Neuromyelitis optica spectrum disorder presenting in an octogenarian

Abstract

This case describes an 81-year-old woman with a history of Sjögren’s syndrome presenting with recurrent falls and poor balance. She subsequently developed new and rapidly evolving neurology including hyperaesthesia, spastic paraplegia and sphincteric dysfunction. Following serial clinical reviews and detailed investigations, MRI (brainstem and cervicothoracic spine) and a seropositive result for aquaporin 4 IgG, a diagnosis of neuromyelitis optica spectrum disorder (NMOSD) was made. This case describes the clinical course of this index patient with an unusual late age of onset. The report also includes a discussion on NMOSD. We review aspects of terminology, brief epidemiology, pathogenesis, notable autoimmune associations, variance in clinical presentation and current diagnostic criteria. We also review the importance of distinguishing NMOSD from multiple sclerosis in view of the significant implications for treatment and prognosis.

Background

This case is of clinical interest due to:

1. A ‘rare disease’

   • A BMJ Case Reports—Criteria of Interest.
2. The late age at onset

   • Presentation in an octogenarian; not exclusive to age, but more often described in ages 30–50 years.
3. The atypical presentation

   • Neuromyelitis optica spectrum disorders—NMOSD masquerading as the common presentation of ‘falls in an older patient’.

4. The findings of coexistent seropositive conditions rheumatoid arthritis, Sjögren’s syndrome (SS) and NMOSD.

Potentially also of relevance to BMC Case Reports—Criteria of Interest:

• ‘Unusual association of diseases/symptoms.

• Findings that shed new light on the possible pathogenesis of a disease or an adverse effect.

Case presentation

An 81 year-old-woman of Asian descent presented to hospital with a 3-week history of reduced mobility and recurrent falls. She described non-specific symptoms of lethargy and poor balance. She had recently been treated for a possible lower respiratory tract infection with haemoptysis. She was afebrile, had no chest pain and was not breathless.

Her notable medical history included mild vascular dementia, transient ischaemic attacks, hypothyroidism, bilateral knee replacements due to rheumatoid arthritis, SS, sleep apnoea and restless legs. Her medications included trazodone, levothyroxine, fluvastatin and furosemide.

She was teetotal and a non-smoker. Prior to admission, she mobilised with a wheeled trolley, wore refractory lenses and managed infrequent episodes of stress urinary incontinence with an absorbent pad.

In hospital, her Glasgow Coma Scale consistently scored 15/15. However, over the course of 2 weeks (following admission to hospital), she developed rapidly evolving features. These included gait imbalance, fleeting hyperaesthesia and allodynia to her limbs (with lower limb predominance) and patchy sensory loss (with the reliability of the latter findings and assessments influenced by dementia). She had presented initially to hospital with bilateral mild (4/5 strength) lower limb weakness that evolved to dense spastic paraplegia (0/5 strength) over a 2-week period. She also developed urinary retention and constipation. Testing for a sensory level was attempted (for the modalities of light touch and pin prick) and roughly localised to thoracic T4–T6 sensory levels. However, the validity and inter-rater reliability of serial bedside testing for a definite sensory level were interpreted with caution, as the background of dementia influenced testing. The superficial abdominal reflexes were absent but offered limited interpretative value in the context of truncal obesity, older age and multiparity. There were no visual or pupillary symptoms or signs of note. Other important negative findings included absence of meningism, ptosis, gaze paresis, nystagmus, dysarthria, aphasia, dysphonia, dysphagia, facioparesis, bradykinesia and fasciculations. Jaw jerk was not exaggerated. Lhermitte’s sign was absent. Tendon reflexes were difficult to interpret with reliability. Planter responses were equivocal. Respiratory, cardiac, abdominal and skin examinations were unremarkable.

Investigations

Haematology and biochemistry

Her mean corpuscular volume was 79 fL (reference 79–98). Apart from the mild microcytosis, a series of blood tests were either unremarkable or minimally discriminating (full blood count, urea and electrolytes, glucose, calcium, magnesium, liver function tests, coagulation screen, creatine kinase, B₁₂, folate, immunoglobulins, paraprotein screen, reticulocyte count, C reactive peptide and erythrocyte sedimentation rate). No abnormal haemoglobin subtypes were noted on electrophoresis. Iron studies were interpreted as indicative of a functional iron-deficiency state. Her 25-hydroxy vitamin D level was deficient at 21 nmol/L (>50). Thyroid function tests suggested under supplementation with a fT4 of 18 pmol/L (reference 9–21) and TSH of 10.4 mu/L (reference 0.2–4.5).

Urine

Urine cultures grew a drug-resistant Klebsiella oxytoca, sensitive to gentamicin. Urine Bence-Jones protein was negative.

Radiology

Chest X-ray was normal. A series of three MRI spine scans over a 2-week period (precontrast and postcontrast with gadolinium) demonstrated an area of signal change in the brainstem, most marked in the pons. Areas of central ill-defined/patchy intramedullary high signal change were also described in the upper cervical cord (C2–C4 levels) and in the cervicothoracic cord (C6–T2 levels) (see figure 1). These areas had mild associated cord expansion. There was neither brainstem nor cord enhancement following the administration of contrast (gadolinium). The conus and cauda equina regions were normal.

Figure 1.

Red arrows indicate areas of high signal within the spinal cord (sagittal T2-weighted image).

In addition, non-contrast CT and (pregadolinium and postgadolinium contrast enhanced) MRI brain scans showed cortical atrophy and widespread established subcortical, deep white matter ischaemic change. A CT chest, abdomen and pelvis with contrast (screening for occult neoplasia and possible paraneoplastic manifestations) did not identify malignancy but noted incidental findings of high burden bilateral main and segmental pulmonary arterial emboli.

Microbiology and virology

Blood cultures were negative. Cerebrospinal fluid (CSF) analysis demonstrated low paired CSF glucose 2.36 mmol/L (2.3–4.5) and CSF total protein 0.35 g/L (0.14–0.45). CSF was macroscopically clear and colourless. CSF microscopy showed no organisms on routine gram stain or mycobacterial staining. The CSF also returned culture negative after 8 weeks of prolonged incubation. CSF red cell count 14×10⁶/ L, white cell count 17×10⁹/ L (polymorphs 4%, lymphocytes 95% and eosinophils 1%). A CSF PCR panel was negative for herpes simplex virus 1 and 2, varicella-zoster, enterovirus and parechovirus.

Targeted immunology: targeted immunology

Paraneoplastic antineuronal antibodies (anti-Hu, anti-Yo and anti-Ri) were negative. Anti-Ro (SS: SS-A) antibodies were weakly positive, but other components of the extractable nuclear antibody (ENA) panel were negative. Antibodies to cyclic citrullinated peptide were positive at 30.0 U/mL (0–4.8). A serum antiaquaporin-4 (AQP4-IgG) antibody assay returned positive. (Comment on AQP4 testing: At the time of this patient’s immunology test for AQP4, the laboratory methodology coincided with a period of concordance testing between the Oxford live cell based assay and the commercially available EI—EuroImmun AG fixed cell based assay. Testing was processed via the Neuroimmunology Service at Oxford University Hospitals National Health Service (NHS) Trust. The accuracy of the commercially available assay was reported as being highly comparable to that performed by NHS Oxford Laboratory, with a reported average of 97.5%. As the results derived from both methods were concordant in this patient, the serum AQP4 antibody assay report was issued as a singular (positive) result.)^1–3

Differential diagnosis

New

• The non-neurological diagnoses included iron-deficiency state (also possibly explaining the restless leg syndrome), vitamin D deficiency, thyroid hormone under supplementation and bilateral pulmonary embolism (possibly associated with reduced mobility and also relevant to the noted haemoptysis).

• The neurological differential diagnoses were progressively reviewed in an evolving manner to exclude a cauda equina syndrome, consideration of possible spinal cord acute ischaemic stroke and then towards considering possible transverse myelitis or multiple sclerosis (MS).

• Other possible differentials that were deemed less likely included Guillain-Barre syndrome, mononeuritis multiplex and chronic inflammatory demyelinating polyneuropathy. The neurological differentials were progressively narrowed down with serial clinical reviews by the medicine of the elderly and neurology teams, and ultimately guided by evolving radiology, CSF and immunology results.

PMH related

• Clinical, radiological and serological tests also suggested the presence of chronic rheumatoid arthritis and SS.

Treatment

General treatment modalities

Her initial general treatment focused on optimal management of other conditions (both pre-existing and new diagnoses). She received intravenous treatment for a urinary tract infection (guided by urine culture and sensitivities); intravenous iron supplementation (poor tolerance of oral iron); up titration of oral levothyroxine (guided by thyroid function tests); artificial tears (for SS) and oral vitamin D supplementation (for deficiency state). Following the incidental identification of bilateral pulmonary emboli on CT, she was treated with subcutaneous Low Molecular Weight Heparin (LMWH) and subsequently switched to oral apixaban (after an interval following the lumbar puncture).

Specific treatment modalities

Following confirmation of NMOSD as the definitive diagnosis, acute management was initiated under the guidance of the local neurologists. The initial/acute attack was treated with a 5-day course of high-dose intravenous methylprednisolone with no clinical improvement. Five sessions of plasma exchange (PLEX) were intended, but due to poor tolerance on account of discomfort and dementia, only one session was achieved. Maintenance therapy was with a tapering high dose of oral prednisolone and proton pump inhibitor (omeprazole) cover. Concurrent maintenance dose of oral azathioprine (after ascertaining normal erythrocyte thiopurine metabolites—TPHT activity) was also initiated following the course of high-dose oral steroids.

Outcome and follow-up

The NMOSD resulted in persistent spastic paraplegia (strength 0/5). For symptomatic benefit, oral pregabalin (for neuropathic pain) and oral baclofen (for lower limb spasticity related symptoms) were also introduced with good effect. The double incontinence was managed with a long-term urethral catheter, oral laxatives, assisted bowel and personal care. Her recovery was complicated by development of a grade 4 sacral pressure sore requiring involvement from tissue viability specialists, antibiotics and low-pressure vacuum therapy. Despite an initial desire to facilitate discharge home with an extensive care package and appropriate equipment, her evolving complex care needs led to a growing recognition from the multidisciplinary team and her family that she required long-term 24 hours care. She was transferred to an NHS complex clinical care unit. The NMOSD resulted in a major and life-changing impact on quality of life. Postdischarge NMOSD follow-up and support was intended via our tertiary neurology service. Sadly, the patient died some 8 months after the initial diagnosis.

Discussion

Definition and terminology

NMOSD is a demyelinating inflammatory disease of the central nervous system (CNS) which can affect the optic nerves, brain, brainstem and spinal cord⁴ and is particularly associated with optic neuritis or transverse myelitis. Previously termed ‘neuromyelitis optica’ or ‘Devic’s syndrome’ and historically thought to be a subtype or variant of MS, NMOSD is a complex immune-mediated demyelinating disease, usually associated with a relapsing clinical course of acute attacks.⁵ It has a predilection for the optic nerves and spinal cord but can also target other areas of the CNS resulting in heterogeneous clinical presentations.⁴ Recognition and diagnosis of NMOSD has been transformed by the identification of a disease-specific antibody (AQP4 IgG), which combined with greater appreciation of the spectrum of clinical manifestations, resulting in the 2015 nosology adjustment away from ‘neuromyelitis optica’ in favour of the more accurate ‘NMOSDs.’⁴

Brief epidemiology

Reported incidences of NMOSD range from 0.053 to 0.4 per 100 000 with prevalence rates sited as 0.52 to 4.4 per 100 000 individuals.^{6 7} However, these data are limited due to the condition often being misdiagnosed as MS (up to 29% initially being misdiagnosed as MS in some studies).⁷ The average age at presentation is approximately 40 years old with a female predominance resembling other autoimmune disorders and stronger than that seen in MS; with women constituting 70%–90% of affected individuals in NMOSD.^{6 7} There also appears to be a predilection for non-Caucasians, although more recent studies suggest that this distinction in prevalence is not as significant as previously believed.⁸

Pathogenesis

The key characteristic of this disease is the presence of antibodies directed against the AQP4 water channel.⁶ AQP4 is the main water channel in the brain, predominantly expressed on the cell membrane of astrocytic end feet.⁶ In the majority of patients, there are polyclonal IgG1 autoantibodies which are capable of modulating the AQP4 water channel from the surface of astrocyte end feet by promoting endocytosis. The antibodies induce complement-mediated lysis of the target cells.⁵ Antibody binding results in down regulation of the AQP4 channel and subsequent astrocyte injury via the classic complement pathway.⁹ Antibody-complement complex formation generates a further immune response with demyelination and oligodendrocyte injury occurring as secondary insults.⁹ The predilection for specific regions of the CNS that is observed in NMOSD, for example, optic nerves and spinal cord corresponds to areas of higher AQP4 expression and areas with more permeability between the epithelial cells making up the blood–brain barrier.^{6 9}

Notable associations

NMOSD has well-recognised associations with other autoimmune diseases, particularly seen in combination with systemic lupus erythematosus, thyroid autoimmunity or SS,⁵ as exhibited in our patient. Overlapping manifestations of multiple autoimmune disorders can present significant diagnostic challenges.¹⁰ There is increasing recognition of SS coexisting and mimicking NMOSD, with 1 study of 616 patients with SS reporting a 7% co-existence with NMOSD.^{10 11} As SS can commonly present with extraglandular features (particularly optic neuritis, transverse myelitis and other CNS involvement), this makes the diagnosis particularly challenging in these individuals, and as demonstrated in our case presentation.

Why it is important to distinguish NMOSD from MS

As an inflammatory disorder of the CNS, presenting with features of demyelinating disease, most commonly optic neuritis and transverse myelitis, it was previously thought that NMO may have presented a restricted form of MS.⁴ However, improved understanding of the pathogenesis of the condition, particularly with the identification of the disease-specific AQP4 autoantibody has confirmed that the conditions are distinct entities.⁵ Improved sensitivity for AQP4 IgG detection and greater recognition of the non-opticospinal disease characteristics seen in NMO, combined with better recognition of MRI features has improved identification of individuals with NMOSD who may have previously been labelled as having MS. This distinction should not be seen as pedantic, as treatment modalities for NMOSD and MS are significantly different. MS disease modifying treatments can exacerbate NMOSD, highlighting the need for accurate early diagnosis.⁵

Common forms of clinical presentation

Presentation is with features of demyelinating disease of the CNS. The most common symptoms are optic neuritis and transverse myelitis.^{4 7}

The best defined features of NMOSD remain:

• Acute attacks of bilateral or rapidly sequential optic neuritis usually leading to visual loss.

• Transverse myelitis, presenting with limb weakness, bladder dysfunction and sensory loss.

• Simultaneous presentation of both optic neuritis and transverse myelitis with a typically relapsing course.^{4 6}

Acute attacks of myelitis and optic neuritis are generally more severe and, if untreated, remission is poorer than in MS, which leads to more rapid permanent disability.¹² Unlike MS, a primary progressive clinical course is very rare.¹² However, there is increasing recognition of the heterogeneity of the condition as clinical features reflect lesions in different areas of the CNS, particularly the optic nerve, spinal cord, area postrema, hypothalamus, brainstem and cerebral hemispheres. Consequently, a diverse spectrum of symptoms such as intractable hiccups, nausea, visual loss and paralysis may occur depending on the location of NMO lesions as illustrated in table 1.⁹

Table 1.

Clinical features and typical presentations of NMO (adapted from Broadley et al)⁹

Location of NMO lesion	Core clinical presentation	Typical clinical features
Optic nerves	Optic neuritis	Severe Bilateral and rapidly sequential Painless Poor recovery
Spinal cord	Acute myelitis	Bilateral Motor and sensory Sphincter involvement
Area postrema	Area postrema syndrome	Persistent vomiting Intractable hiccups nausea
Brainstem	Acute brainstem syndrome	Ataxia Limb weakness Cranial nerve palsies
Diencephalon	Diencephalic syndrome	Narcolepsy Daytime somnolence Hypothermia
Cerebrum	Cerebral syndrome	Encephalopathy Seizures

NMO, neuromyelitis optica.

On retro-analysis of our index patient’s symptom profile, it became apparent that (in addition to earlier described features that were noted following presentation to hospital), she had experienced other non-clustered symptoms. These symptoms had run an intermittent course and lasted for varying periods in the year preceding the confirmed diagnosis of NMOSD. At one point, she had experienced a prolonged bout of hiccups (up to 3 weeks), previous episodes of intermittent ‘pins and needles’ (paraesthesia) to both hands, and also episodic facial hyperaesthesia/allodynia.

The historical episode of sensory symptoms (eg, paraesthesia to both hands) may have also suggested a previous episode of transverse myelitis. This retrospective conclusion would also be supported by the fact that the patient had multiple lesions on the spinal cord. Typically, myelitis associated with neuromyelitis optica is associated with a single spinal cord lesion (rather than multiple), and so the radiological presence of multiple discrete lesions in our patient would also suggest previous NMOSD-related attacks.

Within the spectrum of possible presentations, there remain a number of these that are particularly suggestive of NMOSD. These are optic neuritis which is simultaneously bilateral and often associated with severe residual visual loss; a complete (as opposed to partial) spinal cord syndrome with prominent paroxysmal tonic spasms and an ‘area postrema syndrome’—consisting of intractable hiccups or nausea and vomiting.^{4 5} Other, more atypical presentations reported in the literature include cutaneous manifestations and encephalitis.¹⁰ Area postrema presentation, previously considered ‘atypical’ symptoms now constitute core clinical characteristics in the revised diagnostic criteria established in 2015 (see table 2).⁴ In fact, the new diagnostic criteria allow for a diagnosis to be made in individuals without clinical features of optic nerve or spinal cord involvement.⁴

Table 2.

NMOSD diagnostic criteria for adults⁴

Core clinical characteristics.	1. Optic neuritis. 2. Acute myelitis. 3. Area postrema syndrome. 4. Acute brainstem syndrome. 5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions. 6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions.
Diagnostic criteria for NMOSD with AQP4-IgG.	1. At least one core clinical characteristic. 2. Positive test for AQP4-IgG using best available detection method. 3. Exclusion of alternative diagnoses.
Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4 status.	At least two core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements: At least one core clinical characteristic must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis lesions or area postrema syndrome. Dissemination in space (two or more different core clinical characteristics). Fulfilment of additional MRI requirements as applicable. Negative test for AQP4-IgG using best available detection method. Exclusion of alternative diagnoses.
Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknown AQP4-IgG status.	Acute optic neuritis: requires brain MRI showing: Normal findings or only non-specific white matter lesions. Optic nerve MRI with T2-hyperintense lesions or T1-weighted gadolinium-enhancing lesion extending over>half optic nerve length or involving optic chiasm. Acute myelitis: requires associated intramedullary MRI lesion extending over ≥3 contiguous segments OR ≥3 contiguous segments of focal spinal cord atrophy in patients with history compatible with acute myelitis. Area postrema syndrome: requires associated dorsal medulla/area postrema lesions. Acute brainstem syndrome: requires associated periependymal brainstem lesions.

AQP4, aquaporin-4; NMOSD, neuromyelitis optica spectrum disorder.

Treatment considerations

It is important to caveat the following subsection by acknowledging there is no treatment option, that is, at this time, supported by randomised controlled studies. It is important to mention that current recommendations are based mainly on retrospective or small prospective uncontrolled series.

Although diagnostic criteria stratify into AQP4 positive and negative individuals, there is currently no evidence that AQP4 serological status has a bearing on treatment decisions. Acute attacks are managed with courses of intravenous corticosteroid (usually methylprednisolone for 5 days).⁵ A series of PLEX procedures may be used for severe attacks which are not steroid responsive, but studies have yet to demonstrate their efficacy over intravenous steroid as a first-line treatment which is also true of other treatment modalities such as intravenous immunoglobulins.⁵

The goal of management is to prevent attacks. Disability in NMO is attack related and the disease rarely transforms into a secondary progressive disease course, as is more commonly seen in MS.^{13 14} Prolonging disease-free remissions should result in clinical improvement and neurological stability, therefore, early introduction of preventative immunotherapy following an acute attack should have a greater impact on long-term disability in NMOSD compared with MS.¹⁴ This again highlights that early accurate diagnosis, and distinction from MS is essential.^{5 14}

For longer term preventative therapy, the foundation of all treatments is immunosuppression but no specific regimen has been demonstrated to be superior in the absence of completed randomised, placebo-controlled trials.^{5 15} Mycophenolate mofetil, azathioprine and rituximab are the most commonly used agents for long-term immunosuppression in patients who have established relapsing disease. Evidence suggests that the majority of patients can achieve remission with one of the first two drugs they try.⁵ In current practice, choice of agent is mainly determined by comorbidities, disease activity and availability. Other second-line treatments which have demonstrated benefit include methotrexate, tocilizumab and mitoxantrone. A number of MS disease modifying drugs should be avoided in NMOSD due to their detrimental effect on NMOSD. Similarly, if there is any diagnostic uncertainty between MS versus NMOSD, then a ‘NMOSD suitable’ immunosuppression approach is recommended.^{4 5}

Owing to improved understanding of NMOSD pathophysiology, there are a number of other immunomodulating therapies such as eculizumab (a complement-targeting monoclonal antibody) being explored in NMOSD randomised controlled trials.¹⁵

Prognosis

Unfortunately, NMOSD has a poor prognosis with a median survival of 8 years from time of diagnosis with an overall 10-year mortality of 20%–25%.^{16 17} Relapse occurs in up to 90% of patients and in half of all patients this occurs within 1 year of the initial attack.¹⁷ Age at disease onset appears to be a significant predictor of disability type, as visual disability has been more commonly seen in young-onset patients; whereas there is a higher risk of motor disability seen in older patients, irrespective of their initial-onset symptom.^17–19 In a large UK and Japan-based study, after a median disease duration of 75 months, 18% had developed permanent bilateral visual disability, 34% permanent motor disability, 23% had become wheelchair dependent and 9% had died.¹⁸ Overall prognosis of NMOSD is significantly poorer than MS on account of more severe attacks combined with less recovery.^{7 10 14} This further supports the importance of early and accurate diagnosis.

Patient’s perspective.

It was frustrating that it took so long for our mother to be diagnosed with neuromyelitis optica but we are grateful that it was picked up as it allowed the correct treatment to be started promptly after diagnosis. As autoimmune diseases run in the family, we feel frustrated at ourselves for not ensuring she was on correct medication for her autoimmune disorders. Given the length of time she was in hospital, we found it difficult to explain to her what was wrong with her, on account of her dementia, while trying to keep her positive and motivated. Mum set a very good example in never complaining about her pain or loss of dignity always smiling in front of family and friends. She had a great sense of humour throughout her illness. Following the diagnosis, we wanted to care for her at home and for her to be able to spend quality time with family, especially her husband of 66 years who has Alzheimer’s dementia. We therefore found it difficult to come to terms with the reality that this would not be possible due to the rapid deterioration in her condition.

Learning points.

• Neuromyelitis optica spectrum disorders (NMOSD) may present in older patients, for example, masquerading as falls.

• Optic neuritis and acute myelitis remain the core clinical characteristics of NMOSD, but are not essential diagnostic criteria.

• Where accessible, targeted MRI (eg, brain, optic nerve and/or spinal cord) and targeted serology (eg, aquaporin 4 antibodies) are helpful in diagnoses.

• NMOSD may present in patients with other auto-immune conditions, for example, seropositive Sjögren’s syndrome, rheumatoid arthritis and systemic lupus erythematosus.

• It is important to make an early distinction between NMOSD and multiple sclerosis. Although clinical manifestations are often very similar, there are important differences in treatment modalities, clinical course and overall prognosis.