Relapsing acute transverse myelitis: a specific entity

European Journal of Neurology 2005, 12: 681–684

REVIEW ARTICLE

Relapsing acute transverse myelitis: a specific entity T. Seiferta, C. Enzingera, S. Ropelea,b, M. K. Storcha, S. Strasser-Fuchsa and F. Fazekasa,b a

Department of Neurology, Graz Medical University, Graz, Austria; and bMRI Center, Graz Medical University, Graz, Austria

Keywords:

necrotizing myelitis, neuromyelitis optica, relapsing myelitis, transverse myelitis Received 13 July 2004 Accepted 4 August 2004

Acute transverse myelitis (ATM) not related to systemic disease may present in a relapsing manner. Data in the literature about this condition are scarce. We describe three patients suffering from relapsing myelitis in whom no association with systemic disease, i.e. infectious or connective tissue disease was found. Magnetic resonance imaging (MRI) findings were also distinctly different from multiple sclerosis and consistent with a necrotizing type of inflammation. Despite various treatment strategies, all patients became severely disabled. Relapsing ATM not related to systemic disease appears to be a specific entity which accounts for severe disability and currently lacks effective treatment.

Introduction Magnetic resonance imaging (MRI), for the first time, allows to appreciate differences in the extent and distribution of morphologic abnormalities associated with inflammatory spinal cord diseases. This has also fuelled new interest regarding the syndrome of acute transverse myelitis (ATM), and new diagnostic criteria have been proposed recently (Transverse Myelitis Consortium Working Group, 2002). According to these criteria, acute ATM is defined by bilateral, and not necessarily symmetric, sensory, motor or autonomous dysfunction attributable to the spinal cord, a sensory level, the proof of inflammation within the spinal cord by MRI or cerebrospinal fluid (CSF) examination, and the progression to nadir between 4 h and 21 days following the onset of symptoms. An extra-axial compressive, a vascular (anterior spinal artery thrombosis, arteriovenous malformation) etiology and a history of radiation to the spine have to be excluded. A large number of disorders such as bacterial, viral, fungal or parasitic infections may lead to ATM (Berger and Sabet, 2002). Furthermore, ATM may be caused by connective tissue disease (sarcoidosis, Behcet’s disease, Sjo¨gren’s syndrome, systemic lupus erythematosus, anti-phospholipid syndrome, mixed connective tissue disease) (deSeze et al., 2001) and can be the presenting feature of multiple sclerosis (MS) (Simnad et al., 1997) and neuromyelitis optica (Devic’s syndrome) (Wingerchuk et al., 1999). Acute transverse myelitis is usually a monophasic disease. Relapses of ATM are rare and have been reported in patients with Herpes simplex virus-1 (HSV-1) (Shyu et al., 1993), HSV-2, and hepatitis B virus (HBV) Correspondence: Franz Fazekas MD, Department of Neurology, Graz Medical University, Auenbruggerplatz 22, A-8036 Graz, Austria (tel.: +43 316 385 2981; fax: +43 316 32 55 20; e-mail: franz.fazekas@ meduni-graz.at).

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(Gobbi et al., 2001) infection. Cases of relapsing myelitis in patients with lupus erythematosus (Yamamoto, 1986), antiphospholipid antibody syndrome (Fukazawa et al., 1993), angiitis of the central nervous system (CNS) (Rawlinson and Braun, 1981; Caccamo et al., 1992), and myasthenia gravis (Lindsey et al., 1992) have been documented. Relapses occur in patients with neuromyelitis optica (Wingerchuk et al., 1999). Relapsing myelitis may ultimately lead to clinically definite MS according to Poser’s criteria (Poser et al., 1983). Relapsing ATM not associated with infectious or connective tissue disease and not fulfilling Poser’s criteria for clinically definite MS has been described (Tippet et al., 1991; Pandit and Rao, 1996; Kahl et al., 1998; Garcia-Merino and Blasco, 2000). We want to extend this notion of ÔidiopathicÕ relapsing myelitis by the observation of three more patients who shared features different from the known demyelinating disorders and who had no evidence of any other disorder known to be associated with relapsing ATM.

Patients and methods We identified all patients who had presented to the Department of Neurology at Graz Medical University with a spinal cord syndrome of non-compressive origin between 1992 and 2002. Among these cases, eight patients with relapsing transverse myelopathy were identified. From these patients, we excluded all cases with a history of MS or when clinical or brain MR findings suggested the possibility of MS. Patients were excluded when they had a history of radiation to the spine. Patients showing clinical or serologic evidence of connective tissue disease were also excluded. Serologic screening for connective tissue disease included the following: anti-nuclear, ds-DNA, anti-Ro, anti-La, antiRNP, anti-Scl-70, anti-Jo antibodies, MPO-ANCAs and PR3-ANCAs. To exclude sarcoidosis, all patients

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underwent chest X-ray and were screened for serum angiotensin-converting enzyme (ACE) levels. Coagulopathy was excluded by screening for APC resistence, protein C and protein S deficiency, anti-cardiolipin and b2-microglobulin antibodies. To exclude CNS manifestation of bacterial or viral infection, CSF samples were tested for antibodies against Borrelia burgdorferi, HSV, and varicella zoster virus (VZV). Serologic testing included antibodies against B. burgdorferi, Treponema pallidum, adenovirus, coxsackievirus, enteroviruses, Epstein–Barr virus (EBV), HSV, and VZV. Cases with clinical and MRI signs consistent with thrombosis of the anterior or posterior spinal artery, arteriovenous malformation or dural fistula were excluded. According to these criteria, three patients remained in whom we were unable to define the specific etiology and who had suffered from at least one relapse of transverse myelopathy. For brain and spinal cord imaging, conventional spin-echo PD-weighted (repetition time, TR: 2000– 2600 ms; echo time, TE: 20–30 ms) and post-contrast T1-weighted scans (TR 600–800 ms; TE 15–30 ms; 0.1 mmol/kg gadolinium-DTPA, Magnevist, Schering, Germany) were obtained at 1.5 T (Gyroscan ACS or NT; Philips Medical Systems, Eindhoven, The Netherlands) using a conventional imaging protocol.

Results We found three patients with relapsing spinal cord symptoms and corresponding morphologic abnormalities which could not be attributed to any infectious agent, connective tissue disorder, or vascular abnormality. The specific demographic, clinical, laboratory and morphologic findings are listed in Table 1. The total follow-up period is 34 months (patient A), 42 months (patient B), and 84 months (patient C). All three patients showed large extensive lesions throughout the spinal cord and had a normal brain MRI. Oligoclonal bands were positive in two of the three cases. The CSF cell count ranged from 7 to 49/ll. MRI abnormalities of the spinal cord were uniformly characterized by large lesions extending over several vertebral segments with swelling of the cord, and gadolinium enhancement was usually present (Fig. 1). Following the attacks, MRI spinal cord changes were characterized by segments with focal atrophy and areas of complete tissue destruction within the cord. In all three patients, the repeated episodes of myelitis led to a persistent impairment (dependence on wheelchair). Treatment in the acute stage included high-dose steroids in all cases as well as ceftriaxone and acyclovir. A patient who was put on azathioprine after the first relapse had another episode of myelitis. In another patient, mitoxanthrone was instituted but did not prevent a further relapse either.

Discussion In their review of 79 cases of acute myelopathy, de Seze et al. found recurrent myelitis only in patients with MS and in those with systemic disease. Therefore, including also infectious disorders, relapsing ATM as seen in our patients is certainly a rare event. However, there exist earlier reports which agree with our observations. Katz and Ropper (2000) reported nine patients with necrotic myelopathy. Eight of them showed a saltatory course although their disability progressed even between relapses. The finding of spinal cord hyperintensity and swelling with subsequent atrophy and cavitation which is typical for necrotizing myelitis was confirmed histologically in three of these patients. Among the patients of Katz and Ropper (2000), two patients had prolonged visual-evoked potentials. In addition, one of their patients subsequently developed optic neuritis which suggested neuromyelitis optica. Interestingly, Masuhr et al., (2002) also discussed the possibility of a limited form of neuromyelitis optica in a patient with ÔidiopathicÕ relapsing myelitis and pathological visual-evoked potentials. This point is well taken, as the necrotizing type of spinal cord inflammation is also a hallmark of neuromyelitis optica (Wingerchuk et al., 1999). Therefore, both disorders might well share pathophysiologic pathways or a specific organ susceptibility while the difference of neuromyelitis optica from MS is increasingly being recognized (Wingerchuk et al., 1999). In this context, it has to be acknowledged that the follow-up period of our study imposes some limitations as we cannot exclude that future attacks may also involve other parts of the CNS of our patients, including the optic nerve. In one patient, the absence of involvement of the visual tracts also relies on the patient’s history and the clinical examination only as we did not obtain visual-evoked potentials. Nevertheless, the repeated and so far exclusive involvement of the spinal cord by necrotizing myelopathy has been a striking and noteworthy observation in these individuals. Recently, Kim (2003) identified 15 patients with recurrent myelitis not related to MS or other systemic disease, but none of these patients actually suffered from a relapsing transverse myelitis as we describe here. Four patients presented initially with transverse myelitis, and relapses occurred as partial transverse myelitis. Two other patients, who initially presented with partial transverse myelitis, suffered from transverse myelitis at relapse. Furthermore, the extent of spinal cord involvement on MRI appears to have been much less extensive in most of the cases of Kim (2003). This indicates that the pathomechanism in our cases are different from those of Kim (2003). All studies about patients with relapsing ATM agree on extensive spinal cord hyperintensity and swelling as

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Relapsing acute transverse myelitis

Table 1 Clinical and magnetic resonance imaging (MRI) data of our patients

First event Patient A (female) Age (years) Time interval (months) CSF cell count CSF protein (mg/dl) IgG index Oligoclonal bands VEP Sensory level Motor disturbance Autonomic failure Therapy Spinal cord lesion Brain MRI

7 38 0.57 Negative Normal Th 5 bilateral Paraparesis Urinary retention MP, CFT, ACV

147 134 0.81 Positive n.d. Th 6 bilateral Paraparesis

Autonomic failure Therapy

Urinary incontinence MP, ACV, CFT

Spinal cord lesion

Th 2–9

Brain MRI

Normal

Autonomic failure Therapy Spinal cord lesion Brain MRI

Second relapse

20 5 35 0.43 Negative n.d. Th 5 bilateral Paraplegia Urinary retention MP, tizanidine, baclofen Th 5–9 n.d.

– – – – – – – – – –

12 17 54 n.d. Positive n.d. C 4 bilateral, left trigeminal Paraparesis, paresis left arm Urinary retention MP, CFT, azathioprine medulla – Th1; Th 4–11 n.d.

12 n.d. n.d. n.d. n.d. n.d. Th 3 bilateral

– –

53

Motor disturbance

Patient C (male) Age (years) Time interval (months) CSF cell count CSF protein (mg/dl) IgG index Oligoclonal bands VEP Sensory level Motor disturbance

First relapse

64

C 2–Th 8 Normal

Patient B (female) Age (years) Time interval (months) CSF cell count CSF protein (mg/dl) IgG index Oligoclonal bands VEP Sensory level

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Paraparesis, paresis left arm Urinary retention Azathioprine n.d. n.d.

53 39 131 0.56 Negative n.d. Th 5 bilateral Tetraparesis Urinary/bowel retention MP, CFT, ACV, baclofen C 4–Th 9 Normal

61 7 7 n.d. 47 n.d. 0.61 n.d. Positive n.d. Normal n.d. C5 Th 5 Paraparesis, Paraparesis, paresis left arm paresis left arm Urinary/bowel Urinary/bowel incontinence incontinence MP, CFT, ACV, MP, CFT, plasma exchange, MT ACV, MT C 1–Th 10 C1–Th 10 Normal n.d.

n.d., not done; CSF, cerebrospinal fluid; VEP, visual-evoked potentials; MP, methylprednisolone; CFT, ceftriaxone; ACV, acyclovir; MT, mitoxanthrone. Normal brain MRI includes age-related punctuate white matter hyperintensities in a nonperiventricular localization.

an early finding in this disorder. The cranio-caudal extension of spinal cord lesions varied but usually extended over multiple vertebral segments, and there was no evidence of MS-like involvement of the brain.

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Oligoclonal bands were found in one patient, respectively, in the reports of Pandit and Rao (1996) and Kahl et al. (1998). Despite the small numbers, the diagnostic recognition of ÔidiopathicÕ relapsing transverse myelitis

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(a)

(b)

(c)

(d)

(e)

(f)

Figure 1 Sagittal MRI of cervical and upper thoracic spinal cord of patient C at the first clinical event of myelopathy (a, b) and at the first (c, d) and second (e, f) relapse. T2 sequences (a, c, e) reveal cranio-caudal lesion extension. The change in localization and extension of gadolinium enhancement (b, d, f) over time indicates relapsing inflammatory activity (arrows).

appears desirable. First, this would add to a more complete description of the spectrum of immune mediated inflammatory processes of the central nervous system. In this context, we suggest an extension of the diagnostic criteria of Wingerchuk et al. (1999) for neuromyelitis optica to the entity of relapsing ATM based on the hallmark finding of necrotizing myelitis on MRI. Secondly, and much more importantly, relapsing ATM appears to be associated with rapidly increasing disability, at least in the elderly, and we need to establish some kind of therapeutic concept. At present, no long-term treatment recommendation can be given. Reported treatments include azathioprine and methotrexate (Kahl et al., 1998) as well as cyclophosphamide, lomustine, and plasma exchange (Katz and Ropper, 2000), but convincing beneficial effects have not been established for any of those. Therefore, an international registry should be encouraged to further define the frequency of this abnormality and, subsequently, to address specific therapeutic approaches in a more standardized manner.

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