11ß-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial.

Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability and investigated indicators of in vivo efficacy of the 11ß-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18-55 years with active idiopathic intracranial hypertension (>25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with matching placebo over 12 weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 39.2 (SD = 12.6) kg/m2] were randomized to AZD4017 (n = 17) or placebo (n = 14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: -2.8, 95% confidence interval: -7.1 to 1.5; P = 0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group [mean change: -4.3 cmH2O (SD = 5.7); P = 0.009] but not in the placebo group [mean change: -0.3 cmH2O (SD = 5.9); P = 0.8]. AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11ß-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure (P = 0.005, R = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11ß-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

The incidence of idiopathic intracranial hypertension in Scotland: a SOSU study.

BACKGROUND: Idiopathic intracranial hypertension most commonly affects women of childbearing age and usually causes headache and intermittent visual obscurations. Some patients suffer permanent visual loss. The major modifiable risk factor associated with IIH is obesity. Scotland has one of the poorest records for obesity in the western world, with a prevalence in 2016 of 29% in the adult population. We aimed to establish the incidence of idiopathic intracranial hypertension (IIH) in Scotland. METHODS: All new cases of IIH seen in Scotland were collected over a 1-year period. Cases were reported by ophthalmologists through the Scottish Ophthalmic Surveillance Unit (SOSU) and by neurologists directly to the investigators using encrypted NHS emails. An open dialogue was maintained between the investigators and specialist neuro-ophthalmology clinics throughout the year to minimise the risk of under-reporting. Cases were defined using the Modified Dandy Diagnostic Criteria. RESULTS: One hundred and forty-four confirmed cases of IIH were reported. One hundred and ten out of 144 patients were female and aged 15-44. The mean BMI in this group was 38.9. CONCLUSIONS: The incidence of IIH in Scotland is at least 2.65/100,000. This figure rises to 37.9/100,000 in obese females aged 15-44. This figure is higher than previously published and is probably a result of increasing levels of obesity across the nation. The significant morbidity caused by IIH, in this young population raises the question of whether enough is being done to prevent and treat Scotland's obesity crisis.

The Guillain-Mollaret triangle in action.

The Guillain-Mollaret triangle comprises the ipsilateral red nucleus in the midbrain, the inferior olive in the medulla and the contralateral dentate nucleus in the cerebellum: together, these form the dentato-rubro-olivary pathway. Pathology in this triangle disinhibits (and so activates) the inferior olivary nucleus. The olivary nucleus then hypertrophies and its rhythmical discharges may manifest clinically as oculopalatal tremor. We describe three cases with either oculopalatal tremor or MRI evidence of olivary hypertrophy caused by vascular insults to this triangle. It is not clear why only some patients have the oculopalatal tremor. Olivary hypertrophy can be confused with demyelination if the imaging is not put into clinical context. Oculopalatal tremor may occur without olivary hypertrophy since the nucleus atrophies with time. Oculopalatal tremor does not respond to medical treatment. A better understanding of the mechanism of the discharge at a cellular level may lead to more targeted medical treatments.

Symptomatic management in multiple sclerosis.

Multiple sclerosis (MS) is the commonest cause of disability in young adults. While there is increasing choice and better treatments available for delaying disease progression, there are still, very few, effective symptomatic treatments. For many patients such as those with primary progressive MS (PPMS) and those that inevitably become secondary progressive, symptom management is the only treatment available. MS related symptoms are complex, interrelated, and can be interdependent. It requires good understanding of the condition, a holistic multidisciplinary approach, and above all, patient education and empowerment.