Motor Neuron Disease (MND) is a neurological disorder which is probably caused by immune-mediated dysfunction of the axon at the nodes of Ranvier or the myelin sheath, even if the immune pathogenesis has not been completely elucidated in clinical trials.
The presence of anti-GM1 IgM antibodies in serum from almost 50% of patients with MND seems to suggest an activation of GM1-specific B cells.
Treatment trials have uncovered a unique pattern of responsiveness to immune modulatory treatment in MND; treatment with IVIG has been shown to be beneficial in randomized controlled trials.
Which is the pharmacological mechanism justifying the beneficial effects of IVIG in MND patients?
Are there strong RCT evidence about IVIG use in MND in scientific literature?
Is the beneficial effect really useful for patients?
Thanks,
Riccardo
Dear Riccardo,
Motoneuron disease (MND) is ~12% familial (genetic) and 88% sporadic (no known cause). Because of this high variability it has been very hard to find the causes and potential treatments for this terrible disease. By the time patients show symptoms of the disease, already around 30-40% of motoneurons are lost. Recent research indicate that the prior to appearance of symptoms at the pre-symptomatic stage, there is increased excitatory synaptic hyperactivity in motoneurons. Motoneurons have long axons and therefore their normal function requires more energy, and synaptic hyperactivity likely increases metabolic demand even further. Energy-dependent ionic pumps that maintain intracellular sodium/calcium homeostasis are chronically challenged by activity and selectively overwhelmed by hyperactivity which eventually causes sustained membrane depolarization leading to excitotoxicity, activating microglia to phagocytose vulnerable/degenerating motoneurons under neuropathological conditions (see attached my recent review for details).
Now, coming to your great question about IVIg? Intravenous (IV) immunoglobulin (Ig) is made from human plasma which contains antibodies that help the immune system to function properly. IVIg is given to patients whose immune system is not functioning properly. I think the way IVIg works is by calming down the activation of microglia and thus reducing their phagocytic activity (see Fig 9 in paper below), and therefore increasing the chance of recovery for vulnerable motoneurons. Please note in Figure 9 that microglia also attacks the dendritic structure of the motoneurons. Thus I would think that the earlier the treatment starts the better may be the survival and quality of life for the patient.
best wishes, Refik
Article Emerging Roles of Filopodia and Dendritic Spines in Motoneur...
IVIG bind to macrophage receptors (microglia) thus inactivating them, similarly helping when given to patients suffering from immune thrombocytopenia (even though the antibodies persist, the macrophages are inactivated and thrombocytes preserved).
Hope this concept helps in answering to your question.
Abstract
The effect of intravenous immunoglobulin (IVIg) treatment was studied in five patients with lower motor neuron disease associated with highly raised anti-GM1 antibodies but without evidence of conduction block on neurophysiological examination. The patients received IVIg treatment (0.4 g/kg for five consecutive days) in an open study. Only one patient responded to IVIg treatment, which was confirmed in a double blind, placebo controlled study (two placebo treatments and two IVIg treatments in a randomised order). However, after six months of maintenance IVIg treatment (0.4 g/kg weekly) muscle weakness gradually deteriorated below pretreatment levels despite continued treatment. It is concluded that the presence of raised anti-GM1 antibodies does not identify a subgroup of patients with lower motor neuron disease who respond to IVIg treatment and although some patients with lower motor neuron disease may initially respond, IVIg treatment does not seem to be sufficient as long term treatment.
Article Intravenous immunoglobulin treatment in lower motor neuron d...
Dear Ali,
Thank you for pointing out this study. I wonder if the benefits would have been more significant if the application started much eariler prior to significant loss of motoneurons when symptoms are obvious (see my comment above)? My argument is that any such treatment will not bring back the lost motoneurons, and therefore treatment at pre-symptomatic stages, at least in the familal cases, may be far more beneficial.
best wishes, Refik
There seems to be some confusion here in re multifocal motor neuropathy (MMN), which seemingly is immune-mediated and therefore susceptible to IVIg, vs. motor neuron disease (MND) more generally, the most common of which is ALS (the label used in the US), in which IVIg has not proved efficacious.
Multifocal motor neuropathy (MMN) responds to IVIg, but motor neuron disease (MND) does not. Sometimes MMN can be misdiagnosed as MND. Therefore, small case series have suggested a trial of IVIg in some "atypical" MND. However, this remains controversial and most MND patients will not respond to treatment.
Article Is IVIg therapy warranted in progressive lower motor neuron ...
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