Aquaporin-4-positive neuromyelitis optica in a male Caucasian patient: A rare demographic presentation

Abstract

Neuromyelitis optica with a positive aquaporin-4 antibody is a rare autoimmune condition, which has a higher prevalence in females, and disproportionately affects Black and Asian persons with a typical age of first presentation between the ages of 30 and 40. We report a unique case of a 69-year-old Caucasian male who presented following a fall along with generalised weakness, unilateral myotomal pain, and urinary dysfunction. His medical history included two previous venous thromboembolic events, for which he was anticoagulated with warfarin. Extensive investigations, including MRI of the whole spine and lumbar puncture, revealed longitudinally extensive transverse myelitis and a positive aquaporin-4 antibody, confirming neuromyelitis optica. The patient was treated with intravenous methylprednisolone, plasma exchange, and immunoglobulin therapy, followed by rehabilitation. This case highlights the importance of considering neuromyelitis optica in atypical patient demographics and that early recognition through neurological assessment, imaging, and antibody testing is critical in preventing severe disability.

Introduction

Neuromyelitis optica (NMO) with a positive aquaporin-4 (AQP4) antibody is rare. As of 2023, the National Institute for Health and Care Excellence reported just under 700 cases of this condition across the United Kingdom. ¹ The rarity of this condition is further portrayed within a global context, with data suggesting an overall annual incidence of only 0.16/100,000 population. ² The syndrome results from an autoimmune response that leads to demyelination of the central nervous system.

Clinically this condition is reported as presenting broadly but with certain hallmark symptoms. ³ Optic neuritis and transverse myelitis are hallmark features and are the primary cause for the potential disabling effects of the condition. Further clinical manifestations include but are not limited to symmetric paraplegia, sensory loss, and bladder dysfunction. ⁴ Neuropathic pain, sexual dysfunction, and subsequent mimicking of brainstem encephalitis have also been reported in cases of NMO globally. ⁵

Epidemiologically, NMO typically presents for the first time in patients between the ages of 30 and 40. ⁶ There is a higher prevalence of NMO in females, who suffer just over 80% of the cases that are reported. NMO also affects Black and Asian persons disproportionately. ⁷ It must however be appreciated that males and other ethnic groups can be affected, although are less frequently reported according to current literature.

We present a case that opposes these classical epidemiological features whilst highlighting the importance of key classical presentation hallmarks and thorough investigations to ensure accurate diagnosis of this potentially disabling condition if not diagnosed and treated promptly.

Case presentation

This case report describes a 69-year-old Caucasian male who presented to the emergency department with a 2-day history of generalised body aches.

The patient was an active electrician with a past medical history which included two previous venous thromboembolism events for which he had been on warfarin for over 10 years. He did not smoke or use recreational substances and had no significant family history for neurological disease.

Eight days prior to this presentation, he developed fatigue and mild generalised myalgia. On the day of admission, he woke up with pain in his left anterior thigh, accompanied by weakness that resulted in a sudden unwitnessed fall. On further questioning, he reported discomfort in the back of his neck and generalised numbness on the left side of his body preceding the fall. Alongside these symptoms, he also had reduced urine output within the 24 h prior to admission and experienced marked urinary incontinence just prior to his fall. He denied losing consciousness and notably had no visual symptoms. This was consistent throughout his entire stay in hospital.

The patient was admitted under the Acute Medical Unit for monitoring and potential imaging. The following day, his condition rapidly deteriorated, with a Medical Research Council Muscle Power Scale grading of four-fifths in his left lower limb worsening to complete paralysis.

Due to his clinical presentation in the department, he was subsequently reviewed by neurology specialists who embarked on a focused examination. A complete cranial nerve examination showed that his pupils were equal and reactive to light with no relative pupillary defect or ophthalmalgia (eye pain). There was no facial or bulbar weakness, and fundoscopy showed no disc swelling. Tone was normal in all limbs, and there was no clonus (a neurological sign characterised by abnormal and involuntary muscle contractions). However, reflexes were absent at the supinators bilaterally, the left biceps, and both triceps. The right biceps reflex was also diminished but knee reflexes were elicited bilaterally. Finally, a sensory examination showed reduced proprioception from C1 bilaterally with complete loss from T7 to T12 on the left. Joint position sense was present bilaterally but vibration, whilst preserved at the distal interphalangeal joints in the upper limbs, was reduced throughout the lower limbs. Due to the overall deterioration in his motor and sensory function, further investigations were required.

Investigations

Initial blood tests were unremarkable, and a Computed Tomography (CT) head showed no evidence of intracranial injury or skull fracture. However, the aforementioned examination findings prompted an urgent MRI of the whole spine, which revealed a very extensive continuous abnormal T2 high signal extending from the upper cervical to the lower thoracic cord with mild cord expansion. This finding suggested no relation to degenerative changes, was inconsistent with cord infarction and not indicative of multiple sclerosis.

As a result, an inflammatory or infectious aetiology was suspected as the cause of his clinical presentation, warranting further investigation. Subsequently, a lumbar puncture was conducted for analysis of cerebrospinal fluid (CSF). From this, a sample was sent for antibodies which later showed positive AQP4 antibodies (AQP4-IgG). Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies and a viral screen came back as negative.

There were no reported clinical features suggestive of a systemic autoimmune disease such as arthralgia, rash, sicca symptoms, and constitutional complaints. However, no formal autoimmune screening tests (e.g. Antinuclear Antibody [ANA] test, Extractable Nuclear Antigen [ENA] panel, and ANA-Blot) were performed in this patient, so the presence of a coexisting systemic autoimmune condition cannot be definitively excluded (Figure 1 and Table 1).

Figure 1.

Sagittal T2 weighted MRI spine images demonstrating LETM extending from the level of C2 down to T9. Due to the patient’s scoliosis, the full extent of the lesion is not captured in a single sagittal plane and is shown across two images.

Table 1.

Lumbar puncture results demonstrating elevated protein and mild pleocytosis with normal glucose and no organisms seen on microscopy.

Category	Test/parameter	Result
Other	Opening pressure	12 cm H2O
Microscopy and cell count	Organisms	Not seen
	WBCs	14/µL
	RBCs	9/µL
	WBCs	6/µL
	RBCs	4/µL
PCR (nucleic acid detection)	Herpes simplex virus	Not detected
	Varicella zoster virus	Not detected
	Enterovirus	Not detected
CSF biochemistry	Total protein	1.30 g/L (high)
	Glucose	3.4 mmol/L
	Albumin	0.981 g/L (high)
	IgG	0.189 g/L (high)

CSF: cerebrospinal fluid.

Treatment

Our patient was admitted in mid-October 2024 with acute neurological symptoms consistent with a demyelinating disorder. He was initiated on intravenous methylprednisolone 1 g daily for 5 days. On the fourth day of treatment, due to limited clinical improvement, a consultant neurologist recommended plasma exchange (PLEX). He was transferred to another facility, where he received one cycle of PLEX followed by a course of intravenous immunoglobulin (IVIG). IVIG was administered ~2 weeks after admission, based on partial response to steroids and PLEX, and a strong clinical suspicion of autoimmune disease. Subsequent antibody testing confirmed AQP4-IgG positivity, consistent with NMO, justifying the additional immunotherapy. During his stay, he was noted to have absent upper limb reflexes and intrinsic muscle wasting. Neurophysiological studies were advised to investigate possible radiculopathy.

Following treatment, he returned to the original facility for rehabilitation. Over the following weeks, he made steady progress. He was able to transfer using a banana board and became largely independent in daily activities. Sensory function improved, especially around the upper trunk, although the left leg remained significantly weak. Despite several failed attempts at trial without a catheter, bladder function did not recover sufficiently, and he was discharged with a long-term urinary catheter in place. Bladder retraining is ongoing at the time of writing this case report.

He commenced long-term immunosuppression with prednisolone and mycophenolate mofetil. Initially on prednisolone 40 mg daily and mycophenolate 500 mg twice daily from mid-November, his regimen was gradually adjusted: prednisolone tapered to 30 mg, then 20 mg daily; mycophenolate increased to 1 g twice daily. He was discharged in late March 2025 after a total hospital stay of ~5.5 months with this maintenance therapy to continue long term under outpatient supervision.

Outcome and follow-up

Our patient had poor trunk stability, left lower limb weakness, and mild left upper limb weakness with a sensory level at T6. During his stay in the rehabilitation ward, he worked twice daily with the therapy team using exercises with a thera bike, strength exercises for upper and lower limbs, hydrotherapy, wheelchair skills, pivot transfer practice, and facilitated walking. Following this structured programme along with the medical interventions noted above, he was deemed medically optimised for discharge. He has been referred to an orthotist for a knee and ankle foot orthosis to maintain his knee in extension in addition to follow up in a neurology clinic.

Discussion

The overall evolution of this patient’s symptoms as well as the outcomes of the investigations carried out during his hospital stay were in keeping with a diagnosis of NMO. Radiological investigation formed a major part in the differential diagnosis and comprehensive imaging was conducted for our patient. A full plain MRI spine showed an extensive continuous abnormal T2 high signal extending from the upper mid C2 through mid T9 level with mild cord expansion. This had been considered unrelated to the presence of mild to moderate spinal canal stenosis with cord flattening as well as the mild cord compression in the cervical region. There also appeared to be a ‘H’ sign which occurs commonly in MOG antibody disease, despite this test coming back as negative. ⁸ A further MRI, carried out 5 days later, confirmed longitudinally extensive transverse myelitis (LETM) but no enlarged vascular flow voids within the spinal canal or abnormal vessels on post-contrast images to suspect a vascular malformation. However, on examination of his upper limbs, his strength was preserved but reflexes were completely absent. This was considered extremely rare. There were several potential causes for this. Firstly, it could have been due to minor changes in the cervical cord, however, a radicular or peripheral nerve aetiology was considered more likely. Evidence suggests a link between HSV-2 and myeloradiculitis, but for completeness, a viral PCR for both HSV-1 and HSV-2 was conducted and returned as negative. ⁹

Despite the use of extensive imaging in this case, diagnosis of NMO, as outlined by the ‘International Panel for NMO Diagnosis’, is determined largely by the results of the AQP4 antibody test and, clinically, the presence of optic neuritis. It is important to further discuss this international consensus diagnostic criteria for NMO spectrum disorders (NMOSD) which was published in 2015.^9,10 This splits the diagnosis of NMOSD into those positive for AQP4-IgG and those without testing or a negative result. Focusing on the group which are positive for AQP4-IgG given the relevance to our case, a positive antibody result requires the presence of only one of six clinical manifestations for a diagnosis to be made. Conversely, the diagnostic criteria are more stringent for those with a negative test result or an ‘unknown status’ of AQP4-IgG; this criteria necessitates the presence of two core symptoms, one of which must be optic neuritis.^9–11 As highlighted particularly in the update, there is emphasis on the importance of excluding differentials particularly through clinical, laboratory, and imaging findings. In this case, the patient was diagnosed with the condition solely based on their acute myelitis and positive antibody test result, despite the absence of any visual symptoms. This highlights the importance of immunological diagnostic methods as it allows the consideration and even diagnosis of this condition in the absence of a classical presentation whilst ensuring to exclude differential diagnoses.^9,10

Furthermore, AQP4 only became a diagnostic tool in 2004 which may suggest cases of transverse myelitis classified as ‘idiopathic’, such as those seen in a 2003 study titled ‘Idiopathic Recurrent Transverse Myelitis’ may have had underlying autoimmune pathology. ¹² It is reported that this antibody test is highly specific ranging from ‘85% to 99%’, which makes it a crucial tool in differentiating between NMO and multiple sclerosis. ¹³ In this case, the combination of an absence of optic neuritis and oligoclonal bands on CSF testing in conjunction with a positive AQP4 antibody test allowed us to conclusively rule out multiple sclerosis.

However, there have been cases where NMO has been diagnosed with a negative AQP4 test result. As demonstrated in the case report written by Khadka et al. in the year 2022 in regards to a 35-year-old man in Nepal, this gentleman presented with bilateral limb paresis in association with urinary incontinence and bowel dysfunction. He had further positive MRI findings with ‘abnormal signal changes of the spinal cord from C6 to T8’. Subsequently, he was treated with steroids due to the LETM. Despite his clinical presentation and scan results offering similarity to our case, his antibody test was negative. However, within his hospital stay he endured severe blurring to his vision further scanning of which revealed left-sided optic neuritis. With the presence of optic neuritis in addition to further core symptoms, this patient was diagnosed with NMO. Our patient on the other hand, despite having a plethora of neurological findings on examination and in his clinical history, and an MRI showing LETM, in the absence of his positive AQP4, would not have been diagnosed with NMO. ¹⁴ This highlights the significance of immunological markers in diagnosing the condition and ensures that potential relapses can be quickly detected and treated. Research shows that delay in diagnosis is a contributing factor to the potential chronic disabling consequences of NMO as well as increasing the severity of potential acute relapse. ¹⁵ Therefore, prompt autoantibody testing following such neurological presentations should take place to allow treatment to be commenced quickly. ⁵ This allowed our patient to eventually obtain functional outcomes required for discharge home.

Similar to our case and diagnosis, a report conducted in 2021 presented a 38-year-old patient who came into hospital with 1 week history of left-sided weakness. This patient had positive MRI findings and antibody test results which were consistent with a diagnosis of NMO. However, crucially this patient, who was Ethiopian in origin, complained of an 8 months history of vision loss. ¹⁶ Eye-related issues are further seen in a significant number of the currently published cases relating to NMO. This is another part of our case which differs from the current literature as our patient did not have any eye-related issues preceding and throughout this event. This highlights further that in a condition of NMO, it is critical to look past the classical hallmark features and epidemiological predominance.

Conclusions

In conclusion, we believe this case accentuates the fact that NMO can present at any age and should be considered in the differential diagnosis of anyone presenting with limb weakness and bladder dysfunction. Although this patient was 69 years old, a review of literature shows no previous reports of NMO presenting in this age group. The absence of any reports of relapses for this age group, particularly with the first presentation being of this age, makes it difficult to predict long-term outcomes for our patient. The importance of a comprehensive neurological examination, radiological investigation, and antibody testing shows us that diagnosis can be made promptly to ensure treatment is commenced and prevent long-term disability.