AUTONOMIC DYSFUNCTION IN NEUROMYELITIS OPTICA AND NMO SPECTRUM DISORDERS A PROSPECTIVE OBSERVATIONAL STUDY

AUTONOMIC DYSFUNCTION IN NEUROMYELITIS OPTICA AND NMO SPECTRUM DISORDERS A PROSPECTIVE OBSERVATIONAL STUDY A dissertation submitted in partial fulfillment of Doctor of Medicine- Brach I Neurology Degree Examination of the Tamil Nadu Dr.M.G.R Medical University, Chennai to be held in August 2014 1

ABSTRACT Title:AUTONOMIC DYSFUNCTION IN NEUROMYELITIS OPTICA AND SPECTRUM DISORDERS. Name of Candidate: Murthy TV Course: D.M. branch I, Neurology August 2014 INTRODUCTION: In NMO and spectrum disorders which has predilection for the critical areas in the brain and spinal cord causing Autonomic disturbances leading to varied autonomic dysfunction. AIMS AND OBJECTIVES: To assess the frequency, severity and spectrum of autonomic dysfunction in patients with Neuromyelitis optica and spectrum disorders. MATERIAL and METHODS: 20 patients studied by using Revised Criteria for NMO and spectrum disorders(2006). The autonomic dysfunction was assessed both autonomic symptoms(using COMPASS score) and autonomic function tests (Finopress TM) were done. The limited CASS score utilised for estimation of severity of autonomic dysfunction as the SSR was not available in all patients. The frequency and severity of autonomic dysfunction was estimated using the both autonomic symptoms and autonomic function tests. RESULTS: 20 Patients (13 females, males) showed autonomic dysfunction 95% during the active phase of the disease and 80% at the time of remission. The most common autonomic symptoms were of gastrointestinal, genitourinary, sudomotor and sexual dysfunction. On AFT tests the parasympathetic dysfunction(80%) predominantly involved than sympathetic(65%). The autonomic dysfunctions not correlating with the disease duration or EDSS score at remission, due to low EDSS scores at admission. CONCLUSION. The prevalence of Autonomic symptoms very high in Neuromyelitis Optica and Spectrum disorders. Autonomic function test abnormalities are found in 80% of patients during remission and 95% during the active phase. The parasympathetic cardiovascular abnormality rates(80%) more common than sympathetic cardiovascular function abnormality(65%). There was correlation between between EDSS scores at active phase with MRI changes due to involvement specific areas of brain and spinal cord(hypothalamus, area postrema, midbrain and periventricular areas).

INTRODUCTION. Neuromyelitis optica (Devics disease) and spectrum disorders are demyelinating inflammatory disorders involving the optic nerves and the long segments of the spinal cord ( 3) contiguous vertebral segments(1). This disorder is characterized by pathogenic specific IgG anti- aquaporin4 antibodies(aqp4)(1). Anti-aquaporin4 antibody was detected by indirect immunoflorescence and helps to differentiate between NMO and spectrum disorders from Multiple sclerosis with high sensitivity and specificity(2)(3). Anti aquaporin(aqp4) antibodies belong to complement activating IgG1 subclass, binding to antigens resulting in activation of complement mediated cell cytotoxicity. Anti aquaporin(aqp4) antibodies present in up to 80% in Neuromyelitis optica, 5 to 27% in relapsing optic neuritis and 14-57% in long extensive transverse myelitis(letm)(4)(5). This antibody titre in the sera can be correlated with the severity of the disease. These antibodies can be present in the several years before the onset of clinical symptoms. In these disorders due to involvement of the autonomic nervous system pathways, either in the brain or the spinal cord, autonomic dysfunction can be seen. In NMO, there is involvement of hypothalamus and area postrema of brain stem, which can lead to anorexia, weight loss, obesity, syndrome of inappropriate secretion of antidiuretic hormone, posterior reversible encephalopathy syndrome, hypothermia, fever of unknown origin, bradycardia, hypotension and anhidrosis. Patients may have recurrent vomiting, hiccups and alteration in blood pressure due to involvement of area postrema(2)(6)(7). Due to involvement of central parts of the long segments of spinal cord(5); the autonomic nervous system is involved. The area postrema lacks blood brain barrier, which makes it more susceptible to recurrent attacks(2). Even though the literature has mentioned that involvement of autonomic nervous system due to involvement of specific areas in brain and spinal cord, there has been no systematic study looking at the frequency and severity of autonomic dysfunction. In a retrospective study done in our hospital with 25 patients with NMO, there was involvement of the bladder in 92.3%, bowel in 61.5%, sexual dysfunction in 19% and fatigue in 16.1% of these patients. 2

In disease like multiple sclerosis, there are studies that looked at the frequency, type and severity of involvement of the autonomic dysfunction. Hence, the present study was designed to study the frequency and severity of autonomic dysfunction in patients with NMO and NMO spectrum disorders. Detection and treatment of the autonomic dysfunction in these patients helps to improve the quality of life and also to prevent mortality(8). AIMS AND OBJECTIVES: 1. To assess the frequency, severity and spectrum of autonomic dysfunction in patients with Neuromyelitis optica and spectrum disorders 2. To correlate the degree of dysfunction with disability scores(edss) and MRI lesions 3

REVIEW OF LITERATURE:. In patients with NMO and spectrum disorders, the involvement of the specific areas of autonomic pathways and centres in the brain like, area postrema, hypothalamus, periaqueductal region and central parts of the cord. Due to involvement of these regions patients have brain stem symptoms like hiccoughs, intractable vomiting, vertigo, giddiness, coma. The involvement of the hypothalamus leads to anorexia, SIADH, obesity, hypothermia, hypotension, bradycardia, recurrent coma, hypopituitorism(2). There are studies of involvement of the autonomic nervous system in multiple sclerosis but there were no review of literature in NMO and NMO spectrum disorders. Epidemiology, etiopathogenesis, clinical profile of NMO and NMOSD In 1844 Giovanni Battista first described the case of optic neuritis with long cord myelitis.. Devic in 1894 first explained the clinical features of patient presented with optic neuritis with long cord myelitis (9). The exact cause of the disease was not known. NMO was associated with many systemic autoimmune diseases, antecedent vaccinations. Due to availability of magnetic resonance imaging and development of highly sensitive and specific aquaporin antibodies, the diagnosis of NMO and NMO spectrum disorders became more common than previously. Previously all these case were considered as multiple sclerosis as they also involve the brain and spinal cord(3). NMO and NMOSD patients had damage to certain critical areas of the brain like hypothalamus, area postrema, internal capsule apart from optic nerves and the spinal cord due to presence of the aquaporin channels. 4

Epidemiology NMO affects the females more than males up to 8:1 (females>males). (1). In countries like India the incidence of NMO ranges from 10 to 20% of the demyelinating disease. Its common in whites when compared to Asian countries, so the disease prevalence was more in western countries. Pandit et al. reported the incidence of NMO was 8 to 10% of demyelinating disease. Optic neuritis precedes the NMO in African patients when compared to western patients.(10)(11). The incidence of NMO in different countries like Japan(20 to 30% of the demyelinating disease), west Indians (28%), east Asian(27%). The literature in Latin American countries were lacking. Due to detection of the aquaporin antibodies in 2004 leads to identification of these patients became easy as these patients were diagnosed as multiple sclerosis or monophasic optic neuritis. The familial inheritance of NMO was rare but has been reported and The usual age of presentation during the 3 rd to 4 th decade. NMO can affect both children and adults. Aquaporin antibody positivity in NMO patients common in females than males. Females are prone for relapsing disease when compared to males. ETIOPATHOGENESIS: Role of Aquaporin -4antibodies (AQP4 Ab): Lennon et al first described the serum autoantibody(nmo IGg) which had high sensitivity and specificity(72% and 90% respectively in patients with neuromyelitis optica. Later aquaporin-4(aqp4), channels were the main targets found in the pathogenesis of NMO (12)(11). These NMO auto antibodies are absent in patients without NMO or NMO spectrum disorders. So its presence had high clinical significance, since it is absent in other demyelinating disorders like multiple sclerosis. Since these. patients were labeled as multiple sclerosis as there were no specifc markers to establish the diagnosis. The NMO IGg auto 5

antibodies present in about 50% of the patients who presents with features of NMO having systemic autoimmune disease like Sjogren s syndrome or SLE (11)(13). So this NMO antibodies helps to differentiate between NMO and MS patients with high specificity and sensitivity. The aquaporin antibodies present in about of 60% of the patients of Asian Opticospinal MS, which were initially diagnosed as Asian variant of Multiple sclerosis(10)(14). Aquaporin 4 channels are present in the ependymal cells, optic nerves, hypothalamic nuclei, area postrema and spinal cord. These channels also present out side the CNS like kidney, GIT, Glandular epithelium but the significance to NMO was not known(13)(2). Immunoprecipitation technique helps to detect these antibodies with high sensitivity and helps to differentiate it from demyelinating diseases like multiple sclerosis.. Anti aquaporin(aqp4) antibodies are IgG1 subclass antibodies, leads to complement mediated damage at the aquaporin channels in the brain and the spinal cord(15). Anti aquaporin(aqp4) antibodies present in (up to 80% )in Neuromyelitis optica, (5 to 27%) relapsing optic neuritis and (25-60% ) long extensive transverse myelitis(letm) respectively. The severity of the NMO disease correlated with the antibody titres in the serum(16). The reason for normal renal function or GI function due to low concentration of these channels in these area when compared to aquaporin sites in the brain and spinal cord (high concentration). 6

FIGURE 1 : Cartoon showing Immunopathogensis of NMO spectrum disorders The aquaporin antibodies attached to luminal surface of the receptors in th astrocytes, piamater, microvessels, Virchow robins space leading to disruption of the blood brain barrier and complement mediated damage. The antibodies present in the serum many years before development of optic neuritis or myelitis. The methods used and sensitivity and specificity mentioned below(1)(4). 7

TABLE 1 : Sensitivity and specificity of anti-aqp4-ab detection methods(12) Method Sensitivity(%) Specificity(%) Indirect Immunofluroscence 86 91 Cell Based Assays 91 100 Immunoprecipitation Assays 83 100 CLINICAL PRESENTATION: In Neuromyelitis optica presents with relapsing episodes of optic neuritis or myelitis or both in more than ninety percent of the patients. The remaining ten percent of the patients presents with simultaneous optic neuritis with myelitis which is usually have monophasic phase. In Neuromyelitis optic,patients have more disabilities due to optic neuritis /myelitis Attacks when compared to multiple sclerosis. The disabilities are more common in Neuromyelitis optica and if not treated at the earliest will lead to severe neurological disability. Neuromyelitis optica patients, who had high EDSS scores 6, were found to have grossly impaired mobility in more than 50% of the patients. The chances of developing blindness was reported to be more than half of the patients with optic neuritis over a period of 6 to 7 years.(17)(18). Small subgroup of NMO patients will follow benign course and less disability even after 8 to 10 years of duration of the disease. The death in NMO was due to involvement of the brainstem and long cervical cord causing damage to cardio respiratory centers. The death rates were less in the recent years due to early detection of the aquaporin antibodies and treatment with stronger immune therapy. The early introduction of strong immunosuppressive agent in these disease will reduce the morbidity, mortality and reduce the chances of relapse.(20)(11). When the patient presents to the neurologist with isolated optic 8

neuritis or isolated myelitis or brain stem involvement, it will be difficult to diagnose the NMO at the initial setting. So NMO should always be kept in the differential diagnosis and the aquaporin antibodies to tested in these patients, since early detection will leads to proper treatment management for these patients(19)(11). Neuromyelitis optica and NMO spectrum disorders presents with uncommon clinical features like convulsions, PRESS, cranial nerve palsies, recurrent coma, intractable vomiting, hiccoughs and SIADH. NMO and NMOSD patients presents with features of autoimmune disorders like SLE, Myasthenia gravis, Sjogren s syndrome, hypothyroidism These involvement of these disorders are not seen in demyelinating diseases like multiple sclerosis(17)(14). Laboratory findings in NMO A. Cerebrospinal fluid: Oligoclonal bands present in very less percentage of patients when compared to multiple sclerosis(30% vs 85%) (10)(11). The CSF cell count usually were in normal range but can increase during active stage of disease (16). The lymphocytic pleocytosis commoner than the neutrophilic pleocytosis. During the relapse the neutrophic pleocytosis is common which will not be found in multiple sclerosis. The neutrophilic pleocytosis is characteristic of the relapse.the cell count can go >500/µl. NMO patients very commonly show normal csf analysis in optic neuritis. (17)(11). 9

B Magnetic resonance imaging MRI is critical tool which helps to differentiate between multiple sclerosis. The MRIO changes in brain and spinal cord have varied presentation. In 60 to 65% of the NMO patients have involvement of the brain stem which may evolve to involve the cervical cord or it may remain silent. In optic neuritis, MRI brain may be normal unless contrast is used which show enhancement of the optic nerves. In NMO brain mri may show nonspecific white matter changes in optic neuritis. NMO and spectrum disorders involves 3 segments of the vertebral column. The areas of involvement usually central and cavitation and necrosis were common in these patients. The long cord segment involvement detected by T2 sagittal MRI spine. In cases of Multiple sclerosis these lesions were of small size and they involve the periphery of the cord and they rarely exceeds the one segment. The autoimmune disorders like SLE, Sjogren s and Sarcoidosis can present with long cord segment involvement. These autoimmune disorders should always be considered in the differential diagnosis of isolated long cord myelitis.(4)(21). The lesions in the cord can undergo atrophy or they may recover depending on severity of damage, due to recurrent attacks or improper immunotherapy (10). Mri in the brain involve very important sites like hypothalamus, are postrema, dorsal brain stem. These areas are more typical of neuromyelitis optica than the multiple sclerosis. The white matter lesions can appear like cloud pattern on gadolinium. Which is not seen in multiple sclerosis. The callosal involvement is different in NMO patients which causes heterogeneous involvement but in MS its mainly pericallosal involvement 9perpendicular to the callosum which are not found in NMO patients. Brain lesions tend to be located at sites of high aquaporin-4 expression such as the diencephalon, the hypothalamus, and the aqueduct and may appear large and edematous, also in the corpus callosum(22). The typical sites of involvement in brain showed in the following figure. PRESS can be rare presentation of NMO due to involvement of the vasomotor area in the brains stem. 10

FIGURE 2: typical MRI features of NMO and spectrum disorders: Typical MRI sites of involvement in NMO and NMO spectrum disorders A MRI brain showing edematous periventricular lesion B Tumefactive frontal lobe lesion C Lesions involving the posterior limb of internal capsule D Cloud like enhancement of the lesion E Heterogeneous involvement of the corpus callosum 11 F Bilateral involvement of hypothalamus G midbrain lesions H Involvement of area postrema I Central brain stem lesion.

Revised diagnostic criteria for Neuromyelitis Optica 2006(18) DEFINITE NEUROMYELITIS OPTICA Optic Neuritis Acute Myelitis At least 2 of 3 supporting criteria 1. Contiguous spinal cord lesions on MRI involving >3 vertebral segments 2. Brain MRI not meeting the diagnostic criteria for Multiple sclerosis 3. NMO IgG seropositive status NEUROMYELITIS OPTICA SPECTRUM DISODERS Limited forms of Neuromyelitis optica(1) a. Idiopathic single or recurrent events of longitudinal extensive myelitis (>3vertebral segments of spinal cord seen on MRI) b. Optic Neuritis: recurrent or simultaneous bilateral Optic neuritis or longitudinal extensive myelitis associated with systemic autoimmune disease 12

Optic neuritis or longitudinal extensive myelitis associated with brain lesions typical of Neuromyelitis optica (corpus callosum, periventricular, hypothalamus or brainstem) NMO and NMO spectrum disorders with connective tissue disorders(17) Recurrent optic neuritis. and long segment( 3 vertebral column) is common in Neuromyelitis optica and NMO spectrum disorders. The NMO is seen in systemic autoimmune disorders like Sjogrens syndrome, SLE, hypothyroidism, myasthenia gravis. When these disorders presents with Longitudinal extensive transverse myelitis (LETM) or optic neuritis, it should be considered that both presence of 2 autoimmune disorders rather than the systemic manifestation of the connective tissue disorder. So these patients has to be screened for aquaporin antibodies when they present with features of neuromyelitis optica.(16)(25)(2). Pittock et al. showed aquaporin antibodies help to distinguish long cord myelitis as clinical presentation of systemic autoimmune disorder like SLE (26). The aquaporin antibodies appear in the serum many years before the clinical presentation of the neuromyelitis optica (10). Janius et al found that the aquaporin antibodies are present in patients of systemic autoimmune disease who presents with myelitis or optic neuritis. Hence it is highly specific and helps to diagnose the disorder of 2 autoimmune disease in the same patient (25)(26). The presence of aquaporin antibodies in these disorders mainly due to similar immunological process of antibody mediated mechanism. Patients with one autoimmune disease are predisposed to developing another autoimmune disease. NMO spectrum disorders presents with optic neuritis or myelitis have presence of autoimmune markers like ANA, dsdna SSA which doesn t meet the criteria to establish the diagnostic criteria for specific autoimmune disorders(27)(23)(10). The presence of the autoimmune markers in NMOSD associated with 13

poorer prognosis when compared to patients with absence of these markers (21). Yanagawa et al, found that in limited NMOSD the detection of aquaporin antibodies and early therapy with strong immunotherapy will lead to better prognosis(5). changing concepts of neuromyelitis optica:. A century ago the clinical features of isolated optic neuritis, long segment myelitis were considered as monophasic demyelinating disorder. These disorders initially treated as multiple sclerosis. The development of aquaporin antibodies revolutionized the concept of NMO, as these antibodies are seropositive only in these disorders and absent in multiple sclerosis. Recently they also present as isolated manifestation of systemic autoimmune disorders like SLE, Sjogren s syndrome.(16). 14

MATERIAL AND METHODS: Study setting- The study was conducted in Christian Medical College and Hospital, a 1800 bedded tertiary hospital in South India. It was conducted in the Department of Neurology. Eligible subjects were recruited from the Neurology outpatient clinics or wards. Study design- The study design was prospective cross-sectional study. The study design and methods were approved by the Institutional review board of Christian Medical College, Vellore Participants-Patients with Neuromyelitis optica and spectrum disorders seen in the Department of Neurology, Christian Medical College, Vellore over 4 months period (Feb 2014 May 2014) will be screened for inclusion in the study. INCLUSION CRITERIA: Patients diagnosed as having neuromyelitis optic/ spectrum disorders based on the following criteria, Revised diagnostic criteria for Neuromyelitis Optica 2006 DEFINITE NEUROMYELITIS OPTICA Optic Neuritis Acute Myelitis At least 2 of 3 supporting criteria 4. Contiguous spinal cord lesions on MRI involving >3 vertebral segments 5. Brain MRI not meeting the diagnostic criteria for Multiple sclerosis 6. NMO IgG seropositive status 15

NEUROMYELITIS OPTICA SPECTRUM DISODERS Limited forms of Neuromyelitis optica a. Idiopathic single or recurrent events of longitudinal extensive myelitis (>3vertebral segments of spinal cord seen on MRI) b. Optic Neuritis: recurrent or simultaneous bilateral Optic neuritis or longitudinal extensive myelitis associated with systemic autoimmune disease Optic neuritis or longitudinal extensive myelitis associated with brain lesions typical of Neuromyelitis optica (corpus callosum, periventricular, hypothalamus or brainstem) EXCLUSION CRITERIA: Post or para infectious encephalomyelitis- ADEM Multiple sclerosis diagnosed by Mc Donald s Criteria Causes other than inflammatory conditions diagnosed by radiological, biochemical and microbiological tests. Diabetes Mellitus Hypertension 16

Chronic renal disease Coronary artery disease and cardiac failure/ cardiomyopathy will be excluded form the study. Subject enrolment: If a patient fulfilled criteria for inclusion then they were approached for informed consent. If the patient consented clinical and demographic data was collected the patient underwent a standardized neurological examination. Clinical Parameters: EDSS Score (Expanded disability status scale) and MRC scale (Medical Research Council scale for muscle power) COMPASS 31 scoring system was used to score severity of autonomic symptoms. The minimum raw score is zero and Maximum is 75. Equipment and data acquisition The Finometer PRO is a non-invasive beat to beat blood pressure measurement and hemodynamic monitoring system that incorporates proprietary Model flow methodology for cardiac output measurement and other hemodynamic parameters. The finometer advantage is its accurate and robust continuous measurement in an all-in-one concept. The finometer not only captures the continuous blood pressure waveform, but also automatically computes up to 15 important beat to beat hemodynamic parameters including: 17

1. Systolic, diastolic and mean arterial pressures 2. Cardiac output. 3. Stroke volume 4. Total peripheral resistance 5. Pulse rate variability 6. Inter-beat interval 7. Baro-reflex sensitivity The finometer PRO provides accuracy through return to flow calibration using an inflatable arm cuff and direct graphic parameter visualization on a built-in flat screen. Variables 1. Demographic data 2. EDSS and MRC 3. Neurological examination 4. Nerve conduction studies 5. Sympathetic skin response 6. Evoked Potentials 7. MRI Brain and spine 8 Aquaporin antibodies 9 Uroflometry 18

Study outcome: Primary outcome was autonomic dysfunction as detected by COMPASS 31 score or autonomic function testing detected by limited CASS score. Analysis: Data entry was done using SPSS software (version 16). Statistical calculations were done using SPSS software. Chi-square test was used to compare categorical variables, and student t test was used for comparison of continuous variables. Odds ratio (OR) and confidence intervals (CI) were calculated. P value of less than 0.05 was considered statistically significant. The Spearman rho tested correlations among continuous variables. 19

RESULTS Summary of autonomic symptoms in patients with NMO and NMO Spectrum disorders: TABLE 2: Baseline Characteristics Values Age in years, mean +/- SD 34.35±14.95 Female, n/t (%) 13/20(65%) Duration of disease 2.95±1.701 At autonomic testing Active disease In Remission 5/20(25%) 15/20(75%) EDSS during the ANS testing Mild Moderate Severe 16/20(80%) 1/20(5%) 3/20(15%) Aquaporin antibodies n/t (%) 04/20(20%) Presence of Vasculitic markers n/t(%) 04/20(20%) Involvement of brain and spine n/t(%) Normal MRI Involvement of brain(brainstem, hypothalamus, periaqueductal region, pericallosal) Involvement of spine(>3segments) Involvement of Both brain and spine 1/20(5%) 1/20(5%) 6/20(30%) 12/20(60%) CSF Nucleated cells (cells/dl), mean ± SD 48.55 ± 114.57 Protein (mg/dl), mean ± SD 62.90± 57.79 OCB present 1/20(5%) VEP n/t(%) Bilateral anterior optic pathway dysfunction Unilateral anterior optic pathway dysfunction Normal 15/20(75%) 1/20(5%) 4/20(20%) 20

Twenty Neuromyelitis optica and spectrum patients (13 female, 7males) were studied whose ages ranged from 17 to 68 years (mean 34.35±14.95). The Kurtzke EDSS scores ranged from 0 to 9 with 16 were mild, 1(5%)patient had moderate score and 3(15%) had severe scores. A total of 15 patients (75%) were in remission and 5(25%) patients were having active disease during autonomic function testing. In our study NMO were 16 patients and Nmo spectrum were 4. There was no significant correlation between the male and female patients for age, Kurtzke EDSS score, or duration of disease. TABLE 3 : Symptomatology Symptoms Symptomatology at active phase of disease /No. of patients Symptomatology at the time of ANF test /No. of patients** Gastrointestinal 19/20(95%) 16/20(80%) Genitourinary 17/20(85%) 14/20(70%) Secretomotor (sicca) 10/20(50%) 3/20(15%) Orthostatic intolerance 15/20(75%) 4/20(20%) Sexual dysfunction 7/20(35%) 7/20(35%) Sudomotor 16/20(80%) 13/20(65%) ** 15(75%) Patients were in remission at the time of ANF test Autonomic symptoms: 80% of the patients had autonomic dysfunction and there was no significant correlation with the patient age, duration of the disease or the EDSS score The symptoms at active phase of the disease correlating with the EDSS score. 21

The Autonomic systems which are involved in the study were gastrointestinal(80%), genitourinary (70%) sudomotor in 65% patients, sexual in 35%, orthostatic symptoms in 20% and secretomotor in 15%.These autonomic symptoms were very high during the active phase of the disease. The most common autonomic symptom was gastrointestinal(80%) out of m which constipation(60%) was the most common followed by fecal urgency(20%). In Urinary symptoms urinary urgency (35%) was the most common symptom and 20% patients still were catheterized due to severe Neurogenic bladder. The Gastrointestinal or urinary symptoms not correlated with age, duration or EDSS scores(relapse). In sudomotor symptoms, hypohidrosis was most reported symptom. Orthostatic symptoms present in 20% of the patients. sexual dysfunction (35%)predominantly erectile dysfunction was reported by male patients. TABLE 4: Severity and distribution of autonomic deficits in patients with NMO and NMO Spectrum disorders Autonomic function tests abnormalities, n (%) Total 16 /20 (80%) Cardiovagal 16/20(80%) Adrenergic 13/20(65%) Limited CASS(Composite autonomic system score) Limited CASS 4/20(20%) normal Limited CASS (1-3), n (%) 16/20(80%) Limited CASS (4-6), n (%) 0/20(0) Limited CASS (6-10), n (%) 0(0) *** limited CASS done as SSR data not available in all patients 22

TABLE 5 : Blood pressure changes in Valsalva maneuver in patients with NMO and NMO Spectrum disorders: Exaggerated early blood pressure phase 2 fall, n/t (%) 20mmHg(normal) 17/20(85%) 20-40 mm Hg 2/20 (10%) 40 mm Hg 1/20(5%) Normal late phase 2 response, n/t (%) 10/20(50%) Blunted late phase 2 response, n/t (%) 10/20(50%) Normal phase 4 blood pressure over shoot, n/t (%) Absent phase 4 blood pressures over shoot, n/t (%) POTS(postural orthostatic tachycardia syndrome(n) 12/20(60%) 8/20(40%) 2/20(10%) TABLE 6 : Abnormalities in head up tilt table test in patients with NMO and NMO Spectrum disorders Orthostatic hypotension n/t (%) Present 3/20 (15%),2/3 were symptomatic Absent 17/20(85%) Autonomic function tests: Postural hypotension; 3 patients had postural hypotension(15%) out of which 2 patients were symptomatic 23

Figure 3 : A- showing patient having POTS with increase in heart rate but no change in BP B-. Showing the patient with postural hypotension. A B sympathetic cardiovascular Dysfunction: Sympathetic CV dysfunction found in 5(25%) of our patients, out of which 2 were symptomatic. Postural orthostatic tachycardia syndrome was present in 2 patients (10%). There was no significant association between duration of disease or EDSS scores. 24

TABLE 7 :Severity of adrenergic score in patients with NMO and NMO spectrum disorders: Adrenergic score n/t(%) 0 7/20(35%) 1 12/20(60%) 2 1/20(5%) 3 0/20(0) 4 0/20(0) TABLE 8 : Heart rate variability with deep breathing and valsalva ratio in patients with NMO and NMO Spectrum disorders Heart rate variation with deep breathing n/t (%) Normal 5/20(25%) Decreased 50% of minimum 8/20(40%) Decreased 50 % of minimum 7/20(35%) Valsalva ratio, n/t (%) Normal 7/20(35%) Decreased 50% of minimum 4/20(20%) Decreased 50 % of minimum 9/20(45%) parasympathetic cardiovascular dys function: Sinus arrhythmia were abnormal in 15(75%) patients. Valsalva ratio were abnormal in 13 patients(65%). But they were not correlating with the duration of disease or EDSS scores. This could probably due to the fact that majority of our patients in the study were in 25

remission with low EDSS scores. There was significant correlation between the test groups and the controls(p value0.004). TABLE 9 :Severity of cardiovagal dysfunction in patients with NMO and NMO Spectrum disorders Cardiovagal score n/t (%) 0 4/20(20%) 1 15/20(75%) 2 1/20(5%) 3 0(00) TABLE 10 : SSR dysfunction in patients with NMO and NMO Spectrum disorders SSR n/t (%) Present in both upper limbs and lower limbs 4/20 ** Absent in lower limbs 3/20(15%)** Absent in both lower limbs and upper limbs 0/20 ** SSR done in only 7 patients out of 20. 26

Sympathetic skin response: 15% patients showed absent SSR. The SSR was done only in 7 patients, out of which 4 were normal. The absent SSR found in 3 patients all are from the lower limbs only. There was significant correlation with the duration, activity of the disease or EDSS scores. Cardiovagal scores were abnormal in 16 patients(80%). All were of mild degree(1 to 3 scores). This was probably due to the fact that majority of the patients were in remission, Limited Composite autonomic system score was used in our study as the SSR data was not available in all of our patients. Limited CASS was abnormal in 16(80%) of the patients. Majority were in the mild score(1 to 3) due the reason that most of the patients were in remission. MRI changes including the brain and spinal cord were found in 12 (60%), only cord in 6 patients(30%) only brain in 1 patient. But there was no significant correlation with the disease duration or EDSS score as 75% patients were in remission. CSF analysis showed lymphocytic pleocytosis with mean of 48.5±114.5. The csf protein mean 62.9±57.70. OCB present only in 1 patient. There was no correlation with disease duration or EDSS scores. VEP (visual evoked potential) were abnormal in 80% of the patients. Only 4 patients had normal VEP who had only myelitis. The aquaporin antibodies and vasculitic markers were present in 4 patients(20%) of the patients. There was no correlation with disease duration and EDSS scores 27

TABLE 11 : Comparison of Heart rate variability parameters (assessed by power spectrum analysis) and Valsalva Ratio HRV variable Study group (n=20) Control group(n=10) P value LF nu at rest 46.58±18.11 141.25±223.7 0.392 HF nu at rest 30.29±25.74 22.24±26.26 0.767 LF nu at tilt 162.8±92.4 169.9±66.1 0.453 HF nu at tilt 30.29±28.75 20.37±28.38 0.02 Valsalva Ratio 1.47±0.41 1.89±0.35 0.011 RSA 9.88±7.64 18.95±5.38 0.004 Phase 2 drop in Valsalva (mm Hg) 82.05±18.67 97.80±23.59 0.05 28

FIGURE 3: Spectral analysis of heart rate variability At Rest(control) At Tilt(control) At Rest(patient) At Tilt(patient) Figure: The (top figure)control showed normal peak at high frequency which is reduced in the patient(lower figure) 29

DISCUSSION. There were no systematic studies looking at the severity, frequency of autonomic symptoms and spectrum of the autonomic dysfunction, even though the predilection for critical areas of autonomic nervous system pathways in these disorders. This the first study looking in to the severity, frequency of autonomic symptoms and severity of the autonomic dysfunction(2). Our study is a prospective study done on Neuromyelitis optica and spectrum disorders. 20 patients were studied(5 active and 15 were in remission). The symptoms related to autonomic dysfunction during the active phase of our study was high. The Gastrointestinal symptoms were 95% at active phase and at the time of autonomic function tests it was 80%. The Genitourinary symptoms were 85% at active phase and at the time of autonomic function tests it was 70%. The secretomotor symptoms were 50% at active phase and at the time of autonomic function tests it was only 15% The sexual symptoms was 35% both during active and during the the time of autonomic function tests. The orthostatic symptoms were 75% at active phase and at the time of autonomic function tests it was 20%. The sudomotor symptoms were 80% at active phase and at the time of autonomic function tests it was 65%. This variation of high frequency of symptoms during the active phase is due to involvement of the autonomic pathways both in the brain and the spinal cord. In MS the reported incidence of autonomic dysfunction ranges from 39 to 68%(28). The most common symptoms related to gastrointestinal (80%) system of which constipation was the most common symptom. In MS patients, the reported incidence ranges from 39 to 68% when compared to MS, our study has higher incidence. There was no correlation with disease duration and EDSS scores as 80% of our patients had low EDSS scores(24). The micturition symptoms (70%) of which urinary urgency was the most frequent symptom. They were not correlating with duration of disease or EDSS scores(29)(27))(30). The erectile impotence 30

was reported by 35% of the patients, mostly males. When compared to MS patients the reported range of incidence of erectile impotence is 26 to 72%. There was no significant correlation between duration of disease or EDSS scores or MRI changes in the brain or spinal cord. There was no significant correlation as majority of our patients(75%) were in remission. The sudomotor symptoms(65%) were not significantly associated with duration of disease or EDSS scores(33). Orthostatic symptoms were reported in 20% of our patients. The reported incidence in MS patients ranges from 0 to 49%. Orthostatic symptoms not significantly correlating with duration of disease or EDSS scores(34). There were no significant association between abnormalities of autonomic function tests, autonomic symptoms, age, sex or disease duration. In MS also there was no relationship between abnormal autonomic function tests and clinical features(28). Parasympathetic cardiovascular tests were abnormal in 80% of the our patients. The reported incidence from MS patients ranging from 23 to 80%. In MS the parasympathetic dysfunction was related to progression of disability where as sympathetic dysfunction was related to clinical activity of disease. In our study the abnormalities of parasympathetic cardiovascular autonomic function tests were not significantly associated with duration of disease or EDSS scores(29). Sinus arrhythmia was found abnormal in 75% of our patients and the reported data from MS patients ranges from 13 to 80%. The Valsalva ratio found abnormal in 65% patients and the reported incidence in MS patients ranges from 0 to 21%(33)(8)(35). Sympathetic cardiovascular tests were abnormal in 65% of our patients. In MS patients the reported incidence ranges from 13 to 60%. There was no significant association with duration of disease or EDSS scores. In MS the sympathetic CV dysfunction correlated with clinical activity of the disease(36). Postural hypotension was present in 3 patients(15%) in our study out of which 2 were symptomatic. Both patients had severe disability on EDSS score(9)(7). In MS the reported incidence ranges 31

from 7 to 14%. POTS (postural orthostatic tachycardia ) present in 2 patients in our study which were asymptomatic clinically(33). The parasympathetic cardiovascular abnormality rates more common than sympathetic cardiovascular function abnormality. In MS, the reported incidence of sympathetic and parasympathetic cardiovascular autonomic function test abnormalities were similar(34).. There was no correlation between cardiovascular symptoms and autonomic tests of cardiovascular function except for 2patients who symptomatic orthostatic hypotension (38)(39)(37). SSR abnormalities found in 15% of our patients. In MS the reported incidence ranges from 53 to 94%. In our study the SSR was done only in 7 patients, out of which 3 were abnormal(40)(39)(41)(42). The limited CASS was abnormal in 80% of our patients and score was of mild(1to3). There was no significant correlation between disease duration or EDSS scores(43)(44)(45). Power spectrum analysis of heart rate variability was done by using the Fourier analysis of regular beat-to beat intervals(r-r) which were recorded for 5 minutes and converted into a continuous function by linear interpolation and resample at 5 Hz. In power spectrum, LF indicates predominantly sympathetic and HF indicates Parasympathetic activity. In normal population, HF>LF during rest and LF>HF during standing or tilt. In our study (NMO and spectrum patients) we found that HF spectrum at tilt was low and it indicates parasympathetic dysfunction predominantly(46). In our study the involvement of brain and spinal cord( 3segments) present in 60% of the patients. The involvement of the specific areas of autonomic nervous system areas leads to autonomic dysfunction in these patients. The EDSS scores at admission correlated with the MRI changes(p value<0.05) but it was not correlating during the remission(17)(21)(39). There are review of literatures in autonomic dysfunction in multiple sclerosis. Even though the literature showed involvement of autonomic areas in brain and spinal cord in NMO and spectrum disorders, but the studies were not done to show the frequency and severity of involvement of autonomic dysfunction. In our study we found that 32

the incidence of autonomic dysfunction was more when compared to MS. So more studies are required to establish the severity and frequency of autonomic dysfunction. Limitations of our study: 1 Small sample size. 2 Majority of the patients were in remission with low EDSS scores 3 SSR not done in all patients 4 modified COMPASS score not done. 5 QSART not included in the study This was the first study looking at the severity, frequency of autonomic symptoms and severity of dysfunction of autonomic function tests. The majority of the patients were in remission, so future prospective studies were required to look into the autonomic dysfunction during different phases of the disease. 33

CONCLUSIONS: 1. The prevalence of Autonomic dysfunction is high in Neuromyelitis Optica and Spectrum disorders found to be 80% of patients during remission and 95% during the active phase. 2. The parasympathetic cardiovascular abnormality (80%) more common than sympathetic cardiovascular function abnormality (65%). 3. The cardiovascular, gastrointestinal, sudomotor, secretomotor and sexual dysfunction likely due to damage to the autonomic nervous system regulatory areas in the brain and spinal cord. The autonomic symptom abnormalities were 95% at relapse and 80% during remission. 4. There was correlation between between EDSS scores at active phase with MRI involvement in specific areas of brain and spinal cord (hypothalamus, area postrema, midbrain and periventricular areas). 5 Spectral analysis of Heart Rate Variability showed parasympathetic autonomic dysfunction. 34

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ANNEXURES DATA COLLECTION PROFORMA ANS dysfunction in NMO and spectrum disease Name: Address: Hospital Number: Telephone/E-mail: DOB: Age: Seen by: History Co-morbidities : Hypertension General Examination: Diabetes IHD Temp: Pulse: Obesity reg/irreg Renal failure Blood pressure: Multiple sclerosis lying/ sitting/ standing/ Height: Weight: BMI : 41

Autonomic questionairre COMPASS 31 1. In the past year, have you ever felt faint, dizzy, goofy, or had difficulty thinking soon after standing up from a sitting or lying position? 1 Yes 2 No (if you marked No, please skip to question 5) 2. When standing up, how frequently do you get these feelings or symptoms? 1 Rarely 2 Occasionally 3 Frequently 4 Almost Always 3. How would you rate the severity of these feelings or symptoms? 1 Mild 2 Moderate 3 Severe 4. In the past year, have these feelings or symptoms that you have experienced: 1 Gotten much worse 2 Gotten somewhat worse 3 Stayed about the same 4 Gotten somewhat better 5 Gotten much better 6 Completely gone 5. In the past year, have you ever noticed color changes in your skin, such as red, white, or purple? 1 Yes 2 No (if you marked No, please skip to question 8) 6. What parts of your body are affected by these color changes? (Check all that apply) 1 Hands 2 Feet 7. Are these changes in your skin color: 1 Getting much worse 2 Getting somewhat worse 3 Staying about the same 4 Getting somewhat better 5 Getting much better 6 Completely gone 42

8. In the past 5 years, what changes, if any, have occurred in your general body sweating? 1 I sweat much more than I used to 2 I sweat somewhat more than I used to 3 I haven t noticed any changes in my sweating 4 I sweat somewhat less than I used to 5 I sweat much less than I used to 9. Do your eyes feel excessively dry? 1 Yes 2 No 10. Does you mouth feel excessively dry? 1 Yes 2 No 11. For the symptom of dry eyes or dry mouth that you have had for the longest period of time, is this symptom: 1 I have not had any of these symptoms 2 Getting much worse 3 Getting somewhat worse 4 Staying about the same 5 Getting somewhat better 6 Getting much better 7 Completely gone 12. In the past year, have you noticed any changes in how quickly you get full when eating a meal? 1 I get full a lot more quickly now than I used to 2 I get full more quickly now than I used to 3 I haven t noticed any change 4 I get full less quickly now than I used to 5 I get full a lot less quickly now than I used to 13. In the past year, have you felt excessively full or persistently full (bloated feeling) after a meal? 43