Bilateral cranial nerve 6 palsy in a patient with multiple sclerosis and vitamin D-dependent rickets

ABSTRACT

The development of multiple sclerosis (MS) is multifactorial. Elevated levels of vitamin D may lower the risk and reduce relapses by immunomodulatory mechanisms. Conversely, vitamin D-dependent rickets (VDDR), an inheritable form of rickets secondary to impairment in vitamin D synthesis or action, may increase MS risk. This has been described in three patients with VDDR type 1A. Here, we present a patient with VDDR type 2 – unclear if type 2A or 2B based on historical genetic testing – who subsequently developed MS. She presented with 8 weeks of binocular horizontal diplopia and was found to have 8 prism dioptres of esotropia in primary gaze and a mild limitation of abduction in both eyes. Radiological workup was consistent with MS demyelination. She was started on solumedrol infusions, with full resolution of the esotropia and abduction deficits. She has since been transitioned to ocrelizumab with vitamin D supplementation and has not had a relapse to date. It is important to consider MS in patients genetically predisposed to low vitamin D levels or functional impairment, as with VDDR. Vitamin D supplementation can achieve remission in some forms of VDDR, and its role in MS prevention in these patients should be considered. In patients with type 2A or 2B VDDR, who have impairment in receptor function, additional treatment modalities require investigation. Lastly, demyelination is a rare cause of bilateral cranial nerve 6 palsy. This case illustrates the importance of considering MS in cranial nerve palsies, particularly in patients with vitamin D deficiencies or functional impairment.

Introduction

Multiple sclerosis (MS) is an autoimmune chronic inflammatory disorder of the central nervous system with zones of inflammation and resulting demyelination with plaque formation. While the cause is unknown, it is considered to be multifactorial with genetic and environmental factors playing a role. Of the environmental factors, sunlight and vitamin D are thought to be influential, particularly given the geographic variation in MS prevalence.¹ Sunlight is the main source of vitamin D, and low sunlight exposure (and thus low levels of vitamin D) is thought to increase the risk of MS.² High levels of vitamin D are thought to lower the risk of MS and reduce relapses by possible immunomodulatory mechanisms, such as the induction of T regulatory cells and cytokines including interleukin-10 and tumour necrosis factor-alpha.^2,3

Vitamin D-dependent rickets (VDDR) is an inheritable form of rickets secondary to impairment in vitamin D synthesis and action. As such, this condition may be linked to MS. VDDR type 1A, also known as pseudo-vitamin-D-deficient rickets, is inherited in an autosomal recessive fashion and is caused by a deficiency of 1-alpha hydroxylase due to a mutation in CYP27B1.⁴ Supplementation with calcitriol, 1,23 dihydroxyvitamin D3, or 1 alpha-hydroxyvitamin D3 can achieve remission. Type 1B is also autosomal recessive and is due to a deficiency in 25-hydroxylase secondary to a mutation in CYP2R1; it can also be treated with calcitriol.

Type 2A, commonly known as vitamin D-resistant rickets, is due to a defect in the vitamin D receptor gene, thus causing resistance to 1,25-dihydroxyvitamin D (vitamin D 1,25-[OH]). It is similarly autosomal recessive; however, these patients tend to have severe, early-onset rickets, and supplementation may not improve the condition, particularly in patients with nonsense mutations in the DNA-binding domain. Type 2B, whose inheritance pattern is unknown, is clinically similar to type 2A but is due to abnormal expression of a hormone response element-binding protein, which interferes with the vitamin D receptor function. In these patients, there are low levels of 25-hydroxyvitamin D (vitamin D 25-OH) with compensatory elevated levels of vitamin D 1,25(OH). Types 2A and 2B can only be distinguished by genetic testing.^5,6

Given that vitamin D deficiency may place patients at risk for MS, it is possible that patients with VDDR may also be at an increased risk. In a case series examining three patients in two families with VDDR type 1A (confirmed by genetic testing with a mutation in CYP27B1), all three patients developed MS.⁷ Here, we present a case of a patient with type 2 VDDR who subsequently developed MS.

Case report

A 50-year-old female with a history of myopia, asthma, hyperlipidaemia, hypothyroidism, pre-diabetes, and type 2 VDDR presented to the ophthalmology clinic with an 8-week history of binocular horizontal diplopia, worse in the distance. On the initial examination, she was found to have a visual acuity of 20/30 in the right eye (OD) and 20/25 in the left eye (OS). She had normal intraocular pressures, pupillary responses, colour vision, and confrontational visual fields. She did, however, have a mild limitation in abduction in both eyes. She also had an esotropia of 8 prism dioptres on primary gaze at distance and 2 prism dioptres at near, as well as 10 prism dioptres on right gaze and 14 prism dioptres on left gaze. Her anterior ocular and dilated fundus examinations were otherwise unremarkable.

She had magnetic resonance imaging (MRI) of the brain and orbits, which showed non-enhancing signal abnormality of the abducens fascicles and midline dorsal pontine tegmentum (Figure 1), likely due to a demyelinating plaque. The MRI also revealed many periventricular and subcortical white matter signal abnormalities, suspicious of demyelination related to MS (Figure 2).

Figure 1.

Axial fluid-attenuated inversion recovery sequence through the level of the pons demonstrating a hyperintense lesion in the dorsal pons in the region of the bilateral cranial nerve 6 fascicles (arrowed).

Figure 2.

Sagittal fluid-attenuated inversion recovery sequence demonstrating multiple ovoid hyperintense lesions in the periventricular white matter compatible with multiple sclerosis (arrowed).

On further questioning, she reported an episode of right-sided weakness and paraesthesia 14 years previously with incomplete resolution. Therefore, she was diagnosed with relapsing-remitting MS. Her laboratory work-up was unremarkable apart from a low vitamin D 25-OH level of 24 ng/mL and an elevated vitamin D 1,25(OH) level of 388 pg/mL, consistent with her history of type 2 VDDR. She was started on solumedrol, with resultant symptomatic improvement after a total of three infusions. Her visual acuity improved (20/25 OD and 20/20 OS); she was orthotropic and regained full extraocular motility in both eyes. She was transitioned to ocrelizumab maintenance therapy with vitamin D3 1000 international units daily. She had had no further relapses over a 6-month follow-up period.

Discussion

As aforementioned, low vitamin D levels are thought to correlate with an increased MS risk and vice versa. In a prospective, case–control study of 257 patients with MS, vitamin D levels were studied and compared against matched controls. A higher serum level of vitamin D was associated with a lower risk of MS in White Caucasians, particularly those under the age of 20.⁸ Similarly, the MS Sunshine study found that serum vitamin D levels were associated with a lower MS risk in White Caucasians.⁹ Given this association, the risk of MS in patients with VDDR should certainly be considered. Our case, in addition to the three cases published by Torkildsen and colleagues, illustrates how these patients may indeed be at risk for MS.

The association between vitamin D levels and the risk of MS may not be the same among various races. The previously mentioned study by Munger et al. found that in Hispanics and Blacks, who generally had even lower levels of vitamin D, there was no association between vitamin D and MS risk.⁸ The MS Sunshine study also did not find an association between vitamin D levels and MS in Black or Hispanic patients. However, it did find that lifetime ultraviolet radiation exposure was associated with a lower MS risk in Blacks and White Caucasians but was not statistically significant in Hispanics.⁹ Therefore, the association between vitamin D levels and MS risk may vary among populations, and additional studies could help further assess these distinctions. VDDR has been seen in a variety of populations from Norway to Korea.^4,7 Thus, the relationship between race, other genetic factors, and environment is worth further investigation as it may impact the likelihood of VDDR patients developing MS.

In regard to additional genetic factors, the three patients in the aforementioned case series by Torkildsen et al. were also later found to carry the MS risk allele HLA DRB1*15. This allele may also play an influential role in the development of MS, based on the interaction with vitamin D.¹⁰ The development and progression of MS is a complex, multifactorial entity that may be influenced by vitamin D, and whose actions may also be influenced by other environmental and genetic factors, which require further investigation.

Nonetheless, with the scientific evidence available, supplementation with vitamin D should be considered in all patients with VDDR. Studies also indicate that vitamin D supplementation may have a valuable role in patients with MS. A meta-analysis of vitamin D supplementation in MS found a beneficial role, however with an uncertainty in the appropriate dose, and with possible worse outcomes with higher doses.¹¹ In patients with VDDR, vitamin D supplementation is known to be beneficial in achieving remission in types 1A or 1B and possibly in types 2A or 2B.⁶ Thus, not only may early vitamin D supplementation help prevent the development of MS, it may help prevent relapses later on and can help achieve remission in VDDR itself. While the exact role of vitamin D supplementation in VDDR type 2A or 2B is unknown, given the potential benefit in all forms of MS, our patient was treated with vitamin D supplementation acknowledging that additional treatment modalities for types 2A and 2B require research. Additional studies examining supplementation and dosages are warranted.

Furthermore, our case illustrates that those with impaired vitamin D receptor function, and not only a deficiency in vitamin D, are at risk. Patients with type 2A or 2B VDDR are known to have elevated levels of vitamin D 1,25(OH), as with our patient. Despite this, the impairment in receptor function can result in similar clinical findings as vitamin D deficiency. However, in such cases, supplementation with vitamin D alone may not achieve remission. Hence, further investigation into treating patients with VDDR type 2A or 2B, who are known to at times respond poorly to calcium or calcitriol supplementation,⁵ is needed.

Lastly, our case illustrates the importance of considering MS in patients who present with cranial nerve palsies. One retrospective review of 69 cases of bilateral cranial nerve 6 palsy found the most common aetiologies to be trauma, vascular lesions, and tumour, accounting for 85.5% of patients.¹² Another study, examining 578 cases of single pairs of cranial neuropathies, noted the cranial nerve 6 palsy to be the most common, accounting for 40.5% of cases. Demyelination was the determined aetiology in 4/234 (1.7%) of these cases.¹³ Thus, MS should be included in the differential diagnosis for patients with cranial nerve palsies and perhaps more so with concurrent vitamin D deficiencies.

In summary, this is the first documented case of MS development in a patient with type 2 VDDR to our knowledge. The Norwegian case series by Torkildsen et al. illustrates the risk of MS development in patients with type 1A VDDR. Combined, these cases indicate that patients with either a deficiency in vitamin D or an impairment in its action (namely, VDDR type 1A, 1B, 2A, or 2B) could be at risk for MS. Thus, any patient with VDDR, even if presenting with cranial nerve palsies alone, should be investigated for MS. Furthermore, these patients would likely benefit from close monitoring and vitamin D supplementation to prevent MS development, avoid MS relapses, and/or achieve remission from VDDR. Additional studies exploring the relationship between genetic factors, environment, race, and the like should be explored, as should the role of vitamin D supplementation in preventing development or relapses of MS.

Funding Statement

The authors reported that there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the authors.