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Acute Disseminating Encephalomyelitis in Neuromyelitis Optica Closing the Floodgates FREE

Roni Eichel, MD; Zeev Meiner, MD; Oded Abramsky, MD, PhD; Marc Gotkine, MBBS
[+] Author Affiliations

Author Affiliations: Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Hebrew University Hadassah Medical School, Jerusalem, Israel.


Arch Neurol. 2008;65(2):267-271. doi:10.1001/archneurol.2007.59.
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Published online

ABSTRACT

Objective  To report the clinical and radiological features of 2 patients with neuromyelitis optica (NMO) associated with severe acute disseminating encephalomyelitis. The first patient had anti–aquaporin 4 antibodies (NMO-IgG) but no lesion enhancement, in contrast to the second patient who was seronegative for NMO-IgG but had clear lesion enhancement on magnetic resonance imaging.

Design  Clinical, laboratory, and radiological analysis of 10 patients presenting with features compatible with an NMO-spectrum disorder, 2 of whom developed acute disseminating encephalomyelitis.

Setting  Inpatient ward at the Department of Neurology, Hadassah University.

Patients  Patients admitted during a 1-year period with features compatible with an NMO-spectrum disorder.

Interventions  Medical histories and imaging data were reviewed and serum samples were analyzed for the presence of NMO-IgG.

Main Outcome Measures  Clinical and paraclinical evidence of brain involvement.

Results  Of 10 patients tested, 5 were positive for NMO-IgG. One seropositive and 1 seronegative patient had an acute disseminating encephalomyelitis–like episode. In both cases, the clinical, laboratory, and electroencephalographic findings supported a diagnosis of acute disseminating encephalomyelitis. Magnetic resonance imaging demonstrated extensive bilateral white matter lesions in both patients. Lesions in the seropositive patient were notably lacking in enhancement following gadolinium injection, whereas robust lesion enhancement was observed in the seronegative patient.

Conclusions  Acute disseminating encephalomyelitis without lesion enhancement on magnetic resonance imaging may represent a childhood manifestation of seropositive NMO. The lack of enhancement suggests an intact blood-brain barrier and supports a unique mechanism of edema induction due to dysfunction of water channels.

Figures in this Article

Neuromyelitis optica (NMO) encompasses a group of inflammatory diseases characterized by recurrent episodes of myelitis and optic neuritis.1 The discovery of antibodies directed against the water channel aquaporin 4 (AQP4), referred to as NMO-IgG, has allowed a broadening of the NMO spectrum, which recognizes that involvement of central nervous system structures other than the optic nerves and spinal cord is not uncommon, and has prompted a suggested revision of the diagnostic criteria for NMO.1 Indeed, a characteristic pattern of brain involvement has been delineated in which the hypothalamic and periventricular areas are affected.2

Here we describe a patient with seropositive NMO whose clinical course included an episode closely resembling acute disseminating encephalomyelitis without lesion enhancement on magnetic resonance imaging (MRI). For comparison, we describe a seronegative patient with a similar presentation but with gadolinium enhancement (GDE) of white matter lesions. We propose that the unexpected lack of GDE reflects a distinct mechanism of edema generation in seropositive but not seronegative NMO.

METHODS

All of the patients admitted to our center during a 1-year period (September 1, 2005, to August 31, 2006) were assessed for the possible presence of an NMO-spectrum disorder according to the newly suggested diagnostic criteria.1 We included all of the patients with recurrent optic neuritis, those with acute myelitis that was recurrent or extensive (≥ 3 contiguous segments), and those with combined optic neuritis and acute myelitis. We did not include patients with nonextensive myelitis who had MRI results meeting the diagnostic criteria for multiple sclerosis by Paty et al.3 Serum from all of the included patients was tested for the presence of NMO-IgG (DBA Mayo Medical Laboratories, Rochester, Minnesota).

RESULTS

FINAL DIAGNOSES AND EVIDENCE OF BRAIN INVOLVEMENT

Ten patients were included for NMO-IgG testing, of whom 5 tested positive. Four patients ultimately satisfied revised NMO criteria, of whom 2 were seropositive for NMO-IgG (Table).

Table Graphic Jump LocationTable. Clinical and Laboratory Characteristics of All of the Patients Included for Neuromyelitis Optica–IgG Testing

Two patients had an acute episode with an encephalopathic component and radiological evidence of extensive brain involvement.

REPORT OF CASES
Case 1

A 13-year-old boy presented with rapidly progressive leg weakness and urinary retention. Clinical examination revealed a parapyramidal syndrome with sensory loss below the midthoracic region with no evidence of systemic disease. His cerebrospinal fluid was mildly lymphocytic (10 cells/mL) without oligoclonal bands. Spinal MRI demonstrated an intramedullary lesion extending from C7 to T8 with cord swelling (Figure 1A); at that time, visual-evoked potentials and MRI results of the brain were normal (Figure 2A). A 1-week course of intravenous methylprednisolone was followed by full resolution of all of the clinical features within 7 days of treatment cessation.

Place holder to copy figure label and caption
Figure 1.

Spinal cord imaging. A, Magnetic resonance imaging of the spine of patient 1 shows a multisegmental intramedullary T2-weighted lesion suggestive of longitudinal myelitis. B, Magnetic resonance imaging of the spine of patient 2 shows patchy intra-axial T2-weighted lesions in multiple cervical and thoracic segments.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Brain imaging. In patient 1, normal fluid-attenuated inversion recovery magnetic resonance imaging results at the time of initial myelitis presentation (A), and extensive bilateral white matter brain lesions on fluid-attenuated inversion recovery magnetic resonance imaging (B) that do not enhance following gadolinium injection (C). In patient 2, normal fluid-attenuated inversion recovery magnetic resonance imaging results at the time of initial presentation with bilateral optic neuritis (D), and bilateral multifocal white matter lesions on fluid-attenuated inversion recovery magnetic resonance imaging (E) with gadolinium enhancement (F).

Graphic Jump Location

Four months later, he presented with acute motor dysphasia and right hemiparesis progressing to severe confusion and somnolence within 12 hours. T2-weighted and fluid-attenuated inversion recovery MRI images of the brain revealed extensive bilateral hyperintense lesions affecting the white matter of the subcortex, centrum semiovale, and brainstem without GDE (Figure 2B and C). His cerebrospinal fluid contained a grossly elevated protein level (419 mg/dL) and 5 lymphocytes per milliliter. Electroencephalography performed during confused wakefulness recorded a bilateral symmetrical δ rhythm consistent with encephalopathy (Figure 3). A 5-day course of intravenous steroids was followed by complete clinical resolution within 2 weeks. Neither episode was preceded by clinical features of systemic infection or vaccination.

Place holder to copy figure label and caption
Figure 3.

Electroencephalography results of patient 1 show a diffuse bilateral δ rhythm consistent with encephalopathy.

Graphic Jump Location

Despite bimonthly treatment with intravenous steroids, during the following 2 years he had 5 episodes compatible with acute relapsing myelitis and 3 episodes of optic neuritis. Monthly treatment with plasmapheresis and steroids was initiated, and during the subsequent 3 years the patient experienced a single episode suggestive of mild myelitis associated with a delay of the treatment protocol interim period from 4 to 6 weeks.

A brain MRI repeated at age 17 years revealed partial resolution of lesions. At age 19 years, his serum tested positive for NMO-IgG.

Case 2

A 21-year-old woman presented with acute bilateral visual loss progressing during 2 days to total blindness with minimally reactive pupils. Brain MRI results (Figure 2D) were initially normal. Cerebrospinal fluid analysis revealed 216 lymphocytes per milliliter and a very high protein content (527 mg/dL). A high-dose steroid regimen was initiated; however, 4 days later she developed acute spastic quadriparesis, urinary retention, and confusion. Electroencephalography showed generalized slowing, and a repeat brain MRI revealed deep white matter foci with GDE (Figure 2E and F). Magnetic resonance imaging of the spine revealed an extensive patchy lesion with partial enhancement (Figure 1B). Her serum tested negative for the presence of NMO-IgG. Subsequent rehabilitation and treatment with plasmapheresis and steroids were followed by moderate improvement in motor function, although her vision remained unchanged.

COMMENT

Patient 1 satisfied the recently proposed diagnostic criteria for NMO1 and tested positive for NMO-IgG. Notably, he had a single episode of acute resolving encephalopathy with diffuse involvement of brain white matter occurring within 4 months of his initial myelitic presentation at age 13 years.

While this episode may be described as acute disseminating encephalomyelitis–like, the absence of GDE is not typical of acute disseminating encephalomyelitis.6 A similar radiological finding occurred in a 13-year-old girl with seropositive NMO and diffuse white matter lesions.7

In contrast, brain MRI during the encephalopathic episode of patient 2, who was seronegative for NMO, revealed robust lesion enhancement. We propose that the unexpected lack of enhancement in seropositive but not seronegative patients with NMO reflects the unique mechanism of edema induction associated with NMO-IgG.

The NMO-IgG targets AQP4, and seropositivity is 76% sensitive and 94% specific for NMO.1 The recent finding of reduced immunoreactivity of AQP4 in NMO lesions suggests that the loss of AQP4 function may be pathogenetic in patients with an NMO-spectrum disorder.8

Whereas spinal and optic nerve NMO lesions are usually severe with demyelination and cavitation, brain lesions are often a transient consequence of inflammation without demyelination and may be due to temporary disruptions in water transport.8

Aquaporin 4 passively transports water molecules into and out of the brain via the perivascular membrane according to osmotic gradients and plays a role in both the generation and elimination of brain edema.9 Importantly, loss of perivascular AQP4 activity in the basal state results in cellular swelling, ostensibly due to a failure to eliminate water generated from cellular metabolism.9 Thus, brain edema developing as a result of functional impairment of AQP4 would be expected to occur in the context of an intact blood-brain barrier, which may explain the lack of enhancement of brain lesions in some seropositive patients.

Expression of AQP4 increases during brain maturation in rats. Although comparable human data are unavailable, we speculate that in contrast to adults, children may be more sensitive to a loss of AQP4 function owing to a relative lack of these water channels.10 We suggest that patients, particularly children presenting with an acute disseminating encephalomyelitis–like disease without enhancement of brain MRI lesions, should be examined for the presence of NMO-IgG.

ARTICLE INFORMATION

Correspondence: Marc Gotkine, MBBS, Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem 91120, Israel (marc@gotkine.com).

Accepted for Publication: June 8, 2007.

Author Contributions:Study concept and design: Gotkine. Acquisition of data: Eichel, Meiner, Abramsky, and Gotkine. Analysis and interpretation of data: Gotkine. Drafting of the manuscript: Eichel and Gotkine. Critical revision of the manuscript for important intellectual content: Eichel, Meiner, Abramsky, and Gotkine. Obtained funding: Abramsky. Administrative, technical, and material support: Eichel, Meiner, Abramsky, and Gotkine. Study supervision: Abramsky and Gotkine.

Financial Disclosure: None reported.

Funding/Support: This work was supported in part by the Agnes Ginges Fund for Research in Neurology.

REFERENCES

Wingerchuk  DMLennon  VAPittock  SJLucchinetti  CFWeinshenker  BG Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66 (10) 1485- 1489
PubMed Link to Article
Pittock  SJWeinshenker  BGLucchinetti  CFWingerchuk  DMCorboy  JRLennon  VA Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 2006;63 (7) 964- 968
PubMed Link to Article
Paty  DWOger  JJKastrukoff  LF  et al.  MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 1988;38 (2) 180- 185
PubMed Link to Article
Gotkine  MFellig  YAbramsky  O Occurrence of CNS demyelinating disease in patients with myasthenia gravis. Neurology 2006;67 (5) 881- 883
PubMed Link to Article
Kister  IHerbert  JSwerdlow  MLBergamaschi  RPiccolo  GOger  J Occurrence of CNS demyelinating disease in patients with myasthenia gravis. Neurology 2007;68 (16) 1326- 1327
PubMed Link to Article
Schwarz  SMohr  AKnauth  MWildemann  BStorch-Hagenlocher  B Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology 2001;56 (10) 1313- 1318
PubMed Link to Article
Pittock  SJLennon  VAKrecke  KWingerchuk  DMLucchinetti  CFWeinshenker  BG Brain abnormalities in neuromyelitis optica. Arch Neurol 2006;63 (3) 390- 396
PubMed Link to Article
Roemer  SFParisi  JELennon  VA  et al.  Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 2007;130 (pt 5) 1194- 1205
PubMed Link to Article
Amiry-Moghaddam  MOtsuka  THurn  PD  et al.  An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci U S A 2003;100 (4) 2106- 2111
PubMed Link to Article
Wen  HNagelhus  EAAmiry-Moghaddam  MAgre  POttersen  OPNielsen  S Ontogeny of water transport in rat brain: postnatal expression of the aquaporin-4 water channel. Eur J Neurosci 1999;11 (3) 935- 945
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Spinal cord imaging. A, Magnetic resonance imaging of the spine of patient 1 shows a multisegmental intramedullary T2-weighted lesion suggestive of longitudinal myelitis. B, Magnetic resonance imaging of the spine of patient 2 shows patchy intra-axial T2-weighted lesions in multiple cervical and thoracic segments.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Brain imaging. In patient 1, normal fluid-attenuated inversion recovery magnetic resonance imaging results at the time of initial myelitis presentation (A), and extensive bilateral white matter brain lesions on fluid-attenuated inversion recovery magnetic resonance imaging (B) that do not enhance following gadolinium injection (C). In patient 2, normal fluid-attenuated inversion recovery magnetic resonance imaging results at the time of initial presentation with bilateral optic neuritis (D), and bilateral multifocal white matter lesions on fluid-attenuated inversion recovery magnetic resonance imaging (E) with gadolinium enhancement (F).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Electroencephalography results of patient 1 show a diffuse bilateral δ rhythm consistent with encephalopathy.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Clinical and Laboratory Characteristics of All of the Patients Included for Neuromyelitis Optica–IgG Testing

References

Wingerchuk  DMLennon  VAPittock  SJLucchinetti  CFWeinshenker  BG Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66 (10) 1485- 1489
PubMed Link to Article
Pittock  SJWeinshenker  BGLucchinetti  CFWingerchuk  DMCorboy  JRLennon  VA Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 2006;63 (7) 964- 968
PubMed Link to Article
Paty  DWOger  JJKastrukoff  LF  et al.  MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 1988;38 (2) 180- 185
PubMed Link to Article
Gotkine  MFellig  YAbramsky  O Occurrence of CNS demyelinating disease in patients with myasthenia gravis. Neurology 2006;67 (5) 881- 883
PubMed Link to Article
Kister  IHerbert  JSwerdlow  MLBergamaschi  RPiccolo  GOger  J Occurrence of CNS demyelinating disease in patients with myasthenia gravis. Neurology 2007;68 (16) 1326- 1327
PubMed Link to Article
Schwarz  SMohr  AKnauth  MWildemann  BStorch-Hagenlocher  B Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology 2001;56 (10) 1313- 1318
PubMed Link to Article
Pittock  SJLennon  VAKrecke  KWingerchuk  DMLucchinetti  CFWeinshenker  BG Brain abnormalities in neuromyelitis optica. Arch Neurol 2006;63 (3) 390- 396
PubMed Link to Article
Roemer  SFParisi  JELennon  VA  et al.  Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 2007;130 (pt 5) 1194- 1205
PubMed Link to Article
Amiry-Moghaddam  MOtsuka  THurn  PD  et al.  An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci U S A 2003;100 (4) 2106- 2111
PubMed Link to Article
Wen  HNagelhus  EAAmiry-Moghaddam  MAgre  POttersen  OPNielsen  S Ontogeny of water transport in rat brain: postnatal expression of the aquaporin-4 water channel. Eur J Neurosci 1999;11 (3) 935- 945
PubMed Link to Article

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