Seronegative neuromyelitis optica after cardiac transplantation

Abstract

We report a case of a 42-year-old man who presented with progressive weakness and blindness over the course of several months and met criteria for seronegative neuromyelitis optica. This presentation was in the setting of immunosuppression following cardiac transplant. No infectious causes were found within the neuroaxis, and he ultimately died with complete blindness, quadriplegia, and respiratory failure attributed to panmyelitis and brain stem inflammation despite aggressive therapies.

Neuromyelitis optica (NMO) is a rare inflammatory demyelinating disease that affects the optic nerves, brainstem, and spinal cord, resulting in varying degrees of blindness and paralysis. Once considered a subclass of multiple sclerosis, it has emerged as its own entity with the discovery of an associated autoantibody, aquaporin-4, present in a majority of patients (1). The antibody is absent in a subset of patients (2) where other antibodies are thought to play a role. The anti-MOG antibody may be linked to NMO, but was commercially unavailable for testing at the time of our patient's illness (3). Current treatments are noncurative and include trials of immunosuppressants and immunomodulators (4). We report a case of a patient who, despite being on immunosuppression after a heart transplant, presented with seronegative NMO.

CASE DESCRIPTION

A 42-year-old black man with prior orthotopic heart transplant for nonischemic cardiomyopathy and end-stage renal disease from immunosuppressant therapy presented with severe burning pain in his legs bilaterally. The symptoms were first noticed about 2 years posttransplant and had gradually worsened over 2 months. Initial examination showed hyperesthesia from L2 on the right and L1 on the left. The patient refused a lumbar puncture at that time, citing improved pain with gabapentin, and wished to go home with outpatient follow-up. The patient was fully ambulatory at the time of discharge.

He gradually developed weakness in his legs and noticed some blurry vision. Examination on his second admission, 5 weeks later, showed weakness in both legs, distal (3 of 5) greater than proximal (4- of 5). Deep tendon reflexes were hyperreflexive at the knees with clonus at the ankles. Strength in the upper extremities was mildly decreased (4 of 5). He had a bilateral T8 sensory level, but was not incontinent. Visual acuity was decreased in his right eye with large sluggishly reactive pupils.

Repeat magnetic resonance imaging (MRI) of his spine showed increased T2 hyperintensity throughout the central gray matter with diffuse cord signal change and minimal cord expansion (Figure 1). MRI of the orbits showed fluid attenuation inversion recovery (FLAIR) hyperintensity of the bilateral anterior optic pathway, and MRI of the brain showed brainstem FLAIR signal elevation with subtle contrast enhancement. The cerebral hemispheres showed only some encephalomalacia from known previous asymptomatic strokes that occurred at the time of his cardiac transplant with no signs of demyelination. Comprehensive rheumatologic and infectious workups were unremarkable (Table 1). Aquaporin-4 IgG was negative. Cerebrospinal fluid analysis disclosed an elevated protein (62 mg/dL) with a normal cell count and differential.

Figure 1.

MRI. (a) Sagittal and (b) axial FLAIR hyperintensity in the substantia nigra, medulla, and cervical spinal cord. (c) Cervical and (d) thoracic sagittal T2-weighted images showing cord edema. Subtle pathological enhancement was seen in the cervical spine and lower medulla (not shown).

Table 1.

Extensive negative laboratory workup

Category	Negative testing
Infectious	Adenovirus, PCR bronchoalveolar lavage Arbovirus panel (Eastern Equine, California, St. Louis, Western Equine, West Nile virus), serum and CSF Bartonella antibody panel, serum Cytomegalovirus, PCR CSF Cryptococcal antigen, CSF Venereal Disease Research Laboratory, CSF Epstein-Barr virus antibodies, PCR CSF Herpes simplex virus antibodies, PCR CSF HIV antibody, serum JC virus, PCR CSF Legionella pneumophila direct fluorescent antibody Lyme disease, PCR serum Mycobacterium tuberculosis amplified Mycoplasma antibodies Toxoplasma gondii antibodies, serum and CSF Varicella zoster antibodies, PCR CSF Blood cultures CSF cultures Fungal cultures
Rheumatologic	Aldolase Anti-neutrophil cytoplasmic antibody Anti-cardiolipin antibodies Angiotensin-converting enzyme Anti-citrullinated protein antibody Anti-DNA antibodies Anti-nuclear antibodies Extractable nuclear antigen (Ro, La, RNP, Smith, Jo 1, SCL 70 antibodies)
Other	Paraneoplastic autoantibody panel, CSF (ANNA-1, ANNA-2, ANNA-3, AGNA-1, PCA-1, PCA-2, PCA-Tr, Amphiphysin Ab, CRMP-5 IgG) Oligoclonal bands Immunoglobulin G synthesis index

CSF indicates cerebrospinal fluid; PCR, polymerase chain reaction.

Within a week of hospitalization, the patient was quadriplegic, ventilator dependent, incontinent, and completely blind. He was treated with broad-spectrum antibiotics, antifungals, and antivirals. He was treated for presumed NMO aggressively with high-dose methylprednisolone and plasmapheresis (five cycles) followed by intravenous immunoglobulin (2.3 g/kg), with no response. His hospital course was complicated by healthcare-associated pneumonia and later a gastrointestinal bleed secondary to cytomegalovirus colitis. The patient remained cognitively intact and was transitioned to comfort care per his wishes and died shortly thereafter.

The patient and his father granted an autopsy. His fixed brain weighed 1550 g with significant gyral flattening and sulcal narrowing consistent with edema. The cranial nerves appeared grossly intact, except the right optic nerve appeared smaller than the left. On coronal sectioning, no gross abnormalities were seen throughout the cerebral hemispheres. Sectioning through the cerebellum found a 1.1 × 0.8 cm wedged-shaped area of volume loss with brown discoloration at the left medial posterior aspect. No gross abnormalities were identified in the pons, midbrain, medulla, or spinal cord.

Microscopically (Figure 2), there was a remote incomplete infarct with marked neuron and volume loss in the left cerebellar hemisphere corresponding to the lesion seen grossly. The most significant lesions seen microscopically were located within the midbrain, pontomedullary junction, multiple levels of the spinal cord, and the optic nerves. These areas all showed similar histologic findings characterized by extensive areas of pallor and vacuolization with an inflammatory infiltrate composed predominantly of macrophages. Extensive myelin loss was identified throughout these areas and was highlighted with a Luxol fast blue stain. Additionally, focal axonal loss was also confirmed by a neurofilament immunohistochemical stain. The characteristic features of cytomegalovirus infection were not identified.

Figure 2.

(a) Hematoxylin and eosin–stained section from the optic nerve showing a central area of vacuolization and degeneration (×40). (b) Immunohistochemical stain for CD68 of the optic nerve showing increased macrophages infiltrating throughout the nerve (×40). (c) Luxol fast blue stain of the optic nerve showing a loss of myelin, which is more pronounced centrally (×40). (d) Immunohistochemical stain for neurofilament showing a decreased number of axons within the optic nerve (×40). (e) Hematoxylin and eosin–stained section of the spinal cord showing significant vacuolization and pallor (×100). (f) Immunohistochemical stain for CD68 highlighting background infiltrating macrophages within the spinal cord (×100). (g) Luxol fast blue stain of the spinal cord showing significant myelin loss (×100).

DISCUSSION

Devic and Gault first described patients with NMO in 1894 (5). It is an inflammatory demyelinating disease that initially spares the brain but attacks the optic nerves and spinal cord with varying severity. The condition affects women nine times more frequently than men, with the median age in the fourth decade. The prognosis is poor, as no current therapies are curative.

Originally categorized as a subclass of multiple sclerosis, NMO was later established as a separate disease with the discovery of a specific biomarker, aquaporin-4 IgG (1). Aquaporin-4 is the major water channel in the brain, optic nerve, and spinal cord and thus a major contributor to water homeostasis (6). The sensitivity of this antibody has been reported to be 73% and the specificity, 91% (1, 7). A 2012 retrospective study reported that the presence or absence of the NMO antibody did not alter the overall mortality rate, age of presentation, or relapse rate. Those with seronegative NMO were more likely to have a monophasic course, bilateral eye involvement, and concurrent optic neuritis and myelitis (7), similar to our case.

In 2006, Wingerchuk and colleagues revised the diagnostic criteria for NMO to include the discovered autoantibody (8). The patient must present with optic neuritis and acute myelitis. In addition, two of three of these criteria must be met: 1) MRI shows a spinal cord lesion that spans >3 vertebral segments; 2) patient does not meet the criteria for multiple sclerosis based on MRI; and 3) patient tests positive for aquaporin-4 IgG.

Treatment is limited and usually focused on immunosuppression. The typical algorithm is to start the patient having active demyelination on 1 g per day of intravenous methylprednisolone. If the patient fails to respond or if the symptoms are severe, administration of 2 g/kg of intravenous immunoglobulin, sometimes preceded by plasma exchange, may be considered. Some reports suggest that NMO is more responsive to plasma exchange than to either steroids or intravenous immunoglobulin (4). To reduce relapses, immunosuppression is used, with rituximab, azathioprine, cyclophosphamide, and mycophenolate the agents of choice (4). There are no randomized controlled trials comparing these treatments. Interferon and other therapy used for multiple sclerosis usually have no effect on the disease process and may even be harmful (4).

Our patient failed to respond to any of these therapies. Furthermore, he had already been immunosuppressed with tacrolimus, mycophenolate mofetil, and prednisone. Thus, how he developed this condition in the setting of immunosuppression was puzzling.