Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients

BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients

The major brain endocannabinoid 2-AG controls neuropathic pain and mechanical hyperalgesia in patients with neuromyelitis optica.

Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO). While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST) following the protocol of the German Research Network on Neuropathic Pain (DFNS). Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11) suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG). These data emphasize the high prevalence of neuropathic pain and hyperalgesia in patients with NMO. The degree of mechanical hyperalgesia reflecting central sensitization of nociceptive pathways seems to be controlled by the major brain endocannabinoid 2-AG

Health related Quality of Life: (SF-36).

<p>The scales of the SF-36 score from 0–100, with 0 indicating worst health and 100 the best.</p><p>PF: Physical Functioning, RP: Role Limitations, Physical:, BP: Bodily Pain, GH: General Health, VT: Vitality, SF: Social Functioning, RE: Role Limitations, Emotional, MH: Emotional Well-Being, PCS: Physical Component Summary Score MCS: Mental Component Summary Score.</p><p>n.s.: not significant.</p><p>Z-Score: SF-36 data were normalized to a US-General population (n = 2393).</p

Clinical characteristics of neuropathic pain.

<p>Clinical characteristics of neuropathic pain.</p

Pattern of sensory changes in patients with NMO (normalized to mean and standard deviation of healthy control group).

<p>A: The sensory profile by comprehensive quantitative sensory testing (QST) shows significant sensory loss (negative z-values) for thermal detection (CDT, WDT, TSL) and vibration detection (VDT) in both extremities, significant sensory gain (positive z-values) for noxious heat (HPT) in the hand dorsum. B: Patients with NMO experienced pronounced dysesthesia to non-noxious mechanical and thermal stimulation in both extremities, namely pain to stroking with non-noxious light tactile stimuli (dynamic mechanical allodynia DMA) and paradoxical heat sensation (PHS) to stimulation with non-noxious cold stimuli during the TSL procedure (alternating cold and warm stimuli). *p<0.05, **p<0.01, ***p<0.001, t-test.</p

Thermal thresholds in NMO.

<p>A: Heat pain thresholds in patients with NMO (NMO) compared to healthy controls (HC) differed significantly in the hands, but not feet. <b>B</b>: Patients with NMO (NMO) in patients with an acute MRI-verified cervical lesion (NMO w) were significantly more heat pain-sensitive in both extremities and also tended to be more cold pain-sensitive than patients without (NMO w/o). For both thermal pain modalities the hyperalgesia tended to be more pronounced in the hands than feet. <b>C</b>: Collapsing data from both extremities revealed that patients with an acute MRI-verified cervical lesion (NMO w) were significantly more cold pain-sensitive than patients without (NMO w/o). <b>D</b>: Correlations of heat pain thresholds to the time span since the last relapse of an acute NMO attack was high in the hand (closed circles; r = 0.77) and feet (open circles; r = 0.68). This correlation also persisted at the same level, when normalized for gender and age. The correlations indicated that NMO relapses may have induced a severe heat hyperalgesia that subsided slowly during the course of remission. ⁽*⁾p<0.10, *p<0.05, **p<0.01, ***p<0.001, t-test.</p

Endocannabinoid plasma levels in NMO.

<p>Mean plasma levels of the endogenous cannabinoid lipids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamide (AEA, anandamide) were increased in patients with NMO compared to age matched healthy controls. (*)p<0.10, **p<0.01.</p