Impact of Immune Checkpoint Inhibitors on the Course of Multiple Sclerosis.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are increasingly used in cancer treatment. Their mechanism of action raises the question of possible exacerbation of preexisting multiple sclerosis (MS). The aim of our study was to assess the risk of increased MS activity, defined by the occurrence of a relapse and/or a new MRI lesion, after ICI initiation. METHODS: This French multicentric study collected retrospective and prospective data on patients with MS treated with ICIs after a cancer diagnosis. RESULTS: We identified 18 patients with a median age of 48 years. Three of them (17%), all aged 50 years or younger, with a relapsing-remitting course, showed clinical and/or radiologic signs of MS activity 3 to 6 months after ICI initiation. They had stopped disease-modifying treatment (DMT) several months earlier, at the time of cancer diagnosis. Only one had both clinical and MRI activity, with mild severity and complete recovery. DISCUSSION: Our study suggests that the overall risk of MS activity under ICI is low and could be mainly driven by DMT discontinuation, as in MS in general. Although larger studies are needed for better risk assessment in younger patients with more active disease, ICI should be considered when needed in patients with MS.

Endonasal Endoscopic Optic Canal Decompression for Nontraumatic Optic Neuropathy: Long-Term Visual Outcomes in 36 Patients.

BACKGROUND: The management of compressive optic neuropathy (CON) arising from nontraumatic compression of the optic nerve within the optic canal (OC) remains a topic of controversy. In this study, our aim was to assess the effectiveness and safety of endonasal endoscopic optic nerve decompression (EEOND). In addition, we conducted an analysis of prognostic factors that could potentially influence visual outcomes. METHODS: This retrospective cohort study was conducted between January 2015 and December 2021, involving adult patients (age > 18) diagnosed with CON and treated with EEOND at our specialized skull base expert center. The study evaluated the impact of surgery on visual acuity (VA), mean deficit (MD), and foveal threshold (FT) of the visual field (VF). These parameters were assessed preoperatively and at 3- and 12-month postoperative follow-ups. The relationship between clinical variables and the differences in postoperative to preoperative VA, MD, and FT of the visual field was analyzed through univariate and multivariate approaches. RESULTS: Thirty-six patients (38 eyes) were included, with a mean age of 52 (±12) years, and a female predominance (78%). The mean ophthalmologic follow-up duration was 38 (±32) months. At the 12-month follow-up, 39% of the patients exhibited a VA improvement of ≥0.2 LogMAR. Partial VF improvement (MD improvement ≥25%) was observed in 55% of the patients, whereas 19% experienced complete recovery. In multivariate analysis, the presence of a type 4 OC was identified as the sole negative prognostic factor for visual improvement (VA and VF) at 12 months. Six patients (17%) encountered minor surgical complications, all of which were managed conservatively and had no impact on visual outcomes. CONCLUSIONS: Our study demonstrates that EEOND is a safe and effective procedure, even in cases of severe and long-lasting CON caused by nontraumatic compression of the optic nerve at the level of the OC.

Prognostic factors for significant 6-month recovery in dysthyroid optic neuropathy in a tertiary center: A series of 69 eyes in 38 patients.

PURPOSE: To identify initial features associated with significant recovery in patients with Graves' disease dysthyroid optic neuropathy (DON) treated according to EUGOGO guidelines by intravenous glucocorticoids (ivGC) and decompression surgery in first and second-line, respectively. PATIENTS AND METHODS: Consecutive patients referred to our expert multidisciplinary consultation over a 6-year period underwent systematic exploration: endocrine assessment, ophthalmic examination and radiological exploration. Visual recovery, based on best-corrected visual acuity (BCVA) and visual field (VF), were evaluated at baseline, 1week and 6months. Baseline parameters were then tested for prognostic value on univariate and multivariate analyses. RESULTS: Thirty-eight patients (69 eyes) with DON were included. Significant recovery at 6months was found in 48/69 eyes (70%), partial recovery in 18/69 (26%), and no recovery in 3/69 (4%). Fifty-one eyes (28 patients) required surgical decompression after ivGC. These patients showed more severe presentation at diagnosis, had received significantly less GC for Graves' orbitopathy before onset of DON, and showed greater fat prolapse on CT scans compared to non-operated patients. On multivariate analysis, male gender (P=0.001), cumulative GC dose>1g before DON diagnosis (P=0.048) and initial BCVA≤0.3 (P=0.004) were significantly associated with better outcomes, whereas Clinical Activity Score>5 (P=0.013) was associated with a poorer outcome. CONCLUSION: This study confirms a generally favorable 6-month recovery rate in DON treated according to EUGOGO guidelines and provides new information on baseline predictors of poor evolution. These results may help the respective indications for medical and surgical treatment to be more effectively combined in the future.

The Acute Optic Neuritis Network (ACON): Study protocol of a non-interventional prospective multicenter study on diagnosis and treatment of acute optic neuritis.

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids (days-to-Rx). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON. Trial registration: ClinicalTrials.gov, identifier: NCT05605951.

Core cerebrospinal fluid biomarker profile in anti-LGI1 encephalitis.

OBJECTIVE: To compare CSF biomarkers' levels in patients suffering from anti-Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis to neurodegenerative [Alzheimer's disease (AD), Creutzfeldt-Jakob's disease (CJD)] and primary psychiatric (PSY) disorders. METHODS: Patients with LGI1 encephalitis were retrospectively selected from the French Reference Centre database between 2010 and 2019 and enrolled if CSF was available for biomarkers analysis including total tau (T-tau), phosphorylated tau (P-tau), amyloid-beta Aß1-42, and neurofilaments light chains (Nf L). Samples sent for biomarker determination as part of routine practice, and formally diagnosed as AD, CJD, and PSY, were used as comparators. RESULTS: Twenty-four patients with LGI1 encephalitis were compared to 39 AD, 20 CJD and 20 PSY. No significant difference was observed in T-tau, P-tau, and Aß1-42 levels between LGI1 encephalitis and PSY patients. T-Tau and P-Tau levels were significantly lower in LGI1 encephalitis (231 and 43 ng/L) than in AD (621 and 90 ng/L, p < 0.001) and CJD patients (4327 and 55 ng/L, p < 0.001 and p < 0.01). Nf L concentrations of LGI1 encephalitis (2039 ng/L) were similar to AD (2,765 ng/L) and significantly higher compared to PSY (1223 ng/L, p < 0.005), but significantly lower than those of CJD (13,457 ng/L, p < 0.001). Higher levels of Nf L were observed in LGI1 encephalitis presenting with epilepsy (3855 ng/L) compared to LGI1 without epilepsy (1490 ng/L, p = 0.02). No correlation between CSF biomarkers' levels and clinical outcome could be drawn. CONCLUSION: LGI encephalitis patients showed higher Nf L levels than PSY, comparable to AD, and even higher when presenting epilepsy suggesting axonal or synaptic damage linked to epileptic seizures.

Cranial Nerve Disorders Associated With Immune Checkpoint Inhibitors.

OBJECTIVE: To describe the spectrum, treatment, and outcome of cranial nerve disorders associated with immune checkpoint inhibitor (Cn-ICI). METHODS: This nationwide retrospective cohort study on Cn-ICI (2015-2019) was conducted using the database of the French Refence Center. In addition, a systematic review of the literature (MEDLINE, Scopus, and Web of Science) for records published between 2010 and 2019 was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the search terms cranial nerve or neuropathy or palsy and immune checkpoint inhibitors. RESULTS: Among 67 cases with ICI-related neurologic toxicities diagnosed in our reference center, 9 patients with Cn-ICI were identified (7 men, 78%, median age 62 years [range 26-82 years]). Patients were receiving a combination of anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death 1 (PD-1)/PD-1 ligand (n = 5, 56%) or anti-PD-1 antibodies alone (n = 4, 44%). Cn-ICI involved optic (n = 3), vestibulocochlear (n = 3), abducens (n = 2), facial (n = 2), and oculomotor (n = 1) nerves. Two patients had involvement of 2 different cranial nerves. Treatment comprised corticosteroids (n = 8, 89%), ICI permanent discontinuation (n = 7, 78%), plasma exchange (n = 2, 22%), and IV immunoglobulin (n = 1, 11%). Median follow-up was 11 months (range 1-41 months). In 3 cases (33%), neurologic deficit persisted/worsened despite treatment: 2 optic and 1 vestibulocochlear. Among cases from the literature and the present series combined (n = 39), the most commonly affected cranial nerves were facial (n = 13, 33%), vestibulocochlear (n = 8, 21%), optic (n = 7, 18%), and abducens (n = 4, 10%). Trigeminal, oculomotor, and glossopharyngeal nerves were less frequently affected (total n = 7). CONCLUSION: Cranial nerve disorders can complicate treatment with ICIs. Approximately one-third of the patients had persisting deficits, most frequently involving hearing and vision loss.

A key role for conservative treatment in the management of pituitary apoplexy.

PURPOSE: The management of pituitary apoplexy, a rare emergency neuroendocrine condition, is controversial. The aim of the present study is to compare the outcomes of patients with pituitary apoplexy managed either by a conservative or surgical approach. METHODS: A retrospective cohort study including patients diagnosed between 2007 and 2018 in a tertiary French university hospital. Pituitary Apoplexy Score (PAS) was retrospectively applied in the perspective of therapeutic decision support. RESULTS: Forty-six patients were treated for pituitary apoplexy either with conservative management (n = 27) or surgery (n = 19). At initial evaluation, visual field defects (VFD) and visual acuity impairment were more frequent in patients from the surgery group. At 1 year there were no statistical differences in the rates of complete/near-complete resolution of VFD (100 vs. 91.7%), visual acuity impairment (100 vs. 87.5%), and cranial nerve palsies (83.3 vs. 100%), between conservative and surgical treatment groups. There were more endocrine deficits at 1 year in the surgical group (p = 0.029). PAS (n = 41) was 3.4 on average in the early surgery group and 1.3 in the conservative treatment/delayed surgery group. Among patients with a score < 4, 31.3% were operated at first line and did not present better outcomes than patients managed conservatively. In all, 88.9% of patients with a score ≥ 4 underwent surgery. CONCLUSIONS: PAS may be a reliable parameter for defining therapeutic strategy. Patients with non-severe and nonprogressive neuro-ophthalmological deficits can be managed conservatively without negative impact on outcomes, thus surgery should be reserved only for those patients with a PAS ≥ 4.

Ocular Sarcoidosis.

Sarcoidosis is one of the leading causes of inflammatory eye disease. Any part of the eye and its adnexal tissues can be involved. Uveitis and optic neuropathy are the main manifestations, which may require systemic treatment. Two groups of patients with sarcoid uveitis can be distinguished: one of either sex and any ethnicity in which ophthalmological findings are various and another group of elderly Caucasian women with mostly chronic posterior uveitis. Clinically isolated uveitis revealing sarcoidosis remains a strictly ocular condition in a large majority of cases. Although it can be a serious condition involving functional prognosis, early recognition in addition to a growing therapeutic arsenal (including intravitreal implant) has improved the visual prognosis of the disease in recent years. Systemic corticosteroids are indicated when uveitis does not respond to topical corticosteroids or when there is bilateral posterior involvement, especially macular edema. In up to 30% of the cases that require an unacceptable dosage of corticosteroids to maintain remission, additional immunosuppression is used, especially methotrexate. As with other forms of severe noninfectious uveitis, monoclonal antibodies against tumor necrosis factor-α have been used. However, only very rarely does sarcoid uveitis fail to respond to combined corticosteroids and methotrexate therapy, a situation that should suggest either poor adherence or another granulomatous disease. Optic neuropathy often affects women of African and Caribbean origins. Some authors recommend that patients should be treated with high-dose of corticosteroids and concurrent immunosuppression from the onset of this manifestation, which is associated with a poorer outcome.

Brain volumetric analysis and cortical thickness in adults with saccadic intrusions (ocular flutter or opsoclonus-myoclonus syndrome).

OBJECTIVES: Ocular flutter (OF) and opsoclonus are considered a continuum with a similar pathogenesis. Due to the rarity of this disease in the adult population, little is known about the brain morphological changes in the chronic phase of the disease. PATIENTS AND METHODS: Six magnetic resonance imaging from adults with previous history of OF/Opsoclonus and 12 healthy patients (paired by age and sex) were analyzed in order to identify the long term cortical thickness pattern in this rare disease by using Freesurfer. RESULTS: Patients with OF/Opsoclonus showed reduced cerebellum cortical volume with a subsequent diminution in total cerebellar volume. White mater cerebellum volume was not modified. In addition, we have also identified a significant supratentorial gray matter volume decrease in OF/Opsoclonus patients, involving both the cortical and the subcortical gray matter. CONCLUSIONS: OF/Opsoclonus in adults may be associated with cortical and subcortical gray matter atrophy, as well as decreased cerebellar cortical volume. Further larger prospective studies are necessary to confirm these results.

Hypertrophic Olivary Degeneration and Palatal or Oculopalatal Tremor.

Hypertrophic degeneration of the inferior olive is mainly observed in patients developing palatal tremor (PT) or oculopalatal tremor (OPT). This syndrome manifests as a synchronous tremor of the palate (PT) and/or eyes (OPT) that may also involve other muscles from the branchial arches. It is associated with hypertrophic inferior olivary degeneration that is characterized by enlarged and vacuolated neurons, increased number and size of astrocytes, severe fibrillary gliosis, and demyelination. It appears on MRI as an increased T2/FLAIR signal intensity and enlargement of the inferior olive. There are two main conditions in which hypertrophic degeneration of the inferior olive occurs. The most frequent, studied, and reported condition is the development of PT/OPT and hypertrophic degeneration of the inferior olive in the weeks or months following a structural brainstem or cerebellar lesion. This "symptomatic" condition requires a destructive lesion in the Guillain-Mollaret pathway, which spans from the contralateral dentate nucleus via the brachium conjunctivum and the ipsilateral central tegmental tract innervating the inferior olive. The most frequent etiologies of destructive lesion are stroke (hemorrhagic more often than ischemic), brain trauma, brainstem tumors, and surgical or gamma knife treatment of brainstem cavernoma. The most accepted explanation for this symptomatic PT/OPT is that denervated olivary neurons released from inhibitory inputs enlarge and develop sustained synchronized oscillations. The cerebellum then modulates/accentuates this signal resulting in abnormal motor output in the branchial arches. In a second condition, PT/OPT and progressive cerebellar ataxia occurs in patients without structural brainstem or cerebellar lesion, other than cerebellar atrophy. This syndrome of progressive ataxia and palatal tremor may be sporadic or familial. In the familial form, where hypertrophic degeneration of the inferior olive may not occur (or not reported), the main reported etiologies are Alexander disease, polymerase gamma mutation, and spinocerebellar ataxia type 20. Whether or not these are associated with specific degeneration of the dentato-olivary pathway remain to be determined. The most symptomatic consequence of OPT is eye oscillations. Therapeutic trials suggest gabapentin or memantine as valuable drugs to treat eye oscillations in OPT.

MRI findings in AOA2: Cerebellar atrophy and abnormal iron detection in dentate nucleus.

Ataxia with Oculomotor Apraxia type 2 (AOA2) is one of the most frequent types of autosomal degenerative cerebellar ataxia. The first objective of this work was to identify specific cerebellar atrophy using MRI in patients with AOA2. Since increased iron deposits have been reported in degenerative diseases, our second objective was to report iron deposits signals in the dentate nuclei in AOA2. Five patients with AOA2 and 5 age-matched controls were subjects in a 3T MRI experiment that included a 3D turbo field echo T1-weighted sequence. The normalized volumes of twenty-eight cerebellar lobules and the percentage of atrophy (relative to controls) of the 4 main cerebellar regions (flocculo-nodular, vermis, anterior and posterior) were measured. The dentate nucleus signals using 3D fast field echo sequence for susceptibility-weighted images (SWI) were reported, as a measure of iron content. We found that all patients had a significant atrophy of all cerebellar lobules as compared to controls. The percentage of atrophy was the highest for the vermis, consistent with patients' oculomotor presentation, and for the anterior lobe, consistent with kinetic limb ataxia. We also describe an absence of hypointensity of the iron signal on SWI in the dentate nucleus of all patients compared to control subjects. This study suggests that patients with Ataxia with Oculomotor Apraxia type 2 present MRI patterns consistent with their clinical presentation. The absence of SWI hypointensity in dentate nucleus is a new radiological sign which was identified in all patients. The specificity of this absence of signal must be further determined in AOA2.

Standard-fractionated radiotherapy for optic nerve sheath meningioma: visual outcome is predicted by mean eye dose.

PURPOSE: Radiotherapy has shown its efficacy in controlling optic nerve sheath meningiomas (ONSM) tumor growth while allowing visual acuity to improve or stabilize. However, radiation-induced toxicity may ultimately jeopardize the functional benefit. The purpose of this study was to identify predictive factors of poor visual outcome in patients receiving radiotherapy for ONSM. METHODS AND MATERIALS: We conducted an extensive analysis of 10 patients with ONSM with regard to clinical, radiologic, and dosimetric aspects. All patients were treated with conformal radiotherapy and subsequently underwent biannual neuroophthalmologic and imaging assessments. Pretreatment and posttreatment values of visual acuity and visual field were compared with Wilcoxon's signed rank test. RESULTS: Visual acuity values significantly improved after radiotherapy. After a median follow-up time of 51 months, 6 patients had improved visual acuity, 4 patients had improved visual field, 1 patient was in stable condition, and 1 patient had deteriorated visual acuity and visual field. Tumor control rate was 100% at magnetic resonance imaging assessment. Visual acuity deterioration after radiotherapy was related to radiation-induced retinopathy in 2 patients and radiation-induced mature cataract in 1 patient. Study of radiotherapy parameters showed that the mean eye dose was significantly higher in those 3 patients who had deteriorated vision. CONCLUSIONS: Our study confirms that radiotherapy is efficient in treating ONSM. Long-term visual outcome may be compromised by radiation-induced side effects. Mean eye dose has to be considered as a limiting constraint in treatment planning.

Predicting visual outcome after treatment of pituitary adenomas with optical coherence tomography.

PURPOSE: To evaluate if optical coherence tomography (OCT), by providing an objective measure of the retinal nerve fiber layer (RNFL) thickness, offers a reliable prediction of visual outcome. DESIGN: Prospective cohort study. METHODS: Thirty-seven eyes of 19 consecutive patients from a single hospital suffering from pituitary adenomas compressing the anterior visual pathways were included, and compared with 46 eyes of 23 controls. Exclusion criteria included any previous treatment of pituitary adenoma and high myopia. Seventeen patients underwent trans-sphenoidal surgery and two patients with macroprolactinomas received dopamine agonists. Automated visual fields (VF) and OCT (fast-RNFL program) were performed before treatment, and two weeks and three months after treatment. RESULTS: Among the eyes with a VF defect before treatment, the odds of complete recovery after three months from the initial VF defect was multiplied by 1.29 for each increase by 1 micron of mean RNFL (odds ratio [OR], 1.29; P = .037). This was independent from age and duration of symptoms, which carried their own prognostic value. Inferior RNFL was a very strong prognostic factor; OR, 6.31 per micron (P = .0000). CONCLUSION: RNFL thinning measured by OCT puts the patient at decreased chance of recovery of an initial VF defect three months after treatment in pituitary adenomas compressing the anterior visual pathways. Further studies will establish how useful this tool is for long-term visual outcome.

Saccadic lateropulsion and upbeat nystagmus: disorders of caudal medulla.

A patient developed a primary position upbeat nystagmus and a left saccadic lateropulsion. Magnetic resonance imaging demonstrated a probable cavernoma at right caudal paramedian medullary level. Anatomical correlations are discussed. Saccadic lateropulsion is attributed to olivocerebellar pathway impairment but usually is described in more rostral medullar lesions. Our case would still support this hypothesis because the lesion could have involved the olivocerebellar pathway at its very caudal level. Upbeat nystagmus could be attributed to impairment of the nucleus intercalatus and/or cell groups of the paramedian tract.