Journal club24 August 2015

Dr Ahmad Shahir MawardiNeurology DepartmentHospital Kuala Lumpur

Supervisor:Dr Shanti Viswanathan

Multifocal motor neuropathy (MMN)• uncommon• purely motor neuropathy• a/w asymmetric deficits with predilection for UL

involvement

• Presentation can mimic several neurological conditions e.g MND

• Anti GM-1 antibodies and conduction block are helpful diagnostic clues– not universally present– pts lacking these characteristic findings can

demonstrate similar response to immunodulatory treatment.

Background and prevalence

• Prevalence: 0.3 to 3 cases in 100,000 depending on the case series examined.– underrecognized

• The correct diagnosis was made by the referring neurologist in only 6 of 46 patients (13%) referred to a tertiary neuromuscular center.

Clinical features

• Purely motor neuropathy

• Characterized by motor deficits in the distribution of single nerves without associated sensory loss.

• MND occurs in the distribution of spinal segments rather than single nerves.

• Male: Female (2.7:1).

• Onset: < 50 years (80% of cases)– mean age 40 years, range 20–70 years– seldom in children

Clinical features

• MMN is more asymmetric and does not evolve into generalized weakness as rapidly as CIDP.

• Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) – can look like MMN (also affects single nerves)– + sensory involvement.

• MMN, predominantly the UL– The ulnar, median, and radial nerves are the most commonly affected– differences in the severity of involvement of different muscles supplied by a

common nerve; • this is presumably due to fascicular involvement.

Clinical criteria for the diagnosis of MMN

Clinical features

• Weakness begins in the distal upper limbs (2/3)– difficulties in wrist and finger extension or reduced hand grip. – rarely in the proximal UL.

• LL - distal (1/4)

• No associated objective sensory loss– mild sensory disturbance– vague numbness and tingling in the affected limb. – No alterations in the sensory nerve AP on EDX.

Classic features of MMN and other neuromuscular disorders with similar clinical and electrodiagnostic features

Classic features of MMN and other neuromuscular disorders with similar clinical and electrodiagnostic features

Clinical features

MMN vs MND: 1) MMN affects predominantly (but not exclusively) the upper limbs; 2) MMN usually lacks bulbar or respiratory involvement; 3) muscle weakness in MMN is associated with less atrophy, unless it becomes

severe or longstanding; 4) cramps and fasciculations can occur in MND but are less prominent than in

MMN (50%)5) MMN has no upper motor neuron signs6) MMN has a characteristic electrophysiological pattern of motor CB.

(pathognomonic of MMN)

• Deep tendon reflexes– normal (20%) brisk (8%)

• Respiratory insufficiency due to phrenic nerve involvement (rare)

Clinical features

• The diagnosis of MMN* – clinical criteria (Table 1) – electrophysiologic (Table 3)

criteria– Additional supportive criteria :

definite, probable, or possible (Tables 4 and 5).

*joint task forces from the European Federation of Neurological Societies and the Peripheral Nerve Society

Electrophysiological features

• Motor conduction block (CB)– reduction of muscle AP recorded from a muscle or group of

muscles following proximal nerve stimulation as compared with distal nerve

– indicates a localized failure of AP conduction along a structurally intact axon

– consistent with a myelinopathy– also occur with focal compression of nerves (elbow, wrist, fibular

head)– diagnostic hallmark (MMN)

• However, MMN without CB has also been described – CB is not specific for MMN– can be seen with other types of inflammatory myelinopathies

Electrophysiological features

• Hyperpolarization or depolarization may occur at the site of CB in MMN.

• Pts with a clinical appearance consistent with MMN but without CB respond to IVIg similarly to those with CB – a similar long term prognosis.

• May represent limitations of EDX for identification of CB along very proximal or very distal segments of nerve

Etiology

• Autoimmune, as MMN a/w– elevated serum levels of IgM antibodies against ganglioside

GM1.– response of MMN to immunomodulatory therapy

• From autopsy cases:– Presence of immunoglobulin deposition and inflammatory

demyelination in motor roots– The relative abundance of GM1 in the myelin of motor nerves as

compared to sensory nerves – perivascular demyelination from motor nerve biopsies that are

not found at sensory nerve

Etiology

• There is a link between the GM1 antibody and a motor predominant phenotype– also seen in other immune-mediated neuropathies (pure motor

variant of GBS, AMAN)

• A recent report describes an increased frequency of a HLA haplotype in MMN patients that is seen in patients with MS

• First degree relatives of patients with MMN have a significantly increased incidence of other autoimmune disorders including Hashimoto’s thyroiditis, celiac disease, and type 1 diabetes.

Etiology

• Interestingly, there are cases of toxic motor neuropathy with CB following treatment with infliximab and most patients were treated with IVIg to resolve the weakness.

Natural history

• Asymmetry weakness (in the distribution of single peripheral nerves)

• No muscle atrophy (weakness derives from CB rather than axonal loss)

• There is slow progression with time to a more confluent and segmental pattern – may be difficult to distinguish from MND

• If chronicity --> a/w axonal loss, pts may develop muscle wasting, mimicking motor neuron disease.

Natural history

• Longitudinal assessments of treated MMN patients were performed • 46 pts with MMN demonstrated progression of their disease at a

rate of 1.3 points on the NIS per year after initiating therapy as compared to 4.2 points per year prior to IVIg.

• None of the studied patients lost their job or their ability to work.

• Life expectancy: normal• Spontaneous remission has not been reported.

• Life-threatening respiratory weakness associated with hypoventilation and respiratory insufficiency due to phrenic nerve involvement with diaphragmatic paresis is very rare.

Natural history

• MMN with CB does not differ clinically from MMN without CB

• In a comparative study of these two groups conducted over a 7-year period, – the distribution of peripheral nerves involved, weakness, and ancillary

symptoms of cramps and fasciculations were similar at initial assessment and at follow-up examinations.

– Subtle differences were described but these were not significant– both groups responded equally well to IVIg.

• It is not clear if patients seropositive for anti-GM1 antibodies have a different clinical course than seronegative patients.

Tx: IVIg• Good response : 80% of patients

• Mechanisms: (thought to be) inhibition or consumption of complement depositing at nodes of Ranvier

• Improvement :rapid, usually in the first week but seldom sustained – maintenance dosing required.

• The efficacy has been demonstrated by randomized double-blind placebo-controlled trials (n= 44 )

• Dosage: 2 g/kg administered intravenously over 2–5 days

Tx: IVIg

• Maintenance :– subject to institutional variability, no studies establishing the

optimal dose or interval for maintenance therapy.– In general, maintenance is 0.4 g/kg every week – 1–2 g/kg every

2–6 weeks depending on response and tolerance.– Some authors advocate waiting until clinical improvement has

reached a plateau or patients begin to experience weakness before initiating maintenance therapy

– others institute a specific regimen every 2 weeks with adjustment according to clinical response over time

Tx: IVIg

• Monitoring of pts on IVIg– Renal function – symptomatic therapy for the common flu-like reaction– increased incidence of thrombotic events including stroke and

myocardial infarction, and aseptic meningitis.

Tx: IVIg

• Respond to IVIg therapy is not complete– clinical improvement has been a/w reductions in CB but not in

reductions in GM1 antibody titers.

• Most patients become less responsive to IVIg over time, – requiring higher doses – or more frequent dosing intervals to maintain their

responsiveness. – development of axonal loss with progression of the disease

Tx: Subcutaneous Ig

• Advantage: convenience and possibly fewer side effects in patients requiring frequent infusions.

• Its efficacy has been demonstrated in both open-label studies and a single randomized single-blinded trial.

• Drawback to this therapy is short-term and potential long-term effects of large subcutaneous volumes required for maintenance therapy

Tx: Steroids and plasma exchange• Steroids : worsened weakness (sometimes dramatically)

• Plasma exchange : ineffective in MMN and may result in clinical and electrophysiological worsening.

• In contrast, patients with the clinical phenotype of MMN but with axonal features on electrodiagnostic testing rather than CB (multifocal acquired motor axonopathy) respond IVIg & steroids.

Other therapies- insufficient controlled trials

• Cyclophosphamide, rituximab, mycophenolate mofetil, β-interferon, cyclosporine, azathioprine, and infliximab

• There is most support for cyclophosphamide, even in patients unresponsive to IVIg. – High dose cyclophosphamide has been shown to be effective in up to 50%– low dose cyclophosphamide does not demonstrate efficacy.– The usage is limited by its toxicity in a non-life-threatening illness and the

lack of RCT demonstrating its effectiveness. – Toxicities: bone marrow suppression, alopecia, hemorrhagic cystitis,

delayed bladder cancer, teratogenicity, azoospermia, and infection risk.

Tx : Other therapies

• Although single case reports exist regarding efficacy of other immunosuppressant agents, as noted above, these are small, and further randomized controlled trials are needed to gauge both efficacy and risk to patients with MMN.

Tx : Other therapies

• Rituximab has been shown to achieve clinical improvement even in patients with a declining or insufficient response to IVIg in 5 of 7 reports – much less risk of toxicity compared with cyclophosphamide. – however, are based on a small cumulative number of patients

(total n=28) and are not consistent.

– The largest study (n=14) demonstrated a 13% improvement in strength (versus 3% in controls) over 1 year and a 23% strength improvement over 2 years.

– The next largest study (n=6), however, demonstrated no significant change in strength in IVIg responsive patients and did not allow for reduction in the IVIg dose.

Conclusion

• MMN is an important treatable cause of neuropathy. • Early treatment will improve long term functional

outcome. – MMN must be differentiated from other mimicking conditions

( immunomodulatory therapy is ineffective).

• An accurate diagnosis can be difficult to make due to significant overlap with other conditions and the rarity of MMN.

• Current tx offer significant disease modulation in most patients, – significant economic impact – pts typically develop gradual worsening with less robust

response over time.

Thank you

Patient focused perspectives

• MMN has major impacts on patient function, but, interestingly, in one cohort, 94% of pt remained employed.

• The majority of impact on QoL is related to motor deficits. • Impairment is mainly in the UL function but, with progression of the

ds, there can be a more generalized impact. • Cranial nerve impairment is rare.• Sensory symptoms such as pain and dysesthesia are not

uncommon. – Up to 1/4 of patients present with neuropathic pain as a prominent feature– Many patients will describe mild sensory disturbance– sensory nerve action potentials remain intact on EDX

• Fatigue is a common but often overlooked feature of MMN

Pathophysiology

• Serum against the ganglioside GM1 IgM antibodies found in > 50% of patients

• GM1 localizes to both the axolemma and myelin of peripheral nerves, found abundance at the nodes of Ranvier and adjacent paranodes.

• GM1 is found most abundantly in peripheral motor rather than sensory nerves, and it concentrates in cholesterol-enriched domains of the plasma membrane.

• These domains have a number of functions, the most relevant of which is paranodal stabilization and ion channel clustering.

Pathophysiology

• GM1 facilitate the maintenance of tight junctions through this paranodal stabilization as it also provides an anchor for potassium channels and concentrates sodium channels.– These functions are important for AP propagation and maintenance of

conduction velocity in the peripheral nerves. – Disruption of functions would --> induce failure of conduction across

paranodal regions• Thus, the mechanism of CB may be a primary dysfunction of the axon at the

paranodes or a dysfunction of the myelin sheath causing failure of action potential propagation.

– As these changes would be expected to have more widespread effects than just at the sites of conduction block, this provides a mechanism for the progressive nature of the disorder.

Pathophysiology

• An animal model of MMN does not exist, but the mechanism of damage from IgM GM1 is thought to be similar with animal models of AMAN

• GM1 in combination with galactocerebroside has been identified as a sensitive marker for MMN.

• Enhanced IgM GM1 binding was also found by a different set of authors with a complex of GM1, galactocerebroside, and cholesterol

• Thus, interaction of different types of gangliosides may alter antibody reactivity.

• Other candidate molecules for which there is little direct evidence include disulfated heparin disaccharide, GM1 chaperone molecules, or as yet unidentified glycolipids with functions similar to GM1.