Sixteen syndrome: a rare presentation of central demyelination
- 1 Neurosciences, Monash University Faculty of Medicine Nursing and Health Sciences, Melbourne, Victoria, Australia
- 2 Neurology, Alfred Health, Melbourne, Victoria, Australia
- 3 Rheumatology, Box Hill Hospital, Box Hill, Victoria, Australia
- 4 Neurology, Box Hill Hospital, Box Hill, Victoria, Australia
- 5 Neurosciences, Eastern Health, Monash University, Clayton, Victoria, Australia
- Correspondence to Dr Francesca Bridge; francesca.mary.bridge@gmail.com
Abstract
This case illustrates two diagnostic challenges for clinicians: the rarely described sixteen syndrome and the relationship between tumour necrosis factor (TNF)-alpha inhibitors and central demyelination. Sixteen syndrome affects horizontal eye movements and the facial nerve bilaterally reflecting a lesion in the posterior pontine tegmentum, adjacent to the fourth ventricle. Given its rarity and complexity of clinical signs, this syndrome risks misdiagnosis and mismanagement. The relationship between TNF-alpha inhibitors and demyelination is a complex issue in which causality is yet to be established. This diagnostic challenge poses a management dilemma for clinicians.
Background
We present a case of central nervous system (CNS) demyelination, clinically manifesting in the rarely described ‘sixteen syndrome’, in the setting of tumour necrosis factor (TNF)-alpha inhibitor use. TNF-alpha inhibitors are highly effective therapies for specific autoimmune rheumatological, dermatological and gastrointestinal disorders.1 Although they are generally considered safe, a number of neurological side effects have been reported in the literature.2 Reports of peripheral and central demyelination have been described but an exact causal relationship is yet to be established.2–7
Sixteen syndrome is characterised by impairment of the horizontal eye movements in addition to facial diplegia and is caused by a lesion involving the posterior pontine tegmentum.8 Despite the known association between demyelination and cranial nerve (CN) lesions, the clinical presentation of sixteen syndrome is rare.
This case report is aimed to raise awareness of ‘sixteen syndrome’ and the entity of CNS demyelination in the setting of TNF-alpha inhibitor use, in order to expedite diagnosis and facilitate appropriate management.
Case presentation
A woman in her 40s presented to hospital with horizontal conjugate gaze palsy and facial diplegia. One week prior to presentation, she had experienced gradual onset of horizontal diplopia. Three days later, she developed bilateral facial diplegia, with initial symptoms of drooling from the corner of her mouth and inability to close the right eye. There was no associated upper limb or lower limb weakness or dysaesthesia. She did not experience any bladder or bowel dysfunction.
Clinical examination confirmed the presence of bilateral adduction paresis and bilateral abduction nystagmus, consistent with bilateral internuclear ophthalmoplegia, bilateral lower motor neuron facial nerve palsies and mild asymmetrical hyper-reflexia. The impaired eye movements progressed over subsequent days to a complete horizontal paresis, indicating bilateral abducens nucleus involvement. Vertical eye movements and convergence were intact. There were no other CN abnormalities. These examination findings localise to a lesion within the pons given the involvement of the bilateral involvement of CN III, VI and VII and the medial longitudinal fasiculus (MLF). Upper limb and lower limb neurological examination showed asymmetrical hyper-reflexia more significant on the right than the left, suggesting upper motor neuron involvement, either within the brain or spinal cord. However, plantar reflexes were downgoing. The remainder of the neurological examination was unremarkable.
Six months prior to her current presentation, the patient had experienced bilateral paraesthesias of her feet lasting several weeks. A lumbosacral MRI scan and nerve conduction studies were unremarkable.
Her medical history was significant for ankylosing spondylitis diagnosed 3 years prior having presented with inflammatory lumbar back pain. She fulfilled the Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis.9 10 Plain X-ray revealed bilateral sacroiliitis (New York criteria grade 2), positive HLAB27, erythrocyte sedimentation rate 30 mm/hour and C reactive protein 10 mg/L. There were no extra-axial manifestations of spondyloarthritis. Antinuclear antibody was positive with a titre of 1:160 and speckled staining pattern. Extractable nuclear antigens, double-stranded DNA and complement were normal. Adalimumab was commenced in line with international guidelines.11
Investigations
Investigations included a lumbar puncture which revealed unmatched oligoclonal bands in the cerebrospinal fluid (CSF), however was otherwise unremarkable with two lymphocytes and normal biochemistry. Infectious aetiologies were felt unlikely and therefore not explored. Myelin oligodendrocyte glycoprotein antibodies and neuromyelitis optica (NMO) antibodies were negative. An MRI scan of the brain showed multifocal demyelination including two periventricular lesions perpendicular to the lateral ventricle (‘Dawson fingers’); notably, there was a non-enhancing ovoid lesion in the posterior pontine tegmentum inferiorly bridging the inferior cerebellar peduncles bilaterally without evidence of diffusion restriction (figure 1). An MRI scan of the spine, performed 3 weeks after her initial presentation, showed multifocal short segment spinal demyelination with lesions at C1, C2, C3, C4, C5, C6, T8 and T11 variably involving the posterior, central, lateral and anterior aspects of the cord (figure 2). Visual evoked potentials were not performed.
MRI of the brain, axial fluid-attenuated inversion recovery showing hyperintense ovoid lesion in the posterior pontine tegmentum.
MRI of the spine, sagittal Short Tau Inversion Recovery (STIR) demonstrating short segment eccentric cord plaques at C3 and C4, corresponding to axial T2 image at C3 demonstrating the eccentric plaque at the right lateral aspect of the cord.
Differential diagnosis
According to the 2017 revised McDonald criteria,12 our patient fulfilled the criteria for multiple sclerosis (MS) based on the presence of multifocal demyelinating CNS lesions in at least two of the typical MS locations (brainstem, periventricular and spinal cord) and the presence of oligoclonal bands in the CSF. However, in light of her previous TNF-alpha inhibitor exposure, the treating team considered a number of differential diagnoses. These included MS, independent of the TNF-alpha inhibitor; exacerbation of previously undiagnosed MS in part triggered by the TNF-alpha inhibitor; or TNF-alpha-induced CNS demyelination. The possibility of neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody disease (MOGAD) were considered; NMO and MOGAD antibodies were negative.
Treatment
The patient’s initial management included ceasing adalimumab, commencing a 3-day course of pulsed intravenous 1 g methylprednisolone and vitamin D therapy. The patient required a further 3-day course of intravenous methylprednisolone 2 weeks later for ongoing disabling symptoms.
Outcome and follow-up
The patient reported gradual improvement in facial weakness and diplopia within 5 weeks. A repeat MRI scan of the brain performed 2 months later showed stable disease. There were extensive discussions between the patient and her multidisciplinary treating team, which included neurologists and rheumatologists, about the risk of developing new CNS demyelinating lesions despite cessation of TNF-alpha inhibitors. The decision was made to commence ocrelizumab, a B-cell depleting therapy, given the potential to treat both ankylosing spondylitis and CNS demyelination.
An MRI scan of the brain performed 1 month after starting ocrelizumab and 3 months after cessation of TNF inhibitors showed a new demyelinating lesion within the body of the corpus callosum with diffusion restriction, suggesting an active lesion. This new lesion was asymptomatic and required no change to therapy. On balance, it was felt the patient’s presentation was mostly consistent with the diagnosis of MS as opposed to TNF-alpha inhibitor-induced CNS demyelination.
Despite the use of ocrelizumab, the recurrence of inflammatory lumbar back pain after 6 months necessitated switching from ocrelizumab to secukunimab (anti-interleukin-17A), and biological disease-modifying antirheumatic drug for the treatment of her axial spondyloarthritis.13 The patient elected to cease secukunimab after 10 months of therapy as it was inadequately managing her ankylosing spondylitis symptoms and she was tired of taking therapy. This resulted in a flare of her ankylosing spondylitis, but no new CNS demyelinating activity. She was commenced on upafacitinib (JAK inhibitor) 7 months later. Her MS has remained stable, with no evidence of disease activity.
Discussion
The unusual presentation of ‘sixteen syndrome’
A revision of the neuroanatomy provides important insights into our case (figure 3). The control of horizontal conjugate eye movements comes from a complex neuronal network. Impulses travel from the visual areas of the frontal and parietal lobes to the paramedian pontine reticular formation (PPRF) within the pons.8 14 15 The PPRF directly communicates with the abducens nucleus, which gives rise to two important structures: (1) the abducens nerve, which in turn innervates the ipsilateral rectus and controls abduction of the eye, and (2) the MLF, which innervates the contralateral oculomotor nucleus, which innervates the medial rectus resulting in adduction.8 14 15
Diagram shows the anatomical explaination for sixteen syndrome. Pathological lesion (oval shaded area) in the pontine tegmentum involves bilateral abducens nuclei, MLF and CN VII nerves (or nuclei). CN III, cranial nerve III; CN VI, cranial nerve VI or abducens nerve; CN VII, cranial nerve VII or facial nerve; MLF, medial longitudinal fasiculus. Illustrator: Zelia Ranger.
A spectrum of disorders, referred to as the one-and-a-half spectrum disorders, has been described in the literature.8 16–20 Aside from the key structures which control horizontal eye movements (PPRF, abducens nucleus and MLF), the pons also has a number of other important structures including the corticospinal tract, medial lemniscus, trigeminal nerve (CN V) and facial nerve (CN VII).16 18 The one-and-a-half spectrum disorders follow a nomenclature based on the neuroanatomy of the lesion and the resultant structures involved.8 16 18–20 Our case describes a case of ‘sixteen syndrome’ affecting the bilateral abducens nerves and MLF resulting in complete horizontal gaze palsy and the bilateral facial nerves, resulting in facial diplegia (figure 3).18 Anatomically, these structures are close in topography, located in the ventral aspects of the pons, adjacent to the fourth ventricle.16 21 The facial nerve loops posterior to the abducens nucleus, before exiting the brainstem.16 Thus, it is possible for an isolated pontine lesion,14 16 18 21 22 such as that seen in our case report, to be responsible for the clinical presentation.
Despite the understandable neuroanatomy, very few case reports describing this clinical syndrome have been reported.18 The main aetiologies identified have been demyelination in the setting of MS or NMOSD, infarction, haemorrhage and space-occupying lesions.8 16–18 21 One previous case series has described a similar clinical course to our patient. Their case series describes two women in their 30s who also initially presented with a bilateral intranuclear ophthalmoplegia, which then progressed over 4 days to a complete bilateral horizontal gaze palsy. A similar lesion was found in the pons, felt to be consistent with demyelination. They suggested a possible mechanism for this presentation was a lesion involving bilateral MLF that underwent secondary extension laterally to the adjacent abducens fibres emerging from the abducens nuclei.14
TNF-alpha inhibition and demyelination
An association between TNF-alpha inhibitors and CNS demyelination has been extensively reported in the literature.1–7 23–26 It is well established that TNF-alpha inhibitor use in patients with known MS can increase disease activity and MRI lesion load.27–29 What remains unclear is whether TNF-alpha inhibitors can lead to de novo demyelination either through direct causation or by unmasking those with an underlying predisposition, or if the association is simply coincidental.1 2 4 5 29
Evidence supporting TNF therapy-induced demyelination is that the age of onset of demyelination in those with TNF-alpha inhibitor exposure differs from those with MS. One study examining patients with comorbid rheumatoid arthritis treated with TNF-alpha inhibitors found that CNS demyelination in the setting of TNF-alpha inhibitors had a mean age of onset of 45 years, compared with MS which has a recognised mean age of onset between 20 and 40 years.2 The delayed onset of demyelination in the TNF-alpha inhibitor population implies the mechanism may be separate from autoimmune demyelination seen in MS.
The onset of demyelination has been reported after months or even years following the commencement of TNF-alpha inhibitor therapy.1 2 26 30 Therefore, it is plausible in our case that the demyelination may be related to our patient’s use of a TNF-alpha inhibitor, despite the fact that her symptom onset was greater than 12 months after commencement of adalimumab.
Arguments against a causal role between TNF-inhibitors and demyelination include the fact that although over 2 million patients are treated with TNF-alpha inhibitors, the number of published demyelinating events remains very small.5 Randomised control trials of the developmental and post-marketing programmes, and retrospective long-term safety studies performed by pharmaceutical companies have not found an increased rate of demyelinating events compared with the actual incidence of MS.31 Finally, some case reports have found that when rechallenged with TNF-alpha inhibitors, most patients did not develop new demyelinating events.32
Despite the lack of consensus regarding the role of TNF-alpha inhibitors in demyelination, the recommendation is that TNF-alpha inhibitors should be discontinued at the appearance of CNS demyelination or where symptoms may be due to CNS demyelination.1 2 24 TNF-alpha therapy should also be avoided in any patients with a personal or family history of MS or other demyelinating diseases.2 24 Steroid therapy is felt to be effective in the short term.2 7 The role of maintenance therapy has not been clearly defined; however, B-cell therapy has been suggested as it has a role both in MS demyelination and for a number of the underlying rheumatological conditions treated by TNF-alpha inhibitors.7 25 33 Mixed effectiveness has been reported with some trials reporting effective response to B-cell therapies, and others stating the therapy is only effective if the patient is TNF-alpha inhibitor naive.7 33
Overall, the course of demyelinating disease in patients with concurrent TNF-alpha inhibitor use appears unpredictable. While some case reports describe quiesce of demyelinating activity upon cessation of TNF-alpha therapy, others report ongoing disease activity despite treatment discontinuation.2 25 30 34 35 The risk of recurrent demyelination is not necessarily associated with the duration of TNF-inhibitor therapy use.3 A retrospective cohort study has attempted to identify risk factors for ongoing disease activity. They found that patients were more at risk of a relapsing disease course if they had pre-existent asymptomatic white matter lesions identified on MRI, if they continued treatment with TNF-alpha inhibitor therapy and if they had a retrospective history of neurological symptoms to suggest demyelination.25 Considering this, while TNF-alpha inhibitor discontinuation is recommended, it does not always lead to control of further CNS demyelination.25 Patients require continued clinical and radiological surveillance, especially when these additional risk factors are present.25 36 The exact duration of follow-up remains unknown; however, the current recommendation is a minimum of 2 years.25
Patient’s perspective
Five days before presenting to the hospital with what I described as disturbed vision together with an inability to move my eyes and part of my face, I had been experiencing a terrible headache. But, unfortunately, it was just one of those busy workdays where I did not have time to be unwell, so I just pushed through.
The following day my eyesight was strange, best described as double-vision. I watched my daughter’s dance team performing and what was usually a troupe of 12 girls looked more like 20! Over the coming days, my vision deteriorated further. It got to the point that if a person was standing in front of me, I saw three of them. Furthermore, if they moved, or if a person came into a room, I had to move my whole head to follow them as I could not move my eyes and my vision had to catch up to refocus.
On day three, I took myself to my local ophthalmologist for an eye test - I have worn glasses for 20 plus years. Nothing exceptional was identified, but she did recognise something was not right and referred me to a specialist. It was not until day four that I realised things were not improving and saw my General Practitioner (GP). Immediately I was referred for a Brain MRI.
By this stage, it was no longer just my eyesight; my muscles in my face were 'frozen'. Unbeknown to me whilst drinking a bottle of water, a friend pointed out I was drooling. I could not actually open my mouth correctly - something was really wrong now.
24 hours after the MRI, whilst sitting in my GP’s office thinking I was having a stroke, she contacted the Neurology team at my local hospital and used words like MS lesions. I was terrified.
Quickly my husband sorted out care plans for our two young children (10 and 7 years), and we presented to the local hospital emergency department, where we were greeted by the neurology Registrar at the time. The journey then began.
Immediately the team started to question my medical history. I let them know that I had been diagnosed with ankylosing spondylitis several years earlier, which was now stable through the use of a TNF inhibitor. This immediately raised suspicions. I also advised that several months earlier, I had experienced pins and needles in my feet for five to six weeks. After some investigations, nothing was identified, and it eventually passed.
I was advised that he MRI ordered by my GP had identified demyelination described as MS-like lesions, but the fact that I had been on a biologic TNF inhibitor had to be explored. It was explained to me that my sight and facial movement was impaired because of where the lesion was in my brainstem. This was described as rare.
Immediately I was admitted to the neurology ward, where I stayed for five days. I underwent several tests including a lumbar puncture and many blood tests. My ability to exhale (via a respiratory test) was also being monitored every four hours. By day five, limited facial movement had returned, but my vision remained poor. Before discharge, I commenced infusion of methylprednisolone and, following discharge, received a further two days of infusions at home.
During my hospital stay, the team were cautious in their language. This may be MS, but it may also be a consequence of the TNF inhibitor. It was of great concern to me that I could potentially have to go off this medication. It had been a game-changer in stabilising and managing my ankylosing spondylitis pain. Even in the hospital, I was advising the staff I was due for my fortnightly injection; my husband even brought it into the hospital, but it’s safe to say it was not used and will never be again.
My treating team always consulted with me every step of the way and brought in my rheumatologist to help inform the conversation and path forward. He had not seen such a reaction in a patient leading to even more questions than answers.
Following my first round of Methylprednisolone infusions, things did not settle as quickly as we would have liked. So I went another round over three days. These were hard work, but with a lot of support, we got through.
It was not until five weeks or so after my hospital stay that I could really start to see correctly again. I could now go for short walks without fear of walking into a tree; I could be a car passenger without fear that the driver was driving diagonally down the road; I could watch TV without the need of an eye patch, and I could drink and eat normally. Unfortunately, the fatigue took a lot longer to recover from, and it was close to 3-months before I returned to limited part-time work and 5-months to full-time employment.
At the 4-month mark after the initial event and following a follow-up MRI my neurologist carefully and sensitively advised me that we need to treat this as MS following the development of a new lesion. I think I had prepared myself for this. My medical team has worked together to identify the best path forward to manage both demyelination and ankylosing spondylitis. Today, both are stable.
It was undoubtedly a frightening time in my life – a young woman with young children establishing a career and having the world come crashing down. The rebuilding took a little time, but I am in a good place with good people around me. I am not sure I will ever honestly know how I ended up here. Was the demyelination brought on by the TNF inhibitor? What role, if any, did the TNF inhibitor play? Was MS always in my trajectory but just presented in this rare way? Some questions will never be answered, but I will head into the future with a supportive medical team and a great circle of friends and family by my side.
Learning points
-
Revision of neuroanatomy is essential when localising unusual neurological presentations.
-
The spectrum of “one-and-a-half syndromes” are rare but important to diagnose in order to target investigations and provide timely management.
-
In patients with signs or symptoms suggestive of demyelination or a family history of a demyelinating disorder, tumour necrosis factor (TNF)-alpha inhibitors should be avoided and alternative therapies considered.
-
Patients who develop demyelination on TNF-alpha inhibitors require ongoing clinical and radiological surveillance after the TNF-alpha therapy is ceased.
Ethics statements
Patient consent for publication
Footnotes
-
Contributors The patient was under the clinical care of KB, TB and FB. The case report was written by FB and was edited by KB and TB. All authors critically read and modified the manuscript. FB is the guarantor. All authors approved the final version of the manuscript.
-
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
-
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
-
Competing interests FB has received travel funding from Biogen.
-
Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.
References
Use of this content is subject to our disclaimer