Seronegative neuromyelitis optica spectrum disorder: severe polysymptomatic presentation with successful treatment response

Abstract

We report the case of a 50-year-old caucasian man presenting with lumbar pain, bilateral ataxia, central facial palsy, ophthalmoparesis and urinary retention. Cerebral MRI hinted a hyperintensity of the medulla oblongata and cervical medulla suggestive of myelitis. Cerebrospinal fluid displayed lymphocytic pleocytosis and elevated protein concentration. Without the possibility to rule out an infectious or inflammatory aetiology, antibiotics and corticosteroids were started. Nevertheless, neurological status deteriorated with loss of muscle strength and left eye amaurosis. A neuroaxis MRI exhibited encephalomyelitis with signal abnormalities involving the pons, medulla oblongata, left optic nerve and cervicodorsal medulla. Although negative for aquaporin-4-IgG antibodies, the patient fulfilled criteria for seronegative neuromyelitis optica spectrum disorder with the presence of multiple core clinical characteristics. Through early institution of corticosteroids, plasma exchange and rituximab, good functional recovery was achieved (Expanded Disability Status Scale score of 2). However, left eye amaurosis persisted despite salvage therapy with intravenous immunoglobulin.

Background

Neuromyelitis optica spectrum disorder (NMOSD), an immune-mediated chronic inflammatory disease of the central nervous system, has seen its definition evolve from being considered a variant of multiple sclerosis (MS) to the identification of particular clinical, radiological and even serological features, with the identification of the specific autoantibody against aquaporin-4 (AQP4) water channel.^{1 2} The 2015 International Panel for NMO Diagnosis (IPND) diagnostic criteria were fundamental in unifying and homogenising the concepts surrounding the disorder, with the presence of AQP4-IgG antibodies now sufficient for NMOSD diagnosis when associated with at least one of six different core clinical presentations, or, in the absence of these antibodies, the presence of at least two of these presentations being required for diagnosis: optic neuritis, transverse myelitis, area postrema syndrome, acute brainstem syndrome, acute diencephalic syndrome and symptomatic cerebral syndrome.^{1 3 4} A subgroup of NMOSD patients has also been described, seronegative for AQP4-IgG, but with detectable antibodies against myelin oligodendrocyte glycoprotein (MOG).^{1 5 6}

Women constitute 70%–90% of affected individuals, but a more balanced female to male ratio (2:1) is observed in seronegative patients. Although a rare entity (with prevalence rates ranging from 0.54 per 100 000 in Cuba to 4.4 per 100 000 in Denmark), NMOSD awareness is still relevant, as diverse malignancies, infections, vascular and other inflammatory diseases may present similar symptoms, with a timely recognition and therapy institution being crucial for a favourable outcome.^{3 7}

We present the case of a patient where, even in the absence of antibodies, the diagnosis is firmly made by the presence of other diagnostic clinical features in the presentation. Furthermore, despite the severity of the clinical picture, early recognition of the entity and institution of aggressive therapy resulted in a fully functional individual.

Case presentation

A 50-year-old caucasian man was admitted to our emergency department (ED) due to lumbar pain and gait abnormality. He had a history of hypertension under treatment with nebivolol 2.5 mg/day.

The clinical picture had started 4 days earlier, with sudden onset of cervicalgia. During the following days, pain increased in severity and extended to the lumbar region. These symptoms motivated an observation in the ED 24 hours previously to the over mentioned visit, in which the pain was interpreted as musculoskeletal. The following day the patient developed loss of balance, generalised tremor and ataxia. During the night, he developed urinary retention, fever (38.2°C) and his wife noticed slurred speech, motivating a new attendance to the ED.

Physical examination on admission displayed a somnolent but otherwise haemodynamically stable, oriented and cooperating patient. Neurological examination revealed normal muscle strength and sensory exam but minor left central facial palsy, dysarthria and limitation in the abduction of the left eye. There was also bilateral ataxia, predominantly of the upper limbs.

Investigations

Haematology and biochemistry

Laboratorial examination revealed leucocytosis (white blood cells count of 13.42×10⁹/L) with predominant neutrophilia (84.3%), normal haemoglobin value and platelet count. C reactive protein (CRP) was negative (1.4 mg/L, reference value <5 mg/L) and renal function was normal.

Radiology

Head and lumbar spine contrast-enhanced CT scans revealed no significant abnormalities. Contrast-enhanced cerebral MRI with gadolinium hinted an area of hyperintensity of anterior predominance in the inferior strand of the medulla oblongata and in the cervical medullar segment still covered by the exam, suggestive of myelitis (figure 1).

Figure 1.

(A) Sagital T2W TSE and (B) axial T2W TSE revealing an area of hyperintensity of anterior predominance in the inferior strand of the medulla oblongata and in the cervical medullar segment (arrows).

Cerebrospinal fluid (CSF) analysis

Lumbar puncture displayed clear CSF, with pleocytosis (59 total cells/µL, of which 58 leucocytes/µL, with no polymorphonuclear cells and 100 erythrocytes/µL), elevated CSF protein concentration (2.02 g/L, reference value between 0.15 and 0.45 g/L) and no glucose consumption. Ampicillin, ceftriaxone and acyclovir (aciclovir) were started. Nevertheless, with the findings of the CSF fluid also compatible with inflammatory aetiology (pleocytosis with lymphocytic predominance), combined with a low CRP and the finding of myelitis in the MRI, intravenous methylprednisolone pulses were also instituted (1 g/day for 5 days). Pondering the risk of further neurological decline, the patient was admitted to an Intermediate Care Unit for further study.

Microbiology and virology

Regarding infectious diseases, serologies for HIV, Borrelia (burgodrferi, garinii and afzelii) and Treponema pallidum particle agglutination assay were negative, while microbiologic testing of the CSF also yielded negative results. Antibiotherapy was suspended.

Immunology and malignancy

Relatively to an autoimmune aetiology, assessments presented negative results, including no oligoclonal bands in the CSF. Concerning the possibility of a paraneoplastic process, chest CT scan and abdominal ultrasound imaging were performed, revealing no signs of malignancy, peripheral blood and CSF immunophenotyping were obtained, with unremarkable findings, and screening for antineuronal antibodies (anti-Hu, anti-Yo, anti-Ri, anti-PNMA2, anti CV2/CRMP5 and antiamphiphysin one antibodies) yielded negative results.

Differential diagnosis

A progressive worsening of the neurological status was observed during the first days of hospitalisation, with aggravated mental status, dysarthria and left central facial palsy, sudden onset of left eye amaurosis and complex ophthalmoparesis with limitation in the abduction of both the left and right eyes. A gradual loss of muscle strength (grade 3 in all limbs) was verified, with bilateral ataxia and absent reflexes in the lower limbs. There was absence of persistent hiccups, nausea and vomiting.

Due to the above mentioned deterioration, a complete neuroaxis MRI complemented with orbital evaluation was performed to deepen the previous findings, exhibiting signs of encephalomyelitis, with signal abnormalities involving the pons, medulla oblongata, periaqueductal matter and large lesions extending from the cervical to dorsal segments of the spinal cord with predilection for the anterior columns. Additionally, involvement of the left optic nerve could not be ruled out (figure 2). The patient was observed by an ophthalmologist and optical coherence tomography performed, displaying a swollen peripapillary retinal nerve fibre layer (pRNFL) of the left eye, confirming involvement of the left optic nerve.

Figure 2.

(A) Sagital T2W TSE and (B, E) axial T2W TSE revealing hyperintense lesions involving the pons the medulla oblongata and cervical spinal cord, confirmed in (C) sagital short tau inversion recovery (STIR) as longitudinally extensive. (D) Axial T2W TSE demonstrating a lesion in intraconic segment of the left optic nerve (arrow). (F) Axial T2W TSE with hyperintensity surrounding the periaqueductal matter (arrow).

Considering these findings and the reasonable exclusion of an infectious or paraneoplastic process, the patient fulfilled criteria for NMOSD with unknown AQP4-IgG status. Antibodies to cell surface neuronal antigens and AQP4-IgG antibodies were requested (testing for AQP4 was completed using the commercially available EI—EuroImmun AG fixed cell-based assay).

Treatment

Plasma exchange therapy was started on day 4 of hospitalisation (with a total of seven sessions), therapy with rituximab was instituted (1 g separated by 2 weeks) and corticosteroids were maintained at 1 mg/kg of oral prednisolone. A progressive neurological improvement was achieved, with gradual recovery of the dysarthria, facial palsy, ophthalmoparesis, muscle strength, ataxia and absent reflexes. However, vision loss of the left eye persisted. After re-evaluation by ophthalmology confirmed maintained involvement of the left optic nerve, a decision was made to institute therapy with intravenous immunoglobulin as salvage therapy—2 g/kg over the course of 5 days, followed by 0.5 g/kg monthly administrations over 3 months.^{8 9}

Outcome and follow-up

The patient evolved favourably in terms of functionality with rehabilitation during follow-up, with an Expanded Disability Status Scale score of 2 and MRI at 5 months displaying no pathological findings apart from left optic nerve atrophy, with the visual defect still persisting. Screening for antibodies to cell surface neuronal antigens was negative, including N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), γ-aminobutyric acid, GABA(A), GABA(B), mGluR1 and mGluR5 receptors, LGl1 and Caspr2, DPPX, Neurexin3, Iglon5. AQP4-IgG and MOG antibodies testing by cell-based assay were negative, establishing the diagnosis of NMOSD without AQP4-IgG.¹⁰

Discussion

An early accurate diagnosis in NMOSD is particularly vital. Previous expert opinion suggests that even in doubtful scenarios but where NMOSD is a possibility, immunosuppression is the most prudent option, considering that prompt aggressive treatment is necessary for satisfactory outcomes.¹¹ Nevertheless, the differential diagnosis is vast, including conditions with a markedly distinct management. As an example, therapies used in MS may aggravate NMOSD.^{3 7} Therefore, initial efforts in our case were placed in ruling out these alternative possibilities. After this exclusion, neuroaxis MRI was fundamental in narrowing the diagnostic possibilities: the finding of three core clinical characteristics (optic neuritis, acute myelitis and acute brainstem syndrome) allowed for the diagnosis of NMOSD even before testing for AQP4-IgG antibodies. OCT displayed a swollen pRNFL, a transient finding expectable during the clinical onset of optic neuritis, normally followed by retinal nerve fibre layer and ganglion cell layer thinning.^{12 13}

Considering the neurological and ophthalmological deterioration, aggressive treatment was instituted with corticosteroids, plasma exchange (with increasing evidence of the benefits of its early use)¹⁴ and rituximab (with increasing data displaying its high efficacy, gaining strength as a first-line option).^{15 16} Overall improvement was staggering, but ophthalmological involvement persisted. Intravenous immunoglobulin was administered as salvage therapy for optic neuritis, with no additional recovery.

Thereafter, AQP4-IgG and MOG antibodies tested negative, fulfilling the IPND 2015 diagnostic criteria for NMOSD without AQP4-IgG: (1) presence of at least two core clinical characteristics with one being optic neuritis, acute myelitis or area postrema syndrome, with MRI demonstrating involvement; (2) negative tests for AQP4-IgG and (3) exclusion of alternative diagnosis.⁴

Retrospectively, a symptom initially displayed by the patient could have aided in guiding the diagnostic workup: severe back pain. Increasingly evidence highlights the prevalence and severity of pain in NMOSD, noting greater pain scores and worse quality of life scores comparing, for instance, to MS cohorts.^{17 18}

Visual loss was the only relevant sequelae exhibited by the patient. This fact comes in accordance with previous data that states higher visual disability in male patients.¹⁹ Nevertheless, while rates of visual disability vary among the various reports, they are generally relatively low. Literature descriptions range from 16.2% reported as blind and 28.6% as severely impaired in a Japanese study,²⁰ to visual acuity worse than 6/36 in the best eye in 12% of Japanese patients and 22% of UK patients in another report,¹⁹ and 11 out of 12 patients (92%) presenting mild visual impairment and 1 greater visual loss in an Israeli study.²¹

This case report intends, chiefly, to raise awareness to this entity, both for the potentially severe complications, and for the need of early therapy, many times significantly distinct from some of its differential diagnosis.

Learning points.

• Neuromyelitis optica spectrum disorder (NMOSD), although rare, should be considered even in the absence of the specific autoantibody against aquaporin-4 water channel. This is especially the case, if other NMOSD diagnostic criteria for adults are met.

• Differential diagnosis is difficult and vast, comprising infectious, autoimmune, paraneoplastic and inflammatory causes, including conditions with a markedly distinct management.

• Early aggressive therapy is fundamental in achieving favourable outcomes.