Fulminant Devic disease successfully treated by lymphocytapheresis

Devic disease is a demyelinating disease characterised by acute optic neuritis and transverse myelitis. Although there are differences in the pathogenesis of Devic disease and multiple sclerosis, the treatment for Devic disease is the same as that for multiple sclerosis. We report a patient with Devic disease who was resistant to high‐dose intravenous methylprednisolone and intravenous immunoglobulin (Ig) treatments, but was effectively treated with lymphocytapheresis (LCP). The profiles of cytokines during the clinical course are discussed.

Case report

In August 2001, a 27‐year‐old woman developed acute loss of vision and sensory disturbance in both lower extremities after coughing. The next morning (day 2), she was totally blind and was admitted to our hospital. Neurological examination showed total blindness, papilloedema, moderate muscle weakness of the hip and thigh muscles, positive pathological reflexes of the limbs, hyper‐reflexia and sensory loss below the T4–5 level. Loss of vesicorectal function and perspiration below the chest were also observed.

Laboratory examination disclosed a normal C‐reactive protein level, positive antinuclear (titre 1/160) and antithyroglobulin antibodies (0.8 U/ml (normal range <0.3)) in serum, normal CD4:CD8 ratio (0.90 (normal range 0.69−1.74)) and an increased percentage of CD8 T cells (45% of total T cells (normal range 12−30%)). Anti‐neutrophil cytoplasmic antibodies, anti‐phospholipid antibodies and rheumatoid factor were negative. No significant increase of antibodies in the serum or CSF was seen against the following microorganisms: herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein–Barr virus, enterovirus, hepatitis B virus, mumps, measles, rubella, coxsackie virus, Borrelia burgdorferi, syphilis, chlamydia, legionella and Mycoplasma pneumoniae. Neuromyelitis optica (NMO)‐IgG¹ was negative. CSF analysis was normal except for an increased concentration of myelin basic protein (660 pg/ml (normal limit <102 pg/ml)) on day 2, but pleocytosis (112/mm³) and increased protein concentration (152 mg/dl) were observed on day 12. MRI of the brain showed enlarged optic nerves without enhancement. T2‐weighted MRI of the spinal cord showed high signal intensity in the cervical cord (C6–7) on day 3, and diffuse swelling in the whole spinal cord with T2 hyperintensity on day 15.

Two courses of methylprednisolone treatment (1 g/day for 3 days) were given from day 3, and, in addition, intravenous Ig (0.4 g/kg/day for 5 days) was given from day 16. The patient, however, showed no response to these treatments. Thereafter, she fell into complete tetraplegia, with sensory loss below the neck and frequent sharp pains from the shoulder to neck, which were considered to be painful tonic spasms. Then, on day 23, we performed LCP with a centrifuge, “COBE Spectra” (GAMBRO, Tokyo, Japan), that processed 7–8 l of blood and removed about 3–4×10⁹ lymphocytes per procedure. On the day of treatment the sharp pain disappeared immediately after the first LCP, and the following day her vision showed improvement, going from total blindness to the level of finger counting. Thereafter, LCP was performed once or twice weekly for a total of 11 LCP treatments. Her vision was almost normalised, with improvement of the sensory deficit and recovery of weakness of the upper extremities to grade 4 or 5 on the manual muscle test.

The T‐helper (Th)1:Th2 balance represented by the ratio of intracellular interferon γ to interleukin (IL) 4 in the CD4 T cells increased markedly both before the first LCP (22.2 (normal limit <10)) and after the last LCP (17.5). CSF IL‐6 and serum IL‐12 levels were markedly reduced after the first LCP, even when compared with those on the same day before treatment (table 1). No relapse has occurred in 4 years.

Table 1 Cytokine profile during the clinical course.

	IL‐6 (pg/ml)		IL‐12 (pg/ml)
	Serum	CSF	Serum	CSF
Before the first LCP	3.2	5660	18.5	<7.8
After the first LCP	3.0	121	<7.8	<7.8
After the last LCP	2.8	6.1	<7.8	<7.8

IL, interleukin; LCP, lymphocytapheresis.

Comment

Devic disease presents with a poor prognosis, including death, and frequent sequelae, including visual disturbance or paralysis.² Marked improvement was achieved by 2–5 treatments a week over about 6 weeks in only one other reported case of Devic disease that was treated by lymphocytoplasmapheresis, including the removal of both lymphocytes and plasma.² In our patient, who was resistant to methylprednisolone and intravenous Ig treatments, remarkable improvement of the symptoms, especially visual loss, was immediately obtained by LCP, which removed only lymphocytes but not plasma. LCP might reduce clonally expanding pathogenic T lymphocytes in the peripheral blood, and has been used as an adjunct to standard immunosuppressive treatment for acute transplant rejection. The removal of lymphocytes may therefore augment immunosuppression.³ LCP may have induced the improvement in our patient through these mechanisms.

In our patient, an infectious aetiology was unlikely, and positive antinuclear antibody suggested an autoimmune mechanism. The specific biomarker for NMO, NMO‐IgG, has been reported in NMO and opticospinal multiple sclerosis, suggesting an autoantibody‐driven pathogenesis.¹ The sensitivity of NMO‐IgG for diagnosing NMO is 73%,¹ and our patient would be classified as being in the seronegative group. It has, however, been reported that opticospinal multiple sclerosis, which seems to be similar to NMO with respect to NMO‐IgG,¹ is associated with the Th1‐dominant condition during both the relapse and remission phases.⁴ In our patient, a shift in the Th1:Th2 balance towards Th1 dominance was shown during both the acute and remission phases. Th1 cells possibly play an important part in the pathogenesis of Devic disease. An investigation of this will require further study with more patients.

It has been reported that a proinflammatory cytokine, IL‐6‐secreting cells, or a critical cytokine for T cell‐mediated autoimmunity, IL‐12‐secreting cells, are increased in both the CSF and blood from patients with NMO.⁵ In our patient, increased levels of CSF IL‐6 and serum IL‐12 were consistent with those previously reported, but levels of serum IL‐6 and CSF IL‐12 were normal. Levels of CSF IL‐6 and serum IL‐12 correlated well with disease activity. These cytokine levels may therefore serve as markers of therapeutic effects as well as disease activity in Devic disease. Levels of CSF IL‐6 and serum IL‐12 were reduced immediately after the first LCP, suggesting the direct effect of LCP on cytokines. Clinical improvement is thought to have been induced by LCP, because of the extremely rapid improvement within 1 day after LCP.

In conclusion, LCP may be a therapeutic option in fulminant Devic disease that is unresponsive to other treatments, including methylprednisolone treatment.