Neuromyelitis optica spectrum disorder (NMOSD) presenting as acute transverse myelitis with positive aquaporin 4 antibodies

Abstract

An 80-year-old, previously healthy patient presents with acute transverse myelitis with sensory level at T8. The MRI scan of the spinal cord showed longitudinal extensive transverse myelitis, and she tested positive for aquaporin 4 antibodies in serum. She received treatment with intravenous and oral steroids, with no improvement and then underwent plasma exchange. She was then started on azathioprine for prevention of relapses, while continuing physiotherapy and occupational therapy. Eventually, she was transferred to a specialised spinal cord centre for long-term rehabilitation.

Background

We found this case important for three reasons. First, it is rare and, most likely, underdiagnosed. However, with appropriate, early-on diagnosis, patients with this condition can improve with appropriate treatment. Second, it brings attention to longitudinal extensive transverse myelitis (LETM) as a radiological diagnosis that is different from typical demyelination from multiple sclerosis (MS). This difference is important as it carries different causes, treatments and prognosis. Finally, it discusses the clinical criteria used to diagnose neuromyelitis optica spectrum disorder (NMOSD), which interestingly, can be diagnosed without visual impairment, such as in this case.

Case presentation

An 80-year-old, previously fit and fully independent woman was admitted to our hospital with a 3-day history of acute left lower limb numbness, first noticed on waking. The numbness was initially noticed throughout the leg up to the hip. After 24 hours, the numbness ascended to the left mid-abdominal region, without crossing the midline. The next day, the right lower limb also became numb extending up to the right mid-abdominal region. She noticed rapidly progressive weakness in both lower limbs, to the point of becoming bedbound within the first 48 hours, and she developed urinary and faecal retention within 48 hours of onset. There was no history of infection or fever preceding the onset of symptoms.

On admission, her examination revealed flaccid paraplegia with sensory loss up to T8 dermatome bilaterally for all modalities. Both patellar reflexes were approximately +/++, Achilles reflexes were absent and both plantar reflexes were indifferent. Upper limb strength was 5/5 bilaterally and no cranial nerve abnormality was noted.

On admission, the non-contrast MRI showed a lesion extending from C3 down to the cauda equina (figures 1–3). A contrast MRI, done 3 days later, did not show enhancement. The radiological diagnosis was LETM of unknown aetiology. A brain MRI was requested, looking for signs of optic nerve demyelination, but it only showed mild small vessel disease. All blood investigations, including antibodies for systemic diseases, were normal. Lumbar puncture examination revealed a white blood cell 26 (60% lymphocytes and 40% polymorphonuclear cells), glucose 2.8 mmol/L, and 1.41 g/L of proteins and positive oligoclonal bands in cerebrospinal fluid (CSF), yet negative in serum.

Figure 1.

MRI of the cervical and thoracic cord: inflammatory lesion throughout cervical and thoracic cord.

Figure 2.

MRI of the cervical and thoracic cord: extensive inflammatory lesion extending longitudinally.

Figure 3.

MRI of the lumbar and sacral cord: extensive lesion down to cauda equina.

A 3-hour course of 500 mg intravenous methylprednisolone two times per day failed to improve her symptoms. After that, she was given prednisolone 30 mg once daily, with no improvement either. Soon after, the aquaporin 4 (APQ4) antibodies returned positive and the anti-myelin oligodendrocyte glycoprotein (MOG), negative.

Subsequently, she underwent plasma exchange. Approximately 7 days after her last plasma exchange, her lower limb strength started to improve to 2/5 bilaterally. However, there was no sensory improvement and her sphincter function was still impaired.

She was then started on azathioprine 25 mg two times per day in order to reduce relapses and will be managed as an inpatient in a specialised spinal cord rehabilitation hospital for the foreseeable future.

Investigations

• Antibody testing for APQ4 and anti-MOG.

• MRI of the brain and spinal cord.

• CT of the chest, abdomen and pelvis: to exclude paraneoplastic aetiology.

• Lumbar puncture.

Differential diagnosis

A radiological diagnosis of LETM has a wide range of differential diagnoses that must be carefully investigated to ensure the correct diagnosis is made as this vastly impacts the management of these patients. To exclude a paraneoplastic cause, a CT of the chest, abdomen and pelvis was performed and it did not show any signs of malignancy. An autoantibody screen ruled out common autoimmune causes such as systemic lupus erythematosus and an infection screen was negative, ruling out an infectious cause. The next step was to perform a lumbar puncture that revealed pleocytosis and was positive for oligoclonal bands. This left three remaining diagnostic options: MS, neuromyelitis optica (NMO) and NMOSD. It is important to mention that NMO and NMOSD are two separate clinical entities. Other differential diagnoses to include are sarcoid and MOG antibody disease.^{1 2} The latter requires the presence of anti-MOG in patients who suffer repeated inflammatory attacks of the central nervous system. Our patient was tested for anti-MOG and was negative.

The presence of LETM is rare in MS with the MRI of the spine more commonly showing short multiple lesions of inflammation. With this in mind and the lack of white matter lesions on the MRI of the brain and no signs of optic neuritis, MS was ruled out. The lack of optic neuritis also helped to distinguish between NMO and NMOSD. Optic neuritis must be present, along with transverse myelitis, for a diagnosis of NMO. Therefore, NMOSD was the most likely diagnosis. As previously mentioned, APQ4 and MOG antibodies were tested for, with the patient being positive for APQ4. This then confirmed the diagnosis of NMOSD with positive APQ4.

Treatment

The first-line treatment for NMOSD with positive APQ4 is steroids. Our patient received a 3-hour course of 500 mg intravenous methylprednisolone two times per day, which failed to improve her symptoms. This was followed by prednisolone 30 mg once daily, which also showed no improvement.

For patients who have a diagnosis of NMOSD with positive APQ4, plasma exchange should always be given, unless there are contraindications. Our patient showed signs of improvement shortly after plasma exchange. She was started on azathioprine 25 mg two times per day to reduce the incidence of relapses.

During this time, the patient underwent regular physiotherapy and occupational therapy, while spirometry was performed to ensure there was no respiratory involvement.

Outcome and follow-up

She remains an inpatient in our hospital, receiving daily physiotherapy and occupational therapy. She will be transferred to a spinal cord rehabilitation centre.

Discussion

LETM is a radiological diagnosis that is defined by the presence of a large hyperdensity on MRI spanning over three or more vertebral segments.³ Clinically, this presents as a myelopathy, with motor and sensory loss, and likely sphincter involvement.

LETM has a wide range of differential diagnoses including NMO, NMOSD, MS, and infective, paraneoplastic and autoimmune causes such as systemic lupus erythematosus.⁴ Here we will focus on the diagnostic challenge of distinguishing between NMO, NMOSD and MS. Initially thought to be slightly different versions of the same disease process, research has shown that the underlying pathophysiology is different.⁵

NMO, also known as Devic syndrome, is an antibody-mediated inflammatory disease that targets astrocytes in the central nervous system, expressing APQ4 channels. This results in inflammation of oligodendrocytes.⁶ NMO is diagnosed in the presence of optic neuritis and transverse myelitis. However, there is a great variability in the clinical and radiological NMO presentations, which has led to the development of NMOSD diagnostic criteria, to encompass the large scope of aetiologies.⁷

The diagnosis of NMOSD is based heavily on the detection of AQP4 antibodies and the presence of certain core criteria (box 1). If AQP4 is detected, at least one of the six core criteria is needed to make the diagnosis. If AQP4 is not detected, at least two of the core criteria are needed. One of these criteria needs to be either optic neuritis, acute myelitis with LETM or area postrema syndrome.⁸

Box 1. The six core criteria used in the diagnosis of neuromyelitis optica spectrum disorder (NMOSD).

Core criteria

• Optic neuritis.

• Acute myelitis.

• Area postrema syndrome.

• Acute brainstem syndrome.

• Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD typical diencephalic MRI lesions.

• Symptomatic cerebral syndrome with NMOSD typical brain lesions.

There are several ways to distinguish between the diagnosis of NMO, NMOSD and MS. First, the clinical presentations differ in their progression. The presentation of MS is with relapses and eventually, progressive neurodegeneration; whereas NMO and NMOSD are relapsing diseases, and symptoms do not often progress throughout each relapse. Second, MS is not associated with any specific antibodies, but the presence of oligoclonal bands in CSF is an important finding.⁹ NMO and NMOSD are both associated with two antibodies: AQP4 and MOG. Antibodies to APQ4 are found in >80% of patients with NMO and around 50% of patients with LETM. They are infrequent in optic neuritis without spinal cord involvement.¹⁰ LETM seen on MRI of spines is a good diagnostic factor for NMO and NMOSD, whereas short segments of inflammation indicate MS in the diagnosis. Finally, an MRI of the brain is often normal in NMO and NMOSD but can show characteristic periventricular and white matter lesions in MS.¹¹ These diagnostic differences are detailed in table 1.

Table 1.

Table detailing the diagnostic patterns of NMO, NMOSD and MS

	NMO	NMOSD-positive antibodies	NMOSD-negative antibodies	MS
Clinical presentation	Optic neuritis Transverse myelitis Relapsing	1 core criterion Relapsing	2 core criteria Relapsing	Optic neuritis Transverse myelitis Progressive Relapsing
Laboratory tests	AQP4 antibodies Pleocytosis in CSF	AQP4 antibodies Pleocytosis in CSF	Pleocytosis in CSF	Oligoclonal bands in CSF
Spine MRI	LETM	LETM	LETM	Short multiple lesions
Brain MRI	Often normal Lesions are large and confluent Long lesions in optic nerve	Often normal Lesions are large and confluent Long lesions in optic nerve (if optic neuritis present)	Often normal Lesions are large and confluent Long lesions in optic nerve (if optic neuritis present)	Ovoid lesions adjacent to lateral ventricle and in the inferior temporal lobe white matter Short lesions in optic nerve

AQP4, aquaporin-4; CSF, cerebrospinal fluid; LETM, longitudinal extensive transverse myelitis; MS, multiple sclerosis; NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorder.

The use of disease-modifying treatments typically used in MS can exacerbate NMO and NMOSD.¹² The acute relapses of NMOSD and NMO are instead treated with high-dose methylprednisolone or plasma exchange if refractory to the steroids.¹³ However, there is often poor recovery from acute attacks. Current research into the use of immunosuppressants for treating NMOSD has shown that this is beneficial for reducing disease activity and preventing relapses.¹⁴ Azathioprine has shown to be able to reduce the median disease duration, reduce the rate of relapse and make improvements in Expanded Disability Status Scale score and modified Rankin Scale.^{15 16} Finally, toclizumab has been shown to be effective in patients who are not responding to other immunosuppressants such as rituximab, cyclophosphamide and azathioprine.¹⁷

It is important to note the median age of onset of NMOSD if 40 years old.¹⁸ Late-onset NMOSD is defined as the first presentation after the age of 50 years. This is associated with a higher rate of motor impairment and death.¹⁹ Cases presenting after the age of 75 years are extremely rare. A nationwide investigation into the incidence of NMOSD in China showed an incidence of 0.205 per 100 000 people for people aged 75–79 years reducing to just 0.04 per 100 000 in those over 85 years old.²⁰ This case also demonstrates the wide range of differentials that must be considered when presented with a patient with LETM. Here we have been able to highlight the important investigations and differences in presentation of these differentials. NMOSD is an important and potentially underdiagnosed diagnosis and should always be considered in patients with LETM.

Learning points.

• Longitudinal extensive transverse myelitis (LETM) is a radiological diagnosis that can present as acute transverse myelitis.

• Positive aquaporin-4 (AQP4) antibodies in conjunction with LETM is diagnostic for neuromyelitis optica spectrum disorder.

• AQP4 is the major autoantigen in neuromyelitis optica (NMO). Antibodies to APQ4 are found in >80% of patients with NMO and around 50% of patients with LETM. They are infrequent in optic neuritis without spinal cord involvement.

• Treatment for LETM with acute transverse myelitis is plasma exchange, not intravenous immunoglobulins.