Clinical Trials in Neuro-Ophthalmology

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CRASH: Corticosteroid Randomization After Significant Head Injury Trial (2005)

Objectives

The Corticosteroid Randomization After Significant Head (CRASH) Injury Trial investigated the effects of early corticosteroid administration on death and disability following traumatic brain injury. Data up until this point consisted of underpowered and inconclusive studies.

Design

The CRASH Trial was an international, double-blinded, randomized placebo-controlled trial. From April 1999 to May 2004, 10,008 adults (>16 years old) with head injuries of a Glasgow Coma Score (GCS) of <14 were enrolled across 49 countries and 239 hospitals. 5007 patients were assigned to receive corticosteroids and 5001 patients were assigned to the placebo cohort.

Within 8 hours of injury, patients received a loading dose of 2g of methylprednisolone or placebo. Following this, patients received a maintenance infusion dose of 0.4g/hr of methylprednisolone or placebo in 20ml/hr for 48 hours.

At 6 months following head injury, data was available for 96.7% (9673 patients total – 4854 from the corticosteroid cohort, 4819 from the placebo).

Main Outcome Measures

The primary outcome was rate of death or disability at 6 months following initial head injury. Data on deaths were obtained via patients’ general practitioners, access to death certificate records, or from hospital specific-forms. Disability was assessed via the Glasgow Outcome Scale questionnaire.

Results

At 6 months, death occurred in 25.7% (1248 patients) and 22.3% (1075 patients) in the corticosteroid vs. placebo group, respectively (relative risk 1.15, 95% CI 1.07 - 1.24, p=0.0001). At 6 months, death or severe disability occurred in 38.1% (1828 patients) vs. 36.3% (1728 patients) after receiving corticosteroids vs. placebo respectively (relative risk 1.05, 95% CI 0.99 - 1.1, p=0.079).

Subgroup analysis based on severity of injury (GCS: Severe 3-8, Moderate 9-12, Mild 13-14) and timing of corticosteroid administration (≤1h, >1 to ≤ 3h, >3 to ≤8h) revealed no significant difference in outcomes between corticosteroid and placebo cohorts.

Analysis at 14 days post-injury did not illustrate a significantly higher incident of corticosteroid adverse effects, including infectious or gastrointestinal-bleeding complications.

Limitations of CRASH

Study duration was limited to 6 months after initial head injury.
Cause of death was not collected given the highly traumatized nature and likely multifactorial etiologies for most patients.

Conclusions

This trial demonstrates that for head injury patients aged 16 and up, initiation of corticosteroid therapy is not associated with improved outcomes at 6 months, and possibly increases risk of death and disability. These findings were consistent across severity of injury and time from onset to treatment.

Pearls for Clinical Practice

Corticosteroids should not be routinely used in the treatment of head injury, as they do not improve, and potentially worsen, all-cause mortality and risk of severe disability.
Given the frequent co-occurrence of traumatic optic neuropathy (TON) and TBI, steroids should not be routinely used for TON (see IONTS 1999), given the potential for harm and negligible improvement on TBI outcomes.

IIHTT: Idiopathic Intracranial Hypertension Treatment Trial (2014)

Objectives

The Idiopathic Intracranial Hypertension Treatment Trial ran from 2010-2013 and represents the largest prospective study of patients with intracranial hypertension. At the time, there were no evidence-based guidelines on the treatment of Idiopathic Intracranial Hypertension (IIH), despite an incidence of 1/100,000 patients with 10% of these patients developing bilateral blindness. Thus, this trial sought to develop the evidence for IIH treatment and the effects of these treatments.

Design

165 patients with IIH and mild visual loss were enrolled at 38 sites in the United States and Canada over a 3-year period. Patients were randomly assigned to receive a low-sodium diet with acetazolamide or placebo. Dietary plan and lifestyle modification was offered to all study participants with a target weight loss goal of 6% at 6 months. Patients were started on 500 mg acetazolamide twice a day and increased by 250 mg/day every week to a maximum dosage of 4 g/day.

Titration was stopped if papilledema grade was <1 (Frisén scale) or perimetric mean deviation (PMD) became -1 dB in each eye unless other symptoms were present.
Patients who could not tolerate the drug could decrease to a dose of 125 mg/day.
Treatment failure was defined as worsening by >2 dB in patients with baseline PMD up to -3.5 dB in either eye or worsening by >3 dB in patients with baseline PMD between -3.5 dB to -7 dB in either eye.
Patients who discontinued the drug were still followed for the 6-month duration.

Main Outcome Measures

The primary outcome was a change in PMD from baseline to 6 months in eye with worse PMD at baseline.

Results

At 6 months both treatment groups had improvement in the mean PMD in the study eye with mean improvement greater in the acetazolamide group (1.43 dB improvement from -3.53 dB at baseline to -2.10 dB at 6 months) compared to placebo group (0.71 dB improvement from -3.53 dB at baseline to -2.82 at 6 months). There was improvement in the fellow eye as well, and the pattern of improvement similar in both groups with marked increase in number of normal hemifields at 6 months. The treatment effect was greater in participants with a high papilledema grade at baseline, and 7 participants were[CF1] considered treatment failures (worsening by >2 dB in patients with baseline PMD up to -3.5 dB or worsening by >3 dB in patients with PMD baseline between -3.5 to -7 dB). One failure was in the acetazolamide group and 6 were in the placebo group. Male patients, those with high grade (III-V) papilledema and those with lower baseline visual acuity were more likely to experience treatment failure.

Limitations of IIHTT

19% withdrawal rate: more subjects on acetazolamide than on placebo withdrew from the trial
7 patients were considered treatment failures: male patients, those with high baseline papilledema, those with lower baseline visual acuity were more likely to withdraw
Recruitment was limited to patients with mild vision loss
Subjective nature of the Frisén scale: agreement between initial and subsequent read varied from 55 – 73% for individual graders
Limited photographic equipment at some sites restricted the interpretation of some fundus photos
Short-term follow-up limited conclusions about long-term effects of acetazolamide dosing

Conclusions

This trial demonstrated that a combination of acetazolamide and a weight-loss plan resulted in a marked improvement in visual field function compared to a placebo and weight-loss plan alone. Specifically, the trial highlighted the efficacy of acetazolamide in addressing the symptoms of IIH, thereby offering a potential therapeutic avenue for affected individuals. Furthermore, the emphasis on weight loss as a complementary approach underscores the importance of lifestyle modifications in managing this condition, enriching the multifaceted approach to IIH treatment and care.

Pearls for Clinical Practice

Acetazolamide therapy for IIH is associated with improvement in visual field, CSF opening pressure, papilledema evaluated by fundus photography and OCT, and quality of life in adults with mild visual field loss
Acetazolamide is safe and tolerable at doses up to 4g/day
There is no benefit on headache severity with acetazolamide + weight loss compared to placebo

IONDT: Ischemic Optic Neuropathy Decompression Trial (1995)

Objectives

The Ischemic Optic Neuropathy Decompression Trial (IONDT) investigated the efficacy of optic nerve decompression surgery (ONDS) as treatment for nonarteritic anterior ischemic optic neuropathy (NAION). Previous studies reporting visual improvement after ONDS were not randomized control trials, and often had ill-defined parameters, such as a lack of definition for progressive disease. As the surgery became more popular, the IONDT was conducted to test the efficacy of ONDS compared to conventional observational follow-up alone in a randomized control trial.

Design

The IONDT was a randomized, single-masked, multicenter trial in 25 US clinical centers. From 1992 to 1994, 244 patients who met study-specific criteria for the diagnosis of NAION within 2 weeks of symptom onset and a visual acuity of at least 20/64 or worse and better than no light perception were ultimately recruited. 125 patients were randomized for conventional observational management and the remaining 119 randomized to receive ONDS. 91 of 125 patients undergoing conventional observational management and 95 of the 119 patients who received ONDS completed the study’s 6 months of ophthalmologic follow-up examinations. Surgeries were performed by study certified surgeons according to a study protocol.

Main Outcome Measures

The primary outcome was improvement in visual acuity at 6 months, defined as an improvement of three or more lines. Visual acuity was also measured at 3 months, 12 months, and every 6 months subsequently. Visual acuity worsening by three lines or more at the same follow-up points was used as the study’s measure of safety and to denote progressive NAION in the observational group.

Results

Patients assigned to ONDS did no better than those assigned to observation. 32.6% with surgical intervention had improved visual acuity, as compared to 42.7% of those with only observation. Additionally, 23.9% of patients in the ONDS group showed worsening in visual acuity by at least three lines at the 6-month mark compared to 12.4% seen in the careful follow-up group.

There was no difference in treatment effect between patients with progressive NAION and all other forms.

Limitations of IONDT

Dropout rates of 27.2% and 20.2% for observational and ONDS groups, respectively
Exclusion criteria omits NAION with mild vision loss as well as NLP vision
Difficult to uniformly control surgery for ONDS patients

Conclusions

The IONDT demonstrated that ONDS as treatment for NAION is not only ineffective when compared to observation, but also potentially harmful to patients’ vision. This study urges the abandonment of ONDS as a modality of treatment for patients with NAION. A follow-up evaluation was conducted at the two-year mark on 174 patients from the original IONDT cohort, which yielded no significant differences in mean change in vision from baseline between conventional observation and ONDS.

Pearls for Clinical Practice

Optic nerve decompression surgery is ineffective and may even be harmful in the treatment of NAION.
Within the first 6 months, 42.7% of patients with observation alone improved at least three lines of vision.

IONTS: International Optic Nerve Trauma Study (1999)

Objectives

The International Optic Nerve Trauma Study (IONTS) investigated the efficacy of corticosteroid treatment, optic canal decompression surgery, and observation alone in the setting of traumatic optic neuropathy (TON) given both the inadequately assessed optimal management options in the literature and the profound visual loss implications of this condition.

Design

This study was initially conducted as a randomized controlled pilot study, but due to insufficient recruitment numbers, the IONTS was converted to a comparative nonrandomized interventional study that assessed which management options (corticosteroids, optic canal decompression surgery, and observation without treatment) best improved visual function of patients with indirect TON.

With 76 investigators between 16 countries from 1994 to 1997, 133 patients with TON (127 unilateral and 6 bilateral) qualified for the study’s initial inclusion criteria. Those presenting within 3 days of injury and with at least 1 month of follow-up were included in the primary analysis.

Classification of treatment group was based on the treatment received or begun within 7 days of injury, summarized below:

Observation (n = 9)
- 1 patient received steroids after 7 days
Steroid (n = 85) – only steroids given within 7 days if injury
- 5 patients received surgery after 7 days
Optic canal decompression (n = 33) – with or without corticosteroids, within 7 days on injury
- 32 of 33 patients received steroids in addition to surgery

Main Outcome Measures

The primary outcome was visual acuity at 1 month.

Results

32% of patients in the surgery group, 57% of patients in the untreated group, and 52% of patients in the steroid group had an improvement in visual acuity by at least 3 lines (P = 0.22). After adjustment for baseline visual acuity, there were no significant differences in measurement between any of the treatment groups.

The surgery group had an overall worse presenting visual acuity (either no light perception or light perception only than the other two treatment groups (P < 0.001).

Dosage or timing of corticosteroid treatment or timing of surgical intervention had no statistically significant impact on visual outcomes.

Limitations of IONTS

Nonrandomized study:
- Treatment choice was likely confounded by presenting visual acuity
- Cross-over of treatment modalities may have confounded results (i.e most patients in the surgery group were initially treated with corticosteroids)
- Lack of standardization for surgical indications or technique
No standardized methodology used for either CT technique or grading in assessment for surgical indication
Relatively small number of untreated patients

Conclusions

The IONTS demonstrated that in the treatment of TON, neither corticosteroid therapy, optic canal decompression surgery, or observation alone present a clear visual outcome benefit over one another. Treatment decisions for patients with TON should be made on a case-by-case basis, but there is no evidence supporting either corticosteroids or optic canal decompression surgery.

Pearls for Clinical Practice

Corticosteroid therapy and optic canal decompression did not demonstrate any differences in visual acuity when compared to observation alone.
Dosing of corticosteroids did not have any significant impact on visual acuity.
Timing of corticosteroids or surgery did not have a significant impact on visual acuity.
At the one-month mark, 57% of patients with observation alone improved at least 3 lines of vision.

ONTT: Optic Neuritis Treatment Trial (1998-1991)

Objectives

Optic neuritis is an acute inflammatory disease of the optic nerve that is linked to multiple sclerosis (MS). Most patients have sudden visual loss with visual improvement without treatment. However even if visual acuity recovers, patients have lasting symptoms of visual disability, including changes to color vision, stereopsis, contrast sensitivity, etc. Since the 1950s, corticosteroids have been used to treat this disease, without strong clinical evidence. This study aims to answer:

Does treatment of acute optic neuritis with oral prednisolone or IV methylprednisolone reduce the residual visual dysfunction that is present following resolution?
Does either treatment speed recovery of vision?
Are the complications of the treatments insignificant in relation to the magnitude of the treatment effect?

Design

The ONTT is a multicenter, blinded landmark study that focused on establishing treatment guidelines for optic neuritis. Patients were recruited between July 1988 and June 1991. They were referred to the trial by private physicians or medical specialists outside the clinical centers. In this study, 457 patients were recruited at 15 clinical centers and treated with oral steroid, IV steroid or placebo, and visual recovery was measured at seven follow-up visits during the first 6 months and then annually. The study was continued as the longitudinal optic neuritis study (LONS) with patients followed for 15 years.

3 treatment groups were randomized by permuted block scheme by clinical center:

Intravenous (IV) Group: IV methylprednisolone (250 mg every 6 hours for 3 days) followed by oral prednisone (1 mg/kg rounded to nearest 10 mg for 11 days)
Oral Group: Oral prednisone (1 mg/kg/day for 14 days)
Placebo Group: Oral placebo

All 3 groups underwent taper where oral dose decreased to 20 mg on day 15 and 10 mg on days 16 and 18. Patients were followed at day 4, 15, 30, weeks 7, 13, 19, months 6, 12 and annually. The 6-month visit was the major measurement of visual outcome.

Prior to study initiation, patients underwent magnetic resonance imaging (MRI), blood tests (glucose, anti-nuclear antibody, fluorescence treponemal antibody) and chest X-ray. All MRIs were read at a central reading center by standardized method and were classified as absent, possible, probable or definite with regards to multiple sclerosis diagnosis.

Main Outcome Measures

The primary outcome was the treatment’s ability to decrease residual visual dysfunction following resolution of optic neuritis and its ability to speed recovery as measured by visual field and contrast sensitivity.

Contrast sensitivity scores were calculated from the Pelli-Robson chart
Humphrey visual field analyzer results were characterized by the mean deviation in decibels (dB) for the 76 test points compared to an age-specific normal standard

Results

Two patients were found to have a compressive optic neuropathy and 2 patients were found to not have optic neuropathy and were removed from the study. During the 2 years of follow up, no other patients had signs of systemic disease besides MS.

All but 3% of the patients completed the full course of treatment and 2.4% of patients took 5 pills fewer than prescribed. Two adverse side effects occurred in the IV group: one had acute transient depression and one had acute pancreatitis, both of which resolved without sequelae. Patients in the treatment groups reported more sleep disturbance, mild mood change, stomach upset and facial flushing and had more weight gain than patients in the placebo group (p < 0.001 for each).

There were 13% of patients in the IV group, 27% in the oral group and 15% in the placebo group that had an additional episode of optic neuritis in the 6–24-month follow-up period of the study. As compared to placebo, relative risk of a new episode in the oral group was 1.79 (95% CI 0.74, 2.64) for the affected eye and 2.50 (95% CI 1.15, 5.46) in the contralateral eye. In the IV group, the relative risk of new episode in the affected eye was 0.86 (95% CI 0.42, 1.76) and in the contralateral eye was 0.65 (95% CI 0.23, 1.81).

The rate of return of vision to normal was higher in the IV group than in the placebo group (p = 0.0001 for visual field, p = 0.02 for contrast sensitivity, and p = 0.09 for visual acuity). The differences were greatest on day 4 and day 15, and thereafter the differences between the groups decreased. In this IV vs placebo group at 6 months, the distributions for contrast sensitivity (p = 0.026), visual field (p = 0.054) and color vision (p = 0.033) were still significantly different, although those for visual acuity were not. Between the oral steroid and placebo groups, there was no difference in rate of recovery (p > 0.05 for each measure) or the distribution of any of outcome measures at 6 months (p = 0.85 contrast sensitivity, p = 0.35 visual acuity, p = 0.58 color vision).

Limitations of ONTT

It is unknown whether IV steroids alone would have the same visual outcomes as those who received IV + oral steroids in this study
It is unknown whether initiating treatment sooner after the onset of symptoms could have provided greater benefit
It is unknown whether a higher dose of IV steroids could have provided a greater benefit

Conclusions

The Optic Neuritis Treatment Trial (ONTT) presented pivotal insights on the efficacy of corticosteroid treatments in managing optic neuritis. The study illuminated that IV methylprednisolone and oral steroid taper hastened the recovery of vision, though at 6 months there was no discernible difference in visual acuity. At six months, the recovery of contrast sensitivity, visual field, and color vision for was minimally better in patients who received IV and oral steroid treatment compared to placebo. Adverse effects were minimal and manageable, reinforcing the safety profile of oral and IV steroid treatments.

Pearls for Clinical Practice

IV + oral steroid group recovered vision faster than those who got placebo, but the visual outcome at the end of a 6-month period was only slightly better than in the placebo group
IV + oral steroid was most effective at the first 15 days, with visual function mostly the same at 7 weeks
There was no difference in rate of recovery, or visual function recovery with oral prednisone compared to placebo

New attacks of optic neuritis were highest in patients receiving oral steroids compared to IV steroids and placebo group
There was no benefit in treating patients with steroids if their visual acuity is 20/40 or better
There are limited serious adverse events with IV methylprednisolone therapy