Fabry disease (neurological manifestations)

Fabry disease, also known as Anderson-Fabry disease, is a multisystem X-linked lysosomal storage disorder, with frequent neurological manifestations. These are either due to direct involvement of the central nervous system, the peripheral nervous system and/or the autonomic nervous system. This could also be due to secondary involvement (e.g. thromboembolic stroke from cardiac involvement, chronic hypertensive encephalopathy and hypertensive hemorrhages secondary to renal involvement).

This article would be focusing on the neurological manifestations. For a general discussion of epidemiology, pathology and treatment, please refer to the article on Fabry disease.

Clinical presentation

The clinical presentation of patients with neurological involvement by Fabry disease depends on the specific manifestations. Cryptogenic stroke in young patients is a common presentation ^1,2.

Central nervous system

Neurovascular presentations dominate central nervous system presentations including ¹:

• ischemia

  • acute cerebral infarction

    • posterior circulation infarcts (most common)

    • anterior circulation infarcts

  • lacunar infarcts

  • watershed infarcts

  • chronic small vessel ischemia

• cerebral hemorrhage

  • primary hypertensive hemorrhages

• complications of basilar dolichoectasia

  • brainstem compression

  • brainstem infarction

  • rupture and subarachnoid hemorrhage

  • basilar artery thrombosis

In addition to acute presentation with stroke and hemorrhage, accumulation of small vessel ischemia also contributes to cognitive decline.

Peripheral nervous system

Acroparesthesia is a common manifestation, more so than the above described ischemic changes, and can be debilitating ⁶.

Autonomic nervous system

Autonomic (sympathetic) nervous system involvement can lead to gastrointestinal autonomic dysfunction.

Pathology

Most of the primary central nervous system manifestations of Fabry disease can be attributed to vascular dysfunction. This is believed to be a multifactorial process with damage resulting from deposition of glycolipids (e.g. globotriaosylceramide) in the vascular media and endothelium, as well as higher production of oxygen free-radicals and hyperperfusion ^1,2. In larger vessels, this tends to weaken the vessel walls resulting in dilatation (dolichoectasia), whereas in small vessels this results in thickening of the wall with ensuing stenosis ¹. This is often exacerbated by coexisting hypertension due to renal involvement, endothelial dysfunction and prothrombotic states.

There is a predilection for the vertebrobasilar circulation which accounts for disproportionate frequencies of posterior circulation strokes and basilar artery dolichoectasia ¹.

In 20-25% of patients, mineralization of deep grey matter structures is identified (best seen on MRI as intrinsic high T1 signal). This is believed to be due to local hyperperfusion ¹.

Radiographic features

CT

CT and CTA can demonstrate many of the features of Fabry disease, although generally these are better demonstrated on MRI (see below).

It is worth noting that occasionally hyperdensity in the pulvinar, located posteriorly within the thalamus, can be seen on CT and would correlate to the more frequently seem MRI pulvinar sign ¹.

MRI

In addition to features of cortical or lacunar infarcts, MRI may demonstrate additional sequence-specific findings ¹:

• T1

  • high signals in the deep grey matter

  • pulvinar sign: may be present in up to 20-25% of patients (although contemporary data suggests it is much less common at ~3% ⁷), almost exclusively males ^1,4

• T2

  • white matter hyperintensities particularly in the frontal and parietal lobes, can be seen in both symptomatic and asymptomatic patients

• SWI: cerebral microhemorrhages ^3,8

• MRA

  • dolichoectasia ^1,2,5,8

    • mostly affects larger arteries ¹

    • vertebrobasilar artery (most common)

    • anterior circulation: internal carotid arteries and proximal middle cerebral and anterior cerebral arteries

  • stenosis

    • mostly affects smaller arteries ¹

Treatment and prognosis

For discussion of systemic treatment, please refer to the general article on Fabry disease. It is worth noting, however, that MRI is used to monitor treatment response. Both T2 and T1 changes have been reported to regress with treatment if instituted early enough ². Unfortunately, it has also become apparent that enzyme replacement therapy does not prevent progressive vascular dysfunction and the ensuing complications ².