Nils Erik Gilhus

Guidelines for treatment of autoimmune neuromuscular transmission disorders

Background:  Important progress has been made in our understanding of the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert–Eaton myasthenic syndrome (LEMS) and neuromyotonia (Isaacs’ syndrome).

Screening for tumours in paraneoplastic syndromes: report of an EFNS Task Force

Background:  Paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible.

EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases

Despite high‐dose intravenous immunoglobulin (IVIG) is widely used in treatment of a number of immune‐mediated neurological diseases, the consensus on its optimal use is insufficient. To define the evidence‐based optimal use of IVIG in neurology, the recent papers of high relevance were reviewed and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain‐Barré syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short‐term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended as a second‐line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third‐line therapy in relapsing–remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post‐partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (level A), stiff‐person syndrome (level A), some acute‐demyelinating diseases and childhood refractory epilepsy (good practice point).

Myasthenia gravis: subgroup classification and therapeutic strategies.

Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with myasthenia gravis should be classified into subgroups to help with therapeutic decisions and prognosis. Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis. Agrin-associated myasthenia gravis might emerge as a new entity. The prognosis is good with optimum symptomatic, immunosuppressive, and supportive treatment. Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are first-line immunosuppressive treatments. Additional immunomodulatory drugs are emerging, but therapeutic decisions are hampered by the scarcity of controlled studies. Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis.

Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force

A great variety of neurological diseases require investigation of cerebrospinal fluid (CSF) to prove the diagnosis or to rule out relevant differential diagnoses. The objectives were to evaluate the theoretical background and provide guidelines for clinical use in routine CSF analysis including total protein, albumin, immunoglobulins, glucose, lactate, cell count, cytological staining, and investigation of infectious CSF. The methods included a Systematic Medline search for the above‐mentioned variables and review of appropriate publications by one or more of the task force members. Grading of evidence and recommendations was based on consensus by all task force members. It is recommended that CSF should be analysed immediately after collection. If storage is needed 12 ml of CSF should be partitioned into three to four sterile tubes. Albumin CSF/serum ratio (Qalb) should be preferred to total protein measurement and normal upper limits should be related to patients’ age. Elevated Qalb is a non‐specific finding but occurs mainly in bacterial, cryptococcal, and tuberculous meningitis, leptomingeal metastases as well as acute and chronic demyelinating polyneuropathies. Pathological decrease of the CSF/serum glucose ratio or increased lactate concentration indicates bacterial or fungal meningitis or leptomeningeal metastases. Intrathecal immunoglobulin G synthesis is best demonstrated by isoelectric focusing followed by specific staining. Cellular morphology (cytological staining) should be evaluated whenever pleocytosis is found or leptomeningeal metastases or pathological bleeding is suspected. Computed tomography‐negative intrathecal bleeding should be investigated by bilirubin detection.

EFNS guideline on diagnosis and management of post-polio syndrome. Report of an EFNS task force.

Post‐polio syndrome (PPS) is characterized by new or increased muscular weakness, atrophy, muscle pain and fatigue several years after acute polio. The aim of the article is to prepare diagnostic criteria for PPS, and to evaluate the existing evidence for therapeutic interventions. The Medline, EMBASE and ISI databases were searched. Consensus in the group was reached after discussion by e‐mail. We recommend Halsteads definition of PPS from 1991 as diagnostic criteria. Supervised, aerobic muscular training, both isokinetic and isometric, is a safe and effective way to prevent further decline for patients with moderate weakness (Level B). Muscular training can also improve muscular fatigue, muscle weakness and pain. Training in a warm climate and non‐swimming water exercises are particularly useful (Level B). Respiratory muscle training can improve pulmonary function. Recognition of respiratory impairment and early introduction of non‐invasive ventilatory aids prevent or delay further respiratory decline and the need for invasive respiratory aid (Level C). Group training, regular follow‐up and patient education are useful for the patients’ mental status and well‐being. Weight loss, adjustment and introduction of properly fitted assistive devices should be considered (good practice points). A small number of controlled studies of potential‐specific treatments for PPS have been completed, but no definitive therapeutic effect has been reported for the agents evaluated (pyridostigmine, corticosteroids, amantadine). Future randomized trials should particularly address the treatment of pain, which is commonly reported by PPS patients. There is also a need for studies evaluating the long‐term effects of muscular training.

Pregnancy, delivery, and birth outcome in women with multiple sclerosis

Using data from the compulsory Medical Birth Registry of Norway, the authors investigated the effect of maternal multiple sclerosis (MS) on pregnancy, delivery, and birth outcome in 649 births by MS mothers and 2.1 million control births. The mothers with MS had a higher proportion of neonates small for gestational age and also more frequent induction and operative interventions during delivery.

Myasthenia gravis: Consequences for pregnancy, delivery, and the newborn

Objective: To investigate the effect of maternal myasthenia gravis (MG) on giving birth and on the newborn. Methods: A retrospective cohort study for 1967 through 2000 was undertaken, using data from the Medical Birth Registry of Norway, based on the compulsory notification of all births. The target group consisted of 127 births by mothers with MG. The reference group consisted of all 1.9 million births by mothers without MG. Results: Women with MG had a higher rate of complications at delivery (40.9% vs 32.9%, p = 0.05), and in particular the risk of preterm rupture of amniotic membranes was three times higher in the MG group compared to the reference group (5.5% vs 1.7%, p = 0.001). The rate of interventions during birth was raised (33.9% vs 20.0%, p < 0.001) and cesarean sections doubled (17.3% vs 8.6%, p = 0.001). Five children (3.9%) born by MG mothers had severe anomalies, and three of them died. Conclusions: MG is associated with an increased risk for complications during delivery. This is linked to a higher occurrence of interventions during birth.

Muscle autoantibodies in subgroups of myasthenia gravis patients

Abstract Myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR), but several other muscle autoantibodies have also been identified in patient sera. We studied muscle autoantibodies against AChR, striated muscle tissue sections (SH), titin, citric acid antigen (CA), and ryanodine receptor (RyR) in sera from 146 consecutive MG patients to evaluate whether a single test or several tests together can predict a thymoma. The MG patients were divided into five subgroups; ocular MG, early-onset MG (< 50 years), late-onset MG (≥ 50 years), MG with thymoma, and AChR antibody negative MG. AChR, SH, titin, CA, and RyR antibodies were detected in 85%, 34%, 34%, 25%, and 14% of the MG patients, respectively. For thymoma MG, AChR, SH, titin, CA, and RyR antibodies were detected in 100%, 75%, 95%, 70%, and 70% respectively. SH, titin, CA, RyR antibodies, and computed tomography of the anterior mediastinum have similar sensitivity for thymoma MG. The specificity of RyR, titin, CA, and SH antibodies for thymoma was 70%, 39%, 38%, and 31%, respectively, which is significantly higher for RyR antibodies than for the others. No single muscle antibody assay can predict a thymoma, and a combination of several antibody assays is preferred, although RyR antibody testing alone showed 70% sensitivity and specificity for thymoma MG. SH and CA antibodies provided only little additional information.

MRI assessment of normal ligamentous structures in the craniovertebral junction

We have established an imaging protocol in order to characterise the normal ligamentous structures in the craniovertebral junction. Thirty volunteers without a history of car accident or head or neck trauma underwent MR imaging with 2-mm-thick proton-density-weighted sections in three orthogonal planes. The alar ligaments were clearly seen in every case and had three different configurations in cross-section: round, ovoid or wing-like. A broadening from lateral to medial in the coronal plane was observed in all cases. The transverse ligament was clearly demonstrated in 26 out of 30 cases. The ligament was flattened where it arched across the dens. Towards the insertions the ligament twisted into an oblique-horizontal orientation. The lower tectorial membrane had a median portion merging with the dura, and a lateral portion separated from it. Between the dens and clivus this membrane either merged totally with dura or was partly separated from it by a thin layer of fat. The posterior atlanto-occipital membrane was clearly demonstrated. It either merged with the dura or was partly or totally separated from it by a fat layer. The anterior atlanto-occipital membrane was inconsistently seen and could not be evaluated. Our refined MR protocol improves the visualisation of the craniovertebral ligamentous structures, and may in the future give new insight into post-traumatic neck disorders up to now poorly understood.