‘Twenty syndrome’ in neuromyelitis optica spectrum disorder

Background

In 1967, Fisher was the first person to report a peculiar horizontal movement disorder of eyeballs where there was combination of ipsilateral conjugate horizontal gaze restriction (one) and ipsilateral internuclear ophthalmoplegia (INO) (a half), thus numerically being one-and-a-half syndrome.1 Following that seminal neuro-ophthalmological observation, various numerical neuro-ophthalmological syndromes affecting extraocular movements and cranial nerves have been described, such as eight-and-a-half syndrome, nine syndrome, thirteen-and-a-half syndrome, fifteen-and-a-half syndrome, sixteen syndrome, sixteen-and-a-half syndrome, twenty-and-a-half syndrome and twenty-four syndrome collectively known as ‘one-and-a-half syndrome with its spectrum disorders’.2–5 Lesions involving the combination of either medial longitudinal fasciculus (MLF) plus abducens nerve nucleus or involvement of MLF plus paramedian pontine reticular formation (PPRF) can cause one-and-a-half syndrome.6 As nucleus of abducens is located in close proximity of facial, vestibulocochlear and trigeminal nerve nucleus, they are frequently affected by the same pathologic process causing one-and-a-half spectrum disorders.2 The involvement of a bilateral facial nerve with one-and-a-half syndrome was termed as fifteen-and-a-half syndrome by Bae and Song.7 Unlike INO (which can be caused by vascular, demyelination and space occupying lesions), till date only cerebrovascular diseases involving bilateral pontine tegmentum have been described as the cause of fifteen-and-a-half syndrome.7–9

Here, a case of ‘twenty syndrome’, characterised by one-and-a-half syndrome with facial diplegia, bilateral optic neuritis and left ataxic haemiparesis (1¹/₂+7+7+2+2+¹/₂=20), is being reported for the first time ever in a patient with demyelinating lesions in bilateral pontine tegmentum and optic nerves, ultimately diagnosed as neuromyelitis optica spectrum disorder (NMOSD).

Investigations

Routine metabolic panel including complete haemogram, serum electrolytes, plasma glucose, renal, liver, thyroid function tests and lipid profile were normal. HIV, hepatitis A and B serologies were negative. MRI brain revealed hyperintense lesions in T2 and fluid-attenuated inversion recovery at the bilateral pontine tegmentum and a narrow lesion along the midline in the right of the pons, which run through the pontine tegmentum to the ventral aspect without diffusion restriction and with mild contrast enhancement (figure 1). Magnetic resonance angiography (MRA) of brain and neck vessels was normal. Cerebrospinal fluid (CSF) study ruled out infectious processes (cell count 04, all lymphocytes, red blood cell—0, eosinophils—0, protein 60 mg/dL, glucose—54 mg/dL (corresponding capillary blood glucose was 96 mg/dL, normal IgG Index, no oligoclonal bands (OCBs))). Visual evoked potential (VEP) study revealed prolonged P₁₀₀ latencies and normal P₁₀₀–N₇₀ wave amplitudes seen in both eyes suggestive of demyelinating type of bilateral retino-optic pathway dysfunction (ie, bilateral optic neuritis). Fat-suppressed MRI of orbits revealed bilateral mild intensity changes within optic nerves (right>left) involving asymmetrically posterior aspect of intraorbital, entire intracanalicular and prechiasmal segments of optic nerve (right>left) suggestive of concomitant bilateral long-segment optic neuritis. Optical coherence tomography revealed thinning of peripapillary retinal nerve fibre layer (RNFL) (70 µm). However, macular RNFL was preserved. There was no visual field defect in left eye; however, there was centrocaecal scotoma in the right eye. Spinal MRI did not reveal any abnormality. Paired sera for anti-NMO or antiaquaporin-4 (AQP-4) antibody (detection of IgG antibodies against aquaporin-4 using transfected HEK2 cells as substrate) were sent and it came out to be positive. To rule out other close differentials, antimyelin oligodendrocyte glycoprotein, paired sera IgG index and OCBs, antinuclear antibody (Hep 2 method), autoimmune encephalitis profile, vasculitis screen, antibodies for paraneoplastic encephalitis, serum markers for neurosarcoid (calcium and ACE levels), serum homocysteine and vitamin B12 were done and came out to be negative. The patient was tested negative for HIV and syphilis as well. High resolution CT scan of thorax revealed no sign of pulmonary sarcoid.

Differential diagnosis

On amalgamation of the clinical, biochemical and radiological substrates, following differential diagnoses were considered:

1. Acute demyelination especially acute brainstem syndrome variant of NMOSD (in favour: clinical features of brainstem and area postrema syndrome, positive AQP-4 antibody, bilateral optic neuritis, MRI brain is suggestive of demyelinating lesions at pons and medulla).

2. Acute brainstem encephalitis including autoimmune, paraneoplastic and Bickerstaff brainstem encephalitis (odds: no clinical features of encephalitis, that is, altered sensorium, fever, headache, seizures, normal CSF study, negative paraneoplastic and autoimmune encephalitis antibodies panel, lesser contrast enhancement and negative anti-GQ1b–IgG antibody).

3. Acute to subacute infarction from basilar perforators (odds: usually peripheral, can be central, but brainstem infarcts stop at the midline, clear basilar flow-void, normal MRA, no cardinal risk factors identified from history, clinical findings, and negative laboratory tests including serum homocysteine level, thrombophilia screen, vasculitis panel and autoimmune profile).

4. Osmotic demyelination syndrome or central pontine myelinolysis (CPM) (odds: MRI findings not suggestive of CPM, extrapontine lesions, and no document revealed rapid correction of hyponatremia).

5. Pontine neoplasms including astrocytomas, lymphoma and metastasis (odd: brainstem is asymmetrically expanded with mass effect on adjacent cisterns, local vessels may also be displaced. Brainstem metastasis usually enhances with contrast. Radiologically, we excluded all these possibilities. Moreover, in tumour, there would be chronic course and systemic signs in malignancy, which was absent in this case).

Thus, based on the international consensus diagnostic criteria for NMOSD,10 the final diagnosis was NMOSD (acute brainstem, area postrema syndrome and bilateral optic neuritis) clinically manifesting with 20 syndrome.

Treatment

Initially she was managed symptomatically (ondansetron, esomeprazole, 0.9% saline). After MRI brain revealed demyelination, she was put on intravenous bolus of methylprednisolone (1 g/day for 5 consecutive days) followed by oral prednisolone (40 mg/day), calcium (1000 mg/day), vitamin D3 (2000 IU/day). Following final diagnosis of NMOSD and screening out anti-John Cunningham (JC) virus antibody, she was put on 1 gm intravenous infusion of rituximab, repeated after 2 weeks (as a single course), with premedications (ondansetron, hydrocortisone, pheniramine and paracetamol) and it was planned to repeat the dose at every 6 months intervals for at least 2 years.11 Steroid was tapered off slowly over next 3 months with intention to keep the patient on rituximab prophylaxis to prevent relapse.

Outcome and follow up

After the third dose of methylprednisolone, her dysarthria showed some improvement along with motor power in left upper and lower extremities. After the fifth dose of methylprednisolone, dysarthria was completely gone and haemiparesis improved completely, while visual acuity improved to 6/18. Facial weakness improved completely after 10 days of therapy. INO improved fully after 15 days, but right-sided gaze restriction did not improve fully.

After 15 days of the first dose of rituximab, the patient had no objective neurodeficit. Visual acuity was 6/9 in both eyes. VEP showed signs of improvement of optic neuritis.

At 6 months follow-up, the patient had no residual neurodeficit. MRI brain and orbit were devoid of any stigmata of demyelination. VEP did not show any sign of subclinical optic neuritis. Other blood parameters such as complete haemogram, renal and liver function tests, and chest X-ray were normal repeatedly during follow-up.