The vestibular and oculomotor dysfunction in Fabry disease: a cohort study in China

Abstract

Objective: Whereas a few studies have evaluated vestibular involvement in Fabry disease (FD), the relationship between vestibular/oculomotor abnormalities and disease-specific biomarkers remain unclear. Therefore, we seek to evaluate these quantitatively and analyze their relationship with disease phenotype and biomarkers in FD.

Methods: This cohort study enrolled 37 Chinese FD patients registered in our center. The vestibular/oculomotor examinations were performed, including the videonystagmography, the caloric test and the video head-impulse test. Statistical analyses were made between different subgroups of patients.

Results: Visuo-oculomotor dysfunctions were found in 30/37 (81.1%) patients. Vestibulo-oculomotor dysfunctions were revealed in 9/22 (40.9%) patients. Statistical tests showed: (1) significantly higher Mainz Severity Score Index in patients with prolonged saccade latency [20(18,33) VS 13(9,22), p = 0.008] and vestibulo-oculomotor dysfunction [23(20,31) VS 9(5.5,12.5), p = 0.024], (2) significantly higher total small-vessel disease score in subgroups with prolonged saccade latency [2.5(1,3.5) VS 1(0,2), p = 0.038], defective smooth pursuit [3(2,4) VS 1(0,2), p = 0.003], defective optokinetic nystagmus [4(2,4) VS 1(0.2), p = 0.009] and vestibulo-oculomotor dysfunction [1(1,3) VS 0(0,1), p = 0.028], (3) significantly lower α-Gal A activity (μmol/L/h) in subgroups with defective saccades [0.44(0.25,1.93) VS 1.85(0.75,5.52), p = 0.015] and defective smooth pursuit [0.30(0.17,0.44) VS 0.96(0.39,2.40), p = 0.008], and (4) significantly elevated plasma globotriaosylsphingosine (ng/ml) in patients with defective saccades [74.16(11.05,89.18) VS 10.64(7.08,36.32), p = 0.034], than in patients without those abnormalities.

Conclusion: A high incidence of extensive vestibular and oculomotor dysfunction was observed in patients with FD, with the neuro-otological dysfunction being closely related to the disease burden and biomarkers like α-Gal A activity and lyso-Gb3.

Keywords: Fabry disease; cerebral small vessel disease; eye movement; globotriaosylsphingosine; mainz severity score index; vestibular disorders.

Figure 1.

Flowchart of patient enrollment.

Figure 2.

Visuo-oculomotor deficiencies in Fabry patients. A. Defective saccades of P20, showing increased latencies (black arrows), hypometria (arrow heads) and saccadic intrusions (hollow arrow); B. Defective saccades of P29, showing slow saccades (black arrows) and hypermetria (arrow heads); C. Defective smooth pursuits of P35, showing saccadic pursuits and reduced pursuit gain toward left (0.30) and right (0.33); D. Impaired optokinetic nystagmus of P35, showing reduced gain toward left (0.13) and right (0.10).

Figure 3.

Clinical characteristics of the patients with/without certain visuo-oculomotor deficiencies. (*: p < 0.05; **: p < 0.01).

Figure 4.

Vestibulo-oculomotor examinations and hearing loss in FD patients. A. Caloric test in P19, showing decreased SPV bilaterally (LC+LW = 2.5°/s, RC+RW = 3.3°/s), indicating bilateral weakness of horizontal semicircular canals; B. vHIT in P19, showing reduced gain in 3 semicircular canals bilaterally (LA, LP and RA), inconsistent with the distribution of a single nerve or vessel; C. Pure tone audiometry in P19, showing impaired threshold on the high frequency of the left side (35 dB HL on 4 kHz, 45 dB HL on 8 kHz). D. Dysfunction of semicircular canals in all the patients identified by caloric test and vHIT. E. Comorbidity of vestibular impairment and hearing loss in the patients.

Figure 5.

Clinical characteristics of the patients with/without visuo-oculomotor or vestibulo-oculomotor deficiencies. (*: p < 0.05; **: p < 0.01).

Figure 6.

Schema of the brain structures related with visuo-oculomotor control (left row) and the manifestations of damage to them (right row). (PIVC, parieto-insular vestibular cortex; PIC, posterior insular cortex; FEF, frontal eye fields; DLPFC, dorsolateral prefrontal cortex; PEF, parietal eye fields; basal ganglia, BG; GEN, gaze-evoked nystagmus; SC, superior colliculus; INC, the interstitial nucleus of cajal; PPRF, paramedian pontine reticular formation; DRN, dorsal raphe nucleus; VN, the vestibular nuclei; NPH, the nucleus prepositus hypoglossi.).