Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.

Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date

Aquaporins: important but elusive drug targets.

The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators

Aquaporin water channels in the nervous system.

The aquaporins (AQPs) are plasma membrane water-transporting proteins. AQP4 is the principal member of this protein family in the CNS, where it is expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation. AQP1 is expressed in the choroid plexus, where it facilitates cerebrospinal fluid secretion, and in dorsal root ganglion neurons, where it tunes pain perception. The AQPs are potential drug targets for several neurological conditions. Astrocytoma cells strongly express AQP4, which may facilitate their infiltration into the brain, and the neuroinflammatory disease neuromyelitis optica is caused by AQP4-specific autoantibodies that produce complement-mediated astrocytic damage

Über eine Klasse polynomialer Scharen selbstadjungierter Operatoren im Hilbertraum

HEK293A cells expressing either mouse MOG (mMOG) or rat MOG (rMOG) C terminally tagged with EGFP. (DOCX 2792 kb

Pediatric multiple sclerosis: update on diagnostic criteria, imaging, histopathology and treatment choices

Pediatric multiple sclerosis (MS) represents less than 5% of the MS population, but patients with pediatric-onset disease reach permanent disability at a younger age than adult onset patients. Accurate diagnosis at presentation and optimal long-term treatment is vital to mitigate ongoing neuroinflammation and irreversible neurodegeneration. However, it may be difficult to early differentiate pediatric MS from acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica spectrum disorders (NMOSD) as they often have atypical presentation that differs from that of adult-onset MS. The purpose of this review is to summarize the updated views on diagnostic criteria, imaging, histopathology and treatment choices

What Good Is EMG to the Patient and Practitioner?

ABSTRACT Electromyography (EMG) and nerve conduction studies (NCS) are not only tests to be performed in isolation and reported without consideration of the clinical context, but rather form part of what has been referred to as the electrodiagnostic consultation. Using all of the pertinent information available to the electromyographer performing the test, the electrodiagnostic consultation strives toward the goal of helping the patient and the referring physician to establish a correct diagnosis. Although not without limitations, EMG as an extension of the clinical history and physical examination can be a powerful and sensitive diagnostic tool. Like any tool, however, the final result depends on the skill and expertise with which it is wielded. KEYWORDS: Electromyography (EMG), nerve conduction studies (NCS), electrodiagnosis, neuromuscular disease, diagnostic testing Electromyography (EMG) is the part of electrodiagnostic medicine consisting of recording the variations of electric potential or voltage detected by a needle electrode inserted into skeletal muscle. This electric activity is displayed on a monitor and played over a loudspeaker for simultaneous visual and auditory analysis. In normal resting muscle little or no electric activity is detected, but during voluntary contraction the action potentials of motor units appear. In disorders of the motor unit, electric activity of various types may appear in resting muscle, and the action potentials of the motor units may have abnormal forms and patterns of activity. Abnormalities of the EMG serve as objective criteria of dysfunction of the motor unit. These abnormalities may characterize the nature of the disease process and its localization in the neuron, neuromuscular junction, or muscle fibers. Critical to understanding the role of electrodiagnostic testing in clinical medicine is a clear realization that EMG is an extension of the neurologic examination. SEMINARS IN NEUROLOGY/VOLUME 23, NUMBER 3 2003 Electromyography Terms Motor unit: The anatomic element consisting of an anterior horn cell, its axon, the neuromuscular junctions, and all the muscle fibers innervated by the axon. Insertion activity: Electric activity caused by insertion or movement of a needle electrode within a muscle. Spontaneous activity: Electric activity recorded from muscle at rest after insertion activity has subsided and when there is not voluntary contraction or an external stimulus. Fibrillation potential: The action potential of a single muscle fiber occurring spontaneously or after movement of a needle electrode. Usually fires at a constant rate. Fasciculation potential: The electric activity associated with a fasciculation that has the configuration of a motor unit action potential but occurs spontaneously. Voluntary activity: In EMG, the electric activity recorded from a muscle with consciously controlled contraction. Motor unit action potential (MUAP or MUP): The compound action potential of a single motor unit whose muscle fibers lie within the recording range of an electrode. The following measures may be specified after the recording electrode is placed in the muscle: configuration (including amplitude, duration, number of phases, polarity of each phase, number of turns, variation of shape with consecutive discharges, presence of satellite potentials, spike duration, and rise time) and recruitment characteristics (including threshold of activation, onset frequency, and recruitment frequency-allowing classification into normal, reduced, or rapid recruitment categories). Activation: The process of motor unit action potential firing, with the force of muscle contraction being determined by the number of motor units firing and their firing rate. Nerve Conduction Study Terms Nerve conduction studies: Recording and analysis of electric waveforms of biologic origin elicited in response to electric stimuli. In a patient with weakness, is there evidence of disease of the neuromuscular junction? Routine NCS are often normal in postsynaptic defects of neuromuscular transmission, such as autoimmune myasthenia gravis, whereas presynaptic disorders such as the LambertEaton myasthenic syndrome often show low-amplitude CMAPs in a patient with global hyporeflexia. Special techniques such as slow (typically 2 to 3 Hz) repetitive stimulation of distal and proximal muscle nerves often demonstrate a characteristic abnormal pattern of amplitude and area decrement that correlates with defective neuromuscular transmission. One group of patients that has caused confusion for electromyographers and referring clinicians alike is the cohort with symptoms and often signs of apparent weakness in whom the EMG and NCS are normal. Some of these individuals have poor activation because of pain in the region being tested; a few simple questions and observations of the patient's behavior help the examiner determine whether this is likely to be the case. A second group with poor activation is those who have central nervous system disorders such as stroke, myelopathy, or multiple sclerosis. These individuals invariably have physical findings and other symptoms to corroborate these central disorders that may be interfering with voluntary activation due to upper motor neuron or extrapyramidal pathway dysfunction. Others may not be able to activate fully because of disuse, malnutrition, or prolonged corticosteroid use. A fourth category is those who do not fully activate voluntary muscle for psychological reasons; the absence of pain, lack of central nervous system signs and symptoms, and dearth of other physical factors can lead to their identification. Similarly, the few individuals who are consciously feigning weakness or other deficits for secondary gain usually have no severe pain, spasticity, or other findings that provide a reasonable medical explanation for their lack of voluntary muscle activation. Muscle Wasting In a patient with muscle wasting, EMG can assist in determining whether there may be a neuromuscular explanation. Remembering that electrodiagnostic testing extends the reach of the clinical history and examination; the presence, pace of acquisition, and distribution of neurologic deficits can aid the electromyographer in characterizing which elements of the motor unit, if any, may be involved in the wasted patient at hand. As discussed before, patterns of abnormal findings on NCS and EMG suggest either myopathy, neuromuscular junction disease, neuropathy or motor neuronopathy, or, alternatively, that there is no convincing evidence of disease of muscle, nerve, neuromuscular junction, or anterior horn cell. In the latter case, historical and physical examination clues often point the clinician toward either disuse as an explanation of the muscle wastingwhich may be physical, psychological, or a combination-or toward weight loss associated with underlying medical disease such as cancer, infection (human immunodeficiency virus being one example), diabetic cachexia, or malnutrition associated with anorexia. Fixed Sensory Loss Another category of patient that is effectively interrogated by NCS techniques is that of sensory loss or other persistent sensory symptoms. Sensory NCS can indicate whether or not there is evidence of large-diameter dorsal root ganglion cell or large-caliber sensory axon disease in a particular nerve territory or in a widespread distribution throughout the body. 9 One important observation regarding the individual with clinical sensory loss and normal sensory NCS results is that either the neuropathy affects only small-diameter fibers (so-called small fiber sensory neuropathy), the lesion is central (affecting the dorsal column pathway, for example), 10 or the process is nonorganic. QUESTIONS NOT LIKELY TO BE ANSWERED BY EMG AND NCS Although EMG and NCS can often pinpoint and characterize disease of the peripheral nervous system with clarity and quantitative precision, there are times when the electrodiagnostic methods do not provide a specific answer to the question posed by the referring physician. There are a number of situations that fall into this category. The first is that the referral question is too general, such as "neurologic disease?," "gait disorder?," "weakness?," "fatigue?," or "total body pain?" Part of the reason that some referring physicians make such general requests of electrodiagnostic medicine is lack of familiarity with the testing procedures. To use an example familiar to the majority of physicians, in electrocardiography (ECG), the testing procedures are very uniform, with standardized electrode placement and recording techniques that are virtually identical for every patient undergoing an ECG test. For NCS, on the other hand, the breadth of techniques as well as nerves and muscles capable of being tested is staggering. More than 30 nerves in the face, neck, thorax, upper limb, and lower limb can be assessed using NCS techniques, some with SEMINARS IN NEUROLOGY/VOLUME 23, NUMBER 3 2003 multiple different methods of stimulation and recording. Another reason that EMG may not help the referring provider is that the symptoms may be too recent. In many acute neurogenic processes, for example, NCS abnormalities and all but the most subtle EMG changes are not apparent until 10 to 14 days after the inciting event. In this situation, it is usually more useful to wait at least 2 weeks after onset of acute neurologic symptoms before considering EMG. EXPERIENCING ELECTROMYOGRAPHY AND NERVE CONDUCTION STUDIES Nerve Conduction Studies Perhaps the best way to understand the procedures that patients undergo during EMG and NCS is to experience the testing first hand. During motor NCS, metal electrode disks are taped to the skin overlying the motor point of the muscle being examined. Graded electric stimuli are then delivered first to the proximal limb site of the nerve and then, after several seconds, to the distal limb site of the nerve. The responses are recorded at each site and then measured either manually on paper or by computer for amplitude, latency, and other factors. The NCV is calculated dividing the distance between the two stimulation sites by the time required for the response to traverse the path between them (velocity = distance/time). For sensory NCS, both the stimulation and recording sites overlie the sensory nerve trunk being investigated. A special case arises when the electrodiagnostic medicine specialist is asked to evaluate for the possibility of a neuromuscular junction defect a patient who is currently taking an anticholinesterase medication such as pyridostigmine. In this case, testing is best postponed until the subject can suspend the anticholinesterase agent for at least 8 and preferably 12 hours (if the subject can do so without compromising bulbar function, which is usual for individuals being evaluated for possible myasthenia gravis) so as to avoid a false-negative test result. Electromyography Needle EMG is typically performed by inserting a fine single-use concentric needle electrode (some practitioners prefer monopolar electrodes) just under the surface of the skin into a skeletal muscle. With the muscle at rest, insertional activity is assessed by making multiple tiny advances of the electrode, each a fraction of a millimeter in distance, through the muscle. What are the unintended consequences of performing EMG and NCS? The only recognized general effects of percutaneous NCS are the transient discomfort and apprehension associated with delivery of brief electric shocks to the skin. These stimuli, which are typically 0.01 to 1 msec in duration and between 0 and 100 mA in current strength, are felt as surprising, make the stimulated limb jerk slightly because of activation of innervated and nearby muscles, and are felt as uncomfortable to slightly painful, especially in proximal sites such as the popliteal fossa, supraclavicular fossa, neck, and mastoid region. Although most patients do not regard NCS as more than a minor discomfort, the average 10-point visual analog scale rating of 300 consecutive patients being 3, a few individuals cannot tolerate the procedure and request that testing be discontinued. With the theoretical exception that proximal upper limb stimulation in patients with indwelling central venous catheters or other artificial current paths to the heart might induce malignant cardiac dysrhythmias or activate an implanted defibrillator, there are no known longterm complications of percutaneous NCS. Although infection precautions are the customary practice in modern electrodiagnostic laboratories, there are few if any data regarding the incidence of infection associated with EMG. In most clinical settings disposable electrodes are used for all routine EMG studies. Platinum single-fiber EMG electrodes are sterilized by gas or autoclave employing the same methods used for surgical instruments. In addition, special precautions, including use of disposable NCS electrodes, are taken with patients known to be infected with agents such as hepatitis B virus, hepatitis C virus, CreutzfeldtJakob disease, and human immunodeficiency virus. EMG REPORTING After having read hundreds of EMG reports written at scores of laboratories throughout North America over the last two decades, it is apparent that many electromyographers have difficulty putting together succinct, clearly written summaries and interpretations. Some of this problem may stem from a desire to report on every finding in order to be complete. Another possible reason may be that some electromyographers are uncertain whether a given result is or is not clinically significant and therefore conclude that if every tidbit of information is cataloged in laundry list fashion, no important observation will be excluded even if several superfluous or unimportant details end up cluttering the report. The EMG report should be terse, to the point, and emphasize clinically relevant findings. SEMINARS IN NEUROLOGY/VOLUME 23, NUMBER 3 2003 Here are the EMG results. It is up to you to decide whether they make sense or not." A far more useful approach is to summarize the abnormalities concisely, list any pertinent additional history or physical findings that the electromyographer elicits or observes at the time of the EMG, and finally make a determination of whether or not the findings explain the patient's symptoms and signs. What follow are a few examples of pairs of EMG reports. Each pair consists of a suboptimally crafted summary and interpretation (reports 1A, 2A, and 3A) and then a revised, more useful summary and interpretation of the same patient's EMG visit (reports 1B, 2B, and 3B). Example 1:The Cluttered Noncommittal Report Referral indication: paresthesia and pain. REPORT 1A Summary The left median antidromic sensory response amplitude was 10 µV (normal greater than 15 µV) with a conduction velocity of 53 m/s (normal greater than 54 m/s) and a distal latency of 4.5 ms (normal less than 3.6 ms). The left ulnar antidromic sensory response was 5 µV in amplitude (normal greater than 10 µV) with a conduction velocity of 51 m/s (normal less than 53 ms) and a distal latency of 3.3 ms (normal less than 3.2 ms). The left median/APB motor amplitude was 4.2 mV (normal greater than 4 mV) with conduction velocity of 49 m/s (normal greater than 48 m/s), a motor distal latency of 5.2 msec, and an F wave latency of 30 ms (normal less than 32 ms). The left ulnar/ADM motor amplitude was 6.1 mV (normal greater than 6 mV) with a conduction velocity of 47 m/s (normal greater than 51 m/s), a motor distal latency of 3.4 ms (normal less than 3.6 ms), and an F wave latency of 29.7 ms (normal less than 33 ms). The left fibular/EDB motor response was 1.0 mV in amplitude (normal greater than 2.0 mV) with a conduction velocity of 38 m/s (normal greater than 41 m/s), a motor distal latency of 5.0 ms (normal less than 6.6 ms), and no elicitable F waves. The left sural sensory response was 2.2 µV in amplitude (normal greater than 6 µV) with a distal latency of 4.6 ms (normal less than 4.5 ms). Concentric needle examination showed large motor unit potentials in the left first dorsal interosseous, abductor pollicis brevis, tibialis anterior, and medial gastrocnemius muscles with fibrillation potentials in the abductor hallucis muscles on both sides and a single train of positive sharp waves in the left low lumbar paraspinal muscles. Interpretation The EMG findings suggest either median ulnar, fibular, and tibial mononeuropathies (multiple mononeuropathies), polyneuropathy with su

Can we prevent or treat multiple sclerosis by individualised vitamin D supply?

Apart from its principal role in bone metabolism and calcium homeostasis, vitamin D has been attributed additional effects including an immunomodulatory, anti-inflammatory, and possibly even neuroprotective capacity which implicates a possible role of vitamin D in autoimmune diseases like multiple sclerosis (MS). Indeed, several lines of evidence including epidemiologic, preclinical, and clinical data suggest that reduced vitamin D levels and/or dysregulation of vitamin D homeostasis is a risk factor for the development of multiple sclerosis on the one hand, and that vitamin D serum levels are inversely associated with disease activity and progression on the other hand. However, these data are not undisputable, and many questions regarding the preventive and therapeutic capacity of vitamin D in multiple sclerosis remain to be answered. In particular, available clinical data derived from interventional trials using vitamin D supplementation as a therapeutic approach in MS are inconclusive and partly contradictory. In this review, we summarise and critically evaluate the existing data on the possible link between vitamin D and multiple sclerosis in light of the crucial question whether optimization of vitamin D status may impact the risk and/or the course of multiple sclerosis

Placebo-controlled study in neuromyelitis optica : ethical and design considerations

BACKGROUND: To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported. OBJECTIVE: To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical-scientific integrity. METHODS: We assessed the "standard of care" for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design. RESULTS: The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide. CONCLUSION: The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path

Screening for onconeural antibodies in neuromyelitis optica spectrum disorders

BACKGROUND: Some so-called “non-classical” paraneoplastic neurological syndromes (PNS), namely optic neuritis and myelitis, clinically overlap with neuromyelitis optica spectrum disorders (NMOSD), and conversely, in cancer-associated NMOSD, a paraneoplastic etiology has been suggested in rare cases. Therefore, we retrospectively investigated the prevalence of onconeural antibodies, which are highly predictive for a paraneoplastic etiology, and the prevalence of malignancies in NMOSD patients. METHODS: We retrospectively screened 23 consecutive patients from our clinic with NMOSD (13 were anti-aquaporin-4 [AQP4] antibody positive, 10 were AQP4 negative) for onconeural antibodies using an immunoblot. RESULTS: All patients were negative for a broad spectrum of antibodies targeting intracellular onconeural antigens (Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, Zic4, SOX1, Tr, and amphiphysin). Notably, only two patients had a malignancy. However, neoplastic entities (astrocytic brain tumor and acute myeloid leukemia) were not typical for PNS. CONCLUSIONS: Our data suggest that there is no need to routinely screen anti-AQP4 antibody positive NMOSD patients with a typical presentation for onconeural antibodies. Furthermore, absence of these antibodies in NMOSD, which is typically non-paraneoplastic, confirms their high specificity for PNS