Case 25

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Case 25

HISTORY AND PHYSICAL EXAMINATION

A 70-year-old woman had a slowly progressive motor weakness, which started 20 years ago. At 50 years of age, she noted weakness of the right hand, which did not respond to surgical carpal tunnel release. Right hand weakness progressed to the point that she could not flex her thumb and index finger. She was relatively stable until age 65, when she began to trip and realized that her left foot was weak. Neurologic examination revealed weakness of left foot eversion and dorsiflexion (Medical Research Council [MRC] 4-/5), significant weakness of the right hand long finger flexors, particularly those to the thumb and index finger. There was atrophy of the right thenar muscles. Deep tendon reflexes and sensory examination were normal. Plantar responses were flexors.

During the next few years, she had further worsening that was slightly more rapid than the earlier course. At 68 years of age, the patient noted weakness of the left hand and right shoulder. She has had increasing difficulty abducting her right arm, using her left hand, and controlling her left foot. There have been no bulbar or sphincteric symptoms.

Neurologic examination at 70 years of age revealed normal cranial nerves and sensation. There was atrophy of the right thenar eminence. No fasciculations were observed. Tone was normal. Muscle strength was as follows (modified MRC scale):

	Right	Left
Shoulder abduction	2/5	5/5
Elbow flexion	3/5	5/5
Elbow extension	4−/5	5/5
Pronation	0/5	3/5
Fingers flexion	0/5	3/5
Wrist flexion	1/5	1/5
Wrist extension	2/5	5/5
Finger extension	3/5	4−/5
Finger abduction	4−/5	3/5

	Right	Left
Hip flexion	5/5	5/5
Hip extension	5/5	5/5
Knee extension	5/5	5/5
Knee flexion	5/5	5/5
Foot dorsiflexion	5/5	1/5
Toe dorsiflexion	5/5	0/5
Plantar flexion	5/5	5/5
Ankle inversion	5/5	5/5
Ankle eversion	5/5	1/5

Deep tendon reflexes revealed absent right brachioradialis and biceps reflexes, as well as both ankle jerks. All other reflexes were normal. Sensation was normal. Gait was impaired by left footdrop. Romberg test was negative. An electrodiagnostic (EDX) study was performed.

Please now review the Nerve Conduction Studies and Needle EMG tables.

QUESTIONS

1. Based on clinical grounds, the differential diagnosis should include all of the following except:

A. Motor neuron disease.

B. Chronic inflammatory demyelinating polyneuropathy.

C. Neuropathy associated with anti-myelin-associated glycoprotein (anti-MAG) antibodies.

D. Neuropathy associated with anti-HU antibodies.

E. Neuropathy associated with immunoglobulin M (IgM) gammopathy.

2. Laboratory abnormalities that are potentially associated with this disorder include all of the following except:

A. IgM monoclonal gammopathy.

B. Anti-ganglioside M1 (anti-GM1) antibody.

C. Anti-YO antibody.

D. Anti-MAG antibody.

Case 25: Nerve Conduction Studies

Case 25: Needle EMG

3. The EDX findings observed in this patient are seen least commonly in:

A. Classic amyotrophic lateral sclerosis.

B. Chronic inflammatory demyelinating polyneuropathy.

C. Acute inflammatory demyelinating polyneuropathy.

D. Multifocal motor neuropathy.

EDX FINDINGS AND INTERPRETATION OF DATA

Relevant EDX findings in this case include:

1. Normal sensory nerve action potentials (SNAPs) amplitudes, distal latencies, and conduction velocities throughout.

2. Multifocal conduction blocks, some partial and others near complete. The motor nerves with conduction blocks are the following:

• Both median nerves in the forearms.

• Right radial nerve between the elbow and upper arm (Figure C25-1).

• Left ulnar nerve between the axilla and Erb point (Figure C25-2).

• Right musculocutaneous nerve between the axilla and Erb point (Figure C25-3).

• Left peroneal nerve between the knee and fibular head.

3. Severe impairment of recruitment with scattered fibrillation potentials and increased motor unit action potential (MUAP) duration and polyphasia in muscles that follow multiple peripheral nerve distribution; this correlates anatomically with the sites of conduction block.

Figure C25-1 Right radial nerve motor conduction studies, recording the extensor digitorum communis. Note the severe conduction block (>50% CMAP amplitude reduction and >50% CMAP area reduction) between the elbow (waveform 1) and spiral groove (waveform 2) stimulations. Sensitivity = 2 mV/division.

Figure C25-2 Left ulnar nerve motor conduction studies, recording the abductor digiti minimi, shown superimposed. Waveform 1 = wrist; waveform 2 = elbow; waveform 3 = axilla; waveform 4 = Erb point. Note the conduction block (>50% CMAP amplitude reduction and >50% CMAP area reduction) between the axilla and Erb point stimulation. Sensitivity = 2 mV/division.

Figure C25-3 Right musculocutaneous motor conduction studies, recording the biceps. Note the severe conduction block (>50% CMAP amplitude reduction and >50% CMAP area reduction) between the axilla (waveform 1) and Erb point (waveform 2) stimulations. Sensitivity = 2 mV/division.

In summary, this patient has evidence of multifocal motor neuropathy, with multiple definite conduction blocks. Conduction blocks are common in the chronic acquired demyelinating neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP). However, the preservation of sensory nerve conductions, particularly through nerve segments with motor conduction blocks (such as of the median nerves in the forearms), is a unique feature which is diagnostic of multifocal motor neuropathy (MMN). This motor disorder is not consistent with anti-HU or anti-YO antibody-associated paraneoplastic syndromes associated usually with a sensory neuronopathy (ganglionopathy) or subacute cerebellar degeneration, respectively.

DISCUSSION

Definition and Pathogenesis

Multifocal motor neuropathy (MMN), described in the mid-1980s, is a rare disorder with a prevalence of 1 to 2 individuals per 100 000. It is characterized by specific EDX finding, i.e., motor conduction blocks, which is the gold standard for diagnosis. The disorder is important to recognize since it is treatable and responsive to immunomodulating therapies, and may mimic amyotrophic lateral sclerosis (ALS) which has a poor prognosis for survival.

Many patients with MMN have circulating IgM antibodies to ganglioside M1 (GM1), a glycosphingolipid-incorporating sialic acid residue that is present in both the axolemma and the myelin sheath. Anti-GM1 antibodies frequently recognize the terminal disaccharide moiety of GM1, Gal(1-3)GalNAc, which possesses sialic acid. Although anti-GM1 antibodies bind to motor neurons and the spinal cord, there is ample evidence that the node of Ranvier may be the major site of the effects of anti-GM1 antibodies on peripheral nerves. These antibodies may interfere with sodium channel function localized at the node of Ranvier, as evidenced by the diffuse impairment of nodal resting Na⁺ conductance.

Multifocal motor neuropathy is an immune-mediated neuropathy based on the frequent association with anti-GM1 antibodies and the improvement observed in most patients after immune therapies, particularly intravenous immunoglobulin (IVIG). Also, human sera from patients with MMN produce conduction block when injected in vivo into the peripheral nerves of animals. Pathologic findings at the site of the conduction block include evidence of endoneurial edema, a variable degree of lymphocytic infiltration, demyelination, and onion bulb formation.

CLINICAL FEATURES

Multifocal motor neuropathy presents insidiously with asymmetrical weakness often in the distribution of individual nerves. The age of onset of first symptoms is between 20 and 50 years of age in about 80% of patients, and the disorder is more common in men than women (ratio of 2.6/1). In more than 80% of patients, the weakness starts in the upper limbs, usually hand and forearm muscles. Other than the hypoglossal nerve, cranial nerve involvement is rare. Unilateral or bilateral phrenic nerve palsy causing respiratory failure may occur and is occasionally the presenting symptom. The disorder is slowly progressive, usually for more than 6 months and often years. Sometimes, the history is one of a stepwise progression with episodes of rapid worsening followed by prolonged periods of stabilization. The deep tendon reflexes are variable; they are usually depressed or absent diffusely or in weak limbs only. They may be normal or even brisk in one-third of patients, leading to confusion with ALS. Muscle atrophy is not prominent in weak muscles, despite the degree and chronicity of weakness; it may be present over the long term in the distribution of one or more affected nerves, implicating motor axon loss and predicting poor response to therapy. Mild sensory complaints may be present, but the sensory examination is usually normal except for minor vibration sense abnormalities in the lower extremities. A high titer of anti-GM1 antibody is present in approximately 50% of patients, although this varies between 30 and 80%, probably due to the different methodology utilized for antibody measurement. The cerebrospinal fluid protein is usually normal, but may be elevated in one-third of patients without exceeding 100 mg/dL.

Multifocal motor neuropathy should be distinguished from amyotrophic lateral sclerosis, particularly in patients with predominant or exclusive lower motor neuron findings. Clues on clinical examination of patients with MMN include the distribution of weakness, which follows peripheral nerves rather than spinal segments, the insidious course over many years, and the lack of pyramidal signs. It should be cautioned that preserved or brisk reflexes may be present in one-third of patients with MMN. Also, other forms of anterior horn cell disorders, such the spinal muscular atrophies, brachial amyotrophic diplegia (the flail arm syndrome) and monomelic amyotrophy (Hirayama disease) should be excluded. The flail arm syndrome (brachial amyotrophic diplegia), a variant of the progressive muscular atrophy form of ALS, is characterized by progressive proximal and distal upper limb weakness and ultimate variable involvement of the lower limbs. Monomelic amyotrophy (Hirayama disease) affects young men between the age of 15 and 22 and presents with an asymmetrical wasting and weakness of distal upper limb muscles. The disorder is benign, initially progressive over several years and then becoming static. Finally, MMN should be distinguished from other chronic acquired demyelinating peripheral polyneuropathies that may be associated with conduction block or predominantly motor including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and its variant the Lewis-Sumner syndrome (multifocal acquired demyelinating sensory and motor neuropathy, MADSAM), osteosclerotic myeloma (POEMS syndrome), and MGUS neuropathy.

Diagnostic criteria for MMN were proposed. The aim of these criteria is to strengthen the diagnosis of MMN and exclude other disorders that may mimic it. They mostly emphasize the mononeuropathy multiplex-like distribution of weakness, presence of multifocal motor conduction block, lack of sensory loss and lack of pyramidal signs. Table C25-1 shows recently accepted criteria for accurate diagnosis of MMN.

Table C25-1 Criteria for the Diagnosis of Multifocal Motor Neuropathy

Core Criteria

1. Slowly progressive asymmetric limb weakness in the distribution of at least two named nerves, for more than one month but usually more than 6 months

2. Conduction blocks in motor nerves outside entrapment sites

3. No objective sensory loss

4. Normal sensory nerve conduction studies (of at least 3 nerves), particularly across the same segments with demonstrated motor conduction block

Exclusion Criteria

1. Upper motor signs (spasticity, clonus, extensor plantar responses and pseudobulbar palsy)

2. Marked bulbar involvement

3. Objective sensory loss except for minor vibration sense abnormalities in the legs

4. Diffuse symmetric weakness during the early stages of symptomatic weakness

5. Markedly elevated cerebrospinal fluid protein (>1 g/L)

Supportive Clinical Criteria

1. Predominant upper limb involvement

2. Reduced or absent deep tendon reflexes in a patchy way or diffusely, but sometimes normal or even brisk reflexes

3. Absence of cranial nerve involvement other than the XIIth cranial nerve

4. Cramps and fasciculations

Other Supportive Criteria

1. Elevated serum IgM anti-GM1 antibodies

2. Gadolinium enhancement and/or hypertrophy of the brachial plexus or peripheral nerve sites of conduction block

3. Clinical improvement to IVIG treatment

Definite multifocal motor neuropathy. Core and exclusion criteria with definite conduction block in two or more motor nerves. Probable multifocal motor neuropathy. Core and exclusion criteria with (1) probable conduction block in two or more motor nerves, or (2) definite conduction block in one motor nerve and probable conduction block in another motor nerve, or (3) definite conduction block in one motor nerve and at least one of the “other supportive criteria.”

Adopted with revisions from European Federation of Neurological Societies/Peripheral Nerve Society. Guideline on management of multifocal motor neuropathy. J Periph Nerv Syst 2006:11;1–8; Olney RK, Lewis RA, Putnam TD et al. Consensus criteria for the diagnosis of multifocal motor neuropathy. Muscle Nerve 2003;27:117–121.

The treatment options of MMN are limited. In contrast to CIDP, MMN does not respond, or may even worsen, to corticosteroids or plasma exchange. Human intravenous immunoglobulin (IVIG) is highly effective in almost 80% of patients and is shown to be superior to placebo in four randomized, controlled, double-blind studies. Typically, improvement of strength starts 3 to 10 days after infusion; it peaks at approximately 2 weeks and lasts an average of 2 months. Most respondents become dependent on IVIG therapy because the effect of treatment dosage is short-lived and last several weeks only. Thus, periodic IVIG infusion usually is required, usually every 4 to 8 weeks. The recommended dosage is 2 g/kg infused over 2 to 5 consecutive days, although smaller doses may be sufficient to maintain remission. Improvement is more evident in the distribution of recently affected nerves and those without significant muscle atrophy. Also, improvement is variably associated with a demonstrable decrease in the conduction block in some but not all nerves. Sometimes the effectiveness of IVIG decline slightly over the years, probably due to secondary axonal degeneration. The exact mechanism of the beneficial effect of IVIG is not clear. It is possible that the immune attack is altered, allowing recovery of conduction block by unblocking of the sodium channels at the nodes of Ranvier. In patients who do not respond to IVIG, uncontrolled studies have shown that some patients have also responded to monthly high-dose intravenous pulse cyclophosphamide followed by oral cyclophosphamide as a maintenance therapy. Also, Rituximab, a CD20 monoclonal antibody, may also result in modest and delayed improvement (after a year).

Electrodiagnosis

Multifocal conduction block of motor axons is the hallmark of MMN. The conduction blocks may be seen at any segment of any motor nerve, usually asymmetrically and with predilection to upper extremity nerves. Conduction block, however, is not specific for MMN since it may accompany entrapment and compressive mononeuropathies and most acquired demyelinating polyneuropathies; Hence, finding conduction block on EDX studies should be interpreted in the context of the clinical and other electrophysiological findings. Conduction blocks across common entrapment sites are excluded during the evaluation of MMN. The conduction blocks in MMN are often chronic and persistent for several years. Sometimes, the conduction block is dynamic; it may gradually increase over time or it may occasionally decrease due to decline in distal CMAP amplitude, suggesting secondary axonal degeneration or the appearance of additional very distal conduction blocks. Other EDX signs of demyelination may accompany conduction block. However, these motor nerve abnormalities, such as slowed motor conduction velocities, prolonged distal motor latencies, and prolonged or absent F waves, are not prominent or necessary for the diagnosis of MMN.

There are no uniformly accepted criteria for the identification of conduction block. Conduction block is defined as a decrease in the compound muscle action potential (CMAP) amplitude and area on proximal versus distal nerve stimulation, without evidence of significant temporal dispersion (i.e., prolongation of the CMAP duration; Figure C25-4). Table C25-2 lists recommended practical criteria for the diagnosis of conduction block, particularly in patients with suspected MMN. A detailed and meticulous nerve conduction study of multiple nerves and along many segments of these nerves are essential for the diagnosis of conduction block, which is a prerequisite for establishing the diagnosis of MMN. In general, CMAP amplitude and area decay should be less stringent when evaluating short nerve segments such as with the inching technique (Figure C25-5). This technique may allow precise localization of conduction block by finding an abrupt and focal reduction of CMAP area and amplitude over a very short segment of the nerve. It also helps excluding pseudoconduction block that may be associated with axonal loss and phase cancellation.

Figure C25-4 Right median motor nerve conduction study, recording abductor pollicis brevis, in a 52-year-old man with more than 10 years of bilateral asymmetrical hand weakness due to multifocal motor neuropathy. Note the definite conduction block of the median nerve in the forearm (outside common entrapment site).

Table C25-2 Electrodiagnostic Criteria for Partial Conduction Block in Multifocal Motor Neuropathy ^*

Definite Conduction Block^†^‡

>50% CMAP amplitude reduction and >50% CMAP area reduction with <30% prolongation of CMAP duration

>30% CMAP amplitude reduction and >30% CMAP area reduction with <30% prolongation of CMAP duration over a short nerve segment (such as with the inching technique)

Probable Conduction Block^†^‡

20–50% CMAP amplitude reduction and 20–50% CMAP area reduction, with <30% prolongation of CMAP duration

>50% CMAP amplitude reduction and >50% CMAP area reduction with 30 to 60% prolongation of CMAP duration

>50% CMAP amplitude reduction and >50% CMAP area reduction with <30% prolongation of CMAP duration on stimulations between ankle and knee for the tibial nerve

>50% CMAP amplitude reduction and >50% CMAP area reduction with <30% prolongation of CMAP duration on stimulations between axilla and Erb point (for the median, ulnar, radial or musculocutaneous nerves)

* All amplitudes, areas, and durations reflect negative-peak areas, amplitudes, and durations comparing responses of proximal to distal stimulations.

† Conduction blocks at common entrapment sites are excluded.

‡ These requirements should be more stringent and sometimes cannot be included in nerves with very low distal CMAP amplitudes (<20% of the lower limit of normal or <1 mV).

Figure C25-5 Left ulnar motor nerve conduction study, recording abductor digiti minimi, in the distal forearm utilizing the inching technique in a 45-year-old woman with indolent weakness in the distribution of the left ulnar nerve and elevated anti-GM1 antibodies. The distances marked with asterisks depict the distance of the site of stimulation to the styloid process of the ulna. Note the marked sudden drop in CMAP amplitude and area (with a shift in latency) between 3 cm and 4 cm proximal to the ulnar styloid process.

It is also important to emphasize avoiding over diagnosing conduction block. Table C25-3 reveals some common errors that are made in the EDX laboratory when attempting to diagnose conduction block. Two situations remain the most challenging and controversial. (1) Differentiating conduction block from abnormal temporal dispersion causes the most difficulty since temporal dispersion may result in CMAP amplitude and area reduction, due to the effects of phase cancellation. Computer analysis studies had suggested that a reduction of CMAP area of greater than 50% is always caused by a degree of conduction block. (2) Evaluating for conduction block in the context of axonal loss, such as in peripheral nerves with very low distal CMAPs (<20% of the lower limit of normal or <1 mV) is subject to error. Most proposed criteria intentionally restrict including these nerves to avoid confusion between conduction block and phase cancellation associated with axonal loss.

Table C25-3 Common False-Positive Results in the Diagnosis of Conduction Block

Failure to reach supramaximal percutaneous stimulation (proximal sites, obesity, edema)

Evaluation of long peripheral nerves (tibial nerve, tall subjects)

Abnormal temporal dispersion with phase cancellation

Evaluation of peripheral nerves with very low distal CMAPs (<20% of the lower limit of normal or <1 mV) suggestive of axonal loss

A finding that is unique to MMN is that sensory conductions across segments with motor conduction block are normal (Figure C25-6). Also, despite severe conduction block of the motor nerves, sensory conduction studies, which typically are performed in distal nerve segments (hand or foot), are normal. This distinctive characteristic helps to differentiate MMN from CIDP (and other acquired demyelinating neuropathies), in which the disruption of impulses usually affects both sensory and motor fibers.