An Analysis of Retinal Nerve Fiber Layer Thickness before and after Pituitary Adenoma Surgery and its Correlation with Visual Acuity.

INTRODUCTION: Pituitary adenomas comprise approximately 10% of all intracranial tumors. Initially, subtle changes occur in the field of vision, which are difficult to assess clinically. It has been seen that following surgery of pituitary macroadenoma, total recovery of normal vision occurs in 35% of the patients, improvement of vision occurs in 60%, and in the rest there is no change in vision. Retinal nerve fiber layer thickness (RNFLT) undergoes retrograde degeneration following compression of optic apparatus by pituitary tumor. We planned a study to evaluate RNFLT before and after pituitary adenoma surgery and its correlation with visual acuity. MATERIAL AND METHODS: Twenty patients (40 eyes) with diagnosed pituitary adenoma were included in the study. Preoperative visual acuity, fundus and RNFL thickness were calculated using spectral-domain OCT Optovue, Heidelberg Engineering, Heidelberg, Germany (RT 100 version 5.1), and postoperative measurement was done after 1 and 3 months. Four-quadrant mean of RNFLT was calculated. Results were tabulated and analyzed. STATISTICAL ANALYSIS: Results of the study were analyzed using IBM SPSS Statistics version 19.0. RESULTS: There was no significant change in RNFLT after pituitary adenoma surgery, and it was found that patients with RNFLT within normal range preoperatively showed improvement in visual acuity after pituitary surgery. On the other hand, patients who had thinned-out RNFLT preoperatively showed no improvement in visual acuity. It was also found that once optic disc pallor sets due to chronic compression, then chances of its reversion to normal depend on its grading: only mild pallor disc has some chance to revert to normal, whereas moderate and severe pallor do not revert to normal. CONCLUSION: RNFLT and optic disc can be used as prognostic factors for evaluation of visual outcome in pituitary adenoma surgery.

Hypertrophic Olivary Degeneration and Holmes Tremor: Case Report and Review of the Literature.

BACKGROUND: Hypertrophic olivary degeneration (HOD) is very rare type of degeneration that causes hypertrophy rather than atrophy. The classical presentation of HOD is palatal myoclonus. However, HOD may rarely present with Holmes tremor (HT). HT is unusual symptomatic tremor characterized by combination of rest and intention tremor. It has been reported in small case series, so far. CASE DESCRIPTION: In this study, a man aged 62 years with HOD and HT spreading to the upper and lower extremities after pontine-midbrain hemorrhage due to cavernoma was presented. CONCLUSIONS: Although pontine-midbrain hemorrhage may cause HT in the late period, HOD can be revealed on magnetic resonance imaging. Tract anatomy, especially the Guillain-Mollaret triangle, should be considered to explain the relationship between HT and HOD.

Survival of retinal ganglion cells after damage to the occipital lobe in humans is activity dependent.

Damage to the optic radiations or primary visual cortex leads to blindness in all or part of the contralesional visual field. Such damage disconnects the retina from its downstream targets and, over time, leads to trans-synaptic retrograde degeneration of retinal ganglion cells. To date, visual ability is the only predictor of retinal ganglion cell degeneration that has been investigated after geniculostriate damage. Given prior findings that some patients have preserved visual cortex activity for stimuli presented in their blind field, we tested whether that activity explains variability in retinal ganglion cell degeneration over and above visual ability. We prospectively studied 15 patients (four females, mean age = 63.7 years) with homonymous visual field defects secondary to stroke, 10 of whom were tested within the first two months after stroke. Each patient completed automated Humphrey visual field testing, retinotopic mapping with functional magnetic resonance imaging, and spectral-domain optical coherence tomography of the macula. There was a positive relation between ganglion cell complex (GCC) thickness in the blind field and early visual cortex activity for stimuli presented in the blind field. Furthermore, residual visual cortex activity for stimuli presented in the blind field soon after the stroke predicted the degree of retinal GCC thinning six months later. These findings indicate that retinal ganglion cell survival after ischaemic damage to the geniculostriate pathway is activity dependent.

[Traumatic homonymous hemianopsia and ganglion cell complex changes: Report of 3 cases]. / Hémianopsie latérale homonyme post-traumatique et atteinte des cellules ganglionnaires : à propos de 3 cas.

Homonymous lateral hemianopia follows an attack on the contralateral retrochiasmal visual pathways. In three patients with post-traumatic homonymous hemianopia, optical coherence tomographic (OCT) study of the ganglion cell layer thickness showed hemiretinal thinning contralateral to the visual field defect. This involvement could be explained by trans-synaptic degeneration of the pre-geniculate visual pathways, whose cell nuclei correspond to ganglion cells, which synapse with the damaged retrogeniculate visual pathways.

Retinal Alteration Associated with an Arachnoid Cyst of the Pineal Region.

BACKGROUND: Retinal optical coherence tomography (OCT) is a noninvasive high-resolution imaging technique, which is considered a biomarker of neurodegeneration. Several intracranial lesions can induce retrograde neurodegeneration which can be assessed using OCT. The cysts of the pineal region are usually asymptomatic and most often are an incidental radiologic finding. CASE DESCRIPTION: We describe the case of a 50-year-old woman with an arachnoid cyst of the pineal region who complained of visual symptoms for 3 months. Bilateral macular thinning was demonstrated by OCT both on the preoperative and postoperative examinations, without any other clinical findings that could explain the results. CONCLUSIONS: We suggest that the retinal alteration is caused by retrograde neurodegeneration secondary to the pineal region mass.

[Structural retinal and optic nerve changes in patients with post-geniculate visual pathway damage]. / Strukturnye izmeneniia setchatki i zritel'nogo nerva pri porazhenii tsentral'nogo nevrona zritel'nogo puti.

AIM: To establish the possibility of retrograde trans-synaptic neural degeneration following acquired post-geniculate visual pathway damage. MATERIAL AND METHODS: Twenty-two patients with homonymous hemianopia caused by acquired post-geniculate visual pathway damage were examined. Peripapillary retinal nerve fiber layer (RNFL) thickness and ganglion cell complex (GCC) measurements were assessed with RTVue-100 Fourier-domain optical coherence tomography (OCT). RESULTS: In 12 out of 22 patients we detected binocular GCC thinning that was ipsilateral to post-geniculate involvement. Nine patients showed a decrease in the RNFL thickness. However, topographic correspondence between the post-geniculate lesion and RNFL thickness was established for 2 of them only. GCC thinning was more common in patients with hemianopsia acquired more than 6 months ago (p<0.0009). CONCLUSION: Having assessed the ganglion cell complex and retinal nerve fiber layer with OCT, we have proved possible that trans-synaptic retrograde degeneration develops in patients with post-geniculate visual pathway damage.

Trans-synaptic degeneration of motoneurons distal to chronic cervical spinal cord compression in cervical spondylotic myelopathy.

OBJECTIVE: To assess the effect of chronic cervical spinal cord compression upon remote motor unit function in patients with cervical spondylotic myelopathy (CSM). METHODS: Fifty-three CSM patients and 47 healthy subjects were included. Bilateral motor unit number estimations (MUNEs) were recorded from both abductor digiti minimi and abductor pollicis brevis, and bilateral flexor carpi radialis (FCR) H-reflexes were examined in all subjects along with the nine-hole peg test (NHPT). The main outcome measures included the number of motor units, the average single motor unit potential (SMUP) area, the FCR Hmax/Mmax ratios and the NHPT time. RESULTS: Statistically significant results compared to healthy controls included increased average SMUP area, increased FCR Hmax/Mmax ratio and increased NHPT time (p < 0.05). Abnormal SMUP was observed in 10/53 (18.9%) CSM patients along with reduced motor units in 3 of these 10 patients, while the FCR Hmax/Mmax ratios in the CSM patients with abnormal MUNE were higher than those in others (p < 0.05). There was a positive correlation between the NHPT time and the average SMUP area, and a negative correlation was noted between the NHPT time and the number of motor units (p < 0.05). CONCLUSION: In CSM patients, the motor units below the level of compression may exhibit dysfunction, which is likely a result of trans-synaptic degeneration. Both cervical spinal cord compressive injury and this trans-synaptic degeneration contribute to the impairment of fine motor ability in CSM patients. Therefore, treatment and rehabilitation efforts should account for these two dysfunctions.

Retrograde Degeneration of Retinal Ganglion Cells Secondary to Head Trauma.

PURPOSE: To discuss the clinical case of a patient with transsynaptic retrograde degeneration (TRD) demonstrated by progressive retinal nerve fiber layer loss documented by serial spectral domain optical coherence tomography secondary to traumatic brain injury after 2 months post-trauma. CASE REPORT: A 25-year-old Caucasian male patient presented to a polytrauma rehabilitation center (PRC) for evaluation and treatment secondary to a severe traumatic brain injury (TBI) from a motorcycle accident 2 months before. Spectral-domain optical coherence tomography (SD-OCT) was completed at intervals that ranged between 8 and 42 days for a duration of 119 days. A comparison to the pre-trauma SD-OCT 10 months before revealed progressive thinning of the retinal nerve fiber layer (RNFL) in both eyes over multiple follow-ups post-trauma. Humphrey visual field (HVF) testing revealed an incomplete congruous right homonymous hemianopsia that gradually improved over the follow-ups. Analysis of the macular ganglion cell-inner plexiform layer (GCIPL) thickness displayed loss that corresponded to the pattern of visual field defect. CONCLUSIONS: TRD can occur as soon as 2 months after severe TBI with damage posterior to the lateral geniculate nucleus. Progressive RNFL loss can be tracked with SD-OCT, and the rate of thinning may slowly stabilize over time. Visual field defects can improve months after the trauma but may not correspond to the progressive RNFL loss detected by SD-OCT.

Longitudinal evidence for anterograde trans-synaptic degeneration after optic neuritis.

In multiple sclerosis, microstructural damage of normal-appearing brain tissue is an important feature of its pathology. Understanding these mechanisms is vital to help develop neuroprotective strategies. The visual pathway is a key model to study mechanisms of damage and recovery in demyelination. Anterograde trans-synaptic degeneration across the lateral geniculate nuclei has been suggested as a mechanism of tissue damage to explain optic radiation abnormalities seen in association with demyelinating disease and optic neuritis, although evidence for this has relied solely on cross-sectional studies. We therefore aimed to assess: (i) longitudinal changes in the diffusion properties of optic radiations after optic neuritis suggesting trans-synaptic degeneration; (ii) the predictive value of early optic nerve magnetic resonance imaging measures for late optic radiations changes; and (iii) the impact on visual outcome of both optic nerve and brain post-optic neuritis changes. Twenty-eight consecutive patients with acute optic neuritis and eight healthy controls were assessed visually (logMAR, colour vision, and Sloan 1.25%, 5%, 25%) and by magnetic resonance imaging, at baseline, 3, 6, and 12 months. Magnetic resonance imaging sequences performed (and metrics obtained) were: (i) optic nerve fluid-attenuated inversion-recovery (optic nerve cross-sectional area); (ii) optic nerve proton density fast spin-echo (optic nerve proton density-lesion length); (iii) optic nerve post-gadolinium T1-weighted (Gd-enhanced lesion length); and (iv) brain diffusion-weighted imaging (to derive optic radiation fractional anisotropy, radial diffusivity, and axial diffusivity). Mixed-effects and multivariate regression models were performed, adjusting for age, gender, and optic radiation lesion load. These identified changes over time and associations between early optic nerve measures and 1-year global optic radiation/clinical measures. The fractional anisotropy in patients' optic radiations decreased (P = 0.018) and radial diffusivity increased (P = 0.002) over 1 year following optic neuritis, whereas optic radiation measures were unchanged in controls. Also, smaller cross-sectional areas of affected optic nerves at 3 months post-optic neuritis predicted lower fractional anisotropy and higher radial diffusivity at 1 year (P = 0.007) in the optic radiations, whereas none of the inflammatory measures of the optic nerve predicted changes in optic radiations. Finally, greater Gd-enhanced lesion length at baseline and greater optic nerve proton density-lesion length at 1 year were associated with worse visual function at 1 year (P = 0.034 for both). Neither the cross-sectional area of the affected optic nerve after optic neuritis nor the damage in optic radiations was associated with 1-year visual outcome. Our longitudinal study shows that, after optic neuritis, there is progressive damage to the optic radiations, greater in patients with early residual optic nerve atrophy, even after adjusting for optic radiation lesions. These findings provide evidence for trans-synaptic degeneration.

Wallerian and trans-synaptic degeneration contribute to optic radiation damage in multiple sclerosis: a diffusion tensor MRI study.

BACKGROUND: Optic radiation (OR) damage occurs in multiple sclerosis (MS). OBJECTIVES: The purpose of this study was to explore the contribution of local and distant mechanisms associated with OR damage in MS. METHODS: Diffusion tensor (DT) magnetic resonance imaging (MRI) tractography probability maps of the ORs were derived from 102 MS patients and 11 controls. Between-group differences of OR normal-appearing white matter (NAWM) damage and topographical distribution of OR damage were assessed using quantitative and voxel-wise analyses, considering the influence of previous optic neuritis (ON+) and T2 OR lesions (T2 OR+). RESULTS: OR NAWM diffusivity abnormalities were more severe in ON+ patients vs patients without previous optic neuritis (ON-) and T2 OR+ vs T2 OR- patients. Damage to the anterior portions of the ORs was more severe in ON+ vs ON- patients. Compared to controls and T2 OR- patients, T2 OR+ patients experienced a more distributed pattern of DT MRI abnormalities along the ORs, with an increased axial diffusivity limited to the anterior portions of the ORs. In T2 OR+ group, ON+ vs ON- patients showed DT MRI abnormalities in the middle portion of the ORs, in correspondence with focal lesions. OR damage correlated with OR T2 lesion volume, visual dysfunction and optic nerve atrophy. CONCLUSIONS: Both trans-synaptic degeneration secondary to optic nerve damage and Wallerian degeneration due to local T2 lesions contribute to OR damage in MS.

Retrograde and Wallerian axonal degeneration occur synchronously after retinal ganglion cell axotomy.

Axonal injury and degeneration are pivotal pathological events in diseases of the nervous system. In the past decade, it has been recognized that the process of axonal degeneration is distinct from somal degeneration and that axoprotective strategies may be distinct from those that protect the soma. Preserving the cell body via neuroprotection cannot improve function if the axon is damaged, because the soma is still disconnected from its target. Therefore, understanding the mechanisms of axonal degeneration is critical for developing new therapeutic interventions for axonal disease treatment. We combined in vivo imaging with a multilaser confocal scanning laser ophthalmoscope and in vivo axotomy with a diode-pumped solid-state laser to assess the time course of Wallerian and retrograde degeneration of unmyelinated retinal ganglion cell axons in living rats for 4 weeks after intraretinal axotomy. Laser injury resulted in reproducible axon loss both distal and proximal to the site of injury. Longitudinal polarization-sensitive imaging of axons demonstrated that Wallerian and retrograde degeneration occurred synchronously. Neurofilament immunostaining of retinal whole-mounts confirmed axonal loss and demonstrated sparing of adjacent axons to the axotomy site. In vivo fluorescent imaging of axonal transport and photobleaching of labeled axons demonstrated that the laser axotomy model did not affect adjacent axon function. These results are consistent with a shared mechanism for Wallerian and retrograde degeneration.

Transsynaptic retinal degeneration in optic neuropathies: optical coherence tomography study.

PURPOSE: Recently demonstrated neuronal loss in the inner nuclear layer of the retina in multiple sclerosis (MS) and glaucoma raises the question of a primary (possibly immune-mediated) or secondary (transsynaptic) mechanism of retinal damage in these diseases. In the present study we used optical coherence tomography to investigate retrograde retinal transsynaptic degeneration in patients with long-standing and severe loss of ganglion cells due to optic neuropathy. METHODS: Fifteen eyes of glaucoma patients with visual field defect limited to upper hemifield and 15 eyes of MS patients with previous episode of optic neuritis (ON) and extensive loss of ganglion cells were imaged using spectral-domain optical coherence tomography and compared with two groups of age-matched controls. Combined retinal ganglion cell layer/inner plexiform layer (GCL/IPL) thickness and inner nuclear layer (INL) thickness were analyzed. RESULTS: In the glaucoma group there was a significant (P = 0.0005) reduction of GCL/IPL thickness in the lower (affected) retina compared with normal controls; however INL thickness was not statistically reduced (P = 0.49). In the MS group reduction of GCL/IPL thickness in both hemifields of ON eyes was also significant (P = 0.0001 and P < 0.0001 for inferior and superior retina respectively). However, similar to the glaucomatous eyes, there was no significant reduction of INL thickness in both hemifields (P = 0.25 and P = 0.45). CONCLUSIONS: This study demonstrates no significant loss of INL thickness in parts of the retina with long-standing and severe loss of retinal ganglion cells.

Transneuronal retrograde degeneration of retinal ganglion cells and optic tract in hemianopic monkeys and humans.

Transneuronal retrograde degeneration of retinal ganglion cells after removal of primary visual cortex (area V1) is well established by quantitative neurohistological analysis of the ganglion cell layer in monkeys, but remains controversial in human patients. Therefore, we first histologically examined retinal degeneration in sectioned archived retinae of 26 macaque monkeys with unilateral V1 ablation and post-surgical survival times ranging from 3 months to 14.3 years. In addition, the cross-sectional area of the optic tract was measured in archived coronal histological sections of the brain of every hemianopic monkey and in sections from 10 control monkeys with non-visual bilateral cortical lesions. The ratios of nasal and temporal retinal ganglion cell counts in the contralesional eye and ipsi/contralateral optic tract areas were calculated and compared. They show that the decline was initially more pronounced for the optic tract, slackened after 3 years post-lesion and was steeper for the ganglion cells thereafter. Nevertheless, both measures were highly correlated. Second, we calculated ratios from structural magnetic resonance images to see whether the optic tracts of four human hemianopes would show similar evidence of transneuronal degeneration of their ipsilesional optic tract. The results were consistent with extensive and time-dependent degeneration of the retinal ganglion cell layer. The measures of the optic tracts provide evidence for comparable transneuronal retinal ganglion cell degeneration in both primate species and show that structural magnetic resonance image can both reveal and assess it.

Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy.

Axon degeneration is a hallmark of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Such degeneration is not a passive event but rather an active process mediated by mechanisms that are distinct from the canonical pathways of programmed cell death that mediate destruction of the cell soma. Little is known of the diverse mechanisms involved, particularly those of retrograde axon degeneration. We have previously observed in living animal models of degeneration in the nigrostriatal projection that a constitutively active form of the kinase, myristoylated Akt (Myr-Akt), demonstrates an ability to suppress programmed cell death and preserve the soma of dopamine neurons. Here, we show in both neurotoxin and physical injury (axotomy) models that Myr-Akt is also able to preserve dopaminergic axons due to suppression of acute retrograde axon degeneration. This cellular phenotype is associated with increased mammalian target of rapamycin (mTor) activity and can be recapitulated by a constitutively active form of the small GTPase Rheb, an upstream activator of mTor. Axon degeneration in these models is accompanied by the occurrence of macroautophagy, which is suppressed by Myr-Akt. Conditional deletion of the essential autophagy mediator Atg7 in adult mice also achieves striking axon protection in these acute models of retrograde degeneration. The protection afforded by both Myr-Akt and Atg7 deletion is robust and lasting, because it is still observed as protection of both axons and dopaminergic striatal innervation weeks after injury. We conclude that acute retrograde axon degeneration is regulated by Akt/Rheb/mTor signaling pathways.

Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords.

OBJECTIVE: Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords. BACKGROUND: In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans. METHODS: DTI was performed at 4.7 T on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate-severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. RESULTS: Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate-severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p=0.091). CONCLUSIONS: Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS.

In vivo imaging of retinal ganglion cell axons within the nerve fiber layer.

Purpose. Optic nerve injury causes loss of retinal ganglion cells (RGCs) and their axons. The reduction in RGC counts over time in axonal injury is well studied, but the correlation with the timing of anterograde and retrograde axonal degeneration is less clear. The authors longitudinally imaged RGC axons stained with a chloromethyl derivative of fluorescein diacetate (CMFDA) in live rats after optic nerve injury. Methods. Optic nerves were transected. Three days later CMFDA was intravitreously injected. Confocal scanning laser ophthalmoscopy was performed daily, and mean fluorescence intensity and the number of CMFDA bundles were calculated. RGC soma survival was studied after retrograde fluorescence labeling. Retinal nerve fiber layer (RNFL) thickness was evaluated histologically. Results. CMFDA-positive RGC axon bundles could be imaged in vivo. Axons lost 68% +/- 29% of their fluorescence by 7 days after transection compared with 25% +/- 21% in nontransected eyes. The number of labeled axon bundles decreased by 61% +/- 28% at 7 days after transection compared with 26% +/- 9% in nontransected eyes. The number of retrograde-labeled RGCs detected in vivo declined by 53% at 7 days and by 76% at 14 days after transection. RGC soma and CMFDA axon counts decreased most rapidly between 5 and 7 days after transection. Histologic examination demonstrated a reduction in RNFL thickness 7 days after transection. Conclusions. Intravitreal CMFDA can be used to longitudinally monitor RGC axons within the RNFL in vivo. Imaging the disappearance of retrograde-labeled RGC somas and axons indicates that axonal and somal degeneration occur in parallel after axotomy.

Contribution of white matter lesions to gray matter atrophy in multiple sclerosis: evidence from voxel-based analysis of T1 lesions in the visual pathway.

BACKGROUND: The biological basis of gray matter (GM) atrophy in multiple sclerosis is not well understood, but GM damage seems to be the most critical factor leading to permanent disability. OBJECTIVE: To assess to what extent white matter (WM) lesions contribute to regional GM atrophy in multiple sclerosis. DESIGN: Because optic pathway GM atrophy and optic radiation lesions, rather than being related to each other, could be independent results of the disease, we applied a nonaprioristic WM method to analyze the interrelationships of both phenomena. On a voxel-by-voxel basis, we correlated T1 magnetic resonance imaging-derived lesion probability maps of the entire brain with atrophy of the lateral geniculate nuclei and calcarine/pericalcarine cortices. SETTING: Multiple sclerosis center, University of Navarra, Pamplona, Spain. PATIENTS: Sixty-one patients with multiple sclerosis. MAIN OUTCOME MEASURE: Mapping of WM regions contributing to GM atrophy in the optic pathway. RESULTS: Patients with multiple sclerosis had lateral geniculate nucleus atrophy, which correlated with the presence of lesions specifically in the optic radiations but not in the rest of the brain. Optic pathway lesions explained up to 28% of the change of variance in lateral geniculate nucleus atrophy. Patients also had occipital cortex atrophy, which did not correlate with lesions in the optic radiations or any other WM region. CONCLUSIONS: Focal WM damage is associated with upstream GM atrophy, suggesting that retrograde damage of the perikarya from axonal injury in multiple sclerosis plaques is one of the significant factors in the genesis of GM atrophy, although other neurodegenerative processes are probably at work as well.