Midazolam is an anti-seizure treatment that can be prescribed as a rescue medication for Batten disease. Seizures occur in all types of Batten disease. Midazolam may be prescribed to people with the disease to stop clusters of seizures or seizures that last longer than usual. It should not be used in place of daily anticonvulsants.

Midazolam was originally developed as a liquid formulation by Roche, under the name Versed. It is approved and now can be administered in several ways. New midazolam formulations, such as a nasal spray, are also under investigation.

How midazolam works

Nerve cells communicate with each other via tiny electrical impulses. Seizures happen when there is an uncontrolled surge of electrical activity in the brain. In Batten disease, high amounts of a substance called lipofuscin build up in the brain, causing brain cells to function abnormally and become overactive, sending too many electrical signals to the rest of the body and causing seizures.

Midazolam falls under a class of medications known as benzodiazepines. It works by binding to a specific part of a receptor found on nerve cells called GABA receptors. Normally a neurotransmitter or chemical messenger called GABA binds to and activates this receptor. This inhibits nerve signaling, calming down the brain. Midazolam can activate the GABA receptor in place of GABA, reducing the electrical signaling and helping restore normal brain activity.

Types of midazolam

Injected midazolam

In hospital settings, midazolam can be delivered through an injection to quickly stop a seizure. It is most commonly injected deep into the muscles.

A study published in the European Journal of Paediatric Neurology demonstrated that intramuscular midazolam is as effective as rectal diazepam, a common rescue medicine.

A randomized clinical trial, carried out in a children’s emergency department in Brazil, demonstrated that intramuscular midazolam is more effective than diazepam delivered as an injection into the bloodstream.

Midazolam may also be administered as an injection into the bloodstream.

Intranasal midazolam

Intranasal midazolam is a common off-label rescue medication prescribed for Batten disease. It is prepared using a syringe filled with liquid midazolam. A mucosal atomization device is then attached to the tip of the syringe. The atomization device creates a fine spray that coats the lining of the nasal cavity, known as the nasal mucosa. The medication is absorbed by the body through this lining. If there is a lot of mucus in the nose, it should first be cleared with a tissue. Intranasal midazolam is not meant to be inhaled into the lungs.

Results of a Phase 2 clinical trial (NCT00326612) were published in the Archives of Pediatrics and Adolescent Medicine in 2010. They demonstrated that intranasal midazolam stops seizures and may take less time to work compared to rectal diazepam. It is also easier to administer in public. This supports the results of two studies published in 2002 and 2006.

Nayzilam (previously USL261) is an investigational nasal spray formulation of midazolam. It was originally developed by Proximagen and is now being further developed by UCB. It has been successfully investigated in two Phase 3 clinical trials (NCT01999777 and NCT01390220). A new drug application has been submitted and accepted by the U.S. Food and Drug Administration (FDA), and the results are expected to be announced in 2019.

Oral midazolam

Midazolam can also be taken orally. However, this formulation is not commonly used as a rescue medication as it can be difficult for the patient to swallow during a seizure.

Buccolam is an oromucosal form of midazolam by Shire Pharmaceuticals that is currently only approved in Europe. It is a solution that is delivered to the space between the gum and the cheek (the buccal cavity) using a prefilled syringe. It is absorbed into the body without being swallowed. It has been studied in several clinical trials.

Side effects of midazolam

Common side effects of midazolam are headaches, nausea, vomiting, cough, drowsiness, hiccups, sleepiness, and injection site reactions. Intranasal midazolam can also cause side effects including nasal irritation, stuffy nose, and changes in breathing.

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