Faculty Bibliography

There are varying medical, legal, social, religious and philosophical perspectives about the distinction between life and death. Death can be declared using cardiopulmonary or neurologic criteria throughout much of the world. After solicitation of brain death/death by neurologic criteria (BD/DNC) protocols from contacts around the world, we found that the percentage of countries with BD/DNC protocols is much lower in Africa than other developing regions. We performed an informal review of the literature to identify barriers to declaration of BD/DNC in Africa. We found that there are numerous medical, legal, social and religious barriers to the creation of BD/DNC protocols in Africa including 1) limited number of healthcare facilities, critical care resources and clinicians with relevant expertise; 2) absence of a political and legal framework codifying death; and 3) cultural and religious perspectives that present ideological conflict with the idea of BD/DNC, in particular, and between traditional and Western medicine, in general. Because there are a number of unique barriers to the creation of BD/DNC protocols in Africa, it remains to be seen how the World Brain Death Project, which is intended to create minimum standards for BD/DNC around the world, will impact BD/DNC determination in Africa.

Epilepsy is characterized by an imbalance in neurotransmitter activity; an increased excitatory to an inhibitory activity. Acetylcholine (ACh), serotonin, and norepinephrine (NE) may modulate neural activity via several mechanisms, mainly through its receptors/transporter activity and alterations in the extracellular potassium (K⁺) concentration via K⁺ ion channels. Seizures may disrupt the regulation of inwardly rectifying K⁺ (Kir) channels and alter the receptor/transporter activity. However, there are limited data present on the immunoreactivity pattern of these neurotransmitter receptors/transporters and K⁺ channels in chronic models of epilepsy, which therefore was the aim of this study. Changes in the immunoreactivity of epileptogenesis-related neurotransmitter receptors/transporters (M2, 5-HT2B, and NE transporter) as well as Kir channels (Kir3.1 and Kir6.2) were determined in the cortex, hippocampus and medulla of adult Wistar rats by utilizing a Pentylenetetrazol (PTZ)-kindling chronic epilepsy model. Increased immunoreactivity of the NE transporter, M2, and 5-HT2B receptors was witnessed in the cortex and medulla. While the immunoreactivity of the 5-HT2B receptor was found increased in the cortex and medulla, it was decreased in the hippocampus, with no changes observed in the M2 receptor in this region. Kir3.1 and Kir6.2 staining showed increase immunoreactivity in the cerebral cortex, but channel contrasting findings in the hippocampus and medulla. Our results suggest that seizure kindling may result in significant changes in the neurotransmitter system which may contribute or propagate to future epileptogenesis, brain damage and potentially towards sudden unexpected death in epilepsy (SUDEP). Further studies on the pathogenic role of these changes in neurotransmitter receptors/transporters and K⁺ channel immunoreactivity may identify newer possible targets to treat seizures or prevent epilepsy-related comorbidities.

Tension-type headache (TTH) is the most prevalent neurological disorder worldwide and is characterized by recurrent headaches of mild to moderate intensity, bilateral location, pressing or tightening quality, and no aggravation by routine physical activity. Diagnosis is based on headache history and the exclusion of alternative diagnoses, with clinical criteria provided by the International Classification of Headache Disorders, third edition. Although the biological underpinnings remain unresolved, it seems likely that peripheral mechanisms are responsible for the genesis of pain in TTH, whereas central sensitization may be involved in transformation from episodic to chronic TTH. Pharmacological therapy is the mainstay of clinical management and can be divided into acute and preventive treatments. Simple analgesics have evidence-based effectiveness and are widely regarded as first-line medications for the acute treatment of TTH. Preventive treatment should be considered in individuals with frequent episodic and chronic TTH, and if simple analgesics are ineffective, poorly tolerated or contraindicated. Recommended preventive treatments include amitriptyline, venlafaxine and mirtazapine, as well as some selected non-pharmacological therapies. Despite the widespread prevalence and associated disability of TTH, little progress has been made since the early 2000s owing to a lack of attention and resource allocation by scientists, funding bodies and the pharmaceutical industry.

PURPOSE OF REVIEW/OBJECTIVE:SMART syndrome is a delayed complication of cranial irradiation that can be misconstrued as tumor recurrence or some other intracranial neurological disease. Recognition of this clinical syndrome is imperative as it can obviate the need for invasive diagnostic testing and can provide reassurance to both the patient and their loved ones. RECENT FINDINGS/RESULTS:SMART syndrome is generally considered a reversible clinical syndrome; however, neurological deficits may become permanent. Pathophysiology of SMART syndrome may involve cerebrovascular autoregulation impairment, neuronal dysfunction leading to trigeminovascular system impairment and/or cortical spreading depression, and seizures. In addition to MRI brain with gadolinium, other imaging modalities, such as CT perfusion, MR perfusion, MR spectroscopy, and FDG PET/CT, aid in arriving to the diagnosis sooner. Patients should also undergo electroencephalogram in order to promptly identify and treat seizures. There are currently no clear guidelines on how to effectively treat SMART syndrome, but treatment may involve anti-seizure medication, anti-hypertensives, anti-platelet, and steroid therapy. This review provides a comprehensive understanding of the clinical characteristics of SMART syndrome from presentation to diagnostic evaluation. We also discuss radiographic features and treatment strategies for this rare disease. With increased radiotherapy utilization, prompt clinical recognition of SMART syndrome and further development of a comprehensive diagnostic approach to SMART syndrome utilizing newer radiographic modalities as well as treatment algorithms to effectively treat this clinical condition will be imperative.

Although it is self-evident that education in neurology is important and necessary, how to fund the educational mission is a frequent challenge for neurology departments and clinicians. Department chairs often resort to a piecemeal approach, cobbling together funding for educators from various sources, but frequently falling short. Here, we review the various sources available to fund the educational mission in neurology, understanding that not every department will have access to every source. We describe the multiple different teaching models and formats used by the modern student and educator and their associated costs, some of which are exorbitant. We discuss possible nonfinancial incentives, including pathways to promotion, educational research, and other awards and recognition. Neurological education is commonly underfunded, and departments and institutions must be nimble and creative in finding ways to fund the time and effort of educators.

INTRODUCTION/BACKGROUND:A variety of transgenic and knock-in mice that express mutant alleles of Amyloid precursor protein (APP) have been used to model the effects of amyloid-beta (Aβ) on circuit function in Alzheimer's disease (AD); however phenotypes described in these mice may be affected by expression of mutant APP or proteolytic cleavage products independent of Aβ. In addition, the effects of mutant APP expression are attributed to elevated expression of the amyloidogenic, 42-amino acid-long species of Aβ (Aβ42) associated with amyloid plaque accumulation in AD, though elevated concentrations of Aβ40, an Aβ species produced with normal synaptic activity, may also affect neural function. METHODS:To explore the effects of elevated expression of Aβ on synaptic function in vivo, we assessed visual system plasticity in transgenic mice that express and secrete Aβ throughout the brain in the absence of APP overexpression. Transgenic mice that express either Aβ40 or Aβ42 were assayed for their ability to appropriately demonstrate ocular dominance plasticity following monocular deprivation. RESULTS:Using two complementary approaches to measure the plastic response to monocular deprivation, we find that male and female mice that express either 40- or 42-amino acid-long Aβ species demonstrate a plasticity defect comparable to that elicited in transgenic mice that express mutant alleles of APP and Presenilin 1 (APP/PS1 mice). CONCLUSIONS:These data support the hypothesis that mutant APP-driven plasticity impairment in mouse models of AD is mediated by production and accumulation of Aβ. Moreover, these findings suggest that soluble species of Aβ are capable of modulating synaptic plasticity, likely independent of any aggregation. These findings may have implications for the role of soluble species of Aβ in both development and disease settings.

Previous multi-center imaging studies with ¹⁸F-FDG PET have established the presence of Parkinson's disease motor- and cognition-related metabolic patterns termed PDRP and PDCP in patients with this disorder. Given that in PD cerebral perfusion and glucose metabolism are typically coupled in the absence of medication, we determined whether subject expression of these disease networks can be quantified in early-phase images from dynamic ¹⁸F-FPCIT PET scans acquired to assess striatal dopamine transporter (DAT) binding. Methods: We studied a cohort of early-stage PD patients and age-matched healthy control subjects who underwent ¹⁸F-FPCIT at baseline; scans were repeated 4 years later in a smaller subset of patients. The early ¹⁸F-FPCIT frames, which reflect cerebral perfusion, were used to compute PDRP and PDCP expression (subject scores) in each subject, and compared to analogous measures computed based on ¹⁸F-FDG PET scan when additionally available. The late ¹⁸F-FPCIT frames were used to measure caudate and putamen DAT binding in the same individuals. Results: PDRP subject scores from early-phase ¹⁸F-FPCIT and ¹⁸F-FDG scans were elevated and striatal DAT binding reduced in PD versus healthy subjects. The PDRP scores from ¹⁸F-FPCIT correlated with clinical motor ratings, disease duration, and with corresponding measures from ¹⁸F-FDG PET. In addition to correlating with disease duration and analogous ¹⁸F-FDG PET values, PDCP scores correlated with DAT binding in the caudate/anterior putamen. PDRP and PDCP subject scores using either method rose over 4 years whereas striatal DAT binding declined over the same time period. Conclusion: Early-phase images obtained with ¹⁸F-FPCIT PET can provide an alternative to ¹⁸F-FDG PET for PD network quantification. This technique therefore allows PDRP/PDCP expression and caudate/putamen DAT binding to be evaluated with a single tracer in one scanning session.

Parkinson's disease is the most common age-related motoric neurodegenerative disease. In addition to the cardinal motor symptoms of tremor, rigidity, bradykinesia, and postural instability, there are numerous non-motor symptoms as well. Among the non-motor symptoms, autonomic nervous system dysfunction is common. Autonomic symptoms associated with Parkinson's disease include sialorrhea, hyperhidrosis, gastrointestinal dysfunction, and urinary dysfunction. Botulinum neurotoxin has been shown to potentially improve these autonomic symptoms. In this review, the varied uses of botulinum neurotoxin for autonomic dysfunction in Parkinson's disease are discussed. This review also includes discussion of some additional indications for the use of botulinum neurotoxin in Parkinson's disease, including pain.

AIM/UNASSIGNED:To adopt a computer-based protocol to assess grip fatigability in patients with pediatric-onset multiple sclerosis to provide detection of subtle motor involvement identifying those patients most at risk for future decline. METHOD/UNASSIGNED:Pediatric-onset multiple sclerosis patients were recruited during routine outpatient visits to complete a grip assessment and compared to a group of healthy age- and sex-matched controls. All participants completed a computer-based measurement of standard maximal grip strength and repetitive and sustained grip performance measured by dynamic and static fatigue indices. RESULTS/UNASSIGNED:< .001). CONCLUSION/UNASSIGNED:Brief repeatable grip assessment including measures of dynamic and sustained static output can be a sensitive indicator of upper extremity motor involvement in pediatric-onset multiple sclerosis, potentially identifying those in need of intervention to prevent future disability.

BACKGROUND:The pathogenesis of glioma-related seizures (GRS) is poorly understood. Here in, we aim to identify putative molecular pathways that lead to the development of GRS. METHODS:We determined brain transcriptome from intraoperative human brain tissue of patients with either GRS, glioma without seizures (non-GRS), or with idiopathic temporal lobe epilepsy (iTLE). We performed transcriptome-wide comparisons between disease groups tissue from non-epileptic controls (non-EC) to identify differentially-expressed genes (DEG). We compared DEGs to identify those that are specific or common to the groups. Through a gene ontology analysis, we identified molecular pathways enriched for genes with a Log-fold change ≥1.5 or ≤-1.5 and p-value <0.05 compared to non-EC. RESULTS:We identified 110 DEGs that are associated with GRS vs. non-GRS: 80 genes showed high and 30 low expression in GRS. There was significant overexpression of genes involved in cell-to-cell and glutamatergic signaling (CELF4, SLC17A7, and CAMK2A) and down-regulation of genes involved immune-trafficking (CXCL8, H19, and VEGFA). In the iTLE vs GRS analysis, there were 1098 DEGs: 786 genes were overexpressed and 312 genes were underexpressed in the GRS samples. There was significant enrichment for genes considered markers of oncogenesis (GSC, MYBL2, and TOP2A). Further, there was down-regulation of genes involved in the glutamatergic neurotransmission (vesicular glutamate transporter-2) in the GRS vs. iTLE samples. CONCLUSIONS:We identified a number of altered processes such as cell-to-cell signaling and interaction, inflammation-related, and glutamatergic neurotransmission in the pathogenesis of GRS. Our findings offer a new landscape of targets to further study in the fields of brain tumors and seizures.