Basal Ganglia Injury Research Articles

Growth trajectories and need for oral feeding support among infants with neonatal encephalopathy treated with therapeutic hypothermia.

Identify feeding supports required among infants with neonatal encephalopathy and determine growth trajectories to 3 years. Single-center retrospective cohort study of 120 infants undergoing therapeutic hypothermia. Logistic regression and stratified analyses identified whether clinical factors, EEG-determined encephalopathy severity, and MRI-based brain injury predict feeding supports (nasogastric tube, oral feeding compensations) and growth. 50.8% of infants required feeding supports in the hospital, decreasing to 14% at discharge. Moderate-to-severe encephalopathy and basal ganglia injury predicted feeding support needs. Yet, 35% of mildly encephalopathic infants required gavage tubes. Growth trajectories approximated expected growth of healthy infants. Infants with neonatal encephalopathy-even if mild-frequently experience feeding difficulties during initial hospitalization. With support, most achieve full oral feeds by discharge and adequate early childhood growth. Clinical factors may help identify infants requiring feeding support, but do not detect all at-risk infants, supporting routine screening of this high-risk population.

Distinguishing multicystic from focal encephalomalacia on delayed MRI in children with term hypoxic ischemic injury.

To define cystic patterns resulting from term hypoxic ischemic injury (HII) on delayed Magnetic Resonance Imaging (MRI) and determine associated HII patterns and lesions that reflect the severity of injury, from a database of African children with cerebral palsy. Retrospective review of 1175 children with cerebral palsy due to term HII diagnosed on late MRI, identifying those with cystic changes. These were classified as multicystic or (multi-) focal-cystic, and were evaluated for associated injuries-thalami, basal ganglia, hippocampi, cerebellum, and presence of ulegyria. Three hundred and eighty-eight of 1175 (33%) children had cystic encephalomalacia. Two hundred and seven of 388 (53.3%) had focal-cystic and 181/388 (46.6%) had multicystic injury. The focal-cystic group comprised 87.9% (182/207) with thalamic injury, 25.6% (53/207) with basal ganglia injury, and 15% (31/207) with cerebellar involvement. Basal-ganglia-thalamus (BGT) pattern was present in 43.9% (91/207) and ulegyria in 69.6% (144/207). In the multicystic group, 88.9% (161/181) had thalamic injury, 30.9% (56/181) had basal ganglia injury, and 21% (38/181) had cerebellar involvement. BGT pattern was observed in 29.8% (54/181) and ulegyria in 28.7%. (52/181). Significant associations (p<.05) were found between multicystic injury and caudate/globus pallidus involvement, and between focal-cystic pattern of injury and ulegyria. Cystic encephalomalacia was seen in almost one-third of patients with term HII imaged with delayed MRI, with a similar prevalence of focal-cystic and multicystic injury. Multicystic injury was associated with caudate and globus pallidi involvement, typical of the BGT pattern of HII, whereas the focal-cystic pattern was associated with ulegyria, typical of watershed injury.

Kv1.3 Blockade Alleviates White Matter Injury through Reshaping M1/M2 Phenotypes via the NF-κB Signaling Pathway after Intracerebral Hemorrhage.

White matter injury (WMI) in basal ganglia usually induces long-term disability post intracerebral hemorrhage (ICH). Kv1.3 is an ion channel expressed in microglia and induces neuroinflammation after ICH. Here, we investigated the functions and roles of Kv1.3 activation-induced inflammatory response in WMI and the Kv1.3 blockade effect on microglia polarization after ICH. Mice ICH model was constructed by autologous blood injection. The expression of Kv1.3 was measured using immunoblot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunostaining assays. Then, the effect of administration of 5-(4-Phenoxybutoxy) psoralen (PAP-1), a selectively pharmacological Kv1.3 blocker, was investigated using open field test (OFT) and basso mouse score (BMS). RT-qPCR, immunoblot, and enzyme-linked immunosorbent assay (ELISA) were taken to elucidate the expression of pro-inflammatory or anti-inflammatory factors around hematoma. PAP-1's function in regulating microglia polarization was investigated using immunoblot, RT-qPCR, and immunostaining assays. The downstream PAP-1 signaling pathway was determined by RT-qPCR and immunoblot. Kv1.3 expression was increased in microglia around the hematoma significantly after ICH. PAP-1 markedly improved neurological outcomes and the WMI by reducing pro-inflammatory cytokine accumulation and upregulating anti-inflammatory factors. Mechanistically, PAP-1 reduces NF-κB p65 and p50 activation, thus facilitating microglia polarization into M2-like microglia, which exerts this beneficial effect. PAP-1 reduced pro-inflammatory cytokines accumulation and increased anti-inflammatory factors by facilitating M2-like microglia polarization via the NF-κB signaling pathway. Thus, the current study shows that the Kv1.3 blockade is capable of ameliorating WMI by facilitating M2-like phenotype microglia polarization after ICH.

Comparative evaluation of approach to cardiovascular care in neonatal encephalopathy undergoing therapeutic hypothermia.

To analyze the association between cardiovascular care and adverse outcome in infants undergoing therapeutic hypothermia for neonatal encephalopathy (NE). This was a retrospective cohort study of 176 infants with NE and hypotension, admitted to the SickKids Hospital (Center A, n = 86) or Semmelweis University (Center B, n = 90). The lowest systolic/diastolic blood pressures were comparable amongst centers; however, proportion of cardiovascular support was lower in Center A (51% vs 97% in Center B). Overall rate of death or abnormal MRI (adverse outcome) were comparable between centers, although pattern differed with more basal ganglia injury in Center B. A 24-hour longer duration of cardiovascular support increased the odds for adverse outcome by 14%. We demonstrated that management of hemodynamic instability in infants with NE was markedly different in two high-volume NICUs and showed that longer duration of cardiovascular medication is an independent risk factor for adverse outcome.

Teaching NeuroImage: Reversible Symmetric Basal Ganglia Lesions in a Patient With Diabetes Undergoing Dialysis

A 50-year-old woman with diabetes and renal disease on hemodialysis presented with 1 month of involuntary movements, dysarthria, and gait disturbance. Examination revealed bradykinesia, dystonia, and choreoathetosis. Brain MRI showed symmetric basal ganglia lesions (Figure 1). Basic metabolic panel was stable from baseline with normal bicarbonate but elevated creatinine, blood urea nitrogen, and glucose. Serum and CSF testing was otherwise unremarkable. Repeat MRI 3 months later showed spontaneous lesion regression (Figure 2); however, her symptoms persisted. Findings were attributed to a well-described, but poorly understood, syndrome of basal ganglia injury in diabetic uremic patients due to metabolic and vascular dysregulation.1,2

Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia

Background/aim Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 or mut– enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort. Materials and methods The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT , MMAA , MMAB , MMADHC , MCEE genes. Mutation screening identified 30 different types of mutations. Results While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure. Conclusion We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long-term complications.

Movement disorders after hypoxic brain injury following cardiac arrest in adults.

Post-hypoxic movement disorders and chronic post-hypoxic myoclonus are rare complications after cardiac arrest in adults. Our study investigates the clinical spectrum, neuroimaging results, therapy and prognosis of these debilitating post-hypoxic sequelae. This retrospective study included 72 patients from the neurological intensive care unit at a university hospital, who were diagnosed with hypoxic-ischaemic encephalopathy after cardiac arrest between January 2007 and September 2018. Clinical records were screened for occurrence of post-hypoxic movement disorders and chronic post-hypoxic myoclonus. Affected patients were further analysed for applied neuroprognostic tests, administered therapy and treatment response, and the outcome of these movement disorders and neurological function. Nineteen out of 72 screened patients exhibited post-hypoxic motor symptoms. Basal ganglia injury was the most likely neuroanatomical correlate of movement disorders as indicated by T1 hyperintensities and hypometabolism of this region in magnetic resonance imaging and positron emission tomography computed tomography. Levomepromazine and intrathecal baclofen showed first promising and mostly prompt responses to control these post-hypoxic movement disorders and even hyperkinetic storms. In contrast, chronic post-hypoxic myoclonus best responded to co-application of clonazepam, levetiracetam and primidone. Remission rates of post-hypoxic movement disorders and chronic post-hypoxic myoclonus were 58% and 50%, respectively. Affected patients seemed to present a rather good recovery of cognitive functions in contrast to the often more severe physical deficits. Post-hypoxic movement disorders associated with pronounced basal ganglia dysfunction might be efficiently controlled by levomepromazine or intrathecal baclofen. Their occurrence might be an indicator for a more unfavourable, but often not devastating, neurological outcome.

P.112 Permanent isolated micrographia from traumatic basal ganglia injury

Background: Micrographia is a rare neurological finding in isolation. Most cases of isolated micrographia have been found in association with focal ischemia of the left basal ganglia. Methods: We present a case of post-traumatic micrographia stemming from contusion to the left basal ganglia. We performed a detailed analysis of the patient’s writing at three-year follow-up. Results: A halthy 15 year old male was admitted following a BM accident. CT showed contusion to the left basall ganglia/external capsule. MRI was negative for underlying lesion. He had a short stay in the ICU and then was discharged. Two years later, he expressed concern regarding difficulty with sma, cramped writing at school. Writing analysis revealed micrographia with spontaneous printing as well as printing to dictation, but not with copied English nor Japanese writing. Conclusions: Isolated micrographia is a rare neurological finding. We present the incidence of this symptom folllowing gliding contusion to the et basal ganglia and external capsule.

Permanent isolated micrographia from traumatic basal ganglia injury

Micrographia is a rare neurological finding in isolation. Most cases of isolated micrographia have been found in association with focal ischemia of the left basal ganglia. Here, we present a case of post-traumatic micrographia stemming from contusion to the left basal ganglia.

Hypoxia-Ischemia and Hypothermia Independently and Interactively Affect Neuronal Pathology in Neonatal Piglets with Short-Term Recovery

Therapeutic hypothermia is the standard of clinical care for moderate neonatal hypoxic-ischemic encephalopathy. We investigated the independent and interactive effects of hypoxia-ischemia (HI) and temperature on neuronal survival and injury in basal ganglia and cerebral cortex in neonatal piglets. Male piglets were randomized to receive HI injury or sham procedure followed by 29 h of normothermia, sustained hypothermia induced at 2 h, or hypothermia with rewarming during fentanyl-nitrous oxide anesthesia. Viable and injured neurons and apoptotic profiles were counted in the anterior putamen, posterior putamen, and motor cortex at 29 h after HI injury or sham procedure. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) identified genomic DNA fragmentation to confirm cell death. Though hypothermia after HI preserved viable neurons in the anterior and posterior putamen, hypothermia prevented neuronal injury in only the anterior putamen. Hypothermia initiated 2 h after injury did not protect against apoptotic cell death in either the putamen or motor cortex, and rewarming from hypothermia was associated with increased apoptosis in the motor cortex. In non-HI shams, sustained hypothermia during anesthesia was associated with neuronal injury and corresponding viable neuron loss in the anterior putamen and motor cortex. TUNEL confirmed increased neurodegeneration in the putamen of hypothermic shams. Anesthetized, normothermic shams did not show abnormal neuronal cytopathology in the putamen or motor cortex, thereby demonstrating minimal contribution of the anesthetic regimen to neuronal injury during normothermia. We conclude that the efficacy of hypothermic protection after HI is region specific and that hypothermia during anesthesia in the absence of HI may be associated with neuronal injury in the developing brain. Studies examining the potential interactions between hypothermia and anesthesia, as well as with longer durations of hypothermia, are needed.

On Neuropsychiatric Manifestations of Basal Ganglia Injury: A Report of Three Cases and Literature Review

The basal ganglia have been considered to primarily play a role in motor processing. A growing body of theoretical and clinical evidence shows that in addition to the motor functions the basal ganglia play a key role in perceptual and visual disturbances. This role may be evident in patients with basal ganglia pathology and subsequent manifestation of symptoms that include cognitive, perceptual, and affective disturbances. We present three cases with basal ganglia pathology that demonstrate affective and psychotic symptoms. Two of the cases presented with late onset psychotic disturbances suggesting likely neurological etiologies. The third case presented with treatment refractory psychosis and symptoms that are rare for a diagnosis of schizophrenia. The role of incidental bilateral basal ganglia calcifications in all the cases is discussed. A review of current literature highlighting various neuropsychiatric manifestations of basal ganglia pathologies in various patients with psychiatric symptoms is presented.

Abstract TP509: Patterns of Injury in Children With Perinatal Arterial Ischemic Stroke and Infantile Spasms

Perinatal arterial ischemic stroke (AIS) occurs in 1 in 4000 live births and is the most common stroke in children. Consequences include seizures and a spectrum of cognitive and motor disability. Infantile spasms (IS) is an epileptic encephalopathy of infancy with an incidence of 2 in 10,000 live births. Approximately 5% of IS is caused by perinatal AIS. Patterns of ischemic injury that may predispose infants to IS and predict treatment response have not yet been identified. This retrospective case series of infants with AIS and IS provides detailed descriptions of ischemic distribution, seizure presentation, treatment and outcomes. Inclusion criteria were: term birth, ischemic stroke or encephalomalacia in an arterial distribution identified or presumed to have occurred in the perinatal period, a diagnosis of infantile spasms. Patients with a watershed pattern of injury were excluded. The modified pediatric ASPECTS was used to qualify and quantify the type and distribution of stroke. Areas of injury were identified on MRI and scored from T2/Flair or DWI sequences. Eleven patients with AIS and IS were identified. Of nine who fit inclusion criteria, all had MCA territory involvement with 6/9 having basal ganglia injury. Five had ischemia identified retrospectively after developing IS and four presented as neonates. The highest ASPECTS (bilateral deep MCA) was associated with the worst outcome in motor function and epilepsy control. However, the second-highest ASPECTS (unilateral MCA, bilateral ACA) had mild motor deficits and no seizure recurrence after IS resolution. The three lowest ASPECTS (&lt;10) involved unilateral cortical MCA strokes sparing the deep structures, and also had the best motor outcome and seizure control. The co-occurrence of perinatal AIS and IS often results in significant neurologic disability. Although there was no defined pattern of regional homogeneity, there was a trend towards basal ganglia injury with progression of epilepsy after IS. This study highlights that size of ischemic injury may be less important than location as a predictor of motor outcome and seizure intractability. Future research will focus on identifying areas of injury that may confer increased risk of IS compared to stroke patients who remain seizure-free.

MRI Changes in the Thalamus and Basal Ganglia of Full-Term Neonates with Perinatal Asphyxia

Background: Magnetic resonance imaging (MRI) is the standard neuroimaging technique to assess perinatal asphyxia-associated brain injury in full-term infants. Diffusion-weighted imaging (DWI) is most informative when assessed during the first week after the insult. Objectives: To study the DWI abnormalities of the thalamus and basal ganglia in full-term infants with perinatal asphyxia. Methods: Fifty-five (near) term infants (normothermia n = 23; hypothermia n = 32) with thalamus and/or basal ganglia injury were included. MRI findings were assessed visually and quantitatively calculating apparent diffusion coefficient (ADC) values. Thalamus/basal ganglia ADC ratios were calculated to analyze the differences between these areas. Infants with an early MRI (days 1–3) or later MRI (days 4–7) were compared. Results: Isolated extensive thalamic injury was seen early, and focal thalamic and basal ganglia injury was seen later. On the early MRI, visual assessment underestimated abnormalities in the basal ganglia (59% abnormal vs. 90% abnormal on quantitative assessment; p = 0.015), suggesting the need for quantitative assessment. In infants treated with hypothermia, the thalamus/basal ganglia ADC ratio was lower. Conclusions: Both visual analysis and quantitative evaluation of cerebral MRI after perinatal asphyxia are needed, especially during the first few days after birth. Timing of ADC changes is influenced by therapeutic hypothermia.

Connexin hemichannel blockade improves survival of striatal GABA-ergic neurons after global cerebral ischaemia in term-equivalent fetal sheep

Basal ganglia injury at term remains a major cause of disability, such as cerebral palsy. In this study we tested the hypotheses that blockade of astrocytic connexin hemichannels with a mimetic peptide would improve survival of striatal phenotypic neurons after global cerebral ischaemia in term-equivalent fetal sheep, and that neuronal survival would be associated with electrophysiological recovery. Fetal sheep (0.85 gestation) were randomly assigned to receive a short or long (1 or 25 h) intracerebroventricular infusion of a mimetic peptide or vehicle, starting 90 minutes after 30 minutes of cerebral ischaemia. Sheep were killed 7 days after ischaemia. Cerebral ischaemia was associated with reduced numbers of calbindin-28k, calretinin, parvalbumin and GAD positive striatal neurons (P < 0.05 ischaemia + vehicle, n = 6 vs. sham ischaemia, n = 6) but not ChAT or nNOS positive neurons. Short infusion of peptide (n = 6) did not significantly improve survival of any striatal phenotype. Long infusion of peptide (n = 6) was associated with increased survival of calbindin-28k, calretinin, parvalbumin and GAD positive neurons (P < 0.05 vs. ischaemia + vehicle). Neurophysiological recovery was associated with improved survival of calbindin-28k, calretinin and parvalbumin positive striatal neurons (P < 0.05 for all). In conclusion, connexin hemichannel blockade after cerebral ischaemia in term-equivalent fetal sheep improves survival of striatal GABA-ergic neurons.

An Electronic Health Record Investigation of Lenticulostriate Vasculopathy Features.

Objective Lenticulostriate vasculopathy (LSV) is characterized by linear hyperechogenicities in the basal ganglia found on the head ultrasounds of infants. We reviewed electronic health records of infants with and without LSV to investigate whether physician dictations indicated symptoms which could reflect subtle basal ganglia injury. Study Design In a case-control study, we analyzed data from 46 infants with LSV and 127 controls. Infants were stratified between term and preterm birth. Odds ratios (ORs) and 95% confidence intervals were calculated for tone abnormalities, apnea, feeding difficulties, seizures, and movement abnormalities in the presence of LSV. Results Both term and preterm infants with LSV showed elevated risks for tone abnormalities (OR: 3.6 and 2.9, respectively). Term infants with LSV showed elevated risks for hypotonia (OR: 4.3), apnea (OR: 2.9), and feeding difficulties (OR: 4.1). Preterm infants with LSV showed elevated risks for truncal hypotonia (OR: 3.9) and hyperreflexia (OR: 3.9). Conclusion Our findings provide some evidence that LSV is associated with an increased risk of early signs of abnormal development, possibly relating to signs of subtle basal ganglia injury. Historically LSV has been considered incidental. The associations identified here suggest that LSV findings are worthy of further study.

Discordant Observation of Brain Injury by MRI and Malignant Electroencephalography Patterns in Comatose Survivors of Cardiac Arrest following Therapeutic Hypothermia.

Malignant electroencephalography patterns are considered predictive of poor outcome in comatose survivors of cardiac arrest. We hypothesized that malignant patterns on electroencephalography are associated with evidence of more severe brain injury on MR imaging. Retrospective review of clinical, imaging, and electroencephalography data of 33 adult comatose survivors of cardiac arrest following therapeutic hypothermia was performed. Outcomes measured included discharge destination and survival. Imaging studies were visually scored for severity of brain injury. Mean whole-brain apparent diffusion coefficient and percentage of severely injured brain (ADC < 700 × 10-6 mm2/s) were calculated. Continuous electroencephalographic interpretation was characterized as malignant or nonmalignant. Nonparametric tests were performed to assess the relationship of patient outcome, MR imaging, and electroencephalography patterns. Subjects with anatomic evidence of diffuse brain injury were less likely to have malignant electroencephalography patterns. Subjects with malignant electroencephalography patterns, invariably associated with bad outcomes, were observed to have whole-brain apparent diffusion coefficient measures similar to those in subjects with nonmalignant electroencephalography patterns and good outcome and different from those in subjects with nonmalignant electroencephalography patterns and bad outcomes. Regional hippocampal or basal ganglia injury was associated with a bad outcome regardless of electroencephalography findings. We found discordant evidence of brain injury by MR imaging and electroencephalography, refuting our initial hypothesis. Malignant electroencephalography patterns were generally more frequent in subjects with less severe brain injury by MR imaging. These findings suggest a complementary role of MR imaging and electroencephalography and support the aggressive treatment of malignant electroencephalography patterns in this population.

Basal Ganglia Damage in Experimental Subarachnoid Hemorrhage.

Research suggests that early brain injury following subarachnoid hemorrhage (SAH) is a primary therapeutic target, and early SAH-induced basal ganglia injury is not well studied. The present study examined basal ganglia injury in a rat model of SAH. Adult male Sprague-Dawley rats (n = 78) weighing 275-300 g underwent endovascular perforation to mimic aneurysmal SAH. Sham rats (n = 12) underwent the same procedure but without perforation. Magnetic resonance imaging (T2 MRI) was performed at 24 h after SAH to measure ventricle volumes and brain T2 lesion. Hydrocephalus in SAH rats was defined as a ventricular volume greater than three standard deviations above that in shams. Western blotting and immunochemistry were utilized to assess basal ganglia damage. Sixty rats survived the SAH and 40 % of those animals had T2 lesions in the basal ganglia. Twenty-six SAH rats had hydrocephalus. Rats with hydrocephalus had higher incidence of basal ganglia lesion (69 vs. 18 % in rats without hydrocephalus; p < 0.01). Basal ganglia neuronal injury was also determined by examining the levels of dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32). We found that rats with hydrocephalus had more severe basal ganglia injury with greater DARPP-32 depletion (DARPP-32/beta-actin: 0.38 ± 0.32 vs. 0.86 ± 0.45 in rats without hydrocephalus and 1.10 ± 0.28 in sham, p < 0.05). In conclusion, SAH resulted in severe basal ganglia damage, which is associated with hydrocephalus development.

Brain magnetic resonance imaging and outcome after hypoxic ischaemic encephalopathy

Objective: To correlate pattern of injury on neonatal brain magnetic resonance imaging (MRI) with outcome in infants ≥36 + 0 weeks gestation with hypoxic ischaemic encephalopathy.Methods: Prospective cohort study. Images were blindly reviewed. Children were assessed using a variety of standardised assessments.Results: MRI brain was performed on 88 infants. Follow up was available in 73(83%) infants. Eight of 25(32%) children with normal imaging had below normal assessment scores. Eight infants (12%) had isolated punctate white matter lesions and five of these had abnormal assessment scores. Death and cerebral palsy were seen only in children with imaging scores ≥3 on basal ganglia/thalami (BGT) score or ≥4 on watershed score. No developmental concerns were raised in 3/7(43%) infants with isolated watershed injury. Ten of 13(77%) infants with isolated BGT injury died or developed cerebral palsy. All 23 children with posterior limb of the internal capsule (PLIC) injury displayed developmental difficulties.Conclusions: Almost one-third of infants with a normal MRI brain may be at risk of developmental problems. Punctate foci of white matter injury are common and not always benign. PLIC involvement is usually associated with neurological sequelae including isolated cognitive deficits. Worst outcomes are associated with basal ganglia injury.

Sodium Para-aminosalicylic Acid Protected Primary Cultured Basal Ganglia Neurons of Rat from Manganese-Induced Oxidative Impairment and Changes of Amino Acid Neurotransmitters.

Manganese (Mn), an essential trace metal for protein synthesis and particularly neurotransmitter metabolism, preferentially accumulates in basal ganglia. However, excessive Mn accumulation may cause neurotoxicity referred to as manganism. Sodium para-aminosalicylic acid (PAS-Na) has been used to treat manganism with unclear molecular mechanisms. Thus, we aim to explore whether PAS-Na can inhibit Mn-induced neuronal injury in basal ganglia in vitro. We exposed basal ganglia neurons with 50 μM manganese chloride (MnCl2) for 24 h and then replaced with 50, 150, and 450 μM PAS-Na treatment for another 24 h. MnCl2 significantly decreased cell viability but increased leakage rate of lactate dehydrogenase and DNA damage (as shown by increasing percentage of DNA tail and Olive tail moment). Mechanically, Mn reduced glutathione peroxidase and catalase activity and interrupted amino acid neurotransmitter balance. However, PAS-Na treatment reversed the aforementioned Mn-induced toxic effects. Taken together, these results showed that PAS-Na could protect basal ganglia neurons from Mn-induced neurotoxicity.

Delineating the spectrum of impairments, disabilities, and rehabilitation needs in methylmalonic acidemia (MMA).

Methylmalonic acidemia patients have complex rehabilitation needs that can be targeted to optimize societal independence and quality of life. Thirty-seven individuals with isolated MMA (28 mut, 5 cblA, 4 cblB), aged 2-33 years, were enrolled in a natural history study, and underwent age-appropriate clinical assessments to characterize impairments and disabilities. Neurological examination and brain imaging studies were used to document movement disorders and the presence of basal ganglia injury. A range of impairments and disabilities were identified by a team of physical medicine experts. Movement disorders, such as chorea and tremor, were common (n = 31, 83%), even among patients without evidence of basal ganglia injury. Joint hypermobility (n = 24, 69%) and pes planus (n = 22, 60%) were frequent and, in many cases, under-recognized. 23 (62%) patients required gastrostomy feedings. 18/31 patients >4 years old (58%) had difficulties with bathing and dressing. 16 of 23 school-aged patients received various forms of educational support. Five of the 10 adult patients were employed or in college; three lived independently. Unmet needs were identified in access to rehabilitation services, such as physical therapy (unavailable to 14/31), and orthotics (unavailable to 15/22). We conclude that patients with MMA are challenged by a number of functional limitations in essential activities of mobility, self-care, and learning, in great part caused by movement disorders and ligamentous laxity. Early assessment, referral, and implementation of age-appropriate rehabilitation services should significantly improve independence and quality of life.