Elevated Mood States in Patients With Parkinson's Disease Treated With Deep Brain Stimulation: Diagnosis and Management Strategies.

OBJECTIVE: Deep brain stimulation (DBS) is an effective surgical treatment for patients with Parkinson's disease (PD). DBS therapy, particularly with the subthalamic nucleus (STN) target, has been linked to rare psychiatric complications, including depression, impulsivity, irritability, and suicidality. Stimulation-induced elevated mood states can also occur. These episodes rarely meet DSM-5 criteria for mania or hypomania. METHODS: The investigators conducted a chart review of 82 patients with PD treated with DBS. RESULTS: Nine (11%) patients developed stimulation-induced elevated mood. Five illustrative cases are described (all males with STN DBS; mean age=62.2 years [SD=10.5], mean PD duration=8.6 years [SD=1.6]). Elevated mood states occurred during or shortly after programming changes, when more ventral contacts were used (typically in monopolar mode) and lasted minutes to months. Four patients experienced elevated mood at low amplitudes (1.0 V/1.0 mA); all had psychiatric risk factors (history of impulse-control disorder, dopamine dysregulation syndrome, substance use disorder, and/or bipolar diathesis) that likely contributed to mood destabilization. CONCLUSIONS: Preoperative DBS evaluations should include a thorough assessment of psychiatric risk factors. The term "stimulation-induced elevated mood states" is proposed to describe episodes of elevated, expansive, or irritable mood and psychomotor agitation that occur during or shortly after DBS programming changes and may be associated with increased goal-directed activity, impulsivity, grandiosity, pressured speech, flight of ideas, or decreased need for sleep and may persist beyond stimulation adjustments. This clinical phenomenon should be considered for inclusion in the bipolar disorder category in future DSM revisions, allowing for increased recognition and appropriate management.

Cytokines in uveitis.

PURPOSE OF REVIEW: Increasing evidence supports Th17 cells as key mediators of ocular inflammatory disease. Cytokines that are important for the development and pathologic function of these cells are potential therapeutic targets in patients with immune mediated uveitis. This review provides an overview of these cytokines including recent insights about their roles in ocular inflammation from laboratory and clinical studies. RECENT FINDINGS: Interleukin (IL)-6, IL-10, IL-17, IL-22, IL-23 and tumour necrosis factor-alpha (TNFα) are cytokines that have been examined for their functional role in uveitis and their relationship to pathologic Th17 cells. Studies in animal models, particularly in experimental autoimmune uveitis (EAU), have been instrumental in studying the role of these cytokines in disease pathogenesis. More recently, studies on aqueous, vitreous and serum from patients with uveitis using flow cytometry and multiplex ELISA bead-based methodologies have provided insights into the contribution of Th17 cells and the related cytokines in ocular inflammatory diseases. The central role of IL-23 in determining the pathologic Th17 fate has made it an effective therapeutic target in systemic diseases such as psoriasis and thereby an attractive potential target for patients with immune-mediated uveitis. SUMMARY: Th17 cells, and their related cytokines, are important inflammatory mediators in autoimmune uveitis. Animal and human studies continue to provide new information to direct development of new cytokine-targeted therapies for patients with uveitis.

Nanoparticle-mediated signaling endosome localization regulates growth cone motility and neurite growth.

Understanding neurite growth regulation remains a seminal problem in neurobiology. During development and regeneration, neurite growth is modulated by neurotrophin-activated signaling endosomes that transmit regulatory signals between soma and growth cones. After injury, delivering neurotrophic therapeutics to injured neurons is limited by our understanding of how signaling endosome localization in the growth cone affects neurite growth. Nanobiotechnology is providing new tools to answer previously inaccessible questions. Here, we show superparamagnetic nanoparticles (MNPs) functionalized with TrkB agonist antibodies are endocytosed into signaling endosomes by primary neurons that activate TrkB-dependent signaling, gene expression and promote neurite growth. These MNP signaling endosomes are trafficked into nascent and existing neurites and transported between somas and growth cones in vitro and in vivo. Manipulating MNP-signaling endosomes by a focal magnetic field alters growth cone motility and halts neurite growth in both peripheral and central nervous system neurons, demonstrating signaling endosome localization in the growth cone regulates motility and neurite growth. These data suggest functionalized MNPs may be used as a platform to study subcellular organelle localization and to deliver nanotherapeutics to treat injury or disease in the central nervous system.

Ocular surface neoplasias and human immunodeficiency virus infection.

PURPOSE OF REVIEW: Ocular surface malignancy is a serious complication in HIV infection, but can often result in successful treatment if diagnosed appropriately. In the literature, most reviews focus on information for the ophthalmic community. Here, we provide a review of the literature with the pertinent information for the nonophthalmologist, as they are the first point of contact for most HIV patients. RECENT FINDINGS: Ocular surface squamous neoplasia (OSSN) is the most common nonpigmented ocular surface malignancy. It can be treated well with surgery or topical chemotherapy, the newest method of treatment. When presenting in young patients, a high percentage have been found to be HIV positive. Kaposi's sarcoma is an AIDS-defining malignancy and critical to diagnose. It cannot be cured, but treatment is effective for keeping it controlled. Conjunctival lymphoma can be recognized with the salmon patch appearance. External beam radiation, systemic chemotherapy, and intralesional injections are the mainstays of treatment. SUMMARY: Ocular surface malignancy manifests significantly in the HIV population. OSSN, Kaposi's sarcoma and conjuctival lymphoma all have different clinical presentations. The capacity of the managing physician to recognize these tumours and refer to an ophthalmologist is essential for appropriate treatment.

PARACENTRAL ACUTE MIDDLE MACULOPATHY AND OCULAR ISCHEMIC SYNDROME AFTER INTRANASAL STEROID INJECTION: A CASE REPORT AND REVIEW OF THE LITERATURE.

PURPOSE: To describe a case of paracentral acute middle maculopathy and ocular ischemic syndrome after intranasal steroid injection. METHODS: Case report. RESULTS: Following an intranasal steroid injection, the patient experienced an episode of amaurosis fugax in her right eye lasting several minutes. Afterward, her visual acuity returned to baseline, but she noted a persistent central scotoma. Optical coherence tomography demonstrated paracentral acute middle maculopathy and fluorescein angiography showed staining and leakage to peripheral vessels concerning for diffuse ischemia. CONCLUSION: Steroid injections to the face and nasopharynx may result in ischemic and vaso-occlusive events in the retina. Ophthalmologists and other physicians performing these procedures need to be aware of this potential adverse outcome.

ENDOPHTHALMITIS PRESENTING AS RETINAL VASCULITIS LESS THAN 24 HOURS AFTER AFLIBERCEPT INJECTION: A CASE REPORT.

PURPOSE: We describe a case of endophthalmitis caused by Streptococcus salivarius presenting as a retinal vasculitis less than 24 hours after intravitreal injection. METHODS: A case report. RESULTS: The patient progressed from a hemorrhagic retinal vasculitis to severe endophthalmitis with no view to the posterior segment within 24 hours. The visual acuity progressed from 20 of 20 preinjection to light perception within less than 48 after injection. Vitreous tap and injection was performed within 24 hours of intravitreal aflibercept injection, followed by pars plana vitrectomy the next day. The final visual acuity was hand motions. CONCLUSION: Streptococcus salivarius is a virulent organism that may cause an endophthalmitis early after intravitreal injection with an unusual presentation of hemorrhagic retinal vasculitis. A high index of suspicion for infectious endophthalmitis should be maintained for all patients presenting with ocular inflammation and worsening vision in the days after intravitreal injections.

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts.

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Swept source OCTA reveals a link between choriocapillaris blood flow and vision loss in a case of tubercular serpiginous-like choroiditis.

Optical coherence tomography angiography (OCTA) is a non-invasive technique that is useful in the diagnosis and management of patients with posterior uveitis. Here we report the use of swept source OCTA (SS-OCTA) in a patient with tuberculosis (TB) associated serpiginous like choroiditis (TB-SLC) that made a full visual recovery following treatment with ATT, local and systemic corticosteroids, and systemic immune modulation. By comparing en face images of choriocapillaris (CC) blood flow before and after treatment, we conclude that the patient's visual recovery was associated with resolution of extensive CC flow deficits. This case highlights the utility of SS-OCTA in the multimodal evaluation of patients with choroidal inflammation, and the potential for good visual recovery in patients treated for TB-SLC.

Vitreous and Chorioretinal Lesions in People Who Inject Drugs and Are Hospitalized with Bloodstream and Related Infections.

PURPOSE: To determine the prevalence of and to characterize vitreous and chorioretinal lesions, to identify causative organisms, and to correlate symptoms with ophthalmic involvement in people who inject drugs and are hospitalized with bloodstream infection (BSI), related metastatic foci of infection (MFI), or both. DESIGN: An academic hospital-based cross-sectional study. PARTICIPANTS: Patients admitted with BSI or MFI related to injection drug use (IDU). METHODS: Patients underwent a complete eye examination within 72 hours of enrollment. Characteristics including gender; age; race; injection drug of choice (DOC); presence of coinfection with hepatitis B, hepatitis C, or human immunodeficiency virus; pathogen causing systemic infection and type of infection; and history of prior infection related to IDU were recorded. MAIN OUTCOME MEASURES: Presence of vitreous or chorioretinal findings, or both. RESULTS: Ninety-one unique patients with 96 separate hospitalizations for systemic infection were enrolled from March 28, 2018, through March 30, 2020. Vitreous or chorioretinal involvement was identified in 16 of 96 patients (16.7%). The most common ocular findings were intraretinal or white-centered hemorrhage in 9 of 96 patients, chorioretinal infiltrate in 8 of 96 patients, endophthalmitis in 5 of 96 patients, and cotton wool spots in 3 of 96 patients. Of the patients with ocular involvement, only 7 of 16 patients (44%) were symptomatic, and 5 of these were patients with endophthalmitis; the others showed chorioretinal infiltrates or intraretinal or white-centered hemorrhage and cotton wool spots. Staphylococcus aureus was the most common causative pathogen in patients with and without ocular findings. Presence of ocular symptoms, worse visual acuity, and injection DOC of methamphetamine were correlated with the presence of ocular findings. CONCLUSIONS: Patients without ocular symptoms with systemic infections related to IDU may have chorioretinal findings. Further study is needed to characterize better the epidemiologic features of these infections and to identify risk factors for ocular involvement in people who inject drugs.

Predicting the risk of hyperkalemia in patients with chronic kidney disease starting lisinopril.

PURPOSE: Angiotensin-converting enzyme (ACE) inhibitors are recommended for patients with chronic kidney disease (CKD) because they slow disease progression. But physicians' concerns about the risk of hyperkalemia (elevated serum potassium level), a potentially fatal adverse effect, may limit optimal management with ACE-inhibitors. We synthesized known predictors of hyperkalemia into a prognostic risk score to predict the risk of hyperkalemia. METHODS: We assembled a retrospective cohort of adult patients with possible CKD (at least one estimated glomerular filtration rate (eGFR) value less than 60 ml/min/1.73 m(2)) who started an ACE-inhibitor (i.e., incident users) between 1998 and 2006 at a health maintenance organization. We followed patients for hyperkalemia: (1) potassium value >5.5 mmol/L; or (2) diagnosis code for hyperkalemia. Cox regression synthesized a priori predictors recorded in the electronic medical record into a risk score. RESULTS: We followed 5171 patients and 145 experienced hyperkalemia, a 90-day risk of 2.8%. Predictors included: age, eGFR, diabetes, heart failure, potassium supplements, potassium-sparing diuretics, and a high dose for the ACE-inhibitor (lisinopril). The risk score separated high-risk patients (top quintile, observed risk of 6.9%) from low-risk patients (bottom quintile, observed risk of 0.7%). Predicted and observed risks agreed within 1% for each quintile. The risk increased gradually in relation to declining eGFR with no apparent threshold for contraindicating ACE-inhibitors. CONCLUSIONS: The risk score separated high-risk patients (who may need more intensive laboratory monitoring) from low-risk patients. The risk score should be validated in other populations before it is ready for use in clinical practice.

Endogenous Exophiala dermatitidis endophthalmitis.

PURPOSE: To report a case of endogenous Exophiala dermatitidis endophthalmitis. OBSERVATIONS: An immunosuppressed patient with a history of hairy cell leukemia undergoing chemotherapy presents with rapidly progressing panophthalmitis. The patient was treated medically without improvement and underwent a pars plana vitrectomy which showed multiple retinal abscesses. Vitreous fluid cultures grew a rare fungal organism, Exophiala dermatitidis. CONCLUSIONS AND IMPORTANCE: This is the first reported case of E. dermatitidis causing endogenous endophthalmitis. Rare fungal organisms can present with rapid progression to panophthalmitis in immunocompromised hosts.

Quantitative Analysis of the Choriocapillaris in Uveitis Using En Face Swept-Source Optical Coherence Tomography Angiography.

PURPOSE: To perform a quantitative analysis of choriocapillaris (CC) flow deficits (FDs) in patients with uveitis. DESIGN: Retrospective cross-sectional study. METHODS: Swept-source optical coherence tomography based angiography (SS-OCTA) macular volume scans (3 × 3 mm and 6 × 6 mm) were obtained using the Plex Elite 9000. En face CC images were generated and analyzed using an automated FD identification algorithm. Three quantitative metrics were determined for each eye: FD number (FDN), mean FD size (MFDS), and FD density (FDD). Quantitative metrics were compared between uveitis and control eyes. The uveitis cohort was further subdivided by the presence or absence of choroidal involvement, and quantitative metrics were compared between subgroups and normal control subjects. RESULTS: A total of 38 eyes from 38 control subjects and 73 eyes from 73 uveitis subjects were included in this study. Eyes with uveitis have significantly larger CC MFDS (3- × 3-mm scans; P < .0001; 6- × 6-mm scans; P < .0001) and higher FDD (P = .0002; P = .0076, respectively) compared to control eyes. Additional analysis determined that these differences were due to the choroidal disease subgroup, which demonstrates significantly larger MFDS (3 × 3 = 1,108 µm2; 6 × 6 = 1,104 µm2) compared to both normal control eyes (752 µm2; P < .0001; 802 µm2; P < .0001, respectively) and uveitis patients without choroidal involvement (785 µm2; P < .0001; 821 µm2; P < .0001, respectively). No significant differences were found between the quantitative metrics of control subjects and patients without choroidal involvement. CONCLUSIONS: Automated quantification of CC can identify pathological FDs and provide quantitative metrics describing such lesions in patients with uveitis. Posterior uveitis patients have significantly larger CC FDs than patients with other forms of uveitis.

Use of En Face Swept-Source Optical Coherence Tomography Angiography in Identifying Choroidal Flow Voids in 3 Patients With Birdshot Chorioretinopathy.

Importance: Patients with birdshot chorioretinopathy (BSCR) can experience a delay in diagnosis owing to the challenges of identifying the condition prior to evolution of characteristic choroidal scars. An objective, noninvasive method for detecting early lesions in BSCR might have an effect on preventing vision loss in these patients. Objective: To test the feasibility of swept-source optical coherence tomography angiography (SS-OCTA) in the detection of BSCR choroidal lesions and to use en face image analysis of choroidal layers to localize lesion depth. Design, Setting, and Participants: Prospective, longitudinal, observational case series of 3 patients diagnosed as having BSCR at 1 of 2 tertiary care uveitis centers between August 2017 and October 2017. Exposures: Widefield SS-OCTA and indocyanine green angiography (ICGA). Main Outcomes and Measures: En face SS-OCTA slabs through the choroid were evaluated for the presence of flow voids corresponding to hypocyanescent lesions by ICGA. Baseline and posttreatment images were compared. Results: Six eyes of 3 patients with previously undiagnosed and untreated BSCR were imaged at baseline and after initiation of immune modulation treatment. Two patients had a history of recent-onset BSCR, and the third patient had a history of chronic untreated disease of at least 5 years' duration. All patients were white and between the ages of 50 and 67 years. All eyes demonstrated multiple flow voids on en face SS-OCTA images that corresponded with hypocyanescent lesions by ICGA. Analysis of serial depth en face SS-OCTA flow images identified that in the acute-onset patients, flow voids were located adjacent to large vessels in the Haller layer and regressed with treatment. In the patient with chronic, untreated disease, full-thickness choroidal flow voids were identified that did not regress with treatment. Conclusions and Relevance: For these 3 patients, SS-OCTA provided a noninvasive method for identifying early BSCR lesions previously visible only with ICGA. The depth information provided by SS-OCTA suggests acute lesions originate in the Haller layer, and that in the absence of treatment, damage extends up thorough the superficial choroid, and ultimately to the retinal pigment epithelium and retina. Swept-source OCTA may represent a new and noninvasive method for detecting and monitoring disease activity in BSCR.

Platelet-Activating Factor (PAF) Receptor Antagonism Modulates Inflammatory Signaling in Experimental Uveitis.

BACKGROUND: The phospholipid mediator platelet-activating factor (PAF) activates an inflammatory response that includes arachidonic acid release and prostaglandin production in the eye, increasing vascular permeability and inflammation. The purpose of this study is to investigate the action of LAU-0901, a novel PAF receptor antagonist, on experimental uveitis. METHODS: Uveitis was induced in Lewis rats by lipopolysaccharide treatment. LAU-0901 was then delivered systemically in different concentrations at plus 4 and 16 hours, or vehicle injected as controls. Additional animals were used for histological analyses of untreated, uveitis, and uveitis-plus-LAU-0901 retinas. Conventional histological and immunohistochemical methods were employed. A slit lamp and Spectral Domain-Ocular Coherence Tomography (SD-OCT) retinal imager was used for anterior segment photography and posterior pole OCT. Rats were euthanized 4 hours after the second LAU-0901 injection in this 24-hour model. Aqueous humor was collected and quantified, and also analyzed for tumor necrosis factor alpha (TNF-α). RESULTS: Uveitic eyes demonstrated hypopyon formation, leukocyte infiltration, and an increase in aqueous protein and TNF-α levels. LAU-0901 treatment resulted in a dose-dependent reduction in inflammation, reflected by reduced total protein levels (up to a 64% reduction). Moreover, hypopyon was prevented, leukocytes were absent in vitreous and aqueous humor, and TNF-α levels were reduced by 91%. CONCLUSIONS: The PAF receptor antagonist LAU-0901 decreases ocular inflammation in a rat model of anterior uveitis in a dose-dependent manner, suggesting that use of this molecule may provide a means to attenuate inflammation onset and offer a future alternative or adjunctive treatment for ocular inflammation.

Multimodal imaging evidence of pathology-mediated disease distribution in corticobasal syndrome.

OBJECTIVE: To use multimodal neuroimaging to evaluate the influence of heterogeneous underlying pathology in corticobasal syndrome (CBS) on the neuroanatomical distribution of disease. METHODS: We performed a retrospective evaluation of 35 patients with CBS with T1-weighted MRI, diffusion tensor imaging, and neuropathologic, genetic, or CSF evidence of underlying pathology. Patients were assigned to 2 groups: those with evidence of Alzheimer pathology (CBS-AD) and those without Alzheimer pathology (CBS-non-AD). Group comparisons of CBS-AD and CBS-non-AD assessed clinical features, gray matter (GM) cortical thickness, and white matter (WM) fractional anisotropy. RESULTS: CBS-AD was found in 34% (n = 12) and CBS-non-AD in 66% (n = 23) of CBS patients. Clinical evaluations revealed that CBS-non-AD had a higher frequency of asymmetric rigidity compared to CBS-AD, but groups otherwise did not differ in dementia severity, impairments in cognition, or rates of extrapyramidal symptoms. We found frontoparietal GM and WM disease in each group compared to healthy, demographically comparable controls, as well as multimodal neuroimaging evidence of a double dissociation: CBS-non-AD had WM disease in the corpus callosum, corticospinal tract, and superior longitudinal fasciculus relative to CBS-AD, and CBS-AD had reduced temporoparietal GM relative to CBS-non-AD, including the precuneus and posterior cingulate. CONCLUSIONS: Patients with CBS have a pathology-mediated dissociation of GM and WM disease. Multimodality neuroimaging may be useful for improving in vivo pathologic diagnosis of CBS.

Comparative Effectiveness of Statin Therapy in Chronic Kidney Disease and Acute Myocardial Infarction: A Retrospective Cohort Study.

BACKGROUND: Whether there is a kidney function threshold to statin effectiveness in patients with acute myocardial infarction is poorly understood. Our study sought to help fill this gap in clinical knowledge. METHODS: We undertook a new-user cohort study of the effectiveness of statin therapy by level of estimated glomerular filtration rate (eGFR) in adults who were hospitalized for myocardial infarction between 2000 and 2008. Data came from the Cardiovascular Research Network. The primary clinical outcomes were 1-year all-cause mortality and cardiovascular hospitalizations, with adverse outcomes of myopathy and development of diabetes mellitus. We calculated incidence rates, the number needed to treat, and used Cox proportional hazards regression with propensity score matching and adjustment to control for confounding, with testing for variation of effect by level of kidney function. RESULTS: Compared with statin non-initiators (n = 5583), statin initiators (n = 5597) had a lower propensity score-adjusted risk for death (hazard ratio 0.79; 95% confidence interval [CI], 0.71-0.88) and cardiovascular hospitalizations (hazard ratio 0.90; 95% CI, 0.82-1.00). We found little evidence of variation in effect by level of eGFR (P = .86 for death; P = .77 for cardiovascular hospitalization). Adverse outcomes were similar for statin initiators and statin non-initiators. The number needed to treat to prevent 1 additional death over 1 year of follow-up ranged from 15 (95% CI, 11-28) for eGFR <30 mL/min/1.73 m(2) requiring statin treatment over 2 years to prevent 1 additional death, to 67 (95% CI, 49-118) for patients with eGFR >90 mL/min/1.73 m(2). CONCLUSIONS: Our findings suggest that there is potential for important public health gains by increasing the routine use of statin therapy for patients with lower levels of kidney function.

Regulation of intrinsic axon growth ability at retinal ganglion cell growth cones.

PURPOSE: Mammalian central nervous system neurons fail to regenerate after injury or disease, in part due to a progressive loss in intrinsic axon growth ability after birth. Whether lost axon growth ability is due to limited growth resources or to changes in the axonal growth cone is unknown. METHODS: Static and time-lapse images of purified retinal ganglion cells (RGCs) were analyzed for axon growth rate and growth cone morphology and dynamics without treatment and after manipulating Kruppel-like transcription factor (KLF) expression or applying mechanical tension. RESULTS: Retinal ganglion cells undergo a developmental switch in growth cone dynamics that mirrors the decline in postnatal axon growth rates, with increased filopodial adhesion and decreased lamellar protrusion area in postnatal axonal growth cones. Moreover, expressing growth-suppressive KLF4 or growth-enhancing KLF6 transcription factors elicits similar changes in postnatal growth cones that correlate with axon growth rates. Postnatal RGC axon growth rate is not limited by an inability to achieve axon growth rates similar to embryonic RGCs; indeed, postnatal axons support elongation rates up to 100-fold faster than postnatal axonal growth rates. Rather, the intrinsic capacity for rapid axon growth is due to both growth cone pausing and retraction, as well as to a slightly decreased ability to achieve rapid instantaneous rates of forward progression. Finally, we observed that RGC axon and dendrite growth are regulated independently in vitro. CONCLUSIONS: Together, these data support the hypothesis that intrinsic axon growth rate is regulated by an axon-specific growth program that differentially regulates growth cone motility.

Mitochondrial dynamics regulate growth cone motility, guidance, and neurite growth rate in perinatal retinal ganglion cells in vitro.

PURPOSE: Retinal ganglion cell (RGC) death and failed axonal regeneration after trauma or disease, including glaucomatous and mitochondrial optic neuropathies, are linked increasingly to dysfunctional mitochondrial dynamics. However, how mitochondrial dynamics influence axon growth largely is unstudied. We examined intrinsic mitochondrial organization in embryonic and postnatal RGCs and the roles that mitochondrial dynamics have in regulating neurite growth and guidance. METHODS: RGCs were isolated from embryonic day 20 (E20) or postnatal days 5 to 7 (P5-7) Sprague-Dawley rats by anti-Thy1 immunopanning. After JC-1 loading, mitochondria were analyzed in acutely purified RGCs by flow cytometry and in RGC neurites by fluorescence microscopy. Intrinsic axon growth was modulated by overexpressing Krüppel-like family (KLF) transcription factors, or mitochondrial dynamics were altered by inhibiting dynamin related protein-1 (DRP-1) pharmacologically or by overexpressing mitofusin-2 (Mfn-2). Mitochondrial organization, neurite growth, and growth cone motility and guidance were analyzed. RESULTS: Mitochondrial dynamics and function are regulated developmentally in acutely purified RGCs and in nascent RGC neurites. Mitochondrial dynamics are modulated differentially by KLFs that promote or suppress growth. Acutely inhibiting mitochondrial fission reversibly suppressed axon growth and lamellar extension. Inhibiting DRP-1 or overexpressing Mfn-2 altered growth cone responses to chondroitin sulfate proteoglycan, netrin-1, and fibronectin. CONCLUSIONS: These results support the hypothesis that mitochondria locally modulate signaling in the distal neurite and growth cone to affect the direction and the rate of neurite growth.