A recent Journal of Neuro-Ophthalmology study has indicated a potentially useful approach to diagnosing idiopathic intracranial hypertension (IIH) noninvasively, using DTI-ALPS (Diffusion Tensor Image Analysis ALong the Perivascular Space) to measure fluid flow changes in the glympathic system.
The research was published as part of a new philanthropy-funded program, the IIH Research and Treatment Initiative, launched recently by Mass General Brigham, with the aim of better understanding the processes behind IIH, exploring new treatment options for the disease, and improving diagnosis.
To learn more, The Ophthalmologist spoke with study co-author, Marc A. Bouffard, a neuro-ophthalmologist at Mass General Brigham and Mass Eye and Ear, Boston.
Can you talk about the IIH Research and Treatment Initiative recently launched by Mass General Brigham?
IIH is a relatively common neuro-ophthalmic condition and is increasing in prevalence. Despite being routinely encountered in clinical practice, there are many important but incompletely understood questions pertaining to what causes IIH, how it can be better diagnosed, and how it can be better treated. The goal of the IIH Research and Treatment Initiative is to advance the care of patients on all of those fronts simultaneously with a multi-pronged approach. We're very lucky to have generous philanthropic support, with the scientific interests of the donor aligned with our own in a way that can efficiently advance the care of patients with IIH.
IIH is a clinical diagnosis, but it’s not always straightforward to establish. What we don't have is a blood test or a specific radiographic biomarker. We hope that the work we’re doing under the auspices of the IIH Research and Treatment Initiative can help us develop more reliable ways to diagnose or rule out IIH. A reliable biomarker could help to understand the true limits of this disease. The patients who we consider to meet current clinical diagnostic criteria for IIH may reflect a tip-of-the-iceberg phenomenon. There are things that we know about IIH that may be subject to revision in the future.
It’s important to approach IIH research in light of the existing data, but also to keep an open mind in understanding that we may be learning things that may redefine the disease’s pathophysiology and manifestations.
Your recent research suggests glymphatic dysfunction is a consequence rather than a cause of IIH – why is this distinction clinically important?
We know there are risk factors, things like gender, reproductive status, and habitus. The majority of IIH patients are female, overweight, and of childbearing age. Elucidating the mechanism by which these risk factors cause high pressure inside the head may be the pivotal mechanistic step in understanding how to develop more efficacious interventions. If we can clarify the mechanism by which high pressure develops, we may be able to interfere with that pathophysiologic cascade to treat the disease more efficiently than we currently do.
We certainly weren’t alone in hypothesizing that dysfunction of the glymphatic system might cause intracranial hypertension in these patients. There are a number of editorials and scientific hypothesis letters in various journals, some with catchy titles like “Glymphedema of the Brain,” drawing a parallel with lymphedema, wherein dysfunctional clearance of interstitial fluid leads to fluid accumulation and high pressure in tissue outside the central nervous system. In 2017, a radiographic method leveraging diffusion tensor imaging became available. It was described by a Japanese scientist named Toshiaki Taoka. We chose to apply this technique – diffusion tensor imaging along the perivascular space (DTI-ALPS) – to IIH. DTI-ALPS provides a putative index of fluid transit along one important component of the glymphatic system, referred to as the ALPS-index.
What we hypothesized initially was that the lower the ALPS-index of glymphatic transit, the higher the intracranial pressure would be, which would be reasonably assumed if glymphatic dysfunction caused intracranial hypertension. We measure intracranial pressure diagnostically with lumbar puncture – that’s how we establish the diagnosis.
What we found was not a neat relationship between ALPS-indices and intracranial pressure or its primary physical manifestation, papilledema (optic nerve swelling). Yet, ALPS-indices in patients with IIH were not normal; they tended to cluster in both subnormal and supranormal ranges compared with healthy controls matched for age and body mass index.
We also found a correlation between duration of disease and ALPS-index, with patients presenting with a very short disease duration exhibiting subnormal ALPS indices, and patients with a clearly longer duration presenting with supranormal ALPS-indices which seemed to reach a ceiling value in individuals with a disease duration longer than about a year.
Furthermore, we found a direct correlation between increasing ALPS-index and increasing intracranial pressure among that subset of participants with chronic disease, suggesting the potential for a homeostatic or adaptive response that takes time to develop.
The results of our study are cross-sectional, studying individuals at a single time point. They're not longitudinal – we’re working on obtaining serial ALPS-indices from individuals at multiple time points to clarify whether ALPS-indices truly evolve in an individual over the disease course or whether different baseline ALPS-indices might predispose individuals to a more or less conspicuous disease course.
Even if our results suggest that changes in the glymphatic system might not cause IIH – and thus, it may not be the primary target for therapeutic intervention – the differences between ALPS-indices in patients with IIH and controls suggests potential as a radiographic biomarker and diagnostic aid.
How close do you think we are to ALPS-indices being used as routine biomarkers for suspected IIH?
It's absolutely one of my hopes, but whether we're close remains to be seen. We've looked at receiver operating characteristic curves, validated against a clinical diagnosis by a neuro-ophthalmologist. Our sample sizes have been small, and we're working to enlarge them, but the area under the curve has been promisingly high so far.
This can be a hard disease to diagnose even with the current diagnostic criteria, with potential for ambiguous symptoms, ophthalmic signs, anatomical features on MRI, and even with intracranial pressures measured by lumbar puncture. We're hopeful that ALPS-indices may be diagnostically useful. We're expanding our sample size and broadening the populations we’re studying to understand how good a diagnostic test this is, and how broadly applicable it is.
Though IIH mostly affects obese women of childbearing age, it less commonly affects men, kids, and women who are not overweight or who are postmenopausal. Some individuals have signs on MRI we associate with high intracranial pressure, though they don’t have papilledema. It isn’t clear if the same pathophysiologic process is at work in each of these populations, and the lack of a good biomarker poses challenges in understanding the true spectrum of IIH.
We're hopeful that a physiologically valid and clinically applicable radiographic biomarker for IIH may help define the spectrum of disease. If you only diagnose people who fit your preconceived notion, you end up selecting and reselecting the same population and perhaps not attending to a more diverse demographic who may have the disease and struggle because it's not recognized or treated.
Could this type of ALPS-based imaging potentially help reduce misdiagnosis or overdiagnosis of the condition?
Misdiagnosis and overdiagnosis of IIH are both common problems. Work by collaborators at Emory identified a relatively large proportion of patients referred for management of IIH who did not meet criteria for IIH at all.
Underdiagnosis is an equally substantial problem. In the US, there are currently around 400 full-time equivalent neuro-ophthalmologists for a country of approximately 350 million people. With such a hard-to-establish diagnosis – requiring clinical history, a sophisticated ophthalmic examination, lumbar puncture, and interpretation of complex MRI findings – it becomes extremely important to pioneer a diagnostic test that helps not only neuro-ophthalmologists, but all physicians who may encounter IIH patients earlier in the course of their care.
A valid, sensitive, and specific radiographic biomarker in the hands of general neurologists, headache neurologists, emergency physicians, and general ophthalmologists could reduce overdiagnosis, reduce missed diagnosis, and get the right patients to the right doctors at the right time.
How might these findings change the way neuro-ophthalmologists approach the disorder?
When I was a resident, we thought 20 centimeters of cerebrospinal fluid was the demarcating line between normal and abnormal intracranial pressure. We treated it as binary, but it’s not truly binary. Pressure varies minute to minute, depending on position, abdominal relaxation, and even when the manometer is checked. Later, 25 centimeters of CSF was suggested as a better cutoff, though pressures of 20-25cm CSF could still be accepted as pathologically elevated if additional criteria were met. In children, higher than 28 centimeters of CSF is considered elevated, though there too habitus and sedation introduce additional variability.
Lumbar puncture is the only direct assay of intracranial pressure that we have, but it has its limitations. Indirect assays might serve as helpful adjuncts. In carefully selected patients, a valid surrogate marker of intracranial pressure might obviate the need for invasive testing in some cases. I doubt it would ever eliminate lumbar puncture entirely because in select patients clarifying whether the CSF constituents are normal will always be important, but as a broadly applicable tool, it could be really powerful.
What are your next steps with this research?
We're expanding the sample sizes of the populations we've studied, studying patients longitudinally, and validating findings across hospitals, scanners, and radiologists.
We're also studying new populations, including IIH without papilledema. Many neuro-ophthalmologists believe it exists, although the mechanism is elusive. It seems paradoxical to have intracranial hypertension without papilledema, yet we encounter patients who fit that description.
We're very interested in studying men, children, and other subgroups to determine whether different pathophysiologic mechanisms may be at play. It's possible IIH is not one disease but multiple mechanistic routes to intracranial hypertension. We hope that clarifying this may aid clinical care in these populations.
We're also incorporating other radiographic indices of glymphatic transit – arterial pulsatility, cerebrospinal fluid flow metrics, free water measurements in different brain compartments, perivascular space measurement, and eventually meningeal lymphatic imaging.
Currently, we're studying one branch of the glymphatic pathway – perivascular transit – using DTI-ALPS. Multimodal assessment of the glymphatic system is surely required in IIH. This could represent an exciting opportunity.
Is there anything else you'd like to add?
Diagnostic clarity in IIH is important, whether patients need confirmation or exclusion of IIH, so their symptoms can be addressed appropriately. Mitigating diagnostic ambiguity is critical, especially for patients who struggle to achieve a clear diagnosis with current clinical diagnostic criteria.
We're focused on understanding the full spectrum of disease through glymphatic transit, hopeful that this will improve diagnosis and care not just for patients with typical demographics, but also for non-obese individuals, children, and men. Ultimately, we want to provide better, more tailored, more efficient, and more definitive care for all patients with a question of IIH.
