Archives for October 2018

Neuro-ophthalmology Illustrated Chapter 1 – Examination 1

1. What is the minimum visual acuity needed to correctly read the control plate on the color vision testing plates?
2. Which is the more sensitive color vision test, Hardy-Rand-Rittler or Ishihara for optic neuropathy?
3. What are the causes of acquired unilateral or bilateral reduced color vision?

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

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]

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.


… 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.

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Neuro-ophthalmology questions of the week: NOI20-Conditions Commonly Encountered in Neuro-ophthalmology 5

45. What are the 4 most common neuro-ophthalmic manifestations of mitochondrial disorders?
46. Name 8 mitochondrial disorders with neuro-ophthalmic manifestations?
47. What are the ophthalmic and systemic manifestations of CPEO (chronic progressive external ophthalmoplegia)?
48. What are the ophthalmic and systemic manifestations of LHON (Leber hereditary optic neuropathy)?
49. What are the Chiari malformations?
50. What are the neuro-ophthalmic manifestations of the Chiari I malformation?
51. What are the ophthalmic manifestations of Parkinson?

Recommended Reading – Abnormal Eye Movements in Paraneoplastic Syndromes

Recommended Reading – Abnormal Eye Movements in Paraneoplastic Syndromes

Opsoclonus (Ri antibodies)
931-1 Paraneoplastic Opsoclonus
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)
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

Downbeat Nystagmus
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 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 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.


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

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

Neuro-ophthalmology questions of the week: NOI20 Conditions Commonly Encountered in Neuro-ophthalmology 4

32. What type of iris nodules do the following have:
  a. Neurofibromatosis Type 1
  b, Neurofibromatosis Type 2
  c. Uveitis?

33. A patient has infectious meningitis with severe papilledema. What risk does this pose and what should be done?

34. A patient presents with slowly progressive memory loss, cognitive impairment, oculomasticatory movements (myorhythmia), supranuclear vertical gaze palsy. What curable condition should be considered and what lab tests can be used to make the diagnosis?

35. What are 3 classic causes of raised ICP in a patient with known cancer?

36.  What are neuro-ophthalmic manifestations of paraneoplastic syndromes?

37. What are the ocular manifestations of Neurofibromatosis Type 1?

38.  What are the ocular or CNS manifestations of Neurofibromatosis Type 2?

39. What is the classic triad of findings in tuberous sclerosis?

40. What is the most prominent ocular manifestation of Tuberous sclerosis?

41. What autosomal dominant condition is associated with multiple, bilateral retinal angiomas and intracranial cerebellar hemangioblastomas?

42. What condition should be suspected with findings of telangiectasias of the conjunctival vessels and oculomotor apraxia?

43. A patient has an upper eyelid hemangioma, intraocular hypertension, and homonymous hemianopia, what condition is likely to be present?

44. What are the ocular manifestations of Sturge-Weber syndrome?

Recommended Reading – Vitamin D for the management of multiple sclerosis.

Recommended Reading – Vitamin D for the management of multiple sclerosis.
Jagannath VA1, Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, Robinson SA.
Cochrane Database Syst Rev. 2018 Sep 24;9:CD008422.
doi: 10.1002/14651858.CD008422.pub3.

This review is an update of a previously published review, “Vitamin D for the management of multiple sclerosis” (published in the Cochrane Library; 2010, Issue 12). Multiple sclerosis (MS) is characterised by inflammation, demyelination, axonal or neuronal loss, and astrocytic gliosis in the central nervous system (CNS), which can result in varying levels of disability. Some studies have provided evidence showing an association of MS with low levels of vitamin D and benefit derived from its supplementation.

To evaluate the benefit and safety of vitamin D supplementation for reducing disease activity in people with MS.

We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Specialized Register up to 2 October 2017 through contact with the Information Specialist with search terms relevant to this review. We included references identified from comprehensive electronic database searches and from hand searches of relevant journals and abstract books from conferences.

We included randomised controlled trials (RCTs) and quasi-RCTs that compared vitamin D versus placebo, routine care, or low doses of vitamin D in patients with MS. Vitamin D was administered as monotherapy or in combination with calcium. Concomitant interventions were allowed if they were used equally in all trial intervention groups.

Two review authors independently extracted data and assessed the methodological quality of studies, while another review author sorted any disagreements. We expressed treatment effects as mean differences (MDs) for continuous outcomes (Expanded Disability Status Scale and number of magnetic resonance imaging (MRI) gadolinium-enhancing T1 lesions), as standardised MDs for health-related quality of life, as rate differences for annualised relapse rates, and as risk differences (RDs) for serious adverse events and minor adverse events, together with 95% confidence intervals (CIs).

We identified 12 RCTs enrolling 933 participants with MS; 464 were randomised to the vitamin D group, and 469 to the comparator group. Eleven trials tested vitamin D₃, and one trial tested vitamin D₂. Vitamin D₃ had no effect on the annualised relapse rate at 52 weeks’ follow-up (rate difference -0.05, 95% CI -0.17 to 0.07; I² = 38%; five trials; 417 participants; very low-quality evidence according to the GRADE instrument); on the Expanded Disability Status Scale at 52 weeks’ follow-up (MD -0.25, 95% CI -0.61 to 0.10; I² = 35%; five trials; 221 participants; very low-quality evidence according to GRADE); and on MRI gadolinium-enhancing T1 lesions at 52 weeks’ follow-up (MD 0.02, 95% CI -0.45 to 0.48; I² = 12%; two trials; 256 participants; very low-quality evidence according to GRADE). Vitamin D₃ did not increase the risk of serious adverse effects within a range of 26 to 52 weeks’ follow-up (RD 0.01, 95% CI -0.03 to 0.04; I² = 35%; eight trials; 621 participants; low-quality evidence according to GRADE) or minor adverse effects within a range of 26 to 96 weeks’ follow-up (RD 0.02, 95% CI -0.02 to 0.06; I² = 20%; eight trials; 701 participants; low-quality evidence according to GRADE). Three studies reported health-related quality of life (HRQOL) using different HRQOL scales. One study reported that vitamin D improved ratings on the psychological and social components of the HRQOL scale but had no effects on the physical components. The other two studies found no effect of vitamin D on HRQOL. Two studies reported fatigue using different scales. One study (158 participants) reported that vitamin D₃ reduced fatigue compared with placebo at 26 weeks’ follow-up. The other study (71 participants) found no effect on fatigue at 96 weeks’ follow-up. Seven studies reported on cytokine levels, four on T-lymphocyte proliferation, and one on matrix metalloproteinase levels, with no consistent pattern of change in these immunological outcomes. The randomised trials included in this review provided no data on time to first treated relapse, number of participants requiring hospitalisation owing to progression of the disease, proportion of participants who remained relapse-free, cognitive function, or psychological symptoms.

To date, very low-quality evidence suggests no benefit of vitamin D for patient-important outcomes among people with MS. Vitamin D appears to have no effect on recurrence of relapse, worsening of disability measured by the Expanded Disability Status Scale (EDSS), and MRI lesions. Effects on health-related quality of life and fatigue are unclear. Vitamin D₃ at the doses and treatment durations used in the included trials appears to be safe, although available data are limited. Seven ongoing studies will likely provide further evidence that can be included in a future update of this review.

Update of Vitamin D for the management of multiple sclerosis. [Cochrane Database Syst Rev. 2010]

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Neuro-ophthalmology questions of the week: NOI20-Conditions Commonly Encountered in Neuro-ophthalmology 3

25. Multiple sclerosis is more common in:

a. Men or Women,
b. African-Americans, Caucasians, or Hispanics?

26. What is Lhermitte sign and is it a classic finding in Multiple sclerosis?

27. What are common eye manifestations of multiple sclerosis?

28. What is the 15-year risk of multiple sclerosis after an initial episode of optic neuritis:
a. Overall,
b. With no MRI lesions,
c. With 1 or more lesions on MRI?

29. How common is mild-to-severe eye pain in optic neuritis?

30. What are the characteristics of Neuromyelitis Optica (Devic disease)?

31. What treatment is useful for Neuromyelitis Optica?

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

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
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

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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.

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Neuro-ophthalmology questions of the week: NOI20- Conditions Commonly Encountered in Neuro-ophthalmology 2

14. In which type of patient is Cranial Arteritis common, uncommon and rare – Blacks, Hispanics or Whites?
15. What condition should be considered in any patient over 50 with headaches?
16. What condition should be considered in any patient over 50 with transient or constant diplopia?
17. What percent of patients will have premonitory visual symptoms, usually within the week preceding permanent visual loss from Cranial Arteritis?
18. Name the 7 ophthalmic signs that with AION suggest a high risk for Cranial Arteritis?
19. In what percentage of patients with Cranial Arteritis will the ESR be normal?
20. Is the CRP ever normal in Cranial Arteritis?
21. What other blood tests may be elevated in Cranial Arteritis?
22. How long will patients with Cranial Arteritis generally need to be treated with oral steroids?
23. At what rate should oral prednisone be tapered in Cranial Arteritis?
24. What test is the only test that confirms the diagnosis of temporal arteritis?