J Neurol (2014) 261:954–962 DOI 10.1007/s00415-014-7298-7

ORIGINAL COMMUNICATION

Comparative clinical characteristics of neuromyelitis optica spectrum disorders with and without medulla oblongata lesions Yanqiang Wang • Lei Zhang • Bingjun Zhang Yongqiang Dai • Zhuang Kang • Ciyong Lu • Wei Qiu • Xueqiang Hu • Zhengqi Lu



Received: 29 November 2013 / Revised: 17 February 2014 / Accepted: 20 February 2014 / Published online: 9 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Brainstem involvement, especially the medulla oblongata (MO), has been reported in neuromyelitis optica spectrum disorders (NMOSDs). The purpose of this study was to investigate retrospectively and compare clinical, laboratory, and imaging features of NMOSDs with and without MO lesions. A total of 170 patients with NMOSDs were enrolled, including 44 patients with MO lesions and 126 patients without MO lesions. Clinical features, laboratory tests, and magnetic resonance imaging findings among these patients were assessed. MO lesions were found in 25.9 % of the NMOSDs patients. The mean duration was 13 months. Patients with MO lesions had a higher Annualized relapse rate and Expanded Disability Status Score Scale. Headache, dizziness, nystagmus, dysarthria, intractable hiccup and nausea, choking cough or

Y. Wang, L. Zhang, and B. Zhang contributed equally to this work. Y. Wang  L. Zhang  B. Zhang  Y. Dai  W. Qiu  X. Hu  Z. Lu (&) Department of Neurology, Multiple Sclerosis Center, The Third Affiliated Hospital of Sun Yat-sen University, No 600 Tianhe Road, Guangzhou 510630, Guangdong, China e-mail: [email protected] Y. Wang e-mail: [email protected] L. Zhang Department of Neurology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China Z. Kang Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China C. Lu Department of Statistics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

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dysphagia, movement disorders, and neuropathic pain were more common in MO lesion patients. Patients with MO lesions were more frequently complicated with thyroid diseases. Multiple brain involvement, More importantly, Longitudinally extensive transverse myelitis were more frequently found in patients with MO lesions. MO lesions might be a symbol of more severe neurologic deficits and worse prognosis of NMOSDs. Keywords Neuromyelitis optica spectrum disorders  Medulla oblongata  Longitudinally extensive transverse myelitis  Magnetic resonance imaging

Introduction Neuromyelitis optica spectrum disorders (NMOSDs) have traditionally been considered a series of inflammatory and demyelinating disorders that predominantly involved optic nerve and spinal cord [1–4]. However, recent numerous reports have shown that brain abnormalities are not rare in NMOSDs by magnetic resonance imaging (MRI) with incidences from 13–89 % [5, 6]. NMO-IgG is a specific autoantibody marker for NMOSDs. It binds selectively to aquaporin 4 (AQP4). Current studies have demonstrated the brainstem, especially the pericanal region in the medulla oblongata (MO), is one of the brain regions of high AQP4 expression and it is the most frequently involved area in NMOSDs with brain lesions [7, 8]. The clinical manifestations indicating brainstem involvement such as intractable hiccups, nausea, vomiting, and bulbar dysfunctions were commonly found as the initial and isolated symptoms in NMOSDs [7, 9], and the clinical manifestations, locations of brainstem lesions, might be helpful in the diagnosis, management strategies,

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and prognoses of NMOSDs [9, 10]. Previous studies have only descriptively reported the frequent occurrence, locations, and presentations of the MO lesions in exploring the features of brain damage with NMOSDs [11, 12]. However, few studies have made detailed and systemic analysis of the clinical characteristics of NMOSDs patients with MO lesions. Therefore, we investigated and compared the clinical, laboratory, and MRI features of NMOSDs patients with and without MO lesions.

Methods Ethics statement This research was approved by the ethics committee of the Third Affiliated Hospital of Sun Yat-sen University. All participants involved in this study provided written informed consent. Subjects Patients with NMOSDs who were admitted and diagnosed from March 2008 and March 2013 in the multiple sclerosis (MS) center of the Third Affiliated Hospital of Sun Yat-sen University were consecutively enrolled. Among them, we retrospectively analyzed 44 patients who had MO lesions and 126 patients who had no MO lesions. NMOSDs were defined according to the Wingerchuk 2006 and 2007 criteria [4, 13]. All of the patients were followed up in the outpatient department once a month after discharge. The following parameters were assessed at these visits: Relapses were defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted C24 h and were accompanied by new neurologic signs found by the examining neurologist, disease duration as measured in years since the onset of the first symptoms until last follow-up, disease activity such as total number of relapses and annualized relapse rate (ARR = total number of relapses during 1 year) [14, 15]. Disability was assessed using the Expanded Disability Status Score Scale (EDSS), treatment compliance, and recording any side effects of the medications. Cerebrospinal fluid oligoclonal bands (OCBs), NMO-IgG, antinuclear antibodies (ANA), anti-SSA/Ro antibodies (SSA), anti-SSB/La antibodies(SSB), rheumatoid factor (RF), complement, ESR, CRP, thyroid-related antibodies were tested at the time of the initial diagnosis, prior to corticosteroid treatment. Laboratory tests were also performed in all cases to exclude infectious diseases, vascular diseases, metabolic disorders, and other inflammatory demyelinating diseases. All of the patients received highdose corticosteroids pulses [(methylprednisolone 1 g, IV/

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days for 5 days) for two courses; each treatment interval was 3 days] during the relapse period, and in remission period, all the patients are treated with oral small doses of methylprednisolone (8–12 mg/days, oral) combined with azathioprine (50–100 mg/days). MRI scanning Brain and spinal MRI scans were performed in all patients using a GE 1.5 TMR imager scanner (General Electric, Milwaukee, WI, USA) within 1 week after the onset of the disease. The slice thickness of the axial scans ranged between 3 and 5 mm. Conventional MRI protocols were used in all patients; T1 with and without gadolinium enhancement, (400/15.5 ms, TR/TE) and T2 (2,500–3,500/100 ms, TR/TE) in spinal cord MRI; brain MRI lesions were evaluated and defined according to the Paty criteria, and that described by Ito et al. [16–19]. T1 with and without gadolinium enhancement, (400/15.5 ms, TR/TE), T2 (4,600–4,640/97.8–102 ms, TR/TE), fluid attenuated inversion recovery (FLAIR) (8,800/120 ms, TR/TE) sequences were analyzed to evaluate the number, size, location (basal ganglia, peri-ventricle and periaqueduct, brainstem, cerebellum, hypothalamic and thalamic), configuration (ovoid, punctate, or patchy) and enhancing pattern of the brain lesions in MRI. Atypical brain lesions, such as extensive brain lesions ([3 cm), bilateral diencephalic (thalamic/hypothalamic) lesions, and extension from the cervical cord into the brainstem were defined based on previous reports [17–19]. LETM lesions were defined as an area extending across three or more vertebral segments [12]. All MRI scans were performed prior to corticosteroid treatment. No patients were receiving immunomodulatory treatment at the time of MRI scanning. All MRI scans were analyzed by one experienced neuroradiologist (Zhuang Kang) and one neurologist (Wei Qiu) who were blinded to the diagnostic categorization and the patients’ clinical features; each analyzed all of the MRI scans. The final assessments were made by consensus [10]. Statistical analysis Statistical analysis was performed by SPSS version 13.0. Probability values of \0.05 were considered significant. Categorical data were expressed as N, percentage, and analyzed with Chi-square test. Continuous data with a normal distribution were expressed as the mean ± SD and further analyzed with an independent two-sample Student’s t test. Data that were not normally distributed were analyzed by the Wilcoxon Mann–Whitney U test. All statistical assessments were two-tailed and the level of significance was set at p = 0.05.

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Results Demographics and clinical characteristics of patients with and without MO lesions in NMOSDs The clinical features are summarized in Table 1. The total number of patients recruited for the study from our database was 333. Among them, 170 patients met all the inclusion criteria for NMOSDs. Forty-four of the 170 patients with Table 1 Demographic and clinical characteristics of patients with or without MO lesions in NMOSDs NMOSDs with MO (n = 44)

NMOSDs without MO (n = 126)

p

Gender, F:M

40:4

102:24

0.126

Age, years

37.38 ± 11.81

39.28 ± 15.17

0.451

Age at onset, years

34.16 ± 11.80

35.62 ± 14.57

0.550

Disease duration, years

1.92 (0–23)

2.13 (0–31)

0.693

MO lesions duration, months

13 (0.5–262)

Annualized relapse rate

1.51 (0–16)

0.61 (0–12)

0.001**

EDSS at last visit

3 (1–23)

1.5 (0–9.5)

0.001**

14 (31.8 %)

14 (11.1 %)

0.001**

Dizziness

15 (34.1 %)

9 (7.1 %)

0.001**

Nystagmus

8 (18.2 %)

3 (2.4 %)

0.001**

Dysarthria

3 (6.8 %)

1 (0.8 %)

0.023*

Clinical features, n (%) Headache

IHN

24 (54.5 %)

16 (12.1 %)

0.001**

Choking cough or dysphagia

13 (29.5 %)

2 (1.6 %)

0.001**

Bowel or bladder dysfunction

22 (50 %)

53 (42.1 %)

0.361

Visual impairment

35 (79.5 %)

108 (85.7 %)

0.335

Movement disorders

34 (77.3 %)

65 (51.6 %)

0.001**

Sensory disturbances

30 (68.2 %)

89 (70.6 %)

Neuropathic pain

29 (65.9 %)

Co-existent thyroid diseases

9 (20.5 %)

Laboratory tests of patients with and without MO lesions in NMOSDs The data of laboratory tests are summarized in Table 3. There were no significant differences between patients with and without MO lesions in CSF, regular and biochemical Table 2 The characteristics of patients with medulla lesions (n = 44) Onset of the disease (n = 15)

Later stage of the disease (n = 29)

p

Gender, F:M

25:4

15:0

0.131

Age, years

37.18 ± 6.58

41.27 ± 10.17

0.144

0.760

Age at onset, years

35.98 ± 6.68

37.36 ± 10.68

0.634

37 (29.4 %)

0.006*

Disease duration, years

3 (0.5–228)

14 (4–262)

0.586

7 (5.6 %)

0.004*

MO lesion duration, months

1.25 (0.08–23)

3 (0.25–22)

0.485

NMOSDs neuromyelitis optica spectrum disorders, MO medulla oblongata, ARR annualized relapse rate, EDSS Expanded Disability Status Scale, IHN intractable hiccup and nausea, MO lesion duration duration between at the onset of NMOSDs and at the appearance of MO lesion *p \ 0.05; **p \ 0.01 p values also reflect comparison of percentages in clinical features

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NMOSDs showed MO lesions. The gender ratio, age, and disease duration were similar in NMOSDs patients with and without MO lesions. No differences were found in age at onset or disease duration between these two groups. The annualized relapse rate (ARR) and EDSS score at last visit were higher in patients with MO lesions than in patients without MO lesions, respectively (p = 0.001 and p = 0.001, respectively). Significant differences were found between the patients with and without MO lesions in headache (p = 0.001), dizziness (p = 0.001), nystagmus (p = 0.001), dysarthria (p = 0.023), intractable hiccup and nausea (IHN) (p = 0.001), choking cough or dysphagia (p = 0.001), movement disorders (p = 0.001), neuropathic pain (NP) (p = 0.006), and co-existing thyroid disease (p = 0.004). To investigate when medulla lesions present sporadically from first to last attacks, We retrospectively analyzed 44 patients with MO lesions in NMOSDs, again. Our study found mean duration from the onset of NMOSDs to the appearance of MO lesions was 13 months (range, 0.5–262), and 65.9 % (29/44) patients did not occur the medulla lesions at the onset of the disease. Furthermore, we found that 84.09 % (37/44) of patients with NMOSDs showed MO lesions on the dorsal medulla, the ventral medulla 6.82 % (3/44), and the ventral and dorsal medulla 9.09 % (4/44). The data are summarized in Table 2.

ARR

2.4 (0–6)

1.06 (0–16)

0.349

EDSS at last visit

3 (1–9)

4.5 (1.5–23)

0.208

MO medulla oblongata, ARR annualized relapse rate, EDSS Expanded Disability Status Scale, MO lesion duration duration between at the onset of NMOSDs and at the appearance of MO lesion *p \ 0.05; **p \ 0.01

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Table 3 Biochemical values of patients with or without MO lesions in NMOSDs NMOSDs with MO

NMOSDs without MO

p

WBCs (106)

4 (0–140)

2 (0–40)

0.231

Protein (0.15–0.4 mg/ml)

0.2 (0.1–1.64)

0.23 (0.06–1.12)

0.773

Glucose (2.5–3.9 mg/ml)

3.19 (1.22–6.64)

3.23 (2.3–6.29)

0.622

Chloride (121.0–129.0 mg/ml)

126.3 (2.76–131.3)

127 (119–138.2)

0.207

OCB (?), n (%)

3/20 (15 %)

4/45 (8.9 %)

0.463

CSF index

Serums index CRP (0–6 mg/l)

9.34 ± 5.58

8.67 ± 3.71

0.528

ESR (0–20 mm/H)

20.67 ± 18.85

18.31 ± 15.16

0.493

NMO-IgG (?), n (%)

24/28 (85.7 %)

39/49 (79.6 %)

0.503

ANA (?), n (%) SSA (?), n (%)

13/27 (48.1 %) 6/30 (20 %)

33/87 (37.9 %) 19/94 (19 %)

0.344 0.980

SSB (?), n (%)

5/30 (13.3 %)

9/94 (9.6 %)

0.558

RF (?), n (%)

3/21 (14.3 %)

5/55 (9.1 %)

0.509

IgG (8–16 g/l)

12.46 (7.56–33.22)

11.48 (6.19–29.93)

0.551

IgA (0.7–3.3 g/l)

1.67 ± 0.70

1.85 ± 0.74

0.287

IgM (0.5–2.2 g/l)

1.2 (0.61–2.74)

1.2 (0.45–6.54)

0.843

C3 (0.8–1.6 g/l)

1.06 ± 0.25

1.12 ± 0.26

0.466

C4 (0.1–0.4 g/l)

0.188 (0.11–0.83)

0.201 (0.4–0.88)

0.466

CH50 (23–46 U/ml)

47 (20–680)

48 (0.2–69)

0.635

TPO (0–60 U/ml)

30.8 (5.1–1,300)

25.4 (10–533)

0.718

TG (0–60 U/ml)

37.05 (10–500)

35.25 (1.49–407.1)

0.124

T3 (0.92–2.79 nmol/l)

1.35 (0.7–5.47)

1.78 (0.63–11.08)

0.074

T4 (58.1–140.6 nmol/l)

108.7 (72.9–148)

101.8 (8.9–363.6)

0.440

FT3 (3.5–6.5 pmol/l)

3.98 ± 0.88

4.41 ± 2.87

0.410

FT4 (11.5–22.7 pmol/l)

16.54 ± 3.48

18.77 ± 14.03

0.595

TSH (0.55–4.78 UIU/ml)

1.376 (0.02–16.08)

1.15 (0.01–36.5)

0.609

NMOSDs neuromyelitis optica spectrum disorders, MO medulla oblongata, CSF cerebrospinal fluid, OCB oligoclonal banding, CRP C-reactive protein, ESR erythrocyte sedimentation rate, NMO-IgG anti-AQP4IgG autoantibodies, ANA antinuclear antibodies, SSA anti-SSA/Ro antibodies, SSB anti-SSB/La antibodies, RF rheumatoid factor, TPO anti-thyroidperoxidase antibodies (antiTPO-Ab), TG anti-thyroglobulinantibodies (TgAb), T3 triiodothyronine, T4 thyroxine, FT3 free triiodothyronine, FT4 free thyroxin, TSH thyroid-stimulating hormone * p \ 0.05; ** p \ 0.01

tests, immunological indexes and antibodies, thyroid autoantibodies, NMO-IgG and OCB positivity. Characteristics of brain and spinal cord lesions on MRI of patients with and without MO lesions in NMOSDs The characteristics of brain and spinal cord lesions on MRI of patients with and without MO lesions are summarized in Table 4. Several brain regions were more frequently involved in patients with MO lesions than in patients without MO lesions, including hypothalamic and thalamic (p = 0.001), mesencephalon (p = 0.033), pons (p = 0.001), peri-ventricle and peri-aqueduct (p = 0.007), and cerebellum (p = 0.003) (Fig. 1). The spinal cord lesions were predominantly located in cervical and thoracic cord in both groups. However, the ratio

of cervical cord involvement was significantly higher in the patients with MO lesions than in patients without MO lesions (p = 0.004). Furthermore, longitudinally extensive cervical cord lesions were more frequently found in patients with MO lesions than that in the patients without MO lesions (p = 0.004). Besides, the length of lesions in cervical cord measured by vertebral segments was also significantly longer in patients with MO lesions than that in the patients without MO lesions (p = 0.001). Although no significant difference was found in the ratio of thoracic cord involvement between these two groups (p = 0.451), the length of thoracic cord lesions was significantly longer in the patients without MO lesions than that in the patients with MO lesions (p = 0.016). However, no significant difference existed between the two groups about the combined cervical and thoracic cord lesions (p = 0.451) (Fig. 2).

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Fig. 1 Typical brain MRI lesions in neuromyelitis optica spectrum disorders (NMOSDs) with medulla oblongata (MO) lesions. a–f T2 FLAIR, g, h T2 FRFSE, a lesions in frontal lobe, b lesions in periventricular area, c lesions in hypothalamic region, d lesions in

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cerebellar hemispheres, e lesions in midbrain tegmental area, f lesions in fourth periventricular area, g lesions in the ventrolateral MO, h lesions in the dorsal MO

Fig. 2 Typical transverse myelitis (TM) MRI lesions in neuromyelitis optica spectrum disorders (NMOSDs). Representative MRI of two NMOSDs patients with MO and without MO. Spinal cord MRI: sagittal T2 FRFSE (a, b). a MRI showing LETM of cervical (C1–C6) cord with MO. b MRI showing STM of cervical (C1–2, C3, C5) cord without MO

Discussion The clinical symptoms, locations, and incidences of MO involvement in NMO patients have been reported in previous studies [10, 12, 20, 21]. However, few studies have made comparison of the clinical, laboratory, and MRI features of NMOSDs patients with and without MO

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lesions. To the best of our knowledge, this is the first detailed and systemic comparison in Chinese NMOSDs patients with and without MO lesions. In the present study, we found the following clinical features of NMOSDs patients with MO lesions: higher ARR, more severe disability, more medullary symptoms, more multiple brain lesions, more longitudinally extensive cervical cord

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Table 4 Comparative brain and spinal cord lesions on MRI of patients with or without MO lesions in NMOSDs NMOSDs with MO (n = 44)

NMOSDs without MO (n = 126)

p

Brain lobes

24 (54.5 %)

56 (44.4 %)

0.248

Basal ganglia

10 (22.7 %)

16 (12.7 %)

0.112

Hypothalamic and thalamic

10 (22.7 %)

6 (4.8 %)

0.001** 0.033*

Brain lesions, n (%)

Mesencephalon

5 (11.4 %)

4 (3.2 %)

Pons

16 (36.4 %)

11 (8.7 %)

0.001**

Peri-ventricle and peri-aqueduct

14 (31.8 %)

17 (13.5 %)

0.007*

Cerebellum

7 (15.9 %)

4 (3.2 %)

0.003*

Enhancing:nonenhancing brain lesions

6:38

11:115

0.350

Spinal cord lesions, n (%) Cervical cord

36 (81.8 %)

73 (57.9 %)

0.004*

Segments lesions

4.32 ± 2.96

2.57 ± 2.73

0.001**

LETM STM

31 (70.5 %) 5 (11.4 %)

57 (45.2 %) 15 (11.9 %)

0.004* 0.361

Thoracic cord

28 (63.6 %)

72 (57.1 %)

0.451

Segments lesions

2.86 ± 2.97

5.21 ± 4.48

0.016*

LETM

22 (50 %)

53 (42.1 %)

0.361

5 (11.4 %)

18 (14.3 %)

0.626

Cervical and thoracic cord lesions

STM

31 (70.5 %)

96 (76.2 %)

0.451

Enhancing:nonenhancing spinal cord lesions

3:41

10:116

0.810

MRI magnetic resonance imaging, MO medulla oblongata, NMOSDs neuromyelitis optica spectrum disorders, LETM longitudinally extensive transverse myelitis, STM shorter transverse myelitis *p \ 0.05; **p \ 0.01

lesions, and more frequently complicated with thyroid diseases. Previous studies have indicated that MO was a frequently involved region in NMO with a prevalence ranging from 12.8 to 91.3 % [10, 11, 21–23], and usually located in the dorsal part. In our study, the prevalence of MO lesions was 25.9 % in NMOSDs patients. Dorsal medulla lesions occupied 84.09 % in MO lesions patients. The mean duration from the onset of NMOSDs to the appearance of MO lesions was 13 months. At the onset of the disease, most of the patients (65.9 %) did not occur the medulla lesions. It is easy to understand that some symptoms and signs, including headache, intractable hiccup and nausea (IHN), dysphagia, dizziness, movement disorders, nystagmus, dysarthria, and neuropathic pain (NP) can be caused by lesions in the medulla, but they can also be caused by

lesions in the cerebellum, pons, and spinal cord. So they should not be considered as medullary-only symptoms. In our study, although these clinical manifestations are more frequently found in patients with MO lesions, Medulla lesions may be just one of the factors contributing to these symptoms. Intractable hiccup and nausea are a rare symptom in NMOSDs. Recent studies have reported frequent occurrence of intractable hiccup and nausea in NMO, with incidences from 15.7 to 62 % [23–25]. Our findings showed intractable hiccup and nausea in 54.5 % NMOSDs patients with MO lesions, but only 12.1 % without MO ones. More importantly, about 36.4 % of the patients whose initial clinical manifestation of MO was intractable hiccup and nausea. MO patients had the documented episode of intractable hiccup and nausea as initial presentation [24]. The reason for this might be that area postrema (AP) and nucleus tractus solitarius (NTS) in the dorsomedial medulla and ventrolateral respiratory center (VRC) involvement was more common in NMOSDs with MO lesions than without MO lesions [24]. Dysphagia was found in 29.5 % of NMOSDs with MO lesions. Dysphagia is a rare type of presentation in NMOSDs. We speculated that the neural network in relation to nucleus ambiguus, NTS, and dorsal vagal nuclei in MO may be responsible for this manifestation [26]. Neuropathic pain develops as a consequence of a lesion or disease affecting the somatosensory pathways in the peripheral or central nervous system. Elsone et al. [27] reported that 27.3 % of NMO patients showed neuropathic pain. Our results showed that 65.9 % of the NMOSDs patients with MO lesions suffered from neuropathic pain. One of the most notable reasons is that the MO lesions damaged the spinal nucleus of the trigeminal nerve or peri-aqueductal pathways. Besides, more extensive spinal cord involvement was seen in patients with MO lesions, which raised the possibility of dorsal horn damage and caused neuropathic pain. Little attention was paid to headache in NMOSDs; only some cases reported headache manifestations in NMO patients [28]. However, we found a higher frequency of headache (31.8 %) in patients with MO lesions. The mechanism is not clear. Doi et al. [29] supposed that the periaqueductal gray matter, which is frequently involved in NMOSDs, is considered to be a migraine generator or modulator of headache, but some proposed that the possible mechanism that hypothalamospinal tract, which lies in the dorsolateral medulla, via the peri-acqueductal gray matter, activates the hypothalamus and the trigeminovascular system, which is a known generator of headaches [30]. Also, medullary dorsal lesions provoke the release of substance P, which is considered pivotal elements in causing and maintaining headaches in the trigeminal tract nucleus [31]. Besides, headache may be associated with optic nerve lesions. Unfortunately, not all of the patients could undergo optic

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nerve MR scans. Thus far, only limited data were available, so damage to these areas might be the cause of headache. Similarly, dizziness, nystagmus, and dysarthria are unusual clinical manifestations in the onset or relapse of the diseases. These symptoms and signs can be caused not only by lesions in the medulla but also by lesions in the cerebellum (including the cerebellar peduncles) and pons. Furthermore, NMOSDs are susceptible to be co-existing rheumatic diseases, including Sjo¨gren’s syndrome, systemic lupus erythematous, and rheumatoid arthritis [32– 34]. Our results showed a higher seropositivity rate of ANA, SSA, SSB, and RF in patients with MO lesions but did not reach statistical significance, although Sakuma et al. [35] reported that anti-thyroid antibodies were more frequently found in optic-spinal form of MS than in other types of MS in Japanese. However, in our study, there was no significant difference in concentrations of anti-thyroid antibodies between NMOSDs patients with MO lesions and without MO lesions. So these auto-antibodies might be associated with the disease but not with MO lesions. Meanwhile, we found that the patients with MO lesions were more frequently coexistent thyroid diseases (autoimmune thyroiditis and/or subclinical hypothyroidism) than those without MO lesions, but the reason remained unknown. LETM are thought to be the core presentation, important component of the clinical diagnosis of NMO and a limited form or initial event of NMO [12, 36]. The prevalence of LETM in NMO was 72.4–100 % [10, 21, 35]. Similar to previous studies, our study found that 70.5 % of NMOSDs patients with MO lesions had LETM in cervical cord, especially in the upper cervical cord. The mean segments of lesions in patients with MO lesions were also significantly longer than those in the patients without MO lesions [6, 37]. Besides, the brain abnormalities of NMOSDs, particularly multiple brain damage, have been recently called to clinicians’ attention. Our previous study reported the clinical symptoms and MRI characteristics in NMO patients with multiple brain lesions [38]. However, the relation between MO lesions and multiple brain damage remains unknown. Our results showed a higher frequency of supratentorial and infratentorial involvement in patients with MO lesions. The multiple brain lesions frequently involved hypothalamus, thalamus, mesencephalon, pons, ventricle, aqueduct, and cerebellum. Moreover, these lesions corresponded to brain areas with high levels of AQP4 expression and distribution [6, 19]. However, our findings do not mean that MO lesions are responsible for the appearance of these other lesions. These results may just suggest that there is a cohort of patients in which medulla spinalis, rhombencephalon, mesencephalon, and diencephalon are more susceptible to NMOSDs. Our findings imply that MO patients with multiple brain

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damage may have high clinical disease activity and further disability progression, but further study is needed. Some research has shown that NMO-IgG seropositive patients with NMO had higher relapse number and EDSS score [39–41]. However, in the present study, there were no differences in the seropositivity of NMO-IgG between patients with and without MO lesions. So the differences of relapse number and EDSS score between these two groups might not be caused by seropositivity of NMO-IgG. However, limited by the technical conditions, we did not test the titer of NMO-IgG, which were reported to be associated with the activity of the disease [42]. However, any suggestion of a positive link between the NMO-IgG titers and disease activity, clinical disability must be prompt further investigation with larger, prospective studies. In our study, patients with MO lesions had more severe disability and worse prognosis than those without MO lesions, presented by EDSS on the last follow-up and ARR. There might be several reasons for our finding. First of all, the symptoms and signs of MO involve such as dysphagia, movement disorders, nystagmus, and dysarthria could raised EDSS score. Secondly, the patients with MO lesions were more frequent with severe brain and spinal cord lesions, which might increase disease severity, especially the LETM lesions. Finally, the multiple damage of the central nervous system made the patients hard to get complete recovery and more prone to relapse. Thus, more intensive interference for the early acute stage and the early prevention of relapse might be helpful for the NMOSDs patients with MO lesions. There are some limitations in this study: (a) limited by the technical conditions, we were not able to detect the titers of some auto-antibodies and NMO-IgG; (b) because of the limited number of patients with MO lesions, we were not able to make an analysis for different subtypes of NMOSDs; (c) although brain MRI scans were evaluated within 1 week after the onset of the disease, and even prior systemic therapy. However, the brain lesions can still be not captured in time due to the reversible nature in some NMOSDs patients with and without MO; (d) bias is inevitable in retrospective studies. In conclusion, the patients diagnosed as NMOSDs with MO lesions might have more severe disability, higher relapse rate, and more multiple central nervous system damage. They are more frequently complicated with thyroid diseases. MO lesions might be a symbol of more severe neurologic deficits and worse prognosis of NMOSDs. Conflicts of interest The author declares that there is no conflict of interest.

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Comparative clinical characteristics of neuromyelitis optica spectrum disorders with and without medulla oblongata lesions.

Brainstem involvement, especially the medulla oblongata (MO), has been reported in neuromyelitis optica spectrum disorders (NMOSDs). The purpose of th...
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