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Background: Orthostatic hypotension (OH) is a poorly understood complication of simultaneous pancreas-kidney (SPK) transplantation. We sought to determine the incidence, timing, and relationship of OH to rapid glycemic control in the early posttransplant period., Methods: This was a nonrandomized retrospective single-center review of 75 SPK and 19 kidney-alone (KA) recipients with type 1 diabetes (DM)., Results: OH occurred in 57 (76%) SPK versus 2 (10%) KA recipients (odds ratio [OR] 61.72, 95% confidence interval [CI], 9.69-393.01; P < 0.001). The median onset of OH was 12 (interquartile range [IQR] 9-18) days posttransplant and resolved in 85% of SPK recipients after a median of 2.5 (IQR 1.2-6.3) months. Among SPK recipients, independent risk factors for OH were a shorter duration of DM (OR 0.85, 95% CI, 0.73-0.98; P = 0.03) and rapid glycemic control in the early posttransplant period (OR 1.13, 95% CI, 1.01-1.27; P = 0.04), as evidenced by a larger percent change in hemoglobin A1c (HbA1c) from transplant to month 3. OH patients had a higher median baseline HbA1c [8.3% (IQR 7.2-10.0) versus 7.1% (IQR 6.8-8.3); P = 0.07], lower median 3-month HbA1c [4.8% (IQR 4.6-5.2) versus 5.2% (IQR 5.0-5.4); P = 0.02], and a larger reduction in HbA1c over time as compared to recipients without OH ( P < 0.01)., Conclusions: Our results show that OH is more likely to occur following SPK versus KA transplantation and is strongly associated with rapid glucose normalization within the early posttransplant period., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Medical students need to understand core neuroscience principles as a foundation for their required clinical experiences in neurology. In fact, they need a solid neuroscience foundation for their clinical experiences in all other medical disciplines also because the nervous system plays such a critical role in the function of every organ system. Because of the rapid pace of neuroscience discoveries, it is unrealistic to expect students to master the entire field. It is also unnecessary, as students can expect to have ready access to electronic reference sources no matter where they practice. In the preclerkship phase of medical school, the focus should be on providing students with the foundational knowledge to use those resources effectively and interpret them correctly. This article describes an organizational framework for teaching the essential neuroscience background needed by all physicians. This is particularly germane at a time when many medical schools are reassessing traditional practices and instituting curricular changes such as competency-based approaches, earlier clinical immersion, and increased emphasis on active learning. This article reviews factors that should be considered when developing the preclerkship neuroscience curriculum, including goals and objectives for the curriculum, the general topics to include, teaching and assessment methodology, who should direct the course, and the areas of expertise of faculty who might be enlisted as teachers or content experts. These guidelines were developed by a work group of experienced educators appointed by the Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN). They were then successively reviewed, edited, and approved by the entire UES, the AAN Education Committee, and the AAN Board of Directors., (© 2021 American Academy of Neurology.)

Purpose of Review: Neuroinflammation is increasingly recognized as an important mediator of disease progression in patients with amyotrophic lateral sclerosis (ALS), and is characterized by reactive central nervous system (CNS) microglia and astroglia as well as infiltrating peripheral monocytes and lymphocytes. Anti-inflammatory and neuroprotective factors sustain the early phase of the disease whereas inflammation becomes proinflammatory and neurotoxic as disease progression accelerates. Initially, motor neurons sustain injuries through multiple mechanisms resulting from harmful mutations causing disruptions of critical intracellular pathways. Injured motor neurons release distress signal(s), which induce inflammatory processes produced by surrounding glial cells in the CNS as well as peripheral innate and adaptive immune cells. This review will focus on mechanisms of neuroinflammation and their essential contributions in ALS pathogenesis., Recent Findings: Regulatory T lymphocytes (Tregs) are a subpopulation of immunosuppressive T lymphocytes that become reduced and dysfunctional as the disease progresses in ALS patients. Their degree of dysfunction correlates with the extent and rapidity of the disease. Treg numbers are boosted in transgenic mutant SOD1 (mSOD1) mice through the passive transfer of Tregs or through treatment with an interleukin-2/ interleukin-2 monoclonal antibody complex and rapamycin. Treating the transgenic mice with either of these modalities delays disease progression and prolongs survival. In addition, Treg function is restored when dysfunctional Tregs are isolated from ALS patients and expanded ex vivo in the presence of interleukin-2 and rapamycin. Based on these findings, a first-in-human phase 1 trial has been completed in which expanded autologous Tregs were infused back into ALS patients as a potential treatment. The infusions were safe and shown to 'hit target' by enhancing both Treg numbers and suppressive functions., Summary: A delicate balance between anti-inflammatory and proinflammatory factors modulates the rates of disease progression and survival times in ALS. Tipping the balance toward the anti-inflammatory mediators shows promise in slowing the progression of this devastating disease.

Objective: To determine whether autologous infusions of expanded regulatory T lymphoctyes (Tregs) into patients with amyotrophic lateral sclerosis (ALS) are safe and tolerable during early and later stages of disease., Methods: Three patients with ALS, with no family history of ALS, were selected based on their differing sites of disease onset and rates of progression. Patients underwent leukapheresis, and Tregs were subsequently isolated and expanded ex vivo. Tregs (1 × 10 6 cells/kg) were administered IV at early stages (4 doses over 2 months) and later stages (4 doses over 4 months) of disease. Concomitant interleukin-2 (2 × 10 5 IU/m 2 /injection) was administered subcutaneously 3 times weekly over the entire study period. Patients were closely monitored for adverse effects and changes in disease progression rates. Treg numbers and suppressive function were assayed during and following each round of Treg infusions., Results: Infusions of Tregs were safe and well tolerated in all patients. Treg numbers and suppressive function increased after each infusion. The infusions slowed progression rates during early and later stages of disease. Spearman correlation analyses showed that increased Treg suppressive function correlated with slowing of disease progression per the Appel ALS scale for each patient: patient 1: ρ (rho) = -0.60, p = 0.003; patient 2: ρ = -0.71, p = 0.0026; and patient 3: ρ = -0.54, p = 0.016. Measures of maximal inspiratory pressure also stabilized, particularly in 2 patients, during Treg infusions., Conclusions: These results demonstrate the safety and potential benefit of expanded autologous Treg infusions, warranting further clinical trials in patients with ALS. The correlation between Treg suppressive function and disease progression underscores the significance of using Treg suppressive function as an indicator of clinical status., Classification of Evidence: This study provides Class IV evidence. This is a phase I trial with no controls.

Background: Guillain-Barré syndrome (GBS) is an acute peripheral neuropathy caused by an autoimmune response against myelin of peripheral nerves. GBS has been reported after surgery, in general, and after spinal surgery, in particular. In most cases, GBS developed 1-3 weeks after surgery., Methods: Report of 2 cases of GBS after elective spine surgery that developed in the immediate postoperative period., Results: Within 1 and 3 hours after surgery, respectively, both patients developed ascending loss of motor and sensory function. They were taken back urgently to the operating room for wound exploration to ensure that an epidural hematoma had not developed. Cerebrospinal fluid studies and electromyography/nerve conduction velocity were then rapidly obtained and were compatible with acute inflammatory demyelinating polyradiculoneuropathy. Therapy was initiated with administration of intravenous immunoglobulin and plasmapheresis. Both patients made substantial motor recovery during the course of 1-2 years but have residual sensory abnormalities., Conclusions: GBS developing acutely after spinal surgery is a rare occurrence but should be considered in the differential diagnosis of neurological deterioration after surgery. Rapid diagnosis and treatment are essential for recovery of neurological function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition., Methods: In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983., Findings: Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0.06; HC/HC vs control, p=0.06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0.0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0.03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group., Interpretation: Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease., Funding: Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled study was undertaken to address whether IGF-1 benefited patients with ALS., Methods: A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used., Results: There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period., Conclusions: Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS), an inexorably progressive motoneuron disease, is accompanied by significantly increased markers of inflammation. These inflammatory constituents could protect, harm, do neither, or do both., Objective: Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in patients with sporadic ALS to suppress neuroinflammation and improve clinical outcomes after CNS engraftment., Methods: Six patients with definite ALS received total body irradiation followed by peripheral blood HSCT infusion from human leukocyte antigen identically matched sibling donors. Disease progression and survival were assessed monthly and compared with matched historic database patients. Autopsy samples from brain and spinal cord were examined immunohistochemically and by quantitative reverse-transcriptase polymerase chain reaction. Donor-derived DNA in brain and spinal cord tissue was evaluated for the extent of chimerism., Results: No clinical benefits were evident. Four patients were 100% engrafted; postmortem tissue examination in two of the 100% engrafted patients demonstrated 16% to 38% donor-derived DNA at sites with motoneuron pathology, which may correspond to the observed increased CD68 or CD1a-positive cells. Neither donor DNA nor increased cell numbers were found in several unaffected brain regions. A third minimally engrafted patient had neither donor DNA nor increased infiltrating cells in the CNS., Conclusions: This study demonstrates that peripheral cells derived from donor hematopoietic stem cells can enter the human CNS primarily at sites of motoneuron pathology and engraft as immunomodulatory cells. Although unmodified hematopoietic stem cells did not benefit these sporadic amyotrophic lateral sclerosis patients, such cells may provide a cellular vehicle for future CNS gene therapy.

Background: Approximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes., Methods: We performed a genomewide association analysis using 766,955 single-nucleotide polymorphisms (SNPs) found in 386 white patients with sporadic ALS and 542 neurologically normal white controls (the discovery series). Associations of SNPs with sporadic ALS were confirmed in two independent replication populations: replication series 1, with 766 case patients with the disease and 750 neurologically normal controls, and replication series 2, with 135 case patients and 275 controls., Results: We identified 10 genetic loci that are significantly associated (P<0.05) with sporadic ALS in three independent series of case patients and controls and an additional 41 loci that had significant associations in two of the three series. The most significant association with disease in white case patients as compared with controls was found for a SNP near an uncharacterized gene known as FLJ10986 (P=3.0x10(-4); odds ratio for having the genotype in patients vs. controls, 1.35; 95% confidence interval, 1.13 to 1.62). The FLJ10986 protein was found to be expressed in the spinal cord and cerebrospinal fluid of patients and of controls. Specific SNPs seem to be associated with sex, age at onset, and site of onset of sporadic ALS., Conclusions: Variants of FLJ10986 may confer susceptibility to sporadic ALS. FLJ10986 and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease., (Copyright 2007 Massachusetts Medical Society.)

The aim of this study was to determine the predictors of disease progression in a group of 832 patients with the diagnosis of definite or probable amyotrophic lateral sclerosis (ALS). Disease progression was defined as the time to 20-point change in Appel ALS (AALS) score. The effects of individual prognostic factors on disease progression were assessed with the Kaplan-Meier life-table method. In addition, the prognostic value of each factor was estimated using both univariate and multivariate Cox proportional hazard analyses. The median time to a 20-point change in AALS score in our patient population was 9 months. Age, site of symptom onset, time between first symptom and first examination, total AALS score at first examination, and AALS preslope (rate of disease progression between first symptom and first examination) were significant and independent covariates of disease progression in our population. Identification of predictors of disease progression will facilitate better design of therapeutic trials, permitting the use of disease progression as a primary endpoint and improving baseline stratification of patient populations.

Background: In recent years, considerable effort has been made to improve the treatment of patients with amyotrophic lateral sclerosis (ALS). However, despite the increased use of supportive measures, controversy still exists about overall trends in disease progression and survival., Objective: To analyze whether survival and disease progression in patients with ALS have changed during the past 20 years., Design: By using the Kaplan-Meier life-table method, we compared disease progression (measured as time to a 20-point increase in the Appel ALS score) and survival in 1041 patients diagnosed as having ALS between January 1, 1984, and January 1, 1999 (historical group, n = 647), and between January 2, 1999, and November 1, 2004 (contemporary group, n = 394). The Cox proportional hazards model was used for univariate and multivariate analyses., Results: The median survival from symptom onset was 4.32 years (95% confidence interval [CI], 3.81-4.84 years) in the contemporary group compared with 3.22 years (95% CI, 3.04-3.41 years) in the historical group (P<.001). The contemporary patients progressed more slowly (10 months to a 20-point increase; 95% CI, 9-13 months) compared with patients in the historical group (9 months to a 20-point increase; 95% CI, 8-9 months) (P<.001). In the multivariate Cox proportional hazards model, the observed outcome improvement over time was independent of confounding factors, such as age, sex, diagnostic delay, site of symptom onset, baseline forced vital capacity, and baseline Appel ALS score, and independent of the use of potentially outcome-modifying therapies (riluzole, noninvasive ventilation, and percutaneous gastrostomy)., Conclusions: Contemporary patients had significantly prolonged survival and slower disease progression compared with patients from the historical group. The improved outcome seemed independent of specific ALS outcome-modifying therapies, but we cannot rule out an effect of comorbid conditions, which could have influenced medical treatment and survival. Nevertheless, our observations suggest the possibility that disease course has changed and that ALS is becoming less aggressive over time. Further studies are needed to determine whether there has been a fundamental change in the natural history of the disease or whether our results are because of other unmeasured aspects of improved multidisciplinary care.

Recent studies suggest that motor neuron (MN) death may be non-cell autonomous, with cell injury mediated by interactions involving non-neuronal cells, such as microglia and astrocytes. To help define these interactions, we used primary MN cultures to investigate the effects of microglia activated by lipopolysaccharide or IgG immune complexes from patients with amyotrophic lateral sclerosis. Following activation, microglia induced MN injury, which was prevented by a microglial iNOS inhibitor as well as by catalase or glutathione. Glutamate was also required since inhibition of the MN AMPA/kainate receptor by CNQX prevented the toxic effects of activated microglia. Peroxynitrite and glutamate were synergistic in producing MN injury. Their toxic effects were also blocked by CNQX and prevented by calcium removal from the media. The addition of astrocytes to cocultures of MN and activated microglia prevented MN injury by removing glutamate from the media. The protective effects could be reversed by inhibiting astrocytic glutamate transport with dihydrokainic acid or pretreating astrocytes with H2O2. Astrocytic glutamate uptake was also decreased by activated microglia or by added peroxynitrite. These data suggest that free radicals released from activated microglia may initiate MN injury by increasing the susceptibility of the MN AMPA/kainate receptor to the toxic effects of glutamate.

Background: Markers of oxidative stress and immune activation are significantly elevated in postmortem ALS CNS tissue, although the relevance to pathogenesis is unclear., Objective: To determine the degree and distribution of oxidative stress and immune activation in living ALS patients and whether these levels correlate with the rate of progression or extent of disease., Method: Serum and CSF samples from sporadic ALS (sALS) patients were assayed for 4-hydroxy-2,3-nonenal (HNE), a lipid peroxidation product, and monocyte chemoattractant protein-1alpha (MCP-1alpha), a beta-chemokine, by high-performance liquid chromatography and ELISA and compared with levels measured in disease and normal control subjects by one-way analysis of variance. SALS serum levels were analyzed in relation to rate of progression, stage of disease, and drug therapy., Results: HNE levels were significantly elevated in the sera and spinal fluid of sALS patients compared with control populations and positively correlated with extent of disease but not rate of progression. MCP-1alpha levels were also elevated in the sera of sALS patients, with the exception of the neurodegenerative disease control subjects, but decreased with advancing disease. CSF MCP-1alpha levels were not different between the sampled populations. There was no correlation between serum HNE and MCP-1alpha levels in sALS patients and extent of disease. However, an inverse relationship between HNE and MCP-1alpha was demonstrable in vitro. Low levels of HNE stimulated release of MCP-1alpha from cultured human macrophages, whereas high levels inhibited release of MCP-1alpha., Conclusions: These data confirm the presence of increased oxidative stress and immune activation in ALS patients. HNE is also suggested as a possible biomarker of disease.

Dendritic cells are potent antigen-presenting cells that initiate and amplify immune responses. To determine whether dendritic cells participate in inflammatory reactions in amyotrophic lateral sclerosis (ALS), we examined mRNA expression of dendritic cell surface markers in individual sporadic ALS (sALS), familial ALS (fALS), and nonneurological disease control (NNDC) spinal cord tissues using semiquantitative and real-time reverse transcription polymerase chain reaction (RT-PCR). Immature (DEC205, CD1a) and activated/mature (CD83, CD40) dendritic cell transcripts were significantly elevated in ALS tissues. The presence of immature and activated/mature dendritic cells (CD1a(+) and CD83(+)) was confirmed immunohistochemically in ALS ventral horn and corticospinal tracts. Monocytic/macrophage/microglial transcripts (CD14, CD18, SR-A, CD68) were increased in ALS spinal cord, and activated CD68(+) cells were demonstrated in close proximity to motor neurons. mRNA expressions of the chemokine MCP-1, which attracts monocytes and myeloid dendritic cells, and of the cytokine macrophage-colony stimulating factor (M-CSF) were increased in ALS tissues. The MCP-1 protein was expressed in glia in ALS but not in control tissues and was increased in the CSF of ALS patients. Those patients who progressed most rapidly expressed significantly more dendritic transcripts than patients who progressed more slowly. These results support the involvement of immune/inflammatory responses in amplifying motor neuron degeneration in ALS.

Purpose of Review: Amyotrophic lateral sclerosis, or Lou Gehrig disease, is a progressive neurodegenerative disease of adult onset characterized by a loss of motor neurons in the spinal cord and motor cortex. In the last several years, substantial progress has been made in defining the pathogenesis of motor neuron injury and relationships between disease mechanisms and the selective vulnerability of the motor neuron in both familial and sporadic forms of amyotrophic lateral sclerosis., Recent Findings: Current theories have shifted from a neuron-centered pathology to a focus on the interaction between motor neurons and glia, and their respective contributions to pathways implicated in amyotrophic lateral sclerosis. Although multiple mechanisms clearly can contribute to the pathogenesis of motor neuron injury, recent advances suggest that oxidative stress may play a significant role in the amplification, and possibly the initiation, of disease., Summary: This article reviews the clinical aspects of amyotrophic lateral sclerosis and potential mechanisms of disease pathogenesis in the context of recent data supporting a major role for oxidative stress throughout the disease course. Evidence suggesting an important role for intercellular signaling is emphasized.

The evidence for increased oxidative stress and DNA damage in amyotrophic lateral sclerosis (ALS) prompted studies to determine if the expression of poly(ADP-ribose) polymerase (PARP) is increased in ALS. Using Western analyses of postmortem tissue, we demonstrated that PARP-immunoreactivity (PARP-IR) was increased 3-fold in spinal cord tissues of sporadic ALS (sALS) patients compared with non-neurological disease controls. Despite the increased PARP-IR, PARP mRNA expression was not increased significantly. Immunohistochemical analyses revealed PARP-IR was increased in both white and gray matter of sALS spinal cord. While PARP-IR was predominantly seen in astrocytes, large motor neurons displayed reduced staining compared with controls. This result contrasts sharply to the staining of Alzheimer and MPTP-induced Parkinson diseased tissue, where poly(ADP-ribose) (PAR)-IR was seen mostly in neurons, with little astrocytic staining. PARP-IR was increased in the pellet fraction of sALS homogenates compared with control homogenates, representing potential PARP binding to chromatin or membranes and suggesting a possible mechanism of PARP stabilization. The present results demonstrate glial alterations in sALS spinal cord tissue and support the role of glial alterations in sALS pathogenesis. Additionally, these results demonstrate differences in sALS spinal motor neurons and astrocytes compared to brain neurons and astrocytes in Alzheimer disease and MPTP-induced Parkinson disease despite the presence of markers for oxidative stress in all 3 diseases.

Varicella-zoster virus infection has been implicated in a broad range of neurologic complications. In Hispanic immigrants, primary varicella often appears in adolescents and young adults. We describe the case of a 20-year-old Hispanic man with vasculitis and stroke after primary varicella infection. An association between varicella infection and vasculitis is increasingly being described and should be considered in the evaluation of stroke in young adults.