Therapeutic Advances in Neurological Disorders

Paroxysmal dyskinesias (PDs) are a rare group of hyperkinetic movement disorders mainly characterized by their episodic nature. Neurological examination may be entirely normal between the attacks. Three main types of PDs can be distinguished based on their precipitating events - (i) paroxysmal kinesigenic dyskinesias (PKD), (ii) paroxysmal non-kinesigenic dyskinesias (PNKD) and (iii) paroxysmal exercise-induced (exertion-induced) dyskinesias (PED). The diagnosis of PDs is based on their clinical presentation and precipitating events. Substantial progress has been made in the field of genetics and PDs. Treatment options mainly include anticonvulsants and benefit of treatment is depending on the type of PD. Most important differential diagnosis are non-epileptic psychogenic, non-epileptic organic and epileptic attack disorders, especially nocturnal frontal lobe epilepsy.

There is considerable experimental evidence that hypothermia is neuroprotective and can reduce the severity of brain damage after global or focal cerebral ischaemia. However, despite successful clinical trials for cardiac arrest and perinatal hypoxia-ischaemia and a number of trials demonstrating the safety of moderate and mild hypothermia in stroke, there are still no established guidelines for its use clinically. Based upon a review of the experimental studies we discuss the clinical implications for the use of hypothermia as an adjunctive therapy in global cerebral ischaemia and stroke and make some suggestions for its use in these situations.

Substantial therapeutic progress has been made in myasthenia gravis (MG) even before the era of molecular medicine. Here we characterize modern treatment algorithms that are adapted to disease severity and introduce the principle of escalating treatment strategies for MG. In very mild cases and in some ocular forms of MG, treatment with acetylcholinesterase inhibitors may be sufficient, at least temporarily, but commonly some kind of immunologically active treatment is needed. In generalized MG, a wide array of immunosuppressive treatments has been established through observational studies, some prospective, but most of them have never been tested in a double-blind, prospective and randomized trial. Within the immunologically active drugs, glucocorticosteroids (GCS) and the immunosuppressive drug azathioprine (Aza) have been studied the longest. Aza is still the standard base-line treatment, in particular in cases where high doses of GCS would be needed to maintain remission. If Aza is not tolerated, several alternatives are available including cyclosporine A (Cic A), mycophenolate mofetil, cyclophosphamide, and methotrexate, all of them off-label in most western countries. Tacrolimus is under investigation. More severe cases may profit from drug combinations in which compounds with more rapidly acting drugs (GCS, Cic A) are combined with others showing a more delayed action (Aza). All such combination therapies need to be supervised by an experienced neuroimmunological center because of potentially serious adverse reactions. Serial measurements of anti-acetylcholine receptor antibodies, once these are elevated, is a useful adjunct for monitoring long-term treatment success and may help in weaning from higher to lower doses or to single drugs rather than combinations. For very severe and treatment-resistant cases, co-treatment with intravenous immunoglobulins or different modalities of plasmapheresis may be considered on the short term while the humanized monoclonal anti-CD 20 antibody (rituximab) is a candidate for the long term. In highly refractory cases also immuno-ablation via high-dose cyclophosphamide, followed by hematologic trophic factors such as G-CSF, has been tried successfully. Future developments may include other immunologically active monoclonal antibodies (e.g., anti-CD 52, Campath-1). Up to 10% of patients with MG are associated with a malignant thymoma, often referred to as paraneoplastic MG, as detected by CT scan or MRI, and these patients require thymomectomy and sometimes postsurgical chemotherapy and radiation treatment. In nonthymoma patients with generalised MG, including older children and adults up to the 5th decade, a complete transsternal thymectomy is recommended based on available open trials and expert opinion, preferentially during the first year of disease. Endoscopic surgery may also be effective. Before surgery, pretreatment with immunosuppressive medication or plasmapheresis is usually recommended to ameliorate MG and subsequently reduce perioperative morbidity and mortality which is now near zero in experienced centers. Myasthenic crisis is the life-threatening exacerbation of MG and is best treated by plasmapheresis, mostly combined with immunoadsorption techniques. Intravenous immunoglobulins are a reasonable alternative, but a shortage in supplies and high prices limit its use.

Since the incidental discovery in 1981 that intravenous immunoglobulins (IVIg) are immunomodulatory, they have been investigated in a large number of putative autoimmune diseases. This has led to licensing for idiopathic thrombocytopenic purpura, Kawasaki disease, and in neurological disorders for Guillain-Barré syndrome (GBS). Although not licensed, randomized controlled trials have also shown IVIg efficacy in other neuroimmunological diseases such as multifocal motor neuropathy (MMN), chronic inflammatory demyelinating neuropathy (CIDP), myasthenia gravis, dermatomyositis, and stiff-person syndrome. However, other indications are currently being explored including Alzheimer's disease, postpolio syndrome, and narcolepsy. There are even reports from experimental studies in stroke. The results of recently published clinical trials in both the classical neuroimmunological disorders as well as for new indications are reported and their role in clinical practice is discussed.

The development of neutralizing antibodies (NAbs) is a major problem in multiple sclerosis (MS) patients treated with interferon-beta (IFN-β). Whereas binding antibodies (BAbs) can be demonstrated in the vast majority of patients, only a smaller proportion of patients develop NAbs. The principle in NAb in vitro assays is the utilization of cultured cell lines that are responsive to IFN-β. The cytopathic effect (CPE) assay measures the capacity of NAbs to neutralize IFN-β's protective effect on cells challenged with virus and the MxA induction assay measures the ability of NAbs to reduce the IFN-β-induced expression of MxA, either at the mRNA or the protein level. A titer of ≥20 neutralizing units/ml traditionally defines NAb positivity. NAbs in high titers completely abrogate the in vivo response to IFN-β, whereas the effect of low and intermediate titers is unpredictable. As clinically important NAbs appear only after 9—18 months IFN-β therapy, short-term studies of two years or less are unsuitable for evaluation of clinical NAb effects. All long-term trials of three years or more concordantly show evidence of a detrimental effect of NAbs on relapses, disease activity on MRI, or on disease progression. Persistent high titers of NAbs indicate an abrogation of the biological response and, hence, absence of therapeutic efficacy, and this observation should lead to a change of therapy. As low and medium titers are ambiguous treatment decisions in patients with low NAb titres should be guided by determination of in vivo mRNA MxA induction and clinical disease activity.