Autoimmune Ion Channel Disorders of the Peripheral Nervous System


MG

LEMS: autonomic dysfunction, absent deep tendon reflexes, rare ocular involvement

Congenital myasthenic syndromes: onset in childhood, absence of autoantibodies, no effect of immunotherapy

Motor neuron disorders: fasciculations, muscle atrophy, corticospinal involvement

Proximal myopathies: CPK, EMG findings, muscle imaging and muscle biopsy

Mitocondrial myopathies: bilateral eyelid ptosis and ophthalmoplegia, no diplopia, slow course, muscle biopsy and genetic studies

Polineuropathies: EMG findings

CNS disorders with impairment of cranial nerves: acute/subacute onset, signs of brainstem involvement

Botulism: autonomic and pupillary involvement, rapidity and pattern of progression

LEMS

MG: ocular and bulbar involvement is typical of MG; absence of tendon reflexes and autonomic dysfunction suggest LEMS.

Proximal myopathies: (degenerative, inflammatory myopathies including inclusion body myositis in older patients): CK levels, dysautonomia and neurophysiological findings differentiate LEMS from these conditions.

Inflammatory polyneuropathies: LEMS does not cause sensory symptoms and signs, pain, and CSF is normal; again, neurophysiological data allow the correct diagnosis





37.1.6 Therapy



37.1.6.1 Symptomatic Treatment


Cholinesterase inhibitors inhibit the breakdown of acetylcholine (Ach) at the neuromuscular junction, thus increasing the availability of Ach to bind AChR. Pyridostigmine bromide is the most widely used compound, average doses are 30–90 mg every 4 h. A sustained release form (180 mg) of the drug is available and prescribed at bedtime to improve weakness in the morning.


37.1.6.2 Short-Term Immunomodulation


MG exacerbations can be rapidly improved by short-term immunomodulating strategies, namely plasma exchange (PLEX) or high-dose intravenous immunoglobulins (IVIG).


PLEX

Rapidly reducing the amount of circulating antibodies, induces improvement within the first week of treatment. There is no agreement on the optimal protocol to be adopted; one plasma volume should be processed during each session, performed every other day; a minimum of two, up to 4–6 sessions are performed [1, 8].

More recently, semiselective techniques have been introduced in clinical practice. They use filters able to remove mainly IgG from the patient’s plasma without the need for any replacement fluid. Different adsorbents are available. Filters with Protein A and anti-human IgG are particularly efficient in removing massively circulating IgG and hence pathogenic autoantibodies [9].


IVIG

Are prescribed with the same indications of PLEX; the efficacy of IVIG and PLEX has been investigated in a controlled fashion, and the two options were found to be equally effective at the time point chosen for clinical assessment [10]. The standard dose regimen is of 400 mg/kg/bw/day for 5 days; two administrations of 1 g/kg vs 2 g/kg have been found to be equally effective. IVIG are usually well tolerated.


37.1.6.3 Long-Term Immunomodulation


Cholinesterase inhibitors rarely induce stable and sustained improvement.


Corticosteroids

Corticosteroids (particularly prednisone) are prescribed when the clinical picture is not controlled by cholinesterase inhibitors alone [1]. Prednisone starting dose range is 0.5–1 mg/kg/bw/day. Temporary worsening of the disease can occur during the first week of corticosteroids treatment. Once optimal improvement is obtained, the ongoing dose can be switched to an alternate day regimen and then gradually tapered to the lowest effective dose. The occurrence of relapses or impossibility to withdraw or reach a minimal maintenance dose are indications to start the association with an immunosuppressant.


37.1.6.4 Immunosuppressive Drugs


The majority of patients need long-term maintenance of low-dose corticosteroid to avoid relapses, thus increasing the incidence of side effects. In this regard, immunosuppressive drugs have been introduced as steroid-sparing agents [1].

Azathioprine (AZA), a purine antimetabolite, remains the drug of choice, with a safe profile regarding side effects and tolerability. The onset of benefit can be very slow and take up to 12 months. Treatment is usually started at 50 mg daily and increased by 50 mg every week up to the required dose (2–3 mg/bw/day). A randomized study provided Class I evidence regarding its steroid-sparing effect [11]. Measurement of Thiopurine Methyltransferase (TPMT) activity or checking for TPMT genotype [12] status can be considered to better address the issue of potentially severe side effects.

Alternative immunosuppressive drugs include micophenolate mophetil (MMF), methotrexate (MTX), cyclosporine A (CYA), cyclophosphamide (CYP), and tacrolimus.


MMF

Blocks purine synthesis in both B and T lymphocytes. The common dose is 1 g twice daily. MMF is considered a first-line drug for the treatment of MG, as suggested by observational studies, and is currently prescribed particularly in North America.


MTX

Prescription is indicated in patients who did not respond to first-line immunosuppressive drugs; the maximum dose is 20 mg/week; a recent study showed a similar steroid-sparing effect of MTX and AZA.


CYA

Inhibits T cell function by disruption of calcineurin signaling and reduced production of interleukin 2. However, at the doses proposed with earlier studies (5–6 mg/kg/bw/day), side effects of hypertension and nephrotoxicity are common. CYA should therefore be considered only in patients intolerant or unresponsive to AZA or MMF.


CYP

Is an alkylating agent with strong immunosuppressive activity on B cells. The effect of CYP given in monthly pulsed doses of 500 mg/m2 with positive results. Impressive response has been also obtained after administration of 50 mg/kg IV for 4 days followed by rescue therapy with granulocyte colony-stimulating factor.


Tacrolimus

Is a macrolide compound belonging to the same immunosuppressive class as CYA, with less nephrotoxicity. The doses range from 3 to 5 mg a day, or 0.1 mg/kg/day.


Rituximab

Is a chimeric monoclonal antibody directed against the CD20 antigen on the surface of B cells. Small observational studies reported significant improvement in treatment-refractory MG. Sustained improvement lasted up to 1 year. Improvement has been also reported in refractory anti-MuSK-associated. MG.


37.1.6.5 Thymectomy


The absolute indication to thymectomy is the presence of thymoma. Randomized controlled studies on the effect of surgery in MG without thymoma are not available. A metanalysis of the literature on this topic concluded that thymectomy should be considered as a treatment option for patients with non-thymomatous MG to increase the probability of remission or improvement as stated after ad hoc metanalysis [13]. Thymectomy should not be performed as an emergency procedure; patients with severe forms of the disease must be stabilized with PLEX/IVIG and adequate immunosuppression before surgery. There is general agreement that non-thymomatous MG patients with generalized MG and disease onset before the age of 50 years may benefit from thymectomy. The issue of thymectomy in patients with anti-MuSK MG is still controversial.


37.1.6.6 Myasthenic Crisis


Myasthenic crisis is a severe and potentially life-threatening exacerbation of the clinical picture leading to respiratory insufficiency requiring admission to the intensive care unit (ICU) for assisted ventilation. The expert opinion is that PLEX or IVIG should be performed soon and associated with high-dose corticosteroid therapy (or the ongoing dose increased).


37.1.6.7 Drugs to Be Avoided in MG


Some drugs are contraindicated or must be used with great caution in patients with MG, particularly a restricted group of antibiotics. A list of contraindicated drugs is reported in Table 37.2.


Table 37.2
Drugs to be avoided or contraindicated in MG



































Contraindicated

Penicillamine

To be used with great caution

Curare drugs

Botolinum toxin

Quinine, quinidine and procainamide

Amynoglicosides

Macrolides

Fluoroquinolones

Telithromycine

Magnesium salts i.v.

Interferon alfa

Might worsen MG

Benzodiazepines

Beta-blockers

Lithium salts


37.1.7 Prognosis


The prognosis of MG has not been properly investigated due to the lack of national registries, shortness of follow-up, and heterogenous definition of outcome measures. However, prior to the introduction in 1934 of anticholinesterase inhibitors, about 70 % of patients died of respiratory failure; mortality was subsequently reduced after the introduction of antibiotics, and in the fifties it was further decreased by up to 15 % after the improvement of mechanical ventilation. Later on, the use corticosteroids and immunsoppressive drugs, together with PLEX and IVIG in patients with acute worsening, dramatically changed the natural course of the disease. Mortality rate is about 2 % [1416].

MuSK-positive MG can be more severe than AChR-positive and double-negative MG as demonstrated by the high incidence of bulbar symptoms and respiratory crises, and poor response or intolerance to acetylcholinesterase inhibitors [16, 17]. On the contrary, double-negative patients have a course similar to that of AChR-positive patients [16]. Complete stable remission (CSR), defined as no symptoms or signs of MG for at least 1 year without ongoing treatment, was recorded in 3.6 % of MuSK-positive compared with 22 % in AChR-positive and double-negative MG. In the same large series of MG patients the occurrence of CSR was associated with onset before the age of 40 years and less severe clinical stages at maximal worsening (ocular-generalized MG) [16].

A large cohort of double-seronegative MG patients has been recently reported from Europe; the frequency of LRP4 antibodies was 18.7 %; the clinical features and response to treatment seemed to be similar to that of AChR-positive MG [6]. However, further studies regarding the clinical features and outcome of the subgroup of LRP4-associated MG are needed.



37.2 Lambert-Eaton Myasthenic Syndrome (LEMS)



Key Facts



Nov 10, 2016 | Posted by in NEUROLOGY | Comments Off on Autoimmune Ion Channel Disorders of the Peripheral Nervous System

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