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Abstract

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Case report
  5. Discussion
  6. References

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease often associated with a highly specific autoantibody, aquaporin-4 antibody. Although the classic syndrome involves the optic nerves and spinal cord, aquaporin-4 antibody has been important in defining the true spectrum of NMO, which now includes brain lesions in areas of high aquaporin-4 expression. Brainstem involvement, specifically area postrema involvement in the medulla, has been associated with intractable vomiting in some patients with NMO. We describe a 14-year-old female with positive aquaporin-4 antibody whose clinical course was dominated by severe anorexia with associated weight loss (from 68-41kg; body mass index 25.2–15.6). Magnetic resonance imaging showed lesions in the medulla, pons, and thalami. Although she had asymptomatic radiological longitudinally extensive transverse myelitis, she never had symptoms or signs referable to the spinal cord or the optic nerves. We propose that anorexia and weight loss should be considered part of the NMO spectrum, probably related to area postrema involvement.


Abbreviation
NMO

Neuromyelitis optica

What this paper adds

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Case report
  5. Discussion
  6. References
  •  NMO spectrum disorders can present with anorexia and severe weight loss as the dominant features.
  •  We propose that the anorexia and consequent weight loss are secondary to area postrema involvement, a region rich with aquaporin-4, and a region implicated in neurogenic hypophagia and weight loss.

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease affecting the central nervous system. The classic syndrome results in inflammatory demyelination both of the optic nerves and spinal cord.1 With the discovery of a highly specific serum autoantibody marker, aquaporin-4 antibody, the spectrum of NMO-related conditions is expanding; it includes isolated or relapsing optic neuritis, isolated or relapsing longitudinally extensive transverse myelitis, and variable brain involvement.2,3 A recent paper highlighted vomiting as an early symptom in NMO spectrum disorders, which is thought to be secondary to medullary (area postrema) involvement.4 Here we describe a patient with positive aquaporin-4 antibody whose primary problem was severe anorexia and weight loss. Written parental consent was obtained for publication of this report.

Case report

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Case report
  5. Discussion
  6. References

A 14-year-old female of Hong Kong Chinese origin first started to lose appetite and have a bloating sensation in the stomach. She had daily vomiting of undigested food up to three or four times per day for 2 weeks, necessitating investigation with oesophagogastroduodenoscopy, which was normal. After partial improvement for 2 weeks with symptomatic treatment, her vomiting worsened and was associated with headache and complaints of ‘seeing double’. Neurological examination at this time was normal. However, magnetic resonance imaging (MRI) of her brain showed T1 hypointense and T2 hyperintense lesions in the medulla, pons, and bilateral thalami, without contrast enhancement (Fig. 1). Cerebrospinal fluid showed mild pleocytosis (17mm−3), no malignant cells, negative polymerase chain reaction for enterovirus and herpes simplex virus, negative oligoclonal bands, and normal protein and glucose levels. Biochemistry, including Na+ and K+, was normal. The provisional diagnosis at that time was a clinically isolated syndrome of demyelination of the central nervous system (brainstem). Four weeks later she developed vertical nystagmus that spontaneously remitted after 3 days. Although the nausea and vomiting remitted, she subsequently remained anorexic with associated weight loss for more than 9 months. Her baseline body weight was 68kg (2kg above 97th centile for age) and her body mass index was 25.2. She lost 27kg in 9 months and her body mass index dropped to 15.6 (approximately 40% of her body weight).

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Figure 1.  T2 coronal image of the brain showing hyperintense lesions in bilateral thalamus (right side worse), pons, and medulla.

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Her weight loss was complicated by secondary amenorrhea and hair loss. She remained otherwise well, and enjoyed school life and activities despite the rapid weight loss. There were no mood or sleep problems. Extensive investigations into possible occult malignancies or gastrointestinal causes were negative. These included a complete blood count, erythrocyte sediment rate, lactate dehydrogenase, autoimmune markers and viral studies, stool for occult blood and parasites, computed tomography of the abdomen, and barium meal with follow-up studies. There was evidence of hypothalamic–pituitary axis dysfunction with low levels of luteinizing hormone, follicle stimulating hormone, and oestradiol, although her sodium, thyroid function, prolactin, and response to synacthen were all normal. Repeated psychological and psychiatric evaluation did not found any features suggestive of anorexia nervosa, such as refusal to maintain body weight, intense fear of gaining weight or being fat, or a disturbance in the way in which her body weight or body shape was experienced. There was no history or evidence of emetic or laxative use, or purging with or without binge eating. There was also no evidence of overt anxiety disorder, obsessive compulsive disorder, depression, substance abuse, or personality disorders, which are commonly seen as comorbidities in patients with eating disorders.

Follow-up brain MRI 5 months after presentation showed resolving lesions in the brainstem and thalamus, but diffuse asymptomatic T2 hyperintensity of the whole spinal cord without contrast enhancement or mass effect (Fig. 2). Aquaporin-4 antibody testing was strongly positive at the reference laboratory (Oxford, UK).5 Despite the ongoing weight loss and abnormal brain MRI, there were no further focal neurological signs and she continued her regular activities. There were never any symptoms or signs referable to her optic nerves or spine, and repeated visual evoked potentials were normal. Nine months after symptom onset she remained anorexic with weight loss despite nutritional support. After long discussion and liaison, the family agreed to try immune-suppressive therapies. The patient has been taking prednisolone (40mg per day) for the past 3 months without side effects. Her body weight has increased slowly and we are considering adding mycophenolate as long-term immunosuppressant.

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Figure 2.  T2 sagittal image of spine showing intermittent hyperintense lesions in whole spinal cord, especially in mid-thoracic region.

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Discussion

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Case report
  5. Discussion
  6. References

The antigen involved in NMO–immunoglobulin-G binding is now defined as aquaporin-4,6 the antibodies for which have a proven pathogenic function.7 Brain lesions in patients with NMO tend to localize to the brainstem, hypothalamus, and periventricular areas that have high aquaporin-4 expression.1 A recent neuropathology study on archival brainstem tissue from patients with NMO showed that lesions involving the area postrema and the medullary floor of the fourth ventricle were associated with nausea or vomiting.8 The area postrema is a pivotal component of the brainstem emetic centre and is one of several circumventricular organs where the blood–brain barrier is normally ‘leaky’. It also has connections with hypothalamic and other brainstem nuclei. The lesions in the area postrema are characterized by a prominent non-lytic reaction of glial fibrillary acidic protein-positive astrocytes, which are different from the necrosis and cavitation affecting the grey and white matter in patients with NMO9 and probably represent the pathological substrate for the intractable but reversible nausea and vomiting that sometimes occur in NMO. Apiwattanakul et al. recently reported a series of 12 patients with positive aquaporin-4 antibody whose initial presenting symptoms were intractable vomiting (and nausea), three of whom were children.4 The duration of vomiting varied from days to weeks, and symptoms resolved spontaneously or with immunomodulatory treatment. The interval from initial presentation to subsequent development of optic neuritis or myelitis was also variable.4 Apart from the initial mild and brief vomiting period, our patient’s subsequent course was dominated by anorexia with a sensation of ‘fullness’ in the stomach. We hypothesize that the anorexia in our patient may also have been related to neuronal dysfunction in the area postrema with possible additional involvement of the hypothalamus. Indeed, lesions in the area postrema in animal models can induce hypophagia and weight loss without alteration in intestinal transit or gastric retention.10 Other than vomiting, anorexia, and weight loss, our patient had only had transient neurological symptoms referable to the brainstem. We considered other differential diagnoses including a clinically isolated syndrome of demyelination, multiple sclerosis, infection, vasculitis, central pontine myelinolysis, metabolic causes, and malignancy. However, the clinical findings and investigation results were not supportive of these differential diagnoses. Although our patient also had amenorrhea, which has been used as one of the diagnostic Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria of anorexia nervosa, recent experience suggests that amenorrhea may just reflect the clinical severity of weight loss.11 Our patient’s hair loss could also be explained by her nutritional state. On repeated assessment, our patient did not have any of the essential features of anorexia nervosa other than extreme weight loss. She has been on prednisolone for 3 months, together with intensive nutritional rehabilitation, and is making steady progress in weight gain.

In summary, a limited form of NMO should be considered in the differential diagnoses of unexplained anorexia and weight loss, particularly if there are transient brainstem symptoms or signs. Because NMO is an autoimmune disease, early recognition and treatment with immunosuppressants may decrease relapses and avoid serious disability. Aquaporin-4 antibody may aid an early diagnosis and is increasingly important in defining the true spectrum of NMO.

References

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Case report
  5. Discussion
  6. References