Neuro-Ophthalmology

Recommended Reading – Toxic medications in Leber’s hereditary optic neuropathy

Toxic medications in Leber’s hereditary optic neuropathy.
Kogachi K, Ter-Zakarian A, Asanad S, Sadun A, Karanjia R
Mitochondrion. 2018 Aug 4. pii: S1567-7249(18)30036-9. doi: 10.1016/j.mito.2018.07.007. [Epub ahead of print]

Abstract
Leber’s hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder characterized by acute bilateral vision loss. The pathophysiology involves reactive oxygen species (ROS), which can be affected by medications. This article reviews the evidence for medications with demonstrated and theoretical effects on mitochondrial function, specifically in relation to increased ROS production. The data reviewed provides guidance when selecting medications for individuals with LHON mutations (carriers) and are susceptible to conversion to affected. However, as with all medications, the proven benefits of these therapies must be weighed against, in some cases, purely theoretical risks for this unique patient population.

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… In this article, we review medications that are proposed to increase ROS. Given the association between ROS and conversion, understanding the effects of these agents on mitochondria may assist clinicians to understand the implications of these classes of medications for patients with LHON. Medications on this list can be used in patients with LHON, especially when no alternative exists. As with all therapies, a balance must be struck between the therapeutic benefits and potential harm, which may warrant special consideration for patients with LHON.

Full Text: https://drive.google.com/open?id=12HvHSKJaRj7WOvkJQKWlj8FOVbcSoNbj

Recommended Reading – Abnormal Eye Movements in Paraneoplastic Syndromes

Opsoclonus (Ri antibodies)
931-1 Paraneoplastic Opsoclonus http://www.kaltura.com/index.php/extwidget/preview/partner_id/797802/uiconf_id/27472092/entry_id/0_47rqop2q/embed/auto?
Title: Paraneoplastic Opsoclonus Subject: Opsoclonus; Ocular Flutter; Oscillopsia; Saccadic Oscillations; Paraneoplastic Cerebellar Syndrome; Adenocarcinoma of the Breast; Anti-Ri Antibody; Paraneoplastic Opsoclonus; Paraneoplastic Ocular Flutter; Saccadomania Description: This patient is the index case of the Anti-Ri antibody, published in Annals of Neurology in 1988 (4). The Anti-Ri antibody is recognized to be a paraneoplastic marker in patients with breast and gynecological malignancies (10). The history of this case is particularly important because she was initially misdiagnosed as a case of acute labyrinthitis.

Ocular flutter (Ri antibodies)
https://www.aao.org/annual-meeting-video/ocular-flutter
Rod Foroozan. AAO Subspecialty Day 2011: Neuro-Ophthalmology (AAO sign-in may be required)
In this case discussion from Neuro-Ophthalmology Subspecialty Day 2011, Dr. Rod Foroozan presents a case of ocular flutter, a rare disorder characterized by back-to-back saccades. The abnormal ocular oscillations are believed to result from dysfunction of the pause/burst cells, which govern saccade generation, in the pons. The most common causes can be categorized as inflammatory, infectious or paraneoplastic. Most patients with an infectious cause show spontaneous improvement weeks to months after the onset of symptoms.

Cerebellar degeneration (Yo antibodies)
Paraneoplastic Cerebellar Degeneration. Hain TC. 2016
Downbeat Nystagmus anti-YO paraneoplastic cerebellar degeneration
Downbeat Nystagmus in paraneoplastic cerebellar degeneration in left gaze
Downbeat Nystagmus in paraneoplastic cerebellar degeneration increased with convergence
Website https://www.dizziness-and-balance.com/disorders/central/cerebellar/pcd.htm

Downbeat Nystagmus  https://www.youtube.com/watch?v=FrlsK4MF3Ao
Downbeat Nystagmus is a “central” or brain-related abnormal eye movement that could have no identifiable cause, but it might suggest abnormalities in the brainstem or cerebellum region of the central nervous system, is often seen in cerebellar degeneration syndromes, vitamin B12 or B1 (thiamine) deficiency, magnesium deficiency,  and may be part of a paraneoplastic syndrome.

Elliptical Nystagmus and Oscillopsia
Teaching Video NeuroImages: P/Q-type voltage-gated calcium channel–associated paraneoplastic elliptical nystagmus. Mistry EA, Lee AG, Lai EC. Neurology. 2016.
A 71-year-old chronic smoker had an 11-month history of monocular followed by binocular elliptical nystagmus and oscillopsia (video at Neurology.org). MRI brain showed extensive periventricular T2 signal changes (figure) and CSF showed elevated protein to 102 mg/dL. CSF and serum paraneoplastic panel revealed elevated serum titers of anti-P/Q-type voltage-gated calcium channel (VGCC) and anti-neuronal-type voltage-gated potassium channel antibodies. An underlying malignancy was not found after an extensive investigation. The patient was treated with carbamazepine for symptomatic control, followed by high-dose IV methylprednisolone, resulting in moderate improvement. Anti-VGCC antibodies have been implicated in paraneoplastic nystagmus and small cell lung cancer is the most common associated malignancy.^1,2

Paraneoplastic upbeat nystagmus.

Wray SH, Martinez-Hernandez E, Dalmau J, Maheshwari A, Chen A, King S, Bishop Pitman M, Leigh RJ. Neurology.2011:16;77(7):691-3.
…During attempted fixation of a far target, she had prominent UBN, lid nystagmus, and saccadic intrusions (video on the Neurology® Web site at www.neurology.org). UBN suppressed during near viewing and showed marked dependency on head position, upbeat when erect, absent when supine, reduced when prone, and beating away from the ground (apogeotropic) when lying on either side.
A CT-guided core biopsy revealed a pancreatic endocrine neoplasm.
Paraneoplastic antibody testing, including anti-Ri, Anti-Yo, anti-Hu, anti-Ma1 and Ma2, anti-ZiC4, and anti-CV2, was positive for anti-Hu antibodies at a titer of 1/15,360. The tumor showed robust reactivity with a monoclonal antibody against Hu confirming the expression of this antigen (figure, A and B). Analysis of patient’s serum and CSF for antibodies against the neuropil of brain, brainstem, and cerebellum (usually indicating a cell membrane or cell surface autoantigen) showed both samples had reactivity with the nuclei of neurons (Hu antigen) as well as with an unknown antigen expressed in the neuropil of brain.

Figure

Expression of Hu antigen by the patient’s tumor, and demonstration of an antibody against a neuronal cell surface antigen
The tumor shows intense reactivity with a mouse monoclonal antibody against human Hu (Molecular Probes; Eugene, OR; Cat# A-21271) used at dilution 1:50 (A).
As a contrast, the tumor does not show reactivity with normal mouse immunoglobulin G used at the same dilution (control section, B).
The immunostaining was performed using the avidin-biotin-peroxidase method followed by hematoxylin counterstaining (×200). Using cultures of dissociated rat hippocampal neurons patient’s serum (diluted 1:100) shows reactivity with the neuronal cell surface (C). The immunolabeling was done using live, not permeabilized neurons, as reported.7
Full-Text https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159092/

Paraneoplastic disorders may also cause slow saccades and limited vertical movements (Hu, Ma/Ta antibodies).

A recent review:  Paraneoplastic Neurologic Syndromes. Rosenfeld MR &  Josep Dalmau J. Neurol Clin 36 (2018) 675–685

Recommended Reading – Giant Cell Arteritis Treatment – Anti-Interleukin-6 Antibody

IL-6 Blockade and its Therapeutic Success in Giant Cell Arteritis
Sebastian Unizony, MD, Tanaz A. Kermani, MD, MS: J Neuro-Ophthalmol 2018; 00: 1-8
CONCLUSIONS AND FUTURE PERSPECTIVES
Until recently, therapies that could maintain disease remission and prevent the well-known toxicity associated with excessive CS exposures have been the greatest unmet need for the GCA population. Studies elucidating the role of IL-6 in the inflammatory cascade in general and in the pathogenesis of GCA in particular have been instrumental in the eventual success of IL-6 blockade for the treatment of this condition. Further research is now required to answer several outstanding questions pertaining to the duration of TCZ treatment, the use of CS in patients receiving TCZ (e.g., can TCZ be used in monotherapy?), and whether TCZ is effective in controlling arterial inflammation and preventing large-artery complications. These and other questions will fine tune the use of TCZ for GCA. In addition, IL-6 inhibition has made even more pressing the need for accurate biomarkers to monitor disease activity and response to treatment.

More than 25 years passed from the initial observations that patients with GCA demonstrate an increased IL-6 signal to the demonstration of the efficacy of IL-6 blockade in rigorous clinical trials. We should do better. Fortunately, our understanding of the mechanisms of disease involved in GCA has improved and will likely continue to evolve in the future leading to the discovery of other important pathways and targeted treatment strategies

Full Text https://drive.google.com/open?id=1RUM9u7PRCekCpiDj-l9Ksf2eLCqne3xU  

Anti-Interleukin-6 Antibody as Treatment for Giant Cell Arteritis
Joyce Liao: J Neuro-Ophthalmol 2018; 00: 1-3
Choosing the right treatment for patients with GCA remains challenging. Although there is now an approved alternative to corticosteroids, our experience with TCZ is still limited compared with more than 6 decades of experience with corticosteroids. TCZ has promising efficacy in GCA, but there have been several reports of clinically significant, albeit rare, side effects such as severe neutropenia, recurrent pneumonia, cytomegalovirus, and other infections (30–32). Further research into the pathogenesis of GCA and the development of new therapies that can reverse vision loss and prevent relapse are critically needed.

Full Text https://drive.google.com/open?id=1gW9gf4HKGtg6onQtKliREMb2mYR9otzc

Recommended Reading – Terson Syndrome
Terson syndrome in subarachnoid hemorrhage, intracerebral hemorrhage, and traumatic brain injury. Czorlich P, Skevas C, Knospe V, Vettorazzi E, Richard G, Wagenfeld L, Westphal M. Regelsberger J. Neurosurgical Review. 2015,38,1,129–136

Abstract
This prospective trial was designed to evaluate the incidence of Terson syndrome in patients suffering from subarachnoid hemorrhage, intracerebral hemorrhage, or traumatic brain injury and whether consequences necessarily derive from the intraocular hemorrhage itself. Two ophthalmologic examinations were performed to identify patients with Terson syndrome. Data on initial Glasgow Coma Scale, Hunt and Hess and Fisher grades, aneurysm site and diameter, and volume of hemorrhage in intracerebral hemorrhage patients were correlated to the location and course of Terson syndrome. Follow-up was performed after 3 months, including clinical and ophthalmologic investigations. The data showed that 16 of 83 subarachnoid hemorrhage patients (19.3 %), 2 of 22 intracerebral hemorrhage patients (9.1 %), and 1 of 32 traumatic brain injury patients (3.1 %) suffered from Terson syndrome. Low Glasgow Coma Scale (p = 0.002), high Hunt and Hess grade (p < 0.001), and high Fisher grade (p = 0.002) were found to be associated with a higher incidence of Terson syndrome. The neurological outcome in subarachnoid hemorrhage patients suffering from Terson syndrome was worse compared with that of subarachnoid hemorrhage patients without Terson syndrome (p = 0.005), and vitrectomy was performed in seven eyes of six patients due to poor visual acuity. Terson syndrome is underestimated in patients with subarachnoid hemorrhage and a rare pathology in intracerebral hemorrhage as well as in traumatic brain injury patients. Spontaneous regression of the intraocular hemorrhage may be seen, but in half of the patients, vitrectomy is necessary to prevent permanent visual deterioration.

Full-Text PDF https://drive.google.com/open?id=1UYiSRw8j3r5qgjAcmVDJtmyW264WWE-y

Abstract
Two different clinical entities, essential or secondary neuralgia, are associated with different pathologies. The pathways of CN V comprise the cervical spine, the brainstem, the root of the nerve and the three peripheral branches: V1, V2, and V3. The lesions responsible for neuralgia are neoplastic, vascular, inflammatory, malformative or post-traumatic. The examination protocol should explore the set of CN V pathways. Neurovascular compression is the main cause of essential neuralgia. It is investigated by T2-weighted inframillimeteric volume. Two conditions are necessary to diagnose a neurovascular compression: localized on the root entry zone [(REZ), 2-6mm from the emergence of the pons] and perpendicularly. In the absence of neurovascular compression, thin slices and a gadolinium injection are necessary.

TAKE-HOME MESSAGES
• The range of pathologies responsible for trigeminal neuralgia is vast: neoplastic, vascular, inflammatory, malformative or post-traumatic.
• Two different clinical entities: essential or secondary neuralgia are associated with different pathologies.
• The possible topographical area affected is extensive from the cervical spine to the facial region.
• MRI investigation is based on an initial imaging protocol that can be completed by examination if lesions are detected.
• In this context, clinical understanding of the patient prior to the MRI scan is often a precious aid in directing the examination (essential or secondary neuralgia, affected dermatomes).
• In the case of essential neuralgia, the most commonly observed lesion is neurovascular compression. Diagnosis is based on T2  inframillimetric acquisition by visualising a vessel perpendicular to the REZ (at 2—6 mm from the emergence of the brainstem). 3D TOF then makes it possible to determine the arterial or venous origin of the compression.
• In the case of secondary neuralgia, good understanding of the anatomy of the CN V pathways is necessary.

Figure 11. Left neurovascular compression (arrow). Perpendicular vessel leading to pressure on the nerve on the zone corresponding to REZ (2 mm from the emergence of the brainstem).

Free Full Text https://linkinghub.elsevier.com/retrieve/pii/S2211-5684(13)00245-3