CIDP

Chronic inflammatory demyelinating polyneuropathy – CIDP-

Epidemiology

Prevalence is about 1/200,000 children and 1-7/100,000 adults, but it is generally accepted that the frequency is underestimated.

Clinical description

Onset may occur at any age but is more common in the 5th and 6th decades. Main clinical manifestations include progressive symmetrical weakness in both proximal and distal muscles of lower and/or upper limbs with partial or complete recovery between recurrences, associated with impaired sensation and absent/diminished tendon reflexes. Disease course is relapsing in 30% of cases, chronic and progressive in 60%, and monophasic with full generally permanent recovery in 10%. In 5-30% of cases, cranial nerve dysfunction may occur. Neuropathic pain, respiratory muscle and sub-clinical CNS involvement have been reported. Autonomic system dysfunction can occur. Children have a more rapid onset, greater disability at the peak and a more frequent relapsing course. CIDP may be associated with hepatitis C, inflammatory bowel disease, lymphoma, HIV, organ transplant, melanoma, or connective tissue disorders.

Etiology

CIDP could be due to an immune reaction, resulting in segmental and multifocal demyelination that may induce axonal loss with time.

Diagnostic methods

To be diagnosed with CIDP, patients have to present a 2 month history of progression of demyelinating neuropathy (DN), some have a history of infection. CIDP may also appear more than 8 weeks after Guillain-Barré syndrome (GBS, so-called “acute CIDP”; see this term). Diagnosis is based primarily on clinical and electrophysiological findings. The need for CSF examination and nerve biopsy depends on the level of clinical diagnostic certainty. When manifestations are present for at least 2 months, electroneuromyogram (ENMG) confirms the diagnosis if 3 of the following criteria are present on several nerves: partial motor-nerve (M-N) conduction blocks, reduced M-N conduction velocity, prolonged distal M-N and F-wave latencies. MRI may demonstrate gadolinium enhancement and proximal nerve/root enlargement. Elevated CSF proteins, with no cells, and demyelination/remyelination, often with inflammation, in nerve-biopsy specimens can provide additional supportive data. Biopsy is currently only recommended in cases of clinical suspicion of CIDP in which ENMG is not conclusive. CIDP should be suspected in virtually any multifocal or generalized neuropathy of unknown cause.

Differential diagnosis

Differential diagnoses include chronic acquired polyneuropathies (monoclonal gammopathies, diabetes, toxic neuropathies) or inherited neuropathies (Charcot-Marie-Tooth disease or transthyretin amyloid neuropathy; see these terms).

Management and treatment

The decision to treat depends on initial disease severity, age, general health status and potential contraindications to the 3 validated treatments: steroids, intravenous immunoglobulins (IVIg) or plasma exchanges. Patients with pure motor CIDP should be treated with IVIg rather than steroids. In milder forms, clinical observation and possibly steroid therapy (depending on ENMG results) are advised. Plasmapheresis or a combination of steroids and IVIg can be started if none of these treatments are effective. Refractory cases can be treated with intensive immunosuppression. The effect of interferon beta-1a and alpha, etanercept or rituximab remains uncertain. Neuropathic pain can be treated with antiepileptic medications or tricyclic antidepressants.

Prognosis

Quadriplegia, respiratory failure and death can occur but are rare. Patients may present residual symptoms that can lead to reduced quality of life. However long-term prognosis is usually good.

ORPHANET : Expert reviewer(s):  Pr Jean-Michel VALLAT – Last update: December 2010

ORPHA: 2932

LSS/MADSAM

Lewis-Sumner syndrome = Multifocal acquired demyelinating sensory and motor neuropathy

Lewis-Sumner syndrome (LSS or MADSAM) is a rare acquired demyelinating polyneuropathy characterized by asymmetrical distal weakness of the upper or lower extremities and motor dysfunction with adult onset. It is considered to be a variant of chronic inflammatory demyelinating polyneuropathy.

ORPHA: 48162

GBS - Guillain-Barré Syndrome

Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is the term used to describe a spectrum of rare post-infectious neuropathies that usually occur in otherwise healthy patients. GBS is clinically heterogeneous and encompasses acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN), Miller-Fisher syndrome (MFS; see these terms) and some other regional variants.

Epidemiology

The overall annual incidence of GBS varies between 1/91,000 and 1/55,000. In Europe and North America, AIDP is the most frequent form of GBS (accounting for around 90% of cases) and thus the term GBS in general is synonymous with AIDP in Western countries. The axonal forms account for only 3-5% of cases in Western countries but are much more frequent (30%-50% of GBS cases) in Asia and Latin America.

Etiology

In the majority of cases, an infectious disease precedes the onset of limb weakness with Campylobacter jejuni infection being the most frequently identified initiating event. GBS has also been reported to occur after vaccination or following a surgical intervention.

Management and treatment

Treatment consists of rapid administration of intravenous immunoglobulin (IVIg) or plasma exchange (PE). Physiotherapy and rehabilitation are also important.

Prognosis

The prognosis is variable depending on the form of GBS and ranges from patients with complete recovery, to those who are unable to walk 6 months after disease onset, and to patients in whom the disease has a fatal outcome.

ORPHANET : Expert reviewer(s):  Pr P.A. [Pieter] VAN DOORN – Last update: December 2009

ORPHA: 2103

MMN - Multifocal Motor Neuropathies

Multifocal motor neuropathy (MMN) is a rare neuropathy characterized by progressive, asymmetric muscle weakness and atrophy (wasting). Signs and symptoms may include weakness in the hands and lower arms; cramping; involuntary contractions or twitching; wrist drop or foot drop, and atrophy of affected muscles. MMN is thought to be due to an abnormal immune response, but the underlying cause is not clear. Most people treated with intraveinous immunoglobulin (IVIG) have rapid improvement in weakness, but maintenance IVIG is usually required for sustained improvement. Some immunosupressive therapies  have also been effective in treating MMN. Physical and occupational therapy may be helpful for some people with MMN.

ORPHA: 641

MFS - Miller Fisher Syndrome

Miller Fisher syndrome

Miller Fisher syndrome is a rare acquired nerve disease considered to be a variant of  Guillain-Barré syndrome. The main features are lack of muscle coordination (ataxia), eye muscle weakness resulting in the inability to move the eyes in several directions (ophthalmoplegia), and the absence of tendon reflexes. Symptoms often start several days after a viral illness. Other symptoms include generalized muscle weakness and respiratory failure. The cause is not known, but it is thought to be an autoimmune diseasein which there are autoantibodies that attack the nerves. In most people with Miller Fisher syndrome an antibody (anti-GQ1b) is identified. The presence of these autoantibodies helps confirm the diagnosis of the syndrome. Treatment includes intravenous immunoglobulin (IVIG), plasmapheresis(a plasma exchange procedure in which the antibodies are removed from the blood) and supportive care. The prognosis is usually good, and in most cases, there is almost complete recovery within 6 months. In rare cases, the syndrome may progress and permanent neurological deficits may be present.
ORPHA: 98919

Neuropathies associated with dysglobulinemia

Polyneuropathy associated with IgM monoclonal gammapathy with anti-MAG

Polyneuropathy associated with IgM monoclonal gammapathy (MG) with anti-MAG (myelin-associated-glycoprotein) activity is a demyelinating polyneuropathy characterized clinically by sensory ataxia, tremor, paresthesia, and impaired gait.

Pathophysiology

MAG is a membrane glycoprotein found within the noncompact myelin of Schmidt-Lanterman paranoids and incisions (Figure 1). It plays a role in the compaction of myelin, in the adhesion between the axon and the Schwann cell and in the control of the axonal diameter. Anti-MAG antibodies are immunoglobulins of IgM isotype directed against MAG. They are produced by a clonal population of plasma B cells (Figure 1), either as part of a so-called benign monoclonal gammopathy (MGUS), or as part of a Waldenström disease.

Clinical

This is a rare neuropathy. It affects men more frequently (sex ratio of about 2-3 / 1). It often starts late in the 6th decade. Classically, polyneuropathy is of slow and progressive evolution, with a predominance of sensory symptoms (numbness, tingling of the extremities, disturbance of equilibrium or coordination = ataxia). Sometimes, he associates an attitude and action tremor. A motor deficit can appear during the evolution (deficit of the relievers of the feet, to see weakness of the muscles of the hands). About 25% of patients have a significant functional disability after 10 years of evolution.

Diagnostic

The diagnosis is made using the clinical, biological (anti-MAG antibodies in the blood by ELISA) and electroneuromyographic (EMG) arguments. EMG shows a demyelinating neuropathy reflecting the dysfunction of nerve conduction related to the alteration of the myelin sheath. Axonal loss is often marked. Rarely, a nerve biopsy can be helpful to the diagnosis. It shows specific alterations (demyelination with appearance of decompaction of the outer lamellae of myelin and deposits of IgM on the myelin sheath).

Therapeutic care

Many immunomodulatory or immunosuppressive therapies have been tested in therapeutic trials in order to decrease the amount and / or activity of anti-MAG antibodies and / or producing lymphoplasmocytes. The results are quite disappointing …

Immunoglobulins showed a difference in the short term compared to placebo but the clinical benefit appears limited. The rituximab studied in 2 trials (anti-CD20 monoclonal antibody targeting B cells) has shown in some patients an improvement of several secondary endpoints compared to placebo but there are methodological limitations. When Waldenström’s disease is symptomatic, chemotherapy is offered to the patient by hematologists. “Lure” polymers resembling MAG and allowing binding to anti-MAG ACs present in the blood are being developed.

Symptomatic management includes physiotherapy and the treatment of possible neuropathic pain.

ORPHA: 639

Expert reviewer(s):  Dr [Juliette] Svahn – Last update: June 2018