text reports the scores of each CNCS item at the two assessment times (T0 and T1), both for patients with TBI and NTBI; further, the comparison of the scores at T0 vs. T1 is reported for the two groups.
The TBI group had 10 out of 11 items significantly shifted towards higher awareness and responsivity at T1 with respect to T0. The command responsivity item stepped up 4 scores; The auditory, visual, threat, olfactory, tactile and vocalization items all gained 2 scores. Only the two items probing pain had unchanged medians and modes, as the descriptors already ranked top at T0; thus, no significant change between T0 and T1 was found in these cases.
The NTBI group had all items significantly improved. The threat item stepped up 4 scores; the auditory, command responsivity, visual, tactile n°7 and vocalization items all stepped up 2 scores; the olfactory item had improved mode and significant improvement, according to the statistical test. Tactile n°8 and pain (n°9 and 10) items improved, overall starting from top position at T0; however, they did not pass the strictest statistical test (p = 0.001).
Similarly, for patients older than 48 months, scores at LOCFAS domains in TBI and NTBI are reported in Supplementary Table S7.