SMA May Carry Higher Risk of Fluid Buildup in Brain, Study Finds

Spinal muscular atrophy (SMA) patients may at a fourfold greater risk of hydrocephalus, or abnormal accumulation of cerebrospinal fluid (CSF) in the brain, than their healthy peers, a large U.S. health record-based study suggests.

Data also showed that patients younger than 2 years, those most likely to have more severe disease, had the highest incidence of hydrocephalus.

This brain condition has been reported in patients treated with Spinraza (nusinersen), which is delivered into the CSF. But these results, based on health records before the therapy’s approval, strongly suggest that hydrocephalus may be part of SMA’s natural disease course.

The study, “The incidence of hydrocephalus among patients with and without spinal muscular atrophy (SMA): Results from a US electronic health records study,” was published in the Orphanet Journal of Rare Diseases.

The CSF, which bathes the spinal cord and the brain, not only protects these structures from damage, but also serves as a nutrient source and waste removal system for the brain. An abnormal buildup of this fluid in the hollow cavities of the brain, causing pressure on the brain’s tissues, is called hydrocephalus.

The condition is caused “by obstruction of CSF circulation, due to inadequate absorption of CSF, or less often, by overproduction of the CSF,” the researchers wrote. It can lead to serious brain damage, and if untreated is usually fatal.

Hydrocephalus may be present at birth or may develop over time as a result of injury or disease. When diagnosed at birth, the serious but treatable condition is estimated to occur in about 78–106 cases per 100,000 births. It can affect anyone at any age, but it is most common in infants and older adults.

While there are reports of hydrocephalus in some SMA patients since 2014, the incidence (or rate of new cases) of hydrocephalus “in the SMA population in relation to the general population is currently unknown,” the team wrote.

A small number of hydrocephalus cases have been reported in patients treated with Biogen’s Spinraza outside clinical trials. Spinraza, administered directly into the CSF, became the first disease-modifying therapy approved for SMA in the U.S in 2016.

Without knowing the incidence of hydrocephalus in untreated SMA patients, it is difficult to determine if the neurologic condition is a side effect of Spinraza or part of SMA’s natural course.

Researchers at Biogen retrospectively analyzed electronic health records (EHR) from the U.S. Optum database to estimate hydrocephalus incidence in SMA patients and in matched unaffected individuals between Jan. 1, 2007 and Dec. 22, 2016 (the day before Spinraza’s U.S. approval).

The Optum database is one of the largest and broadest de-identified EHR data assets in the U.S., with records covering about 100 million people.

Using specific health codes, the researchers identified 5,354 SMA patients diagnosed during that period, who were matched by age and sex to 5,354 non-affected individuals (used as controls). SMA patients’ mean age was 45 (range, 0–86 years) and about half (53%) were male. They were followed for a mean of 7.6 years.

Results showed that new cases of hydrocephalus, identified through respective health codes, occurred in 42 SMA patients (mean age, 46.9 years) and nine unaffected individuals (mean age, 59.7 years).

In both groups, the greatest number of hydrocephalus cases occurred in people older than 50 (26 cases in SMA patients, and six cases in controls). Five cases were identified in children younger than age 2, all with an SMA diagnosis.

Hydrocephalus incidence rates per 100,000 person-months (the gathered follow-up months of all individuals in the study) were 15.5 among SMA cases and 3.3 among non-SMA controls. This represented a 4.7 higher risk of hydrocephalus in the SMA group.

An increased risk of hydrocephalus among SMA patients was observed in both males and females, and across ages groups.

Notably, the neurological condition was found to occur more frequently in males than in females among both patients and controls. The highest incidences were found in SMA patients younger than 2 years (likely those diagnosed with more severe forms of the disease), and in adolescents/young adults and adults older than 50 among the control group.

The most frequent type of hydrocephalus was obstructive hydrocephalus (blocking of CSF flow) in SMA patients (37.5%) and idiopathic normal pressure hydrocephalus (enlarged brain cavities without increased pressure) in controls (60%). The team noted that CSF flow obstruction in SMA may be indicative of the disease’s whole-body nature.

While routine brain imaging in SMA patients may contribute to a higher detection of hydrocephalus without symptoms (asymptomatic), the researchers considered that it was unlikely that most of these cases were asymptomatic and entirely responsible for the increased incidence among SMA patients.

These real-world findings from a pre-Spinraza period highlighted that SMA patients had a four times greater risk of developing hydrocephalus than controls.

“Future studies on this topic are needed to determine whether hydrocephalus is part of the natural history of SMA in some patients, and whether there is a causal association between SMA and hydrocephalus,” the researchers wrote.

Still, these findings “are important for the optimization of care and treatment of patients with SMA,” and should prompt further research to “determine if there is a temporal relation between the occurrence of hydrocephalus and treatment with [Spinraza] or other therapies.”