Ivan Adamec

Autonomic dysfunction in multiple sclerosis

Multiple sclerosis (MS) is the leading cause of neurological disability in young adults. Since the pathophysiology of MS is characterized by dissemination in space, as well as in time, the autonomic nervous system is inevitably damaged in the course of the disease in many patients and the proportion of affected patients increases with disease duration. Autonomic dysfunction (AD) in MS is explained by lesions in regions responsible for autonomic regulation such as nuclei in the periventricular region of fourth ventricle in the brainstem as well as medullar lesions. Reports about frequency of AD in MS patients vary notably between groups. Nevertheless its impact on quality of life is substantial but, unfortunately, often overlooked. The aim of this article is to present a concise review of various symptoms and signs of autonomic system dysfunction in MS.

Ocular and Cervical Vestibular Evoked Myogenic Potentials in Patients With Multiple Sclerosis

Objectives: The aim of this study was to evaluate latencies and corrected p13-n23 cervical vestibular evoked myogenic potentials (cVEMP) and n10-p13 ocular vestibular evoked myogenic potentials (oVEMP) amplitudes in patients with relapsing remitting multiple sclerosis (MS). Methods: This was a prospective, case-control study. Thirty patients with MS and 15 healthy controls were included. Cervical vestibular evoked myogenic potentials and oVEMP in response to acoustic clicks of 1 ms duration at the intensity of 130 dB SPL and the stimulation frequency of 1 Hz were studied. Signals were divided in segments of 120 ms duration (20 ms before the stimulus and 100 ms after the stimulus) and averaged. Results: In MS group, there was significant latencies prolongation of all sternocleidomastoid responses (p13 and n23) and n10 response of the ocular muscles. The sternocleidomastoid p13-n23 normalized amplitude was significantly higher in MS patients. Prolonged latencies were found in 57% and conduction block in 7% of patients in at least one sternocleidomastoid response in the MS group. Prolonged latencies were found in 30% and conduction block in 40% of patients in at least one ocular response in the MS group. When cVEMP and oVEMP are combined, 80% had pathological finding. When correlating brainstem clinical, brainstem MRI, and cVEMP findings, there was no statistical significance (brainstem clinical vs. cVEMP P = 0.1; brainstem MRI vs. cVEMP P = 0.82). When correlating brainstem clinical, brainstem MRI and oVEMP findings, there was a statistical significant correlation between brainstem clinical versus oVEMP, P = 0.02, whereas there was no statistical significance between brainstem MRI versus oVEMP (P = 0.38). Conclusions: Combination of cVEMP and oVEMP in MS patients allows better estimation of brainstem lesions.

Alemtuzumab long-term immunologic effect: Treg suppressor function increases up to 24 months

Objective: To analyze changes in T-helper (Th) subsets, T-regulatory (Treg) cell percentages and function, and mRNA levels of immunologically relevant molecules during a 24-month follow-up after alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Multicenter follow-up of 29 alemtuzumab-treated patients with RRMS in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and CARE-MS II trials. Peripheral blood (PB) samples were obtained at months 0, 6, 12, 18, and 24. We evaluated (1) mRNA levels of 26 immunologic molecules (cytokines, chemokines, chemokine receptors, and transcriptional factors); (2) Th1, Th17, and Treg cell percentages; and (3) myelin basic protein (MBP)–specific Treg suppressor activity. Results: We observed 12 relapses in 9 patients. mRNA levels of the anti-inflammatory cytokines interleukin (IL)–10, IL-27, and transforming growth factor–β persistently increased whereas those of proinflammatory molecules related to the Th1 or Th17 subsets persistently decreased after alemtuzumab administration throughout the follow-up period. PB CD4+ cell percentage remained significantly lower than baseline while that of Th1 and Th17 cells did not significantly change. A significant increase in Treg cell percentage was observed at month 24 and was accompanied by an increase in Treg cell suppressive activity against MBP-specific Th1 and Th17 cells. Conclusions: The long-lasting therapeutic benefit of alemtuzumab in RRMS may involve a shift in the cytokine balance towards inhibition of inflammation associated with a reconstitution of the PB CD4+ T-cell subsets that includes expansion of Treg cells with increased suppressive function.

Spinal cord tumor versus transverse myelitis

BACKGROUND CONTEXT Longitudinally extensive transverse myelitis (LETM) is one of the defining features of neuromyelitis optica (NMO). Despite the well-established criteria, clinical and paraclinical features, the disease is often misdiagnosed and erroneously treated. PURPOSE We report on a case of LETM in a patient with spatially limited NMO spectrum disorder that was misdiagnosed as spinal cord tumor and underwent spinal cord biopsy. STUDY DESIGN A 43-year-old female patient is described. METHODS The patient developed spastic tetraparesis over 1 week. Spinal cord magnetic resonance imaging (MRI) revealed LETM, and she was treated with steroids and recovered. Nine months later, her condition worsened and repeat spinal cord MRI was interpreted as a large intramedullary tumor in the cervical region with irregular postcontrast enhancement. Biopsy revealed demyelination. Cerebrospinal fluid (CSF) analysis revealed positive oligoclonal IgG bands, and serum was positive for NMO-IgG antibody. RESULTS The patient was diagnosed with spatially limited NMO spectrum disorder, treated with plasma exchange, high-dose corticosteroids, and cyclophosphamide, and with good recovery. CONCLUSIONS The factors favoring inflammatory LETM are acute or subacute onset of clinical symptoms, positive oligoclonal bands in the CSF, positive NMO-IgG or other antibodies, and brain MRI showing demyelinating lesions. Postcontrast axial MRI sequences of the spinal cord can also be helpful. In doubtful situations, a trial of therapy and follow-up MRI a month later might be a more prudent approach if the patient is not rapidly deteriorating.

Auditory evoked potentials and vestibular evoked myogenic potentials in evaluation of brainstem lesions in multiple sclerosis

OBJECTIVE The aim of this study was to determine the roles of magnetic resonance imaging (MRI), auditory evoked potentials (AEP) and vestibular evoked myogenic potentials (VEMP) in the evaluation of brainstem involvement in multiple sclerosis (MS). PATIENTS AND METHODS Altogether 32 patients with the diagnosis of MS participated in the study. The following data was collected from all patients: age, gender, Expanded Disability Status Scale (EDSS) score, brainstem functional system score (BSFS) (part of the EDSS evaluating brainstem symptomatology), and involvement of the brainstem on the brain MRI. AEP and ocular VEMP (oVEMP) and cervical VEMP (cVEMP) were studied in all patients. RESULTS BSFS, MRI, AEP, oVEMP and cVEMP involvement of the brainstem was evident in 9 (28.1%), 14 (43.8%), 7 (21.9%), 12 (37.5%) and 10 (31.0%) patients, respectively. None of the tests used showed statistically significant advantage in the detection of brainstem lesions. When combining oVEMP and cVEMP 18 (56.3%) patients showed brainstem involvement. This combination showed brainstem involvement in greater percentage than BSFS or AEP, with statistical significance (p=0.035 and p=0.007, respectively). CONCLUSION VEMP is a reliable method in detection of brainstem involvement in MS. It is comparable with MRI, but superior to clinical examination or AEP.

Assessment of prevalence and pathological response to orthostatic provocation in patients with multiple sclerosis.

OBJECTIVE The aim of this study was to determine the prevalence of pathologic response to orthostatic challenge in patients with relapsing remitting multiple sclerosis (RRMS) and the difference of the response in patients in relapse and remission. PATIENTS AND METHODS We included 112 RRMS patients; group 1 included 53 patients in a relapse and group 2, 59 patients in remission. The head up tilt table test was used to provoke an orthostatic reaction. RESULTS 71 (63%) patients (60.4% and 66% of relapse and remission subjects respectively) had a pathological response to orthostatic provocation. Syncope was found in 9 (17%) patients in group 1 compared to 22 (37.3%) in group 2 (p=0.014). Postural orthostatic tachycardia syndrome (POTS) was found in 17 (32%) patients in group 1 compared to 4 (6.8%) in group 2 (p=0.001). There was a significantly negative correlation between the Expanded Disability Status Scale (EDSS) and POTS (-0.201; p=0.034) and a positive correlation between the EDSS and syncope (0.190; p=0.044). CONCLUSION The prevalence of distinct types of orthostatic autonomic dysfunction in different phases of RRMS seems to be in direct correlation with the EDSS. Furthermore, certain autonomic dysfunctions of orthostasis, more specifically syncope and POTS, tend to be increased in remission and relapse respectively.

Postural orthostatic tachycardia syndrome associated with multiple sclerosis

BACKGROUND The aim of this study was to determine if there is a difference in the frequency of postural orthostatic tachycardia syndrome (POTS) in patients with multiple sclerosis (MS) compared to patients with symptoms of orthostatic intolerance and with no evidence of MS or other neurological illness. METHODS We analyzed data gathered from 293 patients who underwent the head-up tilt table test protocol. Group 1 included prospectively analyzed 112 with MS and group 2 included retrospectively analyzed 181 patients who were evaluated because of symptoms of orthostatic intolerance, and with no evidence of MS or other neurological illness. If POTS was identified the head-up tilt table test was repeated and supine as well as standing serum epinephrine and norepinephrine were determined. RESULTS POTS was identified in 39 patients: 21 (19%) in the MS group comparing to 18 (10%) in the non MS group (p=0.035). There was no difference between groups in the occurrence of POTS associated syncope (p=0.52). There was no difference between groups in the epinephrine or norepinephrine in supine and standing positions. While both standing epinephrine and norepinephrine levels were significantly higher compared to levels in the supine position in the non MS group, only standing norepinephrine levels were significantly higher in the MS group. CONCLUSIONS The results of this study suggest that POTS is associated with MS.

Autonomic dysfunction in clinically isolated syndrome suggestive of multiple sclerosis

OBJECTIVES The aim of this study was to determine the extent of autonomic dysfunction in patients with clinically isolated syndrome (CIS) by using a standardized battery of autonomic tests in the form of the Composite Autonomic Scoring Scale (CASS). METHODS This was a prospective, cross sectional study which included 24 consecutive patients who were diagnosed with CIS and 17 healthy controls. In all participants, heart rate and blood pressure responses to the Valsalva maneuver, heart rate response to deep breathing and blood pressure response to passive tilt were performed. In 16 patients, Quantitative Sudomotor Axon Reflex Test (QSART) and catecholamine measurement was performed. RESULTS The proportion of CIS patients with pathological adrenergic index was statistically significantly higher compared to healthy controls (12 vs 2, p=0.018), while there was no difference in cardiovagal index between groups. Five patients had a sudomotor index of 1 (in 4 there was hypohydrosis <50% and in 1 persistent foot hyperhidrosis). When combining adrenergic, cardiovagal and sudomotor index into CASS, 8 patients (50%) had evidence of autonomic dysfunction, 7 mild and one moderate. CONCLUSION Sympathetic nervous system is frequently affected in CIS patients. SIGNIFICANCE CASS is able to detect autonomic nervous system dysfunction in CIS patients.

Primary position upbeat nystagmus

Primary position upbeat nystagmus is a rare clinical finding. We report a patient with clinically isolated syndrome suggestive of multiple sclerosis who presented with primary position upbeat nystagmus. MRI revealed a demyelinating lesion in the lower medulla, which affected the nucleus intercalatus; this type of lesion inhibits the flocculovestibular inhibitory pathway, thereby causing upbeat nystagmus. Nystagmus still persisted after pulsed corticosteroid therapy. This could be due to a loss of central adaptation of the vestibulo-ocular system in our patient, because of more diffuse brainstem damage, shown on vestibular-evoked myogenic potentials as delayed latencies on both sternocleidomastoid muscles and a conduction block for the left extraocular muscles.

The Role of Cervical and Ocular Vestibular- Evoked Myogenic Potentials in the Follow-Up of Vestibular Neuritis

This study evaluates the recovery of vestibular nerve function after vestibular neuritis (VN) by vestibular-evoked myogenic potentials (VEMPs). Twenty-six patients with the diagnosis of VN were included. All patients underwent ocular VEMP (oVEMP) and cervical VEMP (cVEMP) recordings, at 6 days and 6 months from the onset of the symptoms. Of the 26 patients, 14 showed improvement on oVEMP at month 6 (group 1), and 12 showed no change or worsening on oVEMP at 6 months (group 2). At the same time, there was no change in the amplitudes of the cVEMP on either healthy or affected sides in both groups. Inability to perform the Fukuda test, and chronic white matter supratentorial lesions present on brain magnetic resonance imaging (MRI) were more frequent in patients with worse outcome on oVEMP (P = 0.044 and 0.045, respectively). Although involvement of the inferior branch of the vestibular nerve was not associated with oVEMP outcome, oVEMP latencies (N10 and P13) were associated with improvement or worsening in oVEMP amplitudes, showing that prolonged latencies correlate with 6-month improvement in oVEMP amplitudes (Pearson correlation −0.472, P = 0.041 and −0.580, P = 0.009, respectively). This study identified clinical, MRI and neurophysiological predictors of recovery in patients with superior VN, and offers additional insight into, and better understanding of, the role of VEMP in diagnosis and prognosis of patients with VN. Further studies are needed to validate this diagnostic procedure and to assess its clinical usefulness in VN management.