Unilateral deep brain stimulation (DBS) of nucleus ventralis intermedius thalami (Vim) for the treatment of post-traumatic tremor in children: a multicentre experience.

PURPOSE: Deep brain stimulation (DBS) of nucleus ventralis intermedius thalami (Vim) is a validated technique for the treatment of essential tremor (ET) in adults. Conversely, its use for post traumatic tremor (PTT) and in paediatric patients is still debated. We evaluated the efficacy of Vim-DBS for lesional tremor in three paediatric patients with drug-resistant post-traumatic unilateral tremor. METHODS: We retrospectively collected data regarding three patients with unilateral tremor due to severe head injury, with no MRI evidence of basal ganglia lesions. The three patients underwent stereotactic frame-based robot-assisted DBS of Vim contralateral to the tremor side. RESULTS: Mean follow-up was 48 months (range: 36-60 months). Tremor was reduced in all patients with a better control of voluntary movements and improvement of functional status (mean FIM scale improvement + 7 points). No surgical complications occurred. CONCLUSION: Unilateral contralateral DBS of Vim could be efficacious in post-traumatic tremor, even in paediatric patients and should be offered in PTT drug-resistant patients.

Hormonal Dysfunction in Paediatric Patients Admitted to Rehabilitation for Severe Traumatic Brain Injury: Analysis of the Associations with Rehabilitation Outcomes.

Traumatic brain injury is often accompanied by defects in hormone levels, caused by either peripheral gland dysfunctions or by an insufficient central stimulation of hormone production. The epidemiology of endocrinological defects after traumatic brain injury is quite well described, but the consequences of hormone defects are largely unknown, especially in paediatric patients undergoing neurological rehabilitation. Only one previous study reported on a cohort of 20 children with traumatic brain injury and found a low incidence of hormone defects and a correlation between some hormone levels and neurological recovery. In this study, we performed a retrospective chart review on patients affected by severe subacute traumatic brain injury. Their levels of cortisol, ACTH, IGF-1, TSH, free T4, free T3, and prolactin were collected and compared with reference ranges; we then used regression models to highlight any correlation among them and with clinical variables; last, we probed with regression models whether hormone levels could have any correlation with clinical and rehabilitation outcomes. We found eligible data from the records of 52 paediatric patients with markedly severe traumatic brain injury, as shown by an average GCS of 4.7; their age was 10.3 years, on average. The key results of our study are that 32% patients had low IGF-1 levels and in multiple regression models, IGF-1 levels were correlated with neurological recovery, indicating a possible role as a biomarker. Moreover, 69% of patients had high prolactin levels, possibly due to physical pain and high stress levels. This study is limited by the variable timing of the IGF-1 sampling, between 1 and 2 months after injury. Further studies are required to confirm our exploratory findings.

Hacking Pancreatic Cancer: Present and Future of Personalized Medicine.

Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. Despite outstanding progress in personalized medicine achieved for many types of cancer, chemotherapy still represents the mainstay of treatment for PC. Olaparib was the first agent to demonstrate a significant benefit in a biomarker-selected population, opening the doors for a personalized approach. Despite the failure of a large number of studies testing targeted agents or immunotherapy to demonstrate benefits over standard chemotherapy regimens, some interesting agents, alone or in combination with other drugs, have achieved promising results. A wide spectrum of therapeutic strategies, including immune-checkpoint inhibitors tyrosine kinase inhibitors and agents targeting metabolic pathways or the tumor microenvironment, is currently under investigation. In this review, we aim to provide a comprehensive overview of the current landscape and future directions of personalized medicine for patients affected by PC.

Expanding the clinical and neuroimaging features of post-varicella arteriopathy of childhood.

OBJECTIVE: Post-varicella arterial ischemic stroke (AIS) is considered an uncommon cause of pediatric stroke that is considered a self-limiting, monophasic disease. However, in a subset of patients, disease recurs; the prevalence of vasculopathy or AIS recurrence, severity of clinical outcomes, and standardized therapies have not been well characterized. Herein, we determined the clinical-neuroradiological features, long-term evolution, and relationship between acute phase treatment and vasculopathy recurrence in a pediatric population with post-varicella AIS. METHODS: Clinical, laboratory, and neuroradiological features of 22 children with post-varicella AIS between 2010 and 2019 (16 males, mean age at stroke 4 years, range 1.7-10) were reviewed. Statistical analyses were performed using χ2 and Fisher exact tests. RESULTS: Of the 22 cases, mean time from varicella to stroke was 4.5 months with 3 cases presenting more than 12 months after rash; 21 (95%) were not vaccinated for varicella; 3 (13.6%) had posterior circulation involvement; and 5 (22.7%) had AIS or vasculopathy recurrence, of which 4 recurred 6.1 months to 2.8 years after initial clinical onset. Recurrence was associated with lack of antiviral treatment during the first episode (p = 0.02). CONCLUSIONS: Post-varicella AIS can occur months after rash making diagnosis challenging. Because recurrent vasculopathy was seen predominantly in cases not treated with antiviral therapy during initial presentation, it is important to rapidly diagnose post-varicella AIS through clinical criteria and/or virological testing then treat with antivirals to prevent recurrence.

CEA and CYFRA 21-1 as prognostic biomarker and as a tool for treatment monitoring in advanced NSCLC treated with immune checkpoint inhibitors.

AIMS: To assess prognostic value of pre-therapy carcinoembryonic antigen (CEA) and cytokeratin-19 fragments (CYFRA 21-1) blood levels in non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors (ICIs) and their early change as predictor of benefit. MATERIALS AND METHODS: This is a retrospective cohort study including patients with stage IIIB-IV NSCLC who received anti PD-1/PD-L1 in first or advanced lines of therapy in two institutions. A control cohort of patients treated only with chemotherapy has been enrolled as well. RESULTS: A total of 133 patients treated with nivolumab or atezolizumab were included in the test set, 74 treated with pembrolizumab first line in the validation set and 89 in the chemotherapy only cohort. CYFRA 21-1 >8 ng/mL was correlated with overall survival (OS) in the test set, validation set and in univariate and multivariate analysis (pooled cohort hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.24-2.93, p 0.003). Early 20% reduction after the third cycle was correlated with OS for CEA (HR 0.12; 95% CI 0.04-0.33; p < 0.001), and for CYFRA 21-1 (HR 0.19; 95% CI 0.07-0.55; p 0.002). CONCLUSIONS: CYFRA 21-1 pre-therapy assessment provides clinicians with relevant prognostic information about patients treated with ICI. CEA and CYFRA 21-1 repeated measures could be useful as an early marker of benefit.

Long-term survival of two patients with recurrent pancreatic acinar cell carcinoma treated with radiofrequency ablation: A case report.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare type of malignant pancreatic cancer that represents approximately 1% of all pancreatic neoplasms. Due to its very low incidence, only a few retrospective studies are available. Although surgery is the first choice for treatment, most patients experience recurrence (mainly in the liver) and there are no clear recommendations for patients with advanced disease. CASE SUMMARY: We report two patients with PACC treated with surgery who experienced tumour recurrence in the liver. Patient 1 carried a germline mutation in the APC gene. Both patients were treated with gemcitabine plus oxaliplatin and gemcitabine plus capecitabine as first- and second-line therapies, respectively. After a favourable response to chemotherapy, the patients underwent radiofrequency ablation of the remaining liver metastases. For patient 1, we documented a relapse in the liver after a disease-free period of 9 mo, and treatment with gemcitabine plus capecitabine was restarted. The patient achieved a complete response, and he remains alive without evidence of disease recurrence after six years. After radiofrequency ablation, patient 2 experienced disease-free survival for 21 mo, when peritoneal relapse was diagnosed and treated with chemotherapy. The patient achieved a stable disease state for nearly two years; nevertheless, further progressive disease was documented, and he died seven years after the first relapse. CONCLUSION: PACC presents different biological behaviours than pancreatic adenocarcinoma. Multidisciplinary treatment involving local ablative therapies may be considered for PACC.

Polysomnographic Analysis of a Pediatric Case of Baclofen-Induced Central Sleep Apnea.

ABSTRACT: Respiratory disorders may follow brain injury and may also occur because of comorbidities and drug use, especially central depressants or muscle relaxants. Sleep can precipitate respiratory disorders, thus polysomnography can be a powerful diagnostic tool. By revealing breathing patterns that identify specific sleep disorders, polysomnography may unmask adverse pharmacological effects, for instance connecting central depressant drugs with central sleep apneas. We describe the case of a pediatric patient in rehabilitation from brain injury who developed a central sleep apnea following a baclofen dose increase within the therapeutic range, while assuming an under-dosed benzodiazepine. Polysomnography identified a typical respiration pattern, previously observed in adults treated with baclofen and other central depressants. Baclofen tapering resolved the central sleep apnea. Polysomnography, and this specific pattern, may be proposed as diagnostic tools in patients with high dose baclofen that can be used to prevent potential respiratory disorders in children.

Children sustaining a severe acquired brain lesion before age 3 years: a follow-up study at 1 year from insult.

PURPOSE: To describe the functional and cognitive outcome of acquired brain injury of different aetiologies in children before age 3 years, at initial hospitalization and at a 1-year follow-up, after a rehabilitation programme. METHOD: Data were collected at 6 months and at 12 months from the event; cognitive data were collected as soon as possible at T1. The full sample was divided into three groups according to aetiology. RESULTS: At T0, 74 patients showed so severe a cognitive impairment that they could not be evaluated, others presented with motor, linguistic and cognitive deficits. At T1, the proportion of non-evaluable patients decreased to 58 children. Patients with anoxic lesions showed the most unfavourable motor and visual outcome; patients with infectious lesions showed most frequently a motor global delay. CONCLUSIONS: At 1 year from insult about 50% of patients could undergo a cognitive evaluation. Improvement differed according to aetiology.

Mutational burden of resectable pancreatic cancer, as determined by whole transcriptome and whole exome sequencing, predicts a poor prognosis.

Despite the genomic characterization of pancreatic cancer (PC), marked advances in the development of prognosis classification and novel therapeutic strategies have yet to come. The present study aimed to better understand the genomic alterations associated with the invasive phenotype of PC, in order to improve patient selection for treatment options. A total of 30 PC samples were analysed by either whole transcriptome (9 samples) or exome sequencing (21 samples) on an Illumina platform (75X2 or 100X2 bp), and the results were matched with normal DNA to identify somatic events. Single nucleotide variants and insertions and deletions were annotated using public databases, and the pathogenicity of the identified variants was defined according to prior knowledge and mutation-prediction tools. A total of 43 recurrently altered genes were identified, which were involved in numerous pathways, including chromatin remodelling and DNA damage repair. In addition, an analysis limited to a subgroup of early stage patients (50% of samples) demonstrated that poor prognosis was significantly associated with a higher number of known PC mutations (P=0.047). Samples from patients with a better overall survival (>25 months) harboured an average of 24 events, whereas samples from patients with an overall survival of <25 months presented an average of 40 mutations. These findings indicated that a complex genetic profile in the early stage of disease may be associated with increased aggressiveness, thus suggesting an urgent requirement for an innovative approach to classify this disease.

Disordered Consciousness or Disordered Wakefulness? The Importance of Prolonged Polysomnography for the Diagnosis, Drug Therapy, and Rehabilitation of an Unresponsive Patient With Brain Injury.

ABSTRACT: Disorders of consciousness may follow brain injury, due to impairments of wakefulness and/or awareness. Polysomnography can identify elements that may be ascribed to impairments of specific neuroanatomical areas. Recognizing which impairments affect each patient is crucial for diagnosis, prognosis, and to select an appropriate therapy. We present a pediatric case of insufficient wakefulness in a patient with severe disability following a pilocytic astrocytoma. Polysomnography was crucial for diagnosis, as it detected a well-structured pattern with daytime sleep initiations in the REM sleep phase. Treatment with modafinil was successful, as confirmed by polysomnography, leading to partial recovery of the patient's consciousness and communication ability. We suggest that polysomnography is a useful diagnostic tool to direct the pharmacotherapy and rehabilitation of states of reduced consciousness.

Chiral Indolylarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors as New Potent and Broad Spectrum Anti-HIV-1 Agents.

We designed and synthesized a series of chiral indolyarylsulfones (IASs) as new HIV-1 NNRTIs. The new IASs 8-37 showed potent inhibition of the HIV-1 WT NL4-3 strain and of the mutant K103N, Y181C, Y188L, and K103N-Y181C HIV-1 strains. Six racemic mixtures, 8, 23-25, 31, and 33, were separated at semipreparative level into their pure enantiomers. The (R)-8 enantiomer bearing the chiral (α-methylbenzyl) was superior to the (S)-counterpart. IAS derivatives bearing the (S) alanine unit, (S)-23, (S,R)-25, (S)-31, and (S)-33, were remarkably more potent than the corresponding (R)-enantiomers. Compound 23 protected hippocampal neuronal cells from the excitotoxic insult, while efavirenz (EFV) did not contrast the neurotoxic effect of glutamate. The present results highlight the chiral IASs as new NNRTIs with improved resistance profile against the mutant HIV-1 strains and reduced neurotoxic effects.

The sodium salt of the enantiomers of ricobendazole: Preparation, solubility and chiroptical properties.

Albendazole (ABZ) is a sulfanyl-benzimidazole anthelmintic drug used worldwide in the treatment and prevention of parasitic diseases in animals and humans. Following oral administration, ABZ is rapidly oxidized into the pharmacologically active chiral sulfoxide metabolite known as ricobendazole (RBZ). As its achiral precursor, RBZ shows very low intestinal absorption due to its poor solubility in water (0.06mgmL-1). To the best of our knowledge, there is no known example in human medicine of a water-soluble salt form of racemic or enantiomerically pure RBZ. In the present study, we describe in detail the preparation of the sodium (Na) salt of the enantiomers of RBZ through a two-step process: i) the multi-milligram resolution of RBZ by HPLC on the amylose-based Chiralpak IG chiral stationary phase under polar organic mode; ii) the salification of the isolated enantiomers of RBZ by reaction with sodium hydroxide solution. The spectroscopic and chiroptical properties of the RBZ-Na enantiomers were determined. Due to their unique solubility in 0.01M phosphate buffer at physiological pH (14.49mgmL-1) and the high sample throughput obtained on semipreparative separation of the non-salified form, it is potentially possible to develop new anthelmintic enantiopure formulations with improved pharmacokinetic properties and lower toxicity.

Sleep/Wake Modulation of Polysomnographic Patterns has Prognostic Value in Pediatric Unresponsive Wakefulness Syndrome.

STUDY OBJECTIVE: Sleep patterns of pediatric patients in unresponsive wakefulness syndrome (UWS) have been poorly investigated, and the prognostic potential of polysomnography (PSG) in these subjects is still uncertain. The goal of the study was to identify quantitative PSG indices to be applied as possible prognostic markers in pediatric UWS. METHODS: We performed PSG in 27 children and adolescents with UWS due to acquired brain damage in the subacute phase. Patients underwent neurological examination and clinical assessment with standardized scales. Outcome was assessed after 36 mo. PSG tracks were scored for sleep stages and digitally filtered. The spectral difference between sleep and wake was computed, as the percent difference at specific spectral frequencies. We computed (1) the ratio between percent power in the delta and alpha frequency bands, (2) the ratio between alpha and theta frequency bands, and (3) the power ratio index, during wake and sleep, as proposed in previous literature. The predictive role of several clinical and PSG measures was tested by logistic regression. RESULTS: Correlation was found between the differential measures of electroencephalographic activity during sleep and wake in several frequency bands and the clinical scales (Glasgow Outcome Score, Level of Cognitive Functioning Assessment Scale, and Disability Rating Scale) at follow-up; the Sleep Patterns for Pediatric Unresponsive Wakefulness Syndrome (SPPUWS) scores correlated with the differential measures, and allowed outcome prediction with 96.3% of accuracy. CONCLUSIONS: The differential measure of electroencephalographic activity during sleep and wake in the beta band and, more incisively, SPPUWS can help in determining the capability to recover from pediatric UWS well before the confirmation provided by suitable clinical scales.

Late Post-traumatic Epilepsy in Children and Young Adults: Impropriety of Long-Term Antiepileptic Prophylaxis and Risks in Tapering.

BACKGROUND: After traumatic brain injury, epilepsy affects up to 20 % of children. It is a risk factor, for both clinical recovery and cognitive performance; therefore pharmacological therapy is advisable. Current guidelines recommend prophylaxis to be initiated as soon as possible and tapered 1 week after trauma. However, no guideline exists for paediatric patients and the clinical practice is heterogeneous. OBJECTIVE: In our institute, prophylaxis was routinely tapered 6 months after trauma. Therefore we investigated whether this prophylaxis or its tapering influenced the development of post-traumatic epilepsy, together with several clinical-demographic factors. METHODS: The study population comprised all patients with post-traumatic brain injury referred to this institute between 2002 and 2009 who consented to participate. Clinical, epileptological and pharmacological data were collected. The role of prophylaxis and several other predictors on occurrence of post-traumatic epilepsy was analysed through logistic regressions. RESULTS: Two hundred and three patients (145 paediatric) were followed for 57 months on average. Risk factors for epilepsy were past neurosurgery [odds ratio (OR) = 2.61, 95 % confidence interval (CI) 1.15-5.96], presence of epileptiform anomalies (OR = 6.92, 95 % CI 3.02-15.86) and the presence of prophylaxis (OR = 2.49, 95 % CI 1.12-5.52), while higher intelligence quotient (IQ) was protective (OR = 0.96, 95 % CI 0.95-0.98). While evaluating possible different effects within and after 6 months (tapering, for those under prophylaxis), we found that epileptiform anomalies (OR = 7.61, 95 % CI 2.33-24.93, and OR = 8.21, 95 % CI 3.00-22.44) and IQ (OR = 0.96, 95 % CI 0.94-0.98, and OR = 0.97, 95 % CI 0.95-0.98) were always significant predictors of epilepsy, while neurosurgery (OR = 4.38, 95 % CI 1.10-17.45) was significant only within 6 months from trauma, and prophylaxis (OR = 3.98, 95 % CI 1.62-9.75) only afterwards. CONCLUSIONS: These results suggest that prophylaxis was irrelevant when present; furthermore its tapering increased the risk of epilepsy. Since the presence of epileptiform anomalies was the main predictor of post-traumatic epilepsy, such anomalies may be useful to better direct the choice of prophylaxis.

Polysomnographic Sleep Patterns in Children and Adolescents in Unresponsive Wakefulness Syndrome.

OBJECTIVES: We aimed (i) to search for qualitative sleep patterns for pediatric unresponsive wakefulness syndrome (SPPUWS) in prolonged polysomnographic (PSG) recordings in children and adolescents with subacute severe disorders of consciousness due to an acquired brain damage; (ii) to investigate the clinical relevance of SPPUWS and of possible neurophysiological markers (rapid eye movement sleep and sleep spindles) in PSG recordings of pediatric patients with unresponsive wakefulness syndrome (UWS). METHODS: We performed a PSG study in 27 children with UWS due to acquired brain damage in the subacute phase. Patients received a full neurological examination and a clinical assessment with standardized scales. In addition, outcome was assessed after 36 months. RESULTS: We identified 6 PSG patterns (SPPUWS) corresponding to increasing neuroelectrical complexity. The presence of an organized sleep pattern, as well as rapid eye movement sleep and sleep spindles, in the subacute stage appeared highly predictive of a more favorable outcome. Correlation was found between SPPUWS and recovery, as assessed by several clinical and rehabilitation scales. CONCLUSIONS: Polysomnography can be used as a prognostic tool, as it can help determine the capability to recover from a pediatric UWS and predict outcome well before the confirmation provided by suitable clinical scales.

Combined robotic-aided gait training and 3D gait analysis provide objective treatment and assessment of gait in children and adolescents with Acquired Hemiplegia.

To evaluate the feasibility of a fully objective rehabilitative and assessment process of the gait abilities in children suffering from Acquired Hemiplegia (AH), we studied the combined employment of robotic-aided gait training (RAGT) and 3D-Gait Analysis (GA). A group of 12 patients with AH underwent 20 sessions of RAGT in addition to traditional manual physical therapy (PT). All the patients were evaluated before and after the training by using the Gross Motor Function Measures (GMFM), the Functional Assessment Questionnaire (FAQ), and the 6 Minutes Walk Test. They also received GA before and after RAGT+PT. Finally, results were compared with those obtained from a control group of 3 AH children who underwent PT only. After the training, the GMFM and FAQ showed significant improvement in patients receiving RAGT+PT. GA highlighted significant improvement in stance symmetry and step length of the affected limb. Moreover, pelvic tilt increased, and hip kinematics on the sagittal plane revealed statistically significant increase in the range of motion during the hip flex-extension. Our data suggest that the combined program RAGT+PT induces improvements in functional activities and gait pattern in children with AH, and it demonstrates that the combined employment of RAGT and 3D-GA ensures a fully objective rehabilitative program.

Paroxysmal phenomena in severe disabled children with refractory seizures. From clinical to long-video-EEG processing data to re-examine suspect events.

To provide an estimate of the occurrence of misdiagnosis in paroxysmal events in institutionalized children with severe disabilities and refractory epilepsy. A multi-step diagnostic survey, from observational to long-term video-EEG monitoring was performed in 46 severe disabled children. Multirater Kappa statistic was used to assess agreement between investigators and to individualize children who remained with dubious events. Subsequently, prolonged EEG-video monitoring analysis was performed in selected children to define phenomena due to seizures. A total of 128 video records were performed, 64 routine video-EEG and 27 long-monitoring video-EEG data were screened for detailed analysis. Thirty (21 female, 9 male) children (65%) with dubious seizures were identified by video records (concordance K=0.63). Of these, in 18 children (39%) seizures were excluded by routine video-EEG monitoring (K=0.86). Twelve children (26%) required accurate investigations with long-term video-EEG. In 5 children (11%), 3 symptomatic and 2 cryptogenic, very short and subtle seizures were confirmed by investigators concordance (K=0.83). Distinguishing paroxysmal phenomena is a challenge in children with severe disabilities; its most remarkable consequence is inappropriate pharmacological treatment and social costs. Our data suggest that the frequency of misdiagnosis could have been underestimated. The clinicians who manage children with severe disabilities and refractory epilepsy must remain alert to risk of an incorrect treatment.

Evolution of the cognitive profile in school-aged patients with severe TBI during the first 2 years of neurorehabilitation.

OBJECTIVE: Persistent post-injury cognitive, academic and behavioural deficits have been documented in children who sustained severe TBI during the school-age years. The major aim of this study was to examine and follow-up for 2 years the cognitive profile of a sample of post-injured patients (aged 6-16.11), in order to verify to what extent they recovered their intellectual functions after rehabilitation. METHOD: Twenty-six patients who received a specific neuropsychological treatment and three cognitive evaluations with WISC-III were selected from a pool of 77. RESULTS: This group of patients showed a mild cognitive deficit at baseline, which improved over the 2 years to a borderline level. Despite the improvement in intellectual quotients and single sub-test scores achieved through rehabilitation, different recovery times were seen according to the function under study. The most common deficits are in processing speed, inferential and lexical-semantic skills. CONCLUSIONS: Detailed analysis of the WISC-III sub-tests allows for an accurate description of single cognitive functions after TBI. This allows one to make differential diagnoses between functional profiles and plan individualized rehabilitation treatments. Post-injured school-aged patients should receive rehabilitation for a period of at least 2 years, which is the time necessary for an at-least partial reorganization of basic cognitive functions.

Language and cognition in a bilingual child after traumatic brain injury in infancy: long-term plasticity and vulnerability.

PRIMARY OBJECTIVE: This study aimed at investigating the long-term effects of the combination of severity of injury and time of injury in a 6-year-old bilingual Arabic-Italian child who sustained a severe left traumatic brain injury at the age of 7 months. METHODS AND PROCEDURES: Standard neurological, cognitive and neuropsychological assessments were administered at 40 days after surgery and again at 18, 31, 62 and 73 months. MAIN OUTCOMES AND RESULTS: The child presented with developmental arrest at 18 and 31 months. Later on, right hemiparetic and oculomotor signs gradually improved to a significant extent, as well as dysexecutive, visuospatial and praxic deficits. At present, persistent language disorders in a fluent speech characterize the child's profile to a similar extent and type in both languages, suggesting common underlying learning strategies which are ineffective for procedurally acquiring language. CONCLUSIONS: This case confirms that children who sustain severe left hemisphere traumatic brain injury in infancy present with increased vulnerability to linguistic deficits. Left frontotemporal, cortical-subcortical lesions which occur during very early language development may permanently disrupt the procedural language acquisition network required for first language acquisition.