Nuclear Magnetic Resonance Spectroscopy Metabolomics in Idiopathic Intracranial Hypertension to Identify Markers of Disease and Headache, 2022, Grech

[SNT Gatchaman]

Nuclear Magnetic Resonance Spectroscopy Metabolomics in Idiopathic Intracranial Hypertension to Identify Markers of Disease and Headache
Grech O, Seneviratne SY, Alimajstorovic Z, Yiangou A, Mitchell JL, Smith TB, Mollan SP, Lavery GG, Ludwig C, Sinclair AJ

Background and objective: We evaluated the metabolomic profile in CSF, serum and urine of participants with idiopathic intracranial hypertension (IIH) compared to controls and measured changes in metabolism associated with clinical markers of disease activity and treatment.

Methods: A case-control study compared women aged 18-55 years with active IIH (Friedman diagnostic criteria), to a sex, age and body mass index matched control group. IIH participants were identified from neurology and ophthalmology clinics from National Health Service hospitals and underwent a prospective intervention to induce disease remission through weight loss with re-evaluation at 12 months. Clinical assessments included lumbar puncture, headache, papilledema and visual measurements. Spectra of CSF, serum and urine metabolites were acquired utilizing proton nuclear magnetic resonance spectroscopy.

Results: Urea was lower in IIH (CSF; controls median ±IQR 0.196 ±0.008, IIH 0.058 ±0.059, p<0.001, urine; controls 5971.370 ±3021.831, IIH 4691.363 ±1955.774, p=0.009), correlated with ICP (urine p=0.019) and headache severity (CSF p=0.031) and increased by 12 months (CSF 12 months; 0.175 ±0.043, p=0.004, urine; 5210.874 ±1825.302, p=0.043).

The lactate : pyruvate ratio was increased compared to controls (CSF; controls 49.739 ±19.523, IIH 113.114 ±117.298, p=0.023, serum; controls 38.187 ±13.392, IIH 54.547 ±18.471, p=0.004) and decreased at 12 months (CSF; 113.114 ±117.298, p<0.001). Baseline acetate was higher in IIH (CSF; controls 0.128 ±0.041, IIH 0.192 ±0.151, p=0.008), correlated with headache severity (p = 0.030) and headache disability (p = 0.003) and was reduced at 12 months (0.160 ±0.060, p = 0.007).

Ketones 3-hydroxybutyrate and acetoacetate were altered in CSF at baseline in IIH (3-hydroxybutyrate; controls 0.074 ±0.063, IIH 0.049 ±0.055, p = 0.019, acetoacetate; controls 0.013 ±0.007, IIH 0.017 ±0.010, p = 0.013) and normalized at 12 months (0.112 ±0.114, p = 0.019, 0.029 ±0.017, p = 0.015 respectively).

Discussion: We observed metabolic disturbances that are evident in CSF, serum and urine of IIH participants, suggesting global metabolic dysregulation. Altered ketone body metabolites normalized following therapeutic weight loss. CSF:serum urea ratio was altered which may influence ICP dynamics and headache. Elevated CSF acetate, known to stimulate trigeminal sensitization, was associated with headache morbidity. These alterations of metabolic pathways specific to IIH provide biological insight and warrants mechanistic evaluation.

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[SNT Gatchaman]

A few background quotes of potential interest from intro and discussion —

It is well established that IIH occurs almost exclusively (>90%) in women with obesity in association with recent weight gain and truncal adiposity.9-11 Knowledge of the disease is, however, advancing, and IIH is no longer considered to be exclusively a central nervous system disease, with mounting evidence indicating systemic metabolic perturbation in excess to that driven by obesity.

Systemic hormonal dysregulation has been noted in IIH with a distinct profile of androgen excess identified. In addition, metabolic targeting by blocking the cortisol- generating enzyme 11β hydroxysteroid dehydrogenase type 1 has shown therapeutic potential in IIH. Patients with IIH also have a doubled risk of cardiovascular disease when compared with those with obesity alone.

The lactate : pyruvate ratio was repeatedly altered in IIH and is an established marker of anaerobic metabolism and mitochondrial energy metabolism disorders, such as oxidative phosphorylation disorders and pyruvate dehydrogenase deficiency. We identified an increased ratio at baseline in IIH participants compared with that in controls in both the CSF and serum. Elevated CSF lactate : pyruvate ratio is a feature of numerous conditions of raised ICP including traumatic brain injury, subarachnoid hemorrhage and hydrocephalus, suggesting that these metabolic alterations may be a feature of raised ICP.

Of interest, we also demonstrated a negative relationship between CSF urea and headache severity (with high CSF urea being associated with increased headache severity). These findings suggest that alteration of the CSF:serum urea gradient in IIH may be important in driving headache. The importance of urea and perturbed osmotic gradients is noted in individuals after hemodialysis who frequently experience headaches.