Recurrent abducens nerve palsy and hypophosphatasia syndrome

Abstract

A 47-year-old woman presented with six episodes of horizontal binocular double vision over a 2-year period. CT imaging was significant for extensive dural calcification in the spine and calcification of the skull base, likely involving Dorello’s canal. Biochemical testing revealed a persistently low alkaline phosphatase level. Recurrent nerve palsy may possibly be induced by mechanical compression of the sixth cranial nerve in Dorello’s canal from calcification due to hypophosphatasia syndrome.

Background

The abducens nerve (AN) innervates the ipsilateral lateral rectus for eye abduction. It has a long intracranial course, and there are three anatomic areas where the sixth nerve is particularly susceptible to injury: the pontomedullary junction, Dorello’s canal and cavernous sinus. Dorello’s canal is an osteofibrous canal composed of the petrosphenoid ligament (Gruber’s ligament), petrous apex and the lateral border of the upper part of the clivus, where dural tethering renders it vulnerable to intracranial pressure shift and trauma. The AN courses through Dorello’s canal in the petroclival venous confluence. Compression and stretching injury of the nerve can occur within the canal either by direct injury or interfering with its blood supply.

Hypophosphatasia syndrome is an autosomal dominant or recessive inborn error of metabolism caused by loss of function mutations within the gene that encodes the tissue non-specific alkaline phosphatase (ALP). Adult Hypophosphatasia usually presents in middle age. Mild hypophosphatasia phenotype may result from gene mutations exhibiting residual ALP activity.¹ The triad of low ALP, pathological fractures and ectopic calcification should lead to investigation for hypophosphatasia syndrome.² Treatment of this condition in adults is largely supportive.

We present a case of recurrent sixth nerve palsy that may be induced by mechanical compression of the nerve in Dorello’s canal as a result of extensive calcification due to hypophosphatasia syndrome.

Case presentation

A 47-year-old right handed woman presented with six episodes of recurrent sixth nerve palsies, one on the right and five on the left. In September 2015 she developed double vision, first noticed when driving. This was horizontal, worse on looking to the right and at distance. There was no headache, other focal neurological or constitutional symptoms. Her diplopia resolved after a few months. This right sixth nerve palsy was attributed to microvascular disease. She had recurrent episodes of diplopia, worse on looking to the left 10, 16, 20, 24 and 28 months later. In each case double vision was binocular and horizontal. There was no associated headache, extraocular pain, other focal neurological deficit or constitutional symptoms. With every episode, the diplopia was at its worst at about 1 week from onset (maximal separation of images) with gradual recovery starting around 8 weeks. She had complete recovery after the initial three episodes. After the last two episodes she had minor persistent diplopia in left lateral gaze.

The patient has a background of ulcerative colitis in remission for 6 years, hypertension, high cholesterol and chronic neck pain. She is factor V Leiden positive diagnosed after screening for thrombosis in other family members but had never had a thrombosis herself. She quit smoking 12 years ago and drinks 3–4 units of alcohol per week. Her only medication at her first presentation was meloxicam 7.5 mg daily. She was prescribed aspirin, atorvastatin, telmisartan after her first episode. Aspirin was changed to clopidogrel after the second episode. These medications were ceased after her fourth episode.

On clinical examination at the time of her sixth episode, she was in sinus rhythm with a blood pressure of 129/81 mm Hg. Salient findings on neurological examination revealed a visual acuity of 6/5-1 (incorrect letter) and 6/6 on the right and left, respectively. Pupils were size 7 on the right, 8 mm on the left, with normal reactivity to light and accommodation. Colour vision, visual fields and funduscopic examination were normal. There was no ptosis. Extraocular movements revealed a complete absence of left eye abduction. Remaining extraocular movements were normal. There was no ocular or limb fatigability. The remaining cranial nerve examination and neurological examination were essentially normal. Cardiovascular examination was normal. Review of previous records from neurology clinics during episode 1–5 revealed similar findings.

Investigations

A summary of investigations during all of the episodes revealed normal full blood count, renal function and thyroid function tests. Liver function tests were remarkable for a low ALP of 12 (30–110 U/L) but was otherwise normal. Autoimmune and vasculitic testing was normal. Fasting cholesterol was 4.5 mmol/L, triglycerides 1.6 mmol/L, low density lipoprotein: 2.5 mmol/L, high density lipoprotein 1.3 mmol/L. Acetylcholine receptor antibodies and anti-MUSk antibodies were negative. Edrophonium challenge test was negative. Single fibre electromyography was normal. Spinal tap during episode 4 showed a cerebrospinal fluid (CSF) opening pressure of 16.5 cm of H₂0. Microscopy showed 1x10⁹and 127x10¹²red cells. Glucose was 3.2 mmol/L, protein 0.55 g/L. Oligoclonal bands were negative. Cytology was negative for malignancy.

MRI scan of the brain with magnetic resonance angiography (MRA) was performed, including with gadolinium, after episode 2 and during episodes 1, 3, 4 and 5 Intracranial MRA was normal. There were no features of intracranial hypotension and CT myelogram showed no CSF leak. CT temporal bones showed extensive calcification at the skull base and posterior fossa, more prominent on the left at the petroclival region with potential involvement of Dorello’s canal (figure 1). CT spine also showed extensive calcification, including dural calcification throughout the spine. This was most extensive in the cervical spine, with idiopathic skeletal hyperostosis and ossification of the posterior longitudinal ligament, causing mild to moderate central canal stenosis.

Figure 1.

Axial CT at the level of the Dorello canal demonstrates thick dural calcification lining the petrous apex and clivus bilaterally. The prepontine opening of the Dorello canal is not clearly visualised due to ‘heaped’ dural calcification lining the clivus.

Metabolic bone study again showed a very low ALP, with normal procollagen type 1 n propeptide which is a marker for new bone formation. Inorganic phosphate was elevated at 1.89 (0.70–1.50 units). Plasma corrected calcium 2.41 (2.10–2.60 mmol/L), 25-hydroxyvitamin D 65 (>50 nmol/L), parathyroid hormone 5.0 (1.6–6.9 pmol/L) and magnesium 0.86 (0.7–1.10 mmol/L) were all unremarkable. Serum vitamin B₆ was elevated at 7140 (35–110 nmol/L). Vitamin B₆ levels were also measured in the CSF using high performance liquid chromatography. While this method is not validated for routine measurement in the CSF the values were significantly increased in our patient; approximately 13 times the median value of patient control values. CSF analysis did not show crystal deposition. Plasma and urine biochemistry was consistent with hypophosphatasia.

ALPL gene analysis revealed a compound heterozygous mutation. Two heterozygous missense variants. C.50C>T (p.Ser17Phe)—approximately 19% residual function. C.119C>T (p.Ala40Val)—approximately 2% residual function. NM_000478.5(ALPL):c.[50C>T](;)[119C>T] p.[(Ser17Phe(;)Ala40Val)]. Results were consistent with a clinical diagnosis of hypophosphatasia.

The patient’s mother and maternal grandmother both had early loss of teeth around 18 years of age, although the patient herself has not had any significant dental issues in adolescence or adulthood. Clinically this still raised the possibility of the odontoid form of the disease. However a compound heterozygote mutation is not typically in keeping with this family history. Genetic testing of the patient’s mother has been proposed to see whether the identified mutations are in cis or trans. The patient has two adolescent sons who do not have any clinical features of hypophosphatasia. ALP levels were measured in the patient’s children, siblings, mother and maternal grandmother. While some members had low/normal values, no one had an ALP level nearly as low as the patient. It is worth noting that ALP concentrations with respect to age specific reference intervals are difficult to interpret in the adolescent age group due to rapid bone growth.

Differential diagnosis

Isolated recurrent sixth nerve palsy is uncommon. In adults>50 years of age, the differential diagnosis of an isolated chronic recurrent sixth nerve palsy most commonly includes the following: vasculopathy related to hypertension and diabetes mellitus, dolichoectasia/aneurysm, recurrent painful ophthalmoplegic cranial neuropathy, sphenoiditis, familial recurrent sixth nerve palsy and tumour.^3–11

Treatment

The current management of the patient remains supportive as there is limited evidence for enzyme replacement or other medical therapies. A neurosurgical opinion was sought, and surgical intervention was not considered a viable option. A possible underlying inflammatory component was considered due to the relapsing and remitting nature of the disease. A short trial of high dose prednisolone and colchicine did not seem to alter the course of the disease.

Outcome and follow-up

The patient continues to have ongoing episodes of diplopia, predominantly on the left side, with shorter periods of remission between episodes. There is concern that the diplopia may become permanent. The use of botox therapy may be considered in the future.

Discussion

In our patient we hypothesise that extensive calcification of the base of skull and Dorello’s canal resulted in recurrent sixth nerve injury. Severe narrowing of Dorello’s canal was seen bilaterally but worse on the left. This supports the occurrence of the bilateral sixth nerve palsies in this patient with increased frequency of episodes on the left.

The exact pathophysiological mechanism of the relapsing and remitting course of the sixth nerve palsy remains unclear. Pyridoxine deficiency cranial neuropathy was initially thought to be the cause of the ANpalsy; however, a trial of high dose pyridoxine failed to improve the nerve palsy or prevent a recurrence. Having ruled out other causes for the palsy, compression of the AN in Dorello’s canal with episodic demyelination was considered to be the most plausible explanation.

There have been reports of space occupying lesions like chondrosarcomas and other skull base tumours causing relapsing-remitting sixth nerve palsy.^{12 13} Intermittent compression by a structural lesion could create a cycle of demyelination of the nerve and then remyelination to cause recovery of function. This phenomenon of a relapsing-remitting course has also been shown to occur in other oculomotor nerves. In experimental animal studies, after optic nerve crush injury early axonotomy and demyelination was noted but despite continued compression, there was restoration of conduction.¹⁴ A similar process is plausible with the sixth nerve. An alternative mechanism could be direct compression of the arterial supply to the sixth nerve, which can lead to ischaemia followed by aberrant regeneration of the sixth nerve resulting in recovery.

Absence of typical vascular risk factors in a patient with an isolated cranial neuropathy should prompt the clinician to look for an explanation other than microvascular ischaemia. Compressive lesions may sometimes present with a relapsing-remitting course of AN palsy. Although it is common practice to obtain neuroimaging in a patient with recurrent cranial neuropathies, it is important that along with brain parenchymal abnormalities, attention be paid to the bony architecture.

To our knowledge this is the first case of a patient with recurrent sixth nerve palsy which may be induced by compression in the Dorello’s canal from excessive calcification secondary to hypophosphatasia syndrome.

Learning points.

• Patients presenting with isolated sixth nerve palsy with no definite vascular risk factors must have further investigations to look for an underlying aetiology.

• Neuroimaging should be carefully reviewed to detect not only brain parenchymal issues but also bony architectural abnormalities.

• CT is a better tool for detection of skeletal abnormalities than MRI. Diffuse bony abnormality can be missed on MRI brain.

• Hypophosphatasia syndrome presenting in an adult is a very rare entity. Persistently low alkaline phosphatase levels with extensive ectopic calcification should prompt appropriate investigations.