P. Soelberg Sørensen

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).

Appearance and disappearance of neutralizing antibodies during interferon-beta therapy

Background: Neutralizing antibodies (NABs) occur frequently in patients receiving interferon (IFN)-beta for multiple sclerosis (MS), but it is unclear whether occurrence of NABs is predictive for the persistence of NABs during continued IFN-beta therapy. Methods: The authors used an antiviral neutralization bioassay to measure NABs blindly from 6 months up to 78 months in patients with MS who were followed for at least 24 months during treatment with IFN-beta. Patients were classified into three groups: 1) persistently NAB-negative patients, defined as patients without any positive samples at any time; 2) definitely NAB-positive patients, defined as patients who had at least two consecutive positive samples; and 3) patients with fluctuating NAB-positive and NAB-negative samples. Results: A total of 455 patients were included in the study. Overall, 52.3% of the patients were persistently NAB-negative, 40.9% became definitely NAB-positive, and the remaining 6.8% were fluctuating. More patients treated with IFN-beta-1a (Avonex) remained NAB-negative (p < 0.0001), whereas there was no difference between IFN-beta-1b (Betaferon) and IFN-beta-1a (Rebif). Patients who have remained NAB-negative during the first 24 months of therapy rarely developed NABs. On the contrary, the majority of patients, who had been NAB-positive from 12 through 30 months after start of therapy, remained NAB-positive. Conclusions: NABs should be measured in all patients treated with IFN-beta. If patients have been persistently NAB-negative for 24 months, measurements can be discontinued. Patients who have been NAB-positive for a period of 18 months or more usually remain NAB-positive for a long time.

Absence of MxA induction by interferon β in patients with MS reflects complete loss of bioactivity

Background: In patients with multiple sclerosis (MS), neutralizing antibodies (NAbs) appearing during treatment with interferon (IFN) β reduce or in high concentrations abolish bioactivity and therapeutic efficacy. In vivo MxA induction by IFNβ is used as a marker of biologic response to IFNβ. It has been argued that despite absence of MxA induction measured by PCR, some bioactivity might be preserved. In a cohort study, we measured gene expression by gene chip analysis in NAb-negative and NAb-positive patients to test that hypothesis. Methods: The effect of IFNβ was studied by comparing samples collected before and 9–12 hours after an injection. The cohort consisted of 12 NAb-positive patients without MxA response and 12 NAb-negative patients with preserved response. MxA in vivo response was determined in whole blood using real-time PCR. Screening for IFNβ-regulated genes in mononuclear cells was done using gene chips. False discovery rate (FDR) analysis was used as statistical tool. Results: Of 8,793 genes, 5,593 were detectable in at least one patient in both groups. Of these, calculation of FDR revealed 1,077 IFNβ-regulated genes at a 5% level in NAb-negative patients. The corresponding number of IFNβ-regulated genes in NAb-positive patients was zero. Conclusion: In neutralizing antibody (NAb)–positive patients without an MxA response, we were not able to detect differential expression of any of the 1077 interferon (IFN) β-regulated genes identified in NAb-negative patients. Lack of MxA in vivo response in patients with multiple sclerosis with NAbs is a reliable marker of a completely blocked biologic response to IFNβ, with no indication of residual bioactivity.

IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS

Objective: To investigate if IV immunoglobulins (IVIg) in combination with methylprednisolone make recovery from a relapse faster and more complete than methylprednisolone alone. Design/Methods: The authors studied 76 patients with multiple sclerosis (MS) who had an acute relapse with involvement of visual function, upper limb motor function, or gait, and with onset of symptoms between 24 hours and 14 days before. Patients were treated with either IVIg 1 g/kg or placebo (0.1% human albumin), given 24 hours before treatment with IV methylprednisolone 1 g on 3 consecutive days. Results: Both groups improved, but the authors observed no significant difference between IVIg and placebo patients regarding the primary endpoint, the mean change in the Z-score of the individually chosen targeted neurologic deficit (the most affected system) from baseline to 12 weeks (p = 0.89). A slightly better, but not significant remission was seen in the IVIg group in global scores, i.e., Expanded Disability Status Scale (p = 0.23) and Multiple Sclerosis Impairment Scale (p = 0.24), and in time to next relapse (p = 0.22). Conclusions: The results do not justify routine application of IV immunoglobulins as add-on therapy to IV methylprednisolone in the treatment of acute multiple sclerosis attacks.

Neutralizing antibodies hamper IFNβ bioactivity and treatment effect on MRI in patients with MS

We measured neutralizing antibodies (NABs) and the in vivo biologic response to interferon-β on neopterin and β2-microglobulin blood levels. All NAB-negative patients had an in vivo biologic response (full or partial), whereas all high-level positive patients had no response. High-level NAB patients had more MRI activity than NAB-negative patients (p = 0.031). Patients with a full response had less MRI activity than patients without biologic response (p = 0.032).

Sumatriptan has no clinically relevant effect in the treatment of episodic tension-type headache

In a randomized, multi‐centre, double‐blind, placebo‐controlled, parallel group study, the efficacy of 100 mg oral sumatriptan was compared with that of placebo in the treatment of episodic tension‐type headache. The patients were recruited from the general population in the vicinity of the study centres, by randomly mailed invitations. One or more attacks were treated with sumatriptan by 54 patients and with placebo by 57 patients. A seven‐point verbal rating scale was used for hourly assessments of headache relief, 1–4 h after treatment According to the predefined primary end‐point of the study, which was moderate or complete relief of headache 2 and 4 h after treatment of the first attack, there was no significant difference between sumatriptan and placebo treatment Sumatriptan did perform statistically significantly better than placebo at some time points, but the effect was not considered clinically relevant We conclude that sumatriptan should not be used in treatment of tension‐type headache. The marked difference in effect of sumatriptan in treatment of migraine and tension‐type headache argues against the idea that migraine and tension‐type headache are part of a continuum of headache disorders.

Clinical course and prognosis of pseudotumor cerebri. A prospective study of 24 patients.

ABSTRACT— In a prospective study, 24 consecutive patients with pseudotumor cerebri were followed for an average of 49 months with regular neurologic and ophthalmologic examinations. At the first examination the intracranical pressure was between 18 and 45 mm Hg; several patients had pressure waves up to 70 mm Hg and decreased conductance to cerebrospinal fluid outflow. In the majority, medical treatment, usually with diuretics and acetazolamide, induced a rapid relief of symptoms, but about 25% had a more protracted disease course with persistent headache, asthenia and memory disturbances interfering with daily life. Five patients required a shunt operation. Chronic changes of the optic disc developed in nearly half the patients, and one had optic atrophy and severe visual impairment. Repeated measurements of the intracranial pressure and conductance to cerebrospinal fluid outflow showed that abnormalities can persist for a long time, even in cases without symptoms of intracranial hypertension.

Identification of new sensitive biomarkers for the in vivo response to interferon-β treatment in multiple sclerosis using DNA-array evaluation

Objective:u2002 Neutralizing antibodies (NAbs) occur in a proportion of multiple sclerosis (MS) patients treated with interferon (IFN)‐β. NAbs impair the effect of treatment. The biological effect of IFN‐β can be measured as the induction of the myxovirus resistance protein A (MxA) molecule. However, other markers could be more sensitive for evaluating the response to IFN‐β. We used DNA array analysis to identify genes that are strongly induced in blood cells by IFN‐β, and measured their expression in MS patients with different NAb levels.

Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study

Background: Cladribine is a synthetic deoxyadenosine analogue in development as an oral multiple sclerosis (MS) therapy. Objective: To report in detail the safety findings from the 96-week, phase III, double-blind CLARITY study, which evaluated treatment with cladribine tablets in relapsing–remitting MS. Methods: A total of 1,326 patients were randomized 1u2009:u20091u2009:u20091 to two short-course regimens of cladribine tablets (3.5 or 5.25u2009mg/kg cumulative dose over 96 weeks) or placebo. Safety assessments included monitoring for adverse events (AEs), routine physical and neurologic examinations and frequent laboratory parameter assessments. Results: Of the randomized patients, 88.6% completed treatment with cladribine tablets versus 86.3% with placebo. Lymphopenia was the most commonly reported AE in patients treated with cladribine tablets and was anticipated based on the mechanism of action. The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% rated mild-to-moderate by investigators. Herpes zoster infections developed in 20 (2.3%) cladribine-treated patients; all cases were dermatomal. There were no herpes zoster infections in the placebo group. Nine (1.0%) patients experienced events related to uterine leiomyomas in the cladribine tablets groups versus one (0.2%) with placebo. Three isolated cases of malignancy were reported in cladribine-treated patients during the study; a fourth was reported during post-study surveillance. A pre-malignant cervical carcinoma in situ was also reported. The incidence of malignancies during the study did not exceed the expected rate in a population standardized for country, gender and age. Conclusion: The safety and tolerability profile observed in the CLARITY study together with the reported efficacy support the potential for cladribine tablets as an MS therapy.

Increased brain water content in pseudotumour cerebri measured by magnetic resonance imaging of brain water self diffusion.

Brain water self diffusion was investigated by magnetic resonance scanning in 7 patients fulfilling conventional diagnostic criteria for pseudotumour cerebri. Quantitative diffusion measurements were obtained using single spin echo pulse sequences with pulsed magnetic field gradients of different magnitude. In all patients the diffusion images showed an increased diffusion in various brain regions when compared with the diffusion coefficients for corresponding regions in healthy subjects. In 3 pseudotumour patients the increased self diffusion was localized to the periventricular regions, while 4 patients had increased diffusion in the whole brain. The findings indicate the presence of increased brain water content both intra- and extracellularly suggesting that patients with pseudotumour have two defects of pathogenetical significance: intracellular water accumulation and increased resistance to cerebrospinal fluid (CSF) outflow leading to an interstitial oedema.